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WO1996016054A1 - Cycloalkenyl-n-hydroxyureas - Google Patents

Cycloalkenyl-n-hydroxyureas 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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Prior art keywords
alkyl
haloalkyl
optionally substituted
halo
alkoxy
Prior art date
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PCT/IB1995/000821
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French (fr)
Inventor
Akiyoshi Kawai
Rodney W. Stevens
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Pfizer Pharmaceuticals Inc.
Pfizer Inc.
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Publication of WO1996016054A1 publication Critical patent/WO1996016054A1/en

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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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Abstract

Certain novel cycloalkenyl-N-hydroxyurea compounds having the ability to inhibit the 5-lipoxygenase enzyme and having formula (I), and the pharmaceutically acceptable salts thereof, wherein A is selected from optionally substituted phenyl, naphthyl, biphenyl, fluorenyl, furyl, benzo[b]furyl, thienyl, benzo[b]thienyl, pyridyl, quinolyl, indolyl; B is selected from optionally substituted phenylene, furylene, thienylene, pyridylene, thiazolylene, oxazolylene, benzoxazolylene and benzo-thienylene; p is 0, 1 or 2; X is C1-4 alkylene, C2-6 alkenylene, C2-6 alkenylene or the like; Y is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C2-6 alkoxyalkoxy, C1-6 alkylthio, OH, halo, cyano and amino; and Z is selected from H and C1-3 alkyl. These compounds are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals and as the active ingredient in pharmaceutical compositions for treating such conditions.

Description

CYCLOALKENYL-N-HYDROXYUREAS
Technical Field
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.
Background Art
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.
For a review article on lipoxygenase inhibitors, see H. Masamune and
L.S.Melvin, Sr. , Annual Reports in Medicinal Chemistry: 24 (1989) pp71-80 (Academic). More recently, International Patent Publication No. WO 92/09566 discloses a wide variety of N-hydroxyurea and hydroxamic acid compounds as inhibitors of the lipoxygenase enzyme.
Brief Disclosure of the Invention
The present invention provides novel N-hydroxyurea compounds of the following chemical formula (I) :
Figure imgf000004_0001
and the pharmaceutically acceptable salts thereof, wherein
A is selected from the group consisting of
(a) phenyl, naphthyl, biphenylyl and fluorenyl; optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 hydroxyalkyl,
C1-6 alkoxy,
C1-6 alkoxyalkoxy,
C1-6 alkylthio,
hydroxy,
halo,
cyano,
amino,
C1-6 alkylamino,
C2-6 dialkylamino,
C2-8 alkanoylamino,
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,
C2-8 alkylaminocarbonyl,
C3-7 dialkylaminocarbonyl,
carboxy, C2-8 alkoxycarbonyl,
phenyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1- 6 haloalkoxy, cyano or halo,
phenoxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano or halo,
phenylthio optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo,
pyridyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo, or
pyridyloxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo;
(b) furyl optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
halo,
phenyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1- 6 haloalkoxy, cyano or halo,
phenoxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano or halo,
phenylthio optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo,
pyridyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo, or
pyridyloxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo;
(c) benzo[b]furyl optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 alkoxy,
hydroxy, or
halo; (d) thienyl optionally substituted with
C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, or halo,
phenyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano or halo,
phenoxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo,
phenylthio optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo,
pyridyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo, or
pyridyloxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo;
(e) benzo[b] thienyl, optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 alkoxy,
hydroxy, or
halo;
(f) pyridyl optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 alkoxy,
hydroxy, or
halo;
(g) quinolyl optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 alkoxy,
hydroxy or
halo; and
(h) indolyl optionally substituted with C1-6 alkyl,
C1-6 haloalkyl,
C1-6 alkoxy,
hydroxy or
halo;
B is selected from the group consisting of
(a) phenylene optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, cyano or halo;
(b) furylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(c) thienylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(d) pyridylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(e) thiazolylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(f) oxazolylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(g) benzoxazolylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl; and (h) benzothienylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl; p is selected from zero, one and two;
X is selected from the group consisting of
(a) C1-6 alkylene;
(b) C2-6 alkenylene;
(c) C2- 6 alkynylene;
(d) CF2;
(e) CCl2;
(f) -(CHR1)m Z1-(CHR2)n-;
(g) -O-(CHR1)j-Z2-; and
(h) groups of the formula
Figure imgf000007_0001
wherein Z1 is O, S, SO2, NR3, CO, C(=N-OR1) or CH=N-O; Z2 is O, S, SO, or NR2; Z3 is O, S or NR1; R1 , R2 and R3 are each H or C1-6 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 Z1 is O or S, m and n are not zero simultaneously;
Y is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkoxyalkyl,
C2-6 alkoxyalkoxy, C1-6 alkylthio, hydroxy, halo, cyano and amino; and
Z is selected from hydrogen and C1-3 alkyl.
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, 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 C1-4 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 -(CHR1)m-Z1-(CHR2)n-wherein Z1 is O, and either R1 is H, m is one and n is zero, or R2 is H, m is zero and n is one.
Particularly preferred individual compounds of the invention are:
N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea;
(+)-N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea;
(-)-N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea;
N-Hydroxy-N-[[3-[3-(2-phenoxy)ethoxy]phenyl]-2-cyclopenten-1-yl]urea;
N-[[3-(3-Benzyloxy)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea;
N-[3-[3-(4-Fluorophenoxymethyl)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea; and N-[3-[5-(4-Fluorophenylcarbonyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea. Detailed Description of the Invention
In this application, the term "halo" is used to mean radicals derived from the elements fluorine, chlorine and bromine.
The term "pharmaceutically acceptable 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. In one embodiment, compounds of the formula (I) are prepared according to the reaction steps outlined in scheme 1 :
Figure imgf000009_0001
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. Preferably 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 ZNH2. As a modification of this procedure (Z=H) 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.
Alternatively, 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(PPh3)4, PdCl2(PPh3)2 or the like (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986). 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 aforementioned hydroxylamine (II) may be prepared by standard synthetic procedures from corresponding carbonyl compound, i.e. ketone or alcohol compound. For example, 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, can be prepared by a number of different approaches (see WO 92/09566). 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. Alternatively, 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(PPh3)4 or PdCl2(PPh3)2 (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986).
Alternatively, 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.
Alternatively, 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(PPh3)4 or PdCl2(PPh3)2 (for example, J. K. Stille, Angew. Chem. Int. Ed.
Eng., 25, 806 1986).
The hydroxylamine of formula (II) thus obtained by the abovementioned representative procedures is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.
In another embodiment, compounds of the formula (I) are prepared as illustrated in Scheme 2. R4 is phenyl, and R5 is phenyl or lower alkyl:
Figure imgf000011_0001
In this process, 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 ZΝH2 (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 ZNH2 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(PPh3)4, PdCl2(PPh3)2 or the like (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986). 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 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. In the case of non-toxic acid salt, 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. 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, 113-118 (1990), which determines the effect of said compounds on the metabolism of arachidonic acid. Some of the compounds additionally possess the ability to inhibit the CO enzyme.
The ability of 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. Thus, 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.
For treatment of the various conditions described above, 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. When the compounds are administered orally, 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. If 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. For oral administration, 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. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Further lubricating agents such as magnesium stearate are commonly added. In the case of capsules, useful diluents are lactose and dried corn starch. When 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. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solute should be controlled to make the preparation isotonic.
Examples
The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples. Proton nuclear magnetic resonance spectra (NMR) were measured at 270 MHz unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak shapes are denoted as follows: s -singlet, d - doublet, t - triplet, m -multiplet and br - broad.
Example 1
N-[3-[5-(4-FluorophenylmethyI)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea a. 3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopentenone
To a stirred solution of 2-bromo-5-(4-fluorophenylmethyl)thiophene (12.15g; 44.83mM) in dry THF (120ml) was added 1.6M solution of n-BuLi in hexane (28ml; 44.83mM) dropwise at -76 °C under Ν2. After stirring for 1hr, 3-ethoxy-2-cyclopentenone (5.65g; 44.83mM) in THF (30ml) was added dropwise at -76 °C. The mixture was stirred for 1hr at -76 °C, and the mixture was poured into water. The whole was extracted with ethyl acetate (150ml x2), and the combined organic layers washed with water (70ml), brine (100ml), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1: 1) to give 3.75g (31 %) of the subtitle compound. 1H-NMR (CDCl3); 7.27 (d, J=4.7Hz, 1H), 7.21 (dd, J=5.5Hz, 8.4Hz, 2H),
7.02 (t, J=8.4Hz, 2H), 6.82 (d, J=3.6Hz, 1H), 6.24 (s, 1H), 4.14 (s, 2H), 3.00-2.95
(m, 2H), 2.55-2.51 (m, 2H).
b. 3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopentenone oxime
To a stirred solution of 3-[5-(4-fluorophenylmethyl)-2-thienyl]-2-cyclopentenone
(3.75g; 13.79mM) in ethanol (28ml)-pyridine (7ml) was added NH2OH HCl (1.25g;
17.92mM) at room temperature. After stirring overnight, volatiles were removed by evaporation. The residue was dissolved in ethyl acetate (150ml), and the whole washed with diluted aqueous HCl (70ml), water (100ml), brine (100ml), dried over MgSO4, and concentrated in vacuo to give 3.7g (quant.) of the subtitle compound as brown solids.
1H-NMR (CDCl3); 7.20 (dd, J=5.5Hz, 8.4Hz, 2H), 7.00 (t, J=8.4Hz, 2H),
6.97 (d, J=3.6Hz, 1H), 6.71 (d, J=3.6Hz, 1H), 6.33 (s, 1H), 4.10 (s, 2H), 2.89-2.80
(m, 4H).
c. N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxylamine To a stirred solution of 3-[5-(4-fluorophenylmethyl)-2-thienyl]-2-cyclopentenone oxime (3.9g; 13.59mM) in acetic acid (30ml) was added ΝaBH3CΝ (1.28g; 20.38mM) at room temperature. After stirring for 3hr, water (50ml) was added. Volatiles were removed by evaporation, and the residue was poured into aqueous 5% NaOH (300ml). The whole was extracted with ethyl acetate (150ml x2), and the combined organic layers washed with water (70ml x2), brine (70ml), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with CH2Cl2-ethanol (30: 1) to give 1.17g (30%) of the subtitle compound.
1H-NMR (CDCl3); 7.19 (dd, J=5.5Hz, 8.0Hz, 2H), 7.02-6.93 (m, 4H), 6.83 (d, J=3.7Hz, 1H), 6.67 (dd, J = l .1Hz, 3.7Hz, 1H), 5.84 (s, 1H), 4.31-4.23 (m, 1H),
4.07 (s, 2H), 2.89-2.77 (m, 1H), 2.71-2.61 (m, 1H), 2.33-2.19 (m, 1H), 2.10-1.95
(m, 1H).
d. N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea
To a stirred solution of N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxylamine (1.17g; 4mM) in THF (10ml) was added trimethylsilyl isocyanate (0.71g; 5.26mM) at room temperature. After stirring overnight, ethanol (10ml) was added, and volatiles were removed by evaporation. The resulting residue was recrystallized from ethanol to give 0.64g of the title compound, m.p. 196-197 °C (decompose)
1H-NMR (DMSO-d6); 8.92 (s, 1H), 7.32-7.26 (m, 2H), 7.14 (dd, J=2.2Hz,
8.8Hz, 2H), 6.89 (d, J=3.2Hz, 1H), 6.81 (d, J=3.2Hz, 1H), 6.33 (s, 2H), 5.68 (s, 1H), 5.28 (s, 1H), 4.10 (s, 2H), 2.70-2.64 (m, 1H), 2.53-2.46 (m, 1H), 2.15-2.08 (s, 1H), 1.94-1.88 (m, 1H).
Anal. Calcd. for C17H16FN2O2S C; 61.62, H; 4.87, N; 8.45,
Found C; 61.69, H; 5.08, N; 8.48.
e. (+)-N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea and
f. (-)-N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea
The title respective enantiomers were obtained by separation on a chiral stationary phase (DAICEL chiral pak AS) of the racemate N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea. HPLC condition; eluent n-hexane/EtOH =70/30, Flow rate 11.0 ml/min.
The less polar enantiomer; retention time 15.9 min, [α]D= + 16.5 (c=0.2, EtOH). The more polar enantiomer; retention time 19.3 min, [α]D=-19.0 (c=0.2, EtOH).
Example 2
N-Hydroxy-N-[[3-[3-(2-phenoxy)ethoxy]phenyl]-2-cyclopenten-1-yl]urea a. 3-[(2-Phenoxy)ethoxy]benzaldehyde
A mixture of m-hydroxybenzaldehyde (6.1g; 50mM), 0-bromophenetole (11.06g; 55mM) and K2CO3 (13.82g; 100mM) in DMF (150ml) was stirred overnight. Insolubles were filtered off, and the filtrate was diluted with water (300ml), and extracted with ethyl acetate-hexane (2:1, 150ml x2), the combined organic layers washed with water (100ml x2), brine (100ml), dried over MgSO4, and evaporated in vacuo. The resulting residue was recrystallized from ethyl acetate-hexane to give 7.01g (58%) of the subtitle compound. 1H-NMR (CDCl3); 9.97 (s, 1H), 7.50-7.42 (m, 3H), 7.33-7.21 (m, 3H), 7.01- 6.93 (m, 3H), 4.41-4.32 (m, 4H).
b. 1-[3-[(2-Phenoxy)ethoxy]phenyl]-1.4-pentanedione
To a stirred solution of 3-[(2-phenoxy)ethoxy]benzaldehyde (7g; 28.93mM) in ethanol (15ml) was added methyl vinyl ketone (2.4ml; 28.93mM), 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazolium chloride (1.72g; 6.36mM) and triethylamine (8.06ml; 57.9mM) at room temperature. After stirring overnight, volatiles were removed by evaporation. The residue was dissolved in water (250ml), and extracted with ethyl acetate (160ml x2). The combined organic layers were washed with water (100ml), brine (80ml), dried over MgSO4, and evaporated in vacuo. This provided 10g of crude subtitle compound, which was used without further purification.
1H-NMR (CDCl3); 7.61-6.94 (m, 9H), 4.36 (t, J=3.7Hz, 4H), 3.26 (t, J=6.6Hz, 2H), 2.88 (t, J=6.6Hz, 2H), 2.26 (s, 3H).
c. 3-[3-[(2-Phenoxy)ethoxy]phenyl]-2-cyclopentenone
A solution of 1-[3-[(2-phenoxy)ethoxy]phenyl]-1,4-pentanedione (10g;
28.93mM) in 2.5% NaOH solution (120ml) was heated at reflux temperature overnight. After cooling, the solution was extracted with ethyl acetate (150ml x2), the combined organic layers washed with water (70ml), brine (70ml), dried over MgSO4, and evaporated in vacuo. The resulting residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:3) to give 1.3g of the subtitle compound.
1H-NMR (CDCl3); 7.41-6.94 (m, 9H), 6.56 (s, 1H), 4.37 (br. s, 4H), 3.03 (dd, J=3.0Hz, 4.8Hz, 2H), 2.59 (t, J=4.8Hz, 2H).
d. N-Hydroxy-N-[[3-[3-(2-phenoxy)ethoxy]phenyl]-2-cyclopenten-1-yl]urea
The title compound was prepared according to the procedure of Example 1 using 3-[3-[(2-phenoxy)ethoxy]phenyl]-2-cyclopentenone instead of 3-[5-(4-fluorophenylmethyl)-2-thienyl]-2-cyclopentenone.
m.p. 170-173 °C (decompose)
1H-ΝMR (DMSO-d0); 8.92 (s, 1H), 7.29 (q, J=8.4Hz, 3H), 7.12-7.07 (m, 2H), 7.03-6.87 (m, 4H), 6.32 (s, 2H), 6.12 (s, 1H), 5.37-5.33 (m, 1H), 4.33 (br.s, 4H), 2.81-2.69 (m, 1H), 2.62-2.50 (m, 1H), 2.20-2.17 (m, 1H), 2.00-1.90 (m, 1H).
Anal. Calcd. for C20H22Ν2O4 C; 67.78, H; 6.26, N; 7.90, Found C; 67.86, H; 6.29, N; 7.96.
Example 3
N-[[3-(3-BenzyIoxy)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea
The title compound was prepared according to the procedure of Example 1 using 3-(benzyloxy)benzaldehyde instead of 3-[(2-phenoxy)ethoxy]benzaldehyde. m.p. 158-160 °C (decompose)
1H-ΝMR (DMSO-d6); 8.91 (s, 1H), 7.46-7.21 (m, 6H), 7.08-7.04 (m, 2H), 6.93-6.89 (m, 1H), 6.30 (s, 2H), 6.08 (d, J= 1.8Hz, 1H), 5.33 (br.s, 1H), 5.11 (s, 2H), 2.80-2.67 (m, 1H), 2.58-2.48 (m, 1H), 2.17-2.05 (m, 1H), 1.96-1.88 (m, 1H).
Anal. Calcd. for C19H2OΝ2O3 C;70.35, H; 6.21, N; 8.64,
Found C; 70.26, H; 6.22, N; 8.52.
Example 4
N-[[3-(4-Benzyloxy)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea
The title compound was prepared according to the procedure of Example 1 using 4-(benzyloxy)benzaldehyde instead of 3-[(2-phenoxy)ethoxy]benzaldehyde. m.p. 175-177 °C (decompose)
1H-ΝMR (DMSO-d6); 8.90 (s, 1H), 7.46-7.32 (m, 7H), 6.99 (d, J=8.8Hz, 2H), 6.28 (s, 2H), 5.94 (s, 1H), 5.32 (br.s, 1H), 5.12 (s, 2H), 2.79-2.68 (m, 1H), 2.57-2.47 (m, 1H), 2.15-2.06 (m, 1H), 1.96-1.88 (m, 1H).
Anal. Calcd. for C19H2OΝ2O3 C;70.35, H; 6.21, N; 8.64,
Found C; 70.08, H; 6.18, N; 8.68.
Example 5
N,O-Bis(tert-butoxycarbonyl)-N-(3-tributylstannyI-2-cycloalken-1-yl)hydroxylamine
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
(1990)). To a stirred solution of 3-tributylstannyl-2-cyclopenten-1-ol (9.1g; 24.4mM) in THF (70ml) was added triphenylphosphine (7.36g; 28mM), Boc-ΝH-O-Boc (6.52g;
28mM), and diisopropyl azodicarboxylate (5.66g; 28mM) at room temperature. After stirring for 2 hrs, volatiles were removed by evaporation. The resulting residue was purified by flash chromatography eluting with n-hexane-ethyl acetate (50: 1) to give 6g of the title compound.
1H-NMR (CDCl3); 5.76 (s, 1H), 5.33 (br.s, 1H), 2.65-2.52 (m, 1H), 2.45-2.35 (m, 1H), 2.19-2.06 (m, 1H), 1.87-1.75 (m, 1H), 1.49 (s, 18H), 1.65-1.23 (m, 18H), 0.89 (t, J=7.0Hz, 9H).
The title compound is useful to synthesize the compounds of the following
Examples 6, 7, 8 and 9 as the starting compound.
Example 6
N-[3-[5-(4-Fluorophenylcarbonyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea g. N,O-Bis-tert-butoxycarbonyl-N-[3-[5-(4-fluorophenylcarbonyl)-2-thienyl]-2-cyclopenten-1-yl]-hydroxylamine
To a suspension of 2-bromo-5-(4-fluorobenzoyl)thiophene (0.71g; 2.5mM) in dry dioxane (20ml) previously purged with nitrogen, were added N,O-Bis(tert-butoxycarbonyl)-N-(3-tributylstannyl-2-cycloalken-1-yl)hydroxylamine (1.47g;25mM), tetrakis(triphenylphosphine)palladium(0) (58mg; 0.05mM), and 2,6-di-tert-butyl-4-methylphenol (3 crystals). The mixture was heated at gentle reflux for 40hrs and it was then concentrated to dryness. The residue was purified by flash chromatography eluting with n-hexane to give 0.33g (26%) of the subtitle compound.
1H-ΝMR (CDCl3); 7.88 (dd, J=5.5Hz, 8.8Hz, 2H), 7.51 (d, J=4.0Hz, 1H), 7.18 (t, J = 8.8Hz, 2H), 7.08 (d, J=4.0Hz, 1H), 6.17 (d, J=2.2Hz, 1H), 5.49 (br.s, 1H), 2.95-2.85 (m, 1H), 2.75-2.64 (m, 1H), 2.47-2.35 (m, 1H), 2.17-2.05 (m, 1H), 1.50 (s, 18H).
b. N-[3-[5-(4-Fluorophenylcarbonyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea
To a stirred solution of N,O-bis-tert-butoxycarbonyl-N-[3-[5-(4-fluorophenylcarbonyl)-2-thienyl]-2-cyclopenten-1-yl]-hydroxylamine (0.33g; 0.656mM) in dry CH2Cl2 (4ml) was added 2,6-lutidine (0.17ml; 1.44mM) and trimethylsilyl trifluoromethanesulfonate (0.28ml; 1.44mM) at room tempreture. After stirring for 1 hr, volatiles were removed by evaporation. The residue was dissolved in ethyl acetate (80ml), and the whole was washed with saturated ΝH4Cl solution (50ml x3), water (50ml), brine (100ml), dried over MgSO4, and concentrated in vacuo to give 0.237g of the crude hydroxylamine. To a stirred solution of the crude hydroxylamine (0.237g; 0.656mM) in dry
THF (7ml) was added TMSNCO (0.13g; 0.984mM) at room temperature. After stirring for 1 hr, ethanol (10ml) was added and the solvent was evaporated in vacuo.
The residue was recrystallized from ethyl acetate to give 0.15g of the title compound. m.p. 206-207 °C (decompose)
1H-NMR (DMSO-d6); 9.04 (s, 1H), 7.92 (dd, J=5.8Hz, 8.0Hz, 2H), 7.66 (d, J=4.1Hz, 1H), 7.41 (t, J=8.0Hz, 2H), 7.29 (d, J=4.1Hz, 1H), 6.38 (s, 2H), 6.19 (s, 1H), 5.37 (br.s, 1H), 2.84-2.72 (m, 1H), 2.67-2.55 (m, 1H), 2.25-2.12 (m, 1H), 2.05-1.93 (m, 1H).
Anal. Calcd. for C17H15N2O3S C;58.95, H; 4.36, N; 8.09,
Found C; 59.15, H; 4.41, N; 7.79.
Example 7
N-Hydroxy-N-[3-[3-(O-benzyloxycarboxaldoxime)phenyl]-2-cyclopenten-1-yl]urea The title compound was prepared according to the procedures described in Example 6 using 3-(O-benzyloxycarboxaldoxime)phenyliodide instead of 2-bromo-5-(4-fluorobenzoyl)thiophene.
m.p. 166.5-167.5 °C (decompose)
1H-ΝMR (DMSO-d6); 8.94 (s,1H), 8.32 (s, 1H), 7.71 (s, 1H), 7.55-7.32 (m, 9H), 6.32 (s, 2H), 6.12 (s, 1H), 5.35 (br.s, 1H), 5.18 (s, 2H), 2.82-2.71 (m, 1H), 2.63-2.56 (m, 1H), 2.19-2.12 (m, 1H), 2.02-1.93 (m, 1H).
Anal. Calcd. for C20H21Ν3O3: C, 68.36; H, 6.02; N, 11.96.
Found: C, 68.07; H, 5.95; N, 11.80.
Example 8
N-Hydroxy-N-[3-[(5-phenylethenyl)thien-2-yl]-2-cyclopenten-1-yl]urea
The title compound was prepared according to the procedures described in
Example 6 using 2-bromo-5-(phenylethenyl)thiophene instead of 2-bromo-5-(4-fluorobenzoyl)thiophene.
m.p. 179-180 °C (decompose)
1H-ΝMR (DMSO-d6); 8.99 (s,1H), 7.57 (d, J=7.7Hz, 2H), 7.45-7.33 (m, 3H), 7.27 (d, J=7.3Hz, 1H), 7.12 (d, J=3.7Hz, 1H), 7.03 (d, J=3.7Hz, 1H), 6.91 (d,
J= 16.1Hz, 1H), 6.35 (s, 2H), 5.84 (s, 1H), 5.33 (br.s, 1H), 2.82-2.73 (m, 1H), 2.62- 2.54 (m, 1H), 2.21-2.10 (m, 1H), 1.99-1.90 (m, 1H).
Anal. Calcd. for C18H18N2O2S: C, 66.23; H, 5.56; N, 8.58.
Found: C, 66.29; H, 5.60; N, 8.44.
Example 9
N-[3-[3-(4-Fluorophenoxymethyl]phenyl]-2-cyclopenten-1-yl]-N-Hydroxyurea
The title compound was prepared according to the procedures described in Example 6 using 3-(4-fluorophenoxymethyl)phenyliodide instead of 2-bromo-5-(4-fluorobenzoyl)thiophene.
m.p. 155-157 °C (decompose)
1H-ΝMR (DMSO-d6); 8.93 (s, 1H), 7.56 (S, 1H), 7.45-7.34 (m, 3H), 7.12 (t,
J=8.4Hz, 2H), 7.05-6.98 (m, 2H), 6.32 (s, 2H), 6.10 (s, 1H), 5.34 (br.s, 1H), 5.08 (s, 2H), 2.82-2.71 (m, 1H), 2.62-2.50 (m, 1H), 2.18-2.08 (m, 1H), 2.00-1.92 (m, 1H).
Anal. Calcd. for C19H19FΝ2O3: C, 66.66; H, 5.59; N, 8.18.
Found: C, 66.31; H, 5.60; N, 8.16.

Claims

1. A compound of the following chemical formula:
Figure imgf000022_0001
and the pharmaceutically acceptable salts thereof, wherein
A is selected from the group consisting of
(a) phenyl, naphthyl, biphenylyl and fluorenyl; optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 hydroxyalkyl,
C1-6 alkoxy,
C1-6 alkoxyalkoxy,
C1-6 alkylthio,
hydroxy,
halo,
cyano,
amino,
C1-6 alkylamino,
C1-6 dialkylamino,
C2-8 alkanoylamino,
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,
C2-8 alkylaminocarbonyl,
C3-7 dialkylaminocarbonyl, carboxy,
C2-8 alkoxycarbonyl,
phenyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1- 6 haloalkoxy, cyano or halo,
phenoxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo,
phenylthio optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo,
pyridyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo, or
pyridyloxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo;
(b) furyl optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
halo,
phenyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1- 6 haloalkoxy, cyano or halo,
phenoxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano or halo,
phenylthio optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano or halo,
pyridyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano or halo, or
pyridyloxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo;
(c) benzo[b]furyl optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 alkoxy,
hydroxy, or halo;
(d) thienyl optionally substituted with
C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, or halo,
phenyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1- 6 haloalkoxy, cyano or halo,
phenoxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo,
phenylthio optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano or halo,
pyridyl optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,
C1-6 haloalkoxy, cyano or halo, or
pyridyloxy optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano or halo;
(e) benzo[b]thienyl optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 alkoxy,
hydroxy, or
halo;
(f) pyridyl optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 alkoxy,
hydroxy, or
halo;
(g) quinolyl optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 alkoxy,
hydroxy or
halo; and (h) indolyl optionally substituted with
C1-6 alkyl,
C1-6 haloalkyl,
C1-6 alkoxy,
hydroxy or
halo;
B is selected from the group consisting of
(a) phenylene optionally substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, cyano or halo;
(b) furylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(c) thienylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(d) pyridylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(e) thiazolylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(f) oxazolylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(g) benzoxazolylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
(h) benzothienylene optionally substituted with C1-6 alkyl or C1-6 haloalkyl;
p is selected from zero, one and two;
X is selected from the group consisting of
(a) C1-6 alkylene;
(b) C2-6 alkenylene;
(c) C2-6 alkynylene;
(d) CF2;
(e) CCl2;
(f) -(CHR')m-Z'-(CHR2)n-;
(g) -O-(CHR1)j-Z2-; and
(h) groups of the formula
Figure imgf000025_0001
wherein Z' is O, S, SO2, NR3, CO, C(=N-OR1) or CH=N-O; Z2 is O, S, SO2 or NR2; Z3 is O, S or NR1; R1, R2 and R3 are each H or C1-6 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 Z1 is O or S, m and n are not zero simultaneously;
Y is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C2-6 alkoxyalkoxy, C1-6 alkylthio, hydroxy, halo, cyano and amino; and
Z is selected from hydrogen and C1-3 alkyl.
2. A compound according to claim 1 , wherein
A is selected from the group consisting of
phenyl, naphthyl, biphenylyl and fluorenyl; optionally substituted with one or two substituents selected from
C1-4 alkyl,
C1-4 haloalkyl,
C1-4 alkoxy,
C1-4 alkylthio,
halo and
cyano;
B is selected from the group consisting of
phenylene optionally substituted with one substituent selected from C1-4 alkyl,
C1-4 haloalkyl, C1-4 haloalkoxy, cyano and halo; and
thienylene optionally substituted with one substituent selected from C1-4 alkyl and C1-4 haloalkyl;
p is one;
X is selected from the group consisting of
C1-4 alkylene;
C2-6 alkenylene;
C2-6 alkynylene;
-(CHR1)m-Z1-(CHR2)n-; and
-O-(CHR1)j-Z2-;
wherein Z1 is O, S, SO2, CO, or CH=N-O; Z2 is O, S or SO2; R1, R2 and R3 are each H or C1-4 alkyl; m and n are each zero to three; and j is one to three;
Y is selected from hydrogen, C1-3 alkyl and halo; and
Z is hydrogen.
3. A compound according to claim 2, wherein A is phenyl or fluorophenyl and B is phenylene or thienylene.
4. A compound according to claim 3, wherein Y is hydrogen.
5. A compound according to claim 4, wherein X is C1-4 alkylene.
6. A compound according to claim 5, wherein A is 4-fluorophenyl, B is 2,5-thienylene and X is CH2.
7. A compound according to claim 4, wherein X is -(CHR1)m-Z1-(CHR2)n-, wherein Z1 is O, R1 is H and n is zero.
8. A compound according to claim 7, wherein A is phenyl, B is 1,3-phenylene and m is one.
9. A compound according to claim 4, wherein X is -(CHR1)m-Z1-(CHR2)n-, wherein Z1 is O, R2 is H and m is zero.
10. A compound according to claim 9, wherein A is 4-fluorophenyl, B is 1,3-phenylene and n is one.
11. A compound according to claim 1 wherein the compound is selected from: N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea;
(+)-N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea;
(-)-N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea;
N-Hydroxy-N-[[3-[3-(2-phenoxy)ethoxy]phenyl]-2-cyclopenten-1-yl]urea;
N-[[3-(3-Benzyloxy)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea;
N-[3-[3-(4-Fluorophenoxymethyl)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea; and N-[3-[5-(4-Fluorophenylcarbonyl)-2-thienyl]-2-cyclopenten-1-yl]-N-hydroxyurea.
12. A pharmaceutical composition for the treatment of an allergic or inflammatory condition in a mammalian subject which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
13. A method for treatment of a medical condition for which a 5-lipoxygenase inhibitor is needed, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1.
14. A method according to claim 13, wherein the medical condition is an allergic or inflammatory condition.
PCT/IB1995/000821 1994-11-18 1995-10-02 Cycloalkenyl-n-hydroxyureas WO1996016054A1 (en)

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