WO1985002177A1 - Halo-bicyclo-alcanones - Google Patents

Halo-bicyclo-alcanones Download PDF

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Publication number
WO1985002177A1
WO1985002177A1 PCT/US1984/001819 US8401819W WO8502177A1 WO 1985002177 A1 WO1985002177 A1 WO 1985002177A1 US 8401819 W US8401819 W US 8401819W WO 8502177 A1 WO8502177 A1 WO 8502177A1
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bicyclo
dichloro
exo
heptan
ether
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PCT/US1984/001819
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English (en)
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Walter J. Kasha
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Cbd Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/38—Acyl halides
    • C07C53/40—Acetyl halides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/13—Saturated ethers containing hydroxy or O-metal groups
    • C07C43/137—Saturated ethers containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/162—Unsaturated ethers containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C07C45/292—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with chromium derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/457—Saturated compounds containing a keto group being part of a ring containing halogen
    • C07C49/467—Saturated compounds containing a keto group being part of a ring containing halogen polycyclic
    • C07C49/473—Saturated compounds containing a keto group being part of a ring containing halogen polycyclic a keto group being part of a condensed ring system
    • C07C49/477—Saturated compounds containing a keto group being part of a ring containing halogen polycyclic a keto group being part of a condensed ring system having two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/487—Saturated compounds containing a keto group being part of a ring containing hydroxy groups
    • C07C49/507—Saturated compounds containing a keto group being part of a ring containing hydroxy groups polycyclic
    • C07C49/513—Saturated compounds containing a keto group being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/517—Saturated compounds containing a keto group being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to a novel treatment of tumors, to halogenated bicyclo (3.2.0) heptane and bicyclo (3.3.0) octane derivatives and to compositions containing such derivatives useful for treatment of cancer. More specifically, this invention relates to the use in retarding and inhibiting development of tumors of a compound of the formula
  • M 1 is halogen
  • M 2 is halogen or hydrogen
  • p is zero or one and one of the groups X and X' is hydrogen and the other is a group A.
  • That group A is an alkyl group of two to nine carbon atoms with one substituent of the class consisting of hydroxy, methoxy, ethoxy and oxo groups.
  • the alkyl groups can be ethyl, straight-chained and branched propyl, butyl, pentyl, hexyl, heptyl, octyl and nonyl containing such hydroxy, methoxy, ethoxy and oxo sub-stituents.
  • Especially useful have been found such A groups as 5-hydroxyheptyl, 5-methoxyheptyl, 5-oxoheptyl, 5-hydroxy-5-methylheptyl and 5-hydroxy-5-ethylheptyl.
  • Dihaloketene typically used for generation can be a compound M 1 M 2 CH-CO-Halogen, such as dichloroacetyl chloride, and a dehydrohalogenator, e.g. an amine such as triethylamine.
  • the dihaloketene can also be generated from a trihaloacetyl halide by dehalogenation, e.g. using zinc activated with copper. This dihaloketene addition leads to formation of a mixture of isomers, in which the predominant one is the 2-A substituted 6-halogenated bicyclo (3.2.0) heptan-7-one of the formula
  • silica gel can be packed in a column using a standard slurry method or a dry packed column can be used.
  • a solvent mixture of a non-polar and more polar solvent is used.
  • the non-polar solvent is typically an alkane such as pentane, hexane, heptane or the corresponding cycloalkane.
  • the more polar solvent can be an ether, an alkyl alkanoate such as ethyl acetate, an alkanol such as methanol or ethanol or a haloalkane such as dichloromethane or chloroform. Isolation of the 7, 7-dihaloheptan-6-ones and 8,8-dihalooctan-7-ones and the endo isomers has been carried out using high performance liquid chromatography.
  • Compounds of this invention and especially the 6-exo isomers can be used in pharmaceutical compositions for retarding and inhibiting the development of mammalian tumors. These compounds have a high degree of biological activity, displaying especially excellent utility in their capacity to selectively inhibit development of cancer cells. Special utility has been found in cancers known to be influenced by steroids. Cancer inhibition has been specifically demonstrated in a wide variety of cancers including those of breast, lung, kidney and colon. A convenient bioassay for evaluation of this activity, in which these compounds show excellent results, is the Salmon clonogenic assay, Cancer Res.
  • compositions can be effectively administered topically in inert carriers suitable for that purpose, e.g. such alcohols as ethanol and 2-propanol, in salves, ointments, suspensions and emulsions. It has been observed that the compounds of this invention, on topical administration, increase elastin and decrease collagen, in that respect producing an effect resembling that of estrogens.
  • Oral dosage unit formulations include tablets, capsules and other conventional oral forms. As a tablet the compounds are typically present in an amount of from about 1 to about 50% by weight, with the inert carrier constituting the remainder of the tablet. Tablets are compressed in a conventional manner, with typically one percent magnesium stearate being included in the mixture to be tabletted. Liquid oral dosage unit formulations may also be used in which the compounds are incorporated into vehicles conventionally used for lipid soluble compounds.
  • Capsules can employ the oily product, preferably diluted with an inert carrier.
  • the high potency of the 6-exo compounds permits relatively low dosages both systemically via oral or suppository route or through topical (transdermal) application.
  • a concentration of the compounds of from about 0.01 to 5 percent by weight of the composition is useful.
  • Topical application on an infrequent basis, including a sustained release delivery, may indicate a relatively higher amount of the compounds, preferably in the range of from about 0.05 to about 3 percent by weight.
  • a relatively lower concentration of the compounds is indicated where a relatively larger surface area is treated.
  • the compound is indicated for systemic delivery, oral, injection, suppository and sublingual forms may be used.
  • the compound is administered as an oral dosage unit form, such as a tablet, capsule, powder or other traditional dosage unit form.
  • the oral dosage unit form is a tablet which contains a relatively small amount of the compounds.
  • a single oral dosage unit formulation when administered as one oral dosage unit formulation several times per day, generally up to about four times per day, will for a adult male of average weight comprise an amount of about 0.01 to about 40 mg per oral dosage unit form, and preferably from about 0.01 to about 2 mg per oral dosage unit form.
  • the compounds of formula I are valuable chemical intermediates.
  • Dehalogenation i.e. conversion of both the M 1 and M 2 groups to hydrogen, e.g. with zinc, yields potent anti-androgens useful in treatment of acne, keloids and male pattern baldness.
  • Magnesium metal turnings (7.2 gm, 0.299 moles) are added to a three-neck, round-bottom flask equipped with a Friedrich condenser and kept under nitrogen gas. Tetrahydrofuran (300 ml) is transferred to the flask and the contents stirred. A clear, colorless solution of 1-chloro-5-methoxyheptane (48.1 gm, 0.292 moles) is added portionwise and refluxed. The final third portion is added and the mixture stirred for 3 hours. The dark yellow solution is cooled to -25°C, the condenser is removed and replaced with a dry ice addition funnel.
  • the ether phase is washed with solutions of saturated sodium thiosulfate (75 ml) and brine (100 ml) .
  • the solvent is removed under vacuum leaving a clear, light yellow oil.
  • the crude product contains a mixture of the starting material, the desired alcohols and by-products. This mixture is applied to a chromatography column using a 4:1 hexane-ether mixture and eluted with 4:1 hexane-ether.
  • Vacuum distillation at 0.5 mm pressure and about 130 °C yields a mixture of the exo- and endo-isomers of 6, 6-dichloro-2-(5-hydroxyhept-1-yl) bicyclo (3.2.0.)heptan-7-one and 7, 7-dichloro-2-(5-hydroxyhept-1-yl) bicyclo-(3.2.0.)heptan-6-one.
  • Example 2 The product obtained by the dichloroketene reaction with 3- (5-methoxyhept-1-yl) cyclopentene in Example 1 yields a product containing 2 different structural isomers in addition to the endo and exo forms.
  • Both gas chromatography and high performance liquid chromatography confirm the presence of the three principal isomers in this group of 4 isomers.
  • the fourth isomer appears to be present in a quantity less than 1%.
  • Identification and separation of the three principal isomers can be accomplished by use of a Beckman high performance liquid chromatograph equipped with a 165 variable wavelength detector.
  • a Beckman 15cm C-18 column with 5 micron packing was used for all analytical determinations.
  • a 60:40 acetonitrile:water solution is used with a flow rate of 1 ml/min.
  • the detector has wavelength scanning capabilities making it possible to determine the lambda maximum of these isomers. All three major peaks detected by the system had identical UV scans from 200-350 lambda with a lambda max 1 of 213 nm and a lambda max 2 of 319 nm, consistent with a carbonyl group.
  • acetonitrile 1.5 ml of acetonitrile.
  • a 60:40 acetonitrile:water solvent system is used with a flowrate of 20 ml/min.
  • the detector monitors the samples at 210 and 318 nm.
  • a total of 80 tubes (10 ml each) was collected and the samples were analyzed for the desired isomers by capillary gas chromatography. The appropriate tubes were then pooled together and the acetonitrile removed under vacuum.
  • exo 6 , 6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo- (3.2.0)heptan-7-one can also be obtained from the mixture of exo and endo 6,6-dichloro and 7,7-dichloro isomers by applying the crude mixture directly on a flash chromatography column (e.g. 2.5 cm diameter, 200-430 mesh) and eluting with a 6:1 hexane-ether (v/v) solution,
  • the resonance at 3.8 is due to the proton HA, coupled to the proton HB giving a doublet (8Hz) .
  • a large coupling constant is due to the bridgehead protons, HA and HB.
  • the resonance at 3.53 is ascribed to HD, the methine proton on the aliphatic chain.
  • the proton HB is coupled to HA and largely one of the protons, HE. Based on molecular models it is most likely that the bond angle of HB and HF (endo) is close to 90o and therefore the coupling constant is very small compared to HE (exo).
  • Example 2 In the initial Grignard reaction of Example 1, 52.2 gm of 1-chloro-5-ethoxyheptane are substituted for the 5-methoxy homolog and the reaction sequence is conducted as in Example 1. The resulting oily mixture is distilled at about 125 °C and about 0.5 mm pressure. Infrared absorption maxima are observed at 2970, 2934, 2869, 1805, 1462, 1370, 1343, 1224, 1158, 1106, 1081, 1030, 976, 969, 845, 816, 742 and 674 cm -1 . Separation of the isomers is conducted by the method of Example 3 to yield mainly the exo 6,6-dichloro-2- (5-ethoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one.
  • a solution of 5 gm of the isomers obtained in Example 1 in 100 ml of ether is transferred to a 500 ml round bottom glass flask.
  • Excess diazomethane is generated from 60 gm of p-tolylsulfonylmethylnitrosamide by reacting with potassium hydroxide in methanol. The reaction is allowed to proceed for 50 minutes after which glacial acetic acid is added portionwise to destroy the excess diazomethane.
  • the solution is extracted with ether and dried over sodium sulphate. The solvent is removed under vacuum, leaving an orange oil.
  • This oil is applied to a silica gel chromatography column; elution with a 4:1 mixture of hexane and ether and evaporation of the solvent yields the product as a clear liquid.
  • Infrared maxima are observed at 2959, 2934, 2873, 2858, 2820, 1768, 1462, 1404, 1379, 1366, 1193, 1145, 1094, 923, 897, 778, 713, 663, 656, and 652 cm -1 .
  • Example 2 6 gm of the mixture of isomers obtained in Example 1 are added to a 400 ml ether solution of diazomethane, generated from 45 gm of p-tolylsulfonylmethylnitrosamide.
  • Example 8 Exo- and endo- isomers of 6 ,6-dichloro-2- (5-oxohept-1- yl) bicyclo (3.2.0) heptan-7-one and 7,7-dichloro-2- (5-oxohept-1-yl) bicyclo [3.2.0] heptan-6-one.
  • a dry 100 ml 3-necked flask is heated and allowed to cool under nitrogen after which there is first added 2.3 gm of the mixture of isomers obtained in Example 2 followed by 17 ml of dichloromethane. To the stirred reaction mixture there is added 6.4 gm of pyridinium dichromate in a single portion. After 3 hours ether
  • Example 2 To a dry 100 ml 3-necked round bottom flask under nitrogen, equipped with a pressure equalizing dropping funnel, thermometer, and a magnetic stirrer, there is added the mixture of isomers obtained in Example 1 (5 gm) and a catalytic amount (5 mg) of 2,2'-azobisisobutyronitrile. To the stirring solution there is added dropwise tri-n-butyltin hydride (4.7 gm) . The reaction mixture is maintained below 40° C in a water bath. After the addition is complete the reaction mixture is stirred at 30° C until a test of aliquot indicates the disappearance of the hydride, typically after about 3 hours.
  • the ether extracts are combined, dried over sodium sulfate, and the volume is reduced under vacuum leaving crude 6 , 6-dichloro-2-(5-[(1,1-dimethylethyl)dimethylsiloxy]-pent-1-yl) bicyclo (3.2.0) heptan-7-one.
  • the oil is kugelrohred under vacuum and subsequently chromatographed on silica gel using a 4:1 hexane: ether (v/v) solvent system.
  • the fractions are pooled, as (determined by VPC and IR) and the solvent reduced under vaccum leaving a clear colorless oil.
  • a solution of 18.1 gm of this product in 100 ml acetonitrile containing 5% of a 40% aqueous solution of hydrofluoric acid is stirred for 2 hours at room temperature, after which the reaction is partitioned between 200 ml water and 200 ml chloroform.
  • the aqueous phase is separated and extracted with 3 portions of 50 ml of chloroform.
  • the organic phase is washed with 75 ml of brine, dried over sodium sulphate and the volume is reduced under vacuum leaving a crude product.
  • the material is chromatographed on silica gel by using 2:1 hexane:ether (v/v) solvent system.
  • Example 11 Exo- and endo- isomers of 6 , 6-dibromo-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one and 7 ,7-dibromo-2- (5-methoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one.
  • the excess dibromoketene and phosphorus oxychloride are destroyed by the dropwise addition of water.
  • the crude product is filtered and the filtrate is washed with 100 ml brine and a saturated solution of 100 ml sodium bicarbonate until the pH reaches 7.
  • the organic phase is washed again with 100 ml brine and dried over sodium sulfate.
  • the solvent is removed under vacuum leaving a brown liquid.
  • the material is kugelrohred under vacuum and subsequently chromatographed on silica gel with 4:1 hexane: ether (v/v) as the elution solvent.
  • the fraction is pooled (as determined by vapor phase chromatography) and the solvent removed under vacuum leaving a clear oil.
  • Example 12 Exo- and endo- isomers of 6 , 6-difluoro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one and 7 ,7-difluoro-2- (5-methoxyhept-1-yl) bicyclo [3.2.0]heptan-6-one.
  • To a 250 ml 3-necked flask are added 50 gm of chlorodifluoroacetic acid. The flask is cooled in an ice bath and stirred while 116.7 gm of phosphorus tribromide are slowly added in the course of 5 minutes. After completion of the reaction and subsequent refluxing for 2 hours, the chlorodifluoroacetyl chloride is distilled into an ice-cooled receiver as a colorless liquid.
  • Zinc-copper catalyst (3 gm) is added to a stirred solution of 6 ,6-dichloro-2-(5-methoxyhept-1-yl) bicyclo- (3.2.0)heptan-7-one (2 gm, 6 moles) in acetic acid (100 ml) under a nitrogen atmosphere.

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Abstract

Composition pharmaceutique pour l'inhibition de tumeurs, contenant une dose efficace d'un composé de formule (I), où Q représente CO, CH(OH) ou C(OH)CH3, M1 représente un halogène, M2 représente un halogène ou un hydrogène, p vaut 0 ou 1 et l'un des groupes x et x' représente un hydrogène, alors que l'autre représente un hydroxyalcoyle, un méthoxyalcoyle, un éthoxyalcoyle ou un oxoalcoyle, où l'alcoyle contient entre 2 et 9 atomes de carbone, le groupe x étant de préférence en position exo.
PCT/US1984/001819 1983-11-08 1984-11-08 Halo-bicyclo-alcanones WO1985002177A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US55029083A 1983-11-08 1983-11-08
US550,290 1983-11-08
US56717283A 1983-12-30 1983-12-30
US567,172 1983-12-30

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3849505A (en) * 1971-09-24 1974-11-19 Reckitt & Colmann Prod Ltd Bicyclic polyols
US4292432A (en) * 1979-02-09 1981-09-29 Sumitomo Chemical Company, Limited Novel aldol derivatives and production thereof
US4322435A (en) * 1978-01-06 1982-03-30 Sankyo Company Limited Prostacyclin compounds

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705240A (en) * 1966-11-21 1972-12-05 Geigy Chem Corp Phosphoric acid esters,intermediates for making the same,and pest control by means of said esters
EP0107733B1 (fr) * 1982-05-06 1988-10-19 Cbd Corporation Composes cycloaliphatiques pharmaceutiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3849505A (en) * 1971-09-24 1974-11-19 Reckitt & Colmann Prod Ltd Bicyclic polyols
US4322435A (en) * 1978-01-06 1982-03-30 Sankyo Company Limited Prostacyclin compounds
US4292432A (en) * 1979-02-09 1981-09-29 Sumitomo Chemical Company, Limited Novel aldol derivatives and production thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0162894A4 *

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EP0162894A4 (fr) 1987-01-22

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