US3904630A - 8-n-methylpiperazinyl-n'-carbonyldibenzo-bicyclooctadiene and salts thereof - Google Patents

8-n-methylpiperazinyl-n'-carbonyldibenzo-bicyclooctadiene and salts thereof Download PDF

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Publication number
US3904630A
US3904630A US339359A US33935973A US3904630A US 3904630 A US3904630 A US 3904630A US 339359 A US339359 A US 339359A US 33935973 A US33935973 A US 33935973A US 3904630 A US3904630 A US 3904630A
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United States
Prior art keywords
octadiene
methylpiperazinyl
salts
compounds
compound
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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.)
Expired - Lifetime
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US339359A
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English (en)
Inventor
Walton James Hammar
Alvin C Conway
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Riker Laboratories Inc
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Riker Laboratories Inc
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Publication date
Application filed by Riker Laboratories Inc filed Critical Riker Laboratories Inc
Priority to US339359A priority Critical patent/US3904630A/en
Priority to CA193,621A priority patent/CA1037031A/en
Priority to AU66373/74A priority patent/AU467513B2/en
Priority to DE2410982A priority patent/DE2410982C3/de
Priority to GB1029974A priority patent/GB1458892A/en
Priority to FR7407836A priority patent/FR2220268B1/fr
Priority to JP49026718A priority patent/JPS526998B2/ja
Priority to US05/595,288 priority patent/US3969505A/en
Application granted granted Critical
Publication of US3904630A publication Critical patent/US3904630A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C61/16—Unsaturated compounds
    • C07C61/39—Unsaturated compounds containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • German Offenlegungsschrift No. 2,216,884 a reference published subsequent to the present invention, describes antidepressant and anticonvulsant components wherein an amino residue (-NR R is linked to a dibenzobicyclo[3.2.l]octadiene nucleus at the 8 position, i.e. an alkylene or alkenylene group.
  • the invention relates to compounds having the for mula which is named herein (in anti configuration) as 8-anli(N- methylpiperazinyl-N-carbonyl)dibenzobicyclo[3.2.- l]octadiene, and its pharmaceutically acceptable salts.
  • This invention also relates to processes for synthesizing, processes for using, and compositions containing the compounds of the invention.
  • Compounds of the invention are prepared in the free base form by the reaction of N-methylpiperazine with an acyl halide derivative, preferably the chloride, of 8-syn or 8-anti-carboxydibenzobicyclo[ 3.2. 1 ]octadiene, in solution in an inert solvent such as dichloro methane, chloroform, benzene, hexane and the like.
  • an inert solvent such as dichloro methane, chloroform, benzene, hexane and the like.
  • the reaction proceeds rapidly to completion in less than one hour at 20 to 30 C.
  • the product is readily isolated by removal of the solvent, and is purified by recrystallization or other conventional methods.
  • the carboxylic acid is converted to the corresponding acyl halide by reaction with the inorganic acid halide. It has been found that thionyl chloride reacts readily with 8-syn or 8-anti-carboxydibenzobicyclo[3.2. l ]octadiene when the reactants are mixed and briefly heated at their reflux temperature (up to one hour). The acid chloride can be recovered by evaporating excess thionyl chloride and used as described here-.
  • the free base product is readily converted to an acid addition salt by treatment with an approximately equimolar quantity of an acid. This has routinely been accomplished by treating the free base in isopropyl alcohol with acid to precipitate the product salt. Optionally, the precipitation may be facilitated by the addition of a non-solvent.
  • Suitable pharmaceutically acceptable acid addition salts of the invention may be organic or inorganic and include the hydrochloride, hydrobromide, maleate, sulfate, phosphate, acetate, lactate, tartrate, citrate, organic sulfonates such as methanesuh fonates, and the like.
  • the compounds of the invention have been found to be active in standard pharmacological screening tests to detect tranquilizing activity in mammals.
  • the compound has been found to antagonize aggregationinduced mortality following the administration of amphetamine, a test described by Lasagna, L. and Mc- Cann, W. P., Science 125:1241 1957); Burn, J. H. and Hobbs, R., Arch. int. Pharmacodyn 113:290 (1958), and others.
  • mice 17-27 g male mice 17-27 g
  • mice ten mice per cage are administered the test compound and returned to a stock cage for 30 minutes prior to a 10 mg./kg i. p. injection of d,l-amphetamine sulfate.
  • the group of ten mice is placed in a rectangular glass jar approximately 6" 5" l0".
  • a vehicle-pretreated (control) group is similarly included in another jar.
  • the aggregation of animals within about a 30 square inch area produces mortality following the amphetamine close which is non-lethal in individually caged mice.
  • positive control mice Over a five hour period of aggregation, positive control mice exhibit greater than percent mortality, usually -100 percent.
  • Positive control mice are vehicle-pretreated and amphetamine challenged. Active compounds protect against the incidence of group mortality, often reducing the five hour mortality to zero at effective doses.
  • mice 16-24 g. are weighed and administered the test compound at suitable geometrically spaced doses.
  • each treatment group consisting of mice each, is placed within the counting chamber of Woodard activity cages.
  • the cumulative activity counts resulting from mice interrupting infrared light beams within the counting chamber, are noted 15, 30, 45, 60 and 90 minutes after entry.
  • the ratio of the mean tally of three cages per treatment to the mean tally of three control (vehicle only) treated mice is determined and a value of less than unity evaluated as a depressant effect.
  • Additional tests which have been used and which demonstrate tranquilizing activity in the compound of the invention include the Sidman avoidance assay in rats and the antagonism of caffeineinduced locomotor stimulation in mice.
  • the compounds of the invention may be administered by the intraperitoneal or oral route. When administered intraperitoneally, they are administered in solution in a pharmaceutically acceptable solvent, in doses of about 1 to 30 milligrams per kilogram of body weight of the subject. It is presently preferred to use doses of from 2 to milligrams per kilogram of the antiisomer, since doses in this range have been found to be quite effective in animal tests. Such doses provide good therapeutic ratios, because the intraperitoneal LD has been measured to be approximately 282 mg./kg. for the hydrochloride salt.
  • Administering the hydrochloride salt orally doses of 10 to 50 mg./kg. are used to provide a tranquilizing effect.
  • the compound of the invention and its salts are administered in any of the conventional drug dosage forms.
  • the salts are readily water-soluble, and solutions in the known pharmaceutical extending media, or pills or capsules, can be prepared and employed as desired.
  • Both the compound and its salts are solids and are readily combined with diluents to provide pharmaceutical dosage forms of various types.
  • the compound and its salts generally have been found to incorporate some water of crystallization.
  • the water layer is separated and extracted with dichloromethane, then extracted twice with diethyl ether, and the organic layers are combined.
  • the combined organic layers are evaporated under reduced pressure to a non-volatile residue.
  • Diethyl ether is added, and the ether solution is washed with an equal volume of 5 percent aqueous sodium hydroxide solution twice.
  • the aqueous solution is then acidified, washed with dichloromethane; the dichloromethane extracts are combined and dried over magnesium sulfate.
  • This solution is filtered, and the filtrate is evaporated under reduced pressure to provide 8-carboxydibenzobicyclo[3.2.- l]octadiene.
  • This solid product is fractionally recrystallized from benzene to provide a white solid, melting point l-l C. Nuclear magnetic resonance analysis of this isomer shows it to be essentially pure (greater than percent) anti-isomer.
  • the amount of syn-isomer obtained is substantially decreased by maintaining the temperature of the solution to which carbon dioxide is added at 55 C. until the aqueous ammonium chloride solution is added.
  • the anti-8carboxydibenzobicyclooctadiene chloride product (0.032 mole) from Example 2 is dissolved in dichloromethane, and N-methylpiperazine (10 g., 0.10 mole) is added with stirring. After 30 minutes the mixture is washed successively with equal volumes of water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer is then dried over anhydrous sodium sulfate and filtered; then the filtrate is evaporated under vacuum, giving an oil which solidifies when washed with hexane.
  • the solid product is triturated with hexane and filtered, yielding the solid free base, 8-anti-(N-methylpiperazino-N'- carbonyl)dibenzobicyclo[ 3.2. l ]octadiene, m.p. l72l74 C. (uncorrected).
  • the structural assignment is supported by its infrared spectrum.
  • EXAMPLE 5 Using the methods described in Examples 2, 3 and 4, 8-syn-carboxydibenzobicyclo[3.2.l ]octadiene is converted to white solid 8-syn-(N-methylpiperazine-N- carbonyl) dibenzobicyclo[3.2. l ]octadiene hydrochloride, m.p. 265267 C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Anesthesiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US339359A 1973-03-08 1973-03-08 8-n-methylpiperazinyl-n'-carbonyldibenzo-bicyclooctadiene and salts thereof Expired - Lifetime US3904630A (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US339359A US3904630A (en) 1973-03-08 1973-03-08 8-n-methylpiperazinyl-n'-carbonyldibenzo-bicyclooctadiene and salts thereof
CA193,621A CA1037031A (en) 1973-03-08 1974-02-27 8-n-methylpiperazinyl-n'-carbonyldibenzo-bicyclooctadiene and salts thereof
DE2410982A DE2410982C3 (de) 1973-03-08 1974-03-07 Arzneimitel mit Sedativ- und Tranquilizer-Wirkung
GB1029974A GB1458892A (en) 1973-03-08 1974-03-07 8-n-methylpiperazinyl-n-carbonyl-dibenzobicyclooctadiene and salts thereof
AU66373/74A AU467513B2 (en) 1973-03-08 1974-03-07 8-n-methylpiperazintyl-n'carbonyldibenzobicycloodtadiene
FR7407836A FR2220268B1 (enrdf_load_stackoverflow) 1973-03-08 1974-03-07
JP49026718A JPS526998B2 (enrdf_load_stackoverflow) 1973-03-08 1974-03-07
US05/595,288 US3969505A (en) 1973-03-08 1975-07-11 8-N-methylpiperazinyl-N'-carbonyldibenzobicyclooctadiene and salts thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US339359A US3904630A (en) 1973-03-08 1973-03-08 8-n-methylpiperazinyl-n'-carbonyldibenzo-bicyclooctadiene and salts thereof

Related Child Applications (1)

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US05/595,288 Division US3969505A (en) 1973-03-08 1975-07-11 8-N-methylpiperazinyl-N'-carbonyldibenzobicyclooctadiene and salts thereof

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US3904630A true US3904630A (en) 1975-09-09

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US (1) US3904630A (enrdf_load_stackoverflow)
JP (1) JPS526998B2 (enrdf_load_stackoverflow)
AU (1) AU467513B2 (enrdf_load_stackoverflow)
CA (1) CA1037031A (enrdf_load_stackoverflow)
DE (1) DE2410982C3 (enrdf_load_stackoverflow)
FR (1) FR2220268B1 (enrdf_load_stackoverflow)
GB (1) GB1458892A (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976774A (en) * 1975-06-02 1976-08-24 Riker Laboratories, Inc. Antiemetic method

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3641036A (en) * 1969-03-18 1972-02-08 Delalande Sa De ivatives of 5-carbamoyloxymethyl-3-substitutea dd-oxazoli1 0 01 dinoncess of thereof preparation and their therapeutic application
US3682906A (en) * 1968-12-11 1972-08-08 Bayer Ag Certain 2 - hydroxymethyl-3-carboxylic acid amidoquinoxaline-di-n-oxides (1,4)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2081507B1 (enrdf_load_stackoverflow) * 1970-02-13 1974-10-18 Ciba Geigy Ag
FR2129838A1 (en) * 1971-03-16 1972-11-03 Boehringer Mannheim Gmbh Diuretic/saluretic dibenzo cycloheptene - derivs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3682906A (en) * 1968-12-11 1972-08-08 Bayer Ag Certain 2 - hydroxymethyl-3-carboxylic acid amidoquinoxaline-di-n-oxides (1,4)
US3641036A (en) * 1969-03-18 1972-02-08 Delalande Sa De ivatives of 5-carbamoyloxymethyl-3-substitutea dd-oxazoli1 0 01 dinoncess of thereof preparation and their therapeutic application

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976774A (en) * 1975-06-02 1976-08-24 Riker Laboratories, Inc. Antiemetic method

Also Published As

Publication number Publication date
CA1037031A (en) 1978-08-22
GB1458892A (en) 1976-12-15
JPS49124084A (enrdf_load_stackoverflow) 1974-11-27
FR2220268A1 (enrdf_load_stackoverflow) 1974-10-04
AU467513B2 (en) 1975-12-04
FR2220268B1 (enrdf_load_stackoverflow) 1977-11-10
DE2410982C3 (de) 1981-11-05
JPS526998B2 (enrdf_load_stackoverflow) 1977-02-26
DE2410982A1 (de) 1974-09-26
DE2410982B2 (de) 1981-01-15
AU6637374A (en) 1975-09-11

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