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WO1993014062A1 - ANTHELMINTIC β-KETOAMIDES - Google Patents

ANTHELMINTIC β-KETOAMIDES Download PDF

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Publication number
WO1993014062A1
WO1993014062A1 PCT/US1992/010760 US9210760W WO9314062A1 WO 1993014062 A1 WO1993014062 A1 WO 1993014062A1 US 9210760 W US9210760 W US 9210760W WO 9314062 A1 WO9314062 A1 WO 9314062A1
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WIPO (PCT)
Prior art keywords
oxo
hydroxy
tricyclo
diene
deca
Prior art date
Application number
PCT/US1992/010760
Other languages
French (fr)
Inventor
Frederic Edwin Dutton
Original Assignee
The Upjohn Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO1993014062A1 publication Critical patent/WO1993014062A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/88—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having the nitrogen atom of at least one of the carboxamide groups further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/60—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members
    • C07C2603/62—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members containing three- or four-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/60—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members
    • C07C2603/66—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members containing five-membered rings
    • C07C2603/68—Dicyclopentadienes; Hydrogenated dicyclopentadienes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/86—Ring systems containing bridged rings containing four rings

Definitions

  • helminthiasis The diseases or groups of diseases described generally as helminthiasis are due to infection of the animal with parasitic worms known as helminths. Helminthiasis and
  • helminthosis are prevalent and may lead to serious economic problems in valuable domestic warm-blooded animals such as sheep, swine, cattle, goats, dogs, cats, horses, poultry and man.
  • helminths the groups of worms known as nematodes. trematodes and cestodes cause widespread and often-times serious infections in various species of animals including man.
  • the most common genera of nematodes, trematodes and cestodes infecting the animals referred to above are Dictyocaulus, Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Bunostomum, Oesophagostomum , Chabertia, Strongyloides, Trichuris, Fasciola, Dicrocoelium, Enterobius, Ascaris, Toxascaris, Toxocara, Ascaridia, Capillaria, Heterakis, Ancylostoma,
  • Triodontophorus Macracanthorhynchus, Hyostrongylus, and Strongylus. Some of these genera attack primarily the intestinal tract while others inhabit the stomach, lungs, liver and
  • Anthelmintic compounds which also contain a ketoamide structure are disclosed in US
  • Patent 3,746,765 and in Swedish patent 592,048.
  • This invention pertains to a new method for killing and controlling worms (Helminths), and new formulations for killing and controlling worms in animals, and new chemical compounds.
  • the invention is more particularly directed to a new method for killing and controlling parasitic worms in animals with novel ⁇ -ketoamides, and to new anthelmintic formulations comprising the same.
  • the anthelmintic ⁇ -ketoamides have the general structure of Formula I.
  • This invention encompasses: 1) A compound of formula I
  • each variable may be independent of the other variable unless indicated otherwise;
  • the C-C bonds, a, b, and c, are single or double bonds;
  • X is either -NH- or -O-;
  • R 2-1 , R 2-2 and R 2-3 are, each independently: H, Halogen, CF 3 , CN, NO 2 , OCH 3 , NH 2 , CI- C5 alkyl, or C 1 -C 5 alkoxy;
  • n 1 to 3
  • R 4 and R 7 taken together are, -O-, -CH 2 -,
  • R 5 is H, Halogen, or C 1 -C 5 alkyl
  • R 6 is H, Halogen, or C 1 -C 5 alkyl
  • R 5-1 is Halogen
  • a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of formula I and 3) A method of killing or controlling parasitic worms in humans and warm blooded domestic animals which comprises administering a therapeutic or prophylactic dosage of a compound of formula I.
  • Pharmacologically acceptable salts of Formula I are also included as one aspect of this invention.
  • the anthelmintic agents of this invention will find their primary use in the treatment and/or prevention of helminth parasitism in valuable warm-blooded domesticated animals such as sheep, cattle, horses, dogs, swine, goats and poultry; they are also effective in treatment that occurs in other warm blooded animals including man.
  • the compounds of this invention all possess a ⁇ -ketoamide (BKA) template.
  • This ⁇ - ketoamide (BKA) template is then joined to one of four different components.
  • the four components are: oxynorbomene BKAs (CHART A), norbomene BKAs (CHART B), tetracyclic BKAs (CHART C) and fulvene BKAs (CHART D).
  • the compounds of this invention can be made in accordance with the processes illustrated in and the reactions related to CHARTS A, B, C, and D. The reactions are described in general teims immediately below, the detailed preparations are found at the end of this section, followed immediately by the CHARTS, which show the compound structures.
  • Step 1 The starting ketone, 1 ,3-Cyclopentenedione, and furan (used as both reactant and solvent) are refluxed for 3 to 5 days to produce the Diels- Alder adduct, Figure A1.
  • the compound of Figure A1 is stirred with various arylisocyanates and benzoylisocyanates in tetrahydrofuran at room temperature in the presence of an organic base to prepare the oxynorbomene BKAs of CHART A.
  • Steps 2 through 4 below, provide several examples.
  • Step 2 The compound of Figure A1 and 4-bromophenylisocyanate gives Figure A2. From step 2, reactions may proceed in any of several directions; as shown by the following series of reactions.
  • Step 3(a), series (a), Bromine is added to the compound of Figure A2 in CCl 4 to give the dibromo BKA, Figure A3(a).
  • the reactions of Step 3(a) results in a mixture of cis-endo-, cis- exo-, and trans-dibromo isomers which can be subsequently dehydrobrominated (KOH/PTC- /EtOH/25°C/10 days) in Step 4(a) to give the compounds of Figure A4(a).
  • the compound of Figure A2 is treated with dibromoformaldoxime and silver nitrate, to give the bromoisoxazoline, A3(b).
  • Chart B (norbomene ⁇ -ketoamides) Step 1.
  • the Diels- Alder reaction between freshly distilled cyclopentadiene and maleic anhydride (Et 2 O/25o) produces the endo-adduct the compound represented by Figure B 1 (endo- not shown in figure).
  • Step 3 The compound represented by Figure B2 is converted to the ester, Figure B3. by treating it with carbonyl diimidazole and potassium tert-butoxide in tetrahydrofuran at reflux. Pure endo isomer of the compound of Figure B3 was produced by trituration with and partial recrystallization from boiling hexane.
  • Step 4 The norbomene BKAs of CHART B are then prepared by simply combining the compound of Figure B3 with an aromatic amine in toluene and heating the mixture under reflux.
  • the compound of Figure B4 is prepared from the ester, Figure B3, and 2- fluoroaniline.
  • Step 3 The ⁇ -ketoester-acid, Figure C2, is converted to the ester, Figure C3, by heating it with carbonyl diimidazole and potassium tert-butoxide in tetrahydrofuran at reflux.
  • Step 4 The ester, Figure C3, is heated with an aromatic amine such as 4-bromoaniline in toluene at reflux to obtain the compounds of Figure C4.
  • aromatic amine such as 4-bromoaniline in toluene at reflux
  • Step 1 6,6-dimethylfulvene, is prepared by stirring a methanol solution of freshly distilled cyclopentadiene with acetone in the presence of pyrrolidine.
  • the compound of Figure D2(a) is obtained as a 2:1 mixture of exo- and endo-isomers by refluxing the compound of Figure D1 and maleic anhydride in ether overnight.
  • the compound of Figure D2(a) is treated with ethyl lithioacetate at -78°C to give the ⁇ -ketoester-acid, Figure D3(a), as a yellow oil containing several impurities.
  • Figure D3(a) is converted to the cyclized ester, Figure D4(a), by heating it with carbonyldiimidazole and potassium tert- butoxide in tetrahydrofuran.
  • the cyclized ester, Figure D4(a) is reacted with aryl amines to produce the BKAs.
  • One BKA is the compound of Figure D5(a), produced by heating the ester, Figure D4(a) with 4-bromoaniline in toluene under reflux to give the compound of Figure D5(a).
  • Stirring the compound of Figure D1 the fulvene, with cyclopen- tenedione in ether at 25°C for six days gives the compound of Figure D2(b).
  • an isocyanate such as 4-bromophenylisocyanate under the same reaction conditions used for the oxynorbomenes (CHART A)
  • CHART A oxynorbomenes
  • TABLE 1 The left column of TABLE 1 identifies the compounds according to the EXAMPLE number.
  • the EXAMPLE number corresponds to the EXAMPLE numbers in the detailed synthesis below.
  • the other columns of TABLE 1 show the results of the two assays which are described below.
  • ASSAY No. 1 This assay uses cultures of Caenorhabditis elegans maintained in a culture grown in McArtney bottles at 20°C in 10cm 3 of a thymidine-fortified broth containing 10 g Bactotryptone, 5 g Oxoid yeast extract, 10 mg cysteine and 5 mg thymidine dm -3 . Worms for the test are washed from 4-8 day old cultures. Test medium was made by adding 10 cm 3 of well-grown Escherichia coli (3-5 days) to 100 cm 3 M9 buffer plus 5 mg ampicillin and 10 000 Units nystatin. (The M9 buffer is described in Brenner, S. Genetics, 1974, Vol. 77, p.
  • test medium was placed in each well of a Sterilin Repli Dish (Catalogue number 103) and 10 ⁇ l of dimethyl sulphoxide solution of chemical added to each well.
  • worm suspension containing 10-20 worms of mixed age was added to each well and the plates were incubated at 20°C for 7 days.
  • Haemonchus contortus and Trichostrongylus colubriformis Female jirds weighing 30-35 g were obtained and put on a diet of commercial rodent chow containing 0.02 percent hydrocortisone for the duration of the study. All jirds were inoculated with approximately 1,000 exsheathed infective larvae each of H. contortus and T. colubriformis 5 days after the animals had been placed on medicated feed. Treatments were made 10 days post inoculation (PI). On day 13 PI,
  • the preferred compounds of this invention are:
  • Some of the compounds of this invention are useful as intermediates in the synthesis of active compounds. Some compounds may be both active and useful as an intermediate. Some of the useful intermediates are:
  • DX6 3-(2-ethoxycarbonyl-acetyl)-7-isopropylidene-bicyclo[2.2.1 ]hept-5-ene-2-carboxylic acid; DX7 3-hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.0 2,6]deca-3,8-diene-4-carboxylic acid ethyl ester.
  • the compounds of this invention are identified in two ways: by the descriptive name and reference to labeled structures contained in appropriate charts and tables. Occasionally the proper stereochemistry is also represented in the charts.
  • the parenthetical term (C n -C m ) is inclusive such that a compound of (C 1 -C 8 ) would include compounds of one to 8 carbons and their isomeric forms.
  • Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n- hexyl, isohexyl, and n-octyl.
  • Halogen or halo is fluoro, chloro, bromo, iodo or trifluoromethyl.
  • THF is tetrahydrofuran.
  • EtOH is ethanol.
  • EtOAc is ethyl acetate.
  • Et 2 O is diethyl ether.
  • KOH potassium hydroxide.
  • PTC Phase Transer Catalyst, in these reactions the PTC usually used is benzyltriethylammonium chloride.
  • C is carbon.
  • H hydrogen O is oxygen.
  • NMR Nuclear Magnetic Resonance.
  • PPM is parts per million. °C is degree centigrade.
  • L is liter. mL is milliliter. M or mol is mole. mM is milliMole. g is gram. mg is milligram, min is minute.
  • the compounds of this invention can be used as the pure compounds or as mixtures of pure compounds but for practical reasons the compounds are preferably formulated as anthelmintic compositions and administered as a single or multiple dose, alone or in
  • anthelmintics e.g. avermectins, benzimidazoles, levamisole, praziquantel, etc.
  • aqueous or oil suspensions can be administered orally, or the compounds can be formulated with a solid carrier for feeding.
  • an oil suspension can be converted into an aqueous emulsion by mixing with water and injecting the emulsion intramuscularly, subcutaneously or into the peritoneal cavity.
  • the activehelmintics e.g. avermectins, benzimidazoles, levamisole, praziquantel, etc.
  • aqueous or oil suspensions can be administered orally, or the compounds can be formulated with a solid carrier for feeding.
  • an oil suspension can be converted into an aqueous emulsion by mixing with water and injecting the emulsion intramuscularly, subcutaneously or into the peritoneal cavity.
  • the activehelmintics e.g. averme
  • compound(s) can be administered topically to the animal in a conventional pour-on formulation.
  • Pure compounds, mixtures of the active compounds, or combinations thereof with a solid carrier can be administered in the animal's food, or administered in the form of tablets, pills, boluses, wafers, pastes, and other conventional unit dosage forms, as well as sustained release dosage forms which deliver the active compound over an extended period of days, weeks or months. All of these various forms of the active compounds of this invention can be prepared using physiologically acceptable carriers and known methods of formulation and manufacture.
  • Solid carriers conveniently available and satisfactory for physiologically acceptable, unit dosage formulations include com starch, powdered lactose, powdered sucrose, talc, stearic acid, magnesium stearate, finely divided bentonite, and the like.
  • the active agent can be mixed with a carrier in varying proportions from, for example, about 0.001 percent by weight in animal feed to about 90 or 95 percent or more in a pill or capsule. In the latter form, one might use no more carrier than sufficient to bind the particles of active compound.
  • the compounds can be formulated in stable powders or granules for mixing in an amount of feed for a single feeding or enough feed for one day and thus obtain therapeutic efficacy without complication. It is the prepared and stored feeds or feed premixes that require care. A recommended practice is to coat a granular formulation to protect and preserve the active ingredient.
  • a prepared sheep-feed containing about 0.2 percent of the active compound will provide a dosage of about 100 mg per kg body weight for each 100 lb sheep in its daily ration.
  • a solid diluent carrier need not be a homogeneous entity, but mixtures of different diluent carriers can include small proportions of adjuvants such as water; alcohols; protein solutions and suspensions like skimmed milk; edible oils; solutions, e.g., syrups; and organic adjuvants such as propylene glycols, sorbitol, glycerol, diethyl carbonate, and the like.
  • the solid carrier formulations of the inventions are conveniently prepared in unit dosage forms, to facilitate administration to animals. Accordingly, several large boluses (about 20 g weight) amounting to about 54 g of active compound would be required for a single dosage to a 900 lb horse at a dosage rate of 50 mg/kg of body weight. Similarly, a 60 lb lamb at a dosage rate of 100 mg/kg of body weight would require a pill, capsule, or bolus containing about 2.7 g of active compound. A small dog, on the other hand, weighing about 20 lbs. would require a total dosage of about 225 mg at a dosage rate of 25 mg/kg of body weight
  • the solid, unit dosage forms can be conveniently prepared in various sizes and concentrations of active ingredient to accommodate treatment of the various sizes of animals that are parasitized by worms.
  • Liquid formulations can also be used.
  • Representative liquid formulations include aqueous (including isotonic saline) suspensions, oil solutions and suspensions, and oil in water emulsions.
  • Aqueous suspensions are obtained by dispersing the active compound in water, preferably including a suitable surface-active dispersing agent such as canonic, anionic, or nonionic surface-active agents.
  • suitable ones are polyoxyalkylene derivatives of fatty alcohols and of sorbitan esters, and glycerol and sorbitan esters of fatty acids.
  • Various dispersing or suspending agents can be included and representative ones are synthetic and natural gums, tragacanth.
  • the proportion of the active compound in the aqueous suspensions of the invention can vary from about 1 percent to about 20 percent or more.
  • Oil solutions are prepared by mixing the active compound and an oil, e.g. an edible oil such as cottonseed oil, peanut oil, coconut oil, modified soybean oil, and sesame oil. Usually, solubility in oil will be limited and oil suspensions can be prepared by mixing additional finely divided compound in the oil.
  • an oil e.g. an edible oil such as cottonseed oil, peanut oil, coconut oil, modified soybean oil, and sesame oil.
  • solubility in oil will be limited and oil suspensions can be prepared by mixing additional finely divided compound in the oil.
  • Oil in water emulsions are prepared by mixing and dispersing an oil solution or suspension of the active compound in water preferably aided by surface-active agents and dispersing or suspending agents as indicated above.
  • formulations of this invention are administered to animals so as to achieve therapeutic or prophylactic levels of the active compound.
  • Effective dosages of various compounds are contemplated, e.g., in the range of 1 to 75 mg/kg of body weight.
  • dosage rates of about 1 mg to about 800 mg/kg of body weight.
  • a preferred, contemplated range of dosage rates is from about 1 mg to about 50 mg/kg of body weight.
  • concentration of active compound in the formulation selected for administration is in many situations not critical. One can administer a larger quantity of a formulation having a relatively low concentration and achieve the same therapeutic or prophylactic dosage as a relatively small quantity of a relatively more
  • Unit dosage forms in accordance with this invention can have anywhere from less than 1 mg to 500 g of active compound per unit
  • the anthelmintic agents of this invention will find their primary use in the treatment and/or prevention of helminth parasitism in valuable warm-blooded domesticated animals such as sheep, cattle, horses, dogs, swine, goats and poultry, they are also effective in treatment that occurs in other warm blooded animals including man.
  • the compounds of Formula I can be used to treat various helminth diseases in humans, including those caused by Ascaris, Enterobius, Ancylostoma, Trichuris, Strongyloides, Fasciola, Taenia, and/or Onchocerca or other filariae at a dose of from 1 mg/kg to 300 mg/kg of body weight upon oral and/or parenteral administration.
  • Step 1 The starting ketone, 1,3-Cyclopentenedione, and ftiran (used as both reactant and solvent) are refluxed for 3 to 5 days to produce the Diels-Alder adduct, Figure A1.
  • 4-BromophenyIisocyanate (7.24 g, 36.5 mmol) is dissolved in tetrahydrofuran (15 mL) and added to a solution of 5-Hydroxy-10-oxa-tricyclo[5.2.1.0 2,6 ]deca-4,8-dien-3-one (6.00 g, 36.5 mmol) in tetrahydrofuran (40 mL).
  • Triethylamine 5.0 mL, 3-70 g, 36.5 mmol
  • the reaction mixture is concentrated in vacuo and the residue taken up in EtOAc (50 mL) and washed with 2N H 2 SO 4 (2 x 20 mL).
  • EXAMPLE AX11 8,9Dibromo-3-hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.0 2,6 ]dec-3-ene-4-car boxylic acid, 4-bromophenylamide.
  • a solution of diazomethane (CH 2 N 2 ) in Et 2 O (0.5 M, 80 mL, 40 mmol) is prepared as follows: 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) (6.00 g, 40.8 mmol) is added in several small portions with intervening swirling to a two-phase solution of KOH (24 mL, 45%) and Et 2 O (80 mL) maintained near 0°C in a scratch-free, rubber-stoppered, 250 mL Erienmeyer flask. When all the MNNG is added, the two-phase reaction mixture is intermittently swirled for two minutes.
  • MNNG 1-methyl-3-nitro-1-nitrosoguanidine
  • the upper-layer containing the diazomethane is dried by carefully decanting it into another scratch-free, rubber-stoppered, 250 mL, Erienmeyer flask containing several KOH pellets maintained near 0°C.
  • the flask is kept near 0°C and intermittently swirled for two minutes after which the diazomethane solution is either used or briefly stored at 0°C in a stoppered flask.
  • a portion of the diazomethane solution (40 mL, 0.5 M, 20 mmol) is added all at once to a solution of 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 4-bromophenylamide, Figure A2, (1.00 g, 2.76 mmol) in tetrahydrofuran (100 mL) at room temperature.
  • the reaction mixture is allowed to stand 6 minutes.
  • the reaction is quenched by adding glacial HO Ac (3 mL) causing instantaneous discharge of the yellow color.
  • the reaction mixture is concentrated in vacuo and the residue taken up in EtOAc (50 mL).
  • EXAMPLE AX15 3-Amino-5-oxo-10-oxa-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid. 4-bromophenylamide.
  • Anhydrous ammonia is slowly bubbled into a slurry of
  • a solution of n-butyllithium in hexane (190 mL, 1.6 M, 305 mmol) is added dropwise to a solution of diisopropylamine (43 mL, 30.8 g, 305 mmol) in dry tetrahydrofuran (200 mL) at 0°C.
  • the reaction mixture is stirred for 15 min, cooled to -78°C, and a solution of EtOAc (29.8 mL, 26.8 g, 305 mmol) in dry tetrahydrofuran (100 mL) added dropwise.
  • Powdered carbonyldiimidazole (643 mg, 3.96 mmol) is added in a single portion to a solution of 3-Ethoxycarbonylacetyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid.
  • EXAMPLE BX2 (1.00g, 3.96 mmol) in tetrahydrofuran (20 mL) and the mixture heated under reflux. In two hours evolution of CO 2 stops, and the reaction mixture is cooled to 0°C. A solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 7.9 mL, 7.93 mmol) is added dropwise. Stirring is continued at 0°C for 30 minutes and then overnight at room temperature.
  • EXAMPLE BX6 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 5-trifluoromethyI-[1,3,4]thiadiazol-2-ylamide. MP 156°C. Tan-colored powder from EtOAc- EXAMPLE BX7. 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid,
  • EXAMPLE BX10 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 4-methoxyphenyIamide. MP 138°C. Light-brown crystals from EtOAc/hexane.
  • EXAMPLE BX12 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 3,5-bis-trifluoromethylphenylamide. MP 159°C. Pale-yellow crystals from MeOH.
  • EXAMPLE BX13 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 2-fluorophenylamide. MP 131°C. White powder from MeOH.
  • EXAMPLE BX15 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 2-trifluoromethyIphenyIamide. MP 92°C. Pale-yellow powder from MeOH.
  • EXAMPLE BX16 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 2,6-difluorophenylamide. MP 177°C. White crystals from MeOH.
  • EXAMPLE BX17 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxyIic acid, 2,6-difluorobenzylamide. MP 113°C. Tan-colored powder from MeOH.
  • EXAMPLE BX18 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3.8-diene-4-carboxylic acid, 2,4,6-trifluorophenylamide. MP 190°C. White granular solid from MeOH/hexane.
  • EXAMPLE BX19 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 3,5-difluorophenylamide. MP 160°C. Pale-yellow powder from MeOH trituration.
  • EXAMPLE BX20 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 4-fluorophenyl amide. MP 131°C. White crystals from MeOH.
  • EXAMPLE BX21 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 9H-fluoren-2-ylamide. MP 238°C. Light-brown powder from MeOH trituration.
  • EXAMPLE BX23 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 9-oxo-9H-fluoren-2-ylamide. MP 230°C. Green-brown powder from MeOH trituration.
  • EXAMPLE BX24 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, biphenyl-4-ylamide. MP 174°C. White powder from MeOH trituration.
  • EXAMPLE BX25 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 2,2'-dimethylbiphenyl-4-ylamide. Tan-colored powder from MeOH.
  • EXAMPLE BX26 2-(N-(4-trifluoromethylphenyl)carbamoyl)-5H,6H-dibromo-4H,7H- methano-3-hydroxyinden-1-one. MP 221°C. Cream-colored powder from hexane trituration.
  • EXAMPLE BX27 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]dec-3-ene-4-carboxylic acid, 4-bromophenylamide. MP 156°C. Light-brown crystals from MeOH.
  • EXAMPLE BX28 3-Hydroxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxyIic acid, 4-aminophenylamide. MP 189°C. Pale-yellow solid from EtOAc trituration.
  • EXAMPLE BX29 3-Methoxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxyIic acid, ethyl ester. White crystals from pale-yellow oil.
  • EXAMPLE BX30 3-Methoxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, biphenyl-4-ylamide. MP 201°C. White crystals from MeOH. Following the general procedure of Preparation B4, above, plus preparation A8 from the CHART A reactions, except using the appropriate reactants, the following compounds, examples BX31 and BX32, are prepared.
  • EXAMPLE BX31 3-Methoxy-5-oxo-tricyclo[5.2.1.0 2,6 ]deca-3,8-diene-4-carboxylic acid, 4-trifluoromethylphenylamide. MP 190°C. White crystals from MeOH.
  • the ⁇ -ketoester acid, Figure C2 is converted to the ester, Figure C3, by heating with carbonyl diimidazole and potassium tert-butoxide in tetrahydrofuran at reflux.
  • EXAMPLE CX6 (2a.alpha., 3.beta., 3a.beta., 6a-beta., 7.beta., 7a.alpha.)-N-[[2-methyI- 4-(4-trifluoromethyl)phenoxy]phenyl]-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-etheno-3H- cyclobut[f]indene-5-carboxamide, MP 167°C. White powder from trituration with hot MeOH.
  • Preparations D2 through D5 are “series (a)" preparations.
  • Figure D3(a) Without purification the ⁇ -ketoester acid, Figure D3(a), from preparation D3, above, is converted to a cyclized ester by heating it with carbonyld ⁇ midazole and potassium tert-butoxide in tetrahydrofuran, the temperature should not be allowed to exceed 40°C.
  • Preparations D6 through D7 are “series (b)" preparations.
  • 6,6-DimethyIfulvene (5.00g, 47.1 mmol) is added to a solution of cyclopentenedione (2.26 g, 23.5 mmol) in EtO 2 (20 mL). The mixture is stirred for 6 days at room temperamre. chilled to 0°C for two hrs and then filtered.

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Abstract

This invention encompasses compounds of formula (I), wherein X is either -NH- or -O-; R1 is =O, -OH, -OCH3 or -NH2, R1 is =O when b is a double bond and when a is a single bond, when R1 is =O then R3 is -OH, -OCH3 or -NH2; R3 is =O, -OH, -OCH3 or -NH2, R3 is =O when a is a double bond and when b is a single bond, when R3 is =O then R1 is -OH, -OCH3 or -NH2; R2, R4, R5, R6, and R7 are substituted as described. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of formula (I) and a method of killing or controlling parasitic worms in humans and warm blooded domestic animals which comprises administering a therapeutic or prophylactic dosage of a compound of formula (I). Pharmacologically acceptable salts of formula (I) are also included as one aspect of this invention.

Description

ANTHELMINΗC β-KETOAMIDES
BACKGROUND OF THE INVENTION
The diseases or groups of diseases described generally as helminthiasis are due to infection of the animal with parasitic worms known as helminths. Helminthiasis and
helminthosis are prevalent and may lead to serious economic problems in valuable domestic warm-blooded animals such as sheep, swine, cattle, goats, dogs, cats, horses, poultry and man. Among the helminths, the groups of worms known as nematodes. trematodes and cestodes cause widespread and often-times serious infections in various species of animals including man. The most common genera of nematodes, trematodes and cestodes infecting the animals referred to above are Dictyocaulus, Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Bunostomum, Oesophagostomum , Chabertia, Strongyloides, Trichuris, Fasciola, Dicrocoelium, Enterobius, Ascaris, Toxascaris, Toxocara, Ascaridia, Capillaria, Heterakis, Ancylostoma,
Uncinaria, Dirofilaria, Onchocerca, Taenia, Moniezia, Dipylidium, Metastrongylus,
Triodontophorus, Macracanthorhynchus, Hyostrongylus, and Strongylus. Some of these genera attack primarily the intestinal tract while others inhabit the stomach, lungs, liver and
subcutaneous tissues. The parasitic infections causing helminthiasis and helminthosis lead to anemia, malnutrition, weakness, weight loss, unthriftiness, severe damage to the gastrointestinal tract wall and, if left to run their course, may result in death of the infected animals.
INFORMATION DISCLOSURE STATEMENT
Anthelmintic compounds which also contain a ketoamide structure are disclosed in US
Patent 3,746,765, and in Swedish patent 592,048.
SUMMARY OF THE INVENTION
This invention pertains to a new method for killing and controlling worms (Helminths), and new formulations for killing and controlling worms in animals, and new chemical compounds. The invention is more particularly directed to a new method for killing and controlling parasitic worms in animals with novel β-ketoamides, and to new anthelmintic formulations comprising the same.
The anthelmintic β-ketoamides have the general structure of Formula I.
This invention encompasses: 1) A compound of formula I
(Formula I)
Figure imgf000003_0001
wherein
each variable may be independent of the other variable unless indicated otherwise; the C-C bonds, a, b, and c, are single or double bonds;
either a or b are double bonds;
X is either -NH- or -O-;
R1 is =O, -OH, -OCH3 or -NH2,
R1 is =O when b is a double bond and when a is a single bond, when R1 is =O then R3 is -OH, -OCH3 or -NH2;
R3 is =O, -OH, -OCH3 or -NH2,
R3 is =O when a is a double bond and when b is a single bond, when R3 is =O then R1 is -OH, -OCH3 or -NH2;
Figure imgf000005_0001
R2-1, R2-2 and R2-3 are, each independently: H, Halogen, CF3, CN, NO2, OCH3, NH2, CI- C5 alkyl, or C1-C5 alkoxy;
n is 1 to 3,
R4 and R7 taken together are, -O-, -CH2-,
Figure imgf000006_0001
R5 is H, Halogen, or C1-C5 alkyl;
R6 is H, Halogen, or C1-C5 alkyl;
or
R5 and R6 taken together are
Figure imgf000006_0002
wherein
R5-1 is Halogen.
2) A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of formula I and 3) A method of killing or controlling parasitic worms in humans and warm blooded domestic animals which comprises administering a therapeutic or prophylactic dosage of a compound of formula I. The use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the killing or controlling parasitic worms in humans and warm blooded domestic animals. Pharmacologically acceptable salts of Formula I are also included as one aspect of this invention.
The anthelmintic agents of this invention will find their primary use in the treatment and/or prevention of helminth parasitism in valuable warm-blooded domesticated animals such as sheep, cattle, horses, dogs, swine, goats and poultry; they are also effective in treatment that occurs in other warm blooded animals including man.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention all possess a β-ketoamide (BKA) template. This β- ketoamide (BKA) template is then joined to one of four different components. The four components are: oxynorbomene BKAs (CHART A), norbomene BKAs (CHART B), tetracyclic BKAs (CHART C) and fulvene BKAs (CHART D). The compounds of this invention can be made in accordance with the processes illustrated in and the reactions related to CHARTS A, B, C, and D. The reactions are described in general teims immediately below, the detailed preparations are found at the end of this section, followed immediately by the CHARTS, which show the compound structures.
CHART A
Reactions of Chart A (oxynorbomene β-ketoamides)
Step 1. The starting ketone, 1 ,3-Cyclopentenedione, and furan (used as both reactant and solvent) are refluxed for 3 to 5 days to produce the Diels- Alder adduct, Figure A1. The compound of Figure A1 is stirred with various arylisocyanates and benzoylisocyanates in tetrahydrofuran at room temperature in the presence of an organic base to prepare the oxynorbomene BKAs of CHART A. Steps 2 through 4, below, provide several examples.
Step 2. The compound of Figure A1 and 4-bromophenylisocyanate gives Figure A2. From step 2, reactions may proceed in any of several directions; as shown by the following series of reactions.
Step 3(a), series (a), Bromine is added to the compound of Figure A2 in CCl4 to give the dibromo BKA, Figure A3(a).
Step 4(a), series (a). The reactions of Step 3(a) results in a mixture of cis-endo-, cis- exo-, and trans-dibromo isomers which can be subsequently dehydrobrominated (KOH/PTC- /EtOH/25°C/10 days) in Step 4(a) to give the compounds of Figure A4(a).
Step 3(b), series (b). The compound of Figure A2 is treated with dibromoformaldoxime and silver nitrate, to give the bromoisoxazoline, A3(b).
Step 3(c), series (c). Hydrogenation of the compound of Figure A2 produces Figure A3(c).
Step 3(d), series (d). Unlike an ordinary alcohol, reaction of the compounds of Figure A2 with diazomethane readily produces the vinylogous ester, Figure A3(d).
Step 4(d), series (d). The compounds of Figure A3(d), the vinylogous ester, reacts with ammonia to form the vinylogous amide, Figure A4(d).
CHART B
Reactions of Chart B (norbomene β-ketoamides) Step 1. The Diels- Alder reaction between freshly distilled cyclopentadiene and maleic anhydride (Et2O/25º) produces the endo-adduct the compound represented by Figure B 1 (endo- not shown in figure).
Step 2. Reaction of the compound of Figure B 1 with ethyl lithioacetate gives Figure B2 as a mixture of stereoisomers.
Step 3. The compound represented by Figure B2 is converted to the ester, Figure B3. by treating it with carbonyl diimidazole and potassium tert-butoxide in tetrahydrofuran at reflux. Pure endo isomer of the compound of Figure B3 was produced by trituration with and partial recrystallization from boiling hexane.
Step 4. The norbomene BKAs of CHART B are then prepared by simply combining the compound of Figure B3 with an aromatic amine in toluene and heating the mixture under reflux. For example, the compound of Figure B4, is prepared from the ester, Figure B3, and 2- fluoroaniline.
Additional reactions can be performed on the norbomene BKAs themselves. They can be brominated and hydrogenated. The enolic hydroxyl group found in these BKAs, similar to the oxynorbomene BKAs, is very acidic and is best viewed as a vinylogous acid. They can be treated with diazomethane, to give the vinylogous ester. Treatment of the vinylogous ester with methanolic ammonia forms the vinylogous amide.
CHART C
Reactions of Chart C (tetracyclic β-ketoamides)
Step 1. Cyclooctatetraene and maleic anhydride are heated under reflux, in toluene, to give the anhydride. Figure C1.
Step 2. Reaction of the anhydride. Figure C1, with ethyl lithioacetate in tetrahydrofuran at -78°C gives the β-ketoester-acid, Figure C2.
Step 3. The β-ketoester-acid, Figure C2, is converted to the ester, Figure C3, by heating it with carbonyl diimidazole and potassium tert-butoxide in tetrahydrofuran at reflux.
Step 4. The ester, Figure C3, is heated with an aromatic amine such as 4-bromoaniline in toluene at reflux to obtain the compounds of Figure C4.
Other tetracyclic β-ketoamides are similarly prepared.
CHART D
Reactions of Chart D (fulvene β-ketoamides)
Step 1. Figure D-1, 6,6-dimethylfulvene, is prepared by stirring a methanol solution of freshly distilled cyclopentadiene with acetone in the presence of pyrrolidine.
Step 2(a), Series (a). The compound of Figure D2(a) is obtained as a 2:1 mixture of exo- and endo-isomers by refluxing the compound of Figure D1 and maleic anhydride in ether overnight. Step 3(a), Series (a). The compound of Figure D2(a) is treated with ethyl lithioacetate at -78°C to give the β-ketoester-acid, Figure D3(a), as a yellow oil containing several impurities.
Step 4(a), Series (a). Without purification, the β-ketoester. Figure D3(a) is converted to the cyclized ester, Figure D4(a), by heating it with carbonyldiimidazole and potassium tert- butoxide in tetrahydrofuran.
Step 5(a), Series (a). The cyclized ester, Figure D4(a), is reacted with aryl amines to produce the BKAs. One BKA is the compound of Figure D5(a), produced by heating the ester, Figure D4(a) with 4-bromoaniline in toluene under reflux to give the compound of Figure D5(a).
An alternate strategy may also be used. (Chart D, page 1)
Step 2(b), Series (b). Stirring the compound of Figure D1, the fulvene, with cyclopen- tenedione in ether at 25°C for six days gives the compound of Figure D2(b).
Step 3(b), Series (b). Treating the compound of Figure D2(b) with an isocyanate such as 4-bromophenylisocyanate under the same reaction conditions used for the oxynorbomenes (CHART A), gives the compound of Figure D3(b).
Following the general procedures from above, specific compounds can be prepared. At the end of this section detailed preparations/examples describe how to prepare various β- ketoamides of the invention. The detailed procedures are followed by CHARTS and TABLES.
The utility of the compounds of this invention are demonstrated by their activity in biological screens. The results of two screens, or assays, can be found in Table 1.
The left column of TABLE 1 identifies the compounds according to the EXAMPLE number. The EXAMPLE number corresponds to the EXAMPLE numbers in the detailed synthesis below. The other columns of TABLE 1 show the results of the two assays which are described below.
ASSAY No. 1 This assay uses cultures of Caenorhabditis elegans maintained in a culture grown in McArtney bottles at 20°C in 10cm3 of a thymidine-fortified broth containing 10 g Bactotryptone, 5 g Oxoid yeast extract, 10 mg cysteine and 5 mg thymidine dm-3. Worms for the test are washed from 4-8 day old cultures. Test medium was made by adding 10 cm3 of well-grown Escherichia coli (3-5 days) to 100 cm3 M9 buffer plus 5 mg ampicillin and 10 000 Units nystatin. (The M9 buffer is described in Brenner, S. Genetics, 1974, Vol. 77, p. 71.) After 2 hours at room temperature, 2 cm3 of the test medium was placed in each well of a Sterilin Repli Dish (Catalogue number 103) and 10 υl of dimethyl sulphoxide solution of chemical added to each well. One drop of worm suspension containing 10-20 worms of mixed age was added to each well and the plates were incubated at 20°C for 7 days.
After 7 days the plates were viewed under a binocular microscope and assessed for number of worms present A dose level of 50 parts per million (PPM) was chosen for the screen. A score of any number greater than zero suggests activity. A score of 5 means that no live worms were present at the time of scoring. Assay No. 1 is completely described in: K-
Simpkin and G. Coles. J. Chem. Tech. Biotechnol. (1981), Vol. 31, p. 66-69.
ASSAY No. 2 This assay uses jirds, Meriones unguiclatus, infected with both
Haemonchus contortus and Trichostrongylus colubriformis. Female jirds weighing 30-35 g were obtained and put on a diet of commercial rodent chow containing 0.02 percent hydrocortisone for the duration of the study. All jirds were inoculated with approximately 1,000 exsheathed infective larvae each of H. contortus and T. colubriformis 5 days after the animals had been placed on medicated feed. Treatments were made 10 days post inoculation (PI). On day 13 PI,
3 days post treatment the jirds were killed, their stomachs and small intestines removed and examined for worms. The percent reduction in treated relative to the controls is provided in the
Table. Assay No. 2 is completely described in: G. A. Conder, et- al., J. Parasitology, Vol.
77(4) (1991), pl 621-623.
The preferred compounds of this invention are:
EXAMPLE (AX12) 8-Bromo-3-hydroxy-5-oxo-10-oxa- -tricyclo[5.2.1.02,6]dec-3,8-diene-4-carboxyIic acid, 4-bromophenylamide;
EXAMPLE (BX5) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
EXAMPLE (BX7) 3-Hydroxy-S-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene- 4-carboxylic acid,
4-trifluoromethylphenylamide;
EXAMPLE (BX12) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3,5-bis-trifluoromemylphenylamide;
EXAMPLE (BX22) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
7-bromo-9H-fluoren-2-ylamide;
EXAMPLE (BX24) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, biphenyI-4-ylamide;
EXAMPLE (BX26) 2-(N-(4-trifluoromethylphenyI)carbamoyl)-5H,6H-dibromo-4H,7H- methano-3-hydroxy-inden- 1-one;
EXAMPLE (BX27) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxylic acid
4-bromophenyIamide;
EXAMPLE (CX1) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a-alpha-)-N-(4- bromophenyl)-2a,3a-4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]mdene-5- carboxamide,
EXAMPLE (CX6) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-[[2-methyl-4-
(4-trifIuoromethyI)phenoxy]phenyl]-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-etheno-3H- cyclobut[f]indene-5-carboxamide.
EXAMPLE (DX1) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene -4-carboxylic acid, 4-bromophenylamide;
EXAMPLE (DX2) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-
-4-carboxylic acid, 4-trifluoromethylphenylamide.
Some of the compounds of this invention are useful as intermediates in the synthesis of active compounds. Some compounds may be both active and useful as an intermediate. Some of the useful intermediates are:
BX2 3-Ethoxycarbonylacetyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid;
BX4 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, ethyl ester;
BX29 3-Methoxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, ethyl ester, CX7 8-(2-ethoxycarbonyl-acetyl)-tricyclo[4.2.2.0 2,5]deca-3,9-diene-7-carboxylic acid;
CX8
Figure imgf000011_0001
DX6 3-(2-ethoxycarbonyl-acetyl)-7-isopropylidene-bicyclo[2.2.1 ]hept-5-ene-2-carboxylic acid; DX7 3-hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.0 2,6]deca-3,8-diene-4-carboxylic acid ethyl ester.
The compounds of this invention are identified in two ways: by the descriptive name and reference to labeled structures contained in appropriate charts and tables. Occasionally the proper stereochemistry is also represented in the charts. In this document the parenthetical term (Cn-Cm) is inclusive such that a compound of (C1-C8) would include compounds of one to 8 carbons and their isomeric forms. The various carbon moieties are defined as follows: Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n- hexyl, isohexyl, and n-octyl. Halogen or halo is fluoro, chloro, bromo, iodo or trifluoromethyl. THF is tetrahydrofuran. EtOH is ethanol. EtOAc is ethyl acetate. Et2O is diethyl ether. KOH is potassium hydroxide. PTC is Phase Transer Catalyst, in these reactions the PTC usually used is benzyltriethylammonium chloride. C is carbon. H is hydrogen O is oxygen. OH is hydroxy. =O is carbonyl. NMR is Nuclear Magnetic Resonance. PPM is parts per million. °C is degree centigrade. L is liter. mL is milliliter. M or mol is mole. mM is milliMole. g is gram. mg is milligram, min is minute.
The compounds of this invention can be used as the pure compounds or as mixtures of pure compounds but for practical reasons the compounds are preferably formulated as anthelmintic compositions and administered as a single or multiple dose, alone or in
combination with other anthelmintics (e.g. avermectins, benzimidazoles, levamisole, praziquantel, etc.). For example, aqueous or oil suspensions can be administered orally, or the compounds can be formulated with a solid carrier for feeding. Furthermore, an oil suspension can be converted into an aqueous emulsion by mixing with water and injecting the emulsion intramuscularly, subcutaneously or into the peritoneal cavity. In addition, the active
compound(s) can be administered topically to the animal in a conventional pour-on formulation.
Pure compounds, mixtures of the active compounds, or combinations thereof with a solid carrier can be administered in the animal's food, or administered in the form of tablets, pills, boluses, wafers, pastes, and other conventional unit dosage forms, as well as sustained release dosage forms which deliver the active compound over an extended period of days, weeks or months. All of these various forms of the active compounds of this invention can be prepared using physiologically acceptable carriers and known methods of formulation and manufacture.
Representative solid carriers conveniently available and satisfactory for physiologically acceptable, unit dosage formulations include com starch, powdered lactose, powdered sucrose, talc, stearic acid, magnesium stearate, finely divided bentonite, and the like. The active agent can be mixed with a carrier in varying proportions from, for example, about 0.001 percent by weight in animal feed to about 90 or 95 percent or more in a pill or capsule. In the latter form, one might use no more carrier than sufficient to bind the particles of active compound.
In general, the compounds can be formulated in stable powders or granules for mixing in an amount of feed for a single feeding or enough feed for one day and thus obtain therapeutic efficacy without complication. It is the prepared and stored feeds or feed premixes that require care. A recommended practice is to coat a granular formulation to protect and preserve the active ingredient. A prepared sheep-feed containing about 0.2 percent of the active compound will provide a dosage of about 100 mg per kg body weight for each 100 lb sheep in its daily ration.
A solid diluent carrier need not be a homogeneous entity, but mixtures of different diluent carriers can include small proportions of adjuvants such as water; alcohols; protein solutions and suspensions like skimmed milk; edible oils; solutions, e.g., syrups; and organic adjuvants such as propylene glycols, sorbitol, glycerol, diethyl carbonate, and the like.
The solid carrier formulations of the inventions are conveniently prepared in unit dosage forms, to facilitate administration to animals. Accordingly, several large boluses (about 20 g weight) amounting to about 54 g of active compound would be required for a single dosage to a 900 lb horse at a dosage rate of 50 mg/kg of body weight. Similarly, a 60 lb lamb at a dosage rate of 100 mg/kg of body weight would require a pill, capsule, or bolus containing about 2.7 g of active compound. A small dog, on the other hand, weighing about 20 lbs. would require a total dosage of about 225 mg at a dosage rate of 25 mg/kg of body weight The solid, unit dosage forms can be conveniently prepared in various sizes and concentrations of active ingredient to accommodate treatment of the various sizes of animals that are parasitized by worms.
Liquid formulations can also be used. Representative liquid formulations include aqueous (including isotonic saline) suspensions, oil solutions and suspensions, and oil in water emulsions. Aqueous suspensions are obtained by dispersing the active compound in water, preferably including a suitable surface-active dispersing agent such as canonic, anionic, or nonionic surface-active agents. Representative suitable ones are polyoxyalkylene derivatives of fatty alcohols and of sorbitan esters, and glycerol and sorbitan esters of fatty acids. Various dispersing or suspending agents can be included and representative ones are synthetic and natural gums, tragacanth. acacia, alginate, dextran, gelatin, sodium carboxymethylcellulose, methylcellulose, sodium polyvinylpyrrolidone, and the like. The proportion of the active compound in the aqueous suspensions of the invention can vary from about 1 percent to about 20 percent or more.
Oil solutions are prepared by mixing the active compound and an oil, e.g. an edible oil such as cottonseed oil, peanut oil, coconut oil, modified soybean oil, and sesame oil. Usually, solubility in oil will be limited and oil suspensions can be prepared by mixing additional finely divided compound in the oil.
Oil in water emulsions are prepared by mixing and dispersing an oil solution or suspension of the active compound in water preferably aided by surface-active agents and dispersing or suspending agents as indicated above.
In general, the formulations of this invention are administered to animals so as to achieve therapeutic or prophylactic levels of the active compound. Effective dosages of various compounds are contemplated, e.g., in the range of 1 to 75 mg/kg of body weight.
In other animals, and for other kinds of parasitic worms, definitive dosages can be proposed. Contemplated are dosage rates of about 1 mg to about 800 mg/kg of body weight. A preferred, contemplated range of dosage rates is from about 1 mg to about 50 mg/kg of body weight. In this regard, it should be noted that the concentration of active compound in the formulation selected for administration is in many situations not critical. One can administer a larger quantity of a formulation having a relatively low concentration and achieve the same therapeutic or prophylactic dosage as a relatively small quantity of a relatively more
concentrated formulation. More frequent small dosages will likewise give results comparable to one large dose. One can also administer a sustained release dosage system (protracted delivery formulation) so as to provide therapeutic and/or prophylactic dosage amounts over an extended period. Unit dosage forms in accordance with this invention can have anywhere from less than 1 mg to 500 g of active compound per unit Although the anthelmintic agents of this invention will find their primary use in the treatment and/or prevention of helminth parasitism in valuable warm-blooded domesticated animals such as sheep, cattle, horses, dogs, swine, goats and poultry, they are also effective in treatment that occurs in other warm blooded animals including man. The optimum amount to be employed for best results will, of course, depend upon the particular compound employed, species of animal to be treated, the regimen of treatment and the type and severity of helminth infection. Generally good results are obtained with compounds of Formula I by the oral or parenteral route of administration of about 1 to 300 mg/kg of animal bodyweight (such total dose being given at one time, in a protracted manner or in divided doses over a short period of time such as 1-4 days). The technique for administering these materials to animals are known to those skilled in the veterinary and medical fields.
It is contemplated that the compounds of Formula I can be used to treat various helminth diseases in humans, including those caused by Ascaris, Enterobius, Ancylostoma, Trichuris, Strongyloides, Fasciola, Taenia, and/or Onchocerca or other filariae at a dose of from 1 mg/kg to 300 mg/kg of body weight upon oral and/or parenteral administration.
Below are detailed preparations and examples that describe how to prepare various β- ketoamids of the invention. The procedures are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. One skilled in the art will recognize that the compounds represented by formula I can exist in one of two tautomeric forms, the enol or keto form. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants as well as to reaction conditions and techniques- Table II provides a summary of the EXAMPLE numbers, their chemical structures and their names.
CHART A REACTIONS PREPARATIONS FOR CHART A (oxynorbomene β-ketoamides)
Preparation A1. See CHART A, Step 1, Figure A1.
Step 1. The starting ketone, 1,3-Cyclopentenedione, and ftiran (used as both reactant and solvent) are refluxed for 3 to 5 days to produce the Diels-Alder adduct, Figure A1.
Preparation A2. See CHART A, Step 2, Figure A2.
EXAMPLE AX1. 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-bromophenylamide.
4-BromophenyIisocyanate (7.24 g, 36.5 mmol) is dissolved in tetrahydrofuran (15 mL) and added to a solution of 5-Hydroxy-10-oxa-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one (6.00 g, 36.5 mmol) in tetrahydrofuran (40 mL). Triethylamine (5.0 mL, 3-70 g, 36.5 mmol) is added and the reaction mixture stirred at room temperature for 3 hr. The reaction mixture is concentrated in vacuo and the residue taken up in EtOAc (50 mL) and washed with 2N H2SO4 (2 x 20 mL). The organic phase is dried (Na2SO4) and concentrated in vacuo to a light, orange-brown powder. This is triturated with boiling MeOH (partial recrystallization). allowed to cool, filtered, and air dried to give 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3.8-diene-4-carboxylic acid.
4-bromophenylamide as a light tan-colored crystalline solid. A further recrystallization from dilute MeOH gives a white crystalline solid: mp 180 °C; 1Η NMR (300 MHz, CDCl3) δ 2.72 (d, J = 5.3 Hz, 1 H), 3.01 (d, J = 5.4 Hz, 1 H), 3.70 (broad s, 1H), 5.14 (s, 1 H), 6.54 (d, J = 1.8 Hz, 1 H), 7.48 (s, 4 H), 9.57 (s, 2 H). MS(EI) m/e 361 (M+), 363. IR (cm-1, nujol): 1667, 1606. Anal. Calcd for C16H12BrNO4: C, 53.06; H, 3.34; N, 3.87. Found: C, 52.44; H, 3.23; N, 4.71.
Following the general procedure of Preparation A2, above, except using the appropriate reactants, the following compounds are prepared.
EXAMPLE AX2. N-(3-Hydroxy-5-oxo-10-oxa- tricycIo[5.2.1.02,6]deca-3,8-diene-4-carbonyl)benzamide. MP 195°C. White solid from MeOH.
EXAMPLE AX3.
3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide MP 182°C. White crystals from MeOH.
EXAMPLE AX4.
3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid phenylamide. MP 148°. White solid from MeOH.
EXAMPLE AX5.
3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-fluorophenylamide. MP 165°C. White solid from MeOH.
EXAMPLE AX6.
3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-chlorophenylamide. MP 180°C. White powder from MeOH.
EXAMPLE AX7.
3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,6-dichlorophenylamide. MP 191°C. White powder from MeOH.
EXAMPLE AX8.
3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3,5-dichlorophenylamide. MP 203°C. White powder from MeOH.
EXAMPLE AX9.
3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,6-difluorophenylamide. MP 195°C. White powder from MeOH.
Preparation A3. See CHART A, Step 3, series a, page 1, Figure A3(a).
EXAMPLE AX11. 8,9Dibromo-3-hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3-ene-4-car boxylic acid, 4-bromophenylamide.
Bromine (49λ, 154 mg, 0.96 mmol) is added to a solution of
3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid.
4-bromophenylamide, Figure A2. (348 mg. 0.96 mmol) in CHCl3 (25 mL). The reaction mixture is stirred overnight at room temperature and then concentrated in vacuo to a tan-colored solid. This is triturated with Et2O to give the title compound, (mixture of cis-endo-, cis-exo-, and trans-dibromoisomers) as an off-white powder- mp 212 °C; 1H NMR (300 MHz, CDCI3) δ 2-81 (d, J = 6 Hz, 0.29 H), 2.88 (d, J = 5.8 Hz, 0.37 H), 3.11 (d, J = 6 Hz, 0.29 H), 3.18 (d, J = 5-9 Hz, 0.34 H), 3.57 (d. J = 5.8 Hz, 0.34 H), 3.91 (d, J = 5.8 Hz, 0.37 H), 3.98 (d, J = 3-1 Hz, 0-34 H), 4.01 (d, J = 3-1 Hz, 0.34 H), 4.35 (s, 0.58 H), 4.42 (m, 0.74 H), 4.78 (m, 0-68 H), 4-85 (m, 0.74 H), 4-90 (d, 0.58 H), 6.82 (broad s, 1H), 7.48 (s, 4H), 9.49 (s, 1H). MS(EI) m/e 519 (M+), 521, 523, 525. Anal. Calcd for C16H12Br3NO4: C, 36.82; H, 2.32; N, 2.68. Found: C, 37-03; H, 2.35; N, 3.05.
Preparation A4. See CHART A, Step 4, series (a), page 2, Figure A4(a).
EXAMPLE AX12. 8-Bromo-3-hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3- ,8-diene-4-carboxyIic acid, 4-bromophenylamide
Potassium hydroxide (1 mL, 45%) is added to a solution of 8,9-Dibromo-3-hydroxy-5-- oxo-10-oxa-tricyclo[5-2.1.02,6]dec-3-ene-4-carboxylic acid 4-bromophenylamide (60 mg, 0.12 mmol) and benzyltriethylammonium chloride (~7 mg) in EtOH (4 mL). The reaction mixture is stirred at room temperature for 10 days during which time the initially turbid reaction mixture becomes completely clear. The reaction mixture is concentrated in vacuo and the residue taken up in H2O (5 mL). The strongly alkaline mixture is acidified with dilute H2SO4 to pH 1 and extracted with EtOAc. The organic phase is dried (Na2SO4) and concentrated in vacuo to give the title compound as a pale-yellow powder. 1H NMR (300 MHz, CDCl3, both keto-enol isomers are seen on the NMR time-scale) δ 2.85 (d, J = 5.4 Hz, 0.5 H), 2.90 (d, J = 5.4, 0.5 H), 3-15 (d, J = 5.3 Hz, 0.5 H), 3.19 (d, J = 5.4 Hz, 0.5 H), 4.96 (s, 1 H), 5.13 (s, 1 H), 6.54 (s, 0.5 H), 6.56 (s, 1 H), 7.47 (s, 4 H), 8.5 (broad s, 1 H), 9.51 (s, 1 H). MS(EI) m/e 439 (M+), 441, 443. Anal. Calcd for C16H11Br2NO4: C, 43.57; H, 2.51; N, 3.18- Found: C, 43.31; H, 3.01; N, 3.00.
Preparation A5. See CHART A, Step 3, series (b), page 3, Figure A3(b).
EXAMPLE AX10. 3-bromo-N-(4-bromophenyl)-3a,4a,7,7a-8,8a-hexahydro-5-hydroxy-7-oxo- 4,8-Epoxy-4H-indeno[5,6-d]isoxazoIe-6-carboxamide,
A solution of AgNO3 (281 mg, 1.66 mmol) in H2O (1.5 mL) is added dropwise over a period of 60 min to a solution of 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02-6]deca-3,8-diene- -4-carboxylic acid, 4-bromophenylamide (Figure A2, EXAMPLE AX1) (300 mg, 0.828 mmol) and dibromoformaldoxime (336 mg, 1.66 mmol) in tetrahydrofuran (20 mL) at 25°C with vigorous stirring. The reaction mixture is stirred another 60 min and then diluted with EtOAc (150 mL) and filtered. The filtrate is washed repeatedly with H2O until the washings are no longer acidic. The organic phase is given a final wash with saturated brine and dried (N a2SO4). Concentration in vacuo gives a solid which is triturated with boiling MeOH, cooled, filtered, and air-dried to give the title compound (282 mg, 70%) as an off-white, powdery solid consisting of a 1:1 mixture of exo-cis-exo (shown) and endo-cis-exo-isomers: mp 162 °C; 1H NMR (300 MHz, CDCl3) δ 2.73 (d, J = 6 Hz, 0.5H), 2.81 (d, J = 6 Hz, 0.5 H), 3.01 (d. J = 6 Hz, 0.5 H). 3.10 (d, J = 6 Hz, 0.5 H), 3.70-3.74 (m, 1 H), 4.98 (m, 3 H), 5.50 (broad s, 2H), 7.48 (s, 4 H), 9.50 (broad s, 1 H). MS(EI) m/e 482 (M+), 484. IR (cm-1, nujol): 1698. Anal. Calcd for C17H12Br2N2O5: C, 42.18; H. 2.50; N, 5.79. Found: C, 42.02; H, 2.58; N, 5.93.
Preparation A6. See CHART A, Step 3, series (c), page 4, Figure A3(c).
EXAMPLE AX13. 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxylic acid. 4-bromophenylamide.
Ten percent palladium on charcoal (100 mg) is added to a solution of
3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid
4-bromophenylamide, Figure A2, (2.00 g, 5.52 mmol) in tetrahydrofuran (200 mL) and the mixture shaken for 60 min with H2 (40 psia). The reaction mixture is flushed with N2, filtered through celite, and the filtrate concentrated in vacuo. The residue is triturated with boiling MeOH, cooled, filtered, and air-dried to give the title compound as a tan-colored, crystalline solid: mp 193 °C; 1H NMR (300 MHz, CDCl3) δ 1.63 (m, 2 H), 1.87 (m, 2 H), 2.71 (d, J = 5.67 Hz, 1 H), 3.00 (d, J = 5.69 Hz, 1H), 4.75 (m, 2 H), 6.77 (broad s, 2 H), 7.46 (m, 4H), 9.66 (broad s, 1 H). MS(EI) mle 363 (M+), 365. Anal. Calcd for C16H14BrNO4: C, 52.77; H, 3.88; N, 3.85. Found: C, 52.30; H, 3.63; N, 4.03.
Preparation A7. See CHART A, Step 3, series (d), page 5, Figure A3(d).
EXAMPLE AX14. 3-Methoxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-bromophenylamide.
A solution of diazomethane (CH2N2) in Et2O (0.5 M, 80 mL, 40 mmol) is prepared as follows: 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) (6.00 g, 40.8 mmol) is added in several small portions with intervening swirling to a two-phase solution of KOH (24 mL, 45%) and Et2O (80 mL) maintained near 0°C in a scratch-free, rubber-stoppered, 250 mL Erienmeyer flask. When all the MNNG is added, the two-phase reaction mixture is intermittently swirled for two minutes. The upper-layer containing the diazomethane is dried by carefully decanting it into another scratch-free, rubber-stoppered, 250 mL, Erienmeyer flask containing several KOH pellets maintained near 0°C. The flask is kept near 0°C and intermittently swirled for two minutes after which the diazomethane solution is either used or briefly stored at 0°C in a stoppered flask.
A portion of the diazomethane solution (40 mL, 0.5 M, 20 mmol) is added all at once to a solution of 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-bromophenylamide, Figure A2, (1.00 g, 2.76 mmol) in tetrahydrofuran (100 mL) at room temperature. The reaction mixture is allowed to stand 6 minutes. The reaction is quenched by adding glacial HO Ac (3 mL) causing instantaneous discharge of the yellow color. The reaction mixture is concentrated in vacuo and the residue taken up in EtOAc (50 mL). The resulting solution is washed with 1 N NaOH (2 x 50 mL), samrated NaCl (20 mL), dried (Na2SO4), and concentrated in vacuo to a clear, yellow oil containing some solid. This is taken up in boiling MeOH, cooled, and filtered to give the title compound as an off-white, crystalline solid: mp 159 °C; 1H NMR (300 MHz, DMSO-D6) δ 2.73 (d, J = 5.5 Hz, 1 H). 3.24 (d, J = 5.5 Hz. 1 H). 4.32 (s, 3 H), 5.10 (s, 1 H), 5.12 (s, 1 H), 6.52 (dd, J = 1.3 Hz, 5-6 Hz, 1 H), 6.58 (dd, J = 1-3 Hz, 5.8 Hz, 1 H), 7.44 (m, 4 H), 10.3 (s, 1 H). MS(EI) m/e 375 (M+), 377. Anal. Calcd for C16H11F2NO4: C, 54.28; H, 3.75; N, 3.75. Found: C, 53.21; H, 3.65; N, 4.05.
Preparation A8. See CHART A, Step 4, series (d), page 5, Figure A4(d).
EXAMPLE AX15. 3-Amino-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid. 4-bromophenylamide.
Anhydrous ammonia is slowly bubbled into a slurry of
3-met hoxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-bromo-phenyI- amide, Figure A3(d), (300 mg, 0.797 mmol) in MeOH (15 mL) at room temperature during 15 min. The temperature of the reaction mixture rose to 40°C and then subsided. Stirring, is continued for another 30 min. and the reaction mixture concentrated in vacuo to a solid. This is triturated with boiling MeOH, chilled, filtered, and air-dried to give the title compound as a white powder mp 238 °C; 1H NMR (300 MHz, CDCl3) δ 2.35 (m, 1 H), 2.66 (d, J = 5.8 Hz, 1 H), 4.81 (s, 2 H), 6.22 (d. J = 5.8 Hz, 1 H), 6.26 (d, J = 5.8 Hz, 1 H). 7.13 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.4 Hz, 2 H). 8.56 (m, 2 H ), 10.2 (s, 1 H). MS(EI) m/e 360 (M+), 362. Anal. Calcd for C16HI3BrN2O3: C, 53.21; H, 3.63; N, 7.76. Found: C, 51.89; H, 3.58; N, 7.64.
CHART B REACTIONS
PREPARATIONS FOR CHART B (norbomene β-ketoamides) Preparation B1. See CHART B, Step 1, Figure B1.
EXAMPLE BX1 - not claimed.
Freshly distilled cyclopentadiene and maleic anhydride (Et2O/25ºC) undergo a Diels- Alder reaction to produce the compound shown in Figure B1.
Preparation B2 See CHART B, Step 2, Figure B2.
EXAMPLE BX2. 3-Ethoxycarbonylacetyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid.
A solution of n-butyllithium in hexane (190 mL, 1.6 M, 305 mmol) is added dropwise to a solution of diisopropylamine (43 mL, 30.8 g, 305 mmol) in dry tetrahydrofuran (200 mL) at 0°C. The reaction mixture is stirred for 15 min, cooled to -78°C, and a solution of EtOAc (29.8 mL, 26.8 g, 305 mmol) in dry tetrahydrofuran (100 mL) added dropwise. After stirring 15 min, a solution of EXAMPLE BX1, (25.0 g, 152 mmol) in dry tetrahydrofuran (400 mL) is added dropwise. The reaction mixture is stirred for 2 hrs at -78ºC, the reaction is then quenched by adding glacial HOAc (38 mL) all at once, and the mixture allowed to warm to room
temperature. Concentration in vacuo gave a milky oil. This is taken up in water (800 mL), and crushed ice added to reduce the temperature to≤10°C. The mixture is acidified to pH 1 by adding 6N H2SO4 and then extracted with EtOAc (2 x 400 mL). The extracts are combined, dried (Na2SO4), and concentrated in vacuo. Residual HOAc is removed azeotropically by in vacuo concentration from toluene (2 x 200 mL) to give a light-yellow, turbid oil. This is crystallized from toluene (100 mL) by allowing the solution to stand overnight at room temperature. The crystals are washed with hexane and air-dried to give the title compoimd, a mixture of diastereomers, as large, white, dense crystals: mp 91 °C; 1H NMR (300 MHz, CDCl3) δ 1.30 (m, 3 H), 1.41 (d, J = 8.5 Hz, 0.5 H), 1.47 (d, J = 8.5 Hz, 0.5 H). 1.58 (d, J = 8.1 Hz, 0.5 H), 1.67 (d, J = 8.5 Hz, 0.5 H), 2.76 (q, J = 16.5 Hz, 2 H), 3.04 (m, 1 H), 3.11 (s, 0.5 H), 3.18 (s, 0.5 H), 3.28 (s, 1 H), 3.45 (m, 0.5 H), 3.54 (m, 0.5 H), 4.21 (m, 2 H), 6.22 (m, 2 H). MS(EI) m/e 252 (M+). Anal. Calcd for C13H16O5: C, 61.90; H, 6.39; N, 0.00. Found: C, 61.63; H, 6.53; N, 0.19.
Preparation B3. See CHART B, Step 3, page 2, Figure B3.
EXAMPLE BX4. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, ethyl ester.
Powdered carbonyldiimidazole (643 mg, 3.96 mmol) is added in a single portion to a solution of 3-Ethoxycarbonylacetyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid. EXAMPLE BX2, (1.00g, 3.96 mmol) in tetrahydrofuran (20 mL) and the mixture heated under reflux. In two hours evolution of CO2 stops, and the reaction mixture is cooled to 0°C. A solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 7.9 mL, 7.93 mmol) is added dropwise. Stirring is continued at 0°C for 30 minutes and then overnight at room temperature. The mixture is concentrated in vacuo and the residue taken up in 2N H2SO4 (50 mL). This is extracted with EtOAc (2 x 30 mL), and the extracts combined, dried (Na3SO4), and concentrated in vacuo to a clear, light-yellow oil. This is triturated in a small amount of n-hexane at room
temperature, filtered, and air-dried to give the title compoimd as a white powder: mp 133 °C; 1H NMR (300 MHz, CDCl3) δ 1.37 (t, J = 7.2 Hz, 3 H), 1.58 (d, J = 8.6 Hz, 1 H), 1.78 (d, J = 8.6 Hz, 1 H), 3.19 (broad s, 2 H), 3.27 (s, 2 H), 4.35 (q, J = 7.2 Hz, 2 H), 6.01 (s, 2 H). 13C NMR (75 MHz, CDCl3) δ 13.8, 43.9, 52.1, 61.1, 109.5, 133 (broad), 167.7, 198 (broad). MS (EI) m/e 234 (M+). Anal. Calcd for C13H14O4: C, 66.66; H, 6.03; N, 0.00. Found: C, 66.32; H, 5.94; N, 0.38.
Preparation B4. See CHART B, Step 4, page 4, Figure B4.
EXAMPLE BX5. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-cartoxylic acid, 4-bromophenylamide.
3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6] deca-3,8-diene-4-carboxylic acid, ethyl ester, EXAMPLE BX4, Figure B3, (213 mg. 0.909 mmol) and 4-bromoaniline (156 mg. 0.909 mmol) are combined with toluene (5 mL). and the mixture heated under reflux for 90 minutes. The reaction mixture is concentrated in vacuo and the residue crystallized from n-hexane to give the title compound (134 mg, 41%) as a white crystalline solid: 1H NMR (300 MHz, CDCI3) δ 1.63 (d, J = 8.5 Hz, 1 H), 1.84 (d, J = 8.7 Hz, 1 H), 3.12 (dd, J = 6.13 Hz, 4.50 Hz, 1 H), 3.28 (m, 2 H), 3.40 (dd, J = 6.24 Hz, 4.39 Hz, 1 H), 5.98 (s, 1H), 6.04 (s, 1H), 7.46 (m, 4 H). MS (EI) m/e 359 (M+), 361. Anal. Calcd for C17H,4BrNO3: C, 56.69; H, 3.92; N, 3.89. Found: C, 56-42; H, 3-76; N, 3.69.
Following the general procedure of Preparation B4, above, except using the appropriate reactants, the following compounds are prepared.
EXAMPLE BX6. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 5-trifluoromethyI-[1,3,4]thiadiazol-2-ylamide. MP 156°C. Tan-colored powder from EtOAc- EXAMPLE BX7. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide. MP 171°C. White crystals from EtOAc/hexane.
EXAMPLE BX8. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid, 4-cyanophenylamide. MP 216°C. White crystals from EtOAc.
EXAMPLE BX9. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-nitrophenylamide. MP 206°C. Off-white crystals from EtOAc.
EXAMPLE BX10. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-methoxyphenyIamide. MP 138°C. Light-brown crystals from EtOAc/hexane.
EXAMPLE BX11. 3-Hydroxy-5-oxo-tricyclo[5.2.1.0
2,6]deca-3,8-diene-4-carboxylic acid. 2-methyl-4-(4-trifluoromethylphenoxy)phenylamide. MP 165°C. White powder from MeOH.
EXAMPLE BX12. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 3,5-bis-trifluoromethylphenylamide. MP 159°C. Pale-yellow crystals from MeOH.
EXAMPLE BX13. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 2-fluorophenylamide. MP 131°C. White powder from MeOH.
EXAMPLE BX14. 3-Hydroxy-5-oxo-tricyclo[5-2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3-fIuorophenylamide. MP 128°C. White crystals (plates) from MeOH.
EXAMPLE BX15. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 2-trifluoromethyIphenyIamide. MP 92°C. Pale-yellow powder from MeOH.
EXAMPLE BX16. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 2,6-difluorophenylamide. MP 177°C. White crystals from MeOH.
EXAMPLE BX17. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid, 2,6-difluorobenzylamide. MP 113°C. Tan-colored powder from MeOH.
EXAMPLE BX18. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3.8-diene-4-carboxylic acid, 2,4,6-trifluorophenylamide. MP 190°C. White granular solid from MeOH/hexane.
EXAMPLE BX19. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 3,5-difluorophenylamide. MP 160°C. Pale-yellow powder from MeOH trituration.
EXAMPLE BX20. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-fluorophenyl amide. MP 131°C. White crystals from MeOH.
EXAMPLE BX21. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 9H-fluoren-2-ylamide. MP 238°C. Light-brown powder from MeOH trituration.
EXAMPLE BX22. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
7-bromo-9H-fluoren-2-ylamide. MP 262°C. Cream-colored powder from MeOH trituration.
EXAMPLE BX23. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 9-oxo-9H-fluoren-2-ylamide. MP 230°C. Green-brown powder from MeOH trituration.
EXAMPLE BX24. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, biphenyl-4-ylamide. MP 174°C. White powder from MeOH trituration.
EXAMPLE BX25. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 2,2'-dimethylbiphenyl-4-ylamide. Tan-colored powder from MeOH.
Following the general procedure of Preparation B4, above, plus preparation A3 from the CHART A reactions, except using the appropriate reactants, the following compound, Example BX26, is prepared.
EXAMPLE BX26. 2-(N-(4-trifluoromethylphenyl)carbamoyl)-5H,6H-dibromo-4H,7H- methano-3-hydroxyinden-1-one. MP 221°C. Cream-colored powder from hexane trituration.
Following the general procedure of Preparation B4, above, plus preparation A6 from the CHART A reactions, except using the appropriate reactants, the following compounds, examples BX27 and BX28 are prepared.
EXAMPLE BX27. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxylic acid, 4-bromophenylamide. MP 156°C. Light-brown crystals from MeOH.
EXAMPLE BX28. 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid, 4-aminophenylamide. MP 189°C. Pale-yellow solid from EtOAc trituration.
Following the general procedure of Preparation B4, above, plus preparation A7 from the
CHART A reactions, except using the appropriate reactants, the following compounds, examples BX29 and BX30, are prepared.
EXAMPLE BX29. 3-Methoxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid, ethyl ester. White crystals from pale-yellow oil.
EXAMPLE BX30. 3-Methoxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, biphenyl-4-ylamide. MP 201°C. White crystals from MeOH. Following the general procedure of Preparation B4, above, plus preparation A8 from the CHART A reactions, except using the appropriate reactants, the following compounds, examples BX31 and BX32, are prepared.
EXAMPLE BX31. 3-Methoxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-trifluoromethylphenylamide. MP 190°C. White crystals from MeOH.
EXAMPLE BX32. 3-Amino-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-trifluoromethylphenylamide. White crystals from MeOH.
CHART C REACTIONS PREPARATIONS FOR CHART C (tetracyclic β-ketoamides) Preparation C1. See CHART C, Step 1, Figure C1.
Cyclooctatetraene (8.73 g, 83.8 mmol) and maleic anhydride (8.22 g, 83.8 mmol) are combined with toluene and heated under reflux for 24 hrs. The reaction mixmre is concentrated in vacuo to a cream-colored solid. This is recrystallized from 1:2 EtOAc:hexane to give the Diels-Alder adduct an anhydride, as a white crystalline solid: 1H NMR (300 MHz, CDCl3) δ 2.81 (s, 2 H), 3.08 (s, 2 H), 3.24 (s, 2 H), 5.92 (s, 2 H), 6.04 (m, 2 H).
Preparation C2. See CHART C, Step 2, Figure C2.
The adduct, anhydride from preparation Cl, above, is reacted with ethyl lithioacetate in tetrahydrofuran at -78°C to give the β-ketoester acid. Figure C2.
Preparation C3. See Chart C, Step 3, Figure C3.
The β-ketoester acid, Figure C2, is converted to the ester, Figure C3, by heating with carbonyl diimidazole and potassium tert-butoxide in tetrahydrofuran at reflux.
Preparation C4. See Chart C, Step 4, Figure C4.
EXAMPLE CX1. (2a.alpha., 3-beta., 3a-beta., 6a.beta., 7-beta., 7a-alpha.)-N-(4- bromophenyl)-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cycIobut[f]indene-5- carboxamide, MP 232°C. Pale yellow powder from reaction mixture.
The ester, Figure C3, from above, is heated with 4-bromoaniIine in toluene at reflux, according to the general procedures provided in preparation B4 from the reactions of CHART B, except using the appropriate reactants, to give the title compound.
Following the general procedure of Preparation C4, above, plus the procedures provided in preparation B4 from the reactions of CHART B, except using the appropriate reactants, the following compounds, examples CX2 through CX6, are prepared.
EXAMPLE CX2. (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(5- trifluoromethyl-[1,3,4]thiadiazol-2-yl)-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno- 3H-cycIobut[f]indene-5-carboxamide, MP 235°C. White powder from EtOAc.
EXAMPLE CX3. (2a.alpha., 3.beta., 3a-beta., 6a.beta., 7.beta., 7aalpha.)-N-[4-
(trifluoromethyI)phenyI]-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H- cyclobut[f]indene-5-carboxamide, MP 197°C. Off-white powder from EtOAc & hexane.
EXAMPLE CX4. (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(5- bromopyridin-2-yl)-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H- cyclobut[f]indene-5-carboxamide, MP 239°C. Off-white powder from trituration with hot EtOAc.
EXAMPLE CX5. (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(4- cyanophenyl)-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5- carboxamide, MP 253°C. Off-white powder from trituration with hot EtOAc.
EXAMPLE CX6. (2a.alpha., 3.beta., 3a.beta., 6a-beta., 7.beta., 7a.alpha.)-N-[[2-methyI- 4-(4-trifluoromethyl)phenoxy]phenyl]-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-etheno-3H- cyclobut[f]indene-5-carboxamide, MP 167°C. White powder from trituration with hot MeOH.
CHART D PREPARATIONS FOR CHART D (fulvene β-ketoamides) Preparation D 1. See CHART D, Step 1, Figure D1.
A methanol solution of freshly distilled cyclopentadiene with acetone is stirred in the presence of pyrrolidine to produce 6,6-dimethylfulvene, Figure D1.
Preparations D2 through D5 are "series (a)" preparations.
Preparation D2. See CHART D, Step 2, series (a), Figure D2(a).
The fulvene from preparation D1, above, is refluxed with maleic anhydride in ether overnight to produce the anhydride, Figure D2(a).
Preparation D3. See CHART D, Step 3, series (a). Figure D3(a).
The anhydride from preparation D2, above, Figure D2(a), is treated with ethyl lithioacetate at -78°C to give the β-ketoester acid as a yellow oil containing impurities, Figure D3(a).
Preparation D4. See CHART D, Step 4, series (a), Figure D4(a).
Without purification the β-ketoester acid, Figure D3(a), from preparation D3, above, is converted to a cyclized ester by heating it with carbonyldϋmidazole and potassium tert-butoxide in tetrahydrofuran, the temperature should not be allowed to exceed 40°C. The cyclized ester, produced as a dark red oil, is shown in Figure D4(a).
Preparation D5. See CHART D, Step 5, series (a), Figure D5(a).
The cyclized ester from Preparation D4, Figure D4(a) is then used following the general procedure of Preparation B4, from the reactions of CHART B, except using the appropriate reactants, to prepare examples DX1, DX2 and DX3.
EXAMPLE DX1, 3-Hydroxy-10-isopropylidene
-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-bromophenylamide. Light tancolored crystals from MeOH. EXAMPLE DX2. 3-Hydroxy-10-isopropylidene
-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-trifluoromethylphenylamide. Crystalline solid from MeOH.
EXAMPLE DX3. 3-Hydroxy-10-isopropylidene- 5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-cyanophenylamide. Pale-yellow powder from MeOH.
Preparations D6 through D7 are "series (b)" preparations.
Preparation D6. See CHART D, Step 2, Series (b). Figure D2(b).
6,6-DimethyIfulvene (5.00g, 47.1 mmol) is added to a solution of cyclopentenedione (2.26 g, 23.5 mmol) in EtO2 (20 mL). The mixture is stirred for 6 days at room temperamre. chilled to 0°C for two hrs and then filtered. The solids are washed with n-hexane to give Hydroxy-10-isopropylidene-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one, 1:1 mixture of exo and endo isomers, as a white powdery solid: mp 158 °C; 1H NMR (300 MHz, CDCl3) δ 1.52 (s, 3 H), 1.56 (s, 3 H ), 2.52 (s, 1 H), 2.98 (m, 1 H), 3.46 (m, 1 H), 3.59 (m, 1 H), 5.16 (s, 0.5 H), 5.21 (s, 0.5 H), 6.10 (t, J = 2.0 Hz, 1 H), 6.37 (t, J = 1.9 Hz, 1 H).
Preparation D7. See CHART D, Step 3, Series b, Figure D3(b).
The compound from Preparation D6, Figure D2(b) is then used following the general procedure of Preparation A2, from the reactions of CHART A, except using the appropriate reactants, to prepare examples DX4, and DX5.
EXAMPLE DX4. 3-Hydroxy-10-isopropylidene-
5-oxo-tricycIo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid. 4-bromophenylamide, 1:1 mixture of exo and endo isomers. MP 159°C. Off-white powder from MeOH. Light tan-colored crystals from MeOH.
EXAMPLE DX5. N-(3-Hydroxy-5-oxo- tricycIo[5.2.1.02,6]deca-3,8-diene-4-carbonyI)-benzamide. MP 66°C. Tan-colored solid foam.
5
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
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Figure imgf000053_0001
Figure imgf000054_0001

Claims

1. A compound of formula I
(Formula I)
wherein
Figure imgf000055_0001
each variable may be independent of the other variable unless indicated otherwise;
the C-C bonds, a, b, and c, are single or double bonds;
either a or b are double bonds;
X is either -NH- or -O-;
R1 is =O, -OH, -OCH3 or -NH2,
R1 is =O when b is a double bond and when a is a single bond, when R1 is =O then R3 is -OH, -OCH3 or -NH2;
R3 is =O, -OH, -OCH3 or -NH2,
R3 is =O when a is a double bond and when b is a single bond, when R3 is =O then R1 is -OH, -OCH3 or -NH2;
Figure imgf000056_0001
R2-1, R2-2 and R2-3 are, each independently: H, Halogen, CF3, CN, NO2, OCH3, NH2, Cl- C5 alkyl, or C1-C5 alkoxy;
n is 1 - 3,
R4 and R7 taken together are, -O-, -CH2-,
Figure imgf000057_0001
R5 is H, Halogen, or C1-C5 alkyl;
R6 is H, Halogen, or C1-C5 alkyl;
or
R5 and R6 taken together are
Figure imgf000057_0002
wherein
R5-1 is Halogen.
2. A compound of claim 1 wherein
R4 and R7 taken together are -O- 3. A compound of claim 2 wherein
R5 = H or Br,
R6 = H or Br;
or
R5 and R6 taken together are
Figure imgf000058_0001
4. A compound of claim 3 selected from the group consisting of:
(AX1) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
(AX2) N-(3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carbonyl)-benzamide;
(AX3) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide;
(AX4) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid, phenylamide;
(AX5) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-fluorophenyIamide;
(AX6) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-chlorophenylamide;
(AX7) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
2.6-dichIorophenylamide;
(AX8) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2-1.02,6]deca-3,8-diene-4-carboxylic acid,
3 ,5-dichlorophenylamide;
(AX9) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
2,6-difIuorophenylamide.
(AX10) 3-bromo-N-(4-bromophenyI)-3a,4a7,7a,8,8a-hexahydro-5-hydroxy-7-oxo-4,8- epoxy-4H-indeno[5,6-d]isoxazole-6-carboxamide,
(AX11) 8,9-Dibromo-3-hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxyIic acid, 4-bromophenylamide;
(AX12) 8-Bromo-3-hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3,8-diene-4-carboxylic acid, 4-bromophenylamide;
(AX13) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2-1.02,6]dec-3-ene-4-carboxylic acid,
4-bromophenylamide;
(AX14) 3-Methoxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
(AX15) 3-Amino-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide.
5. A compound of claim 1 wherein
R4 and R7 taken together are -CH2-.
6. A compound of claim 5 selected from the group consisting of:
(BX5) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
4-bromophenylamide;
(BX6) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamide;
(BX7) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-trifluoromethylphenylamide;
(BX8) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-cyanophenylamide;
(BX9) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-nitrophenylamide;
(BX10) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-methoxyphenylamide;
(BX11) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2-methyl-4-(4-trifluoromethylphenoxy)phenylamide;
(BX12) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 3,5-bis-trifluoromethylphenylamide;
(BX13) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2-fluorophenylamide;
(BX14) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3-fluorophenylamide;
(BX15) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2-trifluoromethylphenylamide;
(BX16) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,6-difluorophenylamide;
(BX17) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 2,6-difluorobenzylamide;
(BX18) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,4,6-trifluorophenylamide;
(BX19) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3,5-difluorophenylamide;
(BX20) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-fluorophenylamide; (BX21) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
9H-fluoren-2-ylamide;
(BX22) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
7-bromo-9H-fluoren-2-ylamide;
(BX23) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-cartjoxylic acid,
9-oxo-9H-fluoren-2-ylamide;
(BX24) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, biphenyl-4-ylamide;
(BX25) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 2,2'-dimethylbiphenyl-4-ylamide;
(BX26) 2-(N-(4-trifluoromethylphenyl)carbamoyl)-5H,6H-dibromo-4H,7H-methano-3- hydroxy-inden-1-one;
(BX27) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxylic acid
4-bromophenylamide;
(BX28) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-aminophenylamide;
(BX30) 3-Methoxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, biphenyl-4-ylamide;
(BX31) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-trifluoromethylphenylamide;
(BX32) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide.
7. A compound of claim 1 wherein
R4 and R7 taken together are
Figure imgf000060_0001
8. A compound of claim 8 selected from the group consisting of:
(CX1) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(4-bromophenyl)- 2a,3a,4,6a7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide, (CX2) (2a.alpha., 3-beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(5-trifluoromethyl- [1,3,4]thiadiazol-2-yI)-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H- cyclobut[f]indene-5-carboxamide,
(CX3) (2a.alpha, 3.beta, 3a.beta., 6a.beta, 7.beta., 7a.alpha)-N-[4-(uifluoromethyl)phenyl]-
2a,3a4,6a7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide.
(CX4) (2a.alpha., 3.beta, 3a.beta., 6a.beta, 7.beta., 7a.alpha)-N-(5-bromopyridin-2-yl)- 2a,3a,4,6a7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide, (CX5) (2a.alpha., 3.beta, 3a.beta., 6a.beta., 7.beta., 7a.alpha)-N-(4-cyanophenyl)- 2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide, (CX6) (2a.alpha, 3.beta., 3a.beta., 6a.beta, 7.beta., 7a.alpha)-N-[[2-methyl-4-(4- trifluoromethyl)phenoxy]phenyl]-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-etheno-3H- cyclobut[f]indene-5-carboxamide.
9. A compound of claim 1 wherein
R4 and R7 taken together are
Figure imgf000061_0001
10. A compound of claim 10 selected from the group consisting of:
(DX1) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
(DX2) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide;
(DX3) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-cyanophenylamide;
(DX4) 3-Hydroxy-10-isopropyIidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-bromophenylamide, 1:1 mixture of exo and endo isomers;
(DX5) N-(3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carbonyl)benzamide.
11. A compound selected from the group consisting of:
(BX2) 3-Ethoxycarbonylacetyl-bicyclo[2.2.1 ]hept-5-ene-2-carboxylic acid;
(BX4) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid ethyl ester.
(BX29) 3-Methoxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid ethyl ester; (CX7) 8-(2-Ethoxycarbonyl-acetyl)-tricyclo[4.2.2.0 2,5]deca-3,9-diene-7-carboxylic acid;
(CX8)
Figure imgf000062_0001
(DX6) 3-(2-Ethoxycarbonyl-acetyI)-7-isopropylidene-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; (DX7) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.0 2,6]deca-3,8-diene-4-carboxylic acid ethyl ester.
12. A pharm aceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of formula I
(Formula I)
Figure imgf000062_0002
wherein
each variable may be independent of the other variable unless indicated otherwise;
the C -C bonds, a, b, and c, are single or double bonds;
either a or b are double bonds;
X is either -NH- or -O-;
R1 is =O, -OH, -OCH3 or -NH2,
R1 is =O when b is a double bond and when a is a single bond, when R1 is =O then R3 is -OH, -OCH3 or -NH2;
R3 is =O, -OH, -OCH3 or -NH2,
R3 is =O when a is a double bond and when b is a single bond, when R3 is =O then R1 is -OH, -OCH3 or -NH2;
Figure imgf000063_0001
R2-1, R2-2 and R2-3 are, exh independently: H, Halogen, CF3, CN, NO2, OCH3, NH2, Cl- C5 alkyl, or C1-C5 alkoxy;
n is 1 to 3,
R4 and R7 taken together are, -O-, -CH2-,
Figure imgf000064_0001
R5 is H, Halogen, or C1-C5 alkyl;
R6 is H, Halogen, or C1-C5 alkyl;
or
R5 and R6 taken together are
Figure imgf000064_0002
wherein
R5-1 is Halogen.
13. A pharmaceutical composition consisting essentially of a pharmxeutically acceptable carrier and an effective amount of a compound of claim 12 wherein R4 and R7 taken together are, -O-.
14. A pharmaceutical composition consisting essentially of a pharmxeutically acceptable carrier and an effective amount of a compound of claim 12 wherein R4 and R7 taken together are, - CH2-.
15. A pharmaceutical composition consisting essentially of a pharmxeutically acceptable carrier and an effective amount of a compound of claim 12 wherein
R4 and R7 taken together are
Figure imgf000065_0002
16. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of claim 12 wherein R4 and R7 taken together are,
Figure imgf000065_0001
17. A pharmaceutical composition consisting essentially of a pharmxeutically acceptable carrier and an effective amount of a compound of claim 12 where the compound is selected from the group consisting of:
(AXl) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
(AX2) N-(3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carbonyl)-benzamide;
(AX3) 3-Hydroxy-5-oxo-10-oxa-tricycIo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide;
(AX4) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
phenylamide;
(AX5) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-fluorophenylamide;
(AX6) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-chlorophenylamide;
(AX7) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,6-dichlorophenylamide;
(AX8) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3,5-dichlorophenylamide;
(AX9) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 2,6-difluorophenylamide;
(AX10) 3-bromo-N-(4-bromophenyl)-3a,4a,7,7a,8,8a-hexahydro-5-hydroxy-7-oxo-4,8- epoxy-4H-indeno[5,6-d]isoxazole-6-carboxamide,
(AX11) 8,9-Dibromo-3-hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxylic acid, 4-bromophenylamide;
(AX12) 8-Bromo-3-hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3,8-diene-4-carboxylic acid, 4-bromophenylamide;
(AX13) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxyIic acid,
4-bromophenylamide;
(AX14) 3-Methoxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
(AX15) 3-Amino-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
(BX5) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
(BX6) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamide;
(BX7) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifIuoromethylphenylamide;
(BX8) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-cyanophenylamide;
(BX9) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-nitrophenylamide;
(BX10) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-methoxyphenylamide;
(BX11) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2-methyl-4-(4-trifluoromethylphenoxy)phenyIamide;
(BX12) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3 ,5-bis-trifluoromethyIphenylamide;
(BX13) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
2-fluorophenylamide;
(BX14) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3-fluorophenyIamide;
(BX15) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2-trifluoromethylphenylamide;
(BX16) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 2,6-difluorophenylamide;
(BX17) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,6-difluorobenzylamide;
(BX18) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 2,4,6-trifluorophenylamide;
(BX19) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3,5-difluorophenylamide;
(BX20) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-fluorophenylamide;
(BX21) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
9H-fluoren-2-ylamide;
(BX22) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
7-bromo-9H-fluoren-2-ylamide;
(BX23) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 9-oxo-9H-fluoren-2-ylamide;
(BX24) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-caiboxylic acid, biphenyl-4-ylamide;
(BX25) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,2'-dimethyl-biphenyl-4-ylamide;
(BX26) 2-(N-(4-trifluoromethylphenyl)carbamoyl)-5H,6H-dibromo-4H,7H-methano-3- hydroxy-inden-1-one;
(BX27) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxylic acid
4-bromophenylamide;
(BX28) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-aminophenylamide;
(BX30) 3-Methoxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, biphenyl-4-ylamide ;
(BX31) 3-Methoxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide;
(BX32) 3-Amino-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide.
(CX1) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(4-bromophenyl)-
2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide,
(CX2) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(5-trifluoromethyl- [1,3,4]thiadiazol-2-yl)-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H- cyclobut[f]indene-5-carboxamide, (CX3) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-[4-(trifluoromethyl)phenyl]- 2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide, (CX4) (2a.alpha., 3.beta, 3a.beta., 6a.beta., 7.beta., 7a.aIpha.)-N-(5-bromopyridin-2-yl)- 2a,3a4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide, (CX5) (2a.alpha., 3-beta, 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(4-cyanophenyl)-
2a,3a4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide, (CX6) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-[[2-methyl-4-(4- trifluoromethyl)phenoxy]phenyl]-2a3a4,6a7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H- cyclobut[f]indene-5-carboxamide,
(DX1) 3-Hydroxy-10-isopropyIidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-bromophenylamide;
(DX2) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2-1.02,6]deca-3,8-diene-4-carboxyIic acid, 4-trifluoromethylphenylamide;
(DX3) 3-Hydroxy-10-isopropyIidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-cyanophenylamide;
(DX4) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide, 1:1 mixmre of exo and endo isomers;
(DX5) N-(3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carbonyl)benzamide.
18. Use of a compound of Formula I
(Formula I)
wherein
Figure imgf000068_0001
each variable may be independent of the other variable unless indicated otherwise;
the C-C bonds, a, b, and c, are single or double bonds;
either a or b are double bonds;
X is either -NH- or -O-;
R1 is =O, -OH, -OCH3 or -NH2,
R1 is =O when b is a double bond and when a is a single bond, when R1 is =O then R3 is -OH, -OCH3 or -NH2;
R3 is =O, -OH, -OCH3 or -NH2,
R3 is =O when a is a double bond and when b is a single bond, when R3 is =O then R1 is -OH, -OCH3 or -NH2;
Figure imgf000069_0001
R2-1, R2-2 and R2-3 are, each independently: is H, Halogen. CF3, CN, NO2, OCH3, NH2, C1-C5 alkyl, or C1-C5 alkoxy;
n is 1 - 3,
R4 and R7 taken together are, -O-, -CH2-,
Figure imgf000070_0001
R5 is H, Halogen, or C1-C5 alkyl;
R6 is H, Halogen, or C1-C5 alkyl;
or
R5 and R6 taken together are
Figure imgf000070_0002
wherein R5-1 is Halogen, thereof for the manufacture of a medicament fer the therapeutic killing or controlling parasitic worms in humans and warm blooded domestic animals.
19. Use of a compound of claim 18 wherein R4 and R7 taken together are, -O-, or a hydrate, or a pharmxeutically xceptable salt thereof for the manufacmre of a medicament for the killing or controlling parasitic worms in humans and warm blooded domestic animals.
20. Use of a compoimd of claim 18 wherein R4 and R7 taken together are, -CH2-, or a hydrate, or a pharmaceutically acceptable salt thereof for the manufxture of a medicament for the killing or controlling parasitic worms in humans and warm blooded domestic animals.
21. Use of a compound of claim 18 wherein R4 and R7 taken together are,
Figure imgf000071_0001
or a hydrate, or a pharmaceutically acceptable salt thereof for the manufxture of a medicament for the killing or controlling parasitic worms in humans and warm blooded domestic animals.
22. Use of a compound of claim 18 wherein R4 and R7 taken together is,
Figure imgf000071_0002
or a hydrate, or a pharmaceutically acceptable salt thereof for the manufxture of a medicament for the killing or controlling parasitic worms in humans and warm blooded domestic animals.
23. Use of a compound of claim 18 where the compound is selected from the group consisting of:
(AX1) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
(AX2) N-(3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carbonyl)-benzamide;
(AX3) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide;
(AX4) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, phenylamide;
(AX5) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-fluorophenylamide;
(AX6) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-chlorophenylamide;
(AX7) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,6-dichlorophenylamide;
(AX8) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 3 ,5-dichlorophenylamide;
(AX9) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
2, 6-difluorophenylamide.
(AX10) 3-bromo-N-(4-bromophenyl)-3a.4a7,7a8,8a-hexahydro-5-hydroxy-7-oxo-4,8- epoxy-4H-indeno[5,6-d]isoxazole-6-carboxamide,
(AX11) 8,9-Dibromo-3-hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxylic acid, 4-bromophenylamide;
(AX12) 8-Bromo-3-hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3,8-diene-4-carboxylic acid, 4-bromophenylamide;
(AX13) 3-Hydroxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxylic acid,
4-bromophenylamide;
(AX14) 3-Methoxy-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
(AX15) 3-Amino-5-oxo-10-oxa-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-bromophenyIamide;
(BX5) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6] deca-3,8-diene-4-carboxyIic acid,
4-bromophenylamide;
(BX6) 3-Hydroxy-5-oxo-tricyclo[5-2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamide;
(BX7) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
4-trifluoromethylphenylamide;
(BX8) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3.8-diene-4-carboxylic acid,
4-cyanophenylamide;
(BX9) 3-Hydroxy-5-oxo-tricyclo[5-2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-nitrophenylamide;
(BX10) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-methoxyphenyIamide;
(BX11) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2-methyl-4-(4-trifluoromethylphenoxy)phenylamide;
(BX12) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3,5-bis-trifluoromethyIphenylamide;
(BX13) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
2-fluorophenylamide;
(BX14) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid,
3-fluorophenyIamide;
(BX15) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxyIic acid, 2-trifluoromethylphenylamide;
(BX16) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,6-difluorophenylamide;
(BX17) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 2,6-difluorobenzylamide;
(BX18) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,4,6-trifluorophenylamide;
(BX19) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
3,5-difluorophenylamide;
(BX20) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-fluorophenylamide;
(BX21) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
9H-fluoren-2-ylamide;
(BX22) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 7-bromo-9H-fluoren-2-ylamide;
(BX23) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
9-oxo-9H-fluoren-2-ylamide;
(BX24) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, biphenyl-4-ylamide;
(BX25) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
2,2'-dimethylbiphenyl-4-ylamide;
(BX26) 2-(N-(4-trifluoromethylphenyl)carbamoyI)-5H,6H-dibromo-4H,7H-methano-3- hydroxy-inden-1-one;
(BX27) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]dec-3-ene-4-carboxylic acid
4-bromophenylamide;
(BX28) 3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-aminophenylamide;
(BX30) 3-Methoxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, biphenyl-4-ylamide;
(BX31) 3-Methoxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide;
(BX32) 3-Amino-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-trifluoromethylphenylamide.
(CX1) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(4-bromophenyl)- 2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide,
(CX2) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(5-trifluoromethyl- [1,3,4]thiadiazol-2-yI)-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H- cyclobut[f]indene-5-carboxamide.
(CX3) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-[4-(trifluoromethyl)phenyl]-
2a,3a,4.6a,7,7a-hexahydro-6-hydroxy-4-oxo-3.7-Etheno-3H-cyclobut[f|indene-5-carboxamide, (CX4) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(5-bromopyridin-2-yI)-
2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide.
(CX5) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-(4-cyanophenyl)-
2a,3a,4,6a7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H-cyclobut[f]indene-5-carboxamide,
(CX6) (2a.alpha., 3.beta., 3a.beta., 6a.beta., 7.beta., 7a.alpha.)-N-[[2-methyl-4-(4- txifluoromethyl)phenoxy]phenyl]-2a,3a,4,6a,7,7a-hexahydro-6-hydroxy-4-oxo-3,7-Etheno-3H- cyclobut[f]indene-5-carboxamide,
(DX1 ) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide;
(DX2) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid, 4-trifluoromethylphenylamide;
(DX3) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2-1.02,6]deca-3.8-diene-4-carboxyIic acid,
4-cyanophenylamide;
(DX4) 3-Hydroxy-10-isopropylidene-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carboxylic acid,
4-bromophenylamide, 1:1 mixture of exo and endo isomers;
(DX5) N- (3-Hydroxy-5-oxo-tricyclo[5.2.1.02,6]deca-3,8-diene-4-carbonyl)-benzamide.
or a hydrate, or a pharmxeutically acceptable salt thereof for the manufacture of a medicament for the killing or controlling parasitic worms in humans and warm blooded domestic animals.
PCT/US1992/010760 1992-01-16 1992-12-17 ANTHELMINTIC β-KETOAMIDES WO1993014062A1 (en)

Applications Claiming Priority (4)

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US82173392A 1992-01-16 1992-01-16
US07/821,733 1992-01-16
US85340192A 1992-03-18 1992-03-18
US07/853,401 1992-03-18

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US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality

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US3154579A (en) * 1961-04-24 1964-10-27 Velsicol Chemical Corp Bis (polyhalotetrahydro-4, 7-methanoinden-1-yl)-amines
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US3547976A (en) * 1967-07-17 1970-12-15 Searle & Co Derivatives of hexahydro-4,7-methanoindan-2-carboxylic acid

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality

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