Substituted beta-diketones and their use in the treatment of inflammatory bowel disease

Abstract: Compounds of formula wherein n is 0 or 1, R₁ and R₂ are independently methyl, ethyl or cyclopropyl and R is an optionally substituted phenyl or heteroaryl group or salt or ester thereof are useful in the treatment of inflammatory bowel disease.

Description: The present invention relates to substituted β-diketones and their physiologically acceptable salts and esters, which are useful in the treatment of inflammatory bowel diseases. DE-A-2,210,663 discloses 3'-nitro-4'-chlorobenzylidene-acetyl-acetone as an α,β-unsaturated dioxo compound which exhibits a cardiac relaxing and hypertensive effect. DE-A-3,303,066 discloses substituted 1,4-dihydropyridines for the prevention of cardiovascular disorders and for treating troubles of the cerebral and peripheral blood circulation. Bull. Chem. Soc. Japan, 48(3), 1975, pp. 882-884, T. Kawato et al ., discloses the property of chelation of the compounds 3-(p-hydroxybenzylidene)-2,4-pentadione and 3-(m-hydroxybenzylidene)-2,4-pentadione. Bull. Chem. Soc. Japan, 49(59, 1976, pp. 1368-1374, M. Iwata et al ., refers to the condensation products of aromatic aldehydes with ketone promoted by Cu-II, including 3-(2-methoxybenzylidene)-2,4-pentanedione. EP-A-0,008,458 discloses insecticidal triazole compounds useful in the protection of plants and crops. US-A-3,280,069 is concerned with the stability of plastic against UV-light and mentions the compound 3-(o-hydroxybenzylidene)-2,4-pentanedione. Bull. Chim. Soc. France, No. 7-8, 1974, pp. 1683-1690, J.-P. Vecchionacci et al ., discloses the compound benzylidene-3-hexane-2,4-dione (cf. page 1688, table IV). Eur. J. Med. Chem. 22(2), 1988, pp. 111-117, J.R. Dimmock et al ., discloses in its experiments protocol the compounds 4-(phenylmethylene)-3,5-heptanedione and 4-(3,4-dichlorophenylmethylene)-3,5-heptandione. EP-A-0357403 discloses β-diketones which possess cytoprotective efficacy in the stomach and in the duodenum and are useful in the treatment or prophylaxis of gastric and duodenal ulcers. It has now been found that some substituted β-diketones are especially useful in the treatment of inflammatory bowel diseases (IBD). The term IBD encompasses chronic inflammatory conditions of the gastrointestinal tract such as Crohn's disease and ulcerative colitis. The exact cause of the disease is still unknown. Infectious agents, immunological abnormalities, permeability disorders and leukotrienes are some of the factors suggested to play a role in the pathogenesis of IBD. The present medical therapy (sulfasalazine, 5-ASA, corticosteroids) is focused only on the diminishing of the inflammatory response, and there is still a great requirement for a more specific and effective drug for the treatment of IBD (Sutherland, CMAJ 137:799-802, 1987). The present invention provides use of a compound of general formula I wherein n=0 or 1, R 1 and R 2 are independently methyl, ethyl or cyclopropyl and R is an optionally substituted phenyl or heteroaryl group; wherein X 1 is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl; X 2 and X 3 are independently hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy, acetamido or; R 3 S(O) m wherein m=0, 1 or 2 and R 3 is alkyl, aryl or aralkyl; or carbamoyl which is optionally substituted by alkyl, aryl or aralkyl; Y is oxygen or sulfur and X 4 is hydrogen, nitro or halo; or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for use in the treatment of inflammatory bowel disease. The present invention also provides a compound according to the general formula II wherein n=0 or 1, R 1 is methyl, ethyl or cyclopropyl and R 2 is ethyl or cyclopropyl and R is wherein X 1 is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl; X 2 and X 3 are independently hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy, acetamido or; R 3 S(O) m wherein m=0, 1 or 2 and R 3 is alkyl, aryl or aralkyl; or carbamoyl which is optionally substituted by alkyl, aryl or aralkyl or R 1 and R 2 are methyl and R is where X 1 , X 2 and X 3 are as defined above provided that one of X 2 and X 3 is carbamoyl which is optionally substituted by alkyl, aryl or aralkyl, or a pharmaceutically acceptable salt or ester thereof. The invention also provides a new compound according to the general formula III wherein n is 0 or 1, R 1 is methyl and X 1 is as defined above and X 2 is R 3 S(O) m wherein m is 1 or 2 and R 3 is alkyl, aryl or aralkyl and X 3 is hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy or a group as defined for X 2 ; or X 2 and X 3 are both nitro or cyano; or X 2 is nitro and X 3 is formyl or halo or, when X 1 is hydroxy, X 2 may be carboxy, or X 2 and X 3 may both be hydrogen when n=0 and X 1 is alkoxy substituted by aryl, or when n=1 and X 1 is hydroxy or alkoxy optionally substituted by aryl; or a pharmaceutically acceptable salt or ester thereof but excluding 4-(phenylmethylene)-3,5-heptanedione, 4-(3,4-dichlorophenylmethylene)-3,5-heptanedione 3-[(2-chloro-5-nitrophenyl)methylene]-2,4-pentanedione, and 3-(phenylmethylene)-2,4-hexanedione. The term "alkyl" as employed herein refers to an alkyl group having preferably 1 to 2 carbon atoms. The term "alkoxy" as employed herein refers to an alkyl residue as defined above linked to an oxygen atom. The term "aralkyl" as employed herein refers to an alkyl group as defined above having aryl, preferably phenyl as the substituent. The term "aryl" as employed herein refers to a carbocyclic aromatic group containing from 6 to 10 carbon atoms in the ring portion. The group may be a single ring or fused rings. Specific examples are phenyl and naphthyl. The term "heteroaryl" as employed herein refers to a monocyclic or bicyclic aromatic group of carbon atoms containing one or more heteroatoms such as nitrogen, oxygen or sulfur. The preparation of compounds according to the formulae I and II may be carried out in a similar way as described in EP-A-0357403. For example the compounds of formula I may be prepared by reacting a compound of the formula IV R 1 -CO-CH 2 -CO-R 2 in which R 1 and R 2 are as defined above with a compound of formula V R-(CH=CH) n -Z in which n and R are as defined above and Z is CHO or -CH 2 -Q, wherein Q is halogen or some other activated group, in the presence of acidic or basic catalyst to produce a compound of formula I or a compound of formula VI in which n, R 1 , R 2 and R are as defined above, which compound is halogenated to give a compound of the formula VII in which n, R 1 , R 2 and R are as defined above and X is halogen and dehydrohalogenating compound VII to produce a compound of the formula I. The basic catalyst may be for example an organic or inorganic base. The acidic catalyst may be for example a mineral or sulfonic acid. The activated group Q may be a halogen or an alkyl or aryl sulfonate. When halogenating a compound of formula VI elementary halogen, preferably chlorine or bromine may be used, or another known halogenating agent such as sulfuryl chloride may be used. Salts of these compounds may be prepared by known methods. Most commonly used physiologically acceptable salts are sodium, potassium, ammonium, calcium and magnesium salts and hydrochlorides or hydrobromides. Preferred esters of the compounds of formula I are acyl or aroyl derivatives which will hydrolyse under physiological conditions. The above compounds may be formulated to dosage forms using the principles which are known to those having average skill in the art. Suitable solvents, gel forming ingredients, dispersion agents, antioxidants and colourants may be added in a normal way. It is preferred to administer the compounds enterally. When they are given orally, they may be in the form of tablets, granules, capsules, emulsions, suspensions or solutions. It is often advisable to use coated tablets or granules, i.e. so called enterocoated preparations, to ensure that the medicine reaches the desired part of the gastrointestinal tract. Alternatively, the compositions may be given rectally in the form of enemas or suppositories. The effective dose varies considerably depending on location, degree and severity of the disease being treated as well as the age and the general condition of the patient. The effective dose is generally from about 20 to 1000 mg per day, preferably from 50 to 250 mg per day for an adult, once a day or divided into two to five doses. In vivo tests The efficacy of the compounds can be demonstrated by using a model of chronic colonic inflammation in the rat, TNB-induced chronic colitis. TNB-induced chronic colonic inflammation in rats is an animal model which has been shown to resemble highly human IBD. 20 mg of TNB (2,4,6-trinitrobenzenesulfonic acid) in 50 % ethanol was administered into the lumen of the colon via a rubber catheter inserted rectally to Wistar rats. The test compounds were given rectally 1 h prior and 24, 48, 72 and 95 h after TNB. The rats were sacrificed 96 h after TNB and their colons were scored according to occurence of ulcers and inflammation. The number of animals in each group was at least 8. 5-ASA (5-aminosalicylic acid), a clinically used drug for the treatment of IBD was used as a reference compound. The results are presented in the Table 1. The effect of test compounds on the damage score of chronic inflammation induced by TNB. Test compound Dose mg/kg % inhibition against control 5-ASA 100 24 1 30 37 2 30 28 3 10 18 30 57 4 30 54 5 30 43 6 30 41 7 10 60 30 48 8 10 51 30 62 9 30 40 10 10 27 11 30 32 12 30 52 13 30 58 14 30 30 Test compounds 1 3-(4-hydroxyphenyl)methylene-2,4-pentanedione 2 3-(4-methoxyphenyl)methylene-2,4-pentanedione 3 3-(3-nitrophenyl)methylene-2,4-pentanedione 4 3-(4-trifluoromethylphenyl)methylene-2,4-pentanedione 5 3-(4-nitrophenyl)methylene-2,4-pentanedione 6 3-(2-nitrophenyl)methylene-2,4-pentanedione 7 3-(4-cyanophenyl)methylene-2,4-pentanedione 8 3-(3-cyanophenyl)methylene-2,4-pentanedione 9 3-[(4-(N-phenethyl)carboxamido-phenyl)methylene]-2,4-pentanedione 10 3-[(5-nitrofuryl)methylene]-2,4-pentanedione 11 4-[(4-cyanophenyl)methylene]-3,5-heptanedione 12 2-[(4-cyanophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione 13 2-[(3-trifluoromethylphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione 14 2-[(4-carboxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione The test compounds significantly decreased the ulceration and inflammation of the colons. The test compounds were much more potent than the reference compound 5-ASA and should therefore be more effective than 5-ASA in the treatment of human IBD. The following examples illustrate the production of compounds of use according to the invention. Example 1 3-[(4-Phenylsulfonylphenyl)methylene]-2,4-pentanedione To a solution containing 2.1 g of 4-phenylsulfonylbenzaldehyde and 1.5 g of 2,4-pentanedione in 10 ml of 2-propanol was added 1 ml of thionyl chloride with stirring at 20°C. The solution was stirred for 1h at 20°C and evaporated to dryness in vacuo. The residue was crystallized from toluene, mp 102-105°C. Example 2 3-[(4-Methylsulfonylphenyl)methylene]-2,4-pentanedione The procedure described in Example 1 was repeated by using 1.1 g of 4-methylsulfonylbenzaldehyde and 1.5 g of 2,4-pentanedione. The product was crystallized from ether, mp 139-140°C. Example 3 3-[(4-Carboxamidophenyl)methylene]-2,4-pentanedione A mixture containing 1.8 g of 4-carboxamidobenzaldehyde, 1.1 g of 2,4-pentanedione, 0.2 g of piperidine and 0.2 g of acetic acid in 40 ml of toluene was refluxed for 3 h by using a Dean-Stark separator. The warm clean toluene solution was decanted from the tarry residue and cooled. The crystalline product was filtered and dried. Mp 154-155°C. Example 4 4-[(4-Nitrophenyl)methylene]-3,5-heptanedione The procedure described in Example 1 was repeated by using 1.5 g of 4-nitrobenzaldehyde and 2.0 g of 3,5-heptanedione. Yield 1.7 g, yellow oil. Example 5 3-[(3,4-Dichlorophenyl)methylene]-2,4-pentanedione The procedure described in Example 1 was repeated by using 4.26 g of 3,4-dichlorobenzaldehyde and 3.0 g of 2,4-pentanedione. Yield 1.3 g, mp 73°C. Example 6 3-[(4-Chloro-3-nitrophenyl)methylene]-2,4-pentanedione The procedure described in Example 1 was repeated by using 1.85 g of 4-chloro-3-nitrobenzaldehyde and 1.5 g of 2,4-pentanedione. Yield 1.32 g, mp 110-111°C. Example 7 3-[(4-(N-Phenethyl)carboxamidophenyl)methylene]-2,4-pentanedione. The procedure described in Example 1 was repeated by using 2.5 g of 4-(N-phenethyl)carboxamidobenzaldehyde and 1.0 g of 2,4-pentanedione. Yield 0,5 g, mp 146-149°C. Example 8 3-[(4-Formyl-3-nitrophenyl)methylene]-2,4-pentanedione To a solution containing 1.84 g of 2-nitroterephtaldicarboxaldehyde and 1.00 g of 2,4-pentanedione in 10 ml trifluoroacetic acid were added 0.9 ml of thionyl chloride and a catalytic amount of water. The solution was stirred for 2 h at 20°C. 30 ml of water was added and the mixture was extracted with ether. The ether extract was washed several times with Na 2 CO 3 -solution and dried over K 2 CO 3 . After filtration the solvent was evaporated in vacuo. The product was purified by column chromatography. Yield 0.2 g, mp 102-104°C. Example 9 3-[(3,5-Dinitro-4-hydroxyphenyl)methylene]-2,4-pentanedione. The procedure described in Example 1 was repeated by using 2.12 g of 3,5-dinitro-4-hydroxybenzaldehyde and 1.5 g of 2,4-pentanedione. Yield 1.9 g, mp 158°C. Example 10 3-[(3,5-Dinitrophenyl)methylene]-2,4-pentanedione The procedure described in Example 1 was repeated by using 2.53 g 3,5-dinitrobenzaldehyde and 2.43 g of 2,4-pentanedione. Yield 0.8 g, mp 101-105°C. Example 11 3-[3-(4-Methoxyphenyl)propenylene]-2,4-pentanedione To a solution containing 2.45 g of 4-methoxycinnamaldehyde in 90 ml of toluene was added 2.2 g of 2,4-pentanedione, 0,26 g of piperidine and 0.45 g of acetic acid. The solution was refluxed in N 2 atmosphere for 1 h and the water formed in the reaction was azeotropically distilled off by using a Dean-Stark water separator. The solution was evaporated to dryness in vacuo. The residue was trifurated with ether. The crystalls were filtered. Yield 0.65 g, mp 108-110°C. Example 12 3-[(5-Nitrofuryl)methylene]-2,4-pentanedione A solution containing 2.43 g of 5-nitro-2-furanecarboxaldehyde diacetate, 1.5 g of 2,4-pentanedione and 0.1 g of water in 5 ml of tetrahydrofurane was saturated with hydrogen chloride gas at 20°C. The mixture was stirred for 1 h and evaporated to dryness in vacuo. The product was recrystallized from acetic acid. Yield 0.1 g, mp 117-120°C. Example 13 3-[(5-Nitrothienyl)methylene]-2,4-pentanedione The procedure described in Example 12 was repeated by using 2,59 g of 5-nitro-2-thiophenecarboxaldehyde diacetate, 1.5 g of 2,4-pentanedione. Yield 0.5 g, yellow viscous oil. Example 14 3-(3-Pyridylmethylene)-2,4-pentanedione The procedure described in Example 3 was repeated by using 3.21 g of pyridine-3-carboxaldehyde and 3.3 g of 2,4-pentanedione. Yield 2.95 g, mp 52-57°C. Example 15 3-(4-Pyridylmethylene)-2,4-pentanedione hydrochloride A solution containing 1.1 g of pyridine-4-carboxaldehyde and 1.0 g of 2,4-pentanedione in 10 ml of N,N-dimethylformamide was saturated with hydrogen chloride gas at 20°C. The solution was stirred for 1 h at 20°C and then for 2 h at 80°C. The solvent was evaporated in vacuo and the residue was crystallized from ethanol. Yield 0.17 g, mp 175-186°C. Example 16 3-(3-Quinolylmethylene)-2,4-pentanedione hydrochloride The procedure described in Example 3 was repeated by refluxing 2.4 g quinoline-3-aldehyde, 6.6 g 2,4-pentanedione, 0.4 g piperidine and 0.8 g acetic acid in 100 ml toluene. Yield 1.4 g, mp 99-101°C. Example 17 3-[(3-Carboxy-4-hydroxyphenyl)methylene]-2,4-pentanedione A mixture containing 2 g 3-carboxy-4-hydroxybenzaldehyde, 4 ml 2,4-pentanedione and 20 ml tetrahydrofuran was saturated with hydrogen chloride gas. The solution was stirred for 20 h at 50°C and evaporated to dryness in vacuo. The residue was crystallized from ethyl ether, mp. 112-114°C. Example 18 3-[[(4-(2-Phenylethoxy)phenyl]methylene]-2,4-pentanedione The procedure described in example 8 was repeated by using 5.9 g of 4-(2-phenylethoxy)benzaldehyde, 3.9 ml of 2,4-pentanedione, 26 ml of trifluoroacetic acid and 2.1 ml of thionyl chloride. Yield 4.7 g, an viscous oil. Example 19 2-[(4-Acetamidophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione A mixture containing 1.6 g 4-acetamidobenzaldehyde, 1.5 g 1,3.dicyclopropyl-1,3-propanedione, 0.2 ml of piperidine and 0.4 ml of acetic acid in 50 ml of toluene was refluxed for 3 h by using a Dean-Stark separator. After standing over night at room temperature the crystalls were filtered and washed with toluene. The product was recrystallized from ethanol. Yield 2.0 g, mp 166-167°C. Example 20 2-[(4-Methoxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione The procedure described in Example 19 was repeated by using 0.68 g 4-methoxybenzaldehyde and 0.77 g 1,3-dicyclopropyl-1,3-propanedione. Yield 0.46 g, mp 60.5-61.5°C. Example 21 4-[(3-Cyanophenyl)methylene]-3,5-heptanedione The procedure described in Example 19 was repeated by using 1.82 g 3-cyanobenzaldehyde and 3.5 g 3,5-heptanedione. Yield 0.4 g, mp 51-52°C. Example 22 4-[(4-Cyanophenyl)methylene]-3,5-heptanedione The produre described in Example 19 was repeated by using 2.6 g 4-cyanobenzaldehyde and 5.0 g 3,5-heptanedione. Yield 2.8 g, mp 59-60°C. Example 23 3-[(4-Cyanophenyl)methylene]-4-cyclopropyl-2,4-butanedione The procedure described in Example 19 was repeated by using 2.6 g 4-cyanobenzaldehyde and 2.5 g 4-cyclopropyl-2,4-butanedione. The product was purified by column chromatography. Yield 0.37 g, mp 83-85°C. Example 24 2-[(4-Cyanophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione The procedure described in Example 19 was repeated by using 3.78 g 4-cyanobenzaldehyde and 2.23 g 1,3-dicyclopropyl-1,3-propanedione. Yield 1.5 g, mp 100-102°C. Example 25 3-[(5-Bromothienyl)methylene]-2,4-pentanedione To a solution containing 5.73 g 5-bromothiophene-2-carboxaldehyde and 5.0 g 2,4-pentanedione in 25 ml of 2-propanol, 2.9 ml thionylchloride was gradually added. The mixture was stirred for 2 h at 20°C. 120 ml of conc. Na 2 SO 4 -solution was then added and the mixture was extracted with ether. The solvent was evaporated in vacuo and the crystalline residue was washed with cold ether. Yield 3.9 g, mp 70-74°C. Example 26 2-[(3-Trifluoromethylphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione The procedure described in Example 19 was repeated by using 2.15 ml 3-trifluoromethylbenzaldehyde and 2.42 g 1,3-dicyclopropyl-1,3-propanedione. Yield 2.71 g, mp 56-58°C. Example 27 2-[(4-Carboxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione The procedure described in Example 19 was repeated by using 3.0 g 4-carboxybenzaldehyde and 3.06 g 1,3-dicyclopropyl-1,3-propanedione. Yield 1.7 g, mp 175-178°C.

Claims: Claims for the following Contracting States : AT, BE, CH, LI, DE, DK, FR, GB, IT, LU, NL, SE Use of a compound of formula I wherein n=0 or 1, R 1 and R 2 are independently methyl, ethyl or cyclopropyl and R is an optionally substituted phenyl or heteroaryl group; wherein X 1 is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl; X 2 and X 3 are independently hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy, acetamido or; R 3 S(O) m wherein m=0, 1 or 2 and R 3 is alkyl, aryl or aralkyl; or carbamoyl which is optionally substituted by alkyl, aryl or aralkyl; in which "alkyl" is an alkyl group having preferably 1 to 2 carbon atoms, "alkoxy" is an alkyl residue as defined above liked to an oxygen atom, and "aralkyl" is an alkyl group as defined above having aryl, preferably phenyl as the substituent; Y is oxygen or sulphur and X 4 is hydrogen, nitro or halo; or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for use in the treatment of inflammatory bowel disease. The use according to claim 1, in which, in the compound of formula I, X 1 is hydroxy or alkoxy. The use according to claim 1 or 2, in which, in the compound of formula I, one of X 2 and X 3 is nitro, cyano, trifluoromethyl, carboxy or carbamoyl which is substituted by aryl. The use according to claims 1 to 3, in which the compound is 3-(4-hydroxyphenyl)methylene-2,4-pentanedione, 3-(4-methoxyphenyl)methylene-2,4-pentanedione, 3-(3-nitrophenyl)methylene-2,4-pentanedione, 3-(4-nitrophenyl)methylene-2,4-pentanedione, 3-(2-nitrophenyl)methylene-2,4-pentanedione, 3-[(4-(N-phenethyl)carboxamido-phenyl)methylene]-2,4-pentanedione, 3-[(5-nitrofuryl)methylene]-2,4-pentanedione, or 2-[(4-carboxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione or a pharmaceutically acceptable salt or ester thereof. The use according to claims 1 or 3, in which, the compound is 3-(4-trifluoromethylphenyl)methylene-2,4-pentanedione. The use according to claims 1 or 3, in which, the compound is 3-(4-cyanophenyl)methylene-2,4-pentanedione. The use according to claims 1 or 3, in which, the compound is 3-(3-cyanophenyl)methylene-2,4-pentanedione. The use according to claims 1 or 3, in which, the compound is 4-[(4-cyanophenyl)methylene]-3,5-heptanedione. The use according to claims 1 or 3, in which, the compound is 2-[(4-cyanophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. This use according to claims 1 or 3, in which, the compound is 2-[(3-trifluoromethylphenyl)methylene]-1,3-di-cyclopropyl-1,3-propanedione. A compound according to the general formula II wherein n=0 or 1, R 1 is methyl, ethyl or cyclopropyl and R 2 is ethyl or cyclopropyl and R is wherein X 1 is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl; X 2 and X 3 are independently hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy, acetamido, provided that when n=0, X 1 , X 2 and X 3 are not all independently selected from the group consisting of hydrogen, hydroxy and nitro; or R 3 S(O) m wherein m=0, 1 or 2 and R 3 is alkyl, aryl or aralkyl; or carbamoyl which is optionally substituted by alkyl, aryl or aralkyl or R 1 and R 2 are methyl and R is where X 1 , X 2 and X 3 are as defined above provided that one of X 2 and X 3 is carbamoyl which is optionally substituted by alkyl, aryl or aralkyl, in which "alkyl", "alkoxy" and "aralkyl" are as defined herein; or a pharmaceutically acceptable salt or ester thereof, but excluding 4-(phenylmethylene)-3,5-heptanedione, 4-(3,4-dichlorophenylmethylene)-3,5-heptanedione and 3-(phenylmethylene)-2,4-hexanedione. A compound according to claim 11 wherein in the compound of formula II one of X 2 and X 3 is cyano or trifluoromethyl. 2-[(4-Acetamidophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. 2-[(4-Methoxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. 3-[(4-Cyanophenyl)methylene]-4-cyclopropyl-2,4-butanedione. 2-[(4-Cyanophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. 2-[(3-Trifluoromethylphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. 2-[(4-Carboxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione or a pharmaceutically acceptable salt or ester thereof. 4-[(4-Nitrophenyl)methylene]-3,5-heptanedione. 4-[(3-Cyanophenyl)methylene]-3,5-heptanedione. 4-[(4-Cyanophenyl)methylene]-3,5-heptanedione. 3-[(4-Carboxamidophenyl)methylene]-2,4-pentanedione. 3-[(4-(N-phenethyl)carboxamidophenyl)methylene]-2,4-pentanedione. A compound according to the general formula III wherein R 1 is methyl, n is 0 or 1, X 1 is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl, and X 2 is; R 3 S(O) m wherein m is 1 or 2 and R 3 is alkyl, aryl or aralkyl, and X 3 is hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy or a group as defined for X 2 ; or X 2 and X 3 are both cyano; or X 2 is nitro and X 3 is formyl; or when X 1 is hydroxy, X 2 may be carboxy or X 2 and X 3 may both be hydrogen when n=0 and X 1 is alkoxy substituted by aryl, or when n=1 and X 1 is hydroxy or alkoxy optionally substituted by aryl; in which "alkyl" is an alkyl group having preferably 1 to 2 carbon atoms, "alkoxy" is an alkyl residue as defined above linked to an oxygen atom, and "aralkyl" is an alkyl group as defined above having aryl, preferably phenyl as the substituent; or a pharmaceutically acceptable salt or ester thereof. 3-[(4-Phenylsulfonylphenyl)methylene]-2,4-pentanedione. 3-[(4-Methylsulphonylphenyl)methylene]-2,4-pentanedione. 3-[(4-Formyl-3-nitrophenyl)methylene]-2,4-pentanedione. Claims for the following Contracting States : ES, GR Use of a compound of formula I wherein n=0 or 1, R 1 and R 2 are independently methyl, ethyl or cyclopropyl and R is an optionally substituted phenyl or heteroaryl group; wherein X 1 is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl; X 2 and X 3 are independently hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy, acetamido or; R 3 S(O) m wherein m=0, 1 or 2 and R 3 is alkyl, aryl or aralkyl; or carbamoyl which is optionally substituted by alkyl, aryl or aralkyl; in which "alkyl" is an alkyl group having preferably 1 to 2 carbon atoms, "alkoxy" is an alkyl residue as defined above linked to an oxygen atom, and "aralkyl" is an alkyl group as defined above having aryl, preferably phenyl as the substituent; Y is oxygen or sulphur and X 4 is hydrogen, nitro or halo; or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for use in the treatment of inflammatory bowel disease. The use according to claim 1, in which, in the compound of formula I, X 1 is hydroxy or alkoxy. The use according to claim 1 or 2, in which, in the compound formula I, one of X 2 and X 3 is nitro, cyano, trifluoromethyl, carboxy or carbamoyl which is substituted by aryl. The use according to claims 1 to 3, in which the compound is 3-(4-hydroxyphenyl)methylene-2,4-pentanedione, 3-(4-methoxyphenyl)methylene-2,4-pentanedione, 3-(3-nitrophenyl)methylene-2,4-pentanedione, 3-(4-nitrophenyl)methylene-2,4-pentanedione, 3-(2-nitrophenyl)methylene-2,4-pentanedione, 3-[(4-(N-phenethyl)carboxamido-phenyl)methylene]-2,4-pentanedione, 3-[(5-nitrofuryl)methylene]-2,4-pentanedione, or 2-[(4-carboxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione or a pharmaceutically acceptable salt or ester thereof. The use according to claims 1 or 3, in which, the compound is 3-(4-trifluoromethylphenyl)methylene-2,4-pentanedione. The use according to claims 1 or 3, in which, the compound is 3-(4-cyanophenyl)methylene-2,4-pentanedione. The use according to claims 1 or 3, in which, the compound is 3-(3-cyanophenyl)methylene-2,4-pentanedione. The use according to claims 1 or 3, in which, the compound is 4-[(4-cyanophenyl)methylene]-3,5-heptanedione. The use according to claims 1 or 3, in which, the compound is 2-[(4-cyanophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. This use according to claims 1 or 3, in which, the compound is 2-[(3-trifluoromethylphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. A process for the preparation of a compound according to the general formula II wherein n=0 or 1, R 1 is methyl, ethyl or cyclopropyl and R 2 is ethyl or cyclopropyl and R is wherein X 1 is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl; X 2 and X 3 are independently hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy, acetamido, provided that when n=0, X 1 , X 2 and X 3 are not all independently selected from the group consisting of hydrogen, hydroxy and nitro; or R 3 S(O) m wherein m=0, 1 or 2 and R 3 is alkyl, aryl or aralkyl; or carbamoyl which is optionally substituted by alkyl, aryl or aralkyl or R 1 and R 2 are methyl and R is where X 1 , X 2 and X 3 are as defined above provided that one of X 2 and X 3 is carbamoyl which is optionally substituted by alkyl, aryl or aralkyl, in which "alkyl", "alkoxy" and "aralkyl" are as defined herein; or a pharmaceutically acceptable salt or ester thereof, but excluding 4-(phenylmethylene)-3,5-heptanedione, 4-(3,4-dichlorophenylmethylene)-3,5-heptanedione and 3-(phenylmethylene)-2,4-hexanedione, said process comprising reacting a compound of formula IV R 1 -CO-CH 2 -CO-R 2 in which R 1 and R 2 are as defined above with a compound of formula V R-(CH=CH) n -Z in which n and R are as defined above and Z is CHO or -CH 2 -Q, wherein Q is halogen or some other activated group, in the presence of acidic or basic catalyst to produce a compound of formula II or a compound of formula VI in which n, R 1 , R 2 and R are as defined above, which compound is halogenated to give a compound of the formula VII in which n, R 1 , R 2 and R are as defined above and X is halogen and dehydrohalogenating compound VII to produce a compound of the formula II. A process according to claim 11 wherein in the compound of formula II one of X 2 and X 3 is cyano or trifluoromethyl. A process according to claim 11 for the preparation of 2-[(4-Acetamidophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. A process according to claim 11 for the preparation of 2-[(4-Methoxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. A process according to claim 11 for the preparation of 3-[(4-Cyanophenyl)methylene]-4-cyclopropyl-2,4-butanedione. A process according to claim 11 for the preparation of 2-[(4-Cyanophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. A process according to claim 11 for the preparation of 2-[(3-Trifluoromethylphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione. A process according to claim 11 for, the preparation of 2-[(4-Carboxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione or a pharmaceutically acceptable salt or ester thereof. A process according to claim 11 for the preparation of 4-[(4-Nitrophenyl)methylene]-3,5-heptanedione. A process according to claim 11 for the preparation of 4-[(3-Cyanophenyl)methylene]-3,5-heptanedione. A process according to claim 11 for the preparation of 4-[(4-Cyanophenyl)methylene]-3,5-heptanedione. A process according to claim 11 for the preparation of 3-[(4-Carboxamidophenyl)methylene]-2,4-pentanedione. A process according to claim 11 for the preparation of 3-[(4-(N-phenethyl)carboyamidophenyl)methylene]-2,4-pentanedione. A process for the preparation of a compound according to the general formula III wherein R 1 is methyl, n is 0 or 1, X 1 is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl, and X 2 is; R 3 S(O) m wherein m is 1 or 2 and R 3 is alkyl, aryl or aralkyl, and X 3 is hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy or a group as defined for X 2 ; or X 2 and X 3 are both cyano; or X 2 is nitro and X 3 is formyl; or when X 1 is hydroxy, X 2 may be carboxy or X 2 and X 3 may both be hydrogen when n=0 and X 1 is alkoxy substituted by aryl, or when n=1 and X 1 is hydroxy or alkoxy optionally substituted by aryl; in which "alkyl" is an alkyl group having preferably 1 to 2 carbon atoms, "alkoxy" is an alkyl residue as defined above linked to an oxygen atom, and "aralkyl" is an alkyl group as defined above having aryl, preferably phenyl as the substituent; or a pharmaceutically acceptable salt or ester thereof, said process comprising reacting a compound of the formula IV R 1 -CO-CH 2 -CO-R 2 in which R 1 and R 2 are as defined above with a compound of formula V R-(CH=CH) n -Z in which n and R are as defined above and Z is CHO or -CH 2 -Q, wherein Q is halogen or some other activated group, in the presence of acidic or basic catalyst to produce a compound of formula III or a compound of formula VI in which n, R 1 , and R 2 are as defined above and R is phenyl substituted by X 1 , X 2 and X 3 as defined above, which compound is halogenated to give a compound of the formula VII in which n, R 1 , R 2 and R are as defined above and X is halogen and dehydrohalogenating compound VII to produce a compound of the formula III. Process according to claim 24 for the preparation of 3-[(4-Phenylsulfonylphenyl)methylene]-2,4-pentanedione. Process according to claim 24 for the preparation of 3-[(4-Methylsulphonylphenyl)methylene]-2,4-pentanedione. Process according to claim 24 for the preparation of 3-[(4-Formyl-3-nitrophenyl)methylene]-2,4-pentanedione. A compound according to the general formula II wherein n=0 or 1, R 1 is methyl, ethyl or cyclopropyl and R 2 is ethyl or cyclopropyl and R is wherein X 1 is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl; X 2 and X 3 are independently hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy, acetamido, provided that when n=0, X 1 , X 2 and X 3 are not all independently selected from the group consisting of hydrogen, hydroxy and nitro; or R 3 S(O) m wherein m=0, 1 or 2 and R 3 is alkyl, aryl or aralkyl; or carbamoyl which is optionally substituted by alkyl, aryl or aralkyl or R 1 and R 2 are methyl and R is where X 1 , X 2 and X 3 are as defined above provided that one of X 2 and X 3 is carbamoyl which is optionally substituted by alkyl, aryl or aralkyl, in which "alkyl", "alkoxy" and "aralkyl" are as defined herein; or a pharmaceutically acceptable salt or ester thereof, but excluding 4-(phenylmethylene)-3,5-heptanedione, 4-(3,4-dichlorophenylmethylene)-3,5-heptanedione and 3-(phenylmethylene)-2,4-hexanedione. A compound according to the general formula III wherein R 1 is methyl, n is 0 or 1, X 1 is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl, and X 2 is; R 3 S(O) m wherein m is 1 or 2 and R 3 is alkyl, aryl or aralkyl, and X 3 is hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy or a group as defined for X 2 ; or X 2 and X 3 are both cyano; or X 2 is nitro and X 3 is formyl; or when X 1 is hydroxy, X 2 may be carboxy or X 2 and X 3 may both be hydrogen when n=0 and X 1 is alkoxy substituted by aryl, or when n=1 and X 1 is hydroxy or alkoxy optionally substituted by aryl; in which "alkyl" is an alkyl group having preferably 1 to 2 carbon atoms, "alkoxy" is an alkyl residue as defined above linked to an oxygen atom, and "aralkyl" is an alkyl group as defined above having aryl, preferably phenyl as the substituent; or a pharmaceutically acceptable salt or ester thereof. 3-[(4-Methylsulphonylphenyl)methylene]-2,4-pentanedione

Inventors: AHO PAIVI ANNIKKI, BACKSTROM REIJO JOHANNES, HONKANEN ERKKI JUHANI, LINDEN INGE-BRITT YVONNE, LUIRO ANNE MARIA, NISSINEN ERKKI AARNE OLAVI, POHTO PENTTI, PYSTYNEN JARMO JOHAN, AHO, PAIVI ANNIKKI, BACKSTROM, REIJO JOHANNES, HONKANEN, ERKKI JUHANI, LINDEN, INGE-BRITT YVONNE, LUIRO, ANNE MARIA, NISSINEN, ERKKI AARNE OLAVI, POHTO, PENTTI, PYSTYNEN, JARMO JOHAN
Applicants: ORION YHTYMAE OY, ORION-YHTYMAE OY
Application year: 1991
Main classification: A61K31
IPC codes: C07D307, A61K31, C07D333, A61P1, C07D215, C07C65, C07D213, C07C205, C07C255, C07C317, A61P29, C07C49, C07C235, C07C233