WO1995002402A1 - Inhibiteurs de la 5-lipoxygenase - Google Patents

Inhibiteurs de la 5-lipoxygenase Download PDF

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Publication number
WO1995002402A1
WO1995002402A1 PCT/US1994/008096 US9408096W WO9502402A1 WO 1995002402 A1 WO1995002402 A1 WO 1995002402A1 US 9408096 W US9408096 W US 9408096W WO 9502402 A1 WO9502402 A1 WO 9502402A1
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formula
compound
hydroxyurea
alkyl
pharmaceutically acceptable
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Jerry Leroy Adams
Ravi Shanker Garigipati
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • This invention relates to novel compounds, pharmaceutical compositions and methods for inhibiting oxygenated polyunsaturated fatty acid metabolism and disease states caused thereby. Specifically inhibited is the lipoxygenase enzyme pathway of arachidonic acid metabolism in an animal.
  • the metabolism of arachidonic acid occurs by many pathways.
  • One route of metabolism is via the cyclooxygenase (CO) mediated pathway which produces PGH2 which is in turn metabolized to the prostanoids (PGE2, TxA2, and prostacyclin). These products are produced by various cells including polymo ⁇ honuclear leukocytes, mast cells and monocytes.
  • Another route is by the lipoxygenase mediated pathway which oxidizes arachidonic acid initially to 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) which is further metabolized to LTA4, the precursor to the peptidoleukotrienes (LTC4, LTD4, and LTE4) and LTB4. Additionally 5-HPETE is converted to 5-hydroxyeicosatetraenoic acid (5- HETE).
  • Lipoxygenases are classified according to the position ii. the arachidonic acid which is oxygenated. Platelets metabolize arachidonic acid to 12-HETE, while polymo ⁇ honuclear leukocytes (PMNs) contain 5 and 15 lipoxygenases. It is known that 12-HETE and 5,12- diHETE are chemotactic for human neutrophils and eosinophils, and may augment the inflammation process. 5-HPETE is known to be a precursor to the peptidylleukotrienes, formerly known as slow reacting substance of anaphylaxis (SRS-A) and LTB4.
  • SRS-A slow reacting substance of anaphylaxis
  • the SRS family of molecules, such as leukotrienes C4 and D4 have been shown to be potent bronchoconstrictors.
  • LTB4 has been shown to be a potent chemotatic for PMNs.
  • the products of the 5-lipoxygenase pathway are believed to play an important role in initiating and maintaining the inflammatory response of asthma, allergy, arthritis, psoriasis, and inflammatory bowel disease. It is believed that blockage of this enzyme will interrupt the various pathways involved in these disease states and as such inhibitors should be useful in treating a variety of inflammatory diseases, such as those inumerated above.
  • the absence of selective inhibitors of lipoxygenase, as opposed to cyclooxygenase, which are active in vivo has prevented adequate investigation of the role of leukotrienes in inflammation.
  • the arachidonic acid oxygenated products have been identified as mediators of various inflammatory conditions.
  • the various inflammatory disease states caused by these mediators and many other conditions, as discussed herein, are all conditions in which an oxygenated polyunsaturated fatty acid metabolite inhibitor, such as a 5-LO inhibitor, would be indicated.
  • This invention relates to a compound of the Formula (I)
  • R2 R3 is hydrogen, a pharmaceutically acceptable cation, aroyl or a Ci .12 alkanoyl; B is oxygen or sulfur;
  • R4 is NR5R6, alkyl 1.5, halosubstituted alkyl 1-6, hydroxy substituted alkyl i-6, alkenyl 2-6, aryl or heteroaryl optionally substituted by halogen, alkyl ⁇ _6, halosubstituted alkyl 1-6, hydroxyl, or alkoxy 1-6;
  • R5 is H or alkyl 1-6;
  • R6 is H, alkyl ⁇ _6, aryl, arylalkyl 1-6, heteroaryl, alkyl substituted by halogen, hydroxyl, aryl or heteroaryl optionally substituted by a member selected from the group consisting of halo, nitro, cyano, alkyl ⁇ _i2-.
  • alkoxy .(,, halosubstituted alkyli-6, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulphonyl, or alkylsulfinyl; or R5 and R may together with the nitrogen to which they are attached form a ring having 5 to 7 members, which members may be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen; W is O(CH 2 ) s ; s is 0 or 1 ;
  • R ⁇ is a member selected from the group consisting of (CH2) ra -Ar-(X)v, O(CH2) m Ar-(X) v , or S(CH 2 ) ra -Ar-(X) v ;
  • m is 0 or an integer having a value of 1 , 2 or 3;
  • v is an integer having a value of 1, 2 or 3;
  • Ar is phenyl or naphthyl;
  • X is fluorine; provided that when s is 0, R ⁇ is O(CH2) Ar-(X) v , Ar is phenyl, v is 1 and X is 4-fluoro then m is not 0; or the pharmaceutically acceptable salts thereof.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective, non-toxic 5-lipoxygenase pathway inhibiting amount of a compound of the Formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating an oxygenated oolyunsaturated fatty acid (hereinafter OPUFA) mediated disease in an animal in need thereof which comprises administering to such animal, an effective amount of a compound of Formula (I) or pharmaceutically acceptable salts thereof. More specifically this invention relates to a method of treating a lipoxygenase pathway mediated disease in an animal in need thereof which comprises administering to such animal an effective, non-toxic lipoxygenase pathway inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • OPUFA oxygenated oolyunsaturated fatty acid
  • This invention relates to compounds of Formula (I) as described above, pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and methods of treating an OPUFA mediated disease, specifically a 5-lipoxygenase pathway mediated disease comprising administration of a compound of Formula (I) and salts thereof.
  • the compounds of Formula (I) have been found to be useful in inhibiting the enzymes involved in the oxygenated polyunsaturated fatty acid pathway which includes the metabolism of arachidonic acid, in an animal, including humans, in __eed thereof.
  • the compounds of Formula (I) have oral activity and are therefore useful for the treatment of various inflammatory disease states.
  • This invention further relates to a method of treating analgesia in an animal in need thereof, which comprises administering to such animal an effective, analgesia inhibiting amount of a compound of Formula (I).
  • the compounds of Formula (I) possess unexpectedly, superior therapeutic profiles for treatment of OPUFA mediated diseases over the corresponding unsubstituted benzyloxy derivative.
  • the racemate N-3-[6-(2,6-D ⁇ luorobenzyloxy)-2,3-dihydrobenzofuranyl]-N-hydroxyurea has a solubility in water (20°C) of about 11.9 ⁇ g/ml
  • the unsubstituted benzyloxy derivative N-3-[6-(benzyloxy)-2,3-dihydrobenzofuranyl]-N-hydroxyurea has a solubility of about 3.7 ⁇ g/ml.
  • Specific Ri groups of particular interest are the (CH2)m" A r-( ⁇ )v derivatives, in particular phenethyl, and the O(CH2)m _ Ar-(X)v derivatives, in particular the benzyloxy derivatives.
  • Ar is phenyl, and more preferably m is 1.
  • Specific ring substitutions for X include, but are not limited, to the 4-fluoro and the 2-fluoro; the 2,6- di- fluoro, 2,4-difluoro, 2, 5-difluoro and 2,3-di-fluoro derivatives.
  • Preferred substitutions are the 2,6-di-fluoro, and the 2- and 4-fluoro derivatives. More preferred is the 2,6-di-fluoro.
  • a preferred embodiment of this invention is where s is 0.
  • a further preferred embodiment of the present invention is where B is oxygen.
  • Preferred R4 substituent groups are NR5R6 and the alkyl hydroxamate derivatives.
  • R substitutions when R is aryl or arylalkyl are phenyl or benzyl.
  • a more preferred embodiment is where R5 and R6 are independently hydrogen or alkyl. Most preferred are when R5 and R are both hydrogen.
  • a preferred ring placement for Ri when W is O(CH2)s. and s is 0 is the 5- or 6- position of the benzofuran ring, more preferably the 6-position.
  • R4 is preferably alkyl, more preferably an alkyl have 1-6 carbon atoms, such as methyl, ethyl, n- propyl, isopropyl or t-butyl, all optionally substituted, and B is oxygen.
  • R3 is preferably hydrogen or a pharmaceutically acceptable cation.
  • the hydroxamates and hydroxyureas disclosed herein are made through a common intermediate, the hydroxylamine derivatives of Formula (II), all of the N-hydroxy acetamide derivatives of the corresponding hydroxyurea(s) made herein are also considered a preferred embodiment.
  • a preferred embodiment of the present invention are the compounds of Formula (Ia), a subset of compounds of Formula (I):
  • R3 is hydrogen, a pharmaceutically acceptable cation, aroyl or a Ci-12 alkanoyl
  • R4 is NR5R6, alkyl 1 _ ⁇ $, halosubstituted alkyl 1-6, hydroxy substituted alkyl 1-6, alkenyl
  • aryl or heteroaryl optionally substituted by halogen, alkyl 1-6, halosubstituted alkyl 1-6, hydroxyl, or alkoxy i-6;
  • R5 is H or alkyl 1-6
  • R6 is H, alkyl ⁇ _6, aryl, arylalkyl 1-6, heteroaryl, alkyl substituted by halogen or hydroxyl, aryl or heteroaryl optionally substituted by a member selected from the group consisting of halo, nitro, cyano, alkylj.. ⁇ *. alkoxy .
  • R5 and R6 may together form a ring having 5 to 7 members, which members may be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen;
  • Rj is a member selected from the group consisting of (CH2)nr Ar-(X) , or O(CH2)mAr-
  • (X)v, m is 0 or an integer having a value of 1, 2 or 3; v is an integer having a value of 1, 2 or 3; Ar is phenyl or naphthyl; X is fluorine; provided that when s is 0, Rl is 0(CU2) m -(X) , Ar is phenyl, v is 1 and X is 4-fluoro then m is not 0; or the pharmaceutically acceptable salts thereof.
  • Ri is preferably O(CH2) m Ar-
  • (X)v, and m is preferably 1.
  • Ar is preferably phenyl and X is preferably a fluorine substituted 1 to 2 times on the phenyl ring.
  • R4 is preferably NR5R6 wherein both R5 and R6 are preferably hydrogen.
  • Specific embodiments of Formula (I) containing R2 as a hydroxyurea derivative are: N-3-[6-(2,6-Difluorobenzyloxy)-2,3-dihydrobenzofuranyl]-N-hydroxyurea; N-3-[6-(4-Fluorobenzyloxy)-2,3-dihydrobenzofuranyl]-N-hydroxyurea; N-3-[6-(2,4-Difluorobenzyloxy)-2,3-dihydrobenzofuranyl]-N-hydroxyurea; N-3-[6-(2-Fluorobenzyloxy)-2,3-dihydrobenzofuranyl]-N-hydroxyurea;
  • Preferred hydroxyureas of Formula (I) and (Ia) are N-3-[6-(2,6-Difluorobenzyloxy)-2,3-dihydrobenzofuranyl]-N-hydroxyurea;
  • aryl or “heteroaryl” are used herein at all occurrences to mean substituted and unsubstituted aromatic ring(s) or ring systems containing from 5 to 16 carbon atoms, which may include bi- or tri-cyclic systems and may include, but are not limited to heteroatoms selected from O, N, or S.
  • Representative examples include, but are not limited to, phenyl, naphthyl, pyridyl, quinolinyl, thiazinyl, and furanyl.
  • heterorocvclic such as when R5 and R6 together with the nitrogen to which they are attached form a saturated 5-7 membered ring system in which the ring many contain one or more heteroatoms selected from the group consisting of N, O, or S; and may include, but is not limited to, pyrrolidine, piperidine, piperazine, or mo ⁇ holine.
  • lower alkyl or “alkyl” are used herein at all occurrences to mean straight or branched chain radical of 1 to 10 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms,unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
  • aralkyl is used herein to mean C1-4 Ar, wherein Ar is as defined in
  • Formula (I) including, but not limited to phenyl, benzyl, 1- or 2-naphthyl and the like.
  • alkanoyl is used herein to mean -C(O)Ci-io, wherein alkyl is as defined above, including but not limited to methyl, ethyl, isopropyl, n-butyl, t-butyl, and the like.
  • cycloalkyi is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • halo or halogen are used interchangeably herein to mean radicals derived from the elements fluorine, chlorine, bromine, and iodine.
  • lipoxygenase is used herein to mean 5-, 12-, or 15- lipoxygenase, preferably 5-lipoxygenase.
  • OPUA mediated disease or disease state any disease state which is mediated (or modulated) by oxidized polyunsaturated fatty acids, specifically the arachidonic acid metabolic pathway.
  • the oxidation of arachidonic acid by such enzymes as the lipoxygenase enzymes is specifically targeted by the present invention.
  • Such enzymes include, but are not limited to, 5-LO, 12-LO, and 15-LO; which produce the following mediators, including but not limited to, LTB4, LTC4, LTD4, 5,12-diHETE, 5-HPETE, 12- HPETE, 15-H ⁇ TE, 5-HETE,12-HETE and 15-HETE.
  • OUFA interfering amount an effective amount of a compound of Formula (I) or (Ia) which shows a reduction of the in vivo levels of an oxygenated polyunsaturated fatty acid, preferably an arachidonic acid metabolite.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention.
  • Useful intermediates of the present invention are the novel hydroxylamine derivatives of Formula (II) as represented by the formula below.
  • R'3 is hydrogen, benzyl, optionally substituted benzyl , Si(R ⁇ )3, C(O)R5', C(O)OR5 ⁇
  • A is hydrogen or C( ⁇ )OR Z ;
  • R z is benzyl, Si(R x )3, t-butyl, or CH2OCH2CH2Si(Rx)3;
  • R5' is C 1-6 alkyl, aryl, or aralkyl
  • Rx is independently selected from alkyl or aryl; and R' is as defined as Ri in Formula (I); and the remaining variables W, Ar, X, m, s, and v are also as defined above for Formula (I).
  • R3 substituent groups are tetrahydropyranyl; CH2OCH3 when R'3 is Ci alkylC i-3alkoxy; CH2OCH2CH2Si(CH 3 )3, CH2OCH2CH2OCH3 when R'3 is C ⁇ alkylC2alkoxyCi-3alkoxy; C(O)R5 * and C(O)OR5 * with R ⁇ ⁇ as a Ci-6 alkyl, specifically methyl, t-butyl, or phenyl.group and benzyl when R5 is an aralkyl group.
  • R'3 is an optionally substituted benzyl the substituent groups are selected from Ci-6 alkoxy or C 1-6 alkyl.
  • hydroxylamine derivatives of Formula ⁇ are easily converted to the compounds of Formula (I) wherein R4 is NHR5R6 or a hydroxamate derivative using art known procedures.
  • R4 is NHR5R6 or a hydroxamate derivative
  • Various illustrative methods to prepare compounds of Formula (I) are given in U.S. Patent Summers et al., 4,873,259, issued October 10, 1989, pages 7-11, and Adams et al., WO 91/14674, published 3 October 1991 whose disclosures in their entirety are inco ⁇ orated by reference herein.
  • the present compounds of Formula (I) can be prepared by art-recognized procedures from known compounds. Several different synthetic schemes can be used to prepare the compounds of this invention and are described in greater detail below. Many starting materials are readily available to one skilled in the art, including but not limited to, the various mono- and di-substituted 4-chromoanones or 3-hydroxybenzofuranones, as disclosed in Heterocvclic Compounds: Chromenes. Chro anones. and Chromones. Chapters 3 and 4, Ellis Ed., Interscience Publication, Wiley & Sons, New York, or in The Chemistry of Heterocvclic Compounds . Weissberger, A. and Taylor, E. , Editors, Intersciene Publication, Wiley & Sons, New York, Mustafa, A. , Chapter V. Benzofuranones.
  • the compounds of Formula (I) can be produced by a process which comprises A. reacting a compound of Formula (H) as described above, wherein R'3 is hydrogen,
  • step A trimethylsilyl isocyanate as in step A above, to yield protected hydroxyurea derivatives of Formula (I) compounds which is then deprotected, optionally by hydrogenated with ethane thiol in the presence of aluminum trichloride, to yield a compound of Formula (I); or
  • the compounds of Formula (II) can be produced by a process which comprises which process comprises
  • W, R' ⁇ , m, v, Ar, and S are as defined for Formula (II); which is then reduced with borane pyridine complex, borane trimethylamine, or borane tetrahydrofuran or other borane complexes, to yield the hydroxylamine derivatives of Formula (H); or B. reacting a compound of Formula (IV) as defined above with sodium cyanoborohydride or phenyldimethylsilane in anhydride in trifluoroacetic acid to yield the hydroxylamine derivatives of Formula (II); or
  • X is a leaving group, such as a halogen, tosylate, mesylate or a triflate moiety;
  • W, R' ⁇ , s, m, v, and Ar are as defined for Formula (H); with Z-furfulaldehyde oxime and base to yield the corresponding nitrone which is hydrolyzed to yield the corresponding hydroxylamine derivatives of Formula (II);
  • W, R' ⁇ , s, m, v, and Ar are as defined for Formula (II) as described above; with a protected hydroxylamine, such as N,O-bis(t-butyloxycarbonyl)-hydroxylamine) or bisbenzyloxycarbonyl, and triphenylphosophine/ diethyldiazodicarboxylate to produce an intermediate which is treated with acid to yield the hydroxylamines of Formula (II).
  • a protected hydroxylamine such as N,O-bis(t-butyloxycarbonyl)-hydroxylamine) or bisbenzyloxycarbonyl
  • triphenylphosophine/ diethyldiazodicarboxylate to produce an intermediate which is treated with acid to yield the hydroxylamines of Formula (II).
  • the homochiral compounds of Formula (I), as well as the homochiral intermediates of Formula (H) can be prepared by a process which comprises A. (i) reacting a homochiral oxazolidione of Formula (A)
  • R is an optionally substituted aryl, arylmethyl, heteroaryl, or heteroarylmethyl; with phosgene or a phosgene equivalent and a base in anhydrous solvent to yield to form the corresponding acid chloride intermediate of Formula (VII) O O
  • step (iii) reacting the oxaziridine of step (ii) under acid conditions to yield the hydroxylamine salts of Formula (II) compounds; and then optionally reacting under the various pathways described herein to yield optically active final compounds of Formula (I); or D. resolving a mixture of protected or non protected enantiomeric hydroxylamines of Formula (Ha)
  • R* is and * is the chiral carbon attached to the NHOZ moiety
  • Z is hydrogen or a hydroxyl protecting group m, W, s, m, v, Ri, X, and Ar as are defined for Formula (I) or (H) as appropriate; by first treating the mixture of enantiomers of the formula (Ha) with a substantially chirally pure enantiomer of a homochiral organic acid HA* and then separating the acid addition salts by any conventional means well known to those of skill in the art.
  • suitable homochiral organic acids HA* include mild organic acids selected from amongst the homochiral acids conventionally used as resolving agents for racemic amines, for instance a dibasic acid such as (+)/L- or (-)/D-tartaric acid or a derivative thereof such as dibenzoyl- D- or L-tartaric acid or, more preferably, a monobasic acid such as (S)-(+)- or (R)-(-)- mandelic acid [C6HsCH(OH)CO2H]. Mono derivatives of tartaric acid (or other dibasic acids) such as the mono esters or amides may also be used, similarly the mandelate derivatives may also be used. Stronger organic acids such as camphorsulphonic acid should preferably be avoided. Suitable homochiral organic acids are readily available from the normal commercial suppliers. The organic acid should be a substantially pure homochiral enantiomer. It is preferable that the organic acid be at least
  • a preferred chiral acid is (S)-(+)- or (R)-(-)- mandelic acid [C6H5CH(OH)CO2H] to form a mixture of diasteriomeric acid addition salt salts.
  • the acid addition salts are then separated by conventional means well known to those of skill in the art to yield the desired diasteriomeric acid addition salt
  • hydroxyl protecting group is used herein to describe those groups well known in the art which may used to protect a hydroxyl group and which may be added to and removed from the substrate molecule without disturbing the remainder of the molecule. Suitable examples thereof are given in "Protecting Groups in Organic Chemistry", Greene T. W., Wiley, New York, 1981.
  • Preferred values for the hydroxyl protecting group Z include optionally substituted benzyl, methyl(Ci-3)alkoxy, methylethoxy(Ci-3)alkoxy, lower alkoxycarbonyl, tetrahydropyranyl, lower alkanoyl, aroyl, trialkylsilyl and trialkylsilyl- ethoxymethyl.
  • the pair of diastereoisomeric acid addition salts may be separated by any suitable means, for instance fractional crystallization.
  • a 1 : 1 ratio is preferable, although a 2: 1 ratio may also be used.
  • Suitable solvents include those normally used in acid addition salt formation, such as ethyl acetate, acetonitrile, acetone, or an alcohol optionally with acetic acid, for instance methanol, ethanol or isopropanol, preferably methanol or ethanol, and more preferably methanol with acetic acid.
  • Preferably salt formation is carried out with efficient stirring and temperature control, so that, if a suitable solvent is chosen, fractional crystallization may occur in a controlled fashion.
  • Suitable bases include mild amine bases such as aqueous ammonium hydroxide.
  • Suitable solvents include water.
  • hydroxyureas of Formula (I) wherein R4 is NR5R6 is a substituted amine or cyclic amine can be prepared by reaction of the appropriately substituted hydroxylamine hydrochloride of Formula (II) with phosgene to yield the acyl chloride intermediate which is reacted with the appropriate amine to yield the compounds of Formula (I).
  • phosgene is an alkyl chloroformate, such as ethyl chloroformate, in which case the resulting R4 term of Formula (I) will determine the reaction time and temperature needed for the reaction to proceed, i.e. at O° C or below or, if slow at an elevated temperatures of 100°-200° C in the appropriate solvent.
  • the preparation of the hydroxyureas of Formula (I) when -OR3 is a protecting group, as opposed to the free hydroxyl proceeds in a similar manner.
  • the protected hydroxylamine is reacted with phosgene or a phosgene equivalent, such as carbonyl diimidazole or phosgene trimer yielding a protected hydroxylamine intermediate which is reacted with an appropriate amine component (NHR5R6) to yield the protected hydroxyurea of Formula (I).
  • phosgene or a phosgene equivalent such as carbonyl diimidazole or phosgene trimer
  • NHR5R6 an appropriate amine component
  • the reaction of the protected hydroxylamine with trimethylsilyl isocyanate or with sodium or potassium cyanate in an acidic solution as discussed above may be employed to prepare the protected hydroxyurea of Formula (I).
  • Deprotection of the hydroxyl may be by hydrogenation with H2tPd C when R3 is benzyl , by mild acid treatment, such pyridinium para-toluenesulphonate in refluxing methanol or dilute HCl when R3 is tetrahydropyranyl , by a suitable base, such as potassium carbonate when R3 is an alkoyl or aroyl, by u z.
  • R4N + )F anhydrous fluoride
  • R4 * is a suitable alkyl or aryl derivative
  • B Si(R x )3
  • R4 * is a suitable alkyl or aryl derivative
  • R4 * is a suitable alkyl or aryl derivative
  • Pharmaceutically acceptable base addition salts and their preparation are well known to those skilled in pharmaceuticals.
  • Pharmaceutically acceptable bases (cations) of the compounds of Formula (I) and (Ia) which are useful in the present invention include, but are not limited to nontoxic organic and inorganic bases, such as ammonium hydroxide, arginine, organic amines such as triethylamine, butylamine, piperazine and (trihydroxy)methylamine, nontoxic alkali metal and alkaline earth metal bases, such as potassium, sodium and calcium hydroxides.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula (I) which are useful in the present invention include, but are not limited to, maleate, fumarate, lactate, oxalate, methanesulfonate, ethane-sulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate and phosphate salts and such salts can be readily prepared by known techniques to those skilled in the art.
  • the compounds of Formula (I) and (Ia) are useful for treating disease states mediated by the 5-lipoxygenase pathway of arachidonic acid metabolism in an animal, including mammals, in need thereof.
  • the discovery that the compounds of Formula (I) are inhibitors of the 5-lipoxygenase pathway is based on the effects of the compounds of Formula (I) on the production of 5-lipoxygenase products in blood ex vivo and on the 5-lipoxygenase in vitro assays, some of which are described hereinafter.
  • the 5-lipoxygenase pathway inhibitory action of the compounds of Formula (I) and (Ia) was confirmed by showing that they impaired the production of 5-lipoxygenase products such as leukotriene B4 production by RBL-1 cell supernatants. It has also been found that the compounds of Formula (I) do not appear to inhibit prostaglandin production in vitro and are therefore selective 5-lipoxygenase inhibitors.
  • Lipoxygenase products have been identified in exudate fluids from gouty patients. This disorder is characterized by massive neutrophil infiltration during the acute inflammatory phases of the disease. Since a major 5-lipoxygenase product, LTB4, is produced by neutrophils, it follows that inhibition of the synthesis of LTB4 may block an amplification mechanism in gout.
  • Yet another area in which inhibitors of lipid peroxidation involved in the OPUFA mediated can have utility is that generally refered as degenerative neurological disorders, such as Parkinson's disease.
  • Another area is that of traumatic or ischemic injuries, such as stroke, brain or spinal cord injuries and inflammatory disease of the brain and spinal column.
  • More specicially preferred disease states are the mycardial induced ischemic injuries and or reperfusion injuries.
  • Yet another area of utility for inhibitors of the 5-lipoxygenase pathway is in the area of prevention of rejection of organ transplants. [See, e.g., Foegh et al., Adv. Prostaglandin. Thromboxane. and Leukotriene Research. 13, 209-217 (1983).] Yet another utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of tissue trauma. [See, e.g., Denzlinger s Science, 230 (4723), 330-332 (1985)].
  • Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of inflammatory reaction in the central nervous system, including multiple sclerosis. [See, e.g., Mackay et al., Clin. Exp. Immunology.15., 471-482 (1973)].
  • Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of asthma. [See, e.g., Ford-Hutchinson, J. Allergy Clin. Immunol..24, 437-440 (1984)].
  • Another utility for inhibitors of the 5-lipoxygense pathway is in the treatment of Adult Respitory Distress Syndrome. [ See, e.g., Pacitti et. al.. Circ. Shock , 21. 155-168 (1987)].
  • Yet another utility for inhibitors of the 5-lipoxygenase pathway is in the treament of allergic rhinitis.
  • vasculitis Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of vasculitis, immune complex disease, immune complex nephritis, glomerulonephritis, and generally in renal diseases, such as ischemic renal failure, glycerol induced acute renal failure, aminonucleoside induced nephrosis, nephrotoxic nephritis, lupus nephritis, and obstructive nephropathy.
  • ischemic renal failure glycerol induced acute renal failure
  • aminonucleoside induced nephrosis aminonucleoside induced nephrosis
  • nephrotoxic nephritis nephrotoxic nephritis
  • lupus nephritis obstructive nephropathy
  • An additional area of utility for inhibitors of the 5-lipoxygenase pathway is in the opthamalogic area, in particular general inflammation of the corneal anterior and posterior segments due to disease or surgery such as in post surgical inflammation, uveitis, and allergic conjuntivitis.
  • the pharmaceutically effective compounds of this invention are administered in conventional dosage forms prepared by combining a compound of Formula (I) or (Ia)
  • active ingredient in an amount sufficient to produce 5-lipoxygenase pathway inhibiting activity with standard pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • Formula (Ia) is a subset of Formula (I) all dosage forms and dosages apply in a similar manner.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the . .% such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • each parenteral dosage unit will contain the active ingredient [i.e., the compound of Formula (I)] in an amount of from about 30 mg. to about 300 mg.
  • each oral dosage will contain the active ingredient in an amount of from about 50 mg to about 1000 mg.
  • the compounds of Formula (I) may also be administered topically to a mammal in need of the inhibition of the 5-lipoxygenase pathway of arachidonic acid metabolism.
  • the compounds of Formula (I) may be administered topically in the treatment or prophylaxis of inflammation in an animal, including man and other mammals, and may be used in the relief or prophylaxis of 5-lipoxygenase pathway mediated diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
  • a compound of Formula (I) (hereinafter also referred to as the "active ingredient") required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the inflammatory condition and the animal undergoing treatment, and is ultimately at the discretion of the physician.
  • a suitable anti-inflammatory dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
  • topical administration is meant non-systemic administration and includes the application of a compound of Formula (I) externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
  • systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration. While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.
  • the topical formulations of the present invention both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s).
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as: liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C. for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and pro 3ne glycol.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or a-oehis oil.
  • an agent to hasten drying and to cool the skin such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or a-oehis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis.
  • the basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol.
  • the formulation may inco ⁇ orate any suitable surface active agent such as an anionic, cationic or non-ionic sulfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • suitable surface active agent such as an anionic, cationic or non-ionic sulfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • the compounds of Formula (I) may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the daily dosage amount of a compound of Formula (I) administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.
  • This invention relates to a method of treating a disease state which is mediated by the 5-lipoxygenase pathway in an animal in need thereof, including humans and other mammals, which comprises administering to such animal an effective, 5-lipoxygenase pathway inhibiting amount of a Formula (I) compound.
  • Formula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the Formula (I) compound with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the Formula (I) compound is administered to an animal in need of inhibition of the 5-lipoxygenase pathway in an amount sufficient to inhibit the 5-lipoxy- genase pathway.
  • the route of administration may be oral, parenteral, by inhalation or topical.
  • parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • the daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day.
  • the daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day for OPUFA and in particular 5-lipoxygenase treatment. It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a Formula (I) or (II) compound will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular animal being treated, and that such optimums can be determined by conventional techniques.
  • the reaction mixture was stirred for 2 hours at room temperature and the crude solid collected by filtration, washed with water (500 mL) and sucked dry.
  • the wet cake was suspended in water (310 mL) and the pH adjusted to 6.5 with 50% NaOH (40 mL).
  • the mixture was allowed to stir overnight at ambient temperature.
  • the pH was adjusted to 9.5 with concentrated NH4OH, stirred for 1 hour, the product collected by filtration, washed with water (500 mL) and dried at 55 °C under vacuum to afford an off white solid (146.2 g, 90%) which was used without further purification.
  • a lubricating agent such as Span 85 or oleic acid
  • a propellant such as freon, preferably a combination of freon 114 and freon 12
  • a lubricating agent such as Span 85 or oleic acid
  • disperse such in a propellant (c.a.), such as freon, preferably a combination of freon 144 and freon 12, and put into an appropriate aerosol container adapted for either intranasal or oral inhalation administration.
  • mice were age-matched. Their weight range was from 21 to 30 g.
  • the test groups generally contained 3-6 animals.
  • 5-lipoxygenase (5-LO) was isolated from extracts of RBL-1 cells.
  • the assay for assessing inhibition of the 5-LO activity was a continuous assay which monitored the comsumption of oxygen (O2).
  • the cell extract 100 ug was preincubated with the inhibitor or its vehicle in 25 mM BisTris buffer (pH 7.0) that contained 1 mM EDTA, 1 mM ATP, 150 mM NaCl and 5% ethylene glycol for 2 minutes at 20°C (total volume 2.99 ml).
  • Arachidonic acid (10 uM) and CaCl2 (2 mM) were added to start the reaction, and the decrease in O2 concentration followed with time using a Clark-type electrode and the Yellow Spring O2 monitor (type 53) (Yellow Springs, OH). The optimum velocity was calculated from the progress curves. All compounds were dissolved in ethanol with the final concentration of ethanol being 1% in the assay.
  • Drug-induced effects on enzyme activities are described as the concentration of drug caus. a 50% inhi " * : on of oxygen consumption (IC50).
  • Human monocytes were prepa i d from leukosource packs supplied by the American Red Cross.
  • the leukosource packs were fractionated by a two-step procedure described by F. Colatta et al. (J. Immunology 132:936, 1984) that uses sedimentation on Ficoll followed by se mentation on Percoll.
  • the monocyte fraction that results from this technique was comp ⁇ of 80-90% monocytes with the remainder being neutrophils and lymphocytes. In addition, significant number of platelets are present.
  • the monocytes (10-5 cells) were placed into polypropylene tubes and used as a suspended culture.
  • the assay buffer consisted of RPMI 1640 buffer, 2 mM glutamine, 2.5 mM HEPES and 2 mM CaCl2 (total volume 0.475 ml). Compounds (0.005 ml) were added in DMSO, and the cells were preincubated for 10 minutes at 37°C with constant agitation. A23187 (2 uM) was used to stimulate tne cells. After an additional 10 minutes, the buffer was collected by centrifiigation (2500 xg for 15 minutes), and stored at -70°C until assayed. LTB4 production was measured by radioimmunassay which was performed according to the manufacturer's (Advanced Magnetics, Boston, MA) instructions. PGE2 was determined using an RIA kit supplied by New England Nuclear (Boston, MA).
  • mice were pre-treated per os with vehicle or a test compound (dissolved in dimethylacetamide and diluted 1 to 10 with sesame oil) 30 minutes prior to removal of blood.
  • the 5-lipoxygenase product LTB4 was extracted from whole blood following
  • A23187 stimulation Aliquots of pooled heparinized mouse blood (1 ml each aliquot) from male CD1 mice (Charles River) were placed into 4 ml polypropylene tubes. The tubes were preincubated for about five minutes at 37°C. A23187 (60 uM) was added to stimulate eicosanoid production. Several aliquots of blood were not stimulated and, thus, provided background levels for eicosanoid production. All tubes were incubated for about 30 minutes at 37°C. The blood samples were centrifuged at 400 xg for about 15 minutes, and the plasma recovered for extraction. One volume of chilled acetonitrile was added to all at 5°C.
  • the supematants were recovered and diluted with 1% formic acid:l% triethylamine to achieve a final concentration of 20% acetonitrile. These supematants were then loaded onto the extraction cartridge that had been conditioned according to the Manufacturer's instructions (Solid Phase Extraction Columns, J. T. Baker, C 18 3 ml size). The samples were washed with 3 ml of 1% formic acid:l% triethylamine, air dried, and then washed with 3 ml of petroleum ether. After air drying again, the samples were eluted with methyl formate. The eluents were concentrated under vacuum.
  • the concentrates were resuspended in 30% acetonitrile buffered with 50 mM ammonium acetate (200 ul). The recovery of LTB4 was 60%. The 300 ul concentrates were assayed by radioreceptor assay for LTB4 by labortatory protocol.
  • LTB4 PRODUCTION BY HUMAN WHOLE BLOOD Heparinized human blood was collected by venipuncture.
  • the blood was prewarmed (4.5ml of blood per sample) for 5 min at 37° C in a waterbath with constant agitation, then preincubated with the test compound or DMSO for an additional 5 minutes.
  • A23187 (60 ⁇ M) in 0.5ml autologous plasma was added and the blood incubated for 10 min at 37 °C.
  • the reaction was stopped by placing the samples on ice followed by centrifugation at 2500 x g for 15 min at 4°C.
  • the plasma was collected and combined with
  • Phe ⁇ vlbenzoquinone (PBQ, Eastman Kodak Co., Rochester, NY) was dissolved in warm (50°C , ethanol and diluted with distilled water to a final concentration of 0.2 mg/ml.
  • the solution which was protected from light by a foil wrap was administered intraperitoneally at a dose volume of 0.01 ml/gm.
  • mice were pre-treated with vehicle or test compound (dissolved or suspended in 25% PEG 200) for about 15 minutes and then injected with PBQ, following which each mouse was placed into individual 4 liter beakers.
  • CD1 mice show a characteristic abdominal contraction/stretching response which consists of extending one or both of the hind limbs. These responses which occur at a variable frequency (not less than 1-2 seconds apart) were counted on a hand counter. The counting period was for 10 minutes following a 5 minute acclimation period. Results are based on the total number of constrictions observed during the 10 minute period.
  • Example 1 The compound of Example 1 exhibited analgetic activity using the phenylbenzoquinone-induced abdominal constriction assay.

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Abstract

Composés d'hydroxyurée comprenant des dérivés benzyloxylés de substitution par le fluor du dihydrobenzofurane et des dérivés de 4H-2,3-dihydroxybenzopyrane, compositions pharmaceutiques réalisées à partir de ces composés et utilisation de celles-ci comme inhibiteurs des voies des acides gras polyinsaturés oxygénés et de la 5-lipoxygénase.
PCT/US1994/008096 1993-07-14 1994-07-14 Inhibiteurs de la 5-lipoxygenase Ceased WO1995002402A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU73663/94A AU7366394A (en) 1993-07-14 1994-07-14 5-lipoxygenase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9149393A 1993-07-14 1993-07-14
US08/091,493 1993-07-14

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WO1995002402A1 true WO1995002402A1 (fr) 1995-01-26

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WO (1) WO1995002402A1 (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013125732A1 (fr) 2012-02-24 2013-08-29 Takeda Pharmaceutical Company Limited Composé à noyau aromatique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991014674A2 (fr) * 1990-03-27 1991-10-03 Smithkline Beecham Corporation Inhibiteurs de 5-lipoxygenase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991014674A2 (fr) * 1990-03-27 1991-10-03 Smithkline Beecham Corporation Inhibiteurs de 5-lipoxygenase

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013125732A1 (fr) 2012-02-24 2013-08-29 Takeda Pharmaceutical Company Limited Composé à noyau aromatique
JP2015508051A (ja) * 2012-02-24 2015-03-16 武田薬品工業株式会社 芳香環化合物
US9238639B2 (en) 2012-02-24 2016-01-19 Takeda Pharmaceutical Company Limited Aromatic ring compound

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ZA945085B (en) 1995-02-22

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