IE41708B1 - 2,6-dioxo-tetra and hexahydro-pyridine derivatives - Google Patents

Abstract

1457619 2,6 - Dioxo - tetra- and hexahydropyridines ASPRO-NICHOLAS Ltd 23 June 1975 [22 June 1974] 27819/74 Heading C2C The invention comprises the title compounds, and their acid addition salts and quaternary ammonium derivatives, which contain (a) possibly a 1-alkyl substituent, (b) 3- (optionally substituted) Ph and 3-heterocyclyl- C 1-5 -alkyl substituents, as well as (c) 4- and/or 5-attached C 1-4 alkyl or C 3-8 (inclusive of the attached ring carbon atom or atoms) alkylene substituent, the "heterocyclyl" being derived from a non-aromatic N-containing 5-7 membered ring. The "alkyl" and "alkylene" radicals include unsaturated analogues. In an example, 1 - methyl - 2 - (2 - hydroxyethyl)pyridinium methosulphate is reduced to 1-methyl-2-(2- hydroxyethyl)piperidine which with SOCl 2 affords 1 - methyl - 2 - (2 - chloroethyl)piperidine, the latter condensed with m-methoxybenzyl cyanide to give 2 - (m - methoxyphenyl) - 4- (N - methyl - 2 - piperidyl)butyronitrile and then with 4 - (1 - ethoxy - 3 - methylbut - 2 - enylidene)morpholinium fluorosulphonate to give 2 - (1,1 - dimethyl - 2 - ethoxyethyl) - 2 - (mmethoxyphenyl) - 4 - (N - methyl - 2 - piperidyl)- butyronitrile, the latter being cyclized to 4,4-dimethyl - 2,6 - dioxo - 3 - m - methoxyphenyl- 3 - [2 - (N - methyl - 2 - piperidyl)ethyl]piperidine. Therapeutic compositions having C.N.S. activity comprise the title compounds, substituted as described above, and may be administered orally, parenterally or rectally.

Description

The present invention relates to compounds having pharmacological, in particular, central nervous system, especially anti-depressant, activity and provides certain pharmacologically active 3-phenyl3-(heterocyclicamine)alkyl-2,6-dioxo-hydrogenated pyridines and methods for their preparation. As used throughout this Specification, the term heterocyclic amine means a heterocyclic ring having as one of the ring atoms the nitrogen atom of an amino group. The invention provides also pharmaceutical compositions containing one or more of said pyridine derivatives.

We have disclosed in Patent Specification No. 38650 that the parasympatholytic activity of 3-phenyl-3-aminoalkyl-2,6dioxo-tetra-and hexa-hydropyridines can be significantly reduced and a useful central nervous system, especially anti-depressant, activity developed by introducing into the hydrogenated pyridine ring certain substituents in the 4 and/or 5 positions. In particular, we have claimed in that Application 3-pkenyl-3aminoalkyl-2,6-dioxo-tetraand hexa-hydropyridines which are substituted in at least one of the 4 and 5 positions of the hydrogenated pyridine ring by a C^-C^ alkyl group or by a divalent alkylene radical which together with at least one of the carbon atoms at said 4 and 5 positions forms a carbocyclic ring of 3 to 8 carbon atoms, and acid addition salts and quaternary ammonium derivatives thereof. The preferred amino moiety -241708 of the 3-aminoalkyl group is stated in Patent Specification No 38650 to ke 4i(C^-C^)alkylamino, especially dimethyl- or diethyl-amino.

It has now been found that the 3-pbenyl-3-aminoalkyl-2,65 dioxo-tetra and hexa-hydropyridines of Patent Specification No. 38650 in which the 3-aminoalkyl group is constituted by a non-aromatic N-containing heterocyclic ring of five to seven ring atoms joined to the 3 position of the hydrogenated pyridine ring by a C^-C^ alkylene group attached to a ring carbon atom of said heterocyclic ring have a useful level of central nervous system activity approaching that of the aforementioned preferred dialkylamino compounds.

According to the present invention therefore, there are provided 3-phenyl-3-(heterocyclic amine) C^-C^ alkyl-2, 6-dioxo-tetra and hexa-hydrogenated pyridines which are substituted in at least one of the 4 and 5 positions of the hydrogenated pyridine ring by a C^-C^ alkyl group or by a divalent alkylene radical which together with at least one of the carbon atoms at said 4 and 5 position forms a carbocyclic ring of 3 bo 8 carbon atoms and in vfaich the heterocyclic amine is a non-aromatic N-containing heterocyclic ring of five to seven ring atoms joined to the 3-alkyl group at a ring carbon atom, and acid addition salts and <}iaternary ammonium derivatives thereof. -341708 The hydrogenated pyridine ring and the 3-phenyl group may be substituted further by one or more therapeutically compatible (as hereinafter defined) substituents as described in our Patent; Specification No. 38650.

. The non-aromatic N-containing heterocyclic ring may include one or more hetero-ring atoms in addition to the said nitrogen atom, which additional ring atoms may be oxygen, nitrogen or sulphur. Examples of suitable heterocyclic rings include dihydropyridyl, tetrahydropyridyl, piperidyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, . imidazolinyl, pyrazolidinyl, pyrazolinyl, homopiperidyl, homopiperazinyi and homomorpholinyl. The 3-alkyl group may be attached to any one of the ring carbon atoms of the heterocyclic ring but it is preferred that it is attached to a ring carbon atom immediately adjacent to a ring nitrogen atom. The heterocyclic ring may be substituted by one or more . substituents which are therapeutically compatible (as hereinafter defined) with the molecule.

The term therapeutically compatible is used in this Specification in relation to a substituent to mean that the presence of that substituent neither destroys the pharmacological activity of the molecule nor so decreases . said activity and/or increases the toxicity of the molecule that the therapeutic ratio is reduced to five or below. The therapeutic compatibility of a - 4 41708 particular substituent may depend upon the intended site of substitution in the molecule and/or the presence in the molecule of other substituents. Hence a given substituent may be therapeutically compatible in respect of one molecule into Which it is introduced but incompatible, i.e. inactivating, . in respect of another molecule. The compatibility of any substituent in respect of any compound of the invention can be readily assessed by subjecting the relevant substituted compound to standard screening tests such as those referred to hereinafter. It is well within the ability of the averagely skilled man concerned with the development of new drugs to · ascertain which substituents may be present and at what positions in pharmacologically active compounds of the invention.

Examples of substituents likely to be therapeutically compatible with all compounds of the invention are (a) in the phenyl ring, Cj-C^ alkyl optionally substituted by hydroxy or CpC^ alkoxy, hydroxy, C^C^ alkoxy, · halogen and trifluoromethyl: (b) in the hydrogenated pyridine ring, Cj-C^ alkyl at the 1, 4 and/or 5 positions and Cg-Cg alkoxy carbonyl at the 5 position; and (c) in the N-containing heterocyclic ring, Cj -C^ alkyl, on ring carbon or nitrogen atoms, phenyl on ring carbon atoms and phenyl-Cj -C4 alkyl on ring nitrogen atoms. It is presently preferred . that the 3-phenyl ring should be unsubstituted or substituted by at least one Cj -C4 alkoxy, especially methoxy, or halogen, -541708 especially chlorine, that the hydrogenated pyridine ring should be substituted i n the 4 and/or 5 positions by at least two -C, ulkvl, especially methyl, and that the N-containing heterocyclic should be substituted on the nitrogen atom by Cj-C^ alkyl, especially methyl.

. The alkyl or alkylene radicals (including moieties) in compounds of the present invention may be straight or branched chain, saturated or unsaturated hydrocarbon radicals. Unless otherwise stated, it is preferred that each hydrocarbon radical is saturated and contains 6, more especially 4, carbon atoms or less. Any reference in this Specification to a specific alkyl or , alkylene radical having structural isomers includes all of those isomers and mixtures thereof unless a particular isomer is specified. Examples of alkyl radicals are methyl, ethyl, propyl, butyl, amyl, hexyl, ethenyl, ethynyl, propenyl (especially allyl), propynyl (especially propargyl), butenyl. a nd butynyl. Preferred alkyl radicals are methyl and ethyl and preferred . alkylene radicals are 1,2-ethylene and 1,3-propylene for the alkylene moiety of the heterocyclic amine) alkyl group and 1,4-butylene and 1,5-hexylene for alkylene radicals attached to the 4 and/or 5 positions of the hydrogenated pyridine ring.

A preferred class of compounds Of the present invention are those 6“ . . . . wherein R represents hydrogen or Cj -C^ alkyl; Rj, R2 and Rg independently represent hydrogen or Cj-C^ alkyl and R4 represents hydrogen, C^-C^ alkyl or C2-Cg alkoxycarbonyl, provided that at least one of R*, Rg, Rg and R^ represents alkyl, or Rj together with R2 or with Rg represents an alkylene radical which together with their immediately adjacent carbon atom(s) of the hydrogenated pyridine ring forms a carbocyclic ring of 3 to 8 carbon atoms and or R2 respectively and are as defined above (not subject to the proviso), or R2 and R4 together represent a second valency bond joining their immediately adjacent carbon atoms, or Rj together with Rg represents a second valency bond joining their immediately adjacent ring carbon atoms and R2 and R^ are as defined above provided that at least one of them represents alkyl; Y represents Cj-C^ alkyl optionally substituted by hydroxy or Cj-C^ alkoxy, hydroxy, Cj-C^ alkoxy, halogen or trifluoromethyl; m represents zero or an integer up to 5; A represents C, -C- alkylene; Q '-Nzrepresents a non-aromatic N-containing heterocyclic ring of five to seven ring atoms joined to A at a ring carbon atom; Rg represents hydrogen, or -C^ alkyl optionally substituted by Cg-Cg cydoalkylOrby^phenyl; ... ' . \ X represents C,-C, aljcylior phenyl; and ( J' 4p representsVe'ro or /n jnteger. i ! V ' · An especially preferred class of compounds according to the present invention are those of formula I in which R represents Cj-C^ alkyl, especially methyl, or hydrogen; Rj, R2, Rg and R^ independently represent hydrogen or alkyl, especially methyl, provided that at least one of them represents alkyl, or Rj together with Rg represents a second valency bond joining their immediately adjacent ring carbon atoms and Rg and R^ are as defined above provided that at least one of them represents alkyl; Y represents C^-G^ alkoxy, especially methoxy, halogen, especially chlorine, or trifluoromeihyl; m represents zero, 1 or 2; A represents Cj-Cg alkylene, especially of the formula -(CHg^wherein n represents 2, 3 or 4; ^N^epresents piperidyl, piperazinyl or morpholinyl Rg represents hydrogen or, preferably, Cj-C^ alkyl, especially methyl or ethyl; and X represents Cj-C^ alkyl, especially methyl or ethyl; and p represents zero ori. - 841708 Particularly preferred compounds of the present invention include ch3 wherein n' represents 2 or 3; . m represents 1 or 2; and R^', Rg' and R^' independently represent hydrogen or methyl.

The compounds of the present invention which have been pharmacologically screened to date have significantly reduced parasympatholytic activity . compared with known analogous compounds which are unsubstituted in the 4 and 5 positions and have also a relatively high level of central nervous system, in particular anti-depressant, activity as measured by standard screening tests. Moreover, the combination of low parasympatholytic activity and relatively high central nervous system activity indicates , that the compounds of the present invention have a useful level of central nervous system activity approaching that of the aforementioned preferred “9 compounds of Patent Specification No. 38650. . An indication of said useful level of activity can be observed by comparing the mydriatic activity and extent and nature of interaction with amphetamine set forth in Table 1 following for the following compounds:(A) the known parasympholytic Aturbane (Trade Mark) (i.e. 3-phenyl-3-(3-diethyl-amino-ethyl)-2,6-dioxo-piperidine); (B) 4,4-dimethy1-3(3'-methoxyphenyl)-3(N-methyl-2-piperid-2yl-ethyl)piperidine-2,6-dione (a preferred compound of the present invention); and (C) 4,4-dimethy1-3(3'-methoxyphenyl)-3(3N,Ν-dimethylaminopropyl) piperidine-2,6-dione (the most preferred compound of Patent Specification No. 38650 ).

TABLE I Γ5 Compound MYD50 POT/PROL.

AMPHETAMINE A 0.35 ++/+ WO B 36 +/+++ 4.0 C 260 +/+++1.0 The following abbreviations are used in Table 1:20 Μϊϋ^θ rePresenbs the dose in mg/kg body weight at which 50% mydriasis occurs or, where stated, the percentage mydriasis at the specified dose; -1041708 POT represents the degree of potentiation of amphetamine stereotypy measured on a scale of 0 to ++ PROL represents the degree of prolongation of amphetamine stereotypy measured on a scale of 0 to +++, The mydriatic activity of inter alia each of the compounds listed in Table 1 was assessed as described in Patent Specification No, 38b5O , „it is generally accepted that the degree >of mydriasis is an indication of the extent of parasympatholytic activity; the lower the MYD^q, the greater the parasympatholytic activity.

The interaction with amphetamine of inter alia each of the compounds listed in Table 1 was determined using the modification described in Patent Specification No. 38650 of the method described by Quinton R.M. and Halliwell G. in Nature (Lond.) 1963, 200; 178-9.

Xn the Table the degree of potentiation is shown first followed by the degree of prolongation and then the lowest dose at which this effect was observed. Thus, for example, +/+++ 4,0 indicates that the compound induced moderate potentiation and marked prolongation at 4 mg/kg.

The compounds of the present invention can be prepared by the methods disclosed in Patent Specification No. 38650 For example, they can be prepared by methods analogous to those disclosed in U.S. Patent Specifications No's: 2,664,424 and 2,749,346. -1141708 Thue, the compounds of the invention can be prepared by the following methods disclosed in Patent Specification No. 38650. which has now been published in connection with Belgian 5- Patent No. 808,958:A) reaction of ammonia or an amine with a corresponding 2-phenyl-2(heterocyclic amine) alkyl-pentane1, 5-diacid or 2-phenyl-2-(heterocyclic amine) alkyl-pent3-ene-l,5-diacid, or a functional derivative of ether of . those acids; B) heating a corresponding diantide or diammonium salt of a 2-phenyl-2(heterocyclic amine) alkyl-pentane1, 5-diacid or of a 2-phenyl-2(heterocyclic amine) alkylpent- 3-ene-l, 5-diacid; . C) reaction with a condensing agent of a nitrile amide of a corresponding 2-phenyl-2(heterocyclic amine) alkyl-pentane-1,5-diacid or of a 2-phenyl-2(heterocyclic amine)alkyl-pent-3-ene~l,5-diacid, the nitrogen atom of the amide group being substituted by two alkyl groups or . forming part of a saturated heterocyclic ring; D) reaction with a condensing agent of the corresponding 4-(heterocyclic amine)alkyl-4-cyano-4-phenyl-lalkoxy-l-hlialkylamino or saturated heterocyclic aminqlbut-l-ene or but-l,2-diene or a'diquarternary ammonium . derivative thereof. *. -12· ~ · .

A preferred method of preparing the compounds of the invention comprises treating with a condensing agent in manner known per se a mononitrile, dinitrile or nitrile ester of a corresponding 2-phenyl-2ijieterocyclic amine)alkyl-pentane-l, 5-diacid or 2-phenyl-2-(heterocyclicamine)alkyl-pent-3-ene-l, 5-diacid. It is preferred that the said nitrile reactant is a nitrile ester.

According to one embodiment of the present invention, therefore, there is provided a method of preparing compounds of the invention, which m ethod comprises treating in manner known per se the corresponding alkyl ester of 4-(heterocyclic amine)alkyl-4-cyano-4-phenyl-3 and/or 2-alkyl or alkylene-butanoic or but-2-enoic acid (i.e, a pentane or pent-3-ene 1,5-diacid nitrile ester) with a condensing agent. In terms of preparing compounds of formula I, the ester reactant will be of formula 2: \ 0.alkyl -- - 0 wherein the symbols are as defined in connection with formula I. It will be / ' noted ttfat conjpotlnds of the invention in which the 1 position of the 5 ί / f hydrogenated pyridine ring is substituted cannot be prepared directly by this method. -1315.

The condensing agent can be a BrBnsted or Lewis acid such as ihusc disclosed in U.S. Patent Specification No. 2,664, 424, viz. concentrated sulphuric acid, acetic anhydride, tin tetrachloride, titanium tetrachloride, boron trifluoride etherates, zinc chloride, aluminium chloride or . mixtures thereof. It is preferred that the condensing agent is a mixture of a strong protonatittg agent, for example sulphuric or perchloric acid, and a nucleophile, for example acetic acid or anhydride or propionic acid. Usually, the protonating acid will constitute 25 to 50% by volume of the mixture and the reaction will be carried out at an elevated temperature, . advantageously in the range 60° to 120°C, for a period of i to 30 hours.

However, when the phenyl ring is substituted by activating groups, e.g. methoxy, it is preferred to use dilute BrBnsted acids, e.g. 2.5-5N hydrochloric acid. The resultant mixture is then neutralised with a weak base, for example ammonium hydroxide, to a pH in the range 7.5 to 9.5.

- Said neutralisation is strongly exothermic and accordingly is advantage ously carried out with cooling to a temperature in the range of 0° to 30°C. The desired hydrogenated pyridine derivative can be isolated by filtration or by extraction into a suitable solvent, for example chloroform or ether, and subsequent recovery from the solvent. . it is preferred that the aforementioned nitrile esters are prepared in manner known per se from the corresponding nitrile thiolesters, which thiolesters are more readily obtainable. For example, said thiolesters - li 41708 may be created ln the manner described by G.S. Sasln.et al (J.Org.Chem. 1957, 22 1183) or by L.B.Bos et_al (Rec.Trav.Chim. 1963, 82_, 331). In a preferred process, potassium hydroxide is added to the thiolester in a large excess of ethanol and the mixture left overnight at room temperature.

. One or other of the processes referred to above can be employed to prepare all of the compounds of the present invention although in some cases direct formation of a particular compound may not be possible.

However, it will be readily apparent to those skilled in the art that those compounds which cannot be prepared directly by the said processes can . be obtained by methods known per se from related compounds which can be prepared directly. It may be desirable for a substituent in a compound prepared according to one of the aforementioned processes to be converted into another substituent to provide another compound of the invention.

These conversions are carried out in manner known per se. Thus, for example, . it is preferred to prepare the compounds of formula I where Rg represents hydrogen, by hydrogenating in manner known per se an acid addition salt of an analogous compound of said formula in which Rg represents benzyl, which N-benzyl compound has been prepared by the preferred process described above. As a further example, a compound of formula I in . which represents alkoxyearbonyl can readily be converted into the corresponding compound in which R^ represents hydrogen by heating with - 15 41708 a mineral acid, for example hydrochloric acid in acetic acid solution. Further, the tetrahydropyridine compounds of the invention can readily be reduced in manner known per se to the corresponding piperidines of the invention.

· The compounds produced by the foregoing process can be isolated either per se or as acid addition salts or quaternary ammonium derivatives thereof.

The acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inorganic . acids, for example hydrochloric, hydrobromic, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, malic, tartaric, citric, salicylic, o-acetyloxybenzoic, nicotinic or isonicotinic acid, or organic sulphonic acids for example methane sulphonic, ethane sulphonic, . 2-hydroxyethane sulphonic, toluene-p-sulphonic or napthalene-2-sulphonic acid. Apart from pharmaceutically acceptable acid addition salts, other salts are also included within the scope of acid addition salts such as, for example, those with picric or oxalic acid; they may serve as intermediates in the purification of the compounds or in the preparation of other, for . example, pharmaceutically acceptable, acid addition salts, or are useful for Z identification, characterisation or purification of the bases.

A resulting acid addition salt may be converted into the free compound according to known methods, for example, by treating it with a base, such as with a metal hydroxide or alkoxide, for example an alkali metal or alkaline earth metal hydroxide, for example, lithium hydroxide, sodium . hydroxide, potassium hydroxide or calcium hydroxide;-with a metal carbonate, such as an alkali metal or an alkaline earth metal carbonate or hydrogen carbonate, for example, sodium, potassium or calcium carbonate or hydrogen carbonate; with ammonia; or with a hydroxyl ion exchange preparation, or with any other suitable reagent.

. A resulting acid addition salt may also be converted into another acid addition salt according to known methods; for example, a salt with an inorganic acid may be treated with a metal salt, for example a sodium, barium or silver salt, of an acid in a suitable diluent, in which a resulting inorganic salt is insoluble and is thus removed from the reaction medium.

. An acid addition salt may also be converted into another acid addition salt by treatment with an anion exchange preparation.

Quaternary ammonium derivatives of the compounds of this invention are particularly those formed by reaction withC^-Cgalkyl halides, for example, methyl, ethyl, cr propyl chloride, bromide or iodide; di*^20. alkyl sulphates, for example, dimethyl or diethyl sulphate; C^-Cg alkyl C^-Cg alkane sulphonates, for example, methyl or ethyl methane sulphonate or ethane sulphonate; C(g alkyl aryl sulphonates, for example methyl or ethyl p-toluene sulphonates; and phenyl-C^-Cg alkyl halides, for example benzyl or phenethyl chloride, bromide or iodide. Also included are the quaternary ammonium hydroxides and the quaternary ammonium compounds having as anions those of other inorganic or organic acids, for example , those of the acids used for the preparation of the previously-mentioned acid addition salts. The quaternary ammonium compounds do not have the desired pharmacological activity but are useful for separation and identification purposes.

In the composition aspect of the invention, there are provided 10 · pharmaceutical formulations in which form the active compounds of the invention will normally be utilised. Such formulations are prepared in a manner known per se in the pharmaceutical art and usually comprise at least one active compound of the invention in admixture or otherwise in association with a pharmaceutically acceptable carrier therefor. For · making these formulations, the active ingredient will usually be mixed With a carrier, or diluted by a carrier, or enclosed or encapsulated in a capsule, sachet, cachet, paper or other container. A carrier or diluent may be a solid, semi-solid or liquid material which serves as a vehicle, excipient, or medium for the active ingredient. Some examples of such . diluents or carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, liquid paraffin, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, syrup B.P., methyl cellulose, •. *> M ’λ I polyoxyethylene benzoate, talc,,.magnesium stearate or mineral oil.

The formulations of the invention may be adapted for enteral or parenteral use and may be administered to a subject requiring treatment in the form of for example tablets, capsules, suppositories, solutions, suspensions. The dosage required for the treatment of any animal will depend upon the route of a administration and will usually fall within the range 0,01 to 250 mg/kg daily. In the case of humans much further work remains to be done before a safe and effective dosage can be recommended but it is expected that said dosage will be within the range 0.1 to 100 mg/kg daily. Accordingly, formulations of the invention are likely to be provided in dosage unit forms containing from 1 to lOOOmg, more likely 5 to 500 mg and most likely 10 to 250 mg.

The following Examples will further illustrate the preparation of the novel compounds of this invention. All temperatures are given in degrees Centigrade.

Example 1 Preparation of 4 <4-Dimethyl-3(3'-methoxyphenyl)3(N-methyl-2-piperid -2-yl-ethy'l) piperidine-2, o-dione ' A) N~Methyl-2-piperid-2 yl ethanol A solution of dimethyl sulphate (49-6 gj0.39 mole) in diehloromethane was added to a solution of 2-pyridyl ethanol (48.4 S! θ·39 mole) in the same solvent with ice-water cooling.

After leaving at room temperature overnight the solution was of evaporated to leave the N-methylated 2-pyridyl-ethanol -1941708 methosulphate as a viscous oil (54.2 g). A solution of the viscous oil in anhydrous ethanol was hydrogenated ai 50 psi and 60° using Adams platinum oxide (2,5 g) as catalyst. The catalyst was filtered off, the ethanol evaporated, and the residue dissolved in water.

. The solution was made alkaline by the addition of sodium hydroxide solution and extracted with ether. Distillation of the dried ether extract gave N-methyl-2-ptperid-2 yl ethanol b.p. 154-6° / 14 mm (13.4 g; 23.7%).

B) N-Methyl-2-piperid-2-yl ethyl chloride Hydrochloride N-methyl-2-piperid-2-yl ethanol (13,4 g, 0.0939 mole) obtained as . above was added slowly with stirring to an ice-cooled solution of thionyl chloride (13.8 g) in chloroform. After the addition was completed, the mixture was warmed in a warm water bath at 50° for half an hour, the solvent evaporated off and the residue crystallised from isopropanol to give N-methyl-2-piperid-2-yl ethyl chloride hydrochloride m.p. 124° . (13.5 g).

C) 2-(3l-Methoxyphenyl)-4(N-methyl-2-piperidyl)butyronitrile N-methyl-2-piperid-2-yl ethyl chloride hydrochloride (13.5 g) prepared as above was treated with saturated potassium carbonate solution (13 ml) and ether and the ether solution decanted off, dried and evaporated to . give N-methyl-2-piperid-2-yl ethyl chloride (11 g) as a colourless oil. This chloroamine was added slowly to a freshly prepared mixture of m-methoxybenzyl cyanide (15 g), toluene (150 ml; dry), and powdered sodamide (2.66 g) with cooling (by means of a cold water bath) and stirring. A fter the addition was completed, the stirred mixture was refluxed overnight. The basic material was separated from any neutral material (mainly unreacted benzyl cyanide) and distilled. The resultant 2-(3'-methoxyphenyl)'4(N-methyl . 2-piperidyl) butyronitrile was collected at 142-158° / 0.1mm (14.1 g).

D) Ethyl 4-Cyano-3,3-dimethyl-4-(3'-methoxyphenyl)-6-(N-methyl-2piperidyl) hexanoate 2(31-Methoxyphenyl)-4(N-methyl-2-piperidyl)butyronitrile (14,1 g, 0.053 mole) prepared as above was added to a stirred solution of dimsyl sodium (prepared 10· from sodium hydride (2.56 g, 50%; 0.053 mole) and 60 ml dimethyl sulphoxide) cooled in a water bath and under a nitrogen atmosphere. To the stirred mixture was slowly added a solution of 4(1-ethoxy-3 -methyl btrt-2-enyl-idene) morpholinium fluorosulphonate (14.1 g; 0.053 mole) in dimethyl sulphoxide and the mixture was finally heated at 50-60° for 3 hours. The dimethyl15 · sulphoxide was evaporated off at 0.1 mm, the residue washed several times, with dry ether and the ether solutions evaporated to give a reddish oil (ketene-acetal). This oil was dissolved in dioxan (100 ml), water (6 ml) added, and the mixture allowed to stand at room temperature overnight, The mixture was poured into water (500 ml) containing saturated potassium 2θ, carbonate (20 ml) and the separated oil isolated by ether extraction. The ether solution was washed with dilute hydrochloric acid, the acid solution neutralised by the addition of excess potassium carbonate solution and the basic oil extracted with ether. Evaporation of the dried ether extract gave a residue of ethyl 4-cyano-3,3-dimethyl-4(3 '-methoxy phenyl)~6(N-methyl-2-piperidyl) hexanoate. (15.5 g).

· E) 4,4-Dimethyl-3(3-methoxyphenyl)-3(N-methyl-2-piperid-2-yl ethyl) piperidine-2,6-dione A solution of the product ester (15.5 g) obtained as above in 5N hydrochloric acid (60 ml) was refluxed for 6 hours, the acid evaporated off, the residue dissolved in water and the solution treated with dilute ammonium . hydroxide. The precipitated material was separated from the aqueous solution by decantation and triturated with methanol. The resulting solid was filtered off, crystallised first from ethyl acetate and then from methanol to give 4,4-dimethyl-3 (3-methoxy phenyi)-3(N-methyl-2-piperid -2-yl ethyl) piperidine-2, 6-dlone-heml methanolate m.p. 174-176° (1.9 g).

. Found C, 69.81 . H, 8.95 N, 7.28 C Η N O„ 1/2 CH„OH requires C, 69.59 H, 8.77 N, 7.22

Claims (10)

1. Claims s 1. Pharmacologically active 3-jjhenyl-3-(heteroeyclic amine) C^-C^ alkyl-2,6-dioxo-tetra and hexahydropyridines substituted in at least one of tha 4 and 3 positions of the hydrogenated 2. -phenyl-2-(heterocyclic-amine)alkyl-pentane-l,5-diacid or of a 2-phenyl-2-(heterocyclic amine) nlkyl-pent-3-ene-l,5-dineid 20. A method as claimed in Claim 19 wherein the nitrile 5 reactant is a nitrile ester« 21. A method as claimed in Claim 20 wherein a compound as claimed in Claim 5 is prepared from a nitrile ester of the formula 10 wherein the symbols are as defined in Claim 5. 22. A method as claimed in any one of Claims 19 to 21 wherein the condensing agent is a mixture of a strong protonating agent and a nucleophile. 23. A method as claimed in Claim 22 wherein the reaction 15 is carried out by heating in the range 6o° to 120°C. 24. A method as claimed in Claim 19 substantially as hereinbefore described.

2. Compounds as claimed in Claim 1 wherein each alkyl group or moiety is a saturated radical. 15·

3. Compounds as claimed in Claim 1 or Claim 2 wherein the heterocyclic amine is selected from dihydropyridyl, tetrahydropyridyljpiperidyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, homopiperidyl, homopiperazinyl and homomorpholinyl * 20.

4. Compounds as. claiiijpd in any one of the preceding Claims wherein the 3-alkyl jjrc/dp is attached to the heterocyclic amine .·' · /· at a ring carbon atom^immediately adjacent a ring nitrogen atom, 23 41708 510. 15. 20. 5. Amine) nlkyl-pent-3-ene-l,5-diacid, the nitrogen atom of the amide group being substituted by two alkyl groups or forming part of a saturated heterocyclic ring. 27. A compound as claimed in Claim 1 whenever prepared by a method as claimed in Claim 26. 10 28. A method of preparing a compound as claimed in Claim 1 which comprises reaction with a condensing agent of the corresponding 4-(heterocyclic amine) alkyl-4-cyano-4-phenyll-alkoxy-l-(dialkylamino or saturated heterocyclic amin<)-but1-ene or but-l,2-diene or a diquaternary ammonium derivative 15 thereof. 29. A compound as claimed in Claim 1 whenever prepared by a method as claimed in Claim 28. 30. A pharmaceutical composition comprising a compound as claimed in Claim 1 in association with a pharmaceutically 20 acceptable carrier. 31. A pharmaceutical composition as claimed in Claim 30 in which the active compound is as claimed in Claim 3. 32. A pharmaceutical composition as claimed in Claim 31 in which the active compound is as claimed in Claim 14. 33. A pharmaceutical composition as claimed in any one of Claims 3° to 32 in the form of a tablet, capsule, suppository, solution or suspension. 34. A pharmaceutical composition as claimed in any one of 5 Claims 30 to 33 in a dosage unit form containing 1 to 1000 mg of the active compound per dosage unit. 35· A pharmaceutical composition as claimed in Claim 34 containing 5 to 5°0 mg of the active compound per dosage unit. ®5· A compound as claimed in Claim 1 whenever prepared by a method as claimed in any one of Claims 19 to 24. - 28 41708 26. A method of preparing a compound ae claimed in Claim 1 which comprises reaction with a condensing agent of a nitrile amide of a corresponding 2-phenyl-2-(heterocyclic amine) alkyl-pentane-1,5-diacid or of a 2-phenyl-2-(heterocyclic 5 methyl provided that at least one of them represents methyl. 5 ring carbon atom; Rg represents hydrogen or C^-C^ alkyl optionally substituted by Cg-Cg cycloalkyl or by phenyl; X represents C^-C^ alkyl or phenyl; and P represents zero or an integer, 10 and acid addition salts and quaternary ammonium derivatives thereof. 5. Compounds as claimed in claim 1 of t.he formula wherein R represents hydrogen or Cg-C^ alkyl; Rg, Rg and R^ independently represent hydrogen oi Cg-alkyl and R^ represents hydrogen, Cg-C^ alkyl or C-C alkoxycarbonyl, provided that at least one of Rg, Rg, Rg and R^ represents alkyl, Rg together with Rg or with Rg represents an alkylene radical which together with their immediately adjacent carbon atoms(s) of the hydrogenated pyridine ring forms a carbocyclic ring of 3 to 8 carbon atoms and Rg or Rg respectively and R^ are as defined above (not subject to the proviso), or Rg and R^ together represent a second valency bond joining their immediately adjacent carbon atoms, or Rg together with Rg represents a second valency bond joining their immediately adjacent ring carbon atoms and Rg and R^ are as defined above provided that at least one of them represents alkyl; Y represents Cg-C^ alkyl optionally substituted by hydroxy or Cg-C^ alkoxy, hydroxy, Cg-C^ alkoxy, halogen or trifluoromethyl; - 24 2541708 m represents zero or an integer up to 5! Λ represents C.-C r alkylene; o N represents a non-aromatic N-containing heterocyclic ring of five to seven ring atoms joined to Λ at a

5. pyridine ring by an alkyl group of 1 to 4 carbon atoms or by a divalent alkylene radical which together with at least one of the carbon atoms at said 4 and 5 positions forms a carbocyclic ring Of 3 to 8 carbon atoms and in which the heterocycli amine is a non-aromatic N-containing heterocyclic ring of five 10. to seven ring atoms joined to the 3-elkyl group at a ring carbon atom, and acid addition salts and quaternary ammonium derivatives thereof.

6. Compounds as claimed in Claim 5 wherein Rg, Rg , Rg and R^ independently represent hydrogen or c i“ c /j alkyl provided that at least one of them 15 represents alkyl or Rg together with Rg represents a second valency bond joining their immediately adjacent ring carbon atoms and Rg and R^ are as defined above provided that at least one of them represents alkyl; 20 Y represents Cg-C^ alkoxy, halogen or trifluoromethyl; m represents zero, 1 or 2; Rg represents hydrogen or Cg-C^ alkyl; N represents piperidyl, piperazinyl or morpholinyl; X represents Cg-C^ alkyl; 25 P represents zero or 1; and A and R are as defined in Claim 5· - 25 41708

7. Compounds as claimed in Claim 6 wherein Π represents methyl or hydrogen.

8. Compounds as claimed in Claim 6 or Claim 7 wherein Rp Rg, R^ and R^ independently represent hydrogen or

9. Compounds as claimed in any one of Claims 6, 7 and 8 wherein Y represents methoxy, chlorine, or trifiuoromethyi. 10. Compounds as claimed in any one of Claims 6 to 9 wherein A represents an alkylene group of the formula 10 -(CH„) - where n represents 2, 3 or 4. a ΓΧ 11. Compounds as claimed in any one of Claims 6 to 10 wherein R^ represents hydrogen, methyl or ethyl. 12. Compounds as claimed in Claim 11 wherein X represents methyl or ethyl. la wherein m represents 1 or 2; - 26 41708 R 2 ’, R^', and R^' independently represent hydrogen or methyl, and acid addition salts thereof. 14. 4,4-Diitiethyl- 3(3' -me thoxyphenyl )-3( N-me thyl- 2-piperid- l^L $ -ethyl) piperidine-2,6-dione and acid addition salts thereof. 15. A method of preparing a compound as claimed in Claim 1 which comprises reaction of ammonia or an amine with a corresponding 2-phenyl-2-(heterocyclic amine) alkyl-pontane IO -1,5-diacid or a 2-phenyl-2-(heterocyclic amine) alkyl-pent3-ene-l,5-diacid, or a functional derivative of either of those acids. 16. A compound as claimed in Claim 1 whenever prepared by a method as claimed ih Claim 15. 15 17. A method of preparing a compound as claimed in Claim 1 which comprises heating a corresponding diamide or diammonium salt of a 2-phenyl-2-(heterocyclic amine) alkyl-pentane-1,5diacid or of a 2-phenyl-2-(heterocyclic amine) alkyl-pent3-ene-l,5-diacid. 20 18. A compound as claimed in Claim 1 whenever prepared by a method as claimed in Claim 17· 19. A method of preparing a compound as claimed in Claim 1 which comprises reaction with a condensing agent of a - 27 41708 mononitrile, dinitrile or nitrile ester of a corresponding

10. 36. A pharmaceutical composition as claimed in Claim 35 Containing 10 to 250 mg of the active compound per dosage unit.