Classifications

• • 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
  • A61K31/33—Heterocyclic compounds

Definitions

• This invention relates to 5H-dibenzo-[a,d]-10,1l-dihydrocycloheptenes which are substituted at the 5carbon atom with an aminopropyl or aminopropylidene radical and, more particularly, to such compounds having a 10- or ll-hydroxy substituent.
• the invention also includes a novel process for producing these compounds.
• the compounds of the invention are useful in the treatment of mental disease in that they are anti-depressants and serve as mood elevators or psychic energizers, and as intermediates for the preparation of secondary amines, some of which are members of a class having pharmacological activity.
• they may be administered in any of the usual pharmaceutical forms such as powders, capsules, tablets, elixirs, solutions and aqueous suspensions.
• the daily dosage is within the range of from about 5 mg. to about 250 mg, preferably taken in divided amounts over the day,
• the compounds are preferably administered in the form of their acid addition salts and these salts are included within the scope of this invention.
• R and R are similar or dissimilar and may be hydrogen, an alkyl radical having up to 6 carbons, either straight or branched chain, or cycloalkyl having up to 8 carbons or phenyl including phenyl substituted with halogens, alkyl or alkoxy groups or aralkyl such as benzyl, provided that when R and R are other than alkyl radicals the total number of carbon atoms in R and R does not exceed nine; where R and R are lower alkyl radicals, they may be linked together through an atom selected from the group consisting of carbon, nitrogen and oxygen to form a heterocyclic ring having from five to six atoms therein such as l-piperidyl, l-pyrrolidyl, 4-morpholinyl and l-lower alkyl-4-piperazinyl; X and X are
• typical compounds formed in accordance with the present invention are: 5-('ydimethylaminopropylidene)-5H dibenzo-[a,d]-IO-hydroxycycloheptene; 5- (v-methylaminopropylidene) 5H dibenzo-[a,d]-10-hydroxycycloheptene; 5-( y-dimethylaminopropyl) SH-dibenzo-[a,d]-10-hydroxycycloheptene; S-(y-methylaminopropyl -5H-dibenzo- [a,d] -1 O-hydroxycycloheptene; 5- aminopropylidene) 5H-dibenzo-[a,d] IO-hydroxycycloheptene; and 5-( -aminopropyl)-5H-dibenzo-[a,d]-l0-hydroxycycloheptene.
• CHCHzCHzNRR The process of the present invention begins with the known aminopropyl or aminopropylidene compounds which are unsaturated at the 10 and 11 positions.
• the preparation of these compounds is described in numerous places in the literature, for example, in British Patents Nos. 858,187 and 858,188 and Belgian Patents Nos. 577,057 and 578,122.
• These compounds are generally prepared from the known 5I-I-dibenzo-[a,d]-cycloheptene- 5-ones which may be substituted with X and X substituents.
• the starting compounds for the ketones, and particularly those having substituents on the benzene rings may be made by following the teachings of T. W. Campbell et al. in an article appearing in Helv. Chem. Acta, vol. 36, pp. 1489-1499 (1953).
• the first step involves a novel hydroboration of an aminopropyl or aminopropylidene derivative of a 5H-dibenzo-[a,d]- cycloheptene which is unsaturated at the and 11 positions to form a 10 or 11 boron-substituted intermediate.
• 5-('y-methylaminopropyl)-5I-I-dibenzocycloheptene is hydroborated using diborane as the hydroborating agent to form the amine borane salt of a 10 or 1l-BH derivative of the starting compound.
• Suitable hydroborating agents are the borane aluminum alcoholates, such as borane aluminum isopropylate, which reagent and its hydrocarbon equivalents are described in United States Patent 2,903,470.
• Other boron compounds suitable for use in this reaction contain at least one BH bond in the molecule as, for example, in such compounds as diborane, amineboranes, alkyl boranes, aryl boranes, alkyl-aryl boranes and suitably the aforementioned borane aluminum alcoholates.
• the reaction is preferably carried out in an inert solvent, such as tetrahydrofuran.
• a less reactive agent such as borane aluminum alcoholate
• the hydroboration may be carried out in the absence of a solvent.
• the reaction is conducted under a protective nitrogen atmosphere in order to prevent oxidation of any of the boron compounds.
• the starting compound contains a propylidene side chain
• a minimum reaction temperature and time are used at which only the endocyclic or 10,11-unsaturated bond will react.
• not more than two moles of hydroborating agent are used..
• the desired hydroxy group may be formed at this location by oxidatively hydrolyzing the borane group to a hydroxy group.
• the hydrolysis is carried out in a basic aqueous alcoholic solution containing the oxidizing agent.
• a typical oxidative hydrolysis medium is an aqueous solution of sodium hydroxide in methanol containing hydrogen peroxide, although others may be used as well.
• the amine borane salt of a 10 or 11-BH substituted derivative of 5-( -methylaminopropyl)-5H-dibenzo-[a,d]-cycloheptene is subjected to oxidative hydrolysis to form the amine borane salt of a 10 or ll-hydroxy derivative of S-(y-methylaminopropyD- dibenzo-[a,d]-cycloheptene.
• the final step in the preparation of the novel compounds of the present invention involves an oxidation of the amine borane salt to the free amine.
• This oxidation is preferably carried out using oxidizing agents capable of converting the amine boranes to free amines.
• a preferred oxidizing agent for efiecting this step is iodate ion, although other oxidizing agents may be used as well.
• purification and separation of the desired product from the reaction mixture affords the desired hydroxy compound in high yield.
• the compounds of the present invention are capable of existing in one or more isomeric forms. These forms may be isolated from the reaction mixture by separation procedures known in the art as, for example, by the chromatographic technique described in detail in the examples.
• the amine borane salt thus obtained is dissolved in 200 ml. of methanol and oxidized by slow addition of 90 ml. of a 10% K10 solution at room temperature in 10 ml. of concentrated HCl.
• the run is complete when a presistent brown coloration due to the presence of iodine, is observed.
• the iodine then is removed by the addition of a small amount of sodium thiosulfate.
• the pH is adjusted to about 8.5 by the addition of concentrated NaOH solution and subsequently all of the methanol is removed by vacuum distillation.
• To the residue is added a water-in-ether mixture, the ether layer washed with water and the product extracted from the ether with 1 N HCl solution.
• the acidic extract extract then is alkalized and the base extracted with water, washed with saturated NaCl solution, dried over MgSO and evaporated to dryness in vacuo. 12.6 g. of the product is obtained from the residue, which is purified by crystallization from an ethanol-isopropanol solution as the hemioxalate. After two recrystallations, the following analysis of the hemioxalate is obtained.
• the amine borane salt then is dissolved in a mixture of 1000 ml. of methanol, 100 ml. of HCl and oxidized by slow addition of a 10% K10 solution at 15 until an iodine coloration persists, which is discolorized by the addition of a small amount of sodium thiosulfate. Thereafter, the pH is adjusted to about 8.5 by the addition of concentrated NaOH solution and subsequently ail of the methanol is removed by vacuum distillation. To the residue is added a water-in-ether mixture, the ether layer washed with water and the product extracted from the ether with 1 N HCl solution.
• the acidic extract then is alkalized and the base extracted with water, Washed with saturated NaCl solution, dried over MgSO and evaporated to dryness in vacuo. 12.6 g. of the prodnot is obtained from the residue.
• the product is purified by transformation into the oxalic acid salt by the addition of 500 ml. of 0.5 molar oxalic acid in isopropanol solution to 400 ml. of an isopropanol solution of the impure material. After two recrystallations the following analysis of the oxalate is obtained.
• EXAMPLE VII Separation and isolation of isomeric forms of 5-(7- dimethylaminopropyliaene) SH-dibenzo-[adklO-hydroxy-Z 0,1 1 -dihydr0cycl0heptene 40 grams of the purified form of 5-(ql-dimethylaminopropylidene) 5H dibenzo [a,d]-10-hydroxy-10,1l-dihydrocycloheptene (Example IV) is dissolved in ml. of benzene and chromatographed on 700 g. of alumina.
• the chromatogram is developed by benzene, then with benzene-chloroform mixtures containing 10%, 25%, and 30% chloroform. In the 30% chloroform-containing mixture, 11.0 g. of a crystalline product is obtained. This is purified by triturating with hexane, followed by repeated recrystallizations from benzene. Further purification is achieved by a second chromatography on alumina, followed by recrystallizations from benzene. Large crystals are obtained, M.P. l356.
• a method of making compounds of the formulae CHCH CHZNRR' wherein R and R are selected from the group consisting of hydrogen and alkyl radicals having up to 6 carbon atoms which comprises oxidizing the amine borane salt of the formulae IBHs CHOHZCHZNRR 13H; H OHQCHQGHZNRR wherein R and R are as defined, to produce the desired compound.
• a method of making 5-('y-methylaminopropyl)- 5H dibenzo [a,d]10-hydroXy-1O,1l-dihydrocycloheptene which comprises hydroborating S-(v-methyIaminopropy1)-5H-dibenzo-[a,d]-cyoloheptene with diborane in an inert solvent, oxidatively hydrolyzing the hydroborated product thereof to form the amine borane salt of 5-('ymethylaminopropyl) 5H dibenzo [a,d]-IO-hydroxy- 10,1l-dihydrocycloheptene and oxidizing the amine borane group of the salt with iodate ion to form the desired compound.
• a method of making 5-('y-dimethylaminopropylidene) 5H dibenzo [a,d]-10-hydroxy-10,1l-dihydrocycloheptene which comprises hydroborating 5 dimethylaminopropylidene) 5H dibenzo-[a,d1-cycloheptene with borane aluminum isopropylate, oxidatively hydrolyzing the product of the hydroboration to form the amine borane salt of the desired product and oxidizing the amine borane group of the salt with iodate ion to form the desired compound.
• a method of making 5-('y-methylarninopropyl)- 5H dibenzo [a,d] 10-hydroxy-10,1l-dihydrocycloheptene which comprises hydroborating 5-( -methylaminopropyl) 5H dibenzo [a,d]-cycloheptene with diborane in an inert solvent at about C., oxidatively hydrolyzing the hydrohorated product thereof in basic solution with hydrogen peroxide to form the amine horane salt of -('y methylaminopropyl) 5H dihenzo [a,d]-10-hydroxy- 10,11-dihydrocycloheptene and oxidizing the amine borane group of the salt with iodate ion to form the desired compound.
• a method of making 5-(' -dimethylaminopropylidene) 5H dibenzo [a,d]-10-hydroxy-l0,ll-dihydrocycloheptene which comprises hydroborating S-(y-dimethylaminopropylidene) 5H dibenzo [a,d]-cycloheptene with borane aluminum isopropylate at about 130 C., oxidatively hydrolyzing the product of the hydroboration in basic solution with hydrogen peroxide to form the amine borane salt of the desired product and oxidizing the amine borane group of the salt with iodate ion to form the desired compound.
• a method of making compounds of the formulae CHCHgCHaNRR or i wherein R and R are selected from the group consisting of hydrogen and alkyl radicals having up to 6 carbon atoms which comprises hydroborating the corresponding 10,11-unsaturated compound and oxidatively hydrolyzing the product thereof to produce the amine borane salt of the formulae I EH3 CHCHgCHgNRR' and oxidizing the amine borane group to produce the desired compound.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
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Citations (5)

• 1962
  • 1962-09-14 US US223840A patent/US3234279A/en not_active Expired - Lifetime
• 1963
  • 1963-08-27 GB GB33896/63A patent/GB1030025A/en not_active Expired
  • 1963-09-09 AT AT726563A patent/AT250324B/de active
  • 1963-09-09 DE DE19631468279 patent/DE1468279B2/de active Granted
  • 1963-09-13 CH CH1130063A patent/CH454129A/de unknown
  • 1963-09-13 BR BR152733/63A patent/BR6352733D0/pt unknown
  • 1963-09-13 NL NL63297898A patent/NL145218B/nl unknown
  • 1963-12-12 FR FR957013A patent/FR3215M/fr active Active

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