US2914532A - Lower alkyl 4-phenyl-1-(3-phenylpropyl) piperidine-4-carboxylates and their preparation - Google Patents

Description

United States Patent Bill Elpern, Walnut Creek, Califl, assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware Application September 12, 1955 Serial No. 533,889

No Drawing.

8 Claims.

This invention relates to organic compounds and their preparation, and is concerned with an improvement in the substituent attached to the nitrogen atom of the piperidine ring in the class of chemical compounds identified as lower alkyl 4-phenyl-l-(hydrocarbyl)piperidine 4 carboxylates. In particular, it is concerned with lower alkyl 4-phenyl-1-(3-phenylpropyl)piperidine 4 carboxylates, their acid addition salts, and the preparation of these compounds.

Attempts have been made for some time to develop analgesics having high activity. The highly potent morphine has the disadvantages of causing nausea, vomiting, constipation and respiratory depression, and for these reasons has been supplanted largely by meperidine, ethyl 4-phenyl-l-methylpiperidine t-carboxylate, especially in obstetrics where depression of respiration is highly undesirable. Because of the relatively high dose required, meperidine has to be injected in hypertonic concentrations, with a consequent risk of irritation at the site of administration. This limits the choice of concentrations which can be used and restricts undesirably the free choice of optimum dosage. This situation is advantageously modified with the compounds of my invention since they are many times more potent as analgesics than meperidine and thus can be administered in smaller volumes of solution and at higher therapeutic levels of effectiveness without making the solution hypertonic. This reduces any tendency to undesirable accompanying irritation, and improves the therapeutic usefulness 'of the medicament.

US. Patent 2,167,351 broadly shows lower alkyl 4-aryll-(substituted)piperidinet-carboxylates where the l-substituent is a monovalent hydrocarbon radical. Included among the specific examples are such compounds having l-methyl and l-benzyl substituents, the latter being of primary value as intermediates for the former. The l-methyl compounds are now known and accepted as effective, morphine-like-central analgesics and atropinelike smooth muscle neurospasmolytics in the relief of severe pain. An outstanding example of these l-methyl compounds is the commercially available meperidine hydrochloride, ethyl 4-phenyl-l-methylpiperidine-4-carboxylate hydrochloride. On the other hand, the intermediate 1-benzyl compounds have been found to have a decidedly lower analgesic activity compared with the l-methyl compounds. For example, ethyl 4-phenyl-l-benzylpiperidine- 4-carboxylate as its hydrochloride has been found to be only approximately one-fourth as effective an analgesic as meperidine hydrochloride when tested by the Bass- Vander Brook modification of the DAmour-Smith method. This decrease in activity in going from l-methyl to l-benzyl would indicate that l-phenylalkyl substituents are undesirable, and would thus lead investigators away from these compounds. This actually has been the case in the past twenty years-until I investigated the compounds of this invention.

1 I have now prepared lower alkyl 4-phenyl-l-(3-phenylpropyl)piperidine-4-carboxylates and surprisingly found 2,914,532 Patented Nov. 24, 1959 them to be outstandingly superior as analgesics compared with the corresponding l-benzyl compounds of US. Patent 2,167,351 and, indeed, many times more efiective than the corresponding l-methyl compounds, even meperidine itself. For example, my ethyl 4-phenyl-l-(3-phenylpropyl)piperidine-4-carboxylate as its hydrochloride salt, when measured as hereinbefore mentioned, is approximately fourteen times more effective an analgesic as meperidine hydrochloride, or thus having an analgesic activity approximately fifty-six times that of the corresponding known l-benzyl homolog. In addition to having. this high analgesic activity, my compounds have a relatively low toxicity; for example, said ethyl 4-phenyl-1-(3- phenylpropyl) piperidine 4 earboxylate hydrochloride is only about two and one-half times as toxic [intravenous toxicity in mice when measured by a procedure similar to that described by Hoppe et al., J. Pharm. & Exp. Therap. 95, 502 (1949)] as meperidine hydrochloride, so that its therapeutic index compared with meperidine hydrochloride is approximately five and one-half.

The lower alkyl 4-phenyl-1-(3-phenylpropyl)piperidine- 4-carboxylates in free base form, having the formula Oil; 0 0 O-(lower alkyl) where the lower alkyl radical has from one to six carbon atoms, are prepared by reacting a lower alkyl 4-phenylpiperidine-4-carb0xylate with a 3-phenylpropylating agent such as: (a) a 3-phenylpropyl ester of a strong inorganic acid or an organic sulfonic acid; (b) 3-phenyl-2-propenal (cinnamaldehyde) under catalytic hydrogenation conditions; or (c) 3-pheny1propanal under catalytic hydrogenation conditions. Suitable 3-phenylpropylating agents of type (a) include the B-phenylpropyl bromide, chloride, iodide, sulfate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, and the like, with the bromide being preferred. This reaction is carried out by heating the lower alkyl 4-phenylpiperidine-4-carboxylate with the 3-phenylpropyl ester in the presence or absence of a suitable solvent, but preferably in the presence of a solvent such as a lower alkanol. As a specific illustration of my invention, ethyl 4-phenyl-l-(3-phenylpropyl)piperidine-4- carboxylate is obtained by heating ethyl 4-phenylpiperidineA-carboxylate with 3-phenylpropyl bromide, preferably in refluxing n-butanol with stirring in the presence of an alkaline agent such as sodium carbonate to neutralize the hydrogen halide formed by the reaction. Since the preferred intermediate, ethyl 4-phenylpiperidine-4-carboxylate forms an insoluble carbonate when treated with carbon dioxide, a convenient way of ascertaining whether the reaction is complete or not is merely to treat the reaction mixture with carbon dioxide, the absence of a precipitate indicating completeness of the reaction. The product is isolated in free base form or in the form of its acid addition salt.

The same compound, ethyl 4-phenyl-l-(3-phenylpropyl)-piperidine-4-carboxylate, is formed when ethyl 4phenylpiperidine-4-carboxylate is reacted with 3- phenyl-Z-propenal or S-phenylpropanal and hydrogen under pressure in the presence of a hydrogenation catalyst eifective to reduce carbon-to-nitrogen and carbon-to-carbon double bonds, e.g., palladium chloride on charcoal.

My new lower alkyl 4-phenyll-(3-phenylpropyl)piperidine-4-carboxylates are useful in the free base form or in the form of acid addition :salts, and these salts are within the purview of the invention. The acids vwhich those which produce, when combined with the free base, salts whose anions are relatively innocuous t the animal organism in therapeutic doses of the salts, so that the beneficial physiological properties inherent in the free base are not vitiated by side eifects ascribable to the anions. In practicingmy invention, I found it convenient to employ the hydrochloride salt. However, other appropriate acid addition salts are those derived from mineral acids such as hydrobromic acid, hydriodic acid, nitricacid, phosphoric acid and sulfuric acid; and organic acids such' as acetic acid, citric acid, tartaric acid, lactic acid, quinic acid, methanesulfonic' acid, ethanesulfonic acid, and the like, giving the hydrobromide, hydriodide, nitrate, phosphate or acid phosphate, sulfate or bisulfate,

acetate, citrate or acid citrate, tartrate or bitartrate,

lactate, guinate, methanesulfonate' and ethanesulfonate salts, respectively.

d The following examples Will further illustrate the invention without, however, limiting it thereto.

1 U hEXAMPLEl Lower alkyl 4-phenyl-1-(3-phenylpropyl) piperidine-4- I boxylate or n-hexyl 4-pheny1-1-(3-phenylpropyl) piperi' dine-4-carboxylate in place of ethyl 4-phenyl-1-(3-phenylpropyl)piperidine-4-carboxylate, there is obtained methyl 4-phenyl-1-(3-phenylpropyl)piperidinel-carboxylate hydrochloride, isobutyl 4-phenyl-l-(3-phenylpropyD-piperidinel-carboxylate hydrochloride or n-hexyl 4-phenyl-l- (3-phenylpropyl)piperidine-4-carboxylate hydrochloride, respectively. V a i I also prepared the sulfate, phosphate, methanesulfonate, ethanesulfonate, quinate, lactate (see Example 3), tartrate and acetate'salts of ethyl 4-phenyl-l=(3-phenyl-' propyl)piperidine-4-carboxylate.

Pharmacological evaluation of ethyl 4-phenyl l-(3- phenylpropyl)piperidine-4-carboxylate hydrochloride in carb0xylates.-The preparation of these compounds is illustrated bythe following preparation of ethyl 4-phenyl- 1-(3-phenylpropyl)piperidine-4-carboxylate: A mixture of 13.4 g. of ethyl .4-phenylpiperidine-4-carboxylate hydrochloride, 10.0 g. of B-phenylpropyl bromide, 100 ml. of n-butanol and 20 g. of anhydrous sodium carbonate was refluxed with stirring for twenty-four hours. The reaction mixture was allowed to cool and was filtered. The filtrate was treated with carbon dioxide but no precipitate resulted, indicating that the reaction was complete. the residual oily material distilled under reduced pressure to .yield 16.1 g. of ethyl 4-phenyl-1-(3-phenylpropyl) piperidine4-carboylate, which distilled at 148-160 C. at 0.06 mm.; h 1.5428.

: Theabove described preparation was also carried out I i using ethyl 4ephenylpiperidinel-carboxylate in free base form (11.6 g.) and only one-half as much sodium carbo' nate (10 g.). Alternatively, this preparation can be carried out using other esters such as 3-phenyluropyl pzira-tOluenesulfonate in place of 3-phenylp1'opyl bromide.

Following .the above procedure but using methyl 4-- phenylpiperidine-4-carboxylate, isobutyl 4-phenylpiperidine-4-carboxylate, or n-hexyl 4-phenylpiperidine-4-carboxylate in place of ethyl 4-phenylpiperidine-4 carboxylate, there is obtained methyl 4-phenyl-1-(3-phenylpropyl)piperidinel-carboxylate, isobutyl 4-p'nenyl-1-(3- phenylpropyl)piperidinei-carboxylate, or n-hexyl 4- pheuyl-l-(3phenylpropyl) piperidine-4-carboxylate, respectively..

'EXAMPLEZ Cl, 9.14. Found: C, 71.19; H, 7.91; Cl, 9.10. This hydrochloride was also recrystallized from water and from ethanolcther.

Following the above procedure but using methyl 4- phenyl 1 (3 phenylpropyl)piperidine 4 carboxylate, isobutyl 4 phenyl 1 (3-phenylpropyl)piperidineA-carg piperidine i-carboxylate, 4g. of 85% new aqueous solution administered intraperitoneally or subcutaneously by the Rat Thermal Stimulus Method of Bass and Vander Brook [1. Am. Pharm. Assoc, Sci. Ed., 41, 569-670 (1952)] has shown that this compound is approximately fourteen times as active an analgesic'as ethyl 4-phenyl-l-methylpiperidine -4-carboxylate hydro: chloride. This compound was found to have; an acute toxicity in mice of 15.8:11 mg. per kg. when adminis' tered intravenously in aqueous solution.

, E AMPL t-.

ml. o'f'methanol to standat room temperat" about sixteen days, the mixturehad completely ry lized. The crystallinefmaterialffwas nearerm le:

Then the filtrate was concentrated in vacuo and 1 fysia'n-ized frommethmol oilfield 1th f j i ii hy i ethyl 4 phenyl 1 methylpiperidine 4-c'arboxylate hydrochloride, thus having the same analgesic activity 'as' the corresponding hydrochloride salt of Example 2.

EXAMPLE 4 Ethyl 4-phenyl-1-(3-phenylpropyl) 4-carboxyldte hydro.- chloride.-A mixture of 11.65 g. of ethyl 4-phenylpiperidine-4-carboxylate, 7.1 g. of 3-phenyl-2-propenal (cinnamaldehyde), ml. of ethanol, 9.5 ml. of water, 3.2 ml. of acetic acid, 0.46 g. of sodium acetate and palladium chlo ride on charcoal was treated with hydrogen at an initial pressure of 560 pounds per square inch at room temperature (17 C.). After the reduction had been completed in about forty-five minutes (final pressure, 220 pounds per square inch), the reaction mixture was filtered and to the filtrate was added 25 ml. of concentrated hydro: chloric acid, followed by addition of ether until a white precipitate separated. A recrystallization of thisprecipi tate from water gave the product, ethyl ,4-phenyl-1 -(Ig phenylpropyl)-4-carboxylate hydrochloride, M.P. 168 C identical with the product of Example 2.

Following the above procedure, but using 3-.phenylpropanal in place of 3-phenyl-2-propenal, the sameprod uctis obtained. i

. 3 My lower alkyl 4-phenyl-1-(3-phenylpropyl)piperidine 4-carboxylates can be formulated in liquid preparations,

e.g., aqueous or aqueous-ethanol menstruum, or in solid form, e.g., tablet or powder. The tablet formulation can be prepared using conventional excipients; and thepowder can be compounded in capsule form. These preparations can be administered orallyor, in the case of the aqueous preparations, intramuscularly or intravenously. 1 I

I claim:

1. Lower alkyl 4-phenyl-1-(3-phenylpropyl)piperidine- 4-carboxylates.

2. Pharmacologically acceptable acid addition salts of a lower alkyl 4-phenyl-1-(3-phenylpropyl)piperidine-4- carboxylate.

3. Ethyl 4-phenyl-1-(3-phenylpropyl)piperidine-4 carhoxylate.

4. Ethyl 4-phenyl-1-(S-phenylpropyl)piperidine-4 carboxylate hydrochloride.

5. Ethyl 4-phenyl-1-(3-pl1eny1propyl)piperidine-4 carboxylate lactate.

6. The process of preparing a lower alkyl 4-phenyl-1- (3-phenylpropyl) piperidine4-carboxylate which comprises reacting a lower alkyl 4-phenylpiperidine-4 carboxylate with a 3-phenylpropyl ester of a strong inorganic acid.

7. The process of preparing a lower alkyl 4-phenyl-l- (3-phenylpropyl)piperidine-4-carboxylate which com- References Cited in the file of this patent UNITED STATES PATENTS 2,167,351 Eisleb July 25, 1939 2,486,795 Kaegi Nov. 1, 1949 FOREIGN PATENTS 566,307 Great Britain Dec. 21, 1944 OTHER REFERENCES Beilstein: Handbuch der Organischen Chemie, 1935, vol. 20, pp. 17 and 23.

Claims (1)

1. LOWER ALKYL 4-PHENYL-1(3-PHENYLPROPYL)PIPERIDINE4-CARBOXYLATES.