FI68057C - Foerfarande foer framstaellning av antracyklinderivat - Google Patents

Foerfarande foer framstaellning av antracyklinderivat Download PDF

Info

Publication number: FI68057C
Authority: FI; Finland
Prior art keywords: group; chloroform; adriamycin; derivative; formula
Prior art date: 1979-02-03

Application number

FI800298A

Other languages

English (en)

Finnish (fi)

Other versions

FI68057B (fi

FI800298A7 (fi

Inventor

Hamao Umezawa

Tomio Takeuchi

Hiroshi Naganawa

Kuniaki Tatsuta

Original Assignee

Microbial Chem Res Found

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1979-02-03

Filing date

1980-02-01

Publication date

1985-07-10

1979-02-03 Priority claimed from JP1170279A external-priority patent/JPS55104299A/ja

1979-08-31 Priority claimed from JP11025579A external-priority patent/JPS5634695A/ja

1980-02-01 Application filed by Microbial Chem Res Found filed Critical Microbial Chem Res Found

1980-08-04 Publication of FI800298A7 publication Critical patent/FI800298A7/fi

1985-03-29 Publication of FI68057B publication Critical patent/FI68057B/fi

1985-07-10 Application granted granted Critical

1985-07-10 Publication of FI68057C publication Critical patent/FI68057C/fi

Links

-1 phenylacetyloxy group Chemical group 0.000 claims description 157
150000001875 compounds Chemical class 0.000 claims description 76
238000000034 method Methods 0.000 claims description 44
238000002360 preparation method Methods 0.000 claims description 34
239000002904 solvent Substances 0.000 claims description 28
229940045799 anthracyclines and related substance Drugs 0.000 claims description 24
239000002253 acid Substances 0.000 claims description 23
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
150000003839 salts Chemical class 0.000 claims description 22
125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 18
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 13
125000004423 acyloxy group Chemical group 0.000 claims description 13
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
238000006243 chemical reaction Methods 0.000 claims description 10
JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims description 9
239000003377 acid catalyst Substances 0.000 claims description 9
125000004432 carbon atom Chemical group C* 0.000 claims description 6
238000000926 separation method Methods 0.000 claims description 4
125000000217 alkyl group Chemical group 0.000 claims description 2
RHZUVFJBSILHOK-UHFFFAOYSA-N anthracen-1-ylmethanolate Chemical compound C1=CC=C2C=C3C(C[O-])=CC=CC3=CC2=C1 RHZUVFJBSILHOK-UHFFFAOYSA-N 0.000 claims 1
239000003830 anthracite Substances 0.000 claims 1
125000000962 organic group Chemical group 0.000 claims 1
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 100
229940009456 adriamycin Drugs 0.000 description 73
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 44
AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 41
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
238000002844 melting Methods 0.000 description 31
230000008018 melting Effects 0.000 description 31
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
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WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 28
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125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 25
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239000000843 powder Substances 0.000 description 19
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
239000000047 product Substances 0.000 description 16
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235000017557 sodium bicarbonate Nutrition 0.000 description 15
238000004809 thin layer chromatography Methods 0.000 description 15
239000000203 mixture Substances 0.000 description 14
239000000126 substance Substances 0.000 description 13
MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 12
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125000003118 aryl group Chemical group 0.000 description 12
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239000007858 starting material Substances 0.000 description 12
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GUGHGUXZJWAIAS-QQYBVWGSSA-N Daunorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GUGHGUXZJWAIAS-QQYBVWGSSA-N 0.000 description 8
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125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
239000007787 solid Substances 0.000 description 8
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 7
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UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 6
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238000003776 cleavage reaction Methods 0.000 description 6
238000000354 decomposition reaction Methods 0.000 description 6
FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 6
239000000284 extract Substances 0.000 description 6
239000002244 precipitate Substances 0.000 description 6
230000007017 scission Effects 0.000 description 6
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CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
206010028980 Neoplasm Diseases 0.000 description 5
235000011089 carbon dioxide Nutrition 0.000 description 5
239000002026 chloroform extract Substances 0.000 description 5
229930182470 glycoside Natural products 0.000 description 5
150000002338 glycosides Chemical class 0.000 description 5
230000007062 hydrolysis Effects 0.000 description 5
238000006460 hydrolysis reaction Methods 0.000 description 5
UOTYVBUEKGMADZ-UHFFFAOYSA-N 1,4-dioxane;4-methylbenzenesulfonic acid Chemical compound C1COCCO1.CC1=CC=C(S(O)(=O)=O)C=C1 UOTYVBUEKGMADZ-UHFFFAOYSA-N 0.000 description 4
JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 4
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
241000699670 Mus sp. Species 0.000 description 4
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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239000003054 catalyst Substances 0.000 description 4
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125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 4
229910000027 potassium carbonate Inorganic materials 0.000 description 4
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
230000035484 reaction time Effects 0.000 description 4
239000011780 sodium chloride Substances 0.000 description 4
SKYXLDSRLNRAPS-UHFFFAOYSA-N 1,2,4-trifluoro-5-methoxybenzene Chemical compound COC1=CC(F)=C(F)C=C1F SKYXLDSRLNRAPS-UHFFFAOYSA-N 0.000 description 3
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125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
CJTTXGOOWXOTSV-UHFFFAOYSA-N methyl 3,4-dihydro-2h-pyran-2-carboxylate Chemical compound COC(=O)C1CCC=CO1 CJTTXGOOWXOTSV-UHFFFAOYSA-N 0.000 description 1
230000000813 microbial effect Effects 0.000 description 1
125000000896 monocarboxylic acid group Chemical group 0.000 description 1
238000006386 neutralization reaction Methods 0.000 description 1
239000012457 nonaqueous media Substances 0.000 description 1
238000001668 nucleic acid synthesis Methods 0.000 description 1
239000008194 pharmaceutical composition Substances 0.000 description 1
239000008024 pharmaceutical diluent Substances 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
239000003279 phenylacetic acid Substances 0.000 description 1
229960003424 phenylacetic acid Drugs 0.000 description 1
NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
230000035945 sensitivity Effects 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
239000008247 solid mixture Substances 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
239000000725 suspension Substances 0.000 description 1
238000005708 tetrahydropyranylation reaction Methods 0.000 description 1
DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
229940045145 uridine Drugs 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
230000004580 weight loss Effects 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Engineering & Computer Science (AREA)
Health & Medical Sciences (AREA)
Biochemistry (AREA)
Biotechnology (AREA)
General Health & Medical Sciences (AREA)
Genetics & Genomics (AREA)
Molecular Biology (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Saccharide Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

FI800298A 1979-02-03 1980-02-01 Foerfarande foer framstaellning av antracyklinderivat FI68057C (fi)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
JP1170279A JPS55104299A (en)	1979-02-03	1979-02-03	Anthracycline compounds and their preparation
JP1170279		1979-02-03
JP11025579A JPS5634695A (en)	1979-08-31	1979-08-31	Novel anthracycline derivative and its preparation
JP11025579		1979-08-31

Publications (3)

Publication Number	Publication Date
FI800298A7 FI800298A7 (fi)	1980-08-04
FI68057B FI68057B (fi)	1985-03-29
FI68057C true FI68057C (fi)	1985-07-10

Family

ID=26347196

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
FI800298A FI68057C (fi)	1979-02-03	1980-02-01	Foerfarande foer framstaellning av antracyklinderivat

Country Status (11)

Country	Link
EP (1)	EP0014853B1 (fr)
AR (1)	AR226694A1 (fr)
AT (1)	AT369384B (fr)
AU (1)	AU518278B2 (fr)
CA (1)	CA1136618A (fr)
DE (1)	DE3063557D1 (fr)
DK (1)	DK160616C (fr)
ES (1)	ES8101622A1 (fr)
FI (1)	FI68057C (fr)
NZ (1)	NZ192758A (fr)
PH (1)	PH18200A (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JPS56156300A (en) *	1980-04-26	1981-12-02	Microbial Chem Res Found	Novel preparative method of anthracyclin derivative
JPS6016998A (ja) *	1983-07-07	1985-01-28	Microbial Chem Res Found	アントラサイクリン誘導体の製造方法
GB2169286A (en) *	1985-01-05	1986-07-09	Erba Farmitalia	4'-Deoxy-4'-halodoxorubicin-14-esters
GB2169284A (en) *	1985-01-05	1986-07-09	Erba Farmitalia	4'-Epidoxorubicin-14-esters
GB2169285A (en) *	1985-01-05	1986-07-09	Erba Farmitalia	4'-Deoxydoxorubicin-14-esters
US4889926A (en) *	1987-06-12	1989-12-26	Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai	Method for the synthesis of (2"R)-4'-O-tetra-hydropyranyladriamycim using 14-chloro-daunomycin as an intermediate
GB9026491D0 (en) *	1990-12-05	1991-01-23	Erba Carlo Spa	Anthracycline-conjugates
US5776458A (en) *	1990-12-05	1998-07-07	Pharmacia & Upjohn S.P.A.	Anthracycline-conjugates
IT1282379B1 (it) *	1996-04-24	1998-03-20	Mini Ricerca Scient Tecnolog	Disaccaridi di antracicline antitumorali.
US8173621B2 (en)	2008-06-11	2012-05-08	Gilead Pharmasset Llc	Nucleoside cyclicphosphates
KR20110098849A (ko)	2008-12-23	2011-09-01	파마셋 인코포레이티드	뉴클레오시드 유사체
SG194404A1 (en)	2008-12-23	2013-11-29	Gilead Pharmasset Llc	Synthesis of purine nucleosides
PT2376088T (pt)	2008-12-23	2017-05-02	Gilead Pharmasset Llc	Fosforamidatos de nucleósidos de 2-amino-purina 6-osubstituída
PT2609923T (pt)	2010-03-31	2017-08-30	Gilead Pharmasset Llc	Processo para a cristalização de 2-(((s)- (perfluorofenoxi)(fenoxi)fosforil)amino)propanoato de (s)-isopropilo

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JPS52148064A (en) *	1976-05-31	1977-12-08	Microbial Chem Res Found	Antitumors
GB1561507A (en) *	1976-11-17	1980-02-20	Farmaceutici Italia	Snthracycline disaccharides
JPS5430146A (en) *	1977-08-05	1979-03-06	Microbial Chem Res Found	Novel anthracycline derivatives and their preparation

1980
- 1980-01-10 DK DK011480A patent/DK160616C/da not_active IP Right Cessation
- 1980-01-23 EP EP80100352A patent/EP0014853B1/fr not_active Expired
- 1980-01-23 DE DE8080100352T patent/DE3063557D1/de not_active Expired
- 1980-01-24 AU AU54895/80A patent/AU518278B2/en not_active Ceased
- 1980-01-24 PH PH23547A patent/PH18200A/en unknown
- 1980-01-30 NZ NZ192758A patent/NZ192758A/xx unknown
- 1980-01-31 AT AT0051180A patent/AT369384B/de not_active IP Right Cessation
- 1980-01-31 AR AR279810A patent/AR226694A1/es active
- 1980-02-01 FI FI800298A patent/FI68057C/fi not_active IP Right Cessation
- 1980-02-01 ES ES488209A patent/ES8101622A1/es not_active Expired
- 1980-02-01 CA CA000344911A patent/CA1136618A/fr not_active Expired

Also Published As

Publication number	Publication date
CA1136618A (fr)	1982-11-30
ATA51180A (de)	1982-05-15
ES488209A0 (es)	1980-12-16
EP0014853A1 (fr)	1980-09-03
AT369384B (de)	1982-12-27
FI68057B (fi)	1985-03-29
EP0014853B1 (fr)	1983-06-01
AU5489580A (en)	1980-08-07
ES8101622A1 (es)	1980-12-16
PH18200A (en)	1985-04-25
AU518278B2 (en)	1981-09-24
AR226694A1 (es)	1982-08-13
DK11480A (da)	1980-08-04
DK160616B (da)	1991-04-02
DK160616C (da)	1991-09-02
NZ192758A (en)	1982-03-09
FI800298A7 (fi)	1980-08-04
DE3063557D1 (en)	1983-07-07

Legal Events

Date	Code	Title	Description
1997-09-09	MM	Patent lapsed
2004-08-31	MM	Patent lapsed	Owner name: ZAIDANHOJIN BISEIBUTSU KAGAKU KENKYUKAI

Publication	Publication Date	Title
FI68057C (fi)	1985-07-10	Foerfarande foer framstaellning av antracyklinderivat
US20090247533A1 (en)	2009-10-01	Ecteinascidins
Bourguet-Kondracki et al.	1999	Methanol adduct of puupehenone, a biologically active derivative from the marine sponge Hyrtios species
US5304687A (en)	1994-04-19	Morpholinyl derivatives of doxorubicin and process for their preparation
KISHI et al.	1984	Structure-activity relationships of saframycins
Swersey et al.	1991	Mamanuthaquinone: an antimicrobial and cytotoxic metabolite of Fasciospongia sp.
FI63420C (fi)	1983-06-10	Foerfarande foer framstaellning av terapeutiskt verksamma tetrahydropyranylderivat av antracyklinglykosider
US4303785A (en)	1981-12-01	Antitumor anthracycline antibiotics
JPS63145295A (ja)	1988-06-17	アントラサイクリン誘導体
GACHON et al.	1976	ALBORIXIN, ANEW ANTIBIOTIC IONOPHORE: ISOLATION, STRUCTURE, PHYSICAL AND CHEMICAL PROPERTIES
US4199571A (en)	1980-04-22	Substituted anthracyclines, their preparation and use
EP0687673A1 (fr)	1995-12-20	Dérivés d'oxazole comme agents anti-tumoraux
EP0381989B1 (fr)	1992-02-05	4'-Epi-4'-aminoanthracyclines
Tanaka et al.	1980	Chemical modification of anthracycline antibiotics. I Demethoxycarbonylation, 10-epimerization and 4-O-methylation of aclacinomycin A
US4870058A (en)	1989-09-26	14-Acyloxy-2'-halo-anthracycline anti-cancer antibiotics
CA2088979A1 (fr)	1992-03-13	2-hydroxy- et 2-acyloxy-4-morpholinylanthracyclines
KR840000679B1 (ko)	1984-05-18	안트라사이클린 유도체의 제조방법
GB2120650A (en)	1983-12-07	Rooperol derivatives
US4772688A (en)	1988-09-20	14-acyloxy-2'-halo-anthracycline anti-cancer antibiotics
US4731468A (en)	1988-03-15	Aglycons
US6420357B1 (en)	2002-07-16	Cytotoxic alkaloid derivatives including Asmarine A and B isolated from a sponge
CASSINELLI et al.	1990	New biosynthetic anthracyclines related to barminomycins incorporating barbiturates in their moiety
EP1070067B1 (fr)	2005-03-02	Derives d'alcaloides cytotoxiques tels que l'asmarine a et b isoles a partir d'une eponge
JPS5829960B2 (ja)	1983-06-25	新規アントラサイクリン誘導体及びその製造法
WO1990007519A1 (fr)	1990-07-12	Analogues 3'-desamino d'esorubicine et procedes pour leur utilisattion