US2846437A - Lower alkyl 4-phenyl-1-(substituted-alkyl) piperidine-4-carboxylates and preparationthereof - Google Patents

Description

United States LOWER ALKYL 4-PHENYL-1-(SUBSTITUTED- ALKYL) PIPERIDINE-l-CARBOXYLATES AND PREPARATION THEREOF Bill Elpern, Albany, N. Y., assignor to Sterling Drug Inc., New York, N. Y., a corporation of Delaware No Drawing. Application September 12, 1955 Serial No. 533,899

31 Claims. (Cl. 260-293.4)

compounds identified as lower alkyl 4-phenyl-l-(sub-- stituted)-piperidine-4-carboxylates. In particular, the compounds of this invention are those having a substituted-alkyl radical as the l-substituent.

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 1 methylpiperidine 4 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.

U. S. Patent 2,167,351 broadly shows lower alkyl 4-aryl-l-(substituted)piperidine-4-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 value primarily 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 l-benzyl compounds have been found to have a decidedly lower analgesic activity compared with the l-methyl compounds. For example, ethyl 4-phenyl-1- benzylpiperidine-4-carboxylate as its hydrochloride has been found to be only approximately one-fourth as effective an analgesic is 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, and away from compounds such as those of the instant invention.

I have now prepared certain lower alkyl 4-phenyl-l- (substituted-alkyl)piperidine-4-carboxylates and surprisingly found them to be markedly superior as analgesics atent O compared with the corresponding l-benzyl compounds of U. S. Patent 2,167,351 and, indeed, more efiective than the corresponding l-methyl compounds, even meperidine itself. For example, my ethyl 4-phenyl-l- (3-phenoxypropyl)piperidine-4-carboxylate as its hydrochloride salt, when measured as hereinbefore mentioned, is approximately twelve times as effective an analgesic as meperidine hydrochloride, or thus having an analgesic activity approximately forty-eight times that of the corresponding known l-benzyl compound. In addition to having this high analgesic activity, my compounds have a relatively low toxicity; for example, ethyl 4-phenyl-l- (S-phenoxypropyl)piperidine-4acarboxylate 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.

My compounds in free base form have the formula 0%[5 C 0 O-(lower alkyl) i- Z -At n-butyl, isobutyl, Z-butyl, n-amyl, n-hexyl, and the like.

The monocarbocyclic aryl radical having six ringcarbon atoms is an aryl radical of the benzene series and includes the unsubstituted. phenyl radical and phenyl radicals substituted by substituents such as nitro, amino, (lower alkyl)amino, di-(lower alkyl)amino, (lower alkanoyl)amino, lower alkoxy, lower alkylmercapto, lower alkylsulfonyl, lower alkyl, hydroxy, halo and the like. The substituted-phenyl radicals have preferably from one to three substituents such as those given above; and, furthermore, these substituents can be in any of the available positions of the phenyl nucleus, and where more than one substituent, they can be the same or different and they can be in any of the various position combinations relative to each other. The lower alkyl, (lower alkyDamino, (lower alkanoyl)amino, lower alkoxy, lower alkylmercapto and lower alkylsulfonyl substituents, and the lower alkyl radicals of said di-(lower alkyl) amino substituent, each have preferably from one to six carbon atoms which can be arranged as straight or branched chains.

The lower alkylene radical designated above as X can have from two to six carbon atoms, and preferably has two to four carbon atoms; such preferred embodiments for X include -CH CH CH(CH )CH The compounds of this invention can be prepared by such as the reaction of a lower alkyl 4-phenylpiperidinea 4-carboxylate. with the appropriate aryl-Z-alkanal undercatalytic hydrogenation conditions, can be used.

Preferred Isubgenera of my invention are the come pounds having in free base form the formula H; CQQ-(l ersl l) v on, on,

where the lower alkyl radical has one to six carbon atoms, X is an alkylene radical having from two to four carbon atoms inclusive and having its free valence bonds on different carbon atoms, and Z is O or S. These preferred embodiments are prepared byreacting a lower alkyl 4- phenylpiperidine-4-carboxylate with a 'phenyl-Z-alkylating agent, said agent being preferably a phenoxyalkyl or phenylmercaptoalkyl ester of a strong inorganic acid or an organic sulfonic acid, said ester having the formula, C H Z-X--An, where An is an anion of a strong inorganic acid or an organic sulfonic acid. Illustrative of the phenoxyalkyl or phenylmercaptoal kyl esters used in the process of my invention are "3 -phenoxypropyl bromide, 2-phenylrnercaptoethyl chloride, 4-phenoxybutyl iodide, 2-phenoxypropyl sulfate, 3 -phenylmercaptopropyl rncthe anesulfonate, 2-phenoxyethyl benzenesulfonate, 2-phenylmercaptobutyl para-toluenesulfonate, and the like. The preferred esters are the phenoxyalkyl halides and phenylnrercaptoalkyl halides. The reaction is carried out by heating the lower alkyl 4-phenylpiperidine-4ecarboxylate wit the appropr a phenoxyyl ins o p y capto-alkylating agent; for-example, ethylAc-phenyl-l-(iphenoxypropyl)piperidine-kcarboxylate isobtained by heating ethyl .4-phenylpiperidine-4-carboxylate with 3- phenoxypropyl bromide; and ethyl 4-phenyl-1-( 2.-phenyl- .mercaptoethyl)piperidinertrcarboxylate is obtained by heating ethyl 4-phenylpiperidineA-carbqxylate with 2-" phenylmercaptoethyl chloride. The reaction can be carried out either-in the-presenceor absence of. a suitable solvent, but preferably asolvent'such as a lower alkanol is used. A preferred procedureis to conduct the reaction 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-phenylpiperidine4-carboxylate, forms an insoluble carbonate when treated with carbon dioxide, a convenient way of ascertaining whether the reaction iscomplete or notis'merely to treat the reaction mixture with carbon dioxide, the absence .of axprecipitate indicating'completencss .ofthe reaction. The product is isolated in free base form or in the form of'an acid addition salt. 1

An alternative and preferred procedure forpreparing the compounds of my invention where Z is NH or N(lower alkyl) consists of introducing stepwise the 1-[(a.rylamino) alkyl] substituent onto the piperidine nucleus by reacting a lower alkyl 4-phenylpiperidine-4-carboxylate with a hydroxyalkyl halide, HO-X-halogen, to form a lower alkyl 4-phenyl l--.(hydroxyalkyl)piperidine-4-carboxylate; treating this l-hydroxyalkyl compound witha 4 i the corresponding lower alkyl .4-phenyl-l-(haloalkyl)-' pi etiiae-tarb x lat havia the o mula X-halogen and then reacting the l-haloalkyl compound with an amine having the formula Ar'NHR, where R is hydrogen or a lower alkyl radical as defined and illustrated hereinabove. The last step is generally carried out at a temperature between about 50 C. and 150 C., preferhalogenating agent such asIhiouyl-Chloridb, phosphorus ably on a steam bath atabout '100 C. Illustrative of the preparation of these l-(arylaminoalkyl) compounds are the following preparations ethyl 4-pheny1 1- [3 (3, 4 dime thojxyphenylamino)propyllpiperidine 4- carboxylate by reacting ethyl 4TphenylpiperidineA-car:,

boxylate with 3,-hydroxypropyl chloride, treating the resulting ethyl 4-phenyl-l-(3-hydroxyp QPyl)piperidiner carboxy late with thionyl chloride, and heating the ethyl 4-phenyl-1- 3- chloropropyl )piperidine-4-carb oxylate thus formed with 3,4r-dimethoxyaniline; and'sthe preparation of ethyl 4-phenyl-l-[2-(N.- ethyl N phenylamino)ethyl] piperidinea l-carboxylate by reacting ethyl 4,-phenylpiperidine-.icarboxylate with Z-hydroxyethyl chloride, reacting he r su t n hy .-phe y -(2rhy roxye hy )p p 4.-carboxyl ate with thionyl chlorideand reacting the ethyl 4.- phenyl1-(25Chl0roethyl)piperidine 4 carboxylate thus formed with N-ethylaniline. v

My new lower alkyl 4ephenyl-l-(aryl-Z-alkyl)piperidine-4-carboxylatcs are useful either in the free base form.

or in the form of acid additionsalts, and these salts are within the purview of the invention. The acids which can be used to prepare acid addition salts are preferably those which produce, when combined with the free base, salts whose anions are relatively innocuous to 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 effects ascribable'to the anions. In practicing my'invention, I found it convenient to employ thehydrochloride salt. However, other appropriate acid ,additionsalts are those derived from mineral acids such as hydrobromic acid, hydriodic acid, nitric. acid, phosphoric acid and sulfuric acid and organic acidssuch as acetic acid, citric acid, tartaric acid, lactic acid,quinic acid, methanesulfonic acid, ethanesulfonic acid, and the like, giving the hydrobromide, hydriodide, nitrate, phos-- phate or acid phosphate, sulfate, or bisulfate, acetate, citrateor acid citrate, tartrate or bitartrate, lactate, qui-- nate, methanesulfonate and ethanesulfonate salts, respectively.

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

EXAMPLE 1 (A) Lower alkyl 41Jhenyl-1r (aryloxyazlkyl)piperidine-4- carboxylates butanol and 20 g. of anhydrous sodium carbonate was refluxedwith stirring for twenty-four hours. The reaction mixture was allowed to cool and was filtered. The filtrate was treated with carbon dioxide (either bubbled in or'addcd as the frozen solid) in order to remove any unreacted ethyl .4-phenylpiperidineA carboxylate which forms an insoluble carbonate. After filtering ,off any anim t PI pita a th tr te w s conc n rated in i suin y eld ethy 4r hen rl-t rP W XYPmPYDP PFE crystallizations from water'yielded the product, ethyl 4- phenyl-l-(3-phenoxypropyl)piperidine=4-carboxylate hydrochloride as white needles, melting" at 179.2-l8l.7 C. (corn).

Analysis.-alcd. for CggHggNOa'HCli C, 68.39; H, 7.49; O, 11.88. Found: C, 68.42; H, 7.98; O, 12.14.

Ethyl 4-phenyl-l (3-phenoxypropyl)piperidine-4-carboxylate in the form of its free base was obtained by dissolving a sample of the above-described hydrochloride in water, treating the'aqueous solution with sodium hydroxide'solution, extracting the liberated base with ether, drying the ether extract over anhydrous sodium sulfate, evaporating the ether solution slowly to dryness in vacuo, chilling to induce crystallization, and recrystallizing to constant melting point fromethanol-water. The product, ethyl 4-phenyl-l-(3'-phenoxypropyl)piperidine-4-carboxylate, 'm'elted'at 64.8-66.2 C. (com).

The above-described preparation can also be carried out using ethyl 4-phenylpiperidine-4-carboxylate in free base form (11.6 g.) and only one-halfas much sodium carbonate g.). Alternatively, this preparation is carried out using other esters such as 3-phenoxypropyl paratoluen'esulfonate or 3-phenoxypropyl iodide in place of 3-phenox'y'propyl' bromide.

Following the above procedure but using the appropriate lower 'alkyl 4-phenylp'ip'eridine-4-carboxylate and "using the 'appropriate aryloxy-alkyl'ating agent, there 'is obtained the fbllowing compounds: methyl 4-phenyl-1- (4-plienoxybutyl)piperidine-4-carboxylate, ethyl 4-'pheny1- 1'-[2-(4-'n-'butylphenoxy) ethyllpiperidine-4'carboxylate, npropyl 4 phenyl 1 (3 phenoxypropyhpiperidine 4- carbox'ylate, ethyl 4-phenyl-l- 3-(3,4-dimethoxyphenoxy) propyl]piperidine-4-carboxylate, 'isobutyl 4-phenyl-1-(2- pl'ten'oxypropyl)piperidiue 4-carboxylate, ethyl 4-phenyll. [2 (4 ethylme'rcaptophenoxy)ethyllpiperidine 4- carboxylate, n-hexyl 4-phenyl-l-(3-phenoxypropyl)piperidine 4-ca'rboxy1ate, ethyl 4-pheny -1-[2-(4-ethylsulfonyl- 'phenoxy) ethyllpip'eridine-4-carboxylate, ethyl 4-phenyl-l- 7 (4 nitrophenoxy) ethyllpiperidine 4 carboxylate, ethyl 4 phenyl 1 [2 (4 'dimethylaminophenoxy)- ethyllpiperidine 4 carboxylate, ethyl 4 phenyl l- [2 (4 n' -butylaminophenoxy)ethyllpiperidine 4- carboxylate, ethyl 4-phenyl-1-[2-(2,4-dichlorophenoxy)- ethyllpiperidine 4 --carbox-ylate, ethyl 4 phenyl '1- i'2-- (3 hydroxyphenoxy) ethyllpiperidine 4 carboxyl ate, and the like. Ethyl 4-phenyl-1-[2-(4-aminophenoxy)ethyllpiperidine-4-carboxylate is obtained by reducing the corresponding 1-[2-(4-nitrophenoxy)ethyll com! pound with a reducing agent efiective to reduce'nitro groups to amino groups. Ethyl 4-phenyl-l-[2-(4 acetylam'inophenoxy)ethyl]piperidine-4-carboxylate is obtained by reacting the corresponding 1-[2-(4-aminophenoxy)-. ethyl] compound with acetyl chlorideor aceticanhydride.

Pharmacological evaluation of ethyl 4-phenyl l-(3- 'phenoxypropyl)piperidine-4-carboxylate hydrochloride in aqueous solution administered intraperitoneally' by the Rat Thermal Stimulus Method of Bass andVander'B'rook [1. Am. Pharm. Assoc., Sci. Ed., 41, 569-570 (1952)] has shown that this compound is approximately twelve times as active an analgesic as ethyl 4-phenyl-1-methylpiperidinel-carboxylate hydrochloride, This compound was found to have an' acute toxicity (LD in mice of 13.7:L0.7 mg. per kgfwhen administered intravenously in aqueous solution.

(B) Ethyl 4-phenyl-I-(2-phen0xyethyl)piperidine-4 I carivoxylaze The preparation 'of this' compound was carried out following the procedure described above in Example 1(A) using:13.5 gJ-of ethyl4 phenylpiperidine-4-carboxylate hydrochloride, 10g: of l -phenoxyethylbrbmide, T00 ml,

. i 6 of n-buta'nol'and 20g. ofanhydrous sodium carbonate. The product in the form 'of'its hydrochloride salt melted at 1554-1572 C. (corn) when recrystallized from water.

Analysis.-Calcd. for C H NO -HCl: C, 67.79; H,

- 7.24; O, 12.30. Found: C, 68.05; H, 7.35; O, 12.80.

I Ethyl 4-phenyl-l-(2-phenoxyethyl)piperidine-4-carboxy'late in free base form was prepared according to the procedure described above in Example 1(A) for the conversion of ethyl 4-phenyl-l-(B-phenoxypropyl)piperidine- 4-carboxylate hydrochloride into its free base. The product, ethyl 4-phenyl-1-(Z-phenoxyethyl)piperidine-4-carboxylate, melted at'4l.3-42.5 C. (corn).

Pharmacological evaluation of ethyl 4-phenyl-l-(2- phenoxyethyl)piperidine-4-carboxylate hydrochloride in aqueous solution administered intraperitoneally by the Rat Thermal Stimulus Method of Bass and Vander Brook, ibid., has shown that this compound is'approximately six times as active an analgesic as ethyl 4-ph'enyl-l-methylpiperidine-4-carboxylate hydrochloride.

(C) Ethyl 4-phenyl-1-(4-phenoxybutyl)piperidine-4- carboxylate The preparation of this compound was carried out following the procedure described above in Example 1(A) using 13.4 g. of ethyl 4-'phenylpiperidine-4-carboxylate hydrochloride, 11.5 g. of 4-phenoxybutyl bromide, 20- g. of anhydrous sodium carbonate and 100 ml. of n-butanol. The product in the form of its hydrochloride salt melted at l58.O-l5 9.6 C. (corn). A yield was obtained. AnaIysis.--Calcd. for C H NO -HCl: C, 69.00;H, 7.72; Cl, 8.48. Found: C, 68.91; H, 7.33; CI, 8.22.

Pharmacological evaluation -of ethyl 4-phenyl-l-(4- phenoxybutyl)piperidine-4-carboxylate hydrochloride in aqueous solution administered intraperitoneally by the Rat Thermal Stimulus Method of Bass and Vander Brook, ibid., has shown that this compound is approximately three times as active an analgesic as ethyl 4-phenyllmethylpiperidine-4-carboxylate.

EXAMPLE 2 (A) Lower alkyl 4-phenyl-1-(arylmercaptoalkyl)piperidine-4-ca'rboxylates The preparation of these compounds is illustrated by the following synthesis of ethyl"4-phenyl-1-(2 phenylmercaptoethyDpiperidine-4-carboxylate: A mixture of 'l3'.5 g. of ethyl 4-phenylpiperidine-4-carboxylate, 8.65'g.

of 2-phenyhnercaptoethylchloride, I00 of'n-butan'ol and 15 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, allowed to stand overnight, filtered and the filtrate concentrated in vacuo to yield 'etl'iyl 4-ph'enyl-l-(2-phenylmercaptoethyl)piperi dine-4-carboxylate. This free base was dissolved in one liter of water containing 6 'cc. of concentrated 'hydrochloric acid and filtered immediately. There separated from the filtrate'white crystals'which were recrystallized twice from water to yield the product, ethyl 4-phenyl-l- '(2-phenylrnercaptoethyl)piperidine-4-c'arboxylate hydrochloride, M.-P. 172.6-174.6 C. (corn).

Analysis.-Calcd.' for C H' NO SHCI: S, 7.89; CI, 8.73. Found: S, 8.20; C], 8.83.

Ethyl 4-phenyl-1-(2-phenylmercaptoethyl)piperidine- 4 carboxylate in free base form is obtained by dissolving a solution of the above-describedhydrochloridein water,

treating the aqueous solution with sodium hydroxide solution, extracting the liberated free base with ether, drying the ether solution over anhydrous sodium sulfate, evaporating slowly the ether solution in vacuo, chilling the residual material until crystalline, then recrystallizing this material from ethanol-water. The resulting product is ethyl 4-phenyl-1-(2-phenylmercaptoethyl)piperidine-4- carboxylate.

Following the above procedure for the preparatiofbf 7. a ethyl 4-phenyl-l-(2-phenylmercaptoethyl)piperidine-lcarboxylate' but using methyl 4-phenylpiperidine-4-carboxylate, isopropyl 4-phenylpiperidine-4-carboxylate, nbutyl 4-phenylpiperidine-4-carboxylate, or n-hexyl 4- phenylpiperidine-4-carboxylate in place of ethyl 4'-phenylpiperidinet-carboxylate and using the appropriate phenylmercaptoalkyl chloride in place of phenylmercaptoethyl chloride, there is obtained methyl 4-phenyl-l-(4- phenylmercaptobutyl)piperidine-4-carboxylate, isopropyl 4 phenyl 1 (2 phenylmercaptopropyl)piperidine-4- carboxylate, n butyl 4 phenyl l (2 phenylmercaptov carbonate and 250 propyl)piperidine-4 carboxylate, or n-hexyl 4-phenyl-lv (3-phenylmercaptopropyl)piperidine-4-carboxylate, re-

spectively.

(B) Ethyl 4-phenyl-1-(3-phenylmercaptopropyl)piperidine-4-carboxylate hydrochloride This compound was prepared following the procedure described above for Example 2(A) using*l3.5 g.' of

' ethyl 4-phenylpiperidine-4-carboxylate, 9.32' g. of 3- 4-carboqrylate This compound was prepared'following the procedure described in Example 3(A) using l8.2 g. of 2-phenylsulfonylethyl chloride, 24.0 g. o ethyl 4-phenylpiperidine- 4-carboxylate;hydrochloride, 30 g. of anhydrous sodium of "n-b'utanol. the product, ethyl 4-phenyl-l-(2- obtained 20.4 g... of I 4-carboxylate, M. P.

phenylsulfonylethyl)piperidine 1030-1040 C. (com).

Anzlysis calcd. fOIC H qNO S: c, 65183; H, 6.78; 0; 15.94. Found: c, 65.95; a, 6.86; 0,1 5.70.

. EXAMPLE4' (A) Loweralkyl carbozylates The preparation of these intermediate 7 compounds is illustrated by the following synthesis .of-ethyl; 4-phenylphenylmercaptopropyl chloride, 100 ml. of n-butanol and 15 g. of anhydrous sodium carbonate. The product, ethyl 4-phenyl-l-(3-phenylmercaptopropyl)piperidine-4- carboxylate hydrochloride, melted at 126.8-128.6 C. (corr.).

Analysis.Calcd. for C H NO S.HC1: C, 65.78;'H,

methylpiperidine-4-carboxylate hydrochloride.

EXAMPLE 3 (A) Lower alkyl 4-phenyI-I-(arylsulfonylalkyl)piperidineJ-carboxylates The preparation ofthese compounds is illustrated by the following synthesis of ethyl 4-phenyl-l-(3-phenylsulfonylpropyl)piperidinee4-carboxylate: This compound was prepared following the procedure described in EX- a mple 1(A) using 11 g. of 3-phenylsulfonylpropyl chloride, 13.5 g. of ethyl 4-phenylpiperidine-4-carboxylate hydrochloride, 15 g. of anhydrous sodium'carbonate and 100 ml. of n-butanol. of the product, ethyl 4-phenyl-l-(3-phenylsulfonylpropyl)piperidine-4-carboxylate, M. P. 87.8-89.0 C. (corn).

Analysis.-Calcd. for C H N0 Sr C, 66.48; H, 7.03; 05, 15.41. Found: C, 66.71; 66.45; H, 7,05, 6.85; O, 1 .50. 1

When ethyl 4-phenyl-l-(3-phenylsulfonylpropyl)piperidine-4-carboxylate is treated with hydrogen chloride, its hydrochloride is formed.

Following, the above procedure finylpropyl chloride in place of 3-phenylsulfonylpropyl chloride,- the product obtained is ethyl 4-phenyl-l-(3- phenylsulfinylprcpyl)piperidine-4-carboxylate. 7

Following the above procedure but using the appropriate lower alkyl 4-phenylpiperidine-4-carboxylate 'in place of ethyl 4-phenylpiperidine-4-carboxylate and using the appropriate arylsulfonylallrylchloride, there is oh- -tained the following respective compounds: methyl 4- phenyl 1 (4 phenylsulfonylbutyl)piperidine 4 carboxylate, ethyl 4-phenyl-l-[2- (4-n-butoxyphenylsulfonyl)- ethyl] piperidine-4-carboxylate, ethyl 4-pheny1- 1- 3- (4- nitrophenylsulfonyl propyl] piperidine-4-carboxylate, and the like.

There was thus obtained 7.4 g.

but using 3-phenylsul-.

' about forty-five "minutes 7 I heated slightly on a steam :bath

l-(2-chloroethyl)piperidine-4-carbo latezTo a solution containing 556g. of ethyl4-phenyl 1-(2-hydroxyethyl)- -piperidine-4-carboxylate and a drop-of pyridine in 400 ml. of benzene ,wasfadded'dropwise-over a period of 2.95 ig. o f thionyl chloride. The reaction mixture was at the start of the addition of the thionyl chloride and then heated on a steam 'bath for one and oneehalf hours 'after all of the thionyl chlorides had'bee'n added. The

reaction mixture was allowed to cool andithe white precipitate that had separated was collected and recrystallized once from absolute ethanol and once from 180- propanol, yielding'about 4.7 "g. .of phenyl-l-(Z-chloroethyl) piperidine-4 carboxylate; as: its hydrochloride, M. P. 218.29. C. (corn) ;-(with decomposition). i e

6.98; CI, 10.69. Found:

Following the "abgiye procedure but using appropriate lower alkyl 4,-fim 1-1-(hy o n w mq4-i.

f' the appropriate"; halogenatmg the following methyl 4pheny1'-l-(4 chlorobutyl)piperidine steaiiboxylate, ethyl; r

4' phenyl l (3 1 chlorop'rop'yhpiperidine -'-4 can; v f-' carboxylate, isobutyl 4-phenyl-'l(2-chloropropyl)piperidine-4-carboxylat e, n-h exyl 4-phenyl-l-(3-vchloropropybcarboxylate and using agent, there is obtained boxylate; ethyl 4-phenyl-1-(Z bromoethylJpi piperidine-4-carboxylate, and the like.

(B) Lower alkyl 4-ph y (drylaininoalhbp 1 I 4-earboxylates .1

The preparation of these compounds is illustrated by the following synthesis ofv v aminoethyl)piperidine-4-carboxylate: A mixture contaming 5.58 g. of aniline, 4.0 g. of anhydrous sodium carbonate and 25 ml. ofwater was heated on a steam bath at 90 .C. To this heated solution was added dropwise with stirring over a period of one and one-half hours 5.0

g. of ethyl 4-phenyl-l-(2-chloroethyl)piperidine-4-carboxylate hydrochloridejdissolved in mlof water.

Heating of the'reaction mixture was continued on a steam bath' for an additional organic was concernwas added to the 'organiclayer. washed. with saturated chloride solution,

. trated in vacuoanddistilled in anoil bath at 98"C.;at about 40 mm. pressure to remove theunreacted-sniline- The residue was dissolved in. am and hy ros nehlaiae -was bubbledinto this solution. The. precipitstelthat from absolute'sethanol.

separated was recrys d once I yielding the pr d ethyl carboxylate as its dihydrochloride, M. P.l94.2" C.

Analysis-Calcd. for C H N;O .2l-ICl:'C; 62.12; H, 7.11 O, 7.53. Found: C, 62.42; H, 7.06;,O,"7.50.

Ethyl 4 phenyl 1 (B)...'Ethyl .{fjrhehyl-I (Z-phenylsulfonylethyl)piperidine- There was thus s awns-(banal ty! ipirid m4- three hours. The reaction mixture was allowed to cool, was filtered, and v p yhm mp flh I dine i-carboxylate in the form of its free baseis obtained by-dissolving a sample'of 'the' above-described dihydrochloride in' water, treating the aqueous solution with sodium'hydroxide solution, extracting the liberated base I with'benzene; drying the benzene extract overanhydrous sodium sulfate and evaporating the benzene solution slowly to dryness in vacuo.

Other lower alkyl 4-phenyl-l-(atylaminoalkyDpiperi- -dine-4-'c'arboxylates that are obtained following the fore-.

going procedure using 'theappropriate lower alkyl 4- -i311ei'lyl-l-(ha l'oalkyl)piperidine-4-carboxylate and the appropriate arylamine are: methyl 4-phenyl-l-[4-(3,4-diethoxyphenylaniino) butyl] piperidine-4-carboxylate, ethyl "4' -"phenyl 1 (3 phenylaminopropyl)piperidine 4- "times more active as an analgesic than ethyl 4-phenyl-1- methylpiperidine-4-carboxylate hydrochloride.

The lower alkyl 4-phenyl-l-(substituted-alkyl)piperidine-4-carboxylates of my invention 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 the power can be compounded in capsule form. These preparations can be administered orally, or, in the case of the aqueous preparations, intramuscularly or intravenously.

lela'im: 1 1. A composition of matter selectedtrom the-group 'consistingbf acompoiind having the formula din. C'O'O GoWer'alIryI) where X is a lower alkylene radicalh avingat least two esteem atoms and-having its free'valence bonds on different carbon atoms, Z is"ameni'b'er of the group consistilig'of-(D, S;-SO,'--'SO ,'NH"ahd N (lower alkyl), Ar'is a monocarbocyclic aryl radical having six ring-carbon atoms; and its acid addition salts.

2. Albwer' alkyl l-phenyl:l-(aryloxyallkyllpiperidine- 4-carboxylate having the formula where X is a lower alkylene radical having at least two carbon atoms and having its free valence bonds on different carbon atoms, and Ar is a monocarbocyclic aryl radical having six ring-carbon atoms.

3. An acid addition salt of the compound of claim 2.

10 '4; A lower alkyl' 4-phenyl-l-(arylmercaptbaikynpiperi din 4=carboxylatehaving the formula CeHa C O (Miower alkyl) N iI-S-Ar where X is a lower alkylene radical having at least two carbon-atoms and having its free valencejbonds dif- "ferent carbon atoms, and Ar is a monocarbocy'clic' aryl radical having six ring-carbon atoms. H I

5. An acid addition salt of the compound of 4. 6. A lower alkyl 4-phenyl-l-(arylsulfonylalkyl)pipetidine-4-carboxylate having the formula CGHB COO-(lower alkyl) where X is a lower alkylene radical having at least two carbon atoms and having its free valence bonds on different carbon atoms, and AI is a monocarbocylic aryl radicalhaving six ring-carbon atoms.

7.1An-acid addition salt of the compoundoi'claimj6. '8. A lower alkyl 4-phenyl-l-(arylaminoalkynpiperi- 0 C61 CHa N )LNH-Ar where X is a lower alkylene radical having at least two carbon atoms and having its free valence bonds on different carbon atoms, and Ar is a monocarbocyclic aryl radical having six ring-carbon atoms.

9. An acid addition salt of the compound of claim 8. lOf-Ethyl 4 phenyl-1-( 3-phenoxypropyl)piperidine 4- carboxyl ate.

-11.*-E't'hyl 4 phenyl-l-(3-phenoxypropyllplperidine-4- ca rboxylate hydrochloride. 7 V U 12. 'Ethyl 4 phenyl 1-(2-phenox'yethyl)piperidine-'4- carboxylate hydrochloride. U

' l3.-Ethyl 4-phenyl-l-(Z-phenylarnindetliyDpipetldine- 4 'carboxyla te. I p

14." Ethyl t-phenyl l-(Z-phnylaininbethybbiperidine- 4-carboxylate dihydrochloride. v H v I, V

' 15. The process 5 of" preparinga'c'ompotind having the formula CeHs COO-(lower alkyl) where X is a lower alkylene' radical having at least two carbon atoms and having its free valence bonds on different carbon atoms, Z is a member of the group consisting of 0, S, SO, S0 NH and N(lower alkyl) and Ar is a monocarbocyclic aryl radical having six ring-carbon atoms, which comprises reacting a lower alkyl 4-pheny1- piperidine-4-carboxylate with an aryl-Z-alkyl ester of an acid selected from the group consisting of a strong inorganic acid and an organic sulfonic acid.

16. The process of preparing a lower alkyl 4-phenyl-1- (aryloxyalkynpiperidine r 4 carboxylate having the formula N vi-S-Al' \C Ha Ha I where X is a lower alkylene radical having at least two carbon atoms and having its free valence bonds on different carbon atoms,.and Ar isa monocarbocyclic and radical having six ring-carbon atoms, which comprises heating .a lower alkyl 4-phenylpiperidine-4-carboxylate' with an arylmercaptoalkyl halide.

18. The process of preparing a lower alkyl 4-pheny1-1 (arylsulfonylalkyl)piperidine-4-carboxylate having the formula can COO-(lowerallryl) li-sm-at where X is a lower alkylene radical having at least two carbon atoms and having its free valence bonds on different carbon atoms, and Ar is a monocarbocyclic aryl radical having six ring-carbon. atoms, which comprises heating a lower alkyl 4-phenylpiperidine-4-carboxylate with an arylsulfonylalkyl halide.

19.'The process of preparing ethyl 4-phenyl-1-(3- phenoxypropyl)piperidine-4-carboxylate which comprises heating ethyl 4-phenylpiperidine-4-carboxylate with 3- phenoxypropyl bromide.

.20. The process of preparing a lower alkyl4-phenyl- 1-(arylaminoalkyl)piperidine-4'carboxylate having the formula o .m COO-(loweralkyl) C CHI where'X is a lower alkylene radical having at least two carbon atoms and having its free valence bonds on differ'ent carbon, atoms, R is selected from "the'group, consisting of hydrogen and aloweralkyl radicaland Ar is a monocarbocyclic aryl radical having ring-carbon atoms,' which comprises heating a lower alkyl t -phenyl- 1w(haloaIkyDpiperidine-4-carboxylate with an amine havv 'ing .the formula a 21. The process of preparing ethyl ,4-phenyl-1-(2- phenylaminoethyl)piperidineQl-carboxylate which comprises heating ethyl 4-phenyl-l-(2-chloroethyl) piperidine- 4-carboxylate with aniline. p V 22. The process of preparing a lower alkyl 4-phenyl- 1-(haloalkyl)piperidine-4-carboxylate having the formula can COO-(loweralkyl) /C\ cm on,

where X is a lower alkylene radical having at least two carbon atoms and having its free valence bonds on different carbon atoms, which comprises reacting the corresponding lower alkyl 4-phenyl-1-(hydroxyalkyl)piperidine-4-carboxylate with a halogenating agent.-

23. A lower alkyl 4-phenyl-1-(haloalkyl)piperidine- 4-carboxylate having the formula can COO-(loweralkyll HIHI is... where X is a lower alkylene radical having at least two carbon atoms and having its free valence'bonds on different carbon atoms.

24. Ethyl 4 phenyl carboxylate.

1-(2-phenoxyethyl)piperidine-4- 25. Ethyl 4-phenyl-1-(3-phenylmercaptopropyl)piper- I idine 4-carboxylate.

26. Ethyl 4phenyl-1-(3-phenylmercaptopropyl)piperidine-4-carboxylate hydrochloride.

27. Ethyl 4 phenyl 1-(2-phenylmercaptoethyl)piperidine-4-carboxylate.

28. Ethyl 4 phenyl l-(2-phenylmercaptoethyl)piperidine-4-carboxylate hydrochloride.

29. Ethyl 4 pheny1.- 1(3-phenylsulfonylpropyl)piper-.

idine-4-carboxylate.

30. Ethyl 4 phenyl 1(3-phenylsu1fonylpropyl)piperidine-4-carboxylate hydrochloride. 7

31. Ethyl 4 phenyl 1-(3-phenylaminopropyl)piperidine-' l carbpxylate.

References Cited in the file of this patent Thorp: Journal of the Chemical Society of London for 1948, pp. 559-561, May 1948.

Schaumann: Archives of Experimental Pathology and Pharmacology, vol. 196, pp. 109-136, 1940.

Claims (1)

1. A COMPOSITION OF MATTER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND HAVING THE FORMULA