WO1996015113A1 - Preparation of n-(3-halopropyl)iminostilbene and its conversion to opipramol - Google Patents

Preparation of n-(3-halopropyl)iminostilbene and its conversion to opipramol Download PDF

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Publication number
WO1996015113A1
WO1996015113A1 PCT/US1995/014320 US9514320W WO9615113A1 WO 1996015113 A1 WO1996015113 A1 WO 1996015113A1 US 9514320 W US9514320 W US 9514320W WO 9615113 A1 WO9615113 A1 WO 9615113A1
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iminostilbene
process according
reaction
bromo
chloropropane
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Daniella Gutman
Mishel Ashkar
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Taro Pharmaceutical Industries Ltd
Taro Pharmaceuticals USA Inc
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Taro Pharmaceutical Industries Ltd
Taro Pharmaceuticals USA Inc
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Priority to AU41022/96A priority Critical patent/AU4102296A/en
Priority to EP95939059A priority patent/EP0793652B1/en
Priority to AT95939059T priority patent/ATE192439T1/en
Priority to DE69516715T priority patent/DE69516715T2/en
Priority to CA002204261A priority patent/CA2204261C/en
Publication of WO1996015113A1 publication Critical patent/WO1996015113A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/26—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a double bond between positions 10 and 11
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines

Definitions

  • This invention is concerned with a novel and improved method for preparing the antipsychotic and antidepressant drug, opipramol (I) . More particularly, this invention is concerned with a novel method for converting iminostilbene (II) , also known as dibenzo- [b,f]azepine, into N-(3-halopropyl)iminostilbene, a mixture of 3- chloro- and 3-bromopropyl derivatives, which is a precursor one step removed from opipramol(I) .
  • iminostilbene (II) also known as dibenzo- [b,f]azepine
  • iminostilbene (II) is used as the starting material and is first alkylated with l-bromo-3-chloropropane to yield N-(3-halopropyl)- iminostilbene (III), which is used in turn to alkylate N-(2- hydroxyethyl)piperazine at the secondary amine site to yield opipramol(I) , as shown by the following equations, where X is chlorine or bromine.
  • alkylation of iminostilbene (II) requires the use of a strong base catalyst, such as sodamide.
  • Sodamide has been employed in non-aqueous medi to convert iminostilbene (II) into its anion (V) , which may then be alkylated, a shown by the equations below.
  • R is lower alkyl and X is halogen, preferably Br.
  • the object of this invention is a new and improved method fo the preparation of opipramol.
  • Another object of the invention is a new and improved method for the preparation of the immediate precursor, N-(3-halopropyl)- iminostilbene, in the preparation of opipramol.
  • alkylation of iminostilbene (II) can be carried out with excellent results using a weak base, selected from a phosphate of the formula, M x HP ⁇ 4 (IV), or an acetate of the formula, CH 3 COOM (IVa), wherein M is an alkali metal, alkaline earth metal or ammonium and x is 1 or 2, determined by the valence of M.
  • a weak base selected from a phosphate of the formula, M x HP ⁇ 4 (IV), or an acetate of the formula, CH 3 COOM (IVa), wherein M is an alkali metal, alkaline earth metal or ammonium and x is 1 or 2, determined by the valence of M.
  • the alkylation is also carried out in the presence of a phase transfer agent.
  • iminostilbene (II) is alkylated with l-bromo-3-chloropropane in the presence of a weak base of the formula M x HP0 4 (IV) or CH 3 COOM (IVa) , where M and x are as defined above, and a phase transfer agent, and the resultant N-(3- halopropyl)iminostilbene (III) is reacted with N-(2-hydroxyethyl)- piperazine to yield opipramol (I) .
  • the weak base M x HP0 4 (IV) or CH 3 COOM (IVa) and phase transfer agent With the use of the weak base M x HP0 4 (IV) or CH 3 COOM (IVa) and phase transfer agent, the undesirable elimination of HX from N-(3-halopropyl)iminostilbene (III) does not occur, thereby increasing the net yield of N-(3-halopropyl)iminostilbene (III), improving the efficiency of the process and avoiding the necessity of removing unwanted by-product.
  • the weak base phosphate salts (IV) are preferred and M preferably sodium, potassium or ammonium in formulas (IV) and (IVa) .
  • phase transfer agent examples include quaternary ammonium salts; aryltrialkyl- ammonium salts, such as benzyltriethylammonium chloride, are preferred.
  • the phase transfer agent is used in a catalytically effective amount, preferably 3-10% by weight, based on the weight of iminostilbene.
  • Solvents suitable for the first step of the process include those substantially inert to the reagents of the reaction, which include alkylbenzenes, such as toluene, and also dimethyl- formamide, dimethylacetamide, isopropanol, butanol, and diethylen glycol; alkylbenzenes and particularly toluene are preferred.
  • the alkylation is preferably carried out at a temperature of 80-140°C most preferably at 110°C.
  • l-Bromo-3-chloropropane and the weak base (IV) or (IVa) are each used in approximately stoichiometric equivalents or in exces of the amount required to alkylate iminostilbene (II) .
  • the produc of this alkylation, .N-(3-halopropyl)iminostilbene (III), is a mixture of N-(3-bromopropyl)iminostilbene and N-(3-chloropropyl)- iminostilbene; the particular proportion of 3-chloro- and 3- bromopropyl derivatives is of no importance, since both compounds are readily converted to opipramol (I) by reaction with N-[2- hydroxyethyl]-piperazine.
  • the first step of the process is carried out by heating a solution of iminostilbene (II) containing l-bromo-3-chloropropane and disodium hydrogen phosphate in the presence of a catalytic amount of benzyltriethyl- ammonium chloride.
  • N-(3-halopropyl)iminostilbene (III) in the resultant solution is converted without further isolation into opipramol (I) by reaction in situ with N-[2-hydroxyethyl]- piperazine.
  • N-(3-halopropyl)iminostilbene (III) with N- [2-hydroxyethy1]-piperazine is preferably carried out with an excess of N-[2-hydroxyethyl]-piperazine at a temperature of about 50° to 150°C, most preferably at about H0 ⁇ C, in the presence of a base until the alkylation is substantially complete.
  • the mole ratio of N-(3-halopropyl)iminostilbene (III) to N-[2-hydroxy- ethyl]-piperazine is preferably about 1:1 to 1:3 and most preferably about 1:2.
  • a weak base such as sodium carbonate or potassium carbonate is preferred and is used in amount effective to achieve reaction between iminostilbene (III) and N-[2- hydroxyethyl]-piperazine.
  • the toluene layer is cooled to 30-40°C and 500 ml of a 1.5 N aqueous solution of HC1 or H2SO4 is mixed with the toluene layer; the aqueous layer is separated; the extraction is repeated with an additional 100 ml of the acidic solution and the aqueous extracts are combined.
  • Toluene in an amount of 600 ml is added to the combined aqueous extracts; the mixture is heated to 50°C and ammonium or sodium hydroxide is added until a pH>9.
  • the mixture is agitated for 1/2 hour at 60- 70°C, after which the toluene layer is separated and washed with 100 ml of water and then dried by azeotropic distillation.
  • the toluene layer is then cooled to 0-10°C and centrifuged to obtain the solid product, opipramol (I) .
  • Additional product is obtained by concentrating the toluene residue to about 1/4 of its initial volume and cooling to 0-10°C.
  • the total amount of product obtained is 215 g, having a .p. of 96°C.
  • Opipramol (I) can be further purified by dissolving 200 g of the above-obtained opipramol (I) in 600 ml of acetone; mixing 7 g of active carbon and 5 g of Celite into the solution, filtering and then cooling the solution to 0-lO°C and finally collecting t purified product on a centrifuge.
  • the m.p. of the purified produ is 101°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Saccharide Compounds (AREA)

Abstract

An improved method for preparing opipramol is disclosed, wherein iminostilbene is reacted with 1-bromo-3-chloropropane in the presence of a weak base selected from a hydrogen phosphate salt and an acetate salt and in the presence of a phase transfer agent to produce N-(3-halopropyl)iminostilbene, which is mixture of N-(3-chloropropyl)iminostilbene and N-(3-bromopropyl)iminostilbene, and then N-(3-halopropyl)iminostilbene is reacted with N-(2-hydroxyethyl)piperazine to form opipramol.

Description

PREPARATION OF N-(3-HAL0PR0PYL)IMINOSTILBENE AND ITS CONVERSION TO OPIPRAMOL
Background of Invention
This invention is concerned with a novel and improved method for preparing the antipsychotic and antidepressant drug, opipramol (I) . More particularly, this invention is concerned with a novel method for converting iminostilbene (II) , also known as dibenzo- [b,f]azepine, into N-(3-halopropyl)iminostilbene, a mixture of 3- chloro- and 3-bromopropyl derivatives, which is a precursor one step removed from opipramol(I) .
In a preferred method of synthesizing opipramol (I) , iminostilbene (II) is used as the starting material and is first alkylated with l-bromo-3-chloropropane to yield N-(3-halopropyl)- iminostilbene (III), which is used in turn to alkylate N-(2- hydroxyethyl)piperazine at the secondary amine site to yield opipramol(I) , as shown by the following equations, where X is chlorine or bromine.
Figure imgf000003_0001
According to German Patent 1133729, alkylation of iminostilbene (II) requires the use of a strong base catalyst, such as sodamide. Sodamide has been employed in non-aqueous medi to convert iminostilbene (II) into its anion (V) , which may then be alkylated, a shown by the equations below.
Figure imgf000004_0001
where R is lower alkyl and X is halogen, preferably Br.
When R is free of base-sensitive groups, such a procedure is effective and efficient. However, when l-bromo-3-chloropropane is the alkylating reagent, the desired product, N-(3-halopropyl)- iminostilbene (III) is converted by the strongly basic medium, at least in part, to the illustrated dehydrohalogenated by-product, N-allyl-iminostilbene (Ilia) , which is unsuitable for direct conversion to opipramol (I) .
Summary of the Invention
The object of this invention is a new and improved method fo the preparation of opipramol.
Another object of the invention is a new and improved method for the preparation of the immediate precursor, N-(3-halopropyl)- iminostilbene, in the preparation of opipramol. These and other objects are achieved by the invention described below.
Surprisingly, it has been discovered that alkylation of iminostilbene (II) can be carried out with excellent results using a weak base, selected from a phosphate of the formula, MxHPθ4 (IV), or an acetate of the formula, CH3COOM (IVa), wherein M is an alkali metal, alkaline earth metal or ammonium and x is 1 or 2, determined by the valence of M. Desirably, the alkylation is also carried out in the presence of a phase transfer agent.
According to the invention, iminostilbene (II) is alkylated with l-bromo-3-chloropropane in the presence of a weak base of the formula MxHP04 (IV) or CH3COOM (IVa) , where M and x are as defined above, and a phase transfer agent, and the resultant N-(3- halopropyl)iminostilbene (III) is reacted with N-(2-hydroxyethyl)- piperazine to yield opipramol (I) .
Description of the Invention
With the use of the weak base MxHP04 (IV) or CH3COOM (IVa) and phase transfer agent, the undesirable elimination of HX from N-(3-halopropyl)iminostilbene (III) does not occur, thereby increasing the net yield of N-(3-halopropyl)iminostilbene (III), improving the efficiency of the process and avoiding the necessity of removing unwanted by-product. As the weak base, phosphate salts (IV) are preferred and M preferably sodium, potassium or ammonium in formulas (IV) and (IVa) .
According to the invention, the action of MxHPθ4 (IV) and CH3COOM (IVa) is best achieved by heating the reactants in a solvent in the presence of a phase transfer agent. Useful phase transfer agents include quaternary ammonium salts; aryltrialkyl- ammonium salts, such as benzyltriethylammonium chloride, are preferred. The phase transfer agent is used in a catalytically effective amount, preferably 3-10% by weight, based on the weight of iminostilbene.
Solvents suitable for the first step of the process include those substantially inert to the reagents of the reaction, which include alkylbenzenes, such as toluene, and also dimethyl- formamide, dimethylacetamide, isopropanol, butanol, and diethylen glycol; alkylbenzenes and particularly toluene are preferred. The alkylation is preferably carried out at a temperature of 80-140°C most preferably at 110°C.
l-Bromo-3-chloropropane and the weak base (IV) or (IVa) are each used in approximately stoichiometric equivalents or in exces of the amount required to alkylate iminostilbene (II) . The produc of this alkylation, .N-(3-halopropyl)iminostilbene (III), is a mixture of N-(3-bromopropyl)iminostilbene and N-(3-chloropropyl)- iminostilbene; the particular proportion of 3-chloro- and 3- bromopropyl derivatives is of no importance, since both compounds are readily converted to opipramol (I) by reaction with N-[2- hydroxyethyl]-piperazine.
In a preferred embodiment of the invention, the first step of the process is carried out by heating a solution of iminostilbene (II) containing l-bromo-3-chloropropane and disodium hydrogen phosphate in the presence of a catalytic amount of benzyltriethyl- ammonium chloride. After removal of salts by washing and any excess unreacted l-bromo-3-chloropropane by co-distillation with a higher boiling solvent, N-(3-halopropyl)iminostilbene (III) in the resultant solution is converted without further isolation into opipramol (I) by reaction in situ with N-[2-hydroxyethyl]- piperazine.
The reaction of N-(3-halopropyl)iminostilbene (III) with N- [2-hydroxyethy1]-piperazine is preferably carried out with an excess of N-[2-hydroxyethyl]-piperazine at a temperature of about 50° to 150°C, most preferably at about H0βC, in the presence of a base until the alkylation is substantially complete. The mole ratio of N-(3-halopropyl)iminostilbene (III) to N-[2-hydroxy- ethyl]-piperazine is preferably about 1:1 to 1:3 and most preferably about 1:2. A weak base, such as sodium carbonate or potassium carbonate is preferred and is used in amount effective to achieve reaction between iminostilbene (III) and N-[2- hydroxyethyl]-piperazine. The following examples further illustrate the best mode currently contemplated for carrying out the invention, but the illustrative examples must not be construed as limiting the invention in any manner.
EXAMPLE 1
Preparation of N-(3-Halopropyl)iminostilbene fill)
To a stirred solution of 360 g (2.185 moles) of l-bromo-3- chloropropane in 750 ml of toluene, 150 g (0.777 moles) of iminostilbene (I), 270 g (1.9 moles) of disodium hydrogen phosphate and 7.5 g of benzyltriethylammonium chloride are added. The resulting mixture is heated to reflux until the reaction is substantially complete, which requires about 18 hours, as shown b tic (petroleum ether : ether, 96:4); about 95% of iminostilbene (I) is consumed.
After the reaction mixture is cooled to room temperature, solids are removed from the reaction mixture by filtration and washed with toluene. The toluene and excess l-bromo-3-chloro- propane are removed by distillation under vacuum to a temperature of about 100°C; 150 ml of Isopar G, a high boiling hydrocarbon, are added to the residue and distillation under vacuum is continued to about 100°C. The residue is cooled and 450 ml of toluene are added to provide a crude solution of N-(3- halopropyl)iminostilbene (III). EXAMPLE 2
Preparation of Opipramol (I)
N-(3-halopropyl)iminostilbene (III) in a toluene solution, as prepared in Example 1, in an amount of 600 ml is mixed with 150 g of N-(2-hydroxyethyl)piperazine and 50 g of sodium carbonate and then heated slowly to 110°C, while CO2 evolves. The reaction mixture is heated to reflux for another 16 hours, after which the mixture is cooled to 80°C; 400 ml water are added, mixed and then separated from the toluene layer. The toluene layer is cooled to 30-40°C and 500 ml of a 1.5 N aqueous solution of HC1 or H2SO4 is mixed with the toluene layer; the aqueous layer is separated; the extraction is repeated with an additional 100 ml of the acidic solution and the aqueous extracts are combined. Toluene in an amount of 600 ml is added to the combined aqueous extracts; the mixture is heated to 50°C and ammonium or sodium hydroxide is added until a pH>9. The mixture is agitated for 1/2 hour at 60- 70°C, after which the toluene layer is separated and washed with 100 ml of water and then dried by azeotropic distillation. The toluene layer is then cooled to 0-10°C and centrifuged to obtain the solid product, opipramol (I) . Additional product is obtained by concentrating the toluene residue to about 1/4 of its initial volume and cooling to 0-10°C. The total amount of product obtained is 215 g, having a .p. of 96°C.
Opipramol (I) can be further purified by dissolving 200 g of the above-obtained opipramol (I) in 600 ml of acetone; mixing 7 g of active carbon and 5 g of Celite into the solution, filtering and then cooling the solution to 0-lO°C and finally collecting t purified product on a centrifuge. The m.p. of the purified produ is 101°C.

Claims

What we desire to claim and protect by Letters Patent is:
1. A method for the preparation of N-(3-halopropyl)- iminostilbene, which is mixture of N-(3-chloropropyl)- iminostilbene and N-(3-bromopropyl)iminostilbene, comprising reacting iminostilbene with l-bromo-3-chloropropane in the presence of a weak base selected from a hydrogen phosphate salt of the formula MxHPθ4 and an acetate salt of the formula CH3COOM, wherein M is an alkali metal, alkaline earth metal or ammonium and x is 1 or 2, depending on the valence of M, in the presence of a phase transfer agent and in a solvent substantially inert to the reaction reagents and removing solvent, any excess l-bromo-3- chloropropane and solids present in the reaction mixture to obtain N-(3-halopropyl)iminostilbene.
2. The process according to claim 1 wherein the weak base is a hydrogen phosphate salt of the formula Na2HPθ4 or K2HPO4.
3. The process according to claim 1 in which the phase transfer agent is a quaternary ammonium chloride.
4. The process according to claim 1 in which the phase transfer agent is benzyltriethylammonium chloride.
5. The process according to claim 1 in which the reaction is carried out at a temperature of about 80-140°C.
6. The process according to claim 1 in which said l-bromo-3- chloropropane and said weak base are each present in an amount equal to or greater than their stoichiometric equivalents based o the amount of iminostilbene in the reaction.
7. The process according to claim 1 in which the reaction is carried out at a temperature of about 80-140°C, the weak base is Na2HPθ4 or K2HPO4, the phase transfer agent is benzyltriethyl¬ ammonium chloride and the solvent is toluene.
8. A process for the preparation of opipramol comprising reacting iminostilbene with l-bromo-3-chloropropane in the presence of a weak base selected from a hydrogen phosphate salt of the formula MxHPθ4 and an acetate salt of the formula CH3COOM, wherein M is an alkali metal, alkaline earth metal or ammonium and x is 1 or 2 depending on the valence of M, in the presence of a phase transfer agent and in a solvent inert to the reagents in the reaction, to form a N-(3-halopropyl) iminostilbene, which is a a mixture of N-(3-bromopropyl) iminostilbene and N-(3- chloropropyl)iminostilbene; separating any unreacted l-bromo-3-chloropropane and any salt present from the reaction mixture; reacting the thus formed N-(3-halopropyl)iminostilbene in situ , without isolation from the reaction mixture, with N-(2- hydroxyethyl)piperazine in the presence of a base to form opipramol and separating opipramol from the reaction mixture.
9. The process according to claim 8 wherein, the weak base is a hydrogen phosphate salt of the formula Na2HP04 or K2HPO4.
10. The process according to claim 8 in which the phase transfer agent is a quaternary ammonium chloride.
11. The process according to claim 8 in which the phase transfer agent is benzyltriethylammonium chloride.
12. The process according to claim 8 in which the reaction of iminostilbene with l-bromo-3-chloropropane is carried out at a temperature of about 80-l40°C.
13. The process according to claim 8 in which said l-bromo-3- chloropropane and said weak base are each present in an amount equal to or greater than their stoichiometric equivalents based on the amount of iminostilbene in the reaction.
14. The process according to claim 8 in which the reaction of iminostilbene with l-bromo-3-chloropropane is carried out at a temperature of about 80-l40°C, the hydrogen phosphate salt is Na2HP04 or K2HPO4, the phase transfer agent is benzyltriethy- ammonium chloride and the solvent is toluene.
15. The process according to claim 8 in which the reaction of N-(3-halopropyl)-iminostilbene with N-(2-hydroxyethyl)-piperazine is carried out with an excess of N-(2-hydroxyethyl)-piperazine at a temperature of about 50° to 150°C in the presence of a weak base.
PCT/US1995/014320 1994-11-09 1995-11-09 Preparation of n-(3-halopropyl)iminostilbene and its conversion to opipramol Ceased WO1996015113A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU41022/96A AU4102296A (en) 1994-11-09 1995-11-09 Preparation of n-(3-halopropyl)iminostilbene and its conversion to opipramol
EP95939059A EP0793652B1 (en) 1994-11-09 1995-11-09 Preparation of n-(3-halopropyl)iminostilbene and its conversion to opipramol
AT95939059T ATE192439T1 (en) 1994-11-09 1995-11-09 PRODUCTION OF N-(3-HALOPROPYL)IMINOSTILBENE AND ITS IMPLEMENTATION IN OPIPRAMOL
DE69516715T DE69516715T2 (en) 1994-11-09 1995-11-09 PREPARATION OF N- (3-HALOPROPYL) IMINOSTILLE AND ITS REALIZATION IN OPIPRAMOL
CA002204261A CA2204261C (en) 1994-11-09 1995-11-09 Improved method for preparing opipramol

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US08/336,837 1994-11-09
US08/336,837 US5599929A (en) 1994-11-09 1994-11-09 Method for preparing opipramol

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ITMI20030828A1 (en) * 2003-04-18 2004-10-19 Farchemia Srl PROCEDURE FOR THE PREPARATION OF OPIPRAMOL.

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HK1043793A1 (en) 2002-09-27
US5599929A (en) 1997-02-04
IL115951A (en) 1999-09-22
IL115951A0 (en) 1996-01-31
ATE192439T1 (en) 2000-05-15
TR199501394A2 (en) 1996-06-21
CN1123567C (en) 2003-10-08
DE69516715T2 (en) 2001-02-01
CN1068312C (en) 2001-07-11
CA2204261C (en) 2006-05-16
EP0793652A1 (en) 1997-09-10
EP0793652B1 (en) 2000-05-03
CA2204261A1 (en) 1996-05-23

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