Classifications

• • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/64—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups singly-bound to oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
  • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
  • C07C323/47—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to 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
  • C07D333/26—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
  • C07D333/36—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
  • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D335/08—Naphthothiopyrans; Hydrogenated naphthothiopyrans
• • 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
  • 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
  • C07D409/12—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 chain containing hetero atoms as chain links

Definitions

• This invention relates to compounds having pharmacological utility, to pharmaceutical compositions comprising the compounds, and to medical methods of treatment More particularly, this invention concerns compounds which inhibit lipoxygenase enzymes, to methods and compositions for inhibiting lipoxygenase enzymes in human and other mammalian hosts in need of such treatment.
• 5-Lipoxygenase is the Gist dedicated enzyme in the pathway leading to the biosynthesis of leukotrienes (Samuelsson, B., Science, 120: 568 (1983); Hammarstrom, S., Annual Review of Biochemistry, 52: 355 (1983)). This important enzyme has a rather restricted distribution, being found predominantly in leukocytes and mast cells of most mammals. Normally 5-lipoxygenase is present in the cell in an inactive form; however, when leukocytes respond to external stimuli, intracellular 5-lipoxygenase can be rapidly activated.
• This enzyme catalyzes the addition of molecular oxygen to fatty acids with cis,cis-l,4-pentadiene structures, converting them to l-hydroperoxy-tr__/w,c/-_ -2,4- pentadienes.
• Arachidonic acid the 5-lipoxygenase substrate which leads to leukotriene products, is found in very low concentrations in mammalian cells and must first be hydrolyzed from membrane phospholipids through the actions of phospholipases in response to extracellular stimuli.
• the initial product of 5-lipoxygenase action on arachidonate is 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which can be reduced to 5- hydroxyeicosatetraenoic acid (5-HETE) or converted to leukotriene A4 (LTA 4 ).
• This reactive leukotriene intermediate is enzymatically hydrated to LTB 4 or conjugated to the tripeptide glutathione to produce LTC 4 .
• LTA 4 can also be hydrolyzed nonenzymatically to form two isomers of LTB 4 . Successive proteolytic cleavage steps convert LTC 4 to LTD 4 and LTE 4 .
• SRS-A Slow reacting substance of anaphylaxis
• SRS-A Intravenous administration of SRS-A to guinea pigs results in compromised respiration, primarily due to constriction of small peripheral airways (Drazen, J.M. and Austen, K.F., Journal of Clinical Investigation, 53: 1679, 1974).
• SRS-A also induces vascular permeability when injected intracutaneously in some species, including man (Orange, R.P., Stechschulte, D.J., and Austen, K_F., Federation Proceedings, 28: 1710, 1969).
• human lung fragments from patients with extrinsic asthma generate large amounts of leukotrienes when challenged in vitro (Lewis, R.A., Austen, K.F., Drazen, J.M., Clark, D.A., Marfat, A., and Corey, E.J., Proceedings of the National Academy of Sciences, USA, 77: 3710, 1980.) and synthetic leukotrienes are potent constrictors of human airway smooth muscle in vitro (Dahlen, S.E., Hansson, G., Hedqvist, P., Bjorck, T., Granstrom, E., and Dahlen, B., Proceedings of the National Academy of Sciences, USA, 80: 1712, 1983; Dahlen, S., Hedqvist, P., Hammarstrom, S., and Samuelsson, B., Nature, 288: 484, 1980).
• LTC4 levels were found to be elevated in the blood of children undergoing an acute asthmatic attack (Schwartsburg, S.B., Shelov,S.P., and Van Praag, D. Prostaglandins Leukotrienes and Medicine, 26: 143, 1987). Leukotrienes were also detected in sputum of patients with chronic bronchitis (Zakrezewski, J.T., Barnes, N.C., Piper, P.C., Costello, J.F. Prostaglandins, 33: 663, 1987). These pulmonary effects of LTC4 are characteristic of those observed in asthmatic patients following antigen inhalation and are consistent with a major role for leukotrienes in allergic asthma (Lewis, R.A., Chest, 87: 5S, 1985).
• Leukotrienes are proposed mediators of allergic rhinitis as they are stimulators of mucus secretion and vascular permeability (Schelhamer, J.H., Marom, Z., Sun, F., Bach, M.K., and Kaliner, M., Chest, 81 (Suppl): 36, 1982; Coles, S.J., Neill, K.H., Reid, L.M., Austen, K.F., Nii, Y., Corey, E.J., and Lewis, R.A., Prostaglandins, 25: 155, 1983; Soter, N.A., Lewis, R.A., Corey, E.J., and Austen, K.F., The Journal of Investigative Dermatology, 80: 115, 1983), characteristic events in the pathophysiology of this disorder.
• LTB4 is one of the most potent chemotactic substances known (Smith, M.J H., General Pharmacology, 12: 211, 1981).
• LTB 4 is present in higher than normal levels in psoriatic lesions (Brian, S.D., Camp, R., Dowd, P., Black, A., and Greaves, M., The Journal of Investigative Dermatology, 83: 70, 1984) which have significantly elevated 5-lipoxygenase activity compared to uninvolved or normal skin (Ziboh, V.A., Casebolt, Tl., Marcelo, C.L., and Vcorhees, J.J., The Journal of Investigative Dermatology, 83: 425, 1984).
• the neutrophil infiltrate that characterizes the early stages of this disease may be due to the chemoattractant properties of LTB4 which can induce micropustule formation when applied topically (VandeKerkhof, P.C.M., Bauer, F.W., and deGroud, R.M., The Journal of Investigative Dermatology, 84: 450, 1985).
• LTC 4 and LTD 4 have also been detected in psoriatic skin lesions (Brian, S.D., Camp, R.D.R., Black, A.K., Dowd, P.M., Greaves, M.W., Ford-Hutchinson, A.W., and Charleson, S., Prostaglandins, 29: 611, 1985).
• These mediators act as vasodilators in human skin and may account for the vasodilation and increased blood flow in psoriatic lesions.
• Elevated levels of 5-lipoxygenase products are found in colonic tissue from patients with inflammatory bowel disease; sulfasalazine, a drug used in the treatment of this disease, has been shown to be a weak 5-lipoxygenase inhibitor (Sharon, P. and Stenson, W.F., Gastroenterology, 86: 453, 1984). These observations suggest that increased leukotriene formation may contribute to the characteristic mucosal inflammation of this disorder.
• Endotoxin Shock Leukotrienes elicit many of the pathophysiologic symptoms observed in endotoxin shock, such as cardiac depression, increased vascular permeability leading to tissue edema, and increased leukocyte adhesion to endothelial surfaces (Hagmann, W., Denzlinger, C, and Keppler, D. Production of peptide leukotrienes in endotoxin-shock. FEBS Letters, 180: 309, 1985). Furthermore, endotoxins have been shown to trigger the formation of leukotrienes. It has therefore been proposed that leukotrienes play a key role in the lethal action of endotoxin (Konig, W., Scheffer, J. Bremm, K.D., hacker, J., and Goebel, W., International Archives of Allergy and Applied Immunology, 77: 118, 1985).
• the leukotrienes are potent constrictors of coronary arteries and may play a role in regulating blood flow to the heart.
• LTC 4 and LTD 4 exacerbate ischemia-induced myocardial injury in rabbits (Lefer, A.M. Eicosanoids as Mediators of Ischemia and Shock. Federation Proceedings, 44: 275, 1985).
• infarcted hearts when reperfused, release larger quantities of leukotrienes in response to stimuli than hearts from sham-operated animals (Barst, S. and Mullane, K., Clinical Research, 33: A516, 1985). These results implicate leukotrienes as potential mediators of ischemia.
• Leukotrienes are synthesized in greater amounts in gerbil forebrains after ischemia and reperfusion (Moskowitz, M.A., Kiwak, K.J., Hekimian, K., et al., Science, 224: 886, 1984), concussive injury, or subarachnoid hemorrhage (subarachnoid injection of blood) (Kiwak, K.J., Moskowitz, M.A., and Levine, L., Journal of Neurosurgery, 62: 865, 1985).
• the formation of leukotrienes is temporally associated with the cerebral vasospasm and other abnormalities resulting from the insult.
• a possible role can be suggested for leukotrienes in the pathophysiology resulting from stroke or subarachnoid hemorrhage.
• the enzyme 5-lipoxygenase catalyzes the first step leading to the biosynthesis of all the leukotrienes and therefore inhibition of this enzyme provides an approach to limit the effects of all the products of this pathway.
• Agents capable of abrogating the effects of these potent mediators of pathophysiological processes represent a promising class of therapeutic agents (Brooks, D. W., Bell, R. L., and Carter, G. W. Chapter 8. Pulmonary and Antiallergy Agents, Annual Reports in Medicinal Chemistry , Allen, R. C. ed., Academic Press 1988.
• the compounds of this invention possess activity as inhibitors of 5- and/or 12- lipoxygenase and reduce the biosynthesis of leukotrienes LTB4, LTC 4 , LTD 4 andLTE ⁇
• the compounds and compositions containing these compounds are useful for the treatment of disease states in mammals which involve lipoxygenase enzymes or which involve the leukotrienes LTB , LTC 4 , LTD and LTE 4 .
• novel compounds of this invention are the compounds of Formula I:
• X is selected from alkylene of from one to six carbon atoms; alkenylene of from two to six carbon atoms; and alkylene of from one to six carbon atoms or alkenylene of from two to six carbon atoms substituted by a group selected from hydroxy, halo, cyano, alkoxy, a ⁇ nocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy and alkoxycarbonyl.
• R 1 and R2 are independently selected from hydrogen; hydroxy; alkyl of from one to six carbon atoms; alkyl of from one to six carbon atoms substituted with a substituent selected from hydroxy, halo, cyano, alkoxy, alkylthio, aminocarbonyl, alkylamino ⁇ carbonyl, dialkylaminoc__rbonyl, carboxy and alkoxycarbonyl; carbocyclic aryl; and carbocyclic aryl substituted with a substituent selected from hydroxy, halo, cyano, alkoxy, alkylthio, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy and alkoxycarbonyl; with the proviso that Ri and R 2 are not simultaneously hydroxy.
• R 3 is selected from the group consisting of phenyl; naphthyl; thienyl; and phenyl, naphthyl, or thienyl substituted by alkyl of from one to six carbon atoms, alkenyl of from two to six carbon atoms, cycloalkyl of from three to ten carbon atoms, alkoxy of from one to six carbon atoms, alkylthio of from one to six carbon atoms, halo, nitro, hydroxy; carbocyclic or heterocyclic aiyl; carbocyclic or heterocyclic aryloxy; carbocyclic or heterocyclic aroyl; carbocyclic or heterocyclic arylalkyl wherein the alkyl portion contains from one to six carbon atoms, carbocyclic or heterocyclic arylalkenyl wherein the alkenyl portion contains from two to six carbon atoms, carbocyclic or heterocyclic arylalkynyl wherein the al
• carbocyclic or heterocyclic aryl may be optionally substituted by one, two, or three groups independently selected from the group consisting of halo, nitro, cyano, alkyl, alkoxy, and halosubstituted alkyl.
• M is selected from the group consisting of hydrogen; a pharmaceutically acceptable cation; a metabolically cleavable group, carbocyclic aroyl; -Si(R5) 3 wherein R 5 is independently selected at each occurrence from alkyl of from one to six carbon atoms; - C(O)R ; -CH 2 OR 4 ; -C(O)N(R4) 2 or -C(O)OR4 wherein R is alkyl of one to sk carbon atoms.
• the group M can be hydrogen, a suitable cation, or a group capable of being metabolically cleaved in vivo, in preferred compounds of the present invention M is hydrogen.
• R 3 may be substituted or unsubstituted phenyl, naphthyl or thienyl
• preferred compounds of the present invention are those in which R3 is substituted or unsubstituted thienyl.
• Examples of compounds which are within the scope of the present invention and/or can be used according to the methods of the present invention include, but are not limited to, the following: N-hydroxy-N-(l-(4-butoxyphenyl)ethyl) urea
• Preferred compounds of the invention include, but are not limited to, the following: N-hydroxy-N- 1 -(4-bromophenyl)ethylurea N-hydroxy-N-(l-(4-chlorophenyl)ethyl) urea N-hydroxy-N-( 5-bromothien-2-yl)methyl urea N-hydroxy-N-[l-( 5-bromothien-2-yl)ethyl]urea N-hydroxy-N-[ 3-(phenylthio)thien-2-yl]methyl urea N-hydroxy-N-[ 5-(phenylthio)thien-2-yl]methyl urea N-hydroxy-N-[ 4-(phenylthio)thien-2-yl]methyl urea N-hydroxy-N-[ 5-(phenylthio)thien-3-yl] methyl urea N-hydroxy-N-[ 2-(phenylthio)thien-3-yl]methyl urea
• alkenyl refers to a monovalent straight or branched chain radical of from two to six carbon atoms containing a carbon-carbon-double bond including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
• cycloalkyl refers to monovalent saturated cyclic radicals, preferably of three to eight carbon atoms, including, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
• alkoxy and alkylthio refer to alkyl groups as defined above, linked to the parent molecular moiety through an oxygen atom or a sulfur atom, respectively.
• Alkoxy and alkylthio groups include, for example, methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like, or the corresponding sulfur analogues.
• alkylamino refers to a monovalent group of the formula -NH-alkyl where alkyl is as defined above.
• di-ilkylamino refers to a group of the formula -N(alkyl)(alkyl) where the two alkyl groups are as defined above and may be the same or different.
• aminocarbonyl refers to a group of the formula -C(0)NH 2 -
• alkylaminocarbonyl refers to a group of the formula -C(O)NH(alkyl) where alkyl is as defined above.
• dialkylaminocabonyl refers to a group of the formula -C(0)N(alkyl)(alkyl) where the two alkyl groups are as defined above and may be the same or different.
• alkoxycarbonyl refers to an ester group of the formula -C(0)0(alkyl) where alkyl is as defined above.
• N-hydroxy-N-[l-( 5-(phenylthio)-thien-2-yl)ethyl]urea N-hydroxy-N-[ 3-(4-chlorophenylthio)thien-2-yl]methyl urea N-hydroxy-N-[ 3-(2-pyridylthio)thien-2-yl]methyl urea N-hydroxy-N-3-[ 5-(phenylthio)thien-2-yl]propenyl urea N-hydroxy-N-(3-[ 5-(phenylthio)thien-2-yl]butenyl urea N-hydroxy-N-[ 4-(phenoxy)thien-2-yl]methyl urea N-hydroxy-N-[ 4-(4-chlorophenoxy)thien-2-yl]methyl urea N-hydroxy-N-N-[ 4-(
• N-hydroxy-N- l-(thien-3-yl)ethyl urea N-hydroxy-N-(thien-3-yl)methyl urea; N-hydroxy-N-(thien-2-yl)methyl urea; and N-hydroxy-N-(3-(l-thien-3-yl)propenyl) urea.
• alkyl refers to a monovalent straight or branched chain radical of from one to six carbon atoms, including, but not limited to methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-hexyl and the like.
• halosubstituted alkyl refers to an alkyl group as just defined, substituted by one, two, or three halogen atoms selected from fluorine, chlorine and bromine. Examples of such groups include chloromethyl, bromoethyl, trifluoromethyl, and the like.
• alkanoyl refers to -C(O)H or -C(O)alkyl where alkyl is as defined above. Examples of alkanoyl groups include, but are not limited to formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, and the like.
• carbocyclic aryl refers to a monovalent substituted or unsubstituted aromatic radical comprising a single ring of carbon atoms or two or three fused rings of carbon atoms including, but not limited to, phenyl, 1- or 2-naphthyl, 1-, 2-, or 9-anthracyl, and the like.
• Substituted carbocyclic aryl groups are groups as just defined, substituted with one or two substituents independently selected from hydroxy, halo, alkoxy, alkylthio, alkyl, nitro, amino, alkylamino, dialkylamino, haloalkyl, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl.
• heterocyclic aryl refers to a monovalent 5- or 6-membered substituted or unsubstituted aromatic radical containing one nitrogen, oxygen, or sulfur atom, one nitrogen and one oxygen atom, one nitrogen and one sulfur atom, or one, two, or three nitrogen atoms.
• Heterocyclic aiyl is also meant to include 5- or 6-membered ring systems as just defined, fused to a benzene ring.
• heterocyclic aryl refers to substituted or unsubstituted furyl, benzofuranyl, thienyl, benzo[b]thienyl, pyridyl, indolyl, quinolyl, thiazolyl, benzothiazolyl, and pyrimidyl.
• Substituted heterocyclic aryl groups are heterocyclic aryl groups as just defined, substituted with one or two substituents independently selected from hydroxy, halo, alkoxy, alkylthio, alkyl of from one to six carbon atoms, nitro, amino, alkylamino, dialkylamino, haloalkyl, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl.
• carbocyclic arylalkyl refers to a carbocyclic aryl group as defined above, attached to the parent molecular moiety through an alkylene group of from one to six carbon atoms including, but not limited to, substituted or unsubstituted phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl groups and the like.
• heterocyclic arylalkyl refers to a heterocyclic aryl group as defined above, attached to the parent molecular moiety through an alkylene group of from one to six carbon atoms including, but not limited to, as used herein refers to a heterocyclic aryl group as defined above, attached to the parent molecular moiety through an alkylene group of from one to six carbon atoms including, but not limited to substituted or unsubstituted 2-, 3-, or 4-pyridylmethyl, 2- or 3-thienylmethyl, 2- or 3-furanylmethyl, 2-, 3-, or 4-quinolylmethyl groups and the like.
• carbocyclic arylalkenyl refers to a carbocyclic aryl group, as defined above, attached to the parent molecular moiety through a straight or branched alkenylene group of from two to six carbon atoms.
• groups include, for example, phenylethenyl, 3-phenylpropen-l-yl, 3-phenylpropen-2-yl, 1-naphthylethenyl, and the like.
• heterocyclic arylalkenyl similarly refers to a heterocyclic aryl group as defined above attached to the parent molecular moiety through a straight or branched alkenylene group of from two to six carbon atoms.
• Such groups are exemplified by 3- (pyrid-3-yl)propen-l-yl, 2-(thien-2-yl)ethenyl and the like.
• carbocyclic arylalkynyl refers to a carbocyclic aryl group as defined above, attached to the parent molecular moiety through a divalent straight or branched chain hydrocarbon group of from two to six carbon atoms containing one carbon- carbon triple bond.
• groups include, for example substituted and unsubstituted phenylethynyl, 3-phenyl-propyn-l-yl, 1- or 2-naphthylethynyl, and the like.
• carbocyclic aryloxy and “carbocyclic arylthio” as used herein refer to a carbocyclic aryl group as defined above, attached to the parent molecular moiety through an oxygen or sulfur atom, respectively.
• groups include, for example, substituted or unsubstituted phenoxy, 1-naphthoxy, 2-naphthoxy groups, the sulfur analogues, and the like.
• heterocyclic aryloxy and heterocyclic arylthio refer to a heterocyclic aryl group as defined above, attached to the parent molecular moiety through an oxygen or sulfur atom, respectively.
• heterocyclic aryl groups include 2-, 3-, or 4-pyridyloxy, 2- or 3-thienyloxy, 2-, 3-, or 4-pyridylthio, and the like.
• carbocyclic arylalkoxy and “carbocyclic arylalkylthio” as used herein refer to monovalent radicals in which a carbocyclic arylalkyl group, as defined above, is attached to the parent molecular moiety through an oxygen or sulfur atom, respectively.
• groups include, for example, phenylmethoxy (i.e., benzyloxy), 1-phenylethoxy, 2- phenylethoxy, 1-naphthylmethyloxy, 2-napthylmethyloxy and the like.
• heterocyclic arylalkoxy and “heterocyclic arylalkylthio” as used herein refer to a heterocyclic arylalkyl group as defined above, attached to the parent molecular moiety through an oxygen or sulfur atom, respectively.
• groups include, for example 2-, 3-, or 4-pyridylmethoxy, 2-, 3-, or 4-pyridylmethylthio, 2- or 3-thienylmethoxy, 2- or 3-thienylmethylthio, and the like.
• carbocyclic aroyl refers to -C(O)-(carbocyclic aryl) where carbocyclic aryl is as defined above.
• Carbocyclic aroyl groups include, for example, substituted and unsubstituted benzoyl, 1- or 2-naphthoyl and the like.
• halosubstituted alkyl and "haloalkyl” as used herein refer to an alkyl group, as defined above, in which one to three hydrogen atoms are substituted by a halogen, including, but not limited to, chloromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like.
• metabolically cleavable group denotes a moiety which is readily cleaved in vivo from the compound bearing it, which compound after cleavage remains or becomes pharmacologically active. Metabolically cleavable groups form a class of groups reactive with the N-hydroxy group of the compounds of this invention (where Z is hydrogen) well known to practitioners of the art.
• alkanoyl such as acetyl, propionyl, butyryl and the like
• unsubstituted and substituted aroyl such as benzoyl and substituted benzoyl
• alkoxycarbonyl such as ethoxycarbonyl
• rrialkylsilyl such as trimethyl- and triethylsilyl
• monoesters formed with dicarboxylic acids such as succinyl
• the compounds bearing such groups act as pro-drugs of other lipoxygenase inhibitors.
• the compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group.
• the compounds of the present invention possess an acidic functional substituent such as carboxyl
• the compounds are capable of forming base addition salts.
• pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified N-hydroxy urea compound with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary, or tertiary amine of sufficient basicity to form a salt with the N-hydroxy functional group of the compounds of this invention.
• a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary, or tertiary amine of sufficient basicity to form a salt with the N-hydroxy functional group of the compounds of this invention.
• Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like.
• Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, for example S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci.. 66: 1-19 (1977) which is incorporated herein by reference.)
• the compounds of the present invention comprise a basic substituent such as an amino, alkylamino, or dialkylamino group
• the compounds are capable of forming acid addition salts.
• pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
• Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, laurylsulphonate salts and the like.
• S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci..66: 1-19 (1977) which is incorporated herein by reference.)
• pharmaceutically acceptable cation refers to non-toxic cations including but not limited to those based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, magnesium, aluminum and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the N-hydroxy group of the compounds of this invention.
• Certain compounds possess one or more chiral centers and may thus exist in optically active forms.
• the compounds contain an alkenyl or alkenylene group, there exists the possibility of cis- and trans-iso ⁇ as ⁇ c forms of the compounds.
• the R- and S-isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and ir ⁇ ns-isomers, are contemplated by this invention.
• Additional asymmetric carbon atoms can 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.
• a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods.
• This invention provides a method of treatment of inhibiting 5- and/or 12- lipoxygenase activity in a human or lower mammal host in need of such treatment, which method comprises administration to the human or lower mammal host of a compound previously described in an amount effective to inhibit lipoxygenase activity in the host.
• the compounds of the present invention may be administered orally, parenterally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
• parenteral as used herein includes subcutaneous, intravenous, intraarterial injection or infusion techniques, without limitation.
• topically encompasses administration rectally and by inhalation spray, as well as by the more common routes of the skin and the mucous membranes of the mouth and nose.
• Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to administer an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
• the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
• the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
• 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 more usually 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 daily dose.
• the present invention also provides pharmaceutical compositions which comprise one or more of the compounds of formula I above formulated together with one or more non-toxic pharmaceutically acceptable carriers.
• the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal adininistration.
• compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
• parenteral administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
• compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
• suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
• adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
• the absorption of the drug in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
• Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
• biodegradable polymers such as polylactide-polyglycolide.
• Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
• 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.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
• the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, iso
• the oral compositions 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, rmcrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, rmcrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
• compositions for rectal or vaginal administration 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 room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
• the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
• Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. Synthesis of the Compounds Compounds of this invention can be prepared according to the reaction sequence described in Scheme 1.
• acetophenone, 1 is treated with hydroxylamine in ethanol/pyridine to produce the oxime, 2. This is reduced to the hydroxylamine, 3, with borane pyridine complex and then converted to the hydrochloride salt with HC1 gas. Treatment with phosgene yields carbamoyl chloride, 4, which is reacted without isolation to yield the urea, 5.
• Other reagents may also be used to carry out the same transformations.
• the oxime, 2 may be converted to the corresponding hydroxylamine, 3, using borane d-imemylamine or other borane amine complexes or with sodium cyanoborohydride.
• the hydroxylamine, 3, is treated with trimethylsilyl isocyanate, followed by ammonium chloride workup to give the urea, 5.
• the hydroxylamine, 3, is dissolved in dilute hydrochloric acid and aqueous sodium cyanate is added.
• Bromobenzene (6) is converted to phenyl lithium by treatment with n-butyl lithium at -78°C. Boron trifluoride etherate is then added and this is reacted with acetaldehyde O- benzyl oxime (7) to yield (8).
• the O-benzyl protecting group is removed by catalytic hydrogenation.
• Other reagents may be substituted for those described above.
• phenyl lithium may be prepared by treatment with t-butyl lithium, sec-butyl lithium, or lithium metal instead of n-butyl lithium.
• Other protecting groups may be used for acetaldehyde oxime.
• benzyloxymethoxy, methyloxymethoxy, methoxybenzyl may be used instead of benzyl.
• Scheme 5 outlines the reaction of an aldehyde with nitroethane in methanol with an amine such as n-butylamine as a catalyst.
• the vinyl nitro compound obtained is then reduced with borane:THF and a catalytic amount of NaBR*.
• This procedure is a modified method from a published procedure (J. Org. Chem. 1985, 50, 133).
• the hydroxylamine obtained is then reacted with an isocyanate to provide the corresponding hydroxyurea.
• Method b Using the method of scheme 1, the material prepared as in part a above (4g, 16.4 mmole) was dissolved in toluene (100 mL) and HC1 gas was bubbled through the mixture at a moderate rate for about four minutes. The solution was then heated to reflux and phosgene was bubbled through for another four minutes. After an additional one hour reflux, the mixture was allowed to cool to room temperature and then added to excess cold ammonium hydroxide solution. The precipitate was collected and recrystallized from aqueous ethanol.
• the desired compound was prepared according to the method of example 1, method a, except using hydroxylamine instead of ammonium hydroxide, mp: 157-159°C; NMR (DMSO-d 6 , 300 MHz): 1.46 (d, 3H); 5.03 (s, 2H); 5.14 (q, IH); 6.92 (m, 2H); 7.24 (m, 2H); 7.30-7.50 (m, 5H); 8.31 (brs, IH); 8.88 (brs, IH); 9.34 (brs, IH); Mass spectrum (El): 302, 286, 241, 211, 91, 65.
• the desired material was prepared according the method of example 1, except using 4-hydroxybenzaldehyde instead of 4-hydroxyacetophenone. mp: 147-149°C; NMR (DMSO-d 6 , 300 MHz): 4.42 (s, 2H); 5.08 (s, 2H); 6.31 (brs, 2H); 6.95 (m, 2H); 7.19 (m, 2H); 7.30-7.50 (m, 5H); 9.27 (s, IH); Mass spectrum (CI-NH 3 ): 290 (M+NH 4 )-*-, 273 (M+l)+, 257, 230, 212.
• the desired material was prepared according to the methods of example 1, except using 3,5-dimethoxy-4-hydroxyacetophenone instead of 4-hydroxyacetophenone.
• the desired material was prepared according to the method of example 1 except using 2-phenethylbromide instead of benzyl bromide mp: 126-128°C; NMR (300 MHz, DMSO-d 6 ): 1.36 (d, 3H); 3.02 (d, 2H); 4.16 (d, 2H); 5.23 (q, IH); 6.25 (brs, 2H); 6.84 (m, 2H); 7.23 (m, 2H); 7.32 (m, 5H); 8.98 (brs, IH); Mass spectrum (El): No M+, 283 (M-OH)+, 225, 121, 105.
• the desired material was prepared according to the method of example 1, except using 2-acetonaphthone instead of acetophenone. mp: 140-142°C, NMR (300 MHz, DMSO-d 6 ): 1.51 (d, 3H); 5.46 (q, IH); 6.34 (brs, 2H); 7.45-7.54 (m, 3H); 7.81-7.90 (m, 4H); 9.11 (s, IH); Mass spectrum (El): 230 M+, 213, 155, 127, 115, 77.
• N.N'-dihydroxy-N-(l-f2-naphthyl, ethyl, urea O-benzyl 2-acetonaphthone oxime was prepared according to the method of example 1 part b, except using 2-acetonaphthone instead of 4-phenylmethoxyacetophenone and using O-benzylhydroxylamine instead of hydroxylamine.
• the material prepared as described in part a (3.2g, 11.5 mmole) was dissolved in toluene and HC1 gas was bubbled through at a moderate rate for about 3 minutes. The solution was heated to reflux and phosgene was added over about 5 minutes. The insoluble hydrochloride salt dissolved. After refluxing for one hour the mixture was cooled and added to a solution of hydroxylamine hydrochloride (960mg, 13.8 mmole) and trielhylamine (3.5g, 35mmole) in THF (30mL) and water (5mL). The mixture was poured into 2N HC1 solution and ether was added. The organic phase was dried over MgSO 4 and evaporated.
• N,N , -dihydroxy-N-(l-(2-naphthyl)ethyl) urea was prepared by catalytic hydrogenation of the material prepared in part b, above, using 5% palladium on carbon in ethanol.
• the desired material was prepared according to the method of Example 1, except using 1-b ⁇ omobutane instead of benzyl bromide.
• NMR 300 MHz, CDCI 3 ): 0.97 (t, 3H); 1.46 (m, 2H); 1.53 (d, 3H); 1.76 (m, 2H); 3.94 (t, 2H); 5.23 (brs, 2H); 5.42 (q, IH); 6.71 (s, IH); 6.85 (d, 2H); Mass spectrum (El): 252 M+, 235, 192, 177, 121.
• the desired material is prepared according to the method of Example 1, except using 1-bromobutane instead of benzyl bromide and using 3-hydroxyacetophenone instead of 4-hydroxyacetophenone.
• the desired material is prepared according to the method of Example 1, except using 4-isobutylacetophenone instead of 4-phenylmethoxyacetophenone in part b.
• the desired material is prepared according to the method of Example 1, except using 4-cyclohexylacetophenone instead of 4-phenylmethoxy-acetophenone in part b.
• the desired material is prepared according to the method of Example 16, except using nitroethane instead of nitromethane.
• the material prepared as in part b (10 g, 42 mmole) was dissolved in THF (50 mL) and lithium aluminum hydride (1M in THF, 42 mL) was added rapidly. Fifteen minutes later, 2N HCl was added to quench the reaction. The organic layer was separated and dried with MgS ⁇ 4 and evaporated to give a colorless oil. d. 3-(4-Butoxyphenyl)propanal.
• the alcohol prepared as in part c (9g) was dissolved in methylene chloride (100 mL) and pyridinium chlorochromate (18g, 84 mmole) was added. Three hours later ether was added and the mixture was filtered through silica gel.
• N-hydroxy-N-(3-(4-butoxyphenyl)propyl) urea is prepared according to the method of Example 1, except using the material prepared as in part d above instead of phenylmethoxyacetophenone.
• the desired material is prepared according to the method of Example 22 except using benzylbromide instead of 1-bromobutane.
• the desired material is prepared according the method of Example 1, except using 4- fluorobenzylbromide instead of benzylbromide.
• the desired material is prepared according the method of Example 1, except using 4- methoxybenzylbromide instead of benzylbromide.
• the desired material is prepared acc ⁇ rding to the method of Example 1, except using 3-nitro-4-hydroxybenzaldehyde instead of 4-hydroxyaceto-phenone .
• N-hydroxy-N-(l-(4-phenylmethoxy-3,5-dichlorophenyl) ethyl) urea is prepared according to the method of Example 1, except using the material prepared as in part b above instead of 4-phenylmethoxyacetophenone.
• the desired material is prepared according to the method of Example 1, except using 2-hydroxy-4-phenylmethoxy acetophenone instead of 4- phenylmethoxyacetophenone.
• N-hydroxy-N-(l-(4-phenylthiomethoxyphenyl)e_hyl urea is prepared according to the method of Example 1, except using the material prepared as in part a, above, instead of 4-phenylmethoxyacetophenone.
• the lithium reagent prepared above was added via cannula to the zinc suspension and the resulting mixture stirred for 60 minutes.
• palladium bis(triphenylphosphino)dichloride was dissolved in THF (40 mL), di-isobutylaluminum hydride (l.OM in THF, 3.02 mmole) was added, followed by 4-bromoacetophenone (5.39 g, 27.1 mmole) in THF (30 mL).
• the zinc reagent prepared above was transferred via cannula to this solution and the mixture was stirred for two hours.
• the reaction mixture was evaporated in vacuo and the residue dissolved in ether.
• N-hydroxy-N-(l-(4-(2,4,6-trimethylphenyl)phenyl)ethyl_urea is prepared according to the method of Example 1, but using the material prepared as in part a above instead of phenylmethoxyacetophenone.
• N-hydroxy-N-(l-(4-(2-phenylethenyl .phenyl .ethyl * ) urea a. 4-(2- Phenylethenyl)acetophenone is prepared according to the method of Example 21, parts a and b, except using 4-formylstilbene instead of 4-butoxybenzaldehyde and using methyl magnesium bromide instead of isopropyl magnesium bromide. b. N-hydroxy-N-(l-(4-(2-phenylethenyl)phenyl)ethyl_acetamide is prepared according to the method of Example 1, except using the material prepared as described in part a above instead of phenylmethoxyacetophenone.
• N-hvdroxy-N-( ' l-(4-(2-phenylethyl ' )phenv ethyl') urea a. 4-(2-Phenylethyl)benzaldehyde is prepared by catalytic hydrogenation of 4- formylstilbene over 20% palladium on carbon in methanol. b. N-hydroxy-N-(l-(4-(2-phenylethyl)phenyl)ethyl) acetamide is prepared according to the method of Example 33, except using the material prepared as in part a above instead of 4-formylstilbene .
• Example 2 The material prepared as in Example 1 is dissolved in tetrahydrofuran and one equivalent of sodium hydride is added. After hydrogen evolution ceases, the solvent is removed in vacuo to yield the desired product
• Example 2 The material prepared as in Example 1 is dissolved in tetrahydrofuran and one equivalent of potassium hydride is added. After hydrogen evolution ceases, the solvent is removed in vacuo to yield the desired product
• Example 2 The material prepared as in Example 1 is dissolved in tetrahydrofuran and ammonia is bubbled through. The solvent is removed in vacuo to yield the desired product
• Example 2 The material prepared as in Example 1 is dissolved in tetrahydrofuran and one equivalent of triethylamine is added. The solvent is removed in vacuo to yield the desired product.
• Example 40 The material prepared as in Example 1 is dissolved in tetrahydrofuran and one equivalent of tetraethylammonium hydroxide is added. The solvent is removed in vacuo to yield the desired product Example 40
• the desired compound was prepared by the same method as described for Example 12 except using 3-acetyl-2,5-dimethylthiophene instead of 2-acetyl-5-methylthiophene.
• N-Hydroxy-N-(l-thien-2-ylmethyl) urea To a solution of trimethylsilylisocyanate (3.1 mL, 23.2 mmole) in 10 mL THF at room temperature was added the above hydroxylamine (1.5 g, 11.6 mmole) in 10 mL of THF with stirring. After thirty minutes the reaction was quenched with saturated ammonium chloride solution (10 mL). The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3x, 25 mL). The combined organic extract was dried over MgSU 4 , filtered and concentrated.
• Example 45 The same method as described for Example 45 was used substituting 2-acetyl-5-(2-pyridyl)thiophene from part b instead of 2-thiophenecarboxaldehyde to provide the desired product.
• Example 45 The same method as described for Example 45 was used substituting 5-methyl-2- thien-2-yl carboxaldehyde for 2-thiophenecarboxaldehyde and methylisocyanate for trimethylsilylisocyanate to provide the desired product.
• the resulting residue was purified by chromatography (silica gel, ethyl acetate-hexanes, 25:75, 40:60) followed by crystallization from ethyl acetate-hexanes to provide the desired product (5.03 g, 16.75 mmol) as white needles.
• the desired material is prepared in a similar manner as Example 58 substituting benzyldiethylphosphonate with thien-2-ylmethyldiethyl-phosphonate.
• the desired material is prepared in a similar manner as Example 58 substituting benzyldiethylphosphonate with pyrid-2-ylmethyldiethyl-phosphonate.
• the desired material is prepared in a similar manner as Example 58 substituting benzyldiethylphosphonate with thien-3-ylmethyldiethylphos-phonate.
• the desired material is prepared in a similar manner as Example 58 substituting benzyldiethylphosphonate with 4-chlorobenzyldiethylphos-phonate.
• the desired material is prepared in a similar manner as Example 72 substituting 5- methylthien-2-yl carboxaldehyde with thien-3-yl carbox-aldehyde.
• the desired material is prepared in a similar manner as Example 72 substituting 5- methylthien-2-yl carboxaldehyde with thien-2-yl carboxaldehyde.
• Example 83 The desired material is prepared in a similar manner as Example 72 substituting 5- methylthien-2-yl carboxaldehyde with (5-pyrid-2-yl)thien-3-yl carboxaldehyde.
• Example 83 The desired material is prepared in a similar manner as Example 72 substituting 5- methylthien-2-yl carboxaldehyde with (5-pyrid-2-yl)thien-3-yl carboxaldehyde.
• the desired material is prepared in a similar manner as Example 72 substituting 5- methylthien-2-yl carboxaldehyde with (5-phenylethen-2-yl)thien-2-yl carboxaldehyde.
• the desired material is prepared in a similar manner as Example 72 substituting 5- methylthien-2-yl carboxaldehyde with 5-benzyl_hien-3-yl carboxaldehyde.
• Example 44 The material prepared as in Example 44 is dissolved in dichloromethane and treated with triethylamine and ethoxycarbonylchloride. Aqueous workup and evaporation of the organic extract provides the desired product
• Example 89 The material prepared as in Example 68 is dissolved in dichloromethane and treated with triethylamine and ethoxycarbonylchloride. Aqueous workup and evaporation of the organic extract provides the desired product.
• Example 44 The material prepared as in Example 44 is dissolved in dichloromethane and treated with trimethylsilyl-imidazole. Evaporation of mixture and addition of ether precipitates imidazole which is filtered. Evaporation of the ether provides the desired product
• the desired compound is prepared by the same method as described for Example 44 except using phenylisocyanate instead of trimethylsilylisocyanate. 1
• the desired material is prepared in a similar manner as described for Example 10, except using thien-3-yl carboxyaldehyde instead of 2-acetonaphthone in part a. and methylhydroxylamine hydrochloride instead of hydroxylamine hydrochloride in part b.
• the desired material is prepared in a similar manner as described for Example 10, except using 3-acetylthiophene instead of 2-acetonaphthone in part a. and methylhydroxylamine hydrochloride instead of hydroxylamine hydrochloride in part b.
• the desired material is prepared in a similar manner as described for Example 10, except using 2-acetyl-5-phenylthiophene instead of 2-acetonaphthone in part a.
• Example 95 The desired material is prepared in a similar manner as described for Example 1 except using 6-methoxy-2-acetonaphthone instead of acetophenone.
• the desired material is prepared in a similar manner as described for Example 1 except using 6-methoxy-naphthalen-2-yl carboxyaldehyde instead of acetophenone.
• the desired material is prepared in a similar manner as described for Example 68 except using 6-methoxynaphthalen-2-yl carboxyaldehyde instead of 3-thiophene carboxyaldehyde.
• Example 120 Example 120
• the compound was prepared using the method of Example 98 substituting p- phenylacetophenone for/7-bromoacetophenone. After the hydroxylamine had bee prepared it was acylated in toluene by preparing the hydrochloride salt (HCl gas), heating to reflux, gassing with phsgene for about three minutes, continue to reflux for about one hour, then cool and pour into cold ammonium hydroxide. The crude material thus obtained was presumed to be diacylated, therefore, it was treated with about 2.5 equivalents of lithium hydroxide in isopropanol.
• hydrochloride salt HCl gas
• Example 126 The compound was prepared using the method of Example 97 substituting 3-phenoxybenzaldehyde for/7-bromoacetophenone. mp 155-6°C; IR (KBr) 3480, 3200, 1660, 1620, 1590, 1490, 1450, 1260 cm-i; IH NMR (d 6 Me 2 SO) 4.51 (s, 2), 6.39 (s, 2), 6.32 - 7.42 (m, 9), 9.39 (s, 1) ppm; mass spectrum mle (rel intensity) 276 (25, M++NH 4 ), 259 (100, M++H), 216 (28), 200 (40), 183 (38). Analysis calculated for C 14 H 14 N2O- 3 : C, 65.11, H, 5.46, N, 10.85; found: C, 64.53, H, 5.42, N, 10.81.
• Example 126 Analysis calculated for C 14 H 14 N2O- 3 : C, 65.11, H, 5.46, N, 10.85; found: C,
• the aldehyde ( l.Og, 4.5 mMol) obtained above was dissolved in 1:1 pyridine, ethanol (15 mL). To this stirred solution was added hydroxylamine hydrochloride ( .63g, 9.3 mMol). The reaction was allowed to stirr overnight at room temperature and then concentrated. The residue was partitioned between ether (100 mL) and cold 10% HCl (50 mL). The organic layer was washed with brine and dried (MgS ⁇ 4 ). Concentration afforded the oxime intermediate ( 1.1 g ) as a yellow liquid that was used without further purification.
• the oxime ( l.lg, 5.4 mMol) obtained above was dissolved in ethanol (25 mL) and borane pyridine ( 1.26g, 13.5 mMol) was added via syringe.
• the reaction flask was equipped with a dropping funnel and charged with 6N HCl (14 mL).
• the HCl solution was added at a rate to maintain a gentle reflux.
• the solution was allowed to stir lh at room temperature and concentrated.
• the resulting reside was neutralized with 3N NaOH, and extracted with ethylacetate (3X50 mL).
• the combined organics were washed with water (50 mL) and dried (MgS ⁇ 4 ). Concentration afforded the hydroxylamine intermediate (l.lg) as a white solid and it was used without further purification.
• Example 132 The title compound is prepared from (5-bromothien-2-yl)methyl hydroxylamine from Example 127 by reaction with methyl isocyanate instead of trimethylsilylisocyanate.
• Example 132 The title compound is prepared from (5-bromothien-2-yl)methyl hydroxylamine from Example 127 by reaction with methyl isocyanate instead of trimethylsilylisocyanate.
• the oxime obtained above was dissolved in ethanol (25 mL) and borane pyridine ( 1.26g, 13.5 mMol) was added via syringe.
• the reaction flask was equipped with a dropping funnel and charged with 6N HCl (14 mL).
• the HCl solution was added at a rate to maintain a gende reflux.
• the solution was allowed to stir lh at room temperature and concentrated.
• the resulting reside was neutralized with 3N NaOH, and extracted with 8L ethylacetate (3X50 mL). The combined organics were washed with water (50 mL) and dried (MgS0 4 ). Concentration afforded the desilylated hydroxylamine intermediate.
• n-Butyl lithium (8 mL, 20 mMol, 2.5 M in hexanes) was added and the reaction stirred an additional 15min.
• DMF 5mL
• Water 5 mL
• the reaction mixture was diluted with ether and washed with water (100 mL).
• the aqueous layer was washed with ether and the organic layers combined, washed with brine, dried ( MgS ⁇ 4 ), and concentrated.
• the tide compound was prepared according to the method of Example 134 using furfurylmercaptan instead of thiophenol. mp: 93-95°C; NMR (300MHz, DMSO-d 6 ) ⁇
• the tide compound was prepared according to the method of Example 135 using isopropylmercaptan instead of thiophenol as an off white powder.
• Methylmagnesium bromide was added to an ether soluion of the N,0,dimethyl-3-[ 5- (phenythio)thien-2-yl] acrylamide intermediate from Example 152.
• the crude ketone obtained after aqueous work up was converted to the title compound by the method described for Example 1, to afford an off white powder that contains approximately 10% of the saturated N-hydroxy-N-3-[5-(phenylthio)thien-2-yl]butyl urea.
• the desired product was prepared according to the method of Example 152 using 5-tert- butylthiophene-2-carboxaldehyde instead of 5-(thiophenyl)thiophene-2-carboxaldehyde.
• the reaction mixture was diluted with ether and washed with water (100 mL). The aqueous layer was washed witii ether and the organic layer combined, washed with brine, dried ( MgS ⁇ 4 ), and concentrated. The residue was purified by flash column chromotography ( Si0 2 , eluted with 10% ethylacetate / hexanes) to afford 1.74 g (75%) of the desired aldehyde as a clear oil.
• the tide compound was prepared according to the method of Example 127 using 3- phenoxythiophene-2-carboxaldehyde ( prepared above ) instead of 3-bromothiophene-2- carboxaldehyde.
• reaction was stirred 15 min and additional n-butyllithium ( 24 mL, 60 mMol, 2.5 M in hexanes) was added and the reaction stirred 15min.
• DMF 14 mL
• water 5 mL
• the reaction mixture was diluted with ether and washed with water .
• the aqueous layer was washed with ether and the organic layer combined, washed with brine, dried ( MgSO 4 ), and concentrated.
• IC 50 values concentration of compound producing 50% enzyme inhibition were calculated by linear regression analysis of percentage inhibition versus log inhibitor concentration plots. (Dyer, R D.; Haviv, F.; Hanel, A. M.; Bornemier, D. A.; Carter, G. W. Fed. Proc, Fed. Am. Soc. Exp. Biol. 1984, 43, 1462A). Results for compounds of the foregoing examples are indicated in Table 1.
• Rats were sacrificed 15 minutes after this challenge and the peritoneal fluids were collected and analyzed for leukotriene levels. Test compounds were administered by gavage one hour prior to the antigen challenge. Percent inhibition values were determined by comparing the treatment group to the mean of the control group. From the results of this assay, presented in Table 2, it is demonstrated that compounds of this invention are orally effective in preventing the in vivo biosynthesis of leukotrienes.

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