US3205134A

US3205134A - Antidepressant benzilates of piperazinoalkanols

Info

Publication number: US3205134A
Application number: US152143A
Authority: US
Inventors: John H Biel
Original assignee: Colgate Palmolive Co
Current assignee: Colgate Palmolive Co
Priority date: 1961-11-14
Filing date: 1961-11-14
Publication date: 1965-09-07
Anticipated expiration: 1982-09-07

Description

United States Patent 3,205,134 ANTIDEPRESSANT BENZILATES 0F PIPERAZINOALKANOLS John H. Biel, Milwaukee, Wis., assignor to Colgate- Palmolive Company, a corporation of: Delaware No Drawing. Filed Nov. 14, 1961, Ser. No. 152,143 10 Claims. (Cl. 16765) This invention relates to piperazine derivatives. More particularly, this invention is concerned with pharmaceutical uses for benzilates of piperazinoalkanols as psychotherapeutic agents.

This application is a continuation-in-part of my copending applications Serial No. 14,500 filed March 14, 1960, now U.S. Patent No. 3,125,575, granted March 17, 1964, Serial No. 18,796 filed March 31, 1960, and now abandoned, and Serial No. 24,217 filed April 25, 1960, and now abandoned. Serial No. 14,500 is a continuationin-part of my application Serial No. 735,356 filed May 15, 1958, and now abandoned. Serial No. 18,796 is a continuation-in-part of my application Serial No. 765,940 filed October 8, 1958 and now abandoned. Serial No. 24,217 is a contitnuation-in-part of Serial No. 726,347 filed April 4, 1958, and now abandoned. Serial No. 765,940 is a continuation-in-part of Serial No. 728,085 filed April 14, 1958, and now abandoned and Serial No. 704,246 filed December 23, 1957, and now abandoned.

According to the present invention it has been found that compounds of the formula as the base or an acid addition salt, can be administered to humans to induce an antidepressive effect, central nervous system stimulation and increased motor activity, wherein R and R are members of the group consisting of phenyl and nuclear substituted phenyl groups such as a lower alkylenedioxyphenyl group and particularly methylene dioxyphenyl, a halophenyl such as p-chlorophenyl and p-fluorophenyl, a lower alkoxyphenyl such as pmethoxyphenyl, diethoxyphenyl, dimethoxyphenyl and trimethoxyphenyl, a hydroxyphenyl such as p-hyd-roxyphenyl, an aminophenyl such as p-aminophenyl, a lower alkylphenyl such as p-met-hylphenyl and a halo-lower alkyl-phenyl such as p-trifluoromethylphenyl, R is a member of the group consisting of hydrogen, lower alkyl groups such as methyl, ethyl, pnopyl, isopropyl and butyl and phenyl-lower alkyl groups such as benzyl, phenethyl, phenylisopropyl and similar groups having substituents on the phenyl ring such as a halogen like chlorine and bromine, a lower alkoxy such as methoxy, or a lower alkyl such as methyl, R and R are members of the group consisting of hydrogen and lower alkyl groups such as methyl, ethyl, propyl and butyl, and Y is a lower alkylene having not more than five carbons with at least two carbons between the oxygen and nitrogen atoms to which it is bonded.

These compounds, advisably in the form of nontoxic acid addition salts, exert a pronounced psychotherapeutic eflect when administered to humans. The compounds induce a feeling of relaxation and a relief from anxiety or restlessness. In particular, 4-methylpiperazinoethyl benzilate dihydrochloride as an antihallucinatory, antipsychotic and calming agent. Those compounds in which R, is methyl are of much greater activity as psychotherapeutics than the ethyl and higher alkyl derivatives.

4-methylpiperazinoethyl benzilate, advisably in the "Ice form of a nontoxic acid addition salt, exerts a pronounced psychotherapeutic elfect when administered to a human. Humans to whom the compound, and particularly 4-methylpipera'zinoethyl benzilate hydrochloride, is given, experience a feeling of relaxation and a relief from anxiety or restlessness.

Schizophrenic patients who did not respond to Thorazine [2-chloro 10-(3-dimethylaminopropyl)phenothiazine HCl] or reserpine showed a marked beneficial eifect after oral administration of 4-methylpiperazinoethyl benzilate hydrochloride.

A hallucinating, belligerent and uncontrollable patient ceased to have hallucinations and became very docile and communicative after four 20 mgm. doses of 4-methylpiperazineoethyl benzilate hydrochloride at four hour intervals. Psychomotor epileptics who were actively hallucinating were placed on a comparable dosage of this compound and, in all instances, the hallucinations partly or almost completely vanished. Other known psychotherapeutic drugs in no way influenced the hallucinatory episodes in the epileptic.

It has further been found that the compounds of the above formula in which Y is an unsubstituted straight chain alkylene of two to five carbons between the oxygen and nitrogen atoms to which it is bonded, as the base or an acid addition salt, exert a simultaneous anticholinergic effect in a human in addition to the antidepressive effect, central nervous system stimulation and increased motor activity. This dual action is especially useful in the treatment of patients with psychosomatic diseases, particularly of the gastrointestinal tract such as spastic colitis, gastric duodenal ulcer, diarrhea and other physiological disturbances caused by cholinergic overstimulation. This dual action results from the much higher antispasmodic activity of the compounds in which Y is a sraight chain alkylene rather than a branched alkylene.

Patients in medical wards exhibiting psychogenic disturbances associated with ulcers, spastic colitis and hypertension have responded effectively to 4-me-thylpiperazinoethyl benzilate hydrochloride.

The acute and toxic manifestations of 4-methylpiperazinoethyl benzilate hydrochloride are nil, even in patients with liver and kidney disturbances.

The mechanism of action of 4-methylpiperazinoethyl benzilate, and other compounds in which Y is a straight chain alkylene, in the form of nontoxic acid addition salts, as well as its locus of action in the central nervous system, is entirely different from other psychotherapeutic agents and represents a new approach to the problem of psychopharmacology. These drugs appear to act by virtue of their anticholinergic effect, particularly in regions like the basal ganglia and certain areas of the cerebral cortex where acetylcholine is believed concentrated.

It appears that the compounds in which Y is a branched alkylene are more potent as psychotherapeutics and have lower anticholinerg'ic side effects than compounds in which Y is a straight chain alkylene. The compounds in which Y is a branched alkylene are also mild to moderate muscle relaxants; however, they are not sedatives or hypnotics. However, when Y is a straight chain alkylene different ancillary activities are obtained. For example, l-methyl- 4-piperazinopropyl ben zilate is a mild stimulant while 1-methyl-4-piperazinoethyl benzilate has marked sedative and muscle relaxant actions.

The compounds in which R is hydrogen evidence much higher antispasmodic activity than those where R is lower alkyl. Thus, beta-piperazinoethyl benzilate HCl is a potent antispasmodic.

All of the compounds have antispasmodic activity as acid addition salts and quaternary ammonium salts. The quaternary salts, however, do not exert a psychotherapeutic effect. The compounds in which Y is a straight chain alkylene have greater antispasmodic activity than those compounds in which Y is a branched alkylenc. However, increasing Y from ethylene to propylene raises the antispasmodic activity.

Methoxylation or methylation of one of the phenyl rings of the 1-methyl-4-pipcrazinopropyl benzilates gives compounds that have less pronounced central stimulant properties but increased motor activity. Thus, l-methyl- 4-piperazinopropyl Z-methyl benzilate is a pronounced central stimulant. However, methoxylation or methylation of one of the phenyl rings of the l-methyl-4-piperazinoethyl benzilates gives compounds that have, generally, the same or less central stimulation and a significant muscle relaxant activity. As compared to this, however, 1-methyl-4-piperazinopropyl 4-chlorobenzilate and 1-methy1-4-piperazinoethyl 3-chlorobenzilate have sedative and muscle relaxant eifects. Thus, the introduction of a chloro group into one of the phenyl rings produces a sedative and muscle relaxant efiect. The same is achieved by the fiuoro, trifiuoromethyl and 3,4-methylenedioxyphenyl groups.

The compounds of this invention are not hypnotics.

Oral administration of the compounds is advisable.

In Table 1 following there is given the results of experiments with compounds of the subject invention and with other related compounds which support the statements made above. The compounds were tested as the alkanol to produce the desired 4-substituted piperazino straight chain alkyl benzilate. This process can be represented as follows:

wherein R R R R R and Y have the signficance previously assigned, and R is a lower alkyl group.

Some of the benzilic acids used in the process in the form of lower alkyl esters are methyl benzilate, methyl 4-chlorobenzilate, methyl 2-methylbenzilate, methyl 4- methoxybenzilate, methyl 3-chlorobenzilate, methyl 3,4-

dimethoxybenzilate, methyl 3,4,5-trimethoxybenzilate and methyl 3,4-methy1enedioxybenzilate.

Some of the 4-substituted piperazino straight chain alkanols which can be used in this process are 4-methylpiperazino propanol, 4-ethylpiperazinopropano1, 4-ethyl- 3 zinoethanol,

piperazino-Z-butanol, 4p-methoxyphenylethylpiperazinohydrochlor des. 4-pentanol and 4-phenylpropylp1perazmo-2-propanol.

TABLE 1 (DH Rl 2 N R3 Anti- Activity cage 2 Antagospasnisrn, ratio R3 R; Y R R medic of counts Muscle CNS Biphasic activity Counts before to relax. stim.

Z 1 MgJkg. per counts 5 min. after 9 Ph CGHA Fl CPU 20 1000/1500 3 Yes P C Hl H CH(CH 15 3 Ph CII2CH(CH3) "H CH 0.34 10 2 Ph (CH H CW 83 20 0 m-Cl Pn Cmi H CH: 30 2 p-CH3O Ph C Fl'i H CH3 20 2 (01 19 H CPU 4. 0 30 1 O-CHz Ph (CH;) H CH3 5 0 p-Cl Ph (CH H CH1 5 3 CgH4 2.5-di-CH3 CHa 6. 25 20 1 p-Fl-Ph (CH H CH3 20 2 3,4-methylene (CH 1 H CT T- 25 dioxyphenyl m-CFl3-Ph (CH M Fl cm 10 1000/400 3 N0. o-Cl-Ph (CHg)1 T'T CT-T- 20 100 1000/000 0 1 Ph cm. Fl H 208 10 Ph (01:193- W H 10 Ph H "Ff Ph-CHg- 4. 4 10 Ph (CH H Pit-GE 10 Ph JFT. Ph-iso 1 l6. 7 10 PS Control 3.

1 The dilution, 1 ZXELO, at which the drug will inhibit the spasm produced by 1: 16,000,000 acetylcholine by 50% in the isolated guinea pig ileum.

-An activity cage is a device for measuring the degree of motor activity in animals. It is simply a cage suspended from a string provided with an electronic device for recordmg the cage oscillations or vibrations caused by the animal in the cage. The activity is expressed in terms of counts per 5 minutes. Rats were used in the test.

The degree of reduction in hyperactivity produced by 20 mg./kg. of the drug on that activity induced by 5 mgJkg. of N-methyl-3piper1dyl benzilate HCI (LIB-336) administered 5 minutes after the drug. Thus, the 1000 count induced by JB-336 was reduced to 300 with SIB-808. A 5 minute period was used for the count readings. Rats were the test animals. The activity cage in (2) was used for the test.

The compounds of this invention in which R is not hydrogen can be conveniently produced by several processes, one of which comprises reacting a lower alkyl benzilate with a 4-substituted piperazino straight chain 4 Chlorpromazine was administered to rats at 5 mgJkg. IP and a value of 6 assigned for the muscle relaxation. A value of 4 indicates a moderate to good activity whereas a value of 1 shows slight activity. Muscle relaxation was evaluated by determ ning the degree of muscle tension. either induced or remaining in the rat after the drug CNS stimulation was measured both on the basis of hyperactivity, muscle tension and hypersensitivity.

The figure of 6 is assigned for the central nervous stimulation achieved by the intraperitoneal administration of 5 rug/kg. of N-methyl or N-ethyl-3-pipcridyl benzilate HCL. The test drugs were administered at the same dosage to ratsand a number assigned corresponding to the degree of activity obtained.

. "Biphasic-sedates then stimulates.

Reaction between the lower alkyl benzilate and the 4-substituted piperazino straight chain alkanol is conveniently effected by bringing the reactants together in a suitable inert solvent in the presence of sodiunror. a. sodium alkoxide. Solvents such as n-heptane, toluene, xylene or an excess of the piperazino alkanol can be used for the reaction medium. The mixture is generally heated to promote the reaction with the reflux temperature being preferred. As the reaction proceeds, the lower alcohol which is formed in the reaction is distilled 01f. The reaction is considered completed when low boiling alcohol ceases to distill ofl. The product is recovered by acidifying the reaction mixture, evaporating to dryness, taking the residue up in water, adding a base such as caustic soda to the aqueous solution and extracting with an immiscible solvent. The extract may then be dried and the product recovered by distillation.

Representative of the products which are produced in this way are 4-methylpiperazinopropyl benzilate, 4-ethylpiperazinoethyl benzilate, 4-propylpiperazinobutyl benzilate, 2-methyl-4-methylpiperazinopropyl benzilate, 4- methylpiperazinoethyl benzilate, 4-isopropylpiperazinoethyl benzilate, 4-benzylpiperazinoethyl benzilate, 2- phenethylpiperazino-Z-propy1 benzilate and 4-phenylpropylpiperazinoethyl benzilate.

An alternate method of producing the 4-substituted compounds comprises reacting a di-phenyl substituted halo or acyloxy acetyl halide with a 4-substituted piperazino-straight chain alkanol to produce an intermediate 4-substituted piperazino-straight chain alkyl di-phenyl substituted halo or acyloxy acetate which is subsequently hydrolyzed to the corresponding 4-substituted piperazinostraight chain alkyl'benzilate. This process can be represented as follows:

wherein R R R R R and Y have the significance previously assigned, Z is a reactive halogen and advisably chlorine,- and X is a reactive halogen such as chlorine or a reactive acyloxy group of a lower monocarboxylic acid such as acetoxy.

Representative di-phenyl substituted halo or acyloxy acetyl halides which can be used in the process are diphenyl-chloroacetyl chloride, phenyl 3,4-methylenedi0xyphenyl chloroacetyl chloride, phenyl p-methoxyphenyl acetoxy acetyl chloride and phenyl p-chlorophenyl chloroacetyl chloride.

4-substituted piperazino-straight chain alkanols such as those previously named can be used in the process.

In the first step of this process the reactants can be conveniently brought together in an inert organic solvent such as benzene, toluene, isopropanol, or acetone. An acid acceptor such as triethylamine is generally included in the reaction mixture. Elevated temperatures up to the reflux temperature are generally employed to enhance the rate of reaction and maintain solubility of the reactants. The reaction product-can be recovered from the mixture by conventional methods.

Some of the compounds which are produced in this Way are 4-methylpiperazinopropyl diphenylchloroacetate, 4-ethylpiperazinobutyl phenyl 3,4-methylenedioxyphenyl chloroacetate, 4-isopropylpiperazinopropyl phenyl p-methoxyphenyl chloroacetate, 2-methyl-4-methylpieprazinopropyl diphenylchloroacetate, 4-benzylpiperazino-Z-propyl 6 diphenylchloroacetate and 4-phenethylpiperazino-2-propyl diphenyl chloroacetate.

These and other compounds are readily hydrolyzed to the corresponding 4-substituted piperazino-alkyl benzilates, advisably in the presence of a mineral acid and preferably hydrochloric acid. This hydrolysis can also be readily effected in the animal body.

The compounds with which this invention is concerned, except those where R; is not hydrogen, can also be conveniently produced by reacting a benzilic acid with an wherein R R R R R Y and Z have the significance previously assigned.

The reactants used in this process are essentially the same as those named previously except that the free benzilic acid is used instead of an ester and a 4-suhstituted piperazino alkyl halide instead of the corresponding alkanol. The reaction is readily effected by combining the reactants in an inert solvent such as isopropanol and heating the mixture at an elevated temperature, such as the reflux temperature.

The piperazinoalkyl glycolates having no substituent in the 4-position of the piperazine moiety can be produced from the N-benzyl piperazinoalkyl glycolates by catalytic hydrogenation with cleavage of the N-benzyl group. This process can be represented as follows:

wherein R R R R and Y have the significance previously assigned and is phenyl,

The catalytic reductive cleavage is readily effected by adding the N-benzyl piperazinoalkyl glycolate, advisably as an acid addition salt, to a solvent such as water or a lower alcohol, adding a catalyst such as palladium, and hydrogen under pressure, as up to about psi. A small amount of glacial acetic acid is generally included to promote the reaction. The hydrogenation proceeds quickly and its progress can be measured by the hydrogen uptake. When the hydrogen uptake ceases the reaction can be considered completed. After filtering the reaction mixture, it can be evaporated to dryness and the product triturated with a solvent such as ether and separated by filtration.

Some of the compounds produced in this way from the corresponding 4-benzyl piperazinoalkyl glycolates are beta-piperazinoethyl benzilate, gamma (2 methylpiperazino)-propyl benzilate and beta-piperazinopropyl benzilate.

Acid addition salts are produced by contacting the compounds with a suitable acid such as formic acid, citric acid, maleic acid, sulfuric acid, hydrochloric acid, succinic acid, tartaric acid, benzoic acid or fumaric acid.

Quaternary ammonium salts are formed by contacting the compounds with a suitable alkylating agent such as dimethyl sulfate or an alkyl halide such as methyl chloride or ethyl bromide.

The active agents of this invention may be administered to humans as pure compounds. It is advisable, however, to first combine one or more of the novel compounds with a suitable pharmaceutical carrier to attain a more satisfactory size to dosage relationship.

Pharmaceutical carriers which are liquid or solid may be used. The preferred liquid carrier is water. Flavoring materials may be included in the solutions as desired.

Solid pharmaceutical carriers such as starch, sugar, talc and the like may be used to form powders. The powders may be used as such for direct administration to a patient or, instead, the powders may be added to suitable foods and liquids, including water, to facilitate administration.

The powders may also be used to make tablets, or to fill gelatin capsules. Suitable lubricants like magnesium stearate, binders such as gelatin, and disintegrating agents like sodium carbonate in combination with citric acid may be used to form the tablets.

Unit dosage forms such as tablets and capsules may contain any suitable predetermined amount of one or more of the active agents as a nontoxic acid addition salt and may be administered one or more at a time at regular intervals. Such forms should, however, generally contain a minimum concentration of 0.1% and preferably 1.0%, by weight of the active agent.

A typical tablet may have the composition:

(1) 4-methyl piperazinoethyl benzilate hydrochloride 1O (2) Starch U.S.P. 57 (3) Lactose U.S.P. 73 (4) Talc U.S.P. 9 (5) Stearic acid 6 Powders 1, 2 and 3 are slugged, then granulated, mixed with 4 and 5, and tableted.

Tablets may also be made of the following ingredients from the stated quantities:

. Grams (l) N-methyl piperazinopropyl benzolate hydrochloride 2000 (2) Lactose U.S.P. 800

(3) Dibasic calcium phosphate U.S.P. 1527.2 (4) Starch U.S.P 799.3 (5) Calcium stearate 56.7 (6) Gelatin solution1.5 lb./ gal. of H 0.

Powders 1, 2 and 4 are granulated using enough gelatin solution to wet the mixture. The granules are then combined with the other ingredients, gelatin solution is added to wet the mixture, and it is tableted. The size of the tablets may be varied at will although tablets of 0.25 to 0.50 gm. are satisfactory for many uses; such tablets may contain about 5 to 50 mgm. of the active agent.

Capsules are prepared by filling No. 3 hard gelatin capsules with the following ingredients, throughly mixed:

Mg. 4-methylpiperazinopropyl benzilate hydrochloride Lactose U.S.P. 200 Starch U.S.P. 16 Talc U.S.P. 8

The following examples show the preparation of specific compounds with which this invention is concerned.

Example 1.4-methylpiperazinoethyl benzilate A mixture containing 0.49 mole of methyl benzilate, 0.49 mole of 1-methyl-4-hydroxyethyl piperazine, 325 cc. of n-heptane and 1.2 g. of sodium methoxide was refluxed with stirring with the simultaneous removal of methanol as the reaction proceeded. When the theoretical amount of methanol was collected, the reaction mixture was diluted with additional n-heptane and clarified by filtration. A gummy precipitate formed which was crystallized in water. The solid was removed by filtration, washed with cold water and dried. Yield 128.3 g. (74%), M.P. 88- 90 C.

Analysis.-Calcd. for C21H25N203: N, 7.90. Found: N, 7.17.

Example 2.4-methylpiperazinocthyl bcnzilate dihydrochloride The dihydrochloride salt was prepared by dissolving 0.33 mole of the basic ester in 500 cc. of isopropyl alcohol and adding ethereal hydrochloric acid to the mixture until the solution was stronglyacid '(pH 2-3). The product precipitated immediatelly and was isolated by filtration. Yield 88%, M.P. 210-212 C.

Analysis.Calcd. for C I-I Cl N 0 Cl, 16.40; N, 6.50. Found: Cl, 16.37; N, 6.48.

Example 3.--4-is0pr0pylpipemzinoethyl benzilate and dihydrochloride A mixture containing 37.9 g. (0.22 mole) of 1-(betahydroxyethyl)-4-isopropylpiperazine, 48.4 g. (0.20 mole) of methyl benzilate, 500 cc. of n-heptane and 1.0 g. of sodium methoxide was refluxed until no more methanol distilled over. The reaction mixture was clarified by filtration, the filtrate diluted with ether and washed several times with water. The organic phase was dried with potassium carbonate and the ester base isolated by allowing the solvent to evaporate. The residual oil was dissolved in isopropyl alcohol and the solution acidified with ethereal hydrochloric acid. The crystalline product was isolated by filtration; M.P. 214 C. Yield 71 g. (78% Analysis.--Calcd. for C H Cl N O Cl, 15.58; N, 6.15. Found: Cl, 15.29; N, 6.21.

Example 4.1-methyl-4-piperazin0pr0pyl-4-chl0r0- benzilate dihydrochloride A mixture consisting of 18.43 g. (0.116 mole) of 4- methylpiperazinopropanol, 32.2 g. (0.116 mole) of methyl 4-chlorobenzilate, 0.7 g. of sodium methoxide and 300 cc. of n-heptane was refluxed until 7.3 cc. of methanol was collected. The catalyst was filtered off, and the filtrate was washed twice with cc. of water. The organic material was dried over potassium carbonate and the solvent distilled off. Yield, 45 g. (96.3%).

The base was dissolved in 250 cc. of isopropanol and acidified with ethereal hydrochloric acid. The solid was collected by filtration, washed with ether and dried. Yield, 39.8 g. (75%), M.P. 203 C.

Analysis.Calcd. for C H Cl N O N, 5.89; Cl, 14.90. Found: N, 5.90; Cl, 14.85.

Example 5.-1-mcthyl-4-piperazinopropyl Z-metlzylbenzilate dihydrochloride A mixture consisting of 12.4 g. (0.079 mole) of 4- methylpiperazinopropanol, 20.1 g. (0.079 mole) of methyl Z-methylbenzilate, 0.35 g. of sodium methoxide and 250 cc. of heptane was refluxed until 4.7 cc. .of metha- Example 6.1-methyl 4-piperazinoethyl 4-metlzoxybenzilate dihydroclzloride A mixture consisting of 27.3 g. (0.1 mole) of methyl 4-methoxybenzilate, 14.4 g. (0.1 mole) of 4-methylpiperazinoethanol, 0.8 g. of sodium methoxide and 250 cc. of heptane was refluxed for five hours and 6.5 cc. of methanol was collected. The catalyst was filtered oil and the filtrate was washed twice with 100 cc. of water. The organic material was dried over potassium carbonate and the solvent was distilled. Yield, 43.15 g.

The hydrochloride salt was prepared by dissolving the base in 300 cc. of ether and acidifying with ethereal hydrochloric acid. Yield, 28.25 g. (61.8%), M.P. 204 C.

(dec.).

Analysis.Calcd. for C H Cl N O N, 6.12; CI, 15.50. Found: N, 5.92; Cl, 14.92.

Example 7.-1-methyl-4 piperazinoetlzyl 3-chl0r0- benzilaie dihydrochloride A mixture consisting of 27.7 g. (0.1 mole) of methyl 3-chlorobenzilate, 14.4 g. (0.1 mole) of N-methyl-4- piperazinoethanol, 0.8 g. of sodium methoxide and 250 cc. of heptane was refluxed for six hours and 6.2 cc. of methanol was collected. The product was isolated as described in Example 4. Yield, 35.4 g. (91%).

The hydrochloride salt was prepared as in Example 4. Yield, 19 g. (41.3%), M.P. 221222 C. (dec.).

Analysis.Calcd. for C H Cl N O N, 6.06; Cl,

This compound is prepared as described in Example 6 using methyl 3,4-dimethoxybenzilate in place of methyl 4-methoxybenzilate.

Example 9. -1-methyl-4-piperazinopropyl 3,4,5-trimethoxybenzilate 01130 OCHs 30113 This compound is prepared as' shown in Example 6 using methyl 3,4,5-trimethoxybenzilate in place of methyl 4-methoxybenzilate.

Example 10.1-methyl-4-piperazin0propyl 3,4-me1hylenedioxybenzilate 10 This compound was prepared as shown in Example 6 using methyl 3,4-methylenedioxybenzilate in place of methyl 4-methoxybenzilate.

Example 11 .Gamma- (4-methylpiperazin0) propylbenzilate A mixture consisting of 3.7 g. of gamma-(4-methylpipe'razino)-propyl alcohol, 36.3 g. of methyl benzilate, 0.8 g. of sodium methoxide and 375 cc. of n-heptane was refluxed for six hours removing the methanol formed by azeotropic distillation. The reaction mixture was clarified by filtration, diluted with 200 cc. of chloroform and washed several times with water. The organic phase was r dried with potassium carbonate and the solvent removed by distillation leaving the ester base as the residue. Yield 37.3 g. (67.5%)

The dihydrochl-oride salt was formed in methanol, M.P. 184l85 C. Yield 23 g. (52%).

AIzalysis.-Calcd. for CZQH3DCIZN203I C1, N, 6.34. Found: Cl, 15.84; N, 6.23.

Example 12.'-Gamma-(2,4-dimethylpiperazino)-pr0pyl benzilate and dihydrochloride A mixture containing 20.6 g. of 2,4-dimethylpiper azinopropyl alcohol, 29 g. of methyl benzilate, 300 cc. of n-heptane and 0.3 g. of sodium methoxide was refluxed until no more methanol distilled. The basic ester was isolated in the manner described in the previous example and converted to the dihydrochloride salt in ethyl ether. Yield 43.5 g. (73%), M.P. -103 C.

AnaIysis.Calcd. for C H Cl N O C1, N, 6.15. Found: Cl, 15.77; N, 6.18.

Example 13.'3,4,6=cis-tfimezhylpiperazinoethyl ben- Zilate dihydrochloride A mixture of 16.2 g. (0.094 mole) of 3,4,6-cis-trimethylpiperazinoethanol, 2.7 g. (0.094 mole) of methyl benzilate, 250 cc. of n-heptane, 2 cc. of methanol and 0.6 g. ofsodium methoxide was stirred at reflux until no more methanol was evolved. The basic ester was isolated as indicated previously and converted to the dihydrochloride salt in a mixture of ethyl ether and isopropyl alcohol. The solid was isolated by filtration, M.P. 118 C. Yield 35.3 g. (81%).

Analysis.Calcd. for C23H32Cl2N2031 C1, N, 6.15. Found: Cl, 15.70; N, 6.10.

Example 14.Gamma- (4-methylpiperazino)-propyl 4- fluorobenzilate and dihydrochloride A mixture containing 27.5 g. (0.105 mole) of methyl 4-fluorobenzi1ate, 167 g. (0.105 mole) of gamma-(4- methylpip'era'zino)-propanol, 0.5 g. of sodium methoxide and 300 cc. of n-heptane was stirred and refluxed until no more methanol distilled. The basic ester was isolated in the usual manner and converted to the dihydrochloride salt in isopropyl alcohol by the addition of ethereal hydrochloric acid. Yield 35.8 g. (70%); M.P. 183-184" C.

Analysis.Calcd. for C H gC1 FN O Cl, 15.44; N, 6.10. Found: C1, 15.56; N, 6.16.

Example 15.Gamma-(4-methylpiperazin0)-pr0pyl 3- trifluoromethylbenzilate and dihydrochloride A mixture containing 31 g. (0.10 mole) of methyl 3- trifiuoromethyl benzilate, 15.8 g. (0.10 mole) of gamma- (4-methylpiperazino)-propanol, 0.5 g. of sodium methoxide and 250 cc. of n-heptane was refluxed for 5 hours while 6.5 cc. of methanol was collected by distillation. The basic ester was obtained as in Example 11 and converted to the dihydrochloride salt in isopropyl alcohol, M.P. 183184 C. Yield 37.3 g. (68%).

Analysis.Calcd. for C H Cl F N O Cl, 13.92; N, 5.50. Found: Cl, 13.79; N, 5.58.

1 1 Example 1 6 .-Gamma- (4-methyl piperazino -prpyl o-chlorobenzilate. and dihydrochloride From 6.5 g. (0.041 mile) of 4-methylpiperazinopropanol, 1.5 g. (0.041 mole) of methyl o-chlorobenzilate, 1.0 g. of sodium methoxide and 200 cc. of n-heptaue there was obtained, by the method of Example 11, 14.5 g. of the crude ester base. The latter was converted to the dihydrochloride salt in isopropyl alcohol and the solid recrystallized from the same solvent. Yield 8.75 g. (43%), M.P. 207209 C. after prolonged drying at 100 C.

Analysis.Calcd. for C22H2gC/13N203: Cl, N, 5.89. Found: Cl, 14.56; N, 6.10.

Example 17.-Gamma-(2,4,6-trimethylpiperazino)- propyl benzilate and dihydrochloride From a mixture of 18.6 g. (0.10 mole) of 2,4,6-trimethylpiperazinopropanol, 24.2 g. (0.10 mole) of methyl benzilate, 250 cc. of n-heptane, 0.2 .g. of sodium methoxide and 1 cc. of methanol there was obtained, by the procedure of Example 11, 38.7 g. of the crude ester base. The base was converted to the dihydrochloride in ethyl ether and the latter recrystallized from ethyl acetate and methanol. Yield 23.5 g. (52%). This compound crystallized out as the monohydrate, M.P. l81183 C.

Analysis.Calcd. for C24H35Cl2N204: C1, N, 5.75. Found: Cl, 14.54; N, 5.79.

Example 1 8.-Gamma-(3,4,6-trans-trimethylpiperazino) propyl benzilate and dihydrochloride Example 19.-5-(4-methylpiperazino)-pentyl benzilate and dihydrochloride A mixture containing 18.6 g. (0.010 mole) of 5-(4- methylpiperazino)-pentyl alcohol, 24.2 g. of methyl benzilate, 0.6 g. of sodium methoxide and 300 cc. of nheptane yielded 42.7 g. of the crude ester base by the procedure of Example 11. The dihydrochloride salt was prepared in isopropyl alcohol and recrystallized from a mixture of ethanol and methanol. Yield 38.4 g. (82%),

M.P. 189 C.

Analysis.Calcd. for C24H34C12N2031 C1, N, 5.96. FOllnClZ Cl, 15.46;N, 5.93.

Example 20.4-methylpiperazino-Z-propanol To 100.2 g. (1.0 mole) of methylpiperazine in 1 liter of methanol was added 58.1 g. 1.0 mole) of propylene oxide dissolved in 100 cc. of dry toluene. The reaction mixture was stirred at room temperature for several hours. The product was isolated by fractional distillation in vacuo, B.P. 6061 C. (0.70 mm.). Yield 108 g. (68%); N 1.4701.

Analysis.Calcd. for C H N O: N, 17.70. Found: N, 17.70.

Example 2].4-methylpiperazino-Z-propyl benzilate A mixture containing 48.4 g. (0.20 mole) of methyl benzilate, 31.6 g. (0.20 mole) of 4-methylpiperazino-2- propanol, 1.3 g. sodium methoxide and 500 cc. of nheptane was refluxed with stirring and the methanol formed during the reaction was separated. The sodium methoxide was removed by filtration and the filtrate Washed twice with water. The solvent was removed by distillation and g. of residue. obtained which was the basic ester. 7 The residue was converted to the dihydrochloride salt in isopropyl alcohol with ethereal hydrochloric acid. Yield 49.5 g. (75% M.P. 211-212" C.

Analysis.Calcd. for CzgHgoClzNzOaI C'l, N, 6.34. Found: Cl, 16.11; N, 6.29.

Example 22.4-metlzylpiperazino-Z-propyl benzilate dihydrochloride To 53.0 g. (0.20 mole) of diphenylchloroacetyl chloride in 200 cc. of dry benzene was added 31.6 g. (0.20 mole) 4-rnethy-lpiperazino-Z-propanol in,100 cc. of benzene and 20 cc. of triethylamine. The mixture was stirred and refluxed for two hours, the triethylamine hydrochloride removed by filtration and the filtrate concentrated. The residual oil was taken up with dilute aqueous hydrochloric acid and refluxed for 15 minutes. Any water insoluble material was removed by ether extraction. The aqueous solution was neutralized with potassium carbonate, the benzil'a-te ester extracted with ether and the ether extracts dried with potassium carbonate. The ether was removed by distillation and the basic ester converted to the dihydrochloride ester, 210-2l1 C. Mixed M.P. with product obtained from Example 21 was 211-212 C., yield 40 g.

Example 23.Bela-(4-benzylpiperazino)ethyl benzilate dihydrochloride This compound Was prepared .by the method described in Example 2.1. From 29.1 g. (0.13 mole) of 4-benzylpiper-azinoethanol and 24.2 g. (0.10 mole) methyl benzilate, there was obtained 18.4 g. (37%) of the dihydrochloride upon acidification of the basic ester in ether, M.P. 2242-25 C. dec.

Analysis.-Calcd. for C H Cl N O Cl, 14.08; N, 5.56. Found: Cl, 14.16; N, 5.46.

Example 24 .-Beta- [4-( 1 -phenyl-2-pr0pyl -piperazin0] ethyl berzzilate dihydrochloride A mixture containing 11.7. g. (0.047 mole) of beta-[4- (1-phenyl-2propyl)-piperazino]-ethanol, 10.4 g. (0.047 mole) of methyl benzilate, 250 cc. of n-heptane, 2 cc. of methanol and 0.3 g. of sodium methoxide was stirred at reflux until the distillation of methanol ceased. The warm mixture was clarified by filtration, the filtrate diluted with chloroform and washed twice with 50 cc. of water. The organic phase was dried with potassium carbonate and the solvent removed by distillation leaving 19.5 g. (90.6%) of crude basic ester. The latter was dissolved in 200 cc. of methanol and converted to the dihydrochloride salt by addition of ethereal hydrochloric acid. Yield 11.1 g. (49% M.P. 238239 C.

AHIIIYSiSr-CfllCd. for C H Cl N O Cl, N, 5.27. Found: Cl, 13.37; N, 5.23.

Example 25.Gamma-(4-benzyl-2-methylpiperazin0)- propylbenzilate dihydrochloride A mixture containing 24.2 g. (0.10 mole) of methyl benzilate, 24.8 g. (0.10 mole) of 4-benzyl-2-methylpiperazino-propanol, 0.5 g. of sodium methoxide, and 250 cc. of n-heptane was refluxed for 4 hours while 6 cc. of methanol was collected by distillation. The catalyst was removed by filtration, the filtrate washed with water, dried over potassium carbonate, and concentrated to dryness in vacuo yielding 45.3 g. (99%) of the crude basic ester. The latter was converted to the dihydrochloride salt in acetonitrile. Yield 35.4 g. (67%); M.P. 207-208 C.

Analysis.Calcd. for CzgHggClzNzOgI Cl, N, 5.27. Found: Cl, 13.35; N, 5.35.

Example 26.Beta-piperazinoetlzyl benzilate A mixture containing 25.8 g. of -beta-(4-benzylpiperazino)-ethyl benzilate, 7.2 g. (0.12 mole) of glacial acetic acid, cc. of methanol and 3 g. of palladium-on-charcoal (10%) catalyst was subjected to hydrogenation at 60 psi. of hydrogen. The catalyst was removed by filtration and the filtrate acidified with ethereal hydrochloric acid. The solvent was removed by distillation and the residual solid dissolved in water, neutralized with sodium bicarbonate and the oily layer extracted with tetrahydrofuran. The tetrahydrofuran extracts were dried with potassium carbonate, the solvent removed by distillation and the residue taken up in acetone and converted to the dihydro chloride salt by the addition of ethereal hydrochloric acid. The solid was recrystallized irom a mixture of 300 cc. of isopropyl alcohol and 100 cc. of methanol. Yield 11.3 g. (44%), M.P. 164-165 C.

Analysis.Calcd. for CZQH26C12N203: Cl, N, 6.77. Found: Cl, 17.28; N, 6.47.

Example 27.--Gamma-(Z-methylpiperazino)-prpyl benzilate dihydrochloride A mixture consisting of 26.6 g. (0.05 mole) of gamma- (4-benzyl-2-methylpiperazino)-propyl benzilate dihydrochloride in 200 cc. of methanol was subjected to reductive cleavage at 60 p.s.i. of hydrogen with 3.5 g. of palladium-on-charcoal catalyst. The catalyst was removed by filtration and the solvent by distillation. The residue was recrystallized from 200 cc. of acetonitrile and 300 cc. of isopropyl alcohol. Yield 12.2 g. (55%), M.P. 187188 C.

Analysis.Calcd. for C H Cl N O Cl, 16.06; N, 6.34. Found: Cl, 15.84; N, 6.21.

Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.

I claim:

1. The method of inducing an antidepressive efiect, central nervous system stimulation and increased motor activity in a human which comprises administering to a human a therapeutically effective but nontoxic amount of a member selected from the group consisting of a compound of the formula and R are members of the group consisting of hydrogen and lower alkyl, and Y is a lower alkylene having not more than five carbons with at least two carbons between the oxygen and nitrogen atoms to which it is bonded.

2. The process of claim 1 in which 5 to mg. of the compound is administered orally per day.

3. The process of claim 1 in which the compound is 4-methylpiperazino-2-propyl benzilate.

4. The method of inducing an antidepressive effect, central nervous system stimulation and increased motor activity, and a simultaneous anticholinergic effect, in a human which comprises administering to a human a therapeutically effective but nontoxic amount of a member selected from the group consisting of a compound of the formula N Ra and acid addition salts thereof, wherein R and R are members of the group consisting of phenyl, lower alkylenedioxyphenyl, halophenyl, lower alkoxy-phenyl, hydroxyphenyl, aminophenyl, lower alkylphenyl, and halolower alkyl-phenyl, R is a member of the group consisting of hydrogen, lower alkyl and phenyl-lower alkyl, R; and R are members of the group consisting of hydrogen and lower alkyl, and Y is a lower unsubstituted straight chain alkylene of two to five carbons between the oxygen and nitrogen atoms to which it is bonded.

5. The process of claim 4 in which 5 to 150 mg. of the compound is administered orally per day.

6. The process of claim 4 in which the compound is 4-methylpiperazinoethyl benzilate.

7. The process of claim 4 in which the compound is 1-methyl-4-piperazinopropyl Z-methyl benzilate.

8. The process of claim 4 in which the compound is gamma-(4-methylpiperazino)-propylbenzilate.

9. The process of claim 4 in which the compound is beta-(4-benzylpiperazino)ethy1 benzilate.

10. The process of claim 4 in which the compound is beta-piperazinoethyl benzilate.

References Cited by the Examiner UNITED STATES PATENTS 4/47 Northey 260268 7/61 Biel 167-65 15min? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,205,134 September 7, 1965 John H. Biel It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 5, line 74, for "methylpieprazino-" read -methylpiperazinocolumn 7, line 43, for "benzolate" read benzilate column 10, line 39, for "2.7" read 22.7 column 11, line 3, for "mile" read mole line 4, for "1.5" read 11.5 line 44, for "(0.010 mole)" read (0.10 mole) Signed and sealed this 22nd day of March 1966.

Anon:

EDWARD J. BRENNER ERNEST W. SWIDER Commissioner of Patents Attesting Officer

Claims

1. THE METHOD OF INDUCING AN ANTIDEPRESSIVE EFFECT, CENTRAL NERVOUS SYSTEM STIMULATION AND INCREASED MOTOR ACTIVITY IN A HUMAN HICH COMPRISES ADMINISTERING TO A HUMAN A THERAPEUTICALLY EFFECTIVE BUT NONTOXIC AMOUNT OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA