WO2000025721A2 - Sodium salt of 3-(4-cinnamyl-1-piperazinyl)imino-methyl rifamycin sv and process of preparation - Google Patents

Sodium salt of 3-(4-cinnamyl-1-piperazinyl)imino-methyl rifamycin sv and process of preparation Download PDF

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Publication number
WO2000025721A2
WO2000025721A2 PCT/BG1999/000022 BG9900022W WO0025721A2 WO 2000025721 A2 WO2000025721 A2 WO 2000025721A2 BG 9900022 W BG9900022 W BG 9900022W WO 0025721 A2 WO0025721 A2 WO 0025721A2
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sodium salt
cinnamyl
piperazinyl
sodium
rifamycin
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WO2000025721A3 (en
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Roumiana Gueorguieva Konstantinova
Kiril Asenov Ninov
Velitchka Ilieva Dimova
Anka Veltcheva Evstatieva
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Priority to EP99953444A priority patent/EP1124831B1/en
Priority to US09/831,012 priority patent/US6476036B1/en
Priority to DK99953444T priority patent/DK1124831T3/en
Priority to BR9915035-2A priority patent/BR9915035A/en
Priority to AT99953444T priority patent/ATE248176T1/en
Priority to DE69910810T priority patent/DE69910810T2/en
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Publication of WO2000025721A3 publication Critical patent/WO2000025721A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to the sodium salt of 3-(4-cinnamyl-l-piperazinyl)- iminomethyl-rifamycin SV and process of preparation.
  • the sodium salt shows high activity against Gram-positive and Gram- negative microorg_______3J_-is, __Iy_cobact£r_i_ ⁇ m-tuberculosis, (including atypical and Rifampicin resistant) and therefore may be used in the medical practice.
  • rifamycins are group of antibiotics with high antibacterial activity and they have a wide spectrum of application in the treatment of Mycobacterium infections.
  • Rifampicin is the best known representative of the group of rifamycins.
  • T-9 The therapeutic activity of T-9 in doses 10 mg/kg in generalized tuberculosis in test animals shows full organ sterilization after 60 days of treatment, while a similar therapeutic effect is achieved with Rifamificyn in doses of 80 mg/kg.
  • the compound presents considerably longer serum half life than Rifampicin (T 1/2 : 31 ⁇ 34 hours) tested on animals.
  • the acute toxicity of T-9 in mice is 4000 mg/kg, while this of Rifampicin is 1500 mg/kg. This indicates the compound T-9 as the best perspective among the derivatives of Rifamicyn SN, described in BG No. 36006.
  • the present invention is concerned with the sodium salt of 3-(4- cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV which is new, and a process for its preparation.
  • the new sodium salt provided by the present invention is compound of the general formula II:
  • the new sodium salt of 3-(4-cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV possesses increased antibacterial activity and low toxicity in comparison with the compound tillT-9".
  • the new sodium salt has the advantages: good water solubility and higher bioavalability and possibility for administration as injectable formulation.
  • the sodium salt of 3-(4-cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV can be easily obtained by the following two methods: Method A.
  • the sodium salt of 3-(4-cinnamyl-l-piperazinyl)- iminomethyl rifamycin SV is prepared by reacting equimolar amount of 3-(4-cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV and of appropriate organic or inorganic base, containing sodium, in aqueous medium or in organic solvent medium.
  • the reaction can be carried out in the presence of small amount of sodium ascorbate as an antioxidizing agent to prevent the transformation of the phenol structures in the rifamycin derivative into quinine-structures.
  • the reaction mixture is prepared by adding the corresponding alcohol (methanol, ethanol and the like). More preferably is the use of sodium methylate diluted with methanol or ethanol.
  • the solvent was removed in vacuum (if it is alcoholate) and the resulting solid sodium salt is destilated or is lyophilized (if the reaction is carried out in aqueous medium).
  • the sodium salt may be isolated using distillation of the solving agent in vacuum (when effecting the reaction in an alcoholic medium), or using lyophilization (when effecting the reaction in water). The yield of the sodium salt is practically quantitative and with high purity.
  • the obtained the sodium salt may be purified by recrystallization in a suitable solvent.
  • Method A a sodium salt of 3- formilrifamycin SV which subsequently is reacting with N ⁇ amino-N 4 - cinnamylpiperazin in medium of an inert solvent at room temperature.
  • the solvent was evaporated by distillation in vacuum and the residual product was purified by recrystallization in suitable solvent.
  • the crude product opptionally may be recrystallized by boiling in isopropanol to give the sodium salt as red crystal solid ( 80% yield), soluble in water, methanol, ethanol, acetone and unsoluble in isopropanol.
  • the absorption in UV-spectrum and visible area of 0,001% methanol solution of the product in the interval 200-800 nm in cuvette, with layer with 1 cm, has a maximums wavelength of 251, 338 and 480 nm.
  • Example 4 in a manner analogous to that described in Example land subsituting the 30% methanol solution of sodium methylate, with equimolar quantity of dry sodium methylate the sodium salt was obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV was synthesized. The compound shows high activity against Gram-positive and Gram-negative microorganims, Mycobacterium tuberculosis (including atypical and rifampicin resistant) and may be used in the medical practice. The sodium salt has formula (II). The process for preparation of the sodium salt consists of reacting equimolar quantities of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV and sodium ascorbate with addition of 30 % methanol solution of sodium methylate, followed by filtration and removement of the solvent by distillation under reduced pressure. The compound can also be obtained from the sodium salt of 3-formil rifamycin SV, which is reacting with N1-amino-N4-cinnamypiperazin in medium of inert solvent at room temperature.

Description

SODIUM SALT OF 3-(4-CINNAMYL-l-PIPERAZINYL)IMINO- METHYL RIFAMYCIN SV AND PROCESS OF PREPARATION
Technical field The invention relates to the sodium salt of 3-(4-cinnamyl-l-piperazinyl)- iminomethyl-rifamycin SV and process of preparation. The sodium salt shows high activity against Gram-positive and Gram- negative microorg_______3J_-is, __Iy_cobact£r_i_αm-tuberculosis, (including atypical and Rifampicin resistant) and therefore may be used in the medical practice.
Background of the invention The rifamycins are group of antibiotics with high antibacterial activity and they have a wide spectrum of application in the treatment of Mycobacterium infections. Rifampicin is the best known representative of the group of rifamycins.
In document BG No. 36006 (US. Pat. 4,193,920) are described new azomethyn derivatives of Rifamycin SV with general formula I,
Figure imgf000004_0001
Formula I
These compounds display high activity against Gram-positive and Gram-negative microorganisms and Mycobacterium tbc. This activity is analogical and in some cases is higher than that of Rifamycin. The document BG No. 87451 (US. Pat. 5,095,108 (1992)) describes a process for preparing the insoluble crystal form of 3-(4-cinnamyl-l- piperazinyl)-iminomethyl rifamycin SV (compound, designed as T-9 in the first quoted BG document). The in vivo investigations of the compound show a higher therapeutic effect in comparison with this of Rifampicin. The therapeutic activity of T-9 in doses 10 mg/kg in generalized tuberculosis in test animals shows full organ sterilization after 60 days of treatment, while a similar therapeutic effect is achieved with Rifamificyn in doses of 80 mg/kg. The compound presents considerably longer serum half life than Rifampicin (T1/2: 31 ~ 34 hours) tested on animals. The acute toxicity of T-9 in mice is 4000 mg/kg, while this of Rifampicin is 1500 mg/kg. This indicates the compound T-9 as the best perspective among the derivatives of Rifamicyn SN, described in BG No. 36006.
Disclosure
The present invention is concerned with the sodium salt of 3-(4- cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV which is new, and a process for its preparation. The new sodium salt provided by the present invention is compound of the general formula II:
Figure imgf000005_0001
Formula II
The new sodium salt of 3-(4-cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV possesses increased antibacterial activity and low toxicity in comparison with the compound „T-9". The new sodium salt has the advantages: good water solubility and higher bioavalability and possibility for administration as injectable formulation.
The synthesis of the water soluble sodium salt of T-9 provides better possibilities for administration of the new salt as well in parenteral as in peroral pharmaceutical formulations.
The in vitro studies of the activity of sodium salt (designated T-ll) in comparison with the initial compound T-9 show good antibacterial activity against the Gram-positive microorganisms including aerobic, anaerobic and Mycobacterium (typical and atypical). The pharmacokinetic properties of theknown compound T-9 are improved in the salt - the sodium salt has better resorbtion characteristics stemming from its better water solubility and maintains higher serum levels. The sodium salt has clearly expressed depo activity and secures the maintenance of constant theurapeutical concentrations in the organism for a longer period of time: 40 ~ 50 hours in mice and rats, and about 100 hours in rabbits (Table 1).
Table 1
Non-model pharmacokinetic parameters after use of T-ll and T-9 (base 20 mg/kg) in mice, rats and rabbits
Figure imgf000006_0001
Advantage of the newly- synthesed sodium salt is its good water solubility and the possibility of its application in the fopm of injection solutions (something impossible with the undissolved basic compound T- 9), stability of the obtained water solutions, faster resorbtion and better pharmacokinetic properties in animal tests.
The sodium salt of 3-(4-cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV can be easily obtained by the following two methods: Method A.
In this method the sodium salt of 3-(4-cinnamyl-l-piperazinyl)- iminomethyl rifamycin SV is prepared by reacting equimolar amount of 3-(4-cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV and of appropriate organic or inorganic base, containing sodium, in aqueous medium or in organic solvent medium. Preferably the reaction can be carried out in the presence of small amount of sodium ascorbate as an antioxidizing agent to prevent the transformation of the phenol structures in the rifamycin derivative into quinine-structures. When the reaction is carried out in an aqueous medium , diluted solution of sodium salt is used as a base and when using sodium alcoholates (sodium methylate, sodium ethylate, sodium isopropilate), the reaction mixture is prepared by adding the corresponding alcohol (methanol, ethanol and the like). More preferably is the use of sodium methylate diluted with methanol or ethanol. The solvent was removed in vacuum (if it is alcoholate) and the resulting solid sodium salt is destilated or is lyophilized (if the reaction is carried out in aqueous medium). The sodium salt may be isolated using distillation of the solving agent in vacuum (when effecting the reaction in an alcoholic medium), or using lyophilization (when effecting the reaction in water). The yield of the sodium salt is practically quantitative and with high purity. The obtained the sodium salt may be purified by recrystallization in a suitable solvent.
Method B.
Proceeding as described in Method A is prepared a sodium salt of 3- formilrifamycin SV which subsequently is reacting with N^amino-N4- cinnamylpiperazin in medium of an inert solvent at room temperature.
The solvent was evaporated by distillation in vacuum and the residual product was purified by recrystallization in suitable solvent.
The following examples are given to illustrate more clearly the present invention. Example 1:
4,62 g (0,005 g/moll) of 3-(4-cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV is suspended in 40 ml methanol and 0,1 g sodium ascorbate dissolved in 1 ml water is added. To the obtained suspension 0,9 ml of 30% methanol solution of sodium methylate (equimolar quantity) is added. The suspension immediately turns into a solution because of the formation of the sodium salt. The reaction mixture is filtered to remove the unsolved sediment of sodium ascorbate, and the solvent is concentratrated in vacuum and dried to give the soduim salt as a dark- red solid powder. This product has high purity and the yield is practically quantitative.
The crude product opptionally may be recrystallized by boiling in isopropanol to give the sodium salt as red crystal solid ( 80% yield), soluble in water, methanol, ethanol, acetone and unsoluble in isopropanol.
The absorption in UV-spectrum and visible area of 0,001% methanol solution of the product in the interval 200-800 nm in cuvette, with layer with 1 cm, has a maximums wavelength of 251, 338 and 480 nm.
Analysis: C51H63N4 Na012 M.m 947,03 % content of Na (theoretical): 2,43
% content of Na (determined by the method of atomic-absorption analysis): 2,35
Example 2
In a manner analogous to that described in Example 1 and substituting the methanol with ethanol the sodium salt was obtained.
Example 3
In a manner analogous to that in Example 1 and substituting the methanol with isopropanol the sodium salt was obtained. Example 4 in a manner analogous to that described in Example land subsituting the 30% methanol solution of sodium methylate, with equimolar quantity of dry sodium methylate the sodium salt was obtained.
Example 5
4,62g (0,005g/moll) of 3-(4-cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV is suspended in 100ml of water, and 5 ml IN solution of sodium base is added to the suspension over two to three hours with vigirous stirring. A gradual transformation of the suspension into a solution is observed, due to the formation of the soluble sodium salt. The reaction mixture is filtered and lyophilized to give the sodium salt as dark red powder (quantitative yield).
Analysis: C38H46NNa013
% content of Na (theoretical): 3,07
% content of Na (determined by the method of atomicabsorbation analysis): 3,05
Example 6
5,23g (0,007g/moll) of the obtained product is dissolved in 50 ml tetrahydrofuran and to the solution with continuous stirring 1,52 g (0,007 g/moll) N1-amino-N4-cinnamylpiperazin, dissolved in 20 ml tetrahydrofuran, is added. The reaction mixture is stirred at room temperature for 2 h. The solvent is then redistillated under reduced pressure. The obtained sodium salt of 3-(4-cinnamyl-l-piperazinyl)- iminomethyl rifamycin SV is recrystallized in isopropyl alcohol. Yield 4,97 g (75% ). The product is identical to this obtained by the procedure in Example 1.

Claims

1. Sodium salt of 3-(4-cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV of the general formula:
Figure imgf000010_0001
2. A process for preparing a sodium salt of 3-(4-cinnamyl-l- piperazinyl)-iminomethyl rifamycin SV according to claim 1, characterized with that 3-(4-cinnamyl-l-piperazinyl)-iminomethyl rifamycin SV is reacting with equimolar quantities of organic or inorganic base, containing sodium in aqueous medium or in organic solvent medium, and in the presence of small amount of sodium ascorbate as antioxidant.
3. A process for preparing a sodium salt according to Claim 1, characterized with that the sodium salt of 3-formylrifamycin SV, obtained in accordance with the method described in Claim 2, is reacting with N^amino-N^cinnamylpiperasin in medium of indifferent solvent at room temperature.
4. The use of sodium salt according to Claim 1 for the treatment of diseases caused by bacterial infections.
PCT/BG1999/000022 1998-11-04 1999-11-03 Sodium salt of 3-(4-cinnamyl-1-piperazinyl)imino-methyl rifamycin sv and process of preparation Ceased WO2000025721A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU10204/00A AU1020400A (en) 1998-11-04 1999-11-03 Sodium salt of 3-(4-cinnamyl-1-piperazinyl)imino-methyl rifamycin sv and processof preparation
EP99953444A EP1124831B1 (en) 1998-11-04 1999-11-03 Sodium salt of 3-(4-cinnamyl-1-piperazinyl)imino-methyl rifamycin sv and process of preparation
US09/831,012 US6476036B1 (en) 1998-11-04 1999-11-03 Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-imino-methyl rifamycin SV
DK99953444T DK1124831T3 (en) 1998-11-04 1999-11-03 Sodium salt of 3- (4-cinnamyl-1-piperazinyl) imino-methyl-rifamycin SV and process for its preparation
BR9915035-2A BR9915035A (en) 1998-11-04 1999-11-03 Sodium salt of 3- (4-cinamyl-1-piperazinyl) iminomethyl rifamycin sv and preparation process
AT99953444T ATE248176T1 (en) 1998-11-04 1999-11-03 SODIUM SALT OF 3-(4-CINNAMYL-1-PIPERAZINYL)-IMINOMETHYL-RIFAMYCIN SV AND METHOD FOR THE PRODUCTION THEREOF
DE69910810T DE69910810T2 (en) 1998-11-04 1999-11-03 SODIUM SALT OF 3- (4-CINNAMYL-1-PIPERAZINYL) -IMINOMETHYL-RIFAMYCIN SV AND METHOD FOR THE PRODUCTION THEREOF

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BG102897 1998-11-04
BG102897A BG64021B1 (en) 1998-11-04 1998-11-04 Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin and method for its preparation

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DE (1) DE69910810T2 (en)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009137380A1 (en) * 2008-05-05 2009-11-12 Janssen Pharmaceutica Nv 3-hydrazone piperazinyl rifamycin derivatives useful as antimicrobial agents
JP2018199718A (en) * 2012-08-13 2018-12-20 アディファルム・エアドゥ Pharmaceutical formulations containing 3-formylrifamycin SV and 3- (4-cinnamyl-1-piperazinyl) amino derivatives of 3-formylrifamycin S and methods for their production

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100383143C (en) * 2004-04-29 2008-04-23 薛荔 One-pot processing method for synthesizing rifampicin

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR64108B (en) * 1977-04-15 1980-01-24 Dso Pharmachim Method for the preparation of azomethine-derivatives of rifamycin s.v
SE458505B (en) * 1979-07-10 1989-04-10 Lepetit Spa APPLICATION OF RIFAMYCIN SV AND SALTS THEREOF PREPARING A PREPARATION FOR TREATMENT OF REUMATOID ARTHRITIS AND CERTAIN SALTS AND THEIR PREPARATION
MC1819A1 (en) * 1985-10-18 1988-03-18 Ciba Geigy Ag SUBSTITUTED 4-BENZYL-PIPERAZINYL COMPOUNDS
IT1202424B (en) * 1987-01-26 1989-02-09 Prodotti Antibiotici Spa SALTS OF A RIFAMICINIC DERIVATIVE
EP0284552A1 (en) * 1987-03-06 1988-09-28 Ciba-Geigy Ag 4-Benzyl-piperazinyl-hydrazones
US5095108A (en) * 1990-08-28 1992-03-10 Technologichen Kombinat Za Promishlena Microbiologia Non-solvated crystalline form "A" of 3-(4-cynnamyl-1-piperazinyl)iminomethylrifamycine SV and a method of its production

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009137380A1 (en) * 2008-05-05 2009-11-12 Janssen Pharmaceutica Nv 3-hydrazone piperazinyl rifamycin derivatives useful as antimicrobial agents
JP2018199718A (en) * 2012-08-13 2018-12-20 アディファルム・エアドゥ Pharmaceutical formulations containing 3-formylrifamycin SV and 3- (4-cinnamyl-1-piperazinyl) amino derivatives of 3-formylrifamycin S and methods for their production

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DK1124831T3 (en) 2003-12-22
BG102897A (en) 2000-06-30
EP1124831B1 (en) 2003-08-27
ATE248176T1 (en) 2003-09-15
BR9915035A (en) 2001-10-16
BG64021B1 (en) 2003-10-31
RU2001114830A (en) 2003-07-10
DE69910810T2 (en) 2004-08-19
PT1124831E (en) 2004-01-30
DE69910810D1 (en) 2003-10-02
ES2207296T3 (en) 2004-05-16
EP1124831A2 (en) 2001-08-22
US6476036B1 (en) 2002-11-05
AU1020400A (en) 2000-05-22
WO2000025721A3 (en) 2000-11-16

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