HU211916A9 - N-phenyl-n-(4-piperidinyl)amides useful as analgesics - Google Patents

Description

This application is a partial continuation of U.S. Patent Application Serial No. 07 / 313,311, filed February 15, 1989, which has already expired.

The present invention relates to N-phenyl-N- (4-piperidinyl) amides having valuable analgesic properties. A number of N-phenyl-N- (4-piperidinyl) amides are disclosed in numerous U.S. Patents Nos. 3,164,600, 3,998,834, 4,179,569, 4,584,303 and 4,167,574, for example. The analgesic compounds of the present invention are structurally different from the compounds of the prior art, particularly in the N-substituent of the piperidine ring, i.e., in the compounds of formula (I), as the substituent "Χ". In general, the compounds also differ in that the analgesic effect is relatively short, in the ultra-short to medium range, and is not inactivated by the liver. The present invention also provides certain novel synthetic intermediates for the preparation of compounds of formula (I).

The present invention relates to novel chemical compounds and pharmaceutical compositions containing them. In particular, the chemical compounds of the present invention are N-phenyl-N- (4-piperidinyl) amides of the formula (I) wherein X is alkoxycarbonyl (lower alkyl (preferred), (lower) alkyl). ) -carbonyloxy-lower alkyl, -alkenyloxycarbonyl-lower alkyl, or -C 1-2 alkoxy-C 1-2 alkoxy-carbonyl-lower alkyl )-group;

Ar is phenyl (preferred) or mono-, di- or tri-substituted phenyl, wherein the substituents are independently halogen, lower alkyl, lower alkoxy or trifluoromethyl;

R is lower alkyl, preferably ethyl, or (lower alkoxy) lower alkyl, preferably methoxymethyl;

R ¹ is hydrogen, (C ¹ -C 6) alkoxycarbonyl, preferably methoxycarbonyl or methoxymethyl; and

R ² is hydrogen or methyl, and the optically active and cis-trans isomers of the above compounds and the acid addition salts, preferably the pharmaceutically acceptable acid addition salts thereof.

A further object of the present invention is to provide certain novel acidic intermediates useful for the synthesis of certain compounds of formula (I). The above intermediates have the structure of formula (A) wherein X in the formula (1) attached to the nitrogen atom is replaced by _the group X _a for carboxy-lower alkyl.

In the above definitions, "low carbon means that such a moiety contains 1 to 4 carbon atoms; each of "alkyl", "alkoxy" and "alkenyl" is a straight or branched hydrocarbon, e.g. C 1 -C 10, and include C 1 -C 4 hydrocarbon; and "halogen" refers to groups of less than 127 atomic masses, i.e., fluorine (preferred), chlorine, bromine and iodine.

The compounds of formula (I) of the present invention are potent analgesic agents with a duration of action ranging from ultra short to medium. Such activity is characterized by rapid onset of action and a half-life of generally about. 5 and approx. 40 minutes, according to the results of experiments with rats. In contrast, well-known narcotic analgesics, N (1-phenethyl-4-piperidyl) -propionanilide, commonly known as fentanyl, and its derivatives, sufentanyl and alfentanyl, are active in rats and humans for 60, 80 and 55 minutes. their terminal half-lives are approx. 1.5-7 (16 for geriatric patients), 2.5 and

Between 1.2 and 3 hours (Mahter L.E., Clinical Pharmacokinetics, 1983, 8: 422-446). The significant potential and the very short duration of analgesia provided by the ultra-short acting compounds of the present invention are highly desirable in conditions such as anesthesiology where severe pain should be resolved within a short period of time. Due to the current predominance of short surgical procedures and the increasing proliferation of ambulatory surgery, there is an urgent need for potent but short-acting analgesics, as stated by Dr. Paul AJ Janssen in Janssen: Opioids in Anesthesia [Estafanous, E. G. ed., Butterworth , Boston (1984). The compounds of the invention, together with a pharmaceutically acceptable carrier, are used in the form of a pharmaceutical composition and can be administered to mammals, such as humans, in amounts sufficient to provide analgesia.

Effect of compounds wherein X is alkoxycarbonyl-lower alkyl, such as (lower-alkoxy) -carbonyl (lower-alkyl), wherein the carbon of the alkoxy directly bonded to the oxygen of the alkoxy is methylene or methyl. , i.e., where it is not substituted with more than one alkyl group, generally has a shorter duration. Further, the lower alkyl group of the alkoxycarbonyl (lower alkyl) group is particularly ethyl, i.e., -CH ₂ CH ₂ .

The compounds of formula (I) may be converted into pharmaceutically active acid addition salts with a suitable acid such as an inorganic acid such as hydrogen halides such as hydrochloric acid, hydrobromic acid and the like, and sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid such as acetic acid, propionic acid, hydroxyacetic acid, α-hydroxypropionic acid, 2-oxopropionic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z) -2-butenedioic acid, (E) -2-butenedioic acid, 2- hydroxy-butenedioic,

With 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenoic acid, α-hydroxyphenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, sulfamic acid, a-hydroxy2

EN 211 916 A9 by treatment with benzoic acid, 4-amino-2-hydroxybenzoic acid and the like. In contrast, the salt form can be reacted with an alkali to form the free base form. In addition, the salts may be useful in the preparation of other salts, for example as intermediates in the preparation of a preferred pharmaceutically acceptable salt derivative. The salt may also exist in the form of a solvate such as a hydrate or a hemihydrate.

Some of the compounds of formula (I) contain one or more asymmetric carbon atoms and consequently may exist in the form of various optical isomers or mixtures thereof, for example as racemates. When R ^{2 in the} compound of formula (I) is methyl, there are two asymmetric carbon atoms in the piperidine ring. Further asymmetric carbon atoms may be present in the X substituent, for example when X is -CH (CH ₃ ) CH ₂ COOCH ₃ , -CH ₂ CH (CH ₃ ) COOCH _3, or -CH ₂ COOCH ₂ CH (CH ₃ ) CH ₂ CH ₃ -. group. Enantiomeric forms and mixtures of such forms may be employed using resolution techniques known to those skilled in the art, for example by salt formation with an optically active acid. followed by selective crystallization or conversion to a chiral derivative, followed by selective crystallization or chromatography on silica gel.

When R ² is methyl, the relative positions of said methyl group and the 4-position of the piperidine ring with respect to the plane of the piperidine ring may be cis or trans, as described in Naming and Indexing of Chemical Substances, CA during the Ninth Collective Period (1972-1976). " according to the rules of nomenclature described in the thesis. It is of formula (I). cis or trans isomeric compounds which are substantially free of the other form, for example, may be prepared using the pure cis or trans isomer of the appropriate precursors as starting materials. For example, when an intermediate of formula (XI) wherein R ² is methyl, selective crystallization, are obtained separately for the cis and trans isomers, which can be used conveniently for further synthesis of the corresponding configuration (I) compound. Alternatively, the compounds of formula I in substantially pure cis and trans isomeric forms which are substantially free of the other isomer may be prepared by treating such appropriate precursor forms, e.g. later, the compound of formula (XXI) is chromatographed on silica gel.

The cis and trans forms, on the other hand, can be further resolved into optical enantiomers, each substantially free of its optical counterpart, using methods known in the art, as mentioned above.

All racemic and isomeric forms of the compounds of formula (I), including diastereomeric mixtures, pure diastereomers and enantiomers and mixtures thereof, are within the scope of the present invention.

The compounds of formula (I) may generally be prepared by introducing X into the nitrogen atom of the piperidine ring of an intermediate of formula (II) wherein Ar, R, R ¹ and R ² are as defined above, and are generally known in the art. . Depending on the nature of the substituent X, the following procedures are used.

The compounds of formula (II) are known and can be prepared by known methods. In addition, compounds of formula II wherein R ² is methyl and R ¹ is hydrogen are prepared from 1- (methoxycarbonyl) -3-methyl-4- (1-oxopropyl) arylaminopiperidine. (see examples below), which, in turn, from 3- (methoxycarbonyl) -4-piperidinone hydrochloride by W. M. M. VanBerer et al. (J. Med. Chem. 1974, 77, 1047) and TR Bürke Jr. and et al., J. Med. Chem. 1986, 29, 1087.

Introduction of the aforementioned X groups on the nitrogen of the compound of formula (Π) by alkylation of a compound of formula (II) with a suitable halide of formula (III) wherein "Hal" is bromine (preferred), chlorine or iodine; X represents the aforementioned groups and is conveniently carried out according to Scheme I.

In formulas (Ia) to (ld) and other formulas, the conventional part of the structures, using the conventional symbol for sub-structures, corresponds to the corresponding part of formula (I).

The alkylation of the compound (II) with the compound (ΠΙ) is conveniently carried out in an inert organic solvent such as acetonitrile (preferred), an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene and the like; lower alkanol such as methanol, ethanol, 1-butanol and the like; a ketone such as 4-methyl-2-pentanone and the like; ether such as 1,4-dioxane, tetrahydrofuran,

1,1-oxybisethane and the like; N, N-dimethylformamide; nitrobenzene and the like. A suitable base such as an alkali metal carbonate or bicarbonate, preferably potassium carbonate, may also be added to neutralize the acid liberated in the reaction. Under certain circumstances, the addition of an iodide salt, preferably an alkali metal iodide, such as sodium iodide, is suitable. The reaction temperature is generally satisfactory at ambient temperature (2225 ° C), but may be employed at slightly higher temperatures to increase the reaction rate.

When X is an alkoxycarbonylethyl group, where the ethyl group may be substituted by one or two C 1 -C 2 alkyl groups and the group has a carbon number of 2 to 4, other methods may be used to introduce this group to the nitrogen atom of the compound of formula II and for the preparation of a compound of formula (V), the compound of formula (Π) is conjugated to an α, β-unsaturated carbonyl compound of formula (IV) in an inert organic solvent such as acetonitrile, a lower alkanol, e.g. ME3

A9 in toluene, ethanol and the like, in ether such as diethyl ether, dioxane and the like; and aromatic hydrocarbons such as benzene, toluene and the like, as in Π. shown in the reaction scheme.

The introduction of X into the piperidine nitrogen to produce compounds of formula Ia wherein X is alkoxycarbonyl (lower alkyl) or alkenyloxycarbonyl (lower alkyl) is also carried out it is possible that the compound of formula A in the corresponding acidic form, i.e. the compound of formula I in which X is a carboxy-lower alkyl group, for example a compound of the formula VI in the corresponding alkyl or and esterified using an alkenyl-NN-diisopropyl pseudocarbamide in an organic solvent such as chloroform at a temperature between ambient and reflux temperature. Acids of formula (A), for example in which X _a is a carboxyethyl group, i.e., new intermediates of formula (VI) may be prepared by reacting a compound of formula (Π) with a suitable tertiary compound of formula (III). reaction with tert-butyl ester or tert-butyl acrylate (Michael reaction), the product (VII) is reacted with excess trifluoroacetic acid at 0 ° C to ambient temperature. as shown in the reaction scheme.

AIII. in the Scheme, the CH ₂ = CHCOO-tert-Bu ester may be replaced by other esters, such as R ⁴ R ⁵ C = CR ⁶ COO-tert-Bu, wherein R ⁴ , R ⁵ and R ⁶ are hydrogen, methyl or ethyl. with the proviso that the total number of carbon atoms of the groups R ⁴ , R ⁵ and R ⁶ is from 0 to 2 to obtain other acids of the general formula (A).

Alternatively, the appropriate carboxy (lower alkyl) halide or acrylic acid, the use of acrylic acid is illustrated below by esterification with the appropriate alkyl or alkenyl-NN-diisopropyl pseudocarbamide at ambient to reflux temperature. to give the corresponding halide ester (III) or acrylic acid ester which is then introduced into the ring nitrogen atom of the compound (II) by the above alkylation reaction or Michael conjugation reaction. as shown in the reaction scheme.

All III. all IV. wherein R ³ is alkenyl, the double bond is not directly attached to the oxygen atom of OR ³ . In addition, the CH2 = CH-COOH starting material is replaced by R ⁴ R ^S C = ^CR6 COOH compound of formula wherein R ^4, R ⁵ and R ⁶ are as defined above. (I) Compounds of formula I wherein X is a (lower alkyl) carbonyloxy (lower) alkyl and R ¹ is hydrogen or methoxy-methyl group can be obtained from the corresponding (I-a) of formula The ester is reduced to the corresponding alcohol (VIII), for example by reduction with standard lithium aluminum hydride in an ethereal solution, preferably tetrahydrofuran, at ambient temperature. The alcohol (VIII) thus obtained is then converted to the reverse ester (IX) with a suitable lower alkyl alkyl anhydride such as acetic anhydride, propionic anhydride and the like in an organic solvent such as pyridine. This is illustrated in Scheme V, wherein X in formula (Ia) is (lower alkyl) -CO2- (lower alkyl).

When X is (C 1-2 -alkoxy) - (C 1-2 -alkoxy) -carbonylethyl, where the ethyl may be substituted with 1-2 C 1 -C 2 alkyls and the total number of carbon atoms is 2-4, is conveniently introduced into the ring nitrogen of the compound of formula II by reacting the compound of formula II with an α, β-unsaturated carbonyl reagent of formula X under standard Michael reaction conditions and in a solvent, of which acetonitrile is preferred, reacted to give the corresponding N-substituted product of formula (Va) as described in Scheme VI. showing the reaction scheme.

Compounds of formula (X) containing (C 1 -C 2 alkoxy) methoxycarbonylethyl are reacted with acrylic acid in the presence of a suitable dialkoxyalkane such as dimethoxymethane and diethoxymethane phosphorus pentoxide. The acrylic acid may be replaced by other acids of the formula R ⁴ R ⁵ C = CR ⁶ COOH to give another compound of the invention. Compounds of formula (X) having (C 1 -C 2) alkoxy-ethoxycarbonyl (C 1 -C 4) -alkyl are commercially available.

As mentioned above, the compounds of formula I can exist in diastereomeric and enantiomeric forms. The following schematic description describes specific methods for preparing such diastereomers and enantiomers in pure forms starting from the corresponding precursors.

VII. In the following scheme, the cis / trans mixture of the compound of formula XI is used as starting material. Standard crystallization processes employing organic solvents such as ethyl acetate, ether and hexane mixtures and the like allow separation of the corresponding pure cis isomer XII in crystalline form and the corresponding trans isomer XIII little residual cis isomer remains in the mother liquor. The pure cis isomer of formula (XII) which is substantially free of the corresponding trans isomer and the predominantly trans isomer of formula (XIII) with concentrated hydrogen halide (preferably hydrogen bromide) at the corresponding boiling temperature (XIV) and (XV) ) into 3-methyl-4- (arylamino) piperidines. The resulting pure crystalline cis isomer of formula (XIV) is then isolated and isolated in VIII. can be used to prepare the corresponding cis form of the final compounds of formula (I).

As shown in Section VIII. Synthesis 1, Synthesis 4

The cis precursor of formula (XIV) may be alkylated with a halide of formula (ΠΙ) as described above to provide the corresponding N-substituted compounds of formula (XVI). Acylation of the aryl amino group of the compound of formula (XVI) with a suitable acid chloride (compound of formula RC0Cl in which R is as defined above) gives the corresponding compounds of formula (I) in cis form. The acylation reaction is carried out in the presence of a suitable 4-dialkylamino-pyridine as the acylation catalyst and in a polar aprotic solvent such as acetonitrile (preferred), dimethylformamide, hexamethylphosphoramide and the like at temperatures between 40 ° C and 85 ° C. VIII. Synthesis route 2 represents an alternative process for introducing an alkoxycarbonylethyl or C 1 -C 2 alkoxy - (C 1 -C 2 alkoxy) carbonyl ethyl group into a nitrogen atom of a compound of formula (XIV) previously using the conjugated addition Michael reaction using the α, β-unsaturated carbonyl reactant of formula IV 'to give the corresponding compound of formula XVII in cis form, which is then acylated with RCOC1 as previously described. the cis products of formula (V) or (Va) are obtained. The substituent R 'is as defined in Scheme VIII. in the scheme, alkyl, (C 1 -C 2) alkoxy (C 1 -C 2) alkyl, or alkenyl. By analogy with the above schemes, the acrylic acid ester of formula IV 'may be replaced by a compound of formula R ⁴ R ⁵ C = CR ⁶ COOR' or alkyl.

VIII. In Scheme 2, Synthetic Route 2 illustrates a different method for the preparation of cis (I), cis (V) and cis (Va). The cis precursor of formula (XIV) with benzyl chloroformate (Cbz-Cl) under Shotten-Baumann conditions in two phases consisting of water and an ether such as diethyl ether, tetrahydrofuran, dioxane and the like is capable of binding the acid liberated in the reaction. in the presence of a base such as sodium carbonate or bicarbonate, an alkali metal (preferably sodium) hydroxide, and the like, for approx. The reaction is carried out at a temperature of 0 ° C to 35 ° C to give the ring-substituted compound of formula XVIII, wherein Cbz represents a benzyloxycarbonyl group. Similar acylation of the compound of formula (XVIII) with the compound of formula (RCOC1) yields the corresponding amide of formula (XIX). The hydrogenolysis of the benzyl carbamate group of the compound of formula (XIX) in conventional hydrogen, for example 98-294 kPa, in the presence of a catalyst (e.g. palladium on carbon) in an organic alkanol (e.g. methanol or ethanol) and acetic acid at ambient temperature, yielding a cis precursor of the general formula wherein the ring nitrogen is unsubstituted. This cis precursor of formula (XX) is then converted to the final product of formula (I), (V) or (Va) by appropriate alkylation or Michael addition reaction as described above, but instead of the compounds of formula (II) Compounds of formula XX are used.

As shown in Section VII. Referring to Scheme I, the trans isomers of formulas XIII and XV contain few suitable cis isomers. However, the final products of formula (I) can be obtained from the trans (cis) derivatives of formula (XV) in pure trans form by the method described in IX. using the purification method shown in Scheme II. The trans (cis) isomer of formula (XV) is converted to the corresponding trans (cis) N-benzyloxycarbonyl derivative of formula (XXI) under the Schotten-Baumann conditions described above. The trans (cis) isomers of formula (XXI) can be separated by flash chromatography on silica gel (see, e.g., WC Still et al., J. Org. Chem. 1978, 43, 2923) to give the cis isomer of formula XVIII. and the trans isomer of formula (XXII), each substantially free of the corresponding other isomeric form. The trans isomers thus isolated can then be converted to the corresponding trans-formulated final compounds of formula I using the methods described above (e.g., Scheme VIII, Pathway 3) to the corresponding cis compounds.

A method for the synthesis of the corresponding (+) - and (-) - optical isomers of the pure cis and trans isomers is shown in Scheme X. The racemic cis isomers of formula (XIV) are used as starting materials, although the corresponding trans isomers may be used in the same manner.

The racemic cis compound of formula (XIV) is reacted with R-methylbenzyl isocyanate at elevated temperature (about 100-150 ° C) in the presence of the appropriate 4- (dialkylamino) pyridine catalyst, such as (XXIII) and (XXIV). ) to form a racemic mixture of diastereomeric compounds of formula (I) from which the components can be separated by flash chromatography on silica gel. Subsequently, each of the separated diastereomers is converted to the corresponding enantiomeric piperidine (XXV) and (XXVI) by boiling with hydrobromic acid, and the compounds thus obtained can be used as starting materials for the preparation of the corresponding forms of the compound of formula (I). using the procedures outlined in Scheme II.

The compounds of formula (I) and their isomeric forms and pharmaceutically acceptable acid addition salts thereof are valuable analgesics, as exemplified in animal experiments. Typical in vitro and in vivo assays for analgesic activity are the guinea pig ileum assay and the rat tail retraction assay.

A) In vitro guinea pig determination

The opioid activity of the compounds was assayed using the guinea pig ileum method described by Kosterlitz H.W. and Watt A.J., Br. J. Pharmacol. 33: 266-267 (1968)] and James Μ. K. and Leighton H.J. Pharmacol. Exp. Ther. 240: 138-144 (1987)]

HU 211 916 A9 Tolt. Male Hartley guinea pigs were killed by decapitation and the terminal ileum was removed. The isolated ileum was washed and then placed in Krebs-Henseleit buffer, which was aerated with a mixture of 95% oxygen and 5% carbon dioxide and kept at 37 ° C. The washed ileum was cut into 21.0-2.5 cm pieces and mounted on a platinum ring electrode. The ileum segments were then immersed in 10 ml of a controlled temperature organ bath containing oxygenated KrebsHenseleit buffer. The tissues were coupled to a force displacement transducer and stretched to a resting voltage of 1.0 g. Krebs-Henseleit buffer was composed as follows (in mmol): NaCl 118.1; KCl 4.15; CaCl ₂ 2.5; MgSO ₄ 1.2; KH ₂ PO ₄ 1.23; _NaHCO3 25.5 and glucose 11.1.

The ileum segments at 0.1 Hertz were stimulated for 0.5 milliseconds with supramaximal voltage to induce contraction. The opioid activity of the test compounds can be determined as the inhibition of electrically induced contractions. A non-cumulative concentration-response curve was determined for each compound tested to determine its ability to inhibit contraction in the guinea pig ileum. After the concentration-response curve was completed, naloxone was added to the organ bath to determine if the compound's inhibition of contraction could be reversed. The antagonism of the inhibition by naloxone demonstrates that the inhibitory effect of the compounds is mediated by opioid receptors. Assay results are expressed as EC ₅₀ values (measure of efficacy), the concentration required to elicit 50% of the maximum response, and are expressed in molar units (molar compound / liter).

B) In vivo retraction studies in the rat

The analgesic effect of the compounds is described in D'Amour FE and Smith D. L [J. Pharmacol. Exp. Ther. 72.74-79 (1941)] with a modified form of the rat tail retraction reflex model. Male Sprague-Dawley rats were anesthetized, cannulated into their femoral veins, and allowed to recover overnight. Subsequently, the test compounds were administered intravenously through the cannula and the effect on the latency of tail retraction was measured. This was done by exposing the rat's tail to a radiant heat source and determining the time after which the rat moved its tail. The braiding was adjusted to produce a temperature of 62 ° C within 15 seconds. Tail retraction latency in the absence of active ingredient is 6-8 seconds. Test compounds that exhibit analgesic activity have a prolonged tail retraction latency compared to that measured without the active ingredient. Maximum latency was set at 15 seconds to prevent tissue damage. The assay was checked using known opiodides as standard. The results of these assays were expressed as ED ₅₀ values, the dose at which the tail retraction latency was equal to half the difference between the maximum (15 seconds) and baseline (6-8 seconds). ED50 values are expressed in milligrams of compound / kg body weight. The duration of action is the time (in minutes) required for the tail retraction response to return to baseline after an increased value after drug administration. The duration of action was measured at the lowest dose triggering a 15 second (maximum) tail retraction latency.

Table I lists the results obtained previously in the guinea pig ileum A) and the rat tail retraction studies B) for the given compounds of formula (I). The above results are not intended to limit the invention to the above compounds, but merely exemplify the analgesic activity of the compounds of formula (I). For comparison, the results of three well-known 4-anilidopiperidine analgesics, fentanyl, sufentanil and alfentanil, are also reported.

/. spreadsheet

Example number of compound The assay is EC5 assay ₀ (mol) Test B ED ₅₀ (mg / kg) duration of effect (minutes) 2 maleate l, 66 ± 0.59x IO ⁶ 3.2 10-15 3 maleate 3.60 ± 0.30x 10 ^-6 3.4 10 6 HCl 2.62 ± 0.62x IO ⁶ 4.7 5-10 7 oxalates 3.71 ± 0.20x 10 ^-7 13.4 5-10 8 oxalates 1.03 ± 1.00Χ 10 ^–5 - - 10 oxalates 3.55 ± O, 23x IO ^-9 0.0044 15 12 oxalates l, O2 ± O, 63x 10 ~ ⁸ 0.8 30 14 oxalates 6.89 + 1.61 x IO ' ⁹ 1.4 15 15 oxalates 5, ll ± 0.24x IO ⁷ <0.03 10 16 oxalates 6.72 + 2.10X 10 ' ⁸ 0,016 25 17 oxalates 3.47 + 0.53x10 ^-7 0,028 15 18 oxalates 2.13 ± O, 3Ox IO ^-6 > 3.0 - 19 oxalates l, 18 ± 0.20x 10 ~ ⁷ > 3.0 - 20 oxalates 4.95 ± 0.09x IO ^-6 1.4 25 21 oxalates 2.18 + O, 18x IO ^-6 1.4 15 22 HCl 1.98 + 0.2 ix 10 ~ ⁸ <0.03 30 23 oxalates 7.51 ± O, 81X 10 ' ⁸ 0.51 10 24 oxalates l, 64 ± 0.10x 10 ~ ⁸ > 3.0 - 25 oxalates l, 47 ± 0.09x 10 ' ⁷ 0,052 5 27 HCl 9.29 ± 6.36x IO ' ⁹ <0.003 10 29 oxalates 2.23 ± 1.00x 10 ' ⁸ 0.14 10 34 HCl 6.63 ± l, 96x 10 ' ⁸ 0.0052 10 35 oxalates l, 22 ± 0.09x 10 ^-8 0.26 20 36 oxalates 6.87 ± 0.83x IO ^-9 - -

HU 211 916 A9

The compound would exemplify closure The test is EC ₅₀ (mole) B test Test B ED50 (mg / kg) duration of effect (minutes) fentanyl l, 76 ± 0.36x 10 ' ⁹ 0.0046 60 sufentanil 7.43 ± 1.53x IO * ⁹ 0.0013 80 alfentanil 2.01 ± 0.12x l <r * 0.0045 55

The results listed in Table I show that the compounds of the present invention exhibit opioid activity as shown by naloxone reversible inhibition of electrical contraction of guinea pig ileum. The most preferred compounds are potent analgesics which have an unexpectedly short duration of action compared to the known 4-anilidopiperidine compounds (fentanyl, sufentanyl and alfentanyl). The most preferred compounds include:

1. Methyl 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid (Example 10);

2. Methyl 5- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidinyl} -pentanoic acid (Example 12);

3. 2- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidin} ethyl acetate (Example 16);

4. 3- (4 - [(1-Oxopropyl) -2-fluorophenylamino] -1-piperidin} propionic acid methyl ester (Example 17);

5. Vinyl 3- (4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidinyl) propionic acid (Example 15B);

and pharmaceutically acceptable isomers and salts thereof.

A particular class of compounds of this invention are the alkyl esters of 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidinyl} propionic acid and their pharmaceutically acceptable salts.

The above-mentioned properties of the most preferred compounds are extremely advantageous in that the level of analgesia can be better controlled during an operation or in other situations where precise control of the opioid level is necessary or desirable. These properties also allow for rapid recovery after completion of the surgical procedure or other application of these compounds.

In addition to analgesic activity, the compounds of formula (I) of the present invention are extensively metabolized in the blood and potentially metabolised in the liver, as observed for the most preferred compounds. In contrast, phenyl and alfentanyl have been reported to be primarily metabolised in the liver in humans [cf. e.g., McClain D.A. and Sister Jr. C.C., Clin. Pharm. Ther. 28: 106-114 (1980) and Shuttler J. and Stoeckel H. Anesthesist 31: 10-14 (1982). Rapid elimination or biotransformation to ineffective or less effective products would minimize accumulation at prolonged or repeated dosing. This property was mentioned by White P. F. as one of the properties of the "ideal" intravenous analgesic or anesthetic (Anesthesia and Analgesia 68: 161-171 (1989)). In addition, the rapid degradation of opioid analgesics to ineffective or less potent products in the blood, as is the case with neuromuscular blocking succinylcholine, makes the dose-duration relationship more predictable [Stanski, D. r. and Sister C. C. Jr. Anesthesiology 57: 435438 (1982).

This non-liver inactivation with one of the most preferred compounds, 3- {4- (methoxycarbonyl) -4- [4- (1-oxopropyl) phenylamino] -1-piperidin} propionic acid methyl ester hydrochloride (test compound), which has been shown to be rapidly degraded in rat and human blood in vitro, whereas fentanyl, sufentanyl and alfentanyl are degraded much more slowly.

The comparative study was performed using rat blood as follows. 0.01 microliters of heparinized rat blood was weighed into 18 15 ml plastic centrifuge tubes. The tubes were then placed in a 37 ° C temperature controlled water bath for 2 minutes. Subsequently, 2 µg (1 µg / ml aqueous solution) of the test compound (12 tubes), fentanyl (2 tubes), sufentanil (2 tubes) and alfentanyl (2 tubes) were added to the tubes. Two of the tubes containing test compound were withdrawn after 0.5, 1.0, 2.0, 5.0, 10.0 and 20.0 minutes. After 2 minutes, 2-2 tubes containing fentanyl, sufentanil and alfentanyl were removed from the bath. Immediately after removal,

4- {4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] 1-piperidine} butanoic acid methyl ester oxalic acid salt (Example 11) 0.1 pg / ml Concentrated sodium bicarbonate solution was stirred briefly and 900 μΐ of saturated sodium carbonate solution was added. After the addition of the sodium carbonate solution, the contents of the tubes were mixed and mixed with 10 ml of n-hexane.

The aqueous phase was stirred with the n-hexane phase for 10 minutes and then centrifuged at 2000 x g for 10 minutes. The n-hexane layers were removed, placed in clean tubes and evaporated to dryness under a stream of dry nitrogen. To the evaporation residue was added 100 μΐ of ethyl acetate, the materials were mixed and the solution was analyzed by gas-liquid chromatography. 1 microliter portions of the ethyl acetate solution were coated with 0.32 mm (inner diameter) x 15 m DB5 (5% diphenyl polysiloxane and 95% dimethyl polysiloxane brand name, J & W Scientific, Rancho Cordoba, Calif.). (film thickness: 0.25 μ) was injected into a gas chromatograph equipped with a column. The injection port was maintained at 280 ° C. The detector is a nitrogen-phosphorus detector with a temperature of 270 ° C, a carrier gas helium, and a flow rate of 2 ml / min. The column was heated at 45 ° C for one minute after injection, then heated to 270 ° C at 25 ° C / min for 7 minutes. Under these conditions, the retention time of the internal standard was 11.6 minutes. The retention time of the test compound, fentanyl, sufentanyl and alfentanyl, respectively, was 11.0; 12.1; 12.8 and 14.3 minutes respectively.

In this study, we found that more than 90% of the test compound disappeared within 30 seconds

After incubation with A9, 65%, 85% and 75%, respectively, of the added sufentanyl, alfentanyl and fentanyl were still present at the end of the one hour incubation period. These results illustrate that the test compound is rapidly degraded in rat blood in vitro, in contrast to the three reference compounds, which are very slowly degraded. From these results, it is concluded that the analgesic compounds of the present invention are extensively metabolized in the blood and potentially metabolised in the liver. This property is preferred because it offers another mode of inactivation of the analgesic compound and thus results in a predictable pharmacokinetic profile.

Non-hepatic inactivation of 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino]] piperidine] -propionic acid methyl ester is related to ethyl, propyl, butyl , isopropyl, isobutyl and sec-butyl esters. For these compounds (test compounds in Table II below), it was found that they are rapidly degraded in human blood compared to phosphate buffer.

The comparative assay was performed using human blood as follows. 20 ml of fresh, heparinized human blood was placed in a 37 ° C water bath for 10 minutes. At this time, 400 μΐ of a 2 mg / ml solution of the test compound was added to the blood to give a test compound concentration of 40 pg / ml.

Solutions of test compounds were prepared immediately before the start of the test. Two 500 μΐ blood samples were taken at different times to measure the propionic acid formed during hydrolysis of the test compound and ester. A series of tests were performed on each compound to be tested and the sampling times were determined for a period corresponding to 2-3 times the half-life. Chemical hydrolysis was measured by incubating the test compound in phosphate buffer (0.1M, pH 7.4) instead of blood. Duplicate samples were taken 1.30. 60. After 120, 180, 240 and 300 minutes.

For the incubation mixture, 700 μΐ of acetonitrile and the internal standard 4- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} butanoic acid methyl ester 0.12 50 μΐ of a solution of acetonitrile (mg / ml) was added. Samples were mixed and centrifuged immediately at 30,000 x g for 10 minutes. The supernatant was removed and cooled to 8 ° C. 20 μΐ of the supernatant was injected into the HPLC apparatus for analysis.

HPLC analysis was performed on a 5 μ Spherisorb CN column (250 x 4.6 mm) (Kestone Scientific, Inc., State College, Pa.) At a flow rate of 2 ml / min. The mobile phase was a gradient of 0.1 M phosphate buffer (pH 2.0) and acetonitrile. The amount of acetonitrile was increased from 10-11% in 0-5 minutes to 16% in 10 minutes. The concentration of acetonitrile was maintained at 16% for the remainder of the elution (16 minutes total). Under these conditions, the propionic acid formed by hydrolysis of the ester, the internal standard, and all test compounds except for the ethyl ester had to be resolved. Retention times (minutes): propionic acid 5.1; methyl ester 7.5; internal standard 8.6; ethyl ester 9.0; isopropyl ester 11.1; propyl ester 11.8;

sec-butyl ester 13.9; isobutyl ester 14.4; and butyl ester 14.9.

When the flow rate was reduced to 1 ml / min, the ethyl ester was separated from the internal standard. At this flow rate, the retention times were as follows: propionic acid 10.1 min; internal standard 15.1 minutes and ethyl ester 15.8 minutes. Elution of these materials at 220 nm was detected by following ultraviolet absorption.

Data from the HPLC assay were analyzed as a simple pseudo-first order kinetic model for the disappearance of the test compound. The pseudo-first order rate constant for each compound was calculated from these data with the corresponding half-lives (Tj / 2 min). These results are shown in Table II below. Table 1-3 for 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine] propionic acid. _{Kbu is} the pseudo-first order rate constant for degradation of the test compounds in phosphate buffer and k _{bu is} the constant for blood degradation.

//. spreadsheet

Ester ^k bu Buffer Ü / 4 ^ bu Blood ^l l / 4 methyl 7.4 + 0.6x 10 * ³ 94 2.0 + 0, IX 10 * ² 36.5 ethyl 4.6 + 0.2x 10 * ³ 150 1.8 + 0.7x 10 * ² 38.5 propyl 3.0 + 0.5x 10 * ³ 231 2.5 ± 0.3x 10 ′ ² 27.7 butyl 3, O ± O, 5x 10 * ³ 231 8.5 + 0.6x 10 ' ² 8.2 isopropyl 1.3 + 0.5Χ 10 * ³ 533 l, 0 + 0, lx 10 * ² 69.3 isobutyl 4.0 ± 0.6X 10 * ³ 173 9.0 ± 2.0x 10 * ² 7.7 sec-butyl 2.0 + 0.2x 1 (T ³ 346 9.0 + 1.0x 10 * ³ 77.0

In this study, it was found that the test compounds were rapidly degraded in the blood relative to the buffer. The test compounds undergo rapid degradation in vitro in human blood relative to commercial compounds, fentanyl, sufentanyl and alfentanyl, which have been shown to be primarily metabolised by the liver in vivo [cf. D. A. McClain et al., Clin. Pharm. Ther. 28: 106114 (1982)]. As shown in this study, the analgesic compounds of the invention may be extensively metabolized in the blood and potentially in the liver. This property is considered to be advantageous since the compounds of the present invention would thus not be dependent on redistribution for termination of their action and would thus likely exhibit a more uniform and predictable pharmacokinetic and pharmacodynamic profile.

The compounds of the present invention may be formulated into various pharmaceutical compositions for administration in view of their analgesic activity. For the preparation of the pharmaceutical compositions of the present invention, an effective amount of the analgesic effective amount of a particular compound in base or acid addition salt form is formulated into an intimate mixture with a pharmaceutically acceptable carrier which can vary within wide limits depending on the form of the composition. These pharmaceutical compositions are desirable in unit dosage form and suitable for oral, transdermal, rectal or parenteral administration. For example, when preparing an oral dosage form, any conventional pharmaceutical medium, such as water, glycols, oils, alcohols, and the like, may be used to prepare liquid oral formulations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like for the production of powders, pills, capsules, and tablets. For parenteral formulations, the carrier will usually comprise sterile water, at least in large part, but may also include other ingredients such as solubilizers. Injectable solutions may be prepared, for example, using isotonic saline, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, using suitable liquid carriers, suspending agents, and the like. The acid addition salts of the compound of formula I are obviously more suitable for the preparation of aqueous pharmaceutical compositions due to their increased water solubility over the base.

The aforementioned pharmaceutical compositions are particularly advantageous in unit dosage form for ease of administration and uniformity of administration. Dosage unit form as used herein refers to discrete physical units which may be used in unit dosage form, each unit containing a predetermined amount of the active ingredient calculated with the desired therapeutic effect in association with the desired pharmaceutical carrier. Such unit dosage forms include tablets (scored or coated tablets), capsules, pills, lozenges, wafers, injectable solutions or suspensions, teaspoons, and the like, and separate multiples thereof.

In view of the analgesic activity of the compounds of the present invention, it is obvious that the invention includes a method of preventing or combating pain, i.e., a pharmaceutically acceptable amount of an analgesic effective amount of a compound of formula I or a pharmaceutically acceptable isomer or acid addition salt thereof systemic administration together with analgesia provides analgesia. Although the amount of active ingredient to be administered may vary within wide limits, depending on the particular circumstances of the case, the approx. 0.001 to approx. 10 mg / kg, and preferably ca. 0.01 to approx. Doses of 1.0 mg / kg, which may be administered simultaneously, repeatedly or continuously (for example, as a drop of i.v.), are generally effective. Parenteral, especially intravenous, administration is preferred.

The following examples are intended to illustrate the invention and are not intended to limit its scope.

/. example

4 - [(] - oxopropyl) phenylamino] -} - piperidine-acetic acid methyl ester

500 mg (2.15 mmol) of 4 - [(1-oxopropyl) phenylamino] -piperidine, 0.25 mL (2.58), prepared according to the procedure described in PAJ Janssen et al., U.S. Patent 3,164,600. A mixture of methyl bromoacetate (mmol) and potassium carbonate (594 mg, 4.3 mmol) in acetonitrile (2.5 mL) was stirred at room temperature for 5 hours. The reaction mixture was then diluted with 20 mL of water: ethyl acetate = 1: 1. The phases are separated and the aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and finally concentrated. The residue was chromatographed on silica gel, eluting with a 95: 5 mixture of chloroform and methanol. In this way, 348 mg (53%) of 4 - [(1-oxopropyl) phenylamino] -1-piperidineacetic acid methyl ester were isolated as an oil. To a solution of the free base in ethyl acetate is added an equimolar amount of a solution of maleic acid in ether to give the maleate salt as a white solid, m.p. 130-133 ° C.

Elemental Analysis for: C ₂ H ₂₈ N ₂ O ₇ Found: C, 59.7; H, 6.8%; N, 6.6%;

Calculated: C, 60.0; H, 6.7%; N, 6.7%.

Example 2

3- {4 - [(1-Oxo-propyl) -phenylamino] -1-piperidine} -propionic acid methyl ester

To a solution of 1.0 g (4.31 mmol) of 4 - [(1-oxopropyl) phenylamino] piperidine in 10 mL of acetonitrile was added 776 μΐ (8.62 mmol) of methyl acrylate at room temperature. The solution was stirred for 2 hours at 50 ° C, then cooled to room temperature and evaporated. The oily residue was chromatographed on silica gel, eluting with ethyl acetate, to give 1.34 g (98%) of 3- {4 - [(1-oxopropyl) phenylamino] -1-piperidine J-propionic acid methyl ester. After recrystallization from the maleate salt of ethyl acetate prepared as in Example 1, a white solid m.p. 118-120 ° C.

Elemental Analysis for: C ₂₂ H ₂₈ N ₂ O ₇ Found: C, 60.8; H, 7.0%; N, 6.7%;

Calculated: C, 60.8; H, 7.0%; N, 6.5%.

Example 3

4- {4 - [(] - Oxopropyl) -ferulamino] -1-piperidine) -butyric acid methyl ester

250 mg (1.08 mmol) of 4 - [(1-oxo-propyl) -phenylamino] -piperidine, 224 mg (1.23 mmol), described by GA Olah et al., Synthesis 1982, 963 A mixture of 4-bromobutanoic acid methyl ester prepared according to Method IIa, 81 mg (0.54 mmol) of potassium iodide and 298 mg (2.15 mmol) of potassium carbonate is stirred in 1.1 ml of acetonitrile for 5 hours at room temperature. The mixture was diluted with water and ethyl acetate and worked up as described in Example 1. The remainder is hi9

Chromatograph on A9 gel using ethyl acetate as eluent. 223 mg of 4- {4 - [(1-oxopropyl) phenylamino] -1-piperidine} butanoic acid methyl ester are isolated in the form of an oil. The maleate salt, prepared as described in Example 1, melts at 101.5-103.5 ° C.

Elemental Analysis for: C ₂₃ H ₃₂ N ₂ O ₇ Found: C, 61.3; H, 7.0%; N, 6.2%;

Calculated: C, 61.6; H, 7.2%; N, 6.3%.

Example 4

5- {4 - [(] -Oxopropyl) phenylamino] -1-piperidine} pentanoic acid methyl ester

300 mg (1.29 mmol) of 4 - [(1-oxopropyl) phenylamino] piperidine, 290 mg (1.49 mmol) as described by Synthesis 1982, 963, by GA Olah et al. A mixture of methyl 5-bromo-pentanoic acid ester prepared according to Method IIa (97 mg, 0.65 mmol) and potassium carbonate (357 mg, 2.58 mmol) in acetonitrile (1.3 mL) was stirred at room temperature for 5 hours. The mixture was worked up in the same manner as in Example 1. The residue was chromatographed on silica gel, eluting with 95: 5 ethyl acetate: methanol. 239 mg (53%) of 5- {4 - [(1-oxopropyl) phenylamino] -1-piperidine} pentanoic acid methyl ester are isolated as a white solid. The maleate salt, prepared as described in Example 1, melts at 105-106 ° C.

Elemental Analysis for: C ₂₄ H ₃₄ N ₂ O ₇ Found: C, 62.3; f, H: 7.4; N, 6.0%;

Calculated: C, 62.3; H, 7.4%; N, 6.1%.

Example 5

3- (4 - (() -Oxopropyl) phenylamino] piperidine} propionic acid trifluoroacetate

500 mg (2.15 mmol) of 4 - [(1-oxopropyl) phenylamino] piperidine and 0.37 mL (2.58 mmol) of tert-butyl acrylate

A solution of 2.5 ml of acetonitrile was stirred at room temperature for 24 hours. The solution was evaporated and the residue was chromatographed on silica gel eluting with ethyl acetate. 605 mg (78%) of 3- {4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid tert-butyl ester are isolated in the form of an oil. Trifluoroacetic acid (4 mL) was added to the ester (309 mg, 0.857 mmol). The homogeneous reaction mixture was stirred at room temperature for one hour and then concentrated. Trituration of the oily residue with diethyl ether afforded 316 mg (88%) of 3- {4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid trifluoroacetate as a white solid. The C's are.

Elemental analysis of C | ₉ H ₂₅ N ₂ O ₅ F ₃ Found: C, 54.6%; H, 6.0%; N, 6.7%;

Calculated: C, 54.5; H, 6.0%; N, 6.7%.

Example 6

A) Methoxymethyl acrylate

A separatory funnel was charged with 2 ml (29.17 mmol) of acrylic acid, 2 ml of dimethoxymethane, 0.5 g of phosphorus pentoxide and 20 ml of diethyl ether. The mixture was shaken vigorously for 5 minutes, then another 0.5 g of phosphorus pentoxide was added and the process repeated three times. The solids were separated from the liquid and the ether solution was washed 3 times with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and the ether was distilled off. 450 mg (13%) of methoxymethyl acrylate were obtained as a light yellow oil.

B) 3- (4 - ((1-Oxopropyl) phenylamino] -1-piperidine} propionic acid methoxymethyl ester

A solution of 4 - [(1-oxopropyl) phenylamino] piperidine (150 mg, 0.65 mmol) and methoxymethyl acrylate (182 mg, 1.57 mmol) in acetonitrile (0.8 mL) was stirred at room temperature for 11 hours. . The solution was evaporated and the residue was chromatographed on silica gel using ethyl acetate as eluent. This gave 138 mg (25%) of 3- {4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid (methoxymethyl) ester as an oil. The free base was dissolved in ethyl acetate / diethyl ether (1: 4 v / v) and gaseous hydrogen chloride was passed through the solution. The hydrochloride salt was obtained as a white solid, m.p. 128-131 ° C.

Analysis for C _I9 H ₂₉ N ₂ O ₄ C1 Calc'd: Found: C, 59.0%; H, 7.6%; N, 7.4%;

Calculated: C, 59.3; H, 7.6%; N, 7.3%.

Example 7

2- (4 - ((1-Oxopropyl) phenylamino] -1-piperidine} ethyl acetate

To a solution of 4 - [(1-oxo-propyl) -phenylamino] -piperidine-acetic acid methyl ester (250 mg, 0.82 mmol) in tetrahydrofuran (10 mL) at -78 ° C was added in portions 250 mg (6.57 mmol). lithium aluminum hydride is added. The suspension was stirred for 1 hour at -78 ° C and quenched with 10 ml of 2N sodium hydroxide solution. To the resulting suspension was added magnesium sulfate until it became granular. The suspension is then filtered and the filtrate is evaporated. The residue was chromatographed on silica gel. The eluent was a 9: 1 mixture of chloroform and methanol. This gave 155 mg (68%) of 2- {4 - [(1-oxopropyl) phenylamino] -1-piperidine) ethanol as an oil.

256 mg (0.957 mmol) of 2- {4 - [(1-oxo-propyl) -phenylamino] -1-piperidin} -ethanol, 0.72 mL (7.63 mmol) of acetic anhydride and 50 mg (0.41 mmol) A solution of 4- (dimethylamino) pyridine in 5 ml of pyridine was stirred at 25 ° C for 2 hours. The solution was then concentrated and the oily residue was chromatographed on silica gel using ethyl acetate as eluent. This afforded 243 mg (82%) of 2- {4 - [(1-oxopropyl) phenylamino] -1-piperidine) ethyl acetate as an oil. The free base is dissolved in ethyl acetate and an equimolar amount of oxalic acid is added. The precipitated salt was recrystallized by addition of methanol and heating to dissolution. On cooling, the salt precipitates as a white solid; the oxalate salt melts at 153-155 ° C.

Elemental Analysis for: C ₂₀ H ₂₈ N ₂ O ₇ Found: C, 58.7; H, 6.9%; N, 6.8%;

Calculated: C, 58.8; H, 6.9%; N, 6.9%.

HU 211 916 A9

Example 8

3- (4- (Methoxymethyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid methyl ester

300 mg (1.0 mmol) of 4-methoxymethyl-4 - [(1-oxopropyl) PGH Vand Daele et al. (Arzneim. Forsch. Drug. R. 1976, 26, 1521). -phenylamino] -piperidine and methyl acrylate (325 μ,6, 3.61 mmol) in methanol (20 mL) was stirred for 2 hours at 60 ° C. The reaction solution was cooled to room temperature and evaporated. The oily residue was chromatographed on silica gel, eluting with chloroform / methanol 9: 1 (v / v). This gave 250 mg (64%) of methyl 3- (4-methoxymethyl) -4 - [(loxopropyl) phenylamino] -1-piperidinyl} propionic acid as an oil. The oxalate salt, prepared as described in Example 7, melts at 180-182 ° C.

Elemental Analysis for: C ₂₂ H ₃₂ N ₂ O ₈ Found: C, 58.2; H, 7.2%; N, 6.1%;

Calculated: C, 58.4; H, 7.1%; N, 6.2%.

Example 9

Methyl 2- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -piperidine} -acetic acid

200 mg (0.68 mmol) of 4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenyl] prepared by PGH Vand Daele et al. (Arzneim. Forsch. Drug. Rep. 1976, 26, 1521). -amino] -piperidine, methyl bromoacetate (200 μΐ, 2.11 mmol) and potassium carbonate (200 mg, 5.3 mmol) in acetonitrile (1.1 mL) was stirred for 2 hours at room temperature. The reaction solution was concentrated and chromatographed on silica gel, eluting with a 95: 5 mixture of chloroform and methanol. This gave 142 mg (57%) of 2- (4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine) acetic acid methyl ester as an oil. The oxalate salt, prepared as described in Example 7, melts at 130-135 ° C.

Analysis for C ₂₎ H ₂₈ N ₂ O ₉ Calcd: Found: C, 55.3%; H: 6, l%; N: 6, l%;

Calculated: C, 55.8; H, 6.2%; N, 6.2%.

Example 10

3- (4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino]] piperidine} propionic acid methyl ester

To a solution of 4- (methoxycarbonyl) -4 - [(loxopropyl) phenylamino] piperidine (200 mg, 0.68 mmol) in acetonitrile (1.1 mL) was added methyl acrylate (124 μΐ, 1.36 mmol). . The solution was stirred for 2 hours at 50 ° C, then cooled to room temperature and evaporated. The oily residue was chromatographed on silica gel using ethyl acetate as the eluent. In this way 253 mg (97%)

Methyl 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid is isolated as an oil. The oxalate salt, prepared as described in Example 7 and recrystallized from methanol and 2-butanol, m.p. 170-172 ° C.

Elemental Analysis for C ₂₂ H ₃₀ N ₂ O ₉ : Found: C, 56.5; H, 6.5%; N, 6.0%;

Calculated: C, 56.7; H, 6.4%; N, 6.0%.

Example 11

Methyl 4- (4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine) butanoic acid

150 mg (0.517 mmol) of 4-methoxycarbonyl-4 - [(loxopropyl) phenylamino] piperidine, 187 mg (1 mmol) of methyl 4-bromobutanoate, 39.3 mg of A mixture of potassium carbonate (mmol), sodium iodide (155 mg, 1.0 mmol) and acetonitrile (1 mL) was stirred at 50 ° C for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (1 mL) and filtered. The filtrate was evaporated and the oily residue was chromatographed on silica gel eluting with chloroform / methanol 9: 1 (v / v). 177 mg (88%) of 4- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine) -butyric acid methyl ester are isolated as an oil. The oxalate salt, prepared as described in Example 7, melts at 153-155 ° C.

Elemental Analysis for: C ₂₃ H ₃₂ N ₂ O ₉ Found: C, 57.1; H, 6.6%; N, 5.8%;

Calculated: C, 57.5; H, 6.7%; N, 5.8%.

Example 12

Methyl 5- (4- (methoxycarbonyl) -4-1 (1-oxopropyl) phenylamino) -1-piperidinyl] pentanoic acid

150 mg (0.517 mmol) of 4- (methoxycarbonyl) -4 - [(loxopropyl) phenylamino] piperidine, 200 mg (1 mmol) of methyl 5-bromopentanoate, 40 mg (1 mmol) of potassium carbonate, sodium iodide (155 mg, 1.0 mmol) and acetonitrile (1 mL) were stirred at 52 ° C for 22.5 hours and then at 25 ° C for 12 hours. The reaction mixture was diluted with ethyl acetate (1 mL) and filtered. The filtrate was concentrated and the oily residue was chromatographed on silica gel, eluting with a 90: 9: 1 mixture of chloroform, methanol and triethylamine. 184 mg (88%) of the methyl 5- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidin}} pentanoic acid are isolated as an oil. . The oxalate salt, prepared as described in Example 7, mp 164-166 ° C.

Elemental Analysis for C ₂₄ H ₃₄ N ₂ O ₉ Found: C, 58.0; H, 7.0%; N, 5.7%;

Calculated: C, 58.3; H, 7.0%; N, 5.7%.

Example 13

3- {4- (methoxycarbonyl) -4 - [(l-oxopropyl) phenylamino] -! -piperidine] -propionic acid trifluoroacetate This compound was prepared according to the procedure for Example 5 except that 4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] piperidine equivalent amount is used instead of 4 - [(1-oxopropyl) phenylamino] piperidine. M.p. 189-190 ° C.

Elemental Analysis for: C ₂₁ H ₂₇ N ₂ O ₇ F ₃ Found: C, 53.0; H, 5.7%; N, 5.9%;

date; C: 52.9%; H, 5.7%; N, 5.9%.

Example 14

3- {4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine-J-propionic acid (methoxymethyl) ester

200 mg (0.69 mmol) of 4 - [(1-oxopropyl) phenylamino] 1

A solution of piperidine A9 and methoxymethyl acrylate (120 mg, 1.03 mmol) in acetonitrile (0.7 mL) was stirred at room temperature for 15 hours. The solution was diluted with water / ethyl acetate (1: 1) and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate. 160 mg (57%) of 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} -propionic acid (methoxymethyl) ester are isolated. oil. The oxalate salt, prepared as described in Example 7, mp 141-143 ° C.

Elemental analysis based on the formula C ₂₃ H ₃₂ N ₂ O _I0 ; Found: C, 55.4; H, 6.5%; N, 5.5%;

date; C: 55.6%; H, 6.5%; N; 5.6%.

Example 15

A) 3-Bromopropionic acid vinyl ester

This compound was prepared by R. L. Adelmann, J. Org. Chem.

1949, 1057). To a solution of 3-bromopropionic acid (1.0 g, 6.54 mmol) in vinyl acetate (3.6 mL) was added 100 mg of copper, 104 mg of mercury (II) acetate and 1 drop of concentrated sulfuric acid, respectively. The reaction mixture was stirred at room temperature for 2 days. The heterogeneous mixture was diluted with 10 ml of pentane and then filtered through celite to remove solids. The filtrate was washed twice with water, once with saturated sodium bicarbonate solution and then with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and evaporated. 760 mg (65%) of the vinyl ester of 3-bromopropionic acid are obtained in the form of an oil.

B) 3- {4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino]} piperidine] propionic acid vinyl ester

200 mg (0.689 mmol) of 4- (methoxycarbonyl) -4 - [(loxopropyl) phenylamino] piperidine, 185 mg (1.03 mmol)

A mixture of vinyl ester of 3-bromopropionic acid, 214 mg (1.55 mmol) of potassium carbonate and 1 ml of acetonitrile was stirred for 2 hours at room temperature. The reaction mixture was diluted with water / ethyl acetate (1: 1) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate. In this way, vinyl ester of 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidin} -propionic acid (197 mg, 74%) is isolated. 72 ° C as a white solid. The oxalate salt, prepared as described in Example 7, melts at 156-158 ° C.

Elemental Analysis for: C ₂₃ H ₃₀ N ₂ O ₉ : Found: C; 57.6%; H; 6.4%; N; 5.9%;

Calculated: C, 57.7; H, 6.3%; N, 5.9%.

Example 16

2- (4- (Methoxycarbonyl) -4 - [(] - oxopropyl) phenylamino] -1-piperidine / ethyl acetate

300 mg (1.0 mmol) of 4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] piperidine, 172 mg (1 mmol) of ethyl 2-bromoacetic acid, 79 mg of A mixture of potassium carbonate (0 mmol), sodium iodide (154 mg, 1.0 mmol) and acetonitrile (10 mL) was stirred at 65 ° C for 12 h, then cooled to room temperature and filtered. The filtrate was evaporated and the oily residue was chromatographed on silica gel eluting with ethyl acetate. This gave 300 mg (77%) of 2- {4- (methoxycarbonyl) -4 - [(loxopropyl) phenylamino] -1-piperidin} ethyl acetate as a yellow oil. The oxalate salt, prepared as described in Example 7, melts at 191-193 ° C.

Elemental Analysis for C ₂₂ H ₃₀ N ₂ O ₉ : Found: C, 56.6; H, 6.5%; N, 6.0%;

Calculated: C, 56.6; H, 6.5%; N, 6.0%.

Example 17

3- (4 - ((1-Oxopropyl) -2-fluorophenylamino] -1-piperidine] propionic acid methyl ester

200 mg (0.80 mmol) of 4 - [(1-oxopropyl) -2-fluorophenylamino] piperidine, 0.1 mL (1.12 mmol) of methyl acrylate, 275 mg (2.0 A mixture of potassium carbonate (2 mmol) and methanol (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water / ethyl acetate (1: 1) and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate. 176 mg (65%) of 3- {4 - [(1-oxopropyl) -2-fluorophenylamino] -1-piperidine} propionic acid methyl ester are isolated in the form of an oil which solidifies on standing. The oxalate salt, prepared as described in Example 7, mp 183-184 ° C.

Elemental analysis for C ₂₀ H ₂₇ N ₂ O ₇ F; Found: C, 55.9; H, 6.4%; N, 6.5%;

date; C: 56.3%; H, 6.4%; N, 6.6%.

Example 18

3- (4 - ((1-Oxopropyl) -2-fluorophenylamino} -1-piperidin} propionic acid vinyl ester)

The procedure of Example 15 is followed, however

4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] piperidine is replaced by an equivalent amount of 4 - [(1-oxopropyl) -2-fluorophenylamino] piperidine and the reaction mixture Stir for 16 hours. The vinyl ester of 3- {4 - [(1-oxopropyl) -2-fluorophenylamino] -1-piperidine) propionate (66%) was obtained as an oily substance. The oxalate salt, prepared as described in Example 7, mp 141-143 ° C.

Analysis for C _2I H ₂ F 7 N ₂ O ₇ Calcd: Found: C; 57.6%; H, 6.2%; N, 6.4%;

date; C: 57.5%; H, 6.2%; N, 6.4%.

Example 19

3- (4 - ((1-Oxopropyl) -2-fluorophenylamino] -1-piperidin} propionic acid (3-butenyl) ester

In Example 5, 3- {4 - [(1-oxopropyl) phenylamino] -1-piperidine] -propionic acid trifluoroacetate, m.p. 139.5-141 ° C, was prepared. 4 - [(l12

EN 211 916 A9 oxopropyl) -2-fluorophenylamino] -1-piperidine} propionic acid trifluoroacetate in 1 M phosphate buffer (0.5 M Na ₂ HPO ₄ and 0.5 M Na ₂ HPO _4). ) and stirred for 10 minutes. It was then diluted with chloroform / isopropanol (3: 1) and extracted 5 times. The combined organic layers were dried over sodium sulfate and evaporated. 215 mg (79%) of the free base are obtained. To a solution of 3- {4 - [(1-oxopropyl) -2-fluorophenylamino] -1-piperidine} propionic acid (185 mg, 0.574 mmol) in chloroform (5 mL), 570 mg (2.87 mmol), LJ O- (3-butenyl) -N, N-diisopropyl-pseudocarbamide prepared by the method of Mathias (Synthesis, 1979, 561) was added. The solution was refluxed for 24 hours, cooled and evaporated. The residue was chromatographed on silica gel, eluting with a 1: 1 by volume mixture of hexane and ethyl acetate. 120 mg (56%) of 3- {4 - [(1-oxopropyl) -2-fluorophenylamino] -1-piperidine} propionic acid (3-butenyl) ester are isolated as an oil. . The oxalate salt, prepared as described in Example 7, melts at 165.5166.5 ° C.

Analysis for C 3 H _{3 2} | F Based N ₂ O ₇ Calcd: Found: C, 58.8%; H, 6.8%; N, 6.0%;

Calculated: C, 59.2; H, 6.7%; N, 6.0%.

Example 20

3 - [(2-Methoxy] oxoethyl / phenylamino) -1-piperidine / propionic acid methyl ester

200 mg (0.805 mmol) of 4 - [(2-methoxyloxoethyl) phenylamino] -piperidine prepared by the method of BS Huang et al. (U.S. Patent 4,584,303) and 94 μΐ (1.05 mmol). A solution of methyl acrylate in 1 ml of methanol was stirred at room temperature for 4 hours. The reaction solution was concentrated and the residue was chromatographed on silica gel, eluting with a 95: 5 mixture of chloroform and methanol. This gave 260 mg (97%) of 3- {4 - [(2-methoxy-1-oxoethyl) phenylamino] -1-piperidine) propionic acid methyl ester as an oily substance. The free base is dissolved in diethyl ether and an equimolar amount of oxalic acid is added. The precipitated gum was triturated with ethyl acetate to give the oxalate salt as a white solid, mp 188-190 ° C.

Analysis calculated for C ₂ oH _{2g g of} N ₂ O Calc'd: Found: C, 56.6%; H, 6.7%; N, 6.6%;

Calculated: C, 56.6; H, 6.7%; N, 6.6%.

Example 27

3- (4 - [(2-Methoxy-1-oxoethyl / 2-fluorophenylamino]]] piperidine / propionic acid methyl ester

A solution of 250 mg (0.94 mmol) of 4 - [(2-methoxy-1-oxoethyl) -2-fluorophenylamino] piperidine and 170 μΐ (1.88 mmol) of methyl acrylate in 5.0 mL of methanol was added. Stir at room temperature for 24 hours. The reaction solution was concentrated and the oily residue was chromatographed on silica gel eluting with ethyl acetate. 3- (4 - [(2-Methoxy-1-oxoethyl) -2-fluorophenylamino] -1-piperidine) propionic acid methyl ester (202 mg, 61%) is isolated as an oil. The oxalate salt, prepared as described in Example 7, melts at 186-188 ° C.

Elemental analysis based on C ₂₀ H ₂₇ N ₂ O _g F:

Found: C, 54.3; H: 6, l%; N, 6.4%;

Calculated: C, 54.3; H, 6.2%; N, 6.3%.

Example 22 Methyl (±) - cis - {3- / 3-methyl-4 - [(] - oxopropyl / phenylamino] -1-piperidin} propionic acid

750 mg (3.94 mmol) of (±) -cis-3-methyl-4- (phenylamino) prepared by the method of W. M. M. Bever et al., J. Med. Chem. 1974, 77, 1047. ) piperidine and 710 μΐ (7.88 mmol) of methyl acrylate in 2.5 mL of methanol was stirred for 30 minutes at room temperature. The resulting solution was evaporated and the oily residue was chromatographed on silica gel using ethyl acetate as eluent. There was thus obtained (±) -cis-3- [3-methyl-4- (phenylamino) -1-piperidinyl] propionic acid methyl ester (787 mg, 72%) as an oil.

(±) -cis-3- [3-methyl-4- (phenylamino) -1-piperidinyl] propionic acid methyl ester (500 mg, 1.8 mmol), propionyl chloride (785 μΐ, 9.0 mmol) and 320 mg (2.63 mmol)

A solution of 4- (dimethylamino) pyridine in 10 ml of acetonitrile was heated to reflux for 30 minutes and stirred. The resulting solution was cooled to room temperature and diluted with saturated cold ethyl acetate (2 x 25 mL), and the organic layer was dried over magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel using ethyl acetate as the eluent. 392 mg (65%) of (±) -cis- {3- [3-methyl-4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid methyl ester are isolated as an oil. The free base is dissolved in toluene and the solution is saturated with dry hydrogen chloride and concentrated. The solid is then recrystallized from ethyl acetate to give the hydrochloride salt, m.p. 180-187 ° C.

Elemental analysis based on the formula C ₉ H ₂₉ N ₂ O ₃ C1:

Found: C, 61.5; H, 7.9%; N, 7.9%;

Calculated: C, 61.9; H, 7.9%; N, 7.6%.

Example 23 (+) - Cis - [3- [3-Methyl-4- (1-oxo-propyl / phenylamino] -7-piperidine) -propionic acid / methoxymethyl / ester

(±) -cis-3-methyl-4- (phenylamino) piperidine (350 mg, 1.8 mmol), 2-bromopropionic acid methoxymethyl ester (450 mg, 2.28 mmol), A mixture of potassium carbonate (350 mg, 2.54 mmol), 4- (dimethylamino) pyridine (50 mg, 0.41 mmol) and acetonitrile (3 mL) was stirred at room temperature for 24 hours and then with saturated sodium bicarbonate solution (20 mL). diluted. The resulting mixture was extracted with ethyl acetate (2 x 20 mL) and the organic layers were combined, dried over magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel using ethyl acetate as the eluent. 371 mg (66%) of (±) -cis-3- [3-methyl-4- (phenylamino) -1-piperidine] -propionic acid (methoxymethyl) ester are isolated as an oil.

350 mg (1.14 mmol) (±) -cis-3- [3-methyl-4- (phenylamino) -1-piperidine] -propionic acid (methoxymethyl) ester 250 mg (2.0 mmol) - (dimethylamino) pyridine, 1.0 ml (11.5 mmol) of propionyl chloride in 10 ml of acetonitrile

The batch solution of A9 was refluxed for 30 minutes and stirred, then cooled to room temperature. The reaction solution was diluted with 25 mL of cold saturated sodium carbonate solution and extracted 3 times with 25 mL of ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel, eluting with a 1: 1 mixture of ethyl acetate and hexane. 253 mg (60%) of (±) -cis- {3- [3-methyl-4- (1-oxopropyl) phenylamino] -1-piperidine} propionic acid (methoxymethyl) ester are isolated. a. The oxalate salt, prepared as described in Example 7, melts at 83-92 ° C.

Elemental analysis based on the formula C ₂₂ H ₃₂ N ₂ O _g H ₂ O:

Found: C, 57.4; H, 7.2%; N, 6.2%;

Calculated: C, 57.3; H, 7.2%; N, 7, l%.

Example 24 Allyl (±) -cis (3- [3-Methyl-4- (1-oxo-propyl) -phenylamino] -1-piperidine) -propionic acid

A solution of (±) -cis-3-methyl-4- (phenylamino) piperidine (400 mg, 2.1 mmol) and allyl acrylate (471 mg, 4.2 mmol) in acetonitrile (5 mL) was stirred at room temperature for 4 hours, then evaporate. The oily residue was chromatographed on silica gel using ethyl acetate as the eluent. The allyl ester of (±) -cis-3- [3-methyl-4- (phenylamino) -1-piperidinyl] propionic acid (405 mg, 64%) is isolated as an oil.

Allyl ester of (±) -cis-3- [3-methyl-4- (phenylamino) -1-piperidin] -propionic acid (400 mg, 1.32 mmol), 4- (dimethyl) in 250 mg (2.0 mmol) -amino) -pyridine and 1.15 mL (13.2 mmol) of propionyl chloride in 10 mL of acetonitrile was refluxed for 30 minutes and stirred, then cooled to room temperature. The reaction solution was diluted with 25 mL of cold saturated sodium carbonate solution and extracted 3 times with 25 mL of ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel, eluting with a 1: 1 mixture of ethyl acetate and hexane. In this way, 335 mg (74%) of (±) -cis- {3- [3-methyl-4- (1-oxo-propyl) -phenylamino] -1-piperidin-propionic acid allyl ester are isolated as an oil. The oxalate salt, prepared as described in Example 7, melts at 150-152 ° C.

Elemental Analysis for: C ₂₃ H ₃₂ N ₂ O ₇ Found: C, 61.6; f H, 7.2; N, 6.3%;

Calculated: C, 61.6; H, 7.2%; N, 6.3%.

Example 25 (+) - Cis-2- (3-Methyl-4 - [(] - oxopropyl) phenylamino] piperidine / ethyl acetate

(±) -cis-3-methyl-4- (phenylamino) piperidine (300 mg, 1.57 mmol), bromoethyl acetate (865 μΐ, 789 mmol), 100 mg (0.82 mmol) A mixture of (dimethylamino) pyridine, 250 mg (1.81 mmol) of potassium carbonate and 4 ml of acetonitrile was stirred at room temperature for 6 hours. The resulting mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel, eluting with a 3: 1 by volume mixture of ethyl acetate and hexane. 402 mg (92%) of (±) -cis-2- [3-methyl-4- (phenylamino) -1-piperidine] ethyl acetate are isolated in the form of an oil.

(±) -cis-2- [3-methyl-4- (phenylamino) -1-piperidine] ethyl acetate (400 mg, 1.45 mmol), propionyl chloride (1.25 mL, 14.5 mmol) and A solution of 4- (dimethylamino) pyridine (353 mg, 2.89 mmol) in acetonitrile (10 mL) was heated at reflux for 30 minutes and stirred. The resulting solution was cooled to room temperature, diluted with cold saturated sodium carbonate solution and extracted with ethyl acetate (3 x 25 mL). The organic layer was dried over magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel eluting with ethyl acetate. 389 mg (81%) of (±) -cis-2-3-methyl-4 - [(1-oxopropyl) phenylamino] -1-piperidine} ethyl acetate were isolated as an oil. The oxalate salt, prepared as described in Example 7, melts at 148150 ° C.

Elemental Analysis for: C ₂ H ₃₀ N ₂ O ₇ Found: C, 59.6; H, 7.3%; N, 6.6%;

Calculated: C, 59.7; H, 7.2%; N, 6.6%.

Example 26 (-) - Cis-3S-Methyl-4R - [(N-1R-methylbenzylamido) phenylamino) -1- (N-1R-methylbenzylamido) piperidine and (-) ) -cis-3R-Methyl-4S - [(N1R-methyl-benzyl-amido) -phenylamino] - (N-IR-methyl-benzyl-amido) -piperidine

(±) -cis-3-methyl-4- (phenylamino) piperidine, 2.0 g (10.5 mmol), 4- (dimethylamino) pyridine (250 mg, 2.0 mmol) and A solution of R - (+) -? - methylbenzyl isocyanate (g, 27.2 mmol) was stirred at 120 ° C for 6 hours. The resulting solution was cooled to room temperature, chromatographed on silica gel, eluting with a 1: 1 mixture of ethyl acetate and hexane. Thus, two diastereomers are separated. The less polar isomer was recrystallized from ethyl acetate to give 1.5 g of (-) - cis-3S-methyl-4R [(N-1R-methylbenzylamido) phenylamino] -1- (N-1Rmethyl). benzylamido) piperidine is obtained in the form of a solid, m.p. 172-173 ° C; [?] D = 114.4 '(c = 1.5, MeOH).

Elemental Analysis for: C ₃₀ H ₃₆ N ₃ O ₂ Found: C, 74.4; H, 7.5%; N, 11.6%;

Calculated: C, 74.4; H, 7.5%; N, 11.6%.

The more polar diastereomer was recrystallized from ethyl acetate-hexane to give 1.8 g of (-) - cis-3R-methyl-4S - [(N-1R-methylbenzyl) amido) phenylamino] -1-. (N 1 R -methylbenzylamido) piperidine is obtained in the form of a solid, m.p. 105-106 ° C;

[?] g = -63.6 '(c = 1.8, MeOH).

Example 27 Methyl (-) - cis-3- [3R-methyl-4S - [(1-oxopropyl) phenylamino] -1-piperidine / propionic acid

1.75 g (3.6 mmol) of (-) - cis-3R-methyl-4S - [(N-1R-methylbenzylamido) phenylamino] -1- (N-1R-methylbenzyl) amido) piperidine in 40 ml of 48% hydrogen bromide at reflux for 24 hours

Boil and stir. The mixture was cooled and evaporated. The oily residue was dissolved in water (20 mL) and extracted with diethyl ether (2 x 50 mL). The aqueous phase was basified to pH 10.5 with 5N sodium hydroxide solution and extracted with ethyl acetate (2 x 25 mL). The ethyl acetate extracts were combined, dried over magnesium sulfate and evaporated. The solid residue was recrystallized from ethyl acetate-hexane to give (-) - cis-3R-methyl-4S- (phenylamino) piperidine (610 mg, 89%) as a solid, m.p. 95-97 ° C; [α] 25 D = 7.5 ° (c = 2.5, MeOH).

A solution of (-) - cis-3R-methyl-4S- (phenylamino) piperidine (500 mg, 2.63 mmol), methyl acrylate (473 μΐ, 5.26 mmol) in methanol (10 mL) was stirred at room temperature for 6 hours and then concentrated. . The oily residue was chromatographed on silica gel using ethyl acetate as the eluent. 623 mg (86%) of (-) - cis-3- [3R-methyl-4S- (phenylamino) -piperidine] -propionic acid methyl ester are isolated as an oil; [.alpha.] D @ 20 = + 25.7 DEG (c = 1.85, MeOH).

(-) - Cis-3- [3R-methyl-4S- (phenylamino) -piperidine] -propionic acid methyl ester (600 mg, 2.17 mmol), 4- (dimethylamino) - 250 mg (2.05 mmol). A solution of pyridine and 1.89 ml (21.7 mmol) of propionyl chloride in 10 ml of acetonitrile was refluxed for 30 minutes and stirred. It is then diluted with 50 ml of cold saturated sodium carbonate solution and extracted 3 times with 25 ml of ethyl acetate. The extract was dried over magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel, eluting with a 1: 1 mixture of ethyl acetate and hexane. 453 mg (63%) of (-) - cis-3- {3R-methyl-4S - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid methyl ester are isolated as an oil. The hydrochloride salt. prepared as described in Example 22, m.p. 151-152 ° C.

Elemental analysis of C | ₉ H ₂₉ N ₂ O ₃ Cl Found: C, 62.2; H, 7.9%; N, 7.8%;

Calculated: C, 61.9; H, 7.9%; N, 7.6%.

Example 28 Trans-3-Methyl-4 - [(1-oxo-propyl) -phenylamino] -piperidine

1.2 g (6.35 mmol) of W. van M. Berer et al., J. Med. Chem. 1974, 17, 1047 and TR Bürke Jr. et al., J. Med. Chem. 1986 29, 1087), by crystallization of the pure cis-isomer, essentially containing the trans -isomer, cis and trans-3-methyl-4- (phenylamino) -piperidine, 1 ml (6.98 mmol). benzyl chloroformate, sodium bicarbonate (1 g, 11.8 mmol), diethyl ether (5 mL), ethyl acetate (5 mL) and water (10 mL) were stirred vigorously at room temperature for 1 hour. The organic layer was separated, washed with 2N sodium hydroxide solution (2 x 5 mL), dried over magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel eluting with ethyl acetate to give 1.82 g (91%) of trans-N- (benzyloxycarbonyl) -3-methyl-4- (phenylamino) piperidine as an oil. Less than 5% cis-N- (benzyloxycarbonyl) -3-methyl-4- (phenylamino) piperidine is isolated.

Trans-N- (benzyloxycarbonyl) -3-methyl-4- (phenylamino) piperidine (1.5 g, 4.6 mmol) and 375 mg (3.1 mmol)

To a solution of 4- (dimethylamino) piperidine in 10 mL of acetonitrile was added 3.6 mL (41 mmol) of propionyl chloride. The solution was refluxed for 30 minutes and stirred, then cooled to room temperature and diluted with saturated sodium carbonate solution (30 mL). The resulting mixture was extracted with ethyl acetate (2 x 30 mL), the organic phases were combined, dried over magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel, eluting with a 1: 1 mixture of ethyl acetate and hexane. 1.6 g (91%) of trans-N- (benzyloxycarbonyl) -3-methyl-4 - [(1-oxopropyl) phenylamino] piperidine are isolated in the form of an oil.

1.5 mg (3.94 mmol) of N- (benzyloxycarbonyl) -3-methyl-4 - [(1-oxopropyl) phenylamino] piperidine, 200 mg of 10% palladium on carbon A mixture of the catalyst, 20 ml of methanol and 20 ml of acetic acid was hydrogenated for 24 hours at 344.7 kPa. The resulting suspension was filtered through celite and the filtrate was evaporated. The residue was diluted with ethyl acetate (50 mL), basified to pH 11 with 2N sodium hydroxide solution and shaken. The organic layer was separated, dried over magnesium sulfate and evaporated to give 720 mg (96%) of trans-3-methyl-4 - [(1-oxopropyl) phenylamino] piperidine.

EXAMPLE 29 Methyl Trans-3- [3-Methyl-4 - [(1-oxopropyl) phenylamino] piperidine] propanoic acid

A solution of trans-3-methyl-4 - [(1-oxopropyl) phenylamino] piperidine (250 mg, 1 mmol) and methyl acrylate (182 μΐ, 2 mmol) in methanol (2 mL) was stirred at room temperature for 24 hours and evaporated. . The oily residue was chromatographed on silica gel using ethyl acetate as the eluent. 300 mg (89%) of methyl 3- (3-methyl-4 - [(1-oxo-propyl) -phenylamino] -piperidine} -propionic acid methyl ester are isolated as an oil. The oxalate salt monohydrate, prepared as described in Example 7, melts at 125-130 ° C.

Analysis for C ₂ | based H ₃₂ N ₂ O ₈ Calcd: Found: C, 57.4%; H, 7.0%; N, 6.4%;

Calculated: C, 57.3; H, 7.3%; N, 6.4%.

Example 30 Trans-3- (3-Methyl-4 - [(1-oxo-propyl) -phenylamino} -piperidine} -propionic acid (ethoxymethyl) ester

Trans-3-methyl-4 - [(1-oxopropyl) phenylamino] piperidine (300 mg, 1.2 mmol) and ethoxymethyl acrylate (350 mg, 2.4 mmol) in acetonitrile (10 mL) The mixture was stirred at room temperature for 24 hours and then concentrated. The oily residue was chromatographed on silica gel using ethyl acetate as the eluent. 300 mg (65%) of trans-3- {3-methyl-4 - [(1-oxopropyl) phenylamino] piperidine} propionic acid (ethoxymethyl) ester are isolated as an oil. The oxalate salt, prepared as described in Example 7, melts at 115-116 ° C.

HU 211 916 A9

EXAMPLE 31 Trans-3- [3-Methyl-4 - [(1-oxo-propyl) -phenylamino] -piperidine] -propionic acid allyl ester

A solution of trans-3-methyl-4 - [(1-oxopropyl) phenylamino] piperidine (300 mg, 1.2 mmol) and allyl acrylate (272 mg, 2.4 mmol) was stirred at room temperature for 16 hours and then concentrated. . The oily residue was chromatographed on silica gel using ethyl acetate as the eluent. This gave 300 mg (69%) of the allyl trans-3- {3-methyl-4 - [(1-oxopropyl) phenylamino] piperidine} propionic acid as an oil. The oxalate salt, prepared as described in Example 7, mp 147-148 ° C.

Elemental Analysis for: C ₂₃ H ₃₂ N ₂ O ₇ Found: C, 61.7; H, 7.2%; N, 6.2%;

Calculated: C, 61.6; H, 7.2%; N, 6.2%.

EXAMPLE 32 Trans-2- {3-Methyl-4 - [(1-oxo-propyl) -phenylamino] -piperidine-ethyl-acetate

Trans-3-methyl-4 - [(1-oxopropyl) phenylamino] piperidine, 250 mg (1 mmol), ethyl 2-bromoacetic acid ester, 338 mg (2.0 mmol), 300 mg (2, A mixture of potassium carbonate (2 mmol), sodium iodide (50 mg, 0.3 mmol) and acetonitrile was stirred at room temperature for 16 hours. The resulting mixture was then diluted with 25 mL of saturated sodium bicarbonate solution and extracted with 2 x 25 mL of ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel using ethyl acetate as the eluent. Trans-2- {3-methyl-4 - [(1-oxopropyl) phenylamino] piperidine) ethyl acetate (300 mg, 89%) is isolated as an oil. The oxalate salt monohydrate, prepared as described in Example 7, mp 149-150 ° C.

Elemental Analysis for: C ₂₁ H ₃ N ₂ O ₇ Found: C, 59.6; H, 7.2%; N, 6.6%;

Calculated: C, 59.7; H, 7.2%; N, 6.6%.

Example 33 (±) - Cis - {3-Methyl-4 - [(1-oxopropyl) -2-fluorophenylamino] piperidine.

12.95 g (48.6 mmol) of WFM Van Berer et al. (J. Med. Chem. 1974, 77, 1047) and TR Bürke Jr. et al. (J. Med. Chem. 1986, 29, 1087). ) (except that the aniline was replaced by 2-fluoroaniline), 1- (methoxycarbonyl) -3-methyl-4- (2-fluorophenylamino) piperidine was prepared and

A mixture of propionic anhydride (12.5 mL, 7.2 mmol) was heated at reflux for 15 h. The cooled solution was diluted with ethyl acetate and washed twice with 2N sodium hydroxide solution, five times with saturated sodium bicarbonate solution, once with 1M phosphoric acid and once with saturated sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated. The residue was dissolved in diethyl ether and hexane and kept at 10 ° C for 15 hours. The precipitated solid was collected by filtration and recrystallized from diethyl ether and hexane to give 3.2 g (20%) of cis-1-methoxycarbonyl-3-methyl-4 - [(1-oxopropyl) -2-fluoro -phenylamino] -piperidine was obtained as a solid, m.p. 128-130 ° C. The mother liquors are combined and evaporated to give a mixture of cis and trans isomers with a small amount of other impurities.

3.2 g (9.89 mmol) of cis-1- (methoxycarbonyl) -3-methyl-4 - [(1-oxopropyl) -2-fluorophenylamino] piperidine in 20 ml of 48% slurry with hydrogen bromide was refluxed for 2 hours. During heating, the mixture dissolves. The solution was cooled to 0 ° C and extracted with 5N sodium hydroxide solution, and the organic extract was combined, dried over sodium sulfate and evaporated. This gave 2.0 g (97%) of cis-3-methyl-4- (2-fluorophenylamino) piperidine as an oil.

A mixture of benzyl chloroformate (0.39 mL, 2.76 mmol) and sodium bicarbonate (284 mg, 3.6 mmol) in water (4 mL) and diethyl ether (4 mL) was stirred with vigorous stirring for 500 mg (2.4 mmol). a solution of cis-3-methyl-4- (2-fluorophenylamino) piperidine in 2 mL of diethyl ether was added. After stirring for one hour at ambient temperature, the layers were separated and the organic layer was washed twice with 2N sodium hydroxide solution and once with saturated sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated. There was thus obtained 740 mg (90%) of cis-1- (benzyloxycarbonyl) -3-methyl-4- (2-fluorophenylamino) piperidine as an oil.

740 mg (90%) of cis-1- (benzyloxycarbonyl) -3-methyl-4- (2-fluorophenylamino) piperidine and 395 mg (3.24 mmol) of 4- (dimethylamino) - To a solution of pyridine in 10 mL of acetonitrile was added 0.38 mL (4.32 mmol) of propionyl chloride. The reaction mixture was heated at 50 ° C for 10 hours, then concentrated and the residue was dissolved in ethyl acetate and water. The organic layer was washed twice with saturated sodium bicarbonate solution, once with 1M phosphoric acid, and once with saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated to give 769 mg (89%) of pure cis-1- (benzyloxycarbonyl) -3-methyl-4 - [(loxopropyl) -2-fluorophenylamino]. ) -piperidine is obtained in the form of an oil.

576 mg (1.45 mmol) of cis -1- (benzyloxycarbonyl) 3-methyl-4 - [(1-oxopropyl) -2-fluorophenylamino) piperidine and 100 mg of 10% A mixture of palladium on carbon (25 ml) in methanol (5 ml) and acetic acid (5 ml) was hydrogenated at 344.7 kPa for 5 hours. The reaction mixture was filtered through celite and the filtrate was evaporated. The residue was diluted with ethyl acetate, basified to pH 11 with 2N sodium hydroxide solution and shaken. The separated organic layer was dried over sodium sulfate and evaporated. This gave 333 mg (87%) of an oil as cis-3-methyl-4 - ((loxopropyl) -2-fluorophenylamino) piperidine.

Example 34 Methyl (±) -cis-3- {3-methyl-4 - {(1-oxopropyl) -2-fluorophenylamino] -1-piperidine} propionic acid

(±) -cis- (3-methyl-4 - [(1-oxopropyl) -2-fluorophenylamino] -1-piperidine) (200 mg, 0.757 mmol) and 0.1 mL (1.13 mmol) methyl acrylate was prepared with 2 ml of acetonitrile

The solution of A9 is stirred for 12 hours at room temperature. The solution was evaporated and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (2: 1). 44 mg (17%) of (±) -cis-3- {3-methyl-4 - [(1-oxopropyl) -2-fluorophenylamino] -1-piperidine} propionic acid methyl ester are isolated. in the form of oil. The free base was dissolved in toluene and the solution evaporated to give the hydrochloride salt as a white solid, m.p. 177-178 ° C.

Analysis calculated for C 9 H ₂₈ N ₁ O ₂ C1F ₃ Calc'd: Found: C, 59.0%; H, 7.3%; N, 7.2%;

Calculated: C, 59.0; H, 7.3%; N, 7.2%.

Example 35 (±) -Cis-3- {3-Methyl-4 - [(1-oxopropyl) -2-fluorophenylamino] -1-piperidine} propionic acid (ethoxymethyl ester) 70 mg (0.265 mmol) ) A solution of (±) -cis- {3-methyl-4 - [(1-oxopropyl) -2-fluorophenylamino} piperidine and 73 μΐ (0.265 mmol) ethoxymethyl acrylate in 1 ml acetonitrile After stirring for 18 hours at room temperature, the solution was concentrated and the residue was chromatographed on silica gel eluting with ethyl acetate to give (±) -cis-3- {3-methyl-4 - [(1-oxopropyl) 84 mg (80%). ) -2-Fluorophenylamino] -1-piperidine} -propionic acid methyl ester is isolated as an oil, the free base is dissolved in ethyl acetate, and a solution of oxalic acid in diethyl ether is added to the solution. redissolved in acetate and, upon cooling, the material recrystallized to give the oxalate salt as a white solid, m.p. 96-97 ° C.

Found: C, 56.6%; C NiOH ^ NiNOOgF requires: C, 56.6; H, 6.8%; N, 6.1%;

Calculated: C, 57.0; H, 6.9%; N, 5.8%.

Example 36 Allyl (+) - cis-3- {3-Methyl-4 - [(] -oxopropyl) -2-fluorophenylamino] -7-piperidinecarboxylate (100 mg, 0.378 mmol) A solution of (+) - cis {3-methyl-4 - [(loxopropyl) -2-fluorophenylamino} piperidine and 90 μΐ (0.757 mmol) allyl acrylate in 1 ml acetonitrile was stirred at room temperature for 16 hours. . The solvent was removed and the residue was chromatographed on silica gel, eluting with a 1: 1 mixture of ethyl acetate and hexane. The allyl ester of (±) -cis-3- {3-methyl-4 - [(1-oxopropyl) -2-fluorophenylamino] piperidine) propionic acid (76 mg, 53%) is isolated as an oil. The free base is dissolved in ethyl acetate and a solution of oxalic acid in diethyl ether is added.

The precipitated fibrous precipitate was collected and washed with diethyl ether and ethyl acetate. This gives the oxalate salt monohydrate, m.p. 96-98 ° C.

Elemental analysis based on C ₂₃ H ₃₃ N ₂ O ₈ F:

Found: C, 57.3; H, 6.7%; N, 5.8%;

Calculated: C, 57.0; H, 6.9%; N, 5.8%.

Example 37 (±) -Cis-2- {3-Methyl-4- (1-oxopropyl) -2-fluorophenyl10 amino] piperidine} ethyl acetate

250 mg (0.946 mmol) of (±) -cis- {3-methyl-4 - [(loxopropyl) -2-fluorophenylamino} piperidine, 0.16 mL (1.42 mmol) in 2-bromo A suspension of ethyl acetate, 260 mg (1.89 mmol) of potassium carbonate and a catalytic amount of sodium 15 iodide in 3 ml of acetonitrile was stirred for 10 hours at 40 ° C. The mixture was diluted with water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic extracts were washed once with a saturated sodium chloride solution, dried over sodium sulfate, and then concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate. 241 mg (73%) of (±) -cis-2- {3-methyl-4 - [(1-oxopropyl) 2-fluorophenylamino] -1-piperidine} ethyl acetate were isolated. in the form of oil. The oxalate hemihydrate, prepared as described in Example 7, mp 118-127 ° C.

Elemental analysis for C ₂₁ H ₂₉ N ₂ O ₇ F.0.5H ₂ O:

Found: C, 55.7; H, 6.6%; N, 6.2%;

Calculated: C, 56.1; H, 6.7%; N, 6.2%.

Example 38

A pharmaceutical composition for parenteral or intravenous analgesic administration can be prepared from the following components:

Ingredients: Quantity

3- {4- (Methoxycarbonyl) -4 - [(1-oxo-propyl) -phenylamino] -1-piperidine} -propion40 Acid methyl ester hydrochloride 1 mg

Isotonic saline 1 liter

The above special compound can, of course, also be replaced by other compounds, the amount of which is selected in the composition depending on their analgesic effect.

Example 39

AIII. Compounds of formula (I) listed in Table I are prepared according to the methods described herein using equivalent amounts of the appropriate starting materials.

Table 777

X R R ¹ R ² Price SALT mp (° C) the. - (CH ₂ ) ₂ COOMe et H H 2,4-di-F-Ph oxalate 177-178 b. - (CH ₂ ) ₂ COOnBu et H H 2,4-di-F-Ph oxalate 181-182 c. - (CH ₂ ) ₂ COOtBu et H H 2-F-Ph oxalate 160-162

HU 211 916 A9

X R R ¹ R ² Price SALT mp (° C) d. - (CH ₂ ) ₂ COOMe et H H 2-MeO-Ph oxalate 139-140 e. - (CH ₂ ) ₂ COO (CH ₂ ) ₂ OMe et H H Ph oxalate 164-165 f. - (CH ₂ ) ₂ COO (CH ₂ ) ₂ OEt et H H Ph oxalate 140-141 g .- (CH ₂ ) ₂ COOCH ₂ OMe et H H 2-F-Ph oxalate 131-133 h. -CH (CH ₃ ) CH ₂ COOMe et H H Ph oxalate 148-149.5 i. -CH ₂ CH (CH ₃ ) COOMe et H H Ph oxalate 146-148 j. -4CH ₂ ) ₂ COOMe Me H H 2-Me-Ph oxalate - k. - (CH ₂ ) ₂ COOCH ₂ OMe et H H 2-Et-Ph oxalate - 1. - (CH ₂ ) ₂ COOMe Me MeO-CO H Ph HC1 - m. - (CH ₂ ) ₂ COOMe Me MeO-CH ₂ - H Ph HC1 - n. - (CH ₂ ) ₂ COOMe Me H cis (±) -Me 4-CF ₃ -Ph oxalate - She. - (CH ₂ ) ₂ COOMe et H cis (±) -Me 2-Cl-Ph oxalate -

40-53. example

Following the procedure described in Example 10, and replacing the methyl acrylate of Example 10 with the corresponding alkyl acrylate, the following compounds of formula (1) are prepared; the melting point refers to the oxalate salt:

40. 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid ethyl ester, m.p. 166-167 ° C;

41. Propyl ester of 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] piperidine] propionic acid, m.p. 169-170 ° C;

42. Isopropyl 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidinyl} propionic acid, m.p. 176-177 'C;

43. 3- {4- (Methoxycarbonyl) -4 - ((1-oxo-propyl) -phenylamino) -1-piperidine} -propionic acid (n-butyl) ester, m.p. 153-154 ° C;

44. 3- {4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid isobutyl ester, m.p. 177-178 'C;

45. 3- (4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid (sec-butyl) ester, m.p. 160-161 ° C;

46. 3- {4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid (n-pentyl) ester, m.p. 141-142'C;

47. 3- {4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidin} propionic acid (2-methylbutyl) ester, m.p. 162-163 ° C;

48.3- (4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidinyl] propionic acid isopentyl ester, m.p. 148-149'C;

49. 3- {4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidin} propionic acid neopentyl ester, m.p. 157-158 ° C;

50. 3- {4- (Methoxycarbonyl) -4 - ((1-oxo-propyl) -phenylamino) -1-piperidin} -propionic acid hexyl ester, m.p. 141-142 'C;

51. 3- {4- (Methoxycarbonyl) -4 - [(] - oxopropyl) phenylamino] -1-piperidine} propionic acid heptyl ester, m.p. 129-130 ° C;

52.3- (4- (Methoxycarbonyl) -4 - [(1-oxo-propyl) -phenylamino] -1-piperidine} -propionic acid octyl ester, m.p. 141-142 'C;

53. 3- {4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidin} -propionic acid tert-butyl ester, m.p. 157-158 'C.

40-53. For the synthetic procedure of Example 1, alkyl acrylate starting materials are commercially available, or can be prepared by the literature or the following method using equivalent amounts of the corresponding alcohol instead of 3-methylbutanol.

To a solution of 2.0 g (22.6 mmol) of 3-methylbutanol and 2.05 g (22.6 mmol) of acryloyl chloride in 5 mL of dichloromethane at 0 ° C with stirring, 3.2 mL (22 mL) (7 mmol) of triethylamine was added dropwise. The solution was stirred at room temperature for 30 minutes and then concentrated. The residue was washed with hexane (2 x 10 mL) and the organic solutions were evaporated and filtered through a pad of silica gel to give 3.0 g (93%) of 3-methylbutyl acrylate as an oil.

Of course, the embodiments described herein are merely exemplary, and many changes and modifications can be made by one skilled in the art without departing from the spirit and scope of the invention. All such modifications and alterations are within the scope of the invention as defined in the appended claims.

Claims (47)

PATENT CLAIMS A compound of formula (I) wherein X is alkoxycarbonyl (lower alkyl), (lower alkyl) carbonyloxy (lower alkyl), (alkenyloxycarbonyl) - (C 1 -C 4 alkyl) or (C 1 -C 2 alkoxy) (C 1 -C 2 alkoxy) carbonyl (C 1 -C 4 alkyl); Ar is phenyl or mono-, di- or trisubstituted phenyl, wherein the substituent is independently halogen, lower alkyl, lower alkoxy or trifluoromethyl; HU 211 916 A9 R is lower alkyl or (lower alkoxy) - (lower alkyl; R ¹ is hydrogen, lower alkoxy-carbonyl or methoxymethyl; and R ² is hydrogen or methyl, and the diastereomeric and enantiomeric isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers. 2. A compound according to claim 1, wherein X is lower alkoxycarbonyl. 3. A compound according to claim 1, wherein X is (lower alkyl) carbonyloxy (lower alkyl). The compound of claim 1, wherein X is alkenyloxycarbonyl (lower alkyl). The compound of claim 1, wherein X is (C 1 -C 2 alkoxy) - (C 1 -C 2 alkoxy) carbonyl (C 1 -C 4 alkyl). The compound of claim 1, wherein Ar is phenyl or 2-fluorophenyl. The compound of claim 1, wherein R is ethyl. The compound of claim 1, wherein R ¹ is methoxycarbonyl. The compound of claim 1 which is Methyl 5- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidinyl} pentanoic acid; 2- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamine] -Piperidine} ethyl acetate; Methyl 3- (4 - [(1-oxopropyl) -2-fluorophenylamino] -1-piperidine} propionic acid, or 3- {4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid vinyl ester; or a pharmaceutically acceptable acid addition salt thereof. 10. 3- (4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidinyl} propionic acid alkyl ester and its pharmaceutically acceptable acid addition salts. A compound according to claim 10, wherein the carbon atom directly attached to the oxygen atom in the alkyl group of the alkyl ester is methylene or methyl. A compound according to claim 10, wherein the alkyl portion of the alkyl ester is ca. C 1-10. 13. The compound of claim 10, wherein the alkyl ester is a methyl ester. The diastereomer or enantiomer of a compound according to claim 1. 15. A pharmaceutical analgesic composition which is a compound of formula I wherein X is alkoxycarbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl-, alkenyloxy-. carbonyl) (lower alkyl) or (C 1-2) alkoxy (C1-2) alkoxy) carbonyl (lower alkyl); Ar is phenyl or mono-, di- or trisubstituted phenyl, wherein the substituent is independently halogen, lower alkyl, lower alkoxy or trifluoromethyl; R is lower alkyl or (lower alkoxy) - (lower alkyl); R ¹ is hydrogen, lower alkoxy-carbonyl or methoxymethyl; and R ² is hydrogen or methyl, and comprises an effective amount of an analgesic amount of diastereomeric and enantiomeric isomers thereof, and pharmaceutically acceptable acid addition salts of the compounds and isomers, and a pharmaceutically acceptable carrier. 16. A composition according to claim 15 wherein X is (alkoxycarbonyl) - (lower alkyl). 17. A composition according to claim 15, wherein X is (lower alkyl) carbonyloxy (lower alkyl). 18. The composition of claim 15, wherein X is alkenyloxycarbonyl (lower alkyl). 19. The composition of claim 15, wherein X is (C1-C2) alkoxy (C1-C2) alkoxy-carbonyl (lower alkyl). 20. The composition of claim 15, wherein Ar is phenyl or 2-fluorophenyl. 21. The composition of claim 15, wherein R is ethyl. The composition of claim 15, wherein R ¹ is methoxycarbonyl. 23. The composition of claim 15, wherein the compound is 5- {4- (methoxycarbonyl) -4 - [(l-oxopropyl) phenylamino] -l-piperidin} -pentanoic acid methyl ester; 2- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidin} ethyl acetate; 3- {4 - ((1-Oxopropyl) -2-fluorophenylamino] -1-piperidin} propionic acid methyl ester, or 3- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid vinyl ester; or a pharmaceutically acceptable acid addition salt thereof. 24. 3- {4- (Methoxycarbonyl) -4 - ((1-oxo-propyl) -phenylamino] -1-piperidin} -propionic acid alkyl ester and its pharmaceutically acceptable acid addition salts. 25. The composition of claim 24, wherein the carbon atom directly attached to the oxygen atom in the alkyl group of the alkyl ester is methylene or methyl. 26. The composition of claim 24, wherein the alkyl portion of the alkyl ester is ca. C 1-10. 27. The composition of claim 24, wherein the alkyl ester is a methyl ester. The composition of claim 15, wherein the compound is a diastereomer or enantiomer. HU 211 916 A9 29. The composition of claim 15, wherein the pharmaceutically acceptable carrier is for parenteral administration. 30. A method of alleviating pain in a mammal comprising administering to such a mammal a compound of formula I wherein: X is alkoxycarbonyl-lower alkyl, (lower alkyl) -carbonyloxy-lower alkyl, alkenyloxycarbonyl-lower alkyl or (1-2C) alkoxy. (C 1 -C 2 alkoxy) carbonyl (lower alkyl); Ar is phenyl or mono-, di- or trisubstituted phenyl, wherein the substituent is independently halogen, lower alkyl, lower alkoxy or trifluoromethyl; R is lower alkyl or (lower alkoxy) - (lower alkyl); R 'is hydrogen, lower alkoxy carbonyl or methoxymethyl; and R ² is hydrogen or methyl, and the compound is an effective amount of the optically active and cis-trans isomers and isomers of compounds and pharmaceutically acceptable acid addition salts of analgesia terms. The process of claim 30, wherein X is (alkoxycarbonyl) - (lower alkyl). 32. The process of claim 30, wherein X is (lower alkyl) carbonyloxy (lower alkyl). 33. The process of claim 30, wherein X is alkenyloxycarbonyl (lower alkyl). 34. The process of claim 30, wherein X is (C1 -C2 alkoxy) - (C1 -C2 alkoxy) carbonyl (lower alkyl). The process of claim 30, wherein Ar is phenyl or 2-fluorophenyl. The process of claim 30, wherein R is ethyl. The process of claim 30, wherein R 'is meloxycarbonyl. 38. The method of claim 30, wherein the compound is Methyl 5- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidinyl} pentanoic acid; 2- {4- (methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidin} ethyl acetate; 3- {4 - [(1-Oxopropyl) -2-fluorophenylamino] -1-piperidine} propionic acid methyl ester; obsession 3- {4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidine} propionic acid vinyl ester; or a pharmaceutically acceptable acid addition salt thereof. 39. 3- (4- (Methoxycarbonyl) -4 - [(1-oxopropyl) phenylamino] -1-piperidinyl) propionic acid alkyl ester and its pharmaceutically acceptable acid addition salts, 40. The process of claim 30, wherein the carbon atom directly attached to the oxygen atom in the alkyl group of the alkyl ester is methylene or methyl. 41. The process of claim 30, wherein the alkyl portion of the alkyl ester is ca. C 1-10. 42. The process of claim 30, wherein the alkyl ester is a methyl ester. 43. The process of claim 30, wherein the compound is a diastereomer or an enantiomer. 44. A compound of formula (A): wherein: X _a is carboxy (lower alkyl); Ar is phenyl or mono-, di- or trisubstituted phenyl, wherein the substituents are independently halogen, lower alkyl, lower alkoxy or trifluoromethyl; R is lower alkyl or (lower alkoxy) - (lower alkyl; R ¹ is hydrogen, C ¹ -C 6 alkoxycarbonyl or methoxymethyl; and R ² is hydrogen or methyl. 45. A44. A compound according to claim 1, wherein X _a is carboxyethyl. 46. A compound of formula (I) wherein: X is alkoxycarbonyl (lower alkyl), (lower alkyl) carbonyloxy (lower alkyl), (alkenyloxycarbonyl) (lower alkyl) or (C 1-2) alkoxy - (C 1 -C 2) alkoxy-carbonyl-lower alkyl; Ar is phenyl or mono-, di- or trisubstituted phenyl wherein the substituents are independently halogen, lower alkyl, lower alkoxy or trifluoromethyl; R is lower alkyl or (lower alkoxy) - (lower alkyl); R ¹ is hydrogen, C ¹ -C 6 alkoxycarbonyl or methoxymethyl; and R ² represents a hydrogen atom or a methyl group, and the diastereomeric and enantiomeric isomers, and isomers of the above compounds and the acid addition salts of the compound. 47. A compound of formula (I) wherein: X is (lower alkoxy) carbonyl (lower alkyl), (lower alkyl) carbonyloxy (lower alkyl), alkenyloxycarbonyl (lower alkyl) or (1-2 carbon) alkyl. alkoxy-C1-C2 alkoxy-carbonyl-lower alkyl; Ar is phenyl or mono-, di- or trisubstituted phenyl wherein the substituents are independently halogen, lower alkyl, lower alkoxy or trifluoromethyl; R is lower alkyl or (lower alkoxy) - (lower alkyl; HU 211 916 A9 R ¹ is hydrogen, C ¹ -C 6 alkoxycarbonyl or methoxymethyl; and R ² is hydrogen or methyl, and diastereomeric and enantiomeric isomers thereof, and pharmaceutically acceptable acid addition salts of said compounds and isomers.