CYCLIC HYDROXAMIC ACIDS AND THEIR USE

Abstract: Substituted cyclic hydroxamic acids of general formula (I) in which R1, R2 and R3 are independently hydrogen, halogen, lower alkyl, lower alkoxy, cycloalkoxy, aryloxy which is optionally substituted by 1 to 3 halogen, or aralkyloxy, which is optionally substituted by 1 to 3 halogen, or R1 and R2 together form a -O-CH2-O-group; with the proviso that R3 is not hydrogen when R1 and R2 are both hydrogen; R4 and R5 are independently hydrogen or lower alkyl, R6 is hydrogen or lower alkyl, and physiologically acceptable salts and esters thereof are selective inhibitors of phosphodiesterase IV activity and leukotriene B4 and C4 synthesis without showing any significant effect on phosphodiesterase III activity, and are therefore useful in the treatment of hypersensitivity and inflammatory diseases.

Description: CYCLIC HΪDROXAMXC ACIDS AND THEIR USE The present invention relates to new substituted cyclic hydroxamic acids and physiologically acceptable salts and esters thereof. The invention also relates to the pharmaceutical compositions containing these compounds and to the method for the preparation of the same. The compounds of the present invention are selective inhibitors of phosphodiesterase IV (PDE IV) activity and leu otriene B 4 (LTB 4 ) and C (LTC 4 ) synthesis without having any significant effect on phosphodiesterase III (PDE III) activity. The combinatory effect due to the parallel inhibition of PDE IV activity and LTB 4 and LTC 4 synthesis makes the compounds of the invention especially valuable in the treatment of hypersensitivity and inflammatory diseases such as allergic rhinitis, atopic dermatis, rheumatoid arthritis, psoriasis and especially asthma. Conventionally, acute asthma has been treated using compounds that aid tracheal relaxation. Because these compounds only treat the acute symptom, other medicaments have to be given that treat pathogenic factors of the disease. These medicaments are, for example, compounds having antiinflammatory effect. It has been surprisingly found that the compounds of the invention provide in one and the same compound three valuable characterictics. Inhibition of PDE IV activation and increase of cyclic .AMP concentration leads to the tracheal relaxation, ) and is effective in acute asthma. On the other hand, the inhibition of the synthesis of LTC 4 diminishes bronchoconstriction in asthmatic subjects. At the same time, the inhibition of LTB 4 synthesis has a potent antiinflammatory effect and is therefore believed to be effective in chronic asthma. The compounds according to the present invention are substituted cyclic hydroxamic acids of general formula I in which R x , R 2 and R 3 are independently hydrogen, halogen, lower alkyl, lower alkoxy, cycloalkoxy, aryloxy which is optionally substituted by 1 to 3 halogen, or aralkyloxy, which is optionally substituted by 1 to 3 halogen, or R- j^ and R 2 together form a -0-CH 2 -O-group; with the proviso that R 3 is not hydrogen when R x and R 2 are both hydrogen; R 4 and R 5 are independently hydrogen or lower alkyl, R 6 is hydrogen or lower alkyl, and physiologically acceptable salts and esters thereof. The term "lower alkyl" as employed herein itself or as a part of another group refers to a straight or branched alkyl group having preferably 1 to 4 carbon atoms. The term "lower alkoxy" as employed herein refers to an alkyl residue as defined above linked to an oxygen atom. The term "cycloalkoxy" as employed herein refers to a saturated cyclic hydrocarbon group, preferably of 3 to 7 carbon atoms linked to an oxygen atom. The term "aryloxy" as employed herein refers to an aromatic ring, preferably phenyl, linked to an oxygen atom. The term "aralkyloxy" as employed herein refers to a lower alkoxy group having aryl, preferably phenyl, as the substituent. The te.rm "halogen" as employed herein refers to chlorine, bromine, fluorine or iodine, chlorine and bromine being preferred. Particularly preferred groups of compounds include those in which R x is cycloalkyloxy, e.g. cyclopentyloxy, R 2 is lower alkoxy, e.g. methoxy or ethoxy, and R 6 is hydrogen. The phenyl group in Formula I may be in the 3- or 4-position of the pyrrolidone ring. The 4-position is preferred. US 4,012,495 describes 4-polyalkoxyphenyl-2-pyrrolidones, such as 4- [3- (cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone (rolipram) . These compounds are stated to be useful in the treatment of various neurological and psychic disorders. The hydroxamic acids of the invention are chemically different from the compounds of US 4,012,495. Furthermore, the specific compound of US 4,012,495 (rolipram) is not selective PDE IV inhibitor but also inhibits PDE III. PDE III inhibitors are known to be used as inotropic agents in the treatment of heart failure. Therefore, the selective inhibition of only PDE IV in the trachea would be preferred to eliminate cardiac side effects such as arrhytmia the presence of which, it is suggested, is involved in the use of PDE III inhibitors. The compounds of the formula I may be prepared in accordance with the present invention by selective reduction of the compounds of the formula lla or lib lla in which R x , R 2 , R 3 , R 4 and R 5 are the same as de ined above and R 7 represents a lower alkyl group, with zinc dust, aluminium amalgam or sodium borohydride in the presence of platinium or palladium catalyst in a suitable buffer solution or in an inert solvent. Also electrochemical reduction applying the methof described by Cariou M., Hazard R. , Jubault M., and Tallec A. in J. Electroanal. Chem. 182 (1985), pp. 345-354 is possible. The compounds of formula lla and lib may be prepared by the known methods (Pollini G.P., Barco A., DeGuili G., Synthesis, (1972) , p. 44) from the corresponding cinnamic or 2-phenyl acrylic acid derivatives of formula Ilia and Illb, respectively in which R x , R 2 , R 3 and R 7 are the same as defined above, by Michael addition reaction of nitroalkane in the presence of a basic catalyst such as 1, 1, 3, 3-tetramethylquanidine by using nitroalkane as the solvent at ambient or elevated temperature. The compounds of formula I wherein R 6 is lower alkyl may be prepared by O-alkylation of the compounds of formula I in which R 6 is hydrogen, using lower alkylhalide in basic conditions in an inert solvent such as acetone, N,N-dimethyl- formamide, tetrahydrofuran or N-methylpyrrolidone. Salts of the compounds of the present invention may be prepared by known methods. Most commonly used physiologically acceptable salts are sodium, potassium, ammonium, calcium and magnesium salts. The above compounds may be formulated to dosage forms using the principles which are known to those having average skill in the art. The compounds according to this invention are given to a patient as such or in combination with suitable pharmaceutical material in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions whereby the contents of the active compounds is in the formulation from 1 to 100 weight-%. Choosing the auxiliary ingredients for the formulation is routine for those of ordinary skill in the art. It is evident that suitable solvents, gel forming ingredients, dispersion forming ingredients, antioxidants, colours etc. are used in a normal way. It is preferred way to give the compositions enterally. When they are given orally, they may be in the form of tablets, granules, capsules, emulsions, suspensions or solutions. The effective dose varies considerably depending on location, degree and severity of the disease being treated as well as the age and the genaral conditions of the patient. The effective dose is generally from about to 0,1 to about 10 mg/kg per day, preferably from 0,5 to 5 mg/kg per day for an adult, once a day or divided into two to five doses. The preparation of the compounds according to the invention are described in detail in the following examples. Example 1 l-Hydroxy-4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone. To a solution containing 10.9 g (0.039 mol) methyl 3-cyclopentyloxy-4-methoxycinnamate in 100 ml of nitromethane 5.5 ml 1,1,3,3-tetramethylguanidine was added gradually at ambient temperature. The solution was stirred overnight after which 400 ml of 2 N hydrochloric acid and 100 ml dichloromethane were added. The organic phase was separated and evaporated in vacuo. Yield 13.0 g (100 %) , a yellowish oil which crystallized on standing. A solution containing 13.0 g (0.039 mol) methyl 3- (3-cyclo- pentyloxy-4-methoxyphenyl) -4-nitrobutanoate prepared above in 400 ml tetrahydrofuran containing 4 ml water was gradually added to 3.8 g aluminium foil treated before with a solution of mercuric chloride (1 g) in water. The temperature was held at 15-20 °C by cooling. The mixture was stirred overnight at ambient temperature after which toluene and 200 ml 6 N hydrochloric acid were added. The organic phase was separated and washed with 0.8 M sodium hydrogen carbonate solution and evaporated to dryness in vacuo. The residue was crystallized from a mixture of dichloromethane-ether. Yield 1.7 g (15 %) , mp 126-130°C. Example 2 4- (4-Benzyloxyphenyl) -l-hydroxy-2-pyrrolidone The starting material methyl 3- (4-benzyloxyphenyl) -4-nitro¬ butanoate was obtained by condensation of methyl 4-benzyloxy- cinnamate with nitromethane, yield about 100 % or a yellowish oil. 5.0 g of methyl 3- (4-benzyloxyphenyl) -4-nitrobutanoate was reduced in a similar manner as described in Example 1 to yield 0.3 g 4-(4-Benzyloxyphenyl) -l-hydroxy-2-pyrrolidone, mp 150-155 °C. j Example 3 4- (4-Benzyloxyphenyl) -l-methoxy-2-pyrrolidone. A mixture containing 0.7 g 4-(4-benzyloxyphenyl) 1-hydroxy- 2-pyrrolidone (Example 2), 5.0 ml methyl iodide and 2.0 g potassium carbonate in 5.0 ml N-methylpyrrolidone was stirred for 2 h at 50 °C. 20 ml 1 N sodium hydroxide solution was then added and the solution was extracted with a mixture of 20 ml cyclohexane and 10 ml of ether. The extract was washed with water and concentrated in vacuo whereupon the product crystallized, yield 0.31 g (41 %) , mp 92-97 °C. Example 4 4- (2,3-Dimethoxyphenyl)-l-hydroxy-2-pyrrolidone potassium salt. The starting material methyl 3- (2,3-dimethoxyphenyl) - nitrobutanoate was obtained by condensation of methyl 2,3-dimethoxycinnamate with nitromethane, yield about 100 % of a yellowish oil. 16.0 g methyl 3- (2,3-dimethoxyphenyl) -4-nitrobutanoate was reduced in a similar manner as described in Example 1. The crude product was dissolved in 50 ml of anhydrous ethanol and 45 ml of 0.5 N potassium hydroxide in ethanol, after which 100 ml ether was added. The potassium salt precipitated was filtered. Yield 3.66 g (25 %) , mp 138-143 °C. Example 5 4- [3- (2 , 6-Dichlorobenzyloxy) -4-methoxyphenyl] -1-hydroxy- 2-pyrrolidone The starting material methyl 3- [3- (2, 6-dichlorobenzyloxy) - 4-methoxyphenyl] -4-nitrobutanoate was obtained in a similar way as described in foregoing Examples. Yield about 100 % of a yellowish oil. 21.5 g of methyl 3- [3- (2, 6-dichlorobenzyloxy) 4-methoxy¬ phenyl] -4-nitrobutanoate was reduced as described in Example 1. Yield 7.4 g (39 %) , mp 134-140 °C. Example 6 l-Hydroxy-4- (3,4-methylenedioxyphenyl) -2-pyrrolidone The starting material methyl 3- (3,4-methylenedioxyphenyl) - 4-nitro butanoate was obtained by condensation of methyl 3,4-methylenedioxycinnamate with nitromethane, yield about 100 % of a yellowish oil. 12.0 g of methyl 3, 4-methylenedioxy-4-nitrobutanoate was reduced in a similar manner as described in Example 1. The crude product was crystallized from methanol-water. Yield 0.9 g, mp 119-123°C. Example 7 l-Hydroxy-4- (3,5-di-tert.butyl-4-methoxyphenyl) -2-pyrrolidone The starting material methyl 3- (3,5-di-tert.-butyl-4- methoxypheny1) -4-nitrobutanoate was obtained by condensation of methyl 3,5-di-tert.-butyl-4-methoxycinnamate with nitromethane, yield about 100 % of a yellowish oil. 8.3 g of methyl 3- (3,5-di-tert.-butyl-4-methoxyphenyl) -4- nitrobutanoate was reduced in a similar manner as described in Example 1. The crude product was crystallized from methanol-water, yield 0.35 g, mp 196-200°C. Example 8 l-Hydroxy-4- (2, 4-dichlorophenyl) -2-pyrrolidone The starting material methyl 3- (2,4-dichlorophenyl) -4- nitrobutanoate was prepaded in the usual way from methyl 2, 4-dichlorocinnamate and nitromethane in about theoretical yield. 16.0 g of methyl 3- (2,4-dichlorophenyl) -4-nitrobutanoate was reduced with aluminium amalgam as described in Example 1. The crude product was crystallized from toluene, yield 2.78 g, mp 153-156°C. Example 9 l-Hydroxy-4- (2, 4-dichlorophenyl) -5-methyl-2-pyrrolidone The starting material methyl 3- (2, 4-dichlorophenyl-4- nitropentanoate was prepared in the usual way from methyl 2, 4-dichlorocinnamate and nitroethane in about theoretical yield. 16.0 g of methyl 3- (2, 4-dichlorophenyl) -4-nitropentanoate was reduced with aluminium amalgam as described in Example 1. The crude product was crystallized from dioxanecyclohexane. Yield 1.7 g of a mixture of diastereomers, mp 140-144°C. Example 10 l-hydroxy-4- (2,4-dichlorophenyl) -5,5-dimethyl-2-pyrrolidone The starting material methyl 3- (2,4-diclorophenyl) -5-methyl- 4-nitropentanoate was prepared in the usual way from methyl 2,4-dichlorocinnamate and 2-nitropropane in about theoretical yield. 16.0 g of methyl 3- (2,4-dichlorophenyl) -5-methyl-4- nitropentanoate was reduced with aluminium amalgam as described in Example 1. The crude product was crystallized from methanol, yield 4.9 g, mp 234-237°C. Example 11 l-Hydroxy-5,5-dimethyl-4- (3,4-methylenedioxyphenyl) -2- pyrrolidone The starting material methyl 3- (3,4-methylenedioxyphenyl) -5- methyl-4-nitropentanoate was prepared in the usual way from methyl 3,4-methylenedioxy cinnamate and 2-nitropropane in about theoretical yield. 16.0 g methyl 3- (3, 4-methylenedioxyphenyl) -5-methyl-4- nitropentanoate was reduced with aluminium amalgam as described in Example 1. The crude product was crystallized from toluene, yield 3.8 g, mp 185-189°C. Example 12 l-Hydroxy-5,5-dimethyl-3- (3-chlorophenyl) -2-pyrrolidone The starting material methyl 2- (3-chlorophenyl) -4-methyl- 4-nitropentanoate was obtained by condensation of methyl 2- (3-chlorophenyl) acrylate with 2-nitropropane, yield about 100 % of yellow oil. 18.95 g of methyl 2- (3-chlorophenyl) -4-methyl-4-nitro- pentanoate was reduced with aluminium amalgam as described in Example 1. The crude product was crystallized from toluene- ether, yield 2.5 g, mp 160-162°C. Inhibition of PDE IV and PDE III PDE isoenzymes were isolated using DEAE-Sepharose chromatography as described by Reeves et al. in Biochem. J. , 241 (1987), pp. 535-541. PDE IV and PDE III activities were determined by the method of Alajoutsijarvi and Nissinen as described in Anal. Biochem. 165 (1987), pp. 128-132. Table 1 The selectivity of the inhibition of PDE IV and PDE III of the test compound. 0,9 205 Test compound l-hydroxy-4- (3-cyclopentyloxy-4-methoxyphenyl) - 2-pyrrolidone Inhibition of LTB_. synthesis and LTC_ ι synthesis The inhibition of arachidonic acid induced LTB 4 and LTC 4 synthesis in human basophilic leucocytes was determined with liquid chromatography and UV detection. LTB 4 and LTC 4 were separated first by HPLC with a Spherisorb ODS colon (5 μm, 150 x 4.6 mm) and Spectroflow 400 Kratos Analytical pump. The flow rate was 1 ml/min and the solvents were methanol/water/acetic acid (68/32/0.1), pH 5.0 for LTB 4 and methanol/water/acetic acid/phosphoric acid (65/35/0.07/0.03), pH 5.5 for LTC . The peaks were analyzed f rther with Spektroflow 773 Kratos Analytical UV absorbance detector and leukotrienes were detected at the wavelength of 271 n and 280 nm for LTB 4 and LTC 4 , respectively. The results are given in Table 2 Table 2 The LTB 4 and LTC 4 synthesis inhibition The compound of -t-Cs o LTB 4 IC50 LTC 4 the Example μM μM 1 3.7 3.2

Claims: Claims 1. A compound according to the general formula I in which R x , R 2 and R 3 are independently hydrogen, halogen, lower alkyl, lower alkoxy, cycloalkoxy, aryloxy which is optionally substituted by 1 to 3 halogen, or aralkyloxy, which is optionally substituted by 1 to 3 halogen, or R x and R 2 together form a -0-CH 2 -0-group, with the proviso that R 3 is not hydrogen when R and R 2 are both hydrogen; R 4 and R 5 are independently hydrogen or lower alkyl, R 6 is hydrogen or lower alkyl, or a physiologically acceptable salt or ester thereof. 2. A compound according to claim 1 in which R-^ is cycloalkyloxy, R 2 is lower alkoxy and R 6 is hydrogen. 3. l-Hydroxy-4- (3-cyclopentyloxy-4-methoxyphenyl) - 2-pyrrolidone. 4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier or diluent. 5. Use of a compound as de ined in any one of claims 1 to 3 in the treatment of hypersensitivity or an inflammatory disease. 6. Use as defined in claim 5 wherein the disease is asthma. 7. The compound according to any one of claims 1 to 3 for use in a method of treatment of hypersensitivity or an inflammatory disease. 8. A method of the preparation of a compound of any of the claims 1 to 3 comprising carrying out a Michael addition reaction of a nitroalkane and the compound of formula Ilia or Illb in which R , R 2 , R 3 are as defined in claim 1 or R 7 is lower alkyl, to give the compound of formula lla or lib; lla lib in which R λ , R 2 , R 3 , R and R 5 are the same as defined in claim 1 and R 7 represents a lower alkyl, whereafter the compound of formula lla or lib is selectively reduced to give the compound of formula I. 10. A method of preparation of a compound of formula I as defined in claim 1 in which R 6 is lower alkyl, comprising the o-alkylation of the corresponding compound of formula I in which R 6 is hydrogen.

Inventors: BAECKSTROEM REIJO, HONKANEN ERKKI, LINDEN INGE-BRITT, RAASMAJA ATSO, BAECKSTROEM, REIJO, HONKANEN, ERKKI, LINDEN, INGE-BRITT, RAASMAJA, ATSO
Applicants: ORION YHTYMAE OY, ORION-YHTYMAE OY
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P11, A61P29, A61P37, A61P43, C07D207, C07D405