US3860652A - 8-Aminoalkyl substituted dibenzobicyclo {8 3.2.1{9 {0 octadienes - Google Patents

8-Aminoalkyl substituted dibenzobicyclo {8 3.2.1{9 {0 octadienes Download PDF

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Publication number
US3860652A
US3860652A US194056A US19405671A US3860652A US 3860652 A US3860652 A US 3860652A US 194056 A US194056 A US 194056A US 19405671 A US19405671 A US 19405671A US 3860652 A US3860652 A US 3860652A
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dibenzobicyclo
octadiene
mixture
solution
syn
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US194056A
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Walton James Hammar
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Riker Laboratories Inc
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Riker Laboratories Inc
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Priority to BE790673D priority Critical patent/BE790673A/xx
Application filed by Riker Laboratories Inc filed Critical Riker Laboratories Inc
Priority to US194056A priority patent/US3860652A/en
Priority to CA154,558A priority patent/CA1008853A/en
Priority to GB4095174A priority patent/GB1409075A/en
Priority to CH1575772A priority patent/CH579021A5/xx
Priority to GB4974172A priority patent/GB1409073A/en
Priority to GB3443174A priority patent/GB1409074A/en
Priority to FR7238306A priority patent/FR2158040B1/fr
Priority to AU48255/72A priority patent/AU451041B2/en
Priority to DE2252811A priority patent/DE2252811A1/de
Priority to NL7214626A priority patent/NL7214626A/xx
Priority to JP47108399A priority patent/JPS5130066B2/ja
Priority to US05/530,669 priority patent/US3949091A/en
Priority to US05/530,670 priority patent/US3960944A/en
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups

Definitions

  • the present invention provides certain novel 8- substituted dibenzobicyclo[3.2.l]octadiene compounds with advantageous central nervous system activity.
  • the substituent at the 8 position must be a substituted aminoalkyl group.
  • These compounds are antidepressants with a relatively low degree of side effects. In particular, they have no significant effect on heart rate and blood pressure at doses which produce effects associated with anti-depressant activity in test animals. Other effects on the central nervous system, such as anorexia, are also observed.
  • This invention relates to compounds of the formula Formula I wherein R is hydrogen or lower alkyl, R is lower alkyl and -alkis methylene, ethylene or methylmethylene, and acid addition salts thereof.
  • Lower alkyl as used herein means alkyl radicals having 1 to 4 carbon atoms.
  • the compounds of the invention and their pharmaceutically acceptable acid addition salts are active on the mammalian central nervous system. In particular, they show the pharmacological profile of antidepressant agents.
  • the acid addition salts of the compounds of the present invention with inorganic or organic (carboxylic) acids are useful per se, when said salts are pharmaceutically acceptable, or the salts are useful as intermediates from which the free base compounds may be produced, or the salts may be used as intermediates to prepare other salts.
  • Acid addition salts of the compounds of the present invention can be prepared by reaction of acids with the free base of Formula I.
  • reaction of the free base with stoichiometrically equivalent amounts of acids such as hydrohalic acids, for example, hydrochloric acid, hydrobromic acid and the like; sulfuric acid, phosphoric acid, etc.; or with organic acids such as oxalic acid, acetic acid, lactic acid, tartaric acid, citric acid and the like, provides acid addition salts in relatively pure form.
  • Non-pharmaceutically acceptable acid addition salts can be converted into pharmaceutically acceptable addition salts either by neutralization followed by reaction with a suitable pharmaceutically acceptable acid or by an ion exchange reaction.
  • the group -alkis preferably methylene, the group R is preferably methyl, ethyl or hydrogen and the group R is preferably methyl or ethyl.
  • Most preferred compounds of the invention are salts of the compounds 8- (N-methylaminomethyl)dibenzobicyclo[ 3 2.1 ]octadiene and 8-(N,N-dimethylaminomethyl)dibenzobicyclo[3.2.l]octadiene.
  • the most preferred salt is presently the hydrochloride salt, which is a pharmaceutically acceptable salt.
  • the compounds of the invention have been found to demonstrate anti-depressant activity when evaluated in two rodent test methods commonly used for the detection of such activity. These two tests measure antagonism of the depressant syndrome produced following administration of reserpine or of R0 4-1284 (2- hydroxy-2-ethyl-3-isobutyl-9,lO-dimethoxyl,2,3,4,6,7-hexahydrobenzo(a)-quinolizine). These test methods are described by Sulzer et al, Ann. NY. Acad. Sci. 96:279 (1962).
  • the preferred compounds of the invention for example anti-8-(Nmethylaminomethyl)dibenzobicyclo[ 3.2.1 oct adiene and its salts, demonstrate activity in mice and rats at dose levels the same as those of active doses of imipramine hydrochloride, a well-known antidepressant agent, on a milligram per kilogram body weight basis.
  • This information serves to estimate an effective oral human therapeutic dose of 25 to 100 mg/day, although doses as small as 10 mg/day or as large as 200 mg/day could be suitable in unusual instances.
  • the preferred compounds of the invention have a therapeutic index greater than 5.
  • the compounds of the invention may also be administered orally or parenterally.
  • the compounds of Formula I can be used as medicaments in the form of pharmaceutical preparations.
  • these compounds or their salts can, for example, be formulated in admixture with suitable known organic or inorganic inert pharmaceutical carrier materials. Then may be administered orally in the form of tablets, powders, sustained release pellets and the like, or they may be administered orally or parenterally in the form of aqueous solutions or suspensions.
  • Such dosage forms are readily prepared by conventional methods.
  • the anti-depressant action of the compounds of the present invention is sufficiently extended in duration so that protection from depressed states is obtained for periods of about three hours or more by a single nontoxic dose in animals.
  • the compounds of the invention can be prepared by a process which comprises forming a Grignard reagent from the known compound 8- chlorodibenzobicyclol3.2.l ]-octadiene, converting the Grignard reagent to 8-( hydroxyalkyl)substituted dibenzobicyclo[3.2. l ]octadiene, and treating the latter compound to replace the hydroxyl group with a primary or secondary amine residue having the formula t. R2 wherein R is hydrogen or lower alkyl and R is lower alkyl.
  • the compounds of the invention are conveniently prepared starting with the known compound 8-antichlorodibenzobicyclo[3.2.1]octadiene. This compound is converted to the magnesium Grignard reagent idibor'ane Formula III by a Grignard reaction.
  • This Grignard reagent may be used to prepare the compounds of the invention by numerous synthetic sequences, for example it may be reacted with carbon dioxide using standard techniques to prepare the corresponding S-carboxylic acid in the anti form. The syn form of the acid is also formed and is separated by fractional crystallization.
  • novel carboxylic acids and derivatives thereof which are intermediates in the process are included within the compounds of the invention.
  • the primary alcohol II can be converted to the corresponding amine of Formula II by known synthetic sequences such as conversion first to the primary halide by reaction with hydrohalic acid such as hydrochloric acid or hydrobromic acid, followed by reaction with a primary or secondary amine.
  • hydrohalic acid such as hydrochloric acid or hydrobromic acid
  • the alcohol may be converted to a methanesulfonic or p-toluenesulfonic ester followed by a displacement reaction with a primary or secondary amine.
  • the Grignard reagent described hereinabove is reacted with acetaldehyde to provide the corresponding secondary alcohol of Formula III.
  • This secondary alcohol may be converted to a methanesulfonic or p-toluenesulfonic ester and then to a product compound of Formula I by reaction with a primary or secondary amine.
  • the carboxyl group can be reduced to a hydroxymethyl group, the hydroxymethyl group converted to a methanesulfonic or p-toluenesulfonic ester, the ester group displaced by cyanide, the cyano group reduced to an amino group and the amino group alkylated to a secondary or tertiary amine of Formula I.
  • the amount of syn isomer obtained is substantially decreased by maintaining the temperature of the solution to which carbon dioxide is added at l 5 C. until the aqueous ammonium chloride solution is added.
  • EXAMPLE 2 A solution of 65 ml. of thionyl chloride and 18 g. (0.073 mole) of anti-8-carboxydibenzobicyclo[3.2.- l]octadiene is heated to its reflux temperature and maintained at that temperature for one hour. The thionyl chloride is removed by evaporation under reduced pressure. Benzene is added (about 50 ml.), and the mixture is again evaporated to dryness under reduced pressure. Benzene (75 ml.) is added, the flask is fitted with a gas inlet and a Dry Ice-acetone condenser, and the mixture is cooled to 0 C.
  • Methylamine is added through the gas inlet, and the solution is allowed to warm gradually to room temperature. After adding an excess of methylamine, the mixture is stirred overnight at room temperature. Diethyl ether is added, then water; the organic layer is separated off and then washed with 2 N HCl and 5 percent sodium hydroxide solution, and finally with a saturated sodium chloride solution. The organic layer is dried over magnesium sulfate, filtered, then evaporated under reduced pressure to give the desired product. The residual white solid is recrystallized from ethanol to give anti-8-(N- methylcarboxamido )dibenzobicyclo[ 3.2.l ]octadiene, m.p. 230233 C.
  • dimethylcarboxamido)dibenzobicyclo[3.2.1]octadiene is reduced to provide syn-8-(N,N- dimethylaminomethyl)dibenzobicyclo[3.2.1]octadiene hydrochloride, m.p. 247249 C.
  • EXAMPLE 8 Anti-8-(N-methylcarboxamido)dibenzobicyclo[3.2.- 1]octadiene (16 g., 61 mmole) is dissolved in 120 ml. of tetrahydrofuran and cooled to 0 C. The mixture is stirred while adding a 1 molar solution of borane in 120 ml. of tetrahydrofuran. The mixture is warmed slowly to room temperature and finally heated to reflux temperature and maintained at this temperature overnight. The mixture is cooled to- 0 C., 10 ml. of water are added, the mixture is stirred for 15 minutes, then'the mixture is heated to its reflux temperature for 1.5 hours.
  • EXAMPLE l4 Syn-8-( Z-aminoethyl)dibenzobicyclo[ 3.2.1 ]octadiene (4.5 g., 18 mmole), 11.4 g. of formaldehyde (38 percent aqueous solution) and 13.5 g. of formic acid (97 percent aqueous solution) are mixed and heated on a steam bath for about 18 hours. Concentrated hydrochloric acid (4 ml.) is added, and heating is continued for four hours. The mixture is cooled to about 25 C., and 10 percent aqueous sodium hydroxide is added until the mixture is basic.
  • the mixture is extracted with dichloromethane twice; the organic extracts are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. The mixture is filtered, evaporated under vacuum, and ethyl acetate is added.
  • the organic solution is extracted with aqueous hydrochloric acid, the aqueous layer is separated and made basic with 10 percent sodium hydroxide solution.
  • the basic aqueous solution is extracted with several portions of dichloromethane, the combined extracts are dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under vacuum. The residue is taken up in a few ml. of dichloromethane and purified by column chromatography on neutral alumina, eluting with dichloromethane.
  • the product syn-8-[2-(N,N- dimethylamino)ethyl]dibenzobicyclo[ 3 .2.1 ]octadiene, is converted to its hydrochloride salt in diethyl ether by adding hydrochloric acid to a slight excess and collecting the white precipitate.
  • the product is syn-8-[2- (N,N-dimethylamino)ethyl]dibenzobicyclo[3 .2.1 ]octadiene hydrochloride, m.p. 270-272 C.
  • Anti-8-(N-methylaminomethyl)dibenzobicyclo[3.2.- l]octadiene is converted to anti-8-(N-acetamido-N methylaminomethyl)dibenzobicyclo[3.2.1 ]octadiene by reaction with acetic anhydride in the presence of pyridine, and the product is then reduced to anti-8-(N- ethyl-N-methylaminomethyl)dibenzobicyclo[3 .2.l ]octadiene using the method of Example 6.
  • Anti-8-(N-ethyl-N-methylaminomethyl)dibenzobicyclo[3.2. l ]octadiene is isolated as its hydrochloride salt, a white solid, m.p. 208-210 C.
  • EXAMPLE 16 A mixture of 20 ml. of tetrahydrofuran and 1.7 g. mmole) of magnesium turnings is heated to reflux temperature, and 15 g. (62.5 mmole) of anti-8- chlorodibenzobicyclo[3.2. l ]-octadiene in 40 ml. of tet' rahydrofuran is added dropwise. Five drops of 1,2 dibromoethane are added to assist in forming the Grignard reagent. After the addition is completed, the reaction mixture is maintained at its reflux temperature for three hours.
  • the mixture is then cooled to 0 C., and a large excess of ethylene oxide is bubbled in over a period of 30 minutes, while maintaining the temperature of the stirred reaction mixture at 0 C.
  • the mixture is warmed to approximately 50 C. for about 2 hours, then cooled to about 25 C. and poured into about ml. of a saturated ammonium chloride solution.
  • Methylsulfonyl chloride (2.3 g., 20 mmole) is added slowly to a solution of 4 g. (16 mmole) of anti-8-(2- hydroxyethyl)dibenzobicyclo[ 3.2.1 ]octadiene in 15 ml. of pyridine.
  • the mixture is allowed to warm, with stirring, to about 25 C.
  • the mixture is stirred overnight at this temperature.
  • the mixture is then poured into about 75 m1. of cold 6 N hydrochloric acid; the acidic mixture is extracted with several portions of diethyl ether, and the combined ether extracts are washed with cold water.
  • the ether extracts are then dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness under vacuum to obtain the desired product, anti-8-( 2-methylsulfonoxyethyl )dibenzobicyclo[ 3 2.- l]octadiene.
  • the structure of the product is confirmed by infrared spectrum; the product is used as isolated for the next process step as described in Example 18.
  • EXAMPLE l8 Dimethylamine (6.3 g.) is dissolved in 25 ml. of ethanol. This solution is mixed with 3.5 g. (11 mmole) of anti-8-( Z-methanesulfonoxyethyl )dibenzobicyclo[ 3 .2 l]octadiene. The mixture is heated to reflux temperature and maintained at reflux overnight. The reaction mixture is then evaporated to dryness under vacuum, and the residue is dissolved in a benzenediethyl ether mixture. This solution is extracted with 4 N hydrochloric acid. The aqueous layer is separated, made basic with sodium hydroxide, and extracted with several portions of dichloromethane.
  • the product is isolated from the residue by column chromatography on neutral alumina.
  • the product is placed on the column as a solution in a few ml. of diethyl ether.
  • the column is eluted with hexane, then a benzene-hexane mixture, then with benzene alone, next with diethyl ether, and finally with ethyl acetate.
  • the benzene and ether fractions solidify after evaporation of the solvent to provide the desired product, anti- 8-(l-hydroxyethyl)dibenzobicyclo[3.2.1]octadiene.-
  • the structure of the product is confirmed by its infrared spectrum.
  • EXAMPLE 20 The intermediate compound prepared in Example 19, anti-8-(1-hydroxyethyl)dibenzobicyclo[3.2.l ]octadiene, is reacted with methanesulfonyl chloride according to the method of Example 11 to provide the methylsulfonoxyethyl-substituted intermediate. The structure is confirmed by its infrared spectrum; the intermediate is used without further purification in the next step of the reaction.
  • R is hydrogen or lower alkyl, R is lower alkyl and -alkis methylene, ethylene or methylmethylene; and acid addition salts thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US194056A 1971-10-29 1971-10-29 8-Aminoalkyl substituted dibenzobicyclo {8 3.2.1{9 {0 octadienes Expired - Lifetime US3860652A (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
BE790673D BE790673A (fr) 1971-10-29 Dibenzobicyclo (3.2.1) octadienes substitues en positions 8
US194056A US3860652A (en) 1971-10-29 1971-10-29 8-Aminoalkyl substituted dibenzobicyclo {8 3.2.1{9 {0 octadienes
CA154,558A CA1008853A (en) 1971-10-29 1972-10-19 8-substituted dibenzobicyclo(3.2.1)octadienes
GB3443174A GB1409074A (en) 1971-10-29 1972-10-27 8-substituted dibenzobicyclo-3,2,1 octadienes
CH1575772A CH579021A5 (enrdf_load_html_response) 1971-10-29 1972-10-27
GB4974172A GB1409073A (en) 1971-10-29 1972-10-27 8-substituted dibenzobicyclo-3,2,1 octadienes
GB4095174A GB1409075A (en) 1971-10-29 1972-10-27 8-substituted dibenzobicyclo-3,2,1-octadienes
FR7238306A FR2158040B1 (enrdf_load_html_response) 1971-10-29 1972-10-27
AU48255/72A AU451041B2 (en) 1971-10-29 1972-10-27 8-substituted dibenzobicyclo. 2. 1]octadie
DE2252811A DE2252811A1 (de) 1971-10-29 1972-10-27 In 8-stellung substituierte dibenzobicyclo eckige klammer auf 3,2,1 eckige klammer zu - octadiene
NL7214626A NL7214626A (enrdf_load_html_response) 1971-10-29 1972-10-27
JP47108399A JPS5130066B2 (enrdf_load_html_response) 1971-10-29 1972-10-28
US05/530,669 US3949091A (en) 1971-10-29 1974-12-09 8-Substituted dibenzobicyclo[3.2.1]octadienes for treating depression
US05/530,670 US3960944A (en) 1971-10-29 1974-12-09 8-Carboxamide dibenzobicyclo(3.2.1)octadienes

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US194056A US3860652A (en) 1971-10-29 1971-10-29 8-Aminoalkyl substituted dibenzobicyclo {8 3.2.1{9 {0 octadienes

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US05/530,669 Division US3949091A (en) 1971-10-29 1974-12-09 8-Substituted dibenzobicyclo[3.2.1]octadienes for treating depression
US05/530,670 Division US3960944A (en) 1971-10-29 1974-12-09 8-Carboxamide dibenzobicyclo(3.2.1)octadienes

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BE (1) BE790673A (enrdf_load_html_response)
CA (1) CA1008853A (enrdf_load_html_response)
CH (1) CH579021A5 (enrdf_load_html_response)
DE (1) DE2252811A1 (enrdf_load_html_response)
FR (1) FR2158040B1 (enrdf_load_html_response)
GB (3) GB1409074A (enrdf_load_html_response)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3892756A (en) * 1972-02-04 1975-07-01 Roussel Uclaf Novel dibenzocycloheptenes
US3976774A (en) * 1975-06-02 1976-08-24 Riker Laboratories, Inc. Antiemetic method

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1087174A (en) * 1976-12-08 1980-10-07 Atsuyuki Kojima Tetracyclic compounds and production thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3422104A (en) * 1964-10-20 1969-01-14 Geigy Chem Corp 9,10-dihydro-11-amino-alkylene-9,10-ethanoanthracenes
US3423425A (en) * 1964-06-19 1969-01-21 Ciba Geigy Corp 11-aminoaliphatic - 5,10 - methanodibenzo(a,d)(1,4)cycloheptadienes and the salts thereof
US3452102A (en) * 1966-08-17 1969-06-24 Upjohn Co 1,2-diphenyl-6-methoxy-1,2,3,4-tetrahydro-1,2-naphthalenediols

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3423425A (en) * 1964-06-19 1969-01-21 Ciba Geigy Corp 11-aminoaliphatic - 5,10 - methanodibenzo(a,d)(1,4)cycloheptadienes and the salts thereof
US3422104A (en) * 1964-10-20 1969-01-14 Geigy Chem Corp 9,10-dihydro-11-amino-alkylene-9,10-ethanoanthracenes
US3452102A (en) * 1966-08-17 1969-06-24 Upjohn Co 1,2-diphenyl-6-methoxy-1,2,3,4-tetrahydro-1,2-naphthalenediols

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3892756A (en) * 1972-02-04 1975-07-01 Roussel Uclaf Novel dibenzocycloheptenes
US3976774A (en) * 1975-06-02 1976-08-24 Riker Laboratories, Inc. Antiemetic method

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BE790673A (fr) 1973-04-27
GB1409075A (en) 1975-10-08
AU4825572A (en) 1974-05-02
DE2252811A1 (de) 1973-05-03
NL7214626A (enrdf_load_html_response) 1973-05-02
JPS5130066B2 (enrdf_load_html_response) 1976-08-30
CH579021A5 (enrdf_load_html_response) 1976-08-31
CA1008853A (en) 1977-04-19
GB1409073A (en) 1975-10-08
FR2158040A1 (enrdf_load_html_response) 1973-06-08
JPS4852757A (enrdf_load_html_response) 1973-07-24
AU451041B2 (en) 1974-07-25
GB1409074A (en) 1975-10-08
FR2158040B1 (enrdf_load_html_response) 1976-07-02

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