Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
  • C07C63/33—Polycyclic acids
  • C07C63/331—Polycyclic acids with all carboxyl groups bound to non-condensed rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms

Definitions

• the invention relates to therapeutically active dibenzocycloheptane derivatives, to processes for their preparation, and to pharmaceutical compositions containing them. According to the present invention there are provided new compounds of the general formula I.
• R and R are each selected from the group consisting of a hydrogen atom, a halogen atom and a lower alkyl group, preferably an alkyl group having at most 4 carbon atoms,
• R is a member of the group consisting of a hydrogen atom, an alkyl group, preferably a lower alkyl group such as methyl, ethyl, and propyl, and an aralkyl group, preferably a phenyl-lower alkyl group such as benzyl, phenethyl, alphamethylphenethyl, and the like, n being an integar having the value 1 or 2, and the salts thereof.
• lower alkyl is used in its conventional sense as designating alkyl groups of up to 7 carbon atoms.
• the particularly preferred compounds are those of Formu a I wherein X represents the CH -CH group, R
• R is in the 3-position and represents hydrogen, chloro or methyl, R is hydrogen, and R is methyl.
• the salts of the dibenzocycloheptane derivatives coming within the purview of this invention include the acidaddition salts, more particularly the non-toxic acid addition salts, i.e., salts, which are not harmful to the animal organism when used in therapeutic doses.
• Acids useful for preparing the acid addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid) and organic acids, such as oxalic, maleic, tartaric, citric, acetic, and succinic acid.
• the compounds of this invention are therapeutically active compounds which have utility as stimulants. Apart from their stimulating activity, the compounds also exhibit anti-histaminic and atropine-like properties.
• the toxicity of the compounds according to the invention, expressed in LD on mice, is about 30 mg./kg. after intravenous, and about 600 mg./kg. after oral administration.
• the novel compounds of this invention can be administered orally or parenterally in conventional dosage forms such as tablets, capsules, injection solutions, or the like, by incorporating the appropriate dose of the compound with carriers according to accepted pharmaceutical practice.
• the compounds of this invention can be prepared from the corresponding ketone having the general formula wherein X, R and R have the meaning hereinbefore defined, and this ketone first being converted into a carbinol intermediate of the general formula by reduction of the ketone of general Formula H, by treatment with a reducing agent such as sodium borohydride, sodium amalgam, aluminum isopropoxides and lithium aluminum hydride.
• a reducing agent such as sodium borohydride, sodium amalgam, aluminum isopropoxides and lithium aluminum hydride.
• the resulting alcohol is then interacted with a halide (preferably chloride) of the formula hlalogen R3 IV the reaction preferably being conducted in the presence of a basic condensation reagent such as sodamide.
• Compounds of Formula II, wherein X represents a CH:CH group are preferably obtained by conversion of the CH -CH group into the -CH CH group by conventional methods such as bromination followed by removal of H131".
• a substituted phthalic anhydride is used as a reactant in the above series of reactions, the position of the substituent on the resulting benzalphthalide will depend on the position of the substituent on the phthalic anhydride.
• ortho-substituted phthalic anhydride is condensed with phenylacetic acid, a mixture of 4- and 7- substituted 3-benzalphthalides is obtained.
• phthalic anhydride halophthalic anhydrides, such as 3- and 4-chlorophthalic anhydride, 3- and 4-bromophthalic anhydride, and 3- and 4-fiuorophthalic anhydride
• alkylphthalic anhydrides such as 3- and 4-methyl phthalic anhydride, 3- and 4-ethylphthalic anhydride, 3- and 4-isopropylphthalic anhydride, and 3- and 4-tertiary butylphthalic anhydride.
• phenylacetic acid halo-phenylacetic acids, such as 2-, 3- and 4-chlorophenylacetic acid, 2-, 3- and 4-bromopheny1- acetic acid, and 2-, 3- and 4-fluorophenylacetic acid, alkyl phenylacetic acids, such as 2-, 3- and 4-methyl phenylacetic acid, 2-, 3- and 4-ethylphenylacetic acid, 2-, 3- and 4-isopropylphenylacetic acid, and 2-, 3- and 4-tertiary butylphenyl acetic acid.
• a compound having the formula Rl R2 is reacted with a compound of the general formula I Ra Wherein A and B are different and each represents a halogen (preferably chlorine) atom or. the group-OM, in which M is an alkali metal atom, or A represents a halogen atom or a hydroxyl group and B represents a hydroxyl group and R R and X are as hereinbefore defined.
• the reaction can be carried out in the presence or absence of an inert organic solvent.
• a represents a halogen atom and B an OH-group the reaction can be carried out while using an excess of the amino alcohol or with the addition of another acid-binding substance.
• the chloride of the tri-cyclic alcohol is reacted with an excess of the aminoalcohol at a temperature of about 140-160 C., whereby the hydrochloride of the aminoalcohol and the free base of the desired compound are formed.
• both reaction components are preferably heated, either dry or in solution, in the presence of an organic sulphonic acid, e.g., paratoluene sulphonic acid.
• A represents an O-alkali metal group or a halogen atom
• the compounds can be produced from the corresponding alcohols in a manner known per se.
• the preparation of the acid addition salts from the base suitably takes place by methods known per se, for example, by mixing equivalent quantities of base and acid in an inert organic solvent followed by filtration of the salt.
• Typical compounds of the Formula II which may be used for the manufacture of the compounds according to the invention, e.g. dibenzo-(a,d) 1,4-cycloheptadienone-5 (boiling at 203204) (7 mm. Hg) and dibenzo-(a,e) 1,3,5-cycloheptatrienone-5 (melting point 90-91 C.) are known from the literature.
• the first mentioned compound has been described by W.Deutschs and H. J. Klinkhammer, Ber. 83, 367371 (1950) the latter by E. D. Bergmanu et al., Bull. Soc. Chem. Fr., 18, 684-692 (1951). While the compounds of this invention are produced directly from compounds of the Formula III, these latter compounds are, in efiect, intermediates in producing the compounds of the invention from the corresponding ketones of the Formula II.
• the fol-lowing examples illustrate the invention (all temperatures being in centigrade).
• the first ten examples are directed to the preparation of the ketones of the Formula II and the remaining examples are directed to the preparation of the carbinol intermediates and the final compounds of this invention.
• the reaction mixture is heated rapidly in an oil-bath until the internal temperature reaches 230. During'the next three hours the internal temperature is slowly raised to 240, during which the water formed in the reaction is allowed to distill out. The mixture is then cooled to 90 and the product dissolved in 400 ml. of boiling alcohol, the solution being filtered to separate a small amount of insoluble material and allowed to cool. The benzalphthalide is filtered and washed with cold alcohol. It is sufliciently pure vfor use in the next step.
• EXAMPLE 2 1- and 4-chl0r0 dibenzo (a,d) 1,4-cycl0heptadien0ne-5
• EXAMPLE 3 3-chl0r0 dibenzo (a,d) 1,4-cycl0heptadien0ne-5
• melting point 5557 is obtained.
• the melting point can be increased to 62.5- 63.5 by further crystallization from petroleum ether.
• 4-tertiary butylphenylacetic acid of melting point 79.580.5 is prepared by converting tertiary butyl benzene into 4-tertiary butylbenzyl chloride. This compound in turn is converted into the corresponding cyanide as described by Skinner et al. I. Am. Chem. Soc. 73, 2230 (1951). The nitrile is saponified by treatment under reflux with potassium hydroxide in an aqueous ethanol solution.
• EXAMPLE 8 3-methyl dibenzo (a,d) 1,3,5-cyclheplatrienone-5
• a mixture of 6.7 g. of 3-methyl dibenzo (a,d) 1,4-cycloheptadienone-5, 5.3 g. of N-bromosuccinimide and 0.1 g. of benzoylperoxide is boiled for 2 hours in 25 ml. of carbon tetrachloride under reflux cooling. After cooling, the succinimide is removed by filtration, whereupon the solvents are removed by evaporation.
• the resulting monobromo compound can be recrystallized from petroleum ether (boiling range 60- 80).
• EXAMPLE 13 3-methyl dibenzo (a,e), 1,3,5-cycl0heptatrien0l-5
• An etheral solution of 11.5 g. of 3-methyl dibenzo (a,e) 1,3,S-cycloheptatrienone-S is added to a solution of 1.0 g. of lithiumaluminumhydride in 200 ml. of ether.
• the mixture is then refluxed for 4 hours, after which it is decomposed by addition of moist ether and aqueous acetic acid.
• the ethereal layer is washed with water, dilute sodium hydroxide solution, and again with water, and subsequently dried on sodium sulphate. Evaporation of the solvent yields 8.5 g. of 3-methyldibenzo (a,e) 1,3, S-cycloheptatrienol-S, melting at 1181l9.5 after crystallization from ligroin (boiling range 6080).
• EXAMPLE 14 S-methyldibenzo (a,d) 1,4-cycI0heptadien0l-5 Following the procedure of Example 12, but substituting an equivalent amount of 3-methyldibenzo (a,d) 1,4-cycloheptadienone-5 for the 3-chlorodibenzo (a,d) 1,4- cycloheptadienone-S, 3-methyl dibenzo (a,d) 1,4-cycloheptadienol-S, melting point 124125.5, is obtained in 87% yield.
• EXAMPLE 17 4-(dibenz0 (a,d) 1,4-cycl0heptadien-5-yloxy) l-mctlzylpiperidine salt with maleic acid
• (a) Preparation of 4-(dibenz0 (a,d) 1,4-cycloheptadien-S-yloxy)-1-methyl-piperidine.-130 g. of dibenzo (a,d) l,4-cycloheptadienol-5 is dissolved in benzene and hydrogen chloride is then passed through the solution for half an hour. The solution is dried with calcium chloride, and after filtration, evaporated to dryness to remove all hydrogen chloride The residue (137.1 g.
• dibenzo (a,d) 1,4-cycloheptadien-S-ylchloride) is dissolved in 500 ml. of anhydrous xylene and added to a boiling solution of 138.0 g. l-methyl piperidine-401 in 500 nrl. of anhydrous xylene under stirring.
• the reaction mixture is refluxed for 3 hours. It is then cooled, whereafter water is added. After separation the water layer is extracted with xylene and the combined organic layers are dried with sodium sulphate.
• maleic acid salt can be prepared either from the crude or the distilled base by dissolving the base in as little Warm alcohol as possible and adding to the solution the calculated amount of maleic acid in a small amount of alcohol. The solution is warmed at a temperature of 40 and then ether is added until an opalescence occurs. The salt precipitates on cooling; filtration yield 165 g. of 4-(dibenzo (a,d) 1,4-cycloheptadien--yloxy) 1 methylpiperidine maleinate (64%), melting at about 153-156.
• EXAMPLE 18 3-(dibenzo (a,d) 1,4-cycloheptadien-5-yloxy)-1-methylpyrrolidz'ne salt with maleic acid Following the procedure of Example 17, but substituting an equivalent amount of 1-methylpyrrolidine-3-ol for the l-methyl piperidine-4-ol in Step a, 3-(dibenzo (a,d) 1,4-cycloheptadien-5-yloxy)-1-methy1 pyrrolidine maleinate is prepared in 71% yield. Melting point 106-107".
• a typical dosage unit contains 25 to 50 mg. of the active compound and 75 to 125 mg. of a pharmacologically-acceptable inert carrier.
• a pharmacologically-acceptable inert carrier 25 to 50 mg. of the active compound and 75 to 125 mg. of a pharmacologically-acceptable inert carrier.
• compositions containing the product compounds of the invention are typical examples.
• a compound selected from the group consisting of free bases of the formula wherein X is selected from the and CH CH-,
• R and R are each selected from the group consisting of hydrogen, halogen, and lower alkyl
• R is a member of the group consisting of hydrogen, lower alkyl, and phenyl [lower alkyl],
• WALTER A MODANCE, Primary Examiner.

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Cited By (2)

• 1960
  • 1960-03-29 CH CH351160A patent/CH400108A/de unknown
  • 1960-03-29 CH CH78965A patent/CH410931A/de unknown
  • 1960-04-01 GB GB11550/60A patent/GB943604A/en not_active Expired
• 1963
  • 1963-04-30 US US277013A patent/US3209007A/en not_active Expired - Lifetime
  • 1963-10-09 DK DK474263AA patent/DK106732C/da active
  • 1963-10-18 DE DE19631470127 patent/DE1470127A1/de active Pending
  • 1963-11-12 FR FR953340A patent/FR3745M/fr active Active

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