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WO1998058645A1 - (s)-(-)-n-[3- [5-[(4-fluorophenyl)methyl] -2-thienyl]-1-methyl -2-propynyl]-n-hydroxyuree - Google Patents

(s)-(-)-n-[3- [5-[(4-fluorophenyl)methyl] -2-thienyl]-1-methyl -2-propynyl]-n-hydroxyuree Download PDF

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Publication number
WO1998058645A1
WO1998058645A1 PCT/US1998/012847 US9812847W WO9858645A1 WO 1998058645 A1 WO1998058645 A1 WO 1998058645A1 US 9812847 W US9812847 W US 9812847W WO 9858645 A1 WO9858645 A1 WO 9858645A1
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WIPO (PCT)
Prior art keywords
methyl
leukotrienes
contributed
pharmaceutically acceptable
elevated levels
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PCT/US1998/012847
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English (en)
Inventor
Paul D. Rubin
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Sepracor, Inc.
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Publication date
Application filed by Sepracor, Inc. filed Critical Sepracor, Inc.
Priority to AU81554/98A priority Critical patent/AU8155498A/en
Publication of WO1998058645A1 publication Critical patent/WO1998058645A1/fr

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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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings

Definitions

  • This invention relates to methods of treating asthma and other diseases that arise from 5-lipoxygenase activity.
  • the leukotrienes are a family of highly potent biological substances derived from arachidonic acid and are believed to be involved in mediating a spectrum of human disorders. Considerable evidence suggests that the leukotrienes contribute to the asthmatic response and that they are mediators of other inflammatory diseases. Because several 5-lipoxygenase metabolites are likely to be generated at sites undergoing pathological reactions, and because these metabolites then act in concert to produce the clinical condition, it is thought advantageous to inhibit the formation of the constellation of metabolites to achieve therapeutic benefit. Since 5-lipoxygenase is the first enzymatic step in the conversion of arachidonic acid to leukotrienes, its inhibition decreases the production of all of the pro-inflammatory metabolites.
  • 5-Lipoxygenase inhibitors are therefore useful to treat asthma, allergic rhinitis, rheumatoid arthritis, ulcerative colitis, gout, psoriasis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, inflammatory bowel disease and ischemia induced by myocardial or cerebral injury.
  • S761 has been found to be a potent inhibitor of mammalian 5-lipoxygenase, and, although it also inhibits 12-lipoxygenase and cyclooxygenase, the IC 50 's against these other enzymes are 75 to 300 times higher than against 5-lipoxygenase.
  • S761 was metabolized more than twice as fast as the corresponding R enantiomer, ABT-761. Persons of skill in the art believed that the R enantiomer was superior, and therefore, it was put into clinical trials in the United States in 1994 for asthma, rheumatoid arthritis, psoriasis and ulcerative colitis.
  • ABT-761 the R enantiomer
  • Other adverse events have not been published for ABT-761, but adverse events associated with other 5-lipoxygenase inhibitors, such as zileuton, have included headaches, nausea, fatigue, diarrhea, dyspepsia, chills, dizziness, paresthesia and infections.
  • Patents 5,288,751 and 5,506,261; the preparation of optically pure S761 and its opposite enantiomer(of the R configuration), ABT-761, are described by Brooks et al. [J. Med. Chem. 38. 4768-4775 (1995)]. These disclosures are incorporated herein by reference. S761, which is the subject of the invention, is not presently commercially available.
  • the invention relates to N-hydroxyurea compounds and their use as 5- lipoxygenase inhibitors, and in particular to (S)-(-)-N-[3-[5-[(4-fluorophenyl)-methyl]-2- thienyl]-l-methyl-2-propynyl]-N-hydroxyurea, CAS registry number 154355-79-0. It has now been discovered that the optically pure (-) isomer S761 is an effective agent for treating asthma, rheumatoid arthritis, ulcerative colitis, allergic rhinitis, psoriasis and inflammatory bowel disease and other disorders including those that would benefit from an inhibitory action on 5-lipoxygenase.
  • optically pure (-) S761 provides this effective treatment while substantially reducing the adverse effects associated with ABT-761. These include, but are not limited to, hepatotoxicity, as well as headache, nausea, fatigue, diarrhea, dyspepsia, chills, dizziness and paresthesia.
  • the compound of interest has the S absolute stereochemistry as shown in formula
  • the present invention encompasses a method of treating a condition caused by or contributed to by elevated levels of leukotrienes, while substantially reducing the concomitant liability of adverse effects associated with (R)-(+)-N-[3-[5-[(4- fluorophenyl)methyl]-2-thienyl]- 1 -methyl-2-propynyl]-N-hydroxyurea (ABT-761 ), which comprises administering a therapeutically effective amount of (S)-(-)-N-[3-[5-[(4- fluorophenyl)methyl]-2-thienyl]-l-methyl-2-propynyl]-N-hydroxyurea (S761), or a pharmaceutically acceptable salt thereof, substantially free of its (+) stereoisomer.
  • the method substantially reduces the concomitant liability of adverse effects associated with the administration of ABT-761 by providing an amount of S761 which is insufficient to cause adverse effects associated with the administration of ABT-761, but sufficient to effectively inhibit 5-lipoxygenase for the purpose of treating conditions caused by or contributed to by elevated levels of leukotrienes.
  • Conditions associated with elevated leukotriene levels in humans may include, but are not limited to, asthma, rheumatoid arthritis, ulcerative colitis, allergic rhinitis, psoriasis, gout, Crohn's disease, rheumatoid arthritis, adult respiratory distress syndrome (ARDS), endotoxin shock, inflammatory bowel disease, and ischemia from myocardial or cerebral injury.
  • ARDS adult respiratory distress syndrome
  • endotoxin shock inflammatory bowel disease
  • ischemia from myocardial or cerebral injury Utilizing the optically pure or substantially optically pure S enantiomer S761 results in enhanced efficacy, diminished adverse effects and, accordingly, an improved therapeutic index.
  • the term "adverse effects” includes, but is not limited to, hepatotoxicity, headache, nausea, fatigue, diarrhea, dyspepsia, chills, dizziness and paresthesia.
  • compositions contain at least 90% by weight of S761 and 10% by weight or less of (+) ABT-761.
  • the term “substantially free of the (+) isomer” means that the composition contains at least 99% by weight of S761 , and 1 % or less of (+) ABT-761.
  • the term “substantially free of its (+) stereoisomer” as used herein means that the composition contains greater than 99% by weight of S761.
  • treating asthma means treating, alleviating or palliating such conditions, and thus providing relief from the symptoms of shortness of breath, bronchoconstriction, mucus hypersecretion and slowed mucociliary clearance.
  • treating rheumatoid arthritis means treating, alleviating or palliating such conditions and thus providing relief from the symptoms of painful or tender joints, swollen joints and loss of mobility.
  • treating ulcerative colitis means treating, alleviating or palliating such conditions and thus providing relief from the symptoms of diarrhea, loose stools, rectal bleeding, abdominal and rectal pain and urgency.
  • treating a condition caused, or contributed to, by elevated levels of leukotrienes means treating, alleviating or palliating such disorders associated with elevated leukotriene levels thus providing relief from the symptoms of the aforementioned conditions.
  • the (-) isomer S761 may be obtained by palladium catalyzed condensation of (S)-
  • the magnitude of a prophylactic or therapeutic dose of S761 in the acute or chronic management of disease will vary with the severity and nature of the condition to be treated and the route of administration.
  • the dose and perhaps the dose frequency will also vary according to the age, body weight and response of the individual patient.
  • the total daily dose range for S761 for the conditions described herein is from about 10 mg to about 2000 mg in single or divided doses.
  • a daily dose range should be about 100 mg to about 400 mg in single or divided doses.
  • the therapy should be initiated at a lower dose, perhaps at about 80 mg, and increased up to about 400 mg or higher depending on the patient's global response.
  • Any suitable route of administration may be employed for providing the patient with an effective dosage of S761.
  • compositions of the present invention comprise S761 as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
  • compositions of the present invention include , for example, solutions, elixirs, aerosols, dispersions, suspensions, patches, or solid dosage forms, such as tablets, capsules and troches.
  • Carriers such as starches, sugars, and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like are suitable in the case of oral solid preparations (such as powders, capsules, and tablets), and oral solid preparations are preferred over the oral liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the compounds of the present invention may also be administered by controlled release means and delivery devices such as those described in U.S.Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, the disclosures of which are hereby incorporated by reference.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from about 10 mg to about 600 mg of the active ingredient, and each cachet or capsule contains from about 10 mg to about 600 mg of the active ingredient.
  • the tablet, cachet or capsule contains one of three dosages: about 100 mg, about 200 mg or about 400 mg of S761 for oral administration.
  • the relative activity, potency and specificity of optically pure S761 and its enantiomer (ABT-761) and racemate as an inhibitor of 5-lipoxygenase can be determined by a pharmacological study in vitro according to the methods described in Bell et al. [ Pharm. Exp. Ther. 272. 724-731 (19951and J. Pharm. Exp. Ther. 280. 1366-1373 (1997) ].
  • the tests provide an estimate of relative activity, potency and, through a measure of specificity, an estimate of therapeutic index.
  • the following tests, which are closely related to those described by Bell et al. may also be employed to assess specificity and liability to side effects:
  • RBL-1 cell lysate 5-lipoxygenase inhibitor potency Adherent rat basophilic leukemia (RBL-1) cells are harvested by trypsinization, suspended (approx. 3.0 x 10 7 cells/mL) in buffer at pH 6.8 and lysed by sonication. The lysate is centrifuged and the supernatant-containing 5-lipoxygenase activity stored frozen until used.
  • RBL-1 Adherent rat basophilic leukemia
  • Compounds are evaluated for 5-lipoxygenase inhibitory activity in incubations containing 12% RBL-1 supernatant in assay buffer at pH 6.8 using a modification of the method described by Jakschik et al. [Biochem. Biophys. Res. Comm. 95. 103-1 10 (1980)]
  • Compound (the R-(+) enantiomer ABT-761, the S-(-) enantiomer S761, or the corresponding racemate rac761 ) is dissolved in DMSO and preincubated with the enzyme for 20 min. at 37° C before initiating the 5-lipoxygenase reaction by addition of arachidonic acid (AA) and [ 14 C]AA in aqueous NH 4 OH (0.028%).
  • [ 3 H]-5- hydroxyeicosatetraenoic acid is added with the substrate. Reactions are terminated after 5 min. by acidification with HC1 to pH 3.5. Under these conditions, the majority of the initial product of the reaction, 5-HPETE is further converted to 5-HETE. The reducing agent triphenylphosphine (TPP) is added to convert any remaining 5-HPETE to 5-HETE. Eicosanoids are extracted from acidified incubations using acetone and samples are prepared for TLC analysis by addition of 5-HETE and AA to permit visualization of product and substrate on TLC sheets.
  • TPP triphenylphosphine
  • Human platelets are suspended at about 10 9 cells/mL in assay buffer at pH 7.4. The cells are lysed by sonication, centrifuged and the supernatant containing the 12- lipoxygenase activity stored frozen until used. Compounds are evaluated for 12- lipoxygenase inhibitory activity in incubations containing 25% of the platelet supernatant and 2% DMSO in assay buffer. After 20 min. of preincubation at 37° C, reactions are initiated by adding AA, [ 14 C]AA in aqueous NH 4 OH (0.028%) and the internal recovery standard, [ 3 H]-15-HETE. Reactions are terminated after 5 min. by acidification with HC1 to pH 3.5. Mass standards, 15-HETE, AA, and triphenyl phosphine (TPP) are added and the samples extracted with diethyl ether. Samples are processed essentially as described for the 5-lipoxygenase inhibition assay.
  • Soybean and rabbit reticulocyte 15-Hpoxygenase Compounds can be evaluated for inhibitory activity against soybean lipoxygenase, Type I (Sigma Chemical Co., St. Louis, MO), in incubations containing 20 U of enzyme in 10 mM sodium borate, 150 mM NaCl and 0.1% (w/v) gelatin buffer, pH 8.7. After 20 min. of preincubation with test compounds at 37° C, the reaction is initiated as before. Reactions are terminated after 5 min. by acidification with HC1 to pH 3.5 and mass standards, 15-HETE, AA and TPP are added. Samples are processed essentially as described for the 5-lipoxygenase inhibition assay.
  • Rabbit reticulocyte lipoxygenase is partially purified using ammonium sulfate precipitation followed by CM cellulose chromatography to remove hemoglobin [Schewe et al.. Methods Enzymol. 71. 430-441 (1981)].
  • Compounds are evaluated for inhibitory activity against this enzyme preparation using a procedure similar to the one used for the soybean enzyme.
  • the assay buffer contains 0.1 M potassium-phosphate and 0.05% sodium cholate adjusted to pH 7.4.
  • Sheep seminal vesicle microsomal cyclooxygenase Sheep seminal vesicle microsomal cyclooxygenase. Sheep seminal vesicle microsomes are prepared using a modification of the method described by Wallach and Daniels [Biochem. Biophys Acta 231. 445-457 (1971)]. Test agents are combined in incubations with sheep seminal vesicle gland microsomes (2 mg/mL) and [ 14 C]AA in 0.125 M EDTA buffer, pH 8, containing 1 mM reduced glutathione, 0.5 mM hydroquinone, 0.5 mg/mL of BSA and 2% DMSO. Reactions are terminated after 30 min at 37° C by adding methanol followed by centrifugation.
  • the supernatants are mixed with water-glacial acetic acid (98.3:1.7) and aspirated through C 18 Sep-Paks (Millipore) using a vacuum manifold.
  • the columns are sequentially washed with the following mixtures of methanol-water-glacial acetic acid: 33:66: 1,70:30:0.1 and 100:0:0.
  • the major cyclooxygenase product, PGE 2 elutes with the 70% methanol wash. This eluant is collected directly into liquid scintillation vials and the radioactivity in the sample is measured.
  • Rat leukocyte 5-lipoxygenase and cyclooxygenase Rat leukocytes are obtained from the pleural cavity of male Sprague-Dawley rats injected intrapleurally with 200 ⁇ L of a 0.05% (w/v) carrageenan solution. Contaminating erythrocytes are lysed and the cells washed and resuspended at a concentration of 2 x 10 7 cells/mL in Earle's balanced salts, pH 7.0, containing 20 mM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid and 1 mg/mL of BSA.
  • PMNL polymorphonuclear leukocytes
  • Test compounds and DMSO vehicle final concentration, 2%) are preincubated with the cell suspensions for 15 min at 37° C.
  • Cellular arachidonate metabolism is initiated by adding a calcium ionophore, A23187, (final concentration, 4 ⁇ M) and terminated after 10 min by rapid cooling in an ice bath.
  • Samples are divided into two portions. One portion is centrifuged and the supernatant analyzed for PGE 2 by RIA. The other portion is extracted with methanol containing 50 ng of PGB 2 , as an internal recovery standard. The methanolic extracts are centrifuged and aliquots of the supernatants injected onto a reversed phase C I8 column and eluted with acetonitrile (8 M) and triethylamine formate, pH 3.5 (50:50, v ⁇ v) at a flow rate of 1 mL/min. Eluting product peaks are quantitated by UV absorbance (LTB 4 at 280 nm; 5-HETE at 235 nm) and are corrected for PGB 2 recovery. The lower limit of detection is approximately 100 pg of LTB 4 injected.
  • the level of LTB in aliquots of the methanol-plasma extract is analyzed by RIA or by enzyme immunoassay.
  • cyclooxygenase activity is determined by analysis of plasma samples for thromboxane B 2 by enzyme immunoassay.
  • Rat and dog ex vivo LTB 4 biosynthesis S761, ABT-761 or rac761 is suspended in 0.2% methylcellulose and administered p.o. to beagle dogs and male Sprague-Dawley rats. All animals are fasted overnight before dosing but are allowed water ad libitum. Heparinized blood samples are obtained before and at various times after compound administration in the dog study. Groups of rats are dosed with vehicle or S761 and 1 hr and 15 min later, the animals are sacrificed and blood collected by cardiac puncture into heparized syringes. Aliquots of blood from both species are incubated at 37° C with 50 ⁇ M with calcium ionophore, A23187. After 30 min, the blood is placed in an ice bath and analyzed for LTB 4 as described above.
  • Rat peritoneal anaphylaxis model Rats are passively sensitized by i.p. injection of rabbit anti-BSA in PBS, pH 7.1. Three hours later the rats are injected i.p. with 4 mg of BSA in 5mL of PBS containing 30 mM /-cysteine. Test compound or control vehicle is given by gavage p.o. 1 hr before antigen challenge.
  • the rats are sacrificed 15 min after challenge with C0 2 asphyxiation, the peritoneal cavity opened and the fluid contents collected.
  • the cavities are rinsed with 5 mL of cold phosphate buffered saline (PBS) containing 0.1% gelatin, 0.1 % sodium azide, 10 mM tripotassium EDTA and 30 mM /-cysteine.
  • PBS cold phosphate buffered saline
  • the fluids are mixed with 20 mL of ice-cold methanol and then centrifuged at 1000 x g for 15 min. Fluid volumes are measured and the samples stored frozen until assayed.
  • the incorporation of /-cysteine in the assay essentially prevents metabolic conversion of LTD 4 to LTE 4 , so that the products measured are predominantly LTC 4 and LTD 4 .
  • the immunoreactive leukotriene levels in the biological samples are calculated from a LTC 4 standard curve.
  • AA-induced mouse ear edema model S761 or control vehicle is given by gavage p.o. 15 min before the application of an acetone solution of 2.5% AA to both the inner and outer surfaces of one ear of male mice weighing 20 to 30 g.
  • the opposite ears receive a like treatment of acetone vehicle.
  • One hour later the mice are sacrificed with C0 2 and a section removed from the ears with a biopsy punch. These sections are weighed immediately for wet weight determinations.
  • Edema is calculated as the percentage of increase in ear weight of the AA-treated ear compared to the contralateral acetone-treated ear.
  • Rat pleural reverse passive reaction Rats are injected i.v.
  • Hepatic microsomes are prepared from human liver. Tissue is thawed and then homogenized in 0.15 M KCI in a Polytron homogenizer. The homogenate is centrifuged and the pellet is resuspended and homogenized in 0.15 M KCI. Aliquots are frozen and stored at -70° C. Human lymphocytes are aseptically isolated from fresh, heparinized human blood. Blood is diluted with Eagle's minimal essential medium and layered on Ficoll-Paque.
  • lymphocytes are then removed from the aqueous-Ficoll interface and suspended in medium (15Mm HEPES, pH, 7.4).
  • medium 15Mm HEPES, pH, 7.4
  • the cells are then centrifuged, washed once in the HEPES medium, and resuspended.
  • Cytotoxicity is assessed by the conversion of 3-(4,5 dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) to a purple formazan.
  • MTT 3-(4,5 dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide
  • the conversion of MTT to dye is done in multiwell plates. After preparation, hepatic microsomes or lymphocytes are incubated alone or with the test compound in a concentration range from 1 to 400 ⁇ M at 37° C in a humidified incubator. After incubation, the microsomes/cells are washed with 5% albumin in HEPES-buffered medium and resuspended. The microsomes/cells are then incubated at 37° C in a humidified incubator. After the incubation, 125 ⁇ g of MTT is added to each well. The plates are incubated at 37° C and centrifuged. After centrifugation, 100 ⁇ L of is
  • the S761, lactose and cornstarch are blended until uniform and then the magnesium stearate is blended into the resulting powder, which is sieved and filled into suitably sized, two-piece, hard gelatin capsules using conventional machinery.
  • Other doses may be prepared by altering the fill weight and, if necessary, changing the capsule size to suit.
  • the S761 is blended with the lactose until a uniform blend is formed.
  • the smaller quantity of cornstarch is blended with the water to form the resulting corn starch paste. This is then mixed with the uniform blend until a uniform wet mass is formed. The remaining cornstarch is added to the resulting wet mass and mixed until uniform granules are obtained.
  • the granules are then screened through a suitable milling machine, using a 1/4 inch stainless steel screen.
  • the milled granules are dried in a suitable drying oven until the desired moisture content is obtained.
  • the dried granules are then milled through a suitable milling machine, magnesium stearate is blended in, and the resulting mixture is compressed into tablets of the desired shape, thickness, hardness and disintegration. Tablets of other strengths may be prepared by altering the ratio of active ingredient to the excipients or to the final weight of the tablet.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

Procédés d'utilisation de S761 optiquement pure pour le traitement de l'asthme, de la rhinite allergique, du psoriasis et des infections inflammatoires du tube digestif, qui permet parallèlement de réduire considérablement les effets secondaires associés à l'énantiomère R correspondant et au mélange racémique. La S761, qui est un inhibiteur de la 5-lipoxygénase, est par conséquent utile dans le traitement d'autres états pathologiques associés à des taux élevés de leucotriène. Elle possède une structure de formule (I).
PCT/US1998/012847 1997-06-24 1998-06-19 (s)-(-)-n-[3- [5-[(4-fluorophenyl)methyl] -2-thienyl]-1-methyl -2-propynyl]-n-hydroxyuree WO1998058645A1 (fr)

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AU81554/98A AU8155498A (en) 1997-06-24 1998-06-19 (s)-(-)-n-{3- {5-{(4-fluorophenyl)methyl} -2-thienyl}-1-methyl -2-propynyl}-n-hydroxyurea

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US5065297P 1997-06-24 1997-06-24
US60/050,652 1997-06-24

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2051709A2 (fr) * 2006-08-07 2009-04-29 Via Pharmaceuticals, Inc. Phénylalkyl n-hydroxyurées pour combattre la plaque athérosclérotique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5616596A (en) * 1992-11-06 1997-04-01 Abbott Laboratories Substituted arylalkynyl-and heteroarylalkynl-N-hydroxyurea inhibitors of leukotriene biosynthesis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5616596A (en) * 1992-11-06 1997-04-01 Abbott Laboratories Substituted arylalkynyl-and heteroarylalkynl-N-hydroxyurea inhibitors of leukotriene biosynthesis

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2051709A2 (fr) * 2006-08-07 2009-04-29 Via Pharmaceuticals, Inc. Phénylalkyl n-hydroxyurées pour combattre la plaque athérosclérotique
JP2010500347A (ja) * 2006-08-07 2010-01-07 ブイアイエイ・ファーマシューティカルズ・インコーポレーテッド アテローム性動脈硬化症プラークと闘うためのフェニルアルキルｎ−ヒドロキシ尿素
EP2051709A4 (fr) * 2006-08-07 2011-10-19 Via Pharmaceuticals Inc Phénylalkyl n-hydroxyurées pour combattre la plaque athérosclérotique
JP2013121978A (ja) * 2006-08-07 2013-06-20 Tallikut Pharmaceuticals Inc アテローム性動脈硬化症プラークと闘うためのフェニルアルキルｎ−ヒドロキシ尿素

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