KR790001367B1 - Process for the preparation of rifamycin s and sv derivatives - Google Patents

Abstract

The title compd. [I; A = 4R-1-piperazinyl, R = hydrocarbon group(II; n = 0,1, Z1 = unsubstituted phenyl, substituted phenyl, cycloalkenyl, Z2 = hydrogen, lower alkyl, lower alkenyl, Z3 = lower alkyl, lower alkenyl) with high antibiotic action, were prepd. by treating rifamycin S with the substituted piperazines. I had a tuberculostatic ED50 in mice of 1mg/kg orally.

Description

Method for preparing rifamycin S and SV derivatives

The present invention relates to a lipamycin S compound (I) substituted with an amino group substituted with an aliphatic substituent having a high life-limiting effect of the structural formula I, and a method for preparing a lipamycin SV derivative, which is a corresponding hydroquinone.

Wherein A is a 4R-1-piperazinyl group in which the carbon atom is optionally substituted with a lower alkyl group, and R is a hydrocarbon group of

n = 0 or 1 and Z ₁ is unsubstituted or substituted with lower alkyl, lower alkyl or lower alkenyl group which may be substituted with cycloalkyl or cycloalkenyl group, or unsubstituted phenyl or lower alkyl Phenyl group or cycloalkyl group or cycloalkenyl group, phenyl group may be substituted by halogen, Z ₂ represents hydrogen, lower alkyl, lower alkenyl group, Z ₃ represents a lower bond with lower alkyl, lower alkenyl or optionally Z " Z ₂ and Z ₃ together are lower alkylidene, lower alkenylidene, Z ₁ and Z ₂ together are alkylene or alkenylene groups, but if Z ₃ together with Z "represents a double bond, then Z ₁ + Z ₂ Alkylene or alkenylene groups, Z 'and Z "are hydrogen or lower alkyl groups, respectively, and the above-mentioned cyclic aliphatic groups, and cyclic aliphatic groups formed by Z ₁ + Z ₃ or Z ₁ + Z _{2 which} are alkylene or alkenylene groups. field One or more non-adjacent pairs of CC atoms in a ring are optionally linked directly with each other or indirectly via a lower alkylidene or alkylene group, and one C atom may be substituted in a spiro ring by a lower alkylene group. And these groups contain up to 12 carbon atoms, wherein the alkenyl or cycloalkenyl, or alkenylidene or alkenylene group is a hydrocarbon radical having one or more double bonds.

Lower alkyl, lower alkenyl, lower alkylidene or lower alkenylidene groups having up to seven carbon atoms, in particular one to four atoms, for example methyl, ethyl, propofyl, isopuro Fillers, straight chains or carbons are branched butyl, pentyl, hexyl or heptyl groups, vinyl, allyl or methalyl, 1-furophenyl, methylene, ethylidene, furopylidene, butylidene, isopuropylidene or isobutylidene groups to be. Z ₁ + Z _{3, which} is an alkylene or alkenylene group, is bonded together with a carbon atom of the above-mentioned structural formula to form a cycloalkyl or cyclo alkenyl group having a total carbon number of 12 or less, wherein a cycloalkenyl group is one or more double bonds. Say what you have. Preferably, straight or branched alkylene groups form cycloalkyls having 3-8 in particular 5-6 carbon atoms or cyclo alkenyl groups having 5-8 carbon atoms. The linear alkylene group or the alkenylene group together with the carbon atom of the above structural formula forms an unsubstituted cycloaliphatic ring, and the ring formed in the case of the branched alkylene group is substituted with an alkyl group, especially a C ₁ -C ₄ , lower alkyl group, and above all a methyl group. . Cycloalkyl groups which form rings with 3-8 carbon atoms are for example cyclofurophyll, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 2,6-dimethylcyclohexyl, 3,5- Dimethylcyclohexyl, 1-methyl-4-isofurophyllcyclohexyl (P-menthyl) or 1-methyl-3-isofurophyllcyclohexyl (m-menthyl) group.

Examples of cycloalkyl groups include 1-cyclopenten-1-yl, 2-cyclotenden-1-yl, 3-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 1-cyclohexene-1 -Yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1,3-cyclohexadien-1-yl, 1,4-cyclohexadien-1-yl, 1-P-mentene -4-yl, 2-P-menten-l-yl, 3-P-menten-l-yl or isomers of these groups or corresponding compounds with two double bonds, for example teptinene, pelandene, It is a hydrocarbon of limonene and menadiene.

Cycloalkyl or cycloalkenyl groups represented by Z ₁ or Z ₁ + Z ₂ may be unsubstituted or substituted by lower alkyl and contain no more than 12 carbon atoms and above all 3-8 carbon atoms, in particular 5-6 Cycloalkyl groups cyclic with 5 carbon atoms or cycloalkenyl groups cyclic with 5-8 carbon atoms, these groups being unsubstituted or substituted with lower alkyl groups, in particular C ₁ -C ₄ lower alkyl groups, and above all with methyl groups. It may be one of them. Cycloalkyl or cycloalkenyl groups, either directly or with lower alkylidene or alkylene groups, preferably having 1 to 4 carbon atoms, can be bridged via methylene, ethylene, isopropylidene groups, can be substituted with spiro rings, and polycyclo It forms polycyclic, especially bicyclic, derived from alkanes, bicycloalkyls or spirocycloalkanes or their unsaturated derivatives. Such groups include hydrocarbon radicals such as bicyclohexane, bicycloheptane or bicyclooctane and their derivatives substituted with lower alkyl groups, ie, hydrocarbon hydrogen radicals such as bicyclic terpenes of leuyan, pinane, or borane groups. The aforementioned phenyl groups can be unsubstituted or substituted with halogens such as chlorine, fluorine, cancellation or substituted with C ₁ -C ₇ lower alkyl groups, especially methyl groups.

The R group preferably has up to 35 carbon atoms, particularly 4 to 16 carbon atoms. Lower alkyl groups of Z 'and Z "in formula (III) preferably have from 1 to 7 carbon atoms, in particular from 1 to 4 carbon atoms, with the best methyl group. Among the compounds (I), in particular A is not substituted for carbon atoms And a compound wherein R is a 4R-1-piperazinyl group and R is one of the following groups.

N = 1, 2 in the structural formula

V ₁ and V ₂ are each C ₁ -C ₇ alkyl or alkenyl group, V ₃ is hydrogen or V ₂ together with C ₁ -C ₇ alkylidene or alkenylidene, Ph is unsubstituted or chlorine, fluorine and / or methyl group Phenyl group substituted with.

Cy is a cycloalkyl or cycloalkenyl group which may be optionally substituted with a C ₁ -C ₄ lower alkyl group and forms a ring with 5-6 carbon atoms.

Py is a cycloalkyl or cycloalkenyl group or a phenyl group as described above,

"Alk" is a straight or branched C ₂ -C ₄ alkylene group, or a C ₁ -C ₄ alkylidene group, derivatives thereof substituted with a methyl group on one or both carbon atoms of-(CH) _n .

Alkyl, alkenyl, alkylidene or alkenylidene groups having 1 to 7 carbon atoms described above are for example as described above, in particular having 1 to 4 carbon atoms and having methyl, ethyl, prothyl or vinyl, alkyl, metaallyl groups. And methylene ethylidene, furopylidene, isopuropylidene, vinylidene and 2-furophen-1-ylidene group. The aforementioned C ₂ -C ₄ alkylene group is particularly an ethylene or trimethylene group. Cycloalkyl or cycloalkenyl groups, in particular Cy, are groups in which 5-6 carbon atoms are cyclic and are cyclopentyl or cyclohexyl, or the corresponding mono-unsubstituted and / or lower alkyl-substituted hydrocarbon radicals, for example as described above. It is one of the same. Preferably 1-3 of the aforementioned substituents are optionally present in the aforementioned phenyl or cycloalkyl group rings. Such groups may form bridges as described above and are bicyclic terpene-like radicals as described above.

Also of interest are derivatives of the foregoing compounds, in which V ₂ is partially a C ₁ -C ₇ alkyl or alkenyl group, having the structure (IV)-(IV). Preferred compound (I) is a compound wherein A is 4R-1-piperazinyl unsubstituted at the carbon atom and R is

Where n = 1,2

m = 1-4

P = Hydrogen or C ₁ -C ₄ lower alkyl W ₁ , W ₂ , W ₃ are C ₁ -C ₄ lower alkyl and / or alkenyl groups optionally present on the desired carbon atoms, their unsubstituted cycloaliphatic rings of the formula Derivatives and derivatives of these compounds having cycloaliphatic rings which form bridges according to formula (V), in particular lower alkylidels or alkylenes in which two non-adjacent carbon atoms are directly bonded to carbon or have one or two or four carbon atoms And their derivatives substituted in a molecular ring through another group to another and / or substituted with a (CH ₂ ) n group which is a methyl group on one or both of the carbon atoms.

Examples of the saturated and unsaturated cyclic aliphatic rings of the formula (VII) can be found in the compounds of compound (I), and in the case of unsaturated rings, are the substances of 1- or 2-2 double bonds. In particular lower alkyl or alkenyl groups are particularly involved and the groups forming bridges in the bicyclic or polycyclic groups are in particular those described above for similar cycloaliphatic Cy. Especially in these compounds m = 1 or 2. Such rings carry particularly -2 methyl groups if the compounds are substituted.

Particularly important compounds of the present invention having the partial structural formula (III)-(iii) for the aforementioned R are compounds of n = 1, in particular V ₁ -V ₃ , Py, Cy and alk in the structural formula ( _iii ) As described above or in the formula (V), wherein P is hydrogen and the cycloaliphatic ring is a cyclopentyl, cyclohexyl ring or corresponding group substituted with mono-unsaturated and / or methyl groups, in particular 1-2 methyl groups.

New compounds (I) and (II) are as follows.

3- (4-isobutyl-1-piperazinyl) -rifamycin S and SV, 3- [4- (2-ethylbutyl) -1-piperazinyl] -rifamycin S and SV, 3- [4 -(2-Methylbutyl) -1-piperazinyl] -rifamycin S and SV, 3- [4- (2-methylpentyl) -1-piperazinyl] -rifamycin S and SV, 3- [4 -(2-phenylfurophyll) -1-piperazinyl] -rifamycin S and SV, 3- (4-methallyl-1-piperazinyl] -rifamycin S and SV, 3- [4- (2 -Methyl-3-butenyl-1-piperazinyl] -rifamycin S and SV, 3- (4-cyclohexylmethyl-1-piperazinyl] -rifamycin S and SV, 3- [4- (4 -Methylcyclohexylmethyl) -1-piperazinyl] -rifamycin S and SV, 3- [4- (4-t.butylcyclohexylmethyl) -1-piperazinyl] -rifamycin S and SV, 3 -[4- (4-isobutylcyclohexylmethyl) -1-piperazinyl] -rifamycin S and SV, 3- [4- (4-isofurophyllcyclohexylmethyl) -1-piperazinyl]- Lipycin S and SV, 3- [4- (3,5-methylcyclohexylmethyl) -1-piperazinyl] -rifamycin S and SV, 3- [4- (3,4-di Tylcyclohexylmethyl) -1-piperazinyl] -rifamycin S and SV, 3- [4- (3,5-dimethylcyclohexylmethyl) -1-piperazinyl] -rifamycin S and SV, 3- [4- (3-cyclohexenylmethyl) -1-piperazinyl] -rifamycin S and SV, 3- (4-cyclofurofilmethyl) -1-piperazinyl] -rifamycin S and SV, 3 -(4-cycloheptylmethyl) -1-piperazinyl] -rifamycin S and SV, 3- [4-2-cyclohexylfurotyl) -1-piperazinyl] -rifamycin S and SV, or 3 -[4- (2-cyclohexylfurophyll) -1-piperazinyl] -rifamycin S and SV or 3- [4- (2-cyclohexylbutyl) -1-piperazinyl] -rifamycin S and SV, 3- (4-cyclooctylmethyl) -1-piperazinyl] -rifamycin S and SV, 3- [4- (2-methylcyclohexylmethyl) -1-piperazinyl] -rifamycin S and SV and 3-[(bicyclo [2.2.1] hept-2-yl-methyl-1-piperazinyl] -rifamycin S or SV.

Antibiotic 3-aminolipamycin S and SV compounds are already known. French patent application 1490183 describes rifamycin S and SV compounds in which the 3-position is substituted with an amino group having aliphatic properties. These compounds have high antibiotic activity, especially anti-tuberculosis. The compounds of the present invention are strictly distinguished from the compounds described in the French patents mentioned above, and are also strictly distinguished from known lipamycin derivatives having anti-tuberculosis action in that the anti-tuberculosis effect is larger as shown by animal experiments in mice. . These compounds also exhibit tuberculosis bacteriostatic activity at doses between 1 mg / kg and 40 mg / kg when administered orally to mice infected with Mycobacterium bovis. For example, in this test, 3- (4-isobutyl-1-piperazinyl) -rifamycin SV shows ED 50 at 1 mg / kg. The same test was conducted with 3- (4-cyclohexylmethyl-1-piperazinyl) -rifamycin SV and ED 50 is 1 mg / kg. In addition, the compounds of the present invention are very toxic at very high doses and have a very wide range of therapeutic effects. The LD 50 of 3- (4-cyclohexylmethyl-1-piperazinyl) -rifamycin SV upon oral administration is at least 5,000 mg / kg.

High anti-tuberculosis can be measured by in vitro experiments. In vitro, the minimum inhibitory concentration for mycobacterium bovis is greater than that described above for the known rifampicin, a 3- (4-methyl-1-piperazinyl-aminomethyl) -rifamycin SV, a tuberculosis bacteriostatic lipamycin preparation. 30-fold less for-(4-isobutyl-1-piperazinyl) -rifamycin SV.

In addition, the compounds of the present invention have a good antibiotic action as can be seen by animal experiments on mice. Oral administration of 0.2 mg / kg to 40 mg / kg shows antibiotic activity in mice infected with Staphylococcus aureus. Therefore, these new compounds are used first of all for the treatment of tuberculosis infection and also for the treatment of infectious diseases by other infections such as leprosy or by the same pathogen as staphylococcus. However, new compounds are valuable intermediate products in the preparation of pharmacologically effective compounds.

New compounds according to the invention can be prepared by reacting rifamycin S with an amine corresponding to a group capable of inducing a 3-position.

The piperazinyl group, which is not substituted by another method or has a substituent on the carbon atom, is first introduced into the 3-position of rifamycin S or rifamycin SV by the above-described method, and then reacted with an alkylating agent to react R with the N 'of the piperazinyl group. -Induce in position.

3- (1-piperazinyl) -lipa which may react rifamycin S of the process for the preparation of compounds I and II of the invention with an amine of the structural HA or optionally substituted with a lower alkyl group at the carbon atom of the piperazinyl group The reaction of mycin S or SV with an alkylating agent suitable for the N-alkylation of piperazine leads to R and the separation of the resulting 3-amino substitution product of rifamycin S or rifamycin SV and / or if necessary The resulting hydroquinone is then oxidized to quinone or the resulting quinone is reduced to hydroquinone and / or the resulting compound is converted to a salt.

The reaction of rifamycin S with amine HA is an organic solvent that can liberate hydroxyl groups, preferably solvents such as low polar halogenated aliphatic hydrocarbons (methylene chloride, chloroform) or esters or ethers such as ethyl acetate and butyl acetate. Solvents such as amyl acetate, cellosolve, or tetrahydrofuran, among other things, are carried out in dioxane. When the amine to be reacted is a liquid, it can be suspended by adding a solvent. Suitably excess amine (5-10 moles) is used. It is preferable to react at room temperature and to react slowly at high temperature, for example, at room temperature to 100 ° C. After the reaction, thin layer chromatography can be performed. When reacting 3-1-piperazinyl-rifamycin S or SV or the aforementioned C-methyl homolog with the alkylating agent described above, alkylating agents (X: halogen, ie chlorine, fluorine, oxo) or sulfuric acid, sulfurous acid, in particular Inorganic acids or halogenated sulfuric acids, especially fluorosulfonic acids, containing the same oxygen are used. Such alkylating agents are alkyl halides, for example emulsified, iodide, chlorides of hydrocarbon R or R-monoesters or R-diesters of sulfuric acid or fluorosulfonic acid.

인 아민 존재하에서 수행하는 것이좋다. 구조식 X는 저급알킬기, X1 및 X₂는 각각 지방족 탄화수소이다. X₁및 X₂는 예를들면 C₁-C₁₂바람직하게는 C₁-C₇저급알킬이며 측쇄탄소를 가지고 있으며 X는 바람직하게는 C₁-C₇저급알킬기이다. 무엇보다도 휘니히염기 즉 에틸-디이소푸로필아민을 사용하는 것이 좋다.Reaction of the aforementioned lipamycin compound with such alkylating agents is preferably a tertiary amine, particularly a structural formula, having no base, particularly strong basic nucleophilicity.

It is preferred to carry out in the presence of phosphorus amine. Formula X is a lower alkyl group, X 1 and X ₂ are each an aliphatic hydrocarbon. X ₁ and X ₂ are for example C ₁ -C ₁₂ preferably C ₁ -C ₇ loweralkyl and have branched carbon and X is preferably a C ₁ -C ₇ loweralkyl group. Above all, it is preferable to use a Hunich base, ie ethyl-diisofurophylamine.

The reaction is carried out at temperatures ranging from room temperature to 100 ° C., using 1 mole each of rifamycin compound and alkylating agent in an inert solvent, in particular an aliphatic chlorinated aliphatic hydrocarbon such as methylene chloride or methanol, preferably with an equimolar amount of base.

The reaction time varies depending on the reactants and is performed for half hour to 24 hours or 48 hours.

Starting materials in the present invention are known materials and can be prepared by known methods. For example, 3-piperazino-rifamycin SV, which is used as a starting material, is obtained according to the preparation method of the aforementioned French patent application by reducing rifamycin S and piperazine to ascolic acid.

The reaction product is obtained in part in the form of quinones and in part in the form of hydroquinones. In this case, it is preferable to convert the reaction product into one compound before performing the reaction, that is, oxidize hydroquinone to quinone or reduce quinone to hydroquinone, and then separate 3-amino derivatives. The oxidation is preferably oxidized with an inorganic oxidizing agent, preferably potassium ferricyanate, and the reduction is preferably reduced with ascorbic acid or sodium dithionitite.

The method of separating the reaction product from the reaction mixture is diluted with water and / or neutralized with a water soluble acid such as inorganic or citric acid (preferably) and added a solvent that is not mixed with water, for example chlorinated hydrocarbons (chloroform, methylene chloride) and the reaction product. Is transferred to an organic solvent which can be obtained in a pure state and subjected to dehydration, evaporation, crystallization and / or chromatographic or other purification methods.

The quinones or hydroquinones thus obtained can be easily converted to another compound by treatment with the aforementioned reducing or oxidizing agents. Quinones are in most cases violet red compounds. Hydroquinones are mostly yellow and have good crystallization. Hydroquinones form metal salts, for example alkali metal salts. Quinones and hydroquinones form acid addition salts with acids and in some cases form quaternary ammonium salts with esters of lower alkanols, in particular together with halogenated acids, sulfuric acid and sulfonic acids. In order to make acid addition salts, a suitable acid is used which, among other things, makes a therapeutically available salt. Examples of these acids are hydrogen halide, sulfuric acid, phosphoric acid, nitric acid and perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, for example formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, dried Acids, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxy acid, salicylic acid or pyruvic acid, phenylacetic acid, benzoic acid, P-amino aromatic acid, anthranilic acid, P-hydroxy benzoic acid or P-amino salicylic acid, M Main acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid and ethylene sulfonic acid; Halogenbenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid, methionine, tryptophan, lysine or arginine.

Salts of the new compounds, such as picric acid salts, can convert the base, isolate it and then free the base from the salt to purify the base obtained above.

New compounds can be used in the form of pharmaceutical preparations. They contain a mixture with intestinal or orally administered pharmaceutical organic or inorganic, solid or excipients. Suitable excipients that do not react with new compounds are water, gelatin, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum, furophilene glycol, polyalkylene glycol, white petrolatum , Cholesterol or other known excipients. Pharmaceutical formulations are, for example, in the form of tablets, dragees, ointments, creams, or capsules in liquid form, such as solutions, suspensions, emulsions. They optionally contain additives such as salts or buffers which are sterile and / or preservatives, stabilizers, wetting agents, emulsifiers, solubilizers or osmotic pressures.

New compounds can also be used as veterinary medicines.

The following examples of the present invention are described in detail.

Example 1

90 g of rifamycin S is dissolved in a mixture of 100 ml of dioxane and 96 g of I-isobutylpiperazine and the solution is left at room temperature for 28 hours. Then add water, make acidic with citric acid and treat the reaction product with chloroform. The chloroform solution is washed with sodium chloride solution, dehydrated with magnesium sulfate and evaporated. The residue is dissolved in methanol and the aqueous solution of aqueous ascorbic acid is added dropwise until it becomes pale yellow. After leaving the mixture for a while, the melting point is 170 ° C. when the yellow crystal 3- (4-isobutyl-1-piperazinyl) -rifamycin SV is separated and recrystallized twice with chloroform-methanol-water. More product can be obtained from the last two mother liquors. UV spectrum in 0.01 N alcoholic HCl max (nm): 228 (4.53), 298 (4.28), 433 (3.90)

Example 2

In a similar manner to Example 1, 90 g of rapamycin S was reacted with 100 g of 1- (2-ethylbutyl) -piperazine to give 3- [4- (2-ethylbutyl) -1-piperazinyl] -rifamycin Get SV

Example 3

In a manner similar to Example 1, 90 g rapamycin S was reacted with 100 g of 1- (2-methylbutyl) -piperazine to give 3- [4- (2-methylbutyl) -1-piperazinyl] -rifamycin Get SV

Example 4

The capsule form of the pharmaceutical formulation contains 3- (4-isobutyl-1-piperazinyl) -rifamycin SV as antibiotic.

Composition

3- (4-isobutyl-1-piperazinyl) -rifamycin SV 50.00 mg

Lactose 100.00 mg

Ethyl Cellulose 1.50mg

Stearic acid 1.50mg

153.00mg

Produce

1) Mix the active ingredient with lactose.

2) Dissolve ethyl cellulose in 10 times the amount of methylene chloride.

3) 1) Mix the mixture with 2) solution, pass through 3-5mm mesh sieve, and dry at a temperature not exceeding 40 ℃.

4) The dry granules are passed through a 0.5 mm mesh sieve and mixed with stearic acid powder. The mixture is then filled into capsules of size 2.

Example 5

30 g of 1-cyclohexylmethylpiperazine is added to a solution of 30 g of rifamycin S in 100 ml of dioxane and then the mixture is left at room temperature until the first violet color turns orange brown. Water is then added and the mixture is acidified with citric acid. Take the reaction product to be obtained with chloroform. After the chloroform solution is dehydrated and evaporated, the remaining residue is dissolved in a small amount of methanol and the aqueous aqueous ascorbic acid solution is added dropwise until the first dark color of the methanol solution turns yellow. After being left for a while, 3- (4-cyclohexylmethyl-1-piperazinyl) -rifamycin SV is dropped into crystals and recrystallized twice with chloroform-methanol-water to give a completely pure material. Melting Point 176-178 ° C. The first crystallized mother liquor contains rifamycin SV with the reaction product to be obtained.

UV spectrum in 0.01 N alcoholic HCl, maximum (nm) (log ε): 228 (4.53), 298 (4.28), 433 (3.90)

Example 6

In a similar manner to the previous example, 25 (3) rifamycin S in 40 ml dioxane was reacted with 30 1-cyclofurophyl methylpiperazine to give 3- (4-cyclofurophylmethyl-1-piperazinyl) -lipa. Mycin SV was obtained and crystallized three times with chloroform-methanol-water to obtain yellow crystals having a melting point of 217 ° C.

UV spectrum in 0.01 N alcoholic HCl

Nm (log ε): 225 (4.54), 272 (4.30), 430 (3.81)

Example 7

The pharmaceutical formulation, which is a capsule, contains 3- (4-cyclohexylmethyl-1-piperazinyl) -rifamycin SV as antibiotic.

Composition

3- (4-cyclohexylmethyl-1-piperazinyl) -rifamycin SV 100.00 mg

Lactose 50.00mg

Ethyl Cellulose 1.50mg

Stearic acid 1.50mg

153.00mg

Produce

1) Mix the active substance with lactose.

2) Dissolve ethyl cellulose in 10 times the amount of methylene chloride.

3) Moisten the mixture 1) with 2) solution, pass through 3-5mm mesh body and dry at a temperature not exceeding 40 ℃.

4) The dry granules are passed through a 0.5 mm mesh sieve and mixed with stearic acid powder. The mixture is then filled into capsules of size 2.

Example 8

20 g of rifamycin S is dissolved in a mixture of 100 ml of dioxane and 27 g of N-methallyl piperazine, and the solution is left at room temperature for 35 hours. Water is then added, the mixture is acidified with citric acid and the reaction product is treated with chloroform. The chloroform solution is washed with sodium chloride solution, dehydrated with sodium sulfate and evaporated. The residue is taken up in methanol and the aqueous solution of aqueous ascorbic acid is added dropwise until it is light colored and the mixture is left to stand. After a while the 3- (4-methallyl-1-piperazinyl) -rifamycin SV was isolated as yellow crystals and recrystallized twice with chloroform-methanol-water and the melting point was 172-174 ° C. More product is obtained from the last two mother liquors.

UV spectrum in 0.01 N alcoholic hydrochloric acid

Max (nm) (log ε): 229 (4.59), 298 (4.31), 435 (3.90)

Example 9

In a manner similar to Example 8, 10 g of rifamycin S is reacted with 12 g of 1-allyl piperazine to obtain 3- [4-allyl-1-piperazinyl) -rifamycin SV having a melting point of 174-177 ° C.

UV spectrum (as in Example 8): 228 (4.60), 297 (4.32), 435 (3.91)

Example 10

In a manner similar to Example 8, 10 g of rifamycin S was reacted with 10 g of N- (2-methyl-2-pentenyl) -piperazine to give 3- [4 (2-methyl-2- with melting point 164-166 ° C. Pentenyl) -1-piperazinyl] -rifamycin SV is obtained.

UV spectrum (as in Example 8): 228 (4.58), 298 (4.30), 435 (3.92)

Example 11

In a manner similar to Example 8, 20 g of rifamycin S was reacted with 20 g of N- (2-ethyl-2-butenyl) -piperazine to give 3- [4- (2-ethyl-2 with a melting point of 174-175 ° C. -Butenyl) -1-piperazinyl] -rifamycin SV.

UV spectrum (as in Example 8): 229 (4.60), 298 (4.33), 435 (3.93)

Example 12

In a similar manner to Example 8, 15 g of rifamycin S was reacted with 16 g of N- (2-ethyl-2-hexenyl) -piperazine to give 3- [4- (2-ethyl- with a melting point of 153-156 ° C. 2-hexenyl) -1-piperazinyl] -rifamycin SV is obtained.

UV spectrum (as in Example 8): 229 (4.61), 298 (4.33), 435 (3.94)

Example 13

In a similar manner to Example 8, 20 g of rifamycin S was reacted with 20 g of N- (2,3-dimethyl-2-butenyl) -piperazine to give 3- [4- (2, 3-dimethyl-2-butenyl) -1-piperazinyl] -rifamycin SV is obtained.

UV spectrum (as in Example 8): 230 (4.60), 300 (4.33), 435 (3.93)

Example 14

In a manner similar to Example 8, 10 g of rifamycin S was reacted with 11 g of N- (2-ethylbutyl) -piperazine to give 3- [4- (2-ethylbutyl) -1- having a melting point of 168-170 ° C. Piperazinyl] -rifamycin SV is obtained.

UV spectrum (as in Example 8): 228 (4.47), 299 (4.32), 435 (3.94)

Example 15

Mix 3 g of 3- (1-piperazinyl) with 55 ml of ethanol, 1 ml of water, 1.15 g (2 equivalents) of cyclobutylmethyl bromide and 2.5 ml (about 2 equivalents) of Hunich's base (ethyl-diisofurophylamine) ) -Ripamycin SV is added and refluxed for 20 hours. Water is then added, the mixture is acidified with citric acid and the reaction product is treated with chloroform. Wash with chloroform solution, dehydrate with sodium sulfate and evaporate. The residue is dissolved in methanol, and a small amount of aqueous ascorbic acid solution is added dropwise, and the mixture is left. After a while 3- (4-cyclobutylmethyl-1-piperazinyl) -rifamycin SV is isolated as yellow crystals and slowly decomposes above 195 ° C. when recrystallized twice with chloroform-methanol-water. A little more product is obtained from the last two mother liquors.

UV spectrum in 0.01 N alcoholic hydrochloric acid

Max (nm) (log ε): 230 (4.58), 299 (4.30), 435 (3.90)

Example 16

In a similar manner as in Example 15, 5 g of 3- (1-piperazinyl) -rifamycin SV was reacted with 2.1 g (2 equivalents) of cyclopentylmethylbromide 2.5 ml (2 equivalents) of WHICH base, melting point 180-. Obtain 3- (4-cyclobutylmethyl-1-piperazinyl) -rifamycin SV, which is 185 ° C. (decomposition).

UV spectrum: 228 (4.58), 298 (4.31), 435 (3.92)

(As in Example 8)

Example 17

In a manner similar to Example 15, 10 g of rifamycin S was reacted with 10 g of N- (1,2-dimethyl-furophyll) -piperazine to give 3- [4- (1,2-dimethyl having a melting point of 184-186 ° C. Furophyll) -1-piperazinyl) -rifamycin SV is obtained.

UV spectra: 230 (4.58), 299 (4.33), 435 (3.93) (as in Example 8)

Example 18

When rifamycin S is reacted with the N-substituted piperazine of Table 1 in the following manner, a lipamycin SV derivative substituted with the corresponding N'-substituted 1-piperazinyl group in the 3-position is obtained. It looks like this:

[Produce]

The amount of amine is added to a solution of rifamycin S in dioxane and the mixture is left at room temperature until the first purple to orange red color. Water is then added and the mixture is acidified with citric acid. The reaction product to be obtained is treated with chloroform. After the chloroform solution is dehydrated and evaporated, the residue is dissolved in a small amount of methanol and the aqueous soluble ascorbic acid solution is added dropwise until the first dark yellow color. After being left for a while, the desired product is dropped by precipitation and recrystallized twice with chloroform-methanol-water to obtain a completely pure material.

Melting point is shown in the table. The first recrystallized mother liquor contains rifamycin SV with the reaction product.

Substituted piperazines that are considered starting materials in the table are generally obtained by reacting piperazine with a special alkyl bromide.

In some cases it is advantageous to use the corresponding tosylate instead of bromide, for example piperazine can be reacted with neopentyl tosylate to obtain the N- (neopentyl) -piperazine described above.

Claims (1)

A 3- (1-piperazinyl) -rifamycin S or SV, which may react rifamycin S with an amine of the structural HA or may be substituted with a lower alkyl group at the carbon atom of the pimerazinyl group, is subjected to N-alkylation of piperazine. Reaction with a suitable alkylating agent to introduce R yields a 3-aminosubstituted product of rifamycin S or rifamycin SV, which is oxidized to quinone form before or after separation and reduced to hydroquinone form when the quinone form is aliphatic. A method for preparing a rifamycin S compound of formula (I) substituted with an amino group substituted with an amino acid, and its corresponding hydroquinones (rifamycin SV) and salts thereof.

In the above structural formula A is a 4R-1-piperazinyl group in which the carbon atom is optionally substituted with a lower alkyl group R is a hydrocarbon group of the formula

Wherein n is 0 or 1 and Z ₁ is unsubstituted phenyl or phenyl substituted with lower alkyl or lower alkyl or lower alkenyl or unsubstituted phenyl or lower alkyl which may be substituted with cycloalkyl or cycloalkenyl groups Phenyl group or cycloalkyl group or cycloalkenyl group, phenyl group may be substituted with halogen, Z ₂ is hydrogen, lower alkyl, lower alkenyl group, Z ₃ is lower alkyl, lower alkenyl or optionally Z "together with double bond , Z ₂ and Z ₃ together are lower alkylidene, lower alkenylidene, Z ₁ and Z ₃ together are alkylene or alkenylene group. However, if Z ₃ together with Z "represents a double bond, then Z ₁ + Z ₂ Is also an alkylene or alkenylene group, Z 'and Z "are each hydrogen or a lower alkyl group and are cyclical groups produced by Z ₁ + Z ₃ or Z ₁ + Z ₂ in the above-mentioned cyclic aliphatic groups or alkylene or alkenylene groups Aliphatic In which one or more CC atom pairs not adjacent to each other in the ring are optionally linked directly by another one or indirectly via a lower alkylidene or alkylene group and one C atom may be spiroly substituted by a lower alkylene group And these groups contain up to 12 carbon atoms.