US3454595A - Dibenzocycloalkylenylidene pyrrolidine derivatives - Google Patents

Description

United States Patent O 3,454,595 DIBENZOCYCLOALKYLENYLIDENE PYRROLIDINE DERIVATIVES Yoshio Deguchi, Suita, Hiroshi Nojima, Yao, and Naomichi Kato, Ikeda, Japan, assignors to Fujisawa Pharmaceutical Co., Ltd., Higashiku, Osaka, Japan, a company of Japan No Drawing. Filed July 6, 1966, Ser. No. 563,084 Claims priority, application Japan, July 8, 1965, 40/41,144, 40/41,145; July 13, 1965, 40/ 32,412 Int. Cl. C07d 27/04; A61k 27/00 US. Cl. 260326.81 3 Claims 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.

As used herein the term lower is intended to mean groups containing one to six carbon atoms.

In above Formula I, 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.

It is an object of this invention to provide novel and useful dibenzocycloalkylenylidene pyrrolidine derivatives being of great therapeutic valve.

It is also an object of this invention to provide processes for preparing the same.

Further objects will appear hereinafter.

The compounds represented by the Formula I, their non-toxic acid addition salts and quaternary ammonium salts 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:

wherein R is lower alkyl or aralkyl and X is an acid residue.

In the above Formula III, 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.

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. acetonitrile, propionitrile, butyronitrile or the like] in the presence of a metal halide [c.g. stannic chloride, ammonium chloride, zinc chloride, boron fluoride or the like]. 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. Furthermore, the resulting compounds are treated with 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.

Examples of 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. In the reduction using a metal and an acid, 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. Examples of the catalysts useful in the catalytic reduction method are platinium oxide, palladium-carbon, Raney nickel and the like.

In using an alkali metal or alkaline earth metal boron hydride, 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. When using water as the solvent, 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. When another solvent is employed, it is also advantageous to carry out the reaction in the presence of a small amount of the base mentioned above.

In using alkali metal aluminum hydride, 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. Also, 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.

Thus 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. Examples of 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. In this treatment, 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. When using 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. In this case, if an excess amount of a base is employed, the quaternary ammonium salts corresponding to the free bases and the N-alkylating agents to be used, may be produced. When using the free bases, 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.

As set forth above, 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.

1,2-dimethyl-3- 5H-dibenzo [a,d 5-ylidene) pyrrolidine hydrochloride.

c or e. 1-Methy1 2-ethyl-3-(10,11dihydro- 5H-dibenzo [a,d] cycloheptenel eycloheptenephenethyl chlorides, their bromides, their iodides and the like; monoor di-lower alkyl sulfates and their aralkyl compounds are exemplified by methyl, ethyl, propyl, isopropyl, butyl, benzyl, tolylmethyl, phenethyl, dimethyl, diethyl sulfates and the like. 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.

A few examples of the bases are 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.

The reaction with N-alkylating agents (III) as explained above, may be similarly utilized for converting the Compounds I to the corresponding quaternary ammonium salts.

Also, thus obtained 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.

The Compounds I of this invention may be converted into a suitable non-toxic acid addition salt. 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.

The pharmacological studies carried out with a few representative compounds of this invention gave the following results.

TABLE l.-TOXICITY LDsn (mg/kg. to mice) I.V. P.O

Compound TABLE 2 N arcosis-potentiatlng effect 1 Antihist- Antiacetylcholine efiect 1 potentiating dose -I e) Increase rate s-ylidene) pyrrolidine hydroehlorlde l-Ethyl-2-rnethyl-3-(5,6,7,12-

tetrahydro-dibenzo [a,d] cyclooctene-lz-ylldene) pyrrolldtne hydrochloride.

1 The narcosis-potentiating eEect was determined on mice to which mg.'

Magnus method using the extracted small intestine of guinea-pigs.

The compounds of this invention can be administered orally and parenterally for therapeutical use. The pharmaceutically useful 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. Such compositions comprise solid compositions such as tablets, pills, dispersi=ble powders and granules, and liquid solutions such as injectable solutions, orally administrable solutions and suspensions.

In solid compositions 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 following examples are given solely for the purpose of illustration.

Reference examples for preparing the starting compounds:

(1) 2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrroline.A mixture of 2.6 g. of 5-(3-bromopropylidene)-10,1l-dihydro-SH-dibenzo a,d!] cycloheptene (M.P. 68-72/C.), 0.34 g. of acetonitrile, 5.2 g. of chlorobenzene and 2.1 g. of anhydrous stannic chloride was placed in a closed vessel and heated at 130 C. for three hours. After completing the reaction, 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. of 2-methyl-3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrroline as a brown oil (B.P. 170-l75 C./0.15 mm. Hg).

(2) 2-methyl-3-(5,6,7,12-tetrahydro-dibenzo [a,d] cyclooctene-l2-ylidene)-1-pyrroline.-A mixture of 1.9 g. oi l2-(3-bromopropylidene)-5,6,7,12 tetrahydro dibenzo [a,d] cyclooctene (B.P. 175-l85 C./0.07 mm. Hg), 0.23 g. of acetonitrile, 3.7 g. of chlorobenzene and 2.0 g. of stannic chloride was treated in the same manner as described hereinabove under (1) to yield 0.2 g. of 2- methyl-3-(5,6,7,IZ-tetrahydro-dibenzo [a,d] cyclooctenel2-ylidene)-l-pyrroline as an oily substance.

Ultra-violet absorption spectrum:

rgggf 231.5 my, 6 18,100

max. (inflection) xZiZgP 244 m,., 6 13,840

6 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. To the resulting residue there was added a 10% aqueous sodium hydroxide solution whereafter the separated oily substance was extracted with ether. The ether layer, after drying over magnesium sulfate, was distilled to yield 2-methyl-3- (l0,ll-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine.

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.

Calculated for C H N-HClz C, 76.96; H, 7.10; N, 4.48. Found: C, 76.72; H, 7.01; N, 4.27.

Example 2 @fmt-Q glonig o o H II EES-Hm N (i) To a solution of 9.0 g. of 2-ethyl-3-(10,11-dihydro- 5H dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrroline (M.P. 93-98 C.) dissolved in cc. of methanol, there were added in small portions 2.5 g. of sodium boron hydride with stirring Within one hour and stirring of the solution was continued for two hours. The reaction mixture was acidified with 10% aqueous hydrochloride solution and the methanol was distilled off. The resulting residue, after being alkalized with 20% aqueous sodium hydroxide solution, was extracted with ether. The other layer was dried over magnesium sulfate and then the ether was distilled oil? to yield a slightly yellowish viscous oil. This oil was refined by distillation to yield 6.5 g. of 2-ethy1-3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene- 5-ylidene) pyrrolidine (B.P. 174180- C./ 0.8 mm. Hg).

The substance (6.5 g.) obtained above was dissolved in 65 cc. of absolute ether. This solution was acidified with an ether solution saturated with gaseous hydrochloric acid under ice-cooling to yield 2-ethyl-3-(10,11-dihydro- SI-I-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine hydrochloride in the form of crystals, which were collected by filtration, washed with ether and recrystallized from a mixture of absolute acetone and absolute ether to yield 5.8 g. of white crystals of the melting point 195187 C.

Calculated for C H NCl: C, 77.40; H, 7.42; N, 4.30; CI, 10.88. Found: C, 77.60; H, 7.35; N, 4.08, Cl, 11.00.

(ii) To a solution of 0.7 g. of 2-ethyl-3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine in 10 cc. of absolute methanol, there were added 1.4 g. of ethyl iodide. This solution was refluxed in a waterbath for five hours. After completing the reaction, methanol was distilled off to yield a brown residue, which was crystallized by the addition of ether. The resulting crystals were collected by filtration and washed with ether to yield 1.0 g. of 1,2-diethyl-3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine hydroiodide. This substance was recrystallized from a mixture of absolute acetone and absolute ether to yield crystals of the melting point 214-216 C.

Calculated for C H NI: C, 62.02; H, 6.34; N, 3.15; I, 28.49. Found: C, 62.08; H, 6.21; N, 3.14; I, 28.77.

Example 3 tg o II II orn- I (i) CHa N CzH5N /6 CHI-m CzHs-N (i) To 3.8 g. of 2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrroline, there were added 8 g. of ethyl iodide. This mixture was placed into -a closed vessel and heated at 80 C. in a water-bath for one hour. After completing the reaction, the reaction mixture was cooled and the unreacted ethyl iodide was distilled olf to yield 5.5 g. of l-ethyl-2-methyl-3(10,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrrolinium iodide in the form of yellow crystals. These crystals were recrystallized from a mixture of acetone and ether to yield yellow needles of the melting point 223 C.

Calculated for C H NI: C, 61.54; H, 5.63; N, 3.26. Found: C, 61.17; H, 5.89; N, 3.20.

(ii) 1-ethyl-2-methyl-3-(10,11-dihydro 5H dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrro1inium iodide (4.7 g.) was dissolved in 7 cc. of methanol. To this solution there were added 1.4 g. of sodium boron hydride within about 80 minutes with stirring and stirring of the solution was continued for two hours to complete the reaction. The reaction mixture was acidified with aqueous hydrochloric acid solution and then the methanol was distilled off. The residual solution was alkalized with aqueous sodium hydroxide solution and extracted with ether. The ether layer was dried over magnesium sulfate and the ether was distilled 01f. The resulting residue was further distilled under reduced pressure to yield 2.0 g. of 1-ethyl-2-methyl-3-(10,1l-dihydro 5H dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine (B.P. 167 C./ 4 mm. Hg).

Ultra-violet absorption spectrum:

2.3 240 my, e 12,100

and its H01 salt Calculated for C H N: C, 87.08; H, 8.30; N, 4.61. Found: C, 87.41; H, 8.33; N, 4.76.

This substance was converted into its hydrochloride salt of the melting point 250-253" C. according to the conventional method.

Calculated for C H NHCl: C, 77.96; H, 7.73; N, 4.13. Found: C, 77.95; H, 7.79; N, 4.12.

(iii) 1-ethyl-2-rnethyl-3-(10,11-dihydro 5H dibrenzo [a,d] cycloheptene-S-ylidene) pyrrolidine (1.9 g.) arid 3.8 g. of ethyl iodide were placed into a glass tube which was sealed, and heated at 6080 C. for one hour. After completing the reaction, the reaction mixture was cooled and unreacted ethyl iodide was distilled off to yield 2.8 g. of 1,1-diethyl-2-methyl-3-(10,11-dihydro 5H dibenzo [a.d] cycloheptene-S-ylidene) pyrrolidinum iodide. This substance was recrystallized from a mixture of methanol and ether (M.P. 246 C. with decomposition).

Ultra-violet absorption spectrum:

Calculated for C H NI: C, 62.74; H, 6.58; N, 3.04. Found: C, 62.81; H, 6.53; N, 3.13.

Example 4 n) 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. of 1-methyl-2-ethyl-3-(10,1l-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrrolinium iodide in the form of yellowish brown crystals of the melting point 224227 C.

(ii) l-methyl-2-ethyl-3-(10,11-dihydro 5H dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrrolinium iodide (1.7 g.) was dissolved in 20' cc. of methanol. To this solution there was gradually added 0.6 g. of sodium boron hydride with stirring and stirring of the solution was continued for one hour to complete the reaction. The reaction mixture was acidified with an excess of 10% aqueous hydrochloric acid solution. Thereafter the methanol was distilled olf under reduced pressure. The residual solution was alkalized with 10% aqueous sodium hydroxide solution and extracted with ether. The ether layer was dried over magnesium sulfate and the ether was distilled off.

The residue was further distilled under reduced pressure to yield 0.7 g. of 1-methyl2-ethyl3-(10,1l-dihydro- SH-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine in the form of a clear oily substance.

This substance was dissolved in 70 cc. of ether, there was added thereto ether saturated with dried hydrochloric acid to yield its hydrochloride salt in the form of white crystals. These crystals were separated by filtration and recrystallized from a mixture of acetone and ether to yield 0.6 g. of white crystals of the melting point 210-213 C.

9 Calculated for C H N =HCl AH O: C, 76.39; H, 7.77; N, 4.05. Found: C, 76.92; H, 7.70; N, 3.74.

Example 5 CH2)4 CHzla \C/ l H CH (i) W (ii) (CH2)3 CH1) \C/ \G/ II H CH3 CH3 (111) d t m fi tll s alt a I C2H5N CzHrzHs (i) To 2.0 g. of 2-methyl-3-(5,6,7,12-tetrahydro-dibenzo [a,d] cyclooctene-lZ-ylidene)-1-pyrroline (its hydrochloride has the melting point 259261 C.), there were added 6.5 g. of ethyl iodide. This mixture was placed into a vessel which was closed, and heated at 120 C. on an oil-bath for two hours. After completing the reaction, the reaction mixture was treated with the same manner as described in (i) of Example 4 to yield crystals of 1-ethyl-2-methyl-3-(5,6,7,12 tetrahydro-dibenzo [a,d] cyclooctene-lZ-ylidene)-1-pyrrolinium iodide. These crystals were recrystallized from ethanol to yield 2.5 g. of light yellow crystals of the melting point 309-310 C.

Ultra-violet absorption spectrum:

egg ,3 3,3 5 229 m 6 9,400

(ii) 1-ethyl-2-methyl-3-(5,6,7,1Z-tetrahydro-dibenzo [a, d] cyclooctene-12-ylidene)-l-pyrrolinium iodide (2.5 g.) was dissolved in 25 cc. of methanol. To this solution there were added 0.9 g. of sodium boron hydride taking about one hour with stirring. The reaction mixture was treated in the same manner as described in (ii) of Example 4 to yield a brownish oily substance.

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.

Ultra-violet absorption spectrum:

Calculated for C H N-HCl-H O: C, 76.53; H, 8.10; N, 3.88; Cl, 9.82. Found: C, 76.64; H, 8.19; N, 3.98; Cl, 10.01.

(iii) 1-ethyl-2-methyl-3 (5,6,7,12-tetrahydro-dibenzo [a,d] cyclooctene-lZ-ylidene) pyrrolidine (1.0 g.) and 3.2 g. of ethyl iodide were placed into a glass tube which was sealed and heated at 120-130 C. in an oil-bath for two hours. After completing the reaction, the reaction mixture was cooled and unreacted ethyl iodide was distilled off to yield 1.1 g. of 1,1-diethyl-2-methyl-3-(5,6, 7,12-tetrahydro-dibenzo [a,d] cyclooctene-12-ylidene) pyrrolidinium iodide in the form of brown crystals. These crystals were purified by re-precipitation from a mixture of acetone and ether [M.P. 128130 C. (dec.)].

Ultra-violet absorption spectrum:

Calculated for C H NL /2H O: C, 62.24; H, 7.03; N, 2.90; I, 26.30. Found: C, 62.12; H, 7.09; N, 2.87; I, 26.26.

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.

Ultra-violet absorption spectrum:

xi gf 243 111,1, 6 6,492 271.5 m,., 6 5,770

Calculated for C H NI: C, 61.54; H, 5.63; N, 3.26. Found: C, 61.26; H, 5.68; N, 3.12.

(ii) 1,2-dimethyl-3-(3-methyl-10,ll-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrrolinium iodide (1.7 g.) was dissolved in 10 cc. of methanol. To this solution there was added 1.0 g. of sodium boron hydride and the reaction mixture was treated in the same manner as described in (ii) of Example 4 to yield 1,2-dimethyl-3- (3-methyl-10,1l-dihydro-SH-dibenzo [a,d] cycloheptene- 5-ylidene) pyrrolidine in the form of a faint yellowish viscous oil which showed one spot on a Kieselgel G. thin layer chromatograph (CHCl :C H OH=4:1).

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.

Nuclear magnetic resonance spectrum in CDCl 9.25 1(CH -CH=, doublet) 7.7 q-(CH Ph, singlet) 7.6 1-(CH N=, singlet) 6.5-7.5 (=N-CH CH cn -cn -cz, multiplet) Ultra-violet absorption spectrum:

Calculated for C H NC1: C, 77.73; H, 7.71; N, 4.11. Found: C, 77.58; H, 7.66; N, 4.37.

(iii) 1,2-dimethyl-3-(3 methyl-10,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine and 4.0 g. of methyl iodide were placed into a glass tube which was sealed and heated at 6080 C. for one hour. After completing the reaction, the reaction mixture was cooled and unreacted methyl iodide was distilled off to yield crystals of 1,1,2-trimethyl-3-(3-methyl-10,1l-dihydro-SH- dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidinium iodide. These crystals were recrystallized from acetone and subsequently from a mixture of methanol and acetone to yield white crystals of the melting point 236-238 C.

Ultra-violet absorption spectrum:

Calculated for C H NI: C, 62.02; H, 6.33; N, 3.14. Found: C, 62.02; H, 6.39; N. 2.99.

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.

Calculated for C H NICl: C, 56.97; H, 4.99; N, 3.01. Found: C, 57.13; H, 4.90; N, 3.03.

(ii) 1 ethyl 2-methyl-3-(3-chloro-10,ll-dihydro-SH- dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrrolinium iodide (2.1 g.) was dissolved in 25 cc. of methanol. To this solution there was gradually added 1.0 g. of sodium boron hydride within three hours, and the reaction mixture was treated in the same manner as described in (ii) of Example 4 to yield 1.6 g. of 1-ethyl-2-methyl-3-(3-chloro- 10,11-dihydro-5H-dibenzo [a,d] cyclohepene-S-ylidene) pyrrolidine in the form of an oily substance.

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.

Ultra-violet absorption spectrum:

Example 8 CH2)2 I CHM" C \C/ [I H cum on;

ll i Br @l fi C II CH3? and its H01 salt Q C II CH3 (i) 2-methyl-3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrroline was dissolved in cc. of methanol. To this solution there were added 4.7 g. of benzyl bromide, and the reaction mixture was heated at 90 C. in a water-bath for two and a half hours. The solvent was distilled OE and the resulting residue was washed with ether to yield a viscous oil of 2-methyl-3- (10,11 dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-l-pyrrolinium bromide.

(ii) 2 methyl 3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene)-1-pyrrolinium bromide (3.0 g.) was dissolved in 30 cc. of methanol. To this solution there were added 2.0 g. of sodium boron hydride within one hour, and the reaction mixture was treated in the same manner as described in (ii) of Example 4 to yield 1 benzyl 2-methyl3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine in the form of a brown oil. This oil was distilled to yield 1.4 g. of a yellow oil.

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.

(iii) 1 benzyl-2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine (0.4 g.) and 5.1 g. of methyl iodide were placed into a glass tube which was sealed and treated in the same manner as described in (iii) of the Example 7 to yield 1-benzy1-1,2-dimethyl- 3 (10,11-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidinium iodide in the form of yellow crystals. These crystals were recrystallized from a mixture of methanol and ether to yield white crystals of the melting point 200 C.

What we claim is:

1. A pyrrolidine compound selected from the group consisting of a pyrrolidine compound of the formula R1 II m R4-N.

wherein 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 tartrate.

2. 1,2 dimethyl 3-(10,11-dihydro5H-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine or its hydrochloride. 3. 1-ethyl-2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine or its hydrochloride.

References Cited FOREIGN PATENTS 1,333,960 6/1963 France.

OTHER REFERENCES Noller, Chemistry of Organic Compounds, pp. 264, 661 1965 ALEX MAZEL, Primary Examiner.

J. A. NARCAVAGE, Assistant Examiner.

U.S. Cl. X.R. 424-274