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WO1995017379A1 - Hydroxyurees de cycloalcenyle phenylthiophenyle utilisees comme inhibiteurs de la lypoxygenase - Google Patents

Hydroxyurees de cycloalcenyle phenylthiophenyle utilisees comme inhibiteurs de la lypoxygenase Download PDF

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Publication number
WO1995017379A1
WO1995017379A1 PCT/JP1994/002032 JP9402032W WO9517379A1 WO 1995017379 A1 WO1995017379 A1 WO 1995017379A1 JP 9402032 W JP9402032 W JP 9402032W WO 9517379 A1 WO9517379 A1 WO 9517379A1
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WO
WIPO (PCT)
Prior art keywords
fluorophenylthio
phenyl
compounds
hydroxyurea
hydrogen
Prior art date
Application number
PCT/JP1994/002032
Other languages
English (en)
Inventor
Akiyoshi Kawai
Rodney W. Stevens
Original Assignee
Pfizer Inc.
Pfizer Pharmaceuticals Inc.
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 Pfizer Inc., Pfizer Pharmaceuticals Inc. filed Critical Pfizer Inc.
Priority to AU11207/95A priority Critical patent/AU1120795A/en
Priority to EP95902296A priority patent/EP0736006A1/fr
Publication of WO1995017379A1 publication Critical patent/WO1995017379A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/47—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated

Definitions

  • This invention relates to novel N-hydroxyurea compounds.
  • the compounds of the present invention inhibit the action of lipoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals.
  • This invention also relates to pharmaceutical compositions comprising such compounds.
  • Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes.
  • the first step of the arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase A2. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further metabolized to the leukotrienes.
  • Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel diseases. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions. Recently several review articles on lipoxygenase inhibitors have been reported.
  • a and B independently, are hydrogen, halogen, C,-C 4 alkyl, C r C 4 alkoxy, C C 4 halo- substituted alkyl or C j -C 4 halo-substituted alkoxy;
  • R 1 and R 2 independently, are hydrogen or C ⁇ -C alkyl; X is S, SO or SO 2 ; and Z is methylene or ethylene.
  • the compounds of the formula I inhibit the 5-lipoxygenase enzyme. Therefore the compounds are useful for treating a medical condition for which a 5-lipoxygenase inhibitor is needed, in a mammalian subject, e.g. , a human subject. The compounds are especially useful for treating allergic and inflammatory conditions.
  • This invention also embraces pharmaceutical compositions which comprise a compound of the formula I and a pharmaceutically acceptable carrier.
  • a preferred group of compounds of the invention consists of the compounds of the formula I , wherein R 1 and R 2 are each hydrogen and X is S. Within this preferred group, particularly preferred compounds are those wherein R 1 and R 2 are each hydrogen, X is S, A is 4-fluoro, B is hydrogen and Z is ethylene.
  • Particularly preferred individual compounds of the invention are: N-[3-[3-(4-Fluorophenylthio)phenyl]-2-cyclopenten-l-yl]-N-hydroxyurea,
  • halo is used to mean radicals derived from the elements fluorine, chlorine and bromine.
  • salts refers to salt incorporating non-toxic cations, including, but not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, magnesium, and the like, as well as non- toxic ammonium, substituted ammonium and quaternary ammonium cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methyl- ammonium, diethylammonium, trimethylammonium and triethylammonium.
  • the hydroxylamine II is treated with a suitable trialkylsilyl isocyanate or lower alkyl isocyanate of the formula R 2 NCO, in a reaction-inert solvent, usually at ambient through to reflux temperature.
  • a reaction-inert solvent usually at ambient through to reflux temperature.
  • the reaction temperature is from 20 to 100 °C.
  • Suitable solvents which do not react with reactants and/or products are, for example, tetrahydrofuran, dioxane, methylene chloride or benzene.
  • An alternative procedure employs treatment of the hydroxylamine II with gaseous hydrogen chloride in reaction-inert solvent such as benzene or toluene and then subsequent treatment with phosgene.
  • Reaction temperatures are usually in the range of ambient temperature through to boiling point of solvent, preferably 25 to 80 °C.
  • the intermediate carbamoyl chloride is not isolated but subjected to (i.e. in situ) reaction with aqueous ammonia or amine R 2 NH 2 .
  • the acid addition salt of the hydroxylamine II may be reacted with an equimolar amount of alkali metal cyanate, such as potassium cyanate, in water.
  • alkali metal cyanate such as potassium cyanate
  • hydroxylamine II may be prepared by standard synthetic procedures from corresponding cycloalkenone of the formula III or cycloalkenol of the formula IV.
  • suitable cycloalkenone is converted to its oxime and then reduced to the requisite hydroxylamine II with a suitable reducing agent (for example, see R.
  • Reducing agents of choice are, but not limited to, sodium cyanoborohydride and boron-complexes such as borane- pyridine, borane-triethylamine and borane-dimethylsulfide, however triethylsilane in trifluoroacetic acid may also be employed.
  • the suitable carbonyl compound m, (i.e. cyclobutenones or cyclopentenones), - can be prepared by a number of different methods (see WO 92/9566).
  • the cyclo- butenones may be prepared by the [2+2] cycloaddition of the corresponding ethylenes and dichloroketene followed by reductive dechlorination (for example, see R. L. Danheiser et al. , Tetrahedron Lett., 28, 3299, 1987).
  • the cyclopentenones may be prepared by the intramolecular aldol cyclization of 1,4-diketones, readily accessible from the corresponding aldehydes and methyl vinyl ketone by the Stetter reaction (for example, see L. Novak et al. , Liebigs Annalen Chemie, 509, 1986).
  • the cycloalkenones UI can be prepared by the cross coupling reaction of, for example, the corresponding aryl halides or triflates with the cycloalkenylstannanes or vice versa in the presence of suitable catalyst such as Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 and the like (for example, see J.K. Stille: Ange . Chem. Int. Ed. Engl., 25, 508, 1986).
  • suitable catalyst such as Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 and the like (for example, see J.K. Stille: Ange . Chem. Int. Ed. Engl., 25, 508, 1986).
  • the aforementioned hydroxylamine II can easily be prepared by treating the corresponding cycloalkenol IV with N, O-bis(tert-butyloxycarbonyl)- hydroxylamine under Mitsunobu-type reaction conditions followed by acid catalyzed hydrolysis (for example, employing trifluoroacetic acid) of the N, O-protected intermediate product.
  • the requisite cycloalkenol IV is readily prepared by the 1,2- reduction of the corresponding cycloalkenone III using a suitable reducing agent such as sodium borohydride or sodium borohydride-cerium trichloride.
  • compound of formula V is prepared from the corresponding alcohol IV and a bis-carboxyhydroxylamine, preferably N, Obis(phenoxycarbonyl)- hydroxylamine, and subsequently converted to formula I by treatment with ammonia, ammonium hydroxide, or an amine of structure R 2 ⁇ H 2 (A. O. Stewart and D. W. Brooks. , J. Org. Chem., 57, 5020, 1992).
  • Suitable reaction solvents for reaction with ammonia, ammonium hydroxide or the amine of formula R 2 NH 2 are, for example, water, methanol, ethanol, tetrahydrofuran, benzene and the like, though reaction may be run in the absence of co-solvent, that is, in requisite amine alone.
  • Reaction temperatures are typically in the range of ambient temperature through to boiling point of solvent, preferably 25 to 80 °C.
  • the product of formula I thus obtained is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.
  • the compounds of this invention can exist in stereoisomeric forms by virtue of the presence of one or more chiral centers.
  • the present invention contemplate all such stereoisomers, including enantiomers, diastereomers, and mixtures.
  • the individual isomers of compounds of the formula of this invention can be prepared by a number of methods known to those skilled in the art. For instance, they can be prepared by derivatization of a compound of formula I with a chiral auxiliary followed by separation of the resulting diastereomeric mixture and removal of the auxiliary group to provide the desired isomer, or by separation employing a chiral stationary phase.
  • the pharmaceutically acceptable salts of the novel compounds of the present invention are readily prepared by contacting said compounds with a stoichiometric amount of a non-toxic cation, that is, an appropriate metal hydroxide or alkoxide or amine in either aqueous solution or a suitable organic solvent.
  • a non-toxic cation that is, an appropriate metal hydroxide or alkoxide or amine in either aqueous solution or a suitable organic solvent.
  • the salt may then be obtained by precipitation or by evaporation of the solvent.
  • the compounds of the present invention inhibit the activity of lipoxygenase enzyme. This inhibition can be demonstrated in vitro by an assay using heparinized Human Whole Blood (HWB) cells, according to the method described in British Journal of Pharmacology: 99, 1 13-118 (1990), which determines the effect of said compounds on the metabolism of arachidonic acid.
  • HWB heparinized Human Whole Blood
  • the compounds of examples 1 to 7 were tested in the aforementioned assay and they were shown to possess the efficacy of inhibiting lipoxygenase activity. In this test, the compounds of Examples 1 to 7 show IC o values of 0.05 to 5 ⁇ M in HWB assay, with respect to lipoxygenase activity.
  • the in vivo activity after oral administration of compounds of the invention to ICR mice (male) can be determined using PAF lethality assay in a similar manner as described by J. M. Young et al. ( J. M. Young, P. J. Maloney, S. N. Jubb, and J. S. Clark, Prostaglandins, 30, 545(1985). See also: M. Criscuoli and A. Subissi, Br. J. Pharmac , 90, 203(1987); H. Tsunoda, S. Abe, Y. Sa uma, S. Katayama, and K. Katayama, Prostaglandins Leukotrienes and Essential Fatty Acids, 39, 291(1990)).
  • the compounds of Examples 1 to 7 indicate ED J0 values in the range of 1 to
  • the compounds of the present invention to inhibit lipoxygenase enzyme makes them useful for controlling the symptoms induced by the endogenous metabolites arising from arachidonic acid in a mammalian subject.
  • the compounds are therefore valuable in the prevention and treatment of such disease states in which the accumulation of arachidonic acid metabolites are the causative factor; e.g. allergic bronchial asthma, skin disorders, rheumatoid arthritis and osteoarthritis.
  • the compounds of the present invention and their pharmaceutically acceptable salts are of particular use in the treatment or alleviation of inflammatory diseases in a human subject.
  • the compounds of the formula I of this invention can be administered to a human subject either alone, or preferably in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice.
  • This composition can consist of about 0. 1 to 90% , preferably about 10 to 60% , of the compound of formula I or the salt in liquid or solid form of the unit use.
  • the compounds can be administered to human subjects by various conventional routes of administration including oral or parenteral.
  • the dose range will be from about 0. 1 to 20 mg/kg of body weight of the subject to be treated per day, preferably from about 0.5 to 15 mg/kg of body weight per day, in single or divided doses.
  • parenteral administration is desired, then an effective dose will be from about 0.05 to 10 mg/kg of body weight of the human subject to be treated per day. In some instances it may be necessary to use dosages outside these limits, since the dosages will necessarily vary according to the age, weight and response of the individual patient as well as the severity of the patient's symptoms and the potency of the particular compound being administered.
  • the compounds of the invention and their pharmaceutically acceptable salts can be administered, for example, in the form of tablets, powders, lozenges, syrups or capsules or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and corn starch. Further lubricating agents such as magnesium stearate are commonly added.
  • useful diluents are lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifing and suspending agents. If desired, certain sweetning and/or flavoring agents can be added.
  • sterile solutions of the active ingredient are usually prepared and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solute should be controlled to make the preparation isotonic.
  • the title dextrorotatory enantiomer was obtained by separation on a chiral stationary phase of the racemate N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-l- yl]-N-hydroxyurea.
  • Example 6 (- -/V-r3-r3-(4-Fluorophenylthio)phenyl1-2-cyclopenten-l-yl1-N-hydroxyurea
  • the title levorotatory enantiomer was obtained by separation on a chiral stationary phase of the racemate N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-l- yl]-/V-hydroxyurea.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveaux composés hydroxyuréiques de cycloalcényle phénylthiophényle capables d'inhiber la 5-lipoxygénase, et répondant à la formule (I), et sels pharmaceutiquement acceptables desdits dérivés. Dans ladite formule, A et B sont indépendamment hydrogène, halogène, alkyle C1-C4, alcoxy C1-C4, alkyle C1-C4 substitué par halo ou alcoxy C1-C4 substitué par halo, R1 et R2 sont indépendamment hydrogène ou alkyle C1-C3, X est S, SO ou SO2 et Z est méthylène ou éthylène. Ces composés sont utiles pour traiter ou soulager les maladies inflammatoires, les allergies et les maladies cardio-vasculaires chez les mammifères et en tant que principe actif dans des compositions pharmaceutiques destinées à traiter lesdits états pathologiques.
PCT/JP1994/002032 1993-12-22 1994-12-02 Hydroxyurees de cycloalcenyle phenylthiophenyle utilisees comme inhibiteurs de la lypoxygenase WO1995017379A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU11207/95A AU1120795A (en) 1993-12-22 1994-12-02 Phenylthiophenyl cycloalkenyl hydroxyureas as lipoxygenase inhibitors
EP95902296A EP0736006A1 (fr) 1993-12-22 1994-12-02 Hydroxyurees de cycloalcenyle phenylthiophenyle utilisees comme inhibiteurs de la lypoxygenase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP34561893 1993-12-22
JP5/345618 1993-12-22

Publications (1)

Publication Number Publication Date
WO1995017379A1 true WO1995017379A1 (fr) 1995-06-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/002032 WO1995017379A1 (fr) 1993-12-22 1994-12-02 Hydroxyurees de cycloalcenyle phenylthiophenyle utilisees comme inhibiteurs de la lypoxygenase

Country Status (9)

Country Link
EP (1) EP0736006A1 (fr)
JP (1) JP2756732B2 (fr)
AU (1) AU1120795A (fr)
CA (1) CA2178833A1 (fr)
CO (1) CO4230016A1 (fr)
FI (1) FI946007L (fr)
IL (1) IL111994A0 (fr)
PE (1) PE36395A1 (fr)
WO (1) WO1995017379A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009566A1 (fr) * 1990-11-27 1992-06-11 Pfizer Inc. Nouveaux derives d'acide hydroxamique et de n-hydroxyuree et leur emploi
EP0510948A1 (fr) * 1991-04-23 1992-10-28 Eli Lilly And Company N-Hydroxy-urées comme inhibiteurs de 5-lipoxygénase
WO1993021149A1 (fr) * 1992-04-17 1993-10-28 Pfizer Inc. Derives d'hydroxy-urees cycloalkyliques a substitution phenylique inhibant le lipoxygenase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009566A1 (fr) * 1990-11-27 1992-06-11 Pfizer Inc. Nouveaux derives d'acide hydroxamique et de n-hydroxyuree et leur emploi
EP0510948A1 (fr) * 1991-04-23 1992-10-28 Eli Lilly And Company N-Hydroxy-urées comme inhibiteurs de 5-lipoxygénase
WO1993021149A1 (fr) * 1992-04-17 1993-10-28 Pfizer Inc. Derives d'hydroxy-urees cycloalkyliques a substitution phenylique inhibant le lipoxygenase

Also Published As

Publication number Publication date
JP2756732B2 (ja) 1998-05-25
CO4230016A1 (es) 1995-10-19
JPH09503226A (ja) 1997-03-31
AU1120795A (en) 1995-07-10
PE36395A1 (es) 1995-11-07
FI946007L (fi) 1995-06-23
FI946007A0 (fi) 1994-12-21
CA2178833A1 (fr) 1995-06-29
EP0736006A1 (fr) 1996-10-09
IL111994A0 (en) 1995-03-15

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