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WO1994018158A1 - Spiroalkylhydroxyurees utilisees comme inhibiteurs de lipoxygenase - Google Patents

Spiroalkylhydroxyurees utilisees comme inhibiteurs de lipoxygenase Download PDF

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Publication number
WO1994018158A1
WO1994018158A1 PCT/JP1994/000119 JP9400119W WO9418158A1 WO 1994018158 A1 WO1994018158 A1 WO 1994018158A1 JP 9400119 W JP9400119 W JP 9400119W WO 9418158 A1 WO9418158 A1 WO 9418158A1
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WO
WIPO (PCT)
Prior art keywords
spiro
alkyl
phenoxyphenyl
compound according
compound
Prior art date
Application number
PCT/JP1994/000119
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English (en)
Inventor
Akiyoshi Kawai
Kazunari Nakao
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.
Publication of WO1994018158A1 publication Critical patent/WO1994018158A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/50—Spiro compounds

Definitions

  • This invention relates to novel N-hydroxyurea and hydroxamic acid derivatives.
  • the compounds of the present invention inhibit the action of the lipoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals, especially human subjects.
  • This invention also relates to pharmaceutical compositions comprising such compounds.
  • Arachidonic acid is known to be the biological precursor of several groups of biologically active endogenous metabolites.
  • the first step in the metabolism of arachidonic acid is its release from membrane phospholipids, via the action of phospholipase A2.
  • Arachidonic acid is then metabolized either by cyclooxygenase to produce prostaglandins including prostacyclin, and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes.
  • the leukotrienes are extremely potent substances which elicit a wide variety of biological effects, often in the nanomolar to picomolar concentration range.
  • the peptidoleukotrienes (LTC 4 , LTD 4 , LTE 4 ) are important bronchoconstrictors and vasoconstrictors, and also cause plasma extravasation by increasing capillary permeability.
  • LTB 4 is a potent chemotactic agent, enhancing the influx of leukocytes and inducing their subsequent degranulation at the site of inflammation.
  • a pathophysiological role for leukotrienes has been implicated in a number of human disease states including asthma, rheumatoid arthritis and gout, psoriasis, adult respiratory distress syndrome, inflammatory bowel diseases (e.g. Crohn's disease), endotoxin shock, and ischemia-induced myocardial injury. Any agent that inhibits the action of Hpoxygenases is expected to be of considerable therapeutic value for the treatment of acute and chronic inflammatory conditions.
  • R is C,-C 4 alkyl or -NR'R 2 ;
  • R 1 and R 2 are each, independently, hydrogen or C,-C 4 alkyl; M is hydrogen or pharmaceutically acceptable cation; p and q are independently integers of two or three; the substituent A is optionally substituted phenyl, furyl, or thienyl, wherein the substituent(s) are each, independently, halogen, C,-C 6 alkyl, C ⁇ -C 6 alkoxy, phenoxy or mono- substituted phenoxy, wherein the substituent in the substituted phenoxy is halogen, C r C 4 alkyl, C,-C 4 alkoxy or halosubstituted alkyl; and the substituent A may be attached at any available positions on the spiro- ring.
  • a preferred group of compounds of this invention consists of the compounds of formula I, in which R is NH 2 , p is 2 or 3, q is 2, A is optionally-substituted 3- phenoxyphenyl, A is at the 6-position and the N(OM)-CO-R group is at the 1-position or the 2-position.
  • Preferred individual compounds of the present invention are the following: N-Hydroxy-N-[6-(3-phenoxyphenyl)spiro[3,3]hept-2-yl]urea, N-Hydroxy-N-[6-(3-phenoxyphenyl)spiro[3,3]hept-l-yl]urea, N-[6-(4-Fluorophenyl)spiro[3 , 4] oct- 1-yl] -N-hydroxyurea and
  • the compounds can inhibit the action of lipoxygenase. 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 inflammatory diseases, allergy and cardiovascular diseases.
  • This invention also embraces pharmaceutical compositions which comprise a compound of the formula (I) and a pharmaceutically acceptable carrier.
  • halogen is used herein to mean radicals derived from the elements fluorine, chlorine, bromine and iodine;
  • alkyl is used herein to mean straight or branched hydrocarbon chain radicals including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like;
  • alkoxy is used herein to mean -OR 3 (R 3 is alkyl) including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy and the like;
  • halosubstituted alkyl refers to an alkyl radical as described above substituted with one or more halogens including, but not limited to, chloromethyl, bromoethyl, trifluoromethyl and the like; and the term “pharmaceutically acceptable cation” refers to non-toxic cations, based on alkaline and alkaline
  • phenyl, furyl or thienyl means unsubstituted phenyl, furyl or thienyl, or phenyl, furyl or thienyl having up to three substituents. However, unsubstituted and mono-substituted groups are preferred.
  • the pharmaceutically acceptable salts of the compounds of the invention can be prepared from the compounds of formula I and non-toxic bases including inorganic bases and organic bases. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free acid form with a suitable base such as the above-mentioned pharmaceutically acceptable cation.
  • salts may be prepared from non-toxic acids including inorganic and organic acids.
  • Such acids include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuricorbisulfuric, phosphoric or acid phosphoric, acetic, lactic, citric or acid citric, tartaric or bi-tartaric, succinic, maleic, fumaric, gluconic, saccharic, benzoic, methanesulfonic, benzenesulfonic, p- toluenesulfonic and pamoic acids and the like.
  • compositions of the present invention comprise a compound of formula I as an active ingredient, and a pharmaceutically acceptable carrier.
  • NSAID non-steroidal antiinflammatory drug
  • the compounds of formula I may be prepared by a number of synthetic methods.
  • the spiroalkylhydroxyurea compounds of formula I can be prepared from the corresponding ketone of formula IV by methods similar to those described in WO 92/9566.
  • the hydroxylamine II is treated with trimethylsilyl isocyanate (TMS- NCO) in a reaction-inert solvent usually at ambient through to reflux temperature.
  • Suitable solvents which do not react with reactants and/or products are, for example, tetrahydrofuran (THF), dioxane, methylene chloride or benzene.
  • THF tetrahydrofuran
  • 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.
  • the intermediate carbamoyl chloride is not isolated but subjected to (i.e.
  • hydroxylamine II may be readily prepared by standard synthetic procedures from corresponding carbon yl compound, i.e. ketone or aldehyde.
  • 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, Journal of American Chemical Society, 93, 2897, 1971).
  • a suitable reducing agent for example, see R. F. Borch et al, Journal of American Chemical Society, 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 (TFA) may also be employed.
  • hydroxylamine (II) can easily be prepared by treating the corresponding alcohol with N,O-bis(tert-butyloxycarbonyl)hydroxylamine under
  • hydroxylamine II may also be prepared from suitable halide compound by reaction with O-protected hydroxylamine and subsequent deprotection
  • O-protected hydroxylamines are, but not limited to, O-tetrahydropyranyl-, O-trimethylsilyl- and O-benzylhydroxylamine.
  • Certain compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention contemplates all such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
  • Ketones of formula IV e.g., spiro[3,3]hept-2-one and spiro[3,4]oct-2-one
  • V cycloalkylidene of formula (V)
  • 6-(3-phenoxyphenyl)spiro[3,3]hept-2-one was prepared by the cycloaddition of 3-(3-phenoxyphenyl)cyclobutylidene with dichloroketene followed by the reductive dechlorination with zinc.
  • Ketene and dichlorodifluoroethylene can be also useful as a ketene equivalent (S. L. Manatt, M. Vogel, D. Knutson, and D. Roberts,
  • the cycloalkylidene can be prepared from the corresponding cycloalkanone by the methylenation reported by Wittig, Peterson, Tebbe, Mitsunobu and so on ( E. J.
  • the corresponding cycloalkanone can be prepared by the method described in International Publication No. WO 92/09566.
  • Spiro[3,3]hept-l-one and spiro[3,4]oct-l-one can be prepared by the method reported by Trost ( B. M. Trost and M. J. Bogdonowicz, J. Am. Chem. Soc., 95,
  • 6-(3-phenoxyphenyl)spiro[3,3]hept-l-one was prepared by the oxaspiroannelation of 3-(3-phenoxyphenyl)-cyclobutanone with cyclopropyldi- -7- phenylsulfonium tetrafluoro-borate followed by acid treatment.
  • Spiro[3,4]oct-2-one and spiro[4,4]nona-2-one can be prepared by the intra ⁇ molecular Aldol condensation or the acid catalyzed intramolecular Aldol reaction (S. F. Martin and T.-s. Chou, J. Org. Chem., 43, 1027(1978)).
  • Spiro[4,4]nona-l-one can be also prepared by the intramolecular Aldol cychzation or the metal catalyzed intramolecular hydroacylation ( R. C. Larock, K. Oertie and G. F. Potter , J. Am. Chem. Soc, 102, 190(1980)). These methods are -8- applicable for all the "A" substituents in this patent.
  • the compounds of this invention inhibit the activity of lipoxygenase enzyme. This inhibition has been demonstrated by an assay using rat peritoneal cavity resident cells which determines the effect of said compounds on the metabolism of arachidonic acid.
  • IC JO values in the range of about 0.1 to about 1 / _M, with respect to lipoxygenase activity.
  • 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, osteoarthritis and thrombosis.
  • 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 formula I 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.
  • the compounds can be administered to a human subject by various conventional routes of administration including oral, parenteral and by inhalation.
  • 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 0.1 to 5 mg/kg per day in single or divided doses, more preferably from about 0.1 to 1.0 mg/kg per day in single or divided doses.
  • parenteral administration is desired, then an effective dose will be from about 0.1 to 1.0 mg/kg of body weight of the 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 emulsifying and suspending agents. If desired, certain sweetening 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-(3-Phenoxyphenyl)cyclobutanone, 3-(4-fluorophenyl)cyclopentanone and 3-(3-phenoxyphenyl)cyclopentanone were prepared according to the procedure described in WO 92/9566.
  • Cyclopropyldiphenylsulphonium tetrafluoroborate was prepared according to the procedure reported in "Organic Synthesis", 54, p.27.
  • IR(nujol)cm ' 1630, 1580, 1210, 1150, 980, 690.
  • IR(KBr)cm 1 3500, 1630, 1510, 1440, 1230.
  • the residual oil was extracted with diethyl ether-n-hexane (1:5, 2x200 ml) by decantation. The organic extracts were washed with water (300 ml) and brine (300 ml). The organic layer was dried over MgSO 4 and concentrated in vacuo. The residual oil was dissolved in AcOH (50 ml). To the solution was added Zn powder (2.06 g, 32.0 mM) and the mixture was stirred at room temperature for 0.5hr. The resulting mixture was filtered through a pad of Celite.
  • the filtrate was diluted with diethyl ether-n-hexane (1:2, 300 ml) and washed with water (3x200 ml), saturated aqueous NaHCO 3 (3x200 ml), brine (200 ml). The organic phase was dried over

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne de nouveaux dérivés de N-hydroxyurée et d'acide hydroxamique de la formule chimique (I), dans laquelle R représente alkyle C1-C4 ou -NR?1R2; R1 et R2¿ représentent chacun indépendamment hydrogène ou alkyle C¿1?-C4; M représente hydrogène ou un cation pharmaceutiquement acceptable; p et q représentent indépendamment les nombres entiers deux ou trois; le substituant A représente phényle, furyle ou thiényle facultativement substitué, les substituants étant chacun indépendamment halogène, alkyle C?1-C6¿, alcoxy C¿1?-C6, phénoxy ou phénoxy monosubstitué, le substituant dans le phénoxy substitué étant halogène, alkyle C1-C4, alcoxy C1-C4 ou alkyle halosubstitué; et le substituant A peut être fixé à n'importe quelle position disponible du cycle spiro. Ces composés sont utiles dans le traitement ou dans le soulagement de maladies inflammatoires, d'allergies et de maladies cardiovasculaires chez des mammifères, comme ingrédient actif dans des compositions pharmaceutiques de traitement de telles pathologies.
PCT/JP1994/000119 1993-02-15 1994-01-28 Spiroalkylhydroxyurees utilisees comme inhibiteurs de lipoxygenase WO1994018158A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5/25786 1993-02-15
JP2578693 1993-02-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995014681A1 (fr) * 1993-11-26 1995-06-01 Pfizer Inc. Composes d'isoxazoline utiles comme agents anti-inflammatoires
WO1995024192A1 (fr) * 1994-03-09 1995-09-14 Pfizer Inc. Composes d'isoxazoline agissant comme inhibiteurs de 5-lipoxygenase

Citations (2)

* 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
WO1992009567A1 (fr) * 1990-11-23 1992-06-11 The Wellcome Foundation Limited Composes anti-inflammatoires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009567A1 (fr) * 1990-11-23 1992-06-11 The Wellcome Foundation Limited Composes anti-inflammatoires
WO1992009566A1 (fr) * 1990-11-27 1992-06-11 Pfizer Inc. Nouveaux derives d'acide hydroxamique et de n-hydroxyuree et leur emploi

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995014681A1 (fr) * 1993-11-26 1995-06-01 Pfizer Inc. Composes d'isoxazoline utiles comme agents anti-inflammatoires
US5716967A (en) * 1993-11-26 1998-02-10 Pfizer Inc. Isoxazoline compounds as antiinflammatory agents
CN1046274C (zh) * 1993-11-26 1999-11-10 辉瑞大药厂 用作消炎剂的异噁唑啉化合物
WO1995024192A1 (fr) * 1994-03-09 1995-09-14 Pfizer Inc. Composes d'isoxazoline agissant comme inhibiteurs de 5-lipoxygenase
US5696141A (en) * 1994-03-09 1997-12-09 Pfizer Inc. Isoxazoline compounds as 5-lipoxygenase inhibitors

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