CH605974A5 - 3-(4-Substd.-1-piperazinyl) rifamycin S and SV derivs - Google Patents

Abstract

3-(4-Substd.-1-piperazinyl) rifamycin S and SV derivs as antitubercular agents of high activity and as antibacterials

Description

  

  
 



   The subject of the present invention is the production of new derivatives of rifamycins S and -SV with high antibiotic effectiveness. They are rifamycin S compounds (I) of the following formula which are substituted in the 3-position by an aliphatically substituted amino group
EMI1.1
 and their corresponding hydroquinones, the rifamycin-SV derivatives (compounds II), in which A denotes a 4R-1-piperazinyl radical optionally substituted in the piperazine ring by lower alkyl, where R denotes an optionally substituted hydrocarbon radical of the following formula
EMI1.2
 in which Zl is a lower alkyl or lower alkenyl group, or an unsubstituted or substituted phenyl group by halogen or lower alkyl groups,

   Z2 signifies hydrogen or a lower alkyl or lower alkenyl group and Z3 signifies a lower alkyl or lower alkenyl group and Z2 and Z3 together also represent a lower alkylidene or lower alkenylidene group.



   Lower alkyl, lower alkenyl and lower alkylidene or lower alkenylidene groups are those with up to 7 carbon atoms, e.g. Methyl, ethyl, propyl, isopropyl, straight or branched butyl, pentyl, hexyl or heptyl groups connected in any position, vinyl, allyl or methallyl, -1 propenyl, methylene, ethylidene, propylidene, Butylidene, isopropylidene or isobutylidene groups. If Zl represents a phenyl radical, this can be unsubstituted or substituted by halogen, e.g. Chlorine, fluorine or bromine, or by lower alkyl radicals, i.e. those with 1-7 carbon atoms, in particular by methyl groups, may be substituted.



   Any lower alkyl groups present on the C atoms of the piperazine radical have 1-7 C atoms; they are mainly methyl groups, with 1 or 2 such groups being present in the first place.



   Among the compounds (I) and (II), special mention should be made of those in which the group A denotes a 4R-1-piperazinyl radical unsubstituted on the C atoms, where R is one in the 2-position by two lower alkyl or lower alkenyl groups, each with up to 4 C atoms substituted ethyl group, also compounds in which the group A is a 4R-1-piperazinyl radical unsubstituted on the C atoms, where R is substituted in the 2-position by an unsubstituted or by methyl groups or by chlorine or bromine atoms Phenyl radical and by a lower alkyl, alkenyl or alkylidene group each with up to 4 C atoms, in particular by a methyl group, substituted ethyl group, or by a lower alkyl or alkenyl group with 1-4 C atoms and a lower alkylidene group with 1 4 C atoms in the 2-position substituted ethyl group.

  In these compounds, in the radical R, the lower alkyl groups mentioned are in particular methyl, ethyl or propyl groups, the lower alkenyl groups are in particular vinyl or allyl groups and the lower alkylidene groups are methylene, ethylidene, propylidene or isopropylidene.



   Among the new compounds (I) and (II) are e.g.



  the 3- (4-isobutyl-1-piperazinyl) -rifamycin S- and -SV the 3- [4- (2-ethyl-butyl) -1-piperazinyl] -rifamycin S- and -SV the 3 - [4- (2-methyl-butyl) -1-piperazinyl] -rifamycin S- and -SV the 3- [4- (2-methyl-pentyl) -1-piperazinylj-rifamycin S- and -SV the 3- [4- ( 2-phenyl-propyl) -1-piperazinyl] -rifamycin S- and -SV the 3- [4-methallyl-l-piperazinyl) -rifamycin S- and -SV the 3- [4- (2-methyl-3- butenyl) -1-piperazinyl] -rifamycin S- and -SV.



   3-aminorifamycin -S- and -SV compounds with antibiotic action are already known. Thus, in Patent No. 512 510, rifamycin-S and -SV compounds which are substituted in the 3 position by an amino group of aliphatic character are described. Those compounds have a high antibiotic effect and in particular also have an anti-tubercular effect. The compounds of the present application are now distinguished from the cited compounds of the French patent by an increased antibacterial and anti-tuberculous effect and by lower toxicity, as can be demonstrated both in vitro and in vivo.

  E.g. the minimum inhibitory concentration in vitro against tubercle bacilli with the above-mentioned 3- (4-isobutyl-1-piperazinyl) -rifamycin SV is 30 times lower than with the known tuberculostatic rifamycin remedy rifampicin, 3- (4-methyl-1-piperazinyl-imino-methyl) rifamycin SV.



   The high anti-tuberculous effect of the new compounds can also be demonstrated in animal experiments, e.g. on the mouse. When administered orally to mice infected with Mycobacterium bovis, the compounds show a pronounced tuberculostatic effect (ED 50) in doses between 0.5 mg / kg and 40 mg / kg. For example, the 3- (4-isobutyl-1-piperazinyl) -rifamycin SV has an ED 50 of in this test
1 mg / kg. The compounds are also characterized by a very large therapeutic range, in that a significant toxicity only occurs at a very high dose. E.g. the LD 50 for the above-mentioned specific compound has a value above 1000 mg / kg.



   The compounds also have a good antibacterial effect, as has also been shown in animal experiments, e.g. on the mouse. In mice that have been infected with staphylococci, they show a pronounced antibacterial effect in doses between 0.2 and 40 mg / kg when administered orally.



   The new compounds can therefore be used as remedies, primarily for tuberculous infections, but also for other infections, e.g. Leprosy, or those who e.g. caused by gram-positive microorganisms such as staphylococci. However, the new compounds are also valuable intermediates for the preparation of other useful substances, in particular pharmacologically active compounds. They can also be used as feed additives and for the preservation of food.

  According to the process of the present invention, the new compounds I and II are prepared by adding 3- (1-piperazinyl) -rifamycin S or -SV, which is also formed on one or more of the carbon atoms of the 1-piperazinyl radical by lower alkyl can be substituted, reacts with a suitable agent introducing the radical R and, if desired, converts a quinone obtained into the corresponding hydroquinone or a hydroquinone obtained into the corresponding quinone, and / or converts a compound obtained into a salt.



   When implementing 3-1-piperazinyl-rifamycin S or



  -SV or its mentioned C-alkyl homologues with the mentioned agent introducing the radical R are used in particular compounds of the formula XR in which X is a halogen, such as e.g. Chlorine, bromine or iodine, or the remainder of an oxygen-containing inorganic acid, such as sulfuric acid or sulphurous acid, a halosulphuric acid, such as, in particular, fluorosulphonic acid. Such alkylating agents are e.g. Haloalkyls, e.g. the bromides, iodides or chlorides of the hydrocarbon radical R or the R-mono- or di-esters of sulfuric acid or fluorosulfonic acid.



   The reaction of the rifamycin compound mentioned with these agents is preferably carried out in the presence of a base, in particular a strongly basic, non-nucleophilic tertiary amine, in particular an amine of the formula
EMI2.1
 in which X is a lower alkyl group and X1 and X2 are each a space-filling aliphatic hydrocarbon radical.



  The groups Xl and X2 are e.g. B. Lower alkyl groups with 1-12 C atoms, preferably with 1-7 C atoms, which have a branched carbon chain, while X preferably denotes a lower alkyl group with 1-7 C atoms.



  The so-called Hünig's base is used primarily, i.e. the ethyl-diisopropyl-amine. The reaction is advantageously carried out in an inert solvent, in particular a chlorinated aliphatic hydrocarbon, e.g. Methylene chloride, or an alcohol such as methanol, at temperatures between room temperature and about 100, with 1 mol of the rifamycin compound and the alkylating agent being used, and the base is preferably added in a one-molar ratio. The reaction time varies depending on the reaction components and can be from half an hour to 24 or 48 hours.



   The starting materials for the process of the present application are known or can be prepared in a manner known per se.



   The 3- (1-piperazinyl) -rifamycin SV or the 3- (1-piperazinyl) -rifamycin S or their derivatives which are lower alkyl-substituted in the piperazine ring can be prepared by the process of the above-cited French patent 1,490,183.



   The desired process product is isolated from the reaction mixture e.g. in a manner known per se, e.g. by dilution with water and / or, optionally, by neutralization with an aqueous acid, e.g. Mineral acid or advantageously citric acid, and adding a water-immiscible solvent, e.g. a chlorinated hydrocarbon, e.g. Chloroform or methylene chloride, the reaction product passing into the organic phase, from which it can be obtained by the usual methods, d. H.



  Drying, evaporation and crystallization and / or chromatography or other conventional purification methods, can be obtained in pure form.



   The quinones or hydroquinones obtained in this way can easily be converted into one another, e.g. by treatment with the above-mentioned reducing or oxidizing agents.



   The quinones are mostly purple-red colored compounds.



  The hydroquinones are mostly yellow in color and crystallize well. The hydroquinones form metal salts, of which the alkali salts are particularly important because of their water solubility. With acids, the quinones and the hydroquinones form acid addition salts and optionally also quaternary ammonium salts, in particular with esters of lower alkanols with hydrohalic acids, sulfuric acids or sulfonic acids. Acids which are suitable for the formation of therapeutically useful salts are mainly used to prepare the acid addition salts.

  Examples of these are: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, lemon, ascorbic, maleic, hydroxymaleic or pyruvic acid ; Phenylacetic, benzoic, p aminobenzoic, anthranil, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, emboxylic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene sulphonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid; Methionine, tryptophan, lysine or arginine.

 

   These or other salts of the new compounds, e.g.



  the picrates can also be used to purify the bases obtained by converting the bases into salts, separating them off and in turn liberating the bases from the salts.



  As a result of the close relationship between the bases in free form and in the form of their salts, in the preceding and in the following, the free bases are meaningfully and appropriately also the corresponding salts.



   The new compounds can e.g. find use in the form of pharmaceutical preparations. These contain the compounds in a mixture with a pharmaceutical, organic or inorganic, solid or liquid carrier material suitable for enteral, topical or parenteral administration. For the formation of the same, substances come into question that do not react with the new compounds, e.g. Water, gelatin, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohols, gum, propylene glycol, polyalkylene glycols, petrolatum, cholesterol or other known excipients. The pharmaceutical preparations can e.g. as tablets, dragees, ointments, creams, capsules or in liquid form as solutions, suspensions or emulsions.

  If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizers or salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. The preparations are obtained by customary methods.



   The invention also relates to those embodiments of the above-described process for the preparation of the new 3-aminorifamycin compounds, in which one starts from a compound obtainable at any stage as an intermediate and carries out the missing process steps or forms the starting materials under the reaction conditions.



   The new compounds can also be used in veterinary medicine, e.g. in any of the forms mentioned above.



   The invention is described in the following examples. The temperatures are given in degrees Celsius.



   example 1
730 mg iso-butyl tosylate, 930 mg N-ethyldiisopropylamine in 11 ml abs. Methanol and 3.12 g of 3- (1-piperazinyl) -rifamycin SV are refluxed for 48 hours under a nitrogen atmosphere. After this time the solvent is distilled off and the residue is chromatographed through 200 g of silica gel (Merck 70-230 mesh). The eluent used is chloroform-methanol 9: 1.



   Those fractions which indicate the presence of the desired reaction product after analysis by thin-layer chromatography are combined, dissolved in 15 ml of methanol and 15 ml of chloroform, and 3 ml of sodium ascorbate solution (10% mg) are added under nitrogen. The mixture is stirred for a further 15 minutes and then extracted with chloroform and water. The organic phase is dried over sodium sulphate, evaporated and the residue is recrystallized from a little chloroform and 80% methanol. This gives 3- (4-isobutyl-1-piperazinyl) rifamycin SV in yellow crystals which melt at 1700. UV spectrum in 0.01 nalk. HCI, maxima in nm (10 g e): 228 (4.53), 298 (4.28), 433 (3.90).



   Example 2
By refluxing for 48 hours 1/100 mol (7.95 g) of 3- (1-piperazinyl) rifamycin SV with 1/100 mol + 10% excess of one of the organic bromides listed in the table below in 250 ml of ethanol and in the presence of 1.3 g of N-ethyl-diisopropylamine, the corresponding 3- (1-piperazinyl) -rifamycin-SV compounds substituted in the N'-position of the piperazine radical, which are those given in the table in the second and third columns have physical data. The reaction mixture is worked up in such a way that it is evaporated to dryness and the residue is recrystallized three times from methanol.



   Reaction products org. UV- in 0.01 n
M.p. alcohol HC1 bromide maxima in nm (logo) (2-phenyl-.propyl) -bromide 157-158 "226 (4.59), 298 (4.32),
434 (3.93) (2-methylpentyl) bromide 163 229 (4.59), 300 (4.32),
437 (3.93) (3-methylpentyl) bromide 173 226 (4.58), 298 (4.30),
433 (3.90) (2-benzyl-propyl) bromide 149-150 228 (4.57), 299 (4.32),
435 (3.93) neopentyl tosylate * 1800 227 (4.56),

   430 (3.86),
295 (shoulder) (3,3-dimethylbutyl) bromide 178 "(3-methyl-butyl) bromide 178-179" (3-phenyl-2-propenyl) bromide 165-166 "206 (4.71), 211 ( 4.73),
230 (4.63), 249 (4.60),
295 (4.32), 435 (3.93) methallyl bromide 172-174 "229 (4.59), 298 (4.31),
435 (3.90) 2-methyl-2-pentenyl bromide 164-166 228 (4.58), 298 (4.30),
435 (3.92) 2-ethyl-2-butenyl bromide 174-175 229 (4.60) 298 (4.33),
435 (3.93) 2-ethyl-2-hexenyl-bromide 153-156 "229 (4.61), 298 (4.33),
435 (3.94)
Reaction products
Org.UV- in 0.01 n alcohol.

 

   HCl maxima in nm
Bromide (loge)
2,3-dimethyl-2-butenyl bromide 171-174 "230 (4.60), 300 (4.33),
435 (3.93)
2-ethylbutyl bromide 1681700 228 (4.47), 299 (4.32) 435 (3-94)
435 (3.94)

 

Claims (1)

PATENT CLAIM Process for the preparation of 3-amino-rifamycin-S-derivatives of the following formula EMI4.1 and their corresponding hydroquinones, the rifamycin-SV derivatives, in which A is a 4-R-1-piperazinyl radical optionally substituted in the piperazine ring by lower alkyl, in which R is an optionally substituted hydrocarbon radical of the following formula EMI4.2 means in which Zl is a lower alkyl or lower alkenyl group or an unsubstituted or halogen or lower alkyl substituted phenyl group, Z2 is hydrogen or a lower alkyl or lower alkenyl group and Z3 is a lower alkyl or lower alkenyl group and Z2 and Z3 together also mean one represent lower alkylidene or lower alkenylidene groups, characterized in that 3- (1-piperazinyl) -rifamycin S- or -SV, which can also be substituted by lower alkyl on one or more of the C atoms of the 1-piperazinyl radical, with a suitable agent introducing the radical R implements. SUBCLAIMS 1. The method according to claim, characterized in that 3- (1-piperazinyl) -rifamycin S or -SV is reacted with a compound of the formula RX in which R is the hydrocarbon radical present in the 4-position of the 1-piperazinyl radical and X is iodine, chlorine or bromine or the remainder of an oxygen-containing inorganic acid. 2. The method according to dependent claim 1, characterized in that a compound of the formula RX is used in which X is the radical of a sulfuric acid or a halosulfuric acid or sulfurous acid. 3. The method according to claim, characterized in that the reaction with the agent introducing the radical R is carried out in the presence of a strongly basic, non-nucleophilic tertiary amine of the formula EMI4.3 where X is a lower alkyl group and Xl and X2 each signify a space-filling aliphatic hydrocarbon radical. 4. The method according to dependent claim 3, characterized in that the reaction with the agent to be introduced with the remainder R is carried out in the presence of ethyl diisopropylamine, using equimolar amounts of both components. 5. The method according to claim, characterized in that a process product obtained in quinone form is converted into the corresponding hydroquinone. 6. The method according to claim, characterized in that a process product obtained is converted in hydroquinone form into the corresponding quinone. 7. The method according to claim, characterized in that a compound obtained is converted into a metal salt. 8. The method according to claim or one of the dependent claims 1-7, characterized in that compounds are prepared in which A is a 4-R-1 -piperazinyl radical which is unsubstituted in the piperazine ring. 9. The method according to claim or one of the dependent claims 1-7, characterized in that compounds are prepared in which lower alkyl, lower alkenyl, lower alkylidene or lower alkenylidene groups in radical A are those which have up to 7 carbon atoms. 10. The method according to claim or one of the dependent claims 1-7, characterized in that compounds are prepared in which A is a 4-R-1-piperazinyl radical unsubstituted on the ring carbon atoms, in which R is one in the 2-position by two lower alkyl - or lower alkenyl groups each with up to 4 carbon atoms means substituted ethyl group. 11. The method according to claim or one of the dependent claims 1-7, characterized in that compounds are prepared in which A is a 4-R-1 -piperazinyl radical unsubstituted on the ring C atoms, in which R is an unsubstituted one in the 2-position or a phenyl radical substituted by methyl groups or by chlorine or bromine atoms and an ethyl group substituted by a lower alkyl, alkenyl or alkylidene group each having up to 4 carbon atoms. 12. The method according to claim or one of the dependent claims 1-7, characterized in that compounds are prepared in which A is a 4-R-1-piperazinyl radical unsubstituted on the ring carbon atoms, in which R is a lower alkyl or alkenyl group denotes ethyl group substituted with 1-4 C atoms and a lower alkylidene group with 1-4 C atoms in the 2-position. 13. The method according to claim or one of the dependent claims 1-7, characterized in that the 3 (4-isobutyl-1-piperazinyl) -rifamycin SV or the 3- (4-isobutyl-1-piperazinyl) -rifamycin S is produced . 14. The method according to claim or one of the dependent claims 1-7, characterized in that methallyl-1-piperazinyl) -rifamycin SV or 3- (4-methallyl-l-piperazinyl) -nfamycin S is produced. 15. The method according to claim or one of the dependent claims 1-7, characterized in that the following compounds are prepared: 3- [4- (2-ethyl-butyl) -1-piperazinyl] -rifamycin S- or -SV, the 3 - [4- (2-Methyl-butyl) -1-piperazinyl] -rifamycin S- or SV, the 3- [4- (2-methyl-pentyl) -1-piperazinyl] -rifamycin S- or SV, the 3rd - [4- (2-Phenyl-propyl) -1-piperazinyl] -rifamycin S- or SV or the 3- [4- (2-methyl-3-butenyl) -1-piperazinyl] -rifamycin S or -SV.