SU644388A3 - Method of obtaining s rifamycin compounds (substituted in position 3 with aliphatic-substituted amino group), or their hydroquinones, or their salts, or quaternary ammonium salts - Google Patents

Description

-CH-lC5f)

five

In which n "O or Ij

Z is a lower apkyl or lower alkene group which may also be substituted by an unsubstituted 1 {phenyl, cycloalkyl- substituted phenyl, cycloalkyl or cycloalkenyl or unsubstituted vsm substituted by lower alkyl groups substituted by lower alkyl groups; or a cycloalkenyl group, moreover the finge groups may also be substituted by halogen atoms

1, is a hydrogen atom or a lower alkyl on or a lower alkenyl group;

Za is a lower alkyl or lower alkenyl group, or in the appropriate case, a wiesta with 2- means a double bond and Gl and Z 3 together mean a lower aylidene 1shi lower alkenylidene group and Z and Z-together signify 1; alkyi 1 vid alkleshlenovy group, but. similarly, Z and Z can mean an alkylenic or alkenylene group, eopk Zg with Z. means a double bond 75 each means an atom or a lower alkyl group, in which Z and Z are in the indicated or formed alkylene or alkenyl group and Z, or Z and With 22 cycloaliphatic groups, one or several non-adjacent C – C ring pairs can be bonded to each other in the appropriate case, directly or through a lower alkylidene or alkylene 5o group or one hydrocarbon atom of a lower alkylene group can be spirocyclicly mixed and these groups have no more than 12 atoms; carbon,

or their hydroquinones, or their salts, or quaternary ammonium salts, characterized in that rifamycin S is reacted with an amine of the general formula HA, where A has the given values, followed by isolation of the desired product as derivatives of hydrophinones, or their salts, or Quaternary ammonium salts.

Preferably, straight or branched alkylene groups are used which form cycloalkyl residues with ring carbon atoms and especially with 5-6 ring carbon atoms, or cycloalkenyl residues preferably with 5-8 ring carbon atoms.

Unbranched apkylene groups or alkenelenic groups with the indicated carbon atom of the above formula give unsubstituted cycloaliphatic rings; in the case of branched alkylene groups, the formed rings are replaced by alkyl groups, in particular lower alkyl groups with 1-5 carbon atoms, primarily methyl groups . Such cycloalkyl groups with 3 to 8 carbon atoms in the ring are, for example, cyclonropyl, cyclobutyl, cyclopentyl, cyclohexyl, dicloheptyl, 4-methylcyclohexyl, 2,6-, and methyl cyclohexyl, 3,5-dimethylcyclohexyl —silgroups or 1-methyl-4-isopropylcyclohexyl (p-menthyl) - or 1-methyl-3-iso-pro pylscyclohexyl (m-menthyl) -grush. From the cycloalkesh groups, for example, 1-cyclopenten-1-yl, 2-cyclopenten-1-sh, 3-cyclopenten-1-yl, 2.4 cyclopentadien-1-yl, 1 cyclohexene-1-yl, 2-cyclohexen-1-yl, 3-cyclohex-, 1,3-cyclohexadium 1-yl and 1,4-cyclohexadien-1-yl, 1-P-menten-4-yl, 2-P-menten-1 silt, 3-P menthen-1 III or, if appropriate, other isomers of this group, or the corresponding compounds with two double bonds, for example the hydrocarbon residues of terpenines, phellandrens, limonens or mentadienes. .

Alkyl or cycloalkenyl. a group that is in the appropriate C-BUTH residue 2 or having in this residue, or is-1,2 itself, can be unsubstituted or substituted, lower alkyl groups and does not have more than 12 carbon atoms, it primarily represents unsubstituted go substituted by lower alkyl groups, in particular groups with 1-4 carbon atoms, primarily methyl groups, cycloalkyl residue with 3-8. ring carbon atoms, in particular with ring carbon atoms, or cycloalkenyl residue with 5-8 ring carbon atoms, and may for example be a odnuiz said specific groups of this type,

Cycloalkenyl or cycloalkenyl groups can also have a bridge or be spirocyclicly substituted directly or through a lower alkylidene or alkylene group, preferably with 1-4 carbon atoms, for example, the Methylene, ethylene or isopropylidene group, i.e. they can also form polydicyclic, in particular bicyclic, systems derived from polycyclo or yiiikloalkanes or spirocycloalkanes and their unsaturated derivatives. Such groups are naphimer, hydrocarbon residues of biclohexanes, bicycloshegganes or bicyclic octanes and their derivatives substituted by lower alkyl radicals, for example, bicyclic terpenes of tyuanovic, pinanoic or bornanoic acids. These phenyl residues can be unsubstituted or substituted with halogen, for example chlorine, fluorine or bromine, or lower alkyl residues, i.e. residues with 1-7 carbon atoms, in particular methyl groups. The group R preferably has no more than 35 carbon atoms, in particular, it has 4-16 carbon atoms. Z or 2k lower alkyl groups are lower alkyl groups with 1-7 carbon atoms, preferably 1-4 carbon atoms, for example, one of these groups preferably means a methyl group. Among the proposed compounds, it is necessary to distinguish those Pas A means unsubstituted 4U-1-pip azinolone carbon atoms, where C means one of the following formulas:) - V-Vg cn) “- for (Allc) Py - (CHzU-C-Vg - (CHg) ,, - C -Vg Vs where n is 1 or 2; V and V each means an alkyl or alkenyl pear with 1-7 carbon atoms; hydrogen or together with Vg is alkyl a den or alkenylidene group with 1-7 carbon atoms} / PY - a non-substituted or substituted chlorine or bromine atoms and / or methyl groups; a phenyl group is a dicloalkyl or dicloalkenyl group with 5-8 carbon atoms, and if appropriate it can be replaced alkyl groups with 1-4 carbon atoms} - a dicloapkyl or dicloalkanyl group or a phenyl group as previously defined; 64 86 - an unbranched or branched off apkipenovaya group with 2-4 carbon atoms or alklylienbva group with 1-4 carbon atoms and their derivatives, mixed with one of the two carbon atoms of the (CH2) j methyl group. These alkyl, alkenyl, alkylidene or alkenylidene groups with 1-7 carbon atoms, preferably with 1-4 carbon atoms are, in particular, methyl, ethyl, propyl groups or vinyl, allylic, metal groups or methylenic, ethylNew, propylidene. The isophofyl groups are vinylidene or 2-hpOpen-1-ylidene groups. These al-silylene groups with 2 to 4 carbon atoms, in particular, are an ethylene or trimethylene group. The chloalkyl or cycloalkenyl group Su, in particular, is rpyiv-. sing with 5-6 ring carbon atoms, i.e. diclopentyl or diclohexyl group, or corresponding monounsaturated and / or substituted lower alkyl groups by hydrocarbon residues. Preferably, in the corresponding case, in the indicated phenyl groups, there are 1-3 indicated substituents in the cycloalkyl rings. Such groups may also have a bridge, as described earlier, and then they are nagfimer / remnants of these doubleclic terpenes. Of the new compounds, for example, 3- (4-isobutyl-1-piperazinyl) rifamidine 5 and SV, should be mentioned. 3-1.4- (2-ethylbutyl il) -1-piper ZIN and l} rifamidin S and SV, (2-methylbutyl) -1-piperazinide by reefs din S and 5V, 3-f4- (2-methylbutyl ) -1-piperazinyl} rifamycin S and SV, 3- 4- (2-methylpentyl) -1-piperavinyl with reefs of din S and 5V, (2-phenylpropyl) -1-piperazynil R-samine S and SV, AF: 4- metallo-1-piperazinyl) rifamidin S u5, i 3-14- (2-methyl-3-butenyl) -1 -pipa razinyl} rifamycin S and SV - 4-wild) 1hexylmethyl-1-piperazinyl riamycin S and SV, (( 4-methyldicloxylmethyl) -1-piperazini l reef midin S and SV, -G4- (4-.tre.1M5uglyldogloheksilmetil) -1764 piperaziyil rifamish N S and SY (4 isobutylcyclohexylmetip) 1 -piperaoyinip} reefs Zing S and & V, 3 ".4 (4-" zopropip "ikpohexylmegyl) 1" piperazinyl, Zyfamyu yN 5 and SV, (3,4-methylcyclohexylmethyl) para-sync rifamshnsh S and SV, (3,4-dimethylcyclohexylmethyl-syphamide S-SV and SV, (3,4-dimethylcyclohexylmethyl-syphamide S-SV and SV, (3,4-dimethylcyclohexylmethyl) S to SV, 3 4 (3,5-dimethyl 1shklogeksilmegyl) -1 "-piperazinyl rifaminin 5 and SV, (3- cyclog: exenylmethyl-1-piperazInil rifamycin $ and SV, 3 (4" icclopropylmethyl-1-piperazinyl)) S and SV, 3 | 4 C 1kloheptylmetsh1 1. 2. piperazinyl} and the surname S and SV, .f .-, - - ... - ...-: (2-ad Clohexylpropyl) 1 g1 piperazi nid1rifamydin S and SV, ( 2-cyclohexylbutyl) -1 - piperazinip Driftin 5 and SV,. 3 (4 cyclo-octylmetip-1-piperazinyl) ri Famitsk S and 5Vj (2-methyrcyclohexylmethyl) -1 - piperazschriffamin S and SV,, ..,;.:, ..; (bischilo 2.2.1 hept-a-yl-methyl). - piperazinyl rice {) amidin. S or SV. , The interaction of rifamycin S.c with an amine of the general formula HA is expedient; , U) 0-vy in the free of oxygrc org: solvent, preferably ,, ;; with a polar polarization, for example .. in galleyonannyh.al4zatycheskM ugievo; -dorod Smetylenkhlorde, chloroform),. esters or ethers, for example in yiccycHOM ether, butyl acetate, amiladetteyy celpozolve, or in tetragonal and, and first of all, in dioxane, if the amine to be reacted, liquid, it is not necessary to add, - v solvent. It is advisable to use an excess (mol) of amine. The reaction is proceeded at a temperature from 25 ° C to 100 ° C, but preferably at room temperature TSMnepaTjpe. Over the course of the reaction can be monitored by using chromatographic chromatography. , The starting materials used to carry out this method are known and can be obtained by well-known methods. The product of reactions is often in the reaction of part B of the quinone form and, partly, of the hydroquinone form, and the hydroquinone is oxidized to quinine or the quinone is reduced to hydroquinone and then isolate 3 "-amino" ione in one form or another. The oxidation is preferably carried out with inorganic oxidizing agents, and the reduction is preferably carried out with the help of ascorbic acid or sodium dithionite. The reaction product is obtained from the reaction mixtures thus obtained by well-known methods, for example, dilution with water and / or in the appropriate case by neutralization with an aqueous acid, for example a mineral, preferably citric acid, and adding a solvent that is not mixed with water, for example, chlorinated hydrocarbon (chloroform or methylene chloride), moreover, the reaction product passes into the organic phase, from which it can be obtained in pure form using conventional methods, i.e. drying, evaporation: And for installation and / or cromato 1: aphi or other conventional cleaning methods. The quinones obtained in such a manner or, adrohynones MojiiHo easily Per, evodite each other, for example, by treatment with specified extractants or oxidizers. Quinones in most cases are violet-red-colored compounds. . In most cases, the hydrodynamic cells turn into yellow and crystallize well. Thydrohiones form salts with metals, for example with alkali metals. Quinines and hydroquinones form acid-addition salts, and in accordance with Bjtome Ms case, quaternary ammonium salts with Acids, in particular, with esters of lower alkanols, with halogenohydric acids, sulfuric acids or sulfonic acids. For the production of acid addition salts. It is used before all acids that are suitable for the formation of therapeutic e-salts. Such acids include, for example, hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, aluminum, aromatic or heterocyclic carboxylic or sulfonic acids, for example, formic, acetic, G5 opionic, amber, glycolylate, glycolic acid, glycolic acid. , citric, ascorbic, maleine, oximeylanova or pyruvic; acids, phenyuksusya, benzoic, p-aminobenoic, anthraniline, oxybenzoic, uncap, salicylic or non-aminosalicylic acid methionic, triptophane, lysine or arginine. These or other salts of new compounds, such as picrates, can also be used to clean the semi-bases by transferring the base to salt, isolating it, and releasing it again from the salts of the base. Familin S in a mixture of kz 100 ml of dioxane and 96 g of 1 isobutylpiperazine solution is allowed to stand for 28 at a comiaTHoft temperature. Then added yutvodu, subtitle: south with lemon juice, the reaction product is dissolved in chloroform, the chloroform solution is washed with brine, dried with magnesium sulfate and curled. The wasp-solution was dissolved in methanol, an aqueous solution of ascorbic acid was added to a light yellow color and allowed to stand. After some time, 3 (4-isobutyl-1-α-piperazinyl) rnfamycin SV in a range of yellow crystals is isolated, which after two recrystallization from chloroform / methanol / water melts at 17 ° C. Further amounts are in two last uterine solutions. Example 2. Analogously to example 1, 90 g of rifamycin S is subjected to interaction with 1OO g 1 (2-butylbutyl) pipa razin and thus (2-0tylbutyl) 3, piperazikil | nfamitsii SVP PREM 3 is obtained. Analogously to example 9O g rifamytsin S is subjected to interaction with 100 g of 1 (2 methylbutyl) piperazine and is obtained in such a way as 3 (2-methylbugyl) 1 "piperazi1Il2ryl mitsin 5VP r and meper 4, to a solution of 30 g of rifmycin S in 100 ml of dioxane by adding g They are DZO g 1 cyclohex shmethylpiperazine and allowed to stand at room temperature until the blue color is initially red and the mixture is mixed. and is converted to an orange ury. Water is then added and acidified with citric acid. The desired reaction product is diluted with chloroform. After drying and evaporation of the chloroform solution, the residue is dissolved in a small amount of methanol and a concentrated Aqueous solution of ascorbic ACID is added dropwise BEFORE those nopt until the first L8 color turns golden yellow. For a short time, a 3 (4–1.5 µlohexy Pitmix 1 «-1 -1.p {sherazynil) reef y1 cin SV crystallizes for a short time, which after two recrystallisations from chloroform / methanol / water is obtained in a completely pure wad, so pl. C, EXAMPLE 5. Analogously to Example 4, 25 g of rifamycin S s 40 mp of diogosan with ZO g l-UHKHonponHfiMeTHnnHnepa iHa receive 3 (4 ™ Diclopr pnlmethyl 1 n "perezinylyl) rifamIvSHS syst, after a three-year cristist, a cristist, 3 times a cristist, 3 times a single cristist, 3 times a day, 3 times a single cistrist, 3 times a day, 3 times a day. / methanol / water yellow crystals, T.1PSH.21TS, Example 6 Dissolve 2O g, rifamish S in a mixture of iOO ml dioxa, tia to 27 g N; metal solution and solution is allowed to stand for 35 hours at 35 ° C. e. Thereafter, water is added, acidified with citric acid, and the reaction product is dissolved in chloroform. The choroform solution is washed with a solution of PRVARINE SALT, dried with sodium sulfate and evaporated. The remainder. is dissolved in methanol, an aqueous concentrated solution of ascorbine 1 × SLOT is added dropwise to obtain a light color and allowed to stand. After a short time, 4 MeTanaH: J1-piperazinyl) rifamycin SV are separated and given yellow crystals, which nocifte twice from recrystallized from chloroform. methanol4 / water is melted at 172-. P. Measurement system 7. In analogy to Example 6, 10 g of rfamncin S is reacted with IS g 1 allylpiperazine and thus obtained (4 allyl-1 p (perenyl) rifamination SV, m.p. 174 177 Cs. EXAMPLE 8 Analogously to Example 6 10 g of rifamidine S according to jected reacted with 1O g M - 2-metyl-2-penten-. or 3) and thus get 3 4 (2-methyl-2-pentenyl) 1-piperazinn rifamycin SV, so pl. 164 166С. Example 9. Analogously to Example B, 20 g of rifamkdin S is reacted with 20 g of N- (2-ethyl-.2-bugenyl) -cperazine K to get this way. (2 ethyl 2-butenyl) -4-piperazinyl) ifamycin SV J t. Sh1. 174--175 ° C. Example 10, Analogical 6 example is subjected to the interaction of 15 g of aminoamine S with 16 g of N (2 ethyl-21 xenyl) pyerase, and get such braz (2-ethyl 2 1 Xenia: 1) -1-pi , p, 153 "IMHUHH. Example 11. Analogously to Example 6, 0 g of rifamish S is reacted with 20 g of N (2,3-dimetip α-butenyl) piperazine and is obtained with such ofaz (2,3-dimethyl-2-butenyl) -1-piperaeno-Zrifamycin SV. m.p. 171-174C. Example 12 Analogously to Example 6, 10 g of rifamycin S is reacted with 11 g of N - (2-ethyl6-butyl) piperazine and this is obtained in this way 3-4- {2-ethylbutyl) -l-shparazini .riphamIt: SV, t. pl ,, lee-lTO C. Example 13, Analogously to example 6, the reaction was carried out with Yu g of rifamyin S with 10 g of N - (1,2-ymethylpr6iyl) piperazine and thus (1,2-dimethylpropyl) -1-n perazinyl rifamiin SV, so pl. 184. The structure of the compounds obtained is based on & rshts & U data of the spectra. In table 1, the starting components are derived and the physical constants of the obtained target products. The amines given in the table as starting materials can be obtained in a well-known way. interaction of the corresponding alkyl bromides with piperazine,. In some cases, it is recommended to use a corresponding tosylate instead of bromide. Thus, nat-Shher N- (netpentyl) pipepaaine can be obtained by the interaction of iperazine with neopentyltosyl

thyl piperazine

25M- 2- (Norbornil) methyl pius &

Razin - ..25N-4 Ш1клооктш1метш1) пш1еразин

20N - (2-hMettvcyclogeX1) methyl piperazine

20N- (2-Benzylpropyl) piperazin

6N-Neopentylpiperazine

30K- (3,3-Dimethylbutyl) piperazine

ZON- (3-Methylbutyl) piperazine

20N - (3-Fensh1 2-propenyl) piperazine

170-172

162 171

169-17О 149-150

180

178 178-179

165-166