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United States Patent [19]Feldman et al,

[11] Patent Number:[45] Date of Patent:

5,019,583May 28, 1991

[54] NPHENYL-N-(4-PIPERIDINYL)AMIDESUSEFUL AS ANALGESICS[75] Inventors: Paul L. Feldman, Durham; MichaelK. James, Raleigh; Marcus F.Brackeen, Durham; Michael R.Johnson; Harry J. Leighton, both ofChapel Hill, all of N.C.[73] Assignee: Glaxo Inc., Research Triangle Park,N.C.[21] Appl. No.: 448,497[22] Filed: Dec. 11, 1989

Related U.S. Application Data[63] Continuation-in-part ofSer. No. 311,311,Feb. 15, 1989,abandoned.[51] Int. Cl.5 A61K 31/445; C07D 211/58[52] U.S. Cl 514/327; 514/329;544/244[58] Field of Search 546/224; 514/329, 327[56] References Cited

U.S. PATENT DOCUMENTS3,164,600 10/1961 Janssen 546/2243,998,834 1/1976 Janssen et al. 546/2244 ,1 67 ,5 74 1 0/1 97 8 Janssens 546/1944,179,569 12/1977 Janssen et aI 546/2234,584,303 4/1985 Huang et al 546/3264 ,8 01 ,7 21 1 2/1 98 6 Ryan et al. 548/411

FOREIGN PATENT DOCUMENTS309043 9/1987 European Pat. Off. .

OTHER PUBLICATIONSSrulevitch et al, Design, Synthesis and Sar of Analge-sics, OSAR 1989, pp. 377-381.Primary Examiner-Richard L. RaymondAssistant Examiner-Mark W. RussellAttorney, Agent, or Firm-Salvatore R. Conte[57] ABSTRACfN-Phenyl-N-(4-piperdinyl)arnide derivatives are dis-closed having the general formula (I):

(1)

wherein X isa member selected from the group consist-ing of alkoxy-carbonyl-lower alkyl, lower alkyl-car-bonyloxy-lower alkyl, alkenyloxy-carbonyl-lower al-kyl, and (Cl_2)alkoxy-(Cl_2)-alkoxy-carbonyl-lower al-kyl, and Ar, R, Rl and R2 are defined hereinafter, in-cluding isomeric forms thereof and acid addition saltsthereof. The compounds exhibit analgesic activity hav-ing relatively short durations of analgesic action. Theinvention embraces the compounds (I), pharmaceuticalcompositions of (I) and methods of providing analgesiawith (I). Also included are certain novel intermediatesfor making (I).

47 Claims, No Drawings

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1N -PH EN YL-N -(4-PIPER ID IN YL >AMID ES U SEFU LAS ANALGES IC SThis application is a continuation-in-part of co-pend- 5ing U.S. Ser. No. 07/311,311 ftled Feb. 15, 1989 now

abandoned.BACKGROUND OF THE INVENTION

The invention pertains to the field of N-phenyl-N-(4- 10piperidinyl)amides having potent analgesic activity. Anumber of patents disclose certain N-phenyl-N-(4-piperidinyl)amides having analgesic activity such as, forexample, U.S. Pat. Nos. 3,164,600; 3,998,834; 4,179,569;4,584,303; and 4,167,574. The analgesic compounds of 15this invention differ structurally from the prior art com-pounds by the particular N-substituent on the piperidinering, i.e., the "X" function indicated in the hereafterformula (I) compounds. In general, they also differ bytheir relatively short durations of analgesic action, rang- 20ing from the ultra short to medium range, and theirnon-hepatic means of inactivation. The invention alsoprovides certain novel synthetic intermediates for mak-ing formula (I) compounds.

DETAILED DESCRIPTION OF THEINVENTIONThe invention relates to novel chemical compoundsand pharmaceutical compositions thereof. More partic-ularly, the subject chemical compounds are N-phenyl-N-(4-piperidinyl)amides represented by the formula:

wherein:X is a member selected from the group consisting of:alkoxy-carbonyl-lower alkyl (preferred), lower alkyl-carbonyloxy-Iower alkyl, alkenyloxy-carbonyl-Iower 45alkyl, and (C1-2)alkOXy-(CI_2)alkoxy-carbonyl-loweralkyl.Ar is a member selected from the group consisting ofphenyl (preferred) and mono-, di- and tri-substitutedphenyl, preferably mono-substituted in the 2-position, 50wherein each substituent is independently selectedfrom the group consisting of halo, lower alkyl, loweralkoxy and trifluoromethyl;R is a member selected from the group consisting oflower alkyl, preferably ethyl, and lower alkoxy- 55lower alkyl, preferably methoxymethyl;R 1 is a member selected from the group consisting ofhydrogen, lower alkoxy-carbonyl, preferably me-thoxycarbonyl, and methoxymethyl; andR2is a member selected from the group consisting of 60hydrogen and methyl;and the optically active and cis-trans isomers thereof,and the acid addition salts, preferably the pharmaceuti-cally acceptable acid addition salts, of said compoundsand isomers. 6SAn additional aspect of the subject invention relatesto certain novel acidic intermediates which are useful inthe synthesis of certain formula (I) compounds. Said

5,019,583 2intermediates are represented by formula (A) whereinXa isa carboxy-lower alkyl substituent on the ring nitro-gen, replacing the aforementioned X-substituent in for-mula (I):

(A)

(I)

As used in the foregoing definitions the term "lower"ismeant to modify the so-indicated group by indicatingfrom 1 to 4 carbon atoms; the terms "alkyl", "alkoxy"and "alkenyl" are each meant to respectively includestraight and branch chained hydrocarbons, e.g. of about1 to 10 carbons and include the group of hydrocarbonsof 1 to 4 carbons; and the term "halo" is generic tohalogens of atomic weight less than 127, i.e., fluoro25 (preferred), chIoro, bromo and iodo.The formula (I) compounds of the invention providepotent analgesia with a duration of action ranging fromultra-short to medium. Such activity is characterized byrapid onset and a half-life generally ranging from about30 5 to about 40 minutes in experimental rats. In contrast,the well-known narcotic analgesic, N-(I-phenethyl-4-piperidyl) propionanilide, generically known as fenta-nyl, and its congeners, sufentanil and alfentanil, havedurations of action of 60, 80 and 55 minutes in rats,

35 respectively, and terminal half-lives in humans of about1.5 to 7 (16 for geriatric patients), 2.5and 1.2to 3 hours,respectively (Mather, L. E., Clinical Pharmacokinetics,1983, 8:422-446). The marked potency and very shortduration of analgesia provided by the ultra-short acting40 compounds of this invention are highly desirable incircumstances where severe pain has to be eliminatedover a short period of time, e.g., anesthesiology. Withthe current preponderance of short surgical proceduresand the growing trend towards outpatient surgery,there exists an urgent need for a powerful but shortacting analgesic as stated by Dr. Paul A. J. Janssen inJanssen: Opioids in Anesthesia. (Estafanous, F. G., ed.)

Butterworth, Boston. (19.84). The compounds of theinvention can be used together with a pharmaceuticallyacceptable carrier to provide pharmaceutical composi-tions and can be administered to mammals such as manin amounts sufficient to provide analgesic effects.When X is alkoxy-carbonyl-lower alkyl, e.g. loweralkoxy-carbonyl-lower alkyl, compounds wherein thecarbon of the alkoxy directly attached to the oxygen ofthe alkoxy is a methylene or methyl group, i.e. whereinit is substituted by no more than 1 alkyl group, aregenerally shorter acting. Further, the lower alkyl of thealkoxy-carbonyl-Iower alkyl is, in particular, ethyl ofthe formula -CH2CH2-.The formula (I) compounds may be converted to thetherapeutically active acid addition salt form by treat-ment with an appropriate acid, such as, for example, aninorganic add, such as hydrohalic acid, e.g., hydrochlo-ric, hydrobromic,and the like, and sulfuric acid, nitricacid, phosphoric acid and the like; or an organic acid,such as, for example, acetic, propanoic, hydroxyacetic,

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o~ R \~" ' - X . , (0) --7__j N-I ..Jk,ICOO-.Jk,1l j + Hal-X

N ~IH

3 5,019,583a-hydroxypropanoic, 2-oxopropanoic, ethanedioic,propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydrox-ybutanedioic, 2-hydroxy-l,2,3-propanetricarboxylic,benzoic, 3-phenyl-2-propenoic, a-hydroxy-benzenea- 5cetic, methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic, cyclohexanesulfamic, a-hydroxybenzoic, 4-amino-2-hydroxybenzoic and thelike acids. Conversely, the salt form can be convertedby treatment with alkali into the free base form. In 10addition, the salt forms may be useful in the preparationof other salt forms, for example, as intermediates forconversion into the preferred pharmaceutically accept-able salt derivatives. Furthermore, the particular saltmay exist as a solvate, e.g., a hydrate or a hemihydrate. 15Several of the compounds of formula (I) have one ormore asymmetric carbon atoms in their structure andconsequently they may exist in the form of differentoptical isomeric forms or mixtures e.g., racemates, ofsuch forms. When R2 in formula (I) represents a methyl 20group there are two asymmetric carbon atoms in thepiperidine ring. Additional asymmetric carbon atomsmay also be present in the X-substituent, for example,when X is -CH(CH3)CH2COOCH3, -CH2CH(CH3_)COOCH3 and -CH2COOCH2CH(CH3)CH2CH3. En- 25antiomeric forms and mixtures of such forms may beobtained separately by the application of methods ofresolution known to those skilled in the art such as, forexample, salt formation with an optically active acidfollowed by selective crystallization or chiral derivati- 30zation and in turn followed by selective crystallizationor silica gel chromatography.When R2 is a methyl group, the relative position ofsaid methyl group and of the substituents in the 4-posi-tion of the piperidine ring with respect to the plane of 35the piperidine ring may be cis or trans, according to therules of nomenclature described in "Naming and Index-ing of Chemical Substances for C.A. during the NinthCollective Period (1972-1976) p. 861." Compounds offormula (I) having the cis- or trans-configuration, essen- 40tially free of the other, may be obtained, for example, bystarting their preparation from pure cis- or trans-iso-mers of the appropriate precursors. When, for example,an intermediate of formula (XI) in which R2 stands formethyl is subjected to a selective crystallization, cis- 45and trans-isomers are obtained separately and the thus-obtained forms are conveniently used in the furthersynthesis of compounds of formula (I) having the corre-sponding configuration. Alternatively, substantiallypure forms of the cis- and trans-isomer of compounds of

(II) (III)

4formula (I) may be obtained, substantially free of theother isomer, by separating a mixture of such appropri-ate precursor forms (e.g., see Formula XXI hereinafter)by silica gel chromatography.Cis- and trans-forms may in turn be further resolvedinto their optical enantiomers, each essentially free of itsoptical counterpart, by the application of art-knownmethodologies such as noted previously.All racemic and isomeric forms of the compounds offormula (I), including diastereomeric mixtures, purediastereomers and enantiomers, and mixtures thereof,are intended to be within the scope of this invention.The compounds of formula (I) may generally be pre-pared by introducing the X substituent on to the piperi-dine ring nitrogen of an intermediate of the formula(11):

(II)

wherein Ar, R, R t and R2are as previously defined, bythe application of conventional methodologies knownin the art. Depending on the nature of the X substituent,the following methods may be utilized therefor.The compounds of formula (II) are known com-pounds which are obtainable by art recognized proce-dures. In addition, the compounds of formula (II) inwhich R2 is methyl and R! is hydrogen have been pre-pared (see examples hereinafter) from l-methoxy-car-bonyl-3-methyl-4-[I-oxopropylaryl-amino]piperidines,which are in turn prepared from 3-methoxycarbonyl4-piperidinone hydrochloride using the procedure de-scribed by W. F. M. VanBerer et aI., J. Med. Chem.1974,17,1047 and T. R. Burke, Jr., et aI., J. Med. Chern.1986, 29, 1087.The introduction of the aforementioned X groups onto the ring nitrogen of (II) may conveniently be carriedout by the alkylation reaction of (II) with an appropri-ate halide of formula (III) wherein "Hal" is bromo(preferred), chloro or iodo and X represents the afore-mentioned groups as shown, in Scheme I:

Scheme I

(I-a)

(b)~__/

(I-b)N- t.alkyl-O-CO- t.alkyl

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5 5,019,583 6-continued

Scheme I

(I-c)

20 -continuedScheme IIFormulae (Ia)-(Id) and other formuale utiliz: theconvention of partial structures to denote the remamderof the formula as in formula (I) hereinabove.The alkylation reaction of (II) with (III) is conve- 25niently conducted in an inert organic solvent su~h as,for example, acetonitrile (preferred), an aromatic hy-drocarbon, e.g., benzene, methylbenzene, dimethylben-zene and the like; a lower alkanol, e.g., methanol, etha-nol l-butanol and the like; a ketone, e.g, 4-methyl-2- 30pentanone and the like; an ether, e.g., 1,4-dioxane, tetra-hydrofuran (THF), I,l-oxybisethane and the like; N.'N-dimethylformamide (DMF); nitrobenzene; and the like.The addition of an appropriate base such as, for exam-ple, an alkali metal carbonate or ?~carbonate, pre~erably 35 When X is alkoxy-carbonyl-Ioweralkyl in (I-a) orpotassium carbonate, may be utilized to neutralize .the alkenyloxy-carbonyl-loweralkyl in (I-c), an alternativ.eacid that is liberated during the course of the reaction. method of introducing said X-substituent onto the P I _In some circumstances, the addition of an iodide salt, peridine nitrogen is by esterification of. the correspond-preferably an alkali metal iodide such as sodium iodide, ing acidic formula (A) compounds, i.e., form~la (I)is appropriate. Ambient temperatures (22:-25 C.) are 40 wherein X is carboxy-loweralkyl such as (VI), USIngthegenerally sufficient, although somewhat higher temper- appropriate alkyl or alkenyl N,N-diisopropyl-atures may be employed to enhance the rate of the pseudourea in an organic solvent, for example, cJ:lloro-reaction. form, at ambient to reflux temperatures. The acids ofWhen X is alkoxy-carbonyl-ethyl, wherein the ethyl formula (A), e.g, where X a is a carboxyethyl thus defin-may be substituted with I or 2 CI-2 alkyl groups for a 45 ing (VI), are believed to be novel intermediates, may betotal of 2-4 carbons, an alternative method of introduc- obtained by reacting (II) with an appropriate t-butyling this group on to the ring nitrogen of (II) to yield (V) ester of formula (III) or tertiary butyl acrylate (Michaelis by way of a conjugate addition reaction between (II) Reaction) followed by reacting the thus-obtained prod-and an a,,8-unsaturated carbonyl reactant of formula uct, e.g. (VII), with excess trifluo.roacetic acid at 0.C.(IV) in an inert organic solvent such as, for example, 50 to ambient temperatures according to the followingacetonitrile, a lower alkanol, e.g., methanol, ethanol and Scheme III:the like, an ether, e.g., diethyl ether, dioxane and thelike' and an aromatic hydrocarbon, e.g., benzene, tolu-eneand the like as shown, for example, in Scheme II.

o~ Rr:M - O R 'N 0

I U alkyl~O/v

Scheme III55

Scheme II I ~ M;,~I ~NH + CH2=CHCOO-tBu reaction60 ( I n

II IV

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7 5,019,583-continuedScheme III

OR3IiPrN=C-NHiPr )

(I-a) R3=alkyl(I-c) R3=alkenyl

The ester CH2==CHCOO-tBu in Scheme III may besubstituted by other esters e.g. of the formulaR4RsC==CR6COO-tBu wherein R4, RS and R6 arehydrogen methyl or ethyl provided that the total car- 25bons in R4, RS and R6 is 0-2, to yield other acids ofFormula (A).Alternatively, the appropriate carboxy loweralkyl

halide or acrylic acid, the acrylic acid embodiment 30being shown below, can be esterified with the appropri-ate alkyl or alkenyl-N,N-diisopropyl-pseudourea, forexample, in chloroform at ambient to reflux tempera-tures, to yield the corresponding formula (III) halideester or acrylic ester which is then introduced onto the 35ring nitrogen of a formula (II) compound by means ofthe previously mentioned alkylation reaction or conju-gate addition Michael reaction, as shown in Scheme IV:

Scheme IV

CHCI3CH2=CH-COOH + iPrN=C-NHiPr )IOR3

[ ~ N H+ CH,=CH-COOR'(II)

Michael)reaction

[~~N-CH'CH'COOR' 60(I-a.c)

In both Scheme III and IV, when R3 is alkenyl, the 65double bond is not directly attached to the oxygen ofthe OR3. In addition, the CH2=CH-COOH starting

8material may be substituted by R4RsC==CR6COOHwherein R4, R5and R6are as defined above. An alterna-tive method of preparing the formula (I) compounds

5 wherein X is loweralkyl-carbonyloxy-Ioweralkyl andRIis hydrogen or methoxymethyl is by reduction of thecorresponding ester (l-a) to the corresponding alcohol(VIII), for example, by conventional lithium aluminum

10 hydride reduction in ether solution, preferably THF, atambient temperatures. The thus-obtained alcohol (VIII)is then transformed into the reverse ester (IX) by reac-tion with an appropriate loweralkyl anhydride, for ex-ample, acetic acid anhydride, propionic acid anhydride,and the like, in an organic solvent such as pyridine. Thisis shown in the following Scheme V wherein X is informula (I-a) is loweralkyl-Cfb-loweralkyl:

20Scheme V

o} - R" ' - O R ' LiAlHifTIlF>NIloweralkyl-Cfrj-loweralkyl

40

o} - RA r - X R2l. (VIII)NIloweralkyl-CH20HIloweralkYI anhydridetpYridine45

50

o} - RA r - X R2l j (IX)NIloweralkyl-Or+Cfr-loweralkyl55

When X is CI_2alkoxy-CI_2alkoxy-carbonyl-ethyl,wherein the ethyl may be substituted with 1 or 2 CI-2alkyl groups for a total of 2-4 carbons, the introductionof this group on to the ring nitrogen of (II) may conve-niently be carried out by the reaction of (II) with an a,j3-unsaturated carbonyl reactant of formula (X) accord-ing to standard Michael Reaction conditions and sol-vents, acetonitrile being preferred, to yield the corre-sponding N-substituted product (V-a) as shown inScheme VI:

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9 5,019,583 10Scheme VI

o} - RAr-oN Rl R2

~O ......+ ~ CI_2Ioweralkyl-O-CI_2IoweralkylNIH(II) (X)I Michael

~ Reactiono~ Rr:A ~ O R 'N 0

~o"",-CI_Z10Wera1kYI-O-CI_Z10WeralkYl(V-a)

The compounds of formula (X) having a CI_2alkoxy-methoxy-carbonyl-ethyl function are obtained by the 30reaction of acrylic acid with an appropriate dialkoxyal-kane such as dimethoxymethane and diethoxymethanein the presence of phosphorous pentoxide. The acrylicacid may be substituted by other acids of the formulaR4RsC=CR6COOH to yield other products within the 35invention. The compounds of formula (X) having a

CI_2alkoxy-ethoxy-carbonyl-loweralkyl function areavailable from commercial suppliers.As noted previously, the formula (I) compounds arecapable of existence in diastereomeric and enantiomericforms. The following schematic descriptions exemplifyparticular synthetic paths for preparing such disastere-omers and enantiomers as pure materials starting withappropriate precursors.

Scheme VII

oAr II......N~( r C H '

NICOZCH3XIcis/trans

XIIcis XIVcisCrystallize

oAr

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11 5,019,583 12As depicted in Scheme VII, the cis/trans mixture(XI) is conveniently used as the starting material. Stan-dard crystallization procedures using organic solventssuch as ethyl actate, ether/hexane and the like, affordsseparation of the corresponding pure cis isomer (XII) incrystalline form and the corresponding trans isomer(XIII) in the mother liquor with some residual cis iso-mer. The pure cis isomer (XII), essentially free of thecorresponding trans isomer, and the predominantlytrans isomer (XIII) are each converted to the corre-sponding 3-methyl-4-arylaminopiperidines of respectiveformulas (XIV) and (XV) by treatment with a concen-trated hydrohalic acid (hydrobromic acid preferred) atreflux temperature. Subsequently, the resultant purecrystalline cis isomer (XIV) may then be recovered andutilized in the further synthetic pathways depicted inScheme VIII to obtain the formula (1) final products inthe corresponding cis form.

As shown in pathway 1 of Scheme VIII, the cis pre-cursor (XIV) is subjected to the previously describedalkylation reaction with a formula (III) halide to yieldthe corresponding N-substituted compounds of formula5 (XVI). Acylation of the arylamino group in (XVI) withan appropriate acid chloride (RCaCI in which R is aspreviously defined) provides the respective formula (I)compounds in cis form. The acylation reaction is conve-niently carried out utilizing an appropriate 4-dialk-10 ylaminopyridine as an acylation catalyst and a polaraprotic solvent such as acetonitrile (preferred), di-methyl formamide, hexamethyl phosphoramide and thelike at temperatures ranging from 40 to 85 C.Pathway 2 of Scheme VIn depicts the alternative15 route for introducing an alkoxy-carbonyl-ethyl or CI_2alkoxy-CI_2alkoxy-carbonyl-ethyl substituent on to thering nitrogen of (XIV) by the previously describedconjugate addition (Michael addition) reaction with an

Scheme VIII

XIV oH I IAr .......,/ Ar ...............

~ 3. ~CH3 ~CH3Cbz-CI --7l j --7l jN N1 1Cbz Cbz

XVIII XIX

o 0Ar I I Ar I I.......N...............R .......N...............R

V cis (jCH3 (jCH3or ~ --7Va cisN N 1 1H XXXcis cis

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135,019,583 14a,l3-unsaturated carbonyl reactant of formula (IV') toyield the corresponding cis form of (XVII) which isthen acylated with RCOCI as previously described toyield cis product forms of (V) or (V-a), The symbol R'

cis final products of formulas (I), (V) or (V-a) by therespective alkylation and Michael additional methodol-ogies previously described using (XX) as the (II) com-pound.Scheme IX

XV XXIAr

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15 5,019,583-continued

Scheme X

XXIIII.Separate by silicagel chromatography2. HBr(aqjlreflux

Reaction of racemic cis (XIV) with R-a-methylben-zyl isocyanate at elevated temperatures (about100_150C.) in the presence of an appropriate 4-dialk- 30ylaminopyridine catalyst generates the racemic mixtureof diastereomeric compounds (XXIII) and (XXIV)which are separable by flash silica gel chromatography.Each of the separated diastereomers are then convertedto the respective enantiomeric piperidines (XXV) and 35(XXVI) by treatment with refluxing hydrobromic acidwhich, in turn, may then be used as the starting precur-sor for preparing the corresponding form of the formula(I) compounds in accordance with the previously de-scribed methodologies in Scheme VIII. 40The compounds of formula (I) and the isomeric formsand pharmaceutically acceptable acid addition saltsthereof are useful analgesics, as demonstrated, for exam-ple, in experimental animals. Typical of the in vitro andin vivo testing procedures for analgesic activity are the 45guinea pig ileum assay and the rat tail withdrawal assay,respectively.

A. Guinea Pig Ileum Assay (in vitro)Compounds are tested for opioid activity in the iso-lated guinea pig ileum using the method of Kosterlitz,H. W. and Watt, A. J., Br. J. Pharmacol. 33:266-276(1968) with modifications found in James, M. K. andLeighton, H. J., J. Pharmacol. Exp. Ther. 240:138-144(1987). The terminal ileum is removed from male Hart- 55ley guinea pigs after sacrifice by cervical dislocation.The isolated ileum is washed and placed in Krebs-Hen-seleit buffer oxygenated with 95% 02 and 5% C02mixture and maintained at 37 C. The washed ileum iscut into segments (2.0-2.5 em) and mounted on plati- 60num ring electrodes. The ileal segments are then placedin 10ml temperature-controlled tissue baths containing

oxygenated Krebs-Henseleit buffer. The tissues are con-nected to force-disPlacement transducers and stretchedto a resting tension of 1.0 gram. The composition of 65Krebs-Henseleit buffer is as follows (millimolar): NaCl,118.1; KCl, 4.15; CaCI2, 2.5; MgS04, 1.2; KH2P04,1.23; NaHC03, 25.5 and glucose, 11.1.

16

The ileal segments are stimulated at 0.1 Hertz, 0.5milliseconds duration at a supramaximal voltage to in-duce contractions. Opioid activity in the test com-pounds ismanifested as inhibition of electrically evokedcontractions. A non-cumulative concentration-effectcurve for each test compound is performed to assess theability of the compound to inhibit contraction in theguinea pig ileum. After the concentration-effect curve iscompleted, naloxone is added to the tissue baths todetermine if the compound-induced inhibition of con-traction is reversed. Antagonism of the inhibition bynaloxone confirms that the inhibitory effects of thecompounds are mediated through opioid receptors.Assay results are expressed as ECsovalues (ameasure ofpotency), defined as the concentration producing fiftypercent of the maximal response, and is expressed inmolar units (moles of compoundlliter).

B. Rat Tail Withdrawal Assay (in vivo).The analgesic efficacy of test compounds are evalu-ated in a rat tail withdrawal reflex model modified from

D' Amour, F. E. and Smith D. L., J. Pharmacol. Exp.50 Ther. 72:74-79 (1941). Male Sprague-Dawley rats areanesthetized and implanted with femoral vein cannulaeand allowed to recover overnight. After recovery, thetest compounds are administered intravenously throughthe cannula and effects on tail withdrawal latency aremeasured. Tail withdrawal latency is measured as thetime to tail movement by the rat after exposure of thetail to a radiant heat source. The heat source is cali-brated to produce a temperature of 62" C. after 15 sec-onds. Tail withdrawal latency in the.absence of drugs issix to eight seconds. Test compounds demonstratinganalgesic activity prolong tail withdrawal latency be-yond that seen in the absence of drugs. A maximal la-tency cut-off of fifteen seconds is imposed to preventtissue damage. The assay is verified with known opioidsas standards. Results of these studies are expressed asED so values, calculated as the dose producing a tailwithdrawal latency equal to half the difference betweenthe maximum latency (15 seconds) and the baseline

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175,019,583 18latency (sixto eight seconds). EDso values are expressedas milligrams of compound/kilogram of body weight.Duration of action is defined as the time (in minutes)necessary for the tail withdrawal response to return tobaseline values after being elevated in response to drugadministration. Duration of action is measured at the

lowest dose producing a fifteen second (maximum) tailwithdrawal latency.In Table I, test results obtained from the aforemen-tioned A. guinea pig ileum assay and B. rat tail with-drawal assay are listed for the indicated compounds offormula (I). Said results are not given (or the purpose oflimiting the invention to said compounds but to exem-plify the analgesic activity of all compounds within thescope of formula (I). For comparison purposes, test 15results obtained for three well known 4-anilidopiperi-dine analgesics, fentanyl, sufentanil and alfentanil, arealso listed.

5.3-[4-methoxycarbonyl-4-(I-oxopropyl)phenylamino]-I-piperidine]propanoic acid, vinyl ester (Example15B);and the pharmaceutically acceptable isomers and salts5 thereof. A particular group of compounds of the inven-tion are the alkyl esters of 3-4-methoxycarbonyl-4-(I-oxopropyl)-phenylamino-I-piperidine ]propanoic acidand their pharmaceutically acceptable salts.The aforementioned properties of the most preferred10 compounds are extremely beneficial in that they allowmore control over the level of analgesia in a surgicalsetting or other situation where precise control of opi-oid levels are necessary or desirable. These propertieswould also allow for more rapid recovery after theconclusion of a surgical procedure or after the use ofthese compounds in other circumstances.In addition, to their analgesic activity, the com-pounds (I) of this invention may be subject to extensivemetabolism in blood as well as potential metabolism in________ T_A_B_L_E_I 20 the liver, as has been typically observed with the mostpreferred compounds. In contrast, fentanyl and alfen-tanil are reported to be primarily metabolized in theliver in humans, for example, see McClain, D. A. and

1.66 0.59 x 10-6 3.2 10-15 Hug, Jr., C. C., Clin. Pharm. Ther. 28:106-114 (1980),i:~!g : ~ ~ ! g = : 3.4 5~~0 25 and Schuttler, J. and Stoeckel, H., Anesthesist 31:10-143.71 0.20 x 10-7 I~:~ 5-10 (1982). Rapid elimination or biotransformation to inac-1.03 1.00 x 10-5 tive or less active products would minimize accumula-3.S5 0.23 x 10-9 0.0044 15 tion with prolonged or repeated administration. This1.02 0.63 x 10-8 0.8 30 property has been cited as one of the properties of an6.89 1.61x 10-9 1.4 15 30 "ideal" intravenous analgesic or anesthetic (White, P.5.11 0.24 x 10-7 3.0 inactive or less active products in the blood, as occurs1.18 0.20 x 10-7 >3.0 with the neuromuscular blocker, succinylcholine,4.95 0.09 x 10-6 1.4 252.18 0.18 x 10-6 1.4 IS 35 would allow more predictable correlation of dose with1.98 0.21 x 10-8 3.0 This non-hepatic means of inactivation may be dem-1.47 0.09 x 10-7 0.052 5 h f9.29 6.36 x 10-9

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195,019,583

nitrogen. To the residue from the evaporation, 100,...1ofethyl acetate is added, mixed and the solution analyzedby gas-liquid chromatography. 1 Microliter aliquots ofthe ethyl acetate solution are injected into a gas chro-matograph fitted with a 0.32 mm (internal diame- 5ter) X 15 m column coated with DBS (brand name ofJ&W Scientific, Rancho Cordoba, Calif. for a S% di-phenylpolysiloxane and 9S% dimethylpolysiloxanemixture) to a film thickness ofO.2S u,The injector portis held at 280 C. The detector is a nitrogen phospho- 10rous detector held at 270 C., and the carrier gas ishelium at a flow rate of 2 ml/minute. The column isheld at 4S C. for one minute after injection; then heatedto 270 C. at a rate of 2S CJminute, and held at 270 C.for seven minutes. Under these conditions, the internal 15standard has a retention time of 11.6minutes. The TestCompound, fentanyl, sufentanil and a1fentanil haveretention times of 11.0, 12.1, 12.8 and 14.3 minutes,respectively.In this study, it has been found that more than 90% of 20the Test Compound disappeared after incubation for 30seconds, whereas 6S%. 8S% and 7S% of the addedsufentanil, alfentanil and fentanyl are still present at theend of a one hour incubation period. These results dem- 25onstrate that the Test Compound is rapidly degraded inrat blood in vitro in contrast to the three comparativecompounds, which degrade at a very slow rate. As aconsequence of these findings, the analgesic compoundsof this invention may be subject to extensive metabolism 30in blood as well as potential hepatic metabolism. Thisproperty is viewed as advantageous because it offers analternative means of inactivating the analgesic com-pound and thereby could produce a predictable phar-macokinetic profile. 35Beyond 3-[4-methoxycarbonyl-4-[ (l-oxopropyl)-phenylamino]-I-piperidine]propanioc acid, methyl esterthis non-hepatic means of inactivation may be demon-strated with the related ethyl, propyl, butyl, isopropyl,isobutyl and sec-butyl esters. These compounds (test 40compounds below in Table II) have been found to berapidly degraded in human blood when compared totheir degradation in phosphate buffer.The relative assay using human blood is performed asfollows. Twenty ml of fresh, heparinized human blood 45is placed in a temperature-controlled water bath at 37"C. for 10minutes. At that time, 400,...1of2 mg/ml solu-tion of the test compound is added to the blood to givea blood concentration of 40 ,...glml of the test com-pound. Solutions of the test compounds are prepared 50just before the assay was started. Two SOO,...1of bloodare withdrawn at various timepoints for measurementof the test compound and the propanoic acid formed byester hydrolysis. A trial run was performed with eachtest compound and thereafter timepoints were set for 55sampling over two to three half-lives. Chemical hydro-lysis is measured by incubating the test compounds inphosphate buffer (0.1 M, pH=7.4) instead of blood.Duplicate samples are taken at 1, 30, 60, 120, 180, 240and 300 minutes. 60Acetonitrile (700 ,...1) isadded to the from the incuba- .tion mixture along with SO,...1of a solution of the inter-nal standard (4-[4-methoxycarbonyl-4-[(1-oxopropyl)-phenylamino]-l-piperdine]butanoic acid, methyl ester,0.12 mg/ml in acetonitrile). Samples are mixed and 65immediately centrifuged at 30,000 Xg for 10 minutes.The supernatant is removed and cooled to 8 C. Twentymicroliters of the supernatant is injected into the high

20performance liquid chromatograph (HPLC) for analy-sis.The HPLC analysis is performed using as,.. . Spheri-sorb CN column (2S0X4.6 mm)(Keystone Scientific,Inc., State College, Pa.) with a flow rate of 2 ml/min.The mobile phase for the assay is 0.1 M phosphatebuffer (PH=2.0) and acetonitrile in a gradient elution.Acetonitrile is increased from 10-11% at 0 to Sminutesto 16% by 10minutes. Acetonitrile ismaintained at 16%through the remainder of the elution (16 minutes inclu-sive). These conditions provide for resolution of thepropanoic acid formed by ester hydrolysis, the internalstandard and all of the test compounds except the ethylester. Retention times are (in minutes): propanoic acidS.I; methyl ester 7.S; internal standard 8.6; ethyl ester9.0; isopropyl ester 11.1; propyl ester 11.8; sec-butylester 13.9; iso-butyl ester 14.4.; and butyl ester 14.9.Slowing the flow rate to 1 ml/minute allows theresolution of the ethyl ester from the internal standard.At this flow rate the retention times are 10.1minutes forthe propanoic acid, IS.1 minutes for the internal stan-dard and IS.8 minutes for the ethyl ester. Elution ofthese substances is detected by monitoring ultravioletabsorption at a wavelength of 220 nm.Data from the HPLC assay is analyzed by a simplepseudo-first order kinetic model for disappearance ofthe test compounds. Pseudo-first order rate constantswere calculated for each test compound from these dataalong with the apparent half-lives in minutes (t~).Theseresults are shown in Table II below for the variousesters of 3-[4-methoxycarbonyl 4-[(I-oxopropyl)-phenylamino j-l-piperidine ]propionic acid. Where kBu isthe pseudo-first order rate constant for degradation ofthe test compounds in phosphate buffer and kBl is thesimilar constant for degradation in blood.

TABLE IIBuffer BloodEster kBu tl kbl t!

methyl 7.4 0.6 X 10-3 94 2.0 0.1 X 10-2 36.5ethyl 4.6 0.2 X 10-3 150 1.8 0.7 X 10-2 38.5propyl 3.0 0.5 X 10-3 231 2.5 0.3 X 10-2 27.7butyl 3.0 0.5 X 10-3 231 8.5 0.6 X 10-2 8.2isopropyl 1.3 0.5 X 10-3 533 1.0 0.1 X 10-2 69.3isobutyl 4.0 0.6 X 10-3 173 9.0 2.0 X 10-2 7.7secbutyl 2.0 0.2 X 10-3 346 9.0 1.0 X 10-3 noIn this study, it was found that the test compoundswere rapidly degraded in blood as compared to buffer.

The test compounds were found to be rapidly degradedin human blood in vitro in contrast to the marketedcompounds, fentanyl, sufentanil and a1fentanil, whichhave been found to be primarily metabolized in the liverin vivo see D. A. McClain et al, Clin. Pharm. Ther.28:106-114 (1982). As demonstrated in this study, theanalgesic compounds of this invention may be subject toextensive metabolism in blood as well as potential he-patic metabolism. This property is viewed as advanta-geous because the compounds of this invention wouldnot depend on redistribution for the terminiation oftheir effects and thereby would likely have a more con-sistent and predictable pharmacokinetic and pharmaco-dynamic profile.In view of their analgesic activity, the subject com-pounds may be formulated into various pharmaceuticalforms for administration purposes. To prepare the phar-maceutical compositions of this invention, an effectiveanalgesic amount of the particular compound, in base oracid-addition salt form, as the active ingredient is com-

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21bined in intimate admixture with a pharmaceuticallyacceptable carrier, which carrier may take a wide vari-ety of forms depending on the form of preparation de-sired for administration. These pharmaceutical compo-sitions are desirable in unitary dosage form suitable, for 5example, for administration orally, transdermally, rec-tally or parenterally. For example, in preparing thecompositions in oral dosage form, any of the usual phar-maceutical media may be employed, such as, for exam-ple, water, glycols, oils, alcohols and the like in the case 10of oral liquid preparations such as suspensions, syrups,elixirs and solutions; or solid pharmaceutical carrierssuch as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like inthe case of powders,pills, capsules and tablets. For parenteral compositions, 15 _the carrier will usually comprise sterile water, at least inlarge part, though other ingredients, for example, to aidsolubility, may be included. Injectable solutions, forexample may be prepared in which the carrier com-prises isotonic saline solution, glucose solution or a 20mixture of saline and glucose solution. Injectable sus-pensions may also be prepared in which case al?propri-ate liquid carriers, suspending agents and the like ma.ybe employed. Acid addition salts of (I), due to theirincreased water solubility over the corresponding base 25form, are obviously more suitable in the preparation ofaqueous compositions.It is especially advantageous to formulate the afore-mentioned pharmaceutical compositions in dosage unitform for ease of administration and uniformity of dos- 30age. Dosage unit form, as used herein, refers to phys!-cally discrete units suitable as unitary dosages, each urutcontaining a predetermined quantity of active ingredi-ent calculated in product the desired therapeutic effectin association with the required pharmaceutical carrier. 35

Examples of such dosage unit forms are tablets (includ-ing scored or coated tablets), capsules, pills, powderpackets, wafers, injectable solutions or suspensions,teaspoonsfuls and the like, and segregated multiplesthereof. 40In view of the analgesic activity of the subject com-pounds, it is evident that the present invention providesa method of preventing or combatting pain, that is,providing analgesia, in warm-blooded mammals, in-cluding humans, by the systemic administration of an 45effective analgesic amount of a compound of formula(I) or a pharmaceutically acceptable isomer or acidaddition salt thereof in admixture with a pharmaceuticalcarrier. Although the amount of active ingredient to beadministered may vary within rather wide limits, de- 50pending on the particular circumstances of the case,doses of from about 0.001 to about 10mglkg, and pref-erably from about 0.01 to about 1.0 mglkg, adminis-tered once, repeatedly or continuously (e.g., i.v. drip),are generally found effective. The preferred route of 55administration is parenteral, particularly by the intrave-

5,019,583 22trile (2.5 ml) is stirred at room temperature for fivehours. The reaction mixture is diluted with I:1 waterand ethyl acetate (20 ml total). The phases are separatedand the aqueous phase extracted with ethyl acetate(2X) and the combined organics washed with brine,dried over sodium sulfate and then concentrated. Theresidue is chromatographed on silica gel (95/5CHCb/MeOH) to give 4-[(I-oxopropyl)phenylamino]-l-piperidineacetic acid, methyl ester, as an oil: 348 mg,53% yield. An equimolar amount of maleic acid in etheris added to a solution of the free base in ethyl acetate togive the maleate salt as a white solid; maleate salt: m.p.130-133 C.

Elemental Analysis for C21H28N2Qz:C% H% N%

Found:Calculated: 59.760.0 6. 86. 7 6. 66. 7

EXAMPLE 23-[4-[(I-Oxopropyl)phenylarnino ]-I-piperidine]-propanoic acid, methyl esterTo a solution of 4-[(I-oxopropyl)phenylamino]-piperidine (1.0 gm, 4.31 mmol) in acetonitrile (10 ml) isadded methyl acrylate (776 ILl, 8.62 mmol) at roomtemperature. The solution is stirred at 50 C. for 2hours, cooled to room temperature and concentrated toan oily residue. The residue is chromatographed onsilica gel (EtOAc) to yield 3-[4-[(I-oxopropyl)-phenylamino j-l-piperidine ]propanoic acid, methyl esteras an oil: 1.34gm, 98%. The maleate salt, which is made

as described in Example 1and recrystallized from ethylacetate, is a white solid; maleate salt: m.p. 118-120 C.

Elemental Analysis for C22H28N207:C% H% N%

Found:Calculated: 60.860.87.07.0

6. 76. 5

EXAMPLE 3

4-[(1-0xopropyl)phenylarnino ]-I-piperidineacetic acid,methyl esterA mixture of 4-[(I-oxopropyl)phenylamino]-piperi-dine (500 mg, 2.15 mmol), prepared according to the 65 _

f P A J J al U S P t N Elemental Analysis for C23H32N207:procedure 0 . . . anssen et , .. a. o.3,164,600, methyl bromoacetate (0.25 ml, 2.58 mmol), C % H %and potassium carbonate (594mg, 4.3 mmol), in acetoni-

4-[4-[(1-0xopropyl)phenylamino ]-I-piperidine ]butanoicacid, methyl esterA mixture of 4-[(I-oxopropy])phenylarnino]-piperi-dine (250 mg, 1.08 mmol), methyl 4-bromobutanoate(224 mg, 1.23 mmol), prepared according to the proce-dure of G. A. Olah et al, Synthesis 1982, 963, sodiumiodide (81 mg, 0.54 mmol), and potassium carbonate(298 mg, 2.15 mmol), in acetonitrile (1.1 ml) is stirred atroom temperature for five hours. The mixture is dilutedwith water and ethyl acetate and worked up in an analo-gous manner of Example 1. The residue is chromato-graphed on silica gel (EtOAc) to give 4-[4-[(I-oxo-

60 propyl)phenylarnino]-I-piperidine]butanoic acid,methyl ester as an oil: 223 mg, 62%. The maleate salt ismade as described in ExamPle 1; maleate salt: m.p.101.5-103.5 C.

nous route.The following examples are intended to illustrate, andnot to limit the scope of the present invention.EXAMPLE 1

N%Found: 61.3 7.0 6. 2

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23 5,019,583 24-continued drous Na2S04 and the ether distilled from the productto yield methoxymethyl acrylate as a light yellow oil:

450 mg, 13%.ElementalAnalysisfor CvHnN20z:C% H% N%Calculated: 61.6 7.2 6.3 5 B.

EXAMPLE 43-[4-[(1-0xopropyl)phenylamino ]-I-piperidine]-

propanoic acid, methoxymethyl esterA solution of 4-[(I-oxopropyl)phenylamino]-piperi-

10 dine (150 mg, 0.65 mmol) and rnethoxymethyl acrylate(182 mg, 1.57 mmol), in acetonitrile (0.8 ml) is stirred atroom temperature for eleven hours. The solution isevaporated and the residue chromatographed on silicagel (EtOAc) to give 3-[4-[(I-oxopropyl)phenylamino]-I-piperidine]propanoic acid, methoxymethyl ester as anoil: 138 mg, 25%. Gaseous hydrochloric acid is passedthrough a solution of the free base dissolved in ethylacetate/ether (iratio) to give the hydrochloride salt asa white solid; HCl salt: m.p. 128_131 C.

5-[4-[ 1-0xopropyl)phenylamino ]-l-piperidine ]pen-tanoic acid, methyl ester

A mixture of 4-[(l-oxopropyl)phenylamino]-piperi-dine (300 mg, 1.29 mmol), methyl-c-bromopentanoate(290 mg, 1.49 mmol), prepared according to the proce-dure of G. A. Olah et al, Synthesis 1982, 963) sodium 15iodide (97 mg, 0.65 mmol), and potassium carbonate(357 mg, 2.58 mmol), in acetonitrile (1.3 ml) is stirred atroom temperature for five hours. The crude residue isisolated according to the procedure of Example 1. Theresidue is chromatographed on silica gel (95/5 EtOAc/-MeOH) to give 5-[4-[1-oxopropyl) phenylamino]-l- 20piperidine]pentanoic acid, methyl ester, as a white solid:239 mg; 53%; m.p. 64_66 C. The maleate salt is madeas described in Example 1; maleate salt: m.p. 105_106C.

ElementalAnalysisfor C19H29N204CI:C% H% N%

2 5 Found:Calculated: 59.059.3 7.67.6 7.47.3ElementalAnalysisfor C24Rl4N20rC% H% N% EXAMPLE 7

2-[4-[(I-Oxopropyphenylamino j-l-piperidine ]ethylacetate

Found: 62.3 7.4 6.0_____C_al_cu_la_ted__: 6_2_.3 7_.4 6_._I 30

To a solution of 4-[(1-oxopropyl)phenylamino]-1-3-[4-[(1-0xopropyl)phenylamino]-I-piperidine]- piperidineacetic acid, methyl este{(250 mg, 0.82 mmol)

propanoic acid, trifluoroacetate 35 in tetrahydrofuran (10 ml) at - 78 C. is added lithiumA solution of 4-[(l-oxopropyDphenylamino]-piperi- aluminum hydride (250 mg, 6.57 mmol) in portions. The

dine (500 mg, 2.15 mmol) and t-butyl acrylate (0.37 ml, suspension is stirred at _78 C. for one hour and then2.58 mmol), in acetonitrile (2.5 ml) is stirred at room quenched with 2N sodium hydroxide (10 ml). Magne-temperature for 24 hours. The solution is concentrated 40 sium sulfate is added to the resulting suspension until itand the residue is chromatographed on silica gel becomes granular. The susPension is then filtered and(EtOAc) to give 4-[2-[(1-oxopropyl)phenylamino]-I- the filtrate concentrated to a residue. The residue ispiperidine propanoic acid, t-butyl ester as an oil: 605 chromatographed on silica gel (9/1 CHCb/CH30H) tomg, 78%. To the ester (309 mg, 0.857 mmol) is added yield 2-[4-[(1~oxopropyl)phenylamino]-1-piperidine]e-trifluoroacetic acid (4 ml). The homogeneous reaction 45 thanol as an oil: 155 mg, 68%.mixture is stirred at room temperature for one hour andthen concentrated to an oil which is triturated with A solution of 2-[4-[(I-oxopropyl)phenylamino]-I-ether to give a white solid, 3-[4-[(I-oxopropyl)- piperidine]ethanol (256 mg, 0.957 mmol), acetic anhy-phenylamino]-I-piperi]-dine]propanoic acid, trifluor- dride (0.72 ml, 7.63 mmol), and 4-dimethylaminopyri-oacetate: 316 mg, 88%; m.p. 187-189 C. 50 dine (50 mg, 0.41 mmol) in pyridine (5 ml) is stirred at

25 C. for two hours. The solution is concentrated to anoil which is chromatographed on silica gel (EtOAc) to

N % give 2-[4-[(I-oxopropyl)phenylamino]-1-Found: 54.6 6.0 6.7 piperidine]ethyl acetate as an oil: 243 mg, 82%. AnCalculated: 54.5 6.0 6.7 55 equimolar amount of oxalic acid is added to a solution-------------------------------------- of the free base in ethyl acetate. The precipitated salt is

recrystallized by adding methanol and heating until thesolid goes back into solution. Upon cooling the salt

60 precipitates as a white solid; oxalate salt; m.p. 153-155In a separatory funnel is added acrylic acid (2 ml, C.

29.17 mmol), dimethoxymethane (2 ml), phosphorouspentoxide (0.5 g) and ether (20 ml). The mixture is vig-orously shaken for five minutes and then an additionalaliquot of phosphorous pentoxide is added (0.5 g) and 65the procedure repeated three times. The solids are sepa-rated from the liquid and the ether solution washed withsaturated NaHC03 solution (3 X), then dried over anhy-

EXAMPLE 5

ElementalAnalysisfor CI9H2SN20SF3:C% N%

EXAMPLE 6A. Methoxymethyl acrylate

ElementalAnalysisforC2pH2SN207:C% H% N%

Found:Calculated: 58.758.8 6.96.96.86.9

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4-[4-Methoxycarbonyl-4-[ (l-oxopropyljphenylamino ]-1-piperidinej-butanoic acid, methyl esterA mixture of 4-methoxycarbonyl-4-[(I-oxopropyl)-IS phenylamino]-piperidine (150 mg, 0.517 mmol), methyl4-bromobutanoate (187mg, 1mmol), potassium carbon-ate (39.3 mg, 1 mmol), sodium iodide (155 mg, 1.0mmol) and acetonitrile (1 ml) is stirred at 50 C. for 2hours. The mixture is cooled to room temperature,____________________ 20 diluted with ethyl acetate (1 ml) and filtered. The fil-

trate is concentrated to an oily residue which is chro-matographed on silica gel (9/1 CHCbIMeOH) to yield4-[4-methoxycarbonyl-4-[ (l-oxopropyljphenylamino]-l-piperidinejbutanoic acid, methyl ester as an oil: 17725 mg, 88%. The oxalate salt is made as described in Exam-ple 7; oxalate salt: m.p. 153-155 C.

5-[4-Methoxycarbonyl-4-[ (l-oxopropyljphenylamino]-l-piperidinejpentanoic acid, methyl esterA mixture of 4-methoxycarbonyl-4-(I-oxopropyl)-phenylamino]piperidine (150 mg, 0.517 mmol) methyl5-bromopentanoate (200 mg, 1 mmol), potassium car-bonate (40 mg, 1 mmol) , sodium iodide (1.55 mg, 1mmol) and acetonitrile (1.0 ml) is stirred at 52 C. for22.5 hours andthen at 25 C. for 12hours. The reaction45 mixture is diluted with ethyl acetate (1 ml) and filtered.

-----E-lem-en-tal-A-nal-y-si-s-fo-r-C-21-H-28-N-20-9-:----- The filtrate is concentrated to an oily residue which isC% H % N% chromatographed on silica gel (90/9/1CHCbIMeOH/triethylamine) to yield 5-[4-methoxy-Found: 55 3 6 1 6 1

Calculated: 55:8 6:2 6:2 5 carbonyl-4-[(I-oxopropyl)phenylamino-]I-piperidine]--------------------- 0 pentanoic acid, methyl ester as an oil: 184mg, 88%. Theoxalate salt is made as described in Example 7; oxalatesalt: m.p. 164-166 C.

25EXAMPLE 8

5,019,583

3-[4-Methoxymethyl-4-[(I-oxopropyl)phenylamino ]-1-piperidine]-propanoic acid, methyl ester 5A solution of 4-methoxymethyl-4-[(I-oxopropyl)-phenylamino]piperidine (300 mg, 1.0 mmol), preparedby the procedure ofP. G. H. Van Daele et al, Arzneim.-Forsch. Drug. Res. 1976,26, 1521,methyl acrylate (325J o L I , 3.61mmol) and methanol (20 ml) is stirred at 60' C. 10for 2 hours. The reaction solution is cooled to roomtemperature and concentrated to an oily residue. Theresidue is chromatographed on 'silica gel (9/1CHCbIMeOH) to yield 3-[4-methoxy-methyl-4-[(I-oxopropyl)phenylamino j-l-piperidine ]propanoic acid,methyl ester as an oil: 250 mg, 64%. The oxalate salt ismade as described in Example 7; oxalate salt: m.p.180-182 C.

Elemental Analysisfor C22H32N20g:C% H% N%Found:Calculated:

58.258.4

6. 16.2

7.27 .1

EXAMPLE 94-Methoxycarbonyl-4-[(I-oxopropyl)phenylamino ]-1-piperidineacetic acid methyl ester 30A mixture of 4-methoxycarbonyl-4-[(I-oxopropy])-phenylamino]piperidine (200 mg, 0.68 mmol), preparedaccording to the procedure of P. G. H. Van Daele et aI,Arzneim.-Forsch. Drug Res. 1976, 26, 1521, methyl

bromoacetate (200 JoLI, 2.11 mmol), and potassium car- 35bonate (200 mg, 5.3 mmol), in acetonitrile (1.1 ml) isstirred at room temperature for 2 hours. The reactionmixture is concentrated and chromatographed on silicagel (95/5 CHCbIMeOH) to yield 4-methoxycarbonyl- 404-[(I-oxopropyl)phenylamino ]-l-piperidineacetic acid,methyl ester as an oil: 142mg, 57%. The oxalate salt ismade as described in Example 7; oxalate salt m.p.130-135 C.

EXAMPLE 103~[4-Methoxycarbonyl-4-[( l-oxopropyl)phenylamino]-I-piperidine]propanoic acid, methyl ester 55To a solution of 4-methoxycarbonyl-4-[(I-oxo-propyl)phenylamino]-piperidine (200 mg, 0.68 mmol) inacetonitrile (1.1 ml) is added methyl acrylate (124 JoLI,1.36mmol) at room temperature. The solution is stirred 60at SO C. for 2 hours, cooled to room temperature, andconcentrated to an oily residue. The residue is chro-matographed on silica gel (EtOAc) to give 3-[4-methox-ycarbonyl-4-[( l-oxopropyl)phenylamino ]-I-piperidine]-propanoic acid, methyl ester as an oil: 253 mg, 97%. 65The oxalate salt, which ismade as described in Example7 is recrystallized from methanol and 2-butanone; oxa-late salt: m.p. 170'-172' C.

26

Elemental Analysisfor C22H30N209:C% H% N%

Found:Calculated:

56.556.7

6. 06. 0

6. 56.4

EXAMPLE 11

Elemental Analysisfor C23H32N209:C% H% N%

Found:Calculated: 57.157.5 6. 66. 75,85. 8

EXAMPLE 12

Elemental Analysisfor C2o!H}4N209:C% N%H%

Found:Calculated: 58.058.3 7.07.05. 75. 7

EXAMPLE 133-[4-Methoxycarbonyl-4-[ (l-oxopropyljphenylamino]-

l-piperidinejpropanoic acid, trifluoroacetateThis compound is by following the procedure ofExample 5 except that an equivalent amount of 4-methoxycarbonyl-4-[ (l-oxopropyljphenylamino]-piperidine is substituted for the 4-[(l-oxopropyl)-

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27 5,019,583phenylamino]-piperidine used therein; m.p. 189-190C.

Elemental Analysis for C2IH2ZN20,F3:C% H% N%

Found:Calculated: 53.052.9 5.75.7 5.95.9

EXAMPLE 143-[4-Methoxycarbonyl-4-[ (l-oxopropyl)phenylamino]-I-piperidine]-propanoic acid, methoxymethyl esterA solution of 4-methoxycarbonyl-4-[(I-oxopropyl)- 15phenylamino]piperidine (200 mg, 0.69 mmol) and me-thoxymethyl acrylate (120 mg, 1.03 mmol) in acetoni-trile (0.7 ml) is stirred at room temperature for fifteenhours. The solution is diluted with I:1 water and ethylacetate and the aqueous phase extracted with ethyl 20

acetate (2X). The combined organics are washed withbrine, dried over sodium sulfate and concentrated. Theresidue is chromatographed on silica gel (EtOAc) togive 3-[4-methoxycarbonyl-4-[( l-oxopropyl)-phenylamino j-l-piperidine ]propanoic acid, methox- 25ymethyl ester as an oil: 160mg, 57%. The oxalate salt ismade as described in Example 7; oxalate salt: m.p.141-143 C.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 3 0Elemental Analysis for C2lH uN 20 10:

C% H% N%Found:Calculated: 55.455.6 6.56.5 5.55.6

EXAMPLE 15A. Vinyl 3-bromopropionate

This compound is prepared according to the proce- 40dure of R. L.Adelman, J. Org. Chem. 1949, 1057.To asolution of 3-bromo-propionic acid (1.0g, 6.54mmol) invinyl acetate (3.6 ml) is added copper (100 mg), mercu-ric acetate (104 mg) and concentrated sulphuric acid (1drop) in that order. The reaction is stirred at room 45temperature for two days. The heterogeneous mixtureis diluted with pentane (10 ml) and then filtered throughcelite to remove the solids. The filtrate is washed withwater (2X), saturated sodium bicarbonate (1X) andthen brine. The organics are dried over anbychrous 50sodium sulfate and concentrated to an oil, vinyl 3-bromopropionate: 760 mg, 65%.

B .3[4-Methoxycarbonyl-4-[ (l-oxopropyl)phenylamino]-1-piperidine]propanoic acid, vinyl ester 55A mixture of 4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino]piperidine (200 mg, 0.689 -mmol), vinyl3-bromopropionate (185mg, 1.03mmol), and potassiumcarbonate (214 mg, 1.55 mmol), in acetonitrile (I ml) is 60stirred at room temperature for two hours. The reactionmixture is diluted with I:I water and ethyl acetate and

extracted with ethyl acetate (2X). The combined or-ganics are washed with brine, dried over sodium sulfateand concentrated. The residue is chromatographed on 65silica gel (EtOAc) to yield 3-[4-methoxycarbonyl-4-[(I-oxopropyl)phenylamino ]-I-piperidine ]propanoic acid,vinyl ester as a white solid: 197mg, 74%, m.p. 70-72

28C. The oxalate salt is made as described in Example 7;oxalate salt: m.p. 156-158 C.

5 Elemental Analysis for C23H30N209:C% H% N%Found:Calculated: 57.657.7 5.95.96.46.3

10 EXAMPLE 162-[4-Methoxycarbonyl-4-[ (I-oxopropyl)phenylamino]-I-piperidine ]-ethyl acetateA mixture of 4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino]piperidine (300 mg, 1.0 mmol), 2-bromo-ethyl acetate (172 mg, 1.0 mmol), potassium carbonate(79 mg, 2.0 mmol), sodium iodide (154 mg, 1.0 mmol)and acetonitrile (1.0ml) is stirred at 65 C. for 12hours,cooled to room temperature, and filtered. The filtrate is

concentrated to an oily residue which is chromato-graphed on silica gel (EtOAc) to yield 2-[4-methoxycar-bonyl-4-[(I-oxopropyl)phenylamino ]-I-piperidine ]ethylacetate as a yellow oil: 300 mg, 77%. The oxalate salt ismade as described in Example 7; oxalate salt: m.p,191-193 C.Elemental Analysis for C22HjON209:

C% H% N%Found:Calculated: 56.656.6 6.56.5 6.06.0

35 EXAMPLE 173-[4-[(1-0xopropyl)-2-fl uorophenylamino ]-1-piperidine]propanoic acid, methyl esterA mixture of 4-[(I-oxopropyl)-2-fluorophenylamino]-piperidine (200mg, 0.80mmol), methyl acrylate (0.1ml,1.12 mmol) and potassium carbonate (275 mg, 2.0mmol) in methanol (2ml) isstirred at room temperaturefor two hours. The reaction mixture is diluted with 1:1water and ethyl acetate. After extracting the aqueousphase with ethyl acetate (2X) the combined organicsare washed with brine, then dried over sodium sulfateand concentrated. The residue is chromatographed onsilica gel (EtOAc) to give 3-[4-[(I-oxopropyl)-2-fluoro-phenylamino]-I-piperidine]propanoic acid, methyl esteras an oil which solidifies upon standing: 176 mg, 65%.The oxalate salt is made as described in Example 7;oxalate salt: m.p. 183-184 C.

Elemental Analysis for C:wH17N207F:C% H% N%

Found:Calculated: 6.46.4 6.56.655.956.3

EXAMPLE 183-[(4-[I-Oxopropyl)-2-fluorophenylamino ]-1-

piperidine]propanoic acid, vinyl esterBy following the procedure in Example 15, exceptthat an equivalent amount of 4-[(I-oxopropyl)-2-fluoro-phenylamino]piperidine is substituted for the 4-metho~-ycarbonyl-4-[ (I-oxopropyl)phenylamino ]-piperidineused therein and the reaction mixture is stirred for six-

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295,019,583 30

teen hours, there is obtained 3-[4-[(I-oxopropyl)-2-fluorophenylamino]-I-piperipine]propanoic acid vinylester as an oil: 66% yield. The oxalate salt is made asdescribed in Example 7; oxalate salt: m.p. 141-143 C.

S

Elemental Analysis for C2oH28N20S:C% H% N%

Found:Calculated:

56.656.6

6. 76. 7

6. 66. 6

Elemental Analysis for C2IH27N2(}zF:C% H% N% EXAMPLE 2110 3-[4-[(2-Methoxy-l-oxoethyl)-2-fluorophenylamino ]-1-piperidine]propanoic acid methyl ester

A solution of 4-[(2-methoxy-l-oxoethyl)-2-fluoro-phenylamino]piperidine (250 mg, 0.94 mmol), methyl15 acrylate (170 ILl, 1.88 mmol) and methanol (5.0 ml) is3-[4-[(1-0xopropyl)-2-fluorophenylamino]-I- stirred at room temperature for 24 hours. The reactionpiperidine]propanoic acid, 3-butenyl ester solution is concentrated to an oily residue and chro-A I' f 3 [4-[(1 I) henvlami ] 1 matographed on silica gel (EtOAc) to yield 3-[4-[(2-. . S ? ution 0 . - . -ox?propy p eny ammo - - methoxy-l-oxoethyl)-2-fluorophenylamino]-I-piperidinejpropanoic acid, tnfluoroacetate (370 mg, piperidine]propanoic acid methyl ester as an oil: 2020.848 mmol), m.p. 139.5"-141 C., is prepared in an 20 mg,61%.TheoxalatesaltismadeasdescribedinExam-analogous manner in which 3-[4-[(I-oxopropyl)- ple 7 oxalate salt: m.p. 186-188 C.phenylamino]-I-piperidine]propanoic acid, trifluoroae- 'tate isdescribed in example 5, is dissolved in a 1Mphos-

phate buffer solution (0.5M Na2HP04 and 0.5M Na2H- 25P04) and stirred for ten minutes. The solution is thendiluted with a 3/1 mixture of chloroform/isopropanoland extracted (5X). The combined organics are driedover sodium sulfate and concentrated to the free base:215 mg, 79% yield. A solution of 3-[4-[(I-oxopropyl)-2- 30fluorophenyl-amino ]-I-piperidine]propanoic acid (185mg, 0.574 mmol) in chloroform (5 ml) is added 0-3- []-Cis-3-[3-methyl-4-(I-oxopropyl)phenylamino]-I-butenyl-N,N-diisopropylpseudo urea (570 mg, 2.87 piperidine]propanoic acid, methyl estermmol), prepared using the procedure given in L. J. A solution of ()-cis-3-methyl-4-phenylaminopiperi-Mathias, Synthesis, 1979, 561. The solution is refluxed 35 dine (750 mg, 3.94 mmol), prepared according to thefor 24 hours, cooled, and concentrated. The residue is procedure ofW. F. M. Van Bever et aI., J. Med. Chern.chromatographed on silica gel (lIl hexaneslEtOAc) to 1974, 17, 1047,methyl acrylate (710 ILl, 7.88 mmol), andgive 3-[4-(I-oxopropyl)-2-fluorophenylamino-l- methanol (2.5 ml) is stirred at room temperature for 30piperidine]propanoic acid, 3-butenyl ester as an oil: 120 40 minutes. The resultant solution is concentrated to anmg, 56%. The oxalate salt is made as described in exam- oily residue which is chromatographed on silica gelple 7; oxalate salt: m.p. 165.5-166.5 C.; (EtOAc) to yield ()-cis-3-(3-methyl-4-phenylamino-l-piperidine)propanoic acid, methyl ester as an oil: 787mg,72%.45 A solution of ()-cis-3-(3-methyl-4-phenylamino-lpiperidinej-propanoic acid, methyl ester (500 mg, 1.8mmol), propionyl chloride (785 ILl, 9.0 mmol), and 4-dimethylaminopyridine (320 mg, 2.63 mmol) in acetoni-

trile (10 ml) is stirred and refluxed for 30 minutes. Thes o resultant solution is cooled to room temperature anddiluted with cold saturated ethyl acetate (2X25 ml) and3-[4-[(2-Methoxy-l-oxoethyl)phenylamino]-I- the organic phase dried over magnesium sulfate andpiperidine]propanoic acid, methyl ester concentrated to an oily residue which is chromato-. I graphed on silica gel (EtOAc) to give ()-cis-3-[3-A S?lutl~n .. of 4-[(2-methoxy-I-oxoethy)- S S methyl-4-[(3-oxopropyl)phenylamino]-I-piperidine]-phenylammo~plpendme (200 mg, 0.805 mmol), pre- propanoic acid, methyl ester as an oil: 392 mg, 65%.pared according to the procedures of B. S. Huang et al, The hydrochloride salt is made by dissolving the freeU.S. Pat. No. 4,584,303, and .met~yl acrylate (94 ILl, 1.05 base in toluene, saturating the solution with dry hydro-mmol), in methanol (I ml) IS st~ed at ~oo~ tempera- gen chloride and concentrating to a solid. The solid isture for four hours. The reaction solution IS concen- 60 then recrystallized from ethyl acetate' hydrochloridetrated to a residue which is chromatographed on silica salt: m.p. 180-187 C. 'gel (95/5 CHCbIMeOH) to give the free base, 3-[4-[(2-methoxy-I-oxoethyl)phenylamino j-l-piperidine]-propanoic acid, methyl ester, as an oil: 260mg, 97%. Anequimolar amount of oxalic acid in ether is added to a 65 C _ % _ o H _ % _ o N _ % _ o _ _solution of the free base in ether. The gummy precipi-tate is triturated with ethyl acetate to give the oxalatesalt as a white solid; oxalate salt: m.p. 188-190 C.

EXAMPLE 19

Found: 57.657.5

6. 26. 2

6.46.4Calculated:

Elemental Analysis for C2oH27N20SF:C% H% N%

Found: 54.354.3

6.16. 2

6.46.3Calculated:

EXAMPLE 22

C% H% N%Found:Calculated:

58.8 6.86. 7

6.06.059.2

EXAMPLE 20

Found:Calculated: 61.561.9 7. 97. 97 .97. 6

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315,019,583 32

EXAMPLE 23Anal Calcd. for C23H32N207:

C% H% N%[ ]-Cis-3-[3-methyl-4-( l-oxopropyl)phenylamino ]-1-piperidine]propanoic acid, methoxymethyl ester 5A mixture of ()-cis-3-methyl-4-phenylaminopiperi-dine (350 mg, 1.8 mmol), 2-bromopropanoic acid me-thoxymethyl ester (450 mg, 2.28 mmol), potassium car-bonate (350 mg, 2.54 mmol), 4-dimethyl-aminopyridine(50 mg, 0.41 mmol), and acetonitrile (3 ml) is stirred at 10room temperature for 24 hours and diluted with satu-rated sodium bicarbonate (20 ml). The resultant mixtureis extracted with ethyl acetate (2X20 ml) and the or- A mixture of ()-cis-3-methyl-4-phenylaminopiperi-ganic phases combined, dried over magnesium sulfate, dine (300 mg, 1.57 mmol), bromoethyl acetate (865 ILl,and concentrated to an oily residue which is chromato- 15 789 mmol), 4-dimethyl-aminopyridine (100 mg, 0.82graphed on silica gel (EtOAc) to give ()-cis-3-(3- mmol), potassium carbonate (250 mg, 1.81 mmol), andmethyl-4-phenylamino-1-piperidine)propanoic acid, acetonitrile (4 ml) is stirred at room temperature for 6methoxymethyl ester as an oil: 371 mg; 66%. hours. The resultant mixture is diluted with water (25A solution of ()-cis-3-(3-methyl-4-phenylamino-1- ml) and extracted with ethyl acetate (3X25 ml). Thepiperidine)propanoic acid, methoxymethyl ester (350 20 combined organic phases are dried over magnesiummg, 1.14mmol), 4-dimethyl-aminopyridine (250 mg, 2.0 sulfate and concentrated to an oily residue which ismmol), propionyl chloride (1.0 ml, 11.5 mmol), and chromatographed on silica gel (3/1 EtOAc!Hex) toacetonitrile (10 ml) is stirred and refluxed for 30minutes give ()-cis-2-(3-methyl-4-phenylamino-1-and cooled to room temperature. The reaction solution piperidine)ethyl acetate as an oil: 402 mg, 92%.is diluted with cold saturated sodium carbonate solution 25 A solution of ()-cis-2-(3-methyl-4-phenylamino-1-(25 ml) and extracted with ethyl acetate (3X25 ml). The piperidine)ethyl acetate (400 mg, 1.45mmol), propionylorganic extracts are combined, dried over magnesium chloride (1.25 ml, 14.5mmol), 4-dimethylaminopyridinesulfate and concentrated to an oily residue which is (353 mg, 2.89 mmol), and acetonitrile (10 ml) is stirredchromatographed on silica gel (1/1 EtOAc!Hex) to and refluxed for 30 minutes. The resultant solution isgive ()-cis-3-[3-methyl-4-[(1-oxopropyl)- 30 cooled to room temperature and diluted with a coldphenylamino]-l-piperidine]propanoic acid, methox- saturated sodium carbonate solution (3X25 ml) and theymethyl ester as an oil: 253 mg, 60%. The oxalate salt organic phase over magnesium sulfate and concentratedhemihydrate is made as described in Example 7; oxalate to an oily residue which is chromatographed on silicasalt hemihydrate: m.p. 83_92 C. gel (EtOAc) to give ()-cis-2-[3-methyl-4-[(1-oxo-

35 propyl)phenylamino ]-l-piperidine ]ethyl acetate as an-------------------- oil: 389 mg, 81%. The oxalate salt is made as describedElemental Analysis for C22H32N20g.0.5 H20: . E am I 7 oxalate salt m p 148 150CIn x pe; : .. - .C% H% N%

Found:Calculated:

6 1 . 66 1 . 6

7.27.2 6.36.3

EXAMPLE 25[ ]-Cis-2-[3-methyl-4-[(l-oxopropyl)phenylamino ]-1-piperidine]ethyl acetate

Found: 57.4 7.2 6.2___ ~C~al~cu_la~te~d~: 57_.3 7_.2 6 _ . _ I ~ Elemental Analysis for C2IH30N207:C% H% N%

EXAMPLE 24 Found:Calculated: 59.659.7 7.37.2 6 . 66 . 6[ ]-Cis-3-[3-methyl-4-(1-oxopropyl)phenylamino ]-1-piperidine]propanoic acid, allyl esterA solution of ( )-cis-3-methyl-4-phenylamino piperi-dine (400 mg, 2.1 mmol), allyl acrylate (471 mg, 4.2 (- )-Cis-3S-methyl-4R-(N-1R-methylbenzylamido)-

mmol), and acetonitrile (5ml) is stirred at room temper- phenylamino]-1-(N-1R-methylbenzylamido)piperidineature for 4 hours and concentrated to an oily residue 50 andwhich is chromatographed on silica gel (EtOAc) to (- )-cis-3R-methyl-4S-(N-1R-methylbenzylamido)-give ( )-cis-3-[3-methyl-4-phenylamino-1-piperidine]- phenylamino ]-l-(N -1R-methylbenzylamido )piperidinepropanoic acid, allyl ester as an oil: 405 mg; 64%. A solution of ()-cis-3-methyl-4-phenylaminopiperi-A solution of ()-cis-3-(3-methyl-4-phenylamino-1- dine (2.0 gm, 10.5 mmol), 4-dimethylaminopyridinepiperidine)propanoic acid, allyl ester (400 mg, 1.32 55 (250 mg, 2.0 mmol), and R-(+)-a-methylbenzyl isocya-mmol), 4-dimethylaminopyridine (250 mg, 2.0 mmol), nate (4.0 gm, 27.2 mmol) is stirred at 120for 6 hours.propionyl chloride (1.15 ml, 13.2 mmol), and acetoni- The resultant solution is cooled to room temperaturetrile (10 ml) is stirred and refluxed for 30 minutes and and chromatographed on silica gel (1/1 EtOAc!Hex) tocooled to room temperature. The reaction solution is give two diastereomers. The less polar of the two isdiluted with a solution of cold saturated sodium carbon- 60 recrystallized from EtOAc to give (- )-cis-3S-methyl-ate (25 ml) and extracted with ethyl acetate (3X25 ml). 4R-[(N-1R-methylbenzylamido)phenylamino]-1-(N-1R-The organic extracts are combined, dried over magne- methylbenzylamido)piperidine as a solid: 1.5 gm; m.p.sium sulfate, and concentrated to an oily residue which 172_173C.; [a]d5= -114.4 (c 1.5, MeOH).is chromatographed on silica gel (1/1 EtOAc!Hex) togive ()-cis-3-[3-methyl-4-[(1-oxopropyl)- 65 _phenylamino]-l-piperidine]propanoic acid, allyl ester asan oil: 335 mg: 74%. The oxalate salt is made as de-scribed in Example 7; oxalate salt: m.p. 150-152 C.

45 EXAMPLE 26

Elemental Analysis for ClpH36N302:C% H% N%

Found: 74.4 7.5 1 1 . 6

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and T. R. Burke, Jr. et al., J. Med. Chem. 1986,29, 1087,benzylchloroformate (1 ml, 6.98 mmol), sodium bicar-bonate (1 g, 11.8 mmol), ether (5 ml), ethyl acetate (5ml), and water (to ml) is vigorously stirred at room__ Cal_c_ul_at_ed_: 74_.4 7_.S II_.6___ 5 temperature for one hour. The organic layer is sepa-

rated, washed with 2N NaOH (2X5 ml), dried overmagnesium sulfate, and concentrated to an oily residuewhich is chromatographed on silica gel (EtOAc) togive trans-N-benzyloxycarbonyl-3-methyl-4-phenyl-10 aminopiperidine as an oil: 1.82 g; 91%, followed by lessthan 5% of cis-N-benzyloxycarbonyl-3-methyl-4-phenylaminopiperidine.To a solution of trans-N-benzyloxycarbonyl-3-meth-[- J-Cis-3-3R-methyl-4S-(l-oxopropyl)phenylaminoJ-l- yl-4-phenylaminopiperidine (1.5 g, 4.6 mmol), 4-dime-piperidine]propanoic acid, methyl ester 15 thylaminopyridine (375 mg, 3.1 mmol), and acetonitrileA suspension of (_ )-cis-3R-methyl-4S-(N-IR-meth- (10 ml) is added propionyl chloride (3.6 ml, 41 mmol).ylbenzyl-amido)phenylamino]-1-(N-1R-methylben- The solution is stirred and refluxed for 30 minutes,zylamido)piperidine (1.75 gm, 3.6 mmol) in 48% hydro- cooled to ~oom tem~rature, and diluted with a satu-bromic acid (40 ml) is stirred and refluxed for 24 hours. rated s_olutlo~of sodium ca:bonate (30 ml). The resul-

It is cooled and concentrated to an oil which is dis- 20 tant mixture 1S.extracted with .ethyl a~etate (2X30 ml)solved in water (20 ml) and extracted with ether (2X50 a~d the orgaruc phases combined, dt;ed o~er mag~e-ml). The aqueous phase is basified to pH 10.5 with 5N ~lum sulfate, and concent~~ted to an oily residue Wh1ChNaOH and extracted with ethyl acetate (2X25 ml). The 1S.chromatographed on silica gel (1/1 EtOAcIHex) toethyl acetate extracts are combined, dried over magne- 25 grve trans-N-tx:nzYI~xY~ar:bonYI-3-m~~hYI-4-[(1-oxo-sium sulfate, and concentrated to give a solid which is propyl~-phenylammo]p1pendme as an oil. 1.6 g, 91%.recrystallized from EtOAcIHex giving (+)-cis-3R- A mixture of trans-N-~enzyl?xy~~rbonyl-3-methyl-4-methyl-4S-phenylaminopiperidine as a solid: 610 mg; [(I-oxopropyl)phenylammoJ-P1pendme (1.5 g, 3.9489%; m.p. 95-97 C.; [a]dS=7S (c 2.5, MeOH). mml),1?% Pd-C ~200 mg), methanol (20 ~), andA solution of (+ )-cis-3R-methyl-4S- acetic acid (20 ml) IS hyd~oge.nated at 50 pSI for 24phenylaminopiperidine (500 mg, 2.63 mmol), methyl 30 hours. !he resultant suspension ISfiltered throug~ a be?acrylate (473 ~l 5.26 mmol), and methanol (10 ml) is o~ Celite ~d the filtrate concentrated ",The residue ISstirred at room temperature for 6 hours and concen- d~uted with ethyl acetate (50 ml), b~lfied to. pH 11trated to an oily residue which is chromatographed on WIth 2N .NaOH and shak~n. The orgaruc layer ISsepa- .silica gel (EtOAc) to give (+ )-cis-3-(3R-methyl-4S- rated, dned over magnesium sulfate, and concent~atedphenylamino-l-piperidine)propanoic acid, methyl ester 35 t~ .. trans-3-methyl-4-(I-oxopropyl)-phenylammo]-as an oil: 623mg; 86%; (a]d5= +25.7 (c 1.85,MeOH). piperidine: 720 mg; 96%.A solution of (+ )-cis-3-(3R-methyl-4S-phenylamino- EXAMPLE 29I-piperidine)propanoic acid, methyl ester (600 mg, 2.17mmol), 4-dimethylaminopyridine (250 mg, 2.05 mmol), 40propionyl chloride (1.89 ml, 21.7 mmol), and acetoni-trile (10 ml) is stirred and refluxed for 30 minutes andcooled to room temperature. It is diluted with coldsaturated sodium carbonate (50 ml) and extracted withethyl acetate (3X 25 ml). The extracts are dried over 45magnesium sulfate and concentrated to an oily residuewhich is chromatographed on silica gel (1/1 EtOAc/-Hex) to give (- )-cis-3-(3R-methyl-4S-(I-oxopropyl)-phenyl-aminoJ-1-piperidine]propanoic acid, methyl

ester as an oil: 453 mg; 63%; (a]d5= -3.2" (c 1.5, 50MeOH). The hydrochloride salt is made as described inExample 22; hydrochloride salt: m.p 151-152 C.;

33 5,019,583-continued

Elemental Analysis for CJQH36N302:C% N%H%

The more polar diastereomer is recrystallized fromEtOAcIHex to give (- )-cis-3R-methyl-4S-(N-IR-methyl-benzylamido )phenylamino ]-1-(N-1R-methyl-benzylamido)-piperidine as a solid: 1.8 gm; m.p.lOso-106 C.; [aJd5=-63.6 (c 1.8,MeOH).EXAMPLE 27

Elemental Analysis for C19H29N203CI:C% H% N%

Found:Calculated: 62.261.9 7.87.67. 97. 9

EXAMPLE 28Trans-3-methyl-4-[(l-oxopropyl)phenylamino]-piperi-dineA mixture of cis and trans-3-methyl-4-phenylaminopiperidine (1.2 g, 6.35 mmol) (predomi- 65nantly trans due to isolation of the pure cis isomer bycrystallization), prepared according to the procedure ofw . F. M. Van Berer et al., J. Med. Chem. 1974, 17, 1047

34

Trans-3-(3-methyl-4-[(1-oxopropyl)phenylamino]-piperidine]propanoic acid, methyl esterA solution of trans-3-methyl-4-[(1-oxopropyl)-phenylamino]-piperidine (250 mg, 1 mmol), methyl ac-rylate (182 ~l 2 mmol), and methanol (2 ml) is stirred for24 hours at room temperature, concentrated to an oilyresidue, and chromatographed on silica gel (EtOAc) togive trans-3-(3-methyl-4-(l-oxopropyl)phenylamino]-piperidine]propanoic acid, methyl ester as an oil: 300mg: 89%. The monohydrate oxalate salt is made asdescribed in Example 7; oxalate salt monohydrate: m.p.125-130 C.

Elemental Analysis for C2IH32N208:C% H% N%55 -------------------------------------Found: 57.4 7.0 6.4Calculated: 57.3 7.3 6.4

60 EXAMPLE 30Trans-3-(3-methyl-4-[(l-oxopropyl)phenylamino ]-piperidine]propanoic acid, ethoxymethyl esterA solution of trans-3-methyl-4-(1-oxopropyl)-phenylamino]-piperidine (300 mg, 1.2 mmol), ethox-ymethyl acrylate (350 mg, 2.4 mmol), and acetonitrile(10 ml) is stirred at room temperature for 24 hours,concentrated to an oily residue, and chromatographedon silica gel (EtOAc) to give trans-3-[3-methyl-4-(1-

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355,019,583 36and recrystallized from ether and hexanes to give cis-l-methoxycarbonyl-3-methyl-4-[(I-oxopropyl)-2-fluoro-phenylamino]piperidine as a solid: 3.2 g; 20%; m.p.128-130 C. The mother liquors are combined and5 concentrated to give a mixture of cis and trans isomersalong with some other impurities.

A suspension of cis-I-methoxycarbonyl-3-methyl-4-[(I-oxo-propyl)-2-fluorophenylamino]-piperidine (3.2 g,9.89 mmol) in 48% aqueous HBr (20 ml) is refluxed for10 two hours. Upon heating the mixture dissolution oc-curs. The solution is cooled to 0 C. and 5N NaOH isadded until the pH is between II and 12. The aqueousphase is extracted with methylene chloride (5X) andthe combined organics dried over sodium sulfate and15 concentrated to give cis-3-methyl-4-(2-fluoro-phenylamino)-piperidine as an oil: 2.0 g; 97%.To a rapidly stirred mixture of benzylchloroformate(0.39 ml, 2.76 mmol) and sodium bicarbonate (284 mg,20 3.6 mmol) in water (4 ml) and ether (4 ml) is addedcis-3-methyl-4-(2-fluoro-phenylamino)-piperidine (500mg, 2.4 mmol) as a solution in ether (2 ml). The mixtureisstirred for one hour at ambient temperature, the layersare separated, and the organics washed with 2N NaOH25 (2X) and brine (IX). The organics are dried over so-EXAMPLE 32 dium sulfate and concentrated to give cis-l-benzylox-

Trans-2-[3-methyl-4-[ (l-oxopropyl)phenylamino]- ycarbonyl-3-methyl -4-(2-fluorophenylamino j-piperi-piperidine]ethyl acetate dine as an oil: 740 rng; 90%.To a solution of cis-I-benzyloxycarbonyl-3-methyl-4-A mixture of trans-3-methyl-4-[(I-oxopropyl)- 30 (2-fluoro-phenylamino)-piperidine (740 mg, 2.16 mmol)phenylamino]piperidine (250 mg, 1 mmol), 2-bromo- and 4-dimethylaminopyridine (395 mg, 3.24 mmol) inethyl acetate (338 mg, 2.0 mmol), potassium carbonate acetonitrile (10 ml) is added propionyl chloride (0.38(300 mg, 2.2 mmol), sodium iodide (50 mg, 0.3 mmol), ml, 4.32 mmo!). The reaction is heated to 50 C. for tenand acetonitrile is stirred at room temperature for 16 hours. The mixture is concentrated and the residuehours. The resultant mixture is diluted with a saturated 35 dissolved in ethyl acetate and water. The organic phasesolution of sodium bicarbonate (25 ml) and extracted is washed with saturated sodium bicarbonate (2X), 1Mwith ~thyl ac~tate (2X25 ml)..The organic extracts are phosphoric acid (1X), and brine (I X). The organics arecombined, dn.ed ov~r magn~slU~ sulfate, and concen- dried over sodium sulfate and concentrated to give puret:~ted to an Oily resldu~ which IS chromatographed on cis-l-benzyloxycarbonyl-3-methyl-4-[(I-oxopropyl)-2-silica gel (EtOAc) to give trans-2-[3-methyl-4-[(I-oxo- 40 fl henvlami . idi 1 769 89Of.I) 1]] . uorop eny ammo-pipen me as an 01: mg; -/0.propy pheny ammo piperidine ethyl acetate as an Oil: A t f 1 bib 13th I 4300 mg; 89%. The oxalate salt is made as described in mIXure 0 CIS- - enzy ox~car ~ny ~ ~me y - -E I 7 I tit 149-150 C [(I-oxopropyl)-2-fluorophenylammo]-plpendme (576xamp e ,oxa a e sa . m.p. . mg, 1.45mmol) and 10% Pd-C (100 mg) in methanol (25

ml) and acetic acid (5 ml) is hydrogenated at 50 psi for45 five hours. The reaction mixture is filtered throughcelite and the filtrate is concentrated. The residue isdiluted with ethyl acetate, basified to pH 11 with 2NNaOH and shaken. The separated organics are driedover sodium sulfate and concentrated to give cis-3-50 methyl-4-[(I-oxopropyl)-2-fluorophenylamino]piperi-dine as an oil: 333 mg: 87%.

EXAMPLE 31

oxopropyl)phenylamino ]piperidine [propanoic acid,ethoxymethyl ester as an oil: 300 mg; 65%. The oxalatesalt ismade as described in Example 7;oxalate salt: m.p.115-116 C.

Trans-3-[3-methyl-4-[ (l-oxopropyl)phenylamino]-piperidine]propanoic acid, allyl esterA solution of trans-3-methyl-4-[(I-oxopropyl)-phenylamino]piperidine (300 mg, 1.2mmol), allyl acry-late (272 mg, 2.4 mmol) is stirred at room temperaturefor 16 hours and concentrated to an oily residue whichis chromatographed on silica gel (EtOAc) to give trans-3-[3-methyl-4-[(l-oxopropyl)phenylamino ]piperidine]-propanoic acid, allyl ester as an oil: 300 mg; 69%. Theoxalate salt is made as described in Example 7: oxalatesalt: m.p. 147-148 C.

Elemental Analysis for C21HJ2N207:C% H% N%Found:Calculated: 61.761.6 7.27.2 6.26.2

Elemental Analysis for C21H10N207:C% H% N%

Found..Calculated: 59.659.7 7.27.2 6.66. 6

EXAMPLE 33( )-Cis-3-methyl-4-[ (l-oxopropyl)-2- fluoro-pheny lamino]piperidine

A solution of I-methoxycarbonyl-3-methyl-4-(2- 55fluorophenyl-amino)-piperidine (12.95 g, 48.6 mmol),prepared according to the procedure of W. F. M. VanBerer et al., J. Med. Chern. 1974, 17, 1047 and T. R.Burke, Jr. et al., J. Med. Chern. 1986, 29, 1087, exceptthat 2-fluoroaniIine was substituted for aniline, and pro- 60pionic anhydride (12.5 ml, 7.2 mmol) is refluxed forfifteen hours. The cooled solution is diluted with ethylacetate and washed with 2N sodium hydroxide (2X),saturated sodium bicarbonate (5X), 1M phosphoricacid (1X) and brine (1X). The organics are dried over 65sodium sulfate and then concentrated. The residue isdissolved in ether and hexanes and cooled to X 10 C.for fifteen hours. The solid that precipitated is collected

EXAMPLE 34( )-Cis-3-[3-methyl-4-( l-oxopropyl)-2-fluoro-phenylamino ]-I-piperidine ]propionic acid, methyl ester

A solution of ()-cis-3-methyl-4-[(I-oxopropyl)-2fluorophenylamino]-piperidine (200 mg, 0.757 mmol)and methyl acrylate (0.1 ml, 1.13mmol) in acetonitrile(2 ml) is stirred at room temperature for twelve hours.The solution is concentrated and the residue chromato-graphed on silica gel (2/1 EtOAc/Hex) to yield( )-cis-3-[3-methyl-4-[(l-oxopropyl)-2-fluoro-phenylamino j-l-piperidine ]propanoic acid, methyl esteras an oil: 44 mg, 17% yield. The hydrochloride salt isprepared by bubbling gaseous HCI through a toluenesolution of the free base and concentrating to a whitesolid; hydrochloride salt: m.p. 177-178 c.;

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Elemental Analysis for C2IH29N207F.0.5H20:Elemental Analysis for C23H33N20gF: C % H % N %C % H % N % 30 --------_;;,~---__;-------________ _;:;.~ __ _;;,~ -:-:-___ Found: 55.7 6.6 6.256.6 6.8 6.1 Calculated: 56.1 6.7 6.257.0 6.9 5.8

( )-Cis-3-[3-methyl-4-[(l-oxopropyl)- 2-fluoro-phenylamino-l-piperidine]propanoic acid, allyl esterA solution of ()-cis-3-methyl-4-[(I-oxopropyl)-2-

fluorophenylaminoj-piperidine (100 mg, 0.378 mmol) 40 Ingredientsand allyl acrylate (90 ml, 0.757 mmol) in acetonitrile (I -":':':!!:"::;:;';~-----------I-m-g--3-[4-Methoxycarbonyl-4-[(I-(oxopropyl)ml) isstirred at room temperature for sixteen hours. The phenylaminoJ-1-piperidineJ-solvent is removed and the residue chromatographed propanoic acid, methyl ester,on silica gel (111 EtOAcIHex) to give ()-cis-3-[3- HCI saltmethyl-4-(I-oxopropyl)-2-fluorophenylamino]-I- 45 Isotonic salinepiperidine]propanoic acid, allyl ester as an oil: 76 mg,53%. The oxalate salt monohydrate is made by dis-solving the free base in ethyl acetate and then adding anethereal solution of oxalic acid. The white solid thatprecipitates is collected and washed with ether and 50ethyl acetate; oxalate salt monohydrate: m.p. 96-98C.;

37 5,019,583

Elemental Analysis for CI9H2SN203CIF:C% H% N%

Found:Calculated: 7.37.3 7.27.259.059.0

EXAMPLE 35()-Cis-3-[3-methyl-4-[(I-oxopropyl)-2-fluoro- 10phenylamino ]-l-piperidine ]propanoic acid,ethoxymethyl ester

A solution of ()-cis-3-methyl4.[(I-oxopropyl)-2-fluorophenylamino]-piperidine (70 mg, 0.265 mmol) and 15ethoxymethyl acrylate (73 tJ.1,0.265 mmol) in acetoni-trile (I m1) is stirred at room temperature for eighteenhours. The solution is concentrated and the residuechromatographed on silica gel (EtOAc) to give ()-cis-3-[3-methyl-4-[(I-oxopropyl)-2-fluorophenylamino ]-1- 20piperidine]propanoic acid, ethoxymethyl ester as an oil:84mg, 80% yield. The oxalate salt ismade by dissolvingthe free base in ethyl acetate and adding an etherealsolution of oxalic acid. The gum that precipitates isredissolved in hot ethyl acetate and recrystallizes to 25give a white solid upon cooling; oxalate salt: m.p.96-97 C.;

Found:Calculated:

EXAMPLE 36

38-continued

Elemental Analysis for C23H33N20gF:C% H% N%

5 Calculated: 57.0 6.9 5.8

EXAMPLE 37()-Cis-2-[3-methyl-4-[(I-oxopropyl)-2-fluoro-phenylamino ]-I-piperidine]ethyl acetate

A suspension of ()-cis-3-methyl-4-[(I-oxopropyl)-2-fluorophenylaminoj-piperidine (250 mg, 0.946 mmol),2-bromoethyl acetate (0.16 ml, 1.42 mmol), potassiumcarbonate (260 mg, 1.89 mmol) and a catalytic amountof sodium iodide in acetonitrile (3 ml) is stirred at 45 C.for ten hours. The mixture is diluted with water andethyl acetate. The aqueous is extracted with ethyl ace-tate (2X) and the combined organics washed with brine(I X), then dried over sodium sulfate and concentrated.The residue is chromatographed on silica gel (EtOAc)to give ()-cis-2-[3-methyl-4-[(I-oxopropyl)-2-fluoro-phenylamino ]-I-piperidine ]ethyl acetate as an oil: 241mg, 73%. The oxalate salt hemihydrate is made as de-scribed in Example 7; oxalate salt hemihydrate: m.p.118-127 C.;

35EXAMPLE 38

A pharmaceutical composition for parenteral or in-travenous analgesic administration can be preparedfrom the following ingredients:Amount

I liter

Other compounds on of course can be substituted forthe foregoing specific compound, utilizing a relativeamount of such other compounds in the compositiondepending on the effective analgesic activity of theparticular compound.

EXAMPLE 39Elemental Anai:r:sisfor C~lHllN~OaF: The compounds of formula (I) listed in Table III are5 5 prepared by following the procedures described hereinC% H% N% using equivalent amounts of appropriate starting materi-Found: 57.3 6.7 5.8 also

TABLE IIIX R RI R2 Ar salt m.p. ("c.)

a. -(CH2hCOOMe Et H H 2,4-di-F-Ph oxalate 177-178b. -(CH2hCOOnBu Et H H 2,4-di-F-Ph oxalate 181-182c. -(CH2hCOOtBu Et H H 2-F-Ph oxalate 160-162d. -(CH2hCOOMe Et H H 2-MeO-Ph oxalate 139-140e. -(CH2hCOO(CH2hOMe Et H H Ph oxalate 164-165f. -(CH2hCOO(CH2hOEt Et H' H Ph oxalate 140-141g. -(CH2hCOOCH20Me Et H H 2-F-Ph oxalate 131-133h. -CH(CH3)CH2COOMe Et H H Ph oxalate 148-f49.5i. -CH2CH(CH3)COOMe Et H H Ph oxalate 146-148j. -(CH2hCOOMe Me H H 2-Me-Ph oxalate

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5,019,583 4039TABLE III-continued

X R Rl R2 Ar salt m.p. rc.)k. -(CH2hCOOCH20Me Et H H 2-Et-Ph oxalateI. -(CH2hCOOMe Me MeO-CO- H Ph HCIm . -(CH2hCOOMe Me MeO-CH2- H Ph HCIn. -(CH2hCOOMe Me H cis()-Me4-CF3-Ph oxalateo. -(CH2hCOOMe Et H cis()-Me2-CI-Ph oxalate

EXAMPLES 40-53Following the procedure of Example 10 and substi-tuting an equivalent amound of the appropriate alkylacrylate for the methyl acrylate of Example 10, thefollowing compounds of formula (I) are obtained withmelting points for the oxalate salt being indicated be- 15low:40. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino ]-I-piperidine ]propanoic acid, ethylester m.p. 166-167" C.41. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)- 20phenylamino ]-I-piperidine ]propanoic acid, propylester m.p. 169-170 C.42. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino [-l-piperidine ]propanoic acid, isopropylester m.p. 176-177 C.43. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino [-l-piperidine ]propanoic acid, n-butylester m.p. 153-154 C.44. 3-[4-methoxycarbonyl-4-[( l-oxopropyl)-phenylamino]-I-piperidine]propanoic acid, iso-butyl 30ester m.p. 177-178 C.45. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)-phenyl amino]-I-piperidine ]propanoic acid, sec-butylester m.p. 160-161 C.

46. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)- 35phenylamino j-l-piperidine ]propanoic acid, n-pentylester m.p. 141-142 C.47. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino ]-I-piperidine ]propanoic acid, 2-methyl-butyl ester m.p. 162"-163 C. 4048. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino ]-I-piperidine ]propanoic acid, isopentylester m.p. 148-149 C.49. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino ]-I-piperidine ]propanoic acid, neopentyl 45ester m.p. 157"-158 C.50. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino ]-I-piperidine ]propanoic acid, hexylester m.p. 141-142 C.51. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)- 50phenylamino]-I-piperidine]propanoic acid, heptylester m.p. 129-130 C.52. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino ]-I-piperidine ]propanoic acid, octylester m.p. 141-142" C. 5553. 3-[4-methoxycarbonyl-4-[(I-oxopropyl)-phenylamino ]-I-piperidine ]propanoic acid, tert-butylester m.p. 157-158 C.In the synthesis procedure of Examples 40-53, thealkyl acrylate starting material may be available com- 60mercially, may be synthesized by literature proceduresor may be synthesized by the following procedure,

substituting an equivalent amount of the appropriatealcohol for 3-methyl butanol:To a stirred solution of 3-methyl butanol (2.0 g, 22.6 65mmol) and acryloyl chloride (2.05 g, 22.6 mmol) indichloromethane (5 m I) at 0 C. is added dropwise tri-ethylamine (3.2 m I, 22.7 mmol). The solution is stirred

10 for 30 minutes at room temperature and then concen-trated to a residue. The residue is washed with hexanes(2X 10 ml) and the resultant combined organics areconcentrated and filtered through a plug of silica togive 3.0 g of 3-methylbutyl acrylate as an oil, 93% yield.Itwill be understood that the embodiments describedherein are merely exemplary and that a person skilled inthe art may make many variations and modificationswithout departing from the spirit and scope of the in-vention. All such modifications and variations are in-tended to be included within the scope of the invention

as defined in the appended claims.What is claimed is:1. A compound having the formula (I):25 (I)

whereinX is a member selected from the group consisting of:alkoxy-carbonyl-lower alkyl, lower alkyl-car-bonyloxy-lower alkyl, alkenyloxy-carbonyl-loweralkyl, and (CI_2)alkoxy-(CI_2)alkoxy-carbonyl-lower alkylAr is a member selected from the group consisting ofphenyl and mono- di- and tri-substituted phenyl,wherein each substituent is independently selectedfrom the group consisting of halo, lower alkyl,lower alkoxy and trifluoromethyl;R is a member selected from the group consisting oflower alkyl, and lower alkoxy-lower alkyl;R 1 is a member selected from the group consisting ofhydrogen, lower alkoxy-carbonyl, and methox-ymethyl; and

R2is a member selected from the group consisting ofhydrogen and methyl;and the diastereomeric and enantiomeric isomersthereof, and the pharmaceutically acceptable acid addi-tion salts of said compounds and isomers.2. The compound of claim 1 wherein X is alkoxy-car-bonyl-lower alkyl.3.The compound of claim 1wherein X islower alkyl-carbonyl-oxy-lower alkyl.4. The compound of claim 1wherein X is alkenyloxy-carbonyl-lower alkyl.5. The compound of claim 1 wherein X is (CI_2)al-kOXy-(CI_2)-alkoxy-carbonyl-lower alkyl.6. The compound of claim 1 wherein Ar is phenyl or2-fluorophenyl:7. The compound of claim 1 wherein R is ethyl.8. The compound of claim 1 wherein R! is methoxy-carbonyl.

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41 5,019,5839. The compound of claim 1, wherein said compoundis:5-[4-methoxycarbonyl-4-[( l-oxopropyl)phenylamino l-l-piperidinejpentanoic acid, methyl ester;2-[4-methoxycarbonyl-4-[( l-oxopropyl)phenylamino]- 5l-piperidinejethyl acetate;3-[4-[(l-oxopropyl)-2-fluorophenylamino ]-1-piperidine]propanoic acid, methyl ester; or3-[4-methoxycarbonyl-4-[(I-oxopropyl)phenylamino]-l-piperidinejpropanoic acid, vinyl ester,or pharmaceutically acceptable acid addition saltthereof.10. 3-[4-Methoxycarbonyl-4-[(I-oxopropyl)-phenylamino j-l-piperidine ]propanoic acid, alkyl ester,and the pharmaceutically acceptable acid addition salts 15thereof.11. The compound of claim 10, wherein in the alkylportion of the said alkyl ester, the carbon directly at-tached to the oxygen is a methylene or methyl group.12. The compound of claim 10, wherein said alkyl of 20said alkyl ester is of about 1 to 10 carbons.13. The compound of claim 10, wherein said alkylester is the methyl ester.14. A diastereomer or enantiomer of a compound as 25claimed in claim 1.15. A pharmaceutical analgesic composition compris-ing an effective analgesic amount of a compound havingthe formula (I):

wherein:X is a member selected from the group consisting of:alkoxy-carbonyl-lower alkyl, lower alkyl-car-bonyloxy-lower alkyl, alkenyloxy-carbonyl-loweralkyl, and (CI_2)alkoxy-(CI_2)alkoxy-carbonyl- 45lower alkyl;Ar is a member selected from the group consisting ofphenyl and mono-, di- and tri-substituted phenyl,wherein each substituent is independently selectedfrom the group consisting of