IE45890B1 - 13-oxo-12-azaprostanoic acid analogues - Google Patents

Description

This invention relates to novel compounds having pharmacological activity, to processes for their preparation, to intermediates useful in that process and to pharmaceutical compositions containing them.

More specifically the invention relates to 13-oxo-12azaprostanofc acid analogues.

Natural prostaglandins and analogues thereof are known to possess a wide variety of pharmacological activities.

British Patent Specification No. 1,428,431 discloses that pyrazolidine derivatives of the formula (I): Y CH2(A)m(cH2)nco2R CH2-CH2CH(CH2)pCH3 OH (I) wherein A is CH=CH or C=C; R is H, or alkyl and cyeloalkyl each of up to 12 carbon atoms; m is 0 or 1; n is 0-6; p is 0-6; and Y and Z are 0 or H2 except that Y and Z are both 0 and alkali metal and amine salts thereof when R is H; have similar biological properties to the prostaglandins or are antagonists of prostaglandins.

Japanese Patent Application No: 51001461 discloses the preparation of a compound of formula (IX): COOH & (II) ' and states that this compound has laxative activity.

A novel class of compounds having useful pharmacological activity has now been discovered, which compounds are structurally distinct from the known compounds referred to above. 43890 The present invention provides a compound of the formula (I): m is 0 or 1; n is 4 to 8; X is CO, protected CO, CROH in which R is hydrogen or cl-4 alkyl and in which the OH moiety may be protected; Rj is hydrogen, or COgRj represents an ester group in which the Rj moiety contains 1 to 12 carbon atoms; Rj is hydroxy or protected hydroxy; R2 and R4 are separately hydrogen, Cj_galkyl, Cg_gcycloalkyl, Cg_gcycloalkyl -Cj_galkyl, phenyl, phenyl Cj_g alkyl,, naphthyl, naphthyl Cj_galkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen atom or trifluoromethyl, Cj_g alkyl, Cj_g alkoxy or nitro groups; or ϊ?2 and R4 taken with the carbon atom to which they are joined represent.Cg_g cycloalkyl; Rg is hydrogen, C^_4 alkyl or phenyl; and salts thereof when R is hydrogen.

It is normally preferred that m is 0.

Suitably n is 5,6 or 7, preferably 6, Suitable protected hydroxyl groups CROH and R3 include readily hydrplysable groups such as acylated hydroxy groups in which the acyl radical contains 1 to 4 carbon atoms, for exainple the acetoxy group; and hydroxy groups etherified by readily removable inert groups such as the benzyl.

Preferably Rg is hydroxy, and the hydroxy moiety in CROH is unprotected.

Suitable protected CO groups X include groups formed by conventional carbonyl addition and condensation reactions such as acetals, thioacatals, hanithicketals, oximes, ssni-cazbazcnes and hydrazones . Of such .groups often the acetal type derivative will be most useful, for example when X is a group Examples of suitable groups X include CO, CHOH, 0(0¾) OH and C(C2H5)OH, Preferably X is CO, CHOH or C(CH3)0H, most preferably CO.

R^ is hydrogen or COgR^ represents an ester group in which the R^rroiety contains from 1 to 12 carbon atoms.

Examples of include hydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl and tolyl, while normally hydrogen or alkyl groups are preferred.

Preferably Rg is hydroxy.

Suitable groups Rg or R4 when Rg or R4 is an alkyl group include C4..9 alkyl groups. Such C4_g alkyl groups may be straight chain alkyl groups, such as n-butyl, npentyl, n-hexyl and n-heptyl, or may be alkyl groups branched by one or two methyl groups (at the same or different carbon atoms). Thus for example, Rg or R4 may be a group CHgRg , CH(CH3)RgOr C(CH3)2Rg wherein Rg is a straight chain alkyl group such that the carbon content of the resultant group Rg or R4 is 4 to 9.

In general preferred groups Rg/R^ when 331 alkyl group include straight chain pentyl, hexyl and heptyl groups. Of these, straight chain hexyl is often the most useful. However particularly preferred Rg groups also include hydrogen, and alkyl groups such as hydrogen, methyl and ethyl.

When Rg/R4 is or contains a Cg_g cycloalkyl moiety, the moiety is suitably a eyclohexyl moiety. Examples of suitable Cj._g alkyl moieties when R4 is a Cg_g cycloalkyl - C1_glkyl group include methyl, ethyl, propyl, butyl and amyl.

Rg and R^ taken with the carbon atom to which they are joined may also represent Cg_gcycloalkyl. Preferably this cyclo group is eyclohexyl.

When R_/R. is an aryl group as previously defined, & 4 suitable groups Rg/R^ include phenyl,benzyl, ptenvethyl, i3-phaiylpropyl, 4-phenylbutyl, naphthyl, naphthylmethyl, 2-(naphtyl)ethyl, 3-(naphthyl)propyl and 4-(naphthyl)butyl. These groups may be substituted in the phenyl or naphthyl moiety by normally one, two or three groups or atoms selected from those substituent groups or atoms listed herein before. Examples s ;'r 45890 of suitable substituent groups or atoms include fluorine, chlorine and bromine atoms and CF^ , methyl, ethyl, n- and iso-propyl, methoxy and ethoxy, n- and iso-propoxy and nitro groups.

Examples of suitable, groups R^ include hydrogen, methyl, ethyl, n- and iso-propyl and phenyl. Preferably Rg is hydrogen, methyl or ethyl.

The compounds of the formula (X) may form conventional salts when R^ is hydrogen. Such salts include those with alkali and alkaline earth metals, suitably sodium and potassium, 10 and ammonium and substituted ammonium salts.

One group of compounds within formula (I) of particular interest due to their activity is of formula (II): (ch: OH wherein: m is 0 or 1; · p is 5,6, or 7; X1 is CO, protected CO, CHOH, or C(CH^)OH; is hydrogen or alkyl; R12 is hydrogen or Cj_3 alkyl; R1^ is C4_g alkyl, or a group of formula (III) (IV) or (V) as defined below: (III) 45880 wherein: q is 0 to 5; r is 0 to 3; and W, Y, Z are each independently hydrogen, fluorine, chlorine, bromine, CFg , methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, nor iso-propoxy or nitro groups; R5 is hydrogen, Ci>>4 alkyl or phenyl? and salts thereof when R^ is hydrogen.

Xn formula (XI) it is generally preferred that m is 0. p is most suitably 6, χ4· is preferably CO, protected CO or CHOH, most preferably CO.

R·^ ie suitably hydrogen, methyl or ethyl, preferably methyl or ethyl.

Suitable and preferred groups Rl^ when R^4 is a C4_g alkyl group include those stated to be suitable and preferred alkyl groups for R4 . Examples -of such groups include n-pentyl, n-hexyl, and n-heptyl groups, or such groups branched by a methyl group.

When R^ is a group of formula (III), (IV) or (v), then one or two of W, Y .and Z are normally hydrogen, and r is normally 1.

R5 is suitably hydrogen, methyl or ethyl.

A second group of compounds within formula (I) is of formula (VI): (VI) wherein: 111 m, ρ, X , R ι , R 4 and R5 are as defined in formula (XI), and R^gis a group within those defined in formula (II) lol for R 4 ; or RZg and R 4 together with the carbon atom to which they are joined represent Cg_g .cycloalkyl; and salts thereof when Rj is hydrogen.

Suitable and preferred values for the variables m, p, R and R5 are as described in relation to formula (II).

Suitable and preferred values for R 2 are as described for in relation to formula (II).

The invention also provides a process, for the preparation of a compound of the formula (I), which process comprises decarboxylating a compound of the formula (VII): (VII) m, n, Rj, Rg, Rj, R4and Rsare as described in formula (I), to yield a compound of the formula (I) wherein X is CO; and thereafter if desired converting X in the thus formed compound to protected CO by conventional methods, or to CROH by reduction when R is hydrogen or by reaction with a Ci_4alkyl Grignard reagent or C^_^alkyl metallic complex when R is Cj__4 alkyl, and then optionally protecting the CROH hydroxy moiety.

The decarboxylation reaction may be brought about under basic, acid or neutral conditions in conventional manner. For example when m=0 the reaction is conveniently effected by heating the chosen compound of the formula (VII) in a suitable solvent having a suitable boiling point such as toluene, xylene, or DMF.

After the reaction Rj may be varied by conventional deesterification and/or esterification reactions. Similarly protected CROH and Rg hydroxy moieties may be deprotected by conventional methods. For example, when Rg is a benzyloxy group, the benzyl group may readily be removed by hydrogenolysis. Thus it may be seen that 'protected hydroxy' compounds of the formula (I) are useful intermediates in the preparation of the corresponding 'free hydroxy' compounds of the formula (I).

The conversion of a compound of the formula (I) wherein X is CO to the corresponding oompound wherein X is CHOH may be carried out by conventional methods for reducing a ketone to an alcohol, for example by sodium borohydride reduction.

The conversion of a compound of the formula (I) wherein X is CO to the corresponding compound wherein X is CROH in which R is alkyl may be carried out by conventional Grignard or alkyl metal, (suitably alkyl lithium) reactions.

When R^ is hydrogen, salts of compounds of the formula (I) may be prepared in conventional manner, for example by reacting the chosen compound of the formula (I) with the required base.

It is frequently convenient however to prepare the desired compound of the formula (I) directly from an ester of the formula (VIII), and often this will in fact be the preferred route: (VIII) where COgRyis an ester group. In such a case Ry is preferably a benzyl:.group or a lower alkyl group such as ethyl. Thus treatment of a compound of the formula (VIII) with, for example, lithium iodide dihydrate in anhydrous solvents brings about simultaneous de-esterification and decarboxylation.

It will be appreciated that conpounds of the formulae (VII) and (VIII) are useful intermediates and as such form a useful aspect of this invention.

The compounds of the formula (VIII) may be prepared by the ring closure of the corresponding triester of formula (IX): m, n, Rj , R2 , Rj and are as defined in formula (I), Ry is as defined in formula (VIII), and Rg is a group such that COjRgis an ester group.

In the prooess of the invention the group COjRj in the intermediates of formula (VII), (VIII) and (IX) will normally represent an ester group, and if acids of the formula (I) (wherein Rj is hydrogen) are required they will be obtained by de-esterification of the corresponding compound of the formula (I) wherein CO^Rjis an ester group. Usually the ester group . CO2R8 ·*·η formu^a will be the same ester group as COjRj, and for the sake of convenience the ester group C02R7 will also normally be the same ester group as CO2Rj. The groups COjRj /R^/Rg are suitably Cj_4alkyl esters such as methyl and ethyl esters.

Generally, the ring closure takes place in a dry organic solvent using a strong base such as sodium hydride or sodium ethoxide (or other *OR7or oRg group) to bring about the initial proton abstraction from the a-methylene group.

It has been found that sodium ethoxide in benzene, or potassium t-butoxide in toluene, benzene or hexamethylphosphoramide give good results.

Compounds of the formula (IX) may be prepared by the acylation of a compound of the formula (X): R7°2C_R8°2C (CH2)nCO2Rl (CHI).

(X) with a compound of the formula (XI): (XI) '3 "4 Thia acylation may be carried out by conventional acylation techniques, for example by using activated derivatives of (XI). Most suitably the acylation is carried out by using dicyclohexyl carbodiimide (DCC) as coupling agent.

The acid of formula (XI) may be prepared by conventional methods. It h^s been found that the following reaction scheme is particularly suitable: R2^ C = 0 + RqO*C " CHBr 2 [CO2R9 is an ester·; group e.g R9 is C^alkyl.] /R2 The amine of formula (X) may be prepared by reacting a compound of formula (XII): γ n αοΛ (XII) wherein Υ is a halogen atom such as bromine, with an amino acid ester of formula (XIII): ROC - CH - (CH ) - CH - HH 2 2 2 m 2 2 (XIII) The reaction is carried out in conventional manner for alkylation reactions of this nature.

Compounds within the formula (I) have useful pharmacological activity. For example compounds within formula (I) have anti-gastric secretion activity, cardiovascular activity, platelet aggregation inhibition activity, effect the respiratory tract e.g. bronchodilator activity, and have anti-fertility and smooth muscle activity.

In general it may be said that compounds within the formula (I) have a range of pharmacological activities similar to those shown by the natural prostaglandins, but that these activities tend to be rather more selective. 48890 The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable carrier.

The formulation of the said pharmaceutical compositions 5 will depend on the nature of the activity shown by the chosen compound of the formula (I), and on other factors such as a preference in a particular area of therapy for a particular mode of administration. Xn general however, the compositions may be formulated for administration by any route.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, fillers, tabletting lubricants, disintegrants, and acceptable wetting agents and the like. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (whieh may include edible oils) preservatives, and if desired conventional flavouring or colouring agents, and the like.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) and a sterile vehicle. The compound, depending on the vehicle and concentration, used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepard in substantially the same manner except that the compound is suspended in the vehicle, instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactantor wetting agent is included in the composition to facilitate uniform distribution of the compound.

When appropriate, the compositions of this invention may be presented as an aerosol for oral administration, or asa microfine powder for insufflation.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

It will of course be realized that the precise dosage used in the treatment of any of the hereinbefore described disorders will depend on the actual conpound of the formula (I) used, and also on other factors such as the seriousness of the disorder being treated. 458θθ It has been found that many of the compounds of the formula (I) are inhibitors of gastric secretion, and thus have commercial utility as anti-ulcer agents.

It will of course be realised that the compounds of the 5 formula (I) can have asymmetric centres, and thus are capable of existing in a number of stereoisomeric forms. The invention extends to each of these stereoisomeric forms, and to mixtures thereof. The different stereoisomeric forms may be separated one from the other by the usual methods.

The following Examples 6 and 7 illustrate the inventions EXAMPLE 1. (Compound 1).

Diethyl 2-rN-2-ethoxycarbonylethyl)1 aminoazelate Diethyl 2-bromoazelate (90g) in dry ethanol (50ml) was added dropwise to a refluxing solution of β-alanine ethyl ester (35g) in dry.ethanol (175ml) containing a suspension of sodium carbonate (35g). Reflux was continued for 6 hours.

When the reaotion mixture cooled, the ethanolic solution was decanted, and the remaining solid was well washed with ether. The combined organic solutions were evaporated in vacuo and the residue was dissolved in ether. The ether solution was washed with brine then was dried over magnesium sulphate and evaporated to give a yellow oil (84.6g). The oil was vacuum distilled to remove unreacted starting materials but the residue was not further distilled as it tended to decompose. The diethyl 2-[N-(2-ethoxycarbonylethyl)] aminoazelate (56g) was sufficiently pure for subsequent reactions and could be obtained analytically pure via column chromatography.

IR: 1730 cm [carbonyl of ester] NMR: 6P(q) at 5.9f [-C-O-CH CH J l| fc w 0 EXAMPLE 2 (Conpound 2).

Ethyl 3-hydroxy-3-methyl-n-nonanoate A portion (about 10%) of a mixture of ethyl 2-bromoaoetate (75g) and octan-2-one (64g) in a dry benzene (100ml) was added under nitrogen to dry zinc dust (37.5g). A few crystals of iodine were added to initiate the reaction. The stirrer was started and the remaining mixture of reactants was added, dropwise, at such a rate as to maintain reflux. External heat was applied to continue the reflux for 1¾ hours after the final addition.

The cooled reaction mixture was treated with 20% sulphuric acid (200ml) and the resulting two phases were separated. The aqueous phase.was extracted once with benzene (200ml). The combined benzene solution was washed with 5% sulphuric acid and with 10% sodium carbonate solution, then was dried over magnesium sulphate and evaporated in vacuo to give a clear oil. This was vacuum distilled to yield ethyl 3-hydroxy-3-methyl-n nonanoate (25.1g).

N.B. No attempt was made to maximise the yield of this reaction.

B. pt. IR: NMR: The compounds shown in Table 1 were prepared in a similar manner. 48890 TABLE 1 EtO2 C CH-CC \ HO CompoundR5 r2 r4 3 H ch3 CH2CH2Ph 4 H ch3 Ph 5 H ch3 ch(ch3)c4h9 6 H - (CH2)5- J Compound 3; b. Pt. 120 at 0.3 mm Hg.

IR: 3500 cm 1[OH]j 1710 (carbonyl (of ester)] NMR: 5P(s) at 2.Sr [Ph]? 2P(q) at 5.8^-^-00¾^] lP(s) at 6.5r [OH]; 2P(m) at 7.2^-011^11] 2P(s) at 7.5r [-CHgCOgEt] o Compound 4 B. Pt. 97 at 0.3 mm Hg.

IR: 3500 cm 1[oh]; 1710 cm 1[carbonyl of ester] NMR: 5P(m) at 2,7y [ph]; lP(s) at 5.85y [OH]? 2P(q) at 5.95r [-C-OCH2CH3]; 2P(d) at 7.25γ> [-CH2CO2Et] 3P(s) at 8.05r[CH3]? 3P(t) at 8.9r[-C-OCH2CH3] Compound 5 : I o B. Bt. 84 at 0.06 mm Hg. IR: 3500 cm^[0H]; 1710 cm"’''[carbonyl (of ester)] HMR: 2P(q) at 5.85χ· [-G-CCH CH ]; lP(s) at 6.7tToh1 0 2 3 2P(s) at 7.6y [-CHgCOgEt] Compound 6: B. Pt. 90° at 0.05 mm IR: 3500 cm ^[OH]; 1710 cm '’[carbonyl (of ester)] NMR: 2P(q) at 5.8r [-C-OCH CH 1: lP(s) at 6.7γΓ0Η] II dt 0 0 2P(s) at 7.55r r-CH9C0?Et1 EXAMPLE 3 (Compound 7) 3-Hydroxy-3-methyl-n-nonanoic acid Ethyl-3-hydroxy-3-methyl-n-nonanoate (25g) was refluxed for 3 hours with a 10% solution of potassium hydroxide in dry ethanol (210ml). The ethanol was evaporated in vacuo and the residue was treated with water (100ml). The aqueous solution was washed with ether then was acidified (ice-bath cooling) with dilute hydrochloric acid. The oil that separated was 10 extracted into ether. The ether solution was washed with brine then was dried over magnesium sulphate and evaporated to give a light yellow oil. This was vacuum distilled to yield 3hydroxy-3-methyl-n-nonanoic aoid as a clear syrup (18.1g).

B. Pt. 130° at 0.25 mm Hg IR: Broad band 3100 to 2400 cirT-'-fcOjH] Broad band at 1700 cm1 [carbonyl of acid] NMR: 2P(s) at 2.17f [-COjH; OH] 2P(s) at 7.5r [-ch2co2h] The compounds shown in Table 2 were prepared in a similar manner.

TABLE 2 Re / 5/R2 H<^C-CH-C\^ \ 4 HO CompoundR5 r2R4 8 H ch3 CHgCHgPh 9 HCH3 Ph 10 HCIi3 CHiCHj^Hg 11 H - (CHg) 5 - o Compound 8: 1 B. Pt. 130 at 0.25 mm Hg. —1 —1 IR: 3700 to 2400 cm [-CO,H]; 1710 om [carbonyl (of acid)] NMR: 2P(s) at 2.15r [CO,H + OH]; 2P(s) at 7.5? [-¾ co2h] Compound 9: IR: 3700 to 2400 cm1 [CO2H]; 1690 cm1 [carbonyl (of acid)] Compound 10: IR: 3700 to 2400 om1 [CO2H]; 1700 cm1 [carbonyl (of acid)] NMR: 2P(s) at 2.6r [C02H + OH]; 5P(s) at 2.75r[£h] 2P(broad s) at 7.2r [-CH COH]; 3P(s) at 8.55r [ch3] 2 2 Compound 11: IR: NMR: 2P(s) at 2.6y [CO H + OH]; 2P(s) at 7.5r [CH CO tri 2" 2 2 EXAMPLE 4 (Compound 12) Diethyl 2-[N-(2-ethoxycarbonylethyl)-N-(3-hydroxy-3ll-methyl-n- Dicyclohexylcarbodi-imide (10.3g) in dry dichloromethane (50ml) was added dropwise to a stirred, ice-cold,mixture of 3hydroxy-3-methyl-n-nonanoic acid (9.4g) and diethyl 2-[n-(2ethoxycarbonylethyl)] aminoazelate (17.98g) in dry dichloromethane (150ml). The mixture was allowed to warm to room temperature and stirring was continued overnight. The dicyclohexylurea was filtered off; the filtrate was eyaporated.in vacuo and the residue was dissolved in ether. The ethter solution was IR: 3400 cm''’ [OH]; 1730, 1630 cm'1’ [carbonyl of ester and amide respectively].

The compounds shown in Table 3 were prepared in a similar manner.

TABLE 3 (CH,)- CO,Et Compound n *5 r2 ** 13 6 H ch3 CH2CH2Ph 14 6 H CHg Ph 15 6 H CHg CH(CHg)C4H9 16 6 H - (¾ - Compound 13: Compound 14: Compound 15: IR: 3400 cm1 [OH]; 1725, 1630 cm1 [carbonyls (of ester and amide respectively)].

IR: 3400 cm1 [OH]; 1725, 1630 cm1 [carbonyls (of ester and amide respectively)] IR: 3400 cm1[OH]; 1725, 1630 cm 1[carbonyls (of ester and amide respectively)].

NMR: 7P(m) at 5.9y [3x -C-OCH2CH3+ 1 2P (unresolved m) at 6.5γ Γ-CH - N - C-] Compound 16; IR: 3450 cm1 [OH]: 1730, 1630 cm^ [carbonyls (of ester and amide respectively)]. NMR: \ H 7P(m) at 5.9r [3x -C-OCH.CH, + 2 £ /j,\ 2P (unresolved m) at 6.5y [-CHg-N-C-] 0 EXAMPLE 5 ( compound 17) 1-(31-Hydroxy-3'-methyl-n-nonanoyl)-2-(6 -e thoxycarbonyl-n-hexyl)4-ethoxvcarbonvlpyrrolidin-3-one Diethyl 2- [n- (2 ’ -ethoxycarbonylethyl) -N— (311 -hydroxys'1 -methyl-n-nonanoyl) ] aminoazelate (1.06g) was refluxed with potassium tert butoxide (0.24g) in dry benzene (25ml) for 1¾ hours. The benzene was evaporated in vacuo and the residue was partitioned between very dilute hydrochloric acid and ether. The ether solution was washed with brine then was dried over magnesium sulphate and evaporated to give 1-(31hydroxy-31-methyl-n-nonanoyl)-2-(611 -ethoxycarbonyl-n-hexyl)4-ethoxvcarbonylpyrrolidin-3-one as a pale yellow gum (800mg).

IR: 3370 cm1 [OH]; 1730, 1630 cm1 [carbonyls (of ester and amide respectively)] The compounds shown in Table 4 were prepared in a similar manner.

Compound n *5 r2R4 18 6 Η ch3 ch £H2Ph 19 6 H ch3 Ph 20 6 H ch. CH(CH,)C.H. 21 6 . . H Hch2)5- t$ EXAMPLE 6 (Compound 22) 1-(31-Hydroxy-31-methyl-n-nonanoyl)-2-(6-ethoxycarbonyln-hexyl) pyrrolidin-3-one 1-(31-Hydroxy-31-methyl-n-nonanoyl)-2-(6-ethoxycarbonyln-hexyl)-4-ethoxycarbonylpyrrolidin-3-one (19g) was refluxed with lithium iodide dihydrate (9.5g) in dry demethylformamide (400ml) for 2¾ hours. The dimethylformamide was evaporated in vacuo and the residual oil was partitioned between very dilute hydrochloric acid and ether. The ether solution was washed with 5% sodium bicarbonate solution and with brine then was dried over magnesium sulphate and evaporated in vacuo to give a thick 'dark oil. This was chromatographed on a column of kieselgel (20 : 1 ratio) using chloroform as eluent to give 15 1-(31-hydroxy-31-methyl-n-nonanoyl)-2-(611 -ethoxycarbonyl-nhexyl) pyrrolidin-3-one (3.27g) as a mixture of isomers.

IR: 3300 [oh]; 1750, 1720, 1630 om [carbonyls of ketone, ester and amide respectively] The compounds shown in Table 5 were prepared in a similar manner and in the cases indicated, further chromatographic separation gave two observable isomers. [TLC system: 40% ethyl acetate, 60% petroleum ether - silica plates].

TABLE 5 Compound :n r5 *2 R4 23 6 H CH 3 CH2CH2P11 24(a)(b) 6 H ch3 Ph 25(a)(b) 6 H ch3 CH(CH 3)0419 26 6 H - Ws Compound 23 IR: 3300 cm1 [OH]; 1745, 1720, 1630 cm1 [carbonyls (of ketone, ester and amide respectively)] HMR: 5P(s) at 2.9y [Mi]; lp(s) at 5.35y [oh] " yH 5P(m) at 5.5 to 6.5y [-C-OCH-CH,, -CH,-N-C-] II —2 3 2 II O Mass Spec: Molecular ion at 431 Compound 24 (a) Lower Rf isomer IR: 3350cm1 [oh]; 1740, 1715, 1610 cm1 [carbonyls (of ketone, ester and amide respectively)] NMR: ' 5P(m) at 2.7f[Ph]; lP(s) at 4.45y [OS] u 5P(m) at 5.6 to 6.6y [-C-OCg2CH3; -£H2N ~ 0 Compound 24 (b) Upper Rf isomer Data as for 24 (a) Compound 25 (a) Upper Rf iscmer IR: 3350 cn2 [OH]; 1750, 1730, 1630 cm''· [carbonyls (of ketone^, ester and amide respectively)] NMR: lP(s) at 5.35jj^[OH]: 5P(m) at 5.6f to 6.6r [-Coch2ch3; -CH2-N - C-]· 0 Compound 25 (b) Data as for 25 (a) [NMR - lP(s) at 5.4r [OH]] Coinpound 26 IR: 3400 cm1 [oh]; 1750, 1730, 1630 cm1[carbonyls (of ketone, ester and amide respectively)] NMR: lP(d) at 5.55γ· [OH]; 5P(m) at 5.7 to 6.6y [-{j-P2a,cH ; -ch2 - n - c -] o 0 EXAMPLE 7 (Compound 27) 1-(31-Hyd raxy-31-methyl-n-nonanoyl)-2-(611 -ethoxycarbonyl-nhexyl)-3-hydroxypyrrolidine 1-(31-Hydroxy-31-methyl-n-nonanoyl)-2-(6-ethoxycarbony1n-hexyl) pyrrolidin-3-one (1.46g) in dry ethanol (20ml) was treated dropwise with portions of sodium borohydride (135 mg total) and the resulting solution was stirred at room temperature for 3 hours. The ethanol was evaporated in vacuo at room temperature and the residual oil was partitioned between very dilute hydrochloric acid and ether. The ether solution was washed with brine, dried over magnesium sulphate and evaporated in vacuo to give a yellow oil (1.17g). This was purified via column chromatography to give 1-(31-hydroxy-31methyl-n-nonanoyl)-2-(611 -ethoxycarbonyl-n-hexyl)-3-hydroxypyrrolidine (530mg) as a clear oil which solidified on standing.

IR: 3400 cm [oh]; 1730, 1620 [carbonyls (of ester and amide respectively)]; loss of ketonic carbonyl at 1750 cm NMR: lP(s) at 4.8y 2P(q) and 5P(m) at 5.7 to 6.8r •c-och.ch · —2 3/ 4P (s+t) 7.7 to 8γ· ψ-Η N.

/N ; -£H2C02Et Mass Spec, Molecular ion at 413.

The compounds.shewn in.Table 6 were prepared in a similar manner.

' -, Compound nR5R2R4 28 6 H ch3 ch(ch3)c4h9 29 6 H -(ch2)5- Compound 28 IR: 3450 ¢3^ [OH]; 1730, 1620 cm' [carbonyls(of ester and amide respectively)] loss of ketonic carbonyl at 1750 om NMR: lP(d) at 4.7r [og]; 7P(m) at 5.5 to 6.7y / K V -C—OCH CH ; I 2 3 °S Mass Spec; Molecular ion at 413.

Compound 29 IR: 3350cm-1 [OH]; 1720, 1610 cm1 [carbonyls (of ester and amide respectively)] loss of ketonic carbonyl at 1750 cm NMR: lP(d) at 4.9^ [OH]; 7P (m) at 5.6 to 6.7^ OH -C-OCH CH „ ; -CH -N-C-j W If — 2 3 2 1 0 x Toxicity No apparent side effects were observed after administrat ion of Compound 22 at 100 mg/kg sub-cutaneously in the hamster and intra-duodenally in the rat.

Pharmacological Data The compounds were examined for their ability to inhibit pentagastrin-stimulated gastric acid secretion in the anaesthetised, perfused rat stomach preparation (Ghosh and Schild preparation, ref: M.N. Ghosh and H.O. Sehild, 1958, Brit. J. Pharmacol., 13, 54.) Compound 25(a), the upper isomer, was active in this test in the dose range 500μg-10mg/kg, intravenously, whereas the isomeric mixture of Compound 25(a) and 25(b) was active in the dose range 500gg-lmg/kg, intravenously. Compound 26 was active in the dose range 10-20 mg/kg, intravenously.

The Compounds were also examined for their ability to inhibit gastric acid secretion in the pyloric ligated rat model (Shay rat preparation, ref: H. Shay et al., 1945, Gastroenterology, 5_, 43.

When given intraduodenally at 200mg/kg the isomeric mixture of Compound 25(a) and 25(b) inhibited the total titratable acidity in the stomach by 92%. Contpound 25(a) when given at lOOmg/kg, intraduodenally , lowered the acidity by 43%.

Toxicity No apparent side effects were observed after administration of Compound 22 or Compound 25 (a) at lOOmg/kg, intraduodenally, in the rat or of Compound 22 at 100 mg/kg, subcutaneously, in the hamster.

Claims (31)

1. CLAItB:

1. A compound of the formula (I): (ch 2 : (I) wherein: 5 m is 0 or 1; n is 4 to 8; X is CO, protected CO, CROH in which R is hydrogen or Cj_ 4 alkyl and in whioh the OH moiety may be protected; Rj hydrogen, or COjRj represents an ester group in which 10 the Rj moiety contains 1 to 12 carbon atoms; Rj is hydroxy or protected hydroxy; R 2 and R 4 are separately hydrogen, Cj_ g alkyl; Cg_g cyeloalkyl, Cg_g cycloalky1-Cj_g alkyl, phenyl, pheny1-Cj_g“ alkyl, naphthyl, naphthyl-Cj_g alkyl, any of which phenyl or 15 naphthyl moieties may be substituted by one or more halogen atoms or trifluoromethyl, Cj_ g alkyl, Cj_ g alkoxy or nitro groups; or Rj and R 4 taken together with the carbon atom to which they are joined represent Cg_g cyeloalkyl; Rg is hydrogen, Cj_ 4 alkyl or phenyl; or a salt thereof when 20 Rj is hydrogen.

2. A compound according to claim 1, wherein X is CO, CflOH, or C(CHj)OH.

3. A compound according to claim 1 or 2, wherein n is 5, 6 or 7.

4. A compound according to claim 1, 2 or 3, wherein m is 0.

5. A compound according to any one of claims 1 to 4, wherein R^ is hydrogen or a 4 alkyl group.

6. A compound according to any one of claims 1 to 5, wherein R 2 is hydrogen or a C^_ 4 alkyl group.

7. A compound according to any one of claims 1 to 6, wherein R^ is hydroxy.

8. A compound according to any one of claims 1 to 7, wherein R 4 is a group CH 2 R g , CH(CH 3 ) R g or C(CH 3 ) 2 R g , wherein R g is a straight chain alkyl group suoh that the carbon content of the resultant group is 4-9.

9. A compound according to any one of claims 1-7, where R^ is a phenyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, naphthyl, naphthylmethyl, 2-(naphthyl)ethyl, 3-(naphthyl)propyl, or 4-(naphthyl) butyl group optionally substituted in the phenyl or naphthyl moiety by a fluorine, chlorine, or bromine atom or a CF^ , methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy, or nitro group.

10. A compound according to any one of claims 1 -9, wherein R is hydrogen, methyl or ethyl.

11. A compound of the formula (II): wherein: m is 0 or 1; p is 5, 6 or 7; S X 1 is CO, protected CO, CHOH or C(CH 3 )OH; is hydrogen or C^_4 alkyl; R 1 . is hydrogen or C, alkyl; Z -L“j R^ 4 is C 4 _ 9 alkyl or a group of formulae (III), (IV) or (V): 4589ο wherein: q is 0 - 5; r is 0 - 3; and W, Y, Z are each independently hydregen, fluorine, chlorine, branine, CFg, methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, nor iso-propoxy or nitro groups; is hydrogen, C 1 alkyl or phenyl; or a salt thereof when R^ is hydrogen.

12. A compound according to claim 11, wherein m is 0.

13. A compound according to claim 11 or 12, wherein p is 6.

14. A compound according to any one of claims 11 - 13 wherein X is CHOH.

15. A compound according to any one of claims 11 - 13, wherein X 1 is CO.

16. A compound according to any one of claims 11 - 15, wherein R 1 ^ is hydrogen.

17. A compound according to any one of claims 11 - 15, wherein R-^ is methyl or ethyl.

18. A compound according to any one of claims 11 - 17, wherein Rl^is a C^galkyl group.

19. A compound according to any one of claims 11 - 17, wherein Rl^ is n-pentyl, n-hexyl, or n-heptyl, or such groups branched by a methyl group.

20. A compound according to any one of claims 11 - 19, wherein is a group of formulae (III), (IV), or (V) , wherein one or two of W,Y, and Z is hydrogen and r is 1.

21. A compound according to any one of claims 11 20, wherein Rg is hydrogen, methyl, or ethyl;

22. A compound of the formula (VI): 10 wherein: m, ρ, X 1 , R 1 !, R^, and Rg are as defined in relation to 2 formula (II) in any one of claims 11 - 21 and R 2 is a 2 1 group r1 4 ; or R 2 and & ^together with the carbon atoms to which they are joined represent C5_8cycloalkyl; or a 15 salt thereof when Rj is hydrogen.

23. A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 and a pharmaceutically acceptable carrier.

24. A process for the preparation of a compound of 20 the formula (I) as defined in claim 1, which process comprises decarboxylating a compound of the formula (VII) (VII) <2 , «3 , R^ a °d R-5 are as defined in claim 1, to yield a compound of the formula (I) wherein X is CO, and thereafter if desired converting X in the thus formed compound to protected CO or to CROH by reduction when R is hydrogen or by reaction with a C-^alkyl Grignard reagent or Cj._ 4 alkyl metallic complex when R is 0^_ 4 alkyl and then optionally protecting the CROH hydroxy moiety.

25. A process according to claim 24, wherein the ccnpound of the formula (I) is prepared by simultaneous de-esterificatian and decarboxylation of an ester of the formula (VIII): (CH 2 ) n COgRi wherein COgRy is an ester group. (VIII) V 4δβθ°

26. A process according to claim 25, substantially as hereinbefore described with reference to Example 6 or Example 7.

27. A compound according to claim 1, whenever prepared by a process according to claim 24, 25 or 26.

28. A compound according to claim 1, substantially as hereinbefore described with reference to Example 6 or Example 7.

29. A compound of the formula (VII): wherein the variable groups are as defined in any one of claims 1 to 10.

30. A compound of the formula (VIII): wherein COgR? is an ester group and the other variable groups are as defined in -any one of claims 1 to 10.

31. A compound according to claim 30, substantially as hereinbefore described with reference to Example 5.