EP0711286A1 - Benzoxazinones et benzothiazinones ayant une activite therapeutique - Google Patents

Benzoxazinones et benzothiazinones ayant une activite therapeutique

Info

Publication number
EP0711286A1
EP0711286A1 EP94924778A EP94924778A EP0711286A1 EP 0711286 A1 EP0711286 A1 EP 0711286A1 EP 94924778 A EP94924778 A EP 94924778A EP 94924778 A EP94924778 A EP 94924778A EP 0711286 A1 EP0711286 A1 EP 0711286A1
Authority
EP
European Patent Office
Prior art keywords
mole
alkyl
dihydro
benzoxazin
compound
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94924778A
Other languages
German (de)
English (en)
Inventor
Silvio Levi
Francesca Benedini
Giorgio Bertolini
Gianni Gromo
Jacques Mizrhai
Alberto Sala
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Italfarmaco SpA
Original Assignee
Italfarmaco SpA
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.)
Filing date
Publication date
Application filed by Italfarmaco SpA filed Critical Italfarmaco SpA
Publication of EP0711286A1 publication Critical patent/EP0711286A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
    • C07D265/22—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to the therapeutic use of 2,3-dihydro-4H-l,3-benzoxazin- and -benzo- thiazin-4-ones.
  • 2,3-Dihydro-4H-l,3-benzoxazin-4-ones unsubstituted on the nitrogen atom were described by B.W. Horrom et al., J. Org. Chem., 72, 721 (1950) as endowed with analgesic activity.
  • Other 2,3-dihydro-4H-l,3- benzoxazin-4-ones were disclosed by R.B. Ga mil, J.
  • X is an oxygen or a sulphur atom
  • Y represents methylene, ethylene, (C 3 _ g )alkylene optionally branched, or cyclopentylene, cyclohexylene or cycloheptylene optionally substituted with
  • A is hydroxy; (C,_ g )alkoxy, formyloxy; (C 2 _ g )acyloxy; mercapto; (C, g )alkyl-mercapto; mesyloxy; (C 2 _ g )alkyl- sulfonyloxy; tosyloxy; phenyl-sulfonyloxy optionally substituted
  • R 3 is a (C, g )alkyl group, methylene, ethylene or (C 3 _ g )alky ⁇ lene 0- ⁇ -substituted with a 2,3-dihydro-4H-l,3-benzo- xazin-4-one-N-yl residue;
  • R represents hydrogen, (C, g )alkyl or phenyl; R.. and R 2 are independently hydrogen, halogen, (C, g )alkoxy, trifluoromethyl, and (C, g )alkyl; and the pharmaceutically acceptable acid or base salts thereof, useful as therapeutically active substances.
  • the invention relates to the use of the compounds of formula (I) as agents useful in the cardiovascular field.
  • the alkyl groups essentially identify methyl, ethyl, propyl, i-propyl, butyl, 2-methyl-propyl, n-pentyl, 3-methylbutyl, i- pentyl, n-hexyl and the like, while the alkoxy groups are preferably selected from the group consisting of methoxy, ethoxy, propoxy, i-propoxy, butoxy, 2- methylbutoxy and t-butoxy.
  • linear or branched (C,_ g )alkylene group it is intended, e.g., 2- methylethylene, 1,3-propylene, 1,4-butylene, 2- ethylethylene, 3-methylpropylene, 1,5-pentylene, 2- ethylpropylene, 2-methylbutylene, 1,6-hexylene, 1- ethyl-1-methylpropylene, 3-methylpentylene and the like.
  • (C 2 _ g )acyloxy it is intended, e.g., acetyloxy, propionyloxy, butyryloxy, hexanoyloxy, oxalyloxy, malonyloxy, succinyloxy.
  • the compounds of the present invention are prepared according to procedures known to the skilled in the art.
  • the compounds of formula (I) wherein X, Y, R, R, and R 2 are as defined above, A is hydroxy, (C 1 _ g )alkoxy, formyloxy or (C 2 _ g )acyloxy may be obtained according to what taught by the publication of the Patent application EP-A-0 490 183, by reacting a salicylamide or thiosalicylamide of formula (II)
  • R ⁇ , 2 , x and Y are as defined above, and R ⁇ is hydrogen, (C- L _ g )alkyl or (C 1 _ g )acyl, with an aldehyde of formula (III) R-CHO (III) wherein R is as above, or a derivative or a precursor thereof.
  • the condensation generally occurs in an acidic environment, for example in a system constituted by a strong mineral acid and acetic acid, thereby obtaining compounds of formula (I) wherein R.
  • sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, Q and ⁇ -naphthalenesulfonic acids, phosphoric acids, esters and analogues thereof.
  • the condensation is carried out in the presence of an organic solvent, preferably an inert organic solvent such as ethyl acetate, acetonitrile, benzene, nitrobenzene or chlorobenzene, halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane or 1,1,2- trichloroethylene, cyclohexane, tetrahydrofuran, tetrahydropyran, dimethylformamide, dimethylacetamide.
  • the reaction temperature may vary within quite wide limits without prejudice for the course of the reaction. The preferred range of temperature is comprised between about -10°C and the reflux temperature of the reaction mixture, and the reaction is completed in a period of time ranging between about 2 and about 30 hours.
  • the molar quantities of the reagents of formula (II) and (III) are not critical for the good course of the cyclization, and such reagents may be used in the widest stoichiometric ratios.
  • precursors of the compound of formula (III) such as paraformal ehyde and the paraldehyde are preferably employed.
  • R 3 is a (C, g)alkyl group, methylene, ethylene or (C 3 _ g )alkylene -substituted by a 2,3-dihydro-4H-l,3-benzoxazin-4-one-N-yl residue are desired, a compound of formula (I) wherein A is hydroxy is treated with a suitable carboxylic or sulfonic acid activated in form of anhydride, halide or imidazolide, used in excess, preferably in the presence of an organic base such as pyridine.
  • Suitable solvents for such synthesis are, e.g., chloroform or methylene chloride, while the reaction temperature ranges between about -10°C and the room temperature, and the reaction time is of about 1-20 hours.
  • the reaction temperature ranges between about -10°C and the room temperature, and the reaction time is of about 1-20 hours.
  • a sui ⁇ table amount of the R 3 OH desired alcohol is added at the end of the reaction.
  • the compounds of formula (I) wherein A is hydroxy may yield compounds of formula (I) wherein A is mercapto or (C, g )alkyl-mercapto, by an intermediate of formula (IV)
  • Halo is an halogen atom, preferably chlorine.
  • halogenating agents such as, e.g., thionyl chloride, sulfuryl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxytrichloride, phosphorous tribromide, sulfuryl bromide and the like.
  • Said halogenation reaction occurs in an organic solvent, preferably in an inert organic solvent selected from the ones employed for the synthesis of the compound of formula (I) described above, at a temperature ranging between the room temperature and the reflux temperature of the reaction mixture.
  • the compound of formula (IV) is converted into a compound of formula (I) wherein A is mercapto, by reaction with thiourea in alcoholic solution, at the reflux temperature of the reaction mixture, for about 5-12 hours, and subsequent hydrolysis with strong organic bases such as an alkali metal hydroxide, at the reflux temperature for about 2- 10 hours.
  • the compound of formula (I) wherein A is mercapto may be converted into a compound of formula (I) wherein A is (C. gjalkyl-mercapto, by treatment with the suitable acyl halide in the presence of an organic base such as diazabicycloundecene, according to what taught by Patai, 2nd part, pages 721- 735.
  • the compounds of formula (I) wherein A is hydroxy may also provide compounds of formula (I) wherein A is (C,_g)alkoxy, according to the so-called Williamson's reaction carried out with the suitable acyl halide.
  • compounds of formula (I) may be converted into other compounds of formula (I) by means of suitable procedures for modifying the substituents R 1 and R 2 , wholly familiar to the skilled in the art.
  • the conversion of an R. or ? group into another R. ⁇ or R 2 group having a meaning comprised by formula (I) may occur following conventional procedures familiar to the skilled in the art. These procedures are in the scope of the invention together with the obvious modifications of the just disclosed methods for preparing the compounds of the invention.
  • N-(2 '-hydroxyethyl)-4-methylsalicylamide was prepared according to the procedure of Example 3,A) starting from 20 g of methyl 4- methylsalicylate (Chem. Abs. 64, 6568d) and 9 ml of 2-aminoethanol. Yield: 16.7 g m.p. 78-80°C (hexane) .
  • N-(5'-hydroxypentyDsalicylamide was prepared following the procedure of Example 3,A) starting from 17.6 g of methyl salicylate and 8.5 ml of 5- aminopentanol. Yield: 11 g.
  • the compound was an oil used as such in the subsequent step.
  • N-(2'-hydroxyethyl)-4-methoxy-salicylamide was prepared following the procedure described in
  • Example 3A starting from 16.9 g of methyl 4- methoxysalicylate (J. Org. Chem., 23, 756, 1958) and 7 ml of 2-aminoethanol. Yield: 9.5 g. m.p. 92-94°C (hexane).
  • N-(1'-methyl-2'-hydroxyethyl)salicylamide was prepared following the procedure of Example 3,A) starting from 18 g (0.118 mole) of salicylic acid methyl ester and 18.8 ml of 2-amino-l-propanol. Yield: 19 g.
  • the compound was an oil which was used as such in the subsequent step.
  • N-(2 '-hydroxyethyl)-5-methoxysalicylamide was prepared following the procedure of Example 3,A) starting from 25 g (0.137 mole) of 5-methoxy- salicylic acid methyl ester and 9.94 ml of 2- aminoethanol. Yield: 25 g. The compound was used as such in the subsequent step.
  • N-(2'-hydroxyethyl)-4-trifluoromethyl-salicylamide was prepared following the procedure of Example 3,A) starting from 26 g (0.118 mole) of 4- trifluoromethyl-salicylic acid methyl ester [J. Am. Chem. Soc, 76, 1051-4 (1954)] and 100 ml of 2-aminoethanol. Yield: 24 g. The compound obtained was used as such in the subsequent step.
  • N-(2'-hydroxyethyl)-3-methyl-salicylamide was prepared following the procedure of Example 3,A) starting from 24.2 g (0.145 mole) of 3-methyl- salicylic acid methyl ester and 100 ml of 2- aminoethanol. Yield: 28.9 g. The compound was used as such in the subsequent step.
  • N-(2'-hydroxyethyl)-6-methyl-salicylamide was prepared following the procedure of Example 3,A) starting from 18.8 g (0.113 mole) of 6-methyl- salicylic acid methyl ester and 78 ml of 2- aminoethanol. Yield: 19.3 g. m.p.: 134-135 ⁇ C (hexane).
  • N-(3'-hydroxypropyl)salicylamide was prepared following the procedure of Example 3,A) starting from 20 g (0.131 mole) of salicylic acid methyl ester and 13.2 ml of 3-aminopropanol. Yield: 24 g as an oil which was used as such in the subsequent step.
  • N-(2'-hydroxy-1'-propyl)salicylamide was prepared following the procedure of Example 3,A) starting from 18 g (0.118 mole) of salicylic acid methyl ester and 18.3 ml of l-amino-2-propanol. Yield: 24 g as an oil which was used as such in the subsequent step.
  • Example 1,B starting from 20 g (0.102 mole) of the compound under A) . There were obtained 18 g as an oil.
  • N-(2 '-hydroxyethyl)-4-isopropoxy-salicylamide was prepared following the procedure of Example 3,A) starting from 25.3 g (0.166 mole) of 4-isopropoxy- salicylic acid methyl ester [obtained by treating 4-isopropoxy-salicylic acid prepared according to Synthesis 758-760 (1984), with methanol and sulfuric acid] and 100 ml of 2-aminoethanol. Yield: 22 g. The compound was used as such in the subsequent step.
  • Example 34 starting from 10 g (0.051 mole) of the compound of Example 1, 3.78 ml (0.051 mole) of thionyl chloride and 398 ml (5.17 moles) of isopropyl alcohol.
  • 4,5-Dimethoxy-N-(2'-hydroxyethyl)-salicylamide was prepared by reacting 23 g (0.108 mole) of 4,5- dimethoxy-salicylic acid methyl ester (obtained as described in Synthesis, 758, 1984) with 100 ml of 2-aminoethanol at 170 ⁇ C for 3 hours. After cooling to room temperature, the mixture was taken up in ethyl acetate, washed with 5% aqueous hydrochloric acid and dried over sodium sulfate. Yield: 18 g. The compound was used as such in the subsequent step.
  • 5-Ethyl-N-(2'-hydroxyethyl)-salicylamide was prepared as described in Example 3 A) , starting from 26.8 g (0.148 mole) of 5-ethyl-salicylic acid methyl ester (prepared as described in Synthesis, 758, 1984) and 10.7 ml (0.178 mole) of 2- aminoethanol. Yield: 29.8 g.
  • the compounds of the invention can be considered as potential drugs with a specific antianginal activity.
  • the ill vivo antianginal activity was determined on anaesthetized Sprague Dawley rats (average weight - 350-400 g) , according to the method described by M. Leitold et al., Arzneim. Forsch. 3>, 1454, 1986.
  • the test was carried out by intravenously administering the animals with 1 U.I/kg, equal to 3 mg/kg of Arg- vasopressin which induce a coronary spasm reproducible and electrocardiographically detectable by an increase of the T-wave.
  • the animals were then intravenously treated with four increasing doses of compounds representative of the invention to measure their ED 5Q , i.e. the dose yielding a 50% of inhibition of the increasing of the T-wave.
  • the compounds of the invention showed to have ED 5Q ranging between about 1 and about 300 ⁇ g/Kg. Specifically, the compounds of Examples 1, 2 and 34 showed an ED 5Q of, respectively, 87, 215 and 10.5 ⁇ g/Kg. Also, some compounds were tested as above, but orally administered. For example, the compound of Example 1 showed an ED,. Q of 0.23 mg/Kg.
  • the antianginal activity of the claimed compounds was also tested by the metacholine-induced angina test described by Sakai K. et al., Pharmacol. Met., 5_, 325- 336, 1981, The percentage of inhibition of the ST-wave increase induced by metacholine (0.8 ⁇ g/kg i.v.) was measured after intravenous administration of the compounds of the invention. The results are set forth in the following Table 1.
  • Example % of Inhibition at 3 ⁇ g/kg 1 min. 10 min. 30 min.
  • the ED_ Q of the compound of Example 1 was determined to be 73.5 ⁇ g/kg.
  • the compounds of the invention have an ED 5Q per os ranging between about 100 and about 0.01 mg/kg.
  • the favourable biological properties above are also accompanied by a low toxicity.
  • the D 50 values calculated according to the method of Lichtfield and Wilcoxon, J. Pharm. Expt. Ther. 9 , 99, 1949, are in fact higher than 500 mg/kg i.p. in mouse and 800 mg/kg p.o. in rat.
  • Object of the present invention is also the use of the claimed compounds as antianginal agents and agents useful in the treatment of ischemic cardiopathies, in connection with all the industrial aspects and applications of said use, comprising their incorporation into pharmaceutical compositions. Examples of these compositions are tablets, sugar- coated and film-coated tablets, syrups and phials, these latter being suitable for both the oral and the intramuscular or intravenous administration. They contain the active principle alone or in combination with common pharmaceutically acceptable carriers and excipients.
  • the dosages of active principle used in the antianginal therapy or to treat ischemic cardiopathies may vary within wide limits depending on the specific compound employed, and are chosen to provide the patient with an effective therapeutic protection for.
  • unit doses of from about 0.01 to about 1 mg may be administered from 1 to 4 times a day depending on the patient's necessity (prophylaxis, therapy, emergency).

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de la formule générale (I). Dans cette formule, X représente un atome d'oxygène ou de soufre; Y représente un alkylène ou un cycloalkylène; A représente hydroxy, alcoxy, acyloxy, mercapto, alkylsulfonyloxy, phénylsulfonyloxy, (a) ou (b) où R3 représente un groupe alkyle ou alkylène φ-substitué par 2,3-dihydro-4H-1,3-benzoxazin-4-one-N-yle; R représente hydrogène, alkyle ou phényle; R1 et R2 représentent indépendamment hydrogène, halogène, alcoxy, trifluorométhyle ou alkyle. L'invention concerne également les sels d'un acide ou d'une base pharmaceutiquement acceptable desdits composés. Ces composés et leurs sels sont actifs et utiles comme agents thérapeutiques.
EP94924778A 1993-07-28 1994-07-18 Benzoxazinones et benzothiazinones ayant une activite therapeutique Withdrawn EP0711286A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT93MI001678A IT1264812B1 (it) 1993-07-28 1993-07-28 Derivati benzossazinonici e benzotiazinonici terapeuticamente attivi
ITMI931678 1993-07-28
PCT/EP1994/002354 WO1995004048A1 (fr) 1993-07-28 1994-07-18 Benzoxazinones et benzothiazinones ayant une activite therapeutique

Publications (1)

Publication Number Publication Date
EP0711286A1 true EP0711286A1 (fr) 1996-05-15

Family

ID=11366700

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94924778A Withdrawn EP0711286A1 (fr) 1993-07-28 1994-07-18 Benzoxazinones et benzothiazinones ayant une activite therapeutique

Country Status (13)

Country Link
EP (1) EP0711286A1 (fr)
JP (1) JPH09500878A (fr)
CN (1) CN1128025A (fr)
AU (1) AU7494594A (fr)
CA (1) CA2168099A1 (fr)
FI (1) FI960342A (fr)
HU (1) HUT74587A (fr)
IL (1) IL110473A0 (fr)
IT (1) IT1264812B1 (fr)
NO (1) NO960308L (fr)
TW (1) TW277061B (fr)
WO (1) WO1995004048A1 (fr)
ZA (1) ZA945555B (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102367239B (zh) * 2011-07-20 2015-10-28 沈阳药科大学 2-芳基-2,3-二氢-4h-1,3-苯并噻嗪-4-酮衍生物及其用途
US9056835B2 (en) 2012-08-27 2015-06-16 The University Of Tennessee Research Foundation LPA2 receptor-specific benzoic acid derivatives
ITMI20122221A1 (it) 2012-12-21 2014-06-22 C4T S C A R L Nuovi composti del 2,3-diidro-4h-1,3-benzossazin-4-one, metodo per prepararli e forma farmaceutica che li comprende
KR101918375B1 (ko) * 2013-12-19 2018-11-13 길리애드 사이언시즈, 인코포레이티드 이온 채널 조정제로서의 융합된 헤테로시클릭 화합물

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2443M (fr) * 1962-10-30 1964-04-06 Selvi & C Lab Bioterapico Thio-dérivés de benzo-oxazine ayant des propriétés antiphlogistiques, antipyrétiques et analgésiques.
US3459748A (en) * 1967-04-28 1969-08-05 Squibb & Sons Inc Hydroxyalkylene-substituted benzoxazines and benzothiazines
IT1136575B (it) * 1981-04-15 1986-09-03 Coli Farma Lab Esteri del 2-(2-ossietil)-2,3-diidro-h4-1,3-benzossazin-4-one ad attivita' analgesica e procedimento per la loro preparazione
IT1244472B (it) * 1990-12-14 1994-07-15 Italfarmaco Spa Benzossazinoni e benzotiazinoni ad attivita' cardiovascolare
FR2680172B1 (fr) * 1991-08-05 1993-11-19 Fabre Medicament Pierre Nouvelles piperazinylalcoyl-3 dihydro-2,3 4h-benzoxazine-1,3 ones-4 substituees, leur preparation et leur application en therapeutique.
IT1254884B (it) * 1992-04-16 1995-10-11 Italfarmaco Spa Benzossazinoni e benzotiazinoni ad attivita' cardiovascolare

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9504048A1 *

Also Published As

Publication number Publication date
HU9600165D0 (en) 1996-03-28
TW277061B (fr) 1996-06-01
FI960342A0 (fi) 1996-01-25
IL110473A0 (en) 1994-10-21
AU7494594A (en) 1995-02-28
CA2168099A1 (fr) 1995-02-09
ITMI931678A1 (it) 1995-01-28
NO960308D0 (no) 1996-01-25
IT1264812B1 (it) 1996-10-10
HUT74587A (en) 1997-01-28
JPH09500878A (ja) 1997-01-28
WO1995004048A1 (fr) 1995-02-09
CN1128025A (zh) 1996-07-31
ZA945555B (en) 1995-03-03
FI960342A (fi) 1996-01-25
ITMI931678A0 (it) 1993-07-28
NO960308L (no) 1996-03-13

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