WO2004084903A1 - Utilisation d'une trioxopyrimidine pour le traitement et la prevention de l'angiogenese pathologique oculaire - Google Patents

Utilisation d'une trioxopyrimidine pour le traitement et la prevention de l'angiogenese pathologique oculaire Download PDF

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WO2004084903A1
WO2004084903A1 PCT/EP2004/003206 EP2004003206W WO2004084903A1 WO 2004084903 A1 WO2004084903 A1 WO 2004084903A1 EP 2004003206 W EP2004003206 W EP 2004003206W WO 2004084903 A1 WO2004084903 A1 WO 2004084903A1
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mmp
mice
piperazin
pyrimidine
phenyl
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PCT/EP2004/003206
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English (en)
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Jean-Michel Foidart
Francis Frankenne
Hans-Willi Krell
Vincent Lambert
Agnes Noel
Jean-Marie Rakic
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F. Hoffmann-La Roche Ag
Université de Liège
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • trioxopyrimidine for the treatment and prevention of ocular pathologic angiogenesis
  • the present invention relates to the use of a trioxopyrimidine compound for the treatment and prevention of ocular disorders associated with pathologic angiogenesis such as age- related macular degeneration, diabetic retinopathy or corneal neovascularization.
  • pathologic angiogenesis such as age- related macular degeneration, diabetic retinopathy or corneal neovascularization.
  • Angiogenesis is the process of new blood vessel development and formation and can be found in numerous diseases.
  • angiogenesis is caused by infiltration of the basal lamina by vascular endothelial cells in response to angiogenic growth signals, migration of the endothelial cells, and subsequent proliferation and formation of the capillary tube. Blood flow through the newly formed capillary is initiated after the endothelial cells come into contact and connect with a preexisting capillary.
  • Unregulated angiogenesis becomes pathologic and sustains progression of many neoplastic and non-neoplastic diseases.
  • a number of serious diseases are caused by abnormal neovascularization, including solid tumor growth and metastases, arthritis, some types of eye disorders like age-related macular degeneration (AMD), and psoriasis (see, e.g., reviews by Moses, M.A., and Langer, R., Biotech. 9 (1991) 630-634; Folkman, J., N. Engl. J. Med. 333 (1995) 1757-1763; Auerbach, R., et al., J. Microvasc. Res. 29 (1985) 401-411; Folkman, J., Advances in Cancer Research, eds. Klein and Weinhouse, 1985, Academic Press, New York, pp. 175-203; Patz, A., Am. J.
  • Opthalmol. 94 (1982) 715-743; Folkman, J., et al., Science 221 (1983) 719-725; and Rastinejad, F., et al., Cell 56 ( 1989) 345-355.
  • angiogenesis inhibitors At present, more than 250 angiogenesis inhibitors are described and approximately half of them display activity in in vivo models (Bouma-ter Steege, J.C., et al., Crit. Rev. Eucaryot. Gene Expr. 11 (2001) 319-334).
  • CNV pathological choroidal neovascularization
  • VEGF Vascular endothelial factor
  • PEDF pigment-epithelium derived factor
  • Matrix metalloproteases are a family of zinc- and calcium-dependent proteases that are capable of degrading the extracellular matrix (ECM) and basement membrane (Egeblad, M., and Werb, Z., Nat. Rev. Cancer 2 (2002) 161-174; Overall, CM., and Lopez- Otin, C, Nat. Rev. Cancer 2 (2002) 657-672). They are believed to have pivotal roles in embryonic development and growth (Holmbeck, K., et al., Cell 99 (1999) 81-92; Vu, T.H., et al., Cell 93 (1998) 411-422) as well as in tissue remodeling and repair (Shapiro, S.D., Curr. Opin.
  • MMPs may therefore contribute to the pathogenesis of many tissue-destructive processes, including tumor progression (Rgeblad, M., and Werb, Z., Nat. Rev. Cancer 2 (2002) 161-174; Overall, CM., and Lopez-Otin, C, Nat. Rev. Cancer 2 (2002) 657-672) and aneurysm formation (Carmeliet, P., et al., Nat. Genet. 17 (1997) 439-444).
  • MMP effects are far from being restricted to ECM degradation (Chang, C, and Werb, D., Trends Cell Biol. 11 (2001) S37-43).
  • Peptide growth factors that are sequestered by ECM proteins become available once degraded by MMP-9 (Man ⁇ es, S., et al, J. Biol. Chem. 274 (1999) 6935-6945).
  • MMPs can increase the bioavailability o- f VEGF (Bergers, G., et al., Nat. Cell Biol. 2 (2000) 737-744) but also generate angiogenesis inhibitors such as angiostatin by cleavage of plasminogen (Dong, Z., et al., Cell 8S- (1997) 801-810).
  • MMPs matrix metalloproteinases
  • MMP-9 is not the only pathway for rendering angiogenic factors bioavailable, which occurs in other experimental settings (Bergers, G., et al., Nat. Cell Biol. 2 (2000) 737-744). After laster light induced choroidal neovascularization in rats, MMP-2 mRNA expression was induced whereas MMP-9 mRNA expression was generally low and did not increase following laser treatment (Kvanta, A., et al., Curr. Eye Res. 21 (2000) 684-690). It is further known that in MMP-2-deficient mice there occurs reduced choroidal neovascular membrane formation (Berglin, L., et al., Invest. Ophthalmol. Vis. Sci. 44 (2003) 403-408). It is further discussed that MMP-1 and MMP-14 are involved in corneal degradation (Collier, S.A., Clin., Exp. Ophthalmol. 29 (2001) 340- 344).
  • MMPs Tissue Inhibitors of Metalloproteases
  • Tissue Inhibitors of Metalloproteases Tissue Inhibitors of Metalloproteases
  • Low molecular weight inhibitors of MMPs are derived from the hydroxamic acid compound class and inhibit MMPs in a broad manner, being not selective for MMP-2 and MMP-9, the key MMPs in tumor invasion, metastatic spread, and angiogenesis.
  • MMP inhibiting molecules from another structural class, the trioxopyrimidines have been described, e.g. in WO 97/23465 and WO 01/25217. This class of compounds is extremely potent, and highly selective, with an almost exclusive specificity for MMP-2, MMP-9, while sparing most other members of the MMP family of proteases.
  • MMP inhibitors predominantly of the hydroxamic acid substance class with broad substrate specificity were, and in part still are, in clinical testing for anti-tumor treatment. All of the published clinical results with these inhibitors were disappointing, showing little or no clinical efficacy (Fletcher, L., Nat. Biotechnol. 18 (2000) 1138-1139). The reason for this lack of efficacy in the clinic most likely is the fact that patients could not be given high enough doses for anti-tumor or anti-metastatic activity because of the side effects associated with these broadly acting inhibitors. These dose-limiting side effects were predominantly arthralgias and myalgias (Drummond, A.H., et al., Ann. N.Y. Acad. Sci.
  • WO 98/16503, WO 98/16506, WO 98/16514, and WO 98/16520 describe the use of orthosulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase inhibitors which might be useful for the treatment of macular degeneration.
  • WO 98/16503, WO 98/16506, WO 98/16514, and WO 98/16520 describe the use of orthosulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase inhibitors which might be useful for the treatment of macular degeneration.
  • matrix metalloproteinase inhibitors which might be useful for the treatment of macular degeneration.
  • highly potent substances which can be used for the treatment or prevention of macular degenerative diseases.
  • trioxopyrimidine-based MMP inhibitors which are highly selective for MMP-2, MMP-9 and MMP-14 are useful for the treatment or prevention of ocular pathologic angiogenesis.
  • the invention therefore provides the use of a trioxopyrimidine compound having an inhibitory activity against MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14 defined as
  • MMP-l MMP-14; and c) a ratio of more than 10 for the IC 50 values of MMP-3:MMP-2, MMP-3: MMP-9,
  • IC 50 values are measured by an in vitro assay for MMP enzymatic activity.
  • an assay is described by Stack, M.S., and Gray, R.D., J. Biol. Chem. 264 (1989) 4277-4281. This assay is based on the determination of MMP enzymatic activity on a dinitrophenol substrate and fluorescence measurement of the substrate after cleaving by MMPs.
  • the invention further provides the use of such trioxopyrimidine compounds for the manufacturing of a medicament for the treatment or prevention of ocular pathologic angiogenesis.
  • Matrix metalloproteinases are well-known in the state of the art and are defined, e.g., by their EC numbers (MMP-1 EC 3.4.24.7; MMP-2 EC 3.4.24.24; MMP-3 EC 3.4.24.17, MMP-9 EC 3.4.24.35, MMP-14 EC 3.4.24).
  • Trioxopyrimidines useful for the invention are compounds from a well-known structural class. Such compounds are described in, for example, US Patent Nos. 6,242,455 and 6,110,924; WO 97/23465, WO 98/58915, WO 01/25217, which are incorporated herein by reference, and Grams, F., et al., Biol. Chem. 382 (2001) 1277-1285, and are effective and highly selective for MMP-2, MMP-9, and MMP-14.
  • Ocular pathologic angiogenesis is especially a macular degeneration, such as age-related macular degeneration, diabetic retinopathy and corneal neovascularization.
  • the invention therefore further relates to a method for treating or preventing corneal neovascularization.
  • Corneal neovascularization leads to vision loss in eyes after extensive injury of the limbus.
  • the limbus is a specialized tissue between the cornea and the conjunctiva. After injury or destruction of the limbus, corneal neovascularization due to the inflammation occurs.
  • the use of MMP inhibitors according to the invention inhibits corneal neovascularization and is therefore useful as a therapeutic agent for the treatment of corneal neovascularization, e.g. associated with limbal injury.
  • the disease and current treatments are described by, e.g., Chang, J.H., et al., Curr. Opin. Ophthalmol. 12 (2001) 242-249.
  • the invention therefore further relates to a method for treating or preventing age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • the retinal macula degenerates or becomes disfunctional as a consequence of decreased growth of cells in the macula, increased death or rearrangement of the macular cells.
  • the disease and current treatments are descibed by, e.g., Gottling, J.L., JAMA 288 (2002) 2233-2236.
  • the invention therefore further relates to a method for treating or preventing diabetic retinopathy.
  • Retinal microvascular disfunction in diabetes is a major component of diabetic retinopathy.
  • the disease and current treatments are described by, e.g., Harper, C.A., Clin. Exp. Optom. 82 (1999) 98-101.
  • the trioxopyrimidine-based inhibitors have to be administered to the patient over several months or years (in case of prevention), to the patient in need of such a therapy.
  • the trioxopyrimidine compounds are administered preferably with intravitreal and/or periocular injections, with non-retinotoxic doses ranging between micro and nanomolar concentrations.
  • the exact dosage of the MMP inhibitors will vary, but can be easily determined. In general, the daily dosage of the inhibitors will range between 1 nmol/kg and day to 1 mmol/kg and day.
  • the pharmaceutical compositions are aqueous compositions having physiological compatibility.
  • the compositions include, in addition, auxiliary substances, buffers, preservatives, solvents and/or viscosity modulating agents.
  • Appropriate buffer systems are based on sodium phosphate, sodium acetate or sodium borate.
  • Preservatives are required to prevent microbial contamination of the pharmaceutical composition during use. Suitable preservatives are, for example, benzalkonium chloride, chlorobutanol, methylparabene, propylparabene, phenylethyl alcohol, sorbic acid. Such preservatives are used typically in an amount of 0.01 to 1% weight/volume.
  • Suitable auxiliary substances and pharmaceutical formulations are described in Remington's Pharmaceutical Sciences, 16th ed., 1980, Mack Publishing Co., edited by Oslo et al.
  • an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic.
  • a pharmaceutically acceptable substances include saline, Ringer's solution and dextrose solution.
  • the pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5.
  • the invention further comprises double knockout (MMP-2-/-; MMP-9-) mouse model and its use for the identification of substances inhibiting ocular pathologic angiogenesis.
  • the mouse model includes artificial choroidal neovascularization induced by laser burns at the optic disk of the eyes.
  • neovascularization was estimated by the ratio of the thickness from the bottom of the pigmented choroidal layer to the top of the neovascular membrane to the thickness of the intact-pigmented choroid adjectant.
  • neovascular reaction was determined with computer-assisted image analysis by evaluating the B/C ratio as described previously (Lambert, V., et al, Am. J. Pathol. 161 (2002) 1247-1253 and FASEB J. 15 (2001) 1021- 1027) at day 14 after laser injury of the Bruch's membrane in WT and deficient mice (E).
  • Original magnification 200X .
  • FIG. 1 Zymographic analysis of MMP-2 and MMP-9 in knockouts and WT mice.
  • mice At day 5 after the induction of choroidal neovascularization by laser, animals were sacrificed and posterior segment extract samples (5 ng/lane) from eyes of WT and MMP-2 or MMP-9 deficient mice were analyzed by gelatin zymography (A). As positive control, medium conditioned by human HT1080 cells was included ("HT"). Data represent the results of a single experiment, which was one of three with similar results. In WT mice, a kinetic zymographic evaluation was also performed at different intervals after laser-induced CNV demonstrating a temporal increase in pro-MMP-9 and the appearance of active forms of MMP-2 (B).
  • Frozen ocular sections sections from wild-type (A), MMP-9 -/- (B) and MMP-2 -/- (C) mice reveal the presence of limited amount of fibrin (stained in orange with AEC) in WT mice or single gene deficient mice contrasting with the accumulation of fibrin at the site of restricted choroidal reaction observed in double gene MMP-2,9 deficient animals (D).
  • Figure 5 Decreased CNV formation with MMP inhibitors.
  • MMP-2 -/- mice Itoh, T., et al., J. Biol. Chem. 272 (1997) 22389-22392) and MMP-9 -/- mice (Vu, T.H., et al., Cell 93 (1998) 411-422) were crossed with each other to obtain MMP-2 +/- MMP-9 +/- mice. Then these mice were crossed with each other to obtain MMP-2 -/- MMP-9 -/- (double knockout also designed as MMP2,9 KO), and control wild- type (WT) mice. All mice were genotyped using PCR. Animal experiments were performed in compliance with the Association for Research in Vision and Ophthalmology (ARVO) statement for the Use of Animals in Ophthalmic and Vision Research. The animals were maintained with a 12-h light/12-h dark cycle and had free access to food and water.
  • ARVO Association for Research in Vision and Ophthalmology
  • CNV Choroidal neovascularization
  • Choroidal neovascularization was quantified as previously described (Lambert, V., et al., Am. J. Pathol. 161 (2002) 1247-1253; Lambert, V., et al., FASEB J. 15 (2001) 1021-1027). Briefly, frozen serial sections were cut throughout the entire extent of each burn, and the thickest region (minimum of 5/lesion) selected for the quantification. Using a computer-assisted image analysis system (Olympus Micro Image version 3.0 for Windows 95/NT, Olympus Optical CO.
  • neovascularization was estimated by the ratio (B/C) of the thickness from the bottom of the pigmented choroidal layer to the top of the neovascular membrane (B) to the thickness of the intact-pigmented choroid adjacent to the lesion (C).
  • B/C ratio value was attributed to each laser impact.
  • In situ zymography was performed by incubating cryosections (7 ⁇ m) with 40 ⁇ g/ml fluorescein-conjugated gelatine (Molecular Probes, Eugene, OR) in 50 mM Tris-HCl pH 7.5, 10 mM CaCl2, 150 mM NaCl and 0.05% Brij-35 (Calbiochem, CA, USA) for 12 h at 37°C; sections were washed 3 times with water and mounted with Vectashield. Gelatinase activity was visualized using fluorescent microscopy (Pagenstecher, A., et al., Am. J. Pathol. 157 (2000) 197-210).
  • Cryostat sections (5mm thick) were fixed in paraformaldehyde 1% in 0.07M phosphate buffered saline (PBS) pH 7.0 for 5 min or in acetone for 10 min at room temperature and then incubated with the primary antibody.
  • Antibodies raised against mouse PECAM rat monoclonal, PharMingen, San Diego, California; diluted 1/20
  • mouse MAC-3 mouse MAC-3
  • murine fibrinogen/fibrin (goat polyclonal, Nordic Immunological, Tilburg, The Netherlands; dilutedl/400) were incubated for 1 hr at room temperature.
  • the sections were washed in PBS (3X 10 min) and appropriate secondary antibody conjugated to peroxydase (HRP) were added: rabbit anti- goat IgG (Dako, Glostrup, Denmark, diluted 1/100) and rabbit anti- rat IgG ( Sigma -Aldrich; diluted 1/40) were applied for 30 min.
  • HRP peroxydase
  • AEC+ Dako, 3-amino-9-ethylcarbazole
  • WT mice were IP injected either with Compound I or Batimastat.
  • the daily injections started either the same day as CNV induction (DO), or at D5.
  • choroidal neovascularization was induced in mice by multiple argon laser burns and animals were sacrificed at day 3, 5, 10, 14, 20, 40.
  • the posterior segments (RPE-choroid complex vithout neural retina) were cut out and immediately frozen in liquid nitrogen.
  • rTth reverse transcriptase RNA PCR kit (Applied Biosystems, Foster City, California) and two pairs of primers (Eurogentec, vide, Belgium; oligonucleotides sequences, number of cycles and expected PCR product size are shown in Table 1).
  • the frozen murine tissues w «re first pulverized using a Dismembrator (B.
  • RNA-DNA heteroduplexes were extracted with the RNeasy extraction kit (Quiagen, Paris, France) according to the manufacturer's protocol. 28S rRNA were amplified vith an aliquot of 10 ng of total RNA using the GeneAmp Thermostable mRNA. Reverse transcription was performed at 70°C for 15 min followed by 2 min incubation at 95°C for denaturation of RNA-DNA heteroduplexes.
  • Amplification started by 15 sec at 94°C, 20 sec at 60°C and 10 sec at 72°C RT-PCR products were resolved on 2% agarose gels and analyzed using a Fluor-S Multilmager (BioRad) after staining with ethidium bromide (FMC BioProducts).
  • Neovascularization was estimated at day 14 after induction by immunostaining with anti- PECAM antibodies. This demonstrated a strong inhibition of neovascular progression in MMP2,9 KO mice (Figure ID) compared to single gene deficient ( Figure 1B-C) or WT ( Figure 1A) animals. This confirmed fluorescein angiography data performed before sacrifice ( Figure 1 F) showing a significant reduction (p ⁇ 0.001) in the number of leaking spots (corresponding to newly formed immature microvessels with leakage of fluorescein). In sites developing a neovascular membrane, choroidal pathological reaction was quantified by measuring, on serial sections, the maximal height of the lesion above the choroidal layer observed in neighbouring intact zones.
  • Ocular posterior segment proteins prepared from WT, MMP-9 KO, MMP-2 KO and MMP-2,9 KO mice were analyzed by gelatin zymography (Figure 2A). As expected, no MMP-2 and MMP-9 activity was detected in MMP-2 KO, MMP-9 KO, and (not shown) MMP-2,9 KO mice, respectively. WT mice expressed pro-MMP-2 and -MMP-9 as well as processed MMP-2. The zymograms suggest a compensatory increase in the ocular expression of MMP9 in the MMP-2 knockout mice. However, despite that compensation, MMP-2KO mice were significantly protected from the development of severe CNV. Both MMP-2 and MMP-9 were increasingly processed during the early stages of CNV formation, with the appearance of active forms of MMP-2 ( Figure 2B).
  • MMP9 expression was upregulated during early phases of CNV formation, while MMP2 (constitutively expressed) showed no significant modulation ( Figure 3A-B).
  • the presence of active forms of MMP-2 could theoretically correspond either to a decrease of TIMP expression, or to an increase in the expression of activators (MT1-MMP).
  • RT-PCR analysis demonstrated a constant expression of TIMP-2, but a significant upregulation of MT-l-MMP mRNA ( Figure 3C- D). Effect of MMP deficiency on fibrinolytic activity.
  • Plasminogen activators/plasmin play an important role in choroidal neovascularization (Lambert, V., et al., Am. J. Pathol. 161 (2002) 1247-1253) and it has been previously demonstrated that, at least some MMPs might modulate fibrinolysis through a plasminogen-dependent or independent mechanism (Lijnen, H.R., Biochemistry (Mosc) 67 (2002) 92-98; Pepper, M.S., Arterioscler. Thromb. Vase. Biol. 21 (2001) 1104-1117; Hiraoka, N., et al., Cell 95 (1998) 365-377.
  • Inhibitors were tested in a modified fluorescence-assay as described by Stack, M.S., and Gray, R.D., J. Biol. Chem. 264 (1989) 4277-4281.
  • Human MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14 are commercially available (e.g. Calbiochem).
  • the pro-enzymes were activated with 1 mM APMA (incubation for 30 min at 37°C) immediately before testing.
  • Activated enzyme is diluted to 100 ng/ml in incubation buffer (50 mM Tris, 100 mM NaCl, lOmM CaCl2, pH 7.6).
  • the compounds were dissolved in 100% DMSO.
  • DNP-substrate (Bachem M1855, 255 ⁇ M) was dissolved in incubation buffer.
  • the test tube contains 970 ⁇ l incubation buffer, lO ⁇ l inhibitor solution and lO ⁇ l enzyme solution. The reaction was started by adding the lO ⁇ l substrate solution.
  • IC 50 's are defined as the concentration of inhibitor that gives a signal that is 50% of the positive enzyme control.

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Abstract

L'invention concerne l'utilisation d'un composé de trioxopyrimidine présentant une activité inhibitrice dirigée contre les MMP-1, MMP-2, MMP-3, MMP-9 et MMP-14 définie comme : a) une valeur IC50 inférieure à 5 µM pour chaque MMP-2, MMP-9 et MMP-14 ; b) un rapport supérieur à 100 pour les valeurs IC50 de MMP-1:MMP-2, MMP-1: MMP-9, MMP-1:MMP-14 et c) un rapport supérieur à 10 pour les valeurs IC50 de MMP-3:MMP-2, MMP-3: MMP-9 MMP-3:MMP-14, pour la fabrication d'un médicament destiné au traitement ou à la prévention de l'angiogenèse pathologique oculaire.
PCT/EP2004/003206 2003-03-27 2004-03-26 Utilisation d'une trioxopyrimidine pour le traitement et la prevention de l'angiogenese pathologique oculaire WO2004084903A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023465A1 (fr) * 1995-12-23 1997-07-03 Boehringer Mannheim Gmbh Nouveaux derives d'acide barbiturique, leurs procedes de production et substances pharmaceutiques contenant lesdits derives
WO2001012611A1 (fr) * 1999-08-12 2001-02-22 Pfizer Products Inc. Inhibiteurs de pyrimidine-2,4,6-trione metalloproteinase
WO2001025217A1 (fr) * 1999-10-01 2001-04-12 F. Hoffmann-La Roche Ag Nouveaux derives de pyrimidine-2,4,6-trione, leurs procedes de production et les agents pharmaceutiques contenant ces composes
WO2002034753A2 (fr) * 2000-10-26 2002-05-02 Pfizer Products Inc. Inhibiteurs de metalloproteinase spiro-pyrimidine-2,4,6-trione
WO2002034726A2 (fr) * 2000-10-26 2002-05-02 Pfizer Products Inc. Inhibiteurs de la pyrimidine-2,4,6-trione metalloproteinase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023465A1 (fr) * 1995-12-23 1997-07-03 Boehringer Mannheim Gmbh Nouveaux derives d'acide barbiturique, leurs procedes de production et substances pharmaceutiques contenant lesdits derives
WO2001012611A1 (fr) * 1999-08-12 2001-02-22 Pfizer Products Inc. Inhibiteurs de pyrimidine-2,4,6-trione metalloproteinase
WO2001025217A1 (fr) * 1999-10-01 2001-04-12 F. Hoffmann-La Roche Ag Nouveaux derives de pyrimidine-2,4,6-trione, leurs procedes de production et les agents pharmaceutiques contenant ces composes
WO2002034753A2 (fr) * 2000-10-26 2002-05-02 Pfizer Products Inc. Inhibiteurs de metalloproteinase spiro-pyrimidine-2,4,6-trione
WO2002034726A2 (fr) * 2000-10-26 2002-05-02 Pfizer Products Inc. Inhibiteurs de la pyrimidine-2,4,6-trione metalloproteinase

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