EP0162894A1 - Halo bicyclo alkanones - Google Patents

Halo bicyclo alkanones

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Publication number
EP0162894A1
EP0162894A1 EP84904279A EP84904279A EP0162894A1 EP 0162894 A1 EP0162894 A1 EP 0162894A1 EP 84904279 A EP84904279 A EP 84904279A EP 84904279 A EP84904279 A EP 84904279A EP 0162894 A1 EP0162894 A1 EP 0162894A1
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EP
European Patent Office
Prior art keywords
bicyclo
dichloro
exo
heptan
ether
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Legal status (The legal status 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 status listed.)
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EP84904279A
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German (de)
French (fr)
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EP0162894A4 (en
Inventor
Walter J. Kasha
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Cbd Corp
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Cbd Corp
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Publication of EP0162894A1 publication Critical patent/EP0162894A1/en
Publication of EP0162894A4 publication Critical patent/EP0162894A4/en
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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.Pharmaceutical composition for tumor inhibition, containing an effective dose of a compound of formula (I), in which Q represents CO, CH (OH) or C (OH) CH3, M1 represents a halogen, M2 represents a halogen or a hydrogen, p is 0 or 1 and one of the groups x and x 'represents a hydrogen, while the other represents a hydroxyalkyl, a methoxyalkyl, an ethoxyalkyl or an oxoalkyl, where the alkyl contains between 2 and 9 atoms of carbon, the group x preferably being in the exo position.

Description

HALO BICYCLO ALKANONES 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
wherein Q is C=O, CHOH or C(OH)CH3, M1 is halogen, M2 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.
The compounds of the invention in which p is zero are conveniently prepared from a suitably A-substituted cyclopentene of the formula
by heating with a dihaloketene of the formula M1M2C=CO generating reagent. Dihaloketene typically used for generation can be a compound M1M2CH-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
in the exo form of that compound, as determined by nuclear magnetic resonance. Exo compounds of type II are also preferred as anti-tumor agents. The second most frequent isomer in that mixture is the exo form of the 2-A substituted 7-halogenated bicyclo-(3.2.0)heptan-6-one of the formula
Also obtained, though in smaller amount, are the endo isomers, the A group being in the endo position.
Separation of these isomers can be accomplished by chromatographic separation. Conventional chromatography columns can be used employing silica or alumina to isolate the exo 6,6-dihalo isomers. Thus, 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.
The foregoing bicyclo (3.2.0) heptanes (p=0) , can be converted to the bicyclo (3.3.0) octanes (p=1) by reaction with diazomethane.
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.
Reports, 65 , p. 1, 1981, in which compounds at the levels as low as 0.001 mcg/ml cause selective destruction of tumor cells. These 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.
While topical application of compositions containing these compounds constitutes one embodiment of the invention, other routes for pharmaceutical administration are also contemplated, particularly the oral and suppository routes. 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. Suppositories with the compounds are also contemplated, to provide a rectal suppository administration of the drug and which form takes advantage of the usual suppository ingredients. 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.
Where the compound is indicated for systemic delivery, oral, injection, suppository and sublingual forms may be used. Preferably the compound is administered as an oral dosage unit form, such as a tablet, capsule, powder or other traditional dosage unit form. In a preferred embodiment, 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.
It is to be understood that the extremely small amount of the compound necessary means as a practical matter that a tablet of the usual size will have only a very small percentage of the compound, with the remainder comprising pharmaceutically inert ingredients or fillers such as talcum, maize starch, polyvinyl pyrrolidone and lactose, together with a small amount of a tabletting agent such as magnesium stearate.
The compounds of formula I are valuable chemical intermediates. Dehalogenation, i.e. conversion of both the M 1 and M2 groups to hydrogen, e.g. with zinc, yields potent anti-androgens useful in treatment of acne, keloids and male pattern baldness.
The following examples illustrate the invention:
Example 1 Exo- and endo- isomers of 6, 6-dichloro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heρtan-7-one and 7,7-dichloro-2- ( 5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-6-one.
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. A clear solution of 3-chlorocyclopentene (29.9 gm, 0.292 moles) is added over one hour. Water is added, followed by hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with ether. The combined organic solutions are dried over sodium sulphate. The solvent is removed under vacuum and the crude product is then purified by fractional distillation, yielding 3- (5-methoxyhept-1-yl) cyclopentene as a clear, colorless oil, (b.p. about 54°C/0.1 mm).
To a 1,000 ml three-neck, round-bottom flask, equipped with a reflux condenser containing 3- (5-methoxyhept-1-yl) cyclopentene (15.0 gm, 0.076 moles) in 300 ml of hexane, freshly distilled dichloroacetyl chloride (35.1 gm, 0.240 moles) is added and the solution is stirred by a mechanical stirrer and heated to reflux. Triethylamine (25.2 gm, 0.249 moles), dissolved in 200 ml hexane, is added dropwise and the refluxing solution allowed to stir for 4 hours. The solvent is removed and then the residue is distilled and applied to a silica gel chromatography column of 2.5 cm diameter in a 4:1 hexane-ether solvent mixture. The product is eluted using a 4:1 hexane-ether solvent system. The fractions are monitored using vapor phase chromatography. The solvent is removed under vacuum. There are thus obtained mainly 6, 6-dichloro-2-(5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one and a smaller amount of 7,7-dichloro-2- (5-methoxyhept-2-yl) bicyclo- (3.2.0) heptan-6-one, both mainly in the exo form. Infrared analysis shows maxima at 2963, 2932, 2864, 2857, 2820, 1803, 1461, 1378, 1223, 1197, 1157, 1093, 1030,
968, 914, 842, 821, 802, 778, 740, and 673 cm-1. Substitution of C 14-labeled dichloroacetyl chloride yields the C 14-labeled isomers of the 6,6-dichloro and
7,7-dichloro derivatives above.
Example 2
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.
To a solution of acetonitrile (140 ml) containing a mixture of the isomers of dichloro-2- (5-methoxyhept-1-yl) bicyclo [3.2.0.]heptanones (30.6 gm) obtained as in Example 1 is added sodium iodide (31.4 g) and trimethylsilyl chloride (11.4 g moles). The solution is stirred under an inert atmosphere for four hours after which time 50 ml water is added until the solution changes to a clear red color. The mixture is extracted with diethyl ether (150 ml) and the aqueous phase is discarded. 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. Infrared absorption maxima are observed at 3584, 3534, 3389, 3377, 2959, 2934, 2871, 2856, 1804, 1462, 1409, 1378, 1337, 1317, 1301, 1279, 1252, 1250, 1245, 1180, 1159, 1134, 1119, 1090, 1031, 965, 923, 896, 864, 811, 779, 742 and 676 cm-1. Example 3 Separation of isomers
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. The reaction of this isomeric product with trimethylsilyl iodide according to Example 2 forms a demethoxylated product which also contains the same group of isomers. 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.
Separation of the isomers is accomplished using a
Whatman Magnum 20 column with 50 micron packing of C-18.
A 0.5 gm sample of the isomeric mixture is dissolved in
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. The aqueous phase was extracted with ether and the solvent again removed under vacuum and dried over sodium sulfate, leaving clear yellow oils of 0.2 gm of exo 6, 6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo (3.2.0) heptan- 7-one and 0.1 gm of exo 7,7-dichloro-2-(5- hydroxyhept- 1-yl) bicyclo (3.2.0) heptan-6-one. The product last eluted, the exo- 6,6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo (3.2.0)heptan-7-one gives the following key NMR resonances: 1H 3.82, doublet (1H) , 3.53 multiplet (1H) , 3.37 (d of d) 1H, 2.40 quartet (1H) , 0.944 triplet (3H) . In the case of the exo 7,7-dichloro compound, second to be eluted, the following NMR regions were noted. 1H 4.03 d of d (1H) , 3.53 multiplet (1H) , 3.07 doublet (1H), 2.40 quartet (1H) and 0.948 triplet (3H) . Before the exo 7,7-dichloro compounds, smaller quantities of endo isomers are eluted. The following NMR resonances are noted 3.94 d of d (1H) , 3.53 multiplet (1H), 3.42 d of d (1H), 0.94 triplet (3H) .
The 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,
collecting fractions in 20 ml tubes. The presence of the exo 6,6-dichloro product in tubes can be determined by gas chromatography by comparison with the pure exo 6,6-dichloro product obtained above using high performance liquid chromatography.
Structure assignment of exo 6,6 dichloro-2- (5-hydroxyhept-1-yl) bicyclo (3.2.0) heptan-7-one.
The resonance at 3.8 is due to the proton HA, coupled to the proton HB giving a doublet (8Hz) . Such 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. At 3.37, what appears to be a triplet is actually a doublet of doublets as it is due to HB, the other bridgehead proton. 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). There is a clean quartet at 2.4, most likely due to proton HF. As a result of the cupped shape of the molecule from the fused rings the endo chlorine atom is in closer proximity to proton HF, and therefore, results in a downfield shift. Irradation of HA collapses the apparent triplet at 3.37 to a doublet, since the coupling of HB to HE is unaffected by the irradiation. Irradiation of HB collapses the doublet of HA to a singlet also consistent with the proposed exo 6,6-dichloro isomer structure. If this were actually the endo 6,6-dichloro isomer then proton HA should be coupled to HC and HA would appear as an apparent triplet. Identification of exo 7 ,7-dichloro-2-(5-hydroxyhept-1- yl) bicyclo (3.2.0)heptan-6-one. There is an apparent triplet at 4.03, which is actually a doublet of doublets due to the coupling of HH with the protons of HG and HJ and shifted further downfield as a result of being located on the carbon adjacent to the carbonyl. There may be a small coupling of proton HH with HK (less than 1 Hz) . There is also a quartet at about 2.4 ppm due to proton HK. A doublet corresponding to proton HG at 3.07 is due to the coupling of proton HG to proton HH. There may be a small coupling with proton HI but based on molecular models the bond angles between these protons would be less than 1 Hz. Irradiation of proton HH collapses the doublet (due to proton HG) to a singlet also consistent with the 7,7-dichloro isomer structure. Irradiation of HG results in the change in the resonance of proton HH from an apparent triplet (actually doublet of doublets) to a doublet.
If the aliphatic chain were in the endo position instead of the exo position, proton HG would be coupled to HI and thus give a resonance of an apparent triplet (doublet of doublets) instead of a doublet at 3.07.
Based on molecular models the bond angle between proton HG and HI is almost 90°and would therefore have a very small coupling.
Example 4 Exo- and endo- isomers of 6,6-dichloro-2-(5-ethoxyhept-1-yl)bicyclo[3.2.0]heptan-7-one and 7,7-dichloro-2- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one.
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.
Example 5 Exo- isomer of 6, 6-dichloro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-ol.
To a solution of 50 ml of methanol, 30 ml of water, and 8 gm of sodium hydroxide, there is added in pellet form 0.2 gm of sodium borohydride in a single portion. 1 gm of exo 6, 6-dichloro-2- (5-methoxyheptyl) bicyclo (3.2.0) -heptan-7-one is added and the reaction mixture is heated at 45 °C for 10 hours. The solution is then cooled in an ice bath and concentrated hydrochloric acid is added dropwise until the solution has reached a pH of 1. The reaction mixture is then extracted 3 times with 75 ml ether. The combined ether extracts are washed with sodium bicarbonate and dried over sodium sulphate. The solvent is removed under vacuum, leaving 0.4 gm of a clear yellow product showing infrared maxima at 3447 (broad), 2960, 2934, 2873, 2858, 2824, 1462, 1418, 1375, 1335, 1263, 1178, 1163, 1094, 1042, 962, 936, 920, 858, 849, 842 and 682 cm-1. Substitution of 1 gm of 7, 7-dichloro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-6-one yields 7,7-dichloro- 2- (5-methoxyhept-1-yl) bicyclo (3.2.0)heptan-6-ol with a very similar infrared spectrum. Use of exo 6, 6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo- (3.2.0) heptan-7-one of Example 3 as starting materials yields exo 6, 6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo- (3.2.0) heptan-7-ol.
Example 6 Exo- and endo- isomers of 6,6-dichloro-2-(5-methoxyhept- 1-yl) bicyclo (3.3.0) octan-7-one and 8 , 8-dichloro-2- (5-methoxyhept-1-yl) -7-bicyclo (3.3.0) octan-7-one and 5-hydroxyhept-1-yl-derivatives.
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. Substitution in this reaction of the individual isomers obtained by the separation procedure in Example 3 leads to the corresponding exo- and endo- isomers of 6,6-dichloro-2- (5-methoxyhept-1-yl) bicyclo (3.3.0) octan-7-one and 8, 8-dichloro2- (5-methoxyhept-1-yl) bicyclo [3.3.0] - octan-7-one.
Reaction of the product of Example 4 with diazomethane yields the 6,6-dichloro-2- (5-ethoxy-1-heptyl) bicyclo (3.3.0) octan-7-one which, on dechlorination with zinc and acetic acid, produces 2- (5-ethoxyhept-1-yl) bicyclo (3.3.0) - octan-7-one, IR 2971, 2934, 2860, 1742, 1483, 1462, 1405, 1370, 1345, 1333, 1301, 1243, 1202, 1160, 1111, 1082, 982, 977 and 722 cm-1.
Demethylation of exo 6, 6-dichloro-2-(5-methoxyhept-1-yl) bicyclo (3.3.0) octan-7-pne by the procedure of Example 2 produces exo 6,6-dichloro-2-(5-hydroxyhept-1-yl) bicyclo (3.3.0) octan-7-one Infrared maxima occur at about 3416, 2955, 2868, 2856, 1801, 1462, 1131, 1118, 1029, 987, 967, 741 and 675 cm-1.
Example 7 Exo- and endo- isomers of 6 ,6-dichloro-2- (5-methoxyhept-1-yl) 7-methylbicyclo (3.3.0) octan-7-ol and 8 , 8-dichloro-2- (5-methoxyhept-1-yl) -7-methylbicyclo (3.3.0) octan-7-ol.
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.
The reaction is allowed to proceed for 5 hours after which glacial acetic acid is added dropwise to neutralize the excess diazomethane. The ether solution is washed with sodium bicarbonate and dried over sodium sulphate. The solvent is removed under vacuum, leaving an orange oil. This oil is applied in hexane and ether to a silica gel chromatography column and elution with 4:1 hexane-ether yields the product as a clear liquid. Infrared maxima are observed at 3430, 2931, 2856, 1658, 1461, 1379, 1362, 1328, 1325, 1316, 1244, 1195, 1173, 1162, 1093, 1027, 984, 950, and 923 cm-1. Substitution in this reaction of the individual isomers obtained in Example 3 leads to the corresponding exo- and endo- isomers of 6, 6-dichloro-2- (5-hydroxyhept-1-yl) -7-methylbicyclo (3.3.0) octan-7- ol and 8,8-dichloro-2- (5-hydroxy-hept-1-yl) -7-methylbicyclo (3.3.0) octan-7-ol, the exo-6,6-dichloro isomer being the principal product. 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
(4x50 ml) is added and the solution is shaken vigorously to dissolve any product trapped in the precipitated chromium salts. The solution is filtered through a sintered glass filter with a silica pad. The filtrate is washed successively with 75 ml of water and then 75 ml brine and dried over sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The 5-oxohept-1-yl product is purified by silica gel chromatography using 4:1 hexane: ether (v/v) as the eluting solvent. The fractions containing the product, as determined by vapor phase chromatography, are pooled and the solvent is removed under vacuum leaving a clear yellow oil.
Separation of isomers yielding mainly the exo 6,6-dichloro isomer follows the procedure of Example 3. Infrared maximum were observed at:
2932, 2859, 1799, 1707, 1653, 1457, 1410, 1371, 1289, 1261, 1222, 1161, 1111, 1051, 1027, 963, 953, 915, 862, 843, 803, 733, and 671 cm-1. Example 9
Exo- and endo- isomers of 6-chloro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one and 7-chloro-2- (5-methoxyhept-l-yl) bicyclo [3.2.0]heptan-6-one.
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. Then 35 ml water and 75 ml ether are added and the organic phase is separated and washed with 50 ml brine and dried over sodium sulfate. Evaporation of the solvent under vacuum leaves the crude product, which is then chromatographed on silica gel using 4:1 hexane:ether (v/v) as the elution solvent. The fractions are pooled (as determined by VPC) and the solvent is removed under vacuum leaving the product as a clear colorless oil. (2.5 gm)
Infrared maxima observed: 2960, 2932, 2871, 2855, 1804, 1461, 1448, 1034, 1023, 968, 817, 743, 703 and 676 cm-1. Individual isomers are obtained by the method of Example 3.
Example 10 6 ,6-dichloro-2-(5-hydroxypent-1-yl) bicyclo (3.2.0) heptan--7-one and isomers
To a dry 500 ml 3-necked flask equipped with a magnetic stirrer and under a nitrogen atmosphere there are added 36 gm of 5-chloropentanol and 17.6 gm t-butyl-dimethylsilyl chloride. A suspension of 39.6 gm of imidazole in 40 ml of dimethylformamide is added in a single portion to the stirring solution. After 20 hours, 150 ml water and 100 ml ether are added. The organic phase is separated and 150 ml water and 100 ml ether are added. The organic phase is separated. The aqueous phase is extracted three times with 75 ml ether. The ether solution is washed with 100 ml brine. The ether extracts are combined, dried over sodium sulphate and the volume is reduced under vacuum to yield (5-chloro-1- pentyloxy) (2,2-diraethylethyl) dimethylsilane. Infrared maxima observed at:
2954, 2929, 2895, 2857, 1470, 1461, 1445, 1434, 1405, 1388, 1360, 1312, 1290, 1256, 1216, 1153, 1106, 982, 938, 911, 836, 812, 776, 727, 657 cm-1.
3- (5- [ (1, 1-dimethylethyl) dimethylsiloxy] pent-1-yl)- cyclopentene is prepared by the method of Example 1. The crude product is kugelrohred under vacuum and the product subsequently chromatographed on silica gel using 4:1 hexane:ether (v/v) as the solvent system. The fractions are pooled and the solvent removed under vaccum leaving a clear colorless oil.
27.4 gm of this product in 75 ml of anhydrous ether and 19.4 gm of zinc copper couple are added to a 500 ml
3-necked flask equipped with a magnetic stirrer, reflux condenser and a pressure equalizing funnel under a nitrogen atmosphere.
An etheral solution containing 37 gm of trichloroacetyl chloride and 30.6 gm of phosphorus oxychloride are added dropwise over 2 hours to the stirring solution. The reaction mixture is heated to reflux for 2 hours, after which the reaction is cooled and the zinc is removed by filtration. The filtrate is cooled and water and sodium bicarbonate are added to neutralize the reaction. The organic phase is separated and the aqueous phase is extracted 3 x 75 ml of ether. 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. The fractions are pooled and the solvent is removed under vacuum leaving a clear colorless oil of 6,6-dichloro-2-(5-hydroxypent-1-yl)bicyclo(3.2.0)heptan-7-one and 7,7-dichloro-2-(5-hydroxypent-1-yl) bicyclo (3.2.0) heptan-6-one. The first named product in the exo form, is isolated by the procedure in Example 3. Infrared maxima: 3440, 2935, 2864, 1803, 1650, 1465, 1410, 1247, 1160, 1073, 1050, 930, 750, 735 and 610 cm-1.
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. To a dry 500 ml 3-necked round bottom flask equipped with pressure equalizing dropping funnel, stirrer and condenser are added 34.3 gm of tribromoacetic acid under nitrogen. Then 41.5 gm phosphorus tribromide is added dropwise with stirring. The reaction, proceeding with evolution of gas, is completed in 2 hours and the crude tribromoacetyl bromide is distilled at about 75°C and 10 mm.
Under an inert atmosphere there are added to a 500 ml 3-necked round bottom flask equipped with a magnetic stirrer, reflux condenser, and a pressure equalizing dropping funnel 6.5 gm of zinc-copper couple and 15 gm of 3- (5-methoxyhept-1-yl) cyclopentene dissolved in 100 ml of ether. A solution of 15.1 gm of tribromoacetyl bromide and phosphorus oxychloride (15.6 gm) in 100 ml ether is added dropwise to the stirring solution over 1 hour to generate dibromoketene. The reaction is heated to reflux and allowed to stir until there is no more starting material present as evidenced by vapor phase chromatography. 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.
To a dry 250 ml 3-necked round-bottom flask under an inert atmosphere is added 9.7 gm of zinc-copper couple and 80 ml anhydrous ether. 15.1 gm of chlorodifluoroacetyl chloride in 20 ml ether are added dropwise to the stirring solution and the etheral difluoroketene monomer is distilled into a receiver cooled with an ice bath. To the distillate is added 15 gm of 3- (5-methoxyhept-1-yl)-cyclopentene in 20 ml ether. The reaction is stirred for 1 hour after which time 50 ml of cold water are added. The solution is washed with 75ml saturated sodium bicarbonate. The organic phase is separated, washed with 75ml brine and dried over sodium sulfate. The solvent is removed under vacuum leaving a green oil. The product is kugelrohred under reduced pressure and chromatographed on silica gel using a 4:1 hexanetether (v/v) solvent system. The fractions are pooled (as determined by VPC) and the solvent removed under vacuum leaving a clear light yellow oil. Infrared maxima observed at:
2921, 2847, 2689, 2669, 2650, 2645, 2636, 2621, 2609, 2528, 2517, 2510, 2506, 1771, 1457, 1373, 1358, 1280, 1193, 1160, 1126, 1092, 968, 911, 838, 775, 715, 650 and 646 cm-1.
Anti-Tumor Testing The compounds were tested against a variety of tumors in the Salmon essay (Cancer Res. Report 65:1; 1981). Thus, in a typical test, 3 plates containing 40, 43 and 45 colonies of CHOW-5 (Chinese hamster ovary) cell line were incubated using a solution of 10 meg of exo 6,6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo (3.2.0) -heptan-7-one. All treated colonies were destroyed. All controls survived.
In tests against Walker 256 rat carcinosarcoma, 105 cells were implanted i.p. and the rats were treated i.p. daily on days 1-5. Exo 6 ,6-dichloro-2-(5-methoxyhept-1-yl) bicyclo (3.2.0)heptan-7-one was dissolved in peanut oil. Untreated control rats lived an average of 8.0 days. Rats treated with 20% polyethylene glycol 400 in oil lived 8.5 days. Rats given 1 g/kg of the drug lived 12.5 days, significantly longer. DEHALOGENATION
A. To a single-neck 100ml, round-bottom flask equipped with a condenser are added 6,6-dichloro-2- (5-methoxyhept- 1-yl) -bicyclo (3.3.0)octan-7-one or the 8,8-dichloro-7-one isomer (45.9 gm) . The solution is stirred by magnetic stirring and powdered zinc metal (92 gm) and glacial acetic acid (312 ml) are added and the solution allowed to reflux for six hours, during which time white ZnCl2 precipitates out of solution. The solution is filtered, washed with NaHCO3 and extracted three times with ether. The ether extracts are combined and dried over sodium sulphate. The resulting yellow oil is chromatographed with silica gel and eluted with 3:1 hexane:ether. The fractions are combined, yielding 2-(5-methoxyhept-1-yl)-bicyclo (3.3.0) octan-7-one as a clear, colorless oil.
IR 2928, 2853, 2828, 1740, 1460, 1402, 1735, 1158, 1122, 1093, 1050, 1035, 960, 740 cm-1.
B. 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.
The solution is stirred at room temperature for one hour, then refluxed for 13 hours, after which time the mixture is filtered through a sintered glass funnel and the etheral solution dried over Na2SO4. The solvent is removed under vacuum, leaving the crude product. Chromatography on silica gel yields 2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one (1.2 gm) . IR: 2959, 2933, 2859, 2820, 1778, 1461, 1406, 1386, 1316, 1303, 1260, 1236, 1197, 1154, 1091, 1024, 921, 862, 819 cm-1.
C. Dehalogenation of 6 ,6-dichloro-2-(5-methoxyhept-1-yl)-bicyclo(3.3.0)octan-7-ol produces 2- (5-methoxyhept-1-yl)-bicyclo (3.3.0) octan-7-ol. IR: 3501, 2960, 2932, 2856, 2822, 2736, 1657, 1638, 1635, 1461, 1374, 1303, 1261, 1248, 1246, 1239, 1161, 1132, 1093, 1037, 998, 963, 943, 920, 750, 724 and 690 cm-1.

Claims

WHAT IS CLAIMED IS
1. A pharmaceutical composition for inhibition of tumors which contains an effective dose of a compound of the formula
wherein Q is CO, CH(OH) or C(OH)CH3, M1 is halogen, M2 is halogen or hydrogen, p is 0 or 1 and one of the groups X and X' is hydrogen and the other is a hydroxyalkyl, methoxyalkyl, ethoxyalkyl or oxoalkyl wherein the alkyl contains 2-9 carbon atoms.
2. A composition of claim 1 wherein M1 and M2 are chlorine.
3. A composition of claim 2 wherein p is zero.
4. A composition of claim 3 wherein Q is CO.
5. A composition of claim 4 wherein the compound is exo 6 ,6-dichloro-2-(5-hydroxyhept-1-yl) bicyclo [3.2.0] -heptan-7-one.
6. A composition of claim 4 wherein the compound is exo 6,6-dichloro-2- (5-methoxyhept-1-yl) bicyclo [3.2.0] -heptan-7-one.
7. A composition of claim 4 wherein X is wherein Y and Y' are methyl or ethyl.
8. A composition of claim 4 wherein X is oxalkyl.
9. A composition of claim 8 wherein the compound is exo 6 ,6-dichloro-2- (5-oxohept-1-yl) bicyclo (3.2.0) - heptan-7-one.
10. A compound of the formula
wherein Q is CO, CH(OH) or C(OH)CH3, M1 is halogen,
M2 is halogen or hydrogen, p is 0 or 1 and X is a hydroxyalkyl, methoxyalkyl, ethoxyalkyl or oxoalkyl wherein the alkyl contains 2-9 carbon atoms.
11. A compound of Claim 10 wherein M1 and M2 are chlorine.
12. A compound of Claim 11 wherein p is zero.
13. A compound of Claim 12 wherein Q is CO.
14. A compound of Claim 13 which is exo 6, 6-dichloro-2-(5-hydroxyhept-1-yl) bicyclo [3.2.0] heptan- 7-one.
15. A compound of Claim 13 which is exo 6,6-dichloro- 2-(5-methoxyhept-1-yl) bicyclo [3.2.0] heptan-7-one.
16. A compound of claim 13 wherein X is and wherein Y and Y' are methyl or ethyl.
17. A compound of claim 13 wherein X is oxoalkyl.
18. A compound of claim 17 which is exo
6 , 6-dichloro-2- (5-oxohept-1-yl) bicyclo (3.2.0) heptan-7-one.
EP19840904279 1983-11-08 1984-11-08 Halo bicyclo alkanones. Withdrawn EP0162894A4 (en)

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Citations (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
WO1983004019A1 (en) * 1982-05-06 1983-11-24 Cbd Corporation Cycloaliphatic pharmaceutical compounds

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BE789163A (en) * 1971-09-24 1973-03-22 Reckitt & Colmann Prod Ltd NEW COMPOUNDS FOR THE PREPARATION OF PROSTAGLANDIN
JPS5495552A (en) * 1978-01-06 1979-07-28 Sankyo Co Ltd Prostacyline derivative and its preparation
JPS55105638A (en) * 1979-02-09 1980-08-13 Sumitomo Chem Co Ltd Aldol derivative and its preparation

Patent Citations (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
WO1983004019A1 (en) * 1982-05-06 1983-11-24 Cbd Corporation Cycloaliphatic pharmaceutical compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO8502177A1 *

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