DD204925A5 - PROCESS FOR PREPARING A 4-AMINOIMIDAZOLO (4,5-C) RIFAMYCIN SV OR S - Google Patents

Abstract

The invention relates to a process for the preparation of a 4-aminoimidazolo (4,5-c) rifamycin SV or S with valuable pharmacological, in particular antibiotic and antibacterial properties for the control of infectious diseases. The aim of the invention is the provision of novel highly potent antibiotics with a wide range of uses. According to the invention, 4-aminoimidazoles (4,5-c) rifamycins SV or S of the formula wherein R is hydrogen or acetyl and Am is a secondary amine-derived amino group and salts of corresponding compounds having salt-forming properties are prepared.

Description

? 47i "oö y - / -

Berlin, 30.3.1983 Excretion from AP C 07 D / 233 440 (59 781/18) 61 589/18

A process for the preparation of a 4-aminoimidazolo Γ4> 5-ο1 rifamycins SV or S

Field of application of the invention

The invention relates to a process for the preparation of a 4-aminoimidazolo [4,5-cifrifamycins SV or S of the formulas mentioned below.

Characteristic of the known technical solutions

In addition, information is available on which compounds have hitherto been used to combat bacterial or cocci-induced infection,

There are no data available on processes for preparing 2-aminoimidazoles.

the invention;

The aim of the invention is the Already division of novel highly effective antibiotics with a wide range of applications ·

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation,

The invention now relates to a process for the preparation of novel 2-amino imidazoles, which by their atoms .. C-4 and

LLI

30.3.1.983

C-5 are fused to ring A of a rifamycin compound in the 3j4 position, in particular of JJ, Nd.isubstituierten derivatives of the 4-aminoimidazolo [^ 4 _} 5-cj- rifamycins S7 or S of the formula I, d. hV ·.

CH

CH-

CH-,

I >

OH OH

CH ₃ O / * Vh, c

i?

0- C

CH

OH

OH 1

^0H

At the

30.3.1983 61 589/18

R ι

CH, » ·

O ·

CH.

OH

CH.

OH

0 / \ "3 j GO GH OH I t I

I '

CH-

I! I II

CO "§

At the (IB)

nt.e related IT », ii'-di-substituted 3-aniino-

(3-aminor- famycin-formamide)

O-

GH,

¹ !

OH OH

OH

ii

G-co

i)

CO CH.

(YA) or

al

30.3.1983 61 589/18

R 'OH CH

I tJ f

Oh

CH

^ CH

(VB)

¹ J 1

1 I

CO OH

^;H

R is hydrogen or acetyl and Am is an amino-derived amino group, as well as salts of corresponding compounds with salt-forming properties. "

Due to the very close relationship between the 1,4-quinone and hydroquinone forms (corresponding to rifamycin S and SV) and the ease with which the two forms merge into one another, unless otherwise stated, both forms are different however, SV-Porm IA) is considered to be the preferred one.

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

* π O C Q 7 4 / ZOO / -5- 30.3.1983

61 589/18

The hydrocarbyl radical (hydrocarbyl radical) may be an acyclic carbocyclic or carbocyclic-acyclic hydrocarbon radical which preferably has at most 20 carbon atoms and may be saturated or unsaturated, unsubstituted or substituted. In the hydrocarbyl, one, two or more carbon atoms may be substituted with the Nitrogen atom of the amino group are not directly connected by heteroatoms, in particular oxygen, sulfur or nitrogen, but also phosphorus or silicon, to be replaced; a cyclic hydrocarbyl radical of this type is then specifically referred to as a heterocyclic radical (heterocyclyl).

Unsaturated radicals are those which contain one, two or more multiple bonds, such as double and triple bonds. Cyclic radicals wherein at least one 6-membered carbocyclic or 5- to 8-membered heterocyclic ring contains the maximum number of uncumulated double bonds are termed aromatic. Carbocyclic radicals wherein at least one ring is present as a 6-membered aromatic ring (i.e., benzene ring) are referred to as aryl radicals. - As bi- and polycyclic radicals such polynuclear radicals are referred to, in which two or more rings have at least one common atom and thus form a fused, bridged or spiro-bonded ring system.

Unless otherwise indicated, organic radicals designated "lower" in the present disclosure contain at most 7, preferably at most 4, carbon atoms.

Bin ^ cyclic hydrocarbon radical is in particular a

4/258 / - ^δ - 30.3.1933

* '·.' 61-589 / 18

straight or branched alkyl, alkenyl, alkadienyl or alkynyl radical, especially a lower alkyl, lower alkylene, lower alkadienyl or lower alkynyl radical. lower alkyl is 2. B. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobatyl, sec-butyl or tert-butyl, and n-pentyl, 3-pentyl, isopentyl, 2-methylbutyl, n-hexyl, isohexyl, 2-methylpentyl, 2-ethylbutyl, or n-Heptylj iJiederalkenyl is ζ. Β. Vinyl, allyl, propenyl, isopropenyl, 2- or 3-metallyl, 2- or 3-butenyl, 2-ethyl-2-butenyl and 2,3-diniethyl-2-butenyl; Haloalkynyl is ζ, B, propargyl or 2-butynyl.

A carbocyclic hydrocarbon radical is in particular a mono-, bi- or polycyclic cycloalkyl, gyeloalkenyl or cycloalkadienyl radical, or a corresponding aryl radical containing aromatic rings. Preferably, radicals having at most 12 ring carbon atoms and 3 to 8, in particular 5 and / or 6-membered rings, wherein they also have one or more acyclic radicals, for. B. can carry the above-mentioned, and in particular the Miederalkylreste, or v / urther carbocyclic radicals _o Carbocyclusch-acyclisehe radicals are those in which a aeyclischer radical, especially one with a maximum of 7, preferably a maximum of 4 carbon atoms, one or more carbocyclic, if appropriate, In particular, cycloalkyl-lower alkyl and aryl-lower alkyl radicals, as well as their unsaturated in the ring and / or side chain analogues to mention, and including especially those, which carry at most 2 rings.

Cycloalkyl is z. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, as well as 1- or 2-3-cyclo [2.2.2] octyl, 2-bi-cyclo [2.2, iheptyl 1- or 2-

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Decahydronaphthyl and 1 »or 2-adamantyl, and also 1-, 2- or 3-methylcyclopentyl, 4-tert-butylcyclohexyl, 4,4-Diraethylcyclohexyl, 2,4,6-Triniethylcychexyl and 2,4,4,6-tetra -Giethyl cyclohexyl5.Cycloalkenyl is ζ. B _{9 is} one of the already mentioned cycloalkyl radicals which carries a double bond in the 1-, 2- or 3-position, such as 1-, 2- or 3-cyclopentenyl and 1-, 2- or 3-cyclohexenyl »cycloalkyl-lower alkyl or -niederalkenyl is 2, B, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1- or -2-ethyl or, vinyl, -1-, -2- or -3-propyl or, -allyl, furthermore also Dicyclohexylmethyl and tricyclohexylmethyl; Cycloalkenyl-lower-alkyl or -niederalkenyl is, for example, 1-, 2- or 3-cyclopentenyl or 1-, 2- or 3-cyclohexenyl-methyl, -1- or 2-ethyl or -vinyl, - 1-, 2- or -3-propyl or * -allyl.

Sin aryl iat primarily a phenyl, also a JSaphthyl, such as 1- or 2-Haphthyl, ^a: partially hydrogenated Uaphthyl as inabesondere 1-, 2-, 5- or 6- (1,2,3,4-tetrahydronaphthyl .) a biphenylyl, such as in particular 4-biphenylyl, further also an anthryl, ffluorenyl and azulenyl. Preferred aryl-lower alkyl and -niederalkenyl radicals are z, 3-phenyl-lower alkyl or phenyl-lower alkenyl, such as 3. B. benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyls.Cd, h , Benzhydryl), trityl and i- or 2-naphthylmethyl, or styryl or cinnamyl,

Heterocyclic radicals, including the heterocyclic-acyclic radicals, are in particular monocyclic, but also bicyclic or polycyclic, aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaaa-, triaza- or tetrazacyclic H.este the Arociatisch. can be partially saturated or fully saturated, you can also do it in an analogous way as the above

& - OQ / -8-. 03/30/1983

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bear carbocyclic or aryl radicals, other acyclic, carbocyclic or heterocyclic radicals and be mono-, di- or polysubstituiert. The acyclic part in heterocyclic-acyclic radicals has, for example, the meaning given for the corresponding carbocyclic-acyclic radicals. In the first place, they are unsubstituted or substituted monocyclic monoaza-, monothia- or mono-. oxacyclic radicals, such as aziridinyl, oxiranyl and thiiranyl, and also azepinyl and azocinyl, and in particular heterocyclic radicals having 5 or 6 ring members, such as pyrryl, z. B »2-pyrryl or 3-pyrryl, pyridyl, ζ. 3. 2-, 3- or 4-pyridyl, further thienyl, z. 3. 2- or 3-thienyl, or furyl, z, B. 2-puryl? bicyclic monoaza-, monooxa- or monothiacyclic radicals, such as indolyl, e.g. B. 2- or 3-indolyl, ghinolinyl, z. 2- or 4-ghinolinyl, isoquinolinyl, z, B. 1-isoquinolinyl, benzofuranyl, z, B. 2- or 3-benzofuranyl, or benzothienyl, e.g. 2- or 3-benzothienyl; monocyclic diaza-, triaza-, tetraaza-, ozaza-, thiaza- or thiadiazacyclic radicals such as imidazolyl, e.g. 2-imidazolyl, pyrimidinyl, e.g. B. 2- or 4-pyrimidinyl, triazolyl, z. B. 1,2,4-triazol-3-yl, tetrazolyl, z. B. 1- or 5-ietrazolyl, Osazolyl, z. 2-ozazolyl, isoxazolyl, e.g. 3, 3- or 4-isosazolyl, thiazolyl, e.g. ^e B "2-thiazolyl, isothiazolyl, ζ. B, 3- or 4-isothiazolyl or 1,2,4- or 1 → 10-thiadiazolyl, e.g. B, 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-ylj or bicyclic diaza, oxaza- or thiaazacyclic radicals such as benzimidazolyl, e.g. B _e 2-benzimidazolyl, benzoxazolyl, e.g. B _a 2-Benzoxazolyl, or Benzothiazolyl, ζ. B. 2-3enzthiazolyl. Corresponding partially or completely saturated radicals are z. Tetrahydrothienyl such as 2-tetrahydrothienyl, dihydrofuryl such as 2,5-dihydro-2-furyl, tetrahydrofuryl, v / ie 2-tetrahydro

-9- 30.3.1983 - '61 5S9 / 18

furyl, 2- (1,3-bioxolanyl) -, tetrahydropyranyl such as 2- and 4-tetrahydropyranyl, pyrrolidyl such as 2-pyrrolidyl, tetrahydropyridyl such as Δ-, Δ- or Δ-piperidyl, or piperidyl such as 2-, 3- ^ or 4-piperidyl, which may be substituted at the IT atom, such as lower alkylated , such as ζ. Β. Η-methyl-4-piperidyl, as well as morpholinyl, thiomorpholinyl, piperazinyl and I \ r, 5T'-bis-lower alkylpiperazinyl, in particular Ι, ίΊ-dimethylpiperazinyl, and perhydroezepinyl and perhydroazocinyl. These radicals may also carry one or more acyclic, carbocyclic or heterocyclic radicals, especially the abovementioned radicals. Heterocyclic-acyclic radicals are in particular of acylic radicals having not more than 7, preferably not more than 4, carbon atoms, eg. Derived from the above, and may carry one, two or more heterocyclic radicals, z, B, those mentioned above. _E

As already mentioned, a hydrocarbyl radical (including a heterocyclyl radical) may be substituted by one, two or more identical or different substituents. The following substituents are particularly suitable: free, etherified and esterified Kydros.sup.1 L groups, mercapto and hideralkylthio and optionally substituted phenylthio groups; Halogenatoaie (such as chlorine and Pluor, but also bromine and iodine); formyl (d, h aldehydo) and keto groups, also as acetals or "ketals; 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, protected by conventional protecting groups. Amino groups (such as suitable acylamino

.7258 - / -10- 30.3.1933

~ - ^; 61 539/18

groups and diacylamino groups); further, free sulfo groups present in salicylum (such as alkali metal salt form); free and functionally modified carboxyl groups (such as in salt form or esterified carboxyl groups, optionally one or two-hydrocarbon radicals bearing carbamoyl, ureidocarbonyl or guanidinocarbonyl groups, and cyano groups); as well as optionally functionally modified sulfo groups (such as sulfamoyl or sulfo groups present in salt form) and trifluoromethyl _e

Sine as a substituent present in the hydrocarbyl etherified hydroxyl group is z. B ... a lower alkoxy group, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-But oxy group, which may also be substituted. Thus, such a lower alkoxy group can be obtained by hialogen atoms, in particular in the 2-position (as in the 2,2,2-trichloroethoxy, 2-chloroethoxy or 2-iodoethoxy radical) or by alkenalkoxy radicals, in particular in the 1-position (moreover in the 1-butoxyethoxy radical ) or in the 2-position (as in 2-methoxyethoxy-res), or by a hydroxyl group, in particular in the 2-position (as in the 2-hydroxyethoxy radical). Further, such etherified hydroxyl groups are also optionally substituted phenoxy and phenyl-lower alkoxy, such as. especially benzyloxy, Behzhydryloxy- and Triphenylmethoxy- (trityloxy) - radicals, and Heterocyclyloxyres-te, in particular 2-Tetrahydrofuranyloxy- and 2-Tetrahydrop-yranyloxyresfee. Etherified hydroxyl groups are also to be understood as meaning silylated hydroxyl groups, as are present, for example, in tri-lower alkylsilyloxy, such as trimethylsilyl-oxy- or dimethyl-tert-butylsilyloxy-, or phenyldin-alkylsilyloxybaw, lower-alkyldiphenylsilyloxy groups.

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61 589/18

An esterified hydroxyl group present as a substituent in the hydrocarbyl I is especially one in which the hydrogen atom of the hydroxyl group is replaced by an acyl radical A "e defined below. Furthermore, it may also be a lactonized hydroxyl group ";

An esterified carboxyl group present as a substituent in hydrocarbyl is one in which the hydrogen atom is replaced by one of the above-characterized hydrocarbon radicals, preferably a lower alkyl or phenyl lower alkyl radical as an example of an esterified carboxyl group, especially methoxy, lower alkoxycarbonyl groups such as ethoxy - and tert-butoxy-carbonyl group or Phenylniederalkoxycarbonylgruppen how to call the Bensyloxycarbonylgruppe, as well as a lactionisierte carboxyl Further, an esterified carboxyl group is one which is present as a silyl ester, .d, h * a .Tri- ^v hydrocarbylsilyl, such as tri-lower alkylsilyl and especially trimethylsilyl, carries »

A primary amino group -SiH ₂ ^a ^ ^s substituent of the hydrocarbyl may also be present in protected form, preferably as a corresponding acylamino group of the formula -IiE-Ac,

ATS.

wherein Ac has the meaning characterized below, "Bine secondary amino group carries, instead of one of the two hydrogen atoms, an unsubstituted hydrogen radical" as defined above; it may also be in a protected form, for example as an acylamino group derived therefrom which bears a monovalent acyl radical Ac characterized below: A tertiary amino group occurring as a substituent of the hydrocarbyl is one which, instead of having the same value, is the same or different "residues" which are unsubstituted

47

β 7 ~ ¹² ~ 30.3.1933 * · 61 589/18

Hydrocarbyl radicals correspond to one another. The two hydrocarbyl radicals may be bonded to one another by a carbon-carbon bond or an oxygen, sulfur or optionally substituted nitrogen atom and together with the nitrogen atom of the amino group form a nitrogen-containing heterocyclic radical. As an example of particularly preferred amino groups serving as a substituent of the hydrocarbyl, the following may be mentioned: di-lower alkylamino (such as dimethylamines and diethylamino), pyrrolidino, piperidino, morpholine, thiomorpholines and piperazines or 4-methylpiperazino, optionally by itfiederalkyl, lower alkoxy, halogen and / or nitro substituted diphenylamines and dibenzylaminoi among the protected, in particular halogenated, lower alkoxycarbonylamino, such as. 2,2,2 ~ trichloroethoxycarbonylamino, phenyl-lower alkoxycarbonylamino, such as 4-methoxybenzyloxycarbonylamino, and 2 - (trihydrocarbylsilyl) -ethoxycarbonylamino. as. 2-Triphenylsilylethoxycarbonyl-asoino, 2- (dibutyl-methylsilyl) -ethoxycarbonylamino and 2-trimethyl-silylethoxycarbonylamino ·

The acyl radical Ac of a carboxylic acid is the radical of a monoalkylcarboxylic or aryl-lower alkoxycarbonyl radical, or the formyl radical, or the radical of an optionally substituted acyclic, carbocyclic, carbocyclic-acyclic, heterocyclic or heterocyclic-acyclic carboxylic acid which is one of the above-defined unsubstituted or Particularly preferred are acyl radicals of the following monocarboxylic acids having at most 18 carbon atoms: acyclic carboxylic acids, in particular lower alkanecarboxylic acids, such as the propionic, butyric, isobutene, valerian-,

.4 7

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61 589/18

laovalerian, capron-, Irimethylessig-, Genanth- and methylacetic acid and especially the acetic and formic acid, but also corresponding halogenated, inabesondere chlorinated and brominated, liederalkancar bonsäuren such as chloroacetic acid, dichloroacetic acid, Broniessig- or # -Bromisovaleriansäurej carbocyclic or carbocyclische- acyclic monocarboxylic acids, z, B _e the cyclopropane, gyclobutane, cyclopentane and cyclohexane-carboxylic acid bzw.'die cyclopropane, cyelobutane, cyclopentane or cyclohexane-acetic acid or propionic acid; aromatic carbocyclic carboxylic acids, e.g. B, benzoic acid, which may be monosubstituted or polysubstituted by halogens (such as fluorine, chlorine or bromine) and / or hydroxy, lower alkyl, lower alkyl, trifluoromethyl and / or ureo; Aryl- or aryloxy-lower alkanecarboxylic acids and their chain-unsaturated analogs, eg, optionally, as indicated above for benzoic acid, .substituted phenylacetic acid, phenoxyacetic acids, phenylpropionic acids and cinnamic acids; and heterocyclic acids, z, B, E ¹ uran-2-carboxylic acid, 5-tert-butyl-furan-2-carboxylic acid, 5-bromofuran-2-carboxylic acid, thiophene-2-carboxylic acid, nicotinic or isonicotinic acid, 4-pyridinopropionic acid. and, if appropriate, by substituted alkyl radicals "substituted pyrrole-2 or 3-carboxylic acids; furthermore also entspreche4 Dov-ÖC - ..; ~ * ^A'ialAP: aäur.e ^': ny - :. ^INS: b ⁱ .e ⁱ sondere in, -the Hatur before ^ - coming amino acids of the L- Redhe, z. As glycine, phenylglycine, proline, leucine, valine, _{^{tyrosine,::.-Histidine}} and asparagine, preferably in an Η-protected form, ie in such in which the amino group by a conventional, z, as one of the above substituted referred Amlnoschutzgruppe is _e Among the carboxylic acids, such kotamen particularly contemplated wherein j; the. Ev drQ.c; arbyl even by another.

£ QI ZDO / -14- 30.3.1983

^β 61 589/18

optionally substituted functionally modified carboxyl, d "Yes. Dicarboxylic acids, preferably those containing not more than 12 carbon atoms, which are based on one of the abovementioned optionally substituted acyclic, carbocyclic, carbocyclic-acyclic, heterocyclic and heterocyclic- cyclic hydrocarbyl radicals. For example, the following dicarboxylic acids are designated 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, 1-cyclohexanedicarboxylic acid, a phthal-, quinoline optionally substituted by halogen, in particular chlorine or bromine, and / or lower alkyl, lower alkyl and Hitro - or phenyl succinic acid, as well as tartronic acid, mesoxalic acid, oxalacetic acid, malic acid, tartaric acid, an esterified to the hydroxyl groups or etherified tartaric acid, glutamic acid and aspartic acid, the latter two acids preferably with protected Aminog present. As already stated, the second carboxyl group may be present not only free but also functionally modified, Z ₉ B. as an ester with an alcohol, or as a salt, preferably as a physiologically acceptable salt, with a salt-forming basic component his. In the first place, metal or ammonium salt, such as alkali metal and alkaline earth metal, s. 3, itatrium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, these are especially tertiary monoamines and heterocyclic bases in question, for. 3. triethylamine, tri- (2-hydroxyethyl) amine, 1-Sthy! -Piperidine, and pyridine, collidine or quinoline, into consideration.

-15- 30.3.1983

61 589/18

The invention relates in particular to those rifamycin compounds of the formulas I and V, in which the amino group Am, the partial formula

1 2

in which R and R are each independently an itfiederalkyl or Mederalkenyl which is mono- or polysubstituted by hydroxyl, mercapto, ITiederalkoxyl, E-lower alkoxycarbonyl, an optionally Η-mono- or di-substituted carbamoyl, Forrnyl, oxo, acetalized, or ketalized Oxo and / or a disubstituted amino group may be substituted, a lower alkynyl, a cycloalkyl or cycloalkyl lower alkyl which may optionally have one or two double bonds, an unsubstituted or by halogen, hydroxyl, trifluoromethyl, an optionally ϊΤ-πιοηο- or -di- substituted garbamoyl or mederalkoxycarbonyl monosubstituted or polysubstituted phenyl or phenyl-lower alkyl, or at most bicyclic heterocyclyl or heterocyclylalkyl having at most sv / ei heteroatotnene selected from oxygen, nitrogen and / or sulfur

             '1 2

wherein R and R may be joined together by a simple carbon-carbon bond: or via an oxygen, sulfur (II) or optionally substituted nitrogen atom and together with the araine nitrogen atom form a 4- to 8-membered non-aromatic heterocyclic ring can,

'Lord not specifically defined differently, all terms have the. yoransj _s e.henderi. .Definition, the general and preferred meanings given at the beginning

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Ala Substituent of a saturated radical is a hydroxyl, mercapto or disubstituted amino group preferably 'from the central amino group by at least two carbon atoms, separated atoms} as substituents of an unsaturated radical, these groups are preferably on a saturated carbon atom ₀

In unsaturated non-aromatic radicals, the multiple bond is preferably on carbon atoms which are not directly attached to the central amino group,

1 2

Suitable phenyl-lower alkyl radicals in the meaning of R and R are, in particular, 1-phenylethyl and phenethyl, but especially benzyl; they may also be substituted, as indicated above, where the substituent is preferably in the p-position »

1 2

Suitable heterocyclyl radicals in the meaning of R or R are, in particular, monocyclic radicals, such as those mentioned at the outset, in particular 2- and 4-pyridyl, 2-imidazolyl, 2-benzimidazolyl, 3-indolyl and 4-quinolyl, as heterocyclyl-lower alkyl radicals Furfuryl and thenyl, and with corresponding saturated radicals z, B '' U-methyl-4-piperidyl, 4- ^f- tetrahydropyranyl, tetrahydrofuryl-2-methyl, 1,3-Mojco1-anyl-2-methyl, 2- (1, To emphasize 3-dioxolanyl-2) -ethyl and 2,2-dimethyl-1,3-dioxolanyl-4-methyl _e .

I-aromatic heterocyclic radicals in meaning of Am ,,

1 2 ^Λ which are formed by linking the radicals R and R by means of a simple GG bond, are, for example,

.1 .2 wise, the following: for the Pail, that both radicals R and R liederalkylreste (or the corresponding cycloalkyl, phenyl or heterocyclyl-bearing Uiederalkylreste), come

2 5 8 * 7 ~ ¹⁷ ~ 30.3.1983

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following residues Am. in particular: 1-azetidinyl, 1-Perhydroazepinyl, 1-perhydroazocinyl, and especially 1-pyrrolidinyl and piperidino, which also be substituted by the abovementioned substituents and / or correspondingly substituted or preferably unsubstituted alkyl, cycloalkyl, cycloalkyl-lower alkyl -, phenyl, phenyl-lower alkyl, heterocyclyl and heterocyclyl-niederaikyl radicals, wherein preferably only one such substituent and / or radical is present and the total number of carbon atoms is at most 15; in the analogous case,

1 2

wherein one of the radicals R and R is a cyclic radical, the following radicals Am. in particular: 1-indolinyl, 2-isoindolinyl, 2-and 4-azatricyclo Perhydroisoindolyl | _5,2,2,0 ^'D Jnon-8-en-4 ~ yl, soft also in an analogous manner, and preferably with analog Restriction, be substituted and / or can carry the mentioned carbon-containing radicals. Of all such radicals, the following are to be emphasized: a substituted by hydroxyl or carboxyl T-pyrrolidinyl, - by formyl, carboxyl, lower alkoxycarbonyl, carbamoyl (also ΙΤ, ϊΙ-di-lower alkylcarbamoyl such as "NjH-Diethylcarbamoyl) or oxo (als.ketalisiertes Oxo, such as ethylenedioxy) substituted piperidino wherein the substituent is preferably in the 3 or 4 position, a lower alkyl, 1-hydroxy lower alkyl or 2-hydroxy lower alkyl piperidino, the remainder being preferably in the 4-position 4-di-lower alkylaminopiperidino (such as 4-dimethyano-piperidino), 4-piperidino-piperidino, and 8-aza-1-dioxa-spiro-silyl-s-dec-a-yl (ie 4-piperidone-ethylene-ketal),

aromatic heterocyclic radicals in importance of Am,

1 2

which are formed by the linking of the radicals R and R by means of an oxygen or sulfur (U) atom, are

472

-18- 30 · 3rd-1983 61 589/18

for example, morpholines), thiomorpholines and 3-thiazolidinyl, further also. 3,5-dimethylmorpholino and 2,6-dim.ethylmorpholino. ^v

light-aromatic heterocyclic radicals in the meaning of Am ₁ ,,

12 ^Α

which are formed by linking the radicals R and R by means of an optionally substituted nitrogen atom, are those which contain 2-lower alkyl radicals

12

Derive R and R and wherein the connecting optionally

Substituted nitrogen atom carries a substituent defined as R ^N below. Such a non-aromatic heterocyclic radical is especially one of the partial formula

(Am>

where m and η are each independently an integer from 1 to 5, preferably 2 or 3, where at least 5-gües

JT

Riger is a hydrogen atom, a pormyl group, a functionally modified carboxyl group or an unsubstituted or substituted, not more than 10 C-atoms having hydrocarbyl or heterocyclyl radical

meant - The remains C "H_Ovy, and CLEL are bivalent radii eggεπί ηdx ±

kale, derived from Liederalkanen with 1-6 C-atoms, such as, in the first place ethylene, trimethylene and propylene, but also tetramethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, Bthylethylen, propylethyl ene, butyl ethylene, 1 , 2-Diethylsthy1en and 2,2-dimethyltrimethylene, as well as methylene, ethylidene, propylidene, isopropylidene, etc., but in each case

24/2 5 8 7 - ¹ 9-30.3.1983

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can only stand as one of the two radicals. A functionally modified carboxyl group in the meaning of V 1 is one of the above-defined, in particular an esterified (such as in particular in the form of a liederalkylesters) or present in the amide carboxyl group, such as in particular an unsubstituted or substituted by 1 or 2 Eiederalkylreste carbamoyl group) a A hydrocarbyl or heterocyclyl radical in the meaning of R is one of the abovementioned, and then carry the abovementioned substituents individually or in combination; in the case of the heterocyclyl radical, the free valency proceeds in each case from one carbon atom. Among cyclic radicals monocyclic radicals are preferred, among heterocyclic radicals having at most 2 non-adjacent heteroatoms, and substituted radicals those which carry only one substituent (= functional group).

Among the rifamycin compounds of the formulas IA and IB, respectively, which carry the radical Am, those which are particularly preferred are those which

^ 1 2

in which R and R are each an unsubstituted alkyl with 1-4

1 2

C atoms, or wherein both symbols R and. R together with the nitrogen atom form a saturated, monocyclic, 5-8 ring member-containing heterocyclyl radical, which may also contain an oxygen or sulfur (II) atom as ring member, or in which the radical Am1 is one of those defined above preferred meanings of Am ^ corresponds.

Above all, as the symbol Am 1, the dimethylamines, diethylamino, methyl ethylamino, methylisopropylamino and methylbutylamino groups, and also the 1-pyrrolidyl, piperidino, 1-perhydroazepinyl, 1-perhydroazocinyl, morpholino - And Thiomorpholino rest, as well as an optionally 4-substituted 1-Piperaainylrest of the formula

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61 5.89 / 18

worm R ^ stands for hydrogen or one of the individual

12

Meanings of R or R has. Among the meanings of R, unsubstituted straight-chain and single-branched lower alkyl and fiederalkenyl radicals (such as especially methyl, propyl, isobutyl or allyl) are particularly preferred, furthermore unsubstituted lower alkyl (such as propargyl), cycloalkyl and cycloalkyl-alkyl - (Especially Gycloalkyl-methyl) - with 3-6 ring members, as well as phenyl and benzyl radicals highlight. '.

Particularly noteworthy are the compounds shown in the examples and close to them, in particular salts, thereof.

Those of the general or preferred rifamycin analogues of the above. Formulas I and V, which have sufficient basicity, may be present as acid addition salts, in particular as physiologically acceptable salts, with customary pharmaceutically acceptable acids; of the inorganic acids are the hydrogen halides.

The present invention relates in the first place to the process for the preparation of the above-characterized compounds of the formulas IA and IB, which is characterized in that a U ¹ , H'-disubstituted 3-Aminomethylenaminorifamy Srivat (3-Aminorifamyein-formamidine) of formula

ff ™

30.3.1983 61 589/18

CH

CH ₃ O

CH ₃

CH

OH OH CH ₀ OH 0

'X

CO

(Ν)

• / V \ ^^. N = GH-Am

wherein R and Am have the abovementioned general and preferred meanings or a salt thereof, treated with ammonia and, if desired, a product obtained. .Connection ^{: of} the SV «type oxidized to a compound of the 8-Tvps or an obtained compound of the S-'Ivps. reduced to a compound of the SV type and / or converts a resulting free compound having salt-forming properties into a corresponding salt or a salt obtained in the corresponding free compound. If it is desired to target an SV series SOrrnamidine, "so will ^; : "oxidized this previously-to / corresponding S-series compound.

The reaction according to the invention with ammonia takes place primarily by passing dry ammonia gas into a solution of the rifamycin compound V in a conventional aprotic organic solvent, for example an ether (such as diethyl ether, t, 2-dinitth-pentane or dioxane and especially -fetrahydrofuran ) or halogenated (such as, in particular, chloroform or methylene chloride)

2472

- ²² -

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Temperatures in the range of about -10 ° 'to about + 40 ⁰ C, .vorzugsweise between + 5 ° to + 25 ° C, especially slightly below room temperature.

The starting materials of the formula V can be prepared in a manner known per se γ / earth, z.'B by reacting a 3-Aminorifamy. cin-S compound of the formula

R CH- CH_CH.

II ³ I ³ I ³

CH ₃ O

OH OH

OH. 0

i i!

Il

CH

3SH

 wherein R has the meaning given above, or a SaIa thereof, with a reactive derivative of a Hjlf-disubstituted formamide or thioformamide of the formula

Am-CH = Y

(III)

wherein Y is oxygen or sulfur and Am has the meaning defined initially, and, if desired, oxidizing an obtained compound of the SV type to a compound of the S -! vps or a compound of the S type obtained to a compound of the. SV- Type reduced and / or a

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keeping free compound having salt-forming properties in an appropriate salt or a salt obtained into the corresponding free compound.

The starting materials of the formula II, d. H. the 3-aminorifamycin-S-4-junior (X = UH) or the 3-aminorifamycin S (X = 0), as well as the corresponding 25-deacetyl derivatives, are known compounds "They can also be used as corresponding acid addition salts" Also typical Representatives of the starting materials of the formula III are known or, if they are unknown, can be prepared from known secondary amines or their structural analogs in an analogous manner as the known compounds by conventional methods, - The reactive derivatives of the formamides used for the reaction as a reagent or, thioformamides of formula III are also known by typical representatives or accessible by methods known per se. In many cases, it is even not necessary to isolate these reactive forms as defined chemical entities. Among the reactive derivatives of formamide or thioformamide are primarily acid amide acetals and acid orthoamides, and also acid amide halides, acid amide dially alkylsuliate complexes, and Säurethioamidalkylhalogenid complexes, into consideration; the latter especially if they are used directly for the reaction of the starting material of formula II.

Corresponding formic acid amide acetals are, in particular, those derived from C 1 -C -alkanols which are represented by the formula

AUi-CH (QR ⁴ U (III.)

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in which Am has the meaning given above and R is an alkyl of at most 4 C atoms, especially methyl or ethyl. They are particularly advantageous because they can be easily produced in stable individual form. For preparation, z, B, a secondary amine Am-H is heated with N, U-dimethylformamide-di-lower alkyl acetal (ζ, B, -dimethylacetal), thereby replacing the dimethylamino group with the desired amino group Am, E ¹ Ur volatile secondary amines Am-H is an alternative method better suited to U £ w. the treatment of a!, If-disubstituted formamide dialkyl sulfate complex (see below) with an alkali metal alcoholate of the formula R OM, wherein R 1 "has the abovementioned meaning and M represents an alkali metal, in particular sodium.

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

At the

H-C-Am (III)

aa

- At the

where Am has the meaning given above. For example, they can be replaced by the exchange of lower alkoxy groups OR with the disubstituted ones. amino group Am on heating a H, II-dimethyl thyformamide-diallyl acetal acetal or a formamide acetal of formula III with the secondary secondary amine

a -

Amides of these compounds and methods for their production are known.

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The formic acid amide halides oiaminoyl halides ⁱ )) used are preferably of the formula

I Am ⁺ = CHxIx "(III *,)

in which Am has the abovementioned meaning and X represents bromine or preferably chlorine (the double bond starts from the amino nitrogen of the amino group Am and thus gives it the positive charge). These reagents (ie "iminoyl chlorides" and " Iminoylbromide ") one sets z. B, by treatment of the corresponding formamides of formula III with conventional Halogenieruagsmitteln ago. Preferably, halogenating agents are used which form gaseous by-products during the reaction, such as phosgene, oxalyl halides. .or thionyl halides, but others may be used. "The reaction may be carried out in inert dry organic solvents, for example ether or toluene, in which the amide halide is insoluble in most cases and from which it can be isolated by filtration after completion of the reaction." The acid amide halides are hygroscopic and rather unstable and are therefore preferably used without purification in the reaction according to the invention.

The formamide dialkylsulfate complexes used are especially those of the formula

[.Am ⁺ = CH-OR ⁴ JR ⁴ O-SO ₂ -O "(III _c ) where Am and -R" ¹ "have the meanings given above.

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The Säureamiddialkylsulfatkomplexe can be prepared by treatment of the amides of formula III with dialkyl sulfate, preferably dimethyl sulfate, under known conditions, for. B, analogous to the amide halides IH, prepared by »

When an acid thioamide is used as the starting material, a reactive derivative in the form of a thioureaamidoalkyl halide complex may be formed by treatment with an alkyl halide, for example, C 1 to C 3 alkyl. This reaction is known from the specialist literature.

The reaction conditions for this reaction with the reactive amide derivative depend predominantly on this reaction component. If, for the reaction of a rifamycin compound acid amide acetals of the type of formula III ,. 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, ϊΤ , ΙΤ-diisopropyl-ethylanine, IT-et al piperidine, IT-methylpiperidine, U-methylmorpholine or 2T, iT'-dimethylpiperazine.

In an analogous manner, one also uses the orthoamides of

Formula III _n order

 aa

When acid amide halides, dialkyl sulfate complexes or thioamidoalkyl halide complexes are used, the reaction is also carried out in inert organic solvents which are dry and free of traces of alcohols, preferably in dichloromethane or chloroform.

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in which the reaction components are soluble, however, solvents in which the starting materials are insoluble can also be used, such as, for example, ethers. The reaction is carried out at a temperature between about -70 ° to about 20 °, usually at or below 0 ° and in Presence of at least 1 equivalent of a tertiary amine, for example, one of the immediately above, in particular triethylamine performed. When 1 equivalent of tertiary amine is used for the reaction with a Säureamidhalogenid type III, the reaction product of formula I is _s obtained as a salt if, however, the Dialkylsulfatkomplexe and Thioaaiidalkylhalogenidkomplexe be used with 1 equivalent of the tertiary amine results in the reaction product of the formula In the free form _o When two or more equivalents of the tertiary amine are used, the free form of the compound of formula I, which may be desired to be converted to a salt, always results.

The reaction time depends on the reactants, the temperature and the solvents used in the process. When a free carboxyl occurs in the starting material of formula III, it is preferably temporarily protected as a trimethylsilyl ester or a dimethylsilyl diester the implementation ¹ slightly ^ wiederabge-. columns. This reaction is preferably carried out with an acid amide acetal reagent. The preparation of the silyl esters is known from the literature. The silyl esters of the end-products of formula 1 are preferably cleaved by hydrolysis or alcoholysis under mild conditions,

fj ^ N β "" Λ jsKB

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In the primary reaction mixture of the process according to the invention, the end product is practically only in the more stable 1,4-hydroquinone form. the SV series in which it is also suitably isolated. However, if the quinone form is desired, the crude reaction mixture or an isolated compound of the SV series is treated with an oxidizing agent, in particular one customary for the oxidation of known hydroquinones, e.g. For example, ammonium persulfate, hydrogen peroxide, atmospheric oxygen, or preferably potassium ferricyanide, the oxidation occurs primarily under basic conditions. "If one wishes to convert an S-series compound to the hydroquinone form (as a rifamycin SV derivative), the former is treated with a conventional one Ohinone reducing agents, such as hydrosulfite, dithionite, ferrocyanide or, in particular, ascorbic acid or zinc glacial acetic acid *

Acid addition salts are obtained from corresponding basic compounds in a conventional manner, e.g. B, by careful treatment of these with an equivalent or excess amount of the desired acid, preferably in an inert solvent. Salts with bases are also obtained in conventional manner by the treatment of corresponding acidic compounds with the desired bases (especially in the case of ammonia and organic bases) or with the corresponding metal hydroxides or preferably carbonates, or hydrocarbonates. Internal salts are preferably formed by conventional acidobasic titration to rieutralpuiikt or to the isoelectric point.

The invention also relates to those embodiments of the above process in which a starting material is classified under the Re-

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formed or in the form of a salt, or in which one proceeds from a compound obtainable at any stage as an intermediate compound and performs the missing steps.

Thus, for example, the starting materials of the formula Y of the process according to the invention can be formed in situ by reacting a mixture of a 3-aminorifamycin compound of the formula II and a reactive derivative of an H, 2-disubstituted formamide Formula III mixed above in an aprotic organic solvent, for example, one of the above, and then saturated with ammonia gas, "

The novel compounds of the formula I according to the invention are distinguished, in particular, by their valuable pharmacological properties: according to the results they have in vitro antibiotic, in particular antibacterial properties, such as, for example, On the one hand against gram-positive cocci, such as Staphylococcus aureus (in the concentration range tested 0.005 to 128 y / ml), on the other hand against gram-negative rod bacteria, such as Enterobacteriaceae, z, B, Bscher'iöhia.coli,: Pseudomonas aeruginosa and Proteus morganii (im tested concentration range of 1 to 64 / VmI), as well as mycobaterium tuberculosis (in the concentration range tested from 0.48 to 1.9 fo / ml). Particularly noteworthy as active ingredients are 4-Bimethylamino-, 4- (4-methylpiperazinyl) -, 4- (4-Isobutyipiperazinyl) -, 4-morpholino- and 4-PyrrolidinyI-imidazoloJ4,5-cjrifamycin SY, all of which have a deiitv or on Staphylococcus aureus already at or below the said lowest Konzentrationsgrense and also the Snterobacterien in the specified

247

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Effectively inhibit concentration range. (For the test results, see also Table 1.)

The compounds of the invention may also be used as valuable intermediates for the preparation of other rifamycin derivatives, particularly those with therapeutic use, alone or in combination with another antibiotic or gheniotherapeutic agent, as an anti-infection agent , especially those caused by bacteria or --kokken, z. When used as a remedy, the active ingredient of the invention is preferably administered to a warm-blooded animal, especially humans, in the form of a pharmaceutical preparation together with at least one conventional pharmaceutical carrier or excipient; - administered. (The term "active substance" or "the active substance ' ¹ according to the invention is to be understood above and below as meaning a rifamycin derivative of the above-defined formulas IA or IB, and VA or VB, as well as biocompatible salts thereof, see below.

Bine find particularly valuable application of these active compounds according to the invention as pharmaceutical compositions containing one of the above-defined active ingredients, in particular together with at least one pharmaceutical carrier material, as well as processes for their preparation by non-chemical means. For the preparation of pharmaceutical compositions, any one of the compounds according to the invention, especially one of the particularly emphasized, with a suitable for topical, enteral or parenteral administration

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inorganic or organic carrier material are mixed. "For the same, such substances are considered that do not react with the new compound, such. Gelatin, lactose, starch, magnesium stearate, vegetable oils, benzyl alcohol or other excipients. The pharmaceutical compositions may be formulated into pharmaceutical dosage forms such as tablets, dragees, powders, suppositories, or in liquid form into solutions, suspensions, emulsions, creams or ointments. If necessary, they are sterilized and / or contain adjuvants, such as preservatives, stabilizers, thickeners or emulsifiers »They may also contain other therapeutically valuable substances. The disinfectants can also be mixed with suitable excipients, as is known,

For oral administration tablets, capsules or gelatin capsules containing the active ingredient together with diluents, for. Lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or Polyethyienglykol have "tablets also contain binders, z, B. magnesium aluminum silicate, starches, such as corn, sage, rice or arrowroot starch, gelatin, Tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, s. As starches, agar, alginic acid or salts thereof, such as matrium alginate, and / or effervescent mixtures, or absorption.

247 2

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The pharmaceutical preparations may be sterilized and / or adjuvants, eg. B ₆ preservatives, stabilizers, Hetz and / or emulsifiers, solubilizers, and / or buffers. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances are prepared in a conventional manner, for. Example by means of conventional mixing, solution or lyophilization, prepared and contain from about 0.1 % '- 100%, in particular from about 1 % - about 50 %, Lyophilisate_ up to 100 % of the active ingredient.

Particularly preferably, the above-characterized pharmaceutical preparations are in the form of dosage units. By the term "unit dose" is meant a unitary, ie, single dose containing an antimicrobially effective amount of the active ingredient which is administered to a patient. It can be easily handled and packaged using either a physiologically stable unit active material as such or a mixture thereof with a solid pharmaceutical carrier. The dosage of the active ingredients, for. 3. The one particularly emphasized above, is in principle analogous to those of recognized rifamycin-type antibiotics; However, it also depends, on the one hand, on the species, body weight, age and individual condition of the warm-blooded animal, and on the other hand on the mode of administration and, in particular, on the specific susceptibility of the pathogen, which can be established in the routine test in a known manner. Accordingly, the present invention is also the selection of a dose of the compounds of the invention, which can be administered _} so that the desired activity without simultaneous Ilebeneffekte is achieved. The obtained according to the invention

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Compounds used particularly advantageously for a method of killing or growth retardation (d. H _e inhibition) of an at least one of the active ingredients according to the invention-sensitive microorganism, which by the treatment of this microorganism or infected by a microorganism medium with an antimicrobially effective dose of the inventive Active substances is characterized. By the term "an antimicrobial effective dose" is meant an amount of the active ingredient "sufficient to effectively inhibit the particular microorganism being treated.

The compounds are conveniently administered in dosage units containing no less than OmO25 corresponds to 1 g of the active ingredient (as the free base) and preferably 0.05 to 0.5 g thereof. The active ingredients may be administered in the form of a unit dose once or several times daily at appropriate intervals, but this always depends on the condition of the patient. A daily dose is thus preferably 0 _s 2 to 5.0 g of the active compounds according to the invention, calculated as free base.

Äusfuhrungsbeispiele

The following examples illustrate the above-described Srfindujg; However, they should not be limited in their scope in any way, temperatures are given in degrees Celsius, The composition of solvent mixtures is given in volume ratio. The structure of the isolated compounds is routinely controlled by the mass spectrometric determination of the molecular ion as well as by bilayer analysis. "

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Example 1; 4-dimethylamino- imidazole Ϊ4.5 ~ c irifamycin SV ₈

A solution of 1.5 g of 3-amino-4-iminorifamycin ~ S in 15 ml of tetrahydrofuran with 2.0 g of dimethylformamide-dimethylacetal and allowed to stand at room temperature until the used Refamycinderivat has completely reacted (thin layer chromatography on silica gel, Eluent methylene chloride-acetone 9: 1). Subsequently . The reaction mixture is taken up in ethyl acetate, washed with aqueous citric acid solution and brine, and the solvent is evaporated off. The brown-colored residue is chromatographed on silica gel with eluent methylene chloride / acetone 9: 1j, removing rapidly migrating, dark colored fractions. The yellow-colored fractions are combined, evaporated and the residue is crystallized from diethyl ether / acetone. The dimethylaminoimidazolecrifamycin-3V is dissolved in 3 ml of pale yellow crystals. 1S0-185 (decomposition). In the Maasenspectrum the molecular ion appears at m / s = 7o4. Calculated for G

Example 2; 4-morpholino-imidazolo [4,5-c.lrifamycin SY.

Sine solution of 1.42 g of 3-amino-4-iminorifamycin-S in 15 ml of tetrahydrofuran is added under nitrogen with 0.5 ml of U-formylmorpholinedimethylacetal and 2 ml of triethylamine and allowed to stand at room temperature for 24 hours. The reaction mixture is then taken up in ethyl acetate, washed successively with aqueous citric acid solution and brine, and the ethyl acetate is removed in vacuo. The residue is crystallized from ether / acetone to afford reuborpholinoimidazolorifamycin SV as yellow crystals, mp 192-193 ° (decomposition).

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In the mass spectrum, the molecular ion of the compound is found at m / z = 806 (calculated for C ₄₂ H ₅₄ IiI ₁₁ O ₁₂ = 8O6).

Example 3i 4- (4-methylpiperazine; yl) -imidazole J 4, 5-c-pyrrylamyne SY ,

A solution of 2.0 g of 3-amino-4-imiorifamycin-S in 25 ml of tetrahydrofuran is added to 2.5 g of 1-i-amyl-diethylpiperazine-dimethylacetal and allowed to stand at room temperature until the rifamycin derivative has completely reacted.

Then the reaction mixture is taken up in ethyl acetate, washed with aqueous citric acid solution and with brine and evaporated. The residue is chromatographed on silica gel with methylene chloride / methanol 95: 5. After removing rapidly running dark-colored substances, the following yellow-colored sluatoes are collected and evaporated. Crystallization from ether / acetone gives the U-methylpiperazinylimidazolo-rifamycin-SY in yellow crystals of mp. 185-187 ° (decomposition).

The 100 ΙΐίϊΗζ proton resonance spectrum of the compound, in CDGIo, shows additional signals in addition to the usual rifamycin signals; ^: Beiv, ^3.5-4:; , O- ^: Ppm (CH ^ next to ..KF; ¹ .M) as well as at 2.40 ppm JS).

Example 4: 4- (4-Isobutylpiperazln: / I) -imidazolo L4,5-c] r ifamycin SV.

A reaction mixture of 2.5 g of 3-aminorifamycin S, 20 mf of tetrahydrofuran, 1.5 g of 1-5 ^{l of} ormyl-4-isobutylpiperasindimethylacetal and 1.5 g of triethylamine is allowed to stand at room temperature for 24 hours. Then it is evaporated to dryness in vacuo. The residue which is crude 3- (4-isobutylpiperazinyl)

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Methyleniininorifamycin S containing only minor impurities, is dissolved in 20 ml of tetrahydrofuran. Ammonia gas is bubbled into the solution at room temperature for 30 minutes. Then the solution is evaporated and the yellow-brown residue is chromatographed on polyamide (Woehn) with ether / methylene chloride 5: 1 as the eluent. 3 zones are formed: the eluate of the slowest, yellow-colored zone then contains the desired 4- (4-isobutylpiperazinyl) -imidazolorifamycin-3V, which shows a molecular ion in the mass spectrum at m / z = 861.

(Calculated for C, <E _c -, N ₁ -O ^ =

Example 5: 4- (4-Cyclohexylmethyl-piperazinyl) -imidazolo \ jL ₉ 5_ c] rif amy cin-SV

A solution of 1.5 g of S-amino-cin-8 in 15 ml of tetrahydrofuran is mixed with 3.0 g of 1-pormyl-4-cyclohexylmethylpiperazinedimethylacetal and allowed to stand at room temperature for 8 hours. Thereafter, the reaction mixture is taken up in ethyl acetate, the organic solution is washed successively with aqueous citric acid solution and with brine, dried and evaporated. The residue gives in the chromatography on silica gel with methylene chloride / methanol 97: 3 as the eluent the Cyclohesylmethylpiperazinyl-imidazolorifamycin-SY as the main product. The compound shows in the mass spectrum a molecular ion at m / z = 901 (Calculated for C ₄ QHg ₇ H ₅ O ₁₁ = 901). UV spectrum: (0.01-N alcoholic hydrochloric acid) X _m ^ - (nm) / l: 224/38400, 228/39200, 231/38600, 245 (shoulder), 304/26400, 420/11200.

Example 6: 4-Diethyamino -imidazolo [4 _? 5 ~ cJ rifamycin SY (6) Into the solution of 380 mg diethylaminooiethyleneamino-rifamycin

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Ammonia gas is introduced at room temperature in 15 ml of tetrahydrofuran for 15 minutes at room temperature. The solution is allowed to stand over Hacht and then evaporated to dryness. The yellow-brown residue is chromatographed on silica gel; eluting with mixtures of chloroform with increasing (2-10 %) methanol, the title compound (S ^e 2- ^ ^es > amorphous powder ₀ ) results

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

Example 7: 4-Dipropylamino-iraidagolo l4,5-cyrifamycin SV (7)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of tetrahydrofuran and 4.0 gi ^ H-dipropylformamide dimethyl acetal, the above-mentioned imidazolorifamycin SV (7) (G. ₄₄ Hg ₀ ] J ₄ O ₁₁ , MW = 820). Orange crystals of ether / methylene chloride melting at 175-185 ° (decomposition); MG found: 820

The required as a reagent !!, H-dipropylformamide dimethyl acetal is obtained in an analogous manner as in Example 81 from 10 g of dipropylamine and 20 g iJjli-di-aethylformamid-dimethylacetal.

Example 8: 4 - (^ -isopropyl-IT-methylamino) -imidazolo-14,5-cyrifamycin SV (S)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iniinorifamycin-3 in 50 ml of tetrahydrofuran and 4.0 g of M-isopropyl-ii-methylformaniid-diniethylacetal the

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4- (ffl-Isopropyl-N-methylamino) -imidazolo J4,5-cJ rifamycin SV (8) (G ₄₂ H ₅₆ Ii ₄ O ₁₁ , MW = 792).

The required as reagent li-isopropyl-N-methylformarriid dimethylacetal is obtained in an analogous manner as in Example 80 or, 81as 10 g of 3tf-Isopropyl_B ~ meth.ylamin and 20 g of N, lT-dimethylformamide dimethyl acetal »

Example 9: 4- (H "-sutyl-IT-diethylamino) -imidazole [4,5-cl rifamycin SY (9)

In an analogous manner as described in Example 1, as 4.0 g of 3-amino-4-imiorifamycin S in 50 ml of THP and 4.0 g of B-Batyl-l-methylformamid-diniethylacetal 4- (iI-butyl-N -methylamino) -imidazolo l4,5-c3rifamycin SY (9) (O ^^ s ¹ ^} - ⁰ ! * HG = 80S). MG found: 806.

The required as reagent H-butyl-li-niethylforniainid-diinethvlacetal is obtained in an analogous manner as in Example 80 or '81 from 10 g Batylniethylainin and 20 g of N, F-dimethylformamide di methylacetal.

Example 10: 4- (iT-glylopentyl-1-methylamino) aminoimidazolo 4,5-c rifamycin SY (10)

In an analogous manner, as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 nil THP and 4 _s 0 g of N-cyclopenyl-iT-niethylforßiamid-dimethylacetal 4- (li-glyclopentyl-methylamino ) -imidazolo [4,5-cyrifamycin SY (10) (G ₄ Hj-QN ₄ O ₁ -, MW = 818)

 EC found: 318

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The required as a reagent H-Gyclopentylformamid-diniethylacetal is BZV in an analogous manner as described in Example 80 / _o 81 obtained from 10 g and 20 g Cyclopentylnie.thylamin Hjli-dimethylformamide dimethylaoetal "

Example 11; 4 - (^ -cyclopropylmethyl-1-propylamino) -imidazole Γ4,5-o-rifamycin SY (11)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iniinorifaniycin S in 50 ml of THF and 4.0 g of Ii-cyclopropyl & ethyl-lT-propylformamid-dimethylacetal 4- (Ii-Gyclopropylmethyl-M -propylamino) -imidazolo, 4,5-cifrifamycin SV (11) (G ₄₅ Eg ₀ AT O ₁₁ , MW = 832) »

Is formed from ether yellow crystals of mp, 223-224 °. HG found: 832 ο

The IT-cyclopropyl-ethyl-IT-propylformamide dimethyla.ee t al required as reagent is obtained in an analogous manner as described in Examples 80-82 from 10 g of IT-cyclopropylmethyl-Itf-propylamine and 20 g of ITjiT-dimethylforaiamide-dimethyl acetal.

Example 12: 4- (H-Benzyl-1-methylamino) -imxdasolo | 4.5-cJ

r If at y ^r bi gV K 12) ^r

In an analogous manner as described in Example 1, from 0.7 g of 3-amino-4-iniinorifamycin S in 10 ml of THP and 0.425 g of H-benzyl-iT-methyl-formamide dimethylacetal 0.155 g of 4-UT-BenzyllT- uiethylamino) -irriidazolo J4,5-c] rifamycin SY (12) (Ο ^ γΗ ^ ίΤ ^ O ₁₁ , MW = 852) ο

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The preparation of the reagent is described in Example.

Example 13: 4-Methyl-1 -methyl-1-methyl- 4-piperidyl ) -amino-imidazole »-Γ4,5-c ~] rifamycin SV (13)

In a manner analogous to that described in Example No. 1, from _{3 to} 30 g of 3-amino-4-inaminorifamycin S in 50 ml of THF and 4.0 g of 2-methyl-HO-methyl-piperidylformamide-dimethylacetal are obtained. 4- H-methyl ~ I- (1-methyl-4-piperidyl) amino -imidazoloJ4 »5-cJ rifamycin SY (13) (C ₄₅ Hg ₁ JJ ₅ O _11, MW = 847), prepared MG found: 847 ·

The iT-methyl-IT- (1-methyl-4-piperidyl) -formamide dimethyl acetal required as reagent is prepared in an analogous manner as described in Example 82 from 10 g of 1-methyl-H- (1-methyl -4-piperidyl) amine and 20 g of lijH-dimethylformamide-diniethylacetal.

Example 14: 4-N-Ethyl-IT- (2-hydroxyethyl ) amino-imidazolo 1 * 4,5-el rifamycin SY (14)

In an analogous manner as described in Example 1 is from 4 _} 0 g of 3-amino-4-iminorifamycin 3 in 50 ml of THP and 4.0 g of N-Sthy 1-ϊΤ- (2-hydroxyethyl) -formamid-dimet hylacetal the desired imidasolorifamycin SY (14) ( ^C 42 ^iH - ^r -6 ^ 4 ° -i2 ⁾ ^ ^{G = 808} ^. Methylene chloride / Sther yellow prisms melting at 192-193 ° (decomposition). HG found: 808.

The iI-3-ethyl-H- (2-hydroxyethyl) -fdraacidyl-diniethylacetal required as reagent is prepared in an analogous manner as described in Examples 80-82 from 10 g of IT-Si: ethanol ethanolamine and 20 g of SfjSi-dimethylformamide. obtained dimethylacetal.

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Example 15: 4 - [~ (2,2-Dim ethoxyethyl) -N-methylaciino | - imidazoloL 4> 5-c.] Rifamycin SV (15)

In an analogous manner, as described in Example 1, from 4.0 g of 3-amino-4-iminorifaniycin S in 50 eil THE and 4.0 g of U-methyl-K- (2,2-dlmethoxyethyl) -formamide dimethylacetal the desired Imidazolorifamycin SV (15), mp 162 C (decomposition) made ⁰ ", MW found ^(m / 2 of TMS.-derivative) (G ^ Ht-Gelo ~> MW = 838.). 838

The N-methyl-H- (2,2-dimethoxyethyl) formamide dimethylacetal required as reagent is obtained in an analogous manner as described in Examples 80-82 from 10 g of methylaminoacetaldehyde diniethyl acetal and 20 g of 1: 1, 1-dimethylformamide diniethyl acetal.

Example 16: 4-IH-di- (2-methoxyethyl) -amino-imidazolo-LiUS-c) rifamycin SV "(16)

In analogous manner, as described in Example 1, from 4.0 g. 3-Amino-4-iminorifamycin 8 in 50 ml of THF and 4.0 g of H, N-di (2-methoxy-ethyl) -formamide dimethylacetal 4-jpi- (2-methoxyethyl-amino-1-imidazolo-4,5- cjrifamycin SV (16) (C ^^ HgQlI ^ O ^, MW = 852) MG found: 852 »

The required as a 'S ₃ U-di- (2-methosyethyl) -formamiddimethyl-acetal acetal is in an analogous manner as in Example 80 from 10 g of di- (2-methoxyethyl) -aruin and 20 g of ΙΤ, ΙΤ-dimethylformamide diiätethylacetal obtained.

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Example 17: 4-pi-methyl hyl-γ-JT- (2- digienyl hylaminoethyl) -amyl imidazolo- [4,5-el rifamycin SV ] (17)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin 3 in 50 ml of TED? and 4.0 g of IT-methyl-1- (2-dimethylaminoethyl) -formamide dimethylacetal 4-LMethyl (2-dimethylaminoethyl) -amino-imidazolo [4,5-c] rifamycin SV (17) (G ₄₃ H ₅₉ NO ₁₁ , MW = 821). From methylene chloride triangular crystal platelets melting at 187-188 ° (decomposition) MG found: 821.

The required as reagent SI-Me t hy li> r- (2-dimethylaminoethyl) · formamide-diniethylacetal is prepared in an analogous manner as in Examples 80-82 from 10 g lijl ^ ü 'trimethylethylenediamine and 20 g of Ν, ΕΓ-dimethylformamide obtained dimethylacetal,

Example 18: 4-IjT-Btyl-N- (2-diethylamino) -amino] imidazolo4_s_5-c rifamycin SV (18)

In an analogous manner, as described in Example 1, from 4} Q g of 3 ~ amino-4-iminorifamycin S in 50 ml of THI 'and 4.0 g of IT-ethyl-iT-diethylaminoethyl-formamide dimethyl acetal, the desired iniidazolorifamycin SV (18) (G, ^ Hg ₁ -ELO _11, MG '= 863), mp. 173-174 ⁰ C (decomposition) was prepared.

The required as a reagent ϊΓ-St-hyl-diethyl hylaminoet hy 1 ~ formamide dimethyl acetal is in an analogous manner as in Examples 80-82 of 10 g of ϋ, Ν ¹ , N'-Triethylethylendiamin- and 20 g of ϊΤ, ϊΤ-dimethylformamide -dimethylacetal received «

Example 19: 4- Pyrolidinyl- imidazolo-f4,5-cyrifamycin SV (19)

20 g Dimethylforaianiiddimethylacetal is heated with 10 g

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Pyrrolidine for four hours to .100 ° * then added to toluene to toluene and evaporated in Waaserstrahlvakuum at 50 °. The residue is used without further purification as the crude reagent dirnethoxypyrrolidinomethane. A mixture of 4 g Dimethoxypyrrolidinomethan, 50 ml of tetrahydrofuran and 4 g of 3-amino-4-iminorifanycin S are allowed to stand for six hours at 25 °, the initially deep red color of the reaction mixture gradually turns 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 on silica gel, with a mixture of Bthylacetat with 10 % methanol as the solvent can be purified pyrrolidinyl-imidazolo-rifamycin SV (19) obtained, which forms yellow crystals of mp. 200 ° from acetone / Sther. MW / found: 790 (MS as' TMS derivative m / 2 1078) calculated for G ₁₂ H ₅₄ N ₄ O ₁₁ MW = 790),

Example 20: 4-IndolinylimidazoloC4,5-cyrifamycin SV (20)

In an analogous manner as described in Example 1, from 2.0 g of 3-amino-4-iminorifämycin S in 100 ml of TH? and 3.26 g of li-Pormylindolindimethylacetal 1.1 g of 4-indolinylimidazolo [4,5-c] rifamycin SV (20) (G ₄ SH ₅₃ H ₄ O ₁₁ J MW = 837).

The il-porrnylindoline dimethyl acetal required as reagent is prepared according to Example 82,

Example .21; 4-piperidino-imidazolo-4,5-o-rifamycin SV (21) In an analogous manner as described in Example 1, starting from

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4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of H-formylpiperidine dimethylacetal 4-piperidinyl-imidazolo [4,5-c] rifamycin SV (21) (C ₄₃ H ₅₆ H ₄ O ₁₁ , MG = 802). Yellow crystals of mp 190 °, (decomposition) MW found: 802.

The required as reagent H-formylpiperidine dimethyl acetal is prepared according to Example 83 »

Example 22: 4- (4-Ethoxycarbonyl-1-piperidyl) imidazolo [4,5-c] rifamycin SY (22)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of H-formyl-4-ethoxycarbonylpiperidine-dimethylacetal 4- (4-3thosycarbonylpiperidyl) - L4,5-imidazolo cJrifamycin SY (22) (C ₆ H ₆₀ H ₄ O _13, MW = 876) was prepared. "

The required as reagent H-Pormyl-4-ethoxycarbonylpiperidinediniethylacetal is obtained in an analogous manner as in Examples 80-82 from 10 g of 4-Bthoxycarbonylpiperidin and 20 g!, H-Diniethylformamid-dimethylacetal.

Example 23: 4- (4-Diethiethanolamino-1-piperidyl) diimidazole

4,5-c] rifamycin "SY (23)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of M-formyl-4-di-ethyl-aminopiperidin-dimeth-ylacetal 4 ~ (4- Di -dimethylaminopiperidyl) imidazolo [_4,5-c] rifaniycin SY (23) (C ^ ₁ -Hr ₁ I ₁ -O ₁₁ , MW = 847). Yellow crystals of B £ ethanol-ether, which decompose from / ^ 140, MG found (m / 2 of THS ^ derivative): 847 »

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Daa required as a reagent I-formyl ^ -dimethylaminopiperidinedimethylacetal is obtained in an analogous manner as in Examples 80-82 from 10 g of 4-dimethylaninopiperidine and 20 g of N, l \ [- dimethylforraimidide dimethyl acetal.

Example 24 i (4-? Iperidino-1-piperidyl -) - im.idazolo J4,5-c | SY (24)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iniinorifaniycin S in 50 nil THP and 4.0 g of S-formyl-4-piperidino-piperidin-dimethyl acetal 4- (4 -Piperidihopiperidylimidazolo [4,5-e] rifamycin SY (24) ^ 48 ³ SS ¹ S ⁰ Il ' ^{MW = 887} ^ Prepared »from yellow methylene chloride yellow crystals which decompose from 190 ° C,

The required as reagent n-5 ^l ormyl-4-piperidinopiperidindimethylacetal is obtained in an analogous manner as in Examples 80-82 from 10 g of 4-piperidinopiperidine and 20 g ^, IT-Dimethylfornianiiddiraethylacetal «

Example 25: 4-T 8-Aza-1,4- dioxa-spiro (4,5) -8-decyl-imidazolo C 4-5 -c-rifamycin SY (25)

In an analogous manner as described in Example 1, from 4jO g of 3-amino-4-iminorifaniycin S in 50 nil of THI ¹ and 4.0 g of U-Forrnyl- (4-piperidonethylen-ketal) -diethylacetal the title compound (25) (O ₄₅ H ₅₈ N ₄ O ₁₃ , MW = 862). MG found (MS of TMSc derivative): 862,

The required as a reagent IT-forinyl (4-piperidonethylenlcetal) dimethyl acetal is prepared according to Example 85.

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Example 26: 4- (3-Piethyl-amino-carbony -1-piperidyl ) -imidazole, Du5-el-rifamycin SV (26)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin 3 in 50 ml of THP and 4.0 g of H-formyl-S-diethylaminocarbonylpiperidine dimethyl acetal 4- (3-Diethylaminocarbonylpip ^ ridyl ) imidazolo [4,5-cJ rifamycin SV (26) ^(G 48 ^H 6 ₅ 50 ₁ ^ir 2 ^"MW = ^{9O: 3)>} manufactured.

The required as a reagent IJ-S ¹ Or myl-3-diethyl hylamino carbonylpiperidindimethylacetal is obtained in an analogous manner as in Examples 80-82 from 10 g of piperidine-3-carbonsäurediethyIamid and 20 g of Hjil-Diniethylformamiddimethylacetal,

Example 27: 4- (1-Perhydroazepinyl) -imidazolo [* 4 > 5-cyrifamycin SV (27)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of TH? and 4.0 g of H -pyryl-perhydroazepine-dimethylacetal, the desired imidazolorifamycin SV (27) G ^ H ^ Iff O ₁₁ ,

The i-pormyl-perhydroazepine dimethyl acetal required as reagent is obtained in analogous manner as in Examples 80-82 from 10 g perhydroazepine and 20 g of Ν, Η-dimethylformaniide-diniethylacetal. »

Example 28: ^ -d- Perhydroazocinyl-D-idazolo [4,5-c-Irifamv cin SV (28)

In an analogous manner as described in Example 1 is from 4 ₅ O g 3-Ä ~ amino ~ 4-iminorifamycin S in 50 ml of TEF and 4.0 g IilOrmyl-perhydroazocin-dimethylacetal 'the ¹ X it el connection (28) (G ₄₅ H ₆₀ ^ O ₁₁ , 'MG = 832) from the sap. 180 ^° C (decomposition)

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manufactured, MG found: 832.

The iJ-Pormyl-perhydroazocin-dimethylacetal required as reagent is obtained in an analogous manner as in Examples 80-82 from 10 g of perhydroazocine and 20 g of Ν, Ν-dimethylforciamide-dimethylacetal,

Example 29t 4 ~ (2,6-dimethylmorpholino) imidazolo [4,5-c "} SY (29) "

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-irininorifamycin S in 50 ml of THi ¹ and 4.0 g of 4-formyl-2,6-dimethylmorpholine-dimethylacetal 4- (2, 6-dimethyl-4-morpholinyl) -i-riidazolo-j 4,5-c {rifamycin SY (29) (O, H ^ o N ₄ O ₁₂ , MW = 834). Yellow crystals, which "gradually decompose after 240 without melting" MG found: 834 ·

The 4-pormyl-2,6-dimethylmorpholinedimethylacetal required as reagent is obtained in an analogous manner as in Examples 80-82 from 10 g of 2,6-dimethylnorpholine and 20 g of N, 1 \ T-dimethylforthnanodimethylacetal. «

Example ... 3. 0 ..;. 4 ~ 'Thi osiorpholino ^: -imidazolp;] ϊ ^ j_-cj j; Ifamycin_ _: SV (30) -

In an analogous manner as described in Example 1, from 1.4 g of 3-amino-4-iminorifamycin S in 100 ml of THF and 1.06 g of N-Pormylthiomorpholin-dimethylacetal 0.45 g of 4-Thiomorpholinoimidazolo 4,5-c rifamycin SY (30) (G ₄₂ H ₅₄ N ₄ SO ₁₁ , MW = 822) "

The preparation of I-PörmVlt'hiöaörp ^ oiih-dlmethylaOetal is described in BeisDiel 87 »

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Example 31: 4- (4-5Hylpiperaginyl) imiaazolo [4,5-c] rifainycin SY (31)

In an analogous manner as described in Example 1, from 2.0 g of 3-amino-4-iniinorifainycin S in 100 ml of IHP and 3.18 g of i-formyl-ethylpiperazine dimethylacetal 0.95 g of 4- ( 4-Stjaylpiperazinyl) imidazolo [4,5-c] rifani5'cine SV (31) G ₄₄ H ₅₉ Ii ₅ O ₁₁ , MW = 833). ".;

The i-formyl-4-ethylpiperazine-dimethylacetai required as reagent (b.p .: 98-100 ° C./20 torr) is prepared in an analogous manner as in Example 80 from 11.4% of biphenylpiperazine and 25 g of Si, N-dimethylformamide. diniethylacetal obtained

Example 32: 4- (4-Propylpiperazinyl ) -iaidazolo J4,5-c) rifamycin SV (32)

In an analogous manner as described in Example 1, from 2.0 g of 3-affiino-4-iminorifamycin S in 100 ml of ¹ THP and 3.42 g of i-poryl-4-propylpiperazine dimethyl acetal 0.9 g of 4- ( 4-propylpiperazinyl) imidazolo [4,5-cif rifamycin SV (32) (G ₄ J-Hg ₁ Hf-O ₁₁ , MW = 847).

The required as reagent 1-5Ormyl-4-propylpiperazine diaieth: / lacetal vird ird / in analogous e / eise as in Example 82 from 12.8 g iT-Propylpiperaain and 29.75 g of Ν, Ν-dimethylformamide dimethylacetal obtained

Example 33: 4- (4-butylpiperazinyl) -iaiidazolo J4, 5-clrifaaycin SV (33.1 ")

In an analogous manner as described in Example 1, from 4.0 g: 3-amino-4-iminorifamycin S in 50 ml TES ¹ and 4.0 g 1-

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IPorrnyl - ^ - btitylpiperazine-diniethylacetal gave the desired titanium compound indium (33) (G ₄₆ Hg ₃ N ₅ O ₁₁₅ MW = 861), MW found: 861 _#

The i-formyl-4-butyl-piperazine-dimethylacetal required as reagent is obtained in an analogous manner as in Example 82 from 10 g of M-butylpiperazine and 20 g of diethylformamide-dimethylacetal,

Example 34: 4- (4-Pentylpiperazinyl) -imidazolo J2,5-c] rifamycin SV (34)

In an analogous manner, as described in Example 1, from 2 g of 3-amino-4-ii-o.orifamycin S in 100 ml of TEF and 3.5 g of 1-formyl-4-pentylpiperazine dimethylacetal 1.4 g of 4 - (? 4 entylpiperazinyl) imidazolo [4,5-c] -rifamyc.in SV (34) ^ at ^ s ^^ ⁰ -] -] j MW = 875) made ".

The 1-5 ^{l of} orniyl-4-pentylpiparazine dimethyl acetal required as reagent is obtained in a manner analogous to that in Example 82 from 6.46 g of U-pentylpiperazine and 12.3 g of BT, III dimethylformamide dimethyl acetal.

Example 35; 4-C4 ^ hexylpiperazinyli) ^: -imidazoles »12« 5-c] rifam7cin SY (35)

In an analogous manner as described in Example 1, from 2, or 3-amino-4-iminorifaniycin S in 100 ml of THI ¹ and 4.13 g of 1-formyl-4-hexylpiperazin-dimethylacetal 1.25 g of 4- (4 -Hexylpiperazinyl) -imidazolo-f * 4,5-c] rifamycin SY (35) ( ^G 4s ^H 67% ° 11 'MW = 889).

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The required as reagent 1-I? Ormyl-4-hexylpiperazin-dimethyl ~ acetal (bp.: 125-130 ° C / 0.3 Torr) is in an analogous manner as in Example 80 from 17 g of IT-hexylpiperazine and 29.75 g Ι, ϊί-dimethylformamide diinethylacetal obtained.

Example 36: 4- (4-Heptylpiperazinyl) -iinidazolo rifamycin SV (36)

In an analogous manner as described in Example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of TEF and 4.33 g of 1-formyl-4-heptylpiperazine diGiethylacetar 1.2 g of 4- (4 Heptylpiperazinyl) -i'niidazolo '[4,5-c] rifamycin SY (36) (C.gHggl ^ O ^, HG = 903). '

The 1-formyl-4-heptylpiperazine dimethylacetal required as reagent (b.p .: 128-129 ° C / 0.1 torr) is prepared in an analogous manner as in Example 80 from 18.4 g. 1-heptylpiperazine and 30 g of ϊί, Η-dimethylformamide dimethyl acetal obtained.

Example 37: 4- »Λ- (1-Methylpropyl) -piperazine 1 * 1 -imidazolo r4,5-cl-rifamycin SV (37)

In an analogous W _e ise, as described in Example 1, from 4j'O, .3 g-im.ino - 4-iminorifamycin.vS: -in ,. 50 ml of THP and .: 4, east g of 1-formyl-4- (1-methyl-propyl) pipera2in-dimeth5? Lacetal'die 2itelverbindung (37) ^ ^^ λφ ⁰ ^ * = 861) prepared ^MG.

The 1-Pormy1-4- (1-methylpropyl) -piperazine-dimethylacetal required as reagent is obtained in an analogous manner as described in Example 80 from 10 g of I- (1-methylpropylpiperaine and 20 g of NjiI-dimethylformamide dimethylacetal _o -

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Example 38: 4- r4- (2- Ethyl-butyl) piperazinyl -imidazolo4,5 -o3- rifamycin SV * (38)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iniinorifaßiycin S in 50 ml of THF and 4.0 g of 1-formyl-4- (2-methylbutyl) piperazine dimethylacetal 4- Γ 4- (2-methylbutyl) -1-piperazinyl-1-imidazolo [4,5-q3rifamycin SV (38) (G ₄₇ Hg ₅ U ₅ O ₁₁ , MW = 875) prepared from mp _# 185 ⁰ G (decomposition). MG found: 875,

The 1-formyl-4- (2-niethylbutyl) -piperazine-dicaethylacetal required as reagent is prepared in an analogous manner as in Examples 80-82 from 10 g of iJ- (2-methylbutyl) -piperazine and 20 g of Η, ΕΓ-dimethylformamide. obtained dimethyl acetal «

Example 39: 4-L4- (2-methylpentyl) -piperazine: / 1-imidazolo 1 * 4,5-c] -rifamycin SV (39)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifainycin S in 50 nil ¹ IHF and 4.0 g of 1-formyl-4- (2-inethylpentyl) piperazine-diniethylacetal 4th - £ 1- (2-methylpentyl) -1-piperazinyl-1-imidazolo [4,5-c] rifamycin SV (39) (G ₄₈ Hg ₇ H ₅ O ₁₁ , MW = 889), mp 171-172 ⁰ ( Decomposition). MG found: 889.

The 1-formyl-4- (2-methylene-pentyl) -piperazine-dimethylacetal required as reagent is prepared in an analogous manner as described in Examples 80-82 from TO g H- (2-methylenepentyl) -piperazine and 20 g. IT dimethylformamide dimethylacetal is obtained "

Example 40: 4- [4- (3-H-β-yl-butyl) piperazinyl] -imidazolo L4 "5-cl rifamy-.cnc SV" (40)

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In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-? Ormyl ~ 4- (3 ~ methylbutyi) ~ piperazine dimethyl acetal 4-j 4- (3-methylbutyl) -1-piperazinyl-imidazolo [4,5-c-pyrifamycin SY (40) (C ₄₇ H ₆₅ U ₅ O ₁₁ , MW = 875).

The 1-formyl-4- (3H-diethylbutyl) -piperazine) -diynethylacetamide required as reagent is prepared in an analogous manner as described in Examples 80-82 from 10 g of H- (3-methylbutyl) -piperazine and 20 g of ITjN. Dimethylforoianiiddiuiethylacetal received «

Example 41: .. '4-l4- (i-Bethylpropyl) -piperazinyl imidazolo

4,5-c] rifamycin SY (41)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifaniycin S in 50 ml of THF and 4.0 g of y-formyl - 4 ~ (2-ethylpropyl) -piperazine-diraethylacetal 4th -F4- (2 ~ Sthylpropyl) -1-piperaainyl] imidazolo | _4,5-cj rifamycin SV (41) (G _{47 5} Hg Ii ₅ O _11, MW = 875) was prepared. KG found: 875 *

The 1- ^l-l- methyl-4-bis (2-ethylpropyl) -piperazinedimethyl: acetal required in the same way as in Examples 80-82 from 10 g of I- (2-ethylpropylpiperazine and 20 g of N , IT-Dimethyl-ethylac on al; receive,;;

Example 42i 4-f4 - (3- methylpentyl) -Oiperazinyl-imidazolo- 4,5-el-rifamycin SY (42)

Analogously to the procedure described in Example 1, from 4 _} 0 g of 3-amino-4-iminorifamycin S in 50 ml of I ¹ HF and 4.0 g of 1-formyl-4- (3-methylpentyl) -piperazine-- dimethylacetal 4-t4- (3-methyl-1-phenylpentyl) -1-piperazinyl 3: - iniidolone. | 4, 5 ^ c] rifarnyein SY (42)

MG = 889)

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manufactured * HG found: 889 *

The 1-pormyl-4- (3-methylpentyl) -piperazine-dimethylacetal required as reagent is, in a manner analogous to Examples 80-82, admixed with 10 g of N- (3-methylpentyl) -piperazine and 20 g of Ιί, Ι- Dimethylformaniid dimethylacetal obtained.

Example 43: 4-f4- (1,3-dimethylpropyl ) -pipeazine ; yl] -irnidago- Io Γ4 ^ 5-o1- rifamycin "SV (43)

In an analogous manner as described in Example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of TKF ¹ and 3.2 g of 1-R> rinyl-4- (1,3-dimethylpropyl) - piperazine-diniethylacetal 1.7 g of the title compound (43) (G ₄₇ Hg ₅ N ₅ O ₁₁ , MW = 875).

The required as a reagent 1-I'ormyl-4- (1,3-dimethylpropyl) - piperazine dimethyl acetal is in an analogous manner as in Example 82 from 2.55 g of N- (1,3-dimethylpropyl) piperazine and 4j87 g iijlT-Dimethylforsiamiddimethylacetal obtained.

Example 44: 4- (4-Allylpiperazinyl) imidazolo [4,5-cif rifamycin S? (44)

In an analogous manner, as described in Example 1, from 2.0 g of 3-amino-4-iniinorifamycin S in 100 ml of THF and 3 _S 4 g of i-PoriDyl-4-allylpiperazin-dimethylacetal. 1.2 g of 4- (4-allyl-piperazinyl) -imidazolo-L4j5-c] rifamycin SV (44) (C ^ Xn ^ rO ^, MW = 845).

The i-formyl-4-allylpiperazine dimethyl acetal required as reagent is prepared in analogous manner as in. Example 82 obtained from 5 g of JT-allylpiperazine and 11.9 g of iijiT-dimethylformamide dimethyl acetal *

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At game 45; 4-l4- (3-butenyl) -piperazinyl-imidazolo .4 »5-c-rifamycin SV (45)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iciinorifamycin S in 50 ml of TH? and 4.0 g of 1-furyl-4- (3-batenyl) -piperasin dimethylacetal 4- (4-bis (3-butenyl) -1-piperazinyl] -imidazolo-4,5-o1-rifamycin SV '(45) (G ₄₆ Hg ₁ I ₅ O ₁₁ , MW = 859). MG found: '859.

The required as reagent 1-3? Ormyl-4- (3-butenyl) -piperasindiniethylacetal is in an analogous manner "as in Example 82 from 10 g of I- (3-butenyl) piperazine and 20 g of ΪΓ, Ν-Dinietnylforsiaoiid- difliet hy! acetal ej3halten _o

Example 46; 4-U4- (2-methyl -2-.propyl ) -pipera, zin ~ / l | imldaz: olol 4 _> 5-cj- rifamycin. SV (46 )

In an analogous manner as described in Example 1, from 2.0 g of 3-amino-4-iniinorifamycin 3 in 100 ml of TIiS ¹ and 3.62 g of 1-IF-normyl-4- (2-ethyl-2-propenyl) -piperazine dimethylacetal 1.15 g of the title compound (46) (G ^ gHg ₁ IT ₅ O ₁₁ , MW = 859). '

The required as a reagent 1-5Ormyl-4- (2-niethyl-2-propenyl) ~ piperazindiniethylacetal is in an analogous manner as in Example 82 from 21.13 g of li- (2-iaethyl-2-propenyl) -piperasin and 45 g Hjlf dimethylformamide dimethylacetal received «

Example 47: 4-] * 4- (2-Bth: / 1- (2- butenyl) -piperaz in: / lj-isida- SoIo 4,5-cl-rifamycin SV (4?)

In analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iniinorifaniycin S in 50 ml of THP and 4.0 g of 1-forsiyl-4- (2-ethyl-2-butenyl) -pipera3in-diniethylacetal the

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Title compound (47) (° Α8 ^Ε β5 ^Έ 5 ° 1Ι ^{3 MG = S87} 'prepared, MG found: 887 «

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

Example 48? 4 C4 (2 _{3-dimethyl-2-butenyl?)} -Piper azinylfimldäzolo ~ L4 "5 ~ cTrifam; ycin SV (48)

In an analogous manner as described in Example 1, from 2.0 g of 3-amino-4-i'-inorifainycin S in 100 ml of TKF and 4.0 g of 1-formyl-4- (2,3-dimethyl-2-) butenyl) -piperazine dimethylacetal 0.42 g of 4-J4- (2,3-dimethyl-2-butenyl) -piperasinyl34-iniidaso-Io [4,5-c] rifamycin · SY (48) (G.gHg ^ I ^ O ^, MG = 887).

The required as a reagent 1-I? Ormyl-4- (2,3-aimeth; yl-2-butenyl) -piperazindimethylacetal is prepared in an analogous manner as in Example 82 from 30 g of lT- (2j3-Di! 2iethyl-2-butenyl ) -piperasin and 53 g of NjH-dimethylformamide diacetylacetal.

Example 49: 4 ~ (4-Propylgylplpera2in? / I) -imidazolo'U ₁ 5-cJ rifamycin SY (49)

In an analogous manner as described in Example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THP and 3.7 g of 1-pormyl-4-propargylpipera3in dimethylacetal 1.05 g of 4- (4 -Propargylpiperazinyl) imidazolo- {4,5-c3 rifamycin SY (49) (G ₄₅ H ₅₇ N ₅ O ₁₁ , MW = 843).

The required as reagent i-Pormyl-4-propargylpiperasin-dimetiiy! Acetal ¹ KIrd ... in an analogous manner as. rp. Example 82 from 7.65 g propargylpiperazine and 15.6 g!, - ir-biBieti 'dimethyl acetal obtained »

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Example 50: 4- (4-Cyclopentylpiperazine: 1) -iniidazolo r4,5-cl rifamycin SY (50)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THP and 4.0 g of 1-Pormyl ^ -cyclopentylpiperazine-diniethylacetal 4- (4-glylopentyl-1 piperazinyl) -iniidazolo {[4,5-c] rifamycin SV (50) (G ₄₇ Hg ₃ U ₅ O ₁₁ , MW = 873). MG found: 873. "

The i-formyl-4-cyclopentylpiperazinedimethylacetal required as reagent is obtained in an analogous manner as described in Examples 80-82 from 10 g of N-cyclopentylpiperazine and 20 g of rijH-dimethylformamide dimethylacetal.

Example 51: 4- (4-Cyclohexylpiperazinyl) -imidazoloE4,5-cl

rifamycin SV (51) ·. ·

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THP and 4.0 g of 1-Pormyl ^ -cyclohexylpiperazine dimethylacetal 4- (4-cyclohexyl-1 piperazinyl) imidazolo- [4,5-cyrifamycin SV (51) (G ₄₈ Hg ₅ IT ₅ O ₁₁ , MW = 887).

The i-pormyl-4-cyclohexylpiperazin-dimethylactal required as reagent is obtained in an analogous manner, as described in Examples 80-82, from 10 g of H-cyclohexylpiperaine and 20 g of ϊί, ϊϊ-dimethylformamide dimethylacetal.

Example 52: 4- (4-phenylpiperazinyl) imidazolol4,5-cl rifamycin SV (52)

In an analogous manner as described in Example 1, from 2.0 g of 3-amino-4-iniinorifamycin 3 in 100 ml of TKP Lind 3.32 g of i-formyl-4-phenylpiperazin-diinethylacetal 0.79 g of 4- (4 phenyl

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piperazinyl) -iniidazolo- [4,5-cif rifamycIn SV (52) (Ο, οΗ, -οΠ-Ο. .. MG = 881).

The preparation of the acetal reagent is described in Example 91 »

Example 53: 4-r4- (3-trifluoromethylphenyl) -piperazinyl] imidazoles L4,5-cTrifamycin SV (53)

In an analogous manner, as described in Example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of ¹ THP and 5.14 g of 1-5Orniyl-4- (3-trifl standardized hylphenyD-piperazine- Dimethylacet al 0.73 g of 4-J4- (3-trifluoromethylphenyl) -pipera-2-yl-imidazolo [4,5-c-yrifaaiycin SV (53) (G ₄₉ H ₅₈ If ₅ O ₁₁ F ₃ , HG = 949)

The reagent as required 1-formyl-4- (3-trifluormeth.ylphenyl) -piperazine-dimethylacetal (3DP ". 158-160 G ⁰ / 0.2 -Torr) wirdjin manner analogous to that described in Example 80, from 25 g of ST- (3-trifluoromethylphenyl) -piperazine and 32.4 g of Ιϊ, Ν-dimethylformamide dinethyi acetal obtained

Example 54: 4- (4-Cyclopropyl-Niethyl-piperazinyl) -iiidazolef4,5-c] rifamycin SV (54)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml TaF and 4.0 g of i-F'ormyl ^ -cyclopropylmethylpiperazine dimethyl acetal 4- (4-Gyclopropylmethyl- piperazinyl) -imidazolo [4,5-c] rifamycin SV (54) (G ₄₆ Hg ₁ N ₅ O ₁₁ , HG = 859), MW found: 859

The "i-formyl" -cyclopropylciethylpiperazine dimethyl acetal required as a reagent is prepared in analogous manner as in Example 1.

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Play 80-82 described, obtained from 10 g of Ii-Cyclopropyloiethylpiperazin and 20 g itfjH-dimethylformamide dimethyl acetal.

Example 55: 4 - (4-C? / Clopentylmethylpiperazine ; yl) -imidazolo • f4 ? 5-cT? -Rifamycin S Y (55)

In an analogous manner as described in Example 1, from 1.0 g of 3-AmInO ^ -iminorifamyein S in 50 ml of THF and 1.26 g of i-porinyl -cyclopentylmethylpiperazine dimethylacetal 0.275 g of 4- (4-cyclopentylmethylpiperazinyl) - imidazolo [4,5-cJ rifamycin SV (55) (C ₄₈ Hg ₅ H ₅ O ₁₁ , MW = 887).

The 1-Porniyl-4-cyciopentylmethylpiperazine-dirnetnylacetal required as reagent is obtained in an analogous manner as described in Example 82 from 4.71 g of cyclopentylmethylpiperazine and 9.5 g of NjN-dimetylformamide dimethylacetal,

Example / 56; 4- (4-C7 / cloheptylmethylpiperazinyl) -imidazolo-C4.5-yrifamycin SY (56)

In an analogous manner, as described in Example 1, from 4.0 g of 3-amino-4-iminorifa.Qycin S in 50 ml of THi ¹ and 4.0 g of 1-J? Ormyl-4-cycloh.epty! Methyl ρ iperazine-dimethyi acetal the titanium compound (56) (C ₅₀ Hg ₉ N ₅ O ₁₁ , MW = 915) of mp 179-180 ⁰ C (decomposition) prepared. MG found: 915.

The i-pormyl-4-cycloheptylmethylpiperazine-diniethylacetal required as reagent is obtained in an analogous manner as described in Examples 80-82 from 10 g of H-cycloheptyl-diethylpiperazine and 20 g of N, N-dimethylformamide-dimethylacetal.

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Example 57: 4- (4-Benzylpiperazin yl) -iKiidazolo Γ4 »5 -rifamycin SV (57)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of THP and 4.0 g of 1-formyl-4-benzyl-piperazine dimethylacetal 4 - (4-benzylpiperazinyl ) -imidazolo ^ 4,5-c] rifamycin SV (57) (G ₄ QHg ₁ H ₅ O ₁₁ , MW = 885).

The ala reagent required i-forinyl-4-benzylpiperazine dimethylacetal is prepared in an analogous manner as in Examples 80-82 from 10 g of B-benzylpiperazine. and 20 g of H, H-disiethylformamide dimethyl acetal are obtained,

Example 58: 4-C4- (2-methyl-3-phenyl-propyl) -piperazinyl-1-imidazolone C4 _> 5-c-rifamycin SV (58)

In an analogous manner as described in Example 1, - 4 g of 3-amino-4-iniinorifamycin 3 in 50 ml of THF and 4 g of 1-formyl-4- (2-methyl-3-phenyl-propyl) piperazine dimethyl acetal made the title compound (58) (C ₅₂ Hg ₇ H ₅ O ₁₁ ^{.MG = 93} ° C. Found: 937 × "

The. 1-formyl-4- (2-niethyl-3-phenyl-propyl-1-piperazine-diniethylacetal required as reagent is prepared in an analogous manner as described in Example 82 from 10 g of M- (2-methyl-3-phenylpropyl) -piperazine and 20 g of Ή, ϊΤ-diethylforniamide-diniethyacetalc,

Example 59: 4-r4 ~ (2-Pyridyl) -4-piperazinyl-imidazolo1 4,5- cifamycin SV (59)

In an analogous manner, as described in Example 1, 2.0 g of 3-amino-4-iminorifamycin 3 in 100 ml of THF and 4.01 g

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1-Formyl-4- (2-pyridyl) -piperazine-diniethylacetal 1.28 g of 4- [4- (2-yridyl) piperazinyl] imidazolo [4j5-ciframycin SV (59) (C ₄₇ H ₅₈ U ₆ O ₁₁ , MW = 882).

The required as reagent 1-j? Ormyl-4- (2-pyridyl) -piOerazIndiinethylacetal (bp: 154-156 ° C / 0.7 Torr) is in an analogous manner as described in Example 80, from 25 g of lithium (2-pyridyl) -piperazine and 45 g of NjIJ-dimethylformamide dimethyl acetal

Example 60: 4- f4- (2-P: / ridylmethyl) -piperazinyl- imidazolo JiA , .5- C rifaniycin SY (60)

In an analogous manner as described in Example 1, 2.0 g of 3-amino-4-amino rifamycin S in 100 ml of THT ¹ and 4.26 g of 1-pormyl-4- (2-pyridylmethyl) -piperazin- dimethyl acetal 0.97 g of 4-L4- (2-yridylmethyl) -piperazinyl-1-imidazolo [4,5-cfjrifamycin SV (60) (G ₄₈ H ₆₀ U ₆ O ₁₁ , MW = 896).

The 1-5 ^{l of} methyl-4- (2-pyridylmethyl) -piperazine-dimethylacetal required as reagent (b.p .: 150-160 ° C / 0.1 torr) is prepared in an analogous manner as in Example 80 from 15.85. g li- (2 ^! -Pyridylcaethyl) -piperasin and 29.8 g of U, il-dimethylforinamide diniethylacetal obtained.

Example. 61; 4-l% - / _y 2-Te-ylrahydrofurylmethyl) piperaz ₁ in77lj -__ OaS-clrifa myci.n. SV (61)

In an analogous manner as described in Example 1, from 4.0 g of 3-Aciino-4-iminorifaniycin 3 in 50 ml of THF and 4.0 g of 1-I? Orinyl-4- (2-tetrahydroiurylsethyl) piperazine diethyl acetal the title compound (6i) (C ₄₇ H ₆₃ IT ₅ O ₁₂ , MW = 639) prepared »" β ~? V- ^ - ο θρ χ 3 3

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The required as reagent 1-Forayl-4- (2-tetrahydrof urylinethyl) -piperasin-dinieth.ylacte.l is described in an analogous manner ₅ as in Examples 80-82, from 10 g of lM- (2-Tetrahydrofurylniethyl) -piperazine and 20 g of N, £ F-DimetJaylforma & id-dimetliylacetal obtained _o

Example 62: 4-A-Fe-O, 3-dioxolan-2-yl) -eth 7/11 -piperazinyl-1 -imidazolo fi, 5-cyrifamycin SV (62)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iininorifaniycin-S in 50 ml of THi ¹ and 4.0 g of 1-J? Orciyl-4- [2- (T, 3 -dioxolan-2-yl) -et hylj-piperazine-diniethylacetal the. Title Compound (62) (G "H. N ₅ O ₁₃ , MW = 905). MG found (SiS): 905.

The SOrciainidacetal reagent required is obtained analogously to Example 82 from 10 g of Jüf- ^ 2- (1,3-dioxolan-2-yl) -ethylT-piperazine and 20 g of iJjN-dimethylforciamid-diaaethylacetal.

Example 63: 4-C4- (2-Met'h, oxyethyl ) -piperazine- 1- imidazolone- 4- _r -c] rifamycin. SY _ (β 3.)

As described in Example 1. In an analogous 7 / _else} are aua-2, O g-; ~ 3 AQiino-4-iniinorifaaiycin S. .100 nil THF and 3.19 g of 1-Porniyl-4- (2-Qetho2 : yetb.yl) -pipera2in dimethylacetal 0.43 g of the title compound (63) (C ₄₅ Hg ₁ XT ₅ O ₁₂ , IvIG = 863).

The required as reagent 1 -Pormy 1-4- (2-ra.ethox: yethyl) -piperaain-dimethylacetal (b.p .: 101-103 ° C / 0.2 Torr) is described in an analogous manner, as in Example.80 ^ aus'19 g IJ ^(2-M3th6iye; fhyl) -piperasin and 40 g iT, d-DiniethylformaiJiiddimethylacetal obtained ,,

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Eeiapiel 64: 4- C4- (2- iu-butoxy-ethyl) -piperazinyl-imidazole 14,5-clrifamy c in SV (64)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4 ~ iminorifamycin 3 in 50 ml of TKP and 4.0 g of 1-formyl-4- (2-ethoxyethyl) piperazine dimethylacetal the title compound (64) (G ₄₆ H ₆₃ N ₅ O ₁₂ , MW = 877) of mp 166 C (decomposition), "

The 1-Pormy1-4- (2-ethoxyethyl) piperaine dimethyl acetal required as reagent is prepared in an analogous manner as in Examples 80-82 from 10 g of H- (2-ethoxyethyl) piperazine and 20 g of Μ, ΪΓ-dimethylformamide. obtained dimethyl acetal »

Example 65; 4-L4- (2,2 - 'dimethoxveth: / l) -pi-O -azine: / l | -iaidazol- 14,5-clifamycin SV (65)

in an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifainycin 8 in 50 μl of THP and 4.0 g of 1-sulfinyl-4- (2,2-diaiethoxyethyl) -pipera3in- dimethyl acetal 4- [4- (2,2-dimethoxyethyl) piperazinyl] imidazolo [4,5-cyclic yyne SY (65) (O ₄₆ H ₆₃ U ₅ O ₁₃ , MW = 893) prepared, found MG:

893. '"

The 1-porrayl-4- (2,2-dimethoxyethyl) -piperazine-diniethylacetal required as reagent is prepared in an analogous manner as described in Example 82 from 10 g of iI- (2,2-dimethoxyethyl) -piperazine and 20 g iT, ii-dimethylformamide ~ dimethylacetal er- '. hold"

Example 66: 4- [4- ( 2,2'-Diethox : -ethyl) -piperazinyl-imiciazolo, U4-5 ^ c] -rifamycin.3V (66)

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In an analogous manner, as described in Example 1, from 2.0 g of 3-amino-4-iminorifamycin 3 in 100 ml of THI? and

acetal 2.0 g of the title compound (66.) (C ₄₈ Hg ₇ II O ₁ ^, HG = 921).

The 1-Pormyl-4- (2,2-diethoxyethyl) -piperasine dimethyl acetal required as reagent is prepared in an analogous manner as described in Example 82 from 6.19 g of S- (2,2-diethoxyethyl) piperazine and 8 , 60 g ii,! ~ Dimethylformamide dimethylacetal,

Example 67: 4- (4-Sthoxycarbonylpiperazinyl) -irfiidasolo 14.5-Clrifamycin SY (67)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-iminorifamycin S in 50 ml of TEF and 4.0 g of H-pormyl-II'-ethcxycarbonylpiperazin-dimethylacetal, the Tit elVerbindung (67) (67) ( C ₄₅ H-QlI ₅ O ₁₃ , MW = 877).

The preparation of the Pormamidacetal reagent is described in Example 90,

Example 68; 4- (4-iaopropyloxycarbonylpiperazinyl ) -imidazolo r4s5-c] rifamycin SV (68)

In an analogous manner, as described in Example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THP and 4.16 g of 1-Pormyl-4-isoprop5 ^r lcsycarbonylpiperazin-diT _i ethylacetal 1.17 g 4- (4-isopropyloxycarbonylpiperazinyl) imidazoIo 4,5-c rifamycin SV (68) (C ₁ A ₁ ^ O ₁ -, MW = 891).

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The ala reagent needed 1-Pormyl ~ 4-isopropyloxycarbonylpiperazindiinethylacetal (b.p .: 113-119 ° 0 / 0.15 Torr) -is prepared in an analogous manner, as described in Example 80, from 8.5 g Ef-Isopropyloxycarbonylpiperazin and 1.4,8 g JCJ ₉ IT-Diniethylforniainid diiätethylacetal obtained.

Example 69: 4-L4- (2-dichloroethylamino) -piperazinyl] -nitidazolo! 4,5-ol-rifaiiiycin SV (69)

In an analogous manner as described in Example 1, 2.0 g of 3-amino-4-i-diaminopamycin S in 100 ml of THP and 3 g of 1-formyl-4- (2-diethylaminoethyl) -piperazine-dimethylacetal 1, 05 g of T it el compound (69) (C, gHg JJgO ^ ₁ , MG = 876) prepared.

The required as a reagent 1-pormyl-4- (2-dimethylarainoethyl) piperazine-dioiethylacetal (b.p .: 110-111 ° C / 0.1 Torr) is analogous to Example 80 from 21.26 g of 2-Dinaethylaminoethylpiperazin and 40.28 g! ', li-Diniethylfornianiid dimethylacetal obtained

Example 70: 4- (4-Isobutyrylpiperazinyl) -imidazolo C4,5-c] rifamycin SV (70)

In an analogous manner as described in Example 1, from 2.0 g of 3-amino-4-iininorifaniycin 3 in 100 ml of THP and 3.9 g of 1-Pormyl-4-isobutyrylpiperazin-dimethylacetal 0.6 g of 4- (4 -Isobutyrylpiperazinyl) imidazolo 4,5-c rifamycin 3V (70) (C ₄₆ Hg ₁ H ₅ O ₁₂ , MW = 875).

The 1-Pormyl-4-isobutyryl-piperane-3-dimethylacetal required as reagent (b.p .: 145-150 ° G / 0.5 Torr) is prepared in an analogous manner as described in Example 80 from 25 g of H-isobutyrylpiperazine and 47.4 g ITjH-Diciethylforniamid diüiethylacetal obtained.

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Example 7.1.r..4 - (4-Metfaoxyc £

SV (71)

In an analogous manner as described in Example 1, as 2.0 g of 3 ~ amino-4-iminorifaniycin S in 100 ml of THI? and 3.85 g of i-i-amyl-metiiosycarbonyl-ethyl-piperaine-diniethylacetal 0.75 g of 4- (4-methoxycarbonylmethyl-piperazinyl) -in-idazolo [4,5-c] rifamycin SV (71) (C ₄₅ H ₅₉ IT ₅ O ₁₃ , MW = 877).

The 1-formyl-4-β-diethoxycarbonyneethylpiperaamine-dichloroacetal required as reagent (b.p .: 114-115 ° C / 1 torr) is prepared in an analogous manner as described in Example 80, containing 10 g of iT-methoxycarbonylmethylpiperazine and 75 g H, N-dimethylformamide dinie! acetal.

Example 72: .4 .-- (4-l-3-propyl-l-carbenylthyl ] ethylthipperazine in .!) »

imida zolo ~ C4.5 - c] rifaoiycin SV (72)

In an analogous manner as described in Example 1, v / ground aas 2.0 g of 2-amino-4-iminorifaßiycin S 100 in ail TUP and 4.38 g 1-i ^l orinyl-4-isopropylcarbamoyliiiethyl-piperazin-dim.ethylacetal Oj62 g of the starting compound (72) (O ₄ ^ H ₆₄ UgO ₁₂ , MW = 904).

The 1-pormyl-4-isopropylcarbainoylniethylpiperazine dimethyl acetal required as reagent (b.p .: 166 g / 0.2 torr) is prepared in a manner analogous to that described in Example SO, but 15 g of N-isopropyl-1-piperazine- acetamide and 24.1 g of ϊΙ, ίί-dimethylformamide dimethyl acetal,

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Example 73: 4 ~ (4-morpholinocarbonylmetafiallazazinyl ) ~ imidazolo- [4,5-αΙrifamycin SV (73)

In an analogous manner as described in Example 1, from 2.0 g of 3-amino-4-iniinorifamycin 3 in 100 ml of THP and 4.85 g of i-formyl-ci-quinolcarbonylmethylpiperazin-diacetylacetal 1.03 g of the title compound ( 73) ( ^G 4 ₈ ^H 64- ^T 6 ° 13> ^MW = 932).

The required as reagent 1 ~]? Ormyl-4-morpholinocarbonylmet.hylpiperazindimethylacetal is obtained analogously to Example 82 from 25 g of 4-Piperazinylacet5'lniorpholin and 35 g lijiT-Dioiethylformaoiid-diniethylacetal,

Example 74; 4-l4- (1-Methyl-2-dimethylaminoethyl ) -pioera sinyl imidazole E4,5-α3rifamycin SV (74)

In an analogous manner, as described in Example 1, from 2.0 g of 3-amino-4-iminorifamycin S in 100 ml of THP and 4.15 g of 1-pormyl-4- (1-niethyl-2-dimethylaniinoeth: 7l) -piperasine dimethyl acetal 0.84 g of the title compound (74) (G ^ HggNgO ^^, MW = 890). , '

The required Pormainidacetal reagent (3dp .: 115-117 ° C / 0.2 Torr) is prepared in an analogous manner as described in Example 80 from 17j1 g of ii- (i-methyl-2-dimethylaminoethyl) piperazine and 30 g li, I \ f-Dimethylformarüiddimethylacetal get

Example 75: 4- (4- Isobutyl-2-n- ethyl-piper a3-indinyl-imidazolo-y.4V5-c1 rifamycin * 3V (75)

In an analogous way, as in example .1. 'is prepared from ^ J' ', 0 g of 3-Aaino-4-iminorifamycin S in 50 ml of THF and 4.0 g of 1-

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3-Orcyl-4-isobutyl-2-ethyl-piperazine dimetyl alcohol prepared the title compound (75) (C ₄₇ Hg ₅ N ₅ O ₁₁ JMG = 875) from the snip, 175-180 ° (decomposition) found: 875 ·

The 1-formyl-4-isobutyl-2-methylpiperasine dimethyl acetal required as reagent is obtained analogously to Example 82, 10 g of 1-isobutyl-3-methylpiperazine and 20 g of diethylformamide-diethyl acetal,

Example 76? 4- (4-Isobutyl-2,5- dimethyl-piperazinyl- 1-imidazole Γ4, 5-c ] rifamycin SV (76)

In an analogous manner as described in Example 1, from 4.0 g of 3-amino-4-irininorifa ε-aycin S in 50 ml of TEI ' and 4.0 g of 1-isomyl-4-isobutyl-2.5 ~ dimetylpiperazine-dimethylacetal 4- (4-isobutyl-2,5-dimetyl-piperazinyl) -iaiidazole-4,4-cis-rifamycin 37 (76) (C ^ gHg ^ Si ^ O ^ j: MW = 889) prepared _a MW found 889 · · -

The required as a reagent 1 -]? Ormyl-4-isobutyl-2,5-dimethylpiperazin-disiethylacetal is prepared in an analogous manner, as described in Example 82, from 10 g of 1-isobutyl-2,5-diniethylpiperazine and 20 g U, H. -Diniethylforniainide diiiiet hy! Acetal receive «:

Beo-gp iel : £ [ΪΛ; · 4- (4-isobutyl-perhy drb-1,4-dias ep invl) -i- niidazo-Io C4> 5-cJ-rifamycin 3Y (77).

In an analogous manner as described in Example 1, from 4.0 g of "3-Aniinc-4-iminorifaniycin S in 50 ml of TH" and 4.0 g of 1-porGiyl-4-isobutyl-perhydro-1,4-diasepin -dimethylacetal 4- (4-isobutyl-perhyärp-i, 4-diazeplnyl) -iaiidaz.olo] 4, 5-cjrifamycin SY '(77) (G ₄₇ H ₅ O ₆ ^ n ₁ → ^{3: Λ} m = 875 prepared I £ G found:

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The 1-formyl-4-isobutyl-perhydro-1,4-diazepine dimethyl acetal required as reagent is expressed in "analogous" reactions as described in Examples 80-82, 10 g NI-sobutyl- perhydro-1,4-diasepin and 20 g 'Itf, ii ~ dimethylformamide dimethylacetal er -.- contents. ". '·

Example 78; 'S-dimethylaminomethylamino-Rifaiy / cin S (78)

"1 g of 3-aminorifamycin S is dissolved in-50 ml of absolute methylene chloride, treated with 425 mg of triethylamine (3 equivalents) and 1.28 g of Ν, ΙΊ-dimethylformamide dimethyl acetal (5 equivalents), and the reaction solution 45 minutes The mixture is left to stand 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 and evaporated in vacuo. Colored oily residue is applied to a column of 30 g of silica gel in chloroform and eluted with chloroform with increasing amounts of methanol (2.5 vol .- $). Evaporation gives crude 3-dimethyl-aminomethyleneamino-rifamycin is crystallized from ether / hexane and as a blue-black powder, mp. 150 - 155 ⁰ C, receives.

C it raj education - '''· ^:

Dissolve 400 mg of diethylaminomethyleneamino-rifamycin S. in 5 ml of dioxane, add 0.5 ml of 0.5 M citric acid solution, and lyophilize the solution to give 500 mg of 3-dimethylaminomethyleneamino-rifamycin S-citrate as blue black powder results, - -

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For example, 78A: 3-Bi methyläminoniet _i h: / Ienam ^ o _'i ~ Rifagiyc.in S Y (prepared by reduction of the corresponding rifamycin S-derivatives).

A solution of 0.5 g of 3-Dimethylam; moGiethylenamino-Rifaniy- "cin S in 5 ml methanol is treated with 2 ml of a 10% (w / v) aqueous sodium bicarbonate solution and 5 ml einer'10% (w / v) solution of -K. [i ¹ e (CI'T) r] [potassium ferrocyanide) was added in water, the solution intensiv.gerührt 3 minutes and diluted with each 20-EDLL water and chloroform. the chloroform phase is separated and & d._die .wässerige. phase The combined chloroform extracts are dried and evaporated to give 3-dimethylaminomethyleneamino-rifamycin 8Y as a yellow powder, which, when left in solution, rapidly reverts to quinone by atmospheric oxygen oxidation.

Example 79? S-Diethylaminomethr / lenamino-rifamycin S (79) '

A solution of 1 g of 3-aminoprifamycin 3 in 50 ml of alcohol-free 'Meihylenchlorid is cooled to -70 ⁰ C and with 285 mg. Triethylamine (2 equivalents) and 46Ο mg iminoyl chloride (2.1 equivalents) treated, stirred for 5 minutes at -70 ⁰ C and treated with 50 ml of water. The organic phase is separated off and the aqueous phase is extracted twice with diethyl chloride, the combined organic extracts are dried over sodium sulfate and evaporated in vacuo. The deep blue colored oily residue is applied to an acid of 100 g of silica gel in methyl acetate-hexane (1: 1) and with mixtures of hexane with increasing amounts (50 to 75 % by volume ) of ethyl acetate eluted by evaporation of the appropriate fractions and crystallization of ether-hexane, 3-diethyl-amino-methylene-amino-rifamycin S results as a blue-black powder, mp 133-135.

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The imino chloride used as a reagent can be prepared as follows; '.

A solution of 10.1 g in 50 ml of absolute diethyl ether is in St ickstoffat biosphere with stirring at 0 ⁰ C was added dropwise 12.7 g of oxalyl chloride and stirred for further 3 hours at +50 C. The white precipitate of IminoylChlorids is filtered off with suction in a suction filter, washed with ether and dried under high vacuum. The highly hygroscopic iminochloride is used without further purification for the reaction of 3-aminorifamycin S.

Example 80: 3 ~ (H-Benzyl-ffH-ethylamino) methyleneamino-rifamycin S (80)

A solution of 1.5 g of 3-aminorifamycin '8 in 50 ml of alcohol-free methylene chloride is treated with 637 mg of triethylamine (3 equivalents) and 4.1 g of IT-benzyl-iT-methylformamide dimethyl acetal (10 equivalents), 3 l / The mixture is left to stand at room temperature for 2 hours and mixed with 75 ml of water. The organic phase is separated off and the aqueous extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulphate and evaporated in vacuo. The deep blue colored oily residue is applied to a column of 200 g silica gel in chloroform and eluted with mixtures of chloroform with increasing amounts (1-5 vol.%) Of methanol. Evaporation of the appropriate fractions and crystallization from ether-hexane resulted da3 3- (Ii ~ BenzyllT-methylamino) methyleneamino-rifamycin S as blue-black powder, m.p. 138 -. 140 ⁰ C.

The N-benzyl-H-metiiyiformamide dimethyl acetal reagent used can be obtained as follows:

Q 7 '

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Sin mixture, from. 7.27 g of H-benzyl-Ii-methylariiin and 20 g of FjH-dimethylformamide dimethyl acetal is refluxed for 3 hours ₃ excess reactant in a water jet vacuum at 50 ° oil bath temperature and 20 Torr distilled off $ subjected to the concentrated reaction mixture fractional distillation, H -Benzyl-lv-methylformamide dimethyl acetal distilled at 104 - 106 ° C / 20 Torr »

Example 81; 3-pyrrolidinylmethyleneamino-R- isamycin S (81J ₁

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 dimethyl acetal (5 equivalents), allowed to stand for 1 1/2 hours at room temperature The deep blue colored oily residue is applied to a column of 150 g of silica gel in chloroform and eluted with mixtures of chloroform with increasing amounts (1-5 VoI, %) of methanol. Evaporation of the appropriate fractions and crystallization from methanol-water results in 3-pyrrolidinyl-methyleneamino-rifamycin 8 as a blue-black powder, mp 165-170 ⁰ G,

The if-Forsiylpyrrolidin dimethyl acetal required as reagent can be prepared as follows:

A mixture of 10 g of pyrrolidine and 42 g of ΪΤ, Η-dimethylformamide dimethyl acetal is refluxed for 3 hours, excess reactant distilled off under water pump vacuum at 50 C oil bath temperature and 20 Torr, and the remaining liquid subjected to fractional distillation, IT-formylpyrrolidin-diaiethylacetal distilled at 65 ° C / 20 torr,

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Example 82 ; 3- indolinylmethyl enaniino-rifaniycin S (82)

A solution of 1.5 g of 3-aminorifamycin 3 in 50 ml of alcohol-free methylene chloride is treated with 640 mg of triethylamine (2 equivalents) and 2.5 g of N-formylindolin-dimethrylacetal (5 equivalents), left to stand at room temperature for 1 1/2 hours , gently evaporated in a water-jet vacuum and dried under high vacuum. The deep blue colored oily residue is applied to a column of 200 g of silica gel in chloroform and eluted with mixtures of chloroform with increasing amounts (0.5-5 vol. $) Of methanol. The appropriate fractions are rechromatographed on Sephadex® LH-20, eluting with methanol. Evaporation of the eluate and crystallization from ether-hexane gives 3- (indolinyl) methyleneamino-rifamy'cine 3 as a blue-black amorphous powder with no definite melting point.

¹³ C-MdR (in

(148.8, 141.6, 131.8, 127.8, 125.5, 124.2, 109.9, 46.7, 27.0 ppm.)

The IT formylindoline dimethyl acetal required as a reagent can be obtained as follows:

3in mixture of 6.8 g of indoline and 20 g iJ, IT-dimethylformamide dimethyl acetal is heated at reflux for 3 hours, and the excess reaction agent in the "water pump vacuum at 50 ⁰ distilled off C. oil bath temperature and 20 Torr. The distillation residue, consisting mainly of crude IT Formyl-indoline-diethyl acetal, is extracted with several portions of toluene and the combined solutions are evaporated in a water-jet vacuum The residue obtained is used without further purification for the above reaction.

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Example 8 3: 3-Piperidinomethylene on J.no-rifamycin S (83)

Sine solution of 1 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is mixed with 425 mg. Treated triethylamine (3 equivalents) and 2.24 g IT-formylpiperidine dimethyl acetal "for 2 hours at 0, and with 50 ml of water. The organic phase is separated and the aqueous extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated in vacuo. The deep blue colored oily residue is eluted on a column of 100 g of silica gel in chloroform with increasing amounts (2-5% by volume) of methanol. After evaporation of appropriate fractions and crystallization from ether-hexane, 3-piperidinomethyleneamino-rifamycin S is obtained as a blue-hot powder , Mp 162-165 ⁰ C, received *

The required as reagent iJ-formylpiperidine dimethyl acetal can be prepared as follows: Sin mixture of 6.3 g of piperidine and '20 "g itf, B-DimethylformarniddiEiethylacetal is heated for 3 hours at reflux, excess reagent in a water-jet vacuum at 50 ⁰ G ÖlbadtempBratur and 20 Torr 'distilled off' - and; the remaining liquid subjected to fractional distillation _ei / S-Pol: ^^, distilled at

74 ^S ° C / 2Ö Torr. '

Example 84; 3- (4-methylpiperidinyl) methyleneamino-rifamycin

A solution of 1.5 g of 3-aminorifaniycin S in 50 ml of alcohol-free Metiiylenchlorid is with 637 g "triethylamine (3 equivalents) ιϊήχί 3.6 g of ri-Fbraiyl-4- & e ^: triylpiperidih-dinietl: iyl""'acetal (10 Equivalents), 2 1/2 hours at Rauintemaeratur stand selasaen, and mixed with 50 ml of water «

LLI

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The organic phase is separated and the aqueous extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate, evaporated in vacuo and chromatographed on a column of 200 g of silica gel in chloroform "%) Acetone and evaporation of the appropriate fractions, a residue is obtained, which after crystallization from ether-hexane, the 3- (4-methylpiperihdinyl) -methylenamino-rifamycin S as a blue-black powder, mp 88-90 °, results. '

The required as reagent IT-formyl-4-methylpiperidin-dimethyl acetal can be obtained as follows: A mixture of 5 g of 4-methylpiperidine and 14.9 g of U, &-dimethylformamide dimethyl acetal is heated for 3 hours at reflux, excess reagent distilled off in a water-jet vacuum at 50 ⁰ C oil bath temperature and 20 Torr, and the remaining liquid subjected to fractional distillation N-pormyl-4-methylpiperidine <-dimethylacetal distilled at 78 ° C / 20 Torr,

Example 85: 3- (8-Aza-1 "in 4-dioxa-spiroC4 _<5ldec ~ 8-yl) methylene ~ amino-rifamycin'S (85)

A solution of 2 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is treated with 575 mg of triethylamine (2 equivalents) and 3.6 g of U-formyl-4-piperidone ethylene ketal dimethyl acetal (6 equivalents), 2 1/2 hours left at room temperature and treated with 50 ml of water. The organic phase is separated and the aqueous extracted twice with methylene chloride.

^M s j &^ Fat.¹W /th

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The extracts are dried over sodium sulfate, evaporated in vacuo, and the deep-blue colored oily residue is chromatographed on a column of 200 g of silica gel in toluene. Corresponding fractions obtained by eluting with toluene with increasing amounts (10 to 75% by volume of ethyl acetate) are again chromatographed on Sephadex® LH-20, eluting with methanol. Kach crystallization of the evaporated fractions from methanol-water becomes 3- (8 -Aza-1,4-dioxa-spiro [4,53 <iec-8-yl) -methyleneamino-rifamycin'S as a blue-black powder, mp 178-180 ° 0,

The N-formyl-4-piperidone-ethylene ketal dimethyl acetal required as a reagent can be obtained as follows: A mixture of 20 g of 4-piperidone ethylene ketal and 42 g of JST ₉ S-dimethylformamide dimethy! Acetal is heated at reflux for 3 hours Water jet vacuum distilled off at 50 ⁰ C oil bath temperature and 20 Torr, and the remaining liquid subjected to fractional distillation of ε-formyl-4-piperidone-ethylenecetal dimethylacetal distilled at 111 - 114 ° C / Q, 5 Torr;

Example 86; 3-morpholinylmethyleneamino-rifemvcine S (86)

A cooled to -70 ⁰ C Lösungivon 3-Aminorifamycin S ·;.., · 50 ml of alcohol-free methylene chloride is treated with 1.6 g..Triethylamin- (7.5 equivalents) and 3.36 g Morpholiniminoylchlorid (10 equivalents) Stirred for 1 hour at -40 °, and treated with 50 ml of water. The organic phase is separated and the aqueous extracted twice more with methylene chloride The combined organic extracts are dried over sodium sulfate, and evaporated in Yakuüm.

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The mixture is dissolved in a minimum of methanol and treated with a 10 % (w / 7) aqueous potassium ferricyanide solution in the presence of potassium carbonate. The oxidation mixture is extracted twice with chloroform, the chloroform extracts are dried, evaporated and passed through a 100 g column Silica gel in chloroform is chromatographed by eluting with chloroform with increasing amounts (1-50%) of acetone and evaporation of the appropriate fractions gives a residue which, after crystallization from methanol-water, gives the 3-morpholinylmethyleneamino-rifamycin S as blue. black amorphous powder gives:

C-SMR spectrum (in CDCl-): 16O, 9J 67 $ 2j 49.1 ppm »

The required as a reagent, derived from morpholine iminoyl chloride can be obtained as follows: A solution of 5 g of H-formylmorpholine in 50 ml of absolute ether is treated under nitrogen and stirring at 0 ° dropwise with 5.52 g of oxalyl chloride, and the reaction solution further 3 stirred for hours at +50 ⁰ C * the white precipitate of the iminoyl chloride is filtered off in a pressure filter, washed with ether and dried in a high vacuum "the highly hygroscopic iminoyl chloride is used without further purification in the above reaction"

Example 87: 3-thiomorpholinylmethyleneamino-rifamycin S (87)

A solution of 1.5 g of 3-aminorifamycin S in 50 ml of alcohol-free methylene chloride is added to 637 mg of triethylamine (3 equivalents) and 5.6 g of I-formyl-thiomorpholin-dimethylacetäl (15 equivalents) for 60 minutes at room temperature

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The organic phase is separated and the aqueous extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate, evaporated in vacuo, and the deep blue colored oily residue is passed through a column with 250 g of silica gel 182 ⁰ - chloroform chromatographed · by eluting with chloroform with increasing amounts (1-5% by volume) of methanol and evaporation of appropriate fractions, a residue which, after crystallization from ether-hexane to 3-Thiomorpholinylmethylenamino-rifamycin S as a blue black powder "mp _e 177 results C, results ·

The required as a reagent IJ-Formylthiomorpholin-dimethylacetal can be obtained as follows: A mixture of 5 * 45 g Thiomorpholin and 15 »7 g of ίΙ, ίΓ-Difflethylformamid-dimethyiacetal is heated for 3 hours at reflux, excess reagent in a water jet vacuum at 50 ⁰ C. Distilled off oil bath temperature and 20 Torr, and the remaining liquid subjected to fractional distillation. N-formylthiomorpholine dimethyl acetal distills at 110-113 ° C / 20 torr.

Example 88? 3- (4-Methylpiperazinyl) -methyleneamino-Rifemycin S (88) '

A mixture of 1 g of 3-aminorifamycin S, 425 mg (3 equivalents) of triethylamine and 2.4 g (10 equivalents) of I-methyl-Li ^? Formylpiperazine dimethyl acetal in 50 ml of alcohol-free methylene chloride is allowed to stand at room temperature for 2 1/2 hours and processed analogously as described in Example 10. By chromatography on a column of 120 g

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Silica gel in chloroform, eluting with chloroform with increasing proportion (2 - 20 vol.%) Of acetone, and crystallization from ether-hexane, the title compound as a blue-black powder, mp 148 - 151 ° »obtained.

The required N-methyl - ^ '- formylpiperazine dimethylacetal reagent can be obtained as follows: A mixture of 5 g of H-methylpiperazine and H »9 g of N, N-dimethyl-. Formamide dimethyl acetal is heated at reflux for 3 hours. Following processing analogous to Examples 3-8 and 10 distilled the desired ST-methyl-li'-formylpiperazin-dimethylacetal at 84- 85 ° C / 20 Torr.

Example 89 i 3-i4- (2-Sth: yl-2-butenyl) piperazine? 7li-methylene amino-rifamycin S (89)

A mixture of 2 g. 3-Aminorifamycin S, 575 mg (2 equivalents) of triethylamine, 3.4 g (5 equivalents) of I ¹ -phenyl- ¹ L - (2-ethyl-2-butenyl) -piperazine-dimethylacetal in 50 ml of alcohol-free methylene chloride is added during 2 hours Room temperature left and analogously, as described in Example 4, processed. Chromatography over a column of 250 g of silica gel in chloroform and elution with chloroform increasing (0.5-10% by volume ) of methanol gives a crude product which is further purified by chromatography on Sephadex.lH-20 (elution with methanol) By crystallization from ether-hexane, the title compound as a blue-black powder, mp. 140 - 142 ⁰ C, obtained.

The H'-pormyl-H- (2-ethyl-2-butenyl) -piperazine-dimethyl acetal required as a reagent can be obtained as follows?

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A mixture of 10 g of U- (2-ethyl-2-butenyl) -piperazine and 16.7 g of HjH-dimethylformamide dimethyl acetal is heated at reflux for 5 hours. After processing analogously to Examples 3-8 and 10, the desired H ' Foriayl-1J - ^ - ethyl-2-butenyl) -piperazine dimethyl acetal at 12 ° C / 0.5 torr *

Example 9Oi 3 »(4-Etho: svcarbonylpiperazinyl) methyleneamino-Rifamyci h S (90)

A mixture of 2 g of 3-AmInOrIfBOiJcin S, 575 mg (2 equivalen te) of triethylamine and 3 »27 g (5 equivalents) of N-formyl-pipera zia-N-carboxylic acid ethyl ester dimethylacetal'in 50 ml of alcohol-free methylene chloride is 4 hours at room temperature , allowed to stand and analog _$ as described in Example 4, processed * Chromatography on a column of 250 g silica gel in Chloroform.und Sluieren with chloroform with increasing, proportion (0.5 - = x 10 Yoi _β%) methanol, a crude product the title compound as blue-black powder m.p. «160 obtained which is further purified by chromatography on Sephadex LH-20 ^ (elation with methanol)" is by crystallization from ether-Hesan - 165 ⁰ C, obtained "- '

As a reagent; Benst igt e, II ¹ ethyl-dimethy! can be obtained as follows acetal j

A mixture of 10 ₉ 87 g of piperazine-S-carboxylic acid ethyl ester and 20.44 g of ΪΙ, Η-dimethylformamide dimethy! Acetal is refluxed for 4 hours »After processing analogously to Examples 3 8 and 10 distilled the desired BT'-formyl-piperazine -H-

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Carboxylic acid ethyl ester dimethyl acetal at 128-130 ⁰ G / 0.75 Torr «

Example 91: 3- (4-phenylpiperazinyl) methyleneamino-rifam; ycine 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 -I'-phenyl-1H-phenyl-piperazine-dimethylacetal in 50 ml of alcohol-free methylene chloride is added 6 1 / 4 hours at room temperature and analogously, as described in Example 10, processed »By chromatography on a column of 250 g of silica gel in chloroform and chlorination with chloroform with increasing proportion (O ₅ , 5» 5 VoI * %) methanol is a crude product The product is further purified by chromatography on Sephadex® LH "20 (with methanol). The crystallized from ethanes-hesan gives the title compound as a blue-black powder with no definite melting point."

The ft'-formyl-JT-phenylpiperazine dimethyl acetal required as the reagent can be obtained as follows

A mixture of 10 g of N-phenylpiperazine and 18.3 g of U ₄ H-dimethylforsiamide dimethyl acetal is heated under reflux for 3 hours o Hach processing analogous to Examples 3-8 and 10 distilled the desired H ¹ -formyl-U-phenylpiperazindimethylacetal at 165 -. 167 ° C / 0.5 torr,

Example 92: 3- (4 "aza-tricyclor.5 * 2 _< 2 _< O ^{2> 6} jundec-8-en-4-yl) methyleneamino-RIfamycin S (92)

A mixture of 1 g of 3-aminorifamycin S, 283 mg (2 equiv.

47 2

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triethylamine and 1 ₉ 26 g (4-equivalent) of 4-formyl-4-azatricyclo [5 ₉ 2 ₉ 2 ₉ 0 ²⁹ jundec-S-ene-dimethylacetal "in 50 ml of alcohol-free methylene chloride is stirred for 6 hours. Room temperature and allowed to stand analogously, as described in Example 10 ^. Processed * by chromatography on a column of 100 g of silica gel in chloroform ₉ elution with chloroform with increasing proportion (0 - 10 vol%) methanol and crystallization from methanol-water is the Title compound as blue-black powder Smp. 173-176 ⁰ C, obtained

Example 93s 3-Dipropylaminomethvlenamino-Rifamycin S by reaction with dimethylsulfate complex

2.0 Ν, Ν-Dipropylformämid and 2 _s 0 g of dimethyl sulfate are allowed to stand for 3 hours at room temperature and the resulting oil was washed first with benzene, then twice with ether and freed from residues of the ether in vacuo The oil ₉ containing the N ₉ H-Dipropyiformamid-dimethyl sulfate complex is dissolved in 50 ml of absolute methylene chloride and added with stirring with 500 mg of triethylamine and 2.25 g of 3-aminorifamycin S The reaction solution is allowed to stand at room temperature until the 3-aminorifamycin S reacted completely The reaction mixture is then 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 sulfate and evaporated in vacuo. The blue-colored residue is chromatographed on silica gel , using chloroform with increasing amounts (2-10%) of methanol as the eluent verwendet.'wird _e · D in the form of a blue-black PuI-vera; - resulting in _9- practical 'fine 3' dipropylamine methylene

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-Rifamycin S can be converted analogously to Example 6 with ammonia gas in tetrahydrofuran directly to 4-dipropylamino-imidazoio [4,5-g] rifamycin SV (7) ', which is completely identical to the product of Example 7'

Example 94: 4-O-dimethylamino-imidazolo {4,5-c] rifamycin SY (1) -

In a manner analogous to that described in Example 6, a solution of 1.0 g of 3-dimethylamino-methyleneamino-rifamycin.S (78) in 50 ml of tetrahydrofuran is treated with ammonia gas. "By conventional processing, the title compound (1) is obtained. which is identical to the product of example 1 »,

Example 95: 4-Morpholino-imidazolo Du5-clrifamycin SY (2)

In an analogous manner as described in Example .6, a solution of 0.5 g of 3-morpholinomethyleneamino-rifamycin S (86) in 30 ml of tetrahydrofuran is treated with ammonia gas. "Conventional processing gives the title compound (2) which identical to the product of example 2 « -

Example 96s 4 »(4-» methylpiperazinyl) «» imidazolo) .4 »5-cl rifamycin SY (3)

In an analogous manner as described in Example 6, a solution of 0.5 g of 3- (4-methylpiperazinyl) methyleneamino-rifamycin S (88) in 25 ml of tetrahydrofuran is treated with ammonia gas. By conventional processing, the title compound (3 ) received with the. Product of the example is identical «. ,

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Example 97: 4- (g-Benzyl-H-aethylamino ) "" imidazoio "" 4 " _t " 5 " rifamycin SV (123

2.0 g of 3- (I "B _e n3yl% I-methylamino) -methyl-amino-rifamycin S.

(80) treated in 100'ml-tetrahydrofuran with ammonia gas "The usual processing gives the compound (12) which is identical to the product of Example 12"

Example 98: 4- »pyrrolidinylimidazolo [4t5-c.jrifaniyoin SY (19)

In a similar manner as described in Example 6, a solution of Op45 g. 3-Pyrrolidinylmethylenamino-Rifamycin.S

(81) treated with ammonia gas in 25 ml of tetrahydrofuran. "Conventional processing gives the title compound (19), which is identical to the product of Example 19

Example 99? 4-indolinyl-imidegoloΓ4 «5-o-rifamycin SY (20)

In an analogous manner, as described in Example β, a solution of 0.25 g of 3-indolinylmethyleneamino-Eifamyein S (82) in 15 l of tetrahydrofuran is treated with ammonia gas. "The usual procedure gives the title compound (20), halteii ^^ die:? ait d | ^; Pr ^

Example 1 00? 4- »piperidino-imidazolo 14 ^ 5-cl rifamycin SY (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. Yield is the title compound (21).

bo / - ⁸ 4-. Ι0.3 ... 19Θ3

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which is identical to the product of Example 21 " Example 101: 4- (8-aza-U4-dioxa-spiro) 4 " 51-dec-8-yl) imidazolone

4,5-c rifamycin SV (25)

In an analogous manner, as described in Example 6, weS. a solution of 0.2 g of 3- (8-aza-1,4-dioxa-spiro [4,5] dec-8-yl) -methyleneamiho-rifamycin S (85) in 15 ml of tetrahydrofuran treated with ammonia gas the usual processing, the title compound (25) is obtained, which is identical to the product of example 25. '

Example 102: 4 "(4-thiomorpholinyl) imidazole l4>5'-c] rifamycin SV (30) - '.

In a similar manner as described in Example 6, a solution of 0.5 g of 3-Thiomorpholinomethylenaminö-Rifamycin-S {87) in 30 ml of tetrahydrofuran is treated with ammonia gas · By conventional processing, the title compound (30) obtained with the product of Example 30 is identical. «· '..' -.

Example 103: 4-R4- (2-ethyl-2-butenyl) -pipera-2-halo-imidazolo

4 * 5 "c1rifamycin SV (47)

In an analogous manner, as described in Example β, a solution of 0.5 g of 3- [4- (2-ethyl-2-butenyl) -piperazinyl] -aminomethyleneamino-Rifamycih (89) in 25 ml) tetrahydrofuran is treated with ammonia gas "By usual processing, the title compound (47) identical to the product of Example 47 is obtained *

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Example 104: 4- (4-Bthozycarbonyl-.pipera-2-yl) ~ imida2olo .4.5-clrifamycin SY (67)

In an analogous manner as described in Example 6, a solution of 0.3 g of 3- (4-bethoxycarbonylpipera 2 -nyl) -methylenemino-rifamycin S (90) in 20 ml of tetrahydrofuran is treated with ammonia gas the usual processing will give the title compound (67) "which is identical to the product of Example 67"

Example 105: 4- (4-Methylpiperazinyl) -> imidazolo U »5-cl Rifamycin SY (52) "

_S in a manner analogous as in Example 6, a solution of 0.5 g of 3- (4-phenylpiperazinyl) methyleneamino-Rifamycin.S (91) in 30 ml of tetrahydrofuran is treated with ammonia gas "Due to the conventional processing, the title compound ( 52) which is identical to the product of Example 52 »

Example 106; 4-morpholino-imida2oloL4 _< 5-cl rifamycin SV (2)

In an analogous manner, as described in Example 2, 4.0 g of 3-amino-4-imino-rifamycin ^ ß reacted in 50 ml of tetrahydrofuran with 4 * 0 g tris-morpholino-aiethan By working up according to Example 2 is the title verb indang (2) obtained as yellow Xristallblättchen, mp 192-193 ° (from ether) "v

The tris-morpholino-mefhane used as reagent is obtained as follows: '.

A mixture of 15 ^: g of morpholine and 15 g of Η, Ι-dimethylformamide dimethyl acetal is refluxed for 12 hours under

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Afterwards, all fractions volatile in a water-jet vacuum of up to 130 ° C. are removed from the reaction mixture by distillation and the remaining brown oily residue, which rapidly crystallizes, is stirred and washed with a mixture of ether with a small amount of petroleum ether * The; obtained white crystals (18 g) of Ris-morpholinomethan melt after recrystallization

from chloroform / lther. at 241-243 ° * Calculated for ^ Ε ^ Έ-Ο ^ 27 271.36); 57.54 % O ₉ 9.29 '% H, 15.49 Hj found 57.5 % C, 9.2 % H, 15.4 ^! % U. ·

Example 107: 4 "dimethylaminobimidazoloL4 → 5-c) rifamycin SV (1)

Analogously to Example 1, 4.0 g of 3-amino-4-iminorifaiaycin S in 40 ml of tetrahydrofuran with Sris-dimethylamino-methane (4 ₉ O g) reacted and further processed "The resulting product, mp" 180-185 °, is 4 Dimethylamino-imidazolo f4j5 "c"] rifamycin SV (1) According to Example 1 identical "In an analogous manner, using tris-diethylamiao-methane, 4-diethylamino-imidazolo | 4,5-c] rifamycin SV (S) ₉ indentisch with the product of Example 6, received.

Example 108 *, 4- (4-Aza-t- rcyclo [ 5 _! I2 ^ 2.0 * jundec-e-en-yl-yl) - 'imidazole-Γ4 »5-olifamycin SV (93)

In an analogous manner as described in Example 1, from 4 g of 3-amino-4-iminorifamycin S in 50 ml of THP and 4 g of 4-pormyl-5,2,2,0 * J-undec-4-yl) dimethyl acetal the ¹ dithium compound (93) CC ₄₈ H ₆₀ H ₄ O ₁₁ , MW = 868) prepared '

The preparation of the required as reagent 4 ~ 5Orayl-4 ~ (aza-

Yes" "- *

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tricycle yyy _$ 2 _s 2 _? 0 ^f J = undec-8-en-4-yl) dimethyl acetal is described in Example 92.

Example 109: 4- 4- (2-H; ydrosy-2-meth; ylprop: v ^r l) ""piOerazin; yl -imidazolor4 * 5-c '] rifamycin SY (94)

In an analogous manner as described in Example V, - be prepared from 2.0 g of 3-amino-4 ^ iniinorifaEiycin S in 100 ml of THP and 5 ₉ 2 g of 1-formyl-4- (2-hydroxy-2-sietiiylprqpyl .J-piperazine-dimetyl acetal 0.5 g of the title compound (94) CC ₄₆ Hg ₃ I ₅ O ₁₂ , MW = 877).

The required as reagent 1 "Porayl-4- (2-hydroxy-2-methylpropyl) ~ piperazine dimethyl acetal (bp« 86-90 ° / 1 Torr) is in an analogous manner, as described in Example 80, from 30 g U- (2-trimethylsilyloxy-2-ethyl-propyl) -piperazine and 50 g., I-methylformamide dimethylacetar obtained

Example 110s 4 "4 °" (2 "2-"disieth; yl-1,3 ° dioxolane ~ 4-l-methyl) ° imida-aol 4 * 5-α-rifamycin Sl (95)

In an analogous manner, as described in Example 1, is from 4 g of 3-.Amino-4-isinorrifamycin S in 50 ml of TEF and 4 g of 1 -]? Qrayl-4-C2,2-dimethyl ^: 4 ^? _$ 3-iosolan-4-ylmethyl) piperazine dimethyl acetal, the title compound (95) (C ₄₈ H ₆₅ I ₅ O ₁₃₉ MG-919). 919 ©

The necessary as reagent 1-formyl-4- (2,2-dimethyl-1,3-dioxolan-4-ylQiethyl) is -piperazine-dimethylacetal in an analogous We ^f ise, .as in Example 82 described, from 10 g I " 4 "(2j 2" DimetJay 1-4 ₉ 3-diolan-4-vilmeth-1) -piperazine.

anf 20 i ^: iv ^ Siöitt ^ e

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"61 589/18

Example IIIt 4- (4-Cyclobutyl-Nieth-yl-piperazinyl) -imidazolo- 14,5-c- Virifamycin SY (96)

In an analogous manner as described in Example 1, from 4 g of 3-amino-4-iminorifaniycin S in 50 ml of THP and 4 g of 1-formyl · 4-cyclobutyl-methylpiperazin-dimethylaeetal the title compound (96) (C ₄₇ H ₆₃ IT O ₁₁₉ MG = 873) «

The required as a reagent 1-5 ^l ormyl-4-cyclobutylmethylpiperazin dimethylacetal as described in Example 82 in a manner analogous to _9, from 10 g I-cyclobutylmethyl-piperazine and 20 g Ι, Ι-dimethylformamide dimethyl acetal obtained ₀

Example 112; Formation of salts with bases

To a stirred suspension under nitrogen of _15} 5O g of 4-dimethylamino-4,5-imidazolo £ q3rifamycin SY (1) in 150 ml of water is added dropwise (0.987 equivalent) was added with ₉ O 2O ml of a 1 N-aqueous solution latriumhydroxid , The resulting yellow-colored solution is filtered and the filtrate is subjected to lyophilization. Bas remaining 4-dimethylamino-imidazolo [4,5-c-pyrifamycin SV-sodium salt is an amorphous, water-soluble powder. The solution has a pH of about 7.3 "Pur C ^ H ^ (MW 786.85) calculates 2.92% Ia; found 2.87 % Ia,

In an analogous manner with. a corresponding potassium hydroxide solution, the potassium salt of the compound (1) obtained ₀

In an analogous manner, generally acidic imidazolorifamyls of the SV series (Pormel IA) can be processed to corresponding salts. "

4 7 2 5 8 7 -89- 3Ο · 3.1983

  61 589/18

Example 113: Education; of acid addition scales

To a stirred suspension of 8.75 g of 4- (4-isobutylpiperazinyl) -imidazolo [. 4,5-c] rifamycin SY (4) in 165 ml of water is added 10.0 ml of 1 N aqueous hydrochloric acid (0.985 equivalent) , The mixture is filtered and the filtrate is subjected to lyophilization. The resulting 4- (4-isobutylpiperazinyl) imidazole © '4,5-c rifamycin SY hydrochloride forms a water-soluble yellow amorphous powder * »For C ^ gHg-H ₁ - Calculated: 3.95 % Cl, found: 4.08 % Cl,

In an analogous manner, generally hydrochlorides of basic imidazolone can be prepared. The process is analogously also applicable to the preparation of addition salts of other water-soluble acids.

Example 114: Capsules containing 0.25 g of the active ingredient are prepared as follows: ___

Composition (for 1000 capsules)

Active ingredient 25O ₉ O g

Corn starch .. 5O ₉ O g

Polyvinylpyrrolidone 15 ₉ 0 g

Magnesium stearate 5.0 g

Ethanol qs _e

The active ingredient and the maize starch are mixed and moistened with a solution of the polyvinylpyrrolidone in 50 g of ethanol * The wet mass is passed through a sieve with a mesh size of 3 mm. printed and dried at 45 ^

24/2 5 8 7 -90 »30.3.1983

61 589/18

dry granules are sieved through a sieve with a mesh size of 1 mm and mixed with 5 g of magnesium stearate. The mixture is packed in 0.320 g portions in size 0 capsules

Example 115: Tablets containing 250 mg of the active ingredient are prepared as follows:.

Composition (for 1 tablet):

Active ingredient "250 mg

Microcrystalline cellulose 80 mg

Hatrium carboxymethyl starch 10 mg

Magnesium stearate ^v 3 mg

Talc 7 mg

350 mg

The active ingredient is homogeneously mixed with the additives and added. Tabeltten pressed «

The tablets are coated with 1 mg aqueous varnish for the preparation of the film dragees. «

Instead of sodium-carboxymethyl starch, sodium carboxymethylcellulose can also be used «

Example 116: Plug-in capsules containing 100 mg of the active ingredient _s are prepared as follows:

Composition (for 1000 capsules):

Active ingredient 10O ₉ OO g

Lactose '5O ₉ OO g

Ethyl cellulose 1 _s 50 g

L 1 2 b Ο / -91- 30.3.1983

61 589/18

Stearic acid j ₉ 50 ^

153 ₉ OO g

The active ingredient is mixed with the lactose, the resulting mixture is dissolved with a solution of ethyl cellulose in a quantity of 10 times the weight of methylene chloride, beaten through a 3 mm mesh sieve and dried at a temperature not exceeding. The dry granules are passed through a sieve 0.5 cua mesh size and mixed with the powdered stearic acid ♦ The mixture is then bottled in portions of 0 ₉ 153 g each in size 2 capsules «

As active ingredient in Examples 114-116, any of the compounds (1) - (77), (93-96) ₉ and (78) - (92) can be used. Particularly preferred as active compounds are the.Yer bonds (1), (2), (3), (4), / (10), (12), (19), - (21) and (57), and (82). ''''''"".'

Example 117? Dry pills or vials containing 500 mg of the active ingredient Sj can be prepared as follows

Composition? (for 1 ampoule or Yial):

Active ingredient o ₉ 5 g

Mannitol 0.05 g

water

Bine sterile aqueous solution of the active ingredient and mannitol is sealed under aseptic conditions in 5 ml ampoules or 5 ml viais and tested «

-92- / 30.3.1983

61. 589/18

As "active compound is preferably a Alkalimetallsal z _$ z * as such of Example 112 was used.

Example 118: Experimental Report.

1. Tested compounds are indicated in the following Tables 1 and 2 by the same numbers under which their preparation is given in the preceding examples. «

2y test organisms are given in the following Tables 1 and 2 in a shortened form as follows:

"Staphylococcus aureus loB staph

Staphylococcus aureus 2999 staph. 2999

Escherichia coli 205 Esch. 205 Sscherichia coli 2018 · Esch »2018

Salmonella Typhimurium 277 Salm. 277;

Proteus morganii 2359 prot. 2359

Proteus morganii 1518 Prot. 1518

Pseudoaionas aeruginosa K 799/61 Pseu. 799

Mycobacterium tuberculosis Myc.tub _o

3. Methodology

The antibiotic activity of the test compounds in vitro was determined by the agar dilution method. Ericsson, H.M., and Sherry S.G., 1971 Acta Path. Microb. Scand. Section B, Suppl. Uo. 217 »Vol. 1-90, determined in DST Agara." The minimum concentrations (MIC) still found to inhibit the growth of test organisms are expressed in micrograms per milliliter (μg / ml) for the tested compounds in the Table 1 given.

30 * 3.1983 61 589/18

Table 1

Antibiotic activity of imidagolo 4j5-c rifamycine

Verb ", StapiuStaph" Bach "Eseh. Salm. Prot "Prot" Pseu * Myc. g 1QB 2999 205 2018 277 2359 1518 799

1 0 * 005 0o005 8th 4 16 8th 4 2 0 * 97 2 0 * 01 0 * 005 16 16 3.2 4 4 8th 1.9 3 0.0T 0.0.1 16 16 32 16 16 4 0 * 97 4 0 * 005 0β005 4 4 8th 4 4 8th 0.97 5 0 * 005 Oo 005 4 4 8th 16 8th 16 1 * 9 6 - * - 128 128 128 128 * 128 128 - 7 0005 0005 8th *8th 16 8th 8th 8th 8th 0 * 01 0 _β 01 8th 8th 32 8th 8th 8th - 9 - - 8th 8th 32 - 8th 1 8th - * 10 0 * 005 0 * 005 4 4 16 4 4 8th - 11 , 12:01 12:01 8th 8th 32 8th. 2  '8th 12 0001 0 * 001 8th . 8th 32 8th 1 8th - 13 0.Ö5 0 * 05 8th 8th 32 .. 16 16 8th - 14 Ό.05 0.0.1 8th 16 32 16 16 16 - 15 0 * 005 0 * 005 8th 8th 32 '4 8th 16 "a 16 0 * 01 0o01 8th 8th 32 "4 2 " 8th - 17 0005 0005 32 64 64 .32 64. 64 - 18 0005 0.005 2 4 16 2 4 8th 0.48 19 0005 0005 2 4 8th 4 4 8th' 0.48 20 - 8th 8th 32 8th 4 16 - .. 21 0 * 005 0o005 4 4 16 4 4 16 22 0 * 005 0 * 005 16 8th 32 4 4 16 - 23 0.1 0.1 16 8th 16 16 16 16 - 24 12:05 12:01 8th 4 16 4 8th 16 - 25 0005 0 * 005 8th 16 16 8th 8th 16 , θ # 91 26 0 * 05 0 * 01 16 32 84 16 16 16 - 27 0 * 001 0001 .8th... 8th. 32 ,8th:.. 2, 8th -

-94-

30.3 * 1983 61 589/18

Verb.Stapiu Er. 10B

Stapia, Ash Ssen, Salm Prot _e Prot _e Peen. 2999 205 2018 277 2359 1518 799

28 0.005 0005 4 - 8th 32 4 16 .2 2 8th 29 MB - "32 8th 32 128 8th 8th 8th 30 - " 8th 32 8th 32 8th 8th 32 31 0002 0001 8th 8th 8th 32 8th 8th - 8th 32 0001 0001 8th 8th 8th -32 8th 8th 8th 33 0 * 001 0001 8th 8th 2 32 4 4 32 34 - - · 8th 32 2 32 8th 8th 32 35 - - 8th .8th 8th 32 8th 8th 8th 36 -. 2 8th . 8th 32 8th 8th 8th 38 0005 0005 4 8th 2 16 2 4 16th 39 -. -. 8th 8th 8th 32 8th 8th 32 40 0005 0005 8th 8th 8th 32 8th 8th 16 41 0005 - 8th 16 2 - 8th 8th 32 42 0005 8th 8th "32 8th , 8th 32 43 12:01 0005 8th 4 " 32 8th 8th 16 44 - 8th 8th 32 8th 8th 32 45 " -0.01 00005 1 32 8th 8th 32 46 - .. _-. 8th 32 8th 8th 32 47 00005 0005 4 16 4 4 32 48 0001 0001 8th 32 8th 8th 32 49 -0,001 0001 32 32 8th 8th 8th 50 12:01 12:01 8th 32 8th 8th 8th 51 12:01 - 32 32 8th 8th 8th 52 - 8th 32 8th 8th 32 53 0 * 01 0001 8th 32 8th 2 32 54 0005 0005 8th 32 8th 8th 16 55 12:01 00001 1 32 2 2 32 56 0005 '-. 8th 32 8th  8th" 32 57 0005 0005 4 16 4 ^: 4 16 58 0005 0005 3 v 32 16 16 16

0.97

30.3.1983 61 589/18

Yerb * Stapiu Stapiu Esch " 8th S ch * Salm " "Proto Prot " Pseu * Myc « Ho » 1Ob 2999 205 2018 277 , 2359 1518 799 tab * 59 12:01 12:01 8th 8th 32 8th 2 8th 60 12:02 12:02 32 32 128 32 32 64 61 0005 ' 0005 16 4 32 4 4 32 62 12:02 12:02 32 32 128 8th 8th 32 63. 12:01 12:01 16 8th 32 8th 8th 32 64 0 * 01 0005 16 16 64 16 16 16 - 65 0 * 05 12:01 32 32 128 32 32 32 66 12:01 12:01 16 16 128 16 16 32 ~ " 67 0005 0.005 16 16 64 16 16 32 68 .0.01 -. 32 32 32 32 8th 8th - ' 69 12:05 12:05 32 32 128 32 32 128 70 0o02 0 * 02 32 32 128 32 32 128 71 12:02 12:02 32 32 128 32 32 128 - 72 12:05 12:05 32 32 128 32 32 64 - 73 12:05 12:05 128 128 128 32 32 128 74 0.5 0.5 128 32 128 32 32 128 75 12:01 8th 8th 32 8th 2. 32 - 76 12:01 12:01 32 8th 32 8th 8th 32 - 77 o.oi 12:01 8th 32 8th 8th 8th

- s not tested «

1 r

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Table 2 Antibiotic Activity of Rifamycin Formaniidines __

Verb »Stapii * Staph. Esch «Bach * Salm. Prot. Prot. Pseu. Myc. No · '· loB. 2999 205 2018 277 2354 1518 799 tab.

78 0o05 12:05 16 16 16 16 4 4 0.00045 79 0 * 05. 12:05 32 64 32 16 16 .16 0 * 0037 80 -. 0005 64 64 64 16 32 64 0.0075 81 0005 0005 16 16 ' 8th 4 4 16 0.00022 82 0005 12:01 16 16 16 8th 4 16 0.0037 84 128 12:05 64 , 32 64 16 16 64 mm 85 -. 0005 64 128 32 16 32 64 - 86 0 * 05 12:05 4 ' 4 4 16 - 4 4. mm 87 /0.005 0005 64 64 64 16 32 32 88 0.005 " 0005 16 16 16 64 4 · 8th 0015 89 12:05 0.1 64. 64 64 64 16 16 12:03 90 12:01 12:05 128 64 128 16 16 16 - 91 0005 12:05 16 32 16 16 16 16 O.OOO45 92 128 0005 64 16 64 16 16 64 0.0018

Claims (3)

247 30 * 3 * 1983 61 589/18 Erfindungaansprucn 1 · For the preparation of a 4-aminoimidazolo-f4,5-c] rifamycin S? or S of the formula. R CHo CH, H, OH OH 1Y!  CO HU-C At the (IA) or * 24 7 30.3 * 1983 61 589/18 R GH-CH, CH, (IB) At the wherein H is hydrogen or acetyl and Am is a secondary amine derived amino group bearing two identical or different monovalent hydrocarbyls of the heterocyclyl radicals having at most 20 C atoms ₃ or a corresponding divalent radical 5 which forms a non-aromatic nitrogen containing heterocyclyl radical with the amino group all these radicals mono- or polysubstituted by halogen, hydroxyl, - may be substituted mercapto, JSiederalkosylj Mederalkozycarbonyl, an unsubstituted or I-mono- or di-lower alkylated carbamoyl, formyl ₉ O20, acetalised or ₀ ketalized Οζο and / or a diniederalkylierte amino group, as well. Salts of corresponding compounds having salt-forming properties, characterized in that a U *, I'-disubstituted 3-aminomethyleneamino-rifamycin derivative of the formula 30 * 3 * 1983 61 589/18 R GH ,, GH, C ο. * - ♦ νν ^Λ Λ ν \ ^Λ Λ I i OH OH' COGH CH OH O
ELC i !! SH Il O ^Λ I j! U = CH-Am - CO O wherein R and Am have the meanings mentioned above, or a salt thereof, treated with ammonia and desirably an SV-type compound obtained is oxidized to an S-type compound or an obtained S-type compound to a compound of the SV type and / or converts a resulting free compound having salt-forming properties into a corresponding salt or a salt obtained into the corresponding free compound. ^E Process according to item 1, characterized in that a 3-aminomethyleneaminifamycin S derivative of the formula V in which R is acetyl and Am by the partial formula (At the-) , A -100- 30.3.1983 61 589/18 Wherein each of R and R is independently a lower alkyl or lower alkenyl which is mono- or polysubstituted by hydroxyl, mercapto, triethioalkoxy, lower alkoxycarbonyl, an unsubstituted or U-mono- or di-lower alkylated carbamoyl, portyl, oxo, acetalated or monohydricalkenyl; ketalized oxo and / or a lower alkylated amino group may be substituted; a lower alkynyl represents a cycloalkyl or cycloalkyl-lower alkyl which may optionally have one or two double bonds; an unsubstituted or substituted by halogen, hydroxy _s trifluoromethyl, an unsubstituted or I-mono- or -diediederalkyliertes carbamoyl or JJiederalkoxycarbonyl substituted phenyl or phenyl, wherein "lower" denotes a radical having at most 7 _S, preferably at most 4 "C-atoms, or at most bicyclic heterocyclyl or heterocyclylalkyl having at most two heteroatoms selected from oxygen, nitrogen 12 and / or sulfur, wherein R and R by a simple carbon-carbon bond or via an oxygen, sulfur (II) - or nitrogen atom _t which may optionally be substituted by the radical R defined above, be connected to each other and together with the amino nitrogen can form a 4- to 8-membered non-aromatic heterocyclic ring and react with ammonia. " 3, according to item 1, characterized in that a _3-s Aminomethylaminorifamycin S derivative of the formula V ₉ wherein R is acetyl and the symbol Am is a radical of partial formula 4/2 D 8 / - ¹⁰¹ - 30.3-1933 61 589/18 -IT \ Η-Η "(At _B ) in which m and η are each independently an integer from 1 to 5, forming an at least 5-membered ring, and R is a hydrogen atom, a formyl group, a functionally modified carboxyl group or an unsughened or one as defined in item 1 substituted, not more than 10 carbon atoms' having hydrocarbyl or heterocyclyl radical, wherein in the heterocyclic radical, the free valence in each case starting from a carbon atom * 4 · Yerfahren according to item 1, characterized in that ₉ is a ^ -Aminomethylehaminorifamycin-S derivative of the formula Y, wherein R is acetyl and the symbol Am is a 1-piperazinyl radical of the formula 3 ..- .. ..
means j where R is a Hiederalkyloder H _"s iederalkenyl by the Hydrosyl, mercapto, liederalkozy one or more times, liiederalkosycarbonylj an optionally H-. mono- or -diniederalkyliertes carbamoyl, formyl, Οζο, acetalised or, ketalized oxo, and / or an amino group substituted diniederalkylierte ₉ may be a fiederalkenyl, a cycloalkyl or cycloalkyl-lower alkyl which may optionally have one or two double bonds _{a is} an unsubstituted or halogen, -102- 30.3-1983 61 589/18 Trifluoromethyl, an optionally Η-mono- or -diediederalkyliertes carbamoyl or lower alkoxycarbonyl mono- or polysubstituted phenyl or phenyl, or an at most bicyclic heterocyclyl or Eeterocyclylalkyl having at most two heteroatoms selected from oxygen, nitrogen and / or sulfur, where "lower" is a radical denoted by at most 7, preferably at most 4, carbon atoms, and reacted with ammonia. « Method according to item 1, characterized in that a 3-aminomethyleneaminoramycin S-berivate of the formula Y in which E is acetyl and Am has the meaning of Am _n indicated in point 4, in which the symbol R is a straight-chain or simply branched lower alkyl, lower alkyl alkenyl or lower alkynyl, where "lower" denotes a radical with at most 7 _S, preferably at most 4 C atoms, with ammonia, 6 »Process according to item 1, characterized in that a 3-aminomethyleneaminoramycin S-berivate of the formula V _s in which R is acetyl and Am as indicated in point 4 3 meaning of Am. in which the symbol R is cycloalkyl or cycloalkyl methyl having 3-6 ring members, or denotes a phenyl or benzyl which may be substituted by trifluoromethyl, carbamoyl or lower alkoxycarbonyl, where "lower" denotes a residue having at most 7, preferably at most 4C Called atoms, reacted with ammonia ί * / 4 y Ό / -103-30,3,1983 61 589/18 7 »Method according to item 1, characterized in that. a 3-Aminomethylenaminorifamycin S derivative of the formula V ₉ wherein R is acetyl and Am specified in point 2 1 2 Meaning of Ai ^ has, in which the symbols R and R $ e. represent an unsubstituted alkyl having 1-4 G atoms, or one of them ein.Cycloalkyl or a Cycloalkylrnethyl with 3-5 ring members, or benzyl means, reacted with ammonia « 8. A process according to item 1, characterized in that a 3-aminomethyleneaminifamycin S derivative of the formula V in which R is acetyl and Am is as defined in point 2 1 2 ne meaning of Am, wherein the symbols R and R together with the nitrogen atom denote a saturated, monocyclic, 5-8 ring members containing heterocyclyl radical, which may also contain an oxygen or sulfur (II) atom as a ring member, wherein the heteroatoms are separated from the nitrogen atom by at least 1 C atom, reacted with ammonia 9, A process according to any one of items 1 to 8, characterized in that the end product is produced in the form of the hydroquinone of the SV series * 10 * Process according to item 1, characterized in that 4-dimethylamino-imidazolo J4 ₉ 5-cQrifamycin SV is prepared ₉ by reacting 3-dimethylaminomethyleneamino-rifamycin-S with ammonia * 4 / I DO / ~ ¹ ° 4-30.3.1983 "61 589/18 11. Procedure. according to item 1j, characterized in that 4-morpholino-imidazolo J4,5 »cjrifamycin SY is prepared by reacting 3-morpholinomethyleneamino-rifamycin S with ammonia» 12o method according to item 1 _{9 9} characterized by preparing 4- (4-methylpiperazinyl) -imidazoloJ4,5-cJ rifamycin SV by reacting 3- (4-methylpiperazinyl) -methylenaEiinorifamycin S with ammonia © 13 · Sin method according to item 1, characterized in that ^ (* Isobutylpiperazinyl 4-) imidazolo [4,5-c] rifamycin SV produces 4- by reacting 3- (4-Isobutylpiperazinyl) methyleneamino-rifamycin S with ammonia to converts * 14 * Sin method according to item 1 _9, characterized in that 4-pyrrolidinyl-imidazc "lo>] 4,5-c] 3-rifamycin SV produced by reacting ^ -Pyrrolidinylmethylenamino-rifamycin S with ammonia"