EP0456760A1 - Composes inhibiteurs de lipoxygenase - Google Patents

Composes inhibiteurs de lipoxygenase

Info

Publication number
EP0456760A1
EP0456760A1 EP90903687A EP90903687A EP0456760A1 EP 0456760 A1 EP0456760 A1 EP 0456760A1 EP 90903687 A EP90903687 A EP 90903687A EP 90903687 A EP90903687 A EP 90903687A EP 0456760 A1 EP0456760 A1 EP 0456760A1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
carbocyclic
alkyl
group
urea
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.)
Withdrawn
Application number
EP90903687A
Other languages
German (de)
English (en)
Other versions
EP0456760A4 (en
Inventor
Dee W. Brooks
Karen E. Rodriques
James B. Summers
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.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0456760A1 publication Critical patent/EP0456760A1/fr
Publication of EP0456760A4 publication Critical patent/EP0456760A4/en
Withdrawn legal-status Critical Current

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    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
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    • 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
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
    • C07D213/60—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 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 ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound 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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • 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
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with 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 ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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
    • C07D333/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • This invention relates to compounds which inhibit lipoxygenase enzymes, to pharmaceutical compositions
  • this invention concerns certain aryl-, arylalkyl- and arylcyclopropyl-N-hydroxyurea compounds which inhibit lipoxygenase enzymes, to
  • compositions containing these compounds and to methods of treating disease states mediated by products of the arachidonic acid cascade.
  • the lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid.
  • the enzyme 5-lipoxygenase converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the
  • LTC 4 and LTD 4 are potent constrictors of human airways in vitro and aerosol
  • LTB 4 and 5-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes. They also have been found in the synovial fluid of rheumatoid arthritic patients. The biological activity of the leukotrienes has been reviewed by Lewis and Austin (J. Clinical Invest, 73, 889, 1984) and by Sirois (Adv. Lipid Res. 21, 78, 1985).
  • lipoxygenase enzymes play an important role in the biosynthesis of mediators of asthma, allergy, arthritis, psoriasis, inflammatory bowel disease, gout, adult
  • AA-861 a 5-lipoxygenase inhibitor, disclosed in U.S. Patent 4,393,075, issued July 12, 1983 to Terao et al.
  • pyrazolo pyridines which are 5-lipoxygenase inhibitors, disclosed in European Patent Application of Irikura et al., S.N. 121,806, published October 17, 1984
  • arachidonyl hydroxamic acid a 5- lipoxygenase inhibitor, disclosed in E. J. Corey et al., J. Am. Chem. Soc., 106, 1503 (1984) and European Patent
  • the compounds of this invention possess unexpected activity as inhibitors of lipoxygenase enzymes, and reduce the biosynthesis of leukotrienes B 4 , C 4 , D 4 and E A .
  • the compounds and compositions containing these compounds are useful for the treatment of disease states in mammals, which disease states are mediated by the leukotrienes B 4 , C 4 , D 4 and
  • A is a divalent radical selected from the group
  • alkylene of from one to six carbon atoms, alkenylene, of from two to twelve carbon atoms,
  • X is either absent or is divalent alkylene of from one to four carbon atoms
  • Y is either absent or is divalent alkylene of from one to four carbon atoms
  • R 3 and R 4 are independently selected from hydrogen or alkyl
  • R 5 and R 6 are independently selected from hydrogen, alkyl, or halogen.
  • Ar is selected from the group consisting of
  • Z is selected from oxygen, sulfur and -NR 9 , with the
  • R 7 is selected from the group consisting of alkyl, cycloalkyl, carbocyclic aryl, carbocyclic aralkyl,
  • heterocyclic aryl and heterocyclic aralkyl.
  • R 8 is one, two, or three substituents independently selected from the group consisting of halogen, cyano, hydroxy, alkyl, halosubstituted alkyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, carbocyclic aryl, carbocyclic aryloxy, carbocyclic aroyl, carbocyclic aralkyl, carbocyclic aralkenyl, carbocyclic aralkoxy, carbocyclic arylthioalkoxy, carbocyclic aralkoxyalkyl, carbocyclic arylthioalkoxyalkyl, heteroaryl, and heteroarylalkyl. also be further substituted
  • halo selected from the group consisting of halo, cyano, alkyl, alkoxy, halosubstituted alkyl, - (CH2) p C(O)R 10 , and
  • R10 is selected from the group consisting of alkyl, alkoxy, amino, alkylamino, dialkylamino, and
  • R 9 is selected from the group consisting of hydrogen, alkyl, carbocyclic aralkyl, heteroarylalkyl, alkoyl,
  • R 1 and R 2 are independently selected from hydrogen, substituted alkyl, substituted carbocyclic aralkyl, and substituted cycloalkyl wherein the substituents are selected from the group consisting of alkoxy, halo, cyano, amino, carboxyl, hydroxy, -C(O)R 10 , -OC(O)R 10 , and -NHC(O)R 10 where R 10 is selected from the group consisting of alkyl, alkoxy, amino, alkylamino, dialkylamino, and carbocyclic aryl.
  • M is selected from hydrogen, a pharmaceutically
  • compositions and methods of inhibiting lipoxygenase enzymes and related disorders are also provided.
  • alkyl refers to straight and branched chain saturated hydrocarbon radicals having 1 to 12 carbon atoms. Representative examples of such radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • alkenyl refers to straight and branched chain hydrocarbon radicals having 2 to 12 carbon atoms, and containing at least one carbon-carbon double bond. Representaive of such radicals are ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.
  • alkoxy refers to an alkyl group as previously defined, attached to the remainder of the parent molecule through an oxygen atom.
  • Representative of such radicals are methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like.
  • alkoxyalkyl refers to an alkoxy group, as previously defined, appended to an alkyl radical including, but not limited to, methoxymethyl,
  • alkoxyalkoxyalkyl refers to an alkoxy group appended to an alkoxy group which is appended to an alkyl radical including, but not limited to,
  • alkylene refers to a divalent straight or branched saturated hydrocarbon chain linking groups having 1 to 6 carbon atoms. Representative of such groups are methylene, ethylene, trimethylene, tetramethylene, 2-methyltrimethylene and 2,2-dimethyltrimethylene.
  • alkyleneoxyalkylene refers to - (CH 2 ) m O (CH 2 ) n - wherein m and n are independently selected from 1 to 6.
  • oxyalkylene refers to -O(CH 2 )m _ wherein m is as previously defined.
  • alkenylene refers to a
  • Carbocyclic aryl refers to a substituted or unsubstituted mono or polycyclic aromatic carbocyclic group containing fused or nonfused aromatic ring systems including, but not limited to, phenyl, naphthyl, biphenyl, triphenyl, and the like. Substituents are selected from alkyl, halosubstituted alkyl, alkenyl, hydroxy, halogen, cyano, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and the like.
  • heteroaryl refers to aryl
  • Representative of such groups are pyridyl, thienyl, furyl, indolyl, pyrazinyl, isoquinolyl, quinolyl, imidazolyl, pyrrolyl, pyrimidyl, benzofuryl, benzothienyl, carbazolyl, and the like.
  • Substituents are selected from alkyl,
  • halosubstituted alkyl alkenyl, hydroxy, halogen, cyano, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and the like.
  • Carbocyclic aralkyl refers to a carbocyclic aryl group, as previously defined, appended to an alkyl radical including, but not limited to, benzyl, phenylethyl, naphthylmethyl and the like.
  • carbocyclic aralkenyl refers to a carbocyclic aryl group appended to an alkenyl radical including, but not limited to, cinnamyl, phenylpropenyl and the like.
  • Carbocyclic aralkoxy refers to a carbocyclic aryl group appended to an alkoxy radical.
  • thioalkoxy refers to an alkyl group, as previously defined, attached to the parent molecule through a sulfur atom.
  • carbocyclic arylthioalkoxy refers to a carbocyclic aryl group appended to a thioalkoxy radical including, but not limited to such groups as
  • Carbocyclic aralkoxyalkyl refers to an carbocyclic aralkoxy group, as previously defined, appended to an alkyl radical including, but not limited to, benzyloxymethyl and the like.
  • carbocyclic arylthioalkoxyalkyl refers to a carbocyclic arylthioalkoxy group, as previously defined, appended to an alkyl radical.
  • alkoyl refers to an alkyl group, as previously defined, attached to the parent molecule through a carbonyl group.
  • Carbocyclic aroyl refers to a carbocyclic aryl group, as previously defined, attached to the parent molecule through a carbonyl group.
  • heteroaroyl refers to a heteroaryl group, as previously defined, attached to the parent molecule through a carbonyl group.
  • carbocyclic aryloxy refers to substituted or unsubstituted carbocyclic aryl groups, as previously defined, attached to the parent molecule through an oxygen atom.
  • Representative of such groups are 4- acetylphenoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, and the like.
  • cycloalkyl refers to saturated and unsaturated cyclic or bicyclic radicals having 3 to 8 carbon atoms. Representative of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, 2-chlorocyclohexyl, and the like.
  • halosubstituted refers to a radical as described above substituted with one or more halogens, and which may also be additionally substituted as defined above. Representative of such groups are chloromethyl,
  • salts refers to the relatively non-toxic, inorganic or organic acid addition salts and alkaline earth metal salts of the compounds of this invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the free base with a suitable organic or inorganic acid. Representative salts include the
  • hydrochloride hydrobromide, sulfate, nitrate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, lauryl sulphate, and the like.
  • Representative alkali or alkaline earth metal sales include sodium, calcium, potassium and magnesium salts, and the like.
  • salts of this invention can be per-N-salts.
  • pharmaceutically acceptable cation means a non-toxic cation based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as those based on non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamino, dimethylamino,
  • metabolically cleavable group refers to groups which can be cleaved from the molecule by metabolic processes and be substituted with hydrogen, a salt, or form a group which yields an active enzyme inhibitor when the cleavable group is removed from the molecule.
  • Examples of metabolically cleavable groups include -COR, -COOR, -CONRR and -CH 2 OR radicals where R is selected independently at each occurrence from alkyl, carbocyclic aryl or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy or alkoxy.
  • Representative metabolically cleavable groups include acetyl, methoxy-carbonyl, benzoyl, tetrahydropyranyl, methoxymethyl and trimethylsilyl groups.
  • R and S isomers and mixtures thereof including racemic mixtures as well as the cis and trans isomers and mixtures thereof are contemplated by this invention.
  • Additional asymetric carbon atoms may be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention.
  • the present invention includes one or more of the compounds of Formula I formulated into compositions together with one or more non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles which are collectively referred to herein as carriers, for parenteral injection, for oral administration in solid or liquid form, for rectal administration, and the like.
  • compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally,
  • ointments or drops or as a buccal or nasal spray.
  • compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for example, water, alcohol, glycol, glycerol, and the like
  • a coating such as lecithin
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying,
  • microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the
  • injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • agents delaying absorption for example, aluminum monostearate and gelatin.
  • the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by
  • sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin,
  • inert customary excipient such as sodium citrate or dicalcium phosphate
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid
  • binders as for example, carboxymethylcellulose, alignates, gelatin
  • the dosage forms may also comprise buffering agents.
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate
  • e solution retarders, as for example paraffin
  • absorption accelerators as for example, quaternary ammonium compounds
  • wetting agents as for example, cetyl alcohol and glycerol monostearate
  • adsorbents as for example, kaolin and bentonite
  • lubricants as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof.
  • the dosage forms may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and others well known in this art. They may contain opacifying agents, and can also be of such composition that they release the active compound or
  • embedding compositions which can be used are polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the abovementioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions,
  • liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
  • benzyl alcohol benzyl benzoate
  • propylene glycol 1,3-butylene glycol, dimethylformamide
  • oils in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays and inhalants.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed
  • preservatives buffers or propellants as may be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • liposomes are generally derived from phospholipids or other lipid
  • Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to the lipoxygenase inhibiting compounds of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • compositions of the invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
  • the selected dosage level may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
  • Total daily dose of the compounds of this invention administered to a host in single or divided doses may be in amounts, for example, of from about 0.001 to about 100 mg/kg body weight daily and preferably 0.01 to 10 mg/kg/day.
  • Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the
  • the compounds of this invention can be prepared by the following processes.
  • DPPA diphenyl-phosphoryl azide
  • This amine is treated with HCl followed by phosgene to provide the isocyanate intermediate which is not isolated but directly treated with a
  • cyclopropyl ring can be prepared by the following processes.
  • Process 3 involves the reaction of a cyclopropylcarboxylic acid II, where Ar and X are groups as previously defined, with diphenylphosphorylazide (DPPA) in the presence of triethylamine to form the intermediate isocyanate. III, which is subsequently reacted with a hydroxylamine, NHR 1 OM where R 1 and M are groups as previously defined, to provide the desired hydroxyurea compound IV.
  • DPPA diphenylphosphorylazide
  • Process 4 involves reductive amination of a
  • cyanoborohydride to provide the amine intermediate, VI.
  • This amine is treated with HCl followed by phosgene to provide the isocyanate intermediate which is not isolated but directly treated with a hydroxylamine, R 1 NHOM to provide the desired hydroxyurea compound of the present invention.
  • cyanoborohydride (2.23 g, 35 mmol) were dissolved in methanol (250 mL) and stirred for 3 days. The pH was adjusted to 2.0 with concentrated HCl and the solvent was evaporated. The residue was partitioned between water and ether and the insoluble solids were filtered off and set aside. The water layer was brought to pH 9 with solid NaHCO 3 and with 2N NaOH.
  • the compounds represented in Table 1 can be prepared by the method of Process 1 as described in Example 6 by using the appropriate carboxylic acid precursor shown instead of 2-thiopheneacetic acid and using the appropriate hydroxylamine derivative as shown.
  • the compounds represented in Table 2 can be prepared by the method of Process 2 as described in Example 1 by using the appropriate carbonyl precursor shown instead of 4-phenylmethoxyacetophenone and using the appropriate amine-R 2 derivative and hydroxylamine derivative as shown.
  • the compounds represented in Table 3 can be prepared by the method of Process 3 as described in Example 14 by using the appropriate cyclopropanecarboxylic acid precursor shown instead of trans-2-pheny1-1-cyclopropanecarboxylic acid and using the appropriate hydroxylamine derivative as shown.
  • the compounds of this invention are potent inhibitors of 5-lipoxygenase. Their activity was determined using the 20,000x g supernatant from homogenized RBL-1 cells in a similar manner as that described by Dyer and coworkers (Dyer, R.D.; Haviv, F.; Hanel, A. M.; Bornemier, D. A.; Carter, G. W. Fed. Proc, Fed. Am. Soc. Exp . Biol. 1984, 43, 1462A). Inhibitory potencies for representative examples of this invention are listed in Table 4. IC 50 values (concentration of compound producing 50% enzyme inhibition) were calculated by linear regression analysis of percentage inhibition versus log inhibitor concentration plots.

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Abstract

Certains composés N-aryle-, N-hétéroaryle, N-arylalcoyle-, N-hétéroarylalcoyle-, N-arylcyclopropyle- et N-hétéroarylcyclopropyle-n'-hydroxyurée sont des inhibiteurs de l'activité de l'enzyme de lipoxygénase, et sont par conséquent des agents utiles dans le traitement d'états pathologiques tels que l'asthme, l'arthrite, les allergies, le psoriasis, des affections intestinales inflammatoires, la goutte, le syndrome de souffrance respiratoire chez l'adulte, le choc de l'endotoxine, ainsi que d'autres états inflammatoires dans lesquels les produits de la cascade de l'acide arachidonique sont impliqués.
EP19900903687 1989-02-01 1990-01-25 Lipoxygenase inhibiting compounds Withdrawn EP0456760A4 (en)

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US305321 1989-02-01

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US5260316A (en) * 1991-07-30 1993-11-09 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives
US5334600A (en) * 1991-07-30 1994-08-02 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives
US5350761A (en) * 1991-07-30 1994-09-27 Ciba-Geigy Corporation Indolyl substituted hydroxylamine derivatives
JPH05163229A (ja) * 1991-12-13 1993-06-29 Pfizer Pharmaceut Co Ltd 新規なシクロプロピル誘導体
US5521212A (en) * 1991-12-13 1996-05-28 Pfizer Inc. Cyclopropyl N-hydroxyurea and N-hydroxyacetamides which inhibit lipoxygenase
US5612377A (en) * 1994-08-04 1997-03-18 Minnesota Mining And Manufacturing Company Method of inhibiting leukotriene biosynthesis
HUT76830A (en) * 1994-08-04 1997-11-28 Minnesota Mining & Mfg Process for preparing pharmaceutical compns. inhibiting of leukotriene biosynthesis, contg. urea derivatives
DE69528197T2 (de) * 1994-12-14 2003-06-05 Santen Pharmaceutical Co., Ltd Neue 1,3-dialkylharnstoff-derivate
DE10123845A1 (de) * 2001-05-16 2003-02-13 Bayer Cropscience Gmbh 2,4-Diamino-1,3,5-triazine, Verfahren zur Herstellung und Verwendung als Herbizide und Pflanzenwachstumsregulatoren
US10266488B2 (en) 2013-10-10 2019-04-23 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
AU2017263361B2 (en) * 2016-05-09 2021-08-05 Jubilant Epicore LLC Cyclopropyl-amide compounds as dual LSD1/HDAC inhibitors

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AU506399B2 (en) * 1975-12-30 1980-01-03 Showa Denko Kabushiki Kaisha 3-(2-aryl-2-propyl) ureas
DE2936410A1 (de) * 1979-09-08 1981-03-26 Agfa-Gevaert Ag, 51373 Leverkusen Verfahren zur stabilisierung farbphotographischer materialien sowie farbphotographisches material
US4618692A (en) * 1981-09-03 1986-10-21 Asta-Werke Aktiengesellschaft 4-carbamoyloxy-oxazaphosphorins
US4728670A (en) * 1986-06-04 1988-03-01 E. R. Squibb & Sons, Inc. Biphenyl hydroxamic acids
EP0279263B1 (fr) * 1987-02-10 1993-08-04 Abbott Laboratories Composés inhibant la lipoxygénase, contenant de l'indole, du benzofurane ou du benzothiophène
DE3888574T2 (de) * 1987-04-24 1994-06-30 Abbott Lab Harnstoff-Derivate mit lipoxygenasehemmender Wirkung.

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Title
No further relevant documents have been disclosed. *
See also references of WO9008545A1 *

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CA2046872A1 (fr) 1990-08-02
EP0456760A4 (en) 1992-01-08
GR900100060A (el) 1991-06-28
WO1990008545A1 (fr) 1990-08-09

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