WO1992021678A1 - COMPOSES DE PYRROLO[1,2a]INDOLE INHIBITEURS DE LA LIPOXYGENASE - Google Patents

COMPOSES DE PYRROLO[1,2a]INDOLE INHIBITEURS DE LA LIPOXYGENASE Download PDF

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WO1992021678A1
WO1992021678A1 PCT/US1992/004779 US9204779W WO9221678A1 WO 1992021678 A1 WO1992021678 A1 WO 1992021678A1 US 9204779 W US9204779 W US 9204779W WO 9221678 A1 WO9221678 A1 WO 9221678A1
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alkyl
formula
compound
hydrogen
pyrrolo
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PCT/US1992/004779
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English (en)
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Jerry Leroy Adams
Ravi Shanker Garigipati
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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. BACKGROUND OF THE INVENTION
  • the metabolism of arachidonic acid occurs by many, pathways.
  • One route of metabolism is via the cyclooxygenase (CO) mediated pathway which produces PGH 2 which is in turn metabolized to the prostanoids (PGE 2 , TxA 2 and prostacyclin). These products are produced by various cells including polymorphonuclear 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
  • 5-HPETE 5-hydroxyeicosatetraenoic acid
  • Lipoxygenases are classified according to the position in the arachidonic acid which is oxygenated. Platelets metabolize arachidonic acid to 12-HETE, while polymorphonuclear leukocytes (PMNs) contain 5 and 15 lipoxygenases. It is known that 12-HETE and 5,12-diHETE are chemotactic for human
  • 5- HPETE is known to be a precursor to the peptidylleukotrienes, formerly known as slow reacting substance of anaphylaxis (SRS-A) and LTB 4 .
  • SRS-A slow reacting substance of anaphylaxis
  • LTB 4 has been shown to be a potent bronchoconstrictors.
  • This invention relates to a compound of the Formula (I)
  • R 1 and R 2 are hydrogen and the other is
  • R is hydrogen, a pharmaceutically acceptable cation, aroyl or C 1-12 alkanoyl
  • D is oxygen or sulfur
  • W is CY 1 Y 2 (CH 2 )s
  • Y 1 is hydrogen or (C 1-2 )alkyl
  • s is a number having a value of 0 or 1;
  • R 4 is NR 5 R 6 ; (C 1-6 )alkyl; halosubstituted (C 1-6 )alkyl; hydroxysubstituted-(C 1-6 )alkyl; (C 2-6 )alkenyl; aryl or heteroaryl optionally substituted by halogen, (C 1-6 )alkyl, halosubstituted (C 1-6 )alkyl, hydroxyl, or (C 1-6 )alkoxy;
  • R 5 is H or (C 1-6 )alkyl
  • R 6 is H; (C 1-6 )alkyl; aryl; aryl(C 1-6 )alkyl; heteroaryl; alkyl substituted by halogen or hydroxyl; aryl or heteroaryl optionally substituted by a substituent selected from the group consisting of halo, nitro, cyano, (C 1-12 )alkyl, (C 1 _ 6)alkoxy, halosubstituted (C 1-6 )alkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulphonyl, or alkylsulfinyl; or
  • R 5 and R 6 may together form a ring having 5 to 7 ring atoms, which ring atoms may optionally include a further heteroatom selected from oxygen, sulfur or nitrogen;
  • R 3 , R 7 and R 8 are independent substituent groups which when combined with the parent ring system have a lipophilicity value from about 2.5 to about 50; or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (I) are useful for inhibiting the formation of oxygenated polyunsaturated fatty acids (hereinafter OPUFA).
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a "pharmaceutically acceptable carrier or diluent and an effective amount of an OPUFA pathway inhibiting compound of Formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating an OPUFA mediated disease in an animal in need thereof which comprises administering to such animal, including humans, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • this invention relates to a method of treating a lipoxygenase pathway mediated disease in an animal, including humans, 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.
  • This invention also relates to a method of treating analgesia in an animal in need thereof, including humans, which comprises administering to such animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating an OPUFA mediated disease in an animal in need thereof which comprises administering to such animal, including humans, an effective amount of a compound of formula (II) (a hydroxylamine precursor of a compound of formula (I), hereinafter defined) or a pharmaceutically acceptable salt thereof.
  • 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, methods of treating an OPUFA mediated disease, specifically a 5-lipoxygenase pathway mediated disease comprising
  • the compounds of formula (I) have been found to be useful in inhibiting the enzymes involved in tile oxygenated polyunsaturated fatty acid pathway which includes the metabolism of arachidonic acid, in an animal, including humans, in need thereof.
  • the lipophilicity value provides a quantitative treatment of the effect of structure on the reactivity or ability of the compounds of formula (I) and (II) to act as OPUFA inhibitors. It has been found that compounds of formula (I) and (II) which have certain combinations of substituents R 3 , R 7 and R 8 which raise the lipophilicity value of the parent compound (in which each of R 3 , R 7 and R 8 is hydrogen and s is 0) above the value of 2.5 calculated for the parent compound are active as OPUFA inhibitors. It is however appreciated that there may be some isolated instances where the particular combination of substituents R 3 , R 7 and R 8 may raise the lipophilicity value above 2.5 but neverthe less result in compounds which are not OPUFA inhibitors.
  • the lipophilicity of the R 1 /R 2 /Y 1 groups is not included and each is considered only as hydrogen.
  • the lipophilicity value for the R 3 , R 7 and R 8 moieties in combination with the parent ring is in the range from about 2.5 to about 50, more preferably from about 2.8 to about 25, even more preferably from about 3.0 to about 15 and most preferably from about 3.3 to about 9. Representative examples are shown in Table A below for compounds of formula (I) wherein W is CH 2 and s is 0.
  • R 3 , R 7 and R 8 is each independently selected from the group consisting of hydrogen, halogen, (C 1-10 )alkyl, (C 1-10 )alkoxy, NR 9 R 10 , (CH 2 ) m - Ar-(X)y, O(CH 2 ) m Ar-(X)v, or S(CH 2 ) m -Ar-(X)v; or R 3, R 7 and R 8 may also be a protected amine functionality, such as an N-acyl or sulfonyl amide;
  • n is a number having a value of 0 to 4; preferably m is 0 to 2;
  • v is a number having a value of 1 or 2; preferably v is 1;
  • R 9 and R 10 are independently selected from hydrogen, (C 1-10) alkyl,
  • halosubstituted(C 1-6 )alkyl, (C 5-8) cycloalkyl, (C 2-10 )alkenyl, aryl(C 1-6 )alkoxy, or R 9 and R 10 may together form a saturated or unsaturated ring having 5 to
  • ring atoms which ring atoms may optionally include a further heteroatom selected from oxygen, sulfur or nitrogen;
  • Ar is a member selected from the group consisting of phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, furanyl, imidazoyl, benzimidazoyl, triazolyl, oxazolyl, isoxazolyl, thiazole, or thienyl;
  • X is a member selected from the group consisting of hydrogen, halogen,
  • r is a number having a value of 0, 1 or 2;
  • Y 3 is hydrogen or (C 1-3 )alkyl
  • t is a number having a value of 0 or 1.
  • R 3 is selected from hydrogen, halogen, (C 1-6 )alkoxy, C 1-6 )alkyl or a derivative of the alkylaryl moieties ((CH 2 ) m -Ar-(X ) v , O(CH 2 ) m Ar-(X) v , or S(CH 2 ) m -Ar-(X) v ), where the polymethylene chain (CH 2 )m is of sufficent length to avoid a potential problem of steric hindrance. More preferably, R 3 is hydrogen or flourine.
  • a more preferred embodiment of the present invention is where the (X) v groups are hydrogen, alkoxy, halo, and CF 3 , preferably in the 4-position.
  • the R 5 group is independently selected from hydrogen or a
  • the v term is preferably 1. If the Ar ring is disubstituted, preferably one of the X moieties is alkyl, alkoxy, halo, or CF 3 .
  • R 3 , R 7 and Re groups of interest are halogen, alkoxy, phenethyl, benzyloxy, aryloxy and substituted derivatives thereof.
  • groups are halogen, such as chloro and flouro; halo substituted aryl and aryloxy derivatives, such as 4-chlorobenzyloxy, 4-flurophenoxy, methoxy, phenoxy, benzyloxy, 4-methoxybenzyloxy, 2-phenylethyl, 2-quinoylmethoxy, and 2-naphthylmethoxy.
  • protected amine refers to those standardly used in the art as a non-strongly basic amine, such as those having a pKa above 7.
  • N-acyl amide includes such groups as, but is not limited to, formamide, acetamide, N-acetyl, and N-benzoyl.
  • sulfonylamide includes such groups as, but is not limited to, N-methanesulfonamide.
  • a further preferred embodiment of the present invention is where D is oxygen.
  • R 4 is NR 5 R 6 or (C 1-6 )alkyl.
  • R 5 is aryl or arylalkyl and R 6 is phenyl or hydrogen. More preferably, R 5 and R 6 are independently hydrogen or alkyl.
  • R 7 moiety when for instance R 8 is hydrogen and s is 0, is the 7-position.
  • a preferred disubstitution for the R 7 and R 8 moieties also includes a 7-position substitution.
  • R' is preferably hydrogen or a pharmaceutically acceptable cation.
  • hydroxyurea compounds of formula (I) include the following:
  • 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.
  • 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, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like.
  • alkenyl is used herein at all occurrences to mean a 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-1-propenyl, 1-butenyl, 2-butenyl and the like.
  • aralkyl is used herein to mean Ar(C 1-4 )alkyl, wherein Ar is as defined for formula (I).
  • aroyl is used herein to mean ArC(O)-, wherein Ar is as defined for formula (I), including, but not limited to, phenyl, 1- or 2-naphthyl and the like.
  • alkanoyl is used herein to mean alkylC(O)-, wherein alkyl is as defined above, including but not limited to methyl, ethyl, isopropyl, n-butyl, t- butyl, and the like.
  • cycloalkyl 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 any lipoxygenase enzyme, such as but not limited to, 5-, 8-, 11-, 12-, or 15- lipoxygenase enzymes.
  • OUFA mediated disease or disease state is meant 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, LTB 4 , LTC 4 , LTD 4 , 5,12-diHETE, 5-HPETE, 12-HPETE,
  • 15-HPETE 5-HETE,12-HETE and 15-HETE.
  • OUFA interfering amount an effective amount of a compound of formula (I) or (II) which shows a reduction of the in vivo levels of an oxgyenated 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.
  • B' is hydrogen, benzyl, optionally substituted benzyl , Si(R x )3, C(O)R 5' , C(OX)R 5' , CH 2 OCH 2 CH 2 Si(Rx) 3 , (C ⁇ . 3 )alkoxy(C ⁇ )alkyl, (C 1- 3 )alkoxy(C 2 )alkoxy(C 1 )alkyl, or tetrahydropyranyl;
  • A is hydrogen or C(O)OR Z ;
  • R z is benzyl, Si(R x ) 3 , t-butyl, or CH 2 OCH 2 CH 2 Si(Rx) 3 ;
  • R 5' is C 1-6 alkyl, aryl, or aralkyl
  • R x is independently selected from alkyl or aryl
  • Preferred B' substituent groups are tetrahydropyranyl; -CH 2 OCH 3 (B' is (C 1-3 )alkoxy(C 1 )alkyl); -CH 2 OCH 2 CH 2 Si(CH 3 ) 3 (B' is CH 2 OCH 2 CH 2 Si(Rx) 3 ), -CH 2 OCH 2 CH 2 OCH 3 when (B' is (C 1-3 )alkoxy(C 2 )alkoxy(C 1 )alkyl); C(O)R 5' and C(OX)R 5' with R 5' as (C 1-6 ) alkyl, specifically methyl, t-butyl, or phenyl group or benzyl (R 5' is aralkyl).
  • the substituent groups are selected from (C 1-6 )alkoxy or (C 1-6 )alkyl.
  • hydroxylamines of formula (II) include:
  • a compound of formula (I) may be obtained by a process which comprises treating a compound of formula (II) with a reagent capable of transforming a hydroxylamine [-NH(OH)] functional group into a hydroxyurea [-N(OH)CON-] or a hydroxamic acid derivative [-N(OH)CO-].
  • a reagent capable of transforming a hydroxylamine [-NH(OH)] functional group into a hydroxyurea [-N(OH)CON-] or a hydroxamic acid derivative [-N(OH)CO-].
  • Suitable such reagents are well known in the art and include trimethyl isocyanate, alkali metal cyanate, phosgene or a phosgene equivalent followed by ammonia or an amine (for a hydroxyurea) or an acylating agent such as an acyl chloride or an acid anhydride(for a hydroxyamic acid derivative).
  • an acylating agent such as acetic anhydride in the presence of a base, such as pyridine, followed by hydrolysis with an alkali hydroxide, such as lithium hydroxide, to yield of a hydroxamic acid derivative of formula (I) ;
  • step A (ii) trimethylsilyl isocyanate as in step A above, to yield a protected
  • a compound of formula (II) wherein R 2 is H may be produced by a process which comprises: A. reacting a compound of Formula (III):
  • R" 7 N-OH; and R' 3 , R' 7 , R' 8 and W are as defined for formula (II); which is then reduced with a suitable reducing agent capable of reducing an oxime to a hydroxyamine, for instance a borane complex such as borane pyridine, borane trimethylamine or borane tetrahydrofuran, sodium
  • R' 9 is a leaving group, such as a halogen, tosylate, mesylate or a triflate moiety; and R' 3 , R' 7 , R' 8 and W are as defined for formula (II);
  • R' 10 is OH; and R' 3 , R' 7 , R' 8 and W are as defined for formula (II); with a protected hydroxylamine, such as N,O-bis(t-butyloxycarbonyl)-hydroxylamine or N,O-bis(bisbenzyloxycarbonyl)-hydroxylamine, and triphenylphosophine/ diethyldiazodicarboxylate to produce an intermediate which is then deprotected as desired, such as by treatment with
  • the homochiral compounds of formula (I), as well as the homochiral intermediates of formula (II) can be prepared by a process which comprises
  • R is an optionally substituted aryl, arylmethyl, heteroaryl, or heteroarylmethyl
  • optically active hydroxylamine may then be converted under any of the various pathways described herein to yield optically active compounds of formula (I);
  • R' 11 is NH 2 ; and R' 3 , R' 7 , R' 8 and W are as defined for formula (II); with 4-methoxybenzaldehyde in trhnethylamine;
  • step (ii) oxidizing the intermediate of step (i) to yield the corresponding
  • step (iii) reacting the oxaziridine of step (ii) under acid conditions to yield a hydroxylamine salts of formula (II);
  • optically active hydroxylamine may then be converted under any of the various pathways described herein to yield an optically active compound of formula (I);
  • An optically active amine of formula (VIII) may be obtained by reacting an optically active alcohol of formula (V) with diphenylphosphoryl azide and triphenylphosphine / diethyldiazodicarboxylate (DEAD) to form an optically active azide intermediate which may then be reduced to give the desired product.
  • DEAD triphenylphosphine / diethyldiazodicarboxylate
  • a hydroxyurea compound of formula (I) may be prepared according to the synthetic route shown in Scheme la below :
  • Alkylation of the indole la is performed under basic conditions in the presence of an omega halobutyrate, such as ethyl 4-bromobutyrate, to form If.
  • omega halobutyrate such as ethyl 4-bromobutyrate
  • Dieckmann eyclization may be effected under a variety of conditions, including alcoholic base, such as sodium ethoxide at or near ambient temperature or using strong amide bases (for example, lithium diisopropyl amide, potassium bis(trimethylsilyl)amide) in inert solvents (for example, tetrahydrofuran, diethyl ether, or other ethereal solvents) at lower temperatures (-70 to 0oC) to produce after isolation and decarboxylation, 1g.
  • alcoholic base such as sodium ethoxide at or near ambient temperature
  • strong amide bases for example, lithium diisopropyl amide, potassium bis(trimethylsilyl)amide
  • inert solvents for example, tetrahydrofuran, diethyl ether, or other ethereal solvents
  • Hydroxamic acid derivatives of formula (I) may be obtained from intermediate 1d. This is converted to a diacetate intermediate by addition of an acylating agent, such as acetyl chloride (about 2 equivalents), in the presence of triethylamine (about 3 equivalents) in methylene chloride for about 30 minutes. Acetic anhydride in the presence of other bases such as pyridine may be used as an alternative acylating agent The O-acetate moiety is removed by hydrolysis with an alkali metal hydroxide, such as lithium hydroxide, to yield the corresponding hydroxamic acid of formula (I).
  • an alkali metal hydroxide such as lithium hydroxide
  • the oxime 1d or an O-protected derivative thereof, such as the acetate, may also be reduced by borane-trimethylamine, borane-tetrahydrofuran, sodium cyanoborohydride in methanol, or other borane compounds.
  • the hydroxytetralone derivative 2 is modified to contain an active leaving group, such as the triflate indicated in 7.
  • Other acceptable leaving groups are the bromides, chlorides, iodides, tosylates, and mesylates.
  • a bidentate Pd (II) catalyst such as PdCl 2 (dppf) or Pd(PPh 3 ) 4 , or any other acceptable coupling agent, and a tris(phenethyl)-borane derivative, using the method of Sukuki (A. Suzuki et al, J Amer Chem Soc, Ill, 314-321, 1989) results in the addition of the appropriate R7/R8 group, to yield the corresponding tetralone compound 8.
  • the above cited procedure is especially useful for the
  • R 7 /R 8 group is an alkyl group.
  • organometallics such as alkylzinc, -lithium, -tin or -aluminum reagents may also be useful when R 7 /R 8 is an alkyl group (see references cited in Suzuki paper).
  • organoborane A. Suzuki , Pure & Appl. Chem.. 57, 1749-1758, 1985
  • organozinc R. Keenan et al, Syn. Commun., 19, 793-798, 1989
  • organotin J. K. Stille, Angew. Chem. Int. Ed., 25, 508-524, 1986
  • compound may also be useful in this process step when R 3 is an aryl or olefinic group.
  • R 7 /R 8 is an alkyl, aryl, or olefinic group is the copper mediated coupling of an aryl trifalte, such as 7, using the procedure of
  • hydroxylamine and subsequently reduced with borane in pyridine and hydrochloric acid.
  • the hydroxylamine 9 is converted into the corresponding hydroxyurea 10 by the method outlined in Scheme I.
  • the hydroxylamine 9 may also be converted into the corresponding hydroxamic acid derivative by the method outlined above for Scheme I.
  • a hydroxyurea compound of formula (I) wherein R 4 is NR 5 R 6 and the corresponding amine NHR 5 R 6 is a substituted amine or cyclic amine maybe prepared by treating a hydroxylamine hydrochloride of formula (II) firstly with phosgene to yield an acyl chloride intermediate which may then be treated with the appropriate amine to yield the compound of formula (I).
  • An alkyl chloroformate such as ethyl chloroformate, may be used in place of phosgene in which case the resulting R 1 term of formula (I) will determine the reaction time and temperature needed for the reaction to proceed, i.e. at 0o C or below or, if slow, at an elevated temperatures of 100o-200o C in the appropriate solvent.
  • a hydroxyurea of formula (I) when -OB' is a protecting group, as opposed to a free hydroxyl proceeds in a similiar manner.
  • the protected hydroxylamine is reacted with phosgene or a phosgene equivalent, such as carbonyl diimidazole or phosgene trimer, to give a protected phosgene or a phosgene equivalent, such as carbonyl diimidazole or phosgene trimer, to give a protected
  • the protected hydroxyurea of formula (I) may be employed to prepare the protected hydroxyurea of formula (I). This is followed by any means appropriate for the deprotection of the -OB' group.
  • Deprotection of the hydroxyl may be by hydrogenation with H 2 /Pd/C when B' is benzyl, by mild acid treatment, such pyridinium 4-toluenesulphonate in refluxing methanol or dilute HCl when B' is
  • tetrahydropyranyl by a suitable base, such as potassium carbonate when B' is an alkanoyl or aroyl group, by use of anhydrous fluoride (R 4' N + )F- when B' is Si(R x ) 3 , or by treatment with trifluoroacetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HCl when B' is t-butyloxycarbonyl.
  • a suitable base such as potassium carbonate when B' is an alkanoyl or aroyl group
  • R 4' N + anhydrous fluoride
  • trifluoroacetic acid trimethylsilyltrifilate with 2,6-lutidine
  • anhydrous ether HCl when B' is t-butyloxycarbonyl.
  • a protected hydroxylamine of formula (I) may be obtained by treating the correponding compound of formula (II) in which the hydroxylamine moiety is replaced by an activated leaving group X such as chloro, bromo, mesylate or tosylate, with a protected hydroxylamine NH 2 OB' in which B' is for instance benzyl or tetrahydropyranyl, with heating and in an appropriate solvent.
  • the protected hydroxylamine may then be deprotected using the standard removal conditions for the protecting group employed, to yield the free hydroxylamine offormula (II).
  • the protected intermediate may also used as outlined above to prepare the O-protected hydroxyurea and then deprotected to yield the final compound of formula (I).
  • the above noted process may also be used to make a starting amine compound by use of NH 3 or azide and a suitable reduction step, all well known to those skilled in the art.
  • the starting compounds for the preparation of the hydroxylamine and amine intermediates described above, in which the hydroxylamine or amine moiety is replaced by an activated leaving group, as hereinbefore defined, may be readily obtained from the corresponding ketone or hydroxyl precursors by procedures well known in the art.
  • the starting compound when X is halo, the starting compound may be prepared from the corresponding mesylate or toyslate derivative by reaction thereof with lithium chloride or bromide in acetone.
  • the benzylic sulfonates are highly reactive and are therefore in most cases are used as non-isolated intermediates.
  • the halo compound may be obtained directly from the alcohol by a number of art known procedures.
  • the mesylate or tosylate derivatives may in turn be prepared from the
  • the alcohol by the treatment thereof with mesyl or tosyl chloride in the presence of an appropriate base, for example pyridine or triethylamine, with or without additional solvent.
  • the alcohol may be obtained from the corresponding ketone by the reduction thereof with a suitable reducing agent, such as sodium borohydride or lithium aluminum hydride.
  • hydroxylamine such as O-benzyl hydroxylamine or O-t-butyldiphenylsilyl hydroxylamine under solvolytic conditions, for example in the presence of trifluoroacetic acid.
  • the protected intermediate may then be deprotected, using the standard removal conditions for the protecting group employed, to yield a free hydroxylamine of formula (II).
  • the protected intermediate may also be converted first to the protected urea and then to a final compound of formula (I) as discussed above.
  • the starting material 11 is treated with N,O-bis-(t-butyloxycarbonyl)-hydroxylamine and triphenylphosprjine/diethyldiazodicarboxylate (DEAD), to form the intermediate 12 which is then treated with an appropriate acid, such as trifluroacetic acid or hydrochloric acid, to produce the free hydroxylamines of formula (II).
  • the optically active alcohol 11 may be prepared by
  • optically active alcohol may also be converted to the corresponding optically active halo or sulfonate compound (see D. Mathre, supra). Such steps as noted above are obviously useful as well to make the racemic mixture.
  • the (optically active) alcohol starting material 11 may also be treated with diphenylphosphoryl azide and triphenylphosphine/diethyldiazodicarboxylate (DEAD) to form the (optically active) azide which may then be reduced to the corresponding (optically active) amine 13.
  • DEAD triphenylphosphine/diethyldiazodicarboxylate
  • the sequence starts with an optically active amine 13, obtained through a variety of methods including the classical methods of preparing salts with chiral acids, such as camphor sulfonic acids, such techniques being readily apparent to those skilled in the art.
  • the requisite racemic amine can be prepared from the alcohol 11 or activated derivatives thereof, by the methods previously outlined above, substituting ammonia for (un)substituted
  • the starting material 13 is either the pure "R” or a pure “S” configuration which is then reacted with 4-methoxybenzaldehdye in triethylamine to form the intermediate 14. This may then be oxidized by a variety of agents, such as MCPBA (metachloroperbenzoic acid), MPP (monoperoxyphthalate) or MMPP
  • the optically active amine 13 may be converted directly to the chiral hydroxylamine 16 using dimethyldioxirane (Danishesky, et.al. J. Org. Chem., vol . 55, p1981-1983, 1990) or a peracid anhydride, such as benzoyl peroxide (R.M. Coates et al, J. Org. Chem., 55, 3464-3474, 1990).
  • the hydroxyurea is reacted with the N-chlorocarbonyl derivative of a homochiral oxazolidinone, for example 4-(phenylmethyl)-2-oxazolidinone (see Org. Syn. John Wiley & Sons, Inc., 68, 77 for preparation).
  • a chlorinated hydrocarbon or etheral solvent preferably CH 2 CI 2
  • a base either an amine base such as trialkylamine or pyridine or a solid alkali metal carbonate, such as potassium or calcium, but most preferably triethylamine
  • Chromatography or other physical methods are employed to separate these adducts which are then cleaved under basic conditions, for example using an alkali metal hydroperoxide, such as lithium, in an aqueous-etheral solvent (THF, glyme, digylme, ethyl ether ) at about -20 to about 50°C, preferably from about -5°C to about room temperature, more preferably from about 0°C to about 15°C to yield the individual enantiomers of the hydroxyurea .
  • THF aqueous-etheral solvent
  • the N-chlorocarbonyl derivative may be obtained by treating the
  • phosgene or a phosgene equivalent such as phosgene trimer or carbonyl diimidazole.
  • the temperature will be about -30 to about 0°C for use with phosgene and about 20oC to about 200 oC for a phosgene equivalent.
  • a chloro carbamate [acid chloride]
  • Additional 4-substituted chiral oxazolidinones which may also be used are optionally substituted (R groups) aryl, arylmethyl, heteroaryl, or
  • heteroarylmethyl wherein the substituents include, but are not limited to, mono or disubstituted alkyl, halo, alkoxy, cyano, or any other protected amino, alcohol, carboxy, or sulfur (regardless of oxidation state). Additionally R can be an alkyl moiety of greater than 2 carbons, preferably longer, such as t-butyl or iso-propyl, which may be optionally substituted as well.
  • Representative examples of the aryl and heteroaryl groups include, but are not limited to, phenyl, naphthyl, pyrrolyl, thienyl, thiazinyl and furanyl.
  • oxazolidinones are prepared from the chiral amino alcohols which are readily available from reduction of the chiral amino acids by the general procedure of Evans (Org. Syn., John Wiley & Sons, Inc. 68, 77 and references cited therein) which are incorporated by reference herein.
  • Compounds of formula (I) in which R 1 is hydrogen and R 2 is a hydroxyurea or a hydroxamic acid moiety may be prepared from a precursor prepared by the 1,2-carbonyl transposition of the ketone group in the 1-ketone intermediate to the 2-position (Scheme VI). Many such 1,2-carbonyl transposition procedures are known (see Tetrahedron, 39, 345, 1983 for review).
  • a particularly useful and general procedure is the reduction, dehydration, hydroboration-oxidation sequence ( see Kirkiacharian, B.S.et al, Synthesis. 815, 1990, for
  • 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) which are useful in the present invention include, but are not limited to, non-toxic 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, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate and phosphate salts and such salts can be readily repared by known techniques to those skilled in the art.
  • the compounds of formula (I) 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) was confirmed by showing that they impaired the production of 5-lipoxygenase products such as leukotriene B 4 production by RBL-1 cell supernatants.
  • chemotactic eicosanoids such as the 5-lipoxygenase pathway product known as LTB 4 .
  • LTB 4 the 5-lipoxygenase pathway product
  • 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, LTB 4 , is produced by neutrophils, it follows that inhibition of the synthesis of LTB 4 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 [see Braughler et al., Jour. Biol. Chem., 262, No. 22, 10438-40, 1987, see also Xu et al., J. Neurochemistry, 55, 907-912, 1990; Asano et al., Molecular and Chemical Neuropathology, 10, 101-133, 1989 and Bracken et al, NE. J. Med., 322:1405-1411, 1990]
  • 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.
  • 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., 74, 437-440, 1984]. Additionally another utility for inhibitors of the 5-lipoxygense pathway is in the treatment of Adult Respitory Distress
  • Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of vasculitis, glomerulonephritis, and immune complex disease [see Kadison et al., "Vasculitis: Mechanism of Vessel Damage” in Inflammation: Basic Principles and Clinical Correlates, 703-718, Ed. Gallin et al, Raven Press, N.Y., N.Y., 1988].
  • Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of dermatitis [see Pye et al., “Systemic Therapy” in Textbook of Dermatology, Vol. III, 2501-2528, Ed. Rook et al., Blackwell Scientific
  • 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 [see Rao N. et al. Arch, Ophathmal., 105 (3), 413-419, 1987; Chiou, L. and Chiou, G. J. Ocular Pharmacol. 1, 383-390, 1985; Bazan H., J. Ocular Pharma, 4, 43-49, 1988; and Verbey N.L. et al., Current Eye Research. 7, 361-368, 1988].
  • the pharmaceutically effective compounds of this invention are administered in conventional dosage forms prepared by combining a compound of Formula (I) or (II) ("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
  • 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 art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • 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 tile 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
  • 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
  • the amount of a compound of formula (I) (hereinafter 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
  • 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
  • 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.
  • an active ingredient may 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.
  • topical formulations of the present invention both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carriers) therefor and optionally any other therapeutic
  • 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.
  • aseptic technique examples of 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 propylene 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 arachis 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 tile 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 incorporate any suitable surface active agent such as an anionic, cationic or non-ionic sulfactant such as sorbitan esters or
  • 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.
  • 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.
  • This invention further relates to a method of treating analgesia in an animal in need thereof, which comprisies administering to such animal an effective, analgesia inhibiting amount of a compound of formula (I).
  • 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-lipoxygenase 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 both 5-lipoxygenase and algesia treatment.
  • Example 1 N- ⁇ 1-(2,3-Dihydro-1H-pyrrolo[1,2-a]indolyl) ⁇ -N- hydroxyurea 2,3-Dihydro-1H-pyrrolo[1,2-a]indole-1-one.
  • sodium hydride 2.65 grams (hereinafter g) of 60% dispersion in mineral oil, 66 milimoles (hereinafter mmol)) in toluene (550 milliliters (hereinafter mL)) was added ethyl 2-indolecarboxylate (10.00 g, 53 mmol).
  • the pH was made acidic by the addition of 5% HCl, and the mixture was extracted with CH 2 CI 2 .
  • the organic extract was washed with saturated aqueous NaCl.
  • the solvent was removed in vacuo, and the residue was dissolved in acetic acid (750 mL) containing H 2 O (40 mL). The resulting mixture was heated at reflux for 14 h, then allowed to cool to room
  • Example 2 N- ⁇ 1-(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl) ⁇ - N-hydroxyurea 7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-1-one.
  • ethyl 5-benzyloxy-2-indolecarboxylate 6. g, 23 mmol
  • sodium hydride 1.2 g of 60% dispersion in mineral oil
  • ethyl acrylate 1.6 mL, 25 mmol
  • N- ⁇ 1-(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl ⁇ )-N-hydroxyurea To a solution of N- ⁇ 1-(7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl) ⁇ -N-hydroxyamine (1.00 g, 3.4 mmol) in THF (60 mL) was added
  • N- ⁇ 1-(2,3-Dihydro-7-isopropyl-9-methyl-1H-pyrrolo[1,2-a]indolvyl ⁇ -N- hydroxyurea To a solution of N- ⁇ 1-(2,3-dihydro-7-isopropyl-9-methyl-1H- pyrrolo[1,2-a]mdolyl) ⁇ -N-hydroxyamine (120 mg, 0.5 mmol) in THF (10 mL) was added trimethylsilylisocyanate (0.15 mL, 1.1 mmol). The resulting mixture was heated at reflux for 1.5 h, then allowed to cool to room
  • N- ⁇ 1-(7-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl) ⁇ -N-hydroxyurea To a solution of N- ⁇ 1-(7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl) ⁇ -N-hydroxyamine (1.55 g, 7.5 mmol) in THF (60 mL) was added
  • N- ⁇ 1-(2,3-Dihydro-7-ethyl-1H-pyrrolo[1,2-a]indolyl) ⁇ -N-hydroxyurea To a solution of N- ⁇ 1-(2,3-dihydro-7-ethyl-1H-pyrrolo[1,2-a]indolyl) ⁇ -N-hydroxyamine (0.52 g, 2.4 mmol) in THF (3 mL) was added
  • N- ⁇ 1-(2,3-Dihydro-7-phenoxy-1H-pyrrolo[1,2-a]indolyl) ⁇ -N-hydroxyurea To a solution of N- ⁇ 1-(2,3-dihydro-7 -phenoxy-1H-pyrrolo[1,2-a]indolyl) ⁇ -N-hydroxyamine (3.00 g, 10.7 mmol) in THF (150 mL) was added trimethylsilyl isocyanate (3.0 mL, 21.5 mmol). The resulting mixture was heated at reflux for 5 h, then allowed to cool. The mixture was partitioned between aqueous NH 4 CI and EtOAc, and the organic extract was washed with saturated aqueous NaCl.
  • the reaction mixture was allowed to warm to room temperature and stirred for 5 h.
  • the solution was made basic by the addition of saturated aqueous Na 2 CO 3 , and the solid which formed was collected by filtration and washed with H 2 O to afford the hydroxyamine (1.25 g, 57%).
  • N- ⁇ 1-(2,3-Dihydro-9-methyl-7-phenoxy-1H-pyrrolo[1,2-a]indolyl) ⁇ -N-hydroxyurea To a solution of N- ⁇ 1-(2,3-dihydro-9-methyl-7-phenoxy-1H-pyrrolo[1,2-a]indolyl) ⁇ -N-hydroxyamine (1.25 g, 4.25 mmol) in THF (20 mL) was added trimethylsilyl isocyanate (1.13 mL, 8.50 mmol). The resulting mixture was heated at 60°C for 1 h, then allowed to cool and was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed successively with H 2 O and saturated aqueous NaCl.
  • a pharmaceutical composition of this invention in the form of a capsule is prepared by filling a standard two-piece hard gelatin capsule with 50 mg. of a compound of formula (I), in powdered form, 110 mg. of lactose, 32 mg. of talc and 8 mg. of magnesium stearate.
  • Example 9 Ointment Composition Compound of Formula (I) 1.0 g
  • the compound of formula (I) is dispersed in a small volume of the vehicle and this dispersion is gradually incorporated into the bulk to produce a smooth, homogeneous product which is filled into collapsible metal tubes.
  • the carbowax, beeswax and lanolin are heated together at 60°C and added to a solution of methyl hydroxybenzoate. Homogenization is achieved using high speed stirring and the temperature is allowed to fall to 50°C.
  • the compound of formula (I) is added and dispersed throughout, and the composition is allowed to cool with slow speed stirring.
  • the methyl hydroxybenzoate and glycerin are dissolved in 70 ml of the water at 75°C.
  • the sorbitan monolaurate, polysorbate 20 and cetostearyl alcohol are melted together at 75°C and added to the aqueous solution.
  • the resulting emulsion is homogenized, allowed to cool with continuous stirring and the compound of formula (I) is added as a suspension in the remaining water. The whole suspension is stirred until homogenized.
  • Example 12 Composition for Administration by Inhalation
  • a lubricating agent such as Span 85 or oleic acid
  • a propellant such as freon, preferably a combination of freon 114 and freon 12, and put into an
  • Example 13 Composition for Administration by Inhalation
  • mice were CD1 mice obtained from Charles River Breeding Laboratories, and within a single experiment the mice were age-matched. Their weight range was from 25 to 42 g.
  • the test groups generally contained 3-6 animals.
  • the 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 (O 2 ).
  • the cell extract 100 ug was preincubated with the inhibitor or its vehicle in 25 mM Bis Tris 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 CaCl 2 (2 mM) were added to start the reaction, and the decrease in O 2 concentration followed with time using a Clark-type electrode and the Yellow Spring O2 monitor (type 53) (Yellow Springs, OH).
  • the optimum velodty 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 causing a 50% inhibition of oxygen consumption (IC 50 ).
  • Eicosanoid production from human monocytes in vitro Human monocytes were prepared 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 sedimentation on Percoll. The monocyte fraction that results from this technique was composed of 80-90% monocytes with the remainder being neutrophils and lymphocytes. In addition, significant number of platelets are present.
  • the monocytes (10 6 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 CaCl 2 (total volume 0.475 ml).
  • 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 LTB 4 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.
  • Phenylbenzoquinone-induced abdominal-constriction assay Phenylbenzoquinone (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 bind 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.
  • the ED 50 was determined between the vehicle control mean and test group.
  • the ED 50 was determined using linear regression analysis and was taken as the dose which resulted in a 50% inhibition of the vehicle control constriction response.
  • the compounds shown herein inhibited 5-LO enzyme activity using isolated enzyme, whole cells and mouse blood, ex vivo.
  • This inhibition of fatty acid oxygenase activity did not extend to cyclooxygenase and therefore, these selective 5-LO inhibitors would not be expected to have analgetic activity which is a property of cyclooxygenase inhibitors (Doherty, N.S. Mediators of the Pain of Inflammation. Annual Reports in Med. Chem. 22, 245-252, 1987). It was therefore surprising to find that many of these 5-LO inhibitors had significant and potent analgetic activity. This property enhances the utility of these inhibitors in diseases such as osteoarthritis were the clinical endpoint is pain (Moskowitz, R.W. Treatment of Osteoarthritis. In: Arthritis and Allied Conditions. Ed. D.J. McCarty. Lea and Febiger, Philadelphia, PA ,1181-1189, 1979).

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Abstract

Composés d'hydroxamate/hydroxyurée de pyrrolo[1,2-a]indole, compositions pharmaceutiques contenant lesdits composés et leur utilisation comme inhibiteurs du métabolisme des acides gras oxygénés eet polyinsaturés.
PCT/US1992/004779 1991-06-07 1992-06-05 COMPOSES DE PYRROLO[1,2a]INDOLE INHIBITEURS DE LA LIPOXYGENASE WO1992021678A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1048249C (zh) * 1994-02-04 2000-01-12 沈阳药学院 新氨基吡咯里嗪酮类化合物
US7608626B2 (en) 2004-11-01 2009-10-27 Wyeth Substituted indolizines and derivatives as CNS agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1533190A (fr) * 1964-07-10 1968-07-19 Kyowa Hakko Kogyo Kk Procédé de préparation des dérivés du mitosène
US4134894A (en) * 1978-05-04 1979-01-16 Warner-Lambert Company Pyrrolo[1,2-a]indole compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1533190A (fr) * 1964-07-10 1968-07-19 Kyowa Hakko Kogyo Kk Procédé de préparation des dérivés du mitosène
US4134894A (en) * 1978-05-04 1979-01-16 Warner-Lambert Company Pyrrolo[1,2-a]indole compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1048249C (zh) * 1994-02-04 2000-01-12 沈阳药学院 新氨基吡咯里嗪酮类化合物
US7608626B2 (en) 2004-11-01 2009-10-27 Wyeth Substituted indolizines and derivatives as CNS agents

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