WO2001055171A1 - Mometasone and its preparation - Google Patents

Mometasone and its preparation Download PDF

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Publication number
WO2001055171A1
WO2001055171A1 PCT/GB2001/000183 GB0100183W WO0155171A1 WO 2001055171 A1 WO2001055171 A1 WO 2001055171A1 GB 0100183 W GB0100183 W GB 0100183W WO 0155171 A1 WO0155171 A1 WO 0155171A1
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Prior art keywords
mometasone
reaction
chloride
dione
pregna
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PCT/GB2001/000183
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French (fr)
Inventor
Ivan Villax
Joâo Bandarra
Cao Zhon Bin
William Heggie
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Hovione Limited
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Priority to AU26917/01A priority Critical patent/AU2691701A/en
Publication of WO2001055171A1 publication Critical patent/WO2001055171A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom

Definitions

  • This invention relates to mometasone, 9 ⁇ ,21-dichloro-l l ⁇ , 17 ⁇ - dihydroxy-16 ⁇ -methyl-pregna-l ,4-diene-3,20-dione, and to a process for preparing it from icomethasone, 9 ⁇ -cloro- l l ⁇ ,17 ⁇ ,21 -trihydroxy-16 ⁇ -methyl-pregna-l ,4- diene-3,20-dione (Belgian patent no. 634,881 ).
  • 4,472,393 first prepares the 17-(2-furoate) of 21 -chloro-9 ⁇ ,l l ⁇ -epoxy-17 ⁇ -hydroxy-16 ⁇ -methyl- l,4-pregnadiene-3,20-dione or further uses 16 ⁇ -methyl-l ,4,9(l l )-pregnatriene- 17 ⁇ ,21-diol-3,20-dione as a raw material to prepare the 17- uroate, without passing through mometasone.
  • WO 98/00437 describes a process starting from 9 ⁇ ,l l- epoxy- 17 ⁇ ,21 -dihydroxy- 16 ⁇ -methy 1- 1 ,4-pregnadiene-3,20-dione.
  • the present invention provides a process for preparing 9 ⁇ ,21 -dichloro- 1 1 ⁇ , 17 ⁇ -dihydroxy- 16 ⁇ -methy 1-pregna- 1 ,4-diene-3,20-dione momestasone), which comprises reacting 9 ⁇ -chloro-l l ⁇ , 17 ⁇ ,21-trihydroxy-16 ⁇ - methyl-pregna-l,4-diene-3,20-dione (icomethasone) with a sulfonyl chloride of the formula
  • R is CH 3 or p-CH 3 C 6 H 4 , in the presence of a tertiary amine and solvent; and reacting the 21-sulfonate so obtained with a source of chloride ions in an inert solvent.
  • mometasone per se which is not described in the prior art, is a potent anti-inflammatory agent and is also very useful as a starting compound or intermediary in the preparation of the 17-furoate and other 17-esters, as well as in the preparation of other derivatives.
  • the invention provides mometasone per se.
  • the process of the invention comprises 21-mesylation of icomethasone in the presence of a tertiary amine, followed by reaction of the compound thus obtained with a chloride salt, such as for instance lithium or sodium chloride, in an inert solvent, to obtain mometasone.
  • icomethasone is reacted with a slight excess of p-toluenesulfonyl chloride in the presence of a tertiary amine, preferably triethylamine, in an inert solvent.
  • a lower aliphatic alcohol such as methanol or ethanol, is subsequently added to the reaction mixture to destroy the excess p-toluenesulfonyl chloride.
  • the chloride ions can conveniently be provided by the hydrochlorides of the amines used in the tosylation reaction, such as triethylammonium chloride when triethylamine is used as a base. In this manner, it is possible to carry out the transformation of icomethasone into mometasone of a high purity in a single reactor, without isolating the 21-tosylate of icomethasone, the yield being near to stoichiometric.
  • the mesylation reaction is preferably carried out at low temperature, most preferably between -2°C and +2°C, in pyridine which is used as a base as well as a solvent.
  • pyridine which is used as a base as well as a solvent.
  • the addition of mesyl chloride usually takes from 1 to 2 hours, e.g. about lh 30m, and the reaction time, after adding the reagent at 0°C, is usually approximately 4 hours.
  • the 21-mesylate of icomethasone can thus be obtained highly pure and practically free of traces of substitution in the 11- position.
  • the transformation of the 21-mesylate of icomethasone to mometasone is preferably carried out in N,N-dimethylformamide, using an excess of an alkali metal chloride.
  • Sodium chloride is preferred since it gives an excellent yield and does not require any special care to maintain the mixture free of water as is the case when lithium chloride, a hygroscopic compound, is used.
  • the process of the invention to make mometasone can be carried out in a single reaction vessel without isolation of the sulfonate obtained in the first step.
  • icomethasone can be added to dichloromethane (the water content of which should be lower than 0.03% by K.F.) and the 21-tosylate can be prepared by performing the reaction with an excess of p-toluenesulfonyl chloride under inert nitrogen conditions.
  • the reaction is carried out, preferably, at a temperature of -1°C, with good stirring.
  • triethylamine is added for example, and the temperature is preferably not allowed to rise above 0°C.
  • the amine is added over 2 to 3 hours, e.g. about 2h 30m. After the addition, the mixture is stirred at 0°C for a further period, e.g. 7 hours, to complete the tosylation reaction. At the end of the reaction, excess p-toluenesulfonyl chloride is destroyed by adding (at 0°C) an amount of methanol or ethanol equivalent to the excess of the chloride used.
  • the 21-tosylate of mometasone thus obtained is subsequently converted into mometasone, by heating the reaction mixture, for example to between 35°C and 40°C, and regularly controlling the reaction progress, e.g. by thin layer chromatography or high performance liquid chromatography.
  • the reaction is usually complete after about 6 to 7 hours.
  • the chloride ions necessary for the reaction come from the triethylammonium chloride formed during the tosylation.
  • Mometasone can be isolated by various procedures. For instance, to isolate the product, the solvent can be completely distilled under vacuum and the residue dissolved in dimethyl formamide. Mometasone can be subsequently precipitated by adding the solution dropwise to a mixture of ice and water.
  • the mometasone thus obtained can then be filtered, washed in iced water until the filtrate is free of chloride ions, and dried at 50°C to constant weight.
  • the mometasone can be transformed directly into any 17-ester by the process described in Portuguese Patent 102.343.
  • a 3g of icomethasone are added to 18 ml of dried pyridine at a temperature between 20°C and 25°C, under stirring. After complete dissolution, the solution is cooled down to between -2°C and +2°C, whilst excluding humidity. 1.02 ml of methanesulfonyl chloride is subsequently added, the reaction mixture being maintained at a temperature between -2°C and +2°C. The end of the reaction is detected by thin layer chromatography. [Stationary phase: silica gel, Merck Art. 554; eluent CHCl 3 /MeOH/H 2 0 (90:7.5:0.5).
  • Example 1-B The reaction as described above in Example 1-B is repeated but using 1.49g of lithium chloride instead of 2g sodium chloride, yielding 1.6g of mometasone, identical to the product obtained in said Example.
  • the resulting mixture is then heated to 40°C, under good stirring.
  • the reaction takes 6 to 7 hours and its completion is controlled by thin-layer chromatography. Usually, the reaction is complete after 6 to 7 hours.
  • the solvent is then evaporated under vacuum and 3 ml of dimethylformamide are added.
  • the mometasone product is precipitated by dropwise addition of the solution thus obtained to 50 ml of iced water, under good stirring.
  • the crystalline product is then filtered off and washed with distilled iced water until the mother-liquors do not contain chloride ions.
  • the mometasone thus obtained weighs, after drying, 2.56g.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pain & Pain Management (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)

Abstract

Mometasone (9α,21-dichloro-1 β,17α-dihydroxy-16α-methyl-pregna-1,4-dine-3,20-dione) is prepared from icomethasone (9α-chloro-11β,17α,21-trihydroxy-16α-methyl-pregna-1,4-diene-3,20-dione) by reaction thereof with a sulfonyl chloride of formula R-C1O2S wherein R is CH3 or p-CH3C6H4 in the presence of a tertiary amine and solvent, and the 21-sulfonate so obtained is reacted with a source of chloride ions. The new compound mometasone thus obtained is a potent anti-inflammatory agent.

Description

MOMETASONE AND ITS PREPARATION
This invention relates to mometasone, 9α,21-dichloro-l l β, 17α- dihydroxy-16α-methyl-pregna-l ,4-diene-3,20-dione, and to a process for preparing it from icomethasone, 9α-cloro- l l β,17α,21 -trihydroxy-16α-methyl-pregna-l ,4- diene-3,20-dione (Belgian patent no. 634,881 ).
US patent no. 4,472,393 describes a process for the preparation of mometasone furoate and WO 98/00437 describes an improved process. Mometasone furoate is obtained by both processes without the need to prepare mometasone er se. Thus, the process described in US patent no. 4,472,393 first prepares the 17-(2-furoate) of 21 -chloro-9β,l l β-epoxy-17α-hydroxy-16α-methyl- l,4-pregnadiene-3,20-dione or further uses 16α-methyl-l ,4,9(l l )-pregnatriene- 17α,21-diol-3,20-dione as a raw material to prepare the 17- uroate, without passing through mometasone. WO 98/00437 describes a process starting from 9β,l l- epoxy- 17α,21 -dihydroxy- 16α-methy 1- 1 ,4-pregnadiene-3,20-dione.
These processes introduce the 17-furoate group and substitute the 21- hydroxyl by chlorine before formation of the hydroxyl group in Cl l, since it is feared that otherwise important adverse reactions may occur. However, we have unexpectedly found that the 21 -hydroxyl group can be substituted by 21 -chlorine, even in the presence of the unprotected 1 Iβ-hydroxyl. From this observation, it can be concluded that the presence of the chlorine atom in the 9α-position ensures a a greater stability of the neighbouring hydroxyl group, rendering it non-reactive under the conditions in which the 21 -hydroxyl is substituted by an atom of halogen.
In one aspect, the present invention provides a process for preparing 9α,21 -dichloro- 1 1 β, 17α-dihydroxy- 16α-methy 1-pregna- 1 ,4-diene-3,20-dione momestasone), which comprises reacting 9α-chloro-l l β, 17α,21-trihydroxy-16α- methyl-pregna-l,4-diene-3,20-dione (icomethasone) with a sulfonyl chloride of the formula
R-C102S
wherein R is CH3 or p-CH3C6H4, in the presence of a tertiary amine and solvent; and reacting the 21-sulfonate so obtained with a source of chloride ions in an inert solvent.
We have further found that mometasone per se, which is not described in the prior art, is a potent anti-inflammatory agent and is also very useful as a starting compound or intermediary in the preparation of the 17-furoate and other 17-esters, as well as in the preparation of other derivatives.
In a second aspect, therefore, the invention provides mometasone per se.
In one embodiment, the process of the invention comprises 21-mesylation of icomethasone in the presence of a tertiary amine, followed by reaction of the compound thus obtained with a chloride salt, such as for instance lithium or sodium chloride, in an inert solvent, to obtain mometasone. In another embodiment, icomethasone is reacted with a slight excess of p-toluenesulfonyl chloride in the presence of a tertiary amine, preferably triethylamine, in an inert solvent. Preferably, a lower aliphatic alcohol, such as methanol or ethanol, is subsequently added to the reaction mixture to destroy the excess p-toluenesulfonyl chloride. On heating the reaction mixture at 40°C for a few hours, the tosylate undergoes decomposition in the presence of chloride ions, thus yielding mometasone. The chloride ions can conveniently be provided by the hydrochlorides of the amines used in the tosylation reaction, such as triethylammonium chloride when triethylamine is used as a base. In this manner, it is possible to carry out the transformation of icomethasone into mometasone of a high purity in a single reactor, without isolating the 21-tosylate of icomethasone, the yield being near to stoichiometric.
To obtain a high quality mometasone in a high yield, it is preferred to use highly pure icomethasone starting material. This is readily available nowadays, with a purity above 98%. Special care should preferably be taken to ensure that there is no water in the starting material, and that the reaction solvent, a tertiary amine, is anhydrous.
The mesylation reaction is preferably carried out at low temperature, most preferably between -2°C and +2°C, in pyridine which is used as a base as well as a solvent. When the reaction is carried out at lower temperatures, the reaction time is longer and when higher temperatures are used, a lower quality product is obtained. The addition of mesyl chloride usually takes from 1 to 2 hours, e.g. about lh 30m, and the reaction time, after adding the reagent at 0°C, is usually approximately 4 hours. The 21-mesylate of icomethasone can thus be obtained highly pure and practically free of traces of substitution in the 11- position. The transformation of the 21-mesylate of icomethasone to mometasone is preferably carried out in N,N-dimethylformamide, using an excess of an alkali metal chloride. Sodium chloride is preferred since it gives an excellent yield and does not require any special care to maintain the mixture free of water as is the case when lithium chloride, a hygroscopic compound, is used.
The process of the invention to make mometasone can be carried out in a single reaction vessel without isolation of the sulfonate obtained in the first step. For example, icomethasone can be added to dichloromethane (the water content of which should be lower than 0.03% by K.F.) and the 21-tosylate can be prepared by performing the reaction with an excess of p-toluenesulfonyl chloride under inert nitrogen conditions. The reaction is carried out, preferably, at a temperature of -1°C, with good stirring. After the addition of the chloride, triethylamine is added for example, and the temperature is preferably not allowed to rise above 0°C. Usually, the amine is added over 2 to 3 hours, e.g. about 2h 30m. After the addition, the mixture is stirred at 0°C for a further period, e.g. 7 hours, to complete the tosylation reaction. At the end of the reaction, excess p-toluenesulfonyl chloride is destroyed by adding (at 0°C) an amount of methanol or ethanol equivalent to the excess of the chloride used. The 21-tosylate of mometasone thus obtained is subsequently converted into mometasone, by heating the reaction mixture, for example to between 35°C and 40°C, and regularly controlling the reaction progress, e.g. by thin layer chromatography or high performance liquid chromatography. The reaction is usually complete after about 6 to 7 hours. The chloride ions necessary for the reaction come from the triethylammonium chloride formed during the tosylation. Mometasone can be isolated by various procedures. For instance, to isolate the product, the solvent can be completely distilled under vacuum and the residue dissolved in dimethyl formamide. Mometasone can be subsequently precipitated by adding the solution dropwise to a mixture of ice and water.
The mometasone thus obtained can then be filtered, washed in iced water until the filtrate is free of chloride ions, and dried at 50°C to constant weight. The mometasone can be transformed directly into any 17-ester by the process described in Portuguese Patent 102.343.
The following examples serve to illustrate the invention and are not, in any way, to be considered a limitation thereof.
EXAMPLE 1
A 3g of icomethasone are added to 18 ml of dried pyridine at a temperature between 20°C and 25°C, under stirring. After complete dissolution, the solution is cooled down to between -2°C and +2°C, whilst excluding humidity. 1.02 ml of methanesulfonyl chloride is subsequently added, the reaction mixture being maintained at a temperature between -2°C and +2°C. The end of the reaction is detected by thin layer chromatography. [Stationary phase: silica gel, Merck Art. 554; eluent CHCl3/MeOH/H20 (90:7.5:0.5). Sampling: 5μl of a solution of 8 mg/ml of CHCl3/MeOH (9:1); U.V. peak at 254 nm]. For the reaction to be complete, it is necessary to stir for about 3.5 to 4 hours. The reaction mixture is subsequently added, under good stirring, to a mixture containing 108 ml of water, 72g of ice and 15.9 ml of concentrated hydrochloric acid. It is then stirred for 1 hour, after which the precipitated product is filtered and washed with iced water (about 2 x 20 ml) until neutral pH. After drying to constant weight at 50°C under good air circulation, 3.57 g of icomethasone 21-mesylate were obtained, [a]™° 206 (in dioxane), £,' 309 at 240 nm in methanol; melting point 196-202°C with decomposition.
B 2g of the icomethasone 21 -mesy late obtained above are added to 20 ml of dimethylformamide, under good stirring. When the mesylate is completely dissolved, 2g of sodium chloride are added. The mixture is then heated in a water-bath between 60°C and 65°C until the reaction is complete, which takes 3 to 4 hours. The reaction mixture is then cooled down to 20°C and added to a mixture containing 140 ml of water and 60g of ice, under good stirring. The precipitate is filtered and washed with 150 ml of iced water until the mother-liquors do not contain chloride ions. It is subsequently dried at 50°C to constant weight, yielding 1.7g of mometasone. Melting point 233°C, [a] ° 127 (C,l in dioxane),
Figure imgf000006_0001
354 at 240 nm in methanol (see accompanying single-Figure drawing which is an infrared curve of mometasone).
EXAMPLE 2
The reaction as described above in Example 1-B is repeated but using 1.49g of lithium chloride instead of 2g sodium chloride, yielding 1.6g of mometasone, identical to the product obtained in said Example.
EXAMPLE 3
2.5g of icomethasone are added under nitrogen to 15 ml of dichloromethane and cooled down to -1°C. A solution containing 2.05g of p-toluenesulfonyl chloride in 15 ml of dichloromethane is then added dropwise, maintaining the temperature at -1°C. After stirring for 30 minutes, 2.8 ml of triethylamine are added dropwise, maintaining the temperature at -1°C, which takes about 2.5 to 3 hours. The reaction progress is followed by thin-layer chromatography. After the reaction is complete, which takes about 7 hours, the reaction mixture is added to a mixture containing 0.2 ml of methanol and 2 ml of dichloromethane. The resulting mixture is then heated to 40°C, under good stirring. The reaction takes 6 to 7 hours and its completion is controlled by thin-layer chromatography. Usually, the reaction is complete after 6 to 7 hours. The solvent is then evaporated under vacuum and 3 ml of dimethylformamide are added. The mometasone product is precipitated by dropwise addition of the solution thus obtained to 50 ml of iced water, under good stirring. The crystalline product is then filtered off and washed with distilled iced water until the mother-liquors do not contain chloride ions. The mometasone thus obtained weighs, after drying, 2.56g.

Claims

1 A process for preparing 9α,21-dichloro-l lβ,17α-dihy droxy- 16α- methyl-pregna-l,4-diene-3,20-dione (momestasone), which comprises reacting 9α- chloro- 11 β, 17α,21 -trihy droxy- 16α-methy 1-pregna- 1 ,4-diene-3 ,20-dione (icomethasone) with a sulfonyl chloride of the formula
R-C102S
wherein R is CH3 or p-CH3C6FL , in the presence of a tertiary amine and solvent; and reacting the 21-sulfonate so obtained with a source of chloride ions in an inert solvent.
2 A process according to claim 1, wherein the tertiary amine is pyridine or triethylamine.
3 A process according to claim 1 or 2, wherein the solvent is dichloromethane or an excess of the tertiary amine, such as pyridine.
4 A process according to any of claims 1 to 3, wherein the source of chloride ions is lithium chloride, sodium chloride or triethylamine hydrochloride, and the inert solvent is N,N-dimethylformamide or dichloromethane.
5 A process according to any preceding claim, wherein the 21-sulfonate obtained during the reaction, without isolation, is reacted with the hydrochloride of the tertiary amine present, by heating at 35°C-40°C until the reaction is complete.
6 The compound 9α,21-dichloro- 1 1 β,17α-dihy droxy- 16α-methy 1- pregna-l,4-diene-3,20-dione (mometasone).
PCT/GB2001/000183 2000-01-20 2001-01-18 Mometasone and its preparation WO2001055171A1 (en)

Priority Applications (1)

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Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PT102405A PT102405A (en) 2000-01-20 2000-01-20 METHOD FOR THE PREPARATION OF MOMETHASONE
PT102,405 2000-01-20

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057401A1 (en) * 1981-02-02 1982-08-11 Schering Corporation Aromatic heterocyclic esters of steroids, their preparation and pharmaceutical compositions containing them
WO1998000437A1 (en) * 1996-06-28 1998-01-08 Schering Corporation PROCESS FOR THE PREPARATION OF 17-ESTERS OF 9α,21-DIHALO-PREGNANE-11β,17αDIOL-20-ONES

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057401A1 (en) * 1981-02-02 1982-08-11 Schering Corporation Aromatic heterocyclic esters of steroids, their preparation and pharmaceutical compositions containing them
WO1998000437A1 (en) * 1996-06-28 1998-01-08 Schering Corporation PROCESS FOR THE PREPARATION OF 17-ESTERS OF 9α,21-DIHALO-PREGNANE-11β,17αDIOL-20-ONES

Non-Patent Citations (6)

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Title
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; GONZALEZ BOSCH, JOSE MARIA ET AL: "2-Hydroxybenzoate ester of a chlorinated pregnane steroid", XP002168689, retrieved from STN Database accession no. 106:5328 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PRAKASH, AMITABH ET AL: "Topical mometasone: a review of its pharmacological properties and therapeutic use in the treatment of dermatological disorders", XP002168688, retrieved from STN Database accession no. 128:200360 *
DRAPER R W ET AL: "Unusual Hydroxy-gamma-sultone Byproducts of Steroid 21-Methanesulfonylation. An efficient Synthesis of Mometasone 17-Furoate (Sch 32088)", TETRAHEDRON,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 55, no. 11, March 1999 (1999-03-01), pages 3355 - 3364, XP004158036, ISSN: 0040-4020 *
DRUGS (1998), 55(1), 145-163 *
L. DUNKERTON ET AL: "Affinity -Labelling Corticoids I. Synthesis of 21-Chloroprogesterone, Deoxycorticosterone 21-(1-Imidazole) Carboxylate, 21-Deoxy-21-Chloro Dexamethasone, and Dexamethasone 21-Mesylate, 21-Bromoacetate, and 21-Iodoacetate", STEROIDS., vol. 39, no. 1, 1982, ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY., US, pages 1 - 6, XP002168687, ISSN: 0039-128X *
M. MITSUKUCHI ET AL: "Studies on Topical Antiinflammatory Agents. V. 17-(Alkylthio)- and Methoxyalkanoates of Corticosteroids", CHEMICAL AND PHARMACEUTICAL BULLETIN., vol. 38, no. 3, 1990, PHARMACEUTICAL SOCIETY OF JAPAN. TOKYO., JP, pages 692 - 697, XP002168686, ISSN: 0009-2363 *

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