United States Patent (19) 11 Patent Number: 4,855,293 Collington et al. (45) Date of Patent: Aug. 8, 1989

54 ANTI-INFLAMMATORY COMPOSITIONS ration and Pharmaceutical Formulation, filed 9-14-87, COMPRISING ASYSTEMIC U.S. Ser. No. 096,777. NON-STERODAL ANTI-NFLAMMATORY Collington et al., Cyclopenty Ethers and Their Prepa DRUG AND A CYCLOPENTYLETHER ration and Pharmaceutical Formulation, filed 9-11-87, U.S. Ser. No. 097,334. 75) Inventors: Eric W. Collington, Knebworth; Robert, Gastroenterology 77:761-7 (1979). Harry Finch, Letchworth; Duncan B. Judd, Ware, all of England Primary Examiner-Ronald W. Griffin Attorney, Agent, or Firm-Bernard, Rothwell & Brown 73) Assignee: Glaxo Group Limited, London, England 57 ABSTRACT The use is described of both (i) a systemic non-steroidal (21) Appl. No.: 111,026 anti-inflammatory drug and (ii) a compound of formula 22 Filed: Oct. 21, 1987 (1) 30 Foreign Application Priority Data O (1) Oct. 22, 1986 GB United Kingdom ...... 862.5325 (CH2).X(CH2)CO2R 51) Int. Cl." ...... C07C 177/00; A61K 31/557; A61K 31/55 52 U.S. C...... 514/212; 514/613; HO OY 514/708; 514/165 58 Field of Search ...... 514/212, 613, 708, 165 wherein 56) References Cited n is 1 or 2; m is 2-5 and X is cis or trans-CH=CH- or -CH FOREIGN PATENT DOCUMENTS 2-CH2-; or m is 1-4 and X is -CH=C=CH-; 0178121 4/1986 European Pat. Off. . R is phenyl, substituted phenyl or naphthyl; 1486832 9/1977 United Kingdom . Y is substituted or unsubstituted 3-phenoxy-2-hydrox 2101483 1/1983 United Kingdom . ypropyl in the therapy or prophylaxis of inflamma 2120938 12/1983 United Kingdom . 2148710 6/1985 United Kingdom . tory conditions and for analgesia in humans. 2174702 11/1986 United Kingdom. Pharmaceutical compositions containing both (i) and OTHER PUBLICATIONS (ii) are also described. Collington et al., Cyclopentyl Ethers and Their Prepa 25 Claims, No Drawings 4,855,293 1. (b) 2-naphthyl; ANT-NFLAMMATORY COMPOSTIONS COMPRISING ASYSTEMIC NONSTEROEDAL R6 R7 ANT-NFLAMMATORY DRUG AND A N / Y is -CH2-C-C-OAr CYCLOPENTYLETHER / N R5 OH This invention relates to improvements in the formu lation of anti-inflammatory drugs for the treatment of where R, R6 and R7 is each a hydrogen atom or inflammatory conditions and for analgesia. a methyl group and at least one is a hydrogen Systemic non-steroidal anti-inflammatory drugs, such 10 atom; and as , indomethacin and , are known to Aris a phenyl group (optionally substituted by one or give rise to undesirable side effects. In particular, they two C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsul are known to be ulcerogenic and can thus, for example, phinyl, C1-4 alkylsulphonyl, halogen or trifluoromethyl give rise to gastric and duodenal erosions and ulceration groups); and the physiologically acceptable salts when administered orally. This side effect may be fur 15 thereof. ther enhanced in combination with other factors such as The structural formula herein are to be understood to stress. Since in some treatments these compounds may include the enantiomers of each of the compounds con have to be used for an extended period, such side effects cerned as well as mixtures of the enantiomers including can prove a serious disadvantage. racemates. The present invention is based on our discovery that 20 In the definition of the compounds of formula (1) it is mucosal lesions of the gastrointestinal tract caused by to be understood that the carbon atom carrying the non-steroidal anti-inflammatory drugs can be signifi chain -(CH2)x(CH2)CO2R is in the R-configura cantly reduced by co-administering a cyclopentyl ether tion. described and claimed in GB-A-2174702 and set out in The systemic non-steroidal anti-inflammatory drugs formula (1) below. 25 which may be employed in the compositions of the According to one aspect of the present invention, invention generally also show activity and therefore, we provide a pharmaceutical composition include, for example, aspirin, indomethacin, ibuprofen, which comprises a systemic non-steroidal anti-inflam , , , , di matory drug and a compound of formula (1) flunisal, benorylate, , , fen 30 bufen, feprazone, , , flurbi O (1) profen, , , , and . They may be used in the pharma (CH2).X(CH2)COR ceutical compositions of the invention in their usual 35 dosage amounts, e.g. 50 mg-1 g of aspirin, 10-100 mg of M indomethacin, 5-50 mg of piroxicam and 100-500 mg of S. WM ibuprofen per dosage regime for the drug in question. HO OY Particularly useful systemic non-steroidal anti-inflam wherein matory drugs which may be employed in the composi n is 1 or 2; tions of the invention are indomethacin, piroxicam, m is 2-5 and X is cis or trans-CH-CH- or -CH ibuprofen and naproxen, especially indomethacin. CH- or m is 1-4 and X is -CH=C-CH-; In general, the compounds of formula (1) in which R1 is the carbon atom carrying the group -(CH2)x(CH2)- (a) phenyl optionally substituted by C1-4 alkyl, nCO2R1 and/or the carbon atom in the group Y carry C1-4 alkoxy, C1-4 alkanoyl, methylthio, methyl 45 ing the -OH group (particularly the former) are in the sulphinyl, methylsulphonyl, halogen (e.g. chlo R-configuration and mixtures containing such isomers rine or bromine), -CO2R2 where R2 is a hydro are preferred for use in the compositions of the inven gen atom or C1-4 alkyl or phenyl), -NHCOR2 tion. where R2 is as defined above or is a phenyl The alkyl groups referred to above in the definition of group optionally substituted by hydroxyl, 50 the compounds of formula (1) may be straight or CH3CONH- or branched. When R1 in the compounds of formula (1) is phenyl substituted by a group -CO2H the compounds are capable of salt formation with bases. Examples of suit CONH-), 55 able salts are alkali metal (e.g. sodium and potassium) salts. Compounds of formula (1) in which the various sub stituents and groups have the meanings below are of -CONR'R' (where R3 and R may be the same particular use in all aspects of the invention. or different and are each a hydrogen atom or In compounds where X is -CH=CH- or -CH2C C1-4 alkyl group), -NHCONH2, -CH2CH H2-, m is preferably 3 when n is 1, and m is preferably (CONH2)NHCOCH3, or 2 or 4 when n is 2. When X is -CH-C-CH-, m is preferably 2 and n is 1, and is 1 or 3 when n is 2. When X is -CH=CH- it is preferably cis-CH= 65 CH-. When R is a substituted phenyl group it may be, for example, phenyl substituted in the meta, ortho or, in particular, para positions by a chlorine or bromine atom 4,855,293 3 4. or a methyl, ethyl propyl, n-butyl, t-butyl, methoxy, Preferred compounds of formula (1) for use in the ethoxy, propoxy, butoxy, acetyl, propionyl, methylthio, compositions of the invention are: methylsulphinyl, methylsulphonyl, -CO2H, (1R-1a(Z),243(R),3a)-(-)-4-Acetylphenyl 7-3- -CO2CH3, hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocy clopentyl-5-heptenoate; 1R-1a(Z).243(R),3a)-(-)-4-(Acetylamino)phenyl 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- -CO2CH2CH3, -CO2 oxocyclopentyl-5-heptenoate; (1R-1a(Z).26(R),3a)-(-)-4-(Benzoylamino)phenyl O 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- oxocyclopentyl-5-heptenoate; --NHCHO, -NHCOCH3, benzoylamino, (acetylami (1R-1a(Z).26(R),3a)-(-)-4-(4-(Acetylamino)ben no)benzoylamino, (hydroxy)benzoylamino, -CONH2, zoylaminolphenyl 7-3-hydroxy-2-(2-hydroxy-3- -CONHCH3 -CONCCH3)2, -CONHCH2CH3, phenoxypropoxy)-5-oxocyclopentyl)-5-heptenoate; -CONCH2CH3)2, --NHCONH2, -CH2CH 15 (1R-1a(Z).26(R),3a)-(-)-4-(Aminocarbonyl)phenyl (CONH2)NHCOCH3 or 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- oxocyclopentyl-5-heptenoate; (1R-1a(ZS),2.6(R),3a)-(+)-4-(2-(Acetylamino)-3- amino-3-oxo propylphenyl 7-3-hydroxy-2-(2- -CHCH(CONH2)NHCO group. hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl-5- heptenoate; 1R-1a(Z).243(R),3a)-(-)-3-(Benzoylamino)phenyl Particularly useful substituents which may be present 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- on a substituted phenyl group R include C1-4 alkoxy, oxocyclopentyl-5-heptenoate; C1-4 alkanoyl, methylthio, methylsulphonyl, -CO2R, 25 (1R-1a(Z),2.6(R),3a)-(-) Methyl 4-7-3-hydroxy-2- -NHCOR2, -CONR3R4 where R2, R3 and R4 are as (2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl)- defined for formula (1), -NHCONH2 or -CH2CH 1-oxo-5-heptenyloxybenzoate; (CONH2)NHCOCH3 groups. Especially useful substit (1R-1a(Z).26(R),3all-(-)-4-(4-(Hydroxy)ben uents of this type include methoxy, acetyl, methylthio, zoylamino)phenyl 7-3-hydroxy-2-(2-hydroxy-3- methylsulphonyl, -CO2CH3, -NHCOCH3, ben 30 phenoxypropoxy)-5-oxocyclopentyl)-5-heptenoate zoylamino, (p-acetylamino)benzoylamino, (p-hydroxy)- 1R-1a(Z),2.6(R),3all-2-Naphthalenyl 7-3-hydroxy benzoylamino, -CONH2, -CONCH3)2, -NH 2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopen CONH2 or -CH2CH(CONH2)NHCOCH3. tyl-5-heptenoate; The group R1 is preferably a substituted phenyl group 35 1R-1a(Z),2,3,3a)-4-(Methylsulphonyl)phenyl 7-3- where the substituent may be in the meta, ortho or, in hydroxy-2-2-hydroxy-3-4-(methylthio)phenoxyl particular, para positions, or is a 2-naphthyl group. propoxy-5-oxocyclopentyl-5-heptenoate; Compounds in which R1 is a phenyl group substituted 1R-1a(Z).2g(R'),3a)-(-)-4-(Benzoylamino)phenyl (particularly in the para-position) by a methoxy, acetyl, 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- -CO2CH3, -NHCOCH3, benzoylamino, -CONH2, oxocyclopentyl)-4-heptenoate; -CONCH3)2 or -CH2CH(CONH2)NHCOCH3 group, or R is a 2-naphthyl group, are particularly 9-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- useful. oxocyclopentyl-7-nonenoate; and In the group Y, R6 and R7 are preferably hydrogen (1R-1a,243(R),3a)-(-)-4-(Benzoylamino)phenyl 3 atOnS. 45 hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocy When the Ar phenyl group is substituted, the substit clopentaneheptanoate. uent may be in the meta, ortho or para positions and may be for example methyl, ethyl, propyl, butyl, me A particularly preferred compound for use in the thoxy, ethoxy, propoxy, butoxy, methylthio, methylsul compositions of the invention is the compound of for phinyl, methylsulphonyl, fluoro, chloro, bromo or tri 50 fluoromethyl. Preferably, only a single substituent is mula (1) in which n is 1, m is 3, X is cis-CH=CH-, present. Ri is 4-benzoylaminophenyl and Y is A preferred group of compounds of formula (1) for use in the compositions of the invention are those in which X is cis-CH=CH- and n is 1 and m is 3 or n is 55 2 and m is 2 or 4; R is a phenyl group substituted (pref erably in the para position) by a methoxy, acetyl, -CO2CH3, -NHCOCH3, benzoylamino, -CONH2, -CONCCH3)2 or -CH2CH(CONH2)NHCOCH3 and in a particular aspect of the invention we thus pro group or R is 2-naphthyl; R is a hydrogen atom or a vide a pharmaceutical composition which comprises a methyl group; R6 and R7 are hydrogen atoms; and Aris systemic non-steroidal anti-inflammatory drug and 1R phenyl or phenyl substituted by fluoro or chloro. Com (1a(Z),2.6(R),3all-(-)-4-(benzoylamino)phenyl 7-3- pounds of this type in which the carbon atom carrying hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocy the -(CH2)xOCH2)CO2R group is in the R-configu clopentyl)-5-heptenoate. ration are particularly preferred. Especially preferred 65 Another particularly preferred compound for use in compounds of this type are those in which R1 is a the compositions of the invention is the compound of phenyl group substituted (preferably in the para posi formula () in which n is 2, m is 2, X is cis-CH=CH-, tion) by benzoylamino. R1 is 4-benzoylaminophenyl and Y is 4,855,293 6 In a further aspect of the invention we provide a method of treating inflammatory conditions or condi tions such as dysmenorrhoea in human subjects which comprises administering to the patient effective amounts of a systemic non-steroidal anti-inflammatory drug and a compound of formula (1) in two separate compositions. and in another particular aspect of the invention we The ability of compounds of formula (1) to provide thus provide a pharmaceutical composition which com protection against the gastric and intestinal lesions pro prises a systemic non-steroidal anti-inflammatory drug 10 duced by non-steroidal anti-inflammatory drugs, may and (1R-1a(Z).26(R')3a)-(-)-4-(benzoylamino)phe be determined for example by their ability to inhibit nyl 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- indomethacin, peroxicam or aspirin induced gastric and oxocyclopentyl)-4-heptenoate. intestinal lesions in the rat, following the methods of . The amount of the compound of formula (1) em Whittle, (1976) Eur. J. Pharmacology 40 233 and Ro ployed in the compositions of the invention will be an 15 bert (1975) Gastroenterology 69 1045. amount sufficient to reduce the gastrointestinal distress Compounds of formula (1) do not affect (a) the anti caused by the anti-inflammatory drug and will prefera inflammatory or (b) analgesic activity of non-steroidal bly be in the range of 0.1 to 500 ug/kg body weight anti-inflammatory drugs as determined for example by particularly 1 to 100 pg/kg body weight per dosage their ability not to affect (a) the anti-inflammatory activ unit. 20 ity of indomethacin in the carageenan-induced inflamed The precise dose administered of both the anti-in rat paw, following the method of Winter et. al. (1962) flammatory drug and the compound of formula (1) will Proc. Soc. Exp. Biol. 111 544, or (b) the analgesic activ of course depend on the age and condition of the patient ity of indomethacin in the acetylcholine-induced writh and the frequency of administration (for example 1-4 ing test in the mouse following the method of Tyers times daily). The relative proportions of the anti-inflam 25 (1980) Br. J. Pharmacology 69, 503. matory drug and the compound of formula (1) em The compositions of the invention may be prepared ployed in the composition of the invention will vary by admixture of the active ingredients, and according to depending on the nature of the anti-inflammatory drug a further aspect of the present invention we provide a used but will in general be a simple ratio by weight of process for the preparation of a pharmaceutical compo their usual dosage amounts as described above. 30 sition comprising admixing a systemic non-steroidal The pharmaceutical compositions of the invention anti-inflammatory drug and a compound of formula (1). may be used in the treatment of inflammatory condi The compositions of the invention may be presented tions, particularly acute and chronic arthritides such as with the aid of at least one pharmaceutical carrier or rheumatoid arthritis and osteo-arthritis, chronic mus excipient. Thus, in a further aspect of the invention we culo-skeletal inflammatory conditions such as ankylos 35 provide a pharmaceutical composition comprising as ing spondylitis and polymyalgia, acute and chronic active ingredients a systemic non-steroidal anti-inflam injury and strain, and for analgesia in conditions such as matory drug and a compound of formula (1) together dysmenorrhoea, especially where the use of the anti-in with one or more pharmceutical carriers or excipients. flammatory drug is limited by gastro-intestinal side In a still further aspect of the invention we provide a effects. process for the preparation of a pharmaceutical compo According to a further aspect of the invention we sition which comprises admixing a systemic non-steroi provide the use of a composition containing as active dal anti-inflammatory drug and a compound of formula ingredients a systemic non-steroidal anti-inflammatory (1) together with one or more pharmaceutical carriers drug and a compound of formula (1) in the therapy or or excipients. prophylaxis of inflammatory conditions or for analgesia 45 Particularly useful compositions of the invention are in human subjects. those in a form suitable for oral, buccal or rectal admini In another aspect of the invention, we provide a istration. method of treating inflammatory conditions or condi The compositions may take the form of, for example, tions such as dysmenorrhoea in human subjects which tablets, capsules, powders, solutions or syrups for oral comprises administering to the patient effective 50 administration. The compositions may thus contain as amounts of a systemic non-steroidal anti-inflammatory excipients, for example, binding agents, compression drug and a compound of formula (1) in a single compo aids, fillers, lubricants, disintegrants and wetting agents. sition. Tablets may be coated in a conventional manner, for It will be appreciated that it is not necessary to ad example with a suitable film-forming material such as minister the anti-inflammatory drug and the compound 55 methyl cellulose or hydroxypropylmethyl cellulose. of formula (1) as a single composition in order to Alternatively the tablets may be sugar coated. Liquid achieve an improvement in efficacy. Providing that preparations may also contain, for example, edible oils both compounds are present at the same time in the such as peanut, olive or sesame oils. subject to be treated the compounds may be adminis For buccal administration, the compounds may be tered separately, the compound of formula (1) prefera formulated as tablets or lozenges in conventional man bly being administered first, followed by the anti-in ner; and for rectal administration compositions such as flammatory drug. suppositories or retention enemas, for example contain In another aspect of the invention, therefore, we ing conventional suppository bases such as cocoa butter provide the use of a systemic non-steroidal anti-inflam or other glyceride, can be used. matory drug and a compound of formula (1) in the 65 The compositions of the invention may be prepared presence of each other, for the therapy or prophylaxis according to methods well known in the pharmaceuti of inflammatory conditions or for analgesia in human cal industry. Thus, for example, tablets may be prepared subjects. by direct compression of the active ingredients blended 4,855,293 7 8 with appropriate excipients. Alternatively, the blend of The tablets may be film coated with suitable film active ingredients and excipients may first be granulated forming materials e.g. methyl cellulose or hydroxypro using conventional techniques and the resulting gran pyl methylcellulose using standard techniques. ules compressed into tablets. Tablets may be film coated with suitable film forming materials using standard EXAMPLE B-CAPSULES techniques. Capsules may be prepared by blending the active mg/tablet ingredients and excipients and then filling the blend into Compound of formula (1) 0.2 gelatin capsules using a suitable filling machine. Indonethacin 500 According to a still further aspect of the present 10 Magnesium stearate, BP 1.0 invention we provide a composition containing as ac Starch 1500 2000 tive ingredients a systemic non-steroidal anti-inflamma to fill weight. tory drug and a compound of formula (1) for use in the * A form of directly compressible starch. manufacture of a medicament for the therapy or pro 15 The compound of formula (1) and the indomethacin phylaxis of inflammatory conditions or for analgesia in ae preblended with some of the Starch 1500 then this human subjects. preblend is mixed with the remaining Starch 1500 and It may be convenient to present the anti-inflamma magnesium stearate. The mix is then filled into size No. tory drug and the compound of formula (1) as a two 2 hard gelatin capsule shells using suitable machinery. container pack, one container containing the anti-in 20 Tablets and capsules using other systemic non-steroi flammatory and the other containing the compound of dal anti-inflammatory drugs as described herein may be formula (1). The compounds may then be admixed in prepared in similar fashion to that above. It will how mediately before administration, or, if desired, may be ever be appreciated that the dosage amounts may vary administered sequentially. depending upon the systemic non-steroidal anti-inflam The invention also provides a systemic non-steroidal 25 anti-inflammatory drug and a compound of formula (1) matory drug used. and compositions containing them, in association with We claim: instructions for their use together in the therapy or 1. A method for the therapy or prophylaxis of inflam propylaxis of inflammatory conditions or for analgesia matory conditions or for inducing analgesia in the in human subjects. 30 human body, which comprises administering thereto in When a non-steroidal anti-inflammatory drug and a the presence of each other therapeutically effective compound of formula (1) are administered in two sepa amounts of (i) a systemic non-steroidal anti-inflamma rate compositions the composition containing a com tory drug and (ii) a compound of formula (1) pound of formula (1) may be prepared according to the methods described in GB-A-2174702 and the composi 35 O tion containing a non-steroidal anti-inflammatory drug may be prepared according to conventional methods. (CH2).X(CH2)COR The amount of each compound employed in the two compositions will preferably be in the ranges given N 40 N S above. HOw N OY The following examples illustrate pharmaceutical compositions according to the invention. In the exam wherein ples, the term "compound of formula (1)" may in partic n is l or 2; ular be a compound (1R-1a(Z),26(R'),3a)-(-)-4- 45 m is 2-5 and X is cis or trans-CH=CH- or -CH (benzoylamino)phenyl 7-3-hydroxy-2-(2-hydroxy-3- 2-CH2-; or m is 1-4 and X is -CH=C=CH-; phenoxypropoxy)-5-oxocyclopentyl)-5-heptenoate or R is selected from the group consisting of phenyl, 1R-1a(Z),26(R'),3a)-(-)-4-(benzoylamino)phenyl phenyl which has been substituted by a substituent 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- selected from the group consisting of C1-4 alkyl, oxocyclopentyl)-4-heptenoate. 50 C1-4 alkoxy, C1-4 alkanoyl, methylthio, methylsul phinyl, methylsulphonyl, halogen, -CO2R2 EXAMPLE A-TABLETS (where R2 is a hydrogen atom or C-4 alkyl or These may be prepared by direct compression phenyl), -NHCOR2 (where R2 is selected from the group consisting of a hydrogen atom or C1-4 55 alkyl or phenyl, or a phenyl group substituted by a mg/tablet substituent selected from the group consisting of Compound of formula (1) 0.2 Indomethacin 50,0 hydroxyl, CH3CONH- or Magnesium stearate, BP 2.0 Microcrystalline cellulose, USP 200.0 to compression weight CONH-), The compound of formula (1) and the indomethacin are blended with about 10% of the microcrystalline cellulose then blended with the remaining microcrystal 65 -CONR3R' (where R3 and R4 may be the same or line cellulose and magnesium stearate. The blend is then different and are each a hydrogen atom or C1-4 compressed using 8 mm diameter punches into tablets alkyl group), -NHCONH2, -CH2CH on a suitable machine. (CONH2)NHCOCH3, or 4,855,293 9 10 (-)-4-(benzoylamino)phenyl 7-3-hydroxy-2-(2- hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl)-5-hep tenOate. -CH2CH(CONH2)NHCO ) or 12. A method according to claim 1 in which (i) is piroxicam and in which (ii) is 1R-1a(Z),2{3(R),3all (-)-4-(benzoylamino)phenyl 7-3-hydroxy-2-(2- 2-naphthyl; hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl)-4-hep tenoate. R6 R7 13. A pharmaceutical composition which comprises \ / 10 both a compound (i) and a compound (ii) as defined in Y is -CH2-C-C-OAr; claim 1. / N 14. A method for the therapy or prophylaxis of in Rs OH flammatory conditions or for inducing analgesia in the where R5, R6 and R7 is each a hydrogen atom or a human body, which comprises administering thereto in methyl group and at least one is a hydrogen atom; 15 the presence of each other therapeutically effective and amounts of (i) a systemic non-steroidal anti-inflamma Ar is selected from the group consisting of a phenyl tory drug and (ii) a compound of formula group, a substituted phenyl group wherein said substituents are selected from the group consisting O of one or two C14 alkyl, C14 alkoxy, C1-4 alkylthio, C1-4 alkylsulphinyl, C-4 alkylsulphonyl, halogen or trifluoromethyl groups, or a physiologically accep N tacle salt thereof. 2. A method according to claim 1 in which the com pounds (i) and (ii) are presented as separate composi 25 HO' OY tions for said use. 3. A method according to claim 1 in which (i) is Wherein aspirin, indomethacin, ibuprofen, fenoprofen, keto X is cis-CH=CH- and n is 1 and m is 3 or n is 2 profen, naproxen, mefenamic acid, , benory and n is 2 or 4; late, azapropazone, diclofenac, , feprazone, 30 R1 is a phenyl group substituted by a methoxy, acetyl, fenclofenac, flufenamic acid, , oxyphenbu -CO2CH3, -NHCOCH3, benzoylamino, tazone, phenylbutazone, piroxicam, sulindac or tolme -CONH2, -CONCCH3)2 or -CH2CH tin. (CONH2)NHCOCH3 group or R is a 2-naphthyl 4. A method according to claim 1 in which (i) is group; indomethacin, piroxicam, ibuprofen or naproxen. 35 5. A method according to claim 1 in which (ii) is a R6 R7 compound of formula (I) in which: N / X is cis-CH-CH- and n is 1 and n is 3 or n is 2 Y is -CH2-C-C-OAr; and m is 2 or 4; / N R is a phenyl group substituted by a methoxy, acetyl, R5 OH -CO2CH3, -NHCOCH3, benzoylamino, R is a hydrogen atom or a methyl group; -CONH2, -CONCCH3)2 or -CH2CH (CONH2)NHCOCH3 group or R1 is a 2-naphthyl R6 and R7 are hydrogen atoms; and group; Ar is phenyl or phenyl substituted by fluoro or R is a hydrogen atom or a methyl group; 45 chloro. R6 and R7 are hydrogen atoms; and 15. A method according to claim 14 in which the Ar is a phenyl or phenyl substituted by fluoro or compounds (i) and (ii) are presented as separate compo chloro. sitions for said use. 6. A method according to claim 1 in which in (ii) the 16. A method according to claim 14 in which (i) is carbon atom carrying the group -(CH2).X(CH2)- 50 aspirin, indomethacin, ibuprofen, fenoprofen, keto nCO2R is in the R-configuration. profen, naproxen, mefenamic acid, diflunisal, benory 7. A method according to claim 1 in which (ii) is late, azapropazone, diclofenac, fenbufen, feprazone, (1R-1a(Z.243(R),3a)-(-)-4-(benzoylamino)phenyl fenclofenac, flufenamic acid, flurbiprofen, oxyphenbu 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- tazone, phenylbutazone, piroxicam, sulindac or tolme oxocyclopentyl-5-heptenoate. 55 tin. 8. A method according to claim 1 in which (ii) is 17. A method according to claim 14 in which (i) is (1R-1a(Z).26(R),3a)-(-)-4-(benzoylamino)phenyl indomethacin, piroxicam, ibuprofen or naproxen. 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- 18. A method according to claim 14 in which in (ii) oxocyclopentyl)-4-heptenoate. the carbon atom carrying the group -(CH2)xOCH2)- 9. A method according to claim 1 in which com nCO2R is in the R-configuration. pounds (i) and (ii) are in a form suitable for oral, buccal 19. A method according to claim 14 in which (ii) is or rectal administration. (1R-1a(Z),2{3(R),3a)-(-)-4-(benzoylamino)phenyl 10. A two-container pack for use in the therapy or 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- prophylaxis of inflammatory conditions or for analgesia oxocyclopentyl-5-heptenoate. in humans, one of the containers containing (i) and the 65 20. A method according to claim 14 in which (ii) is other containing (ii) as defined in claim 1. (1R-1a(Z),2.6(R),3a)-(-)-4-(benzoylamino)phenyl 11. A method according to claim 1 in which (i) is 7-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5- piroxicam and in which (ii) is (1R-1a(Z),2{3(R),3a)- oxocyclopentyl)-4-heptenoate. 4,855,293 11 12 21. A method according to claim 14 in which com hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl-5-hep tenOate. pounds (i) and (ii) are in a form suitable for oral, buccal 24. A method according to claim 14 in which (i) is or rectal administration. piroxicam and in which (ii) is (1R-1a(Z),2{3(R),3all 22. A two-container pack for use in the therapy or 5 (-)-4-(benzoylamino)phenyl 7-3-hydroxy-2-(2- prophylaxis of inflammatory conditions or for analgesia hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl)-4-hep in humans, one of the containers containing (i) and the tenoate. other containing (ii) as defined in claim 14. 25. A pharmaceutical composition which comprises 23. A method according to claim 14 in which (i) is both a compound (i) and a compound (ii) as defined in piroxicam and in which (ii) is 1R-1a(Z).26(R),3a)- 10 claim 14. (-)-4-(benzoylamino)phenyl 7-3-hydroxy-202 k sk k sk

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