GB2084575A

GB2084575A - Novel 2-aminoimidazoles

Info

Publication number: GB2084575A
Application number: GB8128704A
Authority: GB
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1980-09-25
Filing date: 1981-09-23
Publication date: 1982-04-15
Also published as: EP0049683A2; ES8306487A1; DD204925A5; PT73726A; AU7559481A; PL233180A1; ES8302732A1; IL63917A0; NO813258L; EP0049683A3; ES505723A0; FI812936L; KR830007667A; ES514883A0; GR75352B; PT73726B; DK421981A

Description

SPECIFICATION Novel 2-aminoimidazoles The present invention relates to novel 2-aminoimidazoles.

The invention provides novel 2-aminoimidazoles which are anellated in the 3,4-position by their atoms C-4 and C-S to ring A of a rifamycin compound, especially N,N-di-substituted derivatives of 4aminoimidazolo[4,5-c] rifamycin SV or S of the formula:

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

As a result of the very close relationship between the 1 ,4-quinone and -hydroquinone form (corresponding to rifamycin S and SV) and the ease with which each form changes into the other, both forms are to be understood as included throughout, unless otherwise specified, but the SV form (IA), is to be regarded as the preferred form.

The amino group Am derived from a secondary amine is one in which the nitrogen atom carries two identical or different monovalent, optionally substituted hydrocarbyl radicals or forms together with a diva lent optionally substituted hydrocarbyl radical a nitrogen-containing non-aromatic heterocyclic radical.

The hydrocarbyl radical (hydrocarbon radical) can be an acyclic, carbocyclic or carbocyclic-acyclic hydrocarbon radical which preferably has a maximum of 20 carbon atoms and may be saturated or unsaturated, substituted or unsubstituted. In the hydrocarbyl radical, one, two or more carbon atoms that are not bonded directly to the nitrogen atom of the amino group, may be replaced by hetero atoms, such as, especially, oxygen, sulphur or nitrogen, but alternatively phosphorus or silicon; a cyclic hydrocarbyl radical of this type is then referred to specifically as a heterocyclic radical (heterocyclyl).

Unsaturated radicals indicate those that contain one, two or more multiple bonds, such as double or triple bonds. Cyclic radicals in which at least one 6-membered carbocyclic or 5-to 8-membered heterocyclic ring contains the maximum number of non-cumulated double bonds, are referred to as aromatic. Carbocyclic radicals in which at least one ring is in the form of a 6-membered aromatic ring (i.e. benzene ring) are designated aryl radicals. Bi- and polycyclic radicals denote those polynuclear radicals in which two or more rings have at least one common atom and thus form an anellated, bridged or spiro-bonded ring system.

Unless otherwise specified, in the present disclosure organic radicals referred to as "lower" contain a maximum of 7, but preferably a maximum of 4, carbon atoms.

An acyclic hydrocarbon radical is especially a straight-chain or branched alkyl, alkenyl, alkadienyl or alkynyl radical, more especially a lower alkyl, lower alkenyl, lower alkadienyl or lower alkynyl radical.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, and also n-penyl, 3-pentyl, isopentyl, 2-methylbutyl, n-hexyl, isohexyl, 2-methylpentyl, 2-ethylbutyl or n-heptyl; lower alkenyl is, for example, vinyl, allyl, propenyl, isopropenyl, 2- or 3-methallyl, 2- or 3butenyl, 2-ethyl-2-butenyl and 2,3-dimethyl-2-butenyl; lower alkynyl is, for example, propargyl or 2butynyl.

A carbocyclic hydrocarbon radical is especially a mono-, bi- or polycyclic cycloalkyl, cycloalkenyl or cycloalkadienyl radical, or a corresponding aryl radical containing aromatic rings. Preferred are radicals having a maximum of 12 ring carbon atoms and 3- to 8-membered, especially 5- and/or 6-membered, rings, and they may also carry one or more acyclic radicals, for example those mentioned above, and especially the lower alkyl radicals, or other carbocyclic radicals. Carbocyclic-acyclic radicals are those in which an acyclic radical, especially one with a maximum of 7, preferably a maximum of 4, carbon atoms, carries one or more carbocyclic, optionally aromatic radicals of the above definition.Special mention shall be given to cycloalkyl-lower alkyl and aryl-lower alkyl radicals, and to their analogues unsaturated in the ring and/or side chain, and among these especially those carrying a maximum of 2 rings.

Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, as well as 1- or 2-bicycío[2,2,2]octyl, 2-bicycío[2,2,1 ]heptyl, 1 or 2-decahydronaphthyl and 1- or 2-adamantyl, and also 1-, 2- or 3-methylcyclopentyl, 4-tert.-butylcyclohexyl, 4,4dimethylcyclohexyl, 2,4,6-trimethylcyclohexyl and 2,4,4,6-tetramethylcyclohexyl; cycloalkenyl is, for example, one of the cycloalkyl radicals already mentioned which carries a double bond in the 1-, 2- or 3position, 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 or -allyl, and also dicyclohexylmethyl and tricyclohexylmethyl; cycloalkenyllower alkyl or -lower alkenyl is, for example, 1-, 2- or 3-cyclopentenyl- or 1-, 2- or 3-cyclohexenylmethyl, -1- or -2-ethyl or -vinyl, or -1-, -2- or -3-propyl or allyl.

An aryl radical is especially a phenyl, and also a naphthyl radical, such as 1- or 2-naphthyl, a partially hydrogenated naphthyl radical, such as especially 1-, 2-, 5- or 6-( 1 ,2,3,4-tetrahydronaphthyl), a biphenylyl, such as especially 4-biphenylyl, and also an anthryl, fluorenyl or azulenyl radical. Preferred aryl-lower alkyl and -lower alkenyl radicals are, for example, phenyl-lower alkyl or phenyl-lower alkenyl, such as, for example, benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl (i.e.

benzyhydryl), trityl and 1- or 2-naphthylmethyl, or styryl or cinnamyl.

Heterocyclic radicals, including the heterocyclic acyclic radicals, are especially monocyclic, but also bi- or polycyclic, aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza-, triaza- or tetrazacyclic radicals, which may be aromatic, partially saturated or completely saturated. They may also, in a manner analogous to the above-mentioned carbocyclic or aryl radicals, carry further acyclic, carbocyclic or heterocyclic radicals and be mono-, di- or poly-substituted The acyclic moiety in heterocyclic-acyclic radicals has, for example, the meaning given for the corresponding carbocyclic-acyclic radicals, Heterocyclic radicals are especially unsubstituted or substituted monocyclic monoaza-, monothia- or monooxacyclic radicals, such as aziridinyl, oxiranyl and thiiranyl, and also azepinyl and azocinyl, and especially heterocyclic radicals having 5 or 6 ring members, such as pyrryl, for example 2-pyrryl or 3pyrryl, pyridyl, for example 2-, 3- or 4-pyridyl, also thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl; bicyclic monoaza-, monooxa- or monothiacyclic radicals, such as indolyl, for example 2- or 3-indolyl, quinolinyl, for example 2- or 4-quinolinyl, isoquinolinyl, for example 1 -isoquinolinyl, benzofuranyl, for example 2- or 3-benzofuranyl, or benzothienyl, for example 2- or 3-benzothienyl; monocyclic diaza-, triaza-, tetraza-, oxaza-, thiaza- or thiadiazacyclic radicals, such as imidazolyl, for example 2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, triazolyl, for example 1 ,2,4-triazol-3- yl, tetrazolyl, for example 1 - or 5-tetrazolyl, oxazolyl, for example 2-oxazolyl, isoxazolyl, for example 3or 4-isoxazolyl, thiazolyl, for example 2-thiazolyl, isothiazolyl, for example 3- or 4-isothiazolyl, or 1,2,4- or 1 3,4-thiadiazolyl, for example 1 ,2,4-thiadiazol-3-yl or 1 ,3,4-thiadiazol-2-yl; or bicyclic diaza-, oxazaor thiazacyclic radicals, such as benzimidazolyl, for example 2-benzimidazolyl, benzoxazolyl, for example 2-benzoxazolyl or benzthiazolyl, for example 2-benzthiazolyl.Corresponding partially or fully saturated radicals are, for example, tetrahydrothienyl, such as 2-tetrahydrothienyl, dihydrofuryl, such as 2,5dihydro-2-furyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, 2-(1 ,3-dioxolanyl)-, tetrahydropyranyl, such as 2- and 4-tetrahydropyranyl, pyrrolidyl, such as 2-pyrrolidyl, tetrahydropyridyl, such as A1-, or or piperideinyl, or piperidyl, such as 2-, 3- or 4-piperidyl, which may be substituted, such as lower alkylated, at the nitrogen atom, such as, for example, N-methyl-4-piperidyl, and also morpholinyl, thiomorpholinyl, piperazinyl and N,N'-bis-lower alkylpiperazinyl, such as especially N,N'dimethylpiperazinyl, as well as perhydroazepinyl and perhydroazocinyl.These radicals may also carry one or more acyclic, carbocyclic or heterocyclic radicals, especially those mentioned above.

Heterocyclic-acyclic radicals are derived especially from acyclic radicals having a maximum of 7, preferably a maximum of 4, carbon atoms, for example those mentioned above, and may carry one, two or more heterocyclic radicals, for example those mentioned above.

As has already been mentioned, a hydrocarbyl radical (including heterocyclyl) may be substituted by one, two or more of the same or different substituents; the following substituents, especially, come into consideration: free, etherified and esterified hydroxy groups; mercapto as well as 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 in the form of acetals or ketals, respectively; azido and nitro groups; primary, secondary and, preferably, tertiary amino groups, which may also be in the form of addition salts with suitable inorganic and organic acids, primary or secondary amino groups protected by conventional protecting groups (such as suitable acylamino groups and diacylamino groups); also free sulphamino groups and sulphamino groups in salt form (such as alkali metal salt form); free and functionally modified carboxy groups (such as carboxy groups in salt form or esterified carboxy groups, carbamoyl, ureidocarbonyl or guanidinocarbonyl groups optionally carrying one or two hydrocarbon radicals, and cyano groups); as well as optionally functionally modified sulpho groups (such as sulphamoyl groups or sulpho groups in salt form) and trifluoromethyl.

An etherified hydroxy group present as a substituent in the hydrocarbyl radical is, for example, a lower alkoxy group, such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert.-butoxy group, which may also be substituted. Such a lower alkoxy group can, for example, be substituted by halogen atoms, especially in the 2-position (such as in a 2,2,2-trichloroethoxy, 2-chloroethoxy or 2-iodoethoxy radical) or by lower alkoxy radicals, especially in the 1-position (such as in a 1 -butoxyethoxy radical) or in the 2-position (such as in a 2-methoxyethoxy radical), or alternatively by a hydroxy group, especially in the 2-position (such as in a 2-hydroxyethoxy radical).Further, etherified hydroxy groups of this type are also optionally substituted phenoxy radicals and phenyl-lower alkoxy radicals, such as, especially, benzyloxy, benzhydryloxy and triphenylmethoxy-(trityloxy-) radicals, as well as heterocyclyloxy radicals, such as especially, 2-tetrahydrofuranyíoxy and 2-tetrahydropyranylbxy radicals. There are'to be understood by etherified hydroxy groups in this context also silylated hydroxy groups, such as are present, for example, in tri-lower alkylsilyloxy, such as trimethylsilyloxy groups, or dimethyl-tert.butylsilyloxy, phenyl-di-lower alkylsilyloxy or lower alkyldiphenylsilyloxy groups.

An esterified hydroxy group present as a substituent in a hydrocarbyl radical is especially one in which the hydrogen atom of the hydroxy group is replaced by one of the acyl radicals Ac defined further below. It may alternatively be a lactonised hydroxy group.

An esterified carboxy group present as a substituent in a hydrocarbyl radical is one in which the hydrogen atom is replaced by one of the above-characterised hydrocarbon radicals, preferably a lower alkyl or phenyl-lower alkyl radical; there may be mentioned as examples of an esterified carboxy group especially methoxy- and lower-alkoxycarbonyl groups, such as ethoxy- and tert.-butoxy-carbonyl groups, or phenyl-lower alkoxycarbonyl groups, such as the benzyloxy-carbonyl group, as well as also a lactonised carboxy group. Furthermore, an esterified carboxy group is one that is present in the form of a silyl ester, i.e. that carries a trihydrocarbylsilyl radical, such as tri-lower alkylsilyl and especially trimethylsilyl.

A primary amino grop -NH2 as a substituent of a hydrocarbyl radical may also be in protected form, preferably in the form of a corresponding acylamino group of the formula -N H-Ac, in which Ac has the meaning given hereinafter. A secondary amino group carries instead of one of the two hydrogen atoms an unsubstituted hydrocarbon radical, as was defined above; it may also be in a protected form, for example in the form of an acylamino group derived therefrom which carries a monovalent acyl radical Ac defined hereinafter.A tertiary amino group present as a substituent of a hydrocarbyl radical is one which instead of the two hydrogen atoms carries the same or different radicals which correspond to the above-characterised unsubstituted hydrocarbyl radicals.The two hydrocarbyl radicals may be bonded to one another by a carbon-carbon bond or an oxygen, sulphur or optionally substituted nitrogen atom, and form together with the nitrogen atom of the amino group a nitrogen-containing heterocyclic radical.The following may be mentioned as examples of especially preferred amino groups serving as substituent of a hydrocarbyl radical; di-lower alkylamino (such as dimethylamino and diethylamino), pyrrolidino, piperidino, morpholino, thiomorpholino and piperazino or 4-methylpiperazino, and diphenylamino and dibenzylamino optionally substituted by lower alkyl, lower alkoxy, halogen and/or nitro; examples of protected amino groups are also especially halo-lower alkoxycarbonylamino, such as 2,2,2-trichloroethoxycarbonylamino, phenyl-lower alkoxycarbonylamino, such as 4 methoxybenzyloxycarbonylamino, as well as 2-(trihydrocarbylsilyl)-ethoxycarbonylamino, such as 2 triphehylsilylethoxycarbonylamino, 2-(dibutylmethylsilyl)-ethoxycarbonylamino and 2trimethylsilylethoxycarbonylamino.

The acyl radical Ac of a carboxylic acid is the radical of a carbonic acid semi-ester, such as a lower alkoxycarbonyl or aryl-lower alkoxycarbonyl, or formyl, or the radical of an optionally substituted acyclic, carbocyclic, carbocyclic-acyclic, heterocyclic or heterocyclic-acyclic carboxylic acid, which is based on one of the above-defined unsubstituted or substituted hydrocarbyl radicals.Especially preferred are acyl radicals of the following monocarboxylic acids having a maximum of 1 8 carbon atoms: acyclic carboxylic acids, especially lower alkanecarboxylic acids, such as propionic, butyric, isobutyric, valeric, isovaleric, caproic, trimethylacetic, oenanthic and diethylacetic acid and, especially, acetic and formic acid, but also corresponding halogenated, especially chlorinated or brominated, lower alkanecarboxylic acids, such as chloroacetic acid, dichloroacetic acid, bromoacetic acid or a-bromoisovaleric acid; carbocyclic or carbocyclic-acyclic monocarboxylic acids, for example cyclopropane-, cyclobutane-, cyclopentane- and cyclohexane-carboxylic acid or cyclopropane-, cyclobutane, cyclopoentane- or cyclohexane-acetic acid or -propionic acid; aromatic carbocyclic carboxylic acids, for example benzoic acid, which may be substituted one or more times by halogen atoms (such as fluorine, chlorine or bromine) and/or by hydroxy, lower alkoxy, lower alkyl, trifluoromethyl and/or nitro; aryl- or aryloxy lower alkanecarboxylic acids and analogues thereof unsaturated in the chain, for example phenylacetic or phenoxyacetic acids, phenyipropionic acids and cinnamic acids, optionally substituted as indicated above for benzoic acid; and heterocyclic acids, for example furan-2-carboxylic acid, 5-tert.-butylfuran-2carboxylic acid, 5-bromofuran-2-carboxylic acid, thiophene-2-carboxylic acid, nicotinic or isonicotinic acid, 4-pyridinepropionic acid, and pyrrole-2- or -3-carboxylic acids optionally substituted by lower alkyl radicals; further also corresponding ct-amino acids, especially the naturally occurring amino acids of the L-series, for example glycine, phenylglycine, proline, leucine, valine, tyrosine, histidine and asparagine, preferably in an N-protected form, i.e. in a form of the type in which the amino group is substituted by a conventional, for example one of the above-mentioned, amino-protecting groups. There also come into consideration among the carboxylic acids especially those in which the hydrocarbyl radical itself is, in addition, substituted by a further optionally functionally modified carboxy group, i.e. dicarboxylic acids, preferably those having a maximum of 12 carbon atoms, which are based on one of the abovecharacterised, optionally substituted acyclic, carbocyclic, carbocyclic-acyclic, heterocyclic and heterocyclic-acyclic hydrocarbyl radicals.For example, the following dicarboxylic acids may be mentioned: oxalic acid, malonic acid, mono or di-lower alkylmalonic acids, succinic acid, glutaric acid, adipic acid, maleic acid, itaconic acid, citraconic acid, angelic acid, 1,1 -cyclopentane- or 1,1cyclohexanedicarboxylic acid, a phthalic, quinolinic or phenylsuccinic acid optionally substituted by halogen, especially chlorine or bromine, and/or by lower alkyl, lower alkoxy and nitro, as well as, also, tartronic acid, mesoxalic acid, oxalacetic acid, malic acid, tartaric acid, a tartaric acid etherified or esterified at the hydroxy groups, glutamic acid and aspartic acid, the latter two acids preferably being present with protected amino groups.As has already been stated, the second carboxy group may be free or may alternatively be functionally modified, for example in the form of an ester with an alcohol, or in the form of a salt, preferably a physiologically tolerable salt, with a salt-forming basic component.

There come into consideration especially metal or ammonium salts, such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines. Among these there come into consideration especially tertiary monoamines and heterocyclic bases, for example triethylamine, tri-(2-hydroxyethyl)-amine, 1ethylpiperidine, and pyridine, collidine or quinoline.

The invention relates especially to those rifamycin compounds of the formula I in which the amino group Am is characterised by the partial formula

in which each of R1 and R2, independently of one another, represents a lower alkyl or lower alkenyl radical which may be substituted one or more times by hydroxy, mercapto, lower alkoxy, lower alkoxycarbonyl, an optionally N-mono or -di-substituted carbamoyl, formyl, oxo, acetalised or ketalised oxo and/or by a di-substituted amino group, a lower alkynyl, a cycloalkyl or cycloalkyl-lower alkyl radical which may optionally have one or two double bonds, an unsubstituted phenyl or phenyl-lower alkyl radical, or phenyl or phenyl-lower alkyl substituted one or more times by halogen, hydroxy, trifluoromethyl, an optionally N-mono or -di-substituted carbamoyl or lower akoxycarbonyl, or represents an at most bicyclic heterocyclyl or heterocyclylalkyl radical having a maximum of two herero atoms selected from oxygen, nitrogen and /or sulphur, wherein R' and R2 may be bonded with one another by a single carbon-carbon bond or by way of an oxygen, sulphur(ll) or optionally substituted nitrogen atom and may form together with the amino nitrogen atom a 4-to 8-membered non-aromatic heterocyclic ring.

Unless specifically defined otherwise, all terms of the foregoing definition have the general and preferred meanings given at the beginning.

As a substituent of a saturated radical, a hydroxy, mercapto or di-substituted amino group is preferably separated from the central amino group by at least two carbon atoms; as substituents of an unsaturated radical these groups are preferably positioned at a saturated carbon atom.

In unsaturated non-aromatic radicals, the multiple bond is preferably positioned on carbon atoms that are not bonded directly to the central amino group.

There come into consideration as phenyl-lower alkyl radicals in the meaning of R1 and R2 especially 1-phenylethyl and phenethyl, but more especially benzyl; they may also be substituted in the manner indicated above, the substituent preferably being in the p-position.

There come into consideration as heterocyclyl radicals in the meaning of R1 and R2 especially monocyclic radicals, such as those mentioned at the beginning, and among those especially 2- and 4pyridyl, 2-imidazolyl, 2-benzimidazolyl, 3-indolyl and 4-quinolyl, and as heterocyclyl-lower alkyl radicals furfuryl and thenyl shall be given special mention and among corresponding saturated radicals, for example, N-methyl-4-piperidyl, 4-tetrahydropyranyl, tetrahydrofuryl-2-methyl, 1 ,3-dioxolanyl-2-methyl, 2-(1 ,3-dioxolanyl-2)-ethyl and 2,2-dimethyl-1, 3-dioxolanyl-4-methyl.

Non-aromatic heterocyclic radicals in the meaning of AmA, which are formed by the linking of the radicals R1 and R2 by means of a single C-C bond, are, for example, the following: in the case where both of the radicals R1 and R2 are lower alkyl radicals (or the corresponding cycloalkyl-, phenyl- or heterocyclyl-carrying lower alkyl radicals), especially the following AmA radicals come into consideration: 1-azetidinyl, 1-perhydroazepinyl, 1-perhydroazocinyl and, especially, 1-pyrroíidinyí and piperidino, which may also be substituted by the above-mentioned substituents and/or may carry correspondingly substituted, or preferably unsubstituted, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, heterocyclyl and heterocyclyl-lower alkyl radicals, wherein preferably only one such substituent and/or radical is present and the maximum total number of carbon atoms is 1 5; in an analogous case in which one of the radicals R1 and R2 is a cyclic radical, the following AmA radicals, especially, come into consideration: 1-indolinyl, 2-isoindolinyl, 2-perhydroisoindolyl and 4-aza tricyclo[5,2,2,026]non-8-en-4-yl, which may also be substituted in an analogous manner and preferably with analogous limitation, and/or may carry the mentioned carbon-containing radicals. Out of all such radicals the following shall be given special mention: and 1-pyrrolidinyl substituted by hydroxy or carboxy, a piperidino substituted by formyl, carboxy, lower alkoxycarbonyl, carbamoyl (also N,N-di-lower alkylcarbamoyl, such as N,N-diethylcarbamoyl) or oxo (also in the form of ketalised oxo, such as ethylenedioxy), the substituent preferably being in the 3- or 4-position, a lower alkyl-, 1 -hydroxy-lower alkyl- or.2-hydroxy-lower alkyl-piperidino, the radical preferably being in the 4-position, a 4-di-lower alkylaminopiperioino (such as 4-dimethylaminopiperidino), 4-Fiperidinopiperidino, and 8-aza- 1 ,4-dioxa- spiro[4,5]dec-8-yl (i.e. 4-piperidino-ethylene-ketal).

Non-aromatic heterocyclic radicals in the meaning of Am A which are formed by the linking of the radicals R1 and R2 by means of an oxygen or sulphur(ll) atom are, for example, morpholino, thiomorpholino and 3-thiazolidinyl, and also 3,5-dimethylmorpholino and 2,6-dimethylmorpholino.

Non-aromatic heterocyclic radicals in the meaning of Am A which are formed by the linking of the radicals R1 and R2 by means of an optionally substituted nitrogen atom are those which are derived from 2 lower alkyl radicals Rt and R2 and in which the linking optionally substituted nitrogen atom carries one of the substituents defined below asRN. A non-aromatic heterocyclic radical of that type is especially such a radical of the partial formula

in which each of m and n, independently of one another, represents an integer of from 1 to 5, but preferably 2 or 3, an at least 5-membered ring being formed, and RN represents a hydrogen atom, a formyl group, a functionally modified carboxy group or an unsubstituted or substituted hydrocarbyl or heterocyclyl radical containing a maximum of 10 carbon atoms.The radicals C mH 2m and CnH2n are divalent radicals which are derived from lower alkanes having from 1-6 carbon atoms, such as, especially, ethylene, trimethylene and propylene, but alternatively tetramethylene, 1 ,1 - dimethylethylene, 1 2-dimethylethylene, ethylethylene, propylethylene, butylethylene, 1,2diethylethylene and 2,2-dimethyltrimethylene, as well as, also, methylene, ethylidene, propylidene, isopropylidene etc., each of which, however, can be only one of the two radicals.A functionally modified carboxy group in the meaning of RN is one of the above-defined carboxy groups, especially an esterified carboxy group (such as especially that in the form of a lower alkyl ester) or a carboxy group in amide form, such as especially an unsubstituted carbamoyl group or a carbamoyl group substituted by 1 or 2 lower alkyl radicals. A hydrocarbyl or heterocyclyl radical in the meaning of RN is one of those mentioned at the beginning and may carry the substituents mentioned at the beginning singly or in combination; in the heterocyclyl radical the free valency originates in each case from a carbon atom. Of the cyclic radicals, monocyclic radicals are preferred, of the heterocyclic radicals those having a maximum of 2 non-adjacent hetero atoms are preferred, and of the substituted radicals those that carry only one substituent (= functional group) are preferred.

Of the rifamycin compounds of the formulae IA and IB which carry the radical AmA most especially preferred are those in which each of R' and R2 represents an unsubstituted alkyl radical having from 1-4 carbon atoms, or in which both of the symbols R' and R2 together with the nitrogen atom form a saturated monocyclic heterocyclyl radical containing from 5-8 ring members which may also contain an oxygen or sulphur(ll) atom as ring member, or in which the radical AmA corresponds to one of the above-defined preferred meanings of AmB.

The symbol AmA represents especially a dimethylamino, diethylamino, methylethylamino, methylisopropylamino or methylbutylamino group, also a 1 -pyrrolidyl, piperidino, 1 -perhydroazepinyl, 1perhydroazocinyl, morpholino or thiomorpholino radical, as well as, also, an optionally 4-substituted 1piperazinyl radical of the formula

in which R3 represents hydrogen or has one of the individual meanings of Rl or R2. Of the meanings of R3, especially unsubstituted straight-chain or single-branched lower alkyl and lower alkenyl radicals (such as, especially, methyl, propyl, isobutyl or allyl) are particularly preferred, but attention is also drawn to unsubstituted lower alkynyl (such as propargyl), cycloalkyl and cycloalkyl-alkyl (especially cycloalkyl-methyl) radicals having from 3-6 ring members, and to phenyl and benzyl radicals.

Special attention is drawn to the compounds mentioned in the Examples and close analogues thereof, especially salts thereof.

Those of the above rifamycin analogues of the formula I characterised generally or characterised as preferred that have adequate basicity may be in the form of acid addition salts, especially physiologically tolerable salts, with customary pharmaceutically acceptable acids; of the inorganic acids there shall be mentioned hydrohalic acids, such as hydrochloric acid, but also sulphuric acid and phosphoric and pyrophosphoric acid, and of the organic acids especially sulphonic acids, such as benzene- orp-toluenesulphonic acid, or lower alkanesulphonic acids, such as methanesulphonic acid, and also carboxylic acids, such as acetic acid, lactic acid, palmitic acid and stearic acid, malic acid, tartaric acid, ascorbic acid and citric acid.

Those of the compounds according to the invention which, as a result of an acid-reacting functional group (especially owing to the phenolic character of the 1 -hydroxy group in compounds of the SV series), have an adequate acidity, may be in the form of salts with bases, especially in the form of physiologically tolerable salts. The following come into consideration as salts: metal and ammonium salts, such as, on the one hand, alkaline earth metal and alkali metal salts (for example calcium, magnesium and, preferably, sodium and potassium salts), and, on the other hand, also ammonium salts derived from ammonia itself or a suitable, preferably physiologically tolerable, organic nitrogencontaining base.There come into consideration as bases both amines, such as lower alkylamines (for example triethylamine), hydroxy-lower alkylamines [for example 2-hydroxyethylamine, di-(2hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine], cycloalkylamines (for example dicyclohexylamine) or benzylamines (for example benzylamine and N,N'-dibenzylethylenediamine), and nitrogen-containing heterocyclic compounds, for example those of aromatic character (such as pyridine or quinoline) or those having an at least partially saturated heterocyclic ring (such as N-ethylpiperidine, morpholine, piperazine or N,N'-dimethylpiperazine). Compounds that contain both an acidic and a basic functional group may be in the form of inner salts.

The present invention relates also to processes for the manufacture of the above-characterised compounds of the formula I.

The compounds of the formula I can be produced in a manner known per se by reacting a 3aminorifamycin S compound of the formula

in which R has the meaning given above, or a salt thereof, in any sequence with ammonia and with a reactive derivative of an N,N-di-substituted formamide or thioformamide of the formula Am-CH=Y (III) in which Y represents oxygen or sulphur and Am has the meaning defined initially, and, if desired, oxidising a resulting compound of the SV type to a compound of the S type, or reducing a resulting compound of the S type to a compound of the SV type and/or converting a resulting free compound with salt-forming properties into a corresponding salt or a resulting salt into the corresponding free compound.

The starting materials of the formula II, i.e. 3-amino-rifamycin S, and the corresponding 25desacetyl derivative, are known compounds. They can be used also in the form of corresponding acid addition salts. Typical representatives of the starting materials of the formula Ill are also known or, if they are unknown, can be produced from known secondary amines or their structural analogues in an analogous manner tithe known compounds by conventional processes. Typical representatives of the reactive derivatives of the formamides and thioformamides of the formula III used as reagent for the reaction are also known or can be obtained according to methods known per se. In many cases it is not even necessary to isolate these reactive forms as individual chemical entities.Of the reactive derivatives of the formamide and thioformamide there come into consideration especially acid amide acetals and acid orthoamides, also acid amide halides, acid amide/dialkyl sulphate complexes, and acid thioamide/alkyl halide complexes, the latter in particular when they are used directly for the reaction of the starting material of the formula II.

Corresponding formic acid amide acetals are especially those derived from C1-C4 alkanols, which are characterised by the formula Am--CH(OR4), (lila), in which Am has the meaning given initially and R4 represents an alkyl radical having a maximum of 4 carbon atoms, especially methyl or ethyl. They are especially advantageous because they can easily be produced in stable individual form. For their manufacture, for example a secondary amine Am-H is heated with an N,N-dimethylformamide-di-lower alkyl acetal (for example -dimethylacetal), by means of which the exchange of the dimethylamino group for the desired amino group Am takes place.For volatile secondary amines Am-H an alternative method is more suitable, i.e. the treatment of a N,N-disubstituted formamide/dialkyl sulphate complex (see further below) with an alkali metal alcoholate of the formula R40M, in which R4 has the meaning given above and M represents an alkali metal, especially sodium.

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

in which Am has the meaning given above. They can be obtained, for example, by the exchange of lower alkoxy groups OR4 for the di-substituted amino group Am by heating an N,N-dimethylformamide-dilower alkyl acetal or a formamide acetal of the formula Illa with the corresponding secondary amine Am-H. Typical representatives of these compounds and processes for their manufacture are known.

The formic acid amide halides ("iminoylhalides") used are preferably characterised by the formula [Am+=CHX]X (111b) in which Am has the meaning given initially and X represents bromine or, preferably, chlorine. (The double bond originates in this case from the amino nitrogen of the amino group Am and thus gives it the positive charge.) These reagents (i.e. "iminoylchloddes" and "iminoylbromides") are produced, for example, by treating the corresponding formamides of the formula Ill with conventional halogenating agents. There are preferably used halogenating agents which during the reaction form gaseous by-products, such as phosgene, oxalyl halides or thionyl halides, but it is also possible to use others.The reaction can be carried out in inert dry organic solvents, for example ether or toluene, in which the amide halide is in most cases insoluble and from which it can be isolated by filtration once the reaction is complete. The acid amide halides are hygroscopic and rather unstable and are therefore preferably used in the reaction according to the invention without purification.

The formamide/dialkyl sulphate complexes used are especially those of the formula [Am+=CH-0Fl4j Fl4O-SO2-O (ills) in which Am and R4 have the meanings given above.

The acid amide/dialkyl sulphate complexes can be produced by treating amides of the formula III with dialkyl sulphate, preferably dimethyl sulphate, under known conditions, for example analogously to the amide halides Illb.

If 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 treating with an alkyl halide, for example C1-C4 iodide. This reaction is known from specialist literature.

in practice, each of the two process stages according to the invention is carried out in a manner known per se, their sequence having no influence on the precise reaction conditions.

The reaction with ammonia is carried out preferably by introducing dry ammonia gas into a solution of the rifamycin compound in a conventional aprotic organic solvent, for example an ether (such as diethyl ether, 1 ,2-dimethoxyethane or dioxan and, especially, tetrahydrofuran) or a halogenated lower alkane (such as, especially, chloroform or methylene chloride) at temperatures in the range of from approximately-lO0 to approximately +400 C, preferably of from +50 to +250C, especially slightly below room temperature.

The reaction conditions for the reaction according to the invention with the reactive amide derivative depend chiefly on the reactants used. If, for the reaction of a rifamycin compound, acid amide acetals of the type of the formula 111a are used, the reaction temperature is between approximately 0 and 400, but usually 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-diisopropylethylamine. N-ethylpiperidine, Nmethyipiperidine, N-methylmorpholine or N,N'-dimethylpiperazine. Reaction is carried out in an analogous manner also with the orthoamides of the formula Lilac.

if acid amide halides, dialkyl sulphate complexes or thioamide/alkyl halide complexes are used, the reaction is likewise carried out in inert organic solvents that are dry and free from traces of alcohol, preferably in dichloromethane or chloroform, in which the reactants are soluble, but it is also possible to use solvents in which the starting materials are insoluble, such as, for example, ether. The reaction is carried out at a temperature of between approximately 700 and approximately 200, usually at or below 00, and in the presence of at least 1 equivalent of a tertiary amine, for example one of those mentioned immediately above, especially triethylamine.If 1 equivalent of the tertiary amine is used for the reaction with an acid amide halide of the type Ills, the reaction product of the formula I is obtained in the form of a salt, but if, on the other hand, 1 equivalent of the tertiary amine is used with the dialkyl sulphate complexes and thioamide/alkyl halide complexes, the reaction product of the formula I is obtained in free form. if two or more equivalents of the tertiary amine are used, it is always the free form of the compound of the formula I that results and this can, if desired, be converted into a salt.

The duration of the reaction depends on the reactants, the temperature and the solvents that are used for the process. If there is a free carbbxy group in the starting material of the formula Ill, it is preferably temporarily protected in the form of a trimethylsilyl ester or a dimethylsilyl diester and readily freed again after the reaction. This reaction is preferably carried out with an acid amide acetal reagent.

The manufacture of the silyl esters is known from the literature. The silyl esters of the end products of the formula I are preferably split by hydrolysis or alcoholysis under mild conditions.

In the primary reaction mixture, the end product is in practice only in the more stable 1 ,4- hydroquinone form of the SV series, in which it is also advantageously isolated. If, however, the quinone form is desired,'the crude reaction mixture, or an isolated compound of the SV series, is treated with an oxidising agent, especially one that is customary for the oxidation of known hydroquinones, for example ammonium persulphate, hydrogen peroxide, atmospheric oxygen or, preferably, potassium ferricyanide; the oxidation is carried out preferably under basic conditions.If it is desired that a compound of the S series be converted into the hydroquinone form (in the form of a rifamycin SV derivative), the former is treated with a customary quinone-reducing 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 conventional manner, for example by careful treatment of these compounds with an equivalent or excess amount of the desired acid, preferably in an inert solvent. Also salts with bases are obtained in conventional manner by treating corresponding acid 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. Inner salts are formed preferably by customary acid/base titration to the neutral point or to the isoelectric point, respectively.

The inventnion relates also to those forms of the above process in which a starting material is formed under the reaction conditions or is used in the form of a salt, or in which a compound obtainable as intermediate at any stage is used-as starting material and the remaining steps are carried out.

Thus, for example, the two stages of the process according to the invention can be carried out in a single operation, for example by saturating with ammonia gas a mixture of a 3-aminorifamycin compound of the formula li and a reactive derivative of an N,N-di-substituted formamide of the abovecharacterised formula Ill in an aprotic organic solvent, for example one of those mentioned above, or especially by treating with the latter reagent a compound of the above-characterised formula IV, which has resulted directly in the same reaction solution by the action of ammonia on the 3-aminorifamycin derivative of the formula II.

It is also possible, however, to form the reactive derivative of the formamide of the formula Ill from its formation components directly in situ, i.e. in the reaction mixture. Such a reactive derivative is obtained in situ, for example, by causing a formamide of the formula Ill with a 1,1 -dihalo-di-lower alkyl ether, preferably 1,1 -dichlorodimethyl ether, in the presence of a tertiary organic base, to react with a 3aminorifamycin compound of the formula II. The reaction can be carried out without isolation of the intermediate formed by this method. (The intermediate is most probably a methoxymethylene derivative of the compound of the formula Ill, which corresponds to the above-described type of the formula Ill but with halogen as anion). The reactions are carried out below or at room temperature and in the presence of an inert solvent, for example chloroform or methylene chloride. A reactive formamide derivative can be obtained in situ by using a secondary amine of the formula Am-H, in which Am has the meaning given above, with a lower alkyl-orthoformate or -orthothioformate of the formula CH(YR4)3, in which Y and R4 have the meanings given above, for example methyl orthoformate or ethyl orthoformate, and with a 3-aminorifamycin compound of the formula II in the presence or boron trifluoride etherate (or an analogous strongly acidic catalyst of the Lewis acid type). The intermediatelyformed reagent is very probably a formamide-di-lower alkyl acetal of the formula 111a or an iminoether salt of the type of the formula Illc. The reactions are carried out below or at room temperature and in the presence of an inert solvent, for example chloroform or methylene chloride.

The invention relates also to a process according to which compounds of the formula IA or IB are produced by reacting a 3-aminorifamycin-S-4-imine of the formula

in which R has the meaning given above, or a salt thereof, with a reactive derivative of a N,N-disubstituted formamide or thioformamide of the formula Am-CH=Y (III) in which Y represents oxygen or sulphur and Am has the meaning defined initially and, if desired, oxidising a resulting compound of the SV type to a compound of the S type or reducing a resulting compound of the S type to a compound of the SV type and/or converting a resulting free compound with salt-forming properties into a-corresponding salt or a resulting salt into the corresponding free compound. The process according to the invention is carried out in the manner indicated above.The two starting materials of the formula IV, i.e. the 3-aminorifamycin-S-4-amine and its 25-desacetyl derivative, are known and the reactive derivatives of a formamide of the formula Ill are those described above, especially those of the formulae Illa-Ilic.

The invention relates also to the process according to which the compounds of the formula IA or IB are produced by treating with ammonia an N',N'-di-substituted 3-aminomethyleneaminorifamycin derivative (3-aminorifamycinformamidine) of the formula

in which R and Am have the general and preferred meanings mentioned above, or a salt thereof, and, if desired, oxidising a resulting compound of the SV type to a compound of the S-type or reducing a resulting compound of the S type to' 'a compound of the SV type and/or converting a resulting free compound with salt-forming properties into a corresponding salt or a resulting salt into the corresponding free compound. If it is desired that a formamidine of the SV series be used as starting material, then this is first of all oxidised to the corresponding compound of the S series.

The intermediates of the above-defined formula V and their analogues of the SV series of the formula

in which R and Am have the general and preferred meanings mentioned above, and their salts, are new and the present invention relates also these.They are produced by the treatment, described above in detail, of the corresponding 3-aminorifamycin S compound of the formula II (also in the form of an acid addition salt thereof), or of a corresponding analogue thereof of the SV series, with one of the abovedefined reactive derivatives of an N,N-di-substituted formamide or thioformamide of the above formula III, especially a derivative of the above-defined formulae Illa--lllc, and, if desired, a resulting compound of the SV type is oxidised to a compound of the S type or a resulting compound of the S type is reduced to a compound of the SV type and/or a resulting free compound with salt-forming properties is converted into a corresponding salt or a resulting salt is converted into the corresponding free compound. The present invention relates also to this manufacturing process.

The novel compounds of the formula I according to the invention are distinguished especially by their valuable pharmacological properties: according to results in vitro they have antibiotic, especially antibacterial, properties, such as, for example, on the one hand against gram-positive cocci, such as Staphylococcus aureus (in the tested concentration range of 0.005 to 128 1v/ml), and on the other hand against gram-negative bacilli, such as enterobacteriaceae, for example Escherichia coli, Pseudomonas aeruginosa and Proteus organic (in the tested concentration range of 1 to 64 y/ml), as well as against Mycobacterium tuberculosis (in the tested concentration range of 0.48-1 .9 y/ml.As active substances, special emphasis is to be given to 4-dimethylamino-, 4-(methylpiperazinyl)-, 4-(4-isobutylpiperazinyl)-, 4-morpholino- and 4-pyrrolidinyl-imidazolo[4,5-c]rifamycin SV, all of which have a distinct inhibitory action against Staphyloccoccus aureus even at or below the mentioned lowest concentration limit and also effectively inhibit the enterobacteria in the specified concentration range. (For test results see also Table 1).

The novel compounds of the formulae V and VI according to the invention are also distinguished by analogous valuable pharmacological properties, that is to say they possess according to results in vitro antibiotic, especially antibacterial, properties, which are practically identical to those of the compounds of the formula I as regards field of application and tested effective concentrations. As active substance, special emphasis is to be given to 3-(4-methyl- and 4-phenyl-piperazinyl)-, 3thiomorpholino- and, especially, 3-indolinylmethyleneaminorifamycin S, all of which have a distinct inhibitory action against Staphylococcus aureus even at the mentioned lowest concentration limit and also effectively inhibit the enterobacteria in the specified concentration range. (For the test results see also Table 2).

The compounds of the formula I according to the invention can also be used as valuable intermediates for the manufacture of other rifamycin derivatives, especially those having a therapeutic use. Based on the above-mentioned favourable pharmacological properties, the invention relates also to the use of the active substances according to the invention, alone or in combination with another antibiotic or chemotherapeutic agent, as agents for combating infections, especially those caused by bacteria or cocci, for example those mentioned above, both as drugs and as germicides.When used as a drug, the active substance according to the invention is administered preferably in the form of a pharmaceutical preparation together with at least one conventional pharmaceutical carrier or adjunct to a warm-blooded animal, especially man. (There is to be understood hereinbefore and hereinafter by the term "active substance" or "active substance according to the invention" a rifamycin derivative of the above-defined formula IA or IB and of the formula V or VI, as well as biologically tolerable salts thereof).

The invention relates also to pharmaceutical preparations containing one of the above-defined active substances, especially together with'a-.t least one pharmaceutically suitable carrier, and processes for the manufacture thereof by non-chemical methods, To manufacture pharmaceutical preparations, each of the compounds according to the invention, but especially one of those given special emphasis, may be mixed with an inorganic or organic carrier suitable for topical, enteral or parenteral administration. The carriers that come into consideration are substances that do not react with the novel compound, such as, for example, gelatin, lactose, starch, magnesium stearate, vegetable oils, benzyl alcohol, or other medicament carriers.The pharmaceutical preparations can be processed into pharmaceutical administration forms, such as tablets, dragées, powders or suppositories, or processed in liquid form to produce solutions, suspensions, emulsions, creams or ointments. These are optionally sterilised and/or contain adjuncts, such as preservatives, stabilisers, wetting agents or emulsifiers. They may also contain, in addition, other therapeutically valuable substances. Also the germicides can, as is known, be mixed with suitable carriers.

For oral administration, tablets, dry-filled capsules or gelatin capsules are used that contain the active substance together with diluents, for example lactose, glucose, saccharose, mannitol, sorbitol, cellulose and/or glycine, and lubricants, for example diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets also contain binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrow-root starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone and, if desired, disintegrators, for example starches, agar, alginic acid or salts thereof, such as sodium alginate, and/or effervescing mixtures, or absorbents, colouring matter, flavourings and sweeteners.Suppositories are especially fatty emulsions or suspensions.

The pharmaceutical preparations can be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers and/or buffers. The pharmaceutical preparations in question, which may, if desired, contain other pharmacologically valuable substances, are produced in a manner known per se, for example by means of convientional mixing, dissolving or lyophilising processes, and contain from approximately 0.1100%, especially from approximately 1% to approximately 50%, and in the case of lyophilisates up to 100%, of the active substance.

The above-characterised pharmaceutical preparations are especially preferably in unit dosage form. "Unit dose" means a unitary, that is to say a single, dose which contains an antimicrobially active amount of the active substance, which is administered to a patient. It is easy to handle and package and it contains, as a physically stable unit, either the active material as such or a mixture thereof with a solid pharmaceutical carrier. The dosage of the active substances, for example of those given special mention above, is in principle analogous to that of recognised antibiotics of the rifamycin type, but is depends firstly on the species, body weight, age and individual condition of the warm-blooded animal, secondly on the method of administration and, especially, on the particular sensitivity of the causative organism, which can be ascertained in known manner in a routine test.Accordingly, the present invention relates also to the selection of a dosage of the compounds according to the invention which can be administered so as to achieve the desired activity without simultaneous side effects.

The invention relates also to a method of killing or inhibiting the growth (i.e. inhibition) of a microorganism that is sensitive to at least one of the active substances according to the invention, which is characterised by the treatment of the microorganism or of a medium infected by that microorganism with an antimicrobially active dosage of one of the active substances according to the invention. The expression "antimicrobially active dosage" shall mean that amount of the active substance which is sufficient for effective inhibition of the relevant microorganism to be treated.

The compounds are advantageously administered in unit doses that do not contain any less 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 unit dosage form one or more times daily at suitable intervals, depending always on the condition of the patient. A daily dosage is thus preferably from 0.2 to 5.0 g of the active substances according to the invention, calculated as free base.

The following Examples illustrate the above-described invention but are not intended in any way to limit the scope thereof. Temperatures are quoted in degrees Centigrade.

The composition of solvent mixtures is quoted in ratios by volume. The structure of the isolated compounds is routinely analysed by mass spectrometry determination of the molecular ion and by elementary analysis.

EXAMPLE 1 4-Dimethylamino-imidazolo[4,5-c]rifamycin SV 2.0 g of dimethylformamide-dimethylacetal are added to a solution of 1.5 g of 3-amino-4iminorifamycin S in 15 ml of tetrahydrofuran and the mixture is left to stand at room temperature until the rifamycin derivative used has reacted fully (thin layer chromatography test over silica gel, eluant methylene chloride/acetone 9:1). The reaction mixture is then taken up in ethyl acetate and washed with aqueous citric acid solution and sodium chloride solution. After evaporating off the solvent, the brown-coloured residue is chromatographed over silica gel with the eluant methylene chloride/acetone 9:1, quick-migrating dark-coloured substances being removed. The yellow-coloured fractions are combined and concentrated by evaporation and the residue is crystallised from diethyl ether/acetone.

The dimethylaminoimidazolorifamycin SV is obtained in the form of light-yellow crystals having a melting point of 180--1850 (decomposition). In the mass spectrum, the molecule ion appears at m/e = 764. Calculated for C40H52N4O11 = 764.

EXAMPLE 2 4-Morpholino-imidazolo[4,5-c]rifamycin SV 0.5 ml of N-formylmorpholine-dimethylacetal and 2 ml of triethylamine are added under nitrogen to a solution of 1.42 g of 3-amino-4-iminorifamycin S in 1 5 ml of tetrahydrofuran and the mixture is left to stand for 24 hours at room temperature. The reaction mixture is then taken up in ethyl acetate and washed in succession with aqueous-citric acid solution and sodium chloride solution and the ethyl acetate is removed in vacuo. The residue crystallises from ether/acetone and yields morpholinoimidazolorifamycin SV in the form of yellow crystals having a melting point of 192193 (decomposition). In the mass spectrum the molecule ion of the compound is found at m/e = 806 (calculated for C42H54N4O12 = 806).

EXAMPLE 3 4-(4-Methylpiperazinyl)-imidazolo[4,5-c] rifamycin SV 2.5 g of 1 -formyl-4-methylpiperazine-dimethylacetal are added to a solution of 2.0 g of 3-amino4-iminorifamycin S in 25 mi of tetrahydrofuran and the mixture is left to stand at room temperature until reaction of the rifamycin derivative used is complete. The reaction mixture is then taken up in ethyl acetate, washed with aqueous citric acid solution and with sodium chloride solution and concentrated by evaporation. The residue is chromatographed over silica gel with methylene chloride/methanol 95:5.

After removing the quick-migrating dark-coloured substances, the yellow-coloured eluates which follow are collected and concentrated by evaporation. Crystallisation from ether/acetone yields Nmethylpiperazinylimidazolo-rifamycin SV in the form of yellow crystals having a melting point of 185187 (decomposition).

100 MHz proton resonance spectrum of the compound in CDCI3 shows, besides the usual rifamycin signals, additional signals at 3.5-4.0 ppm (CHz next to N;M) and at 2.40 ppm (NCH3; S).

EXAMPLE 4 4-(4-lsobutylpiperazinyl)-imidazolo [4,5-cirifa mycin SV A reaction mixture of 2.5 g of 3-aminorifamycin S, 20 ml of tetrahydrofuran, 1.5 g of 1 -formyl-4isobutyl-piperazine-dimethylacetal and 1.5 g of triethylamine is left to stand at room temperature for 24 hours. The mixture is then concentrated to dryness in vacuo. The residue, which contains crude 3-(4isobutyipiperazinyl)-methyleneiminorifamycin S with only few impurities, is dissolved in 20 ml of tetrahydrofuran. Ammonia gas is introduced into the solution at room temperature for 30 minutes until saturation is reached.The solution is then concentrated by evaporation and the yellow-brown residue is chromatographed over polyamide (Woehn) with ether/methylene chloride 5:1 as eluant. 3 zones form: the eluate of the slowest, yellow-coloured zone contains the desired 4-(4-isobutylpiperazinyl)imidazolorifamycin SV, which exhibits a molecule ion at m/e = 861 in the mass spectrum. (Calculated forC46H63N5O1 = 861).

EXAMPLE 5 4-(4-Cylcohexylmethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV 3.0 g of 1-formyl-4-cyclohexylmethylpiperazinedimethylacetal are added to a solution of 1.5 g of 3-amin-4-iminorifamycin S in 1 5 ml of tetrahydrofuran and the mixture is left to stand at room temperature for 8 hours. The reaction mixture is then taken up in ethyl acetate and the organic solution is washed in succession with aqueous citric acid solution and sodium chloride solution, dried and concentrated by evaporation. Chromatography of the residue over silica gel with methylene chioride/methanol 97:3 as eluant yields cyclohexylmethylpiperazinyl-imidazolorifamycin SV as the main product. The compound exhibits a molecule ion at m/e = 901 in the mass spectrum (calculated for C4sH67NO11 = 901).UV-spectrum: (0.01 N alcoholic hydrochloric acid) AmaX(nm)/ 224/38400, 228/39200,231/38600,245 (shoulder), 304/25400,420/11200.

EXAMPLE 6 4-Diethylamino-imidazolo[4,5-cjrifamycin SV Ammonia gas is introduced for 1 5 minutes into a solution of 380 mg of diethylaminomethyleneamino-rifamycin S in 1 5 ml of tetrahydrofuran at room temperature. The solution is left to stand overnight and then concentrated to dryness by evaporation. The yellow-brown residue is chromatographed over silica gel; elution with mixtures of chloroform with an increasing (210%) proportion of methanol yields the title compound (Cz4Hs6N4011) in the form of a yellow amorphous powder.

The manufacture of the starting material is described in Example 79.

EXAMPLE 7 4-Dipropylamino-imidazolo[4,5-cjrifamycin SV (7) In a manner analogous to that described in Example 1 the above-mentioned imidazolorifamycin SV(7)(C44H60NO11, m.w. = 820) is produced from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of tetrahydrofuran and 4.0 g of N,N-dipropylformamide-dimethylacetal. The product is obtained from ether/methylene chloride in the form of orange-coloured crystals which melt at 175185 (decomposition); m.w. found: 820.

The N,N-dipropylformamide-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 81 from 10 g of dipropylamine and 20 g of N,N-dimethylformamidedimethylacetal.

EXAMPLE 8 4-(N-isopropyl-N-methylamino)-imidazolo[4,5-c]rifamycin SV (8) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of tetrahydrofuran and 4.0 g of N-isopropyl-N-methylformamidedimethylacetal 4-(N-isopropyl-N-methylamino)-imidazolo[4,5-cjrifa mycin SV (8) (C42Hs6N4Ot1, m.w. = 792).

The N-isopropyl-N-methylformamide-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 80 and 81 and from lOg of N-isopropyl-N-methylamine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 9 4-(N-Butyl-N-methylamino)-imidazolo[4,5-c]rifamycin SV (9) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-butyl-N-methyiformamide-dimethylacetal 4-(N-butyl N-methylamino)-imidazolo[4,5-cjrifamycin SV (9) (C43H48N40,1, m.w. = 806). M.w. found: 806.

The N-butyl-N-methylformamide-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 80 and 81 from 10 g of butylmethylamine and 20 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 10 4-(N-Cyclo-N-methyla mino)-imidazolo[4,5-c] rifamycin SV (10) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4- iminorifamycin S in 50 ml of THF and 4.0 g of N-cyclopentyl-N-methylformamide-dimethylacetal 4-(Ncyclopentl-N-methylamino)-imidazolo[4,5-c]rifamycin SV (10) (C44H58N4011, m.w. = 818). M.w. found: 818.

The N-cyclopentylformamide-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 80 and 81 from 10 g of cyclopentyl-methylamine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 11 4-(N-Cyclopropylmethyl-N-propylamino)-imidazolo[4,5-c]rifa mycin SV (11) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-cyclopropylmethyl-N-propylformamide-dimethylacetal 4-(N-cyclopropylmethyl-N-propylamino)-imidazolo[4,5-c]rifamycin SV (11) (C4sH60N401,, m.w. = 832).

There are formed from ether yellow crystals having a melting point of 223224 . M.w. found: 832.

The N-cyclopropylmethyl-N-propylformamide-dimethylacetal requires as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-cyclopropylmethyl-Npropylamine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 12 4-(N-Benzyl-N-methylamino)-imidazolo[4,5-cjrifamycin SV (12) In a manner analogous to that described in Example 1 there is produced from 0.7 g of 3-amino-4iminorifamycin S in 10 ml of THF and 0.425 g of N-benzyl-N-methylformamide-dimethylacetal 0.1 55 g of 4-(N-benzyl-N-methylamino)-imidazolo[4,5-cjrifa mycin SV (1 2) (C47H56N4O,1, m.w. = 852).

The manufacture of the reagent is described in Example 80.

EXAMPLE 13 4-[N-Methyl-N-( 1 -methyl-4-piperidyl)-amino]imidazlo[4,5-c]rfiamycin SV (13) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino4-iminorifamycin Sin 50 ml of THF and 4.0 g of N-methyl-N-(1-methyl-4-piperidyl)-formamide- dimethylacetal 4-[N-methyl-N-( -methyl-4-piperidyl)-amino]-imidazolo[4,5-c]rifamycin SV (13) (C45H61N5011, m.w. = 847); m.w. found: 847.

The N-methyl-N-( 1 -methyl-4-piperidyl)-formamide-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 10 g of N-methyl-N-( 1 -methyl-4piperidyl)-amine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 14 4-[N-Ethyl-N-(2-hydroxyethyl)-amino]-imidazolo[4,5-c]rifamycin SV (14) In a manner analogous to that described in Example 1 there is obtained from 4.0 g of 3-amino-4 iminorifamycin S in 50 ml of THF and 4.0 g of N-ethyl-N-(2-hydroxyethyl)-formamide-dimethylacetal the desired imidazolorifamycin SV (14) (C42H56N4012, m.w. = 808). It is obtained from methylene chloride/ether in the form of yellow prisms which melt at 192-1 930 (decomposition). M.w. found: 808.

The N-ethyl-N-(2-hydroxyethyl)-formamide-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-ethylethanolamine and 20 g oi N,N-dimethylformamide-dimethylacetal.

EXAMPLE 15 4-[N-(2,2-Dimethoxyethyl)-N-methylamino]-imidazolo[4,5-c]rifamycin SV (1 5) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-methyl-N-(2,2-dimethoxyethyl)-formamide- dimethylacetal the desired imidazolorifamycin SV (15) (C43Hs8N40,3, m.w. = 838) having a melting point of 1 62 0C (decomposition). M.w. found (rn/2 of TMS4 derivative): 838.

The N-methyl-N-(2,2-dimethoxyethyl)-formamide-dimethylacetal requires as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of methylaminoacetaldehydedimethylacetal and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 16 4-[N-Di-(2-methoxyethyl)-amino]imidazolo[4,5-c]rifamycin SV (16) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N,N-di-(2-methoxyethyl)-formamide-dimethylacetal 4 [di-(2-methoxyethyl)-amino]-imidazolo[4,5-c]rifamycin SV (16) (C44H60N40,3, m.w. = 852). M.w. found: 852.

The N,N-di-(2-methoxyethyl)-formamide-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 80 from 10 g of di-(2-methoxyethyl)-amine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 1 7 4-[N-Methyl-N-(2-dimethylaminoethyl)-amino]-imidazolo[4,5-c]rifamycin SV ( 7) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-methyl-N-(2-dimethylaminoethyl)-formamidedimethylacetal 4-[methyl-(2-dimethylaminoethy)-amino]-imidazolo[4,5-c]rifamycin SV (17) (C43H59N5O11, m.w.=821). it is obtained from methylene chloride in the form of triangular platelet crystais which melt at 187-188 (decomposition); m.w. found: 821.

The N-methyl-N-(2-dimethylaminoethyl)-formamide-dimethylacetal requires as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N,N,N'trimethylethylenediamine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 18 4-[N-Ethyl-N-(2-diethyla minoethyl)-a mino]-i midazo[o [4,5-c] rifa mycin SV ( 1 8) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-ethyl-N-diethylaminoethylformamide-dimethylacetal the desired imidazolorifamycin SV (18) (C45H65N5O11, m.w. = 863) having a melting point of 173-1 740C (decomposition).

The N-ethyl-N-diethylaminoethylformamide-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N,N',N'-triethylethylenediamine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 19 4-Pyrrolidinyl-imidazolo]4,5-c]rifamycin SV (19) 20 g of dimethylformamide-dimethylacetal are heated with 10 g of pyrrolidine at 1000 for four hours. 100 ml of toluene are then added and the mixture is concentrated by evaporation at 500 in a water jet vacuum. The residue is used without further purification in the form of the crude reagent dimethoxypyrrolidinomethane. A mixture of 4 g of dimethoxypyrrolidinomethane, 50 ml of tetrahydrofuran and 4 g of 3-amino-4-iminorifamycin S are left to stand for six hours at 250, the colour of the reaction mixture, which is initially deep red, gradually changing to yellow-brown. The mixture is then acidified with aqueous citric acid solution and the reaction product is taken up in methylene chloride. The reaction product is purified by chromatography over silica gel. Using a mixture of ethyl acetate with 10% methanol as eluant, purified pyrrolidinyl-imidazolorifamycin SV ( 9) is obtained which, from acetone/ether, forms yellow crystals having a melting point of 2000. M.w. found: 790 (MS as TMS4 derivative m/2 1078) calculated for C12Hs4N401, m.w. = 790.

EXAMPLE 20 4-lndolinyl-imidazolo[4,5-c]rifamycin SV (20) In a manner analogous to that described in Example 1 there are produced from 2.0 g of 3-amino4-iminorifamycin S in 100 ml of THF and 3.26 g of N-formylindoline-dimethylacetal 1.1 g of 4 indolinyl-imidazolo[4,5-cjrifamycin SV (20) (C46Hs3N4O,5, m.w. = 837).

The N-formylindoline-dimethylacetal required as reagent is produced in accordance with Example 82.

EXAMPLE 21 4-Piperidino-imidazolo[4,5-c]rifamycin SV (21) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-formylpiperidine-dimethylacetal 4-piperidinylimidazolo[4,5-c]rifamycin SV (21) (C43H56N4O", m.w. = 802). It is in the form of yellow crystals having a melting point of 1900 (decomposition). M.w. found: 802.

The N-formylpiperidine-dimethylacetal requires as reagent is produced in accordance with Example 83.

EXAMPLE 22 4-(4-EthoxyCarbonyl-1-piperidyl)-imidazolo[4,5-c]rifamycin SV (22) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-4-ethoxycarbonyl-piperidine-dimethylacetal 4 (4-ethOxycarbonylpiperidyl)-imidazolo[4,5-c]rifamycin SV (22) (C46H60N4Oa3, m.w. = 876).

The N-formyl-4-ethoxycarbonylpiperidine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of 4-ethoxycarbonylpiperidine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 23 4-(4-Dimethylamino- 1 -piperidyl)-imidazolo[4,5-c]rifamycin SV (23) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4 iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-4-dimethylaminopiperidine-dimethylacetal 4 (4-dimethylaminopiperidyl)-imidazolo[4,5-cjrifamycin SV (23) (C45H6,N50", m.w. = 847). It is obtained from methanol/ether in the form of yellow crystals which decompose from --1400. M.w. found (m/2 of the TMS5 derivative): 847.

The N-formyl-4-dimethylaminopiperidine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of 4-dimethylaminopiperidine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 24 4-(4-Piperidino-1 -piperidyl)-imidazolo[4,5-cjrifamycin SV (24) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-4-piperidinopiperidine-dimethylacetal 4-(4 piperidinopiperidyl-imidazolo[4,5-c]rifamycin SV (24) (C48H65N5O11, m.w. = 887). It is obtained from methanol/methylene chloride in the form of yellow crystals which decompose from 1900.

The N-formyl-4-piperidinopiperidine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of 4-piperidinopiperidine and 20 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 25 4-[8-Aza-1 ,4-dioxaspiro-(4,5)-8-decyl]-imidazolo[4,5-c]rifamycin SV (25) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-(4-piperidoneethyleneketal)-dimethylacetal the title compound (25) (C4sH58N4O,3, m.w. = 862). M.w. found (MS of the TMS5 derivative): 862.

The N-formyl-(4-piperidoneethyleneketal)-dimethylacetal required as reagent is produced in accordance with Example 85.

EXAMPLE 26 4-(3-Diethylaminocarbonyl-1 -piperidyl)-imidazolo[4,5-c]rifamycin SV (26) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-3-diethylaminocarbonylpiperidinedimethylacetal 4-(3-diethylaminocarbonylpiperidyl)-imidazolo[4,5-c]rifamycin SV (26) (C48H65N5O12, m.w. = 903).

The N-formyl-3-diethylaminocarbonylpiperidine-dimethylaceta I required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of piperidine-3-carboxylic acid diethylamide and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 27 4-(1-Perhydroazepinyl)-imidazolo[4,5-c]rifamycin SV (27) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-perhydroazepine-dimethylacetal, the desired imidazolorifamycin SV (27) (C44H58N4011, m.w.=818).

The 1 -formyl-perhydroazepine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of perhydroazepine and 20 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 28 4-( 1 -Perhydroazocinyl)-imidazolo[4,5-c]rifamycin SV (28) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-perhydroazocine-dimethylacetal the title compound (28) (C45H60N4011, m.w. = 832) having a melting point of 1 800C (decomposition). M.w.

found: 832.

The N-formyl-perhydroazocine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of perhydroazocine and 20 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 29 4-(2,6-Dimethylmorpholino)-imidazolo[4,5-c]rifamycin SV (29) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4.0 g of 4-formyl-2,6-dimethylmorpholine-dimethylacetal 4-(2,6 dimethyl-4-morpholinyl)-imidazolo[4,5-c]rifamycin SV (29) (C44H58N4012, m.w. = 834). It is in the form of yellow crystals which gradually decompose from 2400 without melting. M.w. found: 834.

The 4-formyl-2,6-dimethylmorpholine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of 2,6-dimethylmorpholine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 30 4-Thiomorpholino-imidazolo[4,5-c]rifamycin SV (30) In a manner analogous to that described in Example 1 there is produced from 1.4 g of 3-amino-4iminorifamycin S in 100 ml of THF and 1.06 g of N-formylthiomorpholine-dimethylacetal 0.45 g of 4thiomorpholino-imidazolo[4,5-c]rifamycin SV (30) (C42H54N4SO11, m.w. = 822).

The manufacture of N-formylthiomorpholine-dimethylacetal is described in Example 87.

EXAMPLE 31 4-(4-Ethylpiperazinyl)-imidazol6[4,5-c]rifamycin SV (31) In a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4iminorifamycin Sin 100 ml of THF and 3.18 g of 1-formyl-4-ethylpiperazine-dimethylacetal 0.95 g of 4 (4-ethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (31) (C44H58N 5011, m.w. = 833).

The 1 -formyl-4-ethylpiperazine-dimethylacetal (boiling point 981000 C/20 torr) required as reagent is obtained in a manner analogous to that described in Example 80 from 11.4 g of Nethylpiperazine and 25 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 32 4-(4-Propylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (32) In a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4iminorifamycin S in 100 ml of THF and 3.42 g of 1 formyl-4-propylpiperazine-dimethylacetal 0.9 g of 4 (4-propylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (32) (C45H61N5O11, m.w. = 847).

The 1 -formyl-4-propylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 12.8 g of N-propylpiperazine and 29.75 g of N,Ndimethylformamide-dimethylacetal EXAMPLE 33 4-(4-Butylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (33) In a manner analogous to that described in Example 1 there is obtained from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-butylpiperazine-dimethylacetal the desired title compound (33) (C46H63N5O11, m.w. = 861). M.w. found: 861.

The 1-formyl-4-butylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 10 g of N-butylpiperazine and 20 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 34 4-(4-Pentylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (34) In a manner analogous to that described in Example 1 there are produced from 2 g of 3-amino-4iminorifamycin Sin 100 ml of THF and 3.5 g of 1-formyl-4-pentylpiperazine-dimethylacetal 1.4 g of 4 (4-pentylpiperazinyl)-imidazolo[4,5-cjrifamycin SV (34) (C47H65N5Ot,, m.w. = 875).

The 1 -formyl-4-pentylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 6.46 g of N-pentylpiperazine and 12.3 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 35 4-(4-Hexylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (35) In a manner analogous to that described in Example 1 there are produced from 2.0 g of 3-amino4-iminorifamycin S in 100 ml of THF and 4.1 3 g of 1 -formyl-4-hexylpiperazine-dimethylacetal 1.25 g of 4-(4-hexylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (35) (C4aH67N5O", m.w. = 889).

The 1 -formyl-4-hexylpiperazine-dimethylacetal required as reagent (boiling point 125-1 300C/0.3 torr) is obtained in a manner analogous to that described in Example 80 from 1 7 g of N-hexylpiperazine and 29.75 g of N,n-dimethylformamide-dimethylacetal.

EXAMPLE 36 4-(4-Heptylpiperazinyl)-imidazolo[4,5-cjrifamycin SV (36) In a manner analogous to that described in Example 1 there are produced from 2.0 g qf 3-amino4-iminorifamycin S in 100 ml of THF and 4.33 g of 1 -formyl-4-heptylpiperazine-dimethylacetal 1.2 g of 4-(4-heptylpiperazinyl)-imidazolo[4,5-c]rifamycin SV(36) (C49H69N5O", m.w. = 903).

The 1 -formyl-4-heptylpiperazine-dimethylacetal (boiling point 1 28--1 29 OC/0.1 5 torr) required as reagent is obtained in a manner analogous to that described in Example 80 from 18.4 g of Nheptylpiperazine and 30 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 37 4-[4-( 1 -Methylpropyl)-piperazinyl]-imidazolo[4,5-c] rifamycin SV (37) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1 -formyl-4-( 1 -methylpropyl)-piperazine-dimethylacetal the title compound (37) (C46H63N5O,1, m.w. = 861).

The 1 -formyl-4-( 1 -methylpropyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 80 from 10 g of N-(1-methylpropyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 38 4-[4-(2-Methylbutyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (38) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-(2-methylbutyl)-piperazine-dimethylacetal 4 [4-(2-methylbutyl)-1-piperazinyl]-imidazolo[4,5-c]rifamycin SV (38) (C47H65N5O11, m.w. = 875) having a melting point of 1 850C (decomposition). M.w. found: 875.

The 1 -formyl-4-(2-methylbutyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-(2-methylbutyl)-piperazine and 20 g of N,N-dirnethylformamide-dimethylacetal.

EXAMPLE 39 4-[4-(2-Methylpentyl)-piperazinyl]-imidazolo[4,5-c] rifamycin SV (39) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4.0 g of 1 -fonnyl-4-(2-methylpentyl)-piperazine-dimethylacetal 4-[4-(2-methylpentyl)-1-piperazinyl]-imidazolo[4,5-c]rifamycin SV (39) (C48H67N5O", m.w. = 889) having a melting point of 171-1 720C (decomposition). M.w. found: 889.

The 1-formyl-4-(2-methylpentyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-(2-methylpentyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 40 4-[4-(3-Methylbutyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (40) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4.0 g of 1 -formyl-4-(3-methylbutyl)-piperazine-dimethylacetal 4 [4-(3-methylbutyl)-1-piperazinyl]-imidazolo[4,5-c]rifamycin SV (40) (C47H65N50", m.w. = 875).

The 1 -formyl-4-(3-methylbutyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-(3-methylbutyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 41 4-[4-(1 -Ethylpropyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (41) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4.0 g of 1-formyl-4-(2-ethylpropyl)-piperazine-dimethylacetal 4 [4-(2-ethylpropyl)- 1 -piperazinyl]-imidazolo[4.5-c] rifa mycin SV (41) (C47H65N5O", m.w. = 875). M.w.

found: 875.

The 1 -formyl-4-(2-ethylpropyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-(2-ethylpropyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 42 4-[4-(3-Methylpentyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (42) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4.0 g of 1-formyl-4-(3-methylpentyl)-piperazine-dimethylacetal 4-[4-(3-methylpentyl)-1-piperazinyl]-imidazolo[4,5-c]rifamycin SV (42) (C48H67NsO", m.w. = 889).

M.w. found: 889.

The 1 -formyl-4-(3-methylpentyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-(3-methylpentyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 43 4-[4-(1,3-Dimethylpropyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (43) In a manner analogous to that described in Example 1 there are produced from 2.0 g of 3-amino4-iminorifamycin Sin 100 ml of THF and 3.2 g of 1-formyl-4-(1,3-dimethylpropyl)-piperazine- dimethylacetal, 1.7 g of the title compound (43) (C47H65N5O", m.w. = 875).

The 1 -formyl-4-( 1 ,3-dimethylpropyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 2.55 g of N-(1 ,3-dimethylpropyl)-piperazine and 4.87 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 44 4-(4-Allylpiperazinyl)-i midazolo[4,5-c] rifamycin SV (44) In a manner analogous to that described in Example 1 there are produced from 2.0 g of 3-amino4-iminorifamycin S in 100 ml of THF and 3.4 g of 1 -formyl-4-allylpiperazine-dimethylacetal, 1.2 g of 4 (4-allylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (44) (C45H59N50", m.w. = 845).

The 1-formyl-4-allylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 5 g of N-allylpiperazine and 11.9 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 45 4-[4-(3-Butenyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (45) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-(3-butenyl)-piperazhine-dimethylacetal, 4-[4 (3-butenyl)-l -piperazinyl]-imidazolo[4,5-c] rifa mycin SV (45) (C46H6,N5O " m.w. = 859). M.w. (MS) found: 859.

The 1 -formyl-4-(3-butenyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 10 g of N-(3-butenyl)-piperazine and 20 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 46 4-[4-(2-Methyl-2-propenyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (46) In a manner analogous to that described in Example 1 there are produced from 2.0 g of 3-amino4-iminorifamycin Sin 100 ml of THF and 3.62 g of 1-formyl-4-(2-methyl-2-propenyl)-piperazine- dimethylacetal 1.15 g of the title compound (46) (C46H61N5O11, m.w. = 859).

The 1-formyl-4-(2-methyl-2-propenyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 21.13 g of N-(2-methyl-2-propenyl)piperazine and 45 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 47 4-[4-(2-Ethyl-2-butenyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (47) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-(2-ethyl-2-butenyl)-piperazine-dimethylacetal the title compound (47) (C58H65N5O11, m.w. = 887), m.w. found: 887.

The manufacture of the formamide reagent is described in Example 89.

EXAMPLE 48 4-[4-(2,3-Dimethyl-2-butenyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (48) In a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4 iminorifamycin Sin 100 ml of THF and 4.0 g of 1-formyl-4-(2,3-dimethyl-2-butenyl)-piperazine- dimethylacetal 0.42 g of 4-[4-(2,3-dimethyl-2-butenyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (48) (C48H65N50", m.w. = 887).

The 1 -formyl-4-(2,3-dimethyl-2-butenyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 30 g of N-(2,3-dimethyl-2butenyl)-piperazine and 53 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 49 4-(4-Propargylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (49) In a manner analogous to that described in Example 1 there are produced from 2.0 g of 3-amino4-iminorifamycin S in 100 ml of THF and 3.7 g of 1 -formyl-4-propargylpiperazine-dimethylacetal 1.05 g of 4-(4-propargylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (49) (C45H57N50", m.w. = 843).

The 1-formyl-4-propargylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 7.65 g of propargylpiperazine and 1 5.6 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 50 4-(4-Cyclopentylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (50) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-cyclopentylpiperazine-dimethylacetal 4-(4cyclopentyl-1-piperazinyl)-imidazolo[4,5-c]rifamycin SV (50) (C47H63N5OIr, m.w. = 873). M.w. found: 873.

The 1-formyl-4-cyclopentylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-cyclopentylpiperazine and 20 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 51 4-(4-Cyclohexylpiperazinyl)-imidazolo[4,5-c] rifamycin SV (51) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4.0 g of 1-formyl-4-cyclohexylpiperazine-dimethylacetal 4-(4cyclohexyl-1 -piperazinyl)-imidazolo[4,5-c]rifamycin SV (51) (C46H65N5O", M.W. = 887).

The 1-formyl-4-cyclohexylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-cyclohexylpiperazine and 20 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 52 4-(4-Pehnylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (52) In a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4iminorifamycin Sin 100 ml of THF and 3.32 g of 1-formyl-4-phenylpiperazine-dimethylacetal 0.79 g of 4-(4-phenylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (52) (C48H59N5O11, m.w. = 881).

The manufacture of the acetal reagent is described in Example 91.

EXAMPLE 53 4-[4-(3-Trifluoromethylphenyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (53) In a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4iminorifamycin S in 100 ml of THF and 5.14 g of 1-formyl-4-(3-trifluoromethylphenyl)-piperazinedimethylacetal 0.73 g of 4-[4-(3-trifluoromethylphenyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (53) (C49H58N5O"F3, m.w. = 949).

The 1 formyl-4-(3-trifluoromethylphenyl)-piperazine-dimethylacetal (boiling point: 1 58-1 600C/0.2 torr) required as reagent is obtained in a manner analogous to that described in Example 80 from 25 g of N-(3-trifluoromethylphenyl)-piperazine and 32.4 g of N,N-dimethylformamidedimethylacetal.

EXAMPLE 54 4-(4-Cyclopropylmethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (54) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1 -formyl-4-cyclopropylmethyl-piperazine-dimethylacetal 4-(4-cyclopropylmethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (54) (C46H6,N5O", m.w. = 859); m.w.

found: 859.

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

EXAMPLE 55 4-(4-Cyclopentylmethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (55) In a manner analogous to that described in Example 1 there is produced from 1.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 1.26 g of 1 -formyl-4-cyclopentylmethylpiperazine-dimethylacetal 0.275 g of 4-(4-cyclopentylmethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (55) (C48H65N5O", m.w. = 887).

The 1-formyl-4-cyclopentylmethylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 4.71 g of cyclopentylmethylpiperazine and 9.5 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 56 4-(4-Cycloheptyl methylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (56) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-cycloheptylmethylpiperazine-dimethylacetal the title compound (56) (C50H69N5011, m.w. = 915) having a melting point of 179-1 800C (decomposition). M.w. found: 915.

The 1 -formyl-4-cycloheptylmethylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that 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-c] rifamycin SV (57) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4.0 g of 1-formyl-4-benzylpiperazine-dimethylacetal 4-(4 benzylpiperazinyl)-imidazolo[4,5-c]rifamycin (57) (C49H6,N5O", m.w. = 885).

The 1-formyl-4-benzylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-benzylpiperazine and 20 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 58 4-[4-(2-Methyl-3-phenyl-propyl)-piperazinyl]-imidazolo[4,5-cjrifamycin SV (58) In a manner analogous to that described in Example 1 there is produced from 4 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4 g of 1-formyl-4-(2-methyl-3-phenylpropyl)-piperazine- dimethylacetal the title compound (58) (C52H67N5O", m.w. = 937). M.w. found: 937.

The 1 -formyl-4-(2-methyl-3-phenyl-propyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 10 g of N-(2-methyl-3-phenylpropyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 59 4-[4-(2-Pyridyl)-piperazinyl]-imidazolo [4,5-c] rifa mycin SV (59) In a manner analogous to that described in Example 1 there are produced from 2.0 9 of 3-amino4-iminorifamycin Sin 100 ml of THF and 4.01 g of 1-formyl-4-(2-pyridyl)-piperazine-dimethylacetal 1.28 g of 4-[4-(2-pyridyl)-piperazinyl]-imidazolo[4,5-cjrifamycin SV (59) (C47H58N6O", m.w. = 882).

The 1 -formyl-4-(2-pyridyl)-piperazine-dimethylacetal (boiling point: 1 54-1 560C/0.7 torr) required as reagent is obtained in a manner analogous to that described in Example 80 from 25 g of N (2-pyridyl)-piperazine and 45 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 60 4-[4-(2'-Pyridylmethyl)-piperazinyl]-i midazolo[4,5-c] rifamycin SV (60) in a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4iminorifamycin S in 100 ml of THF and 4.26 g of 1 -formyl-4-(2-pyridylmethyl)-piperazinedimethylacetal 0.97 g of 4-[4-(2-pyridylmethyl)-piperazinylj-imidazolo[4,5-cjrifamycin SV (60) (C48H60N6O", m.w. = 896).

The 1-formyl-4-(2-pyridylmethyl)-piperazine-dimethylacetal (boiling point: 150-1 600C/0.1 torr) required as reagent is obtained in a manner analogous 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]-imidazolo[4,5-c]rifamycin SV (61) In a manner analogous to that described in Example 1 there is produced from 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 the title compound (61) (C47H63N5O,2, m.w. = 889). M.w.-found: 889.

The 1-formyl-4-(2-tetrahydrofurylmethyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-(2tetrahydrofurylmethyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 62 4-(4-[2-( 1 ,3-dioxolan-2-yI)-ethyl]-piperazinyl )-imidazolo[4,5-cjrifamycin SV (62) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1 -formyl-4-[2-( 1 ,3-dioxolan -2-yl)ethyl]-piperazinedimethylacetal the title compound (62) (C47H63N50,3, m.w. = 905). M.w. found (MS): 905.

The formamideacetal reagent required is obtained in a manner analogous to that described in Example 82 from 10g of N-[2-(1 ,3-dioxolan-2-yl)-ethyl]-piperazine and 20 g of N,Ndimethylformamide-dimethylacetal.

EXAMPLE 63 4-[4-(2-Methoxyethyl)-piperazinyl]-imidazolo[4,5-c] rifamycin SV (63) In a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4iminorifamycin S in 100 ml of THF and 3.19 g of 1 -formyl-4-(2-methoxyethyl)-piperazinedimethylacetal 0.43 g of the title compound (63) (C45H6,N5O, > , m.w. = 863).

The 1 -formyl-4-(2-methoxyethyl)-piperazine-dimethylacetal (boiling point: 1 01-1 030 C/0.2 torr) required as reagent is obtained in a manner analogous to that described in Example 80 from 1 9 g of N (2-methoxyethyl)-piperazine and 40 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 64 4-[4-(2-Ethoxyethyl)-piperazinyl]-imidazolo[4,5-c] rifamycin SV (64) In a manner analogous to that described in Example 1 there is produced from 4.0 g of,3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1 -formyl-4-(2-ethoxyethyl)-piperazine-dimethylacetal the title compound (64) )C46H63N5O,2, m.w. = 877) having a melting point of 1 660C (decomposition).

The 1 -formyl-4-(2-ethoxyethyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-(2-ethoxyethyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 65 4-[4-(2 ,2-Dimethoxyethyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (65) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1 4ormyl-4-(2,2-dimethoxyethyl)-piperazine- dimethylacetal 4-[4-(2,2-dimethoxyethyl)- 1 piperazinyl]-imidazolo[4,5-cjrifamycin SV (65) (C45H63N5013, m.w. = 893); m.w. found: 893.

The 1 -formyl-4-(2,2-dimethoxyethyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 10 g of N-(2,2-dimethoxyethyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 66 4-[4-(2,2-Diethoxyethyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (66) In a manner analogous to that described in Example 1 there are produced from 2.0 g of 3-amino4-iminorifamycin S in 100 ml of THF and 4.87 g of 1-formyl-4-(2,2-diethoxyethyl)-piperazine- dimethylacetal 2.0 g of the title compound (66) (C48H67N5O,3, m.w. = 921).

The 1 -formyl-4-(2,2-diethoxyethyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 6.19 g of N-(2,2-diethoxyethyl)-piperazine and 8.60 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 67 4-(4-Ethoxycarbonylpiperazinyl)-imidazolo[4,5-c] rifamycin SV (67) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of N-formyl-N'-ethoxycarbonylpiperazine-dimethylacetal the title compound (67) (C45H59N50,3, m.w. = 877).

The manufacture of the formamideacetal reagent is described in Example 90.

EXAMPLE 68 4-(4-ísopropoxycarbonylpipe raziriyl)-i midazolo[4,5-c] rifamycin SV (68) In a manner analogous to that described in Example 1 there are produced from 2.0 g of 3-amino4-iminorifamycin Sin 100 ml of THF and 4.16 g of 1 -formyl-4-isopropoxycarbonyl-piperazinedimethylacetal 1.1 7 g of 4-(4-isopropoxycarbonylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (68) (C46H61N5O13, m.w. = 891).

The 1 -formyl-4-isopropoxycarbonylpiperazine-dimethylacetal (boiling point: 11 8-11 9 0C/0. 1 5 torr) required as reagent is obtained in a manner analogous to that described in Example 80 from 8.5 g of N-isopropoxycarbonylpiperazine and 14.8 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 69 4-[4-(2-Dimethylaminoethyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (69) In a manner analogous to that described in Example 1 there are produced from 2.0 g of 3-amino4-iminorifamycin Sin 100 ml of THF and 3.9 g of 1-formyl-4-(2-dimethylaminoethyl)-piperazinedimethylacetal 1.05 g of the title compound (69) (C46H64N6011, m.w. = 876).

The 1 -formyl-4-(2-dimethylaminoethyl)-piperazine-dimethylacetal (boiling point 110-111 C/0.1 torr) required as reagent is obtained in a manner analogous to that described in Example 80 from 21.26 g of 2-dimethylaminoethylpiperazine and 40.28 g of N,N-dimethylformamide-dimethylacetal.

EXMPLE 70 4-(4-lsobutyrylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (70) In a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4iminorifamycin Sin 100 ml of THF and 3.9 g of 1-formyl-4-isobutyrylpiperazine-dimethylacetal 0.6 g of 4-(4-isobutyrylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (70) (C46H6,N50,2, m.w. = 875).

The 1 -formyl-4-isobutyrylpiperazine-dimethylacetal (boiling point: 1 45-1 500 C/0.5 torr) required as reagent is obtained in a manner analogous to that described in Example 80 from 25 g of Nisobutyrylpiperazine and 47.4 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 71 4-(4-MethoxyCarbonylmethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (71) In a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4iminorifamycin S in 100 ml of THF and 3.85 g of 1-formyl-4-methoxycarbonylmethylpiperazine- dimethylacetal 0.75 g of 4-(4-methoxycarbonylmethylpiperazinyl-imidazolo[4,5-c]rifamycin SV (71) (C4sH5sNsO13, m.w. = 877).

The 1-formyl-4-methoxycarbonylmethylpiperazine-dimethylacetal (boiling point: 114-11 50C/1 torr) required as reagent is obtained in a manner analogous to that described in Example 80 from 10 g of N-methoxycarbonylmethylpiperazine and 75 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 72 4-(4-isopropylcarbamoyimethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (72) In a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4iminorifamycin Sin 100 ml of THF and 4.38 g of 1-formyl-4-isopropylcarbamoylmethylpiperazinedimethylacetal 0.62 g of the title compound (72) (C47H64N6012, m.w. = 904).

The 1 -formyl-4-isopropylcarbamoylmethylpiperazine-dimethylacetal (boiling point: 161--1630C/0.2 torr) required as reagent is obtained in a manner analogous to that described in Example 80 from 15 g of N-isopropyl-1 -piperazine-acetamide and 24.1 g of N,N-dimethylformamide- dimethylacetal.

EXAMPLE 73 4-(4-Morpholinocarbonylmethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (73) In a manner analogous to that described in Example 1 there are produced from 2.0 g of 3-amino4-iminorifamycin Sin 100 ml of THF and 4.85 g of 1-formyl-4-morpholinocarbonyl-methylpiperazinedimethylacetal 1.03 g of the title compound (73) (C4SH64N6013, m.w. = 932).

The 1 -formyl-4-morpholinocarbonylmethylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 25 g of 4piperazinylacetylmorpholine and 35 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 74 4-[4-(1-Methyl-2-dimethylaminoethyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (74) In a manner analogous to that described in Example 1 there is produced from 2.0 g of 3-amino-4iminorifamycin S in 100 ml of THF and 4.1 5 g of 1 -formyl-4-( 1 -methyl-2-dimethylaminoethyl) piperazine-dimethylacetal 0.84 g of the title compound (74) (C47H 66N6O11, m.w. = 890).

The formamideacetal reagent required (boiling point 1 5-11 70C/0.2 torr) is obtained in a manner analogous to that described in Example 80 from 17.1 g of N-(1-methyl-2-dimethylaminoethyl)- piperazine and 30 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 75 4-(4-lsobutyl-2-methylpiperazinyl)-imidazolo[4,5-cjrifamycin SV (75) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-isobutyl-2-methyl-piperazine-dimethylacetal the title compound (75) (C47H65N5O11, m.w. = 875) having a melting point of 175-1 80C (decomposition). M.w. found: 875.

The 1 -formyl-4-isobutyl-2-methylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 10 g of 1 -isobutyl-3-methylpiperazine and 20 g 6fN,Ndimethylformamide-dirnethylacetaI.

EXAMPLE 76 4-(4-lsobutyl-2,5-dimethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (76) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4.0 g of 1-formyl-4-isobutyl-2,5-dimethylpiperazine- dimethylacetal 4-(4-isobutyl-2,5-dimethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (76) (C48H67N5OIl, m.w. = 889). M.w. found: 889.

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

EXAMPLE 77 4-(4-lsobutyl-perhydro- ,4-diazepinyl)-imidazolo[4,5-c]rifamycin SV (77) In a manner analogous to that described in Example 1 there is produced from 4.0 g of 3-amino-4 iminorifamycin S in 50 ml of THF and 4.0 g of 1-formyl-4-isobutyl-perhydro-1,4-diazepine- dimethylacetal 4-(4-isobutyl-perhydro-1 ,4-diazepinyl)-imidazolo[4,5-c]rifamycin SV (77) (C47H65N5OIr, m.w. = 875). M.w. found: 875.

The 1 -formyl-4-isobutyl-perhydro-1 ,4-diazepine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Examples 80-82 from 10 g of N-isobutyl-perhydro-1 ,4- diazepine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 78 3-Dimethylaminomethyleneamino/rifamycin S (78) There are added to 1 g of 3-aminorifamycin S dissolved in 50 ml of absolute methylene chloride 425 mg of triethylamine (3 equivalents) and 1.28 g of N,N-dimethylformamide-dimethylacetal (5 equivalents) and the reaction solution is left to stand at room temperature for 45 minutes. 50 ml of water are added to the mixture, the organic phase is separated off and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. The deep blue-coloured oily residue is applied to a column of 30 g of silica gel in chloroform and eluted with chloroform with increasing proportions of methanol (25% by volume).Concentration by evaporation yields crude 3-dimethylamino-methyleneamino/rifamycin S, .which is crystallised from ether/hexane and obtained in the form of a blue-black powder, m.p.

150-1550C.

Citrate formation 400 mg of 3-dimethylaminomethyleneamino/rifamycin S are dissolved in 5 ml of dioxan, 1 ml of 0.5M citric acid solution is added and the solution is lyophilised, 500 mg of 3dimethylaminomethyleneamino/rifamycin S-citrate resulting in the form of a blue-black powder.

EXAMPLE 78A 3-Dimethylaminomethyleneamino/rifamycin SV (by reduction of the corresponding rifamycin S derivative) 2 ml of a 10% (w/v) aqueous sodium bicarbonate solution and 5 ml of a 10% (w/v) solution of K4[Fe(CN)6] (potassium ferrocyanide) in water are added to a solution of 0.5 g of 3dimethylaminomethyleneamino/rifamycin S in 5 ml of methanol and the solution is stirred intensively for 3 minutes and diluted with 20 ml of water and 20 ml of chloroform. The chloroform phase is separated off and the aqueous phase is extracted a further twice with chloroform. The combined chloroform extracts are dried and concentrated by evaporation, resulting in 3dimethylaminomethyleneamino/rifamycin SV in the form of a yellow powder. On standing in a solution, the latter is very rapidly converted back to the quinone by oxidation by atmospheric oxygen.

EXAMPLE 79 3-Diethylaminomethyleneamino/rifamycin S (79) A solution of 1 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is cooled to -700C, treated with 285 mg of triethylamine (2 equivalents) and 460 mg of iminoylchloride (2.1 equivalents) and stirred for 5 minutes at -700C, and 50 ml of water are added. The organic phase is separated off and the aqueous phase is extracted twice with methylene chloride, and the combined organic extracts are dried over sodium sulphate and concentrated by evaporation in vacuo.The deep blue-coloured oily residue is applied to a column of 100 g of silica gel in ethyl acetate/hexane (1 :1) and eluted with mixtures of hexane with increasing amounts (5075% by volume) of ethyl acetate; concentration by evaporation of the appropriate fractions and crystallisation from ether/hexane yields 3diethylaminomethyleneamino/rifamycin S in the form of a blue-black powder, m.p. 133-1 350C.

The iminoylchloride used as reagent can be produced in the following manner: 12.7 g of oxalylchloride are added dropwise, at OOC, while stirring, to a solution of 10.1 g of diethylformamide in 50 ml of absolute ether in a nitrogen atmosphere and the whole is stirred for a further 3 hours at +500C. The white precipitate of the iminoylchloride is suction-filtered in a pressure filter, washed with ether and dried in a high vacuum. The strongly hygroscopic iminoylchloride is used without further purification for the reaction of 3-aminorifamycin S.

EXAMPLE 80 3-(N-Benzyl-N-methylamino)-methyleneamino/rifamycin S (80) There are added to a solution of 1.5 g of 3-amino-rifamycin S in 50 ml of alcohol-free methylene chloride 637 mg of triethylamine (3 equivalents) and 4.1 g of N-benzyl-N-methylformamidedimethylacetal (10 equivalents), the mixture is left to stand at room temperature for 3- hours and 75 ml of water are added. The orb .,ic phase is separated off and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. The deep blue-coloured oily residue is applied to a column of 200 g of silica gel in chloroform and eluted with mixtures of chloroform with increasing proportions (15% by volume) of methanol.Concentration by evaporation of the appropriate fractions and crystallisation from ether/hexane yields 3-(N-benzyl-N-methylamino)-methyleneamino/rifamycin S in the form of a blueblack powder, m.p. 138--140"C.

The N-benzyl-N-methylformamide-dimethylacetal used as reagent can be obtained in the following manner: A mixture of 7.27 g of N-benzyl-N-methylamine and 20 g of N,N-dimethylformamidedimethylacetal is heated under reflux for 3 hours, excess reactant is distilled off in a water jet vacuum at 50C oil bath temperature and 20 torr, and the concentrated reaction mixture is subjected to fractional distillation. N-Benzyl-N-methylformamide-dimethylacetal distils over at 1 04-1 060C/20 torr.

EXAMPLE 81 3-Pyrrolidinylmethyleneamino/rifamycin S (81) A solution 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 1.43 g of N-formylpyrrolidine-dimethylacetal (5 equivalents), left to stand at room temperature for 1 z hours, carefully concentrated to dryness in a water jet vacuum and dried in a high vacuum. The deep blue-coloured oily residue is applied to a column of 1 50 g of silica gel in chloroform and eluted with mixtures of chloroform with increasing proportions (15% by volume) of methanol.Concentration by evaporation of the appropriate fractions and crystallisation from methanol/water yields 3-pyrrolidinylmethyleneamino/rifamycin S in the form of a blue-black powder, m.p. 1 65-1 700C.

The N-formylpyrrolidine-dimethylacetal required as reagent can be produced in the following manner: A mixture of 10 g of pyrrolidine and 42 g of N,N-dimethylformamide-dimethylacetal is heated under reflux for 3 hours, excess reactant is distilled off in a water jet vacuum at 500C oil bath temperature and 20 torr, and the remaining liquid is subjected to fractional distillation. N Formylpyrrolidine-dimethylacetal distils over at 650C/20 torr.

EXAMPLE 82 3-lndolinylmethyleneamino/rifamycin 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-formylindolinedimethylacetal (5 equivalents), left to stand at room temperature for 13 hours, carefully concentrated by evaporation in a water jet vacuum and dried in a high vacuum. The deep blue-coloured oily residue is applied to a column of 200 g of silica gel in chloroform and eluted with mixtures of chloroform with increasing proportions (0.55% by volume) of methanol. The appropriate fractions are chromatographed again over Sephadexe LH-20 with methanol-as eluant.Concentration by evaporation of the eluate and crystallisation from ether/hexane yields 3-(indolinyl)-methyleneamino/rifamycin S in the form of an amorphous blue-black powder without a definite melting point.

13C-NMR (in CDCl3) (148.8, 141.6, 131.8, 127.8, 125.5, 124.2, 109.9, 46.7, 27.0 ppm).

The N-formylindoline-dimethylacetal required as reagent can be obtained in the following manner: A mixture of 6.8 g of indoline and 20 g of N,N-dimethylformamide-dimethylacetal is heated under reflux for 3 hours and the excess reactant is distilled off in a water jet vacuum at 500C oil bath temperature and 20 torr. The distillation residue, consisting mainly of crude N-formylindolinedimethylacetal, is extracted with several portions of toluene and the combined solutions are concentrated by evaporation in a water jet vacuum. The resulting residue is used without further purification for the above reaction.

EXAMPLE 83 3-Piperidinomethyleneamino/rifamycin S (83) A solution of 1 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is treated with 425 mg of triethylamine (3 equivalents) and 2.24 g of N-formylpiperidine-dimethylacetal, left to stand at 0 for 2 hours and 50 ml of water are added. The organic phase is separated off and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. The deep blue-coloured oily residue is eluted on a column of 100 g of silica gel in chloroform with increasing proportions (25% by volume) of methanol.

Concentration by evaporation of appropriate fractions and crystallisation from ether/hexane yields 3 piperidinomethyleneamino/rifamycin S in the form of a blue-black powder m.p. 1 62-1 650C.

The N-formylpiperidine-dimethylacetal required as reagent can be produced in the following manner: A mixture of 6.3 g of piperidine and 20 g of N,N-dimethylformamide-dimethylacetal is heated under reflux for 3 hours, 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. Nformylpiperidine-dimethylacetal distils over at 740C/20 torr.

EXAMPLE 84 3-(4-Methylpiperidinyl)-methylenea mino/rifa mycin 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-dimethylacetal (10 equivalents), left to stand for 221 hours at room temperature and 50 ml of water are added. The organic phase is separated off and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulphate, concentrated by evaporation in vacuo and chromatographed over a column of 200 g of silica gel in chloroform.Elution with chloroform with increasing proportions (050% by volume) of acetone and concentration by evaporation of the appropriate fractions yields a residue which, when crystallised from ether/hexane, yields 3-(4methylpiperidinyl)-methyleneamino/rifamycin S in the form of a blue-black powder, m.p. 88--900 C.

The N-formyl-4-methylpiperidine-dimethylacetal required as reagent can be obtained in the following manner: A mixture of 5 g of 4-methylpiperidine and 14.9 g of N,N-dimethylformamide-dimethylacetal is heated under reflux for 3 hours, excess reactant is distilled off in a water jet vacuum at 500C oil bath temperature and 20 torr and the remaining liquid is subjected to fractional distillation. N-formyl-4 methylpiperidine-dimethylacetal distils over at 78 0C/20 torr.

EXAMPLE 85 3-(8-Aza-1 ,4-dioxa-spiro[4,5]dec-8-yI)-methyleneamino/rfa mycin S (85) A solution of 2 g of 3-aminorifamycin S in 50 mi of alcohol-free methylene chloride is treated with 575 mg of triethylamine (2 equivalents) and 3.6 g of N-formyl-4-piperidone-ethyleneketal- dimethylacetal (6 equivalents), left to stand for 2- hours at room temperature and 50 ml of water are added. The organic phase is separated off and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation in vacuo and the deep blue-coloured oily residue is chromatographed over a column of 200 g of silica gel in toluene.Appropriate fractions of those obtained by elution with toluene with increasing proportions (1075% by volume) of ethyl acetate are chromatographed again over liephadexe LH-20 using methanol as eluant. Crystallisation from methanol/water of the fractions concentrated by evaporation yields 3-(8-aza-1,4-dioxa-spiro[4,5]dec-8-yl)-methyleneamino/rifamycin S in the form of a blue-black powder, m.p. 178-1 800 C.

The N-formyl-4-piperidone-ethyleneketal-dimethylacetal required as reagent can be obtained in the following manner: A mixture of 20 g of 4-piperidone-ethyleneketal and 42 g of N,N-dimethylformamidedimethylacetal is heated under reflux for 3 hours, 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. Nformyl-4-piperidone-ethyleneketal-dimethylacetal distils over at 1111140 C/0.5 torr.

EXAMPLE 86 3-Morpholinylmethyleneamino/rifamycin S (86) There are added to a solution of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride, which has been cooled to 700 C, 1.6 g of triethylamine (7.5 equivalents) and 3.36 g of morpholineiminoylcyhloride (10 equivalents) and the whole is stirred for 1 hour at 400 and treated with 50 ml of water. The organic phase is separated off and the aqueous phase is extracted a further twice with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is dissolved in a minimum amount of methanol and treated with a 10% (w/v) aqueous potassium ferricyanide solution in the presence of potassium bicarbonate.The oxidation mixture is extracted twice with chloroform, the chloroform extracts are dried, concentrated by evaporation and chromatographed over a column of 100 g of silica gel in chloroform.

Elution with chloroform with increasing proportions (150% by volume) of acetone and concentration by evaporation of the appropriate fractions produces a residue which, after crystallisation from methanol/water, yields 3-morpholinylmethyleneamino/rifamycin S in the form of an amorphous blueblack powder: '3C-NMR spectrum (in CDCI3): 160.9, 67.2, 49.1 ppm.

The iminoylchloride derived from morpholine which is required as reagent can be obtained in the following manner: 5.52 g of oxalylchloride are added dropwise at 00, while stirring, to a solution of 5 g of Nformylmorpholine in 50 ml of absolute ether under nitrogen and the reaction solution is stirred at +500C for a further 3 hours. The white precipitate of the iminoylchloride is suction-filtered in a pressure filter, washed with ether and dried in a high vacuum. The strongly hydroscopic iminoylchloride is used in the above reaction without further purification.

EXAMPLE 87 3-Thiomorpholinylmethyleneamino/rifamycin S (87) There are added to a solution of 1.5 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride 637 mg of triethylamine (3 equivalents) and 5.6 g of N-formyl-thiomorpholine-dimethylacetal (1 5 equivalents), and the mixture is left to stand at room temperature for 60 minutes and treated with 50 ml of water. The organic phase is separated off and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulphate, concentrated by evaporation in vacuo and the deep blue-coloured oily residue is chromatographed over a column of 250 g of silica gel in chloroform.Elution with chloroform with increasing proportions (15% by volume) of methanol and concentration by evaporation of the appropriate fractions produces a residue which, after crystallisation from ether/hexane, yields 3-thiomorpholinylmethyleneamino/rifamycin S in the form of a blue-black powder, mp. 177-1 820C.

The N-formylthiomorpholine-dimethylacetal required as reagent can be obtained in the following manner: A mixture of 5.45 g of thiomorpholine and 15.7 g of N,N-dimethylformamide-dimethylacetal is heated under reflux for 3 hours, excess reactant is distilled off in a water jet vacuum at 500C oil bath temperature and 20 torr and the remaining liquid is subjected to fractional distillation. N Formylthiomorpholine-dimethylacetal distils over at 1 10--1 130C/20 torr.

EXAMPLE 88 3-(4-Methylpiperazinyl)-methylenea mino/rifa mycin S (88) A mixture of 1 g of 3-aminorifamycin S, 425 mg (3 equivalents) of triethylamine and 2.4 g (10 equivalents) of N-methyl-N'-formyrpiperazine-dimethylacetal in 50 ml of alcohol-free methylene chloride is left to stand at room temperature for 2 2 hours and processed in a manner analogous to that described in Example 10. Chromatography over a column of 120 g of silica gel in chloroform, elution with chloroform with an increasing proportion (220% by volume) of acetone, and crystallisation from ether/hexane yields the title compound in the form of a blue-black powder, melting point 1 48-1 51 OC.

The N-methyl-N'-formylpiperazine-dimethylacetal required as reagent can be obtained in the following manner: A mixture of 5 g of N-methylpiperazine and 14.9 g of N,N-dimethylformamide-dimethylacetal is heated under reflux for 3 hours. After processing analogously to Examples 3-8 and 10, the desired N methyl-N'-formylpiperazine-dimethylacetal distils over at 8485 C/20 torr.

EXAMPLE 89 3-[4-(2-Ethyl-2-butenyl)-pipernzinyljmethyleneaminofrifamycin S (89) A mixture of 2 g of 3-aminorifamycin S, 575 mg (2 equivalents) of triethylamine and 3.4 g (5 equivalents) of N'-formyl-N-(2-ethyl-2-butenyl)-piperazine-dimethylacetal in 50 ml of alcohol-free methylene chloride is left to stand for 2 hours at room temperature and processed in a manner analqgous to that described in Example 4. Chromatography over a column of 250 g of silica gel in chloroform and elution with chloroform with an increasing proportion (0.5-1 0% by volume) of methanol results in a crude product which is further purified by chromatography over Sephadexs LH-20 (elution with methanol).Crystallisation from ether/hexane yields the title compound in the form of a blue-black powder, melting point 140-1 420C.

The N'-formyl-N-(2-ethyl-2-butenyl)-piperazine-dimethylacetal required as reagent can be obtained in the following manner: A mixture of 10 g of N-(2-ethyl-2-butenyl)-piperazine and 1 6.7 g of N,N-dimethylformamidedimethylacetal is 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-dimethylacetal distils over at 1 21 or/0.5 torr.

EXAMPLE 90 3-(4-Ethoxycarbonylpiperazinyi)methyleneamino/rifamycin S (90) A mixture of 2 g of 3-aminorifamycin S, 575 mg (2 equivalents) of triethylamine and 3.27 g (5 equivalents) of N'-formylpiperazine-N-carboxylic acid ethyl ester-dimethylacetal in 50 ml of alcohol-free methylene chloride is left to stand at room temperature for 4 hours and processed in a manner analogous to that described in Example 4. Chromatography over a column of 250 g of silica gel in chloroform and elution with chloroform with an increasing proportion (0.5-1 0% by volume) of methanol yields a crude product which is further purified by chromatography over Sephadexe LH-20 (elution with methanol).Crystallisation from ether/hexane yields the title compound in the form of a blue-black powder, melting point 1 60-1 650C.

The N'-formylpiperazine-N-carboxylic acid ethyl ester-dimethylacetal required as reagent can be obtained in the following manner: A mixture of 10.87 g of piperazine-N-carboxylic acid ethyl ester and 20.44 g of N,Ndimethylformamide-dimethylacetal is heated under reflux for 4 hours. After processing analogously to Examples 3-8 and 10 the desired N'-formylpiperazine-N-carboxylic acid ethyl ester-dimethylacetal distils over at 128-1 300C/0.75 torr.

EXAMPLE 91 3-(4-Phenylpiperazinyl)methyleneamino/rifa mycin S (91) A mixture of 1.5 g of 3-aminorifamycin S, 425 mg (2 equivalents) of triethylamine and 3.5 g (7 equivalents) of N'-formyl-N-phenylpiperazine-dimethylacetal in 50 ml of alcohol-free methylene chloride is left to stand at room temperature for 6 1/4 hours and processed in a manner analogous to that described in Example 10. Chromatography over a column of 250 g of silica gel in chloroform and elution with chloroform with an increasing proportion (0.55% by volume) of methanol yields a crude product which is further purified by chromatography over Sephadexs LH-20 (elution with methanol).

Crystallisation from ether/hexane yields the title compound in the form of a blue-black powder without a definite melting point.

The N'-formyl-N-phenylpiperazine-dimethylacetal required as reagent can be obtained in the following manner: A mixture of 10 g of N-phenylpiperazine and 1 8.3 g of N,N-dimethylformamide-dimethylacetal is heated under reflux for 3 hours. After processing analogously to Examples 3-8 and 10, the desired N'formyl-N-phenylpiperazine-dimethylacetal distils over at 165-1 670C/0.5 torr.

EXAMPLE 92 3-(4-Aza-tricyclo [5,2,2,026]u ndec-8-en-4-yl)-methyíenea mino/rifamycin S (92) A mixture of 1 g of 3-aminorifamycin S, 283 mg (2 equivalents) of triethylamine and 1.26 g (4 equivalents) of 4-formyl-4-aza-tricyclo[5,2,2,02,6] undec-8-ene-dimethylacetal in 50 ml of alcohol-free methylene chloride is left to stand at room temperature for 6 hours and processed in a manner analogous to that described in Example 10. Chromatography over a column of 100 g of silica gel in chloroform, elution with chloroform with an increasing proportion (0-1 0% by volume) of methanol and crystallisation from methanol/water yields the title compound in the form of a blue-black powder, melting point 173-1 760C.

EXAMPLE 93 3-Dipropylaminomethyleneamino/rifamycin S by reaction with dimethyl sulphate complex 2.0 g of N,N-dipropylformamide and 2.0 g of dimethyl sulphate are left to stand at room temperature for 3 hours and the resulting oil is washed first with benzene and then twice with ether and residual ether is removed in vacuo. The oil, containing the N,N-dipropylformamide/dimethyl sulphate complex, is dissolved in 50 mi of absolute methylene chloride and, while stirring, 500 mg of triethylamine and 2.25 g of 3-aminorifamycin S are added. The reaction solution is left to stand at room temperature until the 3-aminorifamycin S used has reacted fully. 50 ml of water are then added to the reaction mixture, the organic phase is separated off and the aqueous phase is extracted twice with methylene chloride.The combined organic extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. The blue-coloured residue is chromatographed over silica gel, chloroform with increasing proportions (210%) of methanol being used as eluant. The practically pure 3 dipropylaminomethyleneamino/rifamycin S resulting in the form of a blue-black powder can be directly converted, in a manner analogous to that described in Example 6, by ammonia gas in tetrahydrofuran to 4-dipropylamino-imidazolo[4,5-c]rifamycin SV (7), which is completely identical to the product of Example 7.

EXAMPLE 94 4-Dimethylamino-imidazolo[4,5-c]rifamycin SV (1) In a manner analogous to that described in Example 6 a solution of 1.0 g of 3dimethylaminomethyleneamino/rifamycin S (78) in 50 ml of tetrahydrofuran is treated with ammonia gas. Customary processing yields the title compound (1), which is identical to the product of Example 1.

EXAMPLE 95 4-Morpholino-imidazolo[4,5-c]rifamycin SV (2) In a manner analogous to that described in Example 6 a solution of 0.5 g of 3morpholinomethyleneamino/rifamycin S (86) in 30 ml of tetrahydrofuran is treated with ammonia gas.

Customary processing yields the title compound (2), which is identical to the product of Example 2.

EXAMPLE 96 4-(4-Methylpiperazinyl)-imidazolo[4,5-c] rifa mycin SV (3) In a manner analogous to that described in Example 6 a solution of 0.5 g of 3-(4methylpiperazinyl)-methyleneamino/rifamycin S (88) in 25 ml of tetrahydrofuran is treated with ammonia gas. Customary processing yields the title compound (3), which is identical to the product of Example 3.

EXAMPLE 97 4-(N-Benzyl-N-methylamino)-imidazolo[4,5-c]rifamycin SV (12) 2.0 g of 3-(N-benzyl-N-methylamino)-methyleneamino/rifamycin S (80) in 100 ml of tetrahydrofuran are treated with ammonia gas. Customary processing yields the title compound (12), which is identical to the product of Example 12.

EXAMPLE 98 4-Pyrrolidinyl-imidazolo[4,5-c]rifamycin SV (19) In a manner analogous to that described in Example 6 a solution of 0.45 g of 3pyrrolidinylmethyleneamino/rifamycin S(81) in 25 ml of tetrahydrofuran is treated with ammonia gas.

Customary processing yields the title compound (19), which is identical to the product of Example 19.

EXAMPLE 99 4-lndolinyl-imidazolo[4,5-c]rifamycin SV (20) In a manner analogous to that described in Example 6 a solution of 0.25 g of 3 indolinylmethyleneamino/rifamycin S (82) in 15 ml of tetrahydrofuran is treated with ammonia gas.

Customary processing yields the title compound (20), which is identical to the product of Example 20.

EXAMPLE 100 4-Piperidino-imidazoio[4,5-c]rifamycin SV (21) In a manner analogous to that described in Example 6 a solution of 0.5 g of 3 piperidinomethyleneamino/rifamycin S (83) in 25 ml of tetrahydrofuran is treated with ammonia gas.

Customary processing yields the title compound (21), which is identical to the product of Example 21.

EXAMPLE 101 4-(8-Aza- 1 ,4-dioxa-spiro[4,5]dec-8-yl)-imidazolo[4,5-cjrifa mycin SV (25) In a manner analogous to that described in Example 6 a solution of 0.2 g of 3-(8-aza-1,4-dioxa spiro[4,5]dec-8-yl)-methyleneamino/rifamycin S (85) in 15 ml of tetrahydrofuran is treated with ammonia gas. Customary processing yields the title compound (25), which is identical to the product of Example 25.

EXAMPLE 102 4-(4-Thiomorpholinyl)-imidazolo[4,5-c]rifamycin SV (30) In a manner analogous to that described in Example 6 a solution of 0.5 g of 3 thiomorpholinomethyleneamino/rifamycin S (87) in 30 ml of tetrahydrofuran is treated with ammonia gas. Customary processing yields the title compound (30), which is identical to the product of Example 30.

EXAMPLE 103 4-[4-(2-Ethyl-2-butenyl)-piperazinyl]-imidazolo[4,5-c] rifa mycin SV (47) In a manner analogous to that described in Example 6 a solution of 0.5 g of 3-[4-(2-ethyl-2 butenyl)-piperazinyl]-aminomethyleneamino/rifamycin (89) in 25 ml of tetrahydrofuran is treated with ammonia gas. Customary processing yields the title compound (47), which is identical to the product of Example 47.

EXAMPLE 104 4-(4-Ethoxycarbonylpiperazinyl)-imidazolo[4,5-c]rifamycin SV (67) In a manner analogous to that described in Example 6 a solution of 0.3 g of 3-(4ethoxycarbonylpiperazinyl)-methyleneamino/rifamycin S (90) in 20 ml of tetrahydrofuran is treated with ammonia gas. Customary processing yields the title compound (67), which is identical to the product of Example 67.

EXAMPLE 105 4-(4-Phenylpiperazinyl)-imidazolo[4,5-c] rifa mycin SV (52) In a manner analogous to that described in Example 6 a solution of 0.5 g of 3-(4phenylpiperazinyl)-methyleneamino/rifamycin S (91) in 30 ml of tetrahydrofuran is treated with ammonia gas. Customary processing yields the title compound (52), which is identical to the product of Example 52.

EXAMPLE 106 4-Morpholino-imidazolo[4,5-c]rifamycin SV (2) In a manner analogous to that described in Example 2, 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of tetrahydrofuran are reacted with 4.0 g of tris-morpholino-methane. By working up according to Example 2, the title compound (2) is obtained in the form of yellow platelet crystals, melting point 192193 (from ether).

The tris-morpholino-methane used as reagent is obtained in the following manner: A mixture of 1 5 g of morpholine and 1 5 g of N,N-dimethylformamide-dimethylacetal is heated for 12 hours under reflux with the exclusion of moisture. Afterwards, all constituents that are volatile in a water jet vacuum up to 1300 are removed from the reaction mixture by distillation and the remaining brown oily residue, which quickly starts to crystallise, is stirred with a mixture of ether with a small proportion of petroleum ether and washed. The resulting white crystals (18 g) of tris-morpholinomethane melt at 241243 after recrystallisation from chloroform/ether. Calculated for C13H23N303 (m.w. 271.36): 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-c]rifamycin SV(1) In a manner analogous to that described in Example 1,4.0 g of 3-amino-4-iminorifamycin S in 40 ml of tetrahydrofuran are reacted with tris-dimethylamino-methane (4.0 g) and further processed. The resulting product, melting point 180-185 , is identical to 4-dimehylamino-imidazolo[4,5-c]rifamycin SV (1) according to Example 1. ln an analogous manner, using tris-diethylamino-methane, 4 diethylaminoimidazolo[4,5-c]rifamycin SV (6), which is identical to the product of Example 6, is obtained.

EXAMPLE 108 4-(4-Aza-tricyclo[5,2,2,026]-undec-8-en-4-yl)-imidazolo[4,5-c]rifamycin SV (93) In a manner analogous to that described in Example 1, there is produced from 4 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4 g of 4-formyl-4-aza-tricyclo[5,2,2,02,6]-undec-8-ene- dimethylacetal the title compound (93) (C48H60N40", m.w. = 868).

The manufacture of the 4-formyl-4-aza-tricyclo[5,2,2,02,8]-undec-8-ene-dimethylacetal required as reagent is described in Example 92.

EXAMPLE 109 4-[4-(2-Hydroxy-2-methylpropyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (94) in a manner analogous to that described in Example 1. there is produced from 2.0g of 3-amino-4iminorifamycin S in 100 ml of THF and 5.2 g of 1-formyl-4-(2-hydroxy-2-methylpropyl)-piperazinedimethylacetal 0.5 g of the title compound (94) (C46H63N5Or2, m.w. = 877).

The 1 -formyl-4-(2-hydroxy-2-methylpropyl)-piperazine-dimethylacetal (boiling point 86-900A torr) required as reagent is obtained in an analogous manner to that described in Example 80 from 30 g of N-(2-trimethylsilyloxy-2-methylpropyl)-piperazine and 50 g of N,N-dimethylformamidedimethylacetal.

EXAMPLE 110 4-[4-(2,2-Dimethyl-1 ,3-dioxolan-4-ylmethyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV (95) In a manner analogous to that described in Example 1.there is produced from 4 g of 3-amino-4iminorifamycin Sin 50 ml of THF and 4 g of 1-formyl-4-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)- piperazine-dimethylacetal the title compound (95) (C4aH6sNsO13, m.w. = 919). M.w. found: 919.

The 1-formyl-4-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-piperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 10 g of N-4-(2,2dimethyl-1 ,3-dioxolan-4-ylmethyl)-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 111 4-(4-Cyclobutylmethyl-piperazinyl)-imidazolo[4,5-c]rifamycin SV (96) In a manner analogous to that described in Example 1, there is produced from 4 g of 3-amino-4- iminorifamycin Sin 50 ml of THF and 4 g of 1-formyl-4-cyclobutylmethylpiperazine-dimethylacetal the title compound (96) (C47H63NsO11, m.w. = 873).

The 1-formyl-4-cyclobutylmethylpiperazine-dimethylacetal required as reagent is obtained in a manner analogous to that described in Example 82 from 10 g of N-cyclobutylmethyl-piperazine and 20 g of N,N-dimethylformamide-dimethylacetal.

EXAMPLE 112 Formation of salts with bases 20.0 ml of a 1 N aqueous sodium hydroxide solution (0.987 equivalent) are added dropwise to a suspension, stirred under nitrogen, of 15.50 g of 4-dimethylamino-imidazolo[4,5-c]rifamycin SV (1) in 1 50 ml of water. The resulting yellow solution is filtered and the filtrate is freeze-dried. The 4 dimethylamino-imidazolo[4,5c]-rifamycin SV sodium salt left is an amorphous powder which dissolves in water to give a clear solution; the solution has a pH of approximately 7.3. Calculated for C40Hs1N4ollNa (m.w. 786.85): 2.92: Na; found: 2.87% Na.

In an analogous manner, the potassium salt of the compound (1) is obtained using a corresponding potassium hydroxide solution.

In an analogous manner, imidazolorifamycins of the SV series (formula IA) that have an acid reaction can generally be processed to corresponding salts.

EXAMPLE 113 Formation of acid addition salts 10.0 ml of 1 N aqueous hydrochloric acid (0.985 equivalent) are added to a stirred suspension of 8.75 g of 4-(4-isobutylpiperainyl)-imidazol[4,5-c]rifamycin SV (4) in 1 65 ml of water. The mixture is filtered and the filtrate is freeze-dred. The resulting 4-(4-isobutylpiperazinyl)-imidazolo[4,5-c]rifamycin SV hydrochloride forms a water-soluble yellow amorphous powder. Calculated for C46H63NsO1l.HCi (m.w. 898.489): 3.95% Cl, found: 4.08% Cl.

Hydrochlorides of imidazolo[4,5-c]rifamycins having a basic reaction can generally be produced in an analogous manner. The process can also be used in an analogous manner for the manufacture of addition salts of other water-soluble acids.

EXAMPLE 114 Capsules containing 0.25 g of the active substance are produced as follows: Composition (for 1000 capsules): active substance 250.0 g corn starch 50.0 g polyvinylpyrrolidone 15.0 g magnesium stearate 5.0 g ethanol q.s.

The active substance and the corn starch are mixed together and moistened with a solution of the polyvinylpyrrolidone in 50 g of ethanol. The moist mass is forced through a sieve having a mesh width of 3 mm and dried at 45 . The dry granulate is passed through a sieve having a mesh width of 1 mm and mixed with 5 g of magnesium stearate. The mixture is introduced in 0.320 g portions into size 0 dry-filled capsules.

EXAMPLE 115 Tablets containing 250 mg of the active substance are produced as follows: Composition (for 1 tablet): active substance 250 mg microcrystaliine cellulose 80 mg sodium carboxymethyl starch 10 mg magnesium stearate 3 mg talc 7 mg 350 mg The active substance is mixed homogeneously with the additives and pressed to form tablets.

For the manufacture of fiim-coated dragées, the tablets are each coated with 1 mg of aqueous lacquer.

Instead of sodium carboxymethyl starch, it is possible to use sodium carboxymethylcellulose.

EXAMPLE 116 Dry-filled capsules containing 100 mg of the active substance are manufactured as follows: Composition (for 1000 capsules): active substance 100.00 g lactose 50.00 g ethylcellulose 1.50 g stearic acid 1.50 g 153.00 g The active substance is mixed with the lactose and the resulting mixture is moistened with a solution of ethylcellulose in 10 times its amount by weight of methylene chloride, beaten through a sieve having a mesh width of 3-5 mm and dried at a temperature not exceeding 400. The dry granulate is beaten through a sieve having a mesh width of 0.5 mm and mixed with the pulverulent stearic acid. The mixture is then introduced in 0.153 g portions into size 2 dry-filled capsules.

Any of compounds (1 )-(77), (93)-(96) and also (78)(92) may be used as active substance in Examples 114-11 6. Especially preferred as active substance are compounds (1), (2), (3), (4), (10), (12), (19), (21) and (57), and also (82).

EXAMPLE 117 Dry ampoules of phials containing 500 mg of the active substance can be produced as follows: Composition: (for 1 ampoule or phial): active substance 0.5 g mannitol 0.05 g water Under aseptic conditions, a sterile aqueous solution of the active substance and the mannitol are sealed in 5 ml ampoules or 5 ml phials and tested.

An alkali metal metal salt, for example such as in Example 112, is used as active substance.

EXAMPLE 118 Test evaluation 1. Tested compounds are identified in the following Tables 1 and 2 by the same numbers under which their manufacture was described in the above Examples.

2. Tested organisms are given in the following Tables 1 and 2 in a form abbreviated in the following manner: Staphylococcus aureus 1 0B Staph.lOB Staphylococcus aureus 2999 Staph. 2999 Escherichia coli205 Esch 205 Escherichia colt 201 8 Esch 2018 Salmonella Typhimurium 277 Salm. 277 Proteus morganii 2359 Prot. 2359 Proteus organic 1 518 Prot. 1 518 Pseudomonas aeruginosa K 799/61 Pseu. 799 Mycobacterium tuberculosis Myc. tub.

3. Methodology The antibiotic activity of the test compounds in vitro was determined by the agar dilution method according to Ericsson. H.M. and Sherris, S.C., 1971, Acta Path. Microb. Scand. Section B, Suppl. No.

217, vol. 1-90, in DST Agara. The observed minimum concentrations still inhibiting the growth of the test organisms (MIC = minimum inhibiting concentration) are given in micrograms per millilitre (,ug/ml) for the tested compounds in Table 1.

TABLE 1 Antibiotic activity of the imidazolo[4,5-c]rifamycins

-@@@@@@@@@@@@@@@@@ no. 10B 2999 205 2018 277 2359 1518 799 tub.

1 0.005 0.005 8 4 16 8 4 2 0.97 2 0.01 0.005 16 16 32 4 4 8 1.9 3 0.01 0.01 16 16 32 16 16 4 0.97 4 0.005 0.005 4 4 8 4 4 8 0.97 5 0.005 0.005 4 4 8 16 8 16 1.9 6 - - 128 128 128 128 128 128 - 7 0.005 0.005 8 8 16 8 8 8 - 8 0.0( 0.01 8 8 32 8 8 8, - 9 - - 8 8 32 8 1 8 10 0.005 0.005 4 4 16 4 4 8 11 0.01 0.01 8 8 32 8 2 8 12 0.001 0.001 8 8 32 8 1 8 13 0.05 0.05 8 8 32 16 16 8 14 0.05 0.01 8 16 32 16 16 16 15 0.005 0.005 8 8 32 4 8 16 16 0.01 0.01 8 8 32 4 2 8 17 0.005 0.005 32 64 64 32 64 64 18 0.005 0.005 2 4 16 2 4 8 0.48 19 0.005 0.005 2 4 8 4 4 8 0.48 20 - - 8 8 32 8 4 16 21 0.005 0.005 4 4 16 4 4 16 22 0.005 0.005 16 8 32 4 4 16 23 0.1 0.1 16 8 16 16 16 16 - 24 0;;05 0.01 6 8 4 16 4 8 16 - 25 0.005 0,005 8 16 16 8 8 16 0.97 26 0.05 0.01 16 32 84 16 16 16 - 27 0.001 0.001 8 8 32 8 2 8 - 28 0.005 0.005 4 4 16 2 2 8 0.97 29 - - 32 32 128 8 8 8 - 30 - - 8 8 32 8 8 32 31 0.002 0.001 8 8 32 8 8 8 32 0.001 0.001 8 8 32 8 8 8 - 33 0.001 0.001 8 2 32 4 4 32- TABLE 1 (Continued)

Comp. Staph. Staph Esch. Esch. Salm. Prot. Prot. Pseu. Myc.

no. lOB 2999 205 2018 277 2359 1518 799 tub.

34 - - 8 2 32 8 8 32 - 35 - - 8 8 32 8 8 8 36 - - 8 8 32 8 8 8 38 0.005 0.005 4 2 16 2 4 16 - 39 - - 8 8 32 8 8 32 40 0.005 0.005 8 8 32 8 8 16 - 41 0.005 - 8 2 - 8 8 32 42 0.005 - 8 8 32 8 8 32 - 43 0.01 0.005 8 4 32 8 8 16 - 44 - - 8 8 32 8 8 32 45 0.01 0.005 8 1 32 8 8 32 - 46 - - 32 8 32 8 8 32 47 0.005 0.005 8 4 16 4 4 32 - 48 0.001 0.001 32 8 32 8 8 32 - 49 0.001 0.001 8 32 32 8 8 8 - 50 0.01 0.01 8 8 32 8 8 8 - 51 0.01 - 8 32 32 8 8 8 52 - - 32 8 32 8 8 32 53 0.01 0.01 8 8 32 8 2 32 - 54 0.005 0.n05 8 8 32 8 8 16 55 0.01 0.001 8 1 32 2 2 32 - 56 0.005 - 8 8 32 8 8 32 - 57 0.005 0.005 8 4 16 4 4 16 0.97 58 0.005 0.005 16 3a 32 16 16 16 - 59 0.01 0.01 8 8 32 8 2 8 - 60 0.02 0.02 32 32 128 32 32 64 - 61 0.005 0.005 16 4 32 4 4 32 62 0.02 0.02 32 32 128 8 8 32 - 63 0.01 0.01 16 8 32 8 8 32 - 64 0.01 0.005 16 16 64 16 16 16 - 65 0.05 0.01 32 32 128 32 32 32 - 66 0.01 0.01 16 16 128 16 16 32 - 67 0.005 0.005 16 16 64 16 16 32 - 68 0.01 - 32 32 32 32 8 8 TABLE 1 (Continued)

Comp. Staph. Staph. Esch. Esch. Salm. Prot. Prot. Pseu. Myc.

no. 10B 2999 205 2018 277 2359 1518 799 tub.

69 0.05 0.05 32 32 128 32 32 128 70 0.02 0.02 32 32 128 32 32 128 - 71 0.02 0.02 32 32 128 32 32 128 - 72 0.05 0.05 32 32 128 32 32 64 - 73 0.05 0.05 128 128 128 32 32 128 74 0.5 0.5 128 32 128 32 32 128 - 75 0.01 - 8 8 32 8 2 32 - 76 0.01 0.01 32 8 32 8 8 32 - 77 0.01 0.01 8 8 32 8 8 8, - - = not tested TABLE 2 Antibiotic activity of the rifamycin fomamidines

Comp. Staph. Staph. Esch. Esch. Salm. Ptot. Prot. Peseu. Myc.

ho. 10B 2999 205 2018 277 2354 1518 799 tub.

78 0.05 0.05 16 16 16 16 4 4 0.00045 79 0.05 0.05 32 64 32 16 16 16 0.0037 80 - 0.005 64 64 64 16 32 64 0.0075 81 0.005 0.005 16 16 8 4 4 16 0.00022 82 0.005 0.01 16 16 16 16 8 8 4 16 0.0037 84 128 0.05 64 32 64 16 16 64 - 85 - 0.005 64 128 32 16 32 64 86 0.05 0.05 4 4 4 16 4 4 - 87 0.005 0.005 64 64 64 16 32 32 - 88 0,005 0.005 16 16 16 64 4 8 0.015 89 0.05 0.1 64 64 64 64 16 0.03 90 0.01 0.05 128 64 128 16 16 16 91 0,005 0.05 16 32 16 16 16 16 0.00045 92 128 0.005 64 16 64 16 16 0.0018

Claims

1. A 4-aminoimidazolo[4,5-c]rifamycin SV or S of the formula

in which R represents hydrogen or acetyl and Am represents an amino group derived from a secondary amine and salts of corresponding compounds with salt-forming properties.

2. A 4-aminoimidazolo[4,5-cjrifamycin SV or S according to claim 1 in which the symbol Am in the formula IA and IB represents an amino group which carries two identical or different, monovalent, optionally substituted hydrocarbyl or heterocyclyl radicals having a maximum of 20 carbon atoms, or a corresponding diva lent radical which forms with the amino group a non-aromatic nitrogen-containing heterocyclyl radical.

3. A 4-aminoimidazolo[4,5-c]rifamycin SV or S according to claim 1 in which in the formula IA and IB Am is characterised by the partial formula

in which each of R' and R2, independently of one another, represents a lower alkyl or lower alkenyl radical which may be substituted one or more times by hydroxy, mercapto, lower alkoxy, lower alkoxycarbonyl, an unsubstituted or N-mono- or -di-substituted carbamoyl, formyl, oxo, acetalised or ketalised oxo and/or by a di-substituted amino group; a lower alkynyl; a cycloalkyl or cycloalkyl-lower alkyl radical which may optionally have one or two double bonds; an unsubstituted phenyl or phenyllower alkyl radical, or phenyl or phenyl-lower alkyl substituted by halogen, hydroxy, trifluoromethyl, an unsubstituted or N-mono- or -di-substituted carbamoyl or lower alkoxycarbonyl; or an at most bicyclic heterocyclyl or heterocyclylalkyl radical having a maximum of two hetero atoms selected from oxygen, nitrogen and/or sulphur, wherein R' and R2 may be bonded with one another by a single carbon-carbon bond or by way of an oxygen, sulphur(ll) or optionally substituted nitrogen atom and may form together with the amino nitrogen atom a 4-to 8-membered non-aromatic heterocyclic ring.

4. A 4-aminoimidazolo[4,5-c]rifamycin SV or S according to claim 1 or 2 in which the symbol Am represents a radical of the partial formula

in which each of m and n, independently of one another, represents an integer of from 1 to 5, an at least 5-membered ring being formed, and RN represents a hydrogen atom, a formyl group, a functionally modified carboxy group or an unsubstituted or substituted hydrocarbyl or heterocyclyl radical containing a maximum of 10 carbon atoms, wherein in the case of the heterocyclyl radical the free valency in each case originates from a carbon atom.

5. A 4-aminoimidazolo[4,5-c]rifamycin SV or S according to claim 4 in which the symbol Am represents a 1 -piperazinyl radical of the formula

in which R3 represents hydrogen or a lower alkyl or lower alkenyl radical which may be substituted one or more times by hydroxy, mercapto, lower alkoxy, lower alkoxycarbonyl, an optionally N-mono- or -di substituted carbamoyl, formyl, oxo, acetalised or ketalised oxo and/or by a di-substituted amino group, a lower alkynyl, a cycloalkyl or cycloalkyl-lower alkyl radical which may optionally have one or two double bonds, an unsubstituted phenyl or phenyl-lower alkyl radical, or phenyl or phenyl-lower alkyl substituted one or more times by halogen, hydroxy, trifluoromethyl, an optionally N-mono- or -di-substituted carbamoyl or lower alkoxycarbonyl, or represents an at most bicyclic heterocyclyl or heterocyclyl-alkyl having a maximum of two hetero atoms selected from oxygen, nitrogen and/or sulphur.

6. A 4-aminoimidazolo[4,5-c]rifamycin SV or S according to claim 5 in which the symbol R3 in the partial formula Amc represents a straight-chain or singly branched lower alkyl, lower alkenyl or lower alkynyl radical.

7. A 4-aminoimidazolo[4,5-c]rifamycin SV or S according to claim 5 in which the symbol R3 in the partial formula Amc represents cycloalkyl or cycloalkylmethyl having from 3 to 6 ring members, or represents a phenyl or benzyl radical which may be substituted by trifluoromethyl, carbamoyl or lower alkoxycarbonyl.

8. A 4-aminoimidazolo[4,5-cjrifamycin SV or S according to claim 3 in which each of the symbols R' and R2 in the radical AmA represents an unsubstituted alkyl radical having from 1 to 4 carbon atoms, or one of them represents a cycloalkyl radical or a cycloalkylmethyl radical having from 3 to 6 ring members, or benzyl.

9. A 4-aminoimidazolo[4,5-c]rifamycin SV or S according to claim 3 in which the symbols R' and R2 in the radical AmA represent together with the nitrogen atom a saturated, monocyclic heterocyclyl radical containing from 5-8 ring members, which may also contain an oxygen or sulphur(ll) atom as ring member, the hetero atoms being separated from the nitrogen atom by at least one carbon atom.

10. A compound according to any one of claims 1-9 in the form of the hydroquinone of the SV series.

11. 4-Dimethylamino-imidazolo[4,5-c]rifamycin SV.

12. 4-Morpholino-imidazolo[4,5-c]rifamycin SV.

1 3. 4-(4-Methylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

14. 4-(4-lsobutylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

1 5. 4-(4-CycloheXylmethyl-piperazinyl)-imidazolo[4,5-c]rifamycin SV.

1 6. 4-Diethylamino-imidazolo[4,5-c]rifamycin SV.

1 7. 4-Dipropylamino-imidazolo[4,5-c]rifamycin SV.

1 8. 4-(N-lsopropyl-N-methylamino)-imidazolo[4,5-c]rifamycin SV.

1 9. 4-(N-Butyl-N-methylamino)-imidazolo[4,5-c]rifamycin SV.

20. 4-(N-Cyclopentyl-N-me thylamino)-imidazolo [4, 5-c] rifa mycin SV.

21. 4-( N-Cyclopropyl methyl-N-propyla mino)-i midazolo|4,5-c] rifamycin SV.

22. 4-(N-Benzyl-N-methylamino)-imidazolo[4,5-cjrifamycin SV.

23. 4-[N-Methyl-N-( 1 -methyl-4-piperidyl)-amino]-im idazolo [4,5-c] rifa mycin SV.

24. N-[N-Ethyl-N-(2-hydroxyethyl)-amino]-imidazolo[4,5-c]rifamycin SV.

25. 4-[N-(2,2-Dimethoxyethyl)-N-methylamino]-imidazolo[4,5-c]rifamycin SV.

26. 4-[N-Di-(2-methoxyethyl)-a mino]-im idazolo[4,5-c] rifa mycin SV.

27. 4-[N-Methyl-N-(2-dimethylaminoethyl)-amino]-imidazolo[4,5-c]rifamycin SV.

28. 4-[N-Ethyl-N-(2-diethylaminoethyl)-amino]-imidazolo[4,5-cjrifamycin SV.

29. 4-Pyrrolidinyl-imidazolo[4,5-c] rifa mycin SV.

30. 3-lndolinyl-imidazolo[4,5-c]rifamycin SV.

31. 4-Piperidino-imidazolo[4,5-c]rifamycin SV.

32. 4-(4-Ethoxycarbonyl-1 -piperidyl)-imidazolo[4,5-c]rifamycin SV.

33. 4-(4-Dimethylamino- 1 -piperidyl)-imidazolo[4,5-c]rifamycin SV.

34,4-(4-Piperidino-1-piperidyl)-imidazolo[4,5-c]rifamycin SV.

35. 4-[8-Aza- 1 4-dioxaspipiro-(4,5)-8-decyl]-imidazolo[4,5-c]rifamycin SV.

36,4-(3-Diethylaminocarbonyl-1-piuperidyl)-imidazolo[4,5-c]rifamycin SV.

37. 4-( 1 -Perhydroazepinyl)-imidazolo[4,5-c]rifa mycin SV.

38. 4-( 1 -Perhydroazocinyl)-imidazolo[4,5-c]rifamycin SV.

39,4-(2,6-Dimethyl-morpholino)-imidazolo[4,5-c]rifamycin SV.

40. 4-Thiomorpholino-imidazolo[4,5-c]rifa mycin SV.

41. 4-(4-Ethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

42. 4-(4-Propylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

43. 4-(4-Butylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

44. 4-(4-Pentylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

45. 4-(4-Hexylpiperazinyl)-imidazolo[4,5-c] rifa mycin SV.

46. 4-(4-Heptylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

47.4-[4-(1-Methylpropyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

48.4-[4-(2-Methylbutyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

49.4-[4-(2-Methylpentyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

50.4-[4-(3-Methylbutyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

51. 4-[4-( 1 -Ethylpropyl)-piperazinylj-imidazolo[4,5-cjrifamycin SV.

52.4-[4-(3-Methylentyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

53.4-[4-(1,3-Dimethylpropyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

54. 4-(4-Allylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

55.4-[4-(3-Butenyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

56.4-[4-(2-Methyl-2-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

57.4-[4-2-Ethyl-2-butenyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

58,4-[4-(2,3-Dimethyl-2-butenyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

59.4-(4-Propargylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

60.4-(4-Cyclopentylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

61. 4-(4-Cyclohexylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

62. 4-(4-Phenylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

63.4-[3-(3-Trifluoromethylphenyl)-piperazinyl]-im idazolo[4,5-c] rifa mycin SV.

64.4-(4-Cyclpopropylmethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

65.4-(4-Cyclopentylmethy;piperazinyl)-imidazolo[4,5-c]rifamycin SV.

66.4-(4-Cyclopentylmethy;piperazinyl)-imidazolo[4,5-c]rifamycin SV.

67. 4-(4-Benzylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

68. 4-[4-(2-M ethyl-3-phenyl-propyl)-piperazinyl]-im idazolo[4,5-c] rifamycin SV.

69. 4-[4A2-Pyddyl)-piperazinyl]Dimidazolo[4,5-c]rifamycin SV.

70.4-[4-(2-Pyridylmethyl)-Piperazinyl]-imidazolo[4,5-c]rifamycin SV.

71.4-[4-(2-Tetrahydrofurylmethyl)-Piperazinyl]-imidazolo[4,5-c]rifamycin SV.

72.4-[4-[2-(1,3-Dioxolan-2-yl)-ethyl]-Piperazinyl]-imidazolo[4,5-c]rifamycin SV.

73.4-[4-(2-Methoxyethyl)-Piperazinyl]-imidazolo[4,5-c]rifamycin SV.

74. 4[4-(2-Ethoxyethyl)-piperazinyl]-imidazolo[4,5-c]rifamycin SV.

75.4-[4-(2,2-Dimethoxyethyl)-Piperazinyl]-imidazolo[4,5-c]rifamycin SV.

76. 4-[4-(2,2-Diethoxyethyl)-piperazinyl]-imidazolo [4,5-c] rifa mycin SV.

77.4-(4-Ethoxycarbonylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

78.4-(4-isopropoxycarbonylPiperazinyl)-imidazolo[4,5-c]rifamycin SV.p

79.4-[4-(2-Dimethylaminoethyl)-Piperazinyl]-imidazolo[4,5-c]rifamycin SV.

80.4-(4-isobutyrylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

81.4-(4-MethoxycarbonylmethylPiperazinyl)-imidazolo[4,5-c]rifamycin SV.

82.4-(4-isopropylcarbamoylmethylpiperazinyl)-imidazolo[4,5-c]rifamycin SV.

83.4-(4-MorpholinocarbonylmethylPiperazinyl)-imidazolo[4,5-c]rifamycin SV.

84.4-(4-(1-methyl-2-dimethylaminoethyl)-Piperazinyl]-imidazolo[4,5-c]rifamycin SV.

85.4-(4-lsobutyl-2-methylPiperazinyl)-imidazolo[4,5-c]rifamycin SV.

86.4-(4-lsobutyul-2,5-dimethylPiperazinyl)-imidazolo[4,5-c]rifamycin SV.

87. 4-(4-lsobutyl-perhydro- 1 ,4-diazepinyl)-imidazolo[4,5-c] rifa mycin SV.

88. Sodium salt of 4-dimethylaminoimidazolo[4,5-c]rifamycin SV.

89. 4-(4-Aza-tricyclo[5,2,2,02,6] undec-8-en-4-yl)-imidazolo[4,5-c] rifa mycin SV.

90.4-[4-(2-Hydroxy-2-mèthylpropyl)-Piperazinyl]-imidazolo[4,5-c]rifamycin SV. rifa mycin SV.

91.4-[4-(2,2-Dimethyl-1,3-dioxolan-4-ylmethyl)-Piperazinyl]-imidazolo[4,5-c]rifamycin SV.

92.4-(4-Cyclobutyimethyl-Piperazinyl)-imidazolo[4,5-c]rifamycin SV.

93. A 4-aminoimidazolo[4,5-c]rifamycin SV or S according to any one of claims 1-92 as an antibiotic.

94. Process for the manufacture of a 4-aminoimidazolo[4,5-cjrifamycin SV or S of the formula IA or IB defined in claim 1, characterised in that a) a 3-aminorifamycin-S-4-imine of the formula

in which R has the meaning given in claim 1, is reacted with a reactive derivative of an N,N-disubstituted formamide or thioformamide of the formula Am-CH=Y (III) in which Y represents oxygen or sulphur and Am has the meaning given in claim 1, or b) an N',N'-di-substituted 3-aminomethyleneaminorifamycin derivative of the formula

in which R and Am have the meanings given in claim 1, is treated with ammonia and, if desired, a resulting compound of the SV type is oxidised to a compound of the S type or a resulting compound of the S type is reduced to a compound of the SV type and/or a resulting free compound with salt-forming properties is converted into a corresponding salt or a resulting salt is converted into the coriesponding free compound.

95. Process for the manufacture of a 4-aminoimidazolo[4,5-c]rifamycin SV or S of the formula IA or IB defined in claim 1, characterised in that a 3-aminorifamycin S compound of the formula

in which R has the meaning given in claim 1, or a salt thereof its reacted in any sequence a) with ammonia and b) with a reactive derivative of an N,N-di-substituted formamide or thioformamide of the formula Am-CH=Y (Ill), in which Y represents oxygen or sulphur and Am has the meaning given in claim 1, and, if desired, a resulting compound of the SV type is oxidised to a compound of the S type, or a resulting compound of the S type is reduced to a compound of the SV type and/or a resulting free compound with salt-forming properties is converted into a corresponding salt or a resulting salt is converted into the corresponding free compound.

96. Process according to claim 94 or 95 characterised in that a starting material is formed under the reaction conditions or is used in the form of a salt.

97. A pharmaceutical preparation containing at least one compound of the formula I according to any one of claims 1-92 as active substance.

98. Process for the manufacture of a pharmaceutical preparation according to claim 97, characterised in that a compound of the formula I according to any one of claims 1-92 is processed by non-chemical methods with at least one pharmaceutically suitable carrier.

99. Use of a compound of the formula I according to any one of claims 1-92 as such or in the form of a pharmaceutical preparation according to claim 97, for combating microbial infections.

100. Therapeutic method for combating infections in a warm-blooded animal that is infected with a microorganism sensitive to at least one of the rifamycin derivatives of the formula I, which method is characterised by the treatment of this microorganism or a medium infected by this microorganism with an antimicrobially active dosage of a rifamycin derivative of the formula I according to any one of claims 1-92.

101. Therapeutic method according to claim 100 for combating infections in humans.

102. A formamidine of the formula RiF=CH--Am (Vll) in which Am represents an amino group derived from a secondary amine and Rif represents a diva lent 3-aminorifamycin radical of the formula

in which R represents hydrogen or acetyl, and corresponding salts of such a compound with saltforming properties.

103. A formamidine according to claim 102 in which the symbol Am has one of the meanings given in claims 2-9.

104. A formamidine according to claim 102 or 103 in the quinone form corresponding to the radical Rif(S).

105. 3-Dimethylaminomethyleneamino/rifamycin S.

106. 3-Diethylaminomethyleneamino/rifamycin S.

107. 3-(N-Benzyl-N-methylamino)-methyleneamin S.

108. 3-Pyrrolidinylmethyleneamino/rifamycin S.

109. 3-lndolinylmethyleneamino/rifamycin S.

110. 3-Piperidinomethyleneamino/rifamycin S.

111.3-(4-Methylpiperidinyl)-methyleneamino/rifamycin S.

11 2. 3-(8-Aza-1 ,4-dioxa-spiro[4,5]dec-8-yl)methyleneamino/rifamycin S.

113. 3-Morpholinylmethyleneamino/rifamycin S.

114. 3-Thiomorpholinylmethyleneamino/rifamycin S.

11 5. 3-(4-Methylpiperazinyl)-methyleneamino/rifamycin S.

11 6. 3-[4-(2-Ethyl-2-butenyl)-piperazinyl]-methyleneamino/rifamycin S.

11 7. 3-(4-Ethoxycarbonylpiperazinyl)-methyleneamino/rifamycin S.

11 8. 3-(4-Phenylpiperazinyl)-methyleneamino/rifa mycin S.

11 9. 3-(4-Aza-tricyclo[5.2,2,02,6]undec-8-en-4-yl)-methyleneaminofrifamycin S.

120. A formamidine according to any one of claims 1 02-11 9 as an antibiotic.

121. Process for the manufacture of a formamidine of the formula VII defined in claim 102, characterised in that a 3-aminorifamycin compound of the formula Rif=H2, in which Rif has the meaning given in claim 102, is reacted with a reactive derivative of an N,N-disubstituted formamide or thioformamide of the formula Am-CH=Y (Ill), in which Y represents oxygen or sulphur and Am has the meaning defined in claim 102, and, if desired, a resulting compound of the S type is reduced to a compound of the SV type or a resulting compound of the SV type is oxidised to a compound of the S type and/or a resulting free compound with salt-forming properties is converted into a corresponding salt or a resulting salt is converted into the corresponding free compound.

122. Process according to claim 121, characterised in that a starting material is used in the form of one of its salts.

123. A pharmaceutical preparation containing as active substance at least one formamidine of the formula VII according to any one of claims 102-120.

124. Process for the manufacture of a pharmaceutical preparation according to claim 123, characterised in that a compound of the formula VII according to any one of claims 102-120 is processed by non-chemical methods with at least one pharmaceutically suitable carrier.

125. Use of a compound of the formula VII according to any one of claims 102-120, as such or in the form of a pharmaceutical preparation according to claim 123, for combating microbial infections.

126. Therapeutic method for combating infections in a warm-blooded animal that is infected with a microorganism sensitive to at least one of the rifamycin derivatives of the formula VII which method is characterised by the treatment of this microorganism or a medium infected by this microorganism with an antimicrobially active dosage of a rifamycin derivative of the formula VI according to any one of claims 102-120.

127. Therapeutic method according to claim 126 for combating infections in humans.

128. A compound of formula IA or IB according to claim 1 substantially as described with reference to any of Examples 1 to 77 and 94 to 113.

129. A process for producing a compound of formula IA or IB substantially as described with reference to any of Examples 1 to 77 and 94 to 113.

130. A compound of formula IA or IB when produced by a process claimed in any of claims 94 to 96 and 129.

131. A pharmaceutical preparation according to claim 97 substantially as described with reference to any of Examples 114 to 117.

132. A compound of formula VII according to claim 102 substantially as described with reference to any of Examples 78 to 93.

1 33. A process for the production of a compound of formula VII substantially as described with reference to any of Examples 78 to 93.

134. A compound of formula VII when produced by a process claimed in any of claims 121-122 or 133.