EP0524979A4 - 2(5h)-furanones substituted in the 5 and or in the 4 position, as anti-inflammatory agents - Google Patents

2(5h)-furanones substituted in the 5 and or in the 4 position, as anti-inflammatory agents

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Publication number
EP0524979A4
EP0524979A4 EP19910907029 EP91907029A EP0524979A4 EP 0524979 A4 EP0524979 A4 EP 0524979A4 EP 19910907029 EP19910907029 EP 19910907029 EP 91907029 A EP91907029 A EP 91907029A EP 0524979 A4 EP0524979 A4 EP 0524979A4
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EP
European Patent Office
Prior art keywords
compounds
formula
alkyl
compound
hydrogen
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Ceased
Application number
EP19910907029
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French (fr)
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EP0524979A1 (en
Inventor
Gary C. M. Lee
Michael E. Garst
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Allergan Inc
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Allergan Inc
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Publication of EP0524979A1 publication Critical patent/EP0524979A1/en
Publication of EP0524979A4 publication Critical patent/EP0524979A4/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/60—Two oxygen atoms, e.g. succinic anhydride
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Definitions

  • the present invention is directed to novel 2(5H)- furanones substituted in the 5 position and or in the 4 position, which compounds are active as anti-inflammatory agents.
  • the present invention is also directed to pharmaceutical compositions which comprise one or more of the novel compounds of the invention, to the methods of using these pharmaceutical compositions, and to the chemical processes of making the novel compounds.
  • Manoalide is a compound isolated from a marine sponge [E. D. de Silva et al., Tetrahedron Letters 21:1611-1614 (1980)] which has anti-inflammatory, immunosuppressive and analgesic properties.
  • Manoalide (Compound 1) the structure of which is shown below, includes a 5-hydroxy- 2(5H)-furanone moiety, attached in the 4-position of the furanone ring to the rest of the molecule.
  • Certain analogs of manolide such as s ⁇ co-manoalid ⁇ (Compound 2) and dehydro-seco-manoalid ⁇ (Compound 3) also have anti- inflammatory activity.
  • the present invention covers compounds of Formula 1, and compounds of Formula 2
  • R 2 is H, alkyl of 1 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds;
  • R 3 is H, alkyl of 1 to 20 carbons, arylalkyl, or halogene, and
  • X is H or alkyl of 1 to 20 carbons, CO-X*, CO-O-X*,, CO-NH-X*, PO(OX*,) 2 or PO(OX*,)X*, where X*,independently is H, alkyl of 1 to 20 carbons, phenyl, or substituted phenyl.
  • R A and R 3 cannot be hydrogen.
  • the present invention also covers salts of the above- defined compounds, formed with pharmaceutically acceptable acids or bases, as applicable.
  • the present invention relates to pharmaceutical formulations comprising one or more compounds of Formula 1 or of Formula 2, or both, (or pharmaceutically acceptable salts thereof) in admixture with a pharmaceutically acceptable excipient, for the purpose of treating certain conditions, syndromes or diseases in mammals, including humans.
  • the compounds of the invention have anti-inflammatory, immunosuppressant and anti-proliferative activity. Therefore, the compounds are useful for treating in mammals (including humans) inflammation, rheumatoid arthritis, osteoarthritis, rheumatic carditis, ocular and dermal inflammatory diseases, autoimmune diseases such as allergic diseases. bronchial asthma and myasthenia gravis, and for suppressing unwanted immune responses and retarding proliferation of cell.
  • the present invention relates to the processes of making the compounds of .
  • these processes shown in Reaction Scheme l, 2 , 3 and 4 comprise the steps of reacting an aldehyde of Formula 3 with a lithium or magnesium salt derived from a propiolate este such as ethyl propiolate (Compound 4) , to yield an R ⁇ - substituted 4-hydroxy —ynoate of Formula 4 (R ⁇ defined in connection with Formula 1 and Formula 2) .
  • Hydroganation over a "poisoned" catalyst (Lindlar catalyst) converts the acetylenic (triple) bond into an olephinic (double) bond. This is followed by acid catalyzed cyclization to yield compounds of Formula 1 where R 2 and R 3 are hydrogen.
  • the compounds of Formula 2 can be reduced with a mild reducing agent, such as sodium borohydride to provide the corresponding compounds of Formula 1.
  • a mild reducing agent such as sodium borohydride
  • a theoretical explanation for this reaction is that the carbon in the 5- position of the 5-hydroxy-2(5H)-furanone molecule is an "aldehydic" carbon, ring closed with the carboxylic acid group in the "2-position" of the ring, and that the aldehydic carbon is reduced with sodium borhydride to a primary alcohol, which, thereafter, ring closes with the carboxylic acid to form a lactone of Formula 1.
  • Reaction Scheme 3 In order to obtain compounds of Formula 2 where neither R j nor R 2 are hydrogen, a ketone of Formula 7 (which bears the desired R ⁇ and R 2 groups) is condensed under acidic condition with glyoxylic acid (Compound 5) , as is shown in Reaction Scheme 3.
  • An intermediate condensation product of Formula 8 usually is not isolated because it cyclizes during the condition of the condensation reaction to form the furanones of Formula 2 where the R j and R 2 groups are derived from the starting ketone of Formula 7 and where X is hydrogen.
  • the resulting 5-alkoxy-2(5H)- furanone derivative of Formula 2 where R 3 is hydrogen, is brominated to yield the corresponding 3-bromo-5-alkoxy- 2(5H)-furanone derivative of Formula 2.
  • the alkoxy substituent can be replaced with OH by reaction with aqueous acid.
  • Reaction Scheme 4 shows a hydrogenation step in which the olephinic bond of the intermediate of Formula 11 is partially or fully saturated to provide compounds of Formula 2.
  • Reduction of the compounds of Formula 2 with sodium borohydride provides compounds of Formula 1.
  • Another process of preparing compounds of the invention where neither R 2 nor R 3 are hydrogen involves the reaction a di-substituted maleic acid anhydride of Formula 9 with a Grignard reagent of the formula R 1 -MgBr to provide compounds of Formula 2 where X is hydrogen. Reduction of these compounds with sodium borohydride, yields compounds of Formula 1.
  • the processes leading to the compounds of the invention may involve performance of routine chemical reactions (such as esterification, saponification of esters, oxidation of alcohols to ketones or aldehydes, formation of acetals, ketals, and lactones from aldehydes or ketones, and the like) which are well known to the practicing synthetic organic chemist.
  • routine chemical reactions such as esterification, saponification of esters, oxidation of alcohols to ketones or aldehydes, formation of acetals, ketals, and lactones from aldehydes or ketones, and the like
  • preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or from the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from lower alkyl acids or alcohols. Also preferred are the phenyl or lower alkylphenyl esters.
  • alkyl as used in the present description and claims includes straight chain alkyl. groups, branched chain alkyl groups, cycloalkyl groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. Unless the number of carbons is otherwise specified, "lower alkyl” means the former broad definition of “alkyl” groups but with the restriction that the group has 1 to 6 carbon atoms.
  • long chain alkyl also means the former broad definition of “alkyl” groups but with the restriction that the group has no less than 4 carbon atoms, and no more than approximately 25 carbon atoms.
  • preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms, or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.
  • a pharmaceutically acceptable salt may be prepared for any compound of this invention having a functionality capable of forming such salt, for examle an acid or an amine functionality.
  • a pharmaceutically acceptable salt may be any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
  • Such a salt may be derived from any organic or inorganic acid or base.
  • the salt may be a mono or polyvalent ion.
  • the inorganic ions sodium, potassium, calcium, and magnesium.
  • Organic amine salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide.
  • Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri-acid may also be used.
  • the preferred compounds of the present invention are, with reference to Formula 2 and with respect to the OX substituent in the 5-position of the furanone moiety, those where the substituent is hydroxy, methoxy or acetyloxy (X is H, or CH 3 0 or CH3CO) .
  • the preferred compounds in accordance with the present invention are those where R 1 is hydrogen, long chain alkyl, or arylalkyl.
  • R 1 is hydrogen, long chain alkyl, or arylalkyl.
  • the j ⁇ group is long chain alkyl which is straight chained, or where the ⁇ is arylalkyl containing a straight alkyl chain of 3 carbons.
  • R 2 substituent in the 4-position of the 2(5H)-furanone molecule
  • the compounds of the invention are preferred where R 2 is hydrogen, or alkyl group, particularly straight chain alkyl.
  • R 3 is H, methyl or bromo.
  • the compounds of the present invention are useful in pharmaceutical compositions to produce anti-inflammatory, immunosuppressant and anti-proliferative activity.
  • the diseases, syndromes or conditions of mammals (including humans) which can be treated with pharmaceutical compositions containing one or more compounds of the invention (or salts thereof) include: inflammation, rheumatoid arthritis, osteoarthritis, rheumatic carditis, ocular and dermal inflammatory diseases, autoimmune diseases such as allergic diseases, bronchial asthma and myasthenia gravis, unwanted immune responses and unwanted proliferation of cells, psoriasis, acne, atopic diseases and allergic conjunctivitis.
  • the activity of the compounds of this invention is demonstrated by inhibition of the enzyme phospholipase A 2 in vitro and by reduction of inflammation in the mouse ear anti-inflammatory assay in vivo.
  • Activity of the compounds may also be demonstrated by inhibition of ornithine decarboxylase, a rate limiting enzyme in cellular growth, which indicates use in treating psoriasis and neoplasis.
  • the compounds also modify calcium homeostasis. This activity is shown by effect on intracellular calcium levels in experiments using gastric glands, spleen cells, epithelial cells, GH 3 cells, etc. Calcium is inhibited from entering through the plasma membrane calcium channels and calcium release from intracellular stores is also blocked.
  • Modification of calcium homeostasis is expected to have application in diseases of the nervous system involving modification of membrane lipids or transmitter release (Parkinson's, Alzheimer's), diseases of the cardiovascular system involving application of cardiac or vascular smooth muscle contractility and platelet aggregation (hypertension, cardiac infarction and atherosclerosis) , diseases of the gastrointestinal tract such as ulcer disease, diarrhea, motility due to secretion of acid or Cl", diseases of the kidney involving renal handling of fluid and electrolytes (metabolic acidosis, alkalosis) , and disease of abnormal growth (neoplasia, psoriasis) .
  • diseases of the nervous system involving modification of membrane lipids or transmitter release
  • diseases of the cardiovascular system involving application of cardiac or vascular smooth muscle contractility and platelet aggregation (hypertension, cardiac infarction and atherosclerosis)
  • diseases of the gastrointestinal tract such as ulcer disease, diarrhea, motility due to secretion of acid or Cl
  • diseases of the kidney involving renal
  • the compounds of this invention have activity which is similar to that of manoalide, that is the compounds appear to be devoid of the endocrine properties of the glucocorticoids while having anti-inflammatory and immunosuppressive properties.
  • compositions of this invention comprise compounds of Formula 1 and of Formula 2, and pharmaceutical carriers suitable for the route of administration. Standard methods for formulating pharmaceutical compositions of this type may be found in Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, PA.
  • the pharmaceutical composition may be in the form of a salve, cream, ointment, spray, powder or the like. Standard pharmaceutical carriers for such compositions may be used.
  • compositions for topical administration will contain 0.05-5% of the active ingredient.
  • a typical ointment formulation may contain the following:
  • Glycol solvent 1-15 Surfactant 0-10
  • suitable pharmaceutical carriers include mannitol, lactose, starch, magnesium stearate, talcum, glucose and magnesium carbonate.
  • Oral compositions may be in the form of tablets, capsules, powders, solutions, suspensions, sustained release formulations, and the like.
  • a typical tablet or capsule may contain the following:
  • Parenteral compositions are prepared in conventional suspension or solution forms, as emulsions or as solid forms for reconstruction. Suitable carriers are water, saline, dextrose. Hank's solution. Ringer's solution, glycerol, and the like. Parenteral administration is usually by injection which may be subcutaneous, intramuscular or intravenous.
  • the compounds of this invention may be combined with other known anti-inflammatory/immunosuppressive agents such as steroids or non-steroidal anti-inflammatory agents (NSAID) in the pharmaceutical compositions and methods described herein.
  • NSAID non-steroidal anti-inflammatory agents
  • PMNa Polymorphonuclear leukocytes
  • gastric glands gastric glands, GH 3 cells, A431 cells, spleen cells, human keratinocytes corneal cells, etc. were loaded with the Ca 2+ sensitive fluorescent dye, Fura-2.
  • the appropriate cell type was chosen and the potency and efficacy of the anti- inflammatory furanones on calcium mobilization, calcium channel inhibition was quantitated.
  • the methods used for A431 cells listed below are representative of those used for other cells.
  • A431 cells were detached using a 5-10 min trypsin- EDTA treatment whereas GH 3 cells were treated 2 to 5 min with a 1% pancreatin solution.
  • Cells were immediately washed twice in a 20mM HEPES buffer (pH 7.4) containing 120mM NaCl, 6 mM KC1, 1 mM MgS0 4 , 1 mg/ml glucose and 1 mg/ml pyruvate and 1.4mM calcium (medium A) .
  • Approximately 5 x 10 6 cells were suspended in medium A and incubated with 4uM fura-2-AM for 15 min at 37°C.
  • F was the relative fluorescence measurement of the sample.
  • ma ⁇ was determined by lysing the cells with digitonin (lOOug/ml) in DMSO. After F ma ⁇ was determined the pH was adjusted to 8, with NaOH and Ca 2+ chelated with 3mM EGTA to totally quench the fura-2 sig. ⁇ l and obtain m n .
  • Test compound and phorbol myristate acetate are topically applied simultaneously to the pinnae of the left ears of mice. PMA alone is applied to the right ear. Three hours and 20 minutes after application, the mice are sacrificed, left and right ears removed, and standard sized bores taken. Edema (inflammation) is measured as the difference in weight between left and right ears [Van Annan, C.G., Clin Pharmacol Ther (1974) 16:900-904].
  • the compounds of the present invention can be made by the synthetic chemical pathways which are illustrated above in general terms, and in the specific examples as well.
  • the synthetic chemist will readily appreciate that the conditions described here in general terms, and specifically, can be generalized to any and all compovmds represented by Formula 1 or by Formula 2, as applicable.
  • the synthetic chemist will readily appreciate that the herein described synthetic steps may be varied or adjusted by those skilled in the art without departing from the scope and spirit of the invention. Therefore, the following examples of specific compounds of the invention, and specific examples of the synthetic steps in which the compounds and certain intermediates are made. are set out to illustrate the invention, not to limit its scope.
  • Methylmagnesium bromide (a 3M solution in tetrahydrofuran; 7.8 ml, 23.4 mmol) was added dropwise to a solution of ethyl propiolate (Compound 4, 2.25 g, 22.9 mmol) in tetrahydrofuran (10 ml) at -78° under argon. After 10 minutes, a solution of decyl aldehyde (3.58 g, 22.9 mmol) in tetrahydrofuran (2 ml) was added. Stirring was continued for 1 hour while the cooling bath was warmed to room temperature. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl ether.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Rheumatology (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

Compounds of formula (1), and compounds of formula (2) in which R1 is H, alkyl of 1 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds; R2 is H, alkyl of 1 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds; R3 is H, alkyl of 1 to 20 carbons, arylalkyl, or halogene, and X is H or alkyl of 1 to 20 carbons, CO-X*, CO-O-X*,, CO-NH-X*,, or PO(OX*,)2 or PO(OX*,)X*,, where X*, independently is H, alkyl of 1 to 20 carbons, phenyl, or substituted phenyl, are disclosed. However, in the compounds of the invention illustrated by formula (2), R¿1? and R3 both cannot be hydrogen. The compounds have anti-inflammatory activity.

Description

2(5H)-FURANONES SUBSTITUTED IN TEE 5 AND OR IN THE 4
POSITION, AS ANTI-INFLAMMATORY AGENTS
BACKGROUND OF THE INVENTION
1. Field of the Invention The present invention is directed to novel 2(5H)- furanones substituted in the 5 position and or in the 4 position, which compounds are active as anti-inflammatory agents. The present invention is also directed to pharmaceutical compositions which comprise one or more of the novel compounds of the invention, to the methods of using these pharmaceutical compositions, and to the chemical processes of making the novel compounds. 2. Brief Description of the Prior Art Manoalide is a compound isolated from a marine sponge [E. D. de Silva et al., Tetrahedron Letters 21:1611-1614 (1980)] which has anti-inflammatory, immunosuppressive and analgesic properties. Manoalide (Compound 1) the structure of which is shown below, includes a 5-hydroxy- 2(5H)-furanone moiety, attached in the 4-position of the furanone ring to the rest of the molecule. Certain analogs of manolide, such as sβco-manoalidβ (Compound 2) and dehydro-seco-manoalidβ (Compound 3) also have anti- inflammatory activity. For further description of the biological activity of manoalide and some of its derivatives reference is made to United States Patent Nos. 4,447,445, 4,786,651, 4,789,749 and to European Patent Application No. 0 133 376 (published on February 20, 1985) .
manoalide
Compound 1
Synthetic analogs of manoalide, particularly analogs having various substituents on the furanone moiety of manoalide, are described in several applications for United States Letters Patent by the same inventor as in the present application, the following of which have been allowed and are expected to issue as United States Letters Patent:
Serial No. 259,225 filed on October 18, 1988; Serial No. 281,126 filed on December 7, 1988. Published European Patent Application No. 0 295 056 discloses 4-substituted 5-hydroxy-2(5H)-furanones having anti-inflammatory, immunosuppressive and anti- proliferative activity where the substituents in the 4 position are a variety 1-hydroxyalkyl, 1-acyloxy-alkyl and 1-carbamoyloxy-alkyl groups. United States Patent No. 4,855,320 discloses 5- arylalkyl-4-alkoxy-2(5H)-furanones as anti-convulsive and anti-epileptic agents.
Published European Patent Application No. 0 209 274 discloses 4-alkyl-5-hydroxy-2(5H)-furanones as anti- inflammatory and anti-allergy agents.
Chemical Abstracts Volume 107 236559t (1987) discloses 4-acyloxy 5-hydroxy-2(5H)-furanones.
SUMMARY OF THE INVENTION
The present invention covers compounds of Formula 1, and compounds of Formula 2
Formula 1 Formula 2 in which R^ is H, alkyl of 1 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds;
R2 is H, alkyl of 1 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds; R3 is H, alkyl of 1 to 20 carbons, arylalkyl, or halogene, and
X is H or alkyl of 1 to 20 carbons, CO-X*, CO-O-X*,, CO-NH-X*, PO(OX*,)2 or PO(OX*,)X*,, where X*,independently is H, alkyl of 1 to 20 carbons, phenyl, or substituted phenyl. However, in the compounds of the invention illustrated by Formula 2, both RA and R3 cannot be hydrogen.
The present invention also covers salts of the above- defined compounds, formed with pharmaceutically acceptable acids or bases, as applicable.
In a second aspect the present invention relates to pharmaceutical formulations comprising one or more compounds of Formula 1 or of Formula 2, or both, (or pharmaceutically acceptable salts thereof) in admixture with a pharmaceutically acceptable excipient, for the purpose of treating certain conditions, syndromes or diseases in mammals, including humans. The compounds of the invention have anti-inflammatory, immunosuppressant and anti-proliferative activity. Therefore, the compounds are useful for treating in mammals (including humans) inflammation, rheumatoid arthritis, osteoarthritis, rheumatic carditis, ocular and dermal inflammatory diseases, autoimmune diseases such as allergic diseases. bronchial asthma and myasthenia gravis, and for suppressing unwanted immune responses and retarding proliferation of cell.
RiCHO HC≡CCOjEt BuL> »_. R1CH(OH)C≡CCθ2Et
Formula 3 Formula 4
Lindlar yst
Formula 1 π = R3 = H
Reaction Scheme 1
In still another aspect, the present invention relates to the processes of making the compounds of . Formula 1 and of Formula 2. In general terms, these processes, shown in Reaction Scheme l, 2 , 3 and 4 comprise the steps of reacting an aldehyde of Formula 3 with a lithium or magnesium salt derived from a propiolate este such as ethyl propiolate (Compound 4) , to yield an Rχ- substituted 4-hydroxy —ynoate of Formula 4 (Rλ defined in connection with Formula 1 and Formula 2) . Hydroganation over a "poisoned" catalyst (Lindlar catalyst) converts the acetylenic (triple) bond into an olephinic (double) bond. This is followed by acid catalyzed cyclization to yield compounds of Formula 1 where R2 and R3 are hydrogen.
B1CH(OH)C_=CCOJEt KOH R,CH(OH)Cj_=CCO^.
Formula 4 Formula 5
Jones reagent
--.COC≡CCOjH
Formula 6
H2 / Lindlar catalyst
I R,COCHsCHCOaH |
cyclization
Reaction Scheme 2
KΓ ^r "*"OH
Formula 2 R, « R, * H In order to obtain compounds of Formula 2, as is shown in Reaction Scheme 2, the intermediate R^- substituted 4-hydroxy—ynoate of Formula 4 is saponified to obtain the corresponding free carboxylic acid of Formula 5, which is thereafter oxidized (typically with Jones reagent) to yield the corresponding R1-substituted 4-oxo-alkynoic acid of Formula 6. The intermediate of Formula 6 is hydrogenated over a "poisoned" catalyst, typically Lindlar catalyst, to yield an alkenoic acid intermediate which cyclizes, usually spontanously, to provide compounds of Formula 2 where R2 , R3 and X are hydrogen. As is shown in Reaction Scheme 2, the compounds of Formula 2 can be reduced with a mild reducing agent, such as sodium borohydride to provide the corresponding compounds of Formula 1. A theoretical explanation for this reaction (although the present inventors do not wish to be bound by theory) is that the carbon in the 5- position of the 5-hydroxy-2(5H)-furanone molecule is an "aldehydic" carbon, ring closed with the carboxylic acid group in the "2-position" of the ring, and that the aldehydic carbon is reduced with sodium borhydride to a primary alcohol, which, thereafter, ring closes with the carboxylic acid to form a lactone of Formula 1.
Compounds of Formula 2 where the X substituent is other than hydrogen, can be obtained by acylation, carbamate formation (through reaction with isocyanate) phosphorylation and the like, in accordance with procedures which are within the skill of the practicing organic chemist. 8
Formula 2 Formula 2 X s alkyl
Reaction Scheme 3 In order to obtain compounds of Formula 2 where neither Rj nor R2 are hydrogen, a ketone of Formula 7 (which bears the desired R^ and R2 groups) is condensed under acidic condition with glyoxylic acid (Compound 5) , as is shown in Reaction Scheme 3. An intermediate condensation product of Formula 8 usually is not isolated because it cyclizes during the condition of the condensation reaction to form the furanones of Formula 2 where the Rj and R2 groups are derived from the starting ketone of Formula 7 and where X is hydrogen. Reduction of the 5-hydroxy-2(5H)-furanone compound of Formula 2 (X is H) with sodium borohydride, as shown in Reaction Scheme 3 results in "removal" of the 5-hydroxy group and yields the corresponding compound of Formula 1. Referring still to Reaction Scheme 3, compounds of Formula 2 where R^ is hydrogen, are obtained when the starting material of Formula 7 is an aldehyde rather than a ketone, (in Formula 7 R1=H) . In this case, the condensation reaction with glyoxylic acid (Compound 5) is usually performed in the presence of morpholine hydrochloride. An alkyl substitutent for the 5-hydroxy function (in Formula 2 X=alkyl) is introduced into the molecule by reacting the 5-hydroxy-2(5H)-furanone derivative of Formula 2 with the appropriate alcohol (XOH) in the presence of acid. The resulting 5-alkoxy-2(5H)- furanone derivative of Formula 2 where R3 is hydrogen, is brominated to yield the corresponding 3-bromo-5-alkoxy- 2(5H)-furanone derivative of Formula 2. The alkoxy substituent can be replaced with OH by reaction with aqueous acid.
Formula 9 Formula 10 Formula 11
Formula 2 Formula 2
Formula 1 Formula 1
Reaction Scheme 4 Reaction Scheme 4 summarizes a reaction sequence, in which compounds of the invention can be prepared where neither R2 nor R3 are hydrogen. In accordance with this scheme, a di-substituted maleic acid anhydride (Formula 9) is reacted with the lithium salt of an alkyne (Formula 10) to provide a 5-alkynyl substituted 5-hydroxy-2(5H)- furanone derivative (Formula 11) . In Formula 10 -CC-R^ symbolizes such a precursor of the group R^ which is readily converted by hydrogenation and or other reactions within the skill of the practicing organic chemist, into the group Rχ defined in connection with Formula 1 and Formula 2. Reaction Scheme 4 shows a hydrogenation step in which the olephinic bond of the intermediate of Formula 11 is partially or fully saturated to provide compounds of Formula 2. Reduction of the compounds of Formula 2 with sodium borohydride provides compounds of Formula 1. Another process of preparing compounds of the invention where neither R2 nor R3 are hydrogen, involves the reaction a di-substituted maleic acid anhydride of Formula 9 with a Grignard reagent of the formula R1-MgBr to provide compounds of Formula 2 where X is hydrogen. Reduction of these compounds with sodium borohydride, yields compounds of Formula 1.
In another general aspect, the processes leading to the compounds of the invention may involve performance of routine chemical reactions (such as esterification, saponification of esters, oxidation of alcohols to ketones or aldehydes, formation of acetals, ketals, and lactones from aldehydes or ketones, and the like) which are well known to the practicing synthetic organic chemist. When it is desired to substitute, for example acylate, the 5-hydroxy function of the compounds of Formula 2, an X group (as defined in connection with these formulas) can be introduced into the 5-hydroxy-2(5H)-furanone compounds by conventional means. As it was illustrated in connection with Reaction Scheme 3, introduction of an X alkyl group into the compounds of Formula 2 in reality is formation of an acetal, which can be accomplished by treating the respecting 5-hydroxy-2(5H)-furanone with an alcohol XOH in the presence of acid.
General Embodiments eti ions
The terms "ester", "amine", "amide", "ether" "acetal", "lactone" and all other terms and terminology used here, (unless specifically defined in the present description) refer to and cover any compounds falling within the respective term as that term is classically used in organic chemistry.
Unless specifically noted otherwise, preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or from the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from lower alkyl acids or alcohols. Also preferred are the phenyl or lower alkylphenyl esters.
The term "alkyl" as used in the present description and claims includes straight chain alkyl. groups, branched chain alkyl groups, cycloalkyl groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. Unless the number of carbons is otherwise specified, "lower alkyl" means the former broad definition of "alkyl" groups but with the restriction that the group has 1 to 6 carbon atoms.
The term "long chain alkyl" also means the former broad definition of "alkyl" groups but with the restriction that the group has no less than 4 carbon atoms, and no more than approximately 25 carbon atoms.
Unless specifically noted otherwise, preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms, or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.
Some of the compounds of the invention (Formula 1) contain a non-equilibrating chiral center in the 5 position of the furan ring. Other compounds of the invention may contain one or more additional chiral centers. Accordingly, the compounds of the invention may be prepared as mixtures of enantiomeric compounds (where the enantiomers may or may not be present in equal amounts) or as optically pure enantiomers. When there is more than one chiral center, the compounds of the invention may also be prepared as mixtures of diastereomers, or as pure diastereomers, and each diastereomer itself may be a mixture of enantiomers in 1:1, or other, ratios. Alternatively, each diastereomeric compound may be sterically and optically pure. However, all of the above-noted forms, including optically pure enantiomers and mixtures thereof, as well as all diastereomers, are within scope of the present invention. Some of the compounds of the invention, for example those which contain olephinic double bonds in the side chains, may have cis and trans stereoisomers. The scope of the invention includes both pure stereoisomers as well as mixtures thereof. A pharmaceutically acceptable salt may be prepared for any compound of this invention having a functionality capable of forming such salt, for examle an acid or an amine functionality. A pharmaceutically acceptable salt may be any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
Such a salt may be derived from any organic or inorganic acid or base. The salt may be a mono or polyvalent ion. Of particular interest where the acid function is concerned are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic amine salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri-acid may also be used.
The preferred compounds of the present invention are, with reference to Formula 2 and with respect to the OX substituent in the 5-position of the furanone moiety, those where the substituent is hydroxy, methoxy or acetyloxy (X is H, or CH30 or CH3CO) .
With respect to the ^ susbtituent in the 5 position of the 2(5H)-furanone molecule, the preferred compounds in accordance with the present invention are those where R1 is hydrogen, long chain alkyl, or arylalkyl. Compounds are particularly preferred in this regard where the j^ group is long chain alkyl which is straight chained, or where the ^ is arylalkyl containing a straight alkyl chain of 3 carbons. With respect to the R2 substituent in the 4-position of the 2(5H)-furanone molecule, the compounds of the invention are preferred where R2 is hydrogen, or alkyl group, particularly straight chain alkyl. With respect to position 3 of the 2(5H)-furanones of the invention, compounds are preferred where R3 is H, methyl or bromo.
The most preferred compounds of the invention are those listed just below with reference to Formula 1 or Formula 2:
Formula 1, Compound 6: R1=CH3(CH2)8, R2=H' and R3=H; Formula 2, Compound 7: R 3~H and X=H;
Formula 1, Compound 8: R1=(CH2)3-C6H5,R2=CH3, and R3=CH3
Formula 2, Compound 9: R^H, R2 3SCH3(CH2)7, R 3=Br and X=H, and
Formula 1, Compound 10: j^H, R2=CH3(CH2)7 and R3=H. The compounds of the present invention are useful in pharmaceutical compositions to produce anti-inflammatory, immunosuppressant and anti-proliferative activity. The diseases, syndromes or conditions of mammals (including humans) which can be treated with pharmaceutical compositions containing one or more compounds of the invention (or salts thereof) include: inflammation, rheumatoid arthritis, osteoarthritis, rheumatic carditis, ocular and dermal inflammatory diseases, autoimmune diseases such as allergic diseases, bronchial asthma and myasthenia gravis, unwanted immune responses and unwanted proliferation of cells, psoriasis, acne, atopic diseases and allergic conjunctivitis.
The activity of the compounds of this invention is demonstrated by inhibition of the enzyme phospholipase A2 in vitro and by reduction of inflammation in the mouse ear anti-inflammatory assay in vivo.
Activity of compounds of this invention may also be demonstrated by inhibition of phosphoinositide-specific phospholipase C. This activity has been reported for manoalide and may indicate anti-inflammatory utility. Bennett et al. Molecular Pharmacology 32:587-593 (1987).
Activity of the compounds may also be demonstrated by inhibition of ornithine decarboxylase, a rate limiting enzyme in cellular growth, which indicates use in treating psoriasis and neoplasis.
The compounds also modify calcium homeostasis. This activity is shown by effect on intracellular calcium levels in experiments using gastric glands, spleen cells, epithelial cells, GH3 cells, etc. Calcium is inhibited from entering through the plasma membrane calcium channels and calcium release from intracellular stores is also blocked. Modification of calcium homeostasis is expected to have application in diseases of the nervous system involving modification of membrane lipids or transmitter release (Parkinson's, Alzheimer's), diseases of the cardiovascular system involving application of cardiac or vascular smooth muscle contractility and platelet aggregation (hypertension, cardiac infarction and atherosclerosis) , diseases of the gastrointestinal tract such as ulcer disease, diarrhea, motility due to secretion of acid or Cl", diseases of the kidney involving renal handling of fluid and electrolytes (metabolic acidosis, alkalosis) , and disease of abnormal growth (neoplasia, psoriasis) .
The compounds of this invention have activity which is similar to that of manoalide, that is the compounds appear to be devoid of the endocrine properties of the glucocorticoids while having anti-inflammatory and immunosuppressive properties.
In the methods of this invention, the compounds of the invention are administered to mammals, including humans, in an effective amount to produce the desired activity, preferably in an amount of about 0.05 to 100 mg per day per kilogram of body weight. The amount of the compound depends upon the disease or condition being treated, the severity thereof, the route of administration and the nature of the host. The compounds may be administered topically, orally, parenterally or by other standard routes of administration.
Pharmaceutical compositions of this invention comprise compounds of Formula 1 and of Formula 2, and pharmaceutical carriers suitable for the route of administration. Standard methods for formulating pharmaceutical compositions of this type may be found in Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, PA. For topical administration, the pharmaceutical composition may be in the form of a salve, cream, ointment, spray, powder or the like. Standard pharmaceutical carriers for such compositions may be used. Preferably, compositions for topical administration will contain 0.05-5% of the active ingredient.
A typical cream formulation may contain the following:
Ingredient Part? frY eight
Water/glycol mixture 50-99 (15% or more glycol)
Fatty alcohol 1-20
Non-ionic surfactant 0-10
Mineral oil 0-10 Typical pharmaceutical adjuvants 0-5 Active ingredient 0.05-5
A typical ointment formulation may contain the following:
Ingredients Parts bv Weight White petrolatum 40-94
Mineral oil 5-20
Glycol solvent 1-15 Surfactant 0-10
Stabilizer 0-10
Active ingredient 0.05-5
For oral administration, suitable pharmaceutical carriers include mannitol, lactose, starch, magnesium stearate, talcum, glucose and magnesium carbonate. Oral compositions may be in the form of tablets, capsules, powders, solutions, suspensions, sustained release formulations, and the like. A typical tablet or capsule may contain the following:
Ingredients percent w/w
Lactose, spray-dried 40-99
Magnesium stearate 1-2 Cornstarch 10-20
Active ingredient 0.001-20
Parenteral compositions are prepared in conventional suspension or solution forms, as emulsions or as solid forms for reconstruction. Suitable carriers are water, saline, dextrose. Hank's solution. Ringer's solution, glycerol, and the like. Parenteral administration is usually by injection which may be subcutaneous, intramuscular or intravenous. The compounds of this invention may be combined with other known anti-inflammatory/immunosuppressive agents such as steroids or non-steroidal anti-inflammatory agents (NSAID) in the pharmaceutical compositions and methods described herein.
The assay procedures by which useful biological activity of the compounds of the invention can be demonstrated, are described below. Calcium Channel (mobilization. Inhibition Assay
Polymorphonuclear leukocytes (PMNa) , gastric glands, GH3 cells, A431 cells, spleen cells, human keratinocytes corneal cells, etc. were loaded with the Ca2+ sensitive fluorescent dye, Fura-2. The appropriate cell type was chosen and the potency and efficacy of the anti- inflammatory furanones on calcium mobilization, calcium channel inhibition was quantitated. The methods used for A431 cells listed below are representative of those used for other cells.
A431 cells were detached using a 5-10 min trypsin- EDTA treatment whereas GH3 cells were treated 2 to 5 min with a 1% pancreatin solution. Cells were immediately washed twice in a 20mM HEPES buffer (pH 7.4) containing 120mM NaCl, 6 mM KC1, 1 mM MgS04, 1 mg/ml glucose and 1 mg/ml pyruvate and 1.4mM calcium (medium A) . Approximately 5 x 106 cells were suspended in medium A and incubated with 4uM fura-2-AM for 15 min at 37°C.
After washing the fura-2 loaded cells, the uptake of dye was checked using fluorescence microscopy and found to be evenly distributed in the cytosol of all cells. Fluorescence was continuously recorded with a Perkin-Elmer LS-5 spectrofluorometer. The excitation wavelength was set at 340nm and emission wavelength set at 500nm. The cell suspension was continually stirred, maintained at 37°C and equilibrated for approximately 5 min before addition of various agents. [CaΛ l was calculated using the following formula:
All fluorescence values were measured relative to a EGTA-quenched signal determined as follows: F was the relative fluorescence measurement of the sample. maχ was determined by lysing the cells with digitonin (lOOug/ml) in DMSO. After Fmaχ was determined the pH was adjusted to 8, with NaOH and Ca2+ chelated with 3mM EGTA to totally quench the fura-2 sig.^l and obtain m n.
When quin-2- was used, cells were incubated with lOuM quin-2- at 37°C for 1 hour, washed and then used. Mouse Ear Anti-Inflammatorv Assay
Test compound and phorbol myristate acetate (PMA) are topically applied simultaneously to the pinnae of the left ears of mice. PMA alone is applied to the right ear. Three hours and 20 minutes after application, the mice are sacrificed, left and right ears removed, and standard sized bores taken. Edema (inflammation) is measured as the difference in weight between left and right ears [Van Annan, C.G., Clin Pharmacol Ther (1974) 16:900-904].
Inhibition of Phog holipase A2 The effect of compounds of this invention on bee venom phospholipase A2 is determined by the following procedure: a. Bee venom phospholipase A2 in 10 uM HEPES (pH 7.4) with 1 mM CaCl2 is incubated with vehicle or test agent for 1.0 hour at 41°. b. 1.36 mM phosphotidylcholine, 2.76 mM Triton X- 100 are dispersed in buffer by sonication and then mixed with L-3 phosphotidylcholine, 1-palmitoyl-
2-
(1-14C) palmitoyl for 10 min. Start the reaction by the addition of enzyme (0.495 units/ml) . Incubation for 15 sec. at 41°.
Reaction is terminated by addition of 2.5 ml of isopropanol: n-heptane: 0.5 M H2S04 (40:10:1;
2.0 ml n-heptane and 1.0 ml H 0 added; mixture centrifuged.
2.0 ml n-heptane removed and treated with 200- of silica gel HR60. h. Samples centrifuged; 1 ml of n-heptane SN removed and added to 10 ml scintillation fluid. i. Samples counted on a scintillation counter. Inhibition .of Phosphoinositide-specific Phospholipase C
The effect of compounds of this invention on phosphoinositide-specific phospholipase C may be determined by procedures described by Bennett et al, Molecular Pharmacology 32:587-593 (1987).
Activity Data
In the above-described phospholipase A assay the compounds of the invention were found to provide 50% inhibition (IC50) of bee venom phospholipase A2 at the following concentrations (in micromoles) , as indicated in Table l. Table 1
Phospholipase A2 Assay.
Compound name or number Ic50 ^um^
1* 0.03
7 6
9 0.9 Data for Compound 1 (monoalide) are provided for comparison.
In the above-described phospholipase A2 assay compounds of the invention which are listed in Table 2 were found to provide the following percentage (%) inhibition of bee venom phospholipase A2 at 100 micromolar concentration. Table 2
6 37
8 49
10 53 The compounds of the present invention can be made by the synthetic chemical pathways which are illustrated above in general terms, and in the specific examples as well. The synthetic chemist will readily appreciate that the conditions described here in general terms, and specifically, can be generalized to any and all compovmds represented by Formula 1 or by Formula 2, as applicable. Furthermore, the synthetic chemist will readily appreciate that the herein described synthetic steps may be varied or adjusted by those skilled in the art without departing from the scope and spirit of the invention. Therefore, the following examples of specific compounds of the invention, and specific examples of the synthetic steps in which the compounds and certain intermediates are made. are set out to illustrate the invention, not to limit its scope.
Specific Examples
Example 1
Ethyl 4-hydroxy-6-phenylhex-1-ynoate (Compound 11)
II-Butyl lithium (a 1.6 M solution in hexane; 6.7 ml, 10.7 mmol) was added dropwise to a solution of ethyl propiolate (1.04 g, 10.6 mmol) in tetrahydrofuran (10 ml) at -78° under argon. After 10 minutes, a solution of hydrocinnamaldehyde (1.42 g, 10.6 mmol) in tetrahydrofuran (5 ml) was added. Stirring was continued at -78°C for 2 hours and acetic acid (1 ml) was added. On warming up to 0°, the reaction mixture was poured into water. Extraction (ethyl ether) and evaporation of the dried
(magnesium sulphate) extracts afforded an oil, which was flash chromatographed with silica using 30% ethyl ether/petroleum ether. Fractions with Rf of about 0.28 on evaporation afforded the title ester as a light yellow oil.
1 NMR (CDC13) 1.34 (m, 3H) , 2.10 (m, 2H) , 2.40 (br, IH) , 2.83 (t, 2H, J = 8.3 Hz) , 4.25 (q, 2H, J - 7.3 Hz), 4.50 (t, IH, J » 7.0 Hz) and 7.29 (m, 5H) .
LRMS m/e (% abundance) 233 (M++l, 2), 232 (M+, 7), 186 (24), 185 (42), 170 (51), 169 (30), 158 (24), 142 (37), 141 (100) and 105 (84). 5-(2-Phenvlethvl--2_5H)-furanone (Compound 12)
A solution of ethyl 4-hydroxy-6-phenylhex-l-ynoate (Compound 11, 585 mg, 2.5 mmol) in ether (12 ml) was hydrogenated over Lindlar catalyst (50 mg) at room temperature for 3 hours. The mixture was filtered through celite and the filtrate was refluxed with 2M hydrochloric acid (1 ml) for 2-1/2 hours. On cooling, the mixture was dried (magnesium sulphate) and evaporated to dryness to give an oil, which was purified by preparative thin layer chromatography (tic, 20x20 cm, 2000u silica plate; developed with 30% ethyl ether/petroleum ether) . The title furanone was obtained as colorless prisms (recrystallized from ether) : mp 66-7°.
XH NMR (CDC13) 1.98-2.16 (m, 2H) , 2.86 (m, 2H) , 5.08 (m, IH) , 6.16 (dd, IH, J = 6.0 Hz, 1.6 Hz), 7.36 (m, 5H) and 7.45 (dd, IH, J - 6.0 Hz, 1.6 Hz). 13C NMR (CDC13) 31.3, 34.9, 82.3, 121.5, 126.3, 128.5, 128.6, 140.2, 156.1 and 172.9.
HRMS exact mass calculated for C12H1202 (M+) 188.0837, found 188.0841. Example 2 4-Hvdroxy-6-phenylhex-2-vnoic acid (Compound 13)
A solution of potassium hydroxide (377 mg, 6.7 mmol) in 95% ethanol (10 ml) was added to a solution of ethyl 4- hydroxy-6-phenylhex-l-ynoate (Compound 11, 1.04 g, 4.5 mmol) in the same solvent (10 ml) at 0°, and the reaction mixture was stirred at room temperature for 15 hours. After most of the solvent was removed, the residue was dissolved in water (ca. 15 ml) and extracted with dichloromethane (discarded) . After the extraction the aqueous phase was acidified to pH 1 with dilute hydrochloric acid and extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulphate) extracts gave the title acid as a pale yellow oil (which crystallizes slowly on standing) , which was used directly in the next step. XH NMR (CDC13) 2.16 (m, 2H) , 2.85 (m, 2H) , 4.52 (dd, IH, J - 11.3 Hz, 6.6 Hz), 5.10 (br, 2H) and 7.31 ( , 5H) .
LRMS m/e (% abundance) 204 (M+, 6), 142 (42), 141 (75), 134 (21), 133 (11), 131, (10), 118 (34), 117 (32), 115 (21) and 105 (100) . 4-Keto-6-phenylhex-2-vnoic acid (Compound 14)
A solution of Jones Reagent (a 2.67 M solution in sulphuric acid; 2.07 ml, 5.5 mmol) was added dropwise to a solution of 4-hydroxy-6-phenylhex-2-ynoic acid (Compound 13, 750 mg, 3.7 mmol) in acetone (12 ml) at 0° and the reaction mixture was maintained at 0° for 70 minutes. The mixture was quenched with ethanol (2 ml) and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave the title acid as a yellow oil which was used directly in the next step.
1 NMR (CDC13) 3.02 (S, 4H) , 7.30 (m, 5H) and 8.80 (br, IH, exchanged with D20) .
5-Hvdroxv-5-(2-phenvlethvl_-2-furanone (Compound 15) A solution of 4-keto-6-phenylhex-2-ynoic acid
(Compound 14, 228 mg, 1.1 mmol) in ethyl ether (8 ml) was hydrogenated over Lindlar catalyst (20 mg) at 0° for 80 minutes. The mixture was filtered through celite and the filtrate, after evaporation to dryness, was purified by preparative tic (20x20 cm, lOOOu silica plate; developed with 60% ethyl ether/hexane) . The title furanone was obtained as a colorless oil.
XH NMR (CDC13) 2.31 (dd, 2H, J = 10.8 Hz, 5.5 Hz), 2.78 (dd, 2H, J * 10.8 Hz, 5.5 Hz), 4.80 (br, IH) , 6.11 (d, IH, J - 5.8 Hz), 7.20 (m, 5H) and 7.28 (d, IH, J ■ 5.8 Hz) .
13C NMR (CDCI3) 29.7, 39.1, 107.8, 123.1, 126.4, 128.3, 128.7, 140.3, 154.3 and 171.0.
HRMS exact mass calculated for C12 H12°3 (M+) 204.0786, found 204.0792. Example 3 Ethyl 4-hydroxytridec-2-ynoate (Compound 16)
Methylmagnesium bromide (a 3M solution in tetrahydrofuran; 7.8 ml, 23.4 mmol) was added dropwise to a solution of ethyl propiolate (Compound 4, 2.25 g, 22.9 mmol) in tetrahydrofuran (10 ml) at -78° under argon. After 10 minutes, a solution of decyl aldehyde (3.58 g, 22.9 mmol) in tetrahydrofuran (2 ml) was added. Stirring was continued for 1 hour while the cooling bath was warmed to room temperature. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 30% ethyl ether/petroleum ether. Fractions with Rf of about 0.31 gave, after evaporation, the title ester as a deep, yellow oil.
XH NMR (CDC13) 0.88 (t, 3H, J « 6.4 Hz), 1.27 (br s, 14H) , 1.75 (m, 2H) and 4.25 (q, 2H, J » 6.4 Hz).
LRMS m/e % abundance) 255 (M++l, 5), 254 (M+, 5), 237 (6), 209 (8), 181 (12), 179 (11), 163 (13), 152 (12), 151 (13), 137 (16), 130 (19), 128 (100), 100 (66) and 71 (35). 5-Nonyl-2(5H- -furanone (Compound 6) A solution of ethyl 4-hydroxytridec-2-ynoate
(Compound 16, 230.6 ml, 1.02 mmol) in ether (10 ml) was hydrogenated over Lindlar catalyst (20 mg) at 0° for 1 hour. The mixture was filtered through celite and after evaporation the filtrate gave a residue, which was flash chromatographed on silica using 60% ethyl ether/petroleum ether. Fractions with Rf of about 0.18 gave after evaporation a colorless oil (157 mg, 59%) identified by NMR as ethyl (£)-4-hydroxytridec-2-enoate: H NMR (CDC13) 0.92 (t, 3H, J - 6.7 HZ), 1.31 (br S, 14H) , 1.65 (m, 2H) , 4.97 (q, IH, J - 6.2 Hz), 5.91 (d, IH, J - 12.5 Hz) and 6.41 (dd, IH, J * 12.5 Hz, 7.3 Hz) . The oil on crystallization from petroleum ether, in the presence of a drop of acetic acid, lactonized to give the title furanone as a colorless oil.
XH NMR (CDCI3) 0.92 (t, 3H, J = 6.7 Hz) , 1.30 (br s, 12H) , 1.45 (m, 2H) , 1.75 (m, 2H) , 5.08 (m, IH) , 6.14 (dd, IH, J = 5.9 Hz, 2.6 Hz) and 7.48 (dd, IH, J = 5.3 Hz, 1.4 Hz) .
13C NMR (CDCI3) 14.1, 22.6, 25.0, 29.2, 29.3, 29.4, 31.8, 33.2, 83.4, 121.5, 156.3 and 173.1.
HRMS m/e: exact mass calculated for C13H 20 (M+) 210.1620, found 210.1624. Example 4
4-Hydroxytridec-2-ynoic acid (Compound 17)
A solution of potassium hydroxide (885 mg, 15.8 mmol) in 95% ethanol (35 ml) was added to ethyl 4-hydroxytridec- 2-ynoate (Compound 16, 2.68 g, 10.5 mmol) in the same solvent (5 ml) at 0°. After stirring at room temperature for 9 hours, most of the solvent was removed and water (20 ml) was added. The mixture was extracted thoroughy with dichloromethane (discarded) , acidified to pH 1 with dilute hydrochloric acid and extracted with ethyl acetate. Evaporation of the dried (magnesium sulphate) ethyl acetate extracts gave an off-white solid, which on recrystallization from petroleum ether (at -78°) gave the title acid as colorless prisms: mp 65-6°.
XH NMR (CDCI3) 0.93 (t, 3H, J » 5.7 Hz), 1.31 (br s, 12H), 1.50 (br, IH) , 1.81 (m, 2H) , 4.56 (dt, IH, J = 5.0 Hz, 1.9 Hz) and 5.00 (br, IH) .
LRMS m/e (% abundance) 226 (M+, 5), 137 (13), 124 (12), 121 (18), 107 (26), 100 (94), 97 (33), 95 (27), 93 (43) 85 (48), 83 (63), 79 (55) and 71 (75). 4-Ketotridec-2-vnoic-acid (Compound 18)
Jones reagent (a 2.67 M solution in sulphuric acid; 1.32 ml, 3.5 mmol) was added dropwise to a solution of 4- hydroxytridec-2-ynoic acid (Compound 17, 531.8 mg, 2.4 mmol) in acetone (10 ml) at 0° and the reaction mixture was maintained at 0° for 70 minutes. The mixture was quenched with ethanol (1 ml) and dried with magnesium sulphate. On evaporation, the title acid was obtained as a colorless oil.
XH NMR (CDC13) 0.87 (t, 3H, J - 6.6 Hz), 1.25 (br s, 12H) , 1.67 (m, 2H) , 2.64 (t, 2H, J = 7.2 Hz) and 4.90 (br, IH) .
LRMS m/e (% abundance) 224 (M+, 5), 223 (12), 197 (36), 155 (37), 149 (14), 37 (21), 123 (15), 111 (14), 109 (12) and 97 (34) . 5-Hydroxy-5-nony1-2-furanone (Compound 7)
A solution of 4-ketotridec-2-ynoic acid (Compound 18, 220 mg, 0.98 mmol) in ether (10 ml) was hydrogenated over Lindlar catalyst (10 mg) at 0° for 80 minutes. The mixture was filtered through celite and after evaporation to dryness the filtrate gave an oil, which was purified by preparative tic (20x20 cm, lOOOu silica plate; developed with 60% ethyl ether/petroleum ether) . The title furanone was obtained as colorless prisms (recrystallized from petroleum ether) : mp 54-5°.
XH NMR (CDCI3) 0.88 (t, 3H, J = 7.5 Hz) , 1.26 (br s, 12H) , 1.40 (m, 2H) , 1.98 (m, 2H) , 6.12 (d, IH, J = 6.4 Hz) and 7.16 (d, IH, J - 6.4 Hz). 13C NMR (CDCI3) 14.1, 22.6, 23.4, 29.3, 29.4, 31.8, 37.5, 108.5, 123.0, 154.5 and 170.8.
HRMS m/e: exact mass calculated for C13H2203 (M+) 226.1569, found 226.1568. Example 5 5-Hvdroxv-5-methvl-4-octvl-2-furanone (Compound 19) A mixture of 2-undecanone (10 g, 58.7 mmol), glyoxylic acid monohydrate (Compound 5, 5.15 g, 56 mmol) and 85% phosphoric acid (10 ml) was warmed at 80° for 18 hours. On cooling to room temperature, the mixture was diluted with ethyl ether/dichloromethane (50 ml each) and washed thoroughly with brine. Evaporation of the dried (magnesium sulphate) organic phase gave a yellow oil which 5 on crystallization from ethyl ether/petroleum ether gave 4-ketotridec-2-enoic acid as colorless prisms. NMR (CDC13) 0.96 (t, 3H, J = 7.4 Hz) , 1.34 (br S, 12H) , 1.72 (p, 2H, J - 7.1 Hz) , 2.73 (t, 2H, J = 7.1 Hz) , 6.74 (d, IH, J = 15.7 Hz) and 7.22 (d, IH, J = 15.7 Hz) .
10 The mother liquor from the above recrystallization was concentrated down and was flash chromatographed on silica using 40% ethyl acetate/petroleum ether. Fractions with Rf of about 0.1 gave, after evaporation, the title furanone as a pale yellow oil.
£5 XH NMR (CDC13) 0.92 (t, 3H, J - 7.4 Hz), 1.30 (br S, 12H) , 2.45 (s, 3H) , 2.79 (t, 2H, J = 7.5 Hz) and 6.56 (s, IH) .
13C NMR (CDCI3) 14.1, 22.7, 26.7, 27.0, 29.2, 29.3,
29.8, 31.9, 124.5, 158.0, 171.3 and 200.0. 0 HRMS m/e: exact mass calculated for C13H2203 (M+) 226.1569, found 226.1559. Example 6 5-Methvl-4-octvl-2(5H--furanone (Compound 20)
Sodium borohydride (214 mg, 5.7 mmol) was added to a 5 solution of 5-hydroxy-5-methyl-4-octyl-2-furanone
(Compound 19, 640 mg, 2.8 mmol) in tetrahydrofuran (15 ml) . After stirring at room temperature for 80 minutes, most of the solvent was removed and water (10 ml) was added. Extraction (dichloromethane) and evaporation of 0 the dried (magnesium sulphate) extracts gave a residue, which was flash chromatographed on silica using 60% ethyl ether/petroleum ether. Fractions with Rf of about 0.23 were evaporated to yield the title furanone as a colorless oil, which crystallized slowly on storage at -70°.
XH NMR (CDC13) 0.85 (t, 3H, J = 5.4 Hz) , 1.26 (br s, 10H) , 1.33 (d, 3H, J - 6.9 Hz) , 1.47 (m, 2H) , 2.26 (m, IH) , 2.83 (m, 1H0, 4.33 (q, IH, J = 6.2 Hz) and 5.99 (s, IH) .
13C NMR (CDC13) 14.1, 22.4, 22.6, 29.2, 29.3, 29.5, 29.8, 31.9, 71.1, 113.0, 169.2 and 171.8.
HRMS m/e exact mass calculated for C13H 202 (M+) 210.1620, found 210.1617.
Example 7
4-Ethyl-5-hydroxy-5-methyl-2-furanone (Comound 21)
A mixture of 2-pentanone (17.1 g, .198 mmol), glyoxylic acid monohydrate (Compound 5, 8.05 g 88 mmol) and about 85% phosphoric acid (12 ml) was warmed at ca. 80° for 19 hours. On cooling to room temperature the mixture was diluted with ethyl ether/dichloromethane (100 ml, 1:1) and washed thoroughly with brine. Evaporation of the dried (magnesium sulphate) organic phase gave a yellow viscous oil, which on crystallization from ethyl ether/petroleum ether gave 4-keto-hept-2-enoic acid as colorless prisms: mp 100-2°.
^•H NMR (CDCI3) 1.01 (t, 3H, J = 7.9 Hz), 1.73 (p, 2H, J = 7.1. Hz), 2.70 (t, 2H, J - 7.3 Hz), 6.73 (IH, d, J ■ 15.8 Hz) and 7.19 (d, IH, J = 15.8 Hz).
HRMS m/e: exact mass calculated for C7H1003 (M+) 142.0630, found 142.0622.
The mother liquor from the above crystallization was evaporated to dryness and extracted thoroughly with petroleum ether. The combined extracts were concentrated and cooled to -20° to give the title furanone as colorless prisms: mp 37-8°.
XH NMR (CDCI3) 1.09 (t, 3H, J - 7.8 Hz) , 2.46 (s. 3H) , 2.83 (q, 2H) , J = 7.8 Hz) and 6.57 (s, IH) .
13C NMR (CDC13) 13.6, 20.4, 26.6, 124.6, 158.7, 171.2 and 199.9.
HRMS m/e: exact mass calculated for C7H10O3(M+) 5 142.0630, found 142.0622. Example 8 4-Ethyl-5-methyl-2(5H)-furanone (Compound 22)
Sodium borohydride (646 mg, 17 mmol) was added to a solution of 4-ethyl-5-hydroxy-5-methyl-2-furanone 10 (Compound 21, 1.21 g, 8.5 mmol) in tetrahydrofuran (10 ml) at room temperature. After 1/2 hour, most of the solvent was removed and water (10 ml) was added. Extraction (ethyl acetate) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash I5 chromatographed on silica using 60% ethyl ether/petroleum ether. Fractions with Rf of about 0.23 gave after evaporation, a pale yellow oil, which slowly crystallized on storage at -20°. Recrystallization from ethyl ether/petroleum ether afforded the title furanone as 0 colorless prisms: mp 86-7°. λH NMR (CDC13) 1.16 (t, 3H, J = 7.2 Hz) , 1.39 (d, 3H, J = 5.4 Hz), 2.36 (m, IH) , 2.84 (m, IH) , 4.41 (q, 2H, J = 7.2 Hz) and 6.04 (s, IH) .
13C NMR (CDCI3) 13.8 , 22.3 , 22.8 , 71.0 , 112.9 , 170.3 5 and 171.7 .
HRMS m/e: exact mass calculated for C7H10O2(M+) 126.0681, found 126.0683. Example 9
3.4-Dimethvl-5-hvdroxv-5-f1-octvnvl, -2-furanone (Compound 0 23)
Q-Butyl lithium (a 1.6 M solution in hexane; 6.78 ml, 10.9 mmol) was added dropwise to a solution of 1-octyne (1.13 g, 10 mmol) in tetrahydrofuran (7 ml) at -78° under argon. After 20 minutes, the solution was cannulated dropwise, under argon, to a solution of 2,3-dimethylmaleic anhydride (1.30 g, 10.3, mmol) in tetrahydrofuran (15 ml) cooled at -78°. Stirring was continued for 2 hours while the cooling bath attained room temperature. The mixture was quenched with dilute hydrochloric acid, diluted with water (10 -.1) and extracted with ethyl acetate. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 30% ethyl ether/petroleum ether. Fractions with Rf of about 0.18 on evaporation afforded a light yellow viscous oil, which crystallized out slowly on storage at -20°. Recrystallization from petroleum ether gave the title furanone as colorless prisms: mp 55-6°C. NMR (CDC13) 0.85 (t, 3H, J - 7.4 Hz), 1.24 (_, 6H) , 1.49 (p, 2H, J - 7.9 Hz) , 1.79 (s, 3H) , 2.00 (s, 3H) , 2.21 (t, 2H, J = 7.2 Hz) and 3.93 (br, IH) .
13C NMR (CDCI3) 8.4, 10.5, 13.9, 18.5, 22.4, 27.9,
28.4, 31.1, 74.5, 88.2, 98.0, 124.3, 156.9 and 172.1.
HRMS m/e: exact mass calculated for C14H2003 (M+) 237.1491, found 237.1498. Example 10
3.4-Dimethvl-5-hvdroxv-5-(2-Phenvlpropvl_-2-furanone (Compound 24) A mixture of 3-phenyl-l-bromopropane (521 mg, 2.6 mmol) and magnesium turnings (66 mg, 2.8 mmol) in tetrahydrofuran (5 ml) was refluxed under argon for 90 minutes. After the reaction mixture had been cooled to -78°, a solution of 2,3-dimethylmaleic anhydride (330 mg, 2.6 mmol) in tetrahydrofuran (5 ml) was added dropwise. Stirring was continued overnight (ca. 17 hours) while the cooling bath attained room temperature. The mixture was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 40% ethyl acetate/petroleum ether. Fractions with Rf of about 0.32 on evaporation afforded the title furanone as a pale yellow oil, which on storage at -20° crystallized as colorless prisms: mp 62-3°C. H NMR (CDC13) 1.48 (m, IH) , 1.70 (m, IH) , 1.79 (s, 3H) , 1.89 (s, 3H) , 2.05 (m, 2H) , 2.65 (m, 2H) and 7.25 (m, 5H) .
13C NMR (CDCI3) 8.3, 10.6, 24.7, 35.4, 107.2, 125.1, 125.9, 128.4, 141.5, 158.1 and 172.6.
HRMS m/e: exact mass calculated for C15H1803 (M+) 246.1256, found 246.1270. Example 11
3.4-Dimethvl-5-_2-phenvlpropvl_ -2f5H_-furanone (Compound
8)
Potassium borohydride (503 mg, 9.3 mmol) was added to a solution of 3,4-dimethyl-5-hydroxy-5-(2-phenylpropyl)-2- furanone (Compound 24, 382 mg, 1.6 mmol) in tetrahydrofuran (8 ml) and methanol (6 ml) at room temperature. After 7 hours, most of the solvent was removed and water (10 ml) was added. Extraction (ethyl acetate) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative tic (20x20 cm, 2000u silica plate; developed with 30% ethyl ether/petroleum ether) . The title furanone was obtained as colorless prisms (recrystallized from ethyl ether/petroleum ether) : mp 69-70°.
XH NMR (CDCI3) 1.50 (m, IH), 1.77 (p, 2H, J » 6.8 HZ), 1.82 (S, 3H), 1.92 (S, 3H) , 1.95 (m, IH) , 2.67 (m, 2H) , 4.74 (m, IH) and 7.25 (m, 5H) .
13C NMR (CDCI3) 8.4, 11.9, 26.0, 31.5, 35.4, 82.9, 123.6, 125.9, 128.4, 141.5 and 158.9.
HRMS m/e: exact mass calculated for C15H18o2 (M+) 230.1307, found 230.1311. Example 1? 4-0ctyl-5-hydroxy-2f5H.-furanone (Compound 25)
A mixture of glyoxylic acid monohydrate (Compound 5, 1.19 g, 16.1 mmol), morpholine hydrochloride (1.81 g, 14.6 mmol), water (0.73 ml) and 1-decanal (2.89 ml, 15.4 mmol) in dioxane (6 ml) was stirred at room temperature for 1 hour, followed by reflux for 25 hours. After cooling, most of the solvent was removed by evaporation and the residue was extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was flash chromatographed with 30% ethyl acetate/hexane to give the title furanone.
XH NMR (CDC13): 0.89 (t, 3H, J - 6.6 Hz) , 1.25 (br s, 10H), 1.60 (m, 2H), 2.40 (m, 2H) , 4.70 (br, IH) , 5.84 (s, IH) and 6.00 (s, IH) .
4-Octvl-5-methoxy-2(5H_-furanone (Compound 26) A mixture of 4-octyl-5-hydroxy-2(5H)-furanone
(Compound 25, 244 mg, 1.16 mmol) and 1-toluenesulfonic acid (33 mg, 0.17 mmol) and methanol (5.8 ml) was stirred at room temperature for 2 days. The mixture was diluted with ethyl ether and washed thoroughly with 5% sodium bicarbonate solution. Evaporation of the dried (magnesium sulfate) organic phase gave an oil, which was flash chromatographed on silica using 10% ethyl acetate/hexane to give the title furanone.
XH NMR (CDCI3): 0.89 (t, 3H, J » 7.5 Hz) , 1.28 (br s, 10H), 1.60 (m, 2H) , 2.35 (m, 2H) , 3.56 (s, 3H) , 5.64 (s, IH) and 5.86 (s IH) . 3-Bromo-4-octvl-5-methoxy-2f5H1-furanone (Compound 27)
A solution of bromine (28 icroliter) in carbontetrachloride (0.2 ml) was added to a solution of 4- octyl-5-methoxy-2(5H)-furanone (100 mg, 0.45 mmol) in carbon tetrachloride (0.5 ml) at 0°. The mixture was stirred at room temperature until all the starting material disappeared (as monitored by tic) . After cooling to 0°, pyridine (86 microliter, 1.17 mmol) was added. The mixture was quenched with water and the layers were separated. Evaporation of the dried (magnesium sulfate) organic phase gave an oil, which was purified by flash chromatography using 5% ethyl acetate/hexane to give the title furanone. H NMR (CDC13): 0.89 (t, 3H, J - 6.8 Hz), 1.28 (br s, 15H) , 1.60 (m, 2H) , 2.50 (m, 2H) , 3.58 (s, 3H) and 5.69 (s, IH). 3-Bromo-4-octvl-5-hvdroxv-2(5H--furanone (Compound 9)
A mixture of 3-bromo-4-octyl-5-methoxy-2(5H)-furanone (106 mg, 0.35 mmol) and concentrated hydrochloric acid (0.21 ml) was refluxed until all the starting material disappeared as shown by tic. After cooling, the mixture was diluted with ethyl ether and was neutralized by washing thoroughly with saturated potassium bicarbonate solution.. Evaporation of the dried (magnesium sulfate) organic phase gave an oil, which was flash chromatographed on silica using 10% ethyl acetate/hexane to give the title furanone.
IR (CHCI3): 3389, 1755 and 1651.
XH NMR (CDCI3): 0.87 (t, 3H, J » 7.2 Hz) , 1.27 (br s, 10H) , 1.60 (m, 2H), 2.49 (t, 2H, J - 8.5 Hz) , 4.50 (br, IH) , and 6.05 (s, IH) . 13C NMR (CDCI3): 14.2, 22.7, 26.5, 27.8, 29.2, 29.6, 31.8, 98.8, 112.1 and 163.9.
HRMS exact mass calculated for C12 H20BrO3 (M+H)+ 291.0596, found 291.0590.

Claims

AMENDED CLAIMS
[received by the International Bureau on 26 July 1991 (26.07.91) ; original claims 11,15 and 34 amended; other claims unchanged (4 pages)]
8 . Compounds of Claim 1 wherein R3 is H, or lower alkyl .
9 . Compounds of Claim 1 wherein R3 is bromo .
10 . One or more compounds set forth in Claim 1 , comprised in and admixed with a pharmaceutical composition including a pharmaceutically acceptable excipient .
11 . Compounds of the formula
wherein
Rl is H;
R2 is alkyl of 6 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds;
R3 is bromo or chloro, and
X is H or alkyl or 1 to 20 carbons, CO-X*, CO-0-X*, , CO-NH-X*,, or PO(OX*, )2 or PO(OX*,)X*,, where X*, independently is H, alkyl of 1 to 20 carbons, phenyl, or substituted phenyl.
12. Compounds of Claim 11 wherein Ri is hydrogen, arylalkyl or long chain alkyl.
13. Compounds of Claim 12 wherein Ri is long chain nor a alkyl.
14. Compounds of Claim 12 wherein Ri is 3-aryl-n.- propyl.
15. Compounds of Claim 11 wherein R2 is alkyl.
16. Compounds of Claim 15 wherein R2 is lower alkyl.
17. Compounds of Claim 15 wherein R2 is long chain alkyl.
18. Compounds of Claim 11 wherein R3 is H, or lower alkyl.
19. Compounds of Claim 11 wherein R3 is bromo.
20. Compounds of Claim 11 wherein X is hydrogen, CH3, or CH3CO.
21. One or more compounds set forth in Claim 11, comprised in and admixed with a pharmaceutical composition including a pharmaceutically acceptable excipient.
22. Compounds of the formula
wherein l is H, alkyl of 1 to 20 carbons, ar arylalkyl;
R2 is H, or alkyl of 1 to 20 carbons , and R3 is H, alkyl of 1 to 20 carbons, or halogene.
23. Compounds of Claim 22 wherein Ri is n-nonyl.
24. Compounds of Claim 23 wherein R2 is hydrogen.
25. The compound of Claim 24 wherein R3 is hydrogen.
26. Compounds of Claim 22 wherein Ri is (CH2)3-Cg__5.
27. Compounds of Claim 26 wherein R2 is methyl.
28. The compound of Claim 27 wherein R3 is methyl.
29. Compounds of Claim 26 wherein R3 is methyl.
30. Compounds of Claim 22 wherein Ri is hydrogen.
31. Compounds of Claim 30 wherein R2 is n-octyl•
32. Compounds of Claim 30 wherein R3 is hydrogen.
33. The compound of Claim 31 wherein R3 is hydrogen.
3 . Compounds of the formula
wherein
Rl is H;
R2 is alkyl of 1 to 20 carbons;
R3 is chloro or bromo, and
X is H or alkyl of 1 to 20 carbons.
35. Compounds of Claim 34 wherein Ri is n-nonyl.
36. Compounds of Claim 35 wherein R2 is hydrogen.
37. Compounds of Claim 36 wherein R3 is hydrogen.
38. Compounds of Claim 37 wherein X is hydrogen.
39. Compounds of Claim 34 wherein R3 is bromine 40. Compounds of Claim 39 wherein R2 is n-octyl.
41. Compounds of Claim 41 wherein Ri is hydrogen.
42. The compound of Claim 41 wherein X is hydrogen,
EP19910907029 1990-04-17 1991-03-25 2(5h)-furanones substituted in the 5 and or in the 4 position, as anti-inflammatory agents Ceased EP0524979A4 (en)

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US5639468A (en) * 1995-06-07 1997-06-17 University Of Southern California Method for reducing or preventing post-surgical adhesion formation using manoalide and analogs thereof
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