NO813258L - NEW 2-AMINOIMIDAZOLES, PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THESE, AND THEIR USE - Google Patents

Description

The invention relates to new 2-aminoimidazoles which at their atoms C-4 and C-5 are fused with ring A.

and a Rifamycin compound in the 3, 4th position, especially N,N-disubstituted derivatives of 4-aminoimidazolo/.4»5-c]rifa-mvicin SV or S with formula I i.e.

in which R means hydrogen or acetyl and Am means an amino group derived from a secondary amine, as well as salts of corresponding compounds with salt-forming properties. The invention also relates to methods for the preparation of the compounds with formulas IA and IB, pharmaceutical preparations containing these, as well as the use of these compounds and preparations.

Because of the very narrow relationship between the 1 , 4--chin.on- and -hydroquinone form (corresponding to Rifamycin-S and' SV) and the ease with which the two forms intermingle everywhere where it is not specifically stated otherwise, both forms are included, the SV form (IA) being however to be considered the preferred one.

The amino group Am derived from a secondary amine is one whose nitrogen atom has two identical or different monovalent optionally substituted hydrocarbyl residues or together with a divalent optionally substituted hydrocarbyl residue forms a nitrogen-containing non-aromatic heterocyclic residue.

The hydrocarbyl residue (hydrocarbon residue) can be

an acyclic, carbocyclic or carbocyclic-acyclic hydrocarbon residue which preferably has a maximum of 20 carbon atoms and may be saturated or unsaturated, unsubstituted or substituted. In hydrocar byL.kan 1, 2 or more .C atoms,

which is not immediately connected to the nitrogen atom in the amino group, be - replaced by heteroatoms such as hydrogen, sulfur or nitrogen in particular, but also phos-

for or silicon, a cyclic hydrocarbyl residue of this type is then specifically designated as a heterocyclic residue (heterocyclyl).

Unsaturated residues are those which contain one, two or more multiple bonds such as double-

and triple bonds. Cyclic residues in which at least one 6-membered carbocyclic or 5- to 8-membered heterocyclic ring contains the maximum number of non-cumulative double bonds designated as aromatic. Carbocyclic residues in which at least one ring is present as a 6-membered aromatic ring (i.e. benzene ring) are designated as aryl residues. As bi-

and polycyclic residues are those polynuclear residues in which two or more rings have at least one common atom, and thus form an annelated bridged or spiro-bonded ring system.

When nothing else is stated in the present description, organic residues denoted by "lower" contain a maximum of 7, preferably a maximum of 4 carbon atoms.

An acyclic hydrocarbon radical is in particular a linear or branched alkyl, alkenyl, alkadienyl or alkynyl radical, above all a lower alkyl, lower alkenyl, lower alkadienyl or lower alkynyl radical. Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert.-butyl, as well as n-pentyl, 3-pentyl, iso-pentyl, 2-methylpentyl, n-hexyl, isohexyl, 2- methylpentyl, 2-ethylbutyl or n-heptyl, lower alkenyl is e.g. vinyl, allyl, propenyl, isopropenyl, 2- or 3-methallyl', 2- or 3-butenyl, 2-ethyl-2-butenyl and 2,3-dimethyl-2-butenyl, lower-

alkenyl is e.g. propargyl or 2-butynyl.

A carbocyclic hydrocarbon residue is in particular a mono-, bi- or polycyclic cycloalkyl, cycloalkenyl or cycloalkadienyl residue, or an aryl residue containing corresponding aromatic rings. Residues with a maximum of 12 ring carbon atoms and 3- to 8-, especially 5- and/or 6-membered rings are preferred, since they can also have one or more acyclic residues, e.g. above-mentioned and especially lower alkyl residues or further carbocyclic residues. Carbocyclic-acyclic residues are those in which an acyclic

.rest especially one with a maximum of 7, preferably a maximum

4- carbon atoms have one or more carbocyclic or possibly aromatic residues of the above definition. Particular mention should be made of cycloalkyl-lower alkyl and aryl-lower alkyl residues as well as their unsaturated analogues in the ring and/or side chain, including especially those with a maximum of 2 rings.

Cycloalkyl is e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, as well as 1- or 2-bicycloj/~2,2, gj octyl, 2-bicyclo/"~2, 2,J_7 heptyl in 1- or 2-decahydronaphthyl and 1- or 2-adamantyl, further also 1-, 2- or 3-methylcyclopentyl, 4-tert-butyl-cyclohexyl, 4>4-dimethylcyclohexyl, 2,4-,6-trimethylcyclohexyl and 2,4-,4,6 -te trame t yl cyclohexyl, cycloalkenyl is, for example, one of the already mentioned cycloalkyl residues which have a double bond in the 1-, 2- or 3-position, such as 1-, 2- or 3-cyclopentenyl and 1-, 2 - or 3-cyclohexenyl. Cycloalkyl-lower alkyl or -lower alkenyl is, for example, cyclopropyl-, cyclopentyl-, cyclohexyl- or cycloheptyl-methyl. -1-

or -2-ethyl or -vinyl-,-1-, -2- or -3-propyl resp.

-allyl, further also dicyclohexylmethyl and tricyclohexyl-

methyl, cycloalkenyl-lower alkyl or -lower alkenyl is e.g. 1-, 2- or 3-cyclopentenyl- or 1-, 2- or 3-cyclohexenyl -methyl, -.1- or -2-ethyl resp. -vinyl, -1-, -2-

or -3 propyl or -allyl.

An aryl radical is primarily a phenyl, further a naphthyl, such as 1- or 2-naphthyl, a partially hydrogenated naphthyl, such as especially 1-, 2-, 5- or 6- (1, 2, 3, 4--tetrahydro - naphthyl), a biphenylyl, such as especially 4--biphenylyl, further also an anthryl, fluorenyl and azulenyl, Preferred aryl lower alkyl and -lower alkenyl residues are e.g. phenyl-lower alkyl or phenyl-lower alkenyl, such as, for example, benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenyl-'methyl (ie benzhydryl), trityl and 1- or 2-naphthylmethyl, respectively styryl or cinnamyl.

Heterocyclic residues, including the heterocyclic-acyclic residue are particularly monocyclic,

but also bi- or polycyclic, aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza-, triaza- or tetraazacyclic residues which can be aromatic, partially saturated or fully saturated. They can also, in an analogous manner to the above-mentioned carbocyclic or aryl residues, further acyclic, carbocyclic or heterocyclic residues, and be mono-, di- or polysubstituted. The acyclic part in heterocyclic residues has e.g. the meanings indicated for the corresponding carbocyclic acyclic residues. In the first place, there are unsubstituted or substituted monocyclic monoaza-, mono-thia- or monooxacyclic residues such as aziridinyl, oxiranyl and thiiranyl, further also azepinyl and azocinyl, and especially heterocyclic residues with 5 or 6 ring members, such as pyrryl,

e.g. 2-pyrryl or 3-pyrryl, pyridyl, e.g. 2-, 3- or 4-pyridyl, further thienyl, e.g. 2- or 3-thienyl or furyl, e.g. 2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals, such as indolyl, e.g. 2- or 3-indolyl, quinolinyl, e.g. 2- or 4-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, benzofuranyl, e.g. 2- or 3-benzofuranyl or benzothienyl, e.g. 2- or 3-benzothienyl, monocyclic diaza-, triaza-, tetraaza-, oxa-aza-, thiaza- or thiadiazacyclic radicals, such as imidazolyl, e.g. 2-imidazolyl, pyrimidinyl, e.g. 2- or

•4.-pyrimidinyl, triazolyl, e.g. 1, 2, 4-triazol-3-yl > tetra-

zolyl, e.g. 1- or 5-tetrazolyl, oxazolyl, e.g. 2-oxazolyl, isoxazolyl, e.g. 3- or 4-isoxazolyl, thiazolyl, e.g. 2-thiazolyl, isothiazolyl, e.g. 3- or 4-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g. 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza-, oxaza- or thiaazacyclic residues, such as benzimidazolyl, e.g. 2-benzimidazolyl,"benzoxazolyl,

e.g. 2-benzoxazolyl, or benzthiazolyl, e.g. 2-benz-. thiazolyl.. Corresponding partially or fully saturated residues are e.g. tetrahydrothienyl, as 2-tetrahydrothienyl, dihydrofuryl, as 2,5-dihydro-2-furyl, tetrahydrofuryl, as 2-tetrahydrofuryl, 2-(1,3-dioxolanyl)-, tetrahydropyranyl, as 2- and 4,-tetrahydropyranyl , pyrrolidyl, as 2-pyrrolidyl, tetra-12 3

hydropyridyl, . such as A , A - or A -piperideinyl or piperidyl, such as 2-, 3- or 4-piperidyl, which may be substituted at the N atom as lower alkylated, such as e.g. N-methyl-4-piperidyl, further also morpholinyl, thiomorpholinyl, piperazinyl and N,N'-bis-lower.alkylpiperazinyl, such as especially N,N'-dimethylpiperazinyl, as well as perhydroazepinyl and perhydroazocinyl. These residues may also have one or more acyclic carbocyclic or heterocyclic residues, especially those mentioned above. Heterocyclic-acyclic residues are especially derived from acyclic residues with a maximum of 7, preferably a maximum of 4, carbon atoms, e.g. from the ■ above, and may have one, two or more heterocyclic residues, e.g. the aforementioned.

As already mentioned, a hydrocarbyl residue (including a heterocyclic residue) may be substituted with a,

two, or more similar or different substituents, in the following substituents come into particular consideration: Free, etherified and esterified hydroxyl groups, mercapto- and lower alkylthio- and optionally substituted phenylthio groups, halogen atoms (such as chlorine and fluorine, but also bromine and iodine), formyl- (i.e. aldehydo-) and keto groups, also as acetals, resp. ketals, azido and nitro groups, primary, secondary and preferably tertiary amino groups which may also be present! form of addition salts with suitable inorganic,

and organic acids by usual protective groups protected primary or secondary amino groups (such as proper acylamino groups and diacylamino groups), further free and in salt form (as alkali metal salt form) present sulfamino groups, free and functionally modified carboxyl groups (as present in salt form or esterified carboxyl groups possibly one or two hydrocarbon residues containing carbamoyl, uridocarbonyl or guanidinocarbonyl groups and cyano groups), as well as optionally functionally modified sulfo groups (such as sulfamoyl, or

sulfo groups present in salt form), and trifluoromethyl.

A preferred "hydroxyl group" present as substituents in hydrocarbyl is, for example, a lower alkoxy group such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert.-butoxy group, which can also be substituted. Thus, such a lower alkoxy group can be substituted with halogen atoms, especially in the 2-position (as in the 2,2,2-trichloro-ethoxy-, 2-chloroethoxy- or 2-iodoethoxy acid residue;} or with lower alkoxy acid residues, especially in the 1-position (as in the 1-butoxy-ethoxy residue) or in 2-position (as in the 2-methoxyethoxy residue), but also by a hydroxyl group, especially in the 2-position (as in the 2-hydroxyethoxy residue). Furthermore, such etherified hydroxyl groups are also optionally substituted phenoxy acid residues and phenyl lower acetic acid residues, such as above all benzyloxy, benzhydryloxy and triphenylmethoxy-(trityloxy) residues, such as heterocyclyloxy acid residues, such as especially 2-tetrahydrofuranyloxy and 2-tetrahydropyranyloxy acid residues. With etherified hydroxyl groups, in this compound there are also

to understand silylated hydroxyl groups such as > e.g. present:.-- in trilower alkylsilyloxy-, such as trimethylsilyloxy- or dimethyl-tert.-butylsilyloxy-, or phenyldilaverealkyl-.silyloxy- or lower alkyldiphenylsilyloxy groups.

An esterified hydroxyl group present as a substituent in hydrocarbyl is especially one in which the hydrogen atom of the hydroxyl group is replaced by a further acyl residue Ac defined below. Furthermore, it can also be a lactonized hydroxyl group.

An esterified carboxyl group present as a substituent in hydrocarbyl is one in which the hydrogen atom is replaced by one of the hydrocarbon residues characterized above, preferably a lower alkyl or phenyl lower alkyl residue. As an example of an esterified carboxyl group, it is particularly worth mentioning the methoxy, lower alkoxycarbonyl group,

such as the ethoxy- and tert.-butoxy-carbonyl group or the phenyl-lower oxycarbonyl group, such as the benzyloxycarbonyl group and also a lactonized carboxyl group. Furthermore, an esterified carboxyl group is one that exists as a silyl ester, i.e. a trihydrocarbylsilyl or trilower alkylsilyl, and especially trimethylsilyl.

A primary amino group -NH^ as a substituent of hydrocarbyl can also be present in protected form, preferably as a corresponding acylamino group of the formula -NH-Ac, in which Ac has the meaning below. A secondary amino group has, instead of one of the two hydrogen atoms, an unsubstituted hydrocarbon residue as defined above. It can also be available in a protected form, e.g. as an acylamino group derived from it which has a monovalent acyl residue Ac characterized below. A tertiary amino group occurring as a substituent of hydrocarbyl is one which instead of both hydrogen atoms has the same or different residues, which correspond to the unsubstituted hydrocarbyl residues characterized above-.-. The two hydrocarbyl groups can be linked to each other by means of a carbon-carbon bond or an oxygen, sulfur or optionally substituted nitrogen atom, and together with the nitrogen atom of the amino group form a nitrogen-containing heterocyclic residue. As examples of particularly preferred amino groups that serve as substituents of hydrocarbyl, the following can be mentioned: dilower alkylamino (such as dimethylamino and diethylamino), pyrrolidirio, piperidino, morpholino, thiomorpholino and piperazino or 4-methylpiperazino, optionally with lower alkyl, lower alkoxy, halogen and/or nitro substituted diphenylamino and dibenzylamino, among the protected also particularly halogen-lower oxycarbonylamino, such as 2,2,2-tri-'

chloroethoxycarbonylamino, phenyl lavereal oxycarbonylamino,

such as 4-methoxybenzyloxycarbonylamino, as well as 2-(trihydrocarbylsilyl)ethoxycarbonylamino, such as 2-triphenylsilylethoxycarbonylamino, 2-(dibutylmethylsilyl)ethoxycarbonylamino and 2-trimethylsilylethoxycarbonylamino.

The acyl residue Ac of a carboxylic acid is the residue of a carboxylic acid half-ester, such as a lower alkoxycarbonyl or aryllower oxycarbonyl or formyl or the residue of an optionally substituted acyclic, carbocycliccarbocyclic-acyclic heterocyclic or heterocyclic-acyclic carboxylic acid, which is based on one of the above defined unsubstituted or substituted hydrocarbyl residues. Particularly preferred are acyl residues of the following monocarboxylic acids with a maximum of 18 carbon atoms: Acyclic carboxylic acids, especially lower alkanecarboxylic acids, such as propionic, butyric, isobutyric, valerian, isovalerian, capronic, trimethylacetic, oenanthic and diethylacetic acids and preferably all vinegar

and formic acid, but also corresponding halogenated, especially chlorinated and brominated lower alkane carboxylic acids, such as chloroacetic acid, dichloroacetic acid, bromoacetic acid or α-bromoisovaleric acid, carbocyclic or carbocyclic-acyclic monocarboxylic acids, e.g. cyclopropane-, cyclobutane-, cyclopentane-,

and cyclohexanecarboxylic acid, resp. cyclopropane, cyclobutane, cyclopentane or cyclohexane acetic or propionic acid, aromatic carbocyclic carboxylic acids, e.g. benzoic acid, which may be substituted one or more times by halogens (such as fluorine, chlorine or bromine) and/or hydroxy, lower alkyl, lower alkyl, trifluoromethyl, and/or nitro; aryl or aryloxy lower alkane carboxylic acid and their chain-unsaturated analogs, e.g. optionally as stated above for benzoic acid, substituted phenylacetic acid or phenoxyacetic acids, phenylpropionic acid and cinnamic acid and heterocyclic acids, e.g. furan-2-carboxylic acids, 5-tert-butylfuran-2-carboxylic acids, 5-bromofuran-2-carboxylic acids, thiophene-2-carboxylic acids, nicotinic or isonicotinic acids, 4-pyridinepropionic acid and optionally substituted pyrrole-2- with lower alkyl residues or

-3-carboxylic acids also corresponding α-amino acids, especially the naturally occurring amino acids of the ;L series, e.g. glycine, phenylglycine, proline, leucine, valine, tyrosine, histidine and aspargine, preferably in an N-protected. form, i.e. in one in which the amino group is substituted with a normal one, e.g. one of the above-mentioned amino protecting groups. Among the carboxylic acids, those in which the hydrocarbyl itself is also substituted with a further possibly functionally modified carboxyl, i.e., dicarboxylic acids, preferably those with a maximum of 12 carbon atoms, which are based on one of the above characterized optionally substituted acyclic carbocyclic, carbocyclic-acyclic, heterocyclic and heterocyclic acyclic hydrocarbyl residues are. Examples include the following dicarboxylic acids: Oxalic acids, malonic acid, mono- or dilavealkylmalonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, itaconic acid, citraconic acid, angelic acid, 1,1-cyclopentane- or 1,1-cyclohexanedicarboxylic acid . acid, aspartic acid, the latter two acids being preferably preceded by protected amino groups. As already mentioned, other carboxyl group can not only be free, but also functionally modified, e.g. as an ester, an alcohol or a salt, preferably as a physiologically tolerable salt with a salt-forming basic component. Metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or potassium salts, resp. ammonium salts with ammonia or suitable organic amines. Among these, tertiary monoamines and heterocyclic bases, e.g. triethylamine, tri-(2-hydroxyethyl)amine, 1-ethylpiperidine, as well as pyridine, collidine or quinoline. The invention relates in particular to the rifamycin compounds of formula I, in which the amino group Am is characterized by the partial formula

12

wherein R and R independently of each other mean a lower alkyl or lower alkenyl which may be substituted one or more times by hydroxyl, mdrcapto, lower alkoxy, lower alkoxycarbonyl, an optionally N-^mono- or -di-substituted carbamoyl, formyl, oxo, acetalized resp . ketalized oxo, and/or a disubstituted amino group or a lower alkynyl, a cycloalkyl or cycloalkyl-lower alkyl which may optionally have one or two double bondsT, an unsubstituted or with halogen, hydroxyl, trifluoromethyl, an optionally N-mono-

or -di-substituted carbamoyl or lower alkoxycarbonyl one or more times substituted phenyl or phenyl lower alkyl, or a maximum bicyclic heterocyclyl, or heterocyclylalkyl with a maximum of 2 heteroatoms, selected from oxygen, nitrogen and/or sulphur, R 1 and R 2 can be connected to each other through a simple carbon-carbon bond, or over an ooxygen, sulfur (II)- or optionally substituted nitrogen atom together with the amino nitrogen atom can form a /+- to 8-membered non-aromatic heterocyclic ring.

When not specifically defined otherwise, all terms of the above definition have the general and preferred meanings indicated at the outset.

As a substituent of a saturated residue, a hydroxyl, mercapto or disubstituted amino group is preferably separated from the central amino group by at least two carbon atoms, as a substituent of an unsaturated residue this group is preferably located on a saturated carbon atom.

In unsaturated non-aromatic residues, the multiple bond is preferably located on carbon atoms which are not immediately connected to the central -amino group.

As phenyl lower alkyl residues in the sense of R 1 and R 2 , 1-phenylethyl or phenethyl, above all, however, benzyl, they can also be substituted as stated above, the substituent preferably being in the p-position.

As heterocyclyl residues in the meaning of R 1or

R 2 is particularly taken into account monocyclic residues

as those mentioned at the outset, including above all 2- and 4-pyridyl, 2-imidazolyl, 2-benzimidazolyl, 3-indolyl and 4-quinolyl, as heterocyclyl-lower alkyl residues it is to highlight furfuryl and thenyl,' and among similarly saturated leftovers e.g. N-methyl-4-piperidyl, 4-tetrahydropyrariyl, tetrahydrofuryl-2-methyl, 1,3-dioxolanyl-2-methyl, 2-(1,3-dioxolanyl-2')-ethyl. and 2,2-dimethyl-1,3-dioxalanyl-4-niethyl.

Non-aromatic heterocyclic residues in the sense of Am., which are formed by linking the residues R and R 2 by means of a simple C-C bond are, for example, the following: 12

for the case that both residues R and R are lower alkyl residues (or the corresponding cycloalkyl»fehyl- or heterocyclyl-containing lower alkyl residues), the following residues Am^ come into particular consideration: 1-azetidinyl, 1-perhydro--azepinyl, 1-perhydroazocinyl, above all 1-pyrrolidinyl and piperidino, which may also be substituted by the above-mentioned substituents, and/or may have corresponding, substituted or preferably unsubstituted lower alkyl-, cycloalkyl-, cycloalkyl -lower alkyl -, phenyl-, phenyl-lower alkyl -, heterocyclyl and heterocyclyl-lower alkyl residues, preferably only one such substituent and/or residue is present and the total number of carbon atoms is a maximum of 15, in the analogous case where one of the residues R 1 and R 2 is a cyclic residue, the following residues A.m^especially come into consideration: 1-indolinyl, 2-isoindolinyl, 2-perhydroisoindolyl and 4--aza-tricyclo / 5,2,2, 0 2 '^6 7non-8-en-4-yl» which can also be substituted in ° analogous way and preferably with analogous restriction, and/or may have the aforementioned carbonaceous residues. Among all such residues, the following are to be highlighted: one with hydroxyl or carboxyl

substituted 1-pyrrolidinyl, a formyl, carboxyl, lower alkoxycarbonyl, carbamoyl (also N,N-dilower alkylcarbamoyl, such as N,N diethylcarbamoyl) or oxo (also as ketalized oxo, such as ethylenedioxy) substituted pyridino, the substituent preferably being in 3 - or in-position, a loweralkyl-, 1-hydroxyloweralkyl- or 2-hydroxyloweralkyl-piperidino, the remainder preferably being in the 4-position, a 4-diloweralkylaminopiperidino-(such as 4-dimethylaminopiperidino), 4-piperidinopiperidino, and 8-aza-1 , A-dioxa-spiro^4-».5_7 dec-8-yl (ie 4-piperidino - ethylene ketal).

Non-aromatic heterocyclic residues in the sense of Am., which are formed by linking the residues R and R 2 with the help of an oxygen or sulfur (II) atom, are for example mor-folino, thiomorpholino and 3-thiazolidinyl, further also 3, 5-dimethylmorpholino and 2,6-dimethylmorpholino.

Non-aromatic heterocyclic residues in the sense of Am. which are formed by linking the residues R 1 and R 2 with the aid of an optionally substituted nitrogen atom, are those which derive from 2-lower alkyl residues R<1> and R 2 and in which connecting optionally substituted nitrogen atoms have a substituent defined as R below . Such non-aromatic heterocyclic radical is particularly one of partial formula

wherein m and n, independently of each other, each means an integer from 1 to 5, preferably 2 or 3, forming at least a 5-membered thing, and R N means a hydrogen atom, a formyl group, a functionally modified carboxyl group, or an unsubstituted or substituted with a maximum of 10 C-atom-containing hydrocarbyl or heterocyclyl residues. The remainders ^ m^ 2m°&

^2^2n are bivalent radicals derived from lower alkanes with 1-6 C atoms, such as primarily ethylene, trimethylene and propylene, but also tetramethylene, 1,1-dimethylethylene, 1,2-

dimethylethylene, ethylethylene, propylethylene, butylethylene, 1,2-diethylethylene and 2,2-dimethyltrimethylethylene, as well as methylene, ethylidene, propylidene, isopropylene etc., each of which, however, can only stand as one of the two residues. A functionally modified carboxyl group in the meaning R 11 is one of those defined above, in particular an esterified (such as in particular the carboxyl group present in the form of a lower alkyl ester) or in amide form, such as in particular an unsubstituted or with 1 or 2 lower alkyl residues substituted carbamoyl group). En.hydrocarbyl resp. heterocyclyl radical in the sense of R is one of those mentioned at the beginning, and can have the substituents mentioned at the beginning individually or in combination, with the heterocyclyl radical the free valence starts each time from a C atom. Among cyclic residues, monocyclic residues are preferred, among heterocyclic residues, those with a maximum of 2 non-adjacent heteroatoms, among substituted residues such, which only have an eh substituent (= functional groups).

Among rifamycin compounds of the formulas IA

respectively IB which has the rest Am.-are especially the preferred ones

12

wherein R and R each mean an unsubstituted alkyl with 1-4-C-

1 2

atoms, or in which both symbols R and R together with the nitrogen atom form an optionally 'monocyclic, 5-8 ring-membered heterocyclyl residue which may also contain an oxygen or sulfur (II) atom as a ring member, or in which the residue Am^corresponds to one of above-defined preferred meanings Am-g.

Above all, the symbol Am^ means dimethylamino-, diethylamino-,. the methylethylamino, methylisopropylamino and methylbutylamino group,. furthermore also 1-pyrrolidyl-, piperidino-, 1-perhydroazepinyl-, 1-perhydroazocinyl-, morpholino- and thiomorph olino residue, as well as an optionally 4-substituted 1-piperazinyl residue of formula

wherein R 3 means hydrogen or has one of the individual 12 3 meanings of 'R' and R . Under the meaning of R, primarily unsubstituted linear and single branched lower alkyl and lower alkenyl residues (such as above all methyl, propyl, isobutyl or allyl) are particularly preferred, furthermore unsubstituted lower alkynyl (such as propargyl), cycloalkyl and cycloalkyl-alkyl- (especially cycloalkyl-methyl) with 3-6 ring members, as well as phenyl and benzyl residues.

Of particular note are those shown in the examples,

and their closely analogous compounds as salts thereof.

Those of the above generally or preferably characterized rifamycin analogues of formula I which have a sufficient basicity can be present as acid addition salts, especially as physiologically tolerable salts, with common pharmaceutical usable acids. Of the inorganic acids, it is worth mentioning halogenated hydrogenic acid, such as hydrochloric acid, but also sulfuric acid and phosphoric resp. pyrophosphoric acid, of the organic acids it is primarily the sulphonic acids to mention,

such as benzene or p-toluenesulfonic acid, or lower alkanesulfonic acids, such as methanesulfonic acid, further also carboxylic acids, such as acetic acid, lactic acid, palmitic acid, and stearic acid, malic acid, vinairic acid, ascorbic acid and citric acid.

Those of the compounds according to the invention which, due to an acid-reactive functional group (especially thanks to the phenolic character of the 1-hydroxyl group in the compound of the SV series) have a sufficient acidity, can exist as salts with bases, especially as physiological tolerable salts. As salts come into question: Metal and ammonium salts, of on the one hand alkaline earth metal and alkali metal salts (e.g. calcium, magnesium and preferably sodium and calcium salts), on the other hand also ammonium salts derived from ammonia itself, or a suitable preferably physiologically tolerable organic nitrogenous base. As a base, amines such as lower alkyl amines (e.g. triethylamine), hydroxyl lower alkyl amines £~f can be used. e.g. 2-hydroxyethylamine, di-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine' or tri-(2-hydroxyethyl)amine7»cycloalkylamines, (e.g. dicyclohexylamine) or benzylamines (f .eg benzylamine and N,N<1->dibenzylethylenediamine),

as also nitrogen-containing heterocyclic compounds, e.g. those of an aromatic character, (such as pyridine or quinoline) or those with an at least partially saturated heterocyclic ring, (such as N-ethylpiperidine, morpholine, piperazine or N,N'-dimethyl-piperazine). Compounds that contain both an acid and a basic functional group can exist as internal salts.

The invention also relates to a method for producing the above-mentioned compounds of formula I.

The compound of formula I can be prepared-on i

and in a manner known per se as a 3-aminorifamycin-S compound of formula r pu nu pu

in which R has the above meaning or a salt thereof, is reacted in any order with ammonia and with a reactive derivative of an N,N-disubstituted formamide or thioformamide of formula

in which Y means oxygen or sulfur and Am has the initially defined meaning, and if desired a formed compound of the SV^ type is oxidized to a compound of the S type, or a formed compound of the S type is reduced to a compound of the SV type , and/or a formed free compound with salt-forming properties is converted into a corresponding salt or

a formed salt to the corresponding free compound.

Starting substances with formula II, i.e. 3-amino-rifamycin S, as well as a corresponding 25-desacetyl derivative are known compounds. They can also be used as corresponding acid addition salts. Also typical representatives of. starting materials f are with formula III are known, or if they are not known they can be prepared from known secondary amines, resp. their structural analogues in an analogous manner, as the known compounds by conventional methods. The reactive derivatives of formamides used for reacting the reagent, resp. thioformamides of formula III are also known by typical representatives or available by means of methods known per se. In many cases it is not even necessary to isolate these reactive forms as defined in chemical individuals. Among the reactive derivatives of formamide resp. thioformamide, acid amide acetals and acid orthoamides are primarily mentioned, further also acid amide halides, acid amide-dialkyl sulfate complexes, and acid thioamide alkyl halide complexes, the latter, especially when they are used for reacting directly starting substances with formula II.

Corresponding formic acid amide acetals are especially those derived from C₁-C₂-alkanols, which are characterized by formula

in which Am has the meaning given at the outset, and R 1 means alkyl containing a maximum of 4 C atoms, above all methyl or ethyl. They are particularly advantageous because they can be easily produced in stable, individual form. For the production, you heat e.g. a secondary amine Am-H with N,N-dimethylformamide dilave alkyl acetal (e.g. -dimethyl acetal), whereby an exchange of dimethylamino group for the desired amino group Am takes place. For volatile» secondary amines Am-H

is an alternative method better suited, namely treatment of a

N,N-disubstituted formamide alkyl sulfate complex (see further below) with an alkali metal alcoholate of the formula R^OM, in which R^" has the above meaning, and M means an alkali metal, especially sodium.

The formic acid orthoamides used as reactive formamide derivatives are characterized by formula

wherein Am has the above meaning. They can e.g. is obtained by exchanging a lower alkoxy group OR^ for the disubstituted amino group Am by heating an N,N-dimethylformamide dilower alkyl acetal or a formamide acetal of formula III with the corresponding secondary amine Am-H. Typical-; representatives of these compounds as well as methods for their preparation are known. The formic acid amide halides ("iminoyl halides") used are preferably characterized by formula

in which Am has the initially mentioned meaning,' and X

means bromine or preferably chlorine. (The double bond thereby proceeds from the amino nitrogen of the amino group Am and thus gives it the positive charge). These reagents (i.e. "iminoyl chlorides" and "iminoyl bromides?) are prepared, for example, by treating the corresponding formamides of formula III with ordinary halogenation forged or similar. Preferably, halogenating agents are used which during the reaction form gaseous by-products such as phosgene, bxalyl halides or thionyl halides, however, others can also be used. The reaction can be carried out in inert dry organic solvents, for example in ether or toluene, where the amide halide is in most cases insoluble and can be isolated from it by filtration after completion of the reaction. The acid amide halides are hygroscopic and rather unstable, and are therefore preferably used without purification

in the turnover according to the invention.

The fpramide-dialkylsulfate complexes used are especially those of formula

in which Am and R have the above meaning.

The acid amide dialkyl sulfate complexes can be prepared by treating amides of formula III with dialkyl sulfate, preferably dimethyl sulfate under known conditions, e.g. analogous to the amide halides III^.

When a formic acid thioamide is used as starting material, a reactive derivative in the form of an acid thioamide alkyl halide complex can be formed by treatment with an alkyl halide, for example C 1 -C 2 -alkyl iodide. This reaction is known from the literature.

In practical implementation, each of the two method steps according to the invention is carried out; in a manner known in and of itself, as their sequence has no effect on the specific reaction conditions.

The reaction with ammonia takes place in particular by introducing dry ammonia gas into a solution of rifamycin compounds in a common aprotic, organic solvent, e.g. an ether (such as diethyl ether, 1,2-dimethoxyethane or dioxane and especially tetrahydrofuran) or a halo-generated lower alkane (such as especially chloroform or methylene chloride) at temperatures in the range of approx. -10°C to approx. + 4.0°C, preferably between 5 and 25 C, especially slightly below room temperature.

The reaction conditions for the reaction according to the invention with the reactive amide derivatives depend predominantly on these reaction ionic components. When acid amide acetals of the type with formula III are used for reactions of a rifamycin compound, the reaction temperature is at approx. 0-4-0 C, usually at room temperature. The reaction is carried out in inert organic solvents, for example ether, dichloromethane or chloroform which are preferably alcohol-free, and ■ "preferably in the presence of an organic base such as triethylamine, N,N-diisopropyl-.ethylamine, N-ethylpiperidine, N-jnethylpiperidine , N-methyl-

morpholine or N,N'-dimethylpiperazine.

In an analogous way, one also reacts with ortho amides

with formula III

ah

When acid amide halides, dialkyl sulfate complexes or thioamide alkyl halide complexes are used, the reaction is likewise carried out in inert organic solvents that are dry and free of traces of alcohols, preferably in dichloromethane or chloroform, in which the reaction components are soluble, however, it can also be used solvents in which the starting materials are insoluble, such as ethers. • The turnover is carried out at a temperature between approx. -70<u>to approx. 20 C, usually at or below 0°C, and in the presence of at least one equivalent of a . tertiary amine, for example one of those mentioned immediately above, especially triethylamine. When one equivalent of the tertiary amine is used for the reaction with an acid amide halide of type III, the reaction product of formula I is obtained as a salt, when, on the other hand, 1 equivalent of the tertiary amine dialkyl sulfate complex and the thioamide alkyl halide complex is used, the reaction product of formula I appears in free form. When two or more equivalents of the tertiary amine are used, the free form of the compound of formula I always results, which can, if desired, be converted into a salt.

The reaction time depends on the reaction participants, the temperature and the solvents used in the process. When a free carboxyl occurs in starting substances with formula III, it is preferably protected by

acting as a trimethylsilyl ester or dimethylsilyl ester,

and is easily split off again after turnover. This reaction is preferably carried out with an acid amidacetal reagent. The production of silyl esters is known from the literature. The silyl esters have endings of formula I, preferably split by means of a hydrolysis or an alcoholysis

under mild conditions.

In the primary reaction mixture, the final substance is practically only present in the more stable 1,4-hydroquinone form of the SV series, in which it is also conveniently isolated. If, however, the quinone form is desired, the crude reaction mixture is treated resp. an isolated connection of the SV series with an oxidizing agent, especially one that is common for the oxidation of known hydroquinones, e.g. ammonium persulphate, hydrogen persulphate, air oxygen or preferably potassium ferricyanide, the oxidation takes place especially under basic conditions. If you want to convert a compound of the SV series into the hydroquinone form (such as a rifamycin SV derivative), you treat the first-mentioned with a common quinone reduction agent such as hydrosulphite, dithionite, ferrocyanide or especially ascorbic acid or zinc glacial acetic acid .

Acid addition salts are obtained from corresponding basic compounds in the usual way, e.g. with a careful treatment of these with an equivalent or excess amount of the desired acid, preferably in an inert solvent. Salts with bases are also obtained in the usual way by treating corresponding acidic compounds with the desired bases (especially in the case of ammonia and organic bases) or with the corresponding metal hydroxides or preferably carbonates or hydrocarbonates. Internal salts are preferably formed by normal acid-base titration to the neutral point or to isoelectric point. The invention also relates to the embodiments of the above-mentioned methods where a starting material is formed under the reaction conditions or is used in the form of a salt, or where one starts from a compound obtained at one or another step as an intermediate, and carries out the missing steps.

Thus, one can e.g. carry out the two steps of the method according to the invention in a single operation, e.g. saturates a mixture of a 3-aminorifamycin compound of formula II and a reactive

■derivative of an N,N-disubstituted formamide of the above

formula III in an aprotic organic solvent, e.g. one of the above, with ammonia gas, or especially when using the latter reagent, treating a compound of the above-mentioned formula IV which is formed immediately in the same reaction solution by the action of ammonia on 3-aminorifamycin derivatives of formula II.

It is also possible to form the used reactive derivative of formamide with formula III from its forming components directly in situ, i.e. in the reaction mixture. Such a reactive derivative is obtained, for example, in situ, as a formamide of formula III is used with a 1,1-dihalo-di-lower alkyl ether, preferably 1,1-dichlorodimethyl ether in the presence of a tertiary organic base in the reaction with a 3-aminorifamicin compound of formula II. The turnover can be carried out without isolating the intermediate products formed by this method of working. (Then it is most likely a methoxymethylene derivative of compound III which corresponds to the above-mentioned type of formula III, however with halogen as the anion). ■ The reactions are carried out under or at atmospheric temperature or in the presence of an inert solvent agent, for example chloroform or methylene chloride. A reactive formamide derivative can be obtained in situ by reacting a secondary amine of the formula Am-H, in which Am has the above meaning, with a lower alkyl orthoformate or

-orthothioformate of formula CH(YR^) y in which Y and R 4 have the above-mentioned meanings, e.g. methyl orthoformate or ethyl orthoformate, and with a 3-aminorifamycin compound of formula II in the presence of boron trifluoride etherate (or an analogous strong acidic catalyst of the Lewis acid type). The intermediately formed reagents are most likely a formamide dilave alkyl acetal of formula III or an amino ether salt of the type with formula III. The reaction is carried out below or at room temperature and in the presence of an inert solvent, for example chloroform or methylene chloride. The invention also relates to a method according to which the compounds of formula IA or IB are prepared by a 3-aminorifamycin-S-4-imine of formula

in which R has the above meaning or a salt thereof, is replaced by a reactive derivative of an N,N-disubstituted formamide or thioformamide of formula

in which Y means oxygen or sulphur, and Am has the initially defined meaning, and if desired, a formed compound of the SV type is oxidized to a compound of the S type or a formed compound of the S type is reduced to a compound of the SV- the type, and/or a formed free compound with salt-forming properties is converted into a corresponding salt or a formed salt in the corresponding free compound. The method according to the invention is carried out in the above-mentioned manner. The two starting substances of formula IV, i.e. 3-aminorifamycin-S-4-imine and its 25-desacetyl derivatives are known,

in reactive derivative of a formamide of formula III

are those mentioned above, especially those of formula Illa-II.Ic.

Likewise, the invention also relates to the method according to which the compound of formula IA or IB is prepared in that an N', N<1->disubstituted 3-amino-methyleneaminorifamycin derivative (3-aminorifamycin-formamidine) of formula

wherein R and Am have the above-mentioned general and preferred meanings or a salt thereof, is treated with ammonia and, if desired, a formed compound of the SV type is oxidized to a compound of the SV type or a formed compound of the S type is reduced to a compound of the SV type, and/or a formed free compound with salt-forming properties is converted into a corresponding salt or another salt is converted into the corresponding free compound. When it is desirable to start from a formamidine of the SV series, this is oxidized in advance to a corresponding compound of the SV series. The intermediates of the above formula V and their analogs of the SV series of formula

in which R and Am. have the aforementioned general and preferred meanings, as well as their salts are new and are also covered by the present invention. They are produced with the above-described treatment of the corresponding 3-amino-rifamycin S compound see with formula II (also in the form of a

acid addition salt thereof), resp. a corresponding analogue of this of the SV series with an above-defined reactive deriv-

vat of an N,N-disubstituted formamide or thioformamide of the above-mentioned formula III, especially a derivative of the above-mentioned formula Illa-Ille, and if desired a formed compound of the SV type is oxidized to one compound of the S type, or a formed compound of the S-type is reduced to a compound of the SV-type, and/or, a formed free compound with salt-forming properties is converted to a corresponding salt or a formed salt to the corresponding free compound. This manufacturing method is also covered by the present invention.

The new compounds according to the invention with formula

They are distinguished above all by their valuable pharmacological properties: According to the results of in vitro antibiotics, especially antibacterial properties such as e.g.

on the one hand against gram-positive cocci, such as staphylococcus aureus (in the investigated concentration range 0.005 to 128 y/ml), on the other hand against gram-negative rods such as enterobacteriacea, e.g. Escherichia coli, pseudomonas

aeruginosa and proteus morganii (in the investigated concentration range from 1 to 64 y/ml), as well as against Myobacterium tuberculosis (in the investigated concentration range from 0.4-8 to 1.9

y/ml). Particularly to be highlighted as active substances are 4-_dimethylamino-, 4- - (4--methylpiperazinyl) - , 4_ (4--isobutylpiperazinyl)-4--morph olino - and 4--pyrrolidinyl-imidazolo_/_4-, 5-^7 rifamycin SV, all of which have a clear inhibitory effect on staphylococcus aureus already at or below the mentioned lowest concentration limit, also effectively inhibit the enterobacteria in the specified concentration range (for the test results see also table 1).

The new compounds according to the invention with the formulas V and VI are also distinguished by analogous valuable pharmacological properties, i.e. according to the in vitro results, they have antibiotic, especially antibacterial properties which, with regard to the area of application and the investigated effective concentrations, are practically similar to the compounds with formula I.. In particular to highlight which active substances are. 3-(4--methyl-and .4--phenyl-piperazinyl)-, 3-thiomorph olino - and. especially 3-'indolinylmethyleneaminorifamycin S, which all

has a clear inhibitory effect on Staphylococcus aureus already at the mentioned lowest concentration limit and also effectively inhibits enterobacteria in the specified concentration range. (For the test results "see also Table 2).

The compound according to the invention with formula I

can also find use as valuable intermediates for the production of other rifamycin derivatives, especially those with therapeutic use. In connection with the above-mentioned favorable pharmacological properties, the invention also includes the use of the active substances according to the invention alone or in combination with another antibiotic or chemotherapeutic agent, as a means of combating infections, especially those produced by bacteria or cocci,

e.g. those mentioned, namely as well as a healing agent as well as a disinfectant. When used as a healing agent, the active substance according to the invention is preferably administered in the form of a pharmaceutical preparation together with at least one common pharmaceutical carrier or excipient to a warm-blooded animal, above all humans (under the designation "active substance", or "the active substance according to the invention", is to be understood in the foregoing and the following as a rifamycin derivative of the above-mentioned formula IA or IB, and the formulas V or VI, as well as biologically tolerable salts thereof.

The invention also encompasses pharmaceutical compositions containing one of the above-mentioned active substances, especially together with at least one pharmaceutical carrier material,

as well as methods for non-chemical production. For the production of pharmaceutical preparations, each of the compounds according to the invention can above all one

of those that are particularly highlighted, are formed with an inorganic or organic carrier material suitable for topical, enteral or parenteral application. For this it comes in be-

funneling such substances that do not react with the new compound, such as e.g. gelatins, milk sugar, starches, magnesium stearate, vegetable oils, benzyl alcohol or other pharmaceutical carriers. The pharmaceutical compositions can be processed into pharmaceutical administration forms such as

tablets, dragees, powders, suppositories or in liquid form for solutions, suspensions, emulsions, creams or ointments. Possibly these are sterilized, and/or contain auxiliary substances such as preservatives, stabilizers. sering, wetting or emulsifying agent. They may also contain other therapeutically valuable substances.

As is known, the disinfectants can also be mixed with suitable carriers.

For oral administration, tablets, suppositories or gelatin capsules are used, which contain the active substance together with diluents, e.g. lactose, glucose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets also contain binders, e.g. magne siumaliiminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatins, methylcellulose tragacanth, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and if desired disintegrants, e.g. starches, agar, alginic acid or salts thereof, such as sodium alginate and/or soda mixes, or absorbents, coloring substances, flavorings and sweeteners. Suppositories are primarily fat emulsions or suspensions.

The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting and/or emulsifying agents, solubility mediators and/or buffers. The present pharmaceutical preparations, which if desired may contain additional pharmacologically valuable substances, are produced in a manner known per se, e.g. using usual mixing, dissolving or lyophilization methods and contains from approx. 0.1$ to 100%, especially from approx. 1% to approx. 50% lyophilisates up to 100% of the active substance.

The above-mentioned pharmaceutical preparations are particularly preferably available in the form of dosage units. With the expression "dosing units" it is m-ent uniform,

i.e. the only dose that contains an antimicrobial effect

as the amount of the active substance that is administered to a patient. They can be easily handled and packed, since as a physically stable unit they either contain the active material as such or a mixture thereof with a solid pharmaceutical carrier. The dosage of the active substance, e.g. those particularly highlighted above, take place in principle analogously to those recognized antibiotics of the rifamycin type, however, it also depends on the one hand on the species, body weight, age and individual condition of warm-blooded animals, on the other hand on the method of application, and especially on the causative agent any sensitivity that can be determined in a routine test in a known manner. Accordingly, the invention also includes selection of the dose of the compound according to the invention that can be administered in such a way that a desired activity is achieved without simultaneous side effects.

The invention also relates to a method for the eradication or inhibition of growth, (i.e. inhibition) of micro-organisms sensitive to at least one of the active substances according to the invention, as characterized by treatment of this micro-organism or a medium infected with this micro-organism with an antimicrobial effective dose of an active substance according to the invention. The term "an antimicrobial effective dose" is understood to mean such an amount of the active substance that is sufficient for an effective inhibition of the relevant microorganism to be treated.

The compound is conveniently administered in dosage units which contain no less substance than 0.025 to 1 g of the active substance (as free base), and preferably correspond to 0.05 to 0.5 g thereof. The active substances can be administered in the form of a dosage unit or . several times a day at suitable intervals, which, however, always depends on the patient's condition. The daily dose thus preferably amounts to 0.2 to 5.0 g of the active substances according to the invention, calculated as free base.

However, the invention shall be explained in more detail with the help of some examples. Temperatures are given in degrees Celsius. The composition of the solvent mixture is given in volume ratios. The structure of the isolated compounds is routinely checked by the mass spectrometric determination of the molecular ions, as well as by elemental analysis.

Example 1:

4-Dimethylamino-imidazolo_/_ 4-» 5-c:7rifamycin SV.

A solution of 1.5 g of 3-amino-4-iminorifamycin-S in 15 ml of tetrahydrofuran is mixed with 2.0 g of dimethylformamide-dimethylacetal and left to stand at room temperature until the rifamycin derivative used has reacted completely (thin-layer chromatographic control on silica gel, eluent methylene chloride-acetone 9:1). The reaction mixture is then taken up with ethyl acetic acid, washed with aqueous citric acid solution and sodium chloride solution. After evaporation of the solvent, the brown colored residue is chromatographed on silica gel with the eluent methylene chloride/acetone 9:1, removing rapidly migrating dark colored parts. The yellow fractions are combined, evaporated and the residue crystallized from diethyl ether/acetone. Dimethylaminoimidazolorifamycin-SV is obtained in pale yellow crystals of m.p. 180-185°C during decomposition. In the mass spectrum, the molecular ion appears at m/z = 764-, Calculated for C^qH^N^O-]-| = 764-

Example 2.

4-morpholino-imidazolo/ 4-»5-.c7 rifamycinSV.

A solution of 1.4-2 g of 3-amino-4-iminorifamycin-S in 15 ml of tetrahydrofuran is mixed under nitrogen with 0.5 ml of N-formylmorphodimethyl acetal and 2 ml of triethylamine and left for 24 hours at room temperature. The reaction mixture is then taken up in acetic acid ethyl ester, washed in sequence with aqueous citric acid solution and sodium chloride solution, and ethyl acetate is removed in vacuo. The residue is crystallized from ether/acetone to give morpholinoimidazolo-rifamycin-SV as yellow crystals, m.p. 192-193°C during decomposition.. In the mass spectrum, molecular ions of the compound are found at m/z = 806 (calculated for >jC^H^N^O-j 2 = 806)..

Example 3

4--(4--methylpiperazinyl)-imidazolo_/_~4-, 5~^7rifamycin SV .

2.5 g of 1-formyl-4.-methylpiperazine-dimethylacetal is added to a solution of 2,0 and 3-amino-4-iminorifamine-S in 25 ml of tetrahydrofuran and it is left to completely react with the rifamycin derivative used by room temperature.

The reaction mixture is then taken up in ethyl acetate, washed with aqueous citric acid solution and with sodium chloride solution, and evaporated. The residue is chromatographed on silica gel with methylene chloride/methanol 95:5. After removal of fast-moving dark-colored substances, the following yellow-colored eluates are then collected and evaporated. With crystallization from ether/acetone, N-methylpiperazinylimidazole-rifamycin-SV is obtained in yellow crystals of m.p. 185-187UC during cleavage.

100 MHz proton resonance spectrum of the compound

in CDCl-j shows, next to the usual rifamycin signals, extra signals at 3.5~4->0 ppm (CH^ next to N;M), as well as at 2.4-0 ppm (NCH^; S).

Example 4

4-(4-isobutylpiperazinyl)-imida,zolo_/_ 4> 5-_c7

rifamycin SV. ■

A reaction mixture of 2.5 g of 3-amino-rifamycin-S, 20 ml of tetrahydrofuran, 1.5 g of 1-formyl-4-iso-butylpiperazinedimethylacetal and 1.5 g of triethylamine is allowed to stand for 24 hours at room temperature. It is then evaporated to dryness in a vacuum. The residue containing crude 3-(4-isobutylpiperazinyl)methyleneiminorifamycin S with only minor impurities is dissolved in 20 ml of tetrahydrofuran. In the resolution-in-

is passed at room temperature during 30 minutes ammonia gas to saturation. The solution is then evaporated, and the yellow-brown residue is chromatographed on polyamide (Woehn)

with ether/methylene chloride 5:1 as eluent. 3 zones are formed: The eluate of the slowest yellow colored zone then contains the desired 4-(4--isobutylpiperazinyl)-imidazolorifamycin-SV, which in the mass spectrum shows a molecular ion at m/z = 861. (Calculated for C^^H^ ^N^O^ = 861).

Example 5 4.-(4--cyclohexyl methyl-piperazinyl)-imidazolo J_ U, 5-_c7rifamycin SV.

A solution of 1.5 g of 3-amino-4-iminorifamycin-S in 15 ml of tetrahydrofuran is mixed with 3.0 g of 1-formyl-4-cyclohexylmethylpiperazinedimethylacetal and left to stand at room temperature for 8 hours . The reaction mixture is then taken up in ethyl acetate, the organic solution is washed successively with aqueous citric acid solution and with sodium chloride solution, dried and evaporated. Chromatography on silica gel with methylene chloride/methanol 97:3 as eluent gives the residue cyclohexylmethylpiperazinyl-imidazolo-rifamycin-SV as the main product. The compound shows in the mass spectrum a molecular ion at m/z = 901 (Calculated for C^H^yN^O^ ^ = 901). UV spectrum: (0.01-N alcoholic hydrochloric acid) ^max (nm)/e : 224/38400, 228/39200, 231/38600, 245 (shoulder) 304/26400, 420/11200.

Example 6

4--diethylamino-imidazolcV 4-» 5-_c7rifamycin SV (6).

Ammonia gas is introduced into the solution of 380 mg of diethylaminomethyleneaminorifamycin S in 15 ml of tetrahydrofuran during 15 minutes at room temperature. The solution is left overnight and then evaporated to dryness. The yellow-brown residue is chromatographed on a

silica gel, elution with the mixture of.chloroform with increasing

■ (2-10%). amount of methanol, the title compound appears ^4.2^56^4.^11^S°m & u^~^~' amorphous powder.

The production of starting material is described in example 79.

Example 7

4--dipropylamino-imidazolo_/_ i, 5-c7rifamycin SV (7).

Analogous to that described in example 1, the above-mentioned imidazolorifamycin-SC is prepared from 4-»0 g of 3-amino-4--iminorifamycin,S in 50 ml of tetrahydrofuran and 4->0 g of N,N-dipropylformamide-dimethyl acetal (7 ) (C^^H6oN^O11 molecular weight =820). Orange-coloured crystals of one from ether/methylene chloride, which melt during cleavage at 175-185°C, molecular weight found: 8 20.-

As a reagent, the necessary N,N-dipropylformamide-dimethylacetal is obtained in an analogous manner as in example 81 from 10 g of dipropylamine and 20 g of N,N-dimethylformamide-dimethylacetal.

Example 8■

4--(N-isopropyl-N-methylamino)-imidazolo_/_ 4-» 5-c7

■ rifamycin SV (8).

Analogously, as discussed in example 1, one wants from 4-.0 g

.3-amino-4-iminorifamycin-S in 50 ml of tetrahydrofuran and 4-.0 g of N-isopropyl-N-methylformamide-dimethyl acetal and 4-(N-isopropyl-N-methylamino )-imidazolo/ 4-» 5- ^7rifamycin-SV (8)

(C^H^N^O^, molecular weight = 792).

- ' The necessary reagent N-isopropyl-N-methyl- , formamide-dimethyl acetal■ is obtained analogously as in example 80 resp. 81 from 10 g of N-isopropyl-N-methylamine and 20 g of N,N-dimethylformamide-dimethyl acetal.

Example 9'

4.-(N-butyl-N-methylamino)-imidazolo/i,5-cj rifamycin SV (9).

Analogous, like. in example 1, from 4-»0 g of 3-amino-4--iminorifamycin S in 50 ml of THF and 4-»0 g of N-butyl-N-methyl-formamide-dimethyl acetal, 4--(N- butyl-methylamino )-imidazolo/~4-,5-c7-rifamycin SV (9 ) (C^^H^gN^O11, molecular weight = 806) . Molecular weight found: 806.

The N-butyl-N-methylformamide-dimethylacetal required as a reagent is obtained analogously to example 80 or 81

10 g of butylmethylamine and 20 g of N,N-dimethylformamide-dimethylacetal. Example 10 4.-(N-cyclopentyl-N-methylamino)-imidazole Oj/-4-,5-cJ rifamycin SV (10).

Analogous to that discussed in example 1, from U,Og 3-am.ino-4.-iminorifamycin S in 50 ml THF and 4-.0 N-cyclopentyl N-methylformamide-dimethyl acetal, 4--(N-cyclopentyl-N -methyl-amino')-imidazolo/-4-» 5~,c7 rifamycin SV (10) (C^^H^gN^O^, molecular weight=818). Molecular weight found: 818.

The N-cyclopentylformamide-dimethyl acetal required as a reagent is obtained analogously to example 80 or 81 from 10 g of cyclopentylmethylamine and 20 g of N,N-dimethylformamide-dimethylacetal.

Example 11

4-(N-Cyclopropylmethyl-N-propylamino)-imidazolofl, 5-c7-rifamycin SV (11).

Analogous to example 1, from 4-»0 g of 3-amino-4--iminorifamycin S in 50 ml of THF and 4-»0 g of N-cyclo-propylmethyl-N-propylformamide-dimethylacetal ^-(N-cyclopropylmethyl-N-propylamino )-imidazoloJ/-4., 5-c/ rifamycin SV

(11) (C^5H60N4-°11' molecular weight = 832). It forms from ether

yellow crystals of m.p. 223-224°C. Found molecular weight 832.

The N-cyclopropylmethyl-N-propylformamide-dimethyl acetal required as a reagent is obtained analogously to. discussed in Examples 80-82, from 10 g of N-cyclopropylmethyl-N-propylamine and 20 g of N,N-dimethylformamide-dimethylacetal".

Example 12

4-(N-benzyl-N-methylamino)-imidazolo_/_ 4t5-jc7 rifamycin SV (12).

Analogously to what was discussed in example 1, one would de-

0.7' g of 3-amino-4-iminorifamycin S in 10 ml of THF and 0.425. g N-ben-)'zyl-N-methyl-formamide-dimethylacetal obtain 0.155 g 4-(N-benzyl-N-methylamino)-imidazolo4»5-c7 rifamycin SV (12)

(C47H56N4°11'raomolecular weight = 852).

The preparation of the reagent is discussed in exempgd.

■80.

Example' 1 13

4-/ N-methyl-N-(1-methyl-4-piperidyl)-amino7_iniida-zolo-/ k, 5- £] rifamycin SV (13)..

Analogously, as in example 1, from 4.0 g of 3-•amino-4-iminorifamycin Si 50 ml of THF and 4.0 g of N-methyl-N-(1-methyl-4-piperidyl)-formamide-dimethylacetal get N-methyl-N-(1-methyl-4-piperidyl)-amino7-iniidazolo_/_ 4» 5-.c7 rifamycin SV

■ (13) (C45H61N5°1 -]' molecular weight = 847). Molecular weight found: 847.

As a reagent, the necessary N-methyl-N-(1-methyl-4-piperidyl)-formamide-dimethylacetal is obtained analogously to that described in example 82 from 10 g of N-methyl-N-(1-methyl-4 -piperidyl)-amine and 20 g of N,N-dimethylformamide-dimethyl acetal.

Example 14 in U-J_ N-ethyl-N-(2-hydroxyethyl)-amino7-imidazol rk, 5-cJvxfamycin SV (14 ) .'!i

Analogously to what is mentioned in example 1, 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4»0 g of N-j ethyl-N-(2-hydroxyethyl)-formamide-dimethyl acetal and the j desired imidazolorifamycin SV (14) (^42^56^4^12 '<m>°molecular weight = 808). Yellow prisms from methylene chloride/ether, melting with cleavage at 192-193°C. Molecular weight found: •808. i The N-ethyl-N-(2-hydroxy-ethyl)-formamide-dimethyl-acetal required as a reagent is obtained analogously as described in examples 80-82 from 10 g of N-methylethanolamine and 20 g of N, N- dimethylformamide-dimethylacetal .

, Example 15 I U~ J_ N-(2,2-dimethoxyethyl)-N-methylamlno7_imida-'zolo/ 4,5-e7~rifamycin SV (15).. 'i i_r— : .

Analogous to. mentioned in the example, from 4»0 g of 13-amiho-4-iminorifamycin-S in 50 ml of THF and 4.0 g of N-methyl-N-(2,2-;1 dimethoxyethyl)-formamide-dimethylacetal you get the desired imida- j ! zolorifamycin SV (15) (C ^^H^gN^O^» molecular weight =838) of Ism.p. 162°C during decomposition. Found molecular weight (<m>/2 of !TMS. -derivatives): 838. j The required reagent N-methyl-N-(2,2-dimethoxy-, !ethyl )formamide-dimethyl acetal is obtained analogously as discussed in exeiii- <!>pel 80-82, from ' 10 g methylaminoacetaldehyde dimethyl acetal and 20 g

IN,N-dimethylformamide-dimethyl acetal.

in Example 16

I k- J_ N-di-(2-methoxyethyl)-amino7-iniidazolo J fi, 5-c7rifamycin SV (16>.

Analogously to what was discussed in example 1, you want 4.0 g

<1>3-amino-4-iminorifamycin S in 50 ml THF and 4.0 g N,N-di-(2-

in methoxyethyl)-formamid-dimethylacetal get U~ J_ di-(2-methoxy-

ethyl)-araino7-i"midazolo-£~ k* 5-.c7rifamycin SV (16) (C^^H^qN^O^» molecular weight 852). Found f molecular weight 852.

j The N,N-di-(2-methoxy-ethyl)-formamide-dimethylacetal required as a reagent is obtained analogously as discussed in i

example 80 of 10 g of di-(2-methoxyethyl)amine and 20 g of Ni,N-dimethylformamide-dimethyl acetal.

Example 17 "j .4-/N-methyl-N-(2-dimethylaminoethyl)-amino7-imidazolo-/4-,5-.c_7rifamycin SV (1.7).

j Analogously; as described in example 1, 4.0 g of 13-amino-4-iminorifamycin Si 50 ml of THF and 4.0 g of N-methyl-jN-(2-dimethylaminoethyl)-formamide- dimethyl acetal k- J_ methyl-(2-jdimethylamino-ethyl)-amino7-imidazolo_/ 4, 5-, c7rifamycin SV (17) '(C43H59N5°11' molecular weight = 821). -From methylene chloride triangular crystal plates which melt during cleavage at i1 87-188°C Found molecular weight 821.

i The N-methyl-N-(2-dimethyl-aminoethyl)-formamide-dimethylacetal required as a reagent is obtained analogously as in examples 80-82 from 10 g of N,N,N1-trimethylethylenediamine and 20 g of N,N-jdimethylformamide -dimethyl acetal.

! Example 18

i k- J_ N-e tyl-N-(2-diethylaminoethyl)-amino7-imida-| zolo.-/_4, 5-c7rifamycin SV (18).

In Analog as discussed in example 1, one wants off

<!>4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF obtain 4.0 g of N-! ethyl-N-diethylaminoethyl-formamide-dimethyl acetal for the [desired imidazolorifamycin SV (18) (C^^H^^N^O^, molecular weight = 86.3) of m.p. 173-174 C during decomposition.

The N-ethyl-N-diethylamino-ethylformamide-dimethylacetal required as a reagent is obtained analogously as in examples 80-82 from 10 g of N,N',N'-triethylethylenediamine and 20 g of N,N-dimethylformamide-dimethylacetal .. ,

Example 19

I 4--pyrrolidinyl-imidazoleOj/ 4-, 5-j_7rifamycin SV (19).

J

I 20 g of dimethylformamide dimethyl acetal is heated with 10 g of pyrrolidine for four hours at 100°C. 100 ml of toluene is then added, evaporated in a water jet vacuum at 50°C. The residue is used without further purification as crude reagent dimethoxypyrrolidinemethane. A mixture of

7+ g of dimethoxypyrrolidinomethane, 50 ml of tetrahydrofuran and 4 g of [3-amino-4.-iminorifamycin S, are left for 6 hours at 25°C, with the initially dark red color of the reaction mixture gradually changing to yellowish brown . It is then acidified with an aqueous citric acid solution and the reaction product is taken up with methylene chloride. The ion product of the reaction is purified by chromatography on silica gel. With a mixture of ethyl acetate with.

("10% methanol as eluent, it is possible to obtain pure Jet pyrrolidinyl-imidazolo-rifamycin-SV (19) which from acetone/ether forms yellow crystals of m.p. 200°C Found molecule - weight: 790 ( MS as TMS-4--derivatives<m>/2 1078) calculated' for 1C1 2H5/N4°11 raolekyl weight ='790).

| Example 20

I 4--Indolinyl-imidazolo/_ i, 5-^7rifamycin SV (20)

Analogously as discussed in example 1, one wants to

12.0 g of 3-amino-4--iminorifamycin S in 100 ml of THF and 3.26 g of I N-formylindoline-dimethylacetal obtain 1.1 g of 4--indolinyl-imida-I zolo/~4, 5-c7rif amycin-SV (20) (G^#53®^0^ 1, molecular weight =

[837)..

I The required reagent N-formylindoline-dimethyl-; acetal is prepared according to example 82.

Example 21

4-piperidino-imidazolo_/_ 4-, 5- cJvi. famycin SV (21).

Analogous to that discussed in example 1, you want to off

4.r0 g 3-amino-4-iminorifamycin S in 50 ml THF and 4-»0 g N-formylpiperidine-dimethyl acetal fa 4-piperidinyl-imidazolo

' J/ 4,5-c7 rifamy.cin-SV (21) (C^-H^N^O., 1 , molecular weight 802).

Yellow crystals of m.p. 190°C during decomposition. Molecular weight found: 802.

The N-formylpiperidine-kimethyl acetal required as a reagent is prepared according to example 83.

Example 22.

In 4--(4--ethoxycarbonyl-1 -piperidyl)-imidazolo !/~4,5-c7 rifamycin SV (22).

Analogous to that discussed in example 1, 4, and |3-amino-4-iminorifamycin S in 50 ml THF and 4.0 g N-formyl-4-ethoxycarbonylpiperidine-dimethyl acetal will give 4-(4-ethoxy-carbonylpiperidyl )-imidazolo/U,5-£Irifamycin SV (22) C46H60N4013' molecular weight = 876 )••

The N-formyl-4-ethoxycarbonylpiperidine-dimethyl acetal required as a reagent is obtained analogously to examples 80-82 from 10 g of 4-ethoxycarbonylpiperidine and 20 g of N,N-dimethyl-

in

|formamide-dimethyl acetal.

Example 23

L-(4-dimethylamino-1-piperidyl)-imidazolo/ i, 5- cj rifamycin SV (23). Analogous to that discussed in example 1. one wants off. 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-4- dimethyl-aminopiperidine-dimethylacetal get 4-(4-dimethylamino-piperidyl)-imidazolo/ 4, 5-.c7rifamycin SV (23) (C^^<H>^^<N>^<O>^, I molecular weight = 847). From methanol-ether yellow crystals as I decompose from -~ 140°. Molecular weight found (m/2 of TMS.-deri-|j . Water): 847.j The N-formyl-4-dimethylaminopiperidine-dimethylacetal required as a reagent is obtained analogously as in example 80-82 and 10 g of 4-dimethylaminopiperidine and 20 g N,N-dimethylformamide-dimethyl acetal .

in Example 24

4~ (4-piperidino-1-piperidyl)-imidazolo/ 4, 5-c7 rifamycin SV (24)•

Analogously, as discussed in example 1, you want 4.0. g 3!-amino-4-iminorifam<y>ci<n>Si 50 ml of THF and 4, And N-formyl-4-piperidino-piperidine-dimethyl acetal. obtain i-(4-piperidinopiper-idyl-imidazolo/~4, 5-cj-rifamycin SV (24-) (48H65N$°1 1 ' molecular weight 887). From methanol-methylene chloride yellow crystals which decompose from 190°C.

I The N-formyl-4-piperidino-piperidine-dimethylacetal required as a reagent is prepared analogously as in example 80-

|82 of 10 g of 4-piper>dino-piperidine and 20 g of N,N-dimethylformamide-chymethyl acetal.

Example 25

in 4"\Z 8-aza-1 , 4-dioxaspiro - (4-, 5 )-8-d ecyl7~iniida-jzolo/4, 5-c7-rifa,mycin SV (25).

Analogous to that discussed in example 1, one wants to

4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF of 4.0 g of N-|formyl-(4-piperidoneethylene ketal)-dimethylacetal obtain the title compound (25) (C45H58N4°13'molecular weight = 862). Found: I molecular weight, (MS of TMS^derivatives) : 862.

The N-formyl-(4-piperidone-ethylene ketal)-dimethyl acetal required as a reagent is prepared according to example 85.

Oak sample 26

in 4-(3-diethylaminocarbonyl-1-piperidyl)-imidazolo |y~4,5-c7rifamycin SB (26).

Analogous to that described in example 1, from 4.0 g of I3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-3-diethylaminocarbonylpiperidine-dimethyl acetal, 4-(3-diethyl-aminocarbonylpiperidyl) -imidazolo/4,5-c;7rifamycin SV (26) .

(C48<H>65<N>5°12' molecular weight = 903).

The N-formyl-3-diethylamino-carbonylpiperidinedimethylacetal required as a reagent is obtained analogously as in example

80-82, and 10 g of piperidine-3-carboxylic acid diethylamide and 20 g of I N,N-dimethylformamide dimethyl acetal.

! Example 27

4-(1-perhydroazepinyl)-imidazolo/4,5-c7rifamycin SV (27).

Analogous to that discussed in example 1, one wants from 4.0 g

IN

3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-perhydroazepine-dimethyl acetal give the desired imidazolorifamycin-SV (27) (O^H^N^ 1 , molecular weight = 818).

The 1-formyl-perhydroazepine-dimethylacetal required as a reagent is prepared in an analogous way - as in examples 80-82 from 10 g of perhydroazepine and 20 g of N,N-dimethyl-formamide-dimethylacetal..

[ Example 28 ...

I 4-(1-perhydroazocinyl)-imidazolo/ 4, 5-.c7rif a-jmycin SV ( 28).

Analogously, as discussed in example 1, one wants off

|4.0 g of 3-amino.o-4-iminorifamycin, S in 50 ml of THF and 4.0 g of N-lformyl-perhydroazocine-dimethylacetal obtain I the title compound I (2 8)' CC^5H6QN^O1 1 , molecular weight = 832) of sm.p. 180°C during decomposition. Molecular weight found: 832.

The N-formyl-perhydro-jazocine-dimethyl acetal required as a reagent is obtained analogously to examples 80-82 from 10 g of perhydroazoein and 20 g of N,N-dimethylformamide-dimethyl acetal.

Example 29

J 4-(2,6-Dimethyl-morpholino)-imidazolo/4,5-tri-[famycin SV (29).

Analogously, as discussed in example 1, one will ■ of

In 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 4-formyl-2,6-dimethylmorpholine-dimethyl acetal obtain 4-(2,6-dimethyl-4-morpholinyl)-imidazolo_f" 4, 5-_;7rifamycin SV (29) (^^H^gN^O-) 2' I molecular weight = 834).'Yellow crystals which after, each^b J split from 240°C without melting. Found molecular weight: 834.

j The 4-formyl-2,6-dimethyl-j morpholine-dimethyl acetal required as a reagent is obtained analogously as in examples 80-82 from 10 g of 2,6-dimethylmorpholine and 20 g of N,N-dimethylformamide-dimethyl acetal.

j Example 30

4-thiomorpholino-imidazolo/ 4, 5-_c7rifamycin SV (.30).

j Analogous to example 1, from 1.4 g 3-

I ' ' ■ ' ■

åraino-4-irainorifamycin S in 100 ml of THF and 1.06 g of N-formylthio-morpholine-dimethylacetal obtain 0.4-5 g of 4-thiomorpholino-imidazolo ■' /"~4,5-c7 rifamycin SV (30) ( (C^H^N^ 1 , molecular weight = 822). The production of N-formylthiomorpholine-dimethyl acetal is described in example 87.

IN

Example 31

L-(4-ethylpiperazonyl)-imidazolo/ 4, 5-c7rifamycin bv (31).

Analogous to that discussed in example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 3.18 g of 1-formyl-j4-ethyl-piperazine-dimethyl acetal, 0.95 g of 4~ (U-ethylpipera-Izinyl)-imidazolo/fi,5-£Jrifamycin SV. (31) C^^H^^N^O^, 'molecular weight = 833).

j The 1-formyl-4-ethylpiper-|azine-dimethyl acetal required as a reagent (Boiling point: 98-100°C/20 torr) is obtained analogously j as in example 80 from 11.4 g N-ethylpiperazine and 25 g N, N-jdimethylformamide-dimethyl acetal.

j Example 32

4-(4-propylpiperazinyl)-imidazolo[beta]-4-[5-c]rifamycin SV (32).

Analogously, as discussed in example 1, 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 3.4-2 g of 1-formyl-4-propyl-piperazine. dimethyl acetal obtain 0.9 g of /+-(4--propylpipera-zinyl)-imidazolo/ A,: 5-j_7-rifamycin SV (32) (C^^H^^N^O^,

molecular weight = 84-7).

The 1-formyl-4-propylpiperazine-dimethyl acetal required as a reagent is obtained analogously to example 82 by

12.8 g of N-propylpiperazine and 29.75 g of N,N-dimethylformamide-dimethylacetal.

J Example 33 4--(4--Butylpiperazinyl)-imidazolo/ 4, 5-_c_7rifa-

mycin SV (33).

Analogously, as discussed in example 1, one wants off

4.0 g •3-am,ino-4-ininorifamycin-S in 50 ml THF and 4.0 g- 1-

formyl-4-butyl-piperazine-dimethylacetal few. the desired title compound (33) (C^H^N^ 1 , molecular weight = 861). Molecular weight found: 861.

It as reagent necessary. 1-form<y>1-4-butyl-piperazine-dimethylacetal is obtained analogously as described in example 82 from 10 g of N-butylpiperazine and 20 g of N,N-dimethylformamide-dimethylacetal...

Example 34

4-(4-Pentylpiperazinyl)-imidazolo/ 4» 5-.c7ri-phamycin SV (34) •

Analogously, as discussed in example 1, one wants off

2 g of 3-amino-4-iminorifamycin S in 100 ml. THF obtain 3.5 g of 1-formyl-4-pentylpiperazine-dimethylacetal obtain 1.4 g of 4-(4-pentyl;-'1.:piperazinyl)-imidazolo/-4,5-cJ-rlSamycin SV (34 ) (C^yH^^N^O^ , molecular weight = 875).

The 1-formyl-4-pentylpiperazine-dimethylacetal required as a reagent is obtained analogously to example 82 from 6.46 g of N-pentylpiperazine and 12.3 g of N,N-dimethylformamide-dimethylacetal.

Example 35

4 - (4-hexylpiperazinyl)-imidazolo _/4» 5 - cjvlpha.-mycin SV (35).

Analogously, as described in example 1, 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 4.13 g of 1-formyl-. 4-hexylpiperazine-dimethylacetal obtain 1.25 g of 4-(4-hexylpipera-zinyl)-imidazolo/4,5-.c7rifamycin SV (35) (C^gH^yN^O^ , molecular weight = 889).

The required reagent 1-formyl-4-hexylpiperazine-dimethylacetal (Boiling point: 125-130°C/0.3 torr),

is obtained analogously as in example 80 from 17 g of N-hexylpiperazine and 29.75 g of N,N-dimethylformamide-dimethyl acetal.

Example 36

4-(4-heptylpiperazinyl)-imidazolo/ 4'5-.c7ri-f.amycin SV (36).

Analogously, as discussed in example 1, one wants off

2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF of 4.33 g of 1-formyl-4-heptylpiperazine-dimethylacetal obtain 1.2 g of 4-(4-heptylpiperazinyl)-imidazolo-]_ 4, 5 - cJt±£ amycin SV (36)

(<C>4.9<H>69<N>5°11' molecular weight = 903).

The 1-formyl-4-heptylpiperazine-dimethylacetal required as a reagent (boiling point: 128-129°C/0.15 torr) is obtained analogously as in example 80 from 18.4 g of N-heptylpiperazine and 30 g of N,N-dimethylformamide dimethyl acetal.

Example 37

4-_/_ L-(1 -methylpropyl)-piperazinyl7-imidazolo /~4, 5-c7-rifamycin SV (37).

Analogous to example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-(1-methyl-propyl)piperazine-dimethylacetal, the title compound (3<7 >) (C^6H63N5011,-. molecular weight = 861 ) ..

The 1-formyl-4-(1-methyl-propyl)-piperazine-dimethylacetal required as a reagent is obtained analogously as described in example 80 from 10 g of N-(1-methylpropyl)piperazine and 20 g of N,N-,dimethylformamide-dimethylacetal .

Example 38

1+- J_ i-(2-methyl-butyl)-piperazinyl)-imidazolo /4,5-c7rifamycin SV (38).

Analogous to that discussed in example 1, one will of 4.0 g •3-amino-A-iminorifamycin S in 50 ml THF and 4.0 g 1-formyl-4-(2-methyl-butyl)-piperazin-dimethylacetal get /+-]_ 4~ (2-methyl-.butyl)-1-piperazinyl-7-imidazolo_/_ 4, 5-.c7rifamycin SV (38) ^47^65^5^11'm°lecyl weight = 875)' of m.p. 185°C below , decomposition. Found molecular weight 875.

The 1-formyl-4-(2-methyl-butyl )-piperazine-dimethylacetal required as a reagent is obtained analogously to examples 80-82 from 2 g of N-(2-methylbutyl=-piperazine) and 20 g of N,N-dimethylformamide-dimethyl acetal.

Example 39

%-/_ 4~(2-methylpentyl=-piperazinyl7_imidazolo /~4, 5-c7-rifamycin SV (39).

Analogous to that described in example 1, 4.0 g of 1-formyl-4-(2-methylpentyl)-piperazine-dimethyl acetal will be obtained from 0 g of 3-amino-4-iminorifamycin S in 50 ml of THF. 4-(2-methylpentyl)-1-piperazinyl7imidazolo_/ 4, 5-c7rifamycin SV (39)

(C^8H67N5011,<m>olecyl weight^889)'of m.p. 171-172°C during decomposition.' Found molecular weight: 889.

What is now the required 1-formyl-4-(2-methylpentyl)-piperazine-dimethylacetal is obtained analogously as discussed in examples 80-82 from 10 g of N-(2-methylpentyl)-piperazine and 20 g of N,N- dimethylformamide-dimethyl acetal.

Example 4. 0

4-(3-methylbutyl)-piperazinyl-7-imidazolo

/~4,5-c7rifamycin SV (40).

Analogous to that discussed in example 1, one will of 4.0 g of ,'3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-(3'-methylbutyl)-piperazine-dimethyl acetal obtain 4-7 4-(3- methyl-butyl )-1-piperaziny^-imidazolo/ 4, 5-_c7rifamycin SV (40)

(<C>47H65N5°11'molecular weight -'875).

The 1-formyl-4-(3-methyl-butyl)-piperazine)-dimethylacetal required as a reagent is obtained analogously as described in examples 80-82 from 10 g of ,N-(3-methylbutyl)-piperazine and 20 g of N,N -dimethylformamide-dimethyl acetal.

Example 41

4-(4-(1-Ethylpropyl)-piperazinyl-7-imidazolo

J_ 4, 5-_c7rifamycin SV.;(41)-

Analogous to that discussed in example 1, from 4.0 g of 3-amino-4-iminorifamycin Si 50 ml of THF and 4.0 g of 1-formyl-4-(2-ethylpropyl)-piperazine-dimethyl acetal, 4-/ 4_ (2-ethyl-propyl)-1-piperazinyl7-imidazolo_/_ 4.,5-c7rifamycin SV (41)

^<C>47<H>65<N>5°11, molecular weight = 875), Found molecular weight: 875.

IN

j That which. reagent required 1-formyl-4-(2-ethyl-propyl)-piperazine-dimethyl acetal is obtained analogously as in example 80-82 from 10 g of N-(2-ethylpropyl)-piperazine and 20 g of N,N- dimethylformamide-dimethyl acetal.

Example 42

4--/ 4--(3-methylpentyl)-piperazinyl7-imidazolo j/~4, 5-c7-rifamycin SV (4-2).

Analogously to that discussed in example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-(3-methylpentyl)-piperazine-dimethyl acetal, 4- \ J_ 4-(3-methylpentyl)-1-piperazinyl7_imidazolo/_ 4. 5-c7rifamycinjSV (42) (<G>^8<H>é7W5<0>11, molecular weight =889). Molecular weight found: 8891

The 1-formyl-4-(3-methylpentyl)-piperazine-dimethylacetal required as a reagent is obtained analogously as in example: 80-82 from 10 g of N-(3-methylpentyl)-piperazine and 20 g of N,N- dimethyl-I formamide-dimethyl acetal.

j Example 43

|- 4-/~*4-(1,3-dimethylpropyl)-piperazinyl7-imida-jzolo/4,5-^7-rifamycin SV (43).

J Analogous to that discussed in example 1, you want to av

(2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 3.2 g of 1-!formyl-4-(1,3-dimethylpropyl)-piperazine-dimethylacetal obtain 1.7 g of the title compound (4 <3>) (C^yH^N^ ^ , molecular weight = 875).

j The 1-formyl-4-(1,3-dimethylpropyl)-piperazine-dimethylacetal required as a reagent is obtained analogously as in 1 Example 82 from 2.55 g of N-(1,3-dimethylpropyl)-piperazine and 4.87 g { N,N-dimethylformamide-dimethyl acetal.

in

in Example 44

4-(4-allylpiperazinyl)-imidazolo/4,5-c7rifamycin

' SV (44).

Analogously, as discussed in example 1, one wants off

2.0 g of 3-amino-4--iminorifamycin S in 100 ml of THF and 3.4 g of 1-formyl-4-allyl-piperazine-dimethylacetal obtain 1.2 g of 4-(4-allyl-

I ■

piperazinyl)-imidazolo-[_ 4, 5-_c7rifamycin SV (44) |(C^.5H59N50'1 1 , molecular weight- 845)..

The required .1-formyl-4-allyl-Ipiperazine-dimethyl acetal as a reagent is obtained in an analogous manner to. in Example I82 and 5 g of N-allylpiperazine and 11.9 g of N,N-dimethylaformamide-jdimethyl acetal.

(Example 45

i k- J_ 4-,('3-butenyl)-piperazin'yl7-imidazolo/_ 4,5-c7 jrifamycin SV (45).

!' Analogous to that described in example 1, from 4.0 g of j3-amino-4-iminorifamycin S in 50 ml of THF, 4.0 g of 1-formyl-j4-(3-butenyl)-piperazine-dimethyl acetal will be obtained 4~ (3 -butyenyl )-1 - Ipiperazinyl7-imidazolo/ 4, 5-__7rif amycin, SV (45) (C^^H^^ N^O^ , I molecular weight = 859). Found molecular weight (MS): 859.

I The required reagent 1-formyl-4-(3-butenyl)-piperazine-dimethylacetal is obtained analogously as in example 82 from 10 g of N-(3-butenyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal .

' Example 46

; 4-_/ 4~ (2-methyl-2-propenyl)-piperazinyl7-imidazolo ' /_4, 5-_;7-rifamycin SV (46).

in

j Analogous to that discussed in example 1, from ) 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 3.62 g of 1-formyl-4-(2-methyl-2-propenyl)-piperazine-dimethyl acetal will be obtained In 1.15 g of the title compound (46) (C^^H^^N'^O^, molecular weight =

In 859).

i The reagent required 1-formyl-4-(2-methyl-

In 2-propenyl)-piperazine-dimethyl acetal is obtained in an analogous manner

as in Example 82 of 21.13 g of N-(2-methyl-2-propenyl)-pipera-

j

j zin and 45 g of N,N-dimethylformamide-dimethyl acetal.

' Example 47

4-/~4-(2-ethyl-2-butenyl)-piperazinyl7-imidazolo l~4, 5-c7_rifamycin SV (47).

Analogous to that discussed in example 1, you want 4.0 g

IN

13-Amini-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-■4-(2-ethyl-2-butenyl)-piperazine-dimethylacetal obtain the title (compound (47) (C^gH^ N^O., 1, molecular weight = 887).Found Imolecular weight: 887.

i The preparation of the formamide reagent is discussed in example 89.

in

l Example 48

I 4-/ 4-(2,3~dimethyl-2-butenyl)-piperazinyl7_imida-jzolo-/ 4, 5-j_7rifamycin SV (48).

in 1 '. ——————————————^. ___________ I Analogously as described in example 1, 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 4.0 g of 1-formyl-|4-(2,3-dimethyl- 2-butenyl)-piperazine-dimethyl acetal obtain 0.42 g ' 4-/~~ 4-(2, 3-dimethyl-2-butenyl)-piperazinyl7-iniidazolo/ 5, 4-._7

■rifamycin SV (48) (C^gH^N^ 1 , molecular weight = 887).

j The reagent required 1-formyl-4-(2,3-dimethyl j2-butenyl)-piperazine-dimethyl acetal. is obtained analogously as in example 182 from 30 g of N-(2,3-dimethyl-2-butenyl)-piperazine. and 53 g of N,N-Dimethylformamide-dimethyl acetal.

In Example 49

4-(4-propargylpiperazinyl)-imidazolo/4,5-._7ri-ifamycin SV (49).

in

j Analogous to that described in example -1, from 2.0 g of 13-amino-4-iminorifamycin S in 100 ml of THF and 3.7 g of 1-formyl-1 4-propargylpiperazine-dimethylacetal, 1.05 g of 4-( 4-propargyl-piperazinyl )-imidazolo/ 4, 5-__7rifamycin SV (4<9>) (<C>^^<H>^<-N>^<O>^,j molecular weight = 843).

j The necessary 1 -formyl-4-propargyl-

: piperazine dimethyl acetal is obtained analogously to example 82 of i! 7.65 g of propargylpiperazine and 15.6 g of N,N-dimethylformamide-dimethyl acetal.

! Example 50

4-(4-Cyclopentylpiperazinyl)-imidazolo/-4,5-_c7

In rifamycin SV (50).

i Analogously as discussed in example 1, 4.0 g of vil- mane

IN

S-amino-4--iminorifamycin S in 50 ml- THF and 4.0 g 1-formyl-4-cyclopentylpiperazine-dimethyl acetal obtain Å-(A-cyclopentyl-1 piperazinyl)-imidazolo/ 4, 5-_:7rifamycin SV (50) CC^yH^^N^O^, molecular weight = 873). Molecular weight found: 873. The 1-formyl-A-.cyclopentylpiperazine-dimethylacetal required as a reagent is obtained in an analogous manner as in example 80-82 from 10 g of N-cyclopentylpiperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

• Example 51

, 4-(4-cyclohexylpiperazinyl)-imidazolo/ 4» 5-j_7 jrifamycin SV (51).

Analogous to that described in the example, from (.0 g |3-amino-4-iminorifamycin S' in 50 ml THF and 4.0 g 1-formyl-4-jCyclohexylpiperazine-dimethyl acetal will obtain 4-(4-cyclohexyl-1- ipiperazinyl)-imidazolo / 4» 5-_c7rifamycin SV (51) !(C48H65N5°11'<m>°molecular weight = 887).

The required reagent 1-formyl-4-cyclo-. ihexylpiperazine-dimethylacetal is obtained analogously as discussed in 'examples 80-82 from 10 g of N-cyclohexylpiperazine and 20 g of N,N-

in

dimethylformamide-dimethyl acetal.

l Example 52

4-(4-phenylpiperazinyl)-imidazolo/<->4,5-_7rifamycin

'SV (52).

IN

j Analogous to that discussed in example 1, from 2.0 g of 13-amino-4-iminorifamycin Si 100 ml of THF pg 3.32 g of 1-formyl-1 4-phenyl-piperazine-dimethylacetal, 0.79 g of 4_(4 -phenylpipefa-

' zinyl)-imidazolo/-4, 5-_c7rifamycin SV (52) (C^gH^^N^O^,

' molecular weight 881 ). The preparation of acetal reagent is discussed in

; example 91•

Example 53

4-[-4-(3-trifluoromethylphenyl)-piperazinyl-7-imidazolo/4,5-_crifamycin SV (53).

Analogous to that described in example 1, 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF will yield 5.14 g of 1-formyl-

IN

4-(3-trifluoromethylphenyl)-piperazine-dimethylacetal obtain 0.73 g \ U- f~ A - (3-trifluoromethylphenyl)-piperazinyl7-imidazolo/ 4» 5- cJ irifamycin SV (53). (C^H^N^ y molecular weight = 949).

i The reagent required 1-formyl-4-(3-trifluoro-1methylphenyl)-piperazine-dimethylacetal (boiling point: 158-160<0>C/0.2jtorr) is prepared analogously as in example 80 from 25 g of N- (3-trifluoromethylpyridine)-piperazine and 32.4 g of N,N-dimethylformamide-dimethyl acetal.

l Example 54

i ' 4_(4-cyclopropylme.t<y>l<p>i<p>erazin<y>l)-imida<z>olo<_>f~4»5-_7Rifamycin SV (54).

Analogous to that described in example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-1 4-cyclopropylmethyl"piperazine-dimethyl acetal, 4- (4-cyclo-'propylmethyl-piperazinyl)-imidazolo/ 4,5-_7rifamycin SV (54) i(<C>46<H>61N5°11' molecular weight = 859. Found molecular weight: 859.

I The 1-formyl-4-cyclopropyl-1-methylpiperazine-dimethylacetal required as a reagent is prepared analogously as described

• in example 80-82 from 10 g of N-cyclopropylmethylpiperazine and 20 g

<N,N-dimethylformamide-dimethyl acetal.

^ Example 55

4-(4-cyclopentylmethylpiperazinyl)-imidazolo/~4,5-c7-rifamycin SV (55).

i<1>

i Analogously as discussed in example 1, one wants of 1.0 g ! 3-amino-4-imindi)rifamycin S in 50 ml THF obtain 1.26 g 1-formyl-I 4-cyclopentylmethylpiperazine-dimethyl acetal obtain 0.275 g 4~

j (4-cyclopentylmethyl-piperazinyl)-imidazolo/ 4,5-c7rifamycin SV i (5<5>) 8<H6>5<N>5°11' molecular weight = 88?)-

j The 1-formyl-4-cyclopentyl-1 methylpiperazine-dimethylacetal required as a reagent is prepared in an analogous manner to

in discussed in example 82 of A- t 71 g of cyclopentylmethylpiperazine and r 9.5 g of N,N-dimethylformamide-dimethyl acetal.

Example 56 v

4-(4-cycloheptylmethylpiperazinyl)-imidazolo/-/, 5-_7

rifamycin SV (56).

Analogous to that discussed in example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF, 4.0 g of 1-formyl-4-cycloheptylmethylpiperazine-dimethyl acetal will be obtained, the title compound (56) (C^qH ^^N^O^, molecular weight = 915). Sm.p. 179-180°C during decomposition. Molecular weight found: 915.

The 1-formyl-4-cycloheptylmethylpiperazine-dimethylacetal required as a reagent is obtained in an analogous manner as described in examples 80-82 from 10 g of N-cycloheptylmethylpiperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

Example 57.

4-(4-Benzylpiperazinyl)-imidazolo/4,5-_7rifamycin SV (57) . ,

Analogous to that discussed in example 1, you want to off

4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-benzyl-piperazine-dimethylacetal obtain 4~(4-benzyl-piperazinyl)-imidazolo/ 4,5-_7rifamycin SV (57) (C^^H^^N^O^, molecular weight = 885).

The 1-formyl-4-benzyl-piperazine-dimethylacetal required as a reagent is obtained analogously to examples 80-82

of 10 g of N-benzyl-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

Example 58

4-[4-(2-methyl-3-phenyl-propyl)-piperazinyl7_imidazolo/4,5-_c7rifamycin SV (58).

Analogous to that described in example 1, 4 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4 g of 1-formyl-4-(2-methyl-3-phenyl-propyl).-piperazine-dimethyl acetal will be obtained the title compound (58) (C^H^N^O., 1 molecular weight = 937), Found molecular weight': 937.

The 1-formyl-4-(2-methyl-3-phenyl-propyl)-piperazine-dimethylacetal required as a reagent is obtained analogously as discussed in example 82 from 10 g of N-(2-methyl-3-phenyl-propyl) )-piperazine and 20 g of N,N-dlraethylformamide-dimethyl acetal.

Example 59

4-/ 4--(2-pyridyl)-piperazinyl7_iniidazolo_/ U, 5- cJ rifamycin SV (59).

Analogously to what was discussed in example 1, you want 2.0 g

■3-amino-4-iminorifamycin S in 100 ml, THF and 4.01. g of 1-formyl-4-(2-pyridyl)-piperazine-dimethylacetal obtain 1.28 g of k~ J_ 4-(2-pyridyl)-piperazinyl7~iniidazolo__ 4, 5-_c7rif amycin. SW (59)

(C47H58N6°11 ' molecular weight:z''882) •

The required reagent 1-formyl-4-(2-pyrid<y>1)-piperazine-dimethylacetal (boiling point: 154-156°C/0.7 torr) is obtained. analogously to that described in example 80 of 25 g of N-(2-pyridyl.)-piperazine and 45 g of N,N-dimethylformamide-dimethyl acetal.

Example 60

4-/ 4-(2-pyridylmethyl)-piperazinyl7-imidazolo/~4,5-c7-rifamycin SV (60).

Analogous to that described in example 1, 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF will yield 4.26 g of 1-formyl-4-(2-pyridylmethyl)-piperazine-dimethylacetal, 0.97 g 4-/ 4~

(2-pyridylmethyl)-piperazinyl7_imidazolo/_ 4, 5-c7rifamycin SV (60) (<C>^gH60<N>6<0>11, molecular weight, = 896. The reagent required 1-formyl-4-( 2-pyridyl-methyl)-piperazine.dimethyl acetal (boiling point: 150-160°C/0.1 torr) is prepared analogously to that described in example 80 from 15.85 g of N-(2'-pyridylmethyl)-piperazine and 29, 8 g of N,N-dimethylformamide-dimethylacetal.

Example 61

4-[4-(2-tetrahydrofurylmethyl)-piperazinyl-7-imido-zolo-_/_ 4 , 5-_c7rifamycin SV (61).

Analogous to that discussed in example 1, you want to off

4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-(2-tetrahydrofurylmethyl)-piperazine-dimethylacetal obtain the title compound (6<1>) (C^H^N ^ molecular weight 889).

Found molecular weight: 889.

The 1-formyl-4-(2-tetrahydrofurylmethyl)-piperazine-dimethylacetal required as a reagent is obtained analogously as described in examples 80-82 from 10 g of N-(2-tetrahydrofurylmethyl)-piperazine and 20 g of N ,N-dimethylformamide-dimethyl acetal.

Example 62

4--'{ 4--/ 2-(1 , 3-dioxolan-2-yl)-ethyl 7-pipera^

zinyl j -imidazolo/ 4, 5-_c7rifamycin SV (62).

In an analogous manner to that described in example 1, 4-.0 g of 3-amino-4-ininorifamycin-S in 50 ml of THF and 4>0 g of T-form yl-4--/ 2-(1,3- dioxolan-2-yl) -e tyl7-piperazine-dimethyl - acetal obtain the titelf orbind el sen (6.2) (C^yH^N^O^ y molecular weight= 905). Found molecular weight (MS): 905.

The required formamide acetal reagent is prepared analogously to example 82 from 10 g of N-(2-(1,3-dioxlan-2-yl)-ethyl7-piperazine and 20 g of N,N-dimethylformamide-dimethyl acetal.

Example 63

4--/ 4_(2-Methoxyethyl)-piperazinyl7-imidazolo £~ L, 5-c7rifamycin SV (63).

Analogously to example 1, from 2.0 g of 3-amino-4-iminorifamycin S in .100 ml of THF and 3.19 g of 1-formyl-4-(2-methoxyethyl)-piperazine-dimethylacetal, 0.4-3 g of the title compound (6.3) (C^H61 N501 - , molecular weight = 863).,

The 1-formyl-4-(2-methoxyethyl)-piperazine-dimethylacetal required as a reagent (boiling point 1 01 -1 0-3° C/0.2 torr) is obtained analogously as described in example 80 from 19 g of N-(2 -methoxyethyl)-piperazine and 40 g of N,N-dimethylformamide-dimethyl acetal.

Example 64

4-_/ 4-(2-ethoxyethyl)-piperazinyl7-imidazolo

J_ 4, 5-_c7rifamycin SV (64).

Analogously as discussed in the example. 1 you want off

4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF. and 4.0 g of 1-formyl-4-(2-ethoxyethyl)-piperazine-dimethylacetal obtain the title compound (<64>) (<C>^< H>^<Kf>^<C>'12<»>molecular weight = 877), of m.p.

166°C during decomposition.

The 1-formyl-4-(2-ethoxy-ethyl)-piperazine-dimethyl acetal required as a reagent is obtained analogously as discussed in examples 80-82 from 10 g of N-(2-ethoxyethyl)-piperazine and 20 g of N,N-dimethylformamide -dimethyl acetal.

Example 65 4.-/4--(2,2-Dimethoxyethyl)-piper a zinyl/-imidazolo- /_4,5-c7rifamycin SV (65).

Analogous to that described in example 1, 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-(2,2-dimethoxyethyl)-piperazine-dimethyl acetal will be obtained. 4~/ 4-(2,2-dimethoxyethyl)-piperazinyl7-iniidazolo/~4, 5-_7rifamycin SV (65)

(C46H63N5°13' arolekvlw ~ 893). Molecular weight found: 893 - The 1-formyl-4-(2,2-dimethoxyethyl)-piperazine-dimethyl acetal required as a reagent is obtained analogously as described in example 82 from 10 g of N-(2,2-dimethoxyethyl)-piperazine and 20 g of N,N-dimethylformamide-dimethyl acetal.

Example 66

4-/ 4-(2,2-diethoxyethyl)-piperazinyl7-imidazolo f i', 5-c7-rifamycin SV (66).

Analogous to that discussed in example 1, 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF will yield 4.87 g of iVn formyl-4-(2,2-diethoxyethyl)-piperazine-dimethylacetal, yielding 2, 0 g of the title compound (66) (C^gH^N^ y molecular weight = 921).

The 1-formyl-4-(2,2-diethoxyethyl),-piperazine-dimethyl acetal required as a reagent is obtained analogously as described in example 82 from 6.19 g of N-((2,2-diethoxyethyl)-piperazine and 8.60 g N,N-dimethylformamide-dimethylacetal.

Example 67

4-.(4^ethoxycarbonylpiperazinyl)-imida.zolo/ 4, 5-_7 rifamycin SV (67).

Analogously to example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and '4.0 g of N-formyl-N'-ethoxy-carbonylpiperazine-dimethylacetal, the title compound (67) is obtained

(<C>^5<H>59N5013>molecular weight = 877).

The preparation of formamide acetal reagent is discussed in Example 90.

Example 68

4-(4-isopropyloxycarbonylpiperazinyl)-imidazolo/4,amycin SV (68).

Analogous to that described in example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 4.16 g of 1-formyl-4-isopropyloxycarbonylpiperazine-dimethylacetal, 1.17 g of 4-(4-isopropyloxycarbonylpiperazinyl)- imidazolo/ 4»5-_7 rifamycin SV (68) (C^H^ 3', molecular weight "891).

The required reagent 1-form<y>1^-isopropyl-oxycarbonylpiperazinedimethylacet.al (boiling point: 118-119°C/0.15 torr) is obtained analogously as described in example 80 from 8.5 g of N-isoprop pyloxycarbylpiperazine and 14.8 g of N,N-dimethylformamide-dimethylacetal.

Example 69

4.-/4-(2-Dimethylaminoethyl)-piperazinyl7-imidazolo/~4,5-_7-rifamycin SV (69).

Analogous to that described in example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 3.9 g of 1-formyl-4-(2-dimethylaminoethyl)-piperazine-dimethylacetal, 1.05 g of the title compound (6<9>) (c/i6H6/4N6011 ' molecular weight- 876)-. .. The reagent required 1-formyl-4-(2-dimethylaminoethyl)-piperazine-dimethylacetal (boiling point: 110-111<u>C/0.1 torr) is obtained analogously to example 80 from 21.26 g of 2-dimethylaminoethyl -piperazine and 40.28 g of N,N-dimethylformamide-dimethyl acetal.

Example 70

4-(4-isobutyrylpiperazinyl)-imidazolo/4,5-cJ rifamycin SV' (70) .

Analogously as discussed in example 1 will. from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 3.9 g of 1-formyl-4-isobutyrylpiperazine-dimethyl acetal obtain 0.6 g of 4-(4-isobutyryl-piperazinyl)-imidazolo/. 4, 5-_c7 rifamycin SV (70)

^<C>46<H>61<N>5°12' molecular weight ='875).

The required reagent 1-formyl-4-isobutyr-.yl-piperazine-dimethyl-acetal (Boiling point: U5-1 50 C/0 , 5 torr ) is obtained analogously as described in example 80 from 25 g of N-isobutyryl- piperazine and 4-7-, 4-g N,N-dimethylformamide dimethyl acetal.

Example 71

4-(4-Methoxycarbonylmethylpiperazinyl)-imidazolo /~4,5-c7-rifamycin SV (71).

Analogous to example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 3.85 g of 1-formyl-4-methoxy-carbonylmethylpiperazine-dimethylacetal, 0.75 g of 4-- (4-Methoxy-carbonylmethylpiperazinyl)-imidazolo/ 4, 5-_c7rifamycin SV (71)

(Cj4_5H59N5013>. molecular weight = 877).

The 1-formyl-4-methoxy-carbonylmethyl-piperazine-dimethylacetal required as a reagent (boiling point: 1U-115 C/ 1 torr) is obtained analogously as described in example 80 from 10 g of N-methoxycarbonylmethylpiperazine and 75 g of N,N-dimethylformamide -dimethyl acetal ...

Example 72

4.-(4-Isopropylcarbamoylmethylpiperazinyl)-imidazolo[beta], 5-c7rifamycin SV (72).

Analogous to that described in example 1, 2.0 g of 3-amino-4.-iminorifamycin is prepared. S in 100 ml of THF and 4.38 g of 1-formyl-4- isopropylcarbamoylmethyl-piperazine-dimethylacetal obtain 0.62 g of the title compound (7<2>) (C^H^N^ 2, molecular weight- 914).

The 1-formyl-4-iso-propylcarbamoylmethyl-piperazinedimethylacetal (boiling point: 161 — 163 C/0.2 torr) required as a reagent is obtained analogously to example 80 from 15 g of N-isopropyl-1-ppjperazine-acetam.ide and 24 .1 g N, N .dimethylformamide-dimethyl acetal.

Example 73

4-(4-morpholinocarbonylmethylpiperazinyl)-imidazolo/~4,5-c7rifamycin SV (73).

Analogous to that described in example 1, 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 4.85 g of 1-formyl-4-morpholinocarbonylmethylpiperazine-dimethyl acetal will yield 1.03 g of the title compound - (73 ) ^C48H64N6°13' molecular weight = 932).

The 1-formyl-4-morpholino-carbonylmethylpiperazine-dimethylacetal required as a reagent is obtained analogously to example 82 from 25 g of 4-piperazinylacetylmorpholine and 35 g of N,N-dimethylformamide-dimethylacetal. ,

Example 74

4-/ 4-(1-methyl-2-dimethylaminoethyl)-piperazinyl7_

imidazplo/ 3 , 4-_7rifamycin SV (74).

Analogous to that discussed in example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 4.15 g of 1-formyl-4-(1-methyl-2-dimethylaminoethyl)-piperazine-dimethylacetal you will get 0, 84 g of the title compound (74) (O^yH^N^O.^ , molecular weight = 890).

The required formamide acetal reagent (boiling point 115-117°C/0.2 torr) is obtained analogously to example 80 from 17.1 g of N-(1-methyl-2-dimethylaminoethyl)-piperazine and 30 g of N,N-dimethylformamide dimethyl acetal.

Example 75 L-(4-isobutyl-2-methyl-piperazinyl)-imidazolo /<_>4,5-c7rifamycin SV (75).

Analogous to example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-isobutyl-2-methyl-piperazine-dimethylacetol, the title compound (75) is obtained

(C47H65N5°11 * molecular weight^875) of m.p. 1 75-180°C during cleavage. Molecular weight found: 875.

The 1-formyl-4-isobutyl-2-methylpiperazine-dimethylacetal required as a reagent is obtained analogously to example 82 from 10 g of 1-isobutyl-3-methylpiperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

Example 76

4-(4-isobutyl-2,5-dimethyl-piperazinyl)-imidazolo /~4,5-c7-rifamycin SV (76).

Analogously as discussed, in example 1, 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-isobutyl-2,5-dimethylpiperazine-dimethylacetal get 4,(4-isobutyl-2, 5-dimethylpiperazinyl)-imidazolo/ 4- > 5-_c7rifamycin SV. (76) (C48H67N5°-n » molecular weight = 889)- Found molecular weight : 889).

The 1-formyl-4-isobutyl-2,5-dimethylpiperazine-dimethylacetal required as a reagent is obtained analogously to Example 82 from 10 g of 1-isobutyl-2,5-dimethylpiperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

Example 77

4-(4-isobutyl-perhydro-1,4-diazepinyl)-imidazolo /4,5-c7-rifamycin SV (77).

Analogous to example 1, from 4.0 g of 3-amino-4-imino-rifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-isobutyl-perhydro-1,4-diazepine-dimethyl acetal, 4~ ( 4-isobutyl)-perhydro-1,4-diazepinyl)-imidazolo/4,5-j_7rifamycin SV (77)-(C^-H^^N^O^, molecular weight = 875).

The 1-formyl-4-isobutyl-perhydro-1,4-diazepine-dimethyl ac.etal required as a reagent is obtained analogously to examples 80-82 from 10 g of N-isobutyl-perhydro-1,4-diazepine and 20 g of N,ri -dimethylf ormamide-dimethylacetal ..

Example 78

3-Dimethylaminomethyleneamino-rifamycin S (78).-

Dissolve 1 g of 3-aminorifamycin S in 50 ml abs. methylene chloride, is mixed with 425 mg of triethylamine (3 equivalents) and 1.28 g of N, N . dimethylformamide-dimethyl lac.etal (5 equivalents) and the reaction solution is left for 45 minutes at room temperature temperature. ■ The mixture is mixed with 50 ml of water, the organic phase is separated and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated in vacuo. The dark blue colored oily residue is applied to a column of 30 g of silica gel in chloroform, and eluted with chloroform with increasing amounts of methanol (.2-5 vol%). By evaporation, 3-dimethylamino-methyleneamino-rifamycin S is obtained, which is crystallized from ether/hexane and obtained as a blue-black powder.,) m.p. 150-155°C.

Citrate formation

4-00 mg of 3-dimethylaminomethyleneamino-rifamycin S is dissolved in 5 ml of dioxane and mixed with 1 ml of 0.5-M citric acid solution, and the solution is lyophilised, whereby v500 mg of 3-dimethylaminomethyleneamino-rifamycin S-citrate is produced as a blue-black powder .

Example 78A

3-Dimethylaminomethyleneamino-rifamycin SV (by reduction of corresponding rifamycin S derivatives).

A solution of 0.5 g of 3-dimethylaminomethyleneaminorifamycin S in 5 ml of methanol is mixed with 2 ml of a 10% (w/v) aqueous sodium bicarbonate solution and 5 ml of a 10% (w/v ) solution of Fe(CN)^7potassium ferrocyanide) in water, the solution is stirred vigorously and diluted with 20 ml of water and chloroform each time. The chloroform phase is separated and the aqueous phase is extracted twice more with chloroform. The combined chloroform extracts are dried and evaporated to give 3-dimethylaminomethyleneaminorifamycin SV as a yellow powder. When standing in a solution, the latter is very quickly converted back to quinone by air or oxygen oxidation.

Example 79

3-diethylaminomethyleneaminorifamycin S (79).

A solution of 1 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is cooled to -70°C and treated with 285 mg of triethylamine (2 equivalents) and 4-60 mg of iminoyl chloride (2,1 equivalents) and stirred for 5 minutes at -70° C and mixed with 50 ml of water. The organic phase is separated, and the aqueous phase is extracted twice with methylene chloride, the combined organic extracts are dried over sodium sulphate and evaporated in vacuo. The dark blue colored oily residue is applied to a column of 100 g of silica gel in ethyl acetate-hexane (1:1) and eluted. with the mixture of hexari with increasing amounts (50-75 volume?) of ethyl acetate, by evaporation of the corresponding fractions and crystallization from . ether-hexane yields 3-diethylaminomethyleneamino-rifamycin S as blue-black powder, m.p. 133-135°C.

The iminoyl chloride used as reagent can be prepared as follows: A solution of 10.1 g of diethylformamide in 50 ml of absolute ether is mixed in a nitrogen atmosphere with stirring at 0°C dropwise with 12.7 g of oxalyl chloride, stirred for a further 3 hours with 50<U>G. The white precipitate of iminoyl chloride is suctioned off in a pressure cooker, washed with ether and dried under high vacuum. The highly hygroscopic iminoyl chloride is used without further purification for the conversion of 3-amino-rifamycin S.

Example 80

3-(N-benzyl-N-methylamino)methyleneamino-rifamycin

S (80).

A solution of 1.5 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is treated with 637 mg of triethylamine (3 equivalents) and 4-, 1 g of N-benzyl-N-methylformamide-dimethylacetal (10 equivalents), allowed to stand for 3.5 hours at room temperature, and mixed with 75 ml of water. The organic phase is separated, and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated in vacuo. The dark blue colored oily residue is applied to a column of 200 g of silica gel in chloroform, and eluted with mixtures of chloroform with increased amounts of (1-5 vol) methanol. By evaporation of the corresponding fractions and - crystallization ion r j f Éa ^.'ether-hexane, 3-(N-benzyl-N-methylamino)-methyleneamino-rifamycin S appears as a blue-black powder, m.p. 138-14-0°C.

The reagent used was N-benzyl-N-methylformamide.

dimethyl acetal can be obtained as follows: A mixture of 7.27 g of N-benzyl-N-methylamine and 20 g

N,N-dimethyl-formamide-dimethyl acetal. is heated for 4 hours under reflux, excess reactant is distilled off in a water jet vacuum at 50°C oil bath temperature and 30 torr, and the evaporated reaction mixture is subjected to fractional distillation. N-benzyl-N-methyl-formamide-dimethyl acetal distills at 104.-106°C/20 torr.

Example 81

3-pyrrolidinylmethyleneaminorifamycin S (81).

A resolution of 1,. 4-g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is treated with 298 mg of triethylamine (2 equivalents) and 1.4-3 g of N-formylpyrrolidine-dimethyl acetal (5 equivalents), left for 1.5 hours at room temperature, evaporated in a water jet vacuum gently to dryness, and dried in high vacuum. , The dark blue colored oily residue is applied. a column of 150 g of silica gel in chloroform, and eluted with mixtures of chloroform with increasing amounts (1-5 vol?) of methanol. After evaporation of the corresponding fractions and crystallization from methanol-water, 3-pyrrolidinylmethyleneaminorifamycin S. appears as a blue-black powder, m.p. 165-170°C.

The N-formylpyrrolidine-dimethylacetal required as a reagent can be prepared as follows: A mixture of 10 g of pyrrolidine and 42 g of N.N.dimethylformamide-dimethylacetal is heated for 3 hours under reflux, the excess reactant is distilled off in a water jet vacuum at 50°C oil bath temperature and 20 torr, and the remaining liquid is subjected to fractional distillation. N-formyl-pyrrolidine-dimethylacetal distills at 65°C/20-h orr.

Example 82

3-indolinylmethyleneaminorifamycin S (.82).

A solution of 1.5 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is treated with 640 mg of triethylamine (2 equivalents) and 2.5 g of N-formylindoline dimethyl acetal (5 equivalents) and allowed to stand for 1 1/2 hours at room temperature, gently evaporated in a water jet vacuum, and dried in

high vacuum. The dark blue colored oily residue on

is applied to a column of 200 g silica gel in chloroform and eluted with mixtures of chloroform with increasing amounts (0.5-5 vol?) of methanol. The corresponding fractions are again chromatographed over "Sephadex" LH-20, eluting with methanol. After evaporation of the eluate and crystallization from ether

hexane, 3-(indolinyl)methyleneaminorifamycin S is obtained

as blue-black amorphous powder with no defined melting point.

<13>C-NMR (in CDC13)

(U8.8, U1.6, 131.8, 127.8, 1 25.5, 124.2, 109.9, 46.7, 27.0 ppm).

The N-formylindoline-dimethylacetal required as a reagent can be prepared as follows: A mixture of 6.8 g of indoline and 20 g of N,N-dimethylformamide-dimethylacetal is heated for 3 hours under reflux

run, and the excess reactant is distilled off in a water jet vacuum at 50°C oil bath temperature, and 20 torr. The scaffold residue, consisting mainly of crude N-formyl-indoline-dimethyl acetal', is extracted with several portions of toluene, and the combined solutions are evaporated in a water jet vacuum. The residue formed is used without further purification for the above-mentioned turnover.

Example 83

3-piperidinomethyleneaminorifamycin S (83).

A solution of 1 g of 3-amino-rifamycin Si 50 ml of alcohol-free methylene chloride is treated with 4-25 mg of triethyl-

amine. (3 equivalents) and 2.24 g of N-formyl-piperidine-dimethylacetal are left for 2 hours at 0°C and mixed with 50 ml of water. The organic phase is separated, and the aqueous phase is extracted

twice with methylene chloride, The combined organic extracts are dried over sodium sulfate and evaporated in vacuo.. The dark- . blue colored oily residue is eluted on a column of 100 g silica gel in chloroform with increasing amounts (2-5 vol?) of methanol. After evaporation of corresponding fractions and crystallization from ether-hexane, 3-piperidinomethyleneamino)-rifamycin S is obtained

as blue-black powder, m.p. 162-165°C.

The N-formylpiperidine-dimethylacetal required as a reagent can be prepared as follows: A mixture of 6.3 g of piperidine and 20 g of N,N-dimethylformamide-dimethylacetal is heated for 3 hours under reflux, the excess reactant is distilled off in a water jet vacuum at 50°C oil bath temperature and . 20 torr, and the remaining liquid is subjected to fractional distillation. N-formyl-piperidine-dimethyl acetal distills at 74°C/20 torr.

Example 84

3-(4-methylpiperidinyl)-methyleneamino-rifamycin S (84

A solution of 1.5 g of 3-aminorifamycin ■ S in 50 ml of alcohol-free methylene chloride is treated with 637 mg of triethylamine (3 equivalents) and 3.6 g of N-formyl-4-methylpiperidine-dimethyl acetal (10 equivalents) and allowed to stand for 2 1/2 hours at room temperature and mixed with 50 ml of water. The organic phase is separated, and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulphate and evaporated in vacuo, and chromatographed over a column of 200 g silica gel in chloroform. Elution with chloroform with increasing amounts (1-50 vol?) of acetone and evaporation of the corresponding fractions gives a residue which, after crystallization from ether-hexane, gives 3-(4-methylpiperidinyl)-methyleneaminorifamycin S as a blue-black powder, m.p. . 88-90°C.

The N-formyl-4-methylpiperidine-dimethylacetal required as a reagent can be obtained as follows: A mixture of 5 g of 4-methylpiperidine and 14.9 g of N,N-dimethyl-formamide-dimethylacetal is heated for 13 hours under reflux, the excess reactant is distilled off in a water jet vacuum at 50° oil bath temperature and 20 torr, and the remaining liquid is subjected to fractional distillation. N-formyl-4-methylpiperidine-dimethylacetal is distilled at 78°C/20 h orr.

Example 85

3-(8-aza-1,4-dioxa-spiro'_/4''5-_c7dec-8-yl)methyleneaminorifamycin S (85).

A solution of 2 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is treated with 575 mg of triethylamine

(2 equivalents) and 3.6 g of N-form<y>l-4;<p>piperidone-ethylene ketal-. dimethyl acetal (6 equivalents), leave for 2 1/2 hours at room temperature and mix with 50 ml of water. The organic phase is separated, and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated in vacuo, and the dark blue colored oily residue is chromatographed over a column of 200 g of silica gel in toluene. By elution with the solvent with increasing amounts (10-75 vol?) of ethyl acetate, corresponding fractions formed are again chromatographed on "Sephadex" LH-20, eluting with methanol. After crystallization of the evaporated fractions from methanol-water, 3-(8-aza-dioxa-spiro/L,_5_7dec-8-yl)-methyleneamino-rifamycin is obtained as blue-black powder sm,p. 178-180°C.

The N-formyl-4-piperidin-ethyl ketal-dimethyl acetal required as a reagent can be prepared as follows: A mixture of 20 g of 4-piperidone-ethylene ketal and 4-2 g of N,N-dimethylformamide-dimethyl acetal is heated for 3 hours under reflux , excess reactant is distilled off in a water jet vacuum at 50°C bath temperature and 20 torr, and the remaining liquid is subjected to fractional distillation. N-formyl-4-piperidone-ethylene ketal-dimethyl acetal' is distilled at 11-1U°C/0.5 torr..

Example 86

3-morpholinylmethyleneamino-rifamycin S (86)

A cooled to -70°C solution of 3-amino-rifamycin S in 50 ml of alcohol-free methylene chloride is mixed with 1.6 g of triethylamine (7.5 equivalents) and -3.36'. g of morpholine iminoyl chloride (10 equivalents) is stirred for 1 hour at -40°C,

and treated with 50 ml of water. The organic phase is separated,

and the aqueous is extracted twice with methylene chloride.

The combined organic extracts are dried over sodium sulfate

and evaporated in a vacuum. The residue is dissolved in a minimal amount of methanol, treated with a 10 µg (weight/volume) aqueous potassium ferricyanide solution in the presence of potassium bicarbonate. The oxidation mixture is extracted twice with chloroform, the chloroform extract is dried and evaporated, and chromatographed over a column with 100 g of silica gel in chloroform. By elution with chloroform with increasing amounts (1-50 vol?) of acetone and evaporation of the corresponding fraction, a residue is obtained which, after crystallization from methanol-water, gives 3-morpholinylmethyleneaminorifamycin S as an amorphous powder.

<13>C-NMR spectrum (in CDCl 3 ): 16.0.9, 67.2, 49.1 ppm. The iminoyl chloride required as a reagent derived from morpholine can be obtained as follows: A solution of 5 g of N-formylmorpholine in 50 ml abs. ether. is mixed under nitrogen and with stirring at 0°C dropwise with 5.52 g of oxalyl chloride, and the reaction solution . stir for a further 3 hours at 50°C. The white precipitate of the iminoyl chloride•is sucked off in a pressure cooker, washed with ether, dried in a high vacuum. The highly hygroscopic iminoyl chloride is used without further purification in the above reaction.

Example 87

3-Thiomorpholinylmethyleneaminorifamycin S (87).

A solution of 1.5 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is mixed with 6.37 mg of triethylamine (3 equivalents) and 5.6 g of N-phophyl-thiomorpholine-dimethyl acetal (15 equivalents), allowed to stand for 60 minutes at room temperature, and treated with 50 ml of water. The organic phase is separated, and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated in vacuo, and the dark blue colored

.oily residue is chromatographed in chloroform over a column

with 250 g of silica gel. By ■ elution' with chloroform increasing ';

quantity (1-5 vol?) of methanol evaporation of the corresponding fraction appears after residue which after crystallization from ether-hexane gives 3-thiomorpholinyl-methyleneamino-rifamycin S as' blue-black powder, m.p. 1 77-182°C.

The N-formyl-thiomorpholine-dimethyl acetal required as a reagent can be obtained as follows: A mixture of 5.4-5 g of thiomorpholine and 15.7 g of N, N-dimethylformamide dimethyl acetal is heated for 3 hours under reflux, the excess reactant is distilled off in a water jet vacuum at 50 °C oil bath temperature, pg 20 torr, and the remaining liquid is subjected to fractional distillation. tion. N-formyl-thiomorpholine-dimethylacetal distils at i

■1'10-1 13°C/20 torr.. !

Example 88

3-(4-methylpiperazinyl)-methyleneamino-rifamycin S (8"8).] ; '. „i,.,, j A mixture of 1 g of 3-amino-rifamycin S, 4-25 mg

(■3 equivalents) triethylamine, and 2.4- g (10 equivalents) j N-methyl-N<1->formylpiperazine-dimethyl acetal in 50 ml alcohol-free j

in methylene chloride for 2 1/2 hours at room temperature, j and processed analogously to what is stated in example 10. By chromatography over a column of 120 g of silica gel in chloro-. form, elution with chloroform with increasing amounts (2-20 vol?) of acetone, and crystallization from ether-hexane gives the title compound as a blue-black powder, m.p. 148-151 o CV

The N-methyl-N 1-formylpiperazine-dimethyl acetal required as a reagent can be obtained as follows: A mixture of 5 g

N-methylpiperazine and 14.9 g of N,N-dimethylformamide-dimethylace -tal are heated for 3 hours under reflux. After the processing analogous to examples 3-8 and 10, the desired N-methyl-N',-formylpiperazine-dimethyl acetal is distilled at 84-85 C/20, torr.

Example 89

3~ J_ 4-(2-ethyl-2-butenyl)-piperazinyl7-methyleneamino-rifamycin S (89).

A mixture of 2 g of 3-aminorifamycin S, 575 mg

(2 equivalents) triethylamine, 3.4 g (5 equivalents) N'-formyl-N-(2-ethyl-2-butenyl)-piperazine-dimethylacetal in 50 µl of alcohol-free methylene chloride are left for 2 hours at room temperature, and processed analogously as stated in example 4«. \ By chromatograph! over a column of 250 g silica gel in chloro-j form and elution with chloroform with increasing amounts' (0.5- j 10 vol?) of methanol is obtained after crude product which is further purified by

chromatography on "Sephadex" LH-20 (elution with methanol).] By crystallization from ether-hexane, the title compound is obtained as a blue-black powder, m.p. 140-142°C.

A N '-formyl-(2-ethyl-2-butenyl)-piperazine-dimethyl acetal required as a reagent can be obtained as follows: A mixture of. 10 g of N-(2-ethyl-2-butenyl)-piperazine and 16.7 g of N,N-dimethylformamide-dimethyl acetal are heated under reflux for 5 hours. After processing analogously to examples 3-8 and 10, the desired N'-formyl-N-(2-ethyl-2-butenyl)-piperazine-dimethyl acetal is distilled at 121°C/0.5 torr. j Example 90 !

3-(4-ethoxycarbonylpiperazinyl)methyleneamino-j rifamycin S (90). in

A mixture of 2 g of 3-aminorifamycin S, 575 mg (2 equivalents) of triethylamine and 3.27 g (5 equivalents) of N'-formyl-piperazine-N-carboxylic acid ethyl ester-dimethyl acetal in 50 ml of alcohol-free methylene chloride is prepared 4 hours at room temperature, and processed analogously as stated in example 4. Chromatography over a column of 250 g silica gel in chloroform and elution with chloroform with increasing amounts (0.5-10 vol?) of methanol is obtained a crude product which is further purified by chromatography "Sephadex" LH-20 (elution with methanol). On crystallization from ether-hexane, the title compound is obtained as a blue-black powder, m.p. 160-165°C.

The reagent N<1->formyl-piperazine-N-carboxylic acid ethyl ester-dimethyl acetal can be obtained as follows: A mixture of 10.87 g of piperazine-N-carboxylic acid ethyl ester and 20.44 g of N,N-dimethylformamide-dimethyl acetal is heated A hours during reflux. After the processing analogously to Examples 3-8 and 10, the desired N'-formyl-piperazine-N-carboxylic acid ethyl ester-dimethylacetal distils at 128-130°C/0.75 torr.

Example 91

i A mixture of 1.5 g of 3-aminorifamycin S, £25 mg

(2 equivalents) triethylamine pg 3.5 g (7 equivalents) N'-formyl-N-phenyl-piperazine-dimethyl acetal in 50 ml of alcohol-free methylene chloride is left for 6 1/4 hours at room temperature and processed analogously as indicated in example 10. By chromatography .over a column of 250 g silica gel in chloroform and elution with increasing amounts of chloroform (0.5-5 vol?) in methanol, a crude product is obtained which is further purified by chromatography on "Sephadex" LH-20 (Elution with methanol). On crystallization from ether-hexane, the title compound is obtained as a blue-black powder with no defined melting point.

The necessary N1-formyl-N-phenylpipera- .!

zin-dimethyl acetal can be obtained as follows: j

A mixture of 10 g of N-phenylpiperazine and 18.3 g of N,N-dimethylformamide-dimethyl acetal is heated for 3 hours under | backflow. After processing analogously to example 3-8 pg 10, it distills. desired N<1->formyl-N-phenylpiperazine-dimethylacetal at 165-167°C/0.5 torr. j Example 92 i 3-U-aza-tricyclo/~5, 2, 2, 02'_7undec-8-en-A-yl) methyleneamino-rifamycin S (92)..i A mixture of 1 g of 3-aminorif. amycin S, 283 mg (2 equivalents) of triethylamine and 1.26 g (4 equivalents) of 4-formyl-[+-aza-tricyclo-/5,2,2,0'_7undec-8-ene-dimethyl acetal in 50 ml. alcohol-free methylene chloride is allowed to stand for 6 hours at room temperature, and is processed analogously as indicated in example 10. By chromatography. over an approx. 100 g of silica gel in chloroform, elution with chloroform with increasing amounts (1-10 vol?) of methanol and crystallization from methanol-water gives the compound as a blue-black powder, m.p. ' 1.73-1 76°C .

Example 93

3-dipropylaminomethyleneamino-rifamycin S by reaction with dimethylsulphate complex.

2.0 g of N,.N-dipropylformamide and 2.0 g of dimethylsulphate are allowed to stand for 3 hours at room temperature, and the oil formed is washed first with benzene, then twice with ether, freed from the rest of the ether in vacuum. The oil contains N,N-dipropylformamide-dimethylsulphate-complex-in set, dissolve in 50 ml abs. methylene chloride, and mixed with stirring with 500 mg of triethylamine and 2.25 g of 3-aminorifamycin S. The reaction solution is allowed to stand at room temperature until the 3-aminorifamycin S used has completely reacted. The reaction mixture is then mixed with 50 ml of water, the organic phase is separated, and the aqueous phase

i is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated in vacuo. The blue colored residue is chromatographed on silica gel, using chloroform with increasing amounts (2-10?) of methanol as eluent. The pure 3-dipropylaminemethyleneamino-rifamycin • S which appears in the form of a blue-black powder can, analogously to example 6, be converted with ammonia gas in tetrahydrofuran directly into A-dipropylamino-imidazolo__ 4-^5-_c_7 rifamycin SV (7) which is completely identical to products from Example 7.. ■■•-.'!

IN

Example 94- \

4--Dimethylamino^imidazolo_/_ L, 5-c;7rifamycin SV (1 ) .

Analogously to that described in example 6, a solution of 1.0 g of 3-dimethylaminomethyleneamino-rifamycin S (78) in 50 ml of tetrahydrofuran is treated with ammonia gas. The usual processing yields the title compound (1), which is identical to the product from example 1.

Example 95

4.-morpholino-imidazolo/ 4-, 5-c7rifamycin SV (2).

Analogously to that discussed in example 6, a solution of 0.5 g of 3-morpholinomethyleneaminorifamycin S (86) in 30 ml of tetrahydrofuran is treated with ammonia gas. With the usual processing, the title compound (2) is obtained, which is identical to the product from the example. 2.

Example 96

I + -(4--Methylpiperazinyl)-imidazolo/ 4-, 5-.c7rifamycin SV (3).

Analogously to example 6, a solution of 0.5 g of 3-(4-methylpiperazinyl)-methyleneaminorifamycin S (88) in 25 ml of tetrahydrofuran is treated with ammonia gas. The usual processing yields the title compound (3), which is identical to the product from example 3. in Example 97

4-(N-benzyl-N-methylamino)-imidazolo/4-,5-_7 rifamycin SV (12).

2.0 g of 3-(N-benzyl-N-methylamino)-methyleneaminorifamycin S (80) in 100 ml of tetrahydrofuran is treated with ammonia gas. The aqueous processing yields the title compound (12), which is identical to the product from example 12.

Example 98

4.-pyrrolidinyl-imidazolo/ 4» 5-_c7rifamycin SV (19).

In an analogous manner to example 6, a solution of 0.4-5 g of 3-pyrrolidinylmethyleneaminorifamycin S (81) in 25 ml of tetrahydrofuran is treated with ammonia gas. In a normal processing, the title compound is obtained.(1 9) which is identical to the product from example 19..

Example 99

4--indolinyl-imidazolo/ 4-, 5-_c7rifamycin SV (20).

Analogous to example 6, a solution is processed

of 0.25 g of 3-indolinylmethyleneaminorifamycin S (82) in 15 ml of tetrahydrofuran with ammonia gas. With the usual preparation, the title compound (20) is obtained, which is identical to the product from example 20.

Example 100..

4-piperidino-imidazolo/ 4, 5-_c7rifamycin SV (21).

Analogously to Example 6, a solution of 0.5 g of 3-piperidinomethyleneaminorifamycin S (83) in 25 ml of tetrahydrofuran is treated with ammonia gas. At the permanent for- . in the process, the title compound (21) is obtained, which is identical to the j product from example 21..

Example 101

4-(8-aza-1,4-dioxa-spiro/-4»5-_7dec-8-yl)-imidazolo/ 4., 5-_c7rif amycon SV (25).

Analogous to example 6, a solution of • 0.2 g of 3-(8-aza-1,4-dioxa-spiro/4».5_7dec-8-yl)-methyleneamino-rifamycin S (85) in 15 ml of tetrahydrofuran is treated with ammonia- j gas. In the usual processing, the title compound ice (25) is obtained, which is identical to the product from example 25.. i

in Example 102 j

4-(4-thiomorph olinyl)imidazolo/ 4-, 5-j_7rifamycin'SV (30). i ~ j Analogously to example o, a solution j of 0.5 g of 4.-t.iomorpholino'methyleneamino-rifamycin S (87) in 30 i ml of tetrahydrofuran is treated with ammonia gas. The usual processing yields the title compound (30), which is identical to the product from example 30. Example 103

4-.-/ 4--(2-ethyl-2-butenyl)-piperazinyl7-imidazolo

/ 4., 5-_c_7.-rifamycin SV (4-7).

Analogously to example 6, a solution of 0.5 g of 3-/. 4-(2-ethyl-2-butenyl)-piperazinyl7-aminomethylene-amino-rifamycin (89) in 25 ml of tetrahydrofuran with ammonia gas. The usual processing yields the title compound (47), which is identical to the product from example 47.

Example 104 j

A-(4-ethox<y>carbon<y>l-<pi>perazine<y>l)-imidazolo/-4-<,>5-<_c>_7 !

rifamycin SV (67). ;

1 in Analogous example 6, a solution of 0.3 g of I-(A-ethoxycarbonylpiperazinyl)-methyleneaminorifamycin S (90) in 20 ml of tetrahydrofuran is treated with ammonia gas. The usual processing yields the title compound (67)

.. i which is identical to the product from example 67.'

Example 105

A-(A-phenylpiperazinyl)-imidazolo/ /+, 5- c7 rifamycin SV (52).

Analogously to Example 6, a solution of 0.5 g of 3-(A-phenylpiperazinyl)-methyleneaminorifamycin S (91) in 30 ml of tetrahydrofuran is treated with ammonia gas. In the usual processing, the title compound (52.) is obtained, which is identical in. to the product from example 52..i Example 106 •

A-morpholino-imidazolo/ A» 5-_c7rifamycin SV (2).

Analogous to example 2, 4.0 g of 3-amino-A-imino-■} rifamycin S is reacted in .50 ml of tetrahydrofuran with A>0 g of tris-morpho-j lino-methane. In the work-up according to example '2', the title compound (2) is obtained as yellow crystalline leaves, m.p. 192-193°C

(from ether) .. in The reagent used, tris-morpholino-methane is obtained !

i as follows: i A mixture of 15 g of morpholine and 15 g of N,N-dimethyl-, formamide-dimethyl acetal is heated for ' 12 hours under reflux

run under moisture exclusion. Then all water jet vacuum is removed at 130UC volatile part is by distillation from the react ion mixture and. the remaining brown oily residue which quickly starts to crystallize is carried out with a mixture of ether with a little! petroleum ether and washed. The formed white crystals (-18 g) of tris-'morpholinomethane melt after recrystallization from chloroform/

ether at'241-243°C. For C-]^ E25^ 3°3 (molecular weight 271.36) calculated: 57.54?C, 9.29% H, 15.49? N, found 57.5? C, 9.2? H, 15.4? N.

Example 107

4-Dimethylamino-imidazolo/ 4, 5-.c7rifamycin SV (1).

Analogous to example 1, 4.0 g of 3-amino-4-iminorifamycin S is reacted in 40 ml of tetrahydrofuran with tris-dimethyl-amino-methane (4>0 g), which is further reprocessed. ;The resulting product*m.p. 180-185 is identical to 4-dimethylamino-imidazolo/' 4,5-crifamycin SV (1) according to example 1. Analogously, using tris-diethylamino-methane, 4-diethylamino-imidazolo/4,5- £7rifamycin SB (6) identical to products from Example 6. j Example 108 j

4-(4-aza-tricyclo/5,2,2,02'_7undec-8-en-4_yl)-imidazolo-/4,5-_c7rifamycin SV (93). j

— ; In Analogous example 1, from 4 g of 3-amino-4-iminorifamycin Si 50 ml of THF and 4 g of 4-formyl-4-aza-tricyclo/5,2,2,0 2 '_6 7-undec-ene -4-yl)-dimethylacetal get title- !' the compound (93) (C4.8H60N4-°1 1 ' molecular weight = 868). j

The production of the reagent necessary ! 4-formyl - i - (az a-tri cyclo -/ — 5,2,2,0 2 '_6 7-und ec-8-eh-4-yl) - di met yl -';' acetal is discussed in example 92.

Example 109

4-/ 4-(2-Hydroxy-2-methylpropyl)-piperazinyl/-imidazolo/ 4, 5-__7rifamycin SV (94).

Analogous to example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 5.2 g of 1-formyl-4-(2-hydroxy-2-methylporpyl)-piperazine-dimethyl acetal, 0, 5 g of the title compound (9<4>) (<C>46<H>63<N>5°12' molecular weight = 877).

The required reagent 1-formyl-4-(2-hydroxy-.2-methylpropyl)-piperazine-dimethylacetal (boiling point 86-90°C/ 1 torr) is obtained analogously to example 80 from 30 g of N-(2-trimethylsilyloxy -2-methyl-propyl)-piperazine and 50 g of N,N-dimethylformamide-dimethyl- ■

acetal. in)

Example. 110.

A-/ A~(2,2-Dimethyl-1,3-dioxolan-A-ylmethyl)-piperazinyl7-imidazolo/ i,5-c7rifamycin SV (95).

Analogous to example 1, A g 3-amino-A-iminorifamycin S in 50 ml THF and A g 1-formyl-A-(2,2-dimethyl-1,3-dioxolan-A-ylmethyl)-piperazine-dimethylacetal obtain the title compound (95) (<C>48<H>65<N>5°13<»>molecular weight = 919). Molecular weight found: 919.

The necessary 1-formyl-A-(2,2-dimethyl-1,3-dioxolan-A-ylmethyl)-piperazine-dimethylacetal is obtained analogously

example 82 of 10 g of N-A-(2,2-dimethyl-1,3-dioxolan-A-yl-methyl)-piperazine and 20 g of N,N-dimethylformamide-dimethyl acetal.

Example 111

A~(A-cyclobutylmethyl-piperazinyl)-imidazolo

/~A,5-c7-rifamycin SV (96).

Analogous to that discussed in example 1, from A g 3-amino-A-iminorifamycin in 50 ml of THF and A g 1-formyl-A-cyclobutylmethylpiperazih-dimethyl acetal, the title compound (96) is obtained (C^?H63N5011, molecular weight = 873).

The 1-formyl-A-cyclobutyl-methylpiperazine-dimethylacetal required as a reagent is obtained analogously to example 82 from 10 g of N-cyclobutylmethyl-piperazine and 20 g of N,.N-dimethylformamide-dimethylacetal.

Example 112

Formation of salts with bases.

A nitrogen-stirred suspension of 15.50 g of A-dimethyl-amino-imidazolo/5,A-c7rifamycin SV, (1) in 150 ml of water is mixed dropwise with -20.0 ml of a 1-normal sodium hydroxide solution (0.987 equivalents). The resulting . gulfarve.de solution is filtered, and the filtrate is subjected to freeze-drying. The remaining A-dimethylamino-imidazolo. J_ A, 5-_c/ri.famycin SV-sodium salt is an amorphous powder, readily soluble in water, the solution has a pH of approx. 7.3. For C40H51<N>4°11Na (raw molecular weight 786.85), calculated 2.92% Na,

found 2, 8 7." *Ka.

Analogously, the potassium salt of compound (1) is obtained with a corresponding potassium hydroxide solution.

Analogously, acid-reactive imidazolorifamycins of the SV series can generally be processed. (formula Ia) i. corresponding salts.

Example 113

Formation of acid addition salts.

A stirred suspension of 8.7<5>g of 4-(4-isobutyl-piperazinyl)-imidazolo/4,5-c7rifamycin SV (4) in 165 ml of water is mixed with 10.0 ml of 1-N aqueous hydrochloric acid (0.985 equivalents ). The mixture is filtered, and the filtrate is subjected to freeze-drying. The resulting 4-(4-isobutylpiperazinyl)-imidazolo/4,5-crifamycin SV hydrochloride forms a water-soluble yellow amorphous powder. For" C^H^N^O^ . H.Cl (898.49): 3.95% Cl, found 4.08% Cl.

Analogously, hydrochlorides of basic-reacting imidazolo/4,5-£7rifamycins can generally be prepared. The method is analogously also applicable for the production of addition salts of other water-soluble acids.

Example. 114

Capsules, containing 0.25 g of the active substance, are prepared as follows:

Composition: (for 1000 capsules):

The active substance and the corn starch are mixed and moistened with a solution of polyvinylpyrrolidone in 50 g of ethanol. The moist mass is pressed through a sieve with a mesh size of 3 mm and dried at 4.5°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.

Example 115

Tablets, containing 250 mg of active substance, are prepared as follows:

Composition: (for 1 tablet):

The active substance is mixed homogeneously with the additives and pressed into tablets.

For the production of film dragees, the tablets are each coated with 1 mg of aqueous varnish.

Instead of sodium carboxymethyl starch, sodium carboxymethyl cellulose can also be used.

Example 1 16

Stick capsules, containing 100 mg of the active ingredient, are prepared as follows:

Composition (for 1000 capsules):

The active substance is mixed with the lactose, the resulting mixture is moistened with a solution of ethyl cellulose in a 10-fold weight amount of methylene chloride, passed through a sieve of 3-5 mm mesh size, and dried at a temperature that does not dare rise above 4-0°C. The dry granules are passed through a sieve with a mesh size of 0.5 mm and mixed with the powdered stearic acid. The mixture is then filled in portions of 0.153 g each into size 2 capsules.

As active substances in examples 114-116, one each of the compounds (1)-(77), (93-96) and (78) - (92) can be used. Particularly preferred as active substance are the compounds (1), (2), (3), (4), (10), (12), (19), (21) and (57), as well as (82).

Example 117

Dry ampoules or vials containing 500 mg of the active substance can be prepared as follows:

Composition: (for 1 ampoule or vial):

A sterile aqueous solution of the active substance and mannitol is placed under aseptic conditions in 5 ml ampoules or 5 ml vials, closed and be investigated.

An alkali metal salt, e.g. one such from example 112.

Example - 118

Test report:

1. Examined compounds

is characterized in the following tables 1 and 2 with the same number., where under its preparation is indicated in the previous examples.

2. Test organisms

are set out in the following tables 1 and 2 in an abbreviated form as follows:

3. Methodology.

The antibiotic activity of the test compound in vitro was determined by the agar dilution method according to Ericssom H.M. and Sherris S.C. 1971, Acta Path. Microb. Scand.' Session B, Suppl. No. 217, Volumes 1-90, in DST Agara. They found the growth of the test organism yet. inhibitory minimum concentrations' (MIC = minimum inhibition concentrations) are stated in micrograms per milliliters (ug/ml) for the investigated compounds in Table 1.

Claims (3)

T. Process for the preparation of an A-aminoimidazolo/4-, 5-c7rifamycin SV or S of formula in which R means hydrogen or acetyl and Am means an amino group derived from a secondary amine, as well as salts of corresponding compounds with salt-forming properties, characterized in that a 3-aminorifamycin-S compound see with formula in which R has the above meaning, in any order, is reacted a) with ammonia and b) with a reactive derivative of an N,N-disubstituted formamide or thioformamide of the formula in which Y means oxygen or sulphur, and Am has the above meaning, and if desired a formed compound of the SV type is oxidized to a compound of the S type or a formed compound of the S type is reduced to a compound of the SV typeii and/or a formed free compound with salt-forming properties is converted into a corresponding salt or a formed salt in the corresponding free compound. 2. Method according to claim 1, characterized in that a starting substance is formed under the reaction conditions or is used in the form of a salt. 3. Method according to claim 1 or 2 for the production of an A-aminoimidazolo_/ 4-, 5-c7rifamycin SV or S the formula IA defined in claim 1, resp. IB, characterized by that a) a 3-aminorifamycin-S-4-imine of formula in which R has the meaning stated in claim 1, is reacted with a reactive derivative of an N,N-disubstituted formamide or thioformamide of formula in which Y means oxygen or sulfur and Am has the meaning stated in claim 1, or b) an N1,N'-disubstituted 3-aminomethyleneaminorifamycin derivative of formula in which R and Am have the meaning stated in claim 1, is treated with ammonia, and if desired, a formed compound of the SV type or a compound of the S type is oxidized, or a formed compound of the SV type is -reduced to a compound of SV -type, and/or a formed free compound with salt-forming properties is converted into a corresponding salt, or a formed salt is converted into a corresponding free compound./ L. Process according to one of claims 1-3, characterized in that a 4--aminoimidazol__ 4-, 5-c7rifamycin SV" or S with formula IA or IB, in which Am means an amino group having two identical or different monovalent optionally substituted hydrocarbyl or heterocyclyl residues with a maximum of 20 C atoms, or an equivalent 2-valent residue which with the amino group forms a non-aromatic hydrogen-containing heterocyclyl residue. 5. Method according to one of claims 1-3. characterized in that it . a 4-aminoimidazolo/4-, 5-_c7rifamycin SV or S with formula IA resp. IB, wherein Am is characterized by the partial formula 12 wherein R and R independently of one another each represents a lower alkyl or lower alkenyl which may be substituted one or more times by hydroxyl, mercapto, lower alkoxy, lower alkoxycarbonyl, an unsubstituted or N-m6no- or disubstituted" carbamoyl, formyl, oxo, acetalized or ketalized oxo, and/or a disubstituted amino group, means a lower alkenyl, a cycloalkyl or cycloalkyl-lower alkyl, which may optionally have one or two double bonds, an unsubstituted or with halogen, hydroxy, trifluoromethyl, an unsubstituted or N- mono- or di-substituted carbamoyl or lower alkoxycarbonyl substituted phenyl or phenyl lower alkyl, or a maximally bicyclic heterocyclyl or heterocyclylalkyl with a maximally two heteroatoms, selected from oxygen, nitrogen 12 and/or sulphur, where R and R can be connected to each other by means of a single carbon-carbon bond or via an oxygen, sulphur(il)- or optionally substituted nitrogen, and together with the amino nitrogen atom can form a .4- to 8-membered non-aromatic heterocyclic ring. 6. Method according to one of claims 1-3"characterized in that a U-aminoimidazolo/L,5-crifamycin SV or S of formula IA or S is prepared. IB, in which the symbol Am means a remainder with the partial formula wherein m and n independently each mean an integer from 1 to 5, forming at least a 5-membered ring, and means a hydrogen atom, a formyl group, a functionally modified carboxyl group, or an unsubstituted or substituted maximum 10 C-atom-containing hydrocarbyl or heterocyclyl residue, the hetero.cyclyl residue where the free valence each time proceeds from a C atom.7. Process according to one of claims 1-3, characterized in that a 4-aminoimidazolo/£', 5-_c_7rifamycin SV or S with formula IA or S is prepared. IB, wherein the symbol Am means a 1-piperazinyl residue of formula in which R means a lower alkyl or lower alkenyl which can be substituted one or more times by hydroxyl, mercapto, lower alkoxy, lower alkoxycarbonyl, an optionally mono- or -di-substituted carbamoyl, formyl, oxo, acetalized, resp. ketalized oxo bg/or a disubstituted amino group, further means a lower alkynyl, a cycloalkyl or cycloalkyl-lower alkyl which may optionally have one or two double bonds, an unsubstituted or with halogen, hydroxyl, trifluoromethyl, an optionally N-mono- or di-substituted' carbamoyl or lower alkyl oxycarbonyl singly or multiply substituted phenyl or phenyl lower alkyl, or a maximally bicyclic , heterocyclyl or heterocyclylalkyl with a maximum of two hetero atoms selected from oxygen, nitrogen and/or sulphur. 8. Method according to one of the claims 1-3, characterized in that a 4-amino-imidazolo/4'5-cirlfamycin SV or S with formula IA resp. IB, in which Am has the meaning of Amc in claim 7, in which the symbol R 3 means a linear or single-branched lower alkyl, lower alkenyl or lower alkyl. 9. Method according to one of claims 1-3, characterized in that a 4-aminoimidazolo/4,5-crifamycin SV or S of formula IA or IB is prepared, in which 3 Am has the meaning of Am C specified in claim 7 , in which the symbol R means cycloalkyl or cycloalkylmethyl with 3-6 ring members. or means a phenyl or benzyl, which may be substituted with trifluoromethyl, carbamoyl or lower alkoxycarbonyl. 10. Method according to one of claims 1-3, characterized in that a 4-aminoimidazolo/4,5-_7rifamycin SV or S with formula IA resp. IB, in which Am has the meaning of Am. stated in claim 5. i - ' o ■ h wherein the symbols R and R each mean a substituted alkyl with 1-4 C atoms or a cycloalkyl or a cycloalkylmethyl with 3-6 ring members or benzyl. 11. Method according to one of the claims T-3, characterized in that a 4-aminoimidazolo/4,5-cTrifamycin SV or S with formula IA resp. IB, in which Am has the meaning of Am specified in claim 5. 12 in which the symbols R and R together with the nitrogen atom mean a saturated monocyclic, 5-8 ring-membered heterocyclyl radical which. can also contain an oxygen or sulfur (Il) atom as a ring member, since the heteroatoms are separated from the nitrogen atom by at least . 1 C atom. 12.. Method according to one of claims 1-31, characterized in that the final substance is produced in the form of hydroquinone of the SV series. 13. Method according to one of claims 1-3, characterized in that A-dimethyl- . amino-imidazolo/ 4-» 5-c7rifamycin SV. 14-. Method according to one of claims 1-3, characterized in that 4-morpholino-imidazolo/4,5-c_7rifamycin SV is produced. 15. Method according to one of claims 1-3, characterized in that 4-(4-methyl-piperazinyl)-imidazolo/4-, 5-_c7rifamycin SV is produced. 16. Method according to one of claims 1-3, characterized in that 4-(4-iso-butylpiperazinyl)-imidazolo/""4- is produced. 5-_7rifamycin SV . .17. Method according to one of claims 1-3, characterized in that 4-(4-cyclohexylmethyl-piperazinyl)-imidazolo/4.5-c7rifamycin SV is produced. 18. Method according to one of the claims 1-3, characterized in that 4-diethylamino-imidazolo/4,5-c7rifamycin SV is produced. 19. Method according to one of claims 1-3, characterized in that 4-di- . propylamino-imidazolo/ 4, 5-_c_7rifamycin SV. 2.0. Process according to one of claims 1-3, characterized in that it produces 4-(N-iso- propyl-N-methylamino)-imidazolo/4,5-_/rifamycin SV. 21. Process according to one of claims 1-3, characterized in that 4~ (N-butyl-N-methylamino)-imidazolo/4,5-c7rifamycin SV is produced. 22. Process according to one of the claims 1-3, characterized in that 4-(N-cyclopentyl-N-methylamino)-imidazolo/4''5-c7rifamycin SV.. is produced. 23. Method according to one of the claims 1-3, characterized in that 4- (N-cyclopropylmethyl-N-propylamino)-imidazolo/4-5-cyrifamycin SV is produced. 24. Method according to one of claims 1-3, characterized in that 4-(N-benzyl-N-methylamino)-imidazolo/4,5-crifamycin SV is produced. 25. Process according to one of claims 1-3, characterized in that ..4-/—N-methyl-N-(1-methyl-4-piperidyl)-amino7-imidazolo/—4,5-_7- rifamycinSV. 26. Method according to one of the claims 1-3, characterized in that 4-/_N-ethyl-N-(2-hydroxyethyl)-a minp_7-i midazolo /"* 4,5-_c_7rifamycin SV is produced. 27. Method according to one of claims 1-3, characterized in that 4-[~"N-(2,2-dimethoxyethyl)-N-methylamine]-7-imidazolo]-4,5-c7rifamycin SV is produced. 28. Process according to one of claims 1-3, characterized in that 4-/-N-di-(2-methoxyethyl)-aminep_7-imidazolo/4,5-_c7rifamycin SV is produced. 29. Method according to one of claims 1-3, characterized in that 4-[N-methyl-N-(2-dimethylaminoethyl)-amino7-imidazolo/4,5-_7-rifamycin SV is produced . 30. Method according to one of claims 1-3, characterized in that 4-/-N-ethyl-N-(2-diethylaminoethyl)-amino_7-imidazolo/4>5-c7-rifamycin SV is prepared. 31. Method according to one of claims 1-3, characterized in that 4-pyrrolidi- nyl-imidazolo/ 4, 5-_c_7rifamycin SV. 32. Method according to one of claims 1-3, characterized in that 4-indolinyl-imidazolo/4,5-_rifamycin SV is produced. 33- Method according to one of the claims 1-3, characterized in that 4-piper- ■ idino-imidazolo/4, 5-_c7rifamycin is produced. SV. 34. Method according to one of the -claims 1-3", characterized in that £-(£-ethoxycarbonyl-1-piperidyl).-imidazolo/, 4-»5-c7rifamycin is produced. SV. 35.. Method according to one of the claims 1-3» ■ characterized in that 4-(4-dimethylamino-1-piperidyl)-imidazolo/4,5-_7rifam <y> cin SV is produced. 36. Method according to one of claims 1-3" characterized in that 4-(4- . piperidino-1-piperidyl)-imidazolo/ 4, amycin SV. 37. Process according to one of the claims 1-3" characterized in that 4-[8-aza-1, 4-dioxaspiro-(4-, 5)-8-decyl-7] is produced in midazolo/' 4, 5-_7rifamycin" SV. 38. Method according to one of the claims 1-3" characterized in that 4-(3-sletylaminocarbonyl-1-piperidyl)-imidazolo/4" 5-_7rifamycin SV is produced. 39. Process according to one of the claims 1-3" characterized in that 4-(1-perhydroazepinyl)-imidazolo/4"5-cyrifamycin SV is produced. 40. Method according to one of claims 1-3" characterized in that 4-(1-perhydroazocinyl)-imidazolo/4,5-c7rifamycin SV is produced. 41. Method according to one of claims 1-3" characterized in that 4-(2,6-.. dimethyl-morpholino )-imidazolo/ 4» 5--_7rifamycin SV. 42. Method according to one of the claims 1-3" characterized in that 4-tib-morpholino-imidazolo/4" 5-c7rifamycin SV is produced. 43 . Process according to one of claims 1-3, characterized in that 4-(4-ethyl-piperazinyl)-imidazolo/4-5-crifamycin SV is produced. 44. Method according to one of claims 1-3, characterized in that d& t is prepared 4-(4-propylpiperazinyl)-imidazolo/4»5- <_>7rifamycin SV. 45. Method' according to one of claims 1-3, characterized in that 4-(4- butylpiperazinyl)-imidazolo/ 4> 5-j<_> 7rif amycin SV. 46. Method according to one of claims 1-3, characterized in that 4-(4-pentylpiperazinyl)-imidazolo/4,5-c/rifamycin SV is produced. '47. Method according to one of claims 1-3, characterized in that 4-(4-hexylpiperazinyl)-imidazolo/~4,5-c7rifamycin SV is produced. 48. Method according to one of the claims 1-3, characterized in that 4-(4~heptylpiperazinyl).-imidaKolo/—4,5-,c7rifamycin SV is produced. 49. r" Process according to one of the claims 1-3, characterized in that 4-(4-(1-methylpropyl)-piperazinyl 7 :-<im>id azole o/ 4,5-_7 rifamycin SV is prepared. 50. Method according to one of the claims 1-3, characterized in that 4-/~4~ (2-methyl-butyl-)-piperazinyl-7-imidazolo/4,5-_c7rifamycin SV is produced. 51.. Process according to one of claims 1-3, characterized in that 4-(4-(2-methylpentyl)-piperazinyl-7-imidazolo/4,5-c:7rifamycin SV is produced. 52. Process according to one of claims 1-3, characterized in that 4-(4-(3-methylbutyl)piperazinyl-imidazolo/4,5-crifamycin SV is produced. 53. Method according to one of the claims 1-3, characterized in that 4-/4-(1-ethylpropyl)-piperazinyl-7-imidazolo/4,5-c7rifamycin SV is produced. 54. Method according to one of claims 1-3, characterized in that 4-/ 4~ (3-methylpentyl)-piperazinyl-7-imidazolo/ 4, 5-.c7rifamycin SV is produced. 55. Process according to one of claims 1-3, characterized in that 4-(4-(1,3-dimethylpropyl)-piperazinyl-7-imidazolo/A,5-c7-rifamycin SV is produced. 56. Process according to one of claims 1-3, characterized in that A-(4-allylpiperazinyl)-imidazolo/A,5-c:7rifamycin SV is produced. 57. Method according to one of the claims 1-3, characterized by . that A-_ A-(3-butenyl)-piperazinyl-7-imidazolo/ A, 5-_7rifamycin SV is prepared. 58. Method according to one of claims 1-3, characterized in that A-/A-(2-methyl-2-propenyl)-piperazinyl7-imidazol__ A, 5-_c7~rifamycin SV- is produced 59. Method according to one of claims 1-3, characterized in that 4-/ A~ (2-ethyl-2-butenyl)-pyoerazinyl7_iraidazolo_/ A, 5-c7rifamycin SV is produced. 60. Process according to one of claims 1-3, characterized in that A-/A-(2,3-dimethyl-2-butenyl)-piperazinyl7-irnidazolo/A,5-c7-rifamycin SV.. is produced. 61. Process according to one of claims 1-3, characterized in that A~ (A-propar gylpiperazlnyl)-imidazolo is prepared. A» 5-_c7rifamycin SV. 62. Method according to one of the requirements. 1-3, characterized in that A-(A~ cyclopentylpiperazinyl)-imidazolo/ A. 5-cTri.f amycin SV is prepared. 63. Method, according to one of claims 1-3, characterized in that A-(A-cyclohexylpiperazinyl)-imidazolo/A,5-c7rifamycin SV is produced. 6A. Method according to one of claims 1-3, characterized in that A-(A~ f phenylpiperazinyl)-imidazolo/ A, 5-_c7rifamycin SV is produced. 65. Method according to one of claims 1-3, characterized in that A-/ <-> A- (3-trifluoromethylphenyl)-pip is azinyl7-i midazolo/ 4» 5-_7-rifamycin SV. 66. Method according to one of claims .1-3, characterized in that it. 4-(4-cyclopropylmethylpiperazinyl)-imidazolo/ 4, 5-_c7rifamycin SV is prepared. 67. Method according to one of claims 1-3, characterized in that 4-(4-cyclopentylmethylpiperazinyl)-imidazolo/4,5-c7rifamycin SV is produced. 68. A method according to one of claims 1-3, characterized in that 4-(4-cycloheptylmethylpiperazinyl)-imidazolo/4'5-cyrifamycin SV is produced. 69. Method according to one of claims 1-3, characterized in that 4~ (4-benzylpiperazinyl)-imidazolo/4,5-c7rifamycin SV is produced. 70. Method According to one of the claims 1-3, characterized in that 4-/ 4-(.2 met yl -3 -phenyl-propyl)-pipe r az in yl7_ in midazolo/ 4, 5-_c7rif a- my ein .SV . 71. Process according to one of claims 1-3, characterized in that 4-(4-(2-pyridyl)-piperazinyl-7-imidazolo/4,5-c7rifamycin SV is produced. 72. Method according to one of claims 1-3, characterized in that 4-/ 4- .(2-pyridyl methyl) - piper azinyl7-i midazolo/ 4, 5 -_c7r i f amycin SV . •73. Process according to one of the claims 1-3, characterized in that 4-(4-(2-tetrahydrofurylmethyl)-piperazinyl-7-imidazolo/4,5-_c_7-' rifamycin SV is produced. 74- Method according to one of the claims 1-3, characterized in that 4-{4-/2-(1,3-dioxolan-2-yl)-ethyl7piperazinyl}-imidazolo-/4,5-_c7 rifamycin SV is produced. . 75. Method according to one of claims 1-3, characterized in that 4-/4-(2-methoxyethyl)-piperazinyl-7-imidazolo/4,5-c_7rifamycin SV is produced. 76. Method according to one of claims 1-3, characterized in that 4-(4-(2-ethoxyethyl)-piperazinyl-7-imidazolo/4,5-__7rifamycin SV is produced. 77. Procedure According to one of the claims 1-3."characterized by . that 4-/ 4-(2, 2-dimethoxyethyl)-piperazinyl-7- in midazolo/ 4 is produced.'' 5-_7rifamycin SV . 78. - Process according to claims 1-3, characterized in that 4-(4-(2,2-diethyloxyethyl)-piperazinyl-7-imidazolo) 4,5-cyclamycin SV is produced. 79. Process according to one of claims 1-3, characterized in that 4~ (4~ ethoxycarbonylpiperazinyl)-imidazolo/4, 5-c7rifamycin SV is produced. 80. Method according to one of claims 1-3, characterized in that 4-(4-isopropyloxycarbonylpiperazinyl).-imidazolo/4, 5-cyclamycin SV is produced. 81. Process according to one of claims 1-3, characterized in that 4-/4-(2-dimethylaminoethyl)-piperazinyl-7-imidazolo/4,5-c7rifamycin SV is produced. 82. Process according to one of claims 1-3, characterized in that 4~ (4-isobutyrylpiperazinyl)-imidazolo/4,5-c7rifamycin SV is produced. 83. Method according to one of claims 1-3, characterized in that 4-(4-methoxycarbonylmethylpiperazinyl)-imidazolo/4,5-c7-rifamycin SV is produced. 84. Method according to one of claims 1-3, characterized in that 4-(4-isopropylcarbamoylmethylpiperazinyl)-imidazolo/4,5-_c7~rifamycin SV is produced. 85. Process according to one of claims 1-3, characterized in that 4~ (4-morpholinocarbonylmethylpiperazinyl)-imidazolo/4,5-_c7-rifamycin is produced 86. Method according to one of the claims.1-3, . characterized in that 4-/4_ (1-methyl-2-dimethylaminoethyl)-piperazinyl-imidazolo/4,5-_7 rifamycin SV.. is produced. 87. Method according to one of claims 1-3, characterized in that 4-(4-isobutyl-2,5-dimethyl-piperazinyl)-imidazolo/-4,5-c7-rifamycin SV is produced. 88. Process according to one of claims 1-3, characterized in that 4-(4-isobutyl-2,5-dimethyl-piperazinyl.)-imidazolo/4»5-_7-rifamycin SV is produced. 89. Method according to one of claims 1-3, • characterized in that 4-(4-isobutyl-perhydro-1,4-diazepinyl)-imidazolo/-4,5-c7rifamycin SV is produced; 90. Method according to one of claims 1-3, characterized by . that 4-(4.-aza-tricyclo/5,2,2,O^2 /6Tundec-S-en-A-yl)-imidazolo/4»5-c7-rifamycin SV is produced. 91. ■ Method according to one of claims 1-3, characterized in that 4--(4-(2-hydroxy-2-methylpropyl)-piperazinyl-7-iroidazolo/4-,5-_7'-rifamycin SV is produced. 92. Method according to one of claims 1-3, characterized in that 4-/ 4-(2, 2-dimethyl-1, 3-dioxolan-4-ylmethyl)-piperazinyl-7-imidazolo / 4 1 5-_c7rifamycin SV is produced. 93. Method according to one of the claims 1-3, characterized in that 4-(4-cyclobutylmethyl-piperazinyl)-imidazolo/4»5-_c_7rifamycin SV.. is produced. 94. Method according to one of claims 1-3, characterized in that the final substance is produced in the form of a physiologically tolerable salt. 95. Pharmaceutical preparation containing as active substance at least one compound of formula I, manufactured according to one of claims 1-94-- 96. Method for producing a pharmaceutical ■ preparation according to claim 95, characterized in that eh compound of formula I which is obtainable according to one of. requirements 1-94-, are processed with at least one pharmaceutical carrier material in a non-chemical way. 97. Use of a compound of formula I, obtained according to one of claims 1-94 - alone or in the form of a pharmaceutical preparation according to claim 95 for combating microbial infections.. 98. Process for the preparation of a formamidine of formula wherein Am means an amino group derived from a secondary amine and Rif means a divalent 3-aminorifamycin residue of formula in which R means hydrogen or acetyl, as well as corresponding salts of such a compound with salt-forming properties, characterized by . that a 3-aminorifamycin compound of formula Rif=H_, in which Rif has the above-mentioned meaning, is converted with a reak cation-capable derivative of an N,N-disubstituted formamide or thioformamide of formula in which Y means oxygen or sulphur, and Am has the above meaning, and if desired, a formed compound of the S type is reduced to a compound of the SV type, or one formed for- .bond of the SV type is oxidized to a compound of the S type, and/or a formed free compound with salt-forming properties is converted into a corresponding salt, or a formed salt of the corresponding free compound. 99. Method according to claim 98, characterized in that a starting substance is used in the form of a salt thereof. 100. Process according to claims 98 and 99. for the preparation of a compound of formula VI, in which the symbol Am has one of the meanings in claims 2-9. 101. Method according to claim 98 or 99, characterized in that a formamidine is prepared in the quinone form corresponding to the residue Rif(S). 102. Method according to claim 98 or 99, characterized in that 3-dimethylaminomethyleneaminorifamycin S is produced. 103. Process according to claim 98 or 99, characterized in that 3-diethylaminomethyleneaminorifamycin S is produced. 104.. Method according to claim 98 or 99, characterized in that 3-(N- benzyl-N-methylamino)methyleneamino-rifamycin S. 105. Process according to claim 98 or 99, characterized in that 3-pyrrolidinylmethyleneaminorifamycin S is produced. 106. Method according to claim 98 or 99, characterized in that 3-indolinylmethyleneamino-rifamycin S is produced. 107... Process according to claim 98 or 99, characterized in that 3-piperidinemethyleneaminorifamycin S is produced. 108. Method according to claim 98 or 99, characterized in that 3-(4-methylpiperidinyl)methyleneaminorifamycin S is produced. 109. Method according to claim 98 or 99, characterized in that 3-(8-aza-1,4-dioxa-spiro/A,_7dec-8-yl)methyleneamino-rifamycin S is produced. 110. Method according to claim 98 or 99, characterized in that 3-morpholinylmethyleneaminorifamycin S is produced. 111. Process according to claim 98 or 99, characterized in that 3-thio-■• morpholinylmethyleneamino-rifamycin S is produced. 112. Method according to claim 98 or 99, characterized in that 3-(4-methylpiperazinyl)-methyleneamino-rifamycin S is produced. 11.3. Process according to claim 98 or 99, characterized in that 3-[~~ 4-(2-ethyl-2-butenyl)-piperazinyl-7methyleneamino-rifamycin S is produced. 114. Method according to claim 98 or 99, characterized in that 3-(4-ethoxycarbonylpiperazinyl)methyleneaminorifamycin S is produced. 115. Method according to claim 98 or 99, characterized in that 3-(4-phenylpiperazinyl)methyleneaminorifamycin S is produced. 116. Method according to claim 98 or 99. characterized in that 3-(4-'26 aza-tricyclo_/5,2,2,0~'_7.undec-8-en-4-yl)methyleneamino-rifamycin is produced S. 117. Pharmaceutical preparations containing as active substance at least one formamidine of formula VI obtained according to one of claims 98-116. 118. Process for the production of a pharmaceutical preparation according to claim 117, characterized in that a compound of formula VI obtained according to a of claims 98-116, is processed with at least one pharmaceutical carrier material in a non-chemical way. 119. Use of a compound of formula VI according to one of claims 98-116 alone or in the form of a pharmaceutical preparation according to claim 117 for combating microbial infections.