US3699125A - 1,2,3-trisubstituted pyrrolidine derivatives - Google Patents

Abstract

PYRROLIDINE

1-(Y-R4-),2-R3,3-(2-R2,X2-PHENYL),3-(2-R1,X1-PHENYL)-

1,2,3-TRISUBSTITUTED PYRROLIDINE DERIVATIVES OF THE GENERAL FORMULA:
WHEREIN X1 AND X2 ARE SAME OR DIFFERENT HYDROGEN, HALOGEN, LOWER ALKYL OR LOWER ALKOXY; Y IS HYDROXY OR HALOGEN; R1 AND R2 ARE HYDROGEN OR R1 AND R2 ARE BOUND TOGETHER INTERVENING ETHYLENE, OXYGEN OR SULFUR; R3 IS LOWER ALKYL; AND R4 IS LOWER ALKYLENE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF. THESE COMPOUNDS ARE USEFUL AS ANTI-GASTORIC SECRETION INHIBITING OR ANTI-TREMOR AGENTS.

Description

United States Patent 3,699,125 1,2,3-TRISUBSTITUTED PYRROLIDINE DERIVATIVES Suminori Umio, Kawanishi-shi, and Shizuo Maeno, Osakashi, Japan, assignors to Fujisawa Pharmaceutical Co.,

Ltd., Osaka, Japan No Drawing. Filed Dec. 18, 1969, Ser. No. 886,328 Claims priority, application Japan, Jan. 9, 1969, 44/1,788, 44/1,790, 44/ 1,791 Int. Cl. C07d US. Cl. 260326.81 6 Claims ABSTRACT OF THE DISCLOSURE 1,2,3-trisubstituted pyrrolidine derivatives of the general formula:

wherein X and X are same or different hydrogen, halogen, lower alkyl or lower alkoxy; Y is hydroxy or halogen; R and R are hydrogen or R and R are bound together intervening ethylene, oxygen or sulfur; R is lower alkyl; and R is lower alkylene and pharmaceutically acceptable salts thereof. These compounds are useful as anti-gastoric secretion inhibiting or anti-tremor agents.

This invention relates to new 1,2,3-trisubstituted pyrrolidine derivatives having gastric secretion inhibiting action or anti-tremorine action.

The said 1,2,3-trisubstituted pyrrolidine derivatives are represented by the general Formula I:

wherein X, and X are same or different hydrogen, halogen, lower alkyl or lower alkoxy; Y is hydroxy or halogen; R and R are hydrogen or R and R are bound together intervening ethylene, oxygen or sulfur; R is lower alkyl; and R is lower alkylene.

As used herein and hereinafter the term lower applied to alkyl, alkoxy or alkylene group is intended to mean group having from one to four carbon atoms in alkyl part and said alkyl part may be straight or branched.

In the above and subsequent descriptions, specific examples of each substituent are as follows:

Halogen: chlorine, bromine, fluorine, etc.

Lower alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.

Lower alkoxy: methoxy, ethoxy, propoxy, isopropoxy, etc.

Lower alkylene: ethylene, propylene, 2-methylethylene,

2-methylpropylene, 3-methylpropylene, etc.

It has been found that the compounds [I] and their pharmaceutically acceptable salts (i.e. acid addition salts and quarternary ammonium salts) commonly and characteristically possess gastric secretion inhibiting action or anti-tremor action.

Accordingly, a basic object of this invention is to embody the compounds [I] and their salts. Another object of this invention is to embody the compounds [I] and their salts having gastric secretion inhibiting action or anti-tremor action. A further object of the invention is to embody the compounds [I] and their salts useful as a gastric secretioninhibiting agent or anti-tremor agent (e.g. antiparkinson agent). A still further object of the invention is to embody a process for preparing the compounds [I] and their salts. These and other objects will be apparent to those conversant with the art to which the present invention pertains from the subsequent descriptions.

According to the present invention, the compound of the general Formula I is prepared by reacting the compound of the Formula II;

wherein X X R R and R are the same significance as defined above, or the acid salt thereof with a N-substituting agent selected from the group of 1,2-epoxyalkane [III] and the compound of the formula;

2' l ar-0H V wherein X X R R R and R are the same significance as defined above and Z is an acid residue, in a solvent thereby to provide the compound [I] wherein Y is hydroxy, and when desired, in case of Y being hydroxy in the resulting compound [I], by halogenating the said compound with a halogenating agent thereby to provide the compound [I] wherein Y is halogen.

The method for preparing the compound [I] of this invention as mentioned above can be illustrated in detail in the following.

A fundamental procedure is represented by the following scheme:

wherein X X R R R R Y and Z are the same significance as defined above.

The starting compound [11] may be prepared, for example, by the following methods. That is, 2-lower alkyl- 3-diphenylmethylenepyrrolidine may be prepared by reducing 2-lower alkyl-3-diphenylmethylene 1 pyrroline, which can be prepared according to the method as described in Japanese patent gazette No. 19454/ 19-64, with sodium boron hydride. The other starting compounds, i.e. 2-lower a1kyl-3-( 10,1 l-dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-pyrrolidine,. 2-lower alkyl-3-(xanthene-9- ylidene)pyrrolidine and 2-lower. a1kyl-3-(thioxanthene-9- yliden6)pyrrolidine may be prepared by reducing the corresponding pyrroline compounds, which may be prepared, in the substantially same method as described in the gazette, from each material of -(3-halo-propylidene)- 10,11 dihydro-SH-dibenzo[a,d]cyc1oheptene, 9'-(3-halopropylidene)xanthene and 4,5-dihydrospiro [furan-Z (3H) 9'-9'H-xanthene]. Also, the starting compound [II], wherein the benzene ring(s) is (are) substituted with halogen, lower alkyl or lower alkoxy at the optional position(s), may be prepared in the substantially same manner as aforementioned.

The reaction is'carried out by treating the starting compound [II] or the acid salt thereof with N-substituting agent selected from the group of 1,2-epoxyalkane [III] and the compound of the formula [IV] preferably in the presence of an basic condensing agent. Examples of the acid salt of the starting compound [II] are the salts with a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.) and with an organic acid (e.g. acetic acid, oxalic acid, maleic acid, picric acid, etc.).

Examples of the reagent, 1,2-epoxyalklane [III] include epoxyethane, 1,2-epoxypropane, 1,2-epoxybutane and the like. In the N-substituting agent [IV], examples of an acidic residue represented by the symbol Z are as follows: halogen (e.g. chlorine, bromine, iodine, etc.); sulfuric acid residue; and sulfonic acid residue (e.g. methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, etc.) and the like, provided that when Z is an acid residue of hydrohalogenic acid, i.e. halogen, the halogen should be higher in reactivity than that in the symbol Y. Thereaction is usually carried out in an inert solvent,

but it is not always necessary to employ the solvent when the N-substituting agent itself is liquid and can be also employed as a solvent accordingly. As the solvent are frequently used methanol, ethanol, acetone, chloroform, dioxane, n-hexane, benzene, toluene, xylene, N,N-dimethyl formamide, etc., and the other inert solvents.

Also, the reaction may be preferably carried out in the presence of a basic condensing agent such as an alkalimetal (e.g. sodium, potassium, lithium) and an alkaline earth metal (e.g. calcium) and their hydroxide (e.g. sodiumhydroxide, potassium hydroxide), amide (e.g. sodium amide), alkoxide (e.g. sodium ethoxide), carbonate (e.g.. sodium carbonate, potassium carbonate), and bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate); and an organic tertiary amine (e.g. pyridine, triethylamine, picoline, N-methylmorphorine). These condensing agents are optionally employed depending upon the kinds of the starting compound [II] and the N-substituting agent.

The reaction temperature varies according to the kinds of the starting compound [II], the N-substituting agent, the condensing agent and the solvent to be used, and is nonlimitative, but the reaction is usually etfected under warming or heating around the boiling point of the solvent to be used.

Another fundamental procedure is shown in the following scheme:

wherein X1, X R R R and R are the same significance as defined above and Z' is an acidic residue.

In the above formula, the acidic residue is the same meaning as explained before.

The pyrrolinium compound [V] to be used as the starting materials in this procedure may be prepared, for example, by reacting the corresponding pyrroline 'compounds, which can be prepared according to the method as described before, with a N-substituted agent of the formula: Z'R -OH wherein Z' and R are the same significance as defined above.

The reaction is conducted by reducing the pyrrolinium compound [V] in a solvent. -As the reduction method of this procedure, there may be used any conventional methods which are generally employed for the reduction of an immonium salt, for example, the reduction method using alkali boron hydride (e.g. lithium, sodium or potassium boron hydride), alkali metal hydride (e.g. lithium aluminum hydride) and. the like; the reduction method using a metal (e.g. iron, zinc, tin, etc.) and an acid (e.g. hydrochloric acid, sulfuricacid, acetic acid, etc.); the catalytic reduction method using metallic catalyst (e.g. platinium oxide, palladium-carbon, Raney-nickel, etc.); and so forth. There is no limitation to the reaction temperature and the solvent to be employed in this reaction, and they are optionally selected depending on the reduction methods as described above.

For example, in case the reduction using an alkalimetal boron hydride, the reaction may he usually conducted in a solvent such as water, methanol, ethanol, dioxane, tetrahydrofuran and the like, at room temperature or under heating; in case of the reduction using alkalimetal aluminum hydride, it may be under substantially anhydrous condition in an inert solvent (e.g. ether, tetrahydrofuran, dioxane, etc.) at room temperature or under heating; in case of the catalytic reduction, it may be in a solvent such as methanol, ethanol, dioxane, ether, water, benzene, acetic acid, etc. under warming or heating; and in case of the reduction using an acid and a metal, it may be at the room temperature and the acid can be used as a solvent, too.

'When desired, in case of Y being hydroxy in the compound [I] which is prepared by the fundamental proce dures as mentioned above, the said compound can be halogenated with a halogenating agent thereby to provide the compound [I] wherein Y is halogen as shown by the following scheme:

I'M-OH Bit-halogen wherein X X R R R and R are the same significance as defined above.

The reaction is effected by treating the compound [I] with a halogenating agent.

As the halogenating agent, there may be exemplified hydrogen halide (e.g. hydrogen chloride, hydrogen bromide, hydrogen iodide, etc.), alkalimetal halide (e.g. sodium bromide, potassium bromide, potassium iodide, sodium iodide, etc.), thionylhalide (e.g. thionylchloride, thionylbromide, etc.), phosphorus halide (e.g. phosphorus trichloride, phosphorus tribromide, phosphorus triiodide, phosphorus pentachloride, phosphorus pentabromide, 0 etc.), phosphorus oxyhalide (e.g. phosphorus oxychloride, phosphorus, oxybromide, etc.), alkanesulfonyl halide (e.g. methanesulfonylchloride, ethanesulfonylbromide, methanesulfonylbromide, etc.), phosgen and the like.

In case that the halogenating reaction is conducted with a hydrogen halide or metalhalide, the reaction may be carried out in the presence of sulfuric acid, phosphoric acid, zinc halide, or the like.

There is no particular necessity for using a solvent in the reaction, but, if necessary, the reaction may be also carried out in an inert solvent. Examples of the said solvent are chloroform, tetrahydrofuran, etc.

There is no limitation to the reaction temperature. However, it is usually decided in accordance with the kinds of the compound [I] and the halogenating agent to be used.

When desired, the acid salts of thus prepared compound [I] are produced by causing the pyrrolidine base to react with an acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, citric acid, tartaric acid and lactic acid.

The quarternary ammonium salts are obtained by reacting thus prepared compound [I] with an aliphatic or aromatic agent such as methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate, methyl benzene sulfonate, methyl p-toluene sulfonate, ethyl bromide, propyl bromide and benzyl chloride.

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

(1) Acute toxicity.-Acute toxicity studies of 1-(2- chloroethyl) 2 methyl 3 (10,11 dihydro 5H dibenzo[a,d]cycloheptene 5 ylidene)pyrrolidine hydrochloride (hereinafter refer to compound A) were carried out with male mice (d-d strain). LD values were caiculated by the method of Litchfield Wilcoxon. The results are shown in the following table.

TABLE so g-/ Observation time (hours)-.- 24 72 Route of administration:

Subcutaneous 1, 50 880 Intrap eritoneal 320 285 Oral 605 590 TABLE Pharmacological actions Anti-acetylcholinergic potency N Ora-Experimental Method Gastric secretion inhibiting potency (Shays rat):

Male Wister rat (-150 g. of body weight) was starved for 24 hrs. with free access to water. The pylorus was ligated according to Shays method. Four hours later secretion was collected and volumes measured. Drugs were injected subcutaneously soon after the pylorus ligation.

Magnus method using the extracted ileum of guinea pig:

Guinea pig ileum was placed in the organ bath filled with Tyrodes solution. Drugs were studied for their antagonism with acetylcholine (0.2 #QJIHL).

Antagonism with acetylcholine on blood pressure:

In dogs anesthetized with pentobarbital drugs were examined for their ability to antagonize the depressor action of acetylcholine.

Salivary secretion inhibiting potency.

In dogs anesthetized with pentobarbital, chorda tympani was stimulated electrically. The drops of saliva from the Whartons duct was counted. Drugs were tested for their inhibitory action of these salivary secretions.

Anti-spasmodic potency:

Dogs were anesthetized with morphine-urethane, and the spontaneous motility of the jejunal portion was recorded using balloon-transducer system. The amplitude of each wave was chosen to investigate dose-response relationship.

(3) With 1-(Z-hydroxyethyl)-2-methyl-3-(10,1 l-dihydro-H-dibenzo[a,d] cycloheptene 5 ylidene)pyrrolidine hydrochloride as test compound, were determined antitremor potency, anti-acetylcholine potency and antihistamine potency. The results are shown in the following Table 3.

TABLE 3 Anti-histamine action Anti-acetylcholine action Norm-Experimental Method- Anti-tremor potency:

Ten male mice of 1GB. strain, ranging from 4 to 6 Weeks of age and Weighing between 23 g. and 32 g., were subcutaneously given the test compound in varying doses. Thirty minutes thereafter, each animal Was given 10 mg. per kg. of tremorme dihydrochloride intraperitoneally. Any tremor observed Within 30 minutes was noted. The EDm values to inhibit tremor was determined by the Lichfield-Wilcoxon method.

Anti-acetylcholine potency:

Anti-acetylcholine potency was measured by Magnus method using the isolated intestines of guinea pigs. The ED value to inhibit acetylcholine contraction Was deterrmned by graphing the mean potency at each dose level from an inhibitory potency of the test compound against contraction induced by acetylcholine. The same test as aforementioned was conducted on atropine to determine the equipotent ratio of the test compound with respect to atropine.

Anti-histamine potency:

The anti-histamine potency was determined by using the ISO- lated small intestines of guinea pigs according to the Mag-nus method. The EDw value, at which histamine contraction was inhibited, was determined by graphing the mean potency at each dose level from an inhibitory potency of the test compound against contraction induced by histamine. The same test as aforementioned was conducted on dophene hydramme to determine the equipotent ratio of the test compound with respect to diphene hydrarm'nc.

The compounds [I] canbe administered by the conventional methods, the conventional types of unit dosages or with the conventional pharmaceutical carriers to produce a gastric secretion inhibiting or anti-tremor in human beings and animals. Thus, they can be used in the form of pharmaceutical preparation, which contain them in admixture with a pharmaceutical organic or inorganic carrier material suitable for enteral, parenteral or local application. Oral administration by the use of tablets, capsules or in liquid form such as suspensions, solution or emulsion is particularly advantageous. When formed into tablets, the conventional binding and disintegrating agents used in therapeutic unit dosages can be employed. Illustrative of binding agents there can be mentioned glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate and talc. Illustrative of disintegrating agents there can be mentioned corn starch, keratin, colloidal silica and potato starch. When administered as liquids the conventional liquid carriers can be used.

The unit dosage or therapeutically cffecitve quantity of the compound [I] for human beings for the therapeutic uses of the invention can vary over wide limits such as 5 mg. to 1,000 mg. The upper limit is limited only by the degree of efiect desired and economic considerations. For oral administration it is preferable to employ from about 25 mg. to about 1,000 mg. the therapeutic agent per unit dosage. It is indicated from animal experiments that about 12.5 mg. to about 250 mg. dosages administered orally four times daily as needed will provide a preferred daily dosage. Of course, the dosage of the particular therapeutic agent used can vary considerably, such asthe age of the patient and the degree of therapeutic effect desired. Each unit dosage form of the novel therapeutic compounds can contain from about 5% to about 95% of the novel therapeutic agents by weight of the entire composition with the remainder comprising conventional pharmaceutical carriers. By the term pharmaceutical carrier it is intended to include non-therapeutic materials which are conventionally used with unit dosages and includes fillers, diluents, binders, lubricants, disintegrating agents and $01- vents. Of course, it is possible to administer the novel 8 therapeutics, i.e. the pure compounds, without the use of a pharmaceutical carrier.

The following examples of a preparation are given solely for the purpose of illustration.

EXAMPLE 1 (1) 1,2-epoxypropane (0.6 g.) was added to the solution of 2-methyl-3-(10,1l-dihydro-5H-dibenzo[a,d]cycloheptene-S-ylidene)pyrrolidine in methanol (30 cc.). The mixture was refluxed for 8 hours under heating, and 1,2- epoxypropane (0.3 g.) was added thereto twice in the course of the reaction. The solvent was distilled off under reduced pressure and the residue was dissolved in absolute ether. The ether solution was filtered to remove impurities and to the filtrate was added absolute ethanol solution of maleic anhydride. The precipitated crystals were collected by filtration and recrystallized from a mixture of absolute ethanol and ether to give 2.1 g. of 1-(2-hydroxypropyl )'-2- methyl 3 (10,11-dihydro-5H-dibenzo[a,d] cycloheptene- 5-ylidene)pyrrolidine maleate, as colorless prisms, M.P. 170-172 C.

In the similar manner to the above, the following compounds were obtained from the corresponding pyrrolidine compounds and 1,2-epoxyalkanes.

(2) 1-(Z-hydroxyethyl)-2-methyl-3-(10,1 l-dihydro-SH- dibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine maleate, as colorless prisms, M.P. 206-208 C.

(3) 1-(2-hydroxyethyl)-2-ethyl-3-( 10,11 dihydro 5H- dibenzo[a,d] cycloheptene-S-ylidene)pyrrolidine as crystals, M.P. 99-102 C.

(4) 1 (2 hydroxyethyl) 2-isopropyl-3-(10,1l-dihydro 5H dibenzo [a,d] cycloheptene 5 ylidene)pyrrolidine as yellow oil, 'BiP. 240 C. (oil bath temperature)/ 0.7 mm. Hg.

(5) 1 -(2 hydroxyethyl) 2 methyl-3-(xanthene-9- yl gidengpyrrolidine oxaleate, as yellow granules, M.P.

(6) 1 (2 hydroxyethyl) 2 methyl-3-(3-chloro-10, 11 dihydro-SH-dibenzo[a,d]cycloheptene-S-ylidene)pyrrolidine hydrochloride, as crystals, M.P. 201-203" C.

(7) 1 (2 hydroxyethyl) 2 methyl-3-(3-methyl-l0, 11 dihydro 5H dibenzo[a,d]cycloheptene-S-ylidene) pyrrolidine hydrochloride, as crystals, M.P. 194-196 C.

(8) 1 (2 hydroxypropyl)-2-methyl-3-diphenylmethylenepyrrolidine, as oil.

(9) 1 (2 hydroxyethyl) 2-methyl-3-diphenylmethylenepyrrolidine, as prims, M.P. 130-130.5 C.

l0) 1 (3 hydroxypropyl) 2-methyl-3-(10,1l-dihydro 5H dibenzo[a,d]cycloheptene 5 ylidene)pyrrolidine'as oil.

(11) 1 (2 hydroxyethyl) 2 methyl-3-[a-(p-fluorophenyl)-a-phenyl]methylenepyrrolidine hydrochloride, as crystals, M.P. 24l-243 C.

(12) 1 (2 hydroxyethyl) 2 methyl-3-bis(p-,chlorophenyl)methylenepyrrolidine hydrochloride, as prisms, M.P. 243-245 C.

EXAMPLE 2 (1) 2 methyl 3 (10,11 dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)pyrrolidine (200 mg.), l-bromo-2- propanol (100 mg.) and anhydrous sodium carbonate (150 mg.) were added to absolute ethanol (10 cc.) and the mixture was refluxed for 10 hours under heating. The reaction mixture, after cooled, was filtered and the filtrate was condensed under reduced pressure. The residue was dissolved in absolute ether. The ether solution was filtrated and the filtrate was treated with activated charcoal. Thereto was added absolute ethanol solution or" maleic anhydride. The precipitated crystals were collected by filtration and recrystallized from a mixture of absolute ethanol and ether to give mg. of-1-(2-hydroxypropyl) 2 methyl 3-(10,1l-dihydro-SH-dibenzo [a,d]cycloheptene--yl|idene)pyrrolidine maleate, as colorless prisms, M.P. 170-171 C.

(2) 2 methyl 3 (10,11 dihydro-5H-dibenzo[a,d] cycloheptene-S-ylidene)pyrrolidine (4.7 g.) was dissolved in dimethylformamide (25 cc.), and then Z-bromoethanol (1.9 g.) and pulverized anhydrous potassium carbonate (3.1 g.) were added thereto. The mixture was stirred under heating at 60 C. for 3.5 hours, at 70 C. for 3.5 hours and at 80 C. for 16 hours and then the reaction mixture after cooled, was poured into ice water (150 cc.). The precipitated crystals were extracted with ether. The ether layer was washed with water and the ether was distilled oil. The residue was chromatographed onto column of alumina using ethyl acetate as a developer. The eluted fraction was extracted with hydrochloric acid, and then the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and the ether was distilled off to give 3.0 g. of crude 1-(2- hydroxyethyl) 2 methyl 3-(10,1l-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene)pyrrolidine as oil. This was converted with hydrochloric acid into the hydrochloride, which was recrystallized from ethanol to give the colorless prisms, M.P. 206-208 C.

(3) 2 ethyl 3 (10,11- dihydro 5H dibenzo[a,d] cycloheptene-S-ylidene)pyrrolidine (3.3 g.), triethylamine (5.8 g.), dimethylformamide (8 cc.) and 2-bromoethanol (2.9 g.) were admixed, and the mixture was stirred under heating at 70 C. for 3 hours. The reaction mixture became reddish orange due to precipitated crystals. To this, there was added water and then ether, and the solution was extracted with ether. The ether layer was washed with water and dried, and then the ether was distilled oil to give crude 1-(2-hydroxyethyl)-2-ethyl-3-(10,1l-dihydro- SH-dibenzo [a,d] cycloheptene-S-ylidene pyrrolidine as oil. This was converted with maleic acid into the maleate, which was recrystallized from a mixture of acetone and ether to give 2.4 g. of colorless crystals, M.P. 120 C. This maleate was dissolved in aqueous sodium hydroxide and was extracted with ether. The ether layer was washed with water and dried, and then the ether was distilled off to give 1.9 g. of 1-(2-hydroxyethyl)-2-ethyl-3- (10,11 dihydro-5H-dibenzo[a,d]cycloheptene-S-ylidene) pyrrolidine as crystals, M.P. 99-102 C.

(4) 2 isopropyl 3 (10,1l-dihydro-SH-dibenzo[a,d] cycloheptene-S-ylidene)pyrrolidine (4.0 g.), triethylamine (6.7 g.), dimethylformamide (8 cc.) and 2-bromoethanol 3.3 g.) were admixed and the mixture was stirred under heating at 65 to 70 C. for 16 hours. The reaction mixture became reddish orange due to precipitated crystals. To this, there was added water and then ether, and the solution was extracted with ether. The ether layer was washed with water and dried. The ether was distilled oil? to give 3.0 g. of an oil. The oily substance was purified by distillation under reduced pressure to give 1-(2-hydroxyethyl) 2 isopropyl 3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene)pyrrolidine as yellow oil, B.P. 240 C. (oil bath temperature)/0.7 mm. Hg.

Analysis.-Calculated for C H ON (percent): C, 82.95; H, 8.41; N, 4.03. Found (percent): C, 82.63; H, 8.46; N, 4.21.

(5) 2 methyl 3 (xanthene 9 ylidene)pyrrolidine (1.0 g.), triethylamine (2.03 g.), dimethylformamide (2.0 cc.) and 2-bromoethanol (1.01 g.) were admixed and the mixture was stirred under heating at 65-70 C. for 6 hours. The reaction mixture became reddish orange due to precipitated crystals. To this, there was added water and the ether, and the solution was extracted with ether. The ether layer was washed with water and dried. The ether was distilled off to give 0.4 g. of 1-(2-hydroxyethyl)-2-methyl-3-(xanthene-9-ylidene)pyrrolidine as reddish brown oil. This was converted with oxalic acid into the oxalate, which was recrystallized twice from a mixture of ethanol and ether to give 1-(2-hydroxyethyl)-2- methyl-3-(xanthene-9-ylidene)pyrrolidine oxalate, as yellow granules, M.P. 182 C. (decomposition).

In the similar manner to Example 2-(5), the following compounds were obtained from the corresponding pyrrolidine compounds and haloalcohols.

(6) 1 (2 hydroxyethyl) 2 methyl-3-(3-chloro-10, 11 dihydro-5H-dibenzo[a,d]cycloheptene-S-ylidene)pyrrolidine hydrochloride, as crystals, M.-P. 201-203 C.

(7) 1 (2 hydroxyethyl) 2 methyl-3-(3-methyl-10, l1 dihydro-SH-dibenzo[a,d]cycloheptene-S-ylidene)pyrrolidine hydrochloride, as crystals, M.-P. 194-196 C.

8) 1 (2 hydroxypropyl)-2-methyl-3-diphenylmethylenepyrrolidine, as oil.

(9) 1 (2 hydroxyethyl)-2-methyl-3-diphenylmethylenepyrrolidine, as prims, M.P. -130.5 C.

(10) 1 (3 hydroxypropyl) 2-methyl-3-(10,11-dihydro 5H dibenzo[a,d]cycloheptene-S-ylidene)pyrrolidine as oil.

(11) 1 (2 hydroxyethyl) 2-methyl-3-[a- (p-fluorophenyl)-a-phenyl]methylenepyrrolidine hydrochloride, as crystals, M.P. 241-243 C.

(12) 1 (2 hydroxyethyl) 2 methyl-3-bis(p-chlorophenyl)methylenepyrrolidine hydrochloride, as prisms, M.P. 243-245 C.

13) 2-methyl 3 diphenylmethylenepyrrolidine (250 mg.) was dissolved in dimethylformamide (3 cc.), and pulverized anhydrous potassium carbonate mg.) and 2-chloroethyl p-toluenesulfonate (250 mg.) were added thereto, and then the mixture was stirred for 5 hours at 30 C. To the reaction mixture, there was added ice water (30 cc.) and the solution was extracted with ether. The ether layer was washed and dried, and then the ether was distilled off. The residue was chromatographed onto alumina using ethyl acetate as a developer. The eluted fraction was condensed under reduced pressure to give 200 mg. of 1-(2-chloroethyl)-2-methyl-B-diphenylmethylenepyrrolidine, as oil. This substance was converted with hydrochloric acid into the hydrochloride, which was recrystallized from ethanol to give colorless crystals, M.P. 250-2505 (decomposition).

EXAMPLE 3 (l) 1-(2-hydroxyethyl)-2-methyl 3 (10,11-dihydro- 5H-dibenzo[a,d] cycloheptene-S-ylidene) 1 pyrrolinium bromide (18 g.) was dissolved in 99% ethanol (350 cc.) and sodium boron hydride was added gradually thereto under stirring. The mixture was stirred overnight at the room temperature, and then the solvent was distilled off under reduced pressure. To the residue was added water and ether. The ether layer was collected by separation, washed with ether and dried, and then the ether was distilled ofi to give 13 g. of 1-(2-hydroxyethyl)-2-methyl-3- 10,1 1 dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene) pyrrolidine as oil.

This substance was converted with hydrochloric acid into the hydrochloride, which was recrystallized from ethanol to give crystals, M.P. 205207 C.

(2) To a solution of 1-(2-hydroxyethyl)-2-ethyl-3-(10, 1l-dihydro-SH-dibenzo[a,d]cycloheptene 5 ylidene)- l-pyrroliniurn bromide (5.5 g.) in ethanol (30 cc.) was added sodium boron hydride (1.7 g.) under stirring at room temperature. The mixture was treated in the similar manner to Example 3-(1) to give 4.0 g. of 1-(2-hydroxyethyl)-2-ethyl-3-(10,11-dihydro 5H dibenzo [a,d]cycloheptene-S-ylidene)pyrrolidine, as colorless crystals, M.'P. 103 C.

This substance was converted wtih hydrochloric acid into the hydrochloride, which was recrystallized from a solution of acetone, methanol and ether to give crystals, M.P. 200 C.

(3) To a solution of 1-(2-hydroxyethyl)-2-methyl-3- (3-chloro-10,11-dihydro 5H dibenzo[a,d]cycloheptene- 5-ylidene)-1-pyrrolinium bromide (2.7 g.) in methanol (30 cc.) was added sodium boron hydride (1.0 g.) under cooling and stirring. The mixture was treated in the similar manner to Example 3-(1) to give 2.1 g. of 1-(2-hydroxyethyl)-2-methyl-3-(3-chloro 10,11 dihydro-5H- dibenzo[a,d] cycloheptene ylidene)pyrrolidine as oil. This substance was converted with hydrochloric acid into the hydrochloride, which was recrystallized from a mixture of absoluteethanol and absolute ether twice to give crystals, M.P. 2'01-203 C.

In the similar manner to Example 3-(1), the following compoundswere obtained from the corresponding l-pyrrolinium compounds.

(4) 1-(2-hydroxyethyl)-2-isopropyl 3 (10,11-dihydro 5H dibenzo[a,d1 cycloheptene 5 ylidene)pyrrolidine as yellow oil, B-P. 240 C. (oil bath temperature)/ 0.7 mm. Hg.

(5 1-(2-hydroxyethyl) 2 methyl 3 (xanthene-9- ylidene)pyrrolidine oxalate, as yellow granules, M.P. 182 C.

(6) 1-(2-hydroxypropyl)-2-methyl-3-(10,11 dihydro- 5H dibenzo[a,d]cycloheptene 5 ylidene)pyrrolidine maleate, as colorless prisms, M.P. 170l71 C.

(7) l-(2-hydroxyethyl)-2-methyl-3-(3-methyl 10,11- dihydro-5H-dibenzo[a,d]cycloheptene 5 ylidene)pyrrolidine hydrochloride, as crystals, M.P. 194196 C.

(8) l-(2-hydroxypropyl)-2-methyl 3 diphenylmethylenepyrrolidine, as oil.

(9) 1-(2-hydroxyethyl)-2-methyl 3 diphenylmethylenepyrrolidine, as prisms, M.P. 130-130.5 C.

(10) 1-(3-hydroxypropyl)-2-methyl 3 (10,11-dihydro-SH-dibenzo[a,d]cycloheptene 5 ylidene)pyrro1idine as oil.

(11) l-(2-hydroxyethyl)-2-methyl 3 [a-(p-fiuorophenyl)-u-phenyl] methylenepyrrolidine hydrochloride, as crystals, M.P. 241-243 C.

(12) l-(2-hydroxyethyl)-2-methyl 3 bis(p-chlorophenyl)methylenepyrrolidine hydrochloride, as prisms, M.P. 243-245 C.

EXAMPLE 4 (l) l-(2-hydroxyethy1)-2-rnethyl 3 l0,ll-dihydro- 5H dibenzo[a,d1cycloheptene-S-ylidene)pyrrolidine (1.3 g.) was dissolved in chloroform (5 cc.) and thionylchloride (1.5 g.) was added thereto under cooling. The mixture was refluxed mildly for 1 hour under heating. Chloroform and excess thionylchloride was removed by distillation under reduced pressure, and the residue was recrystallized from hot ethanol to give 0.9 g. of l-(2-chloroethyl)- 2-methyl-3-(l0,l1-dihydro 5H dibenzo[a,d]cycloheptene 5 ylidene)pyrrolidine hydrochloride, as colorless prisms, M.P. 235-236 C.

(2) 1-(2-hydroxyethyl) -2-methyl 3 diphenylmethylenepyrrolidine (1.2 g.) was dissolved in chloroform (5 cc.) and thionylchloride (1.2 g.) was added thereto under cooling. The reaction mixture was refluxed for 45 minutes under heating. Chloroform and excess thionylchloride was removed by distillation under reduced pressure. The residue was recrystallized from hot ethanol to give colorless crystals of 1-(2-chloroethyl) 2 methyl-3-diphenylmethylenepyrrolidine hydrochloride as colorless prism, M.P. 25 8-2585 C.

(3) 1-(2-hydroxyethy1)-2-methyl 3 bis(p chlorophenyl)methylenepyrrolidine hydrochloride (700 mg.) was dissolved in absolute chloroform (14 cc.) and thereto was added thionylchloride (1 cc.) and the reaction mixture was refluxed at 70 C. for 4 hours under heating. The solvent and the excess thionylchloride were removed by distillation. The residue was recrystallized from 99% ethanol to give colorless crystals (600 mg.) of l-(2-chloroethyl)-2-methyl 3 bis(p-chlorophenyl)methylenepyrrolidine hydrochloride, M.P. 250-252 C. In the similar 12 manner to the above, the following compounds were obtained from the corresponding hydroxy compounds.

(4) 1-(3-chloropropyl)-2-methyl- 3 (10,1l-dihydro- 5H dibenzo[a,d]cycloheptene 5 ylidene)pyrrolidine hydrochloride, M.P. 20 1203 C. (decomposition).

- (5) 1-(2-chloroethyl)-2-methyl 3 (3-chloro-l0,1ldihydro-5H-dibenzo[a,d]cycloheptene 5 ylidene)pyr- .rolidine hydrochloride, M.'P. 250-251 C. (decomposi- Rg-R wherein X and X are hydrogen, halogen, lower alkyl or lower alkoxy and may be the same or different,

Y is hydroxy or halogen,

R and R bound together are ethylene,

R is lower alkyl, and

R is lower alkylene and their pharmaceutically acceptable salts.

2. A compound according to claim 1 wherein X and X are hydrogen.

3. A compound according to claim 2 wherein Y is halogen.

4. A compound according to claim 3 wherein Y is chlorine and R is methyl.

5. A compound according to claim 2 wherein Y is hydroxy.

6. A compound according to claim 5 wherein R is methyl.

References Cited UNITED STATES PATENTS 3,454,595 7/1969 Deguchi et a1 260326.81

ALEX MAZEL, Primary Examiner I. A. NARCAVAGE, Assistant Examiner US. Cl. X.R.

260-326.5 SA, 326.5 CA, 326.82, 326.9; 424274 CERTH! .KJA'I In Q1 CQHREQ 1 IGN Patent 3,699,125 Dated October 17,, 1972 lnvcntofls) Suminori Umio and Shizuo Maeno It is certified that error appears in the above-identified patent and that said LctLcrs Potent are hereby corrected as shown below:

In Column 2, lines 4050, structural Formula V should read Signed and sealed this 29th day of April 1973.

(SEAL) Attest:

EDWARD M. FLETCHER, JR. RQBERT GOTTSCHALK Attesting Officer Commissioner of Patents