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WO1996016054A1 - Cycloalcenyl-n-hydroxyurees - Google Patents

Cycloalcenyl-n-hydroxyurees Download PDF

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Publication number
WO1996016054A1
WO1996016054A1 PCT/IB1995/000821 IB9500821W WO9616054A1 WO 1996016054 A1 WO1996016054 A1 WO 1996016054A1 IB 9500821 W IB9500821 W IB 9500821W WO 9616054 A1 WO9616054 A1 WO 9616054A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
haloalkyl
optionally substituted
halo
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB1995/000821
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English (en)
Inventor
Akiyoshi Kawai
Rodney W. Stevens
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Corp Belgium
Pfizer Japan Inc
Pfizer Corp SRL
Original Assignee
Pfizer Corp Belgium
Pfizer Pharmaceuticals KK
Pfizer Corp SRL
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 Corp Belgium, Pfizer Pharmaceuticals KK, Pfizer Corp SRL filed Critical Pfizer Corp Belgium
Publication of WO1996016054A1 publication Critical patent/WO1996016054A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/64—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups singly-bound to oxygen atoms

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.
  • the present invention provides novel N-hydroxyurea compounds of the following chemical formula (I) : and the pharmaceutically acceptable salts thereof, wherein
  • A is selected from the group consisting of
  • N-alkanoyl-N-alkylamino in which the alkanoyl contains from two to eight carbon atoms and the alkyl contains from one to six carbon atoms,
  • phenyl optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1 - 6 haloalkoxy, cyano or halo,
  • phenoxy optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano or halo,
  • phenylthio optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy,
  • pyridyl optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy,
  • pyridyloxy optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy,
  • phenyl optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 haloalkoxy, cyano or halo,
  • phenoxy optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano or halo,
  • phenylthio optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy,
  • pyridyl optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy,
  • pyridyloxy optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy,
  • phenyl optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1 - 6 haloalkoxy, cyano or halo,
  • phenylthio optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy,
  • pyridyl optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy,
  • pyridyloxy optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy,
  • B is selected from the group consisting of
  • X is selected from the group consisting of
  • Z 2 is O, S, SO, or NR 2 ;
  • Z 3 is O, S or NR 1 ;
  • R 1 , R 2 and R 3 are each H or C 1-6 alkyl;
  • m and n are each zero to six;
  • j and q are each one to six; and the dotted line in group (h) represents an optional additional bond; with the proviso that when Z 1 is O or S, m and n are not zero simultaneously;
  • Y is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkoxyalkyl,
  • Z is selected from hydrogen and C 1-3 alkyl.
  • the compounds of the formula (I) inhibit the 5-lipoxygenase enzyme.
  • 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, and cardiovascular diseases.
  • This invention also embraces pharmaceutical compositions which comprise a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a preferred group of compounds of the invention consists of the compounds of the formula (I), wherein A is phenyl or fluorophenyl; B is phenylene or thienylene; p is one; X is C 1-4 alkylene; Y is hydrogen; and Z is hydrogen.
  • Another preferred group of compounds of the invention consists of the compounds of the formula (I), wherein A is phenyl or fluorophenyl; B is phenylene or thienylene; p is one; Y and Z are each hydrogen; and X is -(CHR 1 ) m -Z 1 -(CHR 2 ) n -wherein Z 1 is O, and either R 1 is H, m is one and n is zero, or R 2 is H, m is zero and n is one.
  • Particularly preferred individual compounds of the invention are:
  • 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 compounds of formula (I) may be prepared by a number of synthetic methods.
  • compounds of the formula (I) are prepared according to the reaction steps outlined in scheme 1 :
  • the hydroxylamine (II) is treated with a suitable trialkylsilyl isocyanate or lower alkyl isocyanate of the formula ZNCO, 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 (II) with gaseous hydrogen chloride in a 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 ZNH 2 .
  • the acid addition salt of (II) may be reacted with an equimolar amount of an alkali metal cyanate, such as potassium cyanate, in water.
  • 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 formula (I) can be directly prepared by the cross coupling reaction of the corresponding aryl halides or triflates with the stannylcycloalkenylhydroxyureas or vice versa in the presence of suitable catalyst such as Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 or the like (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986).
  • suitable catalyst such as Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 or the like (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986).
  • Pd(PPh 3 ) 4 PdCl 2 (PPh 3 ) 2 or the like
  • 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.
  • hydroxylamine (II) may be prepared by standard synthetic procedures from corresponding carbonyl compound, i.e. ketone or alcohol compound.
  • suitable carbonyl compound is converted to its oxime and then reduced to the requisite hydroxylamine (II) with a suitable reducing agent (for example, see R. F. Borch et al, J. Am. Chem. Soc., 93, 2897, 1971).
  • Reducing agents of choice are, but not limited to, sodium cyanoborohydride and borane-complexes such as borane-pyridine, borane-triethylamine and borane-dimethylsulfide, however triethylsilane in trifluoroacetic acid may also be employed.
  • the suitable carbonyl compound i.e. cyclobutenones, cyclopentenones, or cyclohexenones
  • the cyclobutenones 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 for the corresponding aldehydes and methyl vinyl ketone by the Stetter reaction (for example, see L. Novak et al., Liebigs Ann. Chem., 509, 1986).
  • the cyclopentenones and the cyclohexenones can be prepared by the addition of the corresponding aryl lithium or aryl magnesium to 3-alkoxy-2-cyclopentenone and 3-alkoxy-2-cyclohexenone, respectively.
  • the cycloalkenones can be prepared by the cross coupling reaction of the corresponding aryl halides or triflates with the cycloalkenylstannanes or vice versa in the presence of suitable catalyst such as Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2 (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986).
  • suitable catalyst such as Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2 (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986).
  • the aforementioned hydroxylamine (II) can easily be prepared by treating the corresponding alcohol 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 (see Japanese Patent No. 1045344).
  • the requisite alcohol is readily prepared by the 1,2-reduction of the corresponding cycloalkenone using a suitable reducing agent such as sodium borohydride, or sodium borohydride-cerium trichloride.
  • the N,O-protected intermediate can be prepared by the cross coupling reaction of the corresponding aryl halides or triflates with the N,O-protected stannylcycloalkenyl-hydroxylamines or vice versa in the presence of suitable catalyst such as Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2 (for example, J. K. Stille, Angew. Chem. Int. Ed.
  • suitable catalyst such as Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2
  • compound of formula (IV) is prepared from the corresponding alcohol and a bis-carboxyhydroxylamine, preferably N,O-bis(phenoxycarbonyl)-hydroxylamine, and subsequently converted to (I) by treatment with ammonia, ammonium hydroxide, or an amine of structure Z ⁇ 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 ZNH 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.
  • the compounds of formula (IV) can be prepared by the cross coupling reaction of the corresponding aryl halides or triflates with the N,O-protected stannylcycloalkenylhydroxylamines or vice versa in the presence of suitable catalyst such as Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 or the like (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986).
  • suitable catalyst such as Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 or the like (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986).
  • Pd(PPh 3 ) 4 PdCl 2 (PPh 3 ) 2 or the like
  • 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 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, in the case of a non-toxic cation, an appropriate metal hydroxide or alkoxide or amine in either aqueous solution or a suitable organic solvent.
  • an appropriate mineral or organic acid in either aqueous solution or a suitable organic solvent can be used.
  • the salt may then be obtained by purification or by evaporation of the solvent.
  • the compounds of the present invention inhibit the activity of lipoxygenase enzyme.
  • HWB Human Whole Blood
  • 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.
  • 3-Tributylstannyl-2-cyclopenten-1-ol was prepared from 3-ethoxy-2-cyclopentenone according to the literature (E. Laborde et al, Tetrahedron Letters, 31, 1837
  • the title compound is useful to synthesize the compounds of the following

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne certains composés cycloalcényl-N-hydroxyurée de formule (I) ayant la capacité d'inhiber l'enzyme 5-lipoxygénase, ainsi que leur sels pharmaceutiquement acceptables. Dans la formule (I), A est choisi parmi naphtyle, biphényle, fluorényle, furyle, benzo[b]furyle, thiényle, benzo[b]thiényle, pyridyle, quinolyle, indolyle et phényle éventuellement substitués; B est choisi parmi furylène, thiénylène, pyridylène, thiazolylène, oxazolylène, benzoxazolylène, benzo-thiénylène et phénylène éventuellement substitués; p vaut 0, 1 ou 2; X représente alkylène C1-4, alcénylène C2-6, alcynylène ou similaire; Y est choisi parmi hydrogène, alkyle C1-6, haloalkyle C1-6, alcoxy C2-6, alcoxyalkyle C2-6, alcoxyalcoxy C2-6, alkylthio C1-6, OH, halo, cyano et amino; et Z est choisi parmi H et alkyle C1-3. Ces composés sont utiles dans le traitement ou l'atténuation de maladies inflammatoires, allergiques et cardio-vasculaires chez les mammifères et en tant que principe actif dans des compositions pharmaceutiques destinées à traiter ces états.
PCT/IB1995/000821 1994-11-18 1995-10-02 Cycloalcenyl-n-hydroxyurees Ceased WO1996016054A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9401955 1994-11-18
JPPCT/JP94/01955 1994-11-18

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WO1996016054A1 true WO1996016054A1 (fr) 1996-05-30

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C

Citations (5)

* 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
JPH05170725A (ja) * 1991-10-25 1993-07-09 Pfizer Pharmaceut Co Ltd 新規なシクロアルキル尿素誘導体および組成物
JPH06293726A (ja) * 1993-04-12 1994-10-21 Pfizer Pharmaceut Co Ltd フェノキシフェニルシクロブテニルヒドロキシ尿素
WO1995003292A1 (fr) * 1993-07-20 1995-02-02 Pfizer Inc. Heteroaryl cycloalcenyl hydroxiurees
WO1995005360A1 (fr) * 1993-08-19 1995-02-23 Pfizer Inc. Phenoxyphenyle cyclopentenyle hydroxyurees

Patent Citations (5)

* 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
JPH05170725A (ja) * 1991-10-25 1993-07-09 Pfizer Pharmaceut Co Ltd 新規なシクロアルキル尿素誘導体および組成物
JPH06293726A (ja) * 1993-04-12 1994-10-21 Pfizer Pharmaceut Co Ltd フェノキシフェニルシクロブテニルヒドロキシ尿素
WO1995003292A1 (fr) * 1993-07-20 1995-02-02 Pfizer Inc. Heteroaryl cycloalcenyl hydroxiurees
WO1995005360A1 (fr) * 1993-08-19 1995-02-23 Pfizer Inc. Phenoxyphenyle cyclopentenyle hydroxyurees

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 9332, Derwent World Patents Index; AN 93-252705 *
DATABASE WPI Week 9502, Derwent World Patents Index; AN 95-009607 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C

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