US3454595A - Dibenzocycloalkylenylidene pyrrolidine derivatives - Google Patents

Dibenzocycloalkylenylidene pyrrolidine derivatives Download PDF

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US3454595A
US3454595A US563084A US3454595DA US3454595A US 3454595 A US3454595 A US 3454595A US 563084 A US563084 A US 563084A US 3454595D A US3454595D A US 3454595DA US 3454595 A US3454595 A US 3454595A
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dibenzo
ylidene
methyl
dihydro
cycloheptene
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Yoshio Deguchi
Hiroshi Nojima
Naomichi Kato
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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    • 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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • ABSTRACT OF THE DISCLOSURE 3 (10,11 dihydro H dibenzo[a,d]cycloheptene- S-ylidene) pyrrolidine compounds or 3-(5,6,7,l2-tetra hydrodibenzo[a,d]cyclooctene 12 ylidene) pyrrolidine compounds which have in 2-position a lower alkyl sub stituent and which may contain in l-position lower alkyl or phenyl lower alkyl substituents, their non-toxic acid addition salts, and their quaternary ammonium salts have a surprisingly high antidepressant activity and thus are useful antidepressants and tranquilizers.
  • Examples of such compounds are 1,2-dimethyl-, 1,2-diethyl-, l-ethyl-Z- methyl-, l-methyl-2-ethyl-, or, respectively l-benzyl-Z- methyl 3 (10,11 dihydro 5H dibenzo [a,d] cycloheptene-5-ylidene) pyrrolidines or the corresponding 3- (5,6,7,l2 tetrahydro dibenzo [a,d] cyclooctene l2- ylidene) pyrrolidines which may contain in one or both benzene rings halogen or lower alkyl, and their hydrochlorides.
  • Rae-m R4 wherein R and R are individually hydrogen, halogen or lower alkyl, R is lower alkyl, R; is hydrogen, lower alkyl or aralkyl, and n is an integer from 2 to 3.
  • lower alkyl of R R R and R may be straight or branched, and includes methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl and hexyl; halogen of R and R includes chlorine, bromine, iodine and fluorine; aralkyl of R includes benzyl, tolylmethyl, phenethyl and the like.
  • the compounds represented by the Formula I are characterized by manifold actions on the central and peripheral nervous systems such as anaesthetic, narcosis-potentiating, tranquilizing, antidepressant, hypotherice mic, antichloinergic or antihistaminic action, and are useful particularly as antidepressants and tranquilizers.
  • the Compounds I of this invention may be prepared by reduction of the dibenzocycloalkylenylidene pyrroline derivatives of the Formula II:
  • R is lower alkyl or aralkyl and X is an acid residue.
  • lower alkyl and aralkyl of R represent the same members as explained before, and an acid residue includes halide such as chloride, bromide and iodide; sulfate (H505); mono lower alkyl sulfate (lower alkyl --SO such as methyl sulfate, ethyl sulfate and the like; arylsulfonate (aryl --SO such as benzenesulfonate, toluenesulfonate and the like; tartrate [HOOC-CH(OH)CH(OH)COO-], and the like.
  • halide such as chloride, bromide and iodide
  • sulfate H505
  • mono lower alkyl sulfate lower alkyl --SO such as methyl sulfate, ethyl sulfate and the like
  • arylsulfonate aryl --SO such as benzenesulfonate, to
  • the starting compounds used in this invention are novel and may be prepared as follows: For example, 2-alkyl-3- 10,11 dihydro 5H dibenzo[a,d]cycloheptene 5- ylidene)-l-pyrroline [n is 2 in the Formula II] or its derivatives which have a substituent on one or both of the benzene ring, are obtained by the reaction of 5-(3- halopropylidene) 10,11 dihydro 5H dibenzo[a,d] cycloheptene or its corresponding derivatives [cf. J. Org. Chem. 27, 4134-4137 (1962)] with an alkanonitrile[e.g.
  • 2 alkyl 3 (5,6,7,12 tetrahydro dibenzo [a,d] cyclooctene-l2-ylidene)-l-pyrroline or its derivatives in which n is 3 in the Formula H, are obtained by subjecting 12 (3 halopropylidene) 5,6,7,12 tetrahydrodibenzo [a,d] cyclooctene compounds to the same procedure as described above.
  • N-alkylating agent e.g. lower alkyl halide, aralkyl halide, monoor di-lower alkyl (or aralkyl) sulfate, lower alkyl -(or aralkyl) arylsulfonate, mono-lower alkyl tartrate or the like to yield the corresponding quaternary ammonium salts.
  • an appropriate N-alkylating agent (III) e.g. lower alkyl halide, aralkyl halide, monoor di-lower alkyl (or aralkyl) sulfate, lower alkyl -(or aralkyl) arylsulfonate, mono-lower alkyl tartrate or the like to yield the corresponding quaternary ammonium salts.
  • the reduction step in this reaction may be carried out by using the methods which are generally employed for the reduction of an ammonium salt, e.g., the reduction methods using alkali metal boron hydride, alkaline earth metal boron hydride or alkali metal aluminum hydride, or using a metal and an acid, or by catalytic reduction and so forth.
  • an ammonium salt e.g., the reduction methods using alkali metal boron hydride, alkaline earth metal boron hydride or alkali metal aluminum hydride, or using a metal and an acid, or by catalytic reduction and so forth.
  • alkali metal or alkaline earth metal boron hydrides as mentioned herein are lithium, sodium or potassium boron hydride; or calcium, magnesium or barium boron hydride.
  • the metals are exemplified by iron, zinc, tin and the like, and the acids are exemplified by an inorganic or organic acid such as hydrochloric acid, sulfuric acid, acetic acid and the like.
  • the catalysts useful in the catalytic reduction method are platinium oxide, palladium-carbon, Raney nickel and the like.
  • the reduction is generally carried out in a solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane or the like, at room temperature or under heating.
  • a solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane or the like
  • water it is highly desirable to use a small amount of a base such as sodium carbonate, sodium hydrogen carbonate or the like in order to stabilize the reagent to be used.
  • a base such as sodium carbonate, sodium hydrogen carbonate or the like
  • the reduction may be carried out, under substantially anhydrous conditions, in an inert solvent such as methanol, diethyl ether, dibutyl ether, tetrahydrofuran, dioxane or the like, at room temperature or under heating, according to the conventional method known in the art.
  • an inert solvent such as methanol, diethyl ether, dibutyl ether, tetrahydrofuran, dioxane or the like
  • the reduction using a metal and an acid, and the catalytic reduction may be carried out in accordance with conventional methods.
  • the catalytic reduction may be carried out under pressure.
  • Compounds I wherein R is hydrogen may be converted to the corresponding Compounds I wherein R is lower alkyl or aralkyl by treating the former compounds with N-alkylating agents of Formula III in the presence or absence of a base.
  • N-alkylating agents are lower alkyl or aralkyl halides, monoor dilower alkyl (or aralkyl) sulfates, lower alkyl (or aralkyl) arylsulfonates, mono-lower alkyl tartrate and the like.
  • the Compounds I wherein R is hydrogen may be employed either in the form of the free bases or in the form of the acid addition salts.
  • the reaction may preferably be carried out in the presence of a base which is advantageously used in an approximately equimolecular amount to the amount of acid addition salts to be reacted.
  • a base which is advantageously used in an approximately equimolecular amount to the amount of acid addition salts to be reacted.
  • the reaction may be advantageously carried out in the absence of a base, or in the presence of an approximately equimolecular amount of a base with an equimolecular or a slight excess amount of the N- alkylating agent.
  • lower alkyl halide is exemplified by methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl chlorides, their bromides, their iodides and the like;
  • aralkyl halide is exemplified by benzyl, tolyl and Compound 2-methyl-3-(10,11-dihydro-5H- dibenzo [a,d] cycloheptene- 5-ylldene) pyrrolidine hydroll-diliydrochloride.
  • Lower alkyl and aralkyl arylsulfonates are exemplified by methyl, ethyl, propyl, isopropyl, butyl, pentyl, benzyl tolylmethyl, phenethyl benzenesulfonates, their toluenesulfonates and the like.
  • Mono-lower alkyl tartrate is exemplified by mono-methyl, mono-ethyl tartrate and the like.
  • bases sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide and the like.
  • the N-alkylating reaction of the Compounds I wherein R is hydrogen may be carried out in lower aliphatic alcohol such as methyl or ethyl alcohol, or in another inert organic solvent. And the reaction proceeds generally under heating and may proceed at a comparatively high temperature and in closed vessel, although these conditions are non-limitative.
  • reaction with N-alkylating agents (III) as explained above, may be similarly utilized for converting the Compounds I to the corresponding quaternary ammonium salts.
  • quaternary ammonium salts of the Compounds I may be converted to the corresponding ammonium hydroxide compounds by treating with silver oxide or alkali metal hydroxide.
  • a suitable non-toxic acid is exemplified by an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfamic acid, sulfuric acid and the like, and an organic acid such as acetic acid, citric acid, tartaric acid, lactic acid, methanesulfonic acid, ethanesulfonic acid and the like.
  • compositions containing the compounds of this invention together with a significant amount of a non-toxic solid or liquid carrier are also included within a scope of this invention.
  • one or more of the active compounds is or are admixed with an inert diluent such as potato starch, lactose, calcium carbonate and further additional substances, if needed, such as a lubricant, e.g. magnesium stearate and the like; a binder, e.g. gelatin and the like; and a disintegrating agent, e.g. cellulose calcium glycolate and the like.
  • Solid compositions also comprise capsules of absorbable material such as gelatin containing one or more active compounds with or without the addition of diluents or excipients.
  • the reaction mixture was cooled, 20% aqueous sodium hydroxide solution was added thereto and the mixture was heated whereafter the chlorobenzene layer was separated. The remaining aqueous layer was extracted with ether. The mixture of the chlorobenzene layer and the ether extract solution was extracted with 20% aqueous hydrochloric acid solution. The resulting aqueous layer was neutralized with 20% aqueous sodium hydroxide solution and extracted with ether. The ether layer was dried over magnesium sulfate and then ether was distilled off to yield 1.1 g.
  • Example 1 CH2) CH2) CH3 CH3 I -HC1 and its H01 salt 2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrroline hydrochloride ('B.'P. 170-175 C./0.15 mm. Hg) (0.7 g.) was dissolved in 7 cc. of methanol. To this solution, 0.17 g. of sodium boron hydride was added in small portions while stirring and cooling with ice and the mixture was kept for one hour to complete the reaction. The reaction mixture was acidified with 10% aqueous hydrochloric acid solution, whereafter the methanol was distilled off.
  • 2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrroline hydrochloride ('B.'P. 170-175 C./0.15 mm
  • This substance was converted into its hydrochloride salt by adding ether containing hydrochloric acid to its solution in absolute ether under ice-cooling.
  • the resulting hydrochloride salt was recrystallized from a mixture of absolute acetone and absolute ether to yield 0.38 g. of colorless crystals of the melting point 222-223 C.
  • This substance was converted into its hydrochloride salt of the melting point 250-253" C. according to the conventional method.
  • Example 4 0135- and its 1101 salt OHs-N--- (i) To 1.2 g. of 2-ethyl-3-(l0,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrroline there were added 5 cc. of methyl iodide. This mixture was placed into a vessel which was closed, and heated at -80 C. in a water-bath for one hour. After completing the reaction, unreacted methyl iodide was distilled olf to yield 1.8 g.
  • This substance was converted into its hydrochloride salt according to the conventional method.
  • the resulting salt was recrystallized from a mixture of ethanol and ether to yield 1.5 g. of 1-ethyl-2-methyl-3-(5,6,7,12-tetrahydro-dibenzo [a,d] cyclooctene-lZ-ylidene) pyrrolidine hydrochloride in the farm of faint brown crystals of the melting point 262-263 C.
  • Example 6 To 1.1 g. of 2-methyl-3-(3-methyl-l0,1l-dihydro-SH- dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrroline there were added 7 cc. of methyl iodide. This mixture was placed into a vessel which was closed and heated at 7 080 C. in a water-bath for one hour. After completing the reaction, unreacted methyl iodide was distilled 011 to yield crystals of 1,2-dimethyl-3-(3-methyl-10,1l-dihydro- SH-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrrolinium iodide. These crystals were recrystallized from acetone to yield yellow needles of the melting point 262 C.
  • This substance was converted into its hydrochloride salt according to the conventional method.
  • the resulting salt was recrystallized from acetone to yield crystals of the melting point 260 C.
  • Example 7 (i) To 2.5 g. of 2-methyl-3-(3-chloro-10,1l-dihydro- SH-dibenzo [a,d] cycloheptane-S-ylidene)-1-pyrroline B.P. above 200 C./0.2-0.3 mm. Hg), there were added 5.0 g. of ethyl iodide. This mixture was heated at 60-80 C. on a water-bath. After completing the reaction, unreethyl 2 methyl-3-(3-chloro-10,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene) -1-pyrrolinium iodide. These crystals were recrystallized from a mixture of methanol and acetone to yield 2.0 g. of crystals of the melting point 272-273 C.
  • This oily substance was converted into its hydrochloride 1 salt according to the conventional method, The resulting salt was recrystallized from a mixture of methanol and acetone to yield crystals of the melting point 257.5-- 259 C.
  • This substance was converted into its hydrochloride salt according to the conventional method.
  • This salt was recrystallized from a mixture of methanol and ether to yield white needles of the melting point 219 C.
  • a pyrrolidine compound selected from the group consisting of a pyrrolidine compound of the formula R1 II m R4-N.
  • R and R are members selected from the group consisting of hydrogen, halogen, and lower alkyl, R is lower alkyl, R; is a member selected from the group consisting of hydrogen, lower alkyl, and phenyl lower alkyl, and n is an integer from 2 to 3, its non-toxic acid addition salts, and its quaternary ammonium salts formed by reaction with a quaternizing agent selected from the group consisting of lower alkyl halide, phenyl lower alkyl halide, monoor di-lower alkyl sulfate, monoor di-phenyl lower alkyl sulfate, monoor di-tolyl lower alkyl sulfate, lower alkyl phenyl sulfonate, phenyl lower alkyl phenyl sulfonate, lower alkyl tolyl sulfonate, phenyl lower alkyl tolyl sulfonate, and mono-lower alkyl tart

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US563084A 1965-07-08 1966-07-06 Dibenzocycloalkylenylidene pyrrolidine derivatives Expired - Lifetime US3454595A (en)

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JP4114465 1965-07-08
JP4114565 1965-07-08
JP4161165 1965-07-10
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US (1) US3454595A (enrdf_load_stackoverflow)
BE (1) BE683678A (enrdf_load_stackoverflow)
CH (1) CH478794A (enrdf_load_stackoverflow)
DE (1) DE1670713B2 (enrdf_load_stackoverflow)
DK (1) DK120237B (enrdf_load_stackoverflow)
ES (1) ES328203A1 (enrdf_load_stackoverflow)
FI (1) FI47359C (enrdf_load_stackoverflow)
FR (1) FR5523M (enrdf_load_stackoverflow)
GB (1) GB1105730A (enrdf_load_stackoverflow)
NL (1) NL151072B (enrdf_load_stackoverflow)
SE (1) SE319770B (enrdf_load_stackoverflow)

Citations (1)

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Publication number Priority date Publication date Assignee Title
FR1333960A (fr) * 1962-07-04 1963-08-02 Sandoz Sa Nouveaux dérivés basiques du dibenzocycloheptane et leur préparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1333960A (fr) * 1962-07-04 1963-08-02 Sandoz Sa Nouveaux dérivés basiques du dibenzocycloheptane et leur préparation

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SE319770B (enrdf_load_stackoverflow) 1970-01-26
DE1670713B2 (de) 1976-07-15
FI47359C (fi) 1973-11-12
BE683678A (enrdf_load_stackoverflow) 1967-01-05
DK120237B (da) 1971-05-03
DE1670713A1 (de) 1970-12-03
NL151072B (nl) 1976-10-15
GB1105730A (en) 1968-03-13
FI47359B (enrdf_load_stackoverflow) 1973-07-31
CH478794A (de) 1969-09-30
FR5523M (enrdf_load_stackoverflow) 1967-11-06
NL6609280A (enrdf_load_stackoverflow) 1967-01-09
ES328203A1 (es) 1967-04-01

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