AP761A - Phosphinate based inhibitors of matrix metalloproteases. - Google Patents

Phosphinate based inhibitors of matrix metalloproteases. Download PDF

Info

Publication number: AP761A
Authority: AP; ARIPO
Prior art keywords: alkyl; phosphinic acid; benzyl; dimethyl; methylcarbamoyl
Prior art date: 1996-07-18

Application number

APAP/P/1997/001043A

Other languages

English (en)

Other versions

AP9701043A0 (en

Inventor

Lawrence Alan Reiter

Original Assignee

Pfizer

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.)

1996-07-18

Filing date

1997-07-17

Publication date

1999-09-13

1997-07-17 Application filed by Pfizer filed Critical Pfizer

1997-07-31 Publication of AP9701043A0 publication Critical patent/AP9701043A0/xx

1999-09-13 Application granted granted Critical

1999-09-13 Publication of AP761A publication Critical patent/AP761A/en

Links

239000003112 inhibitor Substances 0.000 title description 17
239000011159 matrix material Substances 0.000 title description 2
102000005741 Metalloproteases Human genes 0.000 title 1
108010006035 Metalloproteases Proteins 0.000 title 1
ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 63
-1 cis-platinim Chemical compound 0.000 claims abstract description 47
238000004519 manufacturing process Methods 0.000 claims abstract description 14
201000010099 disease Diseases 0.000 claims abstract description 12
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
102000002274 Matrix Metalloproteinases Human genes 0.000 claims abstract description 11
108010000684 Matrix Metalloproteinases Proteins 0.000 claims abstract description 11
230000000694 effects Effects 0.000 claims abstract description 9
229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims abstract description 7
206010028980 Neoplasm Diseases 0.000 claims abstract description 6
229940035676 analgesics Drugs 0.000 claims abstract description 6
239000000730 antalgic agent Substances 0.000 claims abstract description 6
201000011510 cancer Diseases 0.000 claims abstract description 6
231100000433 cytotoxic Toxicity 0.000 claims abstract description 6
230000001472 cytotoxic effect Effects 0.000 claims abstract description 6
239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims abstract description 6
238000011282 treatment Methods 0.000 claims abstract description 6
208000030507 AIDS Diseases 0.000 claims abstract description 5
206010039705 Scleritis Diseases 0.000 claims abstract description 5
206010040047 Sepsis Diseases 0.000 claims abstract description 5
206010040070 Septic Shock Diseases 0.000 claims abstract description 5
208000025865 Ulcer Diseases 0.000 claims abstract description 5
206010003246 arthritis Diseases 0.000 claims abstract description 5
208000028169 periodontal disease Diseases 0.000 claims abstract description 5
208000037803 restenosis Diseases 0.000 claims abstract description 5
230000036303 septic shock Effects 0.000 claims abstract description 5
230000036269 ulceration Effects 0.000 claims abstract description 5
206010014989 Epidermolysis bullosa Diseases 0.000 claims abstract description 4
239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
208000002780 macular degeneration Diseases 0.000 claims abstract description 4
125000000217 alkyl group Chemical group 0.000 claims description 30
108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 23
102000003390 tumor necrosis factor Human genes 0.000 claims description 23
125000000041 C6-C10 aryl group Chemical group 0.000 claims description 19
230000005764 inhibitory process Effects 0.000 claims description 17
238000000034 method Methods 0.000 claims description 16
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
229910052739 hydrogen Inorganic materials 0.000 claims description 13
239000001257 hydrogen Substances 0.000 claims description 13
125000003545 alkoxy group Chemical group 0.000 claims description 12
241000124008 Mammalia Species 0.000 claims description 11
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 11
229910052799 carbon Inorganic materials 0.000 claims description 10
150000003839 salts Chemical class 0.000 claims description 10
239000002253 acid Substances 0.000 claims description 9
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
125000004104 aryloxy group Chemical group 0.000 claims description 6
125000005843 halogen group Chemical group 0.000 claims description 6
125000001544 thienyl group Chemical group 0.000 claims description 6
125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 5
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 4
229910052684 Cerium Inorganic materials 0.000 claims description 4
125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 4
125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
KATBPZLMXQIZLF-UHFFFAOYSA-N (4-benzylphenyl)methyl-[2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-methylpentyl]phosphinic acid Chemical compound C1=CC(CP(O)(=O)CC(CC(C)C)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1=CC=CC=C1 KATBPZLMXQIZLF-UHFFFAOYSA-N 0.000 claims description 3
125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 3
RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 3
125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
125000001153 fluoro group Chemical group F* 0.000 claims description 3
125000004076 pyridyl group Chemical group 0.000 claims description 3
UTSFQPTVPZNJJH-UHFFFAOYSA-N (4-benzylphenyl)methyl-[2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-phenylbutyl]phosphinic acid Chemical compound C=1C=C(CC=2C=CC=CC=2)C=CC=1CP(O)(=O)CC(C(=O)NC(C(=O)NC)C(C)(C)C)CCC1=CC=CC=C1 UTSFQPTVPZNJJH-UHFFFAOYSA-N 0.000 claims description 2
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 claims description 2
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
VWYWYCIQBGGPKK-UHFFFAOYSA-N benzyl-[2-[[3-(4-methoxyphenyl)-1-(methylamino)-1-oxopropan-2-yl]carbamoyl]-6-phenoxyhexyl]phosphinic acid Chemical compound C=1C=CC=CC=1OCCCCC(CP(O)(=O)CC=1C=CC=CC=1)C(=O)NC(C(=O)NC)CC1=CC=C(OC)C=C1 VWYWYCIQBGGPKK-UHFFFAOYSA-N 0.000 claims description 2
125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 2
150000001721 carbon Chemical group 0.000 claims description 2
125000004432 carbon atom Chemical group C* 0.000 claims description 2
229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims description 2
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
125000002541 furyl group Chemical group 0.000 claims description 2
125000000842 isoxazolyl group Chemical group 0.000 claims description 2
125000002971 oxazolyl group Chemical group 0.000 claims description 2
229910052760 oxygen Inorganic materials 0.000 claims description 2
239000008194 pharmaceutical composition Substances 0.000 claims description 2
125000002098 pyridazinyl group Chemical group 0.000 claims description 2
125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
125000000168 pyrrolyl group Chemical group 0.000 claims description 2
125000000335 thiazolyl group Chemical group 0.000 claims description 2
LKOQZTZLLAIOGB-UHFFFAOYSA-N [2-(cyclopropylmethyl)-3-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]amino]-3-oxopropyl]-[[4-[(2-fluorophenyl)methyl]phenyl]methyl]phosphinic acid Chemical compound C=1C=C(CC=2C(=CC=CC=2)F)C=CC=1CP(O)(=O)CC(C(=O)NC(C(=O)NC)C(C)(C)C)CC1CC1 LKOQZTZLLAIOGB-UHFFFAOYSA-N 0.000 claims 1
OWXGCYPTRHGHPT-UHFFFAOYSA-N [2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-methylpentyl]-[[4-[(4-fluorophenyl)methyl]phenyl]methyl]phosphinic acid Chemical compound C1=CC(CP(O)(=O)CC(CC(C)C)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1=CC=C(F)C=C1 OWXGCYPTRHGHPT-UHFFFAOYSA-N 0.000 claims 1
BQHQFSSBHXZZQD-UHFFFAOYSA-N [4-(cyclohexylmethyl)phenyl]methyl-[2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-methylpentyl]phosphinic acid Chemical compound C1=CC(CP(O)(=O)CC(CC(C)C)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1CCCCC1 BQHQFSSBHXZZQD-UHFFFAOYSA-N 0.000 claims 1
239000003795 chemical substances by application Substances 0.000 claims 1
230000007850 degeneration Effects 0.000 claims 1
125000001786 isothiazolyl group Chemical group 0.000 claims 1
125000004437 phosphorous atom Chemical group 0.000 claims 1
229910052698 phosphorus Inorganic materials 0.000 claims 1
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VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
DRDCQJADRSJFFD-UHFFFAOYSA-N tris-hydroxymethyl-methyl-ammonium Chemical class OC[N+](C)(CO)CO DRDCQJADRSJFFD-UHFFFAOYSA-N 0.000 description 1
230000006433 tumor necrosis factor production Effects 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/02—Local antiseptics
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- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/306—Arylalkanephosphinic acids, e.g. Ar-(CH2)n-P(=X)(R)(XH), (X = O,S, Se; n>=1)
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65525—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring
- C07F9/65527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring condensed with carbocyclic rings or carbocyclic ring systems

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Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
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Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Communicable Diseases (AREA)
Oncology (AREA)
Pain & Pain Management (AREA)
Virology (AREA)
Neurology (AREA)
Tropical Medicine & Parasitology (AREA)
Cardiology (AREA)
AIDS & HIV (AREA)
Biomedical Technology (AREA)
Rheumatology (AREA)
Neurosurgery (AREA)
Dermatology (AREA)
Heart & Thoracic Surgery (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Enzymes And Modification Thereof (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

APAP/P/1997/001043A 1996-07-18 1997-07-17 Phosphinate based inhibitors of matrix metalloproteases. AP761A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US2195996P	1996-07-18	1996-07-18

Publications (2)

Publication Number	Publication Date
AP9701043A0 AP9701043A0 (en)	1997-07-31
AP761A true AP761A (en)	1999-09-13

Family

ID=21807061

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
APAP/P/1997/001043A AP761A (en)	1996-07-18	1997-07-17	Phosphinate based inhibitors of matrix metalloproteases.

Country Status (40)

Country	Link
US (1)	US6147061A (is)
EP (1)	EP0923585B1 (is)
JP (1)	JP3299975B2 (is)
KR (1)	KR20000067904A (is)
CN (1)	CN1225639A (is)
AP (1)	AP761A (is)
AR (1)	AR008260A1 (is)
AT (1)	ATE217315T1 (is)
AU (1)	AU712973B2 (is)
BG (1)	BG103111A (is)
BR (1)	BR9710381A (is)
CA (1)	CA2260898C (is)
CO (1)	CO4890852A1 (is)
CZ (1)	CZ11899A3 (is)
DE (1)	DE69712496T2 (is)
DK (1)	DK0923585T3 (is)
EA (1)	EA199900036A1 (is)
ES (1)	ES2175415T3 (is)
GT (1)	GT199700085A (is)
HN (1)	HN1997000099A (is)
HR (1)	HRP970391A2 (is)
HU (1)	HUP9903014A3 (is)
ID (1)	ID19443A (is)
IL (1)	IL127567A0 (is)
IS (1)	IS4928A (is)
MA (1)	MA24270A1 (is)
NO (1)	NO990184L (is)
NZ (1)	NZ333303A (is)
OA (1)	OA10956A (is)
PA (1)	PA8433701A1 (is)
PE (1)	PE88198A1 (is)
PL (1)	PL331254A1 (is)
PT (1)	PT923585E (is)
SI (1)	SI0923585T1 (is)
SK (1)	SK3799A3 (is)
TN (1)	TNSN97122A1 (is)
TR (1)	TR199900066T2 (is)
WO (1)	WO1998003516A1 (is)
YU (1)	YU1899A (is)
ZA (1)	ZA976330B (is)

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Publication number	Publication date
TNSN97122A1 (fr)	2005-03-15
PL331254A1 (en)	1999-07-05
AP9701043A0 (en)	1997-07-31
AU3104297A (en)	1998-02-10
DK0923585T3 (da)	2002-07-01
ID19443A (id)	1998-07-09
PA8433701A1 (es)	1999-12-27
HRP970391A2 (en)	1998-08-31
EA199900036A1 (ru)	1999-06-24
AR008260A1 (es)	1999-12-29
CA2260898C (en)	2002-05-14
JPH11514673A (ja)	1999-12-14
NO990184L (no)	1999-03-15
SK3799A3 (en)	2000-03-13
OA10956A (en)	2001-10-30
NZ333303A (en)	2000-06-23
CA2260898A1 (en)	1998-01-29
YU1899A (sh)	2000-03-21
US6147061A (en)	2000-11-14
CN1225639A (zh)	1999-08-11
DE69712496D1 (de)	2002-06-13
KR20000067904A (ko)	2000-11-25
NO990184D0 (no)	1999-01-15
PT923585E (pt)	2002-08-30
ZA976330B (en)	1999-01-19
HN1997000099A (es)	1997-12-28
TR199900066T2 (xx)	1999-04-21
SI0923585T1 (en)	2002-08-31
HUP9903014A3 (en)	2000-08-28
EP0923585A1 (en)	1999-06-23
JP3299975B2 (ja)	2002-07-08
IS4928A (is)	1998-12-18
BR9710381A (pt)	1999-08-17
WO1998003516A1 (en)	1998-01-29
CZ11899A3 (cs)	1999-11-17
HUP9903014A2 (en)	2000-07-28
MA24270A1 (fr)	1998-04-01
BG103111A (en)	1999-11-30
CO4890852A1 (es)	2000-02-28
GT199700085A (es)	1999-01-06
EP0923585B1 (en)	2002-05-08
IL127567A0 (en)	1999-10-28
DE69712496T2 (de)	2002-08-29
ES2175415T3 (es)	2002-11-16
PE88198A1 (es)	1998-12-21
ATE217315T1 (de)	2002-05-15
AU712973B2 (en)	1999-11-18

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