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WO1990003374A1 - 1,4-dihydrothionapthoquinone and heterocyclic congeners which inhibit lipoxygenase enzymes - Google Patents

1,4-dihydrothionapthoquinone and heterocyclic congeners which inhibit lipoxygenase enzymes Download PDF

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Publication number
WO1990003374A1
WO1990003374A1 PCT/US1989/003492 US8903492W WO9003374A1 WO 1990003374 A1 WO1990003374 A1 WO 1990003374A1 US 8903492 W US8903492 W US 8903492W WO 9003374 A1 WO9003374 A1 WO 9003374A1
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hydrogen
alkyl
phx
compound
phenyl
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French (fr)
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Ayako Yamashita
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • 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
    • C07C323/10—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 singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—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 singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/21—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 singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with the sulfur atom of the thio group bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table

Definitions

  • the present invention provides novel 1,4-dihydrothionatpthoquinone and heterocyclic congeners which are useful as inhibitors of the synthesis of leukotrienes and as inhibitors of the action of lipoxygenase in mammalian metabolism.
  • the leukotrienes are a class of unsaturated fatty acid compounds which are derived from arachidonic acid by the action of lipoxygenase. See, e.g., Samuelsson, Trends in Pharmacological Sciences, 5:227 (1980); and Samuelsson, et al., Annu. Rev. Biochem. 47:997-1029 (1978). For a discussion of leukotriene nomenclature, see Samuelsson, et al., Prostaglandins, 19:645 (1980).
  • the leukotrienes have been discovered as potent constrictors of human bronchi. That is, certain leukotrienes are mediators of the action of slow-reacting substance of anaphylaxis (SRS-A). See, e.g., Dahlen, Nature, 288:484 (1980). These compounds are therefore important mediators of bronchoconstriction in humans.
  • SRS-A slow-reacting substance of anaphylaxis
  • leukotrienes as agonists in immediate hypersensitivity and other pathological conditions have led to research into inhibitors of leukotriene biosynthesis and leukotriene antagonists. See, e.g., Corey, et al., Tetrahedron Letters 21:4243 (1980).
  • Mucus secreted from submucosal glands and surface at the epithelial cells combines with water to form part of the respiratory tract secretions.
  • mucous secretions in the respiratory tract is normal being about 50 to 150 ml per day in man.
  • the excessive production of mucus is an important feature of many pulmonary diseases.
  • chronic bronchitis the flow of mucus increases up to four times.
  • the lack of the ability of the patient to deal with this hyper-production leads to paths of physiological conditions of the airways such as chronic bronchitis, asthma, and cystic fibrosis where there is a defect in consistency in clearance of the mucus. Therefore it is medically desirable to regulate the hypersecretion of mucus (J.G.
  • Leukotrienes particularly leukotriene C 4 (LTC 4 ) and leukotriene D 4 (LTD 4 ) have been shown to be potent mucous secretagogues. Both LTC 4 and LTD 4 increase the release of mucus from human airways in vitro.
  • LTC 4 and LTD 4 increase the release of mucus from human airways in vitro.
  • H.G. Johnson, et al.
  • LTC 4 was effective in stimulating mucus release in vivo in the cat but not in vitro on cat trachea tissue.
  • FPL 55712 an LTC 4 antagonist when given prior to antigen challenge was effective in reversing the tracheal mucus velocity in patients with a history of bronchial asthma but concluded that the clinical significance of FPL 55712 remains to be demonstrated.
  • arachidonic acid In mammalian metabolism, arachidonic acid is transformed to 12-L- hydroperoxy-5,8,10,14-eicosatetraenoic acid by the action of 12-lipoxygenase. See, Hamberg, et al., Proceedings of the National Academy of Science, 71:3400-3404 (1974). Similarly, 5-lipoxygenase transforms arachidonic acid into 5-S-hydroperoxy-6,8,11,14-eicosate- traenoic acid. Thus, an agent which inhibits the action of lipoxygenase would be useful in treating or preventing untoward conditions associated with lipoxygenase products.
  • the 15-lipoxygenase reaction using for example arachidonic acid as substitute, provides 15- hydroperoxyeicosatetiaenoic acid (15-HPETE) which can be converted to 14.15-LTA 4 as reduced to 15-hydroxyeicosatetraenoic acid, (T. Schewe, S.M. Rapoport, H. Kuhn, Adv. Enzymol. 58, 191 (1986).
  • Both the human epithilial cell and trachea produce large amounts of 15-HETE and its metabolites, (D. Henke, M.R. Knowles, R.
  • the pathophysiology of administered 15-HETE include profound increases in mucus production and increases in filtration of polymorphonuclear (PMN) leukocyte cell infiltration into lung tissue (H.G. Johnson, M.L. McNee, F.F. Sun, Am. Rev. Resp. Dis., 131, 917 (1985)).
  • PMN polymorphonuclear
  • Certain napththaquinones are disclosed as intermediates for the preparation of Vitamin K-type derivatives in U.S. patents 4,374,775 and 4,320,065.
  • U.S. patents 4,358,461; 4,388,312; and 4,393,075 disclose certain naphthaquinones as SRS-A and lipoxygenase inhibitors. Intermediates for these latter compounds are disclosed in U.S. patent 4,199,531.
  • W.D. wulff, et al. have described the use of Fischer carbene complexes in the preparation of certain hydroquinone mono ethers in Abstracts 88 and 89 from the Fall 1983 American Chemical Society Meeting in Washington D.C. (August 18-19, 1983).
  • Certain 1-acetoxy-4-methoxy-naphthalenes are also known.
  • 4-methoxy-1-na ⁇ hthalenol, acetate is disclosed in German OLS 2802666.
  • the corresponding 2,3-dimethyl compound is disclosed in F.M. Dean, et al., J. Chem. Soc, Perkin Trans. 1(20):2289-94 (1977).
  • 4-Methoxy-2- phenyl-1-naphthalenol is disclosed in 0. Gonclalves de Lima, et al., Rev. Inst. Antibiot., Univ. Recife 5(1-2):3-9 (1963).
  • the present invention particularly provides:
  • R 1 and R 2 are the same or different and are
  • (PhX) is phenyl substituted by zero to 3 of the following : (a) (C 1 -C 4 )alkyl,
  • n 1, 2, 3, or 4;
  • n O, 1, 2, 3, 4, or 5;
  • -C(O)AA is the acyl portion derived from any naturally occurring alpha-amino acid
  • R 14 and R 15 are the same or different and are:
  • R 16 is (C 1 -C 4 ) alkyl
  • R 17 and R 18 are the same or different and are:
  • W is OCH 3 then Z is (C 1 -C 4 )alkyl.
  • a method for treating or preventing the hypersecretion of mucus in the respiratory tract of an allergic or asthmatic patient in need thereof which comprises administering a compound of Formula I to a patient in an amount effective to treat or prevent said hypersecretion of mucus.
  • R 3 is COCH 3
  • Z is hydrogen
  • R 1 and R 2 are both ethyl, phenyl or a phenyl and a methyl or an ethyl ester.
  • the compounds of the present invention will be named herein using the Chemical Abstracts numbering system (see Naming and Indexing of Chemical Substances for Chemical Abstracts during the Ninth Collective Period (1972-1976), a reprint of section IV from the Volume 76 Index Guide.)
  • D is -CH-CH-
  • the compounds are named as naphthalenes.
  • D is -N(CH 3 )
  • the compounds are named as N- methyl indoles
  • D is -O- and -S-
  • the compounds are named as benzofurans and benzothiophenes , respectively .
  • compounds of this invention are useful to inhibit the formation of slow reacting substance of anaphylaxis (SRS-A) and thus its smooth muscle contracting and secretory effects.
  • SRS-A slow reacting substance of anaphylaxis
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C i -C j ) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • (C 1 -C 3 )alkyl refers to alkyl of one to 3 carbon atoms, inclusive, or methyl, ethyl, propyl, and isopropyl.
  • alkyl of one to 10 carbon atoms, inclusive are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and isomeric forms thereof.
  • C 2 -C 10 alkenyl examples are allyl, 1-methylallyl, 2-methyl- allyl (methallyl), 2-butenyl (crotyl), 3-butenyl, 1,2-dimethylallyl, 1,1-dimethylallyl, 2-ethylallyl, 1-methyl-2-butenyl, 2-methyl-2- butenyl, 3-methyl-2-butenyl, 3-pentenyl, 2,3-dimethyl-2-butenyl, 1,1,2-trimethylallyl, 1,3-dimethyl-2-butenyl, 1-ethyl-2-butenyl, 4- methyl-2-pentenyl, 2-ethyl-2-pentenyl, 4,4-dimethyl-2-pentenyl, 2- heptenyl, 2-octenyl, 5-octenyl, 1,4-dimethyl-1-hexenyl, and the like.
  • PhX examples include phenyl, p-chlorophenyl, m-bromophenyl, 2,4- difluorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,- p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2- methylphenyl, 2 ,4-dichloro-3-methylphenyl, p-nitrophenyl, p-methoxy- phenyl, 3-trifluorophenyl, and 4-hydroxyphenyl.
  • acids which are commonly used for salt formation, are hydrochloric acid, hydrobromic acid, hydroiodic acid, raethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, phosphoric acid, acetic acid, propionate acid, succinic acid, para-toluenesulfonic acid, maleic acid, tartaric acid, and lactic acid.
  • -C(O)-AA is meant the acyl part of an amino acid including the naturally-occurring acids such as: glycine, alanine, valine, leucine, isoleucine, phenylalanine, lysine, proline, tryptophan, methionine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, ornithine, and histidine, and synthetic derivatives thereof.
  • these compounds may be in L or D configuration and are well known and readily available to those skilled in the art.
  • AA-COOH would represent the amino acids themselves.
  • R 3 is definitions (c), (d), or (e)
  • the substituent is an amino acid derivative which may be in the "D” and/or "L” configuration
  • the prefixes "D” and “L” are a means of indicating the relative configurations of various optically active compounds, especially carbohydrates.
  • the compound glyceraldehyde, CH 2 OHCHOHCHO was selected as a standard of reference, because it Is the simplest carbohydrate - an aldotriose - capable of optical isomerism.
  • (+)- Glyceraldehyde was arbitrarily assigned a configuration and was designated D-glyceraldehyde, and (-)-glyceraldehyde was assigned a second configuration and was designated L-glyceraldehyde.
  • D D-glyceraldehyde
  • L L-glyceraldehyde
  • amino acyl compounds of this invention when R 3 is -C(O)- (CR 17 R 18 ) m -(CH 2 ) n -NR 14 R 15 , "C(O)-AA or -C(O)-PhX-NH 2 , are also preferred for drug formulation because they are more easily crystallizable (particularly, the salts) and are more water soluble. On the basis of biological activity and ease of formulation, hydrochloride is preferred.
  • novel compounds of this invention have been shown to be active as Inhibitors of the production of 5-lipoxygenase derived leukotrienes and some of the compounds of this invention have been shown to be active as inhibitors of the lipoxygenase enzyme system. Some of these compounds are effective in both systems. All of the compounds of this invention are active as inhibitors of at least one of these two systems. Accordingly, these novel compounds are useful for administration to mammals, including humans, whenever it is desirable medically to inhibit either of these systems. Inhibitors of either system are useful in the treatment of asthma.
  • all of the compounds of this invention are useful in the treatment of asthma.
  • these compounds are useful as bronchodilators or as inhibitors of mediators such as SRS-A which are released from cells activated by an antigen-antibody complex.
  • mediators such as SRS-A which are released from cells activated by an antigen-antibody complex.
  • these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema.
  • these compounds are administered in a variety of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenter- ally, subcutaneously, or intramuscularly, with intravenous administration being preferred in emergency situations, by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder.
  • dosage forms e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenter- ally, subcutaneously, or intramuscularly, with intravenous administration being preferred in emergency situations, by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder.
  • Doses in the range of about 0.01 to 50 mg per kg of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency
  • these compounds can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophylline); and corticosteroids (ACTH and prednisolone).
  • sympathomimetics isoproterenol, phenylephrine, ephedrine, etc.
  • xanthine derivatives theophylline and aminophylline
  • corticosteroids ACTH and prednisolone
  • the compounds of this invention are particularly useful in treating asthma, but any allergy wherein slow reacting substance of anaphylaxis (SRSA) is thought to be involved as a pharmacological mediator of anaphylaxis can be treated.
  • SRSA slow reacting substance of anaphylaxis
  • the compounds can be used for treatment of such conditions as allergic rhinitis, food allergy and urticaria as well as asthma.
  • the compounds of this invention are effectively administered to human asthma patients by any covenient route such as oral inhalation, aerosol inhalation, parenterally, (orally, intravenously, interperitoneally), transdermally, topically and the like.
  • the amino acyl compounds of this invention are preferred for intravenous infusions and the like. Particularly preferred in this regard Is L-Valine, 1-methylthio-3-n-butyl-4-naphalenyl ester, mono- hydrochloride.
  • the non-acyl-amino compounds of this invention are preferred for topical administration.
  • the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers.
  • a co-solvent such as ethanol, flavoring materials and stabilizers.
  • a dispensing agent such as oleyl alcohol.
  • the lipoxygenase inhibitor compounds of this invention are useful whenever it is desired to inhibit platelet aggregation, reduce the adhesive character of platelets, and remove or prevent the formation of thrombi in mammals, including man, rabbits, dogs, and rats.
  • these compounds are useful in the prevention of myocardial infarcts, to prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions.
  • these compounds are administered systemically, e.g., intravenously, subcutaneously, Intramuscularly, and in the form of sterile implants for prolonged action.
  • the intravenous route of administration is preferred. Doses in the range about 0.005 to about 20 mg per kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of adrainis tration .
  • lipoxygenase inhibitor compounds are further useful as additives to blood, blood products, blood substitutes, or other fluids which are used in artificial extracorporeal circulation or perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body.
  • isolated body portions e.g., limbs and organs
  • aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds.
  • the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of these at a total steady state dose of about 0.001 to 10 mg per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.
  • 5-lipoxygenase inhibitors prevent the production of slow-reacting substance of anaphylaxis (SRS-A), now known to be a mixture of leukotrienes.
  • SRS-A slow-reacting substance of anaphylaxis
  • SRS-A mediates the symptoms and pathophysiology of asthma. See Murphy, et al., Proc. Nat. Acad. Sci. USA, 4275-4279 (1979).
  • SRS-A slow-reacting substance of anaphylaxis
  • 5-Lipoxygenase products have been implicated In essential hypertension (Chand, et al., Microcirculation 1:111-123 (1981), and gout (Rae, et al., Lancet 1122-1124 (Nov. 20, 1982), indicating that the 5-lipoxygenase inhibitors disclosed herein are useful in treating these conditions as well. Further, neutrophil depletion, such as that induced by 5-lipoxygenase inhibitors, has been shown to cause a significant decrease in infarct size following circumflex artery occlusion. See Romson, et al., Circulation 66:85 (1982). Thus, the 5-lipoxygenase inhibitors herein may be useful in the protection of the myocardium following infarct.
  • the lipoxygenase inhibitors of the present invention are also useful for the prevention or treatment of deep vein thrombosis (DVT).
  • This method comprises the administration of a compound of the Formula I to a mammal susceptible to DVT.
  • deep vein thrombosis By “deep vein thrombosis” (DVT) is meant the thrombosis (clot formation) of the lower limb deep veins (deeply situated veins). Such thrombosis is frequently a result of major surgery, massive trauma, myocardial infarction, neoplasia, and pregnancy.
  • the term “deep vein thrombosis” or “DVT” Is meant to encompass the thrombosis resulting from these or any other causes.
  • prevention in this context Is meant the total or partial avoidance of clot formation in the deep veins of a mammal.
  • the present invention includes the treatment of each of various mammalian species, including humans.
  • the present invention is particularly and especially concerned with treating domesticated animals, for example, cattle, dogs, cats and swine.
  • domesticated animals for example, cattle, dogs, cats and swine.
  • Humans are the most preferred mammals to be treated by the methods of this invention.
  • oral formulation and oral administration is, for example, the preferred route for use in humans although parenteral (e.g., intravenous, intraperitoneal, and intramuscular) administration is also employed.
  • the dosage regimen for the lipoxygenase inhibitor compounds used to treat deep vein thrombosis will depend on a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, and most Importantly on the risks and probable consequences of deep vein thrombosis. It is within the skill of the attending physician or veterinarian to determine the risks of deep vein thrombosis, and to prescribe an effective amount of the lipoxygenase inhibitors claimed herein.
  • the dosage is in the range of about 0.01 to about 1 mg/kg/minute by intravenous infusion, or about 0.1 to about 50 mg/kg/day by oral administration. Equivalent dosages for other routes of administra tion are also employed. Similarly, when other lipoxygenase inhibitors are employed, equipotent doses can be administered based on the compound's comparative potency as demonstrated in the standard laboratory test.
  • SRS-A inhibitors e.g., in the treatment of asthma.
  • the present invention further provides a method of treating or preventing the hypersecretion of mucus in the airways or the respiratory tract of a patient in need thereof. More particularly, the present invention provides a method for treating or preventing the hypersecretion of mucus in the respiratory tract of patients with bronchial asthma, chronic bronchitis, cystic fibrosis, bronchorrhea, obstructive bronchitis and other disease conditions associated with hyperplasia of mucus secreting cells and increased mucus secretion.
  • the method of the present invention finds particular use in warm blooded animals including mammals, such as cattle, horses, rodents, dogs, sheep, pigs, monkeys, cats, humans, and birds.
  • the present invention provides a prophylactic as well as therapeutic method of treating hypersecretion of mucus in the airways of a warm blooded animal.
  • the quantity of compound of Formula I to be administered is any amount effective in treating or preventing hypersecretion of mucus in the airways of the patient being treated.
  • the compounds of Formula I are administered, e.g., intravenously, intramuscularly, topically, by aerosol inhalation, bucally or orally.
  • the quantity of compound of Formula I effective in achieving the method here claimed is determined by the particular mode of administration and frequency of administration as well as the age and condition of the patient. Generally the amount of compound administered will range from about 0.001 mg to 10 mg per dose given up to three times per day by aerosol inhalation, with a range from about 0.01 mg to 10 mg per dose being preferred.
  • a dose of about 0.01 to 10 ⁇ g/kg/min is administered with intramuscular injection ranging from 0.5 to 15 mg per dose.
  • intramuscular injection ranging from 0.5 to 15 mg per dose.
  • unit doses of from 1 mg to 100 mg given up to three times per day of compounds of Formula I are effective in practicing the method of the present invention.
  • the quantity of compound applied topically is that which will give comparable blood levels of active ingredient when said substance is administered by any of the other various routes of administration.
  • the compounds of Formula I are formulated into compositions for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, eye drops, oral solutions or suspensions, and oil in water and water in oil emulsions containing suitable quantities of the compound.
  • either solid or fluid unit dosage forms can be prepared.
  • the compound of Formula I is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers.
  • Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.
  • Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared.
  • the forms can be dissolved In an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup.
  • An elixir is prepared by using a hydroalcoholic (ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.
  • Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
  • a suspending agent such as acacia, tragacanth, methylcellulose and the like.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the pharmaceutically useful compound described herein, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions can be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. These compounds can be sterilized by exposure to ethylene oxide or an equivalent gas before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions for inhalation useful in practicing the method of present invention are of three basic types: (1) a powder mixture preferably micropulverized with particle size, preferably from about 2 to 5. microns; (2) an aqueous solution to be sprayed with a nebulizer; (3) an aerosol with volatile propellant in a pressurized container.
  • the powders are quite simply prepared by mixing a suitable pharmaceutically useful compound of Formula I with a solid base which is compatible with lung tissue, preferably lactose.
  • the powders are packaged in a device adapted to emit a measured amount of powder when inhaled through the mouth.
  • Aqueous solutions are prepared by dissolving the appropriate compound of the Formula I in water and adding salt to provide an isotonic solution and buffering to a pH compatible with inhalation.
  • the solutions are dispersed in a spray device or nebulizer and sprayed into the mouth while inhaling.
  • Aerosols are prepared by dissolving an appropriate pharmaceut- ically useful compound of Formula I in water or ethanol and mixing with a volatile propellant and placing in a pressurized container having a metering valve to release a predetermined amount of material.
  • the liquefied propellant employed is one which has a boiling point below 65oF at atmospheric pressure.
  • the liquefied propellant should be non-toxic.
  • suitable liquefied propellants which may be employed are the lower alkanes containing up to 5 carbon atoms, such as butane and pentane, or a lower alkyl chloride, such as methyl, ethyl or propyl chlorides.
  • fluorinated and fluorochlorlnated lower alkanes or mixtures thereof such as, dichlorodifluoromethane, dichlorotetrafluoroethane, trichloromonofluoromethane, dichloromono- fluoromethane, monochlorodifluoromethane, trichlorotrifluoroethane, difluoroethane and monochlorotrifluoromethane.
  • the compounds can be prepared by reaction of the appropriate chromium carbene complex with an alkyne.
  • reaction conditions vary when W is OCH 3 or S(O) q Y.
  • a second oxidation step is required to obtain the S(O) q Y group where q is greater than zero.
  • Methods for conducting the oxidation of a SY group are well known such as N.J. Leonard, C.R. Johnson, J. Org. Chem., 27, 282 (1962).
  • One method can comprise treatment with potassium peroxymonosulfate to prepare the SO 2 Y group.
  • a carbene complex of the Formula A-1 is reacted with an acetylene of the Formula A-2 (preferably 1.5 equivalents).
  • the cycloaddition of the carbene complex A-1 having the -S(O) q Y group forms the subject product only when BF 3 ⁇ Et 2 O (5 mol eq), Ac 2 O (5 mol eq) and NEt 3 (5 mol eq) are present.
  • Conversion of the Ac group to the OH then introduction of the OR 3 group can be done by any conventional means.
  • Both Scheme A and B reactions are preferably undertaken in a solvent such as tetrahydrofuran (THF) in an inert atmosphere (e.g., argon).
  • a solvent such as tetrahydrofuran (THF) in an inert atmosphere (e.g., argon).
  • the reaction temperature is at about 65o C.
  • alkynes are well known, readily available compounds or may be prepared by known means. Formation of the acetylated product A-2 where W is OCH 3 is known, for example, see U.S. Patent 4,737,519, Col. 13 through Col 14, herein incorporated by reference.
  • an addition funnel with a three-way argon-vacuum inlet was placed 0.5 grams of the tetra-n-butylalkoxide carbene.
  • the flask was evacuated and filled with argon three times prior to CH 2 CI 2 addition (38 ml).
  • To an addition funnel was introduced a solution of 0.07 ml of acetyl chloride in 8 ml of CH 2 CI 2 .
  • the carbene solution was cooled to -40o C and the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH 2 CI 2 upon complete addition).
  • the solution was stirred at -40o C for one hour, then cooled to -78o
  • an addition funnel with a three-way argon-vacuum inlet was placed 0.8 grams of the tetra ethylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH 2 CI 2 addition (35 ml).
  • To an addition funnel was introduced a solution of 0.09 ml of acetyl chloride in 8 ml of CH 2 CI 2 , then the carbene solution was cooled to- 40o C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH 2 Cl 2 upon complete addition).
  • an addition funnel with a three-way argon-vacuum inlet was placed 0.8 grams of the tetra-n-propylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH 2 CI 2 addition (35 ml).
  • To an addition funnel was introduced a solution of 0.08 ml of acetyl chloride in 8 ml of CH 2 CI 2 .
  • the carbene solution was cooled to -40o C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH 2 CI 2 upon complete addition).
  • an addition funnel with a three-way argon-vacuum inlet was placed 0.8 grams of the tetra-methylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH 2 CI 2 addition (35 ml).
  • To an addition funnel was introduced a solution of 0.11 ml of acetyl chloride in 8 ml of CH 2 CI 2 .
  • the carbene solution was cooled to -40o C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH 2 Cl 2 upon complete addition).
  • an addition funnel with a three-way argon-vacuum inlet was placed 27 grams of the tetra-n-butylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH 2 CI 2 addition (400 ml).
  • To an addition funnel was introduced a solution of 3.9 ml of acetyl chloride in 80 ml of CH 2 CI 2 .
  • the carbene solution was cooled to -40o C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH 2 CI 2 upon complete addition).
  • the carbene complex as prepared in the first step of Example 10 was mixed with 1-hexyne in DMF under argon at 25o C and was heated at 125-130o C (bath temperature) for 6 hrs, then 100o C (bath temperature) for 15 hrs under argon.
  • the reaction mixture was cooled and diluted with 800 ml of ether.
  • the ether layer was washed with sat. NaCl aq sol. (3 x 300 ml).
  • the solvent was removed by rotary evaporation, and the residue was treated with IN HCl aq sol. (25 ml), CH 2 Cl 2 (400 ml), and MeOH (350 ml) at 25o C for 5 hrs.
  • Table 2 shows 15-lipoxygenas (15-Lo) inhibition data for various compounds at a 20 ⁇ g/ml unit dose.
  • the negative values indicate a percentage increase in 15-Lo products. This result is indicative of an increased production of materials which cross react with the 15- HETE antibodies.
  • Table 3 shows 15-lipoxygenase inhibition data (15-Lo) for a set of compounds at various unit doses in ⁇ g/ml

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Abstract

The present invention provides certain novel 1,4-dihydrothionapthoquinone and heterocyclic cogeners of Formula (I), which are useful as inhibitors of leukotriene biosynthesis and as inhibitors of lipoxygenase. They are thus employed wherever it is medically necessary or desirable to inhibit these systems.

Description

1,4-DIHYDROTHIONAPTHOQUINONE AND HETEROCYCLIC CONGENERS
WHICH INHIBIT LIPOXYGENASE ENZYMES BACKGROUND OF THE INVENTION
The present invention provides novel 1,4-dihydrothionatpthoquinone and heterocyclic congeners which are useful as inhibitors of the synthesis of leukotrienes and as inhibitors of the action of lipoxygenase in mammalian metabolism.
The leukotrienes are a class of unsaturated fatty acid compounds which are derived from arachidonic acid by the action of lipoxygenase. See, e.g., Samuelsson, Trends in Pharmacological Sciences, 5:227 (1980); and Samuelsson, et al., Annu. Rev. Biochem. 47:997-1029 (1978). For a discussion of leukotriene nomenclature, see Samuelsson, et al., Prostaglandins, 19:645 (1980).
The leukotrienes have been discovered as potent constrictors of human bronchi. That is, certain leukotrienes are mediators of the action of slow-reacting substance of anaphylaxis (SRS-A). See, e.g., Dahlen, Nature, 288:484 (1980). These compounds are therefore important mediators of bronchoconstriction in humans.
The role of leukotrienes as agonists in immediate hypersensitivity and other pathological conditions has led to research into inhibitors of leukotriene biosynthesis and leukotriene antagonists. See, e.g., Corey, et al., Tetrahedron Letters 21:4243 (1980).
Mucus secreted from submucosal glands and surface at the epithelial cells combines with water to form part of the respiratory tract secretions. In healthy states mucous secretions in the respiratory tract is normal being about 50 to 150 ml per day in man. The excessive production of mucus, however, is an important feature of many pulmonary diseases. For example, in chronic bronchitis the flow of mucus increases up to four times. The lack of the ability of the patient to deal with this hyper-production leads to paths of physiological conditions of the airways such as chronic bronchitis, asthma, and cystic fibrosis where there is a defect in consistency in clearance of the mucus. Therefore it is medically desirable to regulate the hypersecretion of mucus (J.G. Widdicobe, British Medical Bulletin, 34:57 (1978)). Historically, attempts have been made to treat the symptoms without regulation of the root cause. For example, mucolytics, acetylcysteine containing solutions, as well as iodides have been used. Also, antibiotics are used to treat infec tions in cystic fibrosis because no known drug can regulate the consistency of the mucus in this disease condition.
Leukotrienes, particularly leukotriene C4 (LTC4) and leukotriene D4 (LTD4) have been shown to be potent mucous secretagogues. Both LTC4 and LTD4 increase the release of mucus from human airways in vitro. Z. Maron, et al., Am. Rev. Respir. Dis. 126, 449-451 (1982); S.J. Coles, et al., Prostaglandins 25, 155-170 (1983) and from canine tracheas in vivo. H.G. Johnson, et al.,
International Jr. Immunopharmacol. 5, 178 (1983); H.G. Johnson, et al., Prostaglandins 25, 237-243 (1983). Arachidonic acid, metabolic products of arachidonic acid, monohydroxy-eicosatetraenoic acid, and prostaglandins also release mucus from human airway. Z. Marom, et al., Jr. Clinical Investigations, 67, 1695-1702 (1981).
LTC4 was effective in stimulating mucus release in vivo in the cat but not in vitro on cat trachea tissue. A.C. Peatfield, et al., British Journal of Pharmacology, 77, 391-393 (1982). J.H. Shelhamer, et al., Chest 81, 36S (1982) summarizes the nature of evidence available suggesting that lipoxygenase products generated by the airways in vitro might be responsible for the augmented mucus release.
O. Cromwell, et al., The Lancet, July 25, 1981, pp. 164-165, identified LTB4 and LTD4 in the sputum of cystic fibrosis patients and speculated, therefore, that inhibitors of the lipoxygenase pathway might be capable of reversing the airway obstruction in such patients.
T. Ahmed, et al., Am. Rev. Respir. Dis. 124, 110-114 (1981) demonstrated that FPL 55712, an LTC4 antagonist when given prior to antigen challenge was effective in reversing the tracheal mucus velocity in patients with a history of bronchial asthma but concluded that the clinical significance of FPL 55712 remains to be demonstrated.
In mammalian metabolism, arachidonic acid is transformed to 12-L- hydroperoxy-5,8,10,14-eicosatetraenoic acid by the action of 12-lipoxygenase. See, Hamberg, et al., Proceedings of the National Academy of Science, 71:3400-3404 (1974). Similarly, 5-lipoxygenase transforms arachidonic acid into 5-S-hydroperoxy-6,8,11,14-eicosate- traenoic acid. Thus, an agent which inhibits the action of lipoxygenase would be useful in treating or preventing untoward conditions associated with lipoxygenase products. Just as the actions of the 5-lipoxygenase enzymes lead to leukotrienes of the B4, C4, D4 and E4 series, the 15-lipoxygenase reaction, using for example arachidonic acid as substitute, provides 15- hydroperoxyeicosatetiaenoic acid (15-HPETE) which can be converted to 14.15-LTA4 as reduced to 15-hydroxyeicosatetraenoic acid, (T. Schewe, S.M. Rapoport, H. Kuhn, Adv. Enzymol. 58, 191 (1986). Both the human epithilial cell and trachea produce large amounts of 15-HETE and its metabolites, (D. Henke, M.R. Knowles, R. Boucher, T. Eling, Ann. Rev. Respir. Dis., 135, A508 (1987); J.A. Hunter, W.E. Finkheiner, J.A. Nadel, E.J. Goetzl, M.J. Holtzman, Clin. Res., 33, 78A (1985); Proc. Natl. Acad. Sci. (USA), 82, 4633 (1985)). Antigen challenge of asthmatic patients produced marked increases of 15-HETE in the fluid obtained by bronchoalveolar lavage. (J.J. Murray, A.B. Tonnel, A.R. Brash, L.J. Roberts, II, P. Gosset, R. Workman, A. Capron, J.A. Oates, New England Journal of Medicine, 315, 800 (1986). The pathophysiology of administered 15-HETE include profound increases in mucus production and increases in filtration of polymorphonuclear (PMN) leukocyte cell infiltration into lung tissue (H.G. Johnson, M.L. McNee, F.F. Sun, Am. Rev. Resp. Dis., 131, 917 (1985)).
It can be concluded that compounds which inhibit the formation of 15-HETE type products by interfacing with their biosynthesis would provide a method for the prophylactic or therapeutic treatment of allergy of a reagin or non-reagin indicated nature. Asthma is preferentially treated by compounds of this invention but any allergy wherein LTB4, LTC4, LTD4, LTE4, and/or 15-HETE-type products are thought to be involved as anaphylaxis indicators can be treated.
Therefore, compounds which inhibit the action of lipoxygenase are useful in the treatment of inflammatory conditions where it is desirable to prevent migration of polymorphonuclear leukocytes to the inflammatory site. They are also useful in the treatment of asthma. PRIOR ART
Certain substituted napththaienes, indoles, benzofurans and benzothiophenes are disclosed as lipoxygenase inhibitors in commonly assigned U.S. Patent 4,737,519.
Certain chromium complexes of benzofurans and benzothiophenes are disclosed in K.H. Dotz, et al., Chem. Ber. 111:2517 (1978).
Certain napththaquinones are disclosed as intermediates for the preparation of Vitamin K-type derivatives in U.S. patents 4,374,775 and 4,320,065. U.S. patents 4,358,461; 4,388,312; and 4,393,075 disclose certain naphthaquinones as SRS-A and lipoxygenase inhibitors. Intermediates for these latter compounds are disclosed in U.S. patent 4,199,531. W.D. wulff, et al., have described the use of Fischer carbene complexes in the preparation of certain hydroquinone mono ethers in Abstracts 88 and 89 from the Fall 1983 American Chemical Society Meeting in Washington D.C. (August 18-19, 1983).
A number of substituted 1-hydroxy, 4-methoxy naphthalenes are known. Thus K.H. Dotz, et al., J. Organometal. Chem. 247(2):187-201 (1983) discloses 4-methoxy-1-naphthalenols substituted in the 2 and 3 positions by phenyl, substituted phenyl, methyl, ethyl, octyl, and propyl. 4-Methoxy-2-phenyl-1-naphthalenol is disclosed in K. Buggle, et al., Jr. Chem. Soc., Perkin Trans 1 (6):572-575 (1975). 4-Methoxy- 2.3-diphenyl-1-naphthalenol is disclosed in K.H. Dotz, J. Organmet. Chem. 140(2):177-86 (1977). 4-Methoxy-2,3-dimethyl-1-naph- thalenol is disclosed in K.H. Dotz, et al., Chem. Ber. 110(4):1555-63 (1977). 2-Tert-butyl-4-methoxy-1-naphthol is disclosed in Japanese patent 7010339. U.S. patent 3,948,958 discloses 4-methoxy-3-methyl-- 1-naphthenol. 4-Methoxy-2-methyl-1-naphthenol is disclosed in I.D. Snyder, et al., Journal of the American Chemical Society, 96(26):- 8046-53 (1974). The 2,3- unsubstituted 4-methoxy-1-naphthenol compound is also known. See, e.g., British patent 1,122,085.
Certain 1-acetoxy-4-methoxy-naphthalenes are also known. Thus, 4-methoxy-1-naρhthalenol, acetate is disclosed in German OLS 2802666. The corresponding 2,3-dimethyl compound is disclosed in F.M. Dean, et al., J. Chem. Soc, Perkin Trans. 1(20):2289-94 (1977). 4-Methoxy-2- phenyl-1-naphthalenol is disclosed in 0. Gonclalves de Lima, et al., Rev. Inst. Antibiot., Univ. Recife 5(1-2):3-9 (1963).
SUMMARY OF THE INVENTION
The present invention particularly provides:
a compound of the Formula I or a pharmacologically acceptable acid addition salt thereof wherein R1 and R2 are the same or different and are
(a) hydrogen,
(b) (C1-C10)alkyl,
(c) (C2-C10)alkenyl , or
(d) PhX;
wherein (PhX) is phenyl substituted by zero to 3 of the following : (a) (C1-C4)alkyl,
(b) chloro,
(c) fluoro,
(d) bromo,
(e) nitro,
(f) trifluoromethyl; or
(g) OR4;
wherein D is
(a) -CH=CH-,
(b) -N(CH3),
(c) -S-, or
(d) -O-;
wherein R3 is
(a) CH3-C(O)-,
(b) hydrogen,
(c) -C(O)-(CR17R18)m-(CH2)n-NR14R15,
(d) -C(O)-AA, or
(e) -C(O)-PhX-NH2;
wherein m is 1, 2, 3, or 4;
wherein n is O, 1, 2, 3, 4, or 5;
wherein -C(O)AA is the acyl portion derived from any naturally occurring alpha-amino acid;
wherein R14 and R15 are the same or different and are:
(a) hydrogen,
(b) (C1-C10) alkyl,
(c) -C(O)R16,
(d) -C(O)-PhX, or
(e) -PhX;
with the proviso that R14 and R15 are other than hydrogen when n is zero;
wherein R16 is (C1-C4) alkyl;
wherein R17 and R18 are the same or different and are:
(a) hydrogen,
(b) (C1-C10) alkyl,
(c) -CH2-PhX, or
(d) -PhX;
with the proviso that each occurrence of R17 and R18 is the same or different; wherein PhX-NH2 is an amino-substituted phenyl group additionally substituted by zero to 3 of the following:
(a) (C1-C4) alkyl,
(b) chloro,
(c) fluoro,
(d) bromo,
(e) nitro,
(f) trifluoromethyl, or
(g) OR4;
wherein R4 is
(a) hydrogen, or
(b) (C1-C4)alkyl;
wherein W is
(a) OCH3 or
(b) S(O)qY
wherein q is 0, 1 or 2;
wherein Y is
(a) (C1-C4)alkyl,
(b) (C1-C4) alkenyl,
(c) PhX;
wherein W is S(O)qY then Z is
(a) hydrogen or
(b) (C1-C4)alkyl;
wherein W is OCH3 then Z is (C1-C4)alkyl.
Excluding those compounds where Z is hydrogen, D is ethylene and R1 and R3 are hydrogen, R2 is phenyl, and W is SCH3 or SPh; or where R1 and R2 are methyl, R3 is hydrogen and W is SCH3; or where R1 is hydrogen, R2 is phenyl, R3 is COCH3 and W is SCH3.
A method for treating or preventing the hypersecretion of mucus in the respiratory tract of an allergic or asthmatic patient in need thereof which comprises administering a compound of Formula I to a patient in an amount effective to treat or prevent said hypersecretion of mucus. Excluding those compounds where D is O or -CH=CH-, R3 is COCH3, Z is hydrogen and R1 and R2 are both ethyl, phenyl or a phenyl and a methyl or an ethyl ester.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention will be named herein using the Chemical Abstracts numbering system (see Naming and Indexing of Chemical Substances for Chemical Abstracts during the Ninth Collective Period (1972-1976), a reprint of section IV from the Volume 76 Index Guide.) When D is -CH-CH-, the compounds are named as naphthalenes. When D is -N(CH3), the compounds are named as N- methyl indoles, and when D is -O- and -S-, the compounds are named as benzofurans and benzothiophenes , respectively .
As noted, compounds of this invention are useful to inhibit the formation of slow reacting substance of anaphylaxis (SRS-A) and thus its smooth muscle contracting and secretory effects.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (Ci-Cj) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus (C1-C3)alkyl refers to alkyl of one to 3 carbon atoms, inclusive, or methyl, ethyl, propyl, and isopropyl.
Examples of alkyl of one to 10 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and isomeric forms thereof.
Examples of C2-C10 alkenyl are allyl, 1-methylallyl, 2-methyl- allyl (methallyl), 2-butenyl (crotyl), 3-butenyl, 1,2-dimethylallyl, 1,1-dimethylallyl, 2-ethylallyl, 1-methyl-2-butenyl, 2-methyl-2- butenyl, 3-methyl-2-butenyl, 3-pentenyl, 2,3-dimethyl-2-butenyl, 1,1,2-trimethylallyl, 1,3-dimethyl-2-butenyl, 1-ethyl-2-butenyl, 4- methyl-2-pentenyl, 2-ethyl-2-pentenyl, 4,4-dimethyl-2-pentenyl, 2- heptenyl, 2-octenyl, 5-octenyl, 1,4-dimethyl-1-hexenyl, and the like.
Examples of PhX are phenyl, p-chlorophenyl, m-bromophenyl, 2,4- difluorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,- p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2- methylphenyl, 2 ,4-dichloro-3-methylphenyl, p-nitrophenyl, p-methoxy- phenyl, 3-trifluorophenyl, and 4-hydroxyphenyl.
Examples of acids, which are commonly used for salt formation, are hydrochloric acid, hydrobromic acid, hydroiodic acid, raethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, phosphoric acid, acetic acid, propionate acid, succinic acid, para-toluenesulfonic acid, maleic acid, tartaric acid, and lactic acid.
By -C(O)-AA is meant the acyl part of an amino acid including the naturally-occurring acids such as: glycine, alanine, valine, leucine, isoleucine, phenylalanine, lysine, proline, tryptophan, methionine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, ornithine, and histidine, and synthetic derivatives thereof. These compounds may be in L or D configuration and are well known and readily available to those skilled in the art. Thus, AA-COOH would represent the amino acids themselves.
When R3 is definitions (c), (d), or (e), the substituent is an amino acid derivative which may be in the "D" and/or "L" configuration, the prefixes "D" and "L" are a means of indicating the relative configurations of various optically active compounds, especially carbohydrates. The compound glyceraldehyde, CH2OHCHOHCHO, was selected as a standard of reference, because it Is the simplest carbohydrate - an aldotriose - capable of optical isomerism. (+)- Glyceraldehyde was arbitrarily assigned a configuration and was designated D-glyceraldehyde, and (-)-glyceraldehyde was assigned a second configuration and was designated L-glyceraldehyde. R. T. Morrison & R. N. Boyd, Organic Chemistry 1087-88 (1978). Compounds related configurationally to D-glyceraldehyde are given the designation D, and compounds related to L-glyceraldehyde are given the designation L. Organic Chemistry at 1089. In the present invention, both L and D configurations are observed; however, the L-configuration predominates and is preferred.
To demonstrate the SRS-A inhibitory activity of the compounds of this invention, compounds of this invention were evaluated in a standard laboratory test. This test is conducted in rat mononuclear cells incubated in the presence of cysteine and challenged with a calcium ionophore (which induces SRS-A formation). Among the non- amino compounds of this invention, in this test system, and are preferred. At a concentration of 10 micrograms/ml, these compounds Inhibited the synthesis of SRS-A 100% and 95%, respectively.
The amino acyl compounds of this invention, when R3 is -C(O)- (CR17R18)m-(CH2)n-NR14R15, "C(O)-AA or -C(O)-PhX-NH2, are also preferred for drug formulation because they are more easily crystallizable (particularly, the salts) and are more water soluble. On the basis of biological activity and ease of formulation, hydrochloride is preferred.
Some of the novel compounds of this invention have been shown to be active as Inhibitors of the production of 5-lipoxygenase derived leukotrienes and some of the compounds of this invention have been shown to be active as inhibitors of the lipoxygenase enzyme system. Some of these compounds are effective in both systems. All of the compounds of this invention are active as inhibitors of at least one of these two systems. Accordingly, these novel compounds are useful for administration to mammals, including humans, whenever it is desirable medically to inhibit either of these systems. Inhibitors of either system are useful in the treatment of asthma.
Thus, all of the compounds of this invention are useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as inhibitors of mediators such as SRS-A which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, these compounds are administered in a variety of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenter- ally, subcutaneously, or intramuscularly, with intravenous administration being preferred in emergency situations, by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of about 0.01 to 50 mg per kg of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of administration. For the above use these compounds can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophylline); and corticosteroids (ACTH and prednisolone).
As noted above, the compounds of this invention are particularly useful in treating asthma, but any allergy wherein slow reacting substance of anaphylaxis (SRSA) is thought to be involved as a pharmacological mediator of anaphylaxis can be treated. For example, the compounds can be used for treatment of such conditions as allergic rhinitis, food allergy and urticaria as well as asthma.
The compounds of this invention are effectively administered to human asthma patients by any covenient route such as oral inhalation, aerosol inhalation, parenterally, (orally, intravenously, interperitoneally), transdermally, topically and the like. The amino acyl compounds of this invention are preferred for intravenous infusions and the like. Particularly preferred in this regard Is L-Valine, 1-methylthio-3-n-butyl-4-naphalenyl ester, mono- hydrochloride. The non-acyl-amino compounds of this invention are preferred for topical administration.
For administration by the oral inhalation route with conventional nebulizers or by oxygen aerosolization it is convenient to provide the instant active ingredient in dilute solution, preferably at concentra-tions of about 1 part of medicament to form about 100 to 200 parts by weight of total solution. Entirely conventional additives may be employed to stabilize these solutions or to provide isotonic media, for example, sodium chloride, sodium citrate, citric acid, sodium bissulfite, and the like can be employed.
For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Instead of a co-solvent there can also be used a dispensing agent such as oleyl alcohol. Suitable means to employ the. aerosol inhalation therapy technique are described fully in U.S. Pat. No. 2,868,691 for example.
The lipoxygenase inhibitor compounds of this invention are useful whenever it is desired to inhibit platelet aggregation, reduce the adhesive character of platelets, and remove or prevent the formation of thrombi in mammals, including man, rabbits, dogs, and rats. For example, these compounds are useful in the prevention of myocardial infarcts, to prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, Intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.005 to about 20 mg per kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of adrainis tration .
These lipoxygenase inhibitor compounds are further useful as additives to blood, blood products, blood substitutes, or other fluids which are used in artificial extracorporeal circulation or perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of these at a total steady state dose of about 0.001 to 10 mg per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.
Hammerstrom, et al. Science 197:994-996 (1977) notes the role of 12- lipoxygenase in psoriasis. Doig, et al., Prostaglandins 20:1007- 1019 (1980) and Lin, et al., J. Clin. Invest. 70:1058 (1982) disclose that 5-lipoxygenase inhibitors block platlet thrombus formation. Dawson, et al., in SRS-A and Leukotrienes, 219-226 (Wiley and Sons 1981) note that 5-lipoxygenase inhibitors block neutrophil "recruitment" during inflammatory diseases such as arthritis.
In addition, 5-lipoxygenase inhibitors prevent the production of slow-reacting substance of anaphylaxis (SRS-A), now known to be a mixture of leukotrienes. (Leukotrienes are synthesized using 5- lipoxygenase.) SRS-A mediates the symptoms and pathophysiology of asthma. See Murphy, et al., Proc. Nat. Acad. Sci. USA, 4275-4279 (1979). Thus, the 5-lipoxygenase inhibitors disclosed herein are useful in the treatment of asthma.
5-Lipoxygenase products have been implicated In essential hypertension (Chand, et al., Microcirculation 1:111-123 (1981), and gout (Rae, et al., Lancet 1122-1124 (Nov. 20, 1982), indicating that the 5-lipoxygenase inhibitors disclosed herein are useful in treating these conditions as well. Further, neutrophil depletion, such as that induced by 5-lipoxygenase inhibitors, has been shown to cause a significant decrease in infarct size following circumflex artery occlusion. See Romson, et al., Circulation 66:85 (1982). Thus, the 5-lipoxygenase inhibitors herein may be useful in the protection of the myocardium following infarct.
The lipoxygenase inhibitors of the present invention are also useful for the prevention or treatment of deep vein thrombosis (DVT). This method comprises the administration of a compound of the Formula I to a mammal susceptible to DVT.
By "deep vein thrombosis" (DVT) is meant the thrombosis (clot formation) of the lower limb deep veins (deeply situated veins). Such thrombosis is frequently a result of major surgery, massive trauma, myocardial infarction, neoplasia, and pregnancy. The term "deep vein thrombosis" or "DVT" Is meant to encompass the thrombosis resulting from these or any other causes.
By "prevention" in this context Is meant the total or partial avoidance of clot formation in the deep veins of a mammal.
The present invention includes the treatment of each of various mammalian species, including humans. With respect to non-humans, the present invention is particularly and especially concerned with treating domesticated animals, for example, cattle, dogs, cats and swine. Humans are the most preferred mammals to be treated by the methods of this invention.
Any convenient route of administration is employed. Thus, oral formulation and oral administration is, for example, the preferred route for use in humans although parenteral (e.g., intravenous, intraperitoneal, and intramuscular) administration is also employed.
The dosage regimen for the lipoxygenase inhibitor compounds used to treat deep vein thrombosis will depend on a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, and most Importantly on the risks and probable consequences of deep vein thrombosis. It is within the skill of the attending physician or veterinarian to determine the risks of deep vein thrombosis, and to prescribe an effective amount of the lipoxygenase inhibitors claimed herein. When 1-methylthio-3-n-butyl-4-acetoxynap- thalene or 5-butyl-7-(methylthio)-4-benzofuranol-acetate are used, the dosage is in the range of about 0.01 to about 1 mg/kg/minute by intravenous infusion, or about 0.1 to about 50 mg/kg/day by oral administration. Equivalent dosages for other routes of administra tion are also employed. Similarly, when other lipoxygenase inhibitors are employed, equipotent doses can be administered based on the compound's comparative potency as demonstrated in the standard laboratory test.
The most preferred use of these compounds is as SRS-A inhibitors, e.g., in the treatment of asthma.
The present invention further provides a method of treating or preventing the hypersecretion of mucus in the airways or the respiratory tract of a patient in need thereof. More particularly, the present invention provides a method for treating or preventing the hypersecretion of mucus in the respiratory tract of patients with bronchial asthma, chronic bronchitis, cystic fibrosis, bronchorrhea, obstructive bronchitis and other disease conditions associated with hyperplasia of mucus secreting cells and increased mucus secretion. The method of the present invention finds particular use in warm blooded animals including mammals, such as cattle, horses, rodents, dogs, sheep, pigs, monkeys, cats, humans, and birds. The present invention provides a prophylactic as well as therapeutic method of treating hypersecretion of mucus in the airways of a warm blooded animal.
In practicing the method of treating or preventing the hypersecretion of mucus of the present invention the quantity of compound of Formula I to be administered is any amount effective in treating or preventing hypersecretion of mucus in the airways of the patient being treated. The compounds of Formula I are administered, e.g., intravenously, intramuscularly, topically, by aerosol inhalation, bucally or orally. The quantity of compound of Formula I effective in achieving the method here claimed is determined by the particular mode of administration and frequency of administration as well as the age and condition of the patient. Generally the amount of compound administered will range from about 0.001 mg to 10 mg per dose given up to three times per day by aerosol inhalation, with a range from about 0.01 mg to 10 mg per dose being preferred. For intravenous administration a dose of about 0.01 to 10 μg/kg/min is administered with intramuscular injection ranging from 0.5 to 15 mg per dose. For oral administration unit doses of from 1 mg to 100 mg given up to three times per day of compounds of Formula I are effective in practicing the method of the present invention. The quantity of compound applied topically is that which will give comparable blood levels of active ingredient when said substance is administered by any of the other various routes of administration.
In practicing the method of treating or preventing the hypersecretion of mucus, the compounds of Formula I are formulated into compositions for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, eye drops, oral solutions or suspensions, and oil in water and water in oil emulsions containing suitable quantities of the compound.
For oral administration, either solid or fluid unit dosage forms can be prepared. For preparing solid compositions such as tablets, the compound of Formula I is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers. Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.
Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared. The forms can be dissolved In an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup. An elixir is prepared by using a hydroalcoholic (ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.
Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The pharmaceutically useful compound described herein, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use. Parenteral suspensions can be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. These compounds can be sterilized by exposure to ethylene oxide or an equivalent gas before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
Compositions for inhalation useful in practicing the method of present invention are of three basic types: (1) a powder mixture preferably micropulverized with particle size, preferably from about 2 to 5. microns; (2) an aqueous solution to be sprayed with a nebulizer; (3) an aerosol with volatile propellant in a pressurized container.
The powders are quite simply prepared by mixing a suitable pharmaceutically useful compound of Formula I with a solid base which is compatible with lung tissue, preferably lactose. The powders are packaged in a device adapted to emit a measured amount of powder when inhaled through the mouth.
Aqueous solutions are prepared by dissolving the appropriate compound of the Formula I in water and adding salt to provide an isotonic solution and buffering to a pH compatible with inhalation. The solutions are dispersed in a spray device or nebulizer and sprayed into the mouth while inhaling.
Aerosols are prepared by dissolving an appropriate pharmaceut- ically useful compound of Formula I in water or ethanol and mixing with a volatile propellant and placing in a pressurized container having a metering valve to release a predetermined amount of material.
The liquefied propellant employed is one which has a boiling point below 65ºF at atmospheric pressure. For use in compositions intended to produce aerosols for medicinal use, the liquefied propellant should be non-toxic. Among the suitable liquefied propellants which may be employed are the lower alkanes containing up to 5 carbon atoms, such as butane and pentane, or a lower alkyl chloride, such as methyl, ethyl or propyl chlorides. Further suitable liquefied propellants are the fluorinated and fluorochlorlnated lower alkanes or mixtures thereof, such as, dichlorodifluoromethane, dichlorotetrafluoroethane, trichloromonofluoromethane, dichloromono- fluoromethane, monochlorodifluoromethane, trichlorotrifluoroethane, difluoroethane and monochlorotrifluoromethane.
Generally, the compounds can be prepared by reaction of the appropriate chromium carbene complex with an alkyne. However, the reaction conditions vary when W is OCH3 or S(O)qY.
Where W is OCH3 the reaction can proceed as shown in Scheme A in the presence of AC2O (1-2 mol eq) and NEt3 (1-2 mol eq) to yield the compound. In the absence of Ac2O and NEt3, R3 will be a hydrogen.
Where W is S(O)qY the compound of the present invention can be prepared by the method depicted in Scheme B wherein q=O.
The chemistry requires that the initial cycloaddition reaction (A1 to A2) generate a product where q=O that Is the thioalkyl derivative. A second oxidation step is required to obtain the S(O)qY group where q is greater than zero. Methods for conducting the oxidation of a SY group are well known such as N.J. Leonard, C.R. Johnson, J. Org. Chem., 27, 282 (1962). One method can comprise treatment with potassium peroxymonosulfate to prepare the SO2Y group.
In Scheme B, a carbene complex of the Formula A-1 is reacted with an acetylene of the Formula A-2 (preferably 1.5 equivalents). The cycloaddition of the carbene complex A-1 having the -S(O)qY group forms the subject product only when BF3·Et2O (5 mol eq), Ac2O (5 mol eq) and NEt3 (5 mol eq) are present. Conversion of the Ac group to the OH then introduction of the OR3 group can be done by any conventional means.
Both Scheme A and B reactions are preferably undertaken in a solvent such as tetrahydrofuran (THF) in an inert atmosphere (e.g., argon). Preferably, the reaction temperature is at about 65º C.
The process for preparing the subject compounds is described more fully in the Examples given below. The carbene complexes within the scope of Formula A-1 are well known and readily available or may be prepared by known means. Thus, pentacarbonyl[aryl(methoxy)carbene] chromium wherein the aryl moiety is phenyl, 2-(N-methylpyrrolyl), 2-furyl, or 2-thienyl are described in E.O. Fisher, J. Organometal. Chem. 16:29 (1969); K.H. Dotz, et al., Chem. Ber. 111:2517 (1978); A. Yamashita, et al., Tet. Lett. 23:3765 (1982); and Citilam, et al., Inorg. Synth. 17:95 (1977). Alternatively, the Al carbene complex can be prepared as shown in Method "a" and Method "b".
The alkynes are well known, readily available compounds or may be prepared by known means. Formation of the acetylated product A-2 where W is OCH3 is known, for example, see U.S. Patent 4,737,519, Col. 13 through Col 14, herein incorporated by reference.
The present invention is seen more fully by the Examples given below.
Preparation of various A-1 carbene complex, starting materials, for reaction in Scheme B were prepared as follows in Examples 1-5.
Final preparation of the subject compound was preformed as explained in Scheme B using the various A-2 carbene complexes.
Examples 6-9 show the preparation of various A-2 intermediates which can be reacted to form the final end product as explained in Scheme
B. Examples 10-11 show the preparation of the subject compound where W is OCH3, Scheme A.
Example 1 Preparation of Pentacarbonyl[phenyl(ethylthiol)carbene]chromium from Tetra-n-butylammonium-Pentacarbonyl(phenyl)chromate.
In a 100 ml round bottom flask, equipped with a stirring bar, an addition funnel with a three-way argon-vacuum inlet was placed 0.5 grams of the tetra-n-butylalkoxide carbene. The flask was evacuated and filled with argon three times prior to CH2CI2 addition (38 ml). To an addition funnel was introduced a solution of 0.07 ml of acetyl chloride in 8 ml of CH2CI2. The carbene solution was cooled to -40º C and the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH2CI2 upon complete addition). The solution was stirred at -40º C for one hour, then cooled to -78º
C. To an addition funnel was introduced a solution of 0.08 ml of ethane thiol in 8 ml of CH2CI2. The ethane thiol solution was added dropwise to the carbene solution with vigorous stirring and the lunnel was rinsed with CH2Cl2. The solution was allowed to stir at- 78° C for one hour, then the cooling bath was removed. After the solution was warmed to 25° C, the solvent was removed by rotary evaportaion and the crude product was purified by short path column chromatography (26 grams of silica gel). Elution by ethyl ether gave 0.28 grams (88%) of the ethylthiol phenyl carbene compound.
Example 2 Preparation of Pentacarbonyl[phenyl(ethylthiol)carbene]chromium from Tetraethylammonlum-Pentacarbonyl- (phenyl)chromate.
In a 100 ml round bottom flask, equipped with a stirring bar, an addition funnel with a three-way argon-vacuum inlet was placed 0.8 grams of the tetra ethylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH2CI2 addition (35 ml). To an addition funnel was introduced a solution of 0.09 ml of acetyl chloride in 8 ml of CH2CI2, then the carbene solution was cooled to- 40º C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH2Cl2 upon complete addition). The resulting solution was stirred at -40º C for one hour, then cooled to -78º C. To an addition funnel was Introduced a solution of 0.1 ml of ethane thiol in 8 ml of CH2CI2. The ethane thiol solution was added dropwise to the carbene solution with vigorous stirring and the funnel was rinsed with CH2CI2. The solution was allowed to stir at -78º C for one hour prior to the removal of the bath. After the solution was warmed to 25º C, the solvent was removed by rotary evaporation and the crude product was purified by flash column chromatography (28 grams of silica gel). Elution by diethyl ether gave 0.28 grams (70%) of the phenyl(ethyl- thiol)chromium carbene complex.
Example 3 Preparation of Pentacarbonyl[phenyl(ethylthiol)carbene]chromium from Tetra-n-propylammonium-Pentacarbonyl(phenyl)chrornate.
In a 100 ml round bottom flask, equipped with a stirring bar, an addition funnel with a three-way argon-vacuum inlet was placed 0.8 grams of the tetra-n-propylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH2CI2 addition (35 ml). To an addition funnel was introduced a solution of 0.08 ml of acetyl chloride in 8 ml of CH2CI2. The carbene solution was cooled to -40º C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH2CI2 upon complete addition). The resulting solution was stirred at -40º C for one hour, then cooled to -78º C. To an addition funnel was Introduced a solution of 0.08 ml of ethane thiol in 8 ml of CH2CI2. The ethane thiol solution was added dropwise to the carbene solution with vigorous stirring and the funnel was rinsed with CH2CI2. The solution was allowed to stir at -78º C for one hour prior to the removal of the bath. After the solution had warmed to 25º C, the solvent was removed by rotary evaporation and the crude product was purified by flash column chromatography (28 grams of silica gel). Elution by diethyl ether gave 0.28 grams (83%) of the phenyl(ethyl- thiol)chromium carbene complex.
Example 4 Preparation of Pentacarbonyl[phenyl(ethylthiol)carbene]chromium from Tetramethylammonium-Pentacarbonyl-
(phenyl)chromate.
In a 100 ml round bottom flask, equipped with a stirring bar, an addition funnel with a three-way argon-vacuum inlet was placed 0.8 grams of the tetra-methylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH2CI2 addition (35 ml). To an addition funnel was introduced a solution of 0.11 ml of acetyl chloride in 8 ml of CH2CI2. The carbene solution was cooled to -40º C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH2Cl2 upon complete addition). The resulting solution was stirred at -40° C for one hour, then cooled to -78º C. To an addition funnel was introduced a solution of 0.11 ml of ethane thiol in 8 ml of CH2CI2 and the ethane thiol solution was added dropwise to the carbene solution with vigorous stirring and the funnel was rinsed with CH2CI2. The solution was allowed to stir at -78º C for one hour prior to the removal of the bath. After the solution was warmed to 25º C, the solvent was removed by rotary evaporation and the crude product was purified by flash column chromatography (28 grams of silica gel).
Elution by diethyl ether gave 0.37 grams (80%) of the phenyl ethyl- thiol chromium carbene complex.
Example 5 Preparation of Pentacarbonyl[phenyl(methylthiol)carbene]chromium from Tetra-n-butylammonium-Pentacarbonyl(phenyl)chromate.
In a 1000 ml round bottom flask, equipped with a stirring bar, an addition funnel with a three-way argon-vacuum inlet was placed 27 grams of the tetra-n-butylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH2CI2 addition (400 ml). To an addition funnel was introduced a solution of 3.9 ml of acetyl chloride in 80 ml of CH2CI2. The carbene solution was cooled to -40º C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH2CI2 upon complete addition). The resulting solution was stirred at -40º C for one hour, then cooled to -78º C. To an addition funnel was introduced a solution of 3.0 ml of methane thiol in 80 ml of CH2CI2. The methane thiol solution was added dropwise to the carbene solution with vigorous stirring and the funnel was rinsed with CH2CI2. The solution was allowed to stir at -78º C for one hour prior to the removal of the bath. After the solution was warmed to room temperature, the solvent was removed by rotary evaporation and the crude product was purified by flash column chromatography (300 grams of silica gel). Elution by diethyl ether gave 13 grams (70%) of the phenyl methylthiol chromium carbene complex.
Example 6 Preparation of 1-Ethylthio-3-n-butyl-4-acetoxy- naphthalene.
To a 200 ml three-necked round bottom flask with a stirring bar, an argon-vacuum inlet and two rubber septa was added 3.0 g of the thio carbene. The system was evacuated and filled with argon three times prior to THF addition (600 ml). This was followed by treatment with Ac2O (4.1 ml), Et3N (6.1 ml), BF3-OEt2 (8.4 ml) and 1-hexyne (2 ml). The solution was heated to 65º C for 3 days under argon, after which the solvent was removed by rotary evaporation. The crude product was purified, by flash chromatography, using 10% ether in hexane as the eluent, to give 1.8 g of the oily naphthalene product. Example 7 Preparation of 1-Ethylsulfonyl-3-n-butyl-4-acetoxy- naphthalene.
To a 500 ml round bottom flask with a stirring bar was added 0.6 g of the sulfide dissolved in MeOH (50 ml). The solution was stirred vigorously while a solution consisting of Oxone (1.83 g) in 100 ml of pH 7 buffer was added. After 4 hours, 400 ml of water was added and the aqueous solution was extracted with 4 x 100 ml portions of CH2Cl2. The extracts were dried over Na2SO4, filtered, concentrated and purified via flash chromatography using 30% ether in n-hexane as the eluent, to give 0.65 g (98%) of the sulfone. The product was further purified by recrystallization using ether/hexane, m.p. 109º C. Example 8 Preparation of 1-Methylthio-3-n-butyl-4-acetoxy naphthalene.
In a 1000 ml three-necked round bottom flask, with a stirring bar, an argon-vacuum inlet and two rubber septa, was added 4.0 g of the thiocarbene. The flask was evacuated and filled with argon three times prior to THF addition (400 ml). This was followed by treatment with Ac2O (2.2 ml), Et3N (3.4 ml), BF3.OEt2 (1.8 ml) and 1-hexyne (2.8 ml). The solution was heated to 65º C for 3 days under argon, after which the solvent was removed by rotary evaporation. The crude product was purified by flash chromatography, using 10% ether in hexane as the eluent, to give 1.8 g (44%) of the product. This product was further purified by recrystallization using ether/- pentane, m.p. 89º C.
Example 9 Preparation of 1-Methylsulfonyl-3-n-butyl-4-acetoxy- naphthalene.
To a 500 ml round bottom flask with a stirring bar was added 0.6 g of sulfide dissolved in MeOH (50 ml). The solution was stirred vigorously while a solution consisting of Oxone (1.83 g) in 100 ml of pH 7 buffer was added. After 4 hours, 400 ml of water was added, and the aqueous solution was extracted with 4 x 100 ml portions of CH2CI2. The extracts were dried with Na2SO4, filtered, concentrated and purified via flash chromatography using 30% ether in n-hexane as the eluent, to give 0.63 g (95%) of the sulfone. The product was further purified by recrystallization using ether/hexane, m.p. 107º C.
Example 10 Preparation of 5,6-Diethyl-4-hydroxy-7-methoxy-2- methylbenzofuran.
Preparation of Pentacarbonyl[5-methyl-2-furyl(methoxy) carbenechromiura To a cooled (-78º C, dry ice-acetone bath) solution of 2-methyl- furan in THF, prepared under argon, was added dropwise n-BuLi (n- hexane solution) via syringe under argon over a period of 20 min. The resulting solution was warmed up to 25º C over a period of 6 hrs, and stirred at 25º C for 15 hrs under argon. The resulting yellow solution was introduced to the suspension of Cr(CO)6 in dry ether, prepared under argon, using a liquid transferring cannula at 25º C under argon. The deep red solution was stirred at 25º C for an additional 1 hr, then the solvent was removed by rotary evaporation. The dark brown residue was dissolved In 200 ml H2O, and Me3O-BF4 was portionwise added to the aqueous solution. The aqueous layer was extracted with ether (3 x 400 ml) and the extracts were combined, washed with saturated NaHCO3 aq sol. (2 x 300 ml), sat. NaCl aq sol. (3 x 300 ml), dried over anhydrous Na2SO4, filtered and concentrated. The dark brown residue was chromatographed using flash column (silica gel 600 g). Elution by 5-10% ether in n-hexane isolated 19.8 g (62.6%) of Pentacarbonyl[5-methyl-2-furyl(methoxy)carbene]chromiua as dark purple red solid.
A solution of the carbene complex and 3-hexyne In DMF, prepared under argon at 25º C, was heated at 125-130º C (bath temperature) for 6 hrs, then 100º C (bath temperature) for 15 hrs under argon. The reaction mixture was cooled and diluted with 500 ml of ether. The ether layer was washed with sat. NaCl aq sol. (3 x 250 ml). The solvent was removed by rotary evaporation and the residue was treated with IN HCl aq sol. (10 ml), CH2Cl2 (20 ml), and MeOH (150 ml) at 25º C for 5 hrs. The solvent ws removed by rotary evaporation and the residue was dissolved in 500 ml ether. The ether layer was washed with sat. NaCl aq sol. (2 x 200 ml), dried over anhydrous MgSO4, filtered and concentrated. The residue was chromatographed using a silica gel (400 g used) flash column. Elution by 20-30% ether in n- hexane isolated 1.00 g (54.1%) of 5,6-dIethyl-4-hydroxy-7-methoxy-2- methylbenzofuran as yellow oil.
The IC50 data for this compound is shown in Table 1, Compound 7. Example 11 Preparation of 5-n-Butyl-4-hydroxy-7-methoxy-2-methyl- benzofuran.
The carbene complex as prepared in the first step of Example 10 was mixed with 1-hexyne in DMF under argon at 25º C and was heated at 125-130º C (bath temperature) for 6 hrs, then 100º C (bath temperature) for 15 hrs under argon. The reaction mixture was cooled and diluted with 800 ml of ether. The ether layer was washed with sat. NaCl aq sol. (3 x 300 ml). The solvent was removed by rotary evaporation, and the residue was treated with IN HCl aq sol. (25 ml), CH2Cl2 (400 ml), and MeOH (350 ml) at 25º C for 5 hrs. The solvent was removed by rotary evaporation and the residue was dissolved in 800 ml ether. The ether layer was washed with sat. NaCl aq sol. (2 x 300 ml), dried over anhydrous MgSO4, filtered and concentrated. The residue was chromatographed using a silica gel (400 g used) flash column. Elution by 20% ether in n-hexane gave the product as a white solid.
The IC50 data for this compound is shown in Table I, Compound 8.
Various forms of the subject compounds were evaluated using standard assay procedures (see, Adv. Enzymology, 58, "Enzymology and Physiology of Reticulocyte Lipoxygenase: Comparison with other Lipoxygenases", pp. 192-263 (1986)) to measure their inhibition of 5- lipoxygenase (5-Lo), 15-lipoxygenase (15-Lo), and thromboxane-B2 (TxB2). These results are shown in Table 1 as a measure of 50% inhibition concentration (IC50) in micrograms per milliliter (μg/ml).
Figure imgf000026_0001
Table 2 shows 15-lipoxygenas (15-Lo) inhibition data for various compounds at a 20 μg/ml unit dose. The negative values indicate a percentage increase in 15-Lo products. This result is indicative of an increased production of materials which cross react with the 15- HETE antibodies.
Figure imgf000027_0001
Table 3 shows 15-lipoxygenase inhibition data (15-Lo) for a set of compounds at various unit doses in μg/ml
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001

Claims

1. A compound of the Formula I
Figure imgf000033_0001
or a pharmacologically acceptable acid addition salt thereof wherein R1 and R2 are the same or different and are
(a) hydrogen,
(b) (C1-C10)alkyl,
(c) (C2-C10)alkenyl, or
(d) PhX;
wherein (PhX) is phenyl substituted by zero to 3 of the following:
(a) (C1-C4)alkyl,
(b) chloro,
(c) fluoro,
(d) bromo,
(e) nitro,
(f) trifluoromethyl; or
(g) OR4;
wherein D is
(a) -CH=CH-,
(b) -N(CH3),
(c) -S-, or
(d) -O-;
wherein R3 is
(a) CH3-C(O)-,
(b) hydrogen,
(c) -C(O) - (CR17R18)m- (CH2)n-NR14R15 ,
(d) -C(O)-AA, or
(e) -C(O)-PhX-NH2;
wherein m is 1, 2, 3, or 4;
wherein n is 0, 1, 2, 3, 4, or 5;
wherein -C(O)AA is the acyl portion derived from any naturally occurring alpha-amino acid; wherein R14 and R15 are the same or different and are:
(a) hydrogen,
(b) (C1-C10) alkyl,
(c) -C(O)R16,
(d) -C(O)-PhX, or
(e) -PhX;
with the proviso that R14 and R15 are other than hydrogen when n is zero;
wherein R16 is (C1-C4) alkyl;
wherein R17 and R18 are the same or different and are:
(a) hydrogen,
(b) (C1-C10) alkyl,
(c) -CH2-PhX, or
(d) -PhX;
with the proviso that each occurrence of R17 and R18 is the same or different;
wherein PhX-NH2 is an amino-substituted phenyl group additionally substituted by zero to 3 of the following:
(a) (C1-C4) alkyl,
(b) chloro,
(c) fluoro,
(d) bromo,
(e) nitro,
(f) trifluoromethyl, or
(g) OR4;
wherein R4 is
(a) hydrogen, or
(b) (C1-C4)alkyl;
wherein W is
(a) OCH3 or
(b) S(O)qY;
wherein q is 0, 1 or 2;
wherein Y is
(a) (C1-C4)alkyl,
(b) (C1-C4) alkenyl,
(c) PhX;
wherein W is S(O)qY then Z is
(a) hydrogen or (b) (C1-C4)alkyl;
wherein W is OCH3 then Z is (C1-C4) alkyl;
with a proviso where Z is hydrogen, D is ethylene and where R1 and R3 are hydrogen, R2 is phenyl, and W is SCH3 or SPh; or where R1 and R2 are methyl, R3 is hydrogen and W is SCH3; or where R1 Is hydrogen, R2 is phenyl, R3 is COCH3 and W is SCH3.
2. The compound of Claim 1 wherein R3 is CH3 or COCH3.
3. The compound of Claim 1 wherein R2 is selected from the group consisting of COCH3, C6H5, C2H5, CH=CH2 and C4H9.
4. The compound of Claim 1 wherein R1 is selected from the group consisting of hydrogen, OH, OC2H5, C2H5 , CH3 , CO2C2H5.
5. The compound of Claim 1 wherein D is oxygen or CH=CH.
6. The compound of Claim 1 wherein Z is hydrogen.
7. The compound of Claim 1 wherein W is S(O)qY wherein q is 0 and Y is CH3.
8. The compound of Claim 1 which is
a) 5-ethenyl-6-ethoxy-7-(methylthio)-4-benzofuranol acetate; b) 1-[6-hydroxy-4-methoxy-7-(methylthio)-5-benzofuranyl] ethanone;
c) 5-butyl-7-(methylthio)-4-benzofuranol acetate;
d) 7-(methylthio)-5-phenyl-4-benzofuranol acetate;
e) 4-(methylthio)-2-phenyl-1-naphthalenol acetate;
f) 2-butyl-4-(methylthio)-1-naρhthalenol acetate; or
g) 2-butyl-4-(methylsulfonyl)-1-naphthalenol acetate.
9. The compound of Claim 1 wherein W is OCH3.
10. The compound of Claim 9 which is
(a) 5,6-diethyl-4-hydroxy-7-methoxy-2-methylbenzofuran; or
(b) 5-n-butyl-4-hydroxy-7-methoxy-2-methylbenzofuran.
11. A method for treating or preventing the hypersecretion of mucus In the respiratory tract of a patient in need thereof which comprises:
administering to said patient in an amount effective to treat or prevent said hypersecretion of mucus a compound of Formula I
Figure imgf000036_0001
or a pharmacologically acceptable acid addition salt thereof;
wherein R1 and R2 are the same or different and are
(a) hydrogen,
(b) (C1-C10)alkyl,
(c) (C2-C10)alkenyl, or
(d) PhX;
wherein (PhX) is phenyl substituted by zero to 3 of the following:
(a) (C1-C4)alkyl,
(b) chloro,
(c) fluoro ,
(d) bromo ,
(e) nitro ,
(f) trifluoromethyl; or
(g) OR4;
wherein D is
(a) -CH=CH-,
(b) -N(CH3),
(c) -S-, or
(d) -O-;
wherein R3 is
(a) CH3-C(O)-,
(b) hydrogen,
(c) -C(O)-(CR17R18)m-(CH2)n-NR14R15,
(d) -C(O)-AA, or
(e) -C(O))PhX-NH2;
wherein m is 1, 2, 3, or 4; wherein n is 0 , 1 , 2 , 3 , 4 , or 5 ;
wherein -C(O)AA is the acyl portion derived from any naturally occurring alpha-amino acid;
wherein R14 and R15 are the same or different and are:
(a) hydrogen,
(b) (C1-C10) alkyl,
(c) -C(O)R16,
(d) -C(O)-PhX, or
(e) -PhX;
with the proviso that R14 and R15 are other than hydrogen when n is zero;
wherein R16 is (C1-C4) alkyl;
wherein R17 and R18 are the same or different and are:
(a) hydrogen,
(b) (C1-C10) alkyl,
(c) -CH2-PhX, or
(d) -PhX;
with the proviso that each occurrence of R17 and R18 is the same or different;
wherein PhX-NH2 is an amino-substituted phenyl group additionally substituted by zero to 3 of the following:
(a) (C1-C4) alkyl,
(b) chloro,
(c) fluoro,
(d) bromo,
(e) nitro,
(f) trifluoromethyl, or
(g) OR4;
wherein R4 is
(a) hydrogen, or
(b) (C1-C4)alkyl;
wherein W is
(a) OCH3 or
(b) S(O)qY
wherein q is 0, 1 or 2;
wherein Y is
(a) (C1-C4)alkyl,
(b) (C1-C4) alkenyl, (c) PhX;
wherein W is S (O)qY then Z is
(a) hydrogen; or
(b) (C1-C4) alkyl ;
wherein W is OCH3 then Z is (C1-C4) alkyl;
wherein D is -CH=CH- then Z is hydrogen;
with a proviso where D is -CH=CH- or -N(CH3) and Z is hydrogen, and where D is 0 or -CH=CH-, R3 is COCH3, Z is hydrogen and R1 and R2 are both ethyl, phenyl or a phenyl and a methyl or an ethyl ester.
PCT/US1989/003492 1988-09-28 1989-08-18 1,4-dihydrothionapthoquinone and heterocyclic congeners which inhibit lipoxygenase enzymes Ceased WO1990003374A1 (en)

Priority Applications (1)

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Applications Claiming Priority (2)

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US25046288A 1988-09-28 1988-09-28
US250,462 1988-09-28

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WO (1) WO1990003374A1 (en)

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WO2000010588A3 (en) * 1998-08-18 2001-05-25 Univ California Epidermal growth factor receptor antagonists for treating hypersecretion of mucus in the lungs
US7226661B2 (en) 2003-02-03 2007-06-05 Board Of Regents, The University Of Texas System Synthesis of quinones and phenols on solid support
US7354894B2 (en) 1998-08-18 2008-04-08 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists

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EP0165810A2 (en) * 1984-06-20 1985-12-27 Merck Frosst Canada Inc. Benzofuran and benzothiophene derivatives, their use in inhibiting mammalian leukotriene biosynthesis, and pharmaceutical compositions containing these derivatives
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010588A3 (en) * 1998-08-18 2001-05-25 Univ California Epidermal growth factor receptor antagonists for treating hypersecretion of mucus in the lungs
US7354894B2 (en) 1998-08-18 2008-04-08 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US7358222B2 (en) 1998-08-18 2008-04-15 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US7531500B2 (en) 1998-08-18 2009-05-12 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US7700547B2 (en) 1998-08-18 2010-04-20 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US8048844B1 (en) 1998-08-18 2011-11-01 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US8071074B2 (en) 1998-08-18 2011-12-06 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US7226661B2 (en) 2003-02-03 2007-06-05 Board Of Regents, The University Of Texas System Synthesis of quinones and phenols on solid support

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