EP0522000A1 - Inhibiteurs de 5-lipoxygenase - Google Patents

Inhibiteurs de 5-lipoxygenase

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Publication number
EP0522000A1
EP0522000A1 EP91907085A EP91907085A EP0522000A1 EP 0522000 A1 EP0522000 A1 EP 0522000A1 EP 91907085 A EP91907085 A EP 91907085A EP 91907085 A EP91907085 A EP 91907085A EP 0522000 A1 EP0522000 A1 EP 0522000A1
Authority
EP
European Patent Office
Prior art keywords
formula
alkyl
hydroxyurea
yield
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP91907085A
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German (de)
English (en)
Inventor
Jerry Leroy Adams
Ravi Shanker Garigipati
Don Edgar Griswold
Stanley James Schmidt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0522000A1 publication Critical patent/EP0522000A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/64—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups singly-bound to oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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 PGH2 which is in turn metabolized to the prostanoids (PGE2, TxA2, and prostacyclin).
  • CO cyclooxygenase
  • PGE2 cyclooxygenase
  • TxA2 prostanoids
  • 5-hydroperoxy-eicosatetraenoic acid 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 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 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. The SRS family of molecules, such as leukotrienes C4 and D4 have been shown to be potent bronchoconstrictors.
  • SRS-A slow reacting substance of anaphylaxis
  • 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 iiiflarnrnatory 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.
  • the compounds of Formula (I) have been found to be not only be selective 5-lipoxygenase inhibitors but also, unexpectantly, to possess analgesic activity, not normally associated with compounds having lipoxygenase inhibition.
  • This invention relates to a compound of the Formula (I)
  • R ⁇ N A R 4 R2 and R3 are / ;
  • R is hydrogen, a pharmaceutically acceptable cation, aroyl or a Ci-12 alkoyl
  • B is oxygen or sulfur
  • R4 is NRsRg, alkyl j.g, halosubstituted alkyl 1-6, hydroxy substituted alkyl 1-6, alkenyl 2-6. aiyi or heteroaryl optionally substituted by halogen, alkyl 1-6, halosubstituted alkyl ⁇ . ⁇ , hydroxyl, or alkoxy 1-6;
  • R5 is H or alkyl 1-6;
  • R_ is H, alkyl j.*5, 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, alkyl ⁇ . ⁇ 2, alkoxy .
  • R5 and R ⁇ 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;
  • W is CH2(CH2)s, 0(CH2)s, S(CH2)s, or NR7(CH 2 ) S ;
  • R7 is hydrogen, Cl-4 alkyl, phenyl, Ci-6 alkoyl, or aroyl; s is a number having a value of 0 to 3; provided that when 1 is 1 and W is O(CH2)s,
  • 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, alkyl J.JQ, cycloalkyl 5-8, alkenyl 2-10. hydroxy, (CHY)tcarboxy, O-alkyl ⁇ i ⁇ , S(O) r alkyli-
  • 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 polyunsaturated 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.
  • OPUFA oxygenated polyunsaturated fatty acid
  • 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.
  • This invention further relates to a method of treating algesia in an animal in need thereof which comprises administering to such animal an effective, analgesic amount of a compound of Formula (I), 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) and pharmaceutically acceptable salt thereof, 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, and methods of treating algesia 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 need thereof.
  • the compounds of Formula (I) have oral activity and are therefore useful for the treatment of various inflammatory disease states.
  • the compounds of Formula (I), particularly the hydroxyurea derivatives also possess unexpectedly, a superior analgesic activity, thus providing a method of treatment for algesia in an animal in need thereof.
  • the genus of com ⁇ pounds of Formula (I) useful in the treatment of algesia and as inhibitors of the OPFUA pathway does include compounds wherein q is 1, R4 is NR4R5, W is CH2(CH2) S , s is 1, and Ri is hydrogen, alkyl ⁇ io, or alkoxy 1- 1 0.
  • R is selected from O(CH2)m-Ar-(X)v, (CH2)m-Ar-(X) v , or S(CH2)m-Ar-(X) v ;
  • m is a number having a value of 0 to 3; and
  • v is a number having a value of 1 to 2.
  • Preferred X groups are hydrogen, alkoxy, halo, and CF3, preferrably in the 4-position.
  • X is (CHY)tN(R5)2
  • the R5 group is independently selected from hydrogen or an alkyl of 1-6 carbons yielding an unsubstituted, mono- or di-substituted amine component.
  • Rl groups of interest are alkoxy, phenethyl, benzyloxy, aryloxy, and substituted derivatives thereof. Specifically such groups are methoxy, phenoxy, benzyloxy, 4-methoxybenzyloxy, 4-chlorobenzyloxy, 4-flurophenoxy, 2-phenylethyl, 2- quinoylmethoxy, and 2-naphthylmethoxy.
  • W is CH2(CH2)s or O(CH2)s and s is a number having a value of 0 or 1.
  • a further preferred embodiment of the present invention is where B is oxygen.
  • Preferred R4 substituent groups are NR5R6 and the alkyl hydroxamate derivatives.
  • Preferred R6 substitutions when R is aryl or arylalkyl are phenyl or benzyl.
  • R5 and R6 are independently hydrogen or alkyl. Most preferred is where q is 1 and 1 is 0 for all R2 and R3 substitutent groups and W terms.
  • a preferred ring placement when W is CH2(CH2)s and s is 1 is on the 5- or 6-position of the benzene ring and when s is 0 the preferred position is the 4- or 5-position; applicable substitution patterns are also preferred when W is O(CH2)s, i-e., when s is 1 , the 7- or 8- position, and when s is 0 the 6- or 7- position.
  • R4 is other than a NR5R6 moiety yielding a hydroxamate derivative
  • R4 is preferrably alkyl, more preferably Cl-6, such as methyl, ethyl, n-propyl, isopropyl or t-butyl all optionally substituted
  • B is oxygen and q is 1. More preferred is where W is CH2(CH2)s or O(CH2) s and s is 0 or 1.
  • R' is preferably hydrogen or a pharmaceutically acceptable cation.
  • Some preferred hydroxyurea compounds of Formula (I) compounds which are themselves within the scope of the present invention include the following: N-l-(5-Benzyloxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyurea; N-l-(5-Phenoxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyurea;
  • N-l -(5-Benzyloxyindanyl)-N-hydroxyurea N- 1 -(5-Phenoxyindanyl)-N-hydroxyurea; N- 1 -(5-(4-Flurophenoxyindanyl)-N-hydroxyurea; N-l-(4-Benzyloxyindanyl)-N-hydroxyurea; N- 1 -(4-Phenoxyindanyl)-N-hydroxyurea; N- 1 -(4-(4-FlurophenoxyindanyI)-N-hydroxy urea; N-l-f5-(4-methoxybenzyloxy)-indanyl]-N-hydroxyurea; N-l -(7-Phenoxyindanyl)-N-hydroxyurea;
  • Preferred hydroxamate derivatives of Formula (1) compounds which are within the scope of the present invention are: N-Hydroxy-N- 1 -[6-(2-phenylethyl)- 1 ,2,3,4-tetrahydronaphthyl]acetamide;
  • any N-hydroxy acetamide derivatives of the corresponding hvdroxvamines made herein are also considered a preferred embodiment of this invention.
  • Patricularly preferred hydroxyamines of Formula (II) are N-l-(5-Benzyloxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyamine; N- 1 -(5-Phenoxy- 1 ,2,3,4-tetrahydronaphthyl)-N-hydroxyamine; N-l-[5-(4-Flurophenoxy)-l,2,3,4-tetrahydronaphthyl]-N-hydroxyamine; N- 1 -(6-Benzyloxy- 1 ,2,3,4-tetrahydronaphthyl)-N-hydroxyamine; N- 1 -(6-Phenoxy- 1 ,2,3,4-tetrahydronaphthyl)-N-hydroxyamine; N-l-f6-(4-Ruorophenoxy)-l,2,3,4-tetrahydronaphthyl]-N-hydroxyamine; or N-l-(6
  • 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, 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 Ci-4 Ar, wherein Ar is as defined in Formula (I).
  • aroyl is used herein to mean - C(0) Ar, wherein Ar is as defined in Formula (I), including, but not limited to benzyl, 1- or 2-naphthyl and the like.
  • alkoyl is used herein to mean -C(O)Cl-l ⁇ , 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 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-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. Specifically exemplified compounds are the pairs, (+)-N-l-(6-Benzyloxy-l,2,3,4-tetrahydronaphthyl)-N- hydroxyurea, and (-)-N-l-(6-Benzyloxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyurea; and (+)-N-3-(6-Benzyloxy-2,3-dihydrobenzofuryl)-N-hydroxyurea and (-)-N-3-(6-Benzyloxy- 2,3-dihydrobenzofuryl)-N-hydroxyurea.
  • Useful intermediates of the present invention are the novel hydroxylamine derivatives of Formula OT) as represented by the formula below.
  • the compounds of Formula (IT) have also been found to be compounds useful for inhibition of the OPUFA pathway and in the treatment of algesia.
  • the genus of compounds of Formula (II) useful as OPUFA inhibitors or in the treatment of algesia include compounds wherein B is hydrogen, W is CH2(CH2)s and s is 0 or 1, and compounds wherein B is hydrogen, W is S(CH2) S and s is l".
  • B' is hydrogen, benzyl, optionally substituted benzyl , Si(R ⁇ )3, C(0)R5', C(0)OR5',
  • A is hydrogen or C(O)OR z;
  • R z is benzyl, Si(R x )3, t-butyl, or CH2OCH2CH2Si(Rx)3;
  • R5' is C ⁇ _6 alkyl, aryl, or aralkyl;
  • Rx is independently selected from alkyl or aryl; and the remaining variables Rj, W, Ar, X, Y, R5, R7, m, n, p, s, t , q,- 1, and v are as defined above for Formula (I); provided that when B is hydrogen, W is other than CH2(CH2) S , and s is 0 or 1, and B is hydrogen, W is other than S(CH2) S and s is 1.
  • Preferred B substituent groups are tetrahydropyranyl; CH2OCH3 when B is C ⁇ alkylC ⁇ _3alkoxy; CH2OCH2CH2Si(CH 3 )3 , CH2OCH2CH2OCH3 when B is C ⁇ alkylC2alkoxyCi-3alkoxy; C(O)R5' and C(O)0R5' with R5' as a Cl-6 alkyl, specifically methyl, t-butyl, or phenyl.group and benzyl when R5 is an aralkyl group.
  • B is an optionally substituted benzyl
  • the substituent groups are selected from Ci-6 alkoxy or Cl-6 alkyl.
  • the present compounds of Formula ([) 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.
  • the schemes when illustrated utilize only one particular compound, the 1,2,3,4- tetrahydronaphthalene derivative, it will be seen from the working examples that other compounds of this invention can be prepared in the same manner using the appropriate starting materials, such as 6-methoxy-l-tetralone, 6-methoxy-2-tetralone, 5-hydroxy-2- tetralone, 7-methoxy-2-tetralone, 5-methoxy-indan-l-one, or 7-methoxybenzo-cycloheptan- 1-one.
  • the compounds of Formula (I) can be produced by a process which comprises
  • 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 aluminium trichloride, to yield a compound of Formula (I); or (iii) phosgene or a phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate, resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or a substituted amine; which is then deprotected, optionally by hydrogenation or with ethane thiol in the presence of aluminium trichloride, to yield a compound of Formula (I); or (iv) sodium or potassium cyanate in an acidic solution which is then deprotected, optionally by hydrogenation or with ethane thiol in the
  • the compounds of Formula (II) can be produced by a process which comprises A process for producing a compound of the Formula (II) as defined above, which process comprises
  • W, Ri, R7, s, q, 1, m, v, Ar, S, t, and Y 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 derviatives of Formula (II); or
  • R2 and R 3 are X
  • X is a leaving group, such as a halogen, tosylate, mesylate or a triflate moiety;
  • W, Ri, R7, s, q, 1, m, v, Ar, S, t, and Y are as defined for Formula (II); with Z-furfulaldehyde oxime and base to yield the corresponding nitrone of Formula (VI) which is hydroylzed to yield the corresponding hydroxylamine derviatives of Formula (II);
  • R2 and R3 are OH; W, Ri, R7, s, q, 1, m, v, Ar, S, t, and Y 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 L), as well as the homochiral intermediates of Formula QT) can be prepared by a process which comprises
  • 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
  • R2 and R3 are NH2
  • W, Ri, R7, s, q, 1, m, v, Ar, S, t, and Y are as defined for Formula (II); with 4-methoxybenzaldehyde in trimethylamine; (ii) oxidizing the intermediate of step (i) to yield the corresponding oxaziridine;
  • step (iii) reacting the oxaziridine of step (ii) under acid conditions to yield the hy ⁇ droxylamine salts of Formula (II) compounds; and then optionally reacting under the various pathways described herein to yield optically active final compounds of Formula (J); or
  • the compounds of Formula () can be prepared according to the following synthetic route, as displayed in Scheme I below :
  • compound 1 or any other suitable alkoxy derivative may be treated by a known means to remove the alkyl portion of the alkoxy group, such as using a solution of sodium ethanethiolate in a solvent, such as dry DMF, to which the alkoxy derivative is added and heated.
  • a solvent such as dry DMF
  • an aqueous acidic workup yields the corresponding hydroxy derivative 2.
  • the hydroxy compound 2 is then treated with a metal hydride, such as potassium hydride, and after the gas evolution subsides, a benzylhalide or phenylethyl halide, such benzylbromide, is added.
  • 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 (L).
  • an alkali metal hydroxide such as lithium hydroxide
  • the oxime 4 or O-protected derivatives, 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 PdCl2 (dppf) or Pd(PPh3)4, or any other acceptable coupling agent, and a tris(phenethyl)- borane derivative, using the method of Sukuki (A. Suzuki et. al. J.A.C.S.. Il l, pgs.314- 321, 1989) results in the addition of the appropriate Ri group to yield the corresponding tetralone compound 8.
  • the 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 03) with phosgene to yield the acyl chloride intermediate which is reacted with the appropriate amine to yield the compounds of Formula (J .
  • phosgene is an alkyl chloroformate, such as ethyl chloroformate, in which case the resulting R4 term of Formula Q 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 o -200° C in the appropriate solvent.
  • alkyl chloroformate such as ethyl chloroformate
  • R4 term of Formula Q 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 o -200° C in the appropriate solvent.
  • 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 ONHR5R6) to yield the protected hydroxyurea of Formula 0).
  • 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 ONHR5R6) to yield the protected hydroxyurea of Formula 0).
  • the reaction of the protected hydroxylamine with trimethylsilyl isocyante or with sodium or potasium cyanate in an acidic solution as discussed above may be employed to prepare the protected hydroxyurea of Formula (T). This is followed by any means appropriate for the deprotection of the -OB group.
  • Deprotection of the hydroxyl may be by hydrogenation with H2/Pd/C when B is benzyl , by mild acid treatment, such pyridinium para-toluenesulphonate in refluxing methanol or dilute HCl when B is tetrahydropyranyl , by a suitable base, such as potassium carbonate when B is an alkoyl or aroyl, by use of anhydrous fluoride (R4N + )F" when B is Si(R ⁇ )3, or by treatment with trifluoroacetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HCl when B is t-butyloxycarbonyl.
  • suitable protecting groups and methods for their removal will be found in T.W. Greene, Protective Groups in Organic Svnthesis. Wiley, New York, 1981.
  • a hydroxylamine which is protected such as 0-benzylhydroxylamine or O- tetrahydropyranyl hydroxylamine, or other O-protected hydroxylamines can also be used to produce the hydroxyureas of Formula (I) using as a starting material a compound having an active leaving group X ( in structure 11, Scheme IE replace OH with X), such as Cl, Br, OMs, or OTs by reaction with the hydroxylamine (NH2-OB) with heating in an appropriate solvent to yield a protected intermediate of Formula (II).
  • an active leaving group X in structure 11, Scheme IE replace OH with X
  • Cl, Br, OMs, or OTs by reaction with the hydroxylamine (NH2-OB) with heating in an appropriate solvent to yield a protected intermediate of Formula (II).
  • the protected intermediate may then be deprotected using the standard removal conditions for the protecting group employed to yield the free hydroxylamines of Formula (II), or the protected intermediate may used as outlined above to prepare the O-protected hydroxyurea and then deprotected to yield the final compounds of Formula Q).
  • the above noted process can be used to make the starting amine compounds, chiral or not , as so desired, by use of NH3, or N3 and suitable reduction step, all well known to those skilled in the art.
  • the starting compound, a halo compound can readily be prepared from the mesylate or toyslate derivatives (benzylic sulfonates are highly reactive and thus in most cases are used as non-isolated intermediates) or can be produced directly by a number of art known procedures from the corresponding alcohol.
  • the mesylates or tosylate derivatives can be prepared from the ketone derivatives by reduction to the corresponding alcohol by any number of readily available agents, such as sodium borohydride, or lithium aluminum hydride.
  • the alcohol is then reacted with mesyl or tosyl chloride in the presence of an appropriate base, for example pyridine or triethylamine, with or without additional solvent to form the mesylate or tosylate derivatives which are in turn displaced, for example either by in situ reaction or in a subsequent reaction with lithium chloride or bromide in acetone, to form the corresponding halogenated derivatives.
  • an appropriate base for example pyridine or triethylamine
  • Selected examples of protected compounds of Formula (LI) may also prepared by reaction of the alcohol 11 with a protected hydroxylamine, such as O-benzyl hydroxylamine or O-t-butyldiphenylsilyl hydroxylamine under solvolytic conditions, for example in the presence of trifluoroacetic acid.
  • a protected 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 the free hydroxylamines of Formula 01), or the protected intermediate may be converted first to the protected urea and then to the final compounds of Formula (I) as discussed above.
  • optically active intermediates Another synthetic pathway which will produce the hydroxylamines of Formula (II) and may also used to prepare the optically active intermediates, if the optically active alcohol derivative is used as a starting material is illustrated in Scheme III below.
  • the alcoholic starting material 11 is treated with N,0-bis(t-butyloxycarbonyl)hydroxylamine and triphenylphosphine / diethyldiazodicarboxylate ODEAD) producing 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 enantioselective reduction of the corresponding ketone precursor with an appropriate reducing agent (M.
  • optically active alcohol may also be convened to the corresponding optically active halo or sulfonate compound (see D. Mathre., compounds of Formula (II).
  • steps as noted above are obviously useful as well to make the racemic mixture.
  • the alcoholic starting material 11 is treated with diphenylphosphoryl azide and triphenylphosphine /diethyldiazodicarboxylate (DEAD) producing the optically active azide which can be reduced to the optically active amine 13.
  • optically active compounds of Formula (I) An additional route for preparation of the optically active compounds of Formula (I) is detailed in Scheme IV below.
  • the sequence starts with optically active amines, 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 hydroxylamines.
  • One available review for resolving racemic compounds is by R.M. Secor, Chem. Rev.. 63, 197 (1963).
  • the starting material 13 is either the pure "R” or a pure “S” configuration which is then reacted to form the intermediate 14 with 4-methoxybenzaldehdye in triethylamine.
  • the intermediate 14 is then oxidized by a variety of agents, such as MCPBA (metachloroperbenzoic acid), MPP
  • phosgene or a phosgene equivalent such as phosgene trimer or carbonyl diimidazole
  • a base in an anhydrous solvent
  • phosgene or a phosgene equivalent such as phosgene trimer or carbonyl diimidazole
  • NaH in toluene at reflux
  • a phosgene equivalent be used to temperature range will be from about 20°C to about 200 °C.
  • 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).
  • R can be an alkyl moiety of greater than 2 carbons, preferably longer, such as t-butyl or isopropyl, which may be optionally substituted as well.
  • aryl and heteroaryl groups include, but 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. Vol. 68, p77 and references cited therein) which are incorporated by reference herein.
  • 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 O°C to about 15°C to yield the individual enantiomers of the hydroxyurea .
  • THF aqueous-etheral solvent
  • Scheme VI For the preparation of compounds in which W contains nitrogen a synthetic sequence similar to that outlined in Scheme I is employed (illustrated in Scheme VI).
  • R2 is alkyl or substituted alkyl, this group is attached by reaction of 18 using the appropriate base catalysis and alkylating reagent
  • 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 (J 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 (rrihydroxy)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-sulfbnate, 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 ( ) 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 gx 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 (£) was confirmed by showing that they impaired the production of 5-lipoxygenase products such as leukotriene B4 production by RBL-1 cell supematants.
  • Another area of utility for an inhibitor of the 5-lipoxygenase pathway is in the treatment of psoriasis. It was demonstrated that involved psoriatic skin had elevated levels of LTB4 [See, Brain et al., Lancet, 19, February 19, 1983]. The promising effect of benoxaprofen on psoriasis [See, Allen et al., Brit. J. Dermatol.. 109. 126-129 (1983)], a compound with in vitro lipoxygenase inhibitory activity lends support to the concept that inhibitors of the 5-lipoxygenase pathway can be useful in the treatment of psoriasis.
  • 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.
  • 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)]. Additionally 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.
  • the pharmaceutically effective compounds of this invention are administered in conventional dosage forms prepared by combining a compound of Formula (I) or (13) ("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.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of 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 (J.) 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.
  • 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 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 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.
  • 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 ca ⁇ ier(s) therefor and optionally any other therapeutic ingredient(s).
  • the ca ⁇ rier(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 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 extemal 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, com, 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 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 Q.) 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 (T) 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).
  • treating is meant either prophylactic or therapeutic therapy.
  • mediated is meant caused by or exacerbated by.
  • Such 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 (J 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.
  • the optimal quantity and spacing of individual dosages of a Formula (I) or ( L) 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. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the Formula (I) compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the infrared spectrum of the product indicated a conjugated ketone at 1665 - 1685 cm" 1 .
  • the NMR spectrum indicated the presence of the benzyl methylene at ⁇ 5 and aromatic benzyl protons at ⁇ 7.4.
  • 6-Benzyloxy-l-tetralone oxime To a solution of 6-benzyloxy-l-tetralone (9.7 g, 38 mmol) in dry pyridine (100 mL) was added hydroxylamine hydrochloride (5.3 g, 76 mmol). The resulting mixture was heated at 50°C for 30 min, then was allowed to cool and concentrated under reduced pressure. The residue was crystallized from ethanol to yield the desired oxime (7.3 g, 71%).
  • 6-Methoxy-l-tetralone oxime To a solution of 6-methoxy-l-tetralone (5.19 g, 29.0 mmol) in dry pyridine (50 mL) was added hydroxylamine hydro-chloride (4.41 g, 58.0 mmol). The resulting mixture was heated at 50°C for 40 min and allowed to cool to room temperature. The solvent was removed in vacuo, and the residue was recrystallized from EtOH/ H2O to provide 5.08 g of the oxime (92% yield).
  • IR (cm-1) 3470, 3320, 3200, 2920, 1660.
  • CJMS/ CH4 (m/e, rel. int.) : 207 (M+H+, 7); 146 (22); 131 (100).
  • N- 1 -r6-r4-MethoxvbenzvloxvV 1.2.3.4-tetrahydronaphth vll-N-h vdroxvurea To a solution of N- 1- [6- (4-methoxy benzyloxy)- 1 ,2,3,4-tetrahydronaphthyl]-N-hydroxyamine (160 mg, 0.54 mmol) in THF (8 mL) was added trimethylsilyl isocyanate (0.16 mL, 1.2 mmol).
  • CiMS/NH3 (m/e, rel. int.) : 342 (M+H+, 2); 282 (45); 267 (100); 147 (20); 121 (50).
  • ⁇ liaL Calc. for Ci9H22N2 ⁇ 4-l/4 H2 ⁇ C 65.79, H 6.54, N 8.08; found C 65.89, H 6.41, N 8.07.
  • 6-f 1-TetralonvD trifluoromethylsulfonate To a solution of 6-hydroxy-l -tetralone (see example 1, 324 mg, 2.0 mmol) in CH2CI2 at -30°C was added trifluoromethanesulfonic anhydride (282 mg, 2.0 mmol), 2,6-lutidine (278 mg, 2.6 mmol) and dimethylaminopyridine (60 mg, 0.5 mmol). The resulting solution was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo, and the residue was dissolved in EtOAc and filtered. The filtrate was washed successively with 10% HCl and H2O. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with a gradient of EtOAc/ hexanes (0.5 - 2%) to provide the desired product (490 mg, 83%).
  • reaction mixture was again deoxygenated and heated at 50°C ovemight.
  • the reaction mixture was allowed to cool and concentrated under reduced pressure.
  • the residue was dissolved in EtOAc and washed successively with H2O and saturated aqueous NaCl.
  • the solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a gradient of EtOAc/ hexanes (0.8 - 3%) to provide the desired product (274 mg, 73%).
  • 6-(2-PhenylethylVl-tetralone oxime To a solution of 6-(2-phenylethyl)- 1-tetralone (5.01 g, 20.1 mmol) in dry pyridine (40 mL) was added hydroxylamine hydrochloride (2.79 g, 40.2 mmol). The resulting mixture was heated at 50°C for 30 min and allowed to cool to room temperature. The solvent was removed in vacuo, and the residue was recrystallized from ethanol to provide 5.26 g of the oxime (99% yield).
  • 6-Benzyloxy-3-oximino-2.3-dihydrobenzofuran To a solution of 6-benzyloxy-3-oxo- 2,3-dihydrobenzofuran (5.8 g, 25 mmol) in dry pyridine (38 mL) was added hydroxylamine hydrochloride (3.5 g, 50 mmol). The resulting mixture was heated at 50°C for 1 h, then allowed to cool to room temperature and poured into cold H2O (100 mL). The resulting suspension was stirred for 15 min. The solid which formed was collected by filtration, washed with cold H2O (30 mL) and dried to afford the oxime as a yellow solid (5.9 g, 92%).
  • N-3-(6-Benzyloxy-2.3-dihydro benzofuranyl-N-hydroxyurea To a solution of N-3-(6- benzyloxy-2,3-dihydro)benzofuranyl-N-hydroxyamine (100 g, 0.39 mol) in THF (2.3 L) was added decolorizing activated carbon (Norit A, 10 g), and the resulting mixture was stirred for 15 min. The mixture was filtered, and to the filtrate was added in one portion under an argon atmosphere trimethylsilylisocyanate (77 mL, 0.57 mol). The resulting mixture was heated at 55°C for 1 h, at which time HPLC analysis indicated that the reaction was incomplete.
  • N-2-(7-Methoxy-l .2.3.4-tetrahydronaphthyD-N-hydroxyurea To a solution of N-2-(7- methoxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyamine (150 mg, 0.78 mmol) in dry THF (5 mL) was added trimethylsilyl isocyanate (0.78 mL, 1.56 mmol), and the resulting mixture was heated at 50°C for 1 h. The solvent was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was triturated with Et2 ⁇ and recrystallized from CH2CI2 and MeOH to provide the hydroxyurea (88 mg, 48% yield). m.p. 152 - 53°C.
  • 6-Phenyl-l -tetralone To a solution of zinc chloride (5.1 mL of 1.0 M solution, 5.1 mmol) in dry THF (20 mL) was added phenyl lithium (2.6 mL of 2.0 M solution, 5.1 mmol). The resulting mixture was stirred at room temperature for 30 min and added to a solution containing 6-(l-tetralonyl) trifluoromethylsulfonate (1.09 g, 3.7 mmol, see example 8 for preparation), palladium acetate (7.6 mg, 0.03 mmol) and bis(l,3- diphenylphosphino)-propane (14 mg, 0.03 mmol) in dry THF (50 mL). The resulting mixture was stirred at room temperature for 1 h, and then partitioned between EtOAc and 3
  • 6-Phenyl-l -tetralone oxime To a solution of 6-phenyl-l -tetralone (99 mg, 0.4 mmol) in dry pyridine (6 mL) was added hydroxylamine hydrochloride (90 mg, 1.3 mmol). The resulting mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo, and the residue was recrystallized from EtOH to provide the desired oxime (85 mg, 81%).
  • N-l -f6-Phenyl-l .2.3.4-tetrahvdronaphthylVN-hvdroxyurea a solution of N-l -(6- phenyl-l,2,3,4-tetrahydronaphthyl)-N-hydroxyamine (270 mg, 1.1 mmol) in dry THF (10 mL) was added trimethylsilyl isocyanate (0.30 mL, 2.2 mmol). The resulting mixture was heated at 60°C for 1 h and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with H2O and saturated aqueous NaCl and dried (MgS04).
  • N-l-r5-C4-Methoxybenzyloxy ndany ⁇ -N-hydroxyurea To a solution of N-l-[5-(4- methoxybenzyloxy)indanyl]-N-hydroxyamine (220 mg, 0.8 mmol) in dry THF (4 mL) was added trimethylsilyl isocyanate (0.21 mL, 1.5 mmol). The resulting mixture was heated at 60°C for 1 h, then allowed to cool to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residue was triturated with Et2 ⁇ . Purification by flash chromatography eluting with a gradient of MeOH/ CH2CI2 provided the desired hydroxyurea (154 mg, 61%). m.p. 166 - 167°C.
  • 6-C4-Methoxybenzyloxy>3-oximino-2.3-dihydrobenzof uran To a solution of 6-(4- methoxybenzyloxy)-3-oxo-2,3-dihydrobenzofuran (2.46 g, 9.1 mmol) in dry pyridine (10 mL) was added hydroxylamine hydrochloride (1.24 g, 18.0 mmol). The resulting mixture was heated at 50°C for 2 h and allowed to cool to room temperature. The solvent was removed in vacuo, and the residue was recrystallized first from EtOH H2O and a second time from CH2CI2 to provide 739 mg of the oxime (29% yield).
  • N-l-f5-Benzyloxy-l .2.3.4-tetrahydronaphthylVN-hvdroxyurea To a solution of N-l - (5-benzyloxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyamine (350 mg, 1.49 mmol) in THF was added trimethylsilyl isocyanate (0.46 mL, 3.4 mmol). The resulting mixture was heated at reflux for 1 h and then allowed to cool. The solid which formed was collected by filtration and washed with Et2 ⁇ to afford the title compound (130 mg).
  • iH NM (CDCI3) : ⁇ 7.29 (m, 2H); 7.18 - 7.01 (m, 3H); 6.91 (m, 2H); 6.82 (dd, IH); 4.17 (m, IH); 2.90 - 2.78 (m, IH); 2.62 - 2.49 (m, IH); 2.27 - 2.15 (m, IH); 1.95 - 1.71 (m, 3H).
  • CIMS (NH3); m/e (rel. int.) : 256 [(M+H) + , 100], 240 (88); 238 (74), 223 (39).
  • N-l-C5-Phenoxy-l .2.3.4-tetrahydronaphthylVN-hydroxyurea To a solution of N-l -(5- phenoxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyamine (255 mg, 1.0 mmol) in THF was added trimethylsilyl isocyanate (0.32 mL, 1.0 mmol). The resulting mixture was heated at reflux for 1 h and then allowed to cool. The reaction mixture was concentrated under reduced pressure, and Et2 ⁇ was added to the residue. The solid which formed was collected by filtration to afford the title compound (150 mg, 50%). m.p.
  • reaction mixture was allowed to cool and was partitioned between CH2CI2 and H2O.
  • the aqueous phase was extracted with CH2CI2 (2 x 100 mL) and the combined organic extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4).
  • the solvent was removed in v ⁇ cuo to afford the title compound as a pale yellow oil (2.67 g, 90%).
  • N-l-r5-(4-Fluorophenoxy>1.2.3.4-tetrahydronaphthyl1-N-hvdroxyurea To a solution of N-l-[5-(4-fluorophenoxy)-l,2,3,4-tetrahydronaphthyl]-N-hydroxyamine (79 mg, 0.29 mmol) in THF was added trimethylsilyl isocyanate (0.10 mL, 0.74 mmol). The resulting mixture was heated at reflux for 1 h and then allowed to cool. The reaction mixture was concentrated under reduced pressure, and Et2 ⁇ was added to the residue. The solid which formed was collected by filtration to afford the title compound (40 mg, 44%).
  • 6- 2-PyridinylmethoxyVl -tetralone oxime 6-(2-pyridinylmethoxy)-l- tetralone (560 mg, 2.21 mmol) in dry pyridine (6 mL) under an argon atmosphere was added hydroxylamine hydrochloride (307 mg, 4.42 mmol). The resulting mixture was heated at 50°C for 0.5 h, then allowed to cool to room temperature and concentrated under reduced pressure. The residue was crystallized from EtOH to afford the title compound as a white solid (468 mg, 79%). m. ⁇ .
  • N- 1 -r6-f2-BenzimidazolylmethoxyVf 1.2.3.4-tetrahydronaphthyl ⁇ -N-h vdroxyurea To a solution of N- l-[6-(2-benzimidazolylmethoxy)-(l,2,3,4-tetrahydronaphthyl)]-N- hydroxyamine (115 mg, 0.37 mmol) in dry THF (7 mL) under an argon atmosphere was added trimethylsilyl isocyanate (0.10 mL, 0.74 mmol). The resulting mixture was heated at 60°C for 2 h, then allowed to cool to room temperature and concentrated under reduced pressure. The solid residue was purified by flash chromatography, eluting with 1 : 1 MeOH CH2CI2 to afford the title compound as a white solid (64 mg, 49%). m.p. 158 -
  • N-Hvdroxy-N-l-fS-benzyloxyindanvPacetamide The desired compound is prepared according to the method of Example 23 steps (a) and (b) except using a solution of N-l-(5- benzyloxyindanyl)-N-hydroxyamine as prepared in Example 2, step (d).
  • N-Hvdroxy-N-1 -(6-methoxy-l .2.3.4-tetrahvdronaphthyDacetamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-l-(6-methoxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in Example 3, step (b).
  • Example 27 N-Hydroxy-N- l- ⁇ .2.3.4-tetrahydronaphthyl acetamide
  • N-Hydroxy-N-1 -(I . ⁇ .S ⁇ -tetrahydronaphthyDacetamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-l-(l,2,3,4-tetrahydronaphthyl)-N-hy ⁇ oxyarr ⁇ ine as prepared in Example 4, step (b).
  • N-Hydroxy-N- 1 -r6-C4-methoxybenzyloxy 1.2.3.4-tetrahydronaphthy ⁇ acetamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-l-[6-(4-methoxybenzyloxy)-l,2,3,4-tetrahydronaphthyl]-N- hydroxyamine as prepared in Example 5, step (c).
  • N-Hvdroxy-N-l-[6-f4-chlorobenzyloxy -1.2.3.4-tetrahydronaphthyl1acetamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-l-[6-(4-chlorobenzyloxy)-l,2,3,4-tetrahydronaphthyl]-N- hydroxyamine as prepared in Example 6, step (c).
  • the desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-l-[6-(2-naphthylmethoxy)-l,2,3,4-tetrahydronaphthyl]-N- hydroxyamine as prepared in Example 7, step (c).
  • N-Hydroxy-N-3-(6-benzyloxy-2.3-dihydrobenzofuranyl)acetamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-3-(6-benzyloxy-2,3-dihydrobenzofuranyl)-N-hydroxyamine as prepared in Example 10, step (e).
  • Example 32 N-Hydroxy-N-1 -r6-( " 2-quinolinylmethyloxy 1.2.3.4-tetrahvdronaphthyllacetamide
  • N-Hvdroxv-N-l-r6-r2-quinolinylmethyloxyV1.2.3.4-tetrahvdronaphthvnacetamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-l -[6-(2-quin ⁇ hnylmethyloxy)- 1,2,3, 4-tetrahydronaphthyl]-N- hydroxyamine as prepared in Example 9, step (c).
  • N-Hydroxy-N-2-f7-methoxy-1.2.3.4-tetrahydronaphthyDacetamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-2-(7-methoxy- 1 ,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in Example 11, step (b).
  • N-Hvdroxy-N-l-(7-benzyloxy-1.2.3.4-tetrahydronaphthvDacetamide is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-l-(7-benzyloxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in Example 12, step (d).
  • N-Hydroxy-N- 1 -r5-f 4-methoxybenzyloxy)indany ⁇ acetamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-l-[5-(4-methoxybenzyloxy)indanyl]-N-hydroxyamine as prepared in Example 14, step (c).
  • N-Hydroxy-N- 1 -f5-benzyloxy-l .2.3.4-tetrahydronaphthy acetamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-l-(5-benzyloxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in Example 16, step (c).
  • 6-Phenoxy-l -tetralone A solution of 6-(l-tetralonyl) trifluoromethylsulfonate (447 mg, 1.5 mmol; see example 1 for preparation) and phenol ( 300mg, 3.2 mmol) in dry coUidine (3 mL) containing Cu2 ⁇ (107 mg,0.75 mmol) is heated at 170° C for 72 h. The resulting solution is diluted with ether, washed with 6N HCl and brine and then concentrated in vacuo to yield the desired biaryl ether.
  • 6-Phenoxy-l -tetralone oxime 6-Phenoxy-l -tetralone oxime.
  • hydroxylamine hydrochloride 1.4 g, 24 mmol.
  • N-Hvdroxv-N-l- -phenoxv-l. ⁇ .S ⁇ -terrahvdronaphthvniacetamide N-Hvdroxv-N-l- -phenoxv-l. ⁇ .S ⁇ -terrahvdronaphthvniacetamide.
  • the desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-l-(6-phenoxy-l,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in step (c) above.
  • N-Hydroxy-N- 1 -( -benzyloxy- 1.2.3.4-tetrahydronaphthy propionamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of propionyl chloride and a solution of N-l-(6-benzyloxy-l, 2,3,4- tetrahydronaphthyl)-N-hydroxyamine as prepared in Example 1, step (d).
  • N-Hvdroxy-N-1 -f6-benzyloxy- 1.2.3.4-tetrahvdronaphthylbenzamide The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of benzyl chloride and a solution of N-l-(6-benzyloxy- 1,2,3,4- tetrahydronaphthyl) -N-hydroxyamineas prepared in Example 1, step (c).
  • N-Benzyloxy-N- 1 -r6-f2-phenylethylV 1.2.3.4-tetrahvdronaphthyl1-2.2- dimethylpropionamide.
  • N-benzyloxy-N-l-[6-(2-phenylethyl)-l,2 .4- tetrahydronaphthyl]arnine (3.57 g, 10.0 mmol) in THF is added triethylamine (1.72 mL, 12.5 mmol), followed by trimethylacetyl chloride (1.54 mL, 12.5 mmol).
  • the resulting mixture is stirred at room temperature for 2 h and is filtered.
  • the desired product is obtained by removal of the solvent in vacuo.
  • (+VN-1 -f6-Benzyloxy-l .2.3.4-tetrahydronaphthyIVN-hvdroxyurea The (+)-enantiomer was prepared in a similar fashion, except using the other diastereomer obtained from the separation of (IRS, 4S)-N-l-(6-benzyloxy-l,2,3,4-tetrahydronaphthyl)-N-(N'-4-benzyl-3- carboxyloxazolidin-2-onyl)urea.
  • (+VN-3-( ' 6-Benzyloxy-2.3-dihydrobenzofuryl)-N-hydroxyurea To a solution of one of the diastereomers obtained from the separation of (3RS, 4S)-N-3-(6-benzyloxy-2,3- dihydrobenzofury -N- ⁇ ' ⁇ -benzyl-S-carboxy-oxazolidin ⁇ -ony urea in 3 : 1 THF/ H2O (12 mL) at 0°C was added hydrogen peroxide (6.6 mL of 30% aqueous solution), followed by lithium hydroxide (0.07 g, 1.68 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 1 h.
  • EXAMPLE 45 - CAPSULE COMPOSITION 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 46 - OINTMENT COMPOSITION Compound of Formula (I) 1.0 g White soft paraffin to 100.0 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.
  • EXAMPLE 48- TOPICAL LOTION COMPOSITION Compound of Formula (I) 1.0 g Sorbitan Monolaurate 0.6 g Polysorbate 200.6 g Cetostearyl Alcohol 1.2 g Glycerin 6.0 g Methyl Hydroxybenzoate 0.2 g Purified Water B.P. to 100.00 ml
  • 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 49 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
  • 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 dissolved at appropriate concentrations in ethanol or DMSO (dimetiiylsulfoxide) having a final concentration of less than or equal to 1.0%, and then diluted to their respective concentrations using the buffers indicated in the text.
  • Animals In experiments when mice were used they 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 consumption 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 CaC-2 (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.
  • Drag-induced effects on enzyme activities are described as the concentration of drug causing a 50% inhibition of oxygen consumption OC50).
  • 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 ⁇ 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 the cells. After an additional 10 minutes, the buffer was collected by cenrrifugation (2500 xg for 15 minutes), and stored at -70°C until assayed.
  • 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 CDl 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.
  • 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.
  • CP1 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.
  • the effect of hydroxyurea compounds as inhibitors of 5-LO is shown in Table I.
  • the compounds tested displayed a range of inhibitory activity both in vitro and in vivo.
  • On the RBL-1 supernatant 5-LO enzyme assay several compounds showed activity in and around 1.0 uM IC50.
  • a second group of compounds had activity in the range of 2-3 uM IC50 and a third group had appreciably less activity (15-48 uM IC50), which can be seen from a review of Table 1.
  • Examination of the activity of the first two groups of compounds on human monocyte production of LTB4 corroborated the 5-LO inhibitory activity. All the compounds tested were less than 1 uM IC50. In contrast, none of the compounds showed potent inhibition of cyclooxygenase activity as indicated by production of the prostaglandin, PGE2.
  • N- 1-(5- Benzyloxyindanyl)-N-hydroxyamine yielded a statistically significant percent inhibition of PBQ writhing at a dose of lOmg/kg; N-l-(5-Benzyloxy-l,2,3,4-tetrahydronaphthyl)-N- hydroxyamine, N- l-(5-Phenoxy- 1,2,3,4- tetrahydronaphthyl)-N-hydroxyamine, N- 1-(5- Phenoxyindanyl)-N-hydroxyamine, yielded a statistically significant percent inhibition of PBQ writhing at a dose of 20mg/kg.
  • 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.
  • Stim - stimulated above controls values given in parentheses represent the ED50 in mg/kg

Abstract

On décrit des composés d'hydroxyurée comprenant de l'indane, du dihydrobenzofuranne, du 4H-2,3-dihydrobenzopyranne, du dihydrobenzothiophène, des dérivés d'indole et du 1,2,3,4-tétrahydronaphtalène substitués et non substitués, des compositions pharmaceutiques contenant lesdits composés et leur utilisation comme analgésiques et inhibiteurs de voies d'accès de 5-lipoxygénase.
EP91907085A 1990-03-27 1991-03-25 Inhibiteurs de 5-lipoxygenase Ceased EP0522000A1 (fr)

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AU7587591A (en) 1991-10-21
WO1991014674A2 (fr) 1991-10-03
CA2078126A1 (fr) 1991-09-28
PT97189A (pt) 1991-12-31
WO1991014674A3 (fr) 1992-01-09
IE910980A1 (en) 1991-10-09
TW219934B (fr) 1994-02-01
AU660277B2 (en) 1995-06-22
JPH05505610A (ja) 1993-08-19
NZ237566A (en) 1994-03-25

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