US3227716A - Therapeutically-active dibenzocycloheptane derivatives - Google Patents

Therapeutically-active dibenzocycloheptane derivatives Download PDF

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US3227716A
US3227716A US277014A US27701463A US3227716A US 3227716 A US3227716 A US 3227716A US 277014 A US277014 A US 277014A US 27701463 A US27701463 A US 27701463A US 3227716 A US3227716 A US 3227716A
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dibenzo
acid
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August F Harms
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Koninklijke Pharmaceutische Fabrieken NV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • 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

Definitions

  • This invention relates to therapeutically active dibenzocycloheptane derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
  • X is a radical selected from the group consisting of and 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 carhon-atoms,
  • Y is a member of the group consisting of a lower alkylene group, preferably a saturated straight or branched hydrocarbon chain having at most 6 carbon atoms, and a lower alkylene group interrupted by an oxygen atom, preferably a saturated hydrocarbon chain interrupted by an oxygen atom and having at most 5 carbon atoms,
  • Z is a member of the group consisting of wherein R is a member of the group consisting of a hydrogen atom and a lower alkyl group, preferably an alkyl group having not more than 6 carbon atoms, and R is a member of the group consisting of a lower alkyl group, preferably an alkyl group having not more than 6 carbon atoms,
  • A is a member of the group consisting of H2.
  • R represents a lower alkyl group, preferably an alkyl group having not more than 6 carbon atoms, and salts thereof.
  • Typical compounds of the invention have the following formulae:
  • X represents the CH .CH group
  • Y is a saturated hydrocarbon chain having two to three carbon atoms (i.e., ethylene, trimethylene-1,3, and propylene-1,2)
  • Z represents a dialkyl amino radical, an N- pyrrolidino radical or an N-morpholino radical
  • R is in the 3-position and represents hydrogen, chloro, or methyl, ethyl, propyl, isopropyl, and tertiary butyl, and R is hydrogen.
  • the salt-s 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 acds, such as oxalic, maleic, tartaric, citric, acetic, and succinic acid.
  • the compounds of this invention are therapeutically active com-pounds which have utility as antihistaminics. Apart from their antihistaminic activity, the compounds also exhibit a remarkably strong anti-acetyl choline activity. Moreover, they have a central activity, as appears, inter alia, from their action on tremors induced by the compound 1,4 dipyrrolidinobutyne (2) (tremorine), from the reduction of the compulsive circling in guinea pigs caused by the administration of eserine (physo- 'stigmine), and from the prolongation of the sleeping period of mice after subcutaneous injection.
  • tremorine 1,4 dipyrrolidinobutyne (2)
  • the toxicity of the compounds according to the invention, expressed in LD on mice, is about 40 mg./k-g. after intravenous, and about 200 mg./kg. after subcutaneous, 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 starting keto compound is suitably prepared by interacting a phthalic anhydride with a phenylacetic acid to yield a benzalphthalide derivative, which in turn is reacted with phosphorus and hydroiodic acid to yield the corresponding dibenzyl-o-carbonic acid.
  • the resulting carbonic acid derivative is then cyclized and condensed by treatment with phosphorus pentoxide at an elevated temperature or by treatment of the acid halide of the carbonic acid with a Friedel-Crafts catalyst such as aluminum chloride. This series of reactions is shown by the following equations, wherein R and R have the meanings hereinbefore defined:
  • 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.
  • orthosubstituted phthalic anhydride is condensed with phenylacetic acid, a mixture of 4- and 7-substituted 3-benzalphthalides is obtained.
  • a substituted phenylacetic acid 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 phenylacetic acid.
  • an ortho-substituted phenylacetic acid is condensed with phthalic anhydride and the remaining steps of the process are carried out, a l-substituted dibenzo(a,d)- 1,4-cycloheptadienone-5 is obtained.
  • a meta-substituted phenylacetic acid is used, a mixture of 2-substituted and 4-substituted dibenzo(a,d)-l,4-cycloheptadienones-5 is prepared, which can be separated by fractional crystallization. If a para-substituted phenylacetic acid is used, a 3-substituted dibenzo(a,d)-1,4-cycloheptadienone-5 is obtained.
  • phthalic anhydride halophthalic anhydrides, such as 3- and 4-chlorophthalic anhydride, 3- and 4-bromophthalic anhydride, and 3- and 4-fluorophthalic anhydride
  • alkylphthalic anhydrides such as 3- and 4-methyl phthalic anhydride, 3- and 4-ethylphthalic anhydride, 3- and 4-iso propylphthalic 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-bromophenylacetic 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 is reacted with a compound of the general formula BYZ wherein A and B are diiIerent 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 X, Y and Z, 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 acidbinding substance.
  • the chloride of the tricyclic alcohol is reacted with an excess of the aminoalcohol at a temperature of about 140-1 60 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.
  • 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)-l,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. I. Klinkhammer, Ber. 83, 367371 (1950), the latter by E. D. Bergmann et al., Bull, Soc. Chem. Fr., 18 684692 (1951). While the compounds of this invention are produced directly from compounds of the Formula III, these latter compounds are, in eifect, intermediates in producing the compounds of the invention from the corresponding ketones of the Formula II.
  • the following 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 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 sufiiciently pure for use in the next step.
  • 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., J. 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(zae)-J,3,5-cycloheptatrienone-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 1 Dibenz0(a,d) -1,4-cycl0heptadien0l-5 To a solution of 50 g. of dibenzo(a,d)-l,4-cycloheptadienone-S in 500 ml. of methanol is added a solution of 9.1 g. of sodium borohydride in 100 ml. of Water at room temperature. The temperature is not controlled and rises to 46. The resulting solution is refluxed for one hour. The pH adjusted to 4.0 with acetic acid and then the methanol is distilled off. A light yellow oil precipitates which is extracted with ether, the ether is dried over magnesium sulphate, filtered and allowed to evaporate at room temperature. The residue is triturated with a small amount of hexane to yield about 43 g. of a product melting at about 8085. Recrystallization from 8 hexane yields a pure compound, of constant melting point of about 89-90".
  • EXAMPLE 12 12.1 g. of 3 chlorodibenzo(a,d) 1,4 cycloheptadienone-5 are dissolved in 190 ml. of ethanol (96%). The solution is boiled under reflux for 20 hours with 2.2 kg. of 0.5% sodium amalgam, and is then poured into ice-water acidified with 3 N acetic acid. The precipitate formed is filtered ofl, dried and crystallized from benzine. 9.1 g. of 3-chlorodibenzo(a,d)-1,4-cycloheptadienol-5 are obtained.
  • EXAMPLE 14 3-methyl dibenzo(a,d)-J,4-cycl0heptadien0l-5 Following the procedure of Example 12, but substituting an equivalent amount of 3 methyl dibenzo(a,d) 14 cycloheptadienone 5 for the 3 chlorodibenzo(a,d) 1,4 cycloheptadienone 5, 3 methyl dibenzo(a,d) 1,4 cycloheptadienol 5, melting point 124-125.5, is obtained in 87% yield.
  • EXAMPLE 16 1 -methyl dibenzo(a,d) -1,4-cycl0heptadien0l-5 Substituted dibenzo(a,d) -1,4-
  • the maleinate is prepared by solution of the base in ether and addition of maleic acid in ether until no further precipitate is formed. Melting point of the maleinate: 118120. Yield 65%.
  • EXAMPLE l8 3- (dibenzo (a,d) -1,4-cyclheptadien-5-yloxy -N,N-dimethylpropylamine, salt with oxalic acid Following the procedure of Example 17, but substituting an equivalent amount of 3-dimethylaminopropanol for the dimethylaminoethanol in step a, 3-(dibenzo(a,d)- 1,4-cycloheptadien-5yloxy)-N,N-dimethylpropylamine is prepared.
  • the oxalic acid salt, melting at l35136.5, is obtained in 50% yield by following the procedure of Example 17, step b but substituting oxalic acid for the maleic acid.
  • EXAMPLE 19 4-(dibenz0 (a,d) -1,4-cycl0heptadien-S-yloxy) -N,N-diethylpentylamine, salt Willi oxalic acid Following the procedure of Example 17, but substituting an equivalent amount of 5-diethylaminopentan-2-ol for the dimethylaminoethanol in step a, 4-(dibenzo(a,d)- 1,4 cycloheptadien-S-yloxy)-N,N-diethylpentylamine is prepared. The oxalic acid salt, melting at l48149, is obtained in 43% yield by following the procedure of Example 17, step b, but substituting oxalic acid for the maleic acid.
  • EXAMPLE 22 2- (dibenz0(a,d) -1,4-cycloheptadien-S-yloxy) -N-m0rph0- linylethylamine salt with oxalic acid
  • oxalic acid salt melting at 142- 10 143 is obtained in 55% yield by following the procedure of Example 17, step b, but substituting oxalic acid for the maleic acid.
  • EXAMPLE 23 Z-(dibenzo (a,e) -1,3,5-cycloheptatrien-5-yloxy) -N,N-dimethylethylamine, salt with maleic acid Following the procedure of Example 17, but substituting an equivalent amount of dibenzo(a,e)-l,3,5-cycloheptatrienol-S in step a, the maleic acid salt of 2-dibenzo (a,e) 1,3,5 cycloheptatrien 5 yloxy)-N,N-dimethylethylamine, melting point -128, is prepared in 57% yield.
  • EXAMPLE 24 2-(3-methyl dibenz0(a,d)-],4-cycl0heptadien-5-yl0xy)- N,N-dimethylethylamine, salt with maleic acid Following the procedure of Example 17, but substituting an equivalent amount of 3'methyl dibenzo(a,d)-1,4- cycloheptadienol-S for the dibenzo(a,d)-1,4-cycl0heptadienol-S in step a, the maleic acid salt of 2-(3-methyl dibenzo(a,d)-1,4-cycloheptadien-5-yloxy) N,N dimethylethylamine, melting point 124l25, is obtained in 38% yield.
  • EXAMPLE 25 2- (3-chlor0diberiz0 (a,ei) -],4-cycloheptadien-S-yloxy) N ,N -dimethylethy lam inc, salt with maleic acid Following the procedure of Example 17, but substituting an equivalent amount of 3-chlorodibenzo(a,d)-l,4- cycloheptadienol 5 for the dibenzo(a,d) cycloheptadienol-S in step a, the maleic acid salt of 2-(3-chlorodibenzo(a,d)-l,4-cycloheptadien-S-yloxy) N,N dimethylethylamine, melting point l31132, is obtained in 42% yield.
  • EXAMPLE 26 5 (3-chl0rodi benz0( a,d ,4 -cycl0h eptadien-S -y loxy -N N -dimethyl-S-oxapentylamine, salt with oxalic acid Following the procedure of Example 17, but substituting an equivalent amount of 3-chlorod'ibenzo(a,d)-1,4- cycloheptadienol-S for the dibenzo(a,d)-cycloheptadienOl-S and an equivalent amount of dimethylaminoethoxyethanol for the dimethylaminoethanol in step a, 5 (3 chlorodibenzo(a,d) l,4-cycloheptadien-S-yloxy)- N,N-dimethyl-3-oxapentylamine is prepared.
  • the oxalic acid salt, melting at l24126, is obtained in 20% yield by following the procedure of Example 17, step b, but substituting
  • EXAMPLE 27 Z-(dibenz0(a,d) -1,4-cycl0heptaa'ien-5-yIoxy)- N-monomethylethylamine Following the procedure of Example 17, but substituting an equivalent amount of monomethylaminoethanol for the dimethylaminoethanol in step a, 2-dibenzo(a,d)- 1,4-cycloheptadien-5-yloxy)-N-monomethyl ethylamine is prepared.
  • EXAMPLE 28 3- (dibenz0( a,d) -1,4-cycl0heptadien-5-yloxy -N-piperz'- dinopropylamine, salt with hydrochloric acid Following the procedure of Example 17, but substituting an equivalent amount of N-'y-piperidinopropanol for the dimethylaminoethanol in step a and an equivalent amount of hydrochloric acid for the maleic acid in step b, 3 (dibenzo(a,d) 1,4-cycloheptadien-S-yloxy)-N-piperidinopropylamine, hydrochloric acid salt, is formed.
  • the precipitated sodium chloride is removed *by filtration and the toluene is then removed by distillation under reduced pressure leaving a residue of N -(3-dibenzo(a,d)- 1,4-cycloheptadien-5-yloxy)-propyl-N -methylpiperazine.
  • EXAMPLE 30 5 grams of 3-chlorodibenzo(a,d)-1,4-cycloheptadienol-5 are dissolved in 20 mls. of benzene, whereupon dry hydrochloric acid gas is introduced. The initial turbidity due to the formation of water disappears when the reaction is completed. The water formed is removed by drying with anhydrous calcium chloride and filtration over a dry filter and the excess of dissolved hydrochloric acid gas is expelled with a stream of dry air. After evaporation of the benzene the corresponding chloride remains.
  • the product compounds of this invention are administered in conventional manner, either orally or parenterally, in suitable dosage quantities.
  • a typical dosage unit contains 5 to 25 mg. of the active compound and to 125 mg. of a pharmacologically-acceptable inert carrier.
  • a pharmacologically-acceptable inert carrier for example, a pharmacologically-acceptable inert carrier.

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US277014A 1959-04-01 1963-04-30 Therapeutically-active dibenzocycloheptane derivatives Expired - Lifetime US3227716A (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3317547A (en) * 1965-06-24 1967-05-02 Colgate Palmolive Co Quinuclidyl ethers of dibenzocycloheptadiene
US3350405A (en) * 1964-10-16 1967-10-31 Sterling Drug Inc Amino-lower-alkoxy-dibenzo [a, d] cyclohepten-5-ones and 10, 11-dihydro derivatives thereof
US3357982A (en) * 1964-08-18 1967-12-12 Koninklijke Pharma Fab Nv 1-(5h-dibenzo [a, d] cyclohepten-5-yl)-4-alkylpiperazines
US3369044A (en) * 1962-07-23 1968-02-13 Geigy Chem Corp 5-carboxylic acid halide derivatives of 10, 11-dihydro-5h-dibenzo[a, d]cycloheptene
US3422106A (en) * 1965-05-19 1969-01-14 Fabricationdes Antibiotiques S Aminoethers derived from 9,10-ethano-9,10-dihydro-9-anthrol and their salts and process for preparation thereof
US3466291A (en) * 1966-02-16 1969-09-09 Sandoz Ag 4(2-dialkylaminoethoxy or 2-piperidinoethoxy) - 9,10 - dihydro benzo(4,5)cyclohepta(1,2-b)thiophene derivatives
US3496173A (en) * 1964-05-29 1970-02-17 Rhone Poulenc Sa 10-tertiaryaminoalkoxydibenzo(a,d)cycloheptadiene or salts thereof
US3627832A (en) * 1964-10-16 1971-12-14 Sterling Drug Inc AMINO-LOWER-ALKOXY-DIBENZO{8 a,d{9 CYCLOHEPTENES AND 5-ALKYL and -ARALKYL DERIVATIVES
US4792551A (en) * 1983-07-15 1988-12-20 Syntex (U.S.A.) Inc. 9-anthryloxyaminoalkanes and related compounds as anti-inflammatory and analgetic agents

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5231104A (en) * 1988-07-08 1993-07-27 Pfizer Inc. 1-arylethyl-3-substituted piperidines
GB8816365D0 (en) * 1988-07-08 1988-08-10 Pfizer Ltd Therapeutic agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2948732A (en) * 1960-08-09 N-heterocyclic compounds
US3014911A (en) * 1958-09-29 1961-12-26 Merck & Co Inc Derivatives of dibenzo[a, e]cycloheptatriene

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2948732A (en) * 1960-08-09 N-heterocyclic compounds
US3014911A (en) * 1958-09-29 1961-12-26 Merck & Co Inc Derivatives of dibenzo[a, e]cycloheptatriene

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3369044A (en) * 1962-07-23 1968-02-13 Geigy Chem Corp 5-carboxylic acid halide derivatives of 10, 11-dihydro-5h-dibenzo[a, d]cycloheptene
US3496173A (en) * 1964-05-29 1970-02-17 Rhone Poulenc Sa 10-tertiaryaminoalkoxydibenzo(a,d)cycloheptadiene or salts thereof
US3357982A (en) * 1964-08-18 1967-12-12 Koninklijke Pharma Fab Nv 1-(5h-dibenzo [a, d] cyclohepten-5-yl)-4-alkylpiperazines
US3350405A (en) * 1964-10-16 1967-10-31 Sterling Drug Inc Amino-lower-alkoxy-dibenzo [a, d] cyclohepten-5-ones and 10, 11-dihydro derivatives thereof
US3627832A (en) * 1964-10-16 1971-12-14 Sterling Drug Inc AMINO-LOWER-ALKOXY-DIBENZO{8 a,d{9 CYCLOHEPTENES AND 5-ALKYL and -ARALKYL DERIVATIVES
US3422106A (en) * 1965-05-19 1969-01-14 Fabricationdes Antibiotiques S Aminoethers derived from 9,10-ethano-9,10-dihydro-9-anthrol and their salts and process for preparation thereof
US3317547A (en) * 1965-06-24 1967-05-02 Colgate Palmolive Co Quinuclidyl ethers of dibenzocycloheptadiene
US3466291A (en) * 1966-02-16 1969-09-09 Sandoz Ag 4(2-dialkylaminoethoxy or 2-piperidinoethoxy) - 9,10 - dihydro benzo(4,5)cyclohepta(1,2-b)thiophene derivatives
US4792551A (en) * 1983-07-15 1988-12-20 Syntex (U.S.A.) Inc. 9-anthryloxyaminoalkanes and related compounds as anti-inflammatory and analgetic agents

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OA00466A (fr) 1966-07-15
CH417574A (de) 1966-07-31
SE300617B (en(2012)) 1968-05-06

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