IE46836B1 - N-phenyl-n-(4-piperidinyl)amides - Google Patents

Abstract

N-Phenyl-N-(4-piperidinyl)amides have the following formula in which the substituents are defined in Claim 1; the compounds can also be present as acid addition salts. The compounds of the formula I, in which Z is oxygen, are prepared by reacting a corresponding 4,5-dihydro-1H-tetrazol-5-one with a corresponding N-phenyl-N-(4-piperidinyl)amide. Compounds of the formula I, in which Z = O, are likewise obtained by N-acylating a corresponding 4-piperidinamine. Compounds in which Z = S are prepared from compounds of the formula I, in which Z = O, by reaction with a sulphurating agent. Pharmaceutical compositions having an analgesic effect contain, as the active compound component, at least one novel compound of the formula I or a pharmaceutically acceptable acid addition salt thereof.

Description

The present invention relates to N-phenyl-N-(4-piperidinyl) amides having a (4,5-dihydro-4-R-5-oxo-lH-tetrazol-l-yl)alkyl or (4,5-dihydro-4-R-5-thioxo-lH-tetr az-ol-l-yl)alkyl substituent group in the I-position of the piperidine nucleus.

United States Patent Wo. 3,998,834 describes a number of N-phenyl-N-(4-piperidinyl)amides having analgesic properties. The compounds of this invention differ from the foregoing essentially by the nature of the (4,5-dihydro-4-R-5-oxo-lHtetrazol-I-yl)alkyl or (4,5-dihydro-4-R-5-thioxo-IH-tetrazol-lyl)alkyl group present at the I-position of the piperidine nucleus.

The invention provides an N-phenyl-N-(4-piperidinyl) amide of the general formula-- r5 (1) or a pharmaceutically acceptable acid addition salt thereof, wherein: R is a hydrogen atom, a lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, (lower alkyl)-oxy(lower alkyl),aryl or aryl (lower alky1)group,· R^ is a hydrogen atom, a lower alkyl or aryl group; R is a hydrogen atom or a lower alkyl group; R is a lower alkyloxy-carbonyl, lower alkyloxymethyl or lower alkylcarbonyl group; & R* is a lower alkyl, cycloalkyl, lower alkenyl, lower alkyloxy or arylmethyl group; r5 is a hydrogen atom or a lower alkyl group; g R is a hydrogen atom or halogen atom,or a lower alkyl, lower alkyloxy or trifluoromethyl group; Z is 0 or S; and n is 0 or the integer I; wherein the aryl group as used in the foregoing definitions is a phenyl, substituted phenyl, thienyl or pyridinyl group, the substituted phenyl group having 1 or 2 substitutents which are each independently a halogen atom, a lower alkyl, lower alkyloxy or trifluoromethyl group.

By the term lower alkyl as used herein is meant straight and branched chain alkyl radicals having from 1 to 6 carbon atoms, such as, methyl, ethyl, 1-methylethyl, 1,1dimethylethyl, propyl, butyl, pentyl, and hexyl; by the term cycloalkyl is meant cycloalkyl radicals having from 3 to 6 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; by the term lower alkenyl is meant alkenyl radicals having from 3 to 6 carbon atoms such as, 2-propenyl, 2-butenyl, 3-pentenyl and 2-hexenyl; by the termlower alkynyl is meant alkynyl radicals having from 3 to 6 carbon atoms such as,2-propynyl and 2-butynyl; and by the term lower alkyloxy is meant alkoxyl groups containing from 1 to 6 carbon atoms. 46336 The compounds of formula (I) wherein Z is O„ (I-a), can generally be prepared by the reaction of a 4,5-dihydro-lH-tetrazol5»one derivative of the formula N=N v/ith a N=phenyl"N-(4-piperidinyl)amide of the formula (iii) Wherein Es R, R^ andllLare as ahove-defined and either X1 is hydrogen and X is a radical of the formula -ch~(ch2) -CH-Y (IV) E1 . H or X is hydrogen and X1 is a radical of the formula (V) -446836 ' In the above formulae (IV) and (V) R1,22 and n have the previously indicated meanings and y is chloro, bromo, iodo, methylsulfonyloxy or 4-methylphenylsulfonyloxy.

The reaction of (II) with (III) may be carried out following standard N-alkylating procedures as generally known in the art. Said reaction is advantageously conducted in an appropriate, reaction-inert organic solvent, such as, an aromatic hydrocarbon, e.g. benzene, methylbenzene or dimethylbenzene; a lower alkanol, e.g. methanol, ethanol, 2-propanol or 1-bUtanol; a ketone, e.g. 4-methyl~2-pentanonej an ether, e.g. 1,4-dioxane or 1,1' oxybisethane N,N-dimethylformamide, or nitrobenzene.

The addition to the reaction mixture of an appropriate base, such,as, an alkali metal carbonate or hydrogen carbonate, or an organic base, such as, Ν,Ν-diethylethanamine or N-(l-methylethyl)-2propanamine may be utilized to pick up the acid that is liberated during the course of the reaction. In some cases the addition of an iodide salt, preferably an alkali metaliodide, is appropriate. Somewhat elevated temperatures are advantageously employed to enhance the reaction rate. In some circumstances, especially when one of the substituents R1 and R2 is methyl and the other is hydrogen, a partial rearrangement may occur during the reaction yielding a mixture of position isomers wherein respec1*2 1 tively R is methyl and R is hydrogen and inversely R is hydrogen and R is methyl. Such position isomers can easily be separated from each other by known isolation techniques such as, selective crystallisation from an appropriate solvent system or column-chromatography. -54 6 8 3 6 The compounds o£ formula (I-a) can also he prepared by acylating an appropriate 4-piperidinamine of the formula R5 (VI) Said acylation reaction is conveniently carried out according to known N-acylation procedures., for example, by reacting (VI) with an appropriate acyl halide, S -SO-halo, representing respectively a lower alkylcarbonyl halide, a cycloalkylcarbonyl halide, an arylacetyl halide or a lower alkyl haloformate, following techniques known in the art.

When R is a lower alkyl or cycloaikyl group the acylation may also be carried out with an anhydride derived from the acid R4COOH.

The compounds of formula (I) wherein 2 is S, (I-b), can generally be derived from the corresponding (I-a) by reacting the latter with aa appropriate sulfurating agent such as, for example, Fg^g· reacti°.n may be conveniently carried out by stirring and heating the reactants together in an appropriate reaction-inert organic solvent such as, for example, aa aromatic hydrocarbon such as, benzene, methylbenzene, dimethylbeaaene and the like.

The compounds of formula (I) wherein S represents hydrogen are ' preferably derived from the corresponding (I) wherein S represents phenylmethyl by debenzylating the latter in the usual manner, e. g., by catalytic hydrogenation using an appropriate catalyst such as palladium-on-charcoal. -64683 In the foregoing and subsequent preparations, the reaction products are isolated from the reaction mixture, and, if necessary, further purified by the application of common isolation and purification procedures as generally known in the art.

A number of the compounds within the scope of formula (I) have one or more asymmetric carbon atoms within their structure and consequently exist under different stereochemically isomeric forms. More particularly when 21 or 2 2 are other than hydrogen, the carbon atoms to which they are attached are asymmetric, while additional asymmetric carbon atoms may be present in the lower alkyl groups comprised in 2, 23 and 24.

While in the above preparations there are obtained essen15 tially mixtures, including racemic mixtures, of such stereochemical isomers, such mixtures can generally be resolved into their stereochemically pure isomeric forms by the application of known resolution techniques, e.g., by salt formation with optical isomers of asymmetric acids and selective crystallisation of the salts thus obtained.

The stereochemically isomeric forms of compounds of formula (I) are included within the scope of formula (I).

As a result of their basic properties, the compounds ' of formula (I) can be converted to their therapeutically active, non-toxic acid addition salt form by treatment with an’appropriate acid, such as, for example, an inorganic acid, such as hydrohalic acid, e.g., hydrochloric, hydrobromic, and the like, and sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid, such as, 3Q for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-l,2,3-propanetri., carboxylic, benzoic, 3-phenyl-2-propenoic, c(-hydroxybenzene acetic, methanesulfonic, ethanesulfonic, benzenesulfonic, -746836 4-methylbenzenesulfonic, cyclohexanesulfamic, o( -hydroxybenzoic car 4-amino-2-hydroxybenzoic acid.

Conversely, the salt form can be converted by treatment with alkali into the free base form.

The starting materials of formula (II) wherein X is hydrogen, (Il-a), can easily be prepared by the reaction of an appropriate isocyanate of the formula (VU*) or an acyl chloride of the formula (VII) with sodium azide in the presence of aluminium chloride in an appropriate organic solvent, preferably an ether such as tetrahydrofuran (THF). ' a=ifac=o (M or HaH3/AlCl3 THF · - 'Cl (VII') (Il-a) so The reaction is conveniently carried out by stirring and heating the reactants together in the solvent for several hours. When an acyl chloride of formula (VII1) is used as a reactant at least 2 molar equivalents of the | aside have to be employed and. the use of an additional , excess thereof is generally found appropriate. | f Starting materials of formula (II) wherein X is a radical of the formula (IV), (Π-b), can be obtained by introducing said radical into the corresponding (Il-a) by known methods.

' . I f -846836 In general, said starting materials (ΙΙ-b) can be prepared by carrying out the steps of: i) reacting the appropriate (ΙΙ-a) with a haloalkanol derivative of the formula halo-CH-(CH2)n-CH-0H (VIII) following generally known N-alkylating procedures as previously described herein, to obtain an intermediate of the formula (IX) and; ii) subsequently converting the hydroxy group of the 10 thus obtained (IX) into the ς/roup γ as above identified following art-known procedures of preparing reactive esters starting from the corresponding alcohols. reactive ester (IX) -> formation R-N^ N-CH-(CH0 ) -CH-Y W 1-1 l2 R1 · IT (Il-b) -94 6 8 36 Halides are conveniently obtained by the reaction of (IX) · with an appropriate halogenating- agent, such as, sulfinyl chloride, sulfuryl chloride, phosphor pentachloride, phosphor pentabromide, phosporyl chloride. When the group Y is an iodide, it is preferably derived from the corresponding chloride or bromide by the replacement of that halogen with iodine.

Methanesulfonates and 4-methylbenzenesulfonates· are conveniently prepared by reacting the alcohol with an appropriate sulfonyl halide such as, methane sulfonyl chloride and 4-methylbenzenesulfonyl chloride respectively.

When Y in (ΙΙ-b) is chloro, (II-b-1), the introduction of the chloroalkyl chain can also be performed by the reaction of an appropriate (ΙΙ-a) with an appropriate bromo-chloroalkane derivative of the formula (X) following standard N-alkylating procedures to obtain the corresponding (II-b-1).

(X) (II-b-1) -1046836 Alternatively, the starting materials (lI-b-1) wherein R is other than hydrogen or phenyl can be obtained by introducing the R-substituent into a precursor of the formula H/N-CH-(CHO) -CH-Cl / ι 2'n ι Rc . (XI) Said introduction of R is conveniently carried out by the reaction of (XI) with an appropriate reactive ester RY Wherein R is a· pr evioualy defined but other than hydrogen or phenyl, following standard N-alkylating procedures as described hereinabove. It is to be noted that when said Y in said HY is iodo, the chloro substituent of (XI) may be replaced during the reaction by iodo, especially when an excess of the alkylating iodide is employed.

The precursor compounds of formula (XI) may be prepared following the procedures described in Tetrahedron, 31., 765 (1975) wherein the compound of formula (XI) wherein 1 2 ,15 R and R are both hydrogen and n is 1 is specifically described.

The starting materials of formula (III) wherein X1 is hydrogen, (ΙΙΙ-a), can be prepared according to the procedures outlined in U.S.Pat. No. 3,998,834 wherein a number of such starting materials and their preparation are described.

The starting materials of formula (III) wherein X1 is a radical of the formula (V), (ΙΙΙ-b), can be prepared by N-alkylating a piperidine derivative of the formula (ΙΙΙ-a) with a haloalkanol of the formula (XII) in the usual manner to obtain an intermediate of the formula (XIII) and thereafter converting the hydroxy group of the latter into a reactive ester group as previously described.

R5 3 _l_ 24 H0CH-(CH2)n-CH-halo + UN S' 2" (XII) (Ill-a). reactive ester formation (IXI-b) Intermediates of formula (XIII) herein wherein n is 0 can also be obtained by the reaction of (ΙΙΙ-a) with an appropriately substituted oxirane of the-formula Z\ CH--CH (XIV) -1246836 It is to be noted that when in formula (XIV) one of the 1 2 radicals E and E is methyl, the other being hydrogen, there is substantially, obtained an intermediate (XIII) wherein the methyl substituent is located at the $- position with respect to the piperidine nitrogen. Intermediates of formula (XIII) wherein E1 is phenyl and n is zero and methods of preparing them are also described in U.S.Pat. No. 3,998,834.

The reaction of (XIV) with (Ill-a) is conveniently carried out by stirring and heating the reactants together in an appropriate organic solvent, such as, for example, an aromatic hydrocarbon, e.g., benzene, methylbenzene, diaethylbenzene, and the like; a halogenated hydrocarbon, e.g., dichloromethane and trichloromethane; or a lower alkanol, e.g., methanol, ethanol, 2-propanol and the like; and preferably in a mixture of an aromatic hydrocarbon and a lower alkanol. The reaction may be promoted by the addition of an appropriate base, such as, for example, an alkali metal carbonate or hydrogen carbonate.

Starting materials of formula (ΙΙΙ-b) wherein Y is chlorq (Ill-b -1), can also be prepared directly by the reaction of(III-a) with a bromo-chloroalkane of the formula (XV) following methods similar to those described herein for the preparation of starting materials (II.-b-l) starting from (Il-a).

C1-CH-(CH,-) -CH-Br ι 2'·η. ι .

E (xv) I f i I -1346836 The starting materials of formula (VI) herein can generally be prepared by the reaction of a reactive ester of the formula (H) wherein X represents a radical of the formula (Γ7) with a 4-piperidinamine of the formula following similar procedures as described herein for the preparation of the compounds (l-a) starting from (II) and (IH).

The 4-piperidiaamines of formula (XVI) used as starting materials herein can also be prepared following the procedures described in U.S. Pat. Wo. 3, 998,834 wherein a number of such compounds are specifically described.

The ultimate starting materials in each of the above procedures 'are generally known and they may all be prepared following artknown procedures as are described in the literature for preparing such known compounds. ,14.

The compounds of formula (i) and the pharmaceuticallyacceptable acid addition salts thereof have very interesting pharmacological properties. More particularly they are potent morphine-like analgesics and as such they can be used to depress pain in warm-blooded animals.

The useful analgesic properties of the compounds of formula (I) and acid addition salts thereof are clearly evidenced by the results obtained in the rat tail withdrawal. test, described in Araneimittel-Forschung, 13, 502 (1963) and 21, 862 (1971).

The results in the table I below indicate the LED, x. e. the lowest 100% effective dose in mg/kg upon intravenous administration, and the duration (expressed in minutes) of this effect at the stated dose. -1546836 l I I f e A preferred group of compounds within the scope of formula (I) is represented by those wherein E is a lower alkyl radical. In fact these preferred compounds are highly potent analgesics having a short duration of action.

Analgesics having such a short duration of action are highly desirable in circumstances where acute severe pain has to be eliminated over a short period, e.g., in anaesthesiology.

In view of their analgesic activity, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, an effective analgesic amount of the particular compound, in base or acidaddition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable . in unitary dosage form suitable, preferably, for admini20 stration orally, rectally or by parenteral injection.

For example, in preparing the compostions in oral dosage form, any of the usual pharmaceutical media may be em... ..ployed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of ...... powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.

Injectable solutions, for example may be prepared in which -174 68 3-6 the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers or suspending agents may be employed.

Acid addition salts of (I), due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for :.3 ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in asso15 ciation with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonful or tablespoonsul and segregated multiples thereof.

In view of the analgesic activity of the subject compounds, it is evident that the cortpounds of the present invention can bs used in preventing or combatting pain in warm-blooded . animals, by the systemic administration of an effective analgesic amount of a compound of formula (I) or a pharma25 ceutically acceptable acid addition salt thereof in admixture with a pharmaceutical carrier.

Although the amount of active ingredient to’be administered may vary within rather wide limits, depending on the particular circumstances of the case, doses of from 0.01 mg/kg to 1 mg/kg, administered once or re. peatedly are generally found effective.

The following Examples are intended to illustrate and not to.limit the scope of the present invention. Unless otherwise stated all parts therein are by weight.

Examples I to χ/ττΐ described the preparation of intermediate derivatives. -184683 EXAMPLE I To a stirred mixture of 14.2 parts of ethyl isocyanate, 29.2 parts of sodium azide and 135 parts of dry tetrahydrofuran is -added a solution of 39 parts of aluminium chloride in 225 parts of dry tetrahydrofuran.

Stirring is continued overnight at reflux temperature.

The reaction mixture is cooled and acidified with a hydrochloric acid solution 6N. The whole is evaporated to dry and the product is extracted four times with 2-propanone. The combined extracts are dried, filtered and evaporated. The residue is dried overnight, yielding 18 parts (65%) of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one.

EXAMPLE II Following the procedure of Example I and using an equivalent amount of respectively cyclohexyl isocyanate and isopropyl isocyanate as a starting material there are obtained: 1-cyclohexyl-1,4-dihydro-5H-tetrazol-5-one; and l,4-dihydro-1-(l-methylethyl)-5H~tetrazol-5-one as a resi due.

EXAMPLE III To 990 parts of tetrahydrofuran,- cooled in an icebath, are added portionwise 156 parts of aluminium chloride and the whole is stirred vigorously till all solid enters solution. This solution is added quickly to a stirred suspension of 208 parts of sodium azide in 225 parts of tetrahydrofuran and stirring is continued for 1 hour at reflux temperature. After cooling to -19room temperature, there is added dropwise a solution of 54 parts of butanoyl chloride in 225 parts of tetrahydrofuran at a temperature below-30°C. The whole is heated slowly to-reflux and stirring·is continued over5 night at reflux temperature. Vihile cooling, the reaction mixture is acidified with 800 parts of a hydrochloric acid solution SN and the solvent is evaporated. The residue is stirred in a sodium hydrogen carbonate solution, trichloromethane is added and the layers are separated. The aqueous phase is acidified with concentrated hydrochloric acid and 'the solvent is evaporated.

The residue is stirred in 2-propanoae. The precipitate is filtered off and the filtrate is evaporated, yielding 32 parts of 1,4-dihydro-i-propyl-5H-tetrazol-5-one as ; a residue.

. I i * EXAMPLE IV.

Following the procedure of Example III and using an equivalent amount of an appropriate acyl chloride as a starting material, the following compounds are obtained: t i 1-(1,1-dimethylethyl)-1,4"dihydro-5H-tetrasol-5-one as a ' } residue; · I 1.4- dihydro-l-pentyl-5H-tetrasol-5-one; ί 1.4- dihydro-1-(2-phenylethyl)-5H-tetrazol-5-one as a ( solid residue: · - j ’ . t ι 1,4-<2ihydra-l-{phenylznei}iyl)-5H-tetrazol-5-one; mp. 152C; and | 1-cyclopropyl-1,4=<3iliydro-5H-tetrazol-5-one; mp. 128’C. [ -2046836 EXAMPLE V A mixture of 22 parts of I-ethyl-1,4-dihydro-5H-tetrazol-5one, 45 parts of 1 -bromo-2-chloroethane, 26 parts of sodium carbonate 0. 3 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The aqu'eous phase is extracted three times with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 28.4 parts (80%) of I-(2-chloroethyl)-4-ethyl-l,4-dihydro-5H-tetrazol-5-one as a residue.

EXAMPLE VI Following the procedure of Example V and using equivalent amounts of respectively an appropriate 1,4-dihydro-5H-tetrazol-5one and an appropriate bromochloroalkane as starting materials the following l-(chloroalkyl)-l,4-dihydro-5Ii-tetrazol-5-ones are obtained: l-(2-chloroethyl)-l, 4-dihydro-4-propyl-5H-tetrazol-5-one as a residue; I -(2-chloroethyl)-1,4-dihydro-4-(1 -methylethyl)-5H-tetrazol-5-one aa a residue; I -(2-chloroethyl)-4-(l, 1 -dimethylethyl)-!, 4-dihydro-5H-tetrazol-5-one as a residue; 1-(2-chloroethyl)-!, 4-dihydro-4-pentyl-5H-tetrazol-5-one as a residue; l-(2-chloroethyl)-4-cyclohexyl-1,4-dihydro-5H-tetrazol-5-one aa a residue; -211-(2-chloroethyl)-!, 4-dihydro-4-(2-phenylethyl)-5H-tetrazol-5-one aa a residue; l-(3-chloropropyl)-4-ethyl-I,4-dihydro-5H-tetrazol-5-one as a residue; -(2-chloroethyl)-!, 4-dihydro-4-(phenylmethyl) -5H-tetrazol-5-one as a residue; and -(2 -chloroethyl)-4-cyclopropyl-l, 4-dihydro-5H-tetrazol-5-one as a residue.

EXAMPLE Vn A mixture of 49 parts of iodomethane, 10.5 parts of 1-(2chloroethyl)-l, 4-dihydro-5H-tetrasol-5-one, 15 parts of sodium carbonate, 0.2 parts.of potassium iodide and 240 parts of 4-methyl2-pentanoae is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The aqueous phase i3 extracted with dichloro- ‘ methane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 15 parts (85%) of 1,4-dihydro-l»(2-iodoethyl)-4-methyl-5H-tetrazol-5-one as a residue. -22/4-68 3 6 EXAMPLE VIII A mixture of 19.6 parts of /2-(2-thienyl)ethyl7 4-methylbenzenesulfonate, 10 parts of 1-(2-chloroethyl )-1,4-dihydro-5g-tetrazol-5-one, 10 parts of sodium carbonate and 90 parts of Ν,Ν-dimethylformamide is stirred and heated overnight at 70°c. The reaction mixture is cooled, 100 parts of water are • added and the product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by columnchromatography over silica gel using a mixture of trichloromethane and petroleum ether (70:30 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 15 parts (46.5%) of 1-(2-chloroethyl)-1,4-dihydro-4-^-(2-thienyl)ethyl75H-tetrazol-5-one as a residue.

EXAMPLE IX To 4.5 parts of sulfinyl chloride is added dropwise a mixture of 13 parts of N-/T-(2-hydroxy-220 phenylethyl)-4-(methoxymethyl)-4-piperidiny1/-^phenylpropanamide hydrochloride and 260 parts of dichloromethane. Upon completion, the whole is stirred and refluxed for a few hours. The reaction mixture is • cooled and the solvent is evaporated. The residue is taken up in 2-propanone. The mixture is filtered and the filtrate is treated with activated .charcoal. The. latter is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 9.2 parts (61.7%) of N-/T-(2-chloro2-phenylethyl)-4-(methoxymethyl)-4-piperidinyl7-JIphenylpropanamide monohydrochloride; mp. 145.3°C. -2346836 EXAMPLE X A mixture of 35 parts of 2-methyloxirane, 83 parts of H-/4-(methaxymethyl)-4-piperidinyl7-Nphenylpropanamide, 25 parts of sodium hydrogen car5 bonate, 450 parts of benzene and 30 parts of methanol is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is taken up in water. The product is extracted with trichloromethane.

The extract is dried, filtered and evaporated. The ; residue is converted into the hydrochloride salt in j 2-propanol. The salt is filtered off and crystallized ί from a mixture of 2,2’-oxybispropane and 2-propanol, ; yielding 41.5 parts (37%) of 21-/1-(2-hydroxypropyl)- ! 4-(methoxy»ethyl)-4-piperidinyl7-il-phenylpropanamide I monohydrochloride. j Parts of sulfinyl chloride are stirred and there is added dropwise a solution of 37 parts of Nr/T- (2-hydroxypropyl) -4- (methoxymethyl) -4-p iperidinyl/^-phenylpropanamide monohydrochloride ia 360 parts of dichloromethane. Upon completion, stirring is continued overnight at reflux temperature. The ί reaction mixture is evaporated and. the residue is sus- pended in 2-propanone. The product is filtered off and : dried, yielding 31.5 parts (85%) of N-/i-(2-chloro- } propyl)-4-(methoxymethyl)-4-piperidinyl7-JT-phenyl- [ propanamide monohydrochloride. I ί ί -24ί r k I ί · t t ί fc EXAMPLE XI A mixture of r;8 parts of i-(2-chloroethyl)-4ethyl-1,4-dihydro-5H-tetrazol-5-one, 3.45 parts of H-^f-(methoxymethyl)-4-piperidinyl7-4I-phenylpropana5 mide, 5 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator.

The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (37:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from 2-propanone, yielding 1.5 parts (33.3%) of N- ^l-/2-(4-ethyl-4,5-dihydro-5oxo-1H-tetrazol-l-yl)ethyl7-4-(methoxymethyl)-4piperidinyl j - Ν,-phenylpropanamide monohydrochloride monohydrate; mp. 140.8°C.

EXAMPLE XII Following the procedure of Example XI and using equivalent amounts of the appropriate starting materials, the following compounds are obtained as acid addition salts after treatment of the free base form with an appropriate acid: N-11-/2-(4,5-dihydro-5-oxo-4-propyl-1H-tetrazol-lyl)ethyl7-4-(methoxymethyl)-4-piperidinyl|- JJ-phenylpropanamide ethanedioate (1:2) monohydrate; mp. - 103.8°C. Ν-/Γ-^2-/4,5-dihydro-(l -methylethyl)-5-oxo-lJi-tetra2ol-l -yl7ethyl j-4-(methoxymethyl)-4-piper idinyl^-N_-phenylpr opanamide -25mononitrate monohydrate; mp, 104. 5’C; methyl 1 - , 5-dihyds o-5-oxo -4-/2*-(2-thienyl) ethyl/-1 H-tetrazol1 -yl ^ethyl/-4-^N-l-axoptopyl)-N-phenylamin^-4-piperidinecarbcKylate ethanedioate (1:1) mp. 162, 9eC; N- ^l-^'-(4-ethyl-4,5-dihydro-5-oxo-lH-tetrazol-l-yl)propyl7"4(methoxymethyl)-4-piperidinyl ( -N-phenylpropanamide hydrochloride hemihydrate; mp. 182*C; and ^.-^-^2-^, 5-dihydro-5-oxo-4-(phenylmethyl)-lH-tetrazol-l -yX7ethyl J -4 - (methoxymethyl) -4 -piper id inyl/-N^phenylpr o panamid e ethanedioate (1:1); mp. 166.4’C.

EXAMPLE ΧΠΙ A mixture of 3.6 parts of I-(2-chl0roethyl)-4-ethyl-l, 4dihydro-SH-tetrazol-S'-oae, 6.4 parts of methyl 4-_/bL-(l-oxopropyl)_N.-phenylaming/-4-piperidinecarboxylate hydrochloride, 4 parts of sodium carbonate, 0.1 parts of potassium iodide and 240 parts of 4methyl-2-pentanone is stirred and refluxed overnight with waterseparator. The reaction mixture is cooled and poured onto water.

The organic phase is separated, dried, filtered and evaporated. The residue ia purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 hy volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the ethanedioate'salt in 2-propanone.

The salt is filtered off and dried, yielding 1.5 parts (13%) of methyl l-/|^(4-ethyl-4,5-dihydro»5-oxo-IH-tetrazol-I -yl)ethyj7-4-/>i- (1-oxo propyl-N-phenyismin^r-4-piperidinecarboxylate ethanedioate (2:3); mp. 158. 9*C. -2646836 EXAMPLE XIV Following the procedure of Example XIII and using equivalent amounts of the appropriate starting materials, the following ethanedioate salts are obtained: methyl 1-/2-(4,5-dihydro-5-oxo-4-propyl-1It-tetraZOl-1 -yl) ethyl/—4-/Ti- (l-oxopr opyl-K-pheny laming7-4piperidinecarboxylate ethanedioate (in); mp. 168.4°C; methyl 1-^2-/4,5-dihydro-4-(1-methylethyl)-5-oxo-1Htetrazol-1 -yl/ethylj -4-//- (1-oxoprqpyl) -N-phenylaming7-4piperidinecarboxylate ethanedioate (i:l);mp. 184.2°C; methyl 1-)2-/4-(1,1-dimethylethyl)-4,5-dihydro-50X0-1_H.-tetrazal-1 -yl/ethylj -4-//- (1-axopropyl) -N-phenylamino7-4-piperidinecarboxylate ethanedioate (l:i);mp. 168.1 °C; methyl 1-/2-(4,5-dihydro-5-oxo-4-pentyl-lH^tetrazol1 —yl) ethy 3/-4-^- (1-oxopropyl) -N-phenylainino7-4"plper idineearboxylate ethanedioate (1:1); mp. 153.5aC; . - methyl l-/2’-(4-cyclohexyl-4,5-dihydro-5-oxo-lHr tetrazol-1 -yl) ethyl/-4-//- (1-oxopropyl) -N-phenylaming7-4piperidinecarboxylate ethanedioate (1:1); mp. l73aC; methyl 1-^2-/4,5-dihydro-5-oxo-4-(2-phenylethyl)-1 tetrazol-1 -yl/ethyl} -4-/^- (1-axoprcpyl) -N-phenylaminq7-4piperidinecarboxylate ethanedioate (2:3); mp. 162.2°CJ methyl 1 - j 2-/Γ, 5-dihydro-5-oxo-4-(phenyimethyl)-lIi-tetrazol[ -yl/ethylj -4-/3- (1-axopropyl) -N-phenylaming7-4-plperidinecarboxylate ethanedioate( 1:1): mp. 191.7*C; ι j. & i ! methyl l-^T-(4-cyclopropyl)-4,5-dihydro-5-oxo-lH-tetrazol-l -yl)- ethyl7-4-2^-(l-oxopropyl)-N-phenylamino7-4-piperidinecarbcxylate etiianedioate (2 '3) hemxhydrate; rap, 155.9eC; and methyl 1-^-(4-ethyl-4, 5-dihvdro-5-oxo-lH-tetrazol-I-vl)ethyl7-45 (phenylamino)-4-piperidinecarboxylate ethanedioate (2:3); mp. I72*C.

EXAMPLE XV A mixture of 2,55 parts of 1,4-dihydro-l-(2-iodoethyl)-4methyl-5H-tetrazol-5-one, 3.45 parts of N-[f-(methoxymethyl)-4piperidinyl7~ll«phenylpropaaamide, 2 parts of sodium carbonate, 0.2 ID parts of potassium iodide and 160 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with -water-separator. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The aqueous phase is extracted with diehloromethane. The. combined organic phases are dried, filtered and evaporated,. The residue is purified by column-chromatography over silica gel using a .mixture of trichleromethaae and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the ethanedioate salt in 2-propanone, The salt is filtered off and crystallized from 2-propanone, yielding 2.1 parts (42%). of N- ^1-^-(4, 5-dihydro-4-methyl-5-oxo-lH-tetrazol-l -yl)ethyl/-4(mathoxymethyl)-4--N-nhenvlpropanamide ethanedioate (1:1); mp, 155. 9°G.

EXAMPLE XVI cKopropyl)-£-phmylaming7=4-piperidinecarboxylate ethanedioate (1:1); mp, 185. 9°G; by the reaction of 1,4-dihydro-I-(2-iodeethyl)-4-methylSH-tetrasol-5-oae with methyl 4"/K-(l-oxopropyl)-K-phenylsmin^7-4-piperidineearboxylate. -2846836 EXAMPLE XVII A mixture of 3 parts of 1-ethyl-1,4-dihydro-5H_tetrazol-5-one, 9.4 parts ofX-/T-(2-chloropropyl)-4(methoxymethyl )-4-piperidinyl7-=Zk-phenylpropanamide, 2.5 parts of sodium carbonate, 2.5 parts of .Ν,Ν-diethylethanamine and SO parts of £,^-dimethylformamide is stirred and heated overnight at 70°C. The reaction mixture is cooled, 100 parts of water are added and the product is extracted three times with methylbenzene.

The combined extracts are dried, filtered and evaporated. The residue is purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and methanol (97:3 by volume) and .then a mixture of ethyl acetate and ethanol (99:1 by volume) as eluent.

The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone and 2,2'-oxybispropane. The salt is filtered off and dried, yielding 2.1 parts (18%) of N- 1-/2-(4-ethyl-4,5-dihydro-5-oxo-lHrtetrazol-l-yl)20 1-methylethyl7-4-(methoxymethyl)-4-p iperidinylj -H-phenylpropanamide monohydrochloride; mp. 185.4°C.

EXAMPLE XVIII A mixture of 1.2 parts of 1-ethyl-1,4-dihydro-§if tetrazol-5-one, 3.9 parts of X-/l-(2-chloropropyl)-425 (methoxymethyl )--4-piperidinyl7-lL-phenylpropanamide monohydrochloride, 2 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with waterseparator. The reaction mixture is cooled, poured onto water and the layers are separated. The organic -phase is 6 8 3 6 dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the nitrate salt in 2-propanone.

The salt is filtered off and crystallized twice: first from a mixture of 2,2'-oxybispropane and 2-propanone and then from 2-propanone, yielding 1.5 parts (30%) of N-|i-22-(4-ethyl-4,5-dihydro-5-oxo-ijL-tetrazol-1yl )-1 -methylethyl/-4- (methoxymethyl) -4-p iperidinylj phenylpropanamide mononitrate; mp. 146.6°C.

EXAMPLE XIX Following the. procedure of Example XVIII there is 15 prepared Ji-j1-Q.-(4,5-dihydro-5-oxo-4-phenyl-1H-tetrazol-1-yl)-1-methylethyl7-4-(methoxymethyl) -4-piperidiny^ ^phenylpropanamide mononitrate; mp, 151.2°C; by the reaction of l,4-dihydro-l-phenyl-5Hrtetrazol-5-one with ^-/l-(2-chloropropyl)-4-(methoxymethyl)-4-piperidi20 nyl7-^°phenylpropanafflide monohydrochloride.

EXAMPLE XX A mixture of 3 parts of 1-ethyl-1,4-dihydro-5H.-tetra· zol-5-orie, 8 parts of Mr/l-(2-chloro-2-phenylethyl)-4(methoxyraethyX)-4~piperidinyl7«4i"phenylpropanamide, 0.2 parts of potassium iodide, 5 parts of sodium, carbonate· and 135 parts of l£,Et-dimethylformamide is stirred and heated overnight at 70aC. The reaction mixture is cooled • to room temperature and 150 parts of water are added. -304683 The product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The solid residue is purified by columnchromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of petroleumether and 2,2'-oxybispropane. The product is filtered off and dried, yielding 5.7 parts (65%) of Ji-^1-/2-(4-ethyl-4,5-dihydro-5-oxo-lii-tetrazol-l yl)-2-phenylethyl/-4-(methoxymethyl)-4-piperidinylj-Nphenylpropanamide; mp. 125.7°C.

EXAMPLE XXI A mixture of 3 parts of 1-ethyl-1,4-dihydro-5fltetrazol-5-one, 9.4 parts of N-/T-(2-chloropropyl)-4(methoxymethyl)-4-piperidinyl7-N-phenylpropanamide monohydrochloride, 2.5 parts ofjtt,JJ-diethylethanamine, 2.5 parts of sodium carbonate and 90 parts of Ν,Ν-dimethylformamide is stirred and heated overnight at 70°C. The reaction mixture is cooled and 100 parts of water are added. The product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified twice by columnchromatography over silica gel using first a mixture of trichloromethane and methanol (97:3 by volume) and then a mixture of ethyl acetate and ethanol (99:1 by volume), as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone and 2,2'-oxybispropane. The salt is filtered off and dried, yielding 3.9 parts (33.4%) of·N-^1-/5-(4-ethyl-4,5-dihydro-5-oxo-1j£"tetrazol 1-yl)propyl7-4-(methoxymethyl)-4-p ip er idinylj-N-phenylpropanamide monohydrochloride; mp. 192.7°C. -314 6 8 3 6 EXAMPLE' XXII A mixture of 5. 7 parts of methyl 1 -/2-(4-ethyl-4, 5-dihydro5-oxo-lH-tetrasol-l-yl)ethyl7-4-(phenylamino)-4-piperidinecarboxylate, 1.9 parts of cyclopropanecarbonyl chloride, 2. 7 parts of N.N5 diethylethaaamine and 68 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel-using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and treated with 1 part of ethaaedioic acid. The formed ethanedioate salt is filtered off and crystallised from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 1.5 parts (17.5%) of methyl 4-^-(cycloprapylcarbanylT'-K^phenylenino? —1 -^-(4-ethyl-4,5-dihydro-5-oxo-lH.15 tetraaol-l-yl)ethyf/-4-pigeridinecarboxylate ethanedioate (2:3); mp. 181.5*C.

. EXAMPLE XXIH following the procedures described herein and using appropriate starting materials the following compounds of formula I can still . be prepared:

Claims (20)

1. CLAIMS:1An W-phenyl-ϋ-(4-piperidinyl)amide derivative having the general formula:- wherein: R is a hydrogen atom, a lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, (lower alkyl)oxy(lower alkyl), aryl or aryl(lower alkyl) group; is a hydrogen atom, a lower alkyl or aryl group; R is a hydrogen atom or a lower alkyl group; R is a lower alkyloxy-carbonyl, lower alkyloxymethyl or lower alkylcarbonyl group; is a lower alkyl, cycoalkyl, lower alkenyl, lower alkyloxy or arylmethyl group; r5 is a hydrogen atom or a lower alkyl group; £ R is a hydrogen or halogen atom, or a lower alkyl, lower alkyloxy or trifluoromethyl group; Z is 0 or S; and n is 0 or the integer 1; wherein the aryl group as used in the foregoing definitions is a phenyl, substituted phenyl, thienyl or pyridinyl group, the substituted phenyl group having 1 or 2 substituents independently which are each independently a halogen atom, a lower alkyl, lower alkyloxy or trifluoromethyl group.

2. N -{1-/2-(4-Ethyl-4,S-dihydro-5-oxo-lH-tetrazol-l-yl)ethy17-4-(methoxymethyl)-piperidinyl)-N-phenylpropanamide. 34 46836

3. Methyl 1-/2-(4,5-dihydro-4-methyl-5-oxo-lH-tetrazol-lyl)-etnyl7~4-^/N-(1-oxopropyl)-N-phenylamino7~4-piperidinecar boxylate.

4. Methyl 1-/2-(4-ethyl-4,5-dihydro-5-oxo-lHytetrazol-l-yl)ethy!7-4-/N-(1-oxopropyl)-N-phenylamin^-4-piperidinecarboxylate.

5. Methyl 1-/2-(4,5-dihydro-5-oxo-4-propyl-lH.-tetrazol-l-yl) ethy Ϊ7-/Ϊ1-(1-oxopropyl)-N-phenylaminc7-4-piperidinecarboxylate.

6. N-( 1-/2-(4,5-Dihydro—4-methyl-5-oxo-lJi-tetrazol-l-yl)ethyl7~4-(methoxymethyl)-4-piperidinyl}-J^-phenylpropanamide.

7. N -{ l-/2-(4-ethyl-4,5-dihydro-5-oxo-lH > -tetrazol-l-yl)-lmethylethy17-4-.(methoxymethyl)-4-piperidinylRj-phenylpropanamide.

8. A ccmpound as claimed in claim 1, other than a compound as specifically claimed in any one of claims 2 to 7, substantially as hereinbefore described in the foregoing Examples XI to XXIII.

9. A pharmaceutically acceptable acid addition salt of a ccmpound as claimed in any one of claims 2 to 7.

10. A pnarmaceutical composition comprising a pharmaceutically acceptable carrier and as an active ingredient an effective analgesic amount of a compound as claimed in any one of claims 2 to 8 or a pharmaceutically acceptable addition salt as claimed in claim 9.

11. A process for preparing an N-phenyl-N-(4-piperidinyl)amide derivative having the general formula:- or a pharmaceutically acceptable acid addition salt thereof, wherein R, R 1 , R 2 , R 2 , rS r\ r®, z and n are as defined in claim 1, which process comprises -354,6836 a) reacting a compound having the formula with a _H--phenyl-El·- (4-piperidinyl) amide of the formula ,3 „4 X 1 is hydrogen and X is a radical of the formula -CH-(CH,) _-CH-Y • Z η , (IV) or X is hydrogen and X 1 is a radical of the formula Y-CH-(CH,) „-CHh l 2 R R Z (V) 10 and wherein Y is chloro, bromo, iodo, methylsulfonyloxy, or 4-methylphenylsulfonyloxy residue in a reaction inert organic solvent in the present of a base; or b) ^-acylating a compound having the formula ,5 R-Nf W— CH—(CH,) (VI) 15 according to standard N-acylation procedures in order to prepare a compound having the formula -3646836 or c) preparing compounds having the formula (X) wherein Z is S (I-b)by reacting the corresponding compound of formula 1 in which Z is 0 with an appropriate sulfurating agent while stirring and heating the reactants together in an appropriate reactioninert organic solvent or d) debenzylating compounds of the formula (I) wherein R represents phenylmethyl by known debenzylation techniques, in order to prepare compounds, wherein R represents hydrogen an!, if desired, preparing pharmaceutically acceptable acid addition salts of the products of steps a) to d), and/or also, if desired resolving racemic mixtures into their stereo-chemically pure isomeric forms by known resolution techniques.

12. A process as claimed in claim 11 wherein reaction (a) is carried out at elevated temperatures.

13. A process for preparing^.-(l-/2-(4-ethyl-4,5-dihydro-5oxo-lH-tetrazol-l-yl)ethyl7-4-(methoxymethyl)-4-piperidinyl}tl - phenylpropanamide which comprises reacting 1-(2-chloroethyl )4-ethyl-l,4-dihydro-5H-tetrazol-5-one, with (methoxymethyl)4 - p iper id iny 1/-21-pheny lpr op anamid e.

14. A process for preparing methyl 1-/2-(4,5-dihydro-4-methyl~5oxo-lH-tetrazol-l-yl)e thy 17-4-/5.-(l-o xopropyl)-N-phenylamino74-piperidinecarboxylate which comprises reacting 1,4-dihydro1-(2-iodoethyl)-4-methyl-5H-tetrazol-5-one with methyl 4-/ίί-(1oxopropyl) -N-phenylaming-4-piper idinecarbcxylate.

15. A process for preparing methyl l/2-(4-ethyl-4,5-dihydro-5cxo-llr-tetrazol-l-yl) ethy£7 - 4-/&- (1-oxopropyl) -Ji-phenylamino/4-piperidinecarboxylate, which comprises reacting 1-(2-chloroethyl)4-ethyl-l,4-dihydro-5ji.-tetrazol-5-one with methyl 4-/K-(loxopropyl)-N-phenylamin0/-4-piperidinecarboxylate hydrochloride. -3746836

16. A process for preparing methyl 1-/2-(4,5-dihydro-5-oxo-4propyl-lH-tetrazol-l-yl) ethy37-4-/S-l-oxopropyl) -Ν,-phenyl amine/4-piperidinecarboxylate which comprises reacting 1-(2-chloroethyl) 4-propyl-l,4-dihydro-5H.-tetrazol-5-one with methyl 4-/^-(1oxopropyl)-N-phenylaminc/ r -4-piperidinecarbaxylate hydrochloride.

17. A process for preparing N-[ 1-/2-(4,5-dihydro-4-methyI-5-oxolH-tetrazol-l-yl) ethyl/-4- (methoxymethyl) -4-piperidinyl}-tJ_phenylpropanamide which comprises reacting 1,4-dihydro-l-(2iodoethyl)-4-methyl-5H-tetrazol-5-one with N- /3- (methoxymethyl)4-piperidinyl/cHrphenylpropanamide.

18. A process for preparing N-{1-/Z-(4-ethyl-4,5-dihydro-5oxo-lli-tetr&zol-l-yl)-1-methylethy 1/-4-(methoxymethyl)-4piperidinyl}-^-phenylpropanamide which comprises reacting 1ethyl-1,4-dihydro-5H-tetrazol-5-one with 1(-/1-(2-chloropropyl)4-(methoxymethyl)-4-piperidinyJ7'-N-phenylpropanamide.

19. A process as claimed in claim 11 substantially as hereinbefore described with reference to any one of the foregoing Examples XI to XXIII.

20. A compound as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 11 to 19.