EP0804189A1 - Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia or hypercholesterolaemia or arteriosclerosis or for anticoagulative treatment - Google Patents

Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia or hypercholesterolaemia or arteriosclerosis or for anticoagulative treatment

Info

Publication number
EP0804189A1
EP0804189A1 EP96900095A EP96900095A EP0804189A1 EP 0804189 A1 EP0804189 A1 EP 0804189A1 EP 96900095 A EP96900095 A EP 96900095A EP 96900095 A EP96900095 A EP 96900095A EP 0804189 A1 EP0804189 A1 EP 0804189A1
Authority
EP
European Patent Office
Prior art keywords
treatment
prophylaxis
use according
compound
stated
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Withdrawn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
EP96900095A
Other languages
German (de)
English (en)
French (fr)
Inventor
Michael Shalmi
Niels Korsgaard
Steven Bain
Birgitte Hjort Guldhammer
Jan Ulrik Weis
Charles E. Hart
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.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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 Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP0804189A1 publication Critical patent/EP0804189A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • 3.4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hvperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia or hypercholesterolaemia or arteriosclerosis or for anticoa ⁇ ulative treatment
  • the present invention relates to the use of compounds of the general formula I for the treatment of patients suffering from hyperlipoproteinae- mia, hypertriglyceridaemia, hyperlipidaemia or hypercholesterolaemia and prophylaxis hereof.
  • the present invention furthermore relates to the use of compounds of the general formula I for the treatment of patients suffering from arteriosclerosis including atherosclerosis and prophylaxis hereof, and furthermore to the use of compounds of the general formula I for the treatment of patients in a need of an anticoagulative treatment or prophylaxis, e.g. following a coronary thrombosis or postoperatively i.e. after surgery.
  • the present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
  • IHD Ischemic heart disease
  • atherosclerosis Havel and Rapaport, N Eng J ed 1995; 332: 1491 - 1498.
  • Other frequent manifestations of atherosclerosis is cerebrovascular disease, and intermittent claudication.
  • An important risk factor for the development of atherosclerosis is an atherogenic lipid profile, i.e. hyperlipidaemia with increased LDL-cholesterol and relatively decreased HDL-cholesterol.
  • One object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of hyperlipoproteinae- mia, hypertriglyceridaemia, hyperlipidaemia or hypercholesterolaemia.
  • Another object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of arteriosclerosis including atherosclerosis.
  • Coagulation and thrombosis are important mechanisms involved in the pathogenesis of atherosclerosis and its complications such as vascular occlusion and embolism. Furthermore, blood clotting is important for the development of vascular restenosis following surgical intervention of blocked arteries. Restenosis occurs in about 35% of the patients after 6 months. Current therapy such as heparin , low molecular heparin and aspirin or stents have failed to reduce the incidence of restenosis. New therapeutic possibilities which can inhibit a tendency for thrombosis after endothelial damage are therefore needed.
  • Another further object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of patients in a need of an anticoagulative treatment or prophylaxis, e.g. following a coronary thrombosis or after surgery.
  • Centchroman is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Patent Specification No. 4,447,622; Singh et al., Acta Endocrinal (Cooenh) 126 (1992). 444 - 450: Grubb, Curr Ooin
  • Centchro- man has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781 - 783). Recently, centchroman as a racemate has been found potent as a cholesterol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al., J Min Bon Res 9 (1994), S
  • U.S. patent 5,280,040 describes methods and pharmaceutical composi ⁇ tions for reducing bone loss using 3,4-diarylchromans and their pharma- ceutically acceptable salts.
  • compounds of the general formula I as stated in claim 1 can be used in the treatment or prophylaxis of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia or hyper ⁇ cholesterolaemia and furthermore it has also, surprisingly, been found that compounds of the general formula I as stated in Claim 2 and 3 can be used in the treatment or prophylaxis of arteriosclerosis including atherosclerosis and that compounds of the general formula I as stated in claim 4 can be used in the treatment or prophylaxis of patients in a need of an anticoagulative treatment or prophylaxis, e.g. following a coronary thrombosis or after surgery.
  • the present invention is based in part on the discovery that a representa ⁇ tive 3,4-diarylchroman, centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [p-(beta-pyrrolidinoethoxy)phenyl]-7-methoxychroman) is effective as a hypolipoproteinaemic, hypotriglyceridaemic, hypolipidaemic or hypocho- lesterolaemic compound, inter alia in rabbits fed with cholesterol contain ⁇ ing diet.
  • These animal models are generally recognized models of hyperli- poproteinaemia, hypertriglyceridaemia, hyperlipidaemia or hypercholeste ⁇ rolaemia.
  • 3,4-diarylchromans are useful as therapeutive and preventive hypolipoproteinaemic, hypotriglyceri- daemic, hypolipidaemic or hypocholesterolaemic agents in mammals, including primates such as humans.
  • the present invention is based in part on the discovery that a representative 3,4-diarylchroman, centchroman (3,4-trans-2,2- dimethyl-3-phenyl-4-[p-(beta-pyrrolidinoethoxy)phenyl]-7-methoxychro- man) is also effective against the direct vascular effects of arteriosclero ⁇ sis including atherosclerosis, inter alia in rabbits fed with cholesterol containing diet. These animal models are generally recognized models of arteriosclerosis including atherosclerosis. These data thus indicate that the 3,4-diarylchromans are useful as therapeutic agents against arterio- sclerosis including atherosclerosis in mammals, including primates such as humans.
  • the present invention is yet further based in part on the discovery that a representative 3,4-diarylchroman, centchroman (3,4-trans-2,2-dimethyl- 3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7-methoxychroman) has preventive or therapeutic anticoagulative activities when administered inter alia to rats.
  • These animal models are generally recognized models of patients in a need of an anticoagulative treatment or prophylaxis, e.g. following a coronary thrombosis or after surgery.
  • This invention is related to the treatment or prophylaxis of disorders as defined in the Lipid Research Clinics Program. J.A.M.A. 251 (1984), 351-364 and J.A.M.A. 251 (1984), 365 - 374 or what a person skilled in the art may consider as subject for treatment or prophylaxis.
  • R1 , R4 and R5 are individually hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary aminoMlower alkoxy); and R2 and R3 are indivi ⁇ dually hydrogen or a lower alkyl.
  • lower alkyl includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like.
  • lower alkoxy includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec- amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy and the like.
  • Halogen includes chloro, fluoro, bromo and iodo.
  • the tertiary amino radical may be a N,N-dialkylamine such as a N,N-dimethylamino, N,N- diethylamino, N,N-dipropylamino and N,N-dibutylamino or a polymethy- leneimine, e.g., piperidine, pyrrolidine, N-methylpiperazine or morpholine.
  • (tertiary aminoMlower alkoxy) is a lower alkoxy group which is substituted by a tertiary amino group.
  • Preferred compounds include those in which R ' is lower alkoxy; R ⁇ and R ⁇ are lower alkyl, especially methyl; R ⁇ is hydrogen; and R ⁇ is (tertiary aminoMlower alkoxy) of the polymethyleneimine type.
  • R is in the 7-position and is lower alkoxy, particularly methoxy; each of R ⁇ and R ⁇ is methyl, R 4 is hydrogen, and R 5 is in the
  • the compounds of formula I in the transconfigura- tion. These compounds may be used as racemic mixtures, or the isolated stereoisomers e.g. d- or I- enantiomers, may be used. The trans-l-en- antiomers are more preferred.
  • a particularly preferred compound for use within the present invention is centchroman having the formula IV as stated in claim 14.
  • 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Patent Specification No. 3,340,276 to Carney et al., U.S. Patent Specification No. 3,822,287 to Bolger, and Ray et al., J Med Chem 19 (1976), 276 - 279, the contents of which are incorpo- rated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrange ⁇ ment is disclosed in U.S. Patent Specification No. 3,822,287.
  • the optically active d- and l-enantiomers may be prepared as disclosed by Salman et al. in U.S. Patent Specification No.
  • 3,4-diarylchromans may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, acetic acid, propionic acid, fumaric acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
  • the acid addition salts may be obtained as the direct products of com ⁇ pound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • 3,4-diar ⁇ lchromans and their salts are useful within human and veteri ⁇ nary medicine, for example, in the treatment or prevention of patients suffering from hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia or hypercholesterolaemia or arteriosclerosis including atherosclerosis or in need of anticoagulative treatment or prophylaxis e.g. following a coronary thrombosis or after surgery.
  • 3,4-diarylchromans and their pharmaceutically accept ⁇ able salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal or transdermal administration according to conventional methods.
  • Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release, dermal implants, tablets, etc.
  • diluents such as those disclosed in Remington's Pharmaceutical Sciences. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990.
  • the active compound is prepared in a form suitable for oral administration, such as a tablet or capsule.
  • a pharmaceutically acceptable salt of the compound is com ⁇ bined with a carrier and moulded into a tablet.
  • Suitable carriers include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like.
  • Such compositions may further include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc.
  • Pharmaceutical compositions containing a compound of formula I may be administered one or more times per day or week.
  • An effective amount of such a pharmaceutical composition is the amount that provides a clinical ⁇ ly significant effect as hypolipoproteinaemic, hypotriglyceridaemic, hypolipidaemic or hypocholesterolaemic agents or a clinically significant effect against arteriosclerosis including atherosclerosis or provides a clinically significant effect to patients in a need of an anticoagulative treatment or prophylaxis e.g. following a coronary thrombosis or after surgery.
  • Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art.
  • compositions containing a compound of formula I may be administered in unit dosage form one or more times per day or week. In the alternative, they may be provided as controlled release formulations suitable for dermal implantation. Implants are formulated to provide release of active compound over the desired period of time, which can be up to several years. Controlled-release formulations are disclosed by, for example, Sanders et al., J Pharm Sci 73 (1964), 1294 - 1297, 1984; U.S. Patent Specification No. 4,489,056; and U.S. Patent
  • Examples of preferred compounds of formula I are centchroman as a racemic mixture and as l-centchroman and d-centchroman. Furthermore, 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7- hydroxychroman is a preferred compound. The more preferred compound is trans-l-centchroman (l-3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrro- lidin-1 -yl)ethoxy)phenyl)-7-methoxychroman).
  • Examples of pharmaceutically acceptable acid addition salts are salts with non-toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, acetic acid, propionic acid, succinic acid, fumaric acid, glyconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, metha- nesulphonic acid and malonic acid.
  • inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, succinic acid, fumaric acid, glyconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, metha- nesulphonic acid and malonic acid.
  • sham surgery or ovariectomy was performed on 56 female Sprague-Dawley rats and the animals were assigned to the following treatments (8 rats per group) : 1 ) sham/vehicle; 2) OVX/vehicle, 3) OVX/ethynyl estradiol 0.2 mg/kg; 4) OVX/l-centchroman 1 mg/kg; 5) OVX/l-centchroman 5 mg/kg; 6) OVX/l-centchroman 10 mg/kg;7) OVX/l-centchroman 25 mg/kg.
  • the doses were administered three times per week for 5 weeks by oral gavage. At the conclusion of the experi ⁇ ment serum was collected for determination of cholesterol level (US patent 5,407,955).
  • l-centchroman The effects of l-centchroman on plasma lipids were also investigated in cholesterol fed rabbits.
  • OVX/vehicle 1 1 .0 ⁇ 1 .1 OVX/17- ⁇ -estradiol 50 g/kg 3x/week 7.5 ⁇ 0.5
  • 3x/week Values are mean ⁇ SEM. * indicate significant reduction of serum cholesterol compared to OVX/vehicle treated animals; p ⁇ 0.05.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyrane Compounds (AREA)
EP96900095A 1995-01-13 1996-01-10 Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia or hypercholesterolaemia or arteriosclerosis or for anticoagulative treatment Withdrawn EP0804189A1 (en)

Applications Claiming Priority (13)

Application Number Priority Date Filing Date Title
DK41/95 1995-01-13
DK4195 1995-01-13
DK43/95 1995-01-13
DK4395 1995-01-13
DK6995 1995-01-20
DK69/95 1995-01-20
DK76795 1995-06-30
DK766/95 1995-06-30
DK767/95 1995-06-30
DK777/95 1995-06-30
DK76695 1995-06-30
DK77795 1995-06-30
PCT/DK1996/000014 WO1996021443A1 (en) 1995-01-13 1996-01-10 Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia or hypercholesterolaemia or arteriosclerosis or for anticoagulative treatment

Publications (1)

Publication Number Publication Date
EP0804189A1 true EP0804189A1 (en) 1997-11-05

Family

ID=27545138

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96900095A Withdrawn EP0804189A1 (en) 1995-01-13 1996-01-10 Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia or hypercholesterolaemia or arteriosclerosis or for anticoagulative treatment

Country Status (11)

Country Link
EP (1) EP0804189A1 (no)
JP (1) JPH10511961A (no)
CN (1) CN1168098A (no)
AU (1) AU4329296A (no)
BR (1) BR9606890A (no)
CA (1) CA2208859A1 (no)
CZ (1) CZ212397A3 (no)
HU (1) HUP9800521A3 (no)
IL (1) IL116745A (no)
NO (1) NO973241L (no)
WO (1) WO1996021443A1 (no)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5407955A (en) * 1994-02-18 1995-04-18 Eli Lilly And Company Methods for lowering serum cholesterol and inhibiting smooth muscle cell proliferation, restenosis, endometriosis, and uterine fibroid disease
US6069175A (en) * 1996-11-15 2000-05-30 Pfizer Inc. Estrogen agonist/antagonists treatment of atherosclerosis
AU3023999A (en) * 1998-03-20 1999-10-18 Novo Nordisk A/S Use of 3,4-diphenylchromans for the manufacture of a pharmaceutical composition for lowering plasma levels of lp(a) in a human or sub-human primate
US6465445B1 (en) * 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US7005428B1 (en) 1998-06-11 2006-02-28 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US6613083B2 (en) 2001-05-02 2003-09-02 Eckhard Alt Stent device and method
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
CA2581316C (en) 2004-09-21 2013-09-10 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
EP2635273B1 (en) 2010-11-01 2020-01-08 MEI Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
MX368063B (es) 2014-02-07 2019-09-18 Novogen ltd Compuestos de benzopirano funcionalizados y uso de los mismos.
CN116139125A (zh) 2015-02-02 2023-05-23 梅制药公司 联合治疗

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1543749A1 (de) * 1966-02-16 1969-12-11 Merck Ag E Verfahren zur Herstellung von 3,4-cis-4-Aryl-isoflavanen
US5407955A (en) * 1994-02-18 1995-04-18 Eli Lilly And Company Methods for lowering serum cholesterol and inhibiting smooth muscle cell proliferation, restenosis, endometriosis, and uterine fibroid disease

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9621443A1 *

Also Published As

Publication number Publication date
JPH10511961A (ja) 1998-11-17
CZ212397A3 (en) 1997-11-12
HUP9800521A2 (hu) 1998-12-28
BR9606890A (pt) 1997-10-28
IL116745A (en) 1999-12-22
HUP9800521A3 (en) 1999-12-28
AU4329296A (en) 1996-07-31
MX9705214A (es) 1997-10-31
IL116745A0 (en) 1996-05-14
NO973241D0 (no) 1997-07-11
CA2208859A1 (en) 1996-07-18
NO973241L (no) 1997-07-11
WO1996021443A1 (en) 1996-07-18
CN1168098A (zh) 1997-12-17

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