IE83426B1 - New pharmacologically active catechol derivatives - Google Patents

Abstract

Abstract (CA 111(17)153788y) discloses thiazolidinone derivatives which are useful as aldose reductase inhibitors. Gupta et al in European J. Med. Chem. - Chim. Ther., 17 (5), 448-452, 1982 and Srivastava et al in Pharmazie, 36(4), 252-253, 1981 disclose 2-thioxo-4,6-pyrimidinedione compounds having anticonvulsant activity. Sohda et al. in Chem. Pharm .Bull., 31(2), 560-9, 1983 discloses 2,4-thioxolidione derivatives having antiulcer activity.

Description

The invention relates to new catechol derivatives and pharmaceutically acceptable salts and esters thereof which are useful as medicinal antioxidants. The invention also relates to pharmaceutical compositions containing said compounds and to the method of the preparation of the same.

Medicinal antioxidants are compounds that may be used for the prevention or treatment of tissue damage induced by lipid peroxidation. It is generally believed that cellular damage by oxygen derived radicals, especially those associated with lipid peroxidation, is a significant factor in heart diseases, rheumatoid arthritis, cancer, certain inflammatory diseases, rejection reactions in transplantation, ischemla and even in the aging process.

EP-A-343643 describes pharmaceutical compositions comprising the compounds of formula . Y1 A-ska xx wherein 5 Ar is (l) phenyl unsubstituted, (ii) phenyl substituted by from one to three of lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, NR1oR11, wherein R15 and R11 are independently hydrogen or lower alkyl, N02, mercapto, or alkylthio, (iii) naphthyl; (iv) benzofuranyl, (v) benzothiophenyl, (vi) 2- or 3-thienyl, (vii) 2- or 3-indolyl, (viii) 2- or 3-furanyl, or (ix) 2-, 3-, or 4-pyridyl lower Y and Y1 is oxygen or sulfur; X is sulfur, oxygen, NH or NCH3 and X1 is NH or NCH3 and pharmaceutically acceptable salts thereof which are stated to be 5—lipoxygenase and/or cyclooxygenase inhibitors. Japanese Patent Application No. 1052765, which has been referred to in Chemical Abstract (CA 111(17)153788y) discloses thiazolidinone derivatives which are useful as aldose reductase inhibitors. Gupta et al in European J. Med. Chem. - Chim. Ther., 17 (5), 448-452, 1982 and Srivastava et al in Pharmazie, 36(4), 252-253, 1981 disclose 2-thioxo-4,6-pyrimidinedione compounds having anticonvulsant activity. Sohda et al. in Chem. Pharm .Bull., 31(2), 560-9, 1983 discloses 2,4-thioxolidione derivatives having antiulcer activity.

US—A-4582903 (S.B. Mirviss Stauffer Chemical Co.) discloses an improved method for the production of unsaturated hydantoins (2,4—imidazo|idindiones) which may be used as precursors and intermediates in the synthesis of amino acids. The general formula encompasses several 2,4-imidazolidindione derivatives including phenylmethylidene-2,4-imidazolidindiones. The phenyl ring may be substituted by several substituents such as hydroxy, nitro, cyano and halogen. However, US-A- 4582903 fails to disclose any specific compound of the present invention or its starting materials.

FR-A(Showa Denko K.K.) like US-A-4582903, discloses an improved method for the preparation of 2,4-imidazolidindione derivatives. According to the general formula on page 2, these may be, for example phenylmethyl-2,4- imidazolidindiones, wherein the phenyl ring may be substituted by a halogeno and a hydroxy group. However, no specific examples of compounds where the phenyl is substituted by halogeno are disclosed.

FR-A-2189040 (Canada Packers Ltd) discloses imidazolidindiones and their use as anti-viral agents. The phenyl group may be substituted for example by halogeno, hydroxy or nitro. However, on page 2, paragraph 1, it is stated that it is preferred for the phenyl group to be substituted by two methoxy groups. phenylmethylidene-2,4- EP-A—0037479 and EP-A—0O37480 (Degussa AG) disclose methods for the preparation of phenylmethylidene-2,4-imidazolidindiones, wherein the phenyl group may be substituted by halogen, hydroxy or nitro. Neither of these documents, however, discloses the compounds according to the present invention or their starting materials.

EP-A-0343643 (Warner-Lambert Co.) discloses known and selected novel arylmethylenyl derivatives of thiazolidinones, imidazolidinones and oxazolidinones and their pharmaceutical compositions. EP—A-0323643 covers a large number of compounds but fails to disclose specificallyauy compound of the present invention.

The compounds of the present invention may be represented by the formula I : wherein R1 is an electronegative substituent which is a nitro, halogeno or cyano group and R2 is a group selected from: /X1 N ‘CH2 V V and ‘CH2 "’\_ X2 ' A >‘x1 wherein R is hydrogen, straight or branched C1'Cg alkyl. C5-C7 cycloalkyl, phenyi C1-C3 alkyl or a phenyl group, wherein X1, X2, Y and Z are independently oxygen, sulfur or NH wherein R may be as defined above. in one embodiment, R2 is a group containing a five membered heterocyclic ring which is of formula: Y -CH I / X2 in which X1 and X2 are both NR, wherein R is hydrogen or CH; alkyl, Y is oxygen or sulfur and Z is oxygen or sulfur. Preferred ring systems include 2- thioxoimidazolidinones and 2,5-imidazolidindiones. Examples of such compounds include 4-[(3,4-dihydroxynitrophenyl)methylidene] thioxoimidazolidinone; 4-[(3,4-dihydroxychlorophenyl)methylidene] thioxoimidazolldinone; 4-[(3,4-dihydroxynitrophenyl)methylidene]-2,5- imidazolidindione and 4-[(3,4—dihydroxy-5—cyanopheny|)methylidene]thioxo— imidazolidinone. in another embodiment, R2 is the group in which X1, Y, and Z are independently oxygen or sulfur and X2 is NR, in which R is hydrogen or C14; alkyl. Preferred ring systems include 2-thioxothiazolidinones; 3- methylthioxothiazolidinones; thiazolidin-2,4-diones; 4-thioxooxazolidinones and 4-thioxothiazolidin-2—ones. Specific examples are 5-[ (3,4-dihydroxy nitrophenyl)methylidene]-2~thioxothiazolidinone; 5-[(3,4-dihydroxy- 5- nitrophenyl)methylidene]methyl—2-thioxothiazo|idin one; 5-[(3,4-dihydroxy nitrophenyl)methylidene]thiazolidin-2,4-dione; 5-[(3,4-dihydroxych|orophenyl)- methylidene]-thiazolidin-2,4-dione; 5-[(3,4-dihydroxy nitrophenyl)methylidene] -[(3,4-dihydroxynitrophenyl)methy|idene]thioxo- -b[(3,4-dlhydroxycyanophenyl)methylidene] thioxooxazolidinone; thiazolidinone thioxothlazolidinone.

In another embodiment R2 is the group —/ / -CH E >‘<2 in which X1 and Z are independently oxygen or sulfur and Y and X2 are NR, wherein R is hydrogen. Preferred ring system is 2-aminothiazolinone. A specific example is 5-[(3,4-dihydroxynitrophenyl)methylidene]-2—iminothiazolidinone. in another embodiment R2 is a group ‘containing a six-membered heterocyclic ring which is of formula: C R 0 R l / / I -can >=Y or -CH2 Y I X1 X1 O ‘ 0 wherein Y is oxygen or sulfur, X1 is NR, wherein R is hydrogen or CH, alkyl.

Preferably Y is oxygen. Preferred ring systems include pyrimidine-2,4trione.

Examples of such compounds include 5-[(3,4-dihydroxynitrophenyl)methy|idene]- 2,4,6 (1H,3H,5H)-pyrimidinetrione and 5-[(3,4-dihydroxynitropheny|)methyI]- (lH,3H,5H)pyrimidine-2,4,6-trione. ‘ The term "alkyl" as employed herein by itself or as part of another group refers to both straight and branched chain groups, preferably of 1 to 8 atoms, most preferably of 1 to 4 carbon atoms.

The term "aryl" as employed herein refers to a monocyclic or bicyclic group containing 6 or 10 carbon atoms in the ring portion. A specific example is phenyl.

The term "acyl" as employed herein refers to alkylcarbonyl group, the alkyl group being as defined above.

The term "aroyl" refers to an arylcarbonyl group, the aryl group being defined above.

The term "cycloalkyl" as employed herein refers to saturated cycli hydrocarbon groups having preferably 5 to 7 carbon atoms.

The term "halogeno" as employed herein refers to fluoro, chloro, bromo or iodo substituent. Especially preferred is chloro.

If R is hydrogen the compounds of the present invention may exist also in the corresponding tautomeric forms depending on the pH of the solution.

Thus, when R2 is a five-membered ring, when X1 is NR wherein R is hydrogen the tautomeric forms of the compounds according to formula ta are H Y YH \ / H0 I-IO———— N __ .._._g /‘ HO CH ‘ HO -4 Q >—ca -1 R1 Z R1 Z and the tautomers, when X2 is NR wherein R is hydrogen are Y , YH ____._A W : H°>—-\ «X14 HO \O >~CH=< "‘— Ho/.\-JQ_‘A_)-CH '/ N i /7‘ R1 z {L Y HO.7___\ /x1_/ HO -( >—cz-1 ' >——-— N ZH The tautomeric forms for the compounds wherein R2 is a six membered ring are respectively 0 o . \ lHO4{;:>}CH V >=r v—l5 Ho (3 CH . 7>_YHr , l X1 / x1 1 R1 ° R; l o I 4' I i V H0 The present invention also relates to the method for the preparation of compounds of formula I. The present invention provides a process for the preparation of compounds of formula I, in which process an aldehyde of formula II HC:7_\ HO W CH0 1: wherein R1 is as defined above, is condensed in a base or acid catalyzed reaction with compounds of either formulas Ill or IV having an active methylene group CH2 III X2 o fa \ N X1 wherein X1, X2, Y and Z are as defined above, to give a compound la according to the present invention, whereafter the carbon-carbon double bond in la may be reduced to give the compound lb according to the invention.

The invention also relates to pharmaceutically acceptable salts and esters of the present compounds. Generally, the esters which hydrolyze readily in physiological circumstances are those attached to the phenolic hydroxyl groups in compounds according to formula I. Either one of the hydroxylic groups or both of them may be esterified and on hydrolyzing the ester-forming group or groups are cleaved away and the active compound is liberated. Preferred esters are acyl or aroyi derivatives.

Salts of the compounds, when applicable, may be prepared by known methods.

Physiologically acceptable salts are useful as active medicaments. However, sodium, potassium, ammonium, calcium and magnesium salts are preferred.

The effective dose of the compound varies considerably depending on whether the compounds are given for prophylaxis or for treatment, the severity of the condition to be treated, and the route of administration. The effective dose for human beings is likely to be from about 1 to 1000 mg per day.

The compounds used in this invention are formulated into dosage forms using the principles which are known to the man 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 content of the active compound 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, colors etc are used in a normal way.

The compositions may be administered enterally or parenterally.

The tested compounds were subjected to controlled peroxidation by peroxylradicals originating from the thermal decomposition of 2,2’-azobis-(2-amidinopropane) x HCl at 37°C. The rate of radical formation was followed by Iuminol enhanced chemiluminescence (CL) .From the duration of CL and from the fact that the phenolic antioxidant vitamin E analogue TROLOXR traps two radicals (Barclay,L. et al., J. Am. Chem. Soc. 106: 2479-2481, 1984) the stochiometric factors were calculated. The results are presented in Table 1.

Table 1 The binding of peroxyl radicals by various test. compounds Compound Stochiometric factor 1 7.1 2 5.6 3 4.7 4 4.4 4.2 6 4.0 7 4.0 TFIOLOX 2.0 Ascorbic acid 4 0.7 —[(3,4—dihydroxy—5—chlorophenyl)methylidene]thioxoimidazolidin—5-one -[(3,4-dihydroxycyanophenyl)methylidene]thioxothiazolidinone -[(3,4-dihydroxynitrophenyl)methylidene]-2,5-imidazolindione -[(3,4-dihydroxynitrophenyl)methylidene]thioxothiazolidinone -[(3,4-dihydroxynitrophenyl)methylidene]thioxoimidazolidinone -[(3,4-dihydroxynitrophenyl)methylidene]—2,4,6 (IH,3H,5H)—pyrimidinetrione 7 4-[(3,4—dihydroxy-5—cyanophenyl)methylidene]thioxoimidazolidinone The following examples illustrate the preparation of the compounds according to the invention.

Exa.m.ole_1 -[(3,4-Dihydroxynitrophenyl)methylidene]thioxoimidazolidinone A solution containing 2.9 g (0.025 mol) of 2-thiohydantoin, 4.6 g (0.025 mol) of 3,4- dihydroxynitrobenzaldehyde and 0.25 ml of piperidine in 50 ml of acetic acid was heated for 7-8 h at 1009C. The crystalls were filtered and washed with 2-propanol.

Yield 5.0 g (71%), mp > 350°C (decom.) .

Example_2 -[(3,4-Dihydroxynitrophenyl)methylidene]thioxothiazolidinone A solution containing 2.1 g (0.015? mol) of rhodanine, 2.76 g (0.0151 mol) of 3,4- dihydroxynitrobenzaldehyde and 0.15 ml of piperidine in 10 ml of acetic acid was heated for 7-8 h at l009C. After cooling the crystalls were filtered and washed with 2-propanol. Yield 4.0 g (89 %), mp >350°C (decomp.) .

Example} -[(3,4-Dihydroxynitrophenyl)methylidene]-thiazolidin-2,4-dione A solution containing 0.59 g (0.005 mol) of thiazolidine-2,4-dione, 0.92 g (0.005 mol) of 3,4-dihydroxynitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 7-8 h at 80°C. The crystalls were filtered and washed with ethanol. Yield 1.0 g (72 %), mp 295-298°C.

Example_4 —[(3,4-Dihydroxynitrophenyl)methylidene]iminothiazolidinone A solution containing 0.58 g (0.005 mol) of 2-aminothiazolidinone, 0.92 g (0.005 mol) of 3,4—dihydroxy—5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 24 h at 100°C. The product was filtered and washed with ethanol. Yield 1.2 g (86 %), mp 2509C (decomp. ) .

Exam.ole_5 -[(3,4-Dihydroxynitrophenyl)methylidene]thioxothiazolidinone A solution containing 0.67 g (0.005 mol) of 4-thioxothiazolidinone, 0.92 g (0.005 mol) of 3,4-dihydroxynitrobenzaldehyde and 0.05 ml of piperidine in 10 ml of acetic acid was heated for 8 h at 100°C. The product was filtered and washed with 2-propanol. Yield 1.14 g (76.5 %), mp >350°C (decomp. ) .

Exampl:-L6 -[(3,4-Dihydroxynitrophenyl)methylidene]methylthioxothiazolidinone A solution containing 0.74 g (0,005 mol) of 3-methylthioxothiazolidinone, 0.92 g (0.005 mol) of 3,4-dihydroxynitrobenzaldehyde, 0.05 ml of piperidine in 10 ml of acetic acid was heated for 8 h at 100°C. The product was filtered and washed with 2-propanol. Yield 0.87 g (56 %), mp 274-276°C.

Examplel -[(3,4-Dihydroxy-5—nitropheny|)methylidene]-2,4,6(lH,3H,5H)pyrimidinetrione.

To a solution containing 1.28 g (0.01 mol) of barbituric acid and 1.83 g (0.01 mol) of 3,4-dihydroxynitrobenzaldehyde in 20 ml of 2-propanoi was gradually added .0 ml of thionyl chloride. The mixture was stirred for 100 h at room temperature.

The product was filtered, washed with 2-propanol and recrystallized from acetic acid. Yield 1.28 g (44 %), mp 269-272°C.

ExampJe_8 -[(3,4-Dihydroxynitrophenyl)methylidene]-2,5-imidazolidindione A solution containing 0.65 g of hydantoin, 0.92 g of 3,4—dihydroxy nitrobenzaldehyde and 0.15 g of ammonium acetate in 15 ml of acetic acid was refluxed overnight. The product was filtered and washed with acetic acid and 2- propanol. Yield 0.56 g (42 %) , mp >350°C.

Examp1e_9 —[(3,4-Dihydroxynitrophenyl)methylidene]thioxo oxazolidinone A solution containing 0.25 g of 4-thioxo—2-oxazolone 0.38 g of 3,4—dihydroxy nitrobenzaldehyde and 0.1 ml of piperidine in 5 ml of acetic acid was heated overnight at 100°C. The product was filtered and washed with actic acid. Yield 0.05 g, mp 245°C.

Example_J.Q 4-[(3,4-Dihydroxycyanophenyl)methylidene]thioxoimidazolidinone A solution containing 0.58 g of thiohydantoin, 0.82 g of 3,4-dihydroxy cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid was heated for 4 h at 100°C. The product was filtered and washed with ether. Yield 0.51 g, mp 210-213°C.

Examplejl -[(3,4—Dihydroxy—5-cyanophenyl)methylidene]thioxothiazolidinone A solution containing 0.61 g of rhodanine, 0.72 g of 3,4-dihydroxy cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid was heated for 4 h at 100°C. The product was filtered and washed with 2-propanol. Yield 0.35 g, mp >350°C.

ExampJe_‘L2 4-[(3,4—Dihydroxych|orophenyl)methylidene]thioxoimidazolidinone A solution containing 1.16 g of thiohydantoin, 1.72 g of 3,4-dihydroxy chlorobenzaldehyde and 0.2 ml of piperidine in 20 ml of acetic acid was heated for h at 100°C. The product was filtered and washed with ether. Yield 1.0 g, mp 303- 304 °C.

Examplels -[(3,4-Dihydroxy-5—chlorophenyl)methylidene]-thiazolidin-2,4-dione A solution containing 1.33 g of thiazolidine-2,4-dione, 1.72 g of 3,4-dihydroxy chlorobenzaldehyde and 2 ml of piperidine in 20 ml of acetic acid was heated for five hours at 100 °C. Yield 1.9 g (70 %), mp 299-301°C.

Exan1ple_1A -[(3,4-Dihydroxynitrophenyl)methyl]-(1H,3H,5H)pyrimidine-2,4,6-trione To a suspension of 5-[(3,4-dihydroxynitrophenyl)methylidene]- (1H,3H,5H)pyrimidine-2,4,6-trione (Example 7) (lg) in water (30 ml) a solution of sodiumborohydride (2g) in water (10 ml) was gradually added. The solution was stirred for 15 min at room temperature and acidified with 1 N hydrochloric acid. The product was filtered and washed with water. Yield 0.7 g, mp 263-690.

Claims (1)

1.CLAIMS 1. A compound which is a catechol derivative of the general formula I: HO HO R2 1 R1 5 wherein R1 is nitro, halogeno or cyano group and R2 is a group selected from: Y O R / X1 \ N ..cg=z and ‘CH >=IY Ia ' X2 X1 z 0 and y 0 R 10 ‘X1 wherein X1, X2, Y and Z are independently oxygen, sulfur or NR wherein R is hydrogen, straight or branched CH3 alkyl, C54 cycloalkyl, phenyl CH; alkyl or phenyl group or a pharmaceutically acceptable salt or ester thereof. 15 2. The compound as claimed in claim 1, wherein R1 is cyano. 3. The compound as claimed in claim 1, wherein R1 is nitro. 4. The compound as claimed in claim 1, wherein R1 is halogeno. 5. The compound as claimed in any one of claims 1 to 4, wherein in the compound of formula I, R2 is a group according to formula la, Y . ' /X1 Ia - -CH=< / -X2 z 5 in which X1 and X2 are both NR, wherein R is hydrogen or C1.galkyl, Y is oxygen or sulfur and Z is oxygen or sulfur. 6. The compound as claimed in claim 5, wherein the compound is selected from the group consisting of 4[(3,4-dihydroxynitrophenyl)methylidene]thioxoimidazolidin l 0 one, 4—[(3,4-dihydroxychlorophenyl)methylidene]thioxoimidazolidin— 5-one and 4-[(3,4-dihydroxy-5—nitrophenyl)methylidene]-2,5-imidazolidindione. 7. 4-[3,4-Dihydroxycyanophenyl)methylidene]thioxoimidazolidinone or 15 a pharmaceutically acceptable salt or ester thereof. 8. The compound as claimed in any one of claims 1 to 4, wherein in the compound of formula I, R2 is a group according to formula la, Ia in which X1, Y, and Z are independently oxygen or sulfur and X2 is NR, in which R is hydrogen or C1.3alky|. The compound as claimed in claim 8,. wherein the compound is selected from the group consisting of 5-{(3,4—dihydroxynitrophenyl)methylidene]thioxothiazolidin one, 5-[(3,4-dihydroxynitropheny|)methylidene]methyl thioxothiazolidinone, 5-[(3,4-dihydroxy—5-nitrophenyl)methylidene]-thiazolidin-2,4—dione, 5-[(3,4,-dihydroxychloropheny|)methylidene]-thiazolidin-2,4-dione, 5-[(3,4-dihydroxynitrophenyl)methylidene]thioxo oxazolidinone and 5-[(3,4-dihydroxynitrophenyl)methylidene]thioxothiazolidin one. 5-[(3,4-Dihydroxycyanophenyl)methylidene]thioxothiazolidinone or a pharmaceutically acceptable salt or ester thereof. The compound as claimed in any one of claims 1 to 4, wherein in the compound of formula I, R2 is a group according to formula la, in which X1 and Z are indepe_ndently oxygen or sulfur and Y and X2 are NR, wherein R is hydrogen. 5-[(3,4-Dihydroxynitrophenyl)methylidene]aminothiazolinone or a pharmaceutically acceptable salt or ester thereof. The compound as claimed in any one of claims 1 to 4, wherein in the compound of formula l, R2 is a group according to formula la, in which R2 is o R 0 TR / \ / N }-—N -CH \,=r or -CH2 - >51 X1 ‘\7_x1 I o 0 wherein Y is oxygen or sulfur, X1 is NR, wherein R is hydrogen or C1.galkyl. The compound as claimed in claim 13, wherein Y is oxygen. 5-[(3,4-Dihydroxynitrophenyl)methylidene]-2,4,6(1H,3H,5H)- pyrimidinetrione or a pharmaceutically acceptable salt or ester thereof. 5-[(3,4-Dihydroxynitrophenyl)methyl]-(1H,3H,5H) pyrimidine-2,4,6-trione or a pharmaceutically acceptable salt or ester thereof. The compound according to any one of claims 1 to 16 for use in a method of medical treatment by surgery, therapy or diagnosis. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier or diluent. Use of a compound as defined in any one of claims 1 to 16 for the manufacture of a medicament for use in the prevention or treatment of tissue damage induced by lipid peroxidation. The use according to claim 19 wherein the tissue damaging condition to be treated or prevented is heart disease, rheumatoid arthritis, cancer, an inflammatory disease, rejection reaction in transplantation, ischemia or aging. A method of the preparation of the compound of formula I: ‘HO tnoonz ,1 R1 wherein R1 is nit_ro, halogeno or cyano group and R2 is a group selected from Y 0 /R /x1 j N -cH ‘ and -CI-I >=Y Ia X2 X1 z 0 and J °§_ 'R . N /X‘ ‘ -cH2 l and -CH2 >4 Ib >—X2 , / X1 ' z 0 wherein X1, X2, Y and Z are independently oxygen, sulfur or NR wherein R is hydrogen, straight or branched Cm alkyl, C5.7cycloalky|, phenylC1.galkyl or phenyl group comprising condensing an aldehyde of formula ll _ _ HO ‘ HQ CHO II R1 wherein R1 is as defined above with compounds of either formulas III or IV having an active methylene group n u:\>< N H __L,< :11 >"X2 Z . o ’ R . / , [>‘*N 3. C2 Y . IV >“‘x1 0 wherein X1, X2, Y and Z are as defined above to give the compounds of formula la, whereafter the carbon-carbon double bond in la may be reduced to give the compound lb according to the invention. A compound substantially as hereinbefore described with reference to the Examples. A pharmaceutical composition substantially as hereinbefore described with reference to the Examples. Use of a compound substantially as hereinbefore described with reference to the Examples. A method substantially as hereinbefore described with reference to the Examples. _ 20 _ 26. A method of preparation substantially as hereinbefore described with reference to the Examples. dk\Prelim1l/PS018S