Retinoic acid (RA) supports cellular growth and differentiation (Roop, et al., Retinoids : 10 Years On (Saurat J-H (ed)) : 28-30 (1991)) and has been shown to attenuate or completely reverse the malignant phenotype for many cell lines (Kaburagi, et al., J. Steroid Biochem. 26 : 739-42 (1987)). Retinoic acid is also implicated in cell proliferation in skin conditions. Synthetic retinoids have shown promise in the treatment of oral leukoplakia and head and neck cancer, although their use may be associated with significant toxicity (Armstrong, et al., The Retinoids : Biology, Chemistry and Medicine (Sporn et al (eds)) 2nd Edition : 545-72 (1994)). Retinoids have also been used topically and orally for the treatment of skin diseases, i. e. actinic keratoses (Lotan, FASEB J. 10 : 1031-9 (1996)) (precursors to squamous cell carcinoma), nonmelanoma skin cancer (Lotan, FASEB J. 10 : 1031-9 (1996)), acne vulgaris (Peck, et al., N. Engl. J. Med. 300 : 329-33 (1979)), psoriasis (Dockx, et al., Br. J. Dermatol. 133 : 426-32 (1995)) orders of keratinisation (Futoryan, et al., Nutrition Rev. 52 : 299-310 (1994)). More recently, the benefit of retinoids to photodamaged skin has led to their use in anti-wrinkle cosmetic preparations.

Vitamin A (retinol) is oxidised through retinal by dehydrogenases (Raner, et al., Mol. Pharmacol. 49 : 515-22 (1996)) in the cytoplasm of target cells in low yield to all trans-retinoic acid (RA). RA is at least 100 fold more active than retinol (Williams and Napoli, Proc. Natl. Acad.

Sci. 82 : 4658-62 (1985)) and is considered to account for its biological action. RA has a short half life (c. 1 hour) (Muindi, et al., Proc. Amer. Soc. Clin. Oncol. 10 : 92 (1991)) and therefore the potency of RA is reduced when administered systemically due to metabolism by human liver and intestine cytochrome P450s to the inactive 4-hydroxy-RA and thence by dehydrogenases to the partially active 4- keto-RA and inactive polar metabolites (Williams and Napoli, Proc. Natl. Acad. Sci. 82 : 4658-62 (1985)) (Van Wauwe, et al., Biochem. Pharmacol. 47 : 737-41 (1994)). The specific P450s (P450-RA) responsible for 4-hydroxylation of RA in the human liver have not been characterised, but several reconstituted P450s CYPlA2/2B6/2C8/2D6/2E1/3A4, can catalyse the reaction (Nadin and Murray, Br. J. Clin.

Pharmacol. 41 : 609-12 (1996)).

Repeated exogenous administration of RA leads to a lowering of RA levels due to induction of the metabolising enzymes (Muindi, et al., Blood. 70 : 299-303 (1992)). Recent work has shown that RA induces a RA-inducible RA-metabolising P450 (hP450RA1), which belongs to a novel class of mammalian cytochromes (CYP26), which gives the RA- metabolites previously described (Ray, et al., J. Biol.

Chem. 272 : 18702-8 (1997)) (White, et al., J. Biol. Chem.

272 : 18538-41 (1997)) (AbuAbed, et al., J. Biol. Chem. 273 :

2409-15 (1998)) (Haque, et al., Nutritional Rev. 56 : 84-5 (1998)) Furthermore hP450RAI mRNA expression is highly induced by RA in certain human tumour cell lines and RA- metabolism may correlate with P450RAI expression (White, et al., J. Biol. Chem. 272 : 18538-41 (1997)).

A drug which can potentiate the action of endogenous RA on the cell by inhibiting P450-RA metabolising enzymes would have potential as a clinical agent in the treatment of certain skin conditions and cancer.

The imidazoles, ketoconazole and liarozole, were reported as inhibitors of RA-metabolising enzymes whilst being studied as inhibitors of 17a-hydroxylase : 17, 20-lyase (P450 17a) as agents for the treatment of androgen-dependent prostatic cancer by lowering testosterone levels (Vander Bosche and Willemsens, Retinoids : 10 Years On (Saurat J- H (ed)) : 79-88 (1991)). Ketoconazole lacks specificity towards P450 17a and inhibits several other cytochrome P450 enzymes on the steroidogenic pathway of androgen synthesis and has a poor pharmacokinetic profile and hepatic toxicity has been noted.

Liarozole (R75251), a related compound, also inhibits testicular (but not adrenal) P450 17a and similarly lowers testosterone levels in human volunteers, but its effect on androgen-independent carcinoma has been partially attributed to inhibition of P450-RA with an associated increase in RA levels (Dockx, et al., Br. J. Dermatol. 133 : 426-32 (1995)) (Roseeuw, et al., 182 World Congress of Dermatology, June 12th-18th : P194A (1992) (ketoconazole is

also an inhibitor of this enzyme). This view has been confirmed by experiments showing that RA metabolism in epidermal cells is inhibited (ICso-2yM) and also that endogenous RA levels are increased and the elimination rate from the plasma of injected RA is reduced (Roseeuw, et al., 18th World Congress of Dermatology, June 12th-18th : P194A (1992). Liarozole has also been in trials for the treatment of severe psoriasis (oral) and acne (topical and oral) and it seems likely that this action is due to inhibition of epidermal P450-RA. The ability of oral liarozole to act as a useful drug in the treatment of hormone-resistant prostate cancer, ichthyosis, psoriasis (Dockx, et al., Br. J. Dermatol. 133 : 426-32 (1995)) and acne (Roseeuw, et al., 18"World Congress of Dermatology, June 12th-18th : P194A (1992) has been established by certain workers.

RA-metabolising enzyme inhibitors intended for topical use for skin diseases should show little unwanted systemic effects due to the involvement of other enzymes, e. g. steroidogenic P450 enzymes such as P450 17a, CSCC, 21- hydroxylase. This objective should be achievable due to either poor sub-dermal penetration or, should this occur, low dose effects due to plasma dilution of the small load of drug placed on a restricted area of skin.

It is therefore the aim of the present invention to provide a P450-RA inhibitor of low activity towards other steroidogenic P450 enzymes and therefore low inherent toxicity to alleviate some of the aforementioned problems.

We have now discovered compounds that are inherently less

active inhibitors of P450 17a, the main target of liarozole and ketoconazole, and yet are inhibitors of retinoic acid metabolism with potency comparable with that of ketoconazole. This selectivity for inhibition of retinoic acid metabolism is useful in the treatment of the skin conditions mentioned above and cancer.

According to the present invention, there is provided for use in therapy, a compound of the general Formula (I) : where RI and R2 together are =O or or RI and RI are independently selected from the group consisting of H, CH2OH, OH, halide and CO2Cl4alkyl ; R3 is H and R4 is OH or OT where T is where Rl° is C14alkyl, aryl (Cl4) alkyl, di-aryl (C1-4) alkyl or aryl ; or R3 and R4 together are =O :

(i) when Ri and R2 together are =O ; or (ii) when Ri and R2 are both halide ; or (iii) at least one of R1 and R2 is is CO2C1-4alkyl ; or each of RI and RI is H when R1 and R2 together are not =O ; or R1 and R3 together are when n is 1, z is 0 and R and RI are each H ; R5 and R6 are selected from the group consisting of H, halide, NH2, N (C1-4alkyl)2, NH (C14alkyl) and NO2, with the proviso that Rs and RI are not both H ; RI is H, or R7 is halide when Rs is halide ; each of R8 and R9 is H or halide ; n is 0 or 1 ; y and z are both 0, or one of y and z is 1 and the other of y and z is 0.

There is further provided by the present invention, use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, a compound of the general Formula (I) :

where RI and R2 together are =O or or RI and R2 are independently selected from the group consisting of H, CH2OH, OH, halide and CO2C1-4alkyl ; RI is H and RI is OH or OT where T is where RIO is Cl4alkyl, aryl (Ci. alkyl, di-aryl (C-14) alkyl or aryl ; or R3 and R4 together are =O : (i) when R1 and R2 together are =O ; or (ii) when R1 and R2 are both halide ; or (iii) at least one of R1 and R2 is is CO2C1-4alkyl ; or

each of RI and R4 is H when RI and RI together are not =0 ; or RI and R3 together are when n is 1, z is 0 and R2 and R4 are each H ; R5 and R6 are selected from the group consisting of H, halide, NH2, N (C1-4alkyl)2, NH (C14alkyl) and NO2, with the proviso that R5 and RI are not both H ; R7 is H, or R7 is halide when RI is halide ; each of R8 and R9 is H or halide ; n is 0 or 1 ; y and z are both 0, or one of y and z is 1 and the other of y and z is 0.

Suitably for use according to the present invention, R1 and RI in compounds of Formula (I) are selected from the group consisting of H, OH, Br, CO2Me and CH2OH ; or R1 and R2 together are =O or

or R1 and R3 together are when n is 1, z is 0 and R2 and R4are each H.

More preferably for use according to the present invention, R2 in compounds of Formula (I) represents H when R1 is selected from H, CO2Me and CH2OH. Even more preferably for use according to the present invention in compounds of Formula (I) RI represents C02Me, R2 represents H and R3and R4 together are =O ; or in compounds of Formula (I) R' represents CH2OH, R2 represents H, RI represents H and R4 represents OH.

For use according to the present invention where R4 in compounds of Formula (I) can represent OT, where T is RIO typically represents di-aryl (Cl4) alkyl. Preferably Rl° represents di-aryl (C2-4) alkyl and more preferably R10 represents di-phenyl (C24) alkyl.

It is particularly desirable for use according to the present invention that Rs and RI in compounds of Formula (I) are selected from the group consisting of H, halide, NH2, N (Cl4alkyl) 2, NH (C1-4alkyl) and NO2, with the proviso that at least one of R5 and R6 is NH2, N (C14alkyl) 2, NH (C1-4alkyl) and

NO2 and that both Rs and R6 are not NO2 when RI and R2 together are =O, R3 is H, R4 is OH, RI i s H, R8 is H, R9 is H, n is 1, y is 0 and z is 0. It is preferred for use according to the present invention that R 5 and RI in compounds of Formula (I) are selected from the group consisting of H, Br, Cl, NH2, N (Me) z and NO2, with the proviso that at least one of R 5 and R6 is NH2, N (Me) 2 and NO2 and that both R5 and R6 are not NO2 when R1 and R2 together are =O, R3 is H, R4 is OH, R7 is H, R8 is H, RI is H, n is 1, y is 0 and z is 0.

The present invention further includes for use in therapy, a compound of general Formula (IA) or (IB), or a pharmaceutically acceptable salt or prodrug thereof

where Alk represents C14 alkyl ; R2 is H, CH2OH, OH, halide or CO2C1-4 alkyl ; R5 and R6 are selected from the group consisting of H, halide, NH2, N (C14alkyl) 2, NH (C,-, alkyl) and NO2, with the proviso that Rsand R6 are not both H ; RI is H, or halide when Rs is halide ; and each of R8 and R9 is H or halide.

There is further provided by the present invention, use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, a compound of general Formula (IA) or (IB), or a pharmaceutically acceptable salt or prodrug thereof

(IB) where Alk represents C14 alkyl ; R2 is H, CH20H, OH, halide or CO2C1-4 alkyl ; R5 and RI are selected from the group consisting of H, halide, NH2, N (C1-4alkyl)2, NH (C1-4alkyl) and NO2, with the proviso that Rsand R6 are not both H ; RI is H, or halide when R5 is halide ; and each of R8 and R9 is H or halide.

The present invention further provides for use in therapy, a compound of general Formula (IC) or a pharmaceutically acceptable salt or prodrug thereof, where (IC) Ra is selected from the group consisting of NO2, NH2, NH (C14alkyl) and N (C14alkyl) 2 ;

Rb is selected from the group consisting of H, halide and NO, and b is 1 or 2 ; X can be selected from the group consisting of -C (roc) (Rd) C (Re) (Rf) -, -C (RJ (Rd) (CH2) (Rj (Rf)-, -C (RJ (Rd) 9CH2) dC (Re) (Rf) N (Rg)-and -C (RJ (Rd) (CH2) dN (Rg) C (Re) (Rf) -; wherein Ré and Rd can be independently selected from the group consisting of H, halide, OH, CH2OH and CO2C1-4alkyl ; or RC and Rd together represent =O or ethylenedioxy ; Re and Rf can be selected from the group consisting of H, OH and OCO2Rh, where Rh represents (diaryl) alkyl ; or Re and R together represent =O or ethylenedioxy ; Rg is H or Alkyl ; and d is an integer selected from 1 to 4 ; or X can represent a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =O.

There is further provided by the present invention, use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, a compound of general Formula (IC) or a pharmaceutically acceptable salt or prodrug thereof,

(IC) where Ra is selected from the group consisting of NO2, NH2, NH (Ci, alkyl) and N (C1-4alkyl)2; Rb is selected from the group consisting of H, halide and NO2 and b is 1 or 2 ; X can be selected from the group consisting of -C (Rc) (Rd) C (Re) (Rf)-, -C (RC) (Rd) (CH2) dC (Re) (Rf) -, -C (Rc) (Rd) (CH2) dC (Re) (Rf) N (Rg)-and -C (RJ (Rd) (CH2) dN (Rg) C (Rj (R,)- ; wherein R and Rd can be independently selected from the group consisting of H, halide, OH, CH2OH and CO2C14alkyl ; or Ré and Rd together represent =O or ethylenedioxy ; Re and Rf can be selected from the group consisting of H, OH and OCO2Rh, where Rh represents (diaryl) alkyl ; or Re and Rf together represent =O or ethylenedioxy ; Rg is H or Alkyl ; and d is an integer selected from 1 to 4 ; or X can represent a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =O. Suitably, for use according to the present invention a compound of general Formula (IC) is selected from the following :

wherein Ra, Rb and X are as hereinbefore described in relation to general Formula (IC).

Suitably for use according to the present invention Ra in compounds of Formula. (IC) is selected from the group consisting of NO2, NH, and N (CH3) 1' Suitably for use according to the present invention Rb in compounds of Formula (IC) is selected from the group consisting of H, Br, Cl and NO2.

In a first embodiment for use according to the present invention X in compounds of Formula (IC) is selected from the group consisting of -C (RC) (Rd) C (Re) (Rf) -, -C (Rc) (Rd) (CH20 dC (Re) (Rf) - , -C (Rc) (Rd) (CH,) dC (Re) (Rf) N (Rg)-and -C (RJ (Rd) (CH2) dN (Rg) C (Re) (Rf)-, wherein Rct Rd, Re, Rf, Rg and d are as hereinbefore described in relation to general Formula (IC).

Typically for use according to the present invention X may be selected from the group consisting of-CH2CH (OH)-, -C (=O) C (=O)-, C (halide) 2C (=O)-,-CH2C (ethylenedioxy)-, -CH2CH (OCO2Rh) - where Rh is as hereinbefore described in relation to general Formula (IC),-CH (OH) CH2-, -C (ethylenedioxy) CH2-and-C (=O) CH (OH)-. Preferably for use according to the present invention X can be selected from the group consisting of -CH2CH (OH)-,-C (=O) C (=O)-, -C (Br) 2C (=O)-,-CH2C (ethylenedioxy)-, -CH2CH [OC02-CHRiRj]-where Ri is 2, 4-dichlorophenyl and Rj is 4-nitrobenzyl,-CH (OH) CH2-,-C (ethylenedioxy) CH2-and -C (=O) CH (OH)-.

Alternatively, for use according to the present invention X may be-CH (CO2Cl4alkyl) (CH2) dC (=O)-, wherein d is as hereinbefore described in relation to general Formula (IC).

Preferably for use according to the present invention X in compounds of Formula (IC) is-CH (CO2Me) CH2C (=O)-.

Alternatively, for use according to the present invention X in compounds of Formula (IC) may be-CH (CH2OH) (CH2) dCH (OH)- wherein d is as hereinbefore described in relation to general Formula (IC). Preferably for use according to the present invention X is-CH (CH, OH) CH, CH (OH)-.

Alternatively, for use according to the present invention X in compounds of Formula (IC) may be -CH (CO2C14alkyl) (CH2) dC (=O) NH-, wherein d is as hereinbefore described in relation to general Formula (IC). Preferably for use according to the present invention X in compounds of Formula (IC) is-CH (CO2Me) CH2C (=O) NH-.

Alternatively, for use according to the present invention X in compounds of Formula (IC) may be -CH (CO2C14alkyl) (CH2) dNHC (=O)-, wherein d is as hereinbefore described in relation to general Formula (IC). Preferably X is-CH (CO2Me) CH2NHC (=O)-.

In a second embodiment of general Formula (IC) for use according to the present invention, X represents a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =O. The 5 or 6 membered heterocyclic ring preferably contains an oxygen or

nitrogen heteroatom, which ring is preferably substituted by =O. It is most preferred that the heterocyclic ring is either tetrahydrofuran or pyrrolidine.

Suitably in the case of following Formula (IC) for use according to the present invention (IC) Ra and Rb do not both represent NO2 when X represents -CH (OH) CH2C (=O)-.

Particular compounds for use in therapy or in the manufacture of a medicament for the inhibition of retinoic acid metabolism according to the present invention may include at least one of the following compounds : 1- (2, 4-Dichlorophenyl)-2- (4-nitrophenyl)-1-ethanol ; 1- (2, 4-Dichlorophenyl)-2- (4-nitrophenyl)-1, 2- ethandione ; 2, 2-Dibromo-l- (2, 4-dichlorophenyl)-2- (4-nitrophenyl)- 1-ethanone ; 1- (2, 4-Dichlorophenyl)-1, 1-ethylenedioxy-2- (4- nitrophenyl) ethane ; Di (l- (2, 4-dichlorophenyl)-2- (4-nitrophenyl) ethyl)

carbonate ; 2-(2, 4-Dichlorophenyl)-1-(4-nitrophenyl)-1-ethanol ; <BR> <BR> <BR> <BR> 2- (2, 4-Dichlorophenyl)-1, 1-ethylenedioxy-1- (4- nitrophenyl) ethane ; <BR> <BR> <BR> <BR> 2- (2, 4-Dichlorophenyl)-l- (4-dimethylaminophenyl)-2- hydroxy-1-ethanone ; 1- (2, 4-Dichlorophenyl)-2- (4-dimethylaminophenyl)-1, 2- ethandione ; 2- (4-Aminophenyl)-1- (2, 4-dichlorophenyl)-1, 2- ethandione ; Methyl 2- (4-nitrophenyl)-4-oxo-4-phenylbutanoate ; Methyl 4- (4-bromophenyl)-2- (4-nitrophenyl)-4- oxobutanoate ; Methyl 4- (2-chlorophenyl)-2- (4-nitrophenyl)-4- oxobutanoate ; Methyl 4- (3-chlorophenyl)-2- (4-nitrophenyl)-4- oxobutanoate ; Methyl 4- (4-chlorophenyl)-2- (4-nitrophenyl)-4- oxobutanoate ; Methyl 4- (2, 4-dichlorophenyl)-2- (4-nitrophenyl)-4- oxobutanoate ; Methyl 4- (3, 4-dichlorophenyl)-2- (4-nitrophenyl)-4- oxobutanoate ; Methyl 4- (4-nitrophenyl)-2- (4-nitrophenyl)-4- oxobutanoate ; 3- (4-Nitrophenyl)-1-phenyl-1, 4-butanediol ; 1- (4-bromophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 1- (2-chlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 1- (3-chlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 1- (4-chlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 1- (2, 4-dichlorophenyl)-3- (4-nitrophenyl)-1, 4-

butanediol ; 1- (3, 4-dichlorophenyl)-3- (4-nitrophenyl)-1, 4- butanediol ; 1- (4-nitrophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 3- (4-nitrophenyl)-5-phenyltetrahydro-2-furanone ; 5- (4-Bromophenyl)-3- (4-nitrophenyl) tetrahydro-2- furanone ; 5- (2, 4-dichlorophenyl)-3- (4-nitrophenyl) tetrahydro-2- furanone ; 5- (2, 4-dichlorophenyl)-3- (4-aminophenyl)-2- pyrrolidinone ; Methyl 4- (2, 4-dichlorophenylamino)-4-oxo-2- (4- nitrophenyl) butanoate ; and Methyl 3- (2, 4-dichlorophenyloxoamino)-2- (4- nitrophenyl) propanoate.

The preferred compounds may advantageously be achiral, readily available and potentially metabolically stable in vivo. It is advantageous in some embodiments to have achiral compounds, as resolution into specific enantiomers and/or stereoselective synthesis is not then required.

In some instances, however, compounds according to the present invention can be chiral and one of the resolved enantiomers may possess most of the activity in accordance with general findings for inhibition of P450s. The present invention therefore encompasses both racemic mixtures of such chiral compounds, and resolved enantiomers thereof.

There is further provided by the present invention a method of treating a disease state ameliorated by the presence of

retinoic acid, which method comprises administering to a patient suffering from or susceptible to such a disease state a therapeutically effective amount of a compound as hereinbefore described in connection with use according to the present invention, or a pharmaceutically acceptable salt or prodrug thereof.

The present invention further provides a compound of the general Formula (I), or a pharmaceutically acceptable salt or prodrug thereof where RI and RI together are =O or or R1 and R2 are independently selected from the group consisting of H, CH2OH, OH, halide and CO2C1-4alkyl ; RI is H and R4 is OH or OT where T is where R10 is C,-, alkyl, aryl (C14) alkyl, di-aryl (c14) alkyl or aryl ; or

RI and R4 together are =0 : (i) when R1 and R2 together are =O ; or (ii) when Ri and R2 are both halide ; or (iii) at least one of R1 and R2 is is CO2C14alkyl ; or each of R3 and R4 is H when R1 and R2 together are not =O ; or R1 and R3 together are when n is 1, z is 0 and RI and RI are each H ; R5 and R6 are independently selected from the group consisting of H, halide, NH2, N (C1-4alkyl) 2, NH (C1-4alkyl) and NO2, with the proviso that at least one of R5 and R6 is NH2, N (C1-4alkyl)2, NH (C1-4alkyl) and NO2 and that both R5 and R6 are not NO2 when RI and R2 together are =O, RI is H, R4 is OH, R 7is H, R8 is H, R9 is H, n is 1, y is 0 and z is 0.

R 7is H, or RI is halide when R5 is halide ; each of RI and RI is H or halide ; n is 0 or 1 ; y and z are both 0, or one of y and z is 1 and the other of y and z is 0.

Suitably, in compounds of Formula (I) R1 and R2 are selected

from the group consisting of H, OH, Br, CO2Me and CH2OH ; or RI and R2 together are =O or or Rl and R3 toqether are when n is 1, z is 0 and R2 and R4are each H.

R2 in compounds of Formula (I) preferably represents H when R1 is selected from H, CO2Me and CH2OH. More preferably in compounds of Formula (I), RI represents CO2Me, R2 represents H and R3and R4 together are =O ; or in compounds of Formula (I) R1 represent CH2OH, R2 represent H, R3 represent H and R4 represent OH.

In compounds of Formula (I) where R4 can represent OT, where T is R10 typically represents di-aryl (C14) alkyl. Preferably R10 represents di-aryl (C2-4) alkyl, most preferably R10 represents di-phenly (C2-4) alkyl.

Suitably, R5 and R6 are selected from the group consisting

of H, Br, Cl, NH2, N (Me)2 and NO2, with the proviso that at least one of R5 and R6 is NH2, N (Me)2 and NO2 and that both Rs and R6 are not NO2 when R1 and R2 together are =O, R3 is H, R4 is OH, RI is H, R"is H, R9 is H, n is 1, y is 0 and z is 0.

A further embodiment of the present invention is a compound of general Formula (IA) or (IB), or a pharmaceutically acceptable salt or prodrug thereof (IB) where Alk represents C14 alkyl ; R2 is H, CH2OH, OH, halide or CO2C14 alkyl ;

R5 and RI are selected from the group consisting of H, halide, NH2, N (C1-4alkyl)2, NH (C14alkyl) and NO2, with the proviso that at least one of R5 and RI is NH2, N (C14alkyl) 2, NH (C1-4alkyl) and NO2 and that compounds of Formulae (IA) and (IB) do not include within their scope compounds of Formula (I) where both R5 and R6 are NO2 when R1 and R2 together are =O, R3 is H, R4 is OH, R7 is H, Ra is H, R9 is H, n is 1, y is 0 and z is 0 ; R7 is H, or halide when R5 is halide ; and each of RB and R9 is H or halide.

The present invention further provides a compound of general Formula (IC) or a pharmaceutically acceptable salt or prodrug thereof, (IC) where Ra is selected from the group consisting of NO2, NH2, NH (C,-, alkyl) and N (C1-4alkyl)2; Rb is selected from the group consisting of H, halide and NO2 and b is 1 or 2 ;

X can be selected from the group consisting of -C (RJ (Rd) C (Re) (Rf)-, -C (RC) (Rd) (CH2) dC (Re) (Rf)-, -C (Rc) (CH2)dC(Re) (Rf) N (Rg)-and -C (Rc (Rd) (CH2) dN (Rg) C (Re) (Rf wherein Rc and Rd can be independently selected from the group consisting of H, halide, OH, CH2OH and CO2C1-4alkyl ; or Rc and Rd together represent =O or ethylenedioxy ; Re and Rf can be selected from the group consisting of H, OH and OCO2Rh, where Rh represents (diaryl) alkyl ; or Re and Rf together represent =O or ethylenedioxy ; Rg is H or Alkyl ; and d is an integer selected from 1 to 4 ; or X can represent a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =O, with the proviso that in the case of following Formula (IC) (IC) Ra and Rb do not both represent NO2 when X represents -CH (OH) CH2C (=O)-.

Suitably, a compound of general Formula (IC) is selected from the following :

(IC) wherein Ra, Rb and X are as hereinbefore described in relation to a compound of general Formula (IC).

Suitably, Ra is selected from the group consisting of NO2, NH2 and N (CH3) 2# Suitably, Rb is selected from the group consisting of H, Br, Cl and NO2.

In a first preferred embodiment of the present invention, there is provided compounds of general Formula (IC), where X is selected from the group consisting of

-C (R, (Rd) C (Re) (Rf) -, -C (RJ (Rd) (CH2) dC (Re) (Rf) -, -C (Rc) (Rd) (CH,) dC (Re) (Rf) N (Rg)-and -C (RJ (Rd) (CH2) dN (Rg) C (Re) (Rf)-, wherein Rc, Rd, Re, Rf, Rg and d are as hereinbefore disclosed in relation to compounds of general Formula (IC).

Typically, X may be selected from the group consisting of -CH2CH (OH)-,-C (=O) C (=O)-, C (halide) 2C (=O)-, -CH2C (ethylenedioxy)-,-CH2CH (OCO2Rh)-where Rh is as hereinbefore disclosed in relation to compounds of general Formula (IC),-CH (OH) CH2-,-C (ethylenedioxy) CH2-and -C (=O) CH (OH)-. X is preferably selected from the group consisting of -CH2CH (OH)-,-C (=O) C (=O)-,-C (Br) 2C (=O)-, -CH2C (ethylenedioxy) - , - CH2CH [OCO2 - CHRiRj] - where Ri is 2, 4-dichlorophenyl and Rj is 4-nitrobenzyl, -CH (OH) CH2-,-C (ethylenedioxy) CH2-and-C (=O) CH (OH)-.

Alternatively, X may represent-CH (CO2C14alkyl) (CH2) dC (=O)-, wherein d is as hereinbefore disclosed in relation to compounds of general Formula (IC). X is preferably -CH (C02Me) CH2C (=O)-.

Alternatively, X may represent-CH (CH2OH) (CH2) dCH (OH)-, wherein d is as hereinbefore disclosed in relation to compounds of general Formula (IC). X is preferably -CH (CH2OH) CH2CH (OH)-.

Alternatively, X may represent - CH (CO2C1-4alkyl) (CH2) dC (=O) NH-, wherein d is as hereinbefore disclosed in relation to compounds of general Formula (IC). X is preferably

-CH (CO2Me) CH2C (=O) NH-.

Alternatively, X may represent-CH (CO2Cl 4alkyl) (CH2) dNHC (=O)-, wherein d is as hereinbefore disclosed in relation to compounds of general Formula (IC). X is preferably -CH (CO2Me) CH2NHC (=O)-.

In a second preferred embodiment of the present invention, there is provided compounds of general Formula (IC), where X represents a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =O. X preferably represents a 5 membered heterocyclic ring containing an oxygen or nitrogen heteroatom, which ring is substituted by =O. It is most preferred that the heterocyclic ring is either tetrahydrofuran or pyrrolidine.

According to the present invention, there is further provided one or more of the following compounds : 1- (2, 4-Dichlorophenyl)-2- (4-nitrophenyl)-1-ethanol ; 1- (2, 4-Dichlorophenyl)-2- (4-nitrophenyl)-1, 2-ethandione ; 2, 2-Dibromo-1- (2, 4-dichlorophenyl)-2- (4-nitrophenyl)-1- ethanone ; <BR> 1- (2, 4-Dichlorophenyl)-1, 1-ethylenedioxy-2- (4-nitrophenyl) ethane ; Di (1- (2, 4-dichlorophenyl)-2- (4-nitrophenyl) ethyl) carbonate ; 2- (2, 4-Dichlorophenyl)-1- (4-nitrophenyl)-1-ethanol ; 2- (2, 4-Dichlorophenyl)-1, 1-ethylenedioxy-1- (4- nitrophenyl) ethane ;

2- (2, 4-Dichlorophenyl)-l- (4-dimethylaminophenyl)-2-hydroxy- 1-ethanone ; 1- (2, 4-Dichlorophenyl)-2- (4-dimethylaminophenyl)-1, 2- ethandione ; 2- (4-Aminophenyl)-1- (2, 4-dichlorophenyl)-1, 2-ethandione ; Methyl 2- (4-nitrophenyl)-4-oxo-4-phenylbutanoate ; Methyl 4- (4-bromophenyl)-2- (4-nitrophenyl)-4-oxobutanoate ; Methyl 4- (2-chlorophenyl)-2- (4-nitrophenyl)-4-oxobutanoate ; Methyl 4- (3-chlorophenyl)-2- (4-nitrophenyl)-4-oxobutanoate ; Methyl 4- (4-chlorophenyl)-2- (4-nitrophenyl)-4-oxobutanoate ; Methyl 4- (2, 4-dichlorophenyl)-2- (4-nitrophenyl)-4- oxobutanoate ; Methyl 4- (3, 4-dichlorophenyl)-2- (4-nitrophenyl)-4- oxobutanoate ; Methyl 4- (4-nitrophenyl)-2- (4-nitrophenyl)-4-oxobutanoate ; 3- (4-Nitrophenyl)-1-phenyl-1, 4-butanediol ; 1- (4-bromophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 1- (2-chlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 1- (3-chlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 1- (4-chlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 1- (2, 4-dichlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 1- (3, 4-dichlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 1- (4-nitrophenyl)-3- (4-nitrophenyl)-1, 4-butanediol ; 3- (4-nitrophenyl)-5-phenyltetrahydro-2-furanone ; 5- (4-Bromophenyl)-3- (4-nitrophenyl) tetrahydro-2-furanone ; 5- (2, 4-dichlorophenyl)-3- (4-nitrophenyl) tetrahydro-2- furanone ; 5- (2, 4-dichlorophenyl)-3- (4-aminophenyl)-2-pyrrolidinone ; Methyl 4- (2, 4-dichlorophenylamino)-4-oxo-2- (4-nitrophenyl) butanoate ; or Methyl 3- (2, 4-dichlorophenyloxoamino)-2- (4-nitrophenyl)

propanoate.

There is further provided by the present invention, methods of preparing compounds of Formula (I).

According to a first preferred method according to the present invention, compounds of Formula (I) can be prepared following reaction of a known substituted benzaldehyde derivative of Formula (II) (n) with any of compounds of Formulae (III), (IV) or (V) (III) (IV)

(V) where in the resulting compounds of Formula (I) each of n, y and z is 0.

In compounds of Formula (III) substantially as hereinbefore described Y can represent hydrogen or another suitable group, whereby compounds of Formula (III) can react with either the aldehyde moiety of benzaldehyde derivatives of Formula (II) in a first preferred method according to the present invention or the phenyl ring substituent X-CH2-C (R3) (R4)-of compounds of Formula (VII) in a second preferred method according to the present invention substantially as hereinafter described.

Benzaldehyde derivatives of Formula (II) are generally known compounds. Compounds of Formula (III) can also be known compounds or may be prepared from compounds of Formula (IX) substantially as hereinafter described in a second preferred method according to the present invention.

Benzaldehyde derivatives of Formula (II) are typically reacted with compounds of Formula (III), in a first preferred method according to the present invention, in the

presence of an alkali metal hydroxide and an inert solvent, such as dimethylformanide or the like, to yield compounds of Formula (I) according to the present invention.

In compounds of Formula (IV), Het suitably represents a heterocyclic moiety and X a suitable leaving group, typically a halide (bromide, chloride, fluoride or iodide) or the like. Compounds of Formula (I) are typically obtained from compounds of Formula (IV) via a number of intermediates following reaction of compounds of Formula (II) and (IV) (substantially as hereinafter described in greater detail in the accompanying Examples), suitably by elimination followed by reduction or reaction with an alkylene glycol or the like.

Compounds of Formula (IV) can suitably be obtained from reaction of a heterocyclic group with known benzyl derivatives of Formula (VI) (VI) where X is a leaving group substantially as hereinbefore described with reference to Formula (IV). Typically the reaction is carried out in the presence of an inert solvent, at a temperature below about 30°C.

In benzaldehyde derivatives of Formula (V), Rua can either represent R5 substantially as hereinbefore described with reference to Formula (I) or a precursor thereof that can readily be converted to R5. For example, Rua can represent CH3CONH that can be converted to NH2-, suitably by reflux under acidic conditions followed by addition of a base, such as an alkali metal hydroxide, to release the free amine.

Coupling of benzaldehyde derivatives of Formulae (II) and (V) is typically carried out under reflux in the presence of an alkali metal cyanide (e. g. potassium cyanide) and an alcohol (e. g. ethanol). Initially a diphenyl intermediate having a-C (=O)-CH (OH)- linker between the substituted end phenyl rings can be formed and this can subsequently be converted into a compound of Formula (I) having a dicarbonyl linker-C (=O)- (C=O)- between the phenyl rings.

Benzaldehyde derivatives of Formula (V) are generally known compounds.

According to a second preferred method according to the present invention, compounds of Formula (I) can be prepared by reaction of a compound of Formula (III) substantially as hereinbefore described and a compound of Formula (VII)

where in the resulting compounds of Formula (I), n is 1 and each of y and z is 0. Substantially as hereinbefore described, X is a suitable leaving group, such as a halide (bromide, chloride, fluoride or iodide) or the like.

Compounds of Formula (III) and (VII) are typically reacted under reflux, with stirring, in the presence of an anhydrous solvent, such as an alkali metal (typically potassium) carbonate or the like.

Compounds of Formula (VII) can be obtained from known acetophenone derivatives of Formula (VIII) (vit) typically by halogenation where X in Formula (VII) represents halide substantially as hereinbefore described, suitably in the presence of a catalyst, such as aluminium chloride or the like.

Compounds of Formula (III) where Rl or R2 represents -CO2Alk substantially as hereinbefore described with reference to Formula (I) can be prepared from known phenyl acetic acid derivatives of Formula (IX)

(JX) whereby the carboxylic acid group of compounds of Formula (IX) can be converted into the corresponding ester group -CO2Alk represented by RI in Formula (I). Compounds of Formula (III) are typically obtained from compounds of Formula (IX) by reaction of the latter with an alkylating agent, such as a trialkyl orthoformate or the like, in the presence of a catalytic amount of a mineral acid, such as hydrochloric acid or the like.

Compounds of Formula (I) obtained by a second preferred method according to the present invention can typically form a subgroup of compounds according to the present invention that can suitably be represented by Formula (IA) substantially as hereinbefore described.

Compounds of Formula (I) substantially as hereinbefore described obtained by a method according to the present invention can be converted into further compounds of Formula (I) by suitable interconversion techniques. For example, compounds of Formula (I) where RI represents CO2Alk can be converted into corresponding alcohol derivatives where Rl can represent-CH2OH, employing suitable reducing conditions, such as reaction in the

presence of a reducing agent, typically a borohydride (for example, sodium borohydride) or the like. Alternatively, compounds of Formula (I) can be subjected to oxidative conditions, for example where the moiety-CH (OH)- [represented by either-C (Rl) (R2)-or C (R3) (R4)-in Formula (I)] can be oxidised, suitably to yield corresponding carbonyl, carbonate or alkylenedioxy derivatives as allowed by Formula (I). In a further interconversion reaction, compounds of Formula (I) where RI and R4 together represent =O and both y and z are 0 can be converted via an imino intermediate into further compounds of Formula (I), for example compounds where R1 and R3 together represent -substantially as hereinbefore described and y and z are both 0, or compounds where RI and R4 together represent =O and either y or z is 1.

It will of course be appreciated that compounds of Formula (IC) substantially as hereinbefore described can be prepared by techniques substantially as hereinbefore described for compounds of Formula (I). More particularly, therefore, processes of preparing compounds of Formula (I) substantially as hereinbefore described are also provided by the present invention for the preparation of compounds of Formula (IC). The following processes giving specific reference to Formula (IC) are, therefore, essentially as described for compounds of Formula (I) and the further details and preferences substantially as hereinbefore

described for the preparation of compounds of Formula (I) are similarly applicable for the preparation of compounds of Formula (IC) substantially as hereinafter described.

There is, therefore, further provided by the present invention a process of preparing a compound of Formula (IC) according to the first embodiment of the present invention substantially as hereinbefore described, which process comprises reacting a substituted benzaldehyde derivative of Formula (X) (X) with any one of compounds of Formulae (XIa), (XIb) and (XIc)

where Y in Formula (XIa) is hydrogen or a group reactive with the aldehyde moiety of benzaldehyde derivatives of Formula (X) ; in Formula (XIb) Het is a heterocyclic moiety and X is a leaving group ; Ra, Rb, R and Rd are as hereinbefore described in relation to a compound of general Formula (IC) ; and Rai represents Ra or a precursor thereof that can readily be converted to Ra- There is further provided by the present invention, a process of preparing a compound of Formula (IC) according to the first embodiment of the present invention, wherein a compound of Formula (XIa) is reacted with a compound of Formula (XII) (xn) where in Formula (XIa) Y is hydrogen or a group reactive with the phenyl ring substituent X-CH2-C (Re) (Rf)-of a compound of Formula (XII) ; in Formula (XII) X is a leaving group ; and

Ra, Rb, Rc, Rd, Re, Rf, b and d are as hereinbefore described in relation to a compound of general Formula (IC).

Compounds of Formula (IC) according to the second embodiment of the present invention where X represents a 5 or 6 membered heterocyclic ring substantially as hereinbefore described can be prepared by interconversion techniques substantially as hereinbefore described with reference to compounds of Formula (I).

The present invention further includes within its scope prodrugs of compounds of Formula (I) and in general such prodrugs will be functional derivatives of compounds of Formula (I) which are readily convertible in vivo into the required compound. Conventional procedures for selection and preparation of suitable prodrug derivatives are well known in the art.

Compounds according to the present invention are inhibitors of retinoic acid metabolism substantially as hereinbefore described and are, therefore, useful as therapeutic agents for potentiating the action of endogenous retinoic acid. The compounds according to the invention generally have low activity against other P450 enzymes involved in cortisol production, which is indicative of low toxicity on oral dosing or should systemic absorption occur. For example, compounds according to the present invention are useful as therapeutic agents for treating disease states ameliorated by the presence of retinoic acid, such as skin diseases, (including actinic keratoses, nonmelanoma skin cancer, acne vulgaris, psoriasis, orders of keratinisation and the like,

substantially as hereinbefore described), oncogenic conditions (including oral leukoplakia, head and neck cancer and the like, substantially as hereinbefore described) and other disease states that can be associated with a lack of retinoic acid. The term"treatment"as used herein includes both the amelioration of the symptoms of an established disease state and the prophylaxis of such a disease state.

According to a further aspect of the present invention there is provided a compound of Formula (I) substantially as herein before described, for use in therapy. More particularly, there is further provided by the present invention a compound of Formula (I) substantially as hereinbefore described, for use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, substantially as herein before described.

While it is possible for compounds according to the present invention to be administered as the substantially pure chemicals, it is preferable that such compounds are included in pharmaceutical Formulations. There is, therefore, still further provided by the present invention a pharmaceutical Formulation comprising a compound of Formula (I), substantially as herein before described, together with at least one acceptable carrier, diluent or excipient therefor. The carriers must be"acceptable"in the sense of being compatible with the other ingredients of the Formulation and not deleterious to a recipient thereof.

Formulations according to the present invention include

those suitable for oral, parenteral and topical administration, although the most suitable route will generally depend upon the condition of a patient and the specific disease state being treated. The precise amount of a compound of Formula (I) to be administered to a patient will be the responsibility of an attendant physician, although the dose employed will depend upon a number of factors, including the age and sex of the patient, the specific disease state being treated and the route of administration substantially as described above.

Finally, there is further provided by the present invention a method of treating a disease state ameliorated by the presence of retinoic acid substantially as hereinbefore described which method comprises administering to a patient suffering from or susceptible to a such disease a therapeutically effective amount of a compound of Formula (I), or a prodrug thereof.

The following Table 1 lists exemplary compounds according to the present invention, together with their respective values for inhibition of retinoic acid metabolism (according to the protocol described herein under the heading"In vitro inhibition studies"). This shows that the compounds according to the invention have potency comparable to that of ketoconazole :

Table 1. Inhibition of P450-RA Example Number % Inhibition (100M) 2 C ! . 1 2 ci 83. 1 \ O O 02N \ C-C CI 6 Cl 68. 2 OH /\ CH-C \ CI 7 CI 74. 8 n \ 02NO CH/\ CI Ci 72. 9 0 B r2 11 OZN C-C CI CI 81. 7 4 ci 81. 7 ci 0-c-0 CH2 C-NO2 CI CleC'CH2<z4NO2 Cl 91. 27 H2 H OZN /C-, C CI 0 O C ci 0 \ Cl\ 02N X °\ C CI

Table l. Inhibition of P450-RA continued % Inhibition (IOOpM) Ci 16 Number 49. 4 OZN CH--C CI 15 COOCH3 45. 9 OzN CH-C-C CI Cl 14 COOCH3 0 72. 9 1 H2 11 Ci 31 Fi, 51. 4 croc Hz II H O2N CH-C-C-N CI Cl COOCH3 59. 3 O2N IH-C ? N-C''CI 0 ci 29 0 77. 3 CI 0 52. 0 27 O2N \ Table l. Inhibition of P450-RA continued

Example Number % Inhibition (100yam) 0 28 0 56. 0 0 bu CI 24 CHyOH I 79. 7 02N CH-C-C ci OU 52. 3 1 H2 H 02N CH-C_ c Cl CI cri N C-C \ CI N c c Hic Ketoconazole 85 H I CH - CH2 CH, C- H H

The present invention will now be further illustrated by the following intermediates and examples and exemplary methods for the preparation of compounds according to the present invention, and their biological screening, will, therefore, now be described. Primes on aromatic substituents as used in the following intermediates and examples are for the purposes of identifying the relevant peaks in the NMR spectra. The following intermediates and examples do not limit the scope of the invention in any way.

Intermediate 1 1-(2, 4-Dichlorophenol)-2-(4'nitrophenol)-1-ethanone The title compound of Example 1 (4. 6 g ; 0. 015 mol.) in dry dichloromethane (40 ml) was added to a suspension of pyridinium chlorochromate (6. 5 g ; 0. 03 mol.) in dichloromethane (40 ml), after which the solution turned dark brown. After 1. 5 hours stirring at room temperature, with the reaction followed by TLC, diethyl ether (40 ml) was added and the supernatant liquid was decanted from a black gum. The insoluble residue was washed with diethyl ether and the combined (decolourised) organic solution filtered through Celite (Trade Mark) and the solvent removed under vacuum. The solid residue was dissolved in chloroform, and insoluble unreacted title compound of Example 1 removed by filtration. The chloroform solution was evaporated under vacuum to give a crude cream solid, which yielded upon crystallization (ethanol) Intermediate 1 (4. 2 g ; 90. 3%) as crystalline material. Further crystallization furnished Intermediate 1 as fine colourless needles, m. p. 101°C. Found : C, 54. 27 ; H, 3. 04 ; N, 4. 53.

ClgHgCl2NO3 requires C, 54. 22 ; H, 2. 93 ; N, 4. 52%. vmax (KBr)/cm-1 1719 (C = O), 1515 and 1348 (NO2). #H (300 MHz ; CDCl3) 4. 40 (2H, s, CH2), 7. 31 (1H, dd, J = 1. 7 Hz, J = 8. 3 Hz, Ar C (5)) H), 7. 40 (2H, d, J = 9. 3 Hz, Ar C (2') H and C (6') H), 7. 45 (2H, m, Ar C (3) H and C6) H), 8. 19 (2H, d, J = 9 Hz, Ar C (3') (H) and C (5') H).

Intermediate 2 <BR> <BR> <BR> <BR> <BR> <BR> <BR> 2-Bromo-1- (2, 4-dichlorophenyl)-2- (4'-nitrophenyl)-1- ethanone Phenyltrimethylammonium tribromide (3. 76 g ; 0. 01 mol.) was added in small portions to a solution of Intermediate 1 (3. 12 g ; 0. 01 mol.) in tetrahydrofuran (20 ml), with stirring. After 30 minutes the resultant white precipitate (phenyltrimethylammonium bromide) was removed by filtration. The filtrate was concentrated in vacuo and the yellow residue dissolved in chloroform and washed with water, dried (MgSO4) and evaporated to leave a yellow oil, which solidified on standing. Crystallization (ethanol) gave Intermediate 2 (3. 34 g ; 86%), as cream crystals, m. p.

89-90°C. Found : C, 43. 01 ; H, 1. 99 ; N, 3. 49. C14HBBrCl2NO3 requires C, 43. 22 ; H, 2. 07 ; N, 3. 60%. nmax (KBr)/cmm 1708 (C = O), 1520 and 1345 (NO2). dH (300MHz ; CDCl3) 6. 32 (1H, s, CHBr), 7. 41 (1H, dd, J = 8. 3 Hz, J = 1. 5 Hz, Ar C (5) H), 7. 52 (1H, d, J = 1. 7 Hz, Ar (3) H), 7. 53 (1H, d, J = 8. 0 Hz, Ar C (6) H), 7. 77 (2H, d, j = 8. 7 Hz, Ar C (2') H) and C (6') H), 8. 19 (2H, d, J = 8. 7 Hz, Ar C (3') H and C (5') H).

Intermediate 3 N-Nitobenzylpyridinium bromide Pyridine (16. 2 ml, 0. 2 mol) was added dropwise to a solution of 4-nitrobenzyl bromide (21. 6 g, 0. 1 mol) in dry dichloromethane (200 ml) with maintenance or the reaction temperature below 30°C. After 30 minutes a heavy white precipitate was formed, and 2 hours later was filtered off, washed with dichloromethane and dried under vacuum to give Intermediate 3 (24 g, 83%) as a dense white solid, m. p. 221-222°C [Lit. m. p., 219-221°C]. A second crop was obtained after standing overnight, to give a total yield of 97%. n", aX (KBr)/cm-1 1518 and 1349 (NO2). dH (300 MHz ; CDC13) (6. 21 (2H, s, CH2), 7. 88 (2H, d, J = 8. 9 Hz, Ar C (2) H and C (6) H), 8. 2 (2H, d, J = 8. 9 Hz, Ar C (3) H and C (5) H), 8. 41 (2H, dd, J = 7. 3 Hz, J = 8. 0 Hz Pyr C (3") H and C (5") H), 8. 7 (1H, t, J = 8. 1 Hz, Pyr C (4") H), 9. 4 (2H, d, J = 7. 2 Hz, Pyr C (2") H and C (6") H).

Intermediate 4 <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> N-[2-(2', 4'-Dichlorophenyl)-1-(4-nitrophenyl)-1-ethenyl] pyridinium bromide A mixture of Intermediate 3 (24. 0 g, 0. 08 mol.), 2, 4- dichlorobenzaldehyde (14. 0 g, 0. 08 mol), anhydrous potassium acetate (6. 4 g), acetic acid (10 ml), and acetic anhydride (120 ml) was refluxed at 75-80°C for 48 hours, allowed to cool to room temperature, and the excess potassium acetate removed by filtration. The filtrate was diluted with water (100 ml) and allowed to stand at room temperature for 48 hours with stirring. The mixture was

washed with diethyl ether to remove unreacted materials and the aqueous layer acidified with hydrobromic acid (33% in glacial acetic acid), before concentrating. The bright yellow crystals which precipitated from the solution were filtered off, and the mother liquors concentrated to obtain further crops. The crops were combined and recrystallized (ethanol) to yield Intermediate 4 (5. 8 g ; 16%), as yellow crystals, m. p. > 250°C. nmax (KBr) /-cm-1 1514 and 1346 (NO2). dH (300MHz ; CDCl3) 6. 94 (1H, d, J = 8. 4 Hz, Ar C (6') H), 7. 31 (1H, dd, J = 8. 4 Hz, J = 2. 1 Hz, Ar C (5') H), 7. 79 (1H, d, J = 2. 2 Hz, Ar C (3') H), 7. 81 (2H, d, J = 8. 9 Hz, Ar C (2) H) and C (6) H), 8. 12 (1H, s, =CH-), 8. 32 (2H, d, J = 8. 9 Hz, Ar C (3) H) and C (5) H). 8. 34 (2H, t, J = 6. 4 Hz, Pyr C (3") H and C (5") H), 8. 89 (1H, t, J = 7. 9 Hz, Pyr C (4") H), 9. 24 (2H, d, J = 5. 5 Hz, Pyr C (2") H and C (6") H).

Intermediate 5 2- (2', 4'-Dichloronhenyl)-1- (4-nitrophenvl)-l-ethanone Intermediate 4 (4. 52 g, 0. 01 mol.), pyridine (40 ml), piperidine (8 ml), and water (16 ml) were combined and heated at 80°C for 1 hour. The resulting deep red solution was cooled, evaporated, and ethanol (14 ml) added to the residue. The resulting mixture was then diluted with water (40 ml), acidified with hydrobromic acid (50 ml, 33% in glacial acetic acid) and shaken for 2 minutes. The solid material was filtered off and dried. Crystallization (ethanol) furnished pure Intermediate 5 as white crystals (2. 77 g ; 89. 3%), m. p. 141-142°C. Found : C, 53. 61 ; H, 2. 98 ; N, 4. 19. ClqH9Cl2NO3 requires C, 54. 22 ; H, 2. 93 ; N, 4. 52%. r (KBr)/cm- 1692 (C = 0), 1520 and 1348 (NO2). dH

(300MHz ; CDCl3) 4. 51 (2H, s, CH2), 7. 26 (1H, d, J = 8. 2 Hz, Ar C (6') H), 7. 31 (1H, dd, J = 2. 1 Hz, J = 8. 2 Hz, Ar C (5') H), 7. 50 (1H, d, J = 2. 0 Hz, Ar C (3') H), 8. 23 (2H, d, J = 8. 9 Hz, Ar C (2) H and C (6) H), 8. 40 (2H, d, J = 8. 8 Hz, Ar C (3) H and C (5) H).

Intermediate 6 N-(4-(2-(2', 4'-Dichlorophensl)-2- hydroxvacetyl) phenyl) acetamide Potassium cyanide (1 g) dissolved in water (10 ml) was added to a solution of 4-acetylaminobenzaldehyde, (1. 63 g ; 0. 01 mol.) and 2, 4-dichlorobenzaldehyde (1. 76 g, 0. 01 mol.) in ethanol (30 ml), and the mixture refluxed for 2 hours.

On cooling, the mixture was diluted with water, when an orange oily residue separated. The aqueous phase was decanted off, and the residue dissolved in dichloromethane, washed with water several times, and dried (MgSO4). On evaporating the solvent, a dark orange oil was obtained which on standing gave a yellow solid. Crystallization (ethanol) gave Intermediate 6 (1. 94 g ; 57. 4%) as a yellow crystalline solid, m. p. 180-181°C. Found C : 56. 78 ; H, 3. 88 ; N 3. 97. C16Hl3Cl2NO3 requires C, 56. 82 ; H, 3. 87 ; N, 4. 14%. nmaX (KBr)/cm-1 3352 (OH), 1673 and 1654 (C=O). dH (300MHz ; DMSO-d6) 2. 11 (3H, s, COCH3), 6. 23 (1H, d, J = 7. 0 Hz, CHOH or CHOH), 6. 52 (1H, d, J = 7. 0 Hz, CHOH or CHOH), 7. 45 (1H, dd, J = 8. 4 Hz, J = 1. 7 Hz, Ar C (5') H), 7. 52 (1H, d, J = 8. 4 Hz, Ar C (6') H), 7. 59 (1H, d, J = 1. 7 (Ar C (3') H), 7. 71 (2H, d, J = 8. 5 Hz, Ar C (3) H and C (5) , 7. 97 (2H, d, J = 8. 4 Hz, Ar C (2) H and C (6) H), 10. 38 (1H, s, NH), m/e (APCI, low resolution) 162 and 163 (CH3CONHC6H4COt) 175

and 177 (C6H3Cl2CHOH+).

Intermediate 7 N-(4-(2-(2', 4-Dichlorophensl)-2-oxoacetyl) phenyl) acetamide Copper sulphate (1. 5 g), pyridine (3 ml) and water (1 ml) were heated for 10 minutes, until a homogeneous solution was obtained, when Intermediate 6 (0. 84 g ; 0. 0025 mol.) was added and the mixture heated at 100°C for 2 hours with stirring. On pouring onto water a yellow oil separated which was extracted with dichloromethane, which was washed with HC1 (2M) and water. After drying (MgS04), the solvent was removed in vacuo to give a yellow powder.

Crystallization (ethanol) gave Intermediate 7 (0. 44 g ; 52. 4%) as fine yellow crystals, m. p. 177°C. Found C : 57. 20 ; H, 3. 44 ; N 4. 01. Cl6HllCl2NO3 requires C, 57. 17 ; H, 3. 30 ; N, 4.175. nmax (KBr) cm-1 1681 and 1661 (C=O). dH (300MHz ; DMSO-d6) 2. 13 (3H, s, COCH3), 7. 69 (1H, dd, J = 8. 4 Hz, J = 1. 8 Hz, Ar C (5') H), 7. 82 (2H, d, J = 8. 4 Hz, Ar C (3) H and C (5) H), 7. 87 (1H, d, J = 1. 6 Hz, Ar C (3') H), 7. 92 (1H, d, J = 8. 6 Hz, Ar C (6') H). 7. 96 (2H, d, J = 8. 3 Hz, Ar C (2) H and C (6) H), 10. 49 (1H, s, NH).

Intermediate 8 Methyl 4-nitrophenyl acetate A solution of 4-nitrophenyl acetic acid (5. 03 g, 27. 7 mmol) in methanol (200 cm3), was refluxed with trimethyl orthoformate (10 cm3, 9. 7 g) and a catalytic amount of concentrated hydrochloric acid (1 cm3) for 3 hours. The reaction mixture was left to cool, and the methanol removed

under vacuum. The residue was taken up in ethyl acetate (70 cm3), and washed with saturated sodium bicarbonate (50 cm3) and then water (3 x 50 cm3). The organic layer was dried (MgSO4) and evaporated to give cream coloured crystals of Intermediate 8 (5. 30 g, 98%). M. P. = 52. 7-53. 8°C.

(Found : C, 55. 48 ; H, 4. 73 ; N, 6. 86. CgHgNO4 calculated C, 55. 38 ; H, 4. 65 ; N, 7. 18%). nmax KBr/cm 1724 (CO2CH3), 1512 and 1339 (NO2) ; dH 8. 1 (2H, d, J 8. 8 Hz Ph-H), 7. 4 (2H, d, J 8. 1 Hz Ph-H), 3. 75 (2H, s, CH2), 3. 65 (3H, s, OC_3).

Intermediate 9 2-Bromo-l-phenyl-l-ethanone A catalytic amount of aluminium chloride (0. lg) was added to a solution of acetophenone (lg, 8. 3 mmol) in ether (50 cm3), and stirred at 0°C. Bromine (1. 33g, 8. 3 mmol, 0. 41 cm3) was added dropwise to the solution over a period of 20 minutes and the solution stirred for a further 30 minutes.

The reaction mixture was then quenched with water (10 cm3) and stirred for 10 minutes. The water was separated from the ether and the organic layer dried (MgSO4), filtered and evaporated to give Intermediate 9 as white crystals.

Recrystallised (methanol) (1. 33g, 81%). M. P. 46. 5-48. 7°C. nmax KBr/cm-1 1701. 4 (C=O) ; dH 8. 05 (2H, d, J = 7, 1 Hz Ph. H), 7. 66 (1H, dt, J=7. 4 J = Hz 1. 1 Ph-H), 7. 55 (2H, t, J=7. 3 Hz, PhH), 4. 52 (2H, s, CH2).

Intermediate 10 2-Bromo-1- (2-chlorophenyl)-1-ethanone A dark red oil was obtained with 2-Chloroacetophenone.

Purification by column chromatography on silica gel gave Intermediate 10 as a yellow oil, (62%). Rf = 0. 62 (dichloromethane : petroleum ether 4 : 1 v/v). nmaX/cm~1 1700. 3 (C=O) ; dH 7. 66 (1H, m, Ph-H), 7. 55 (2H, m, Ph-H), 7. 46 (1H, m, Ph-H), 4. 62 (2H, s, CH2).

Intermediate 11 2-Bromo-l- (3-chlorophenyl)-l-ethanone Intermediate 11 (68%) was obtained as a yellow solid with 3-chloroacetophenone. M. P. 35. 6-37°C. nmaX KBr/cm-11686. 9 (C=O) ; dH 8. 00 (1H, t, J=1. 8 Hz Ph-H), 7. 89 (1H, dt, J=1. 3 Hz, J=7. 9 Hz, Ph-H), 7. 62 (1H, dq, J=1. 1 Hz, J=2. 1 Hz, J=7. 9, Ph-H), 7. 47 (1H, t, J=7. 9 Hz, Ph-H), 4. 46 (2H, s, CH2).

Intermediate 12 2-Bromo-1- (4-chlorophenyl)-1-ethanone Intermediate 12 was obtained from 4-chloroacetophenone and on recrystallisation (ether) gave white crystals (71%).

M. P. 93. 7-94. 2°C. nmaxKBr/cm-1 1685. 0 (C=O) ; dH 7. 98 (2H, d, J=8. 6 Hz, Ph-H), 7. 52 (2H, d, J=8. 6 Hz, PhH), 4. 46 (2H, s, CH2).

Intermediate 13 2-Bromo-1- (2, 4-dichlorophenyl)-1-ethanone Intermediate 13 was obtained from 2, 4-dichloroacetophenone and on purification by column chromatography on silica with dichloromethane : petroleum ether (4 : 1 v : v) as eluent gave a clear oil (82%). Rf = 0. 62. (Found : C, 35. 92 ; H, 1. 93.

Cl8HsBrCl2O requires C, 35. 86 ; H, 1. 88%) ; nma, KBr/cm-1 1695. 8 (C=O) ; dH 7. 59 (1H, d, J=8 Hz, Ph-H), 7. 49 (1H, d, J=1. 8 Hz, Ph-H), 7. 38 (1H, dd, J=8. 3 Hz, J=1. 8 Hz, Ph-H), 4. 55 (2H, s, CH2).

Intermediate 14 2-Bromo-1-(3,4-dichlorophenyl)-1-ethanone Intermediate 14 was obtained from 3, 4-dichloroacetophenone and on recrystallisation (ether) gave green crystals (75%).

M. P. 51. 7-52. 6°C. Tlmax KBr/cm-1 1687. 1 (C=O) ; dH 8. 10 (1H, d, J=2. 03, Hz Ph-H), 7. 85 (1H, dd, J=2. 02, Hz, J=8. 42 Hz Ph- H), 7. 64 (1H, d, J=8. 38 Hz, Ph-H), 4. 44 (2H, s, CH2).

Intermediate 15 Methyl4- (2, 4-dichlorophenyl)-4-hydroxyimino-2- (4- nitrophenyl) butanoate A mixture of Example 16 (2. 02 g, 5. 09mmol) and ethanol (50cm3), and a mixture of hydroxylamine hydrochloride (1. 53g, 22mmol) and sodium acetate (1. 80g, 22mmol) in water (50 cm3) were combined and refluxed with stirring for 6 hours. The reaction mixture was left to cool, and then poured into ice water mixture (50 cm3) and left in the

fridge overnight. A waxy green sold formed, and the water/ethanol mixture was decanted. The remaining slush was taken up in ethyl acetate (50 cm3), dried (MgSO4) and concentrated to leave a brown oil (1. 23g, 61%). Purified by preparative TLC with CH2Cl2 : MeOH (19 : 1) as eluent to yield Intermediate 15. (Found : C, 51. 65 ; H, 3. 67 ; N, 6. 88.

C17H14Cl2N2O5 requires C, 51. 40 ; H, 3. 55 ; N, 7. 05%) ; Vmax KBr disc/cm-1 3354 (OH), 1737 (CO2CH3), 1522 and 1347 (NO2).

Example 1 1- (2, 4-Dichlorophenyl)-2- (4'-nitrophenyl)-l-ethanol Freshly ground sodium hydroxide (0. 2 g) was added to a solution of 4-nitrotoluene (20. 57 g ; 0. 15 mol.) and 2, 4- dichlorobenzaldehyde (8. 75 g ; 0. 05 mol.) in dry N, N- dimethylformamide (100 ml), and the reaction stirred under nitrogen at room temperature. The reaction mixture turned dark green within several minutes. After 2 hours the reaction mixture was acidified with concentrated hydrochloric acid (1 ml), diluted with toluene and washed with water. After drying (MgSO4), both solvent and excess 4-nitrotoluene (90°C/0. 25 mmHg) were removed in vacuo, to yield a red oil which solidified on standing to give a yellow solid. The solid was recrystallized (ethanol) to give the title compound of Example 1 (9. 3 g ; 59. 6% yield) as colourless crystals, m. p. 154°C ; Found : C, 53. 91 ; H, 3. 56 ; N, 4. 26, C14HllCl2NO3 requires C, 53. 87 ; H, 3. 55 ; N, 4. 49%. nmax (KBr)/cm-1 3548 (OH), 1514 and 1343 (NO2). d (300MHz ; DMSO- d6) 2. 90 (1H, dd, JAB 13. 5 Hz, JXB = 8. 1 Hz, CHHCHXOH), 3. 06 (1H, dd, JEA = 13. 5 Hz, JXA = 3. 8 Hz, CH HBCHXOH), 5. 15 (1H, ddd, JBX = 8. 2 Hz, Jx = 3. 8 Hz, J = 4. 7 Hz, CHXOH) 5. 75 (1H, d, J = 4. 7, CHOH), 7. 46 (3H, m, Ar C (3) H, C (5) H and C (6) H), 7. 7 (2H, d, J = 8. 7 Hz, Ar C (2') H and C (6') H), 8. 2 (2H, d, J = 8. 7 Hz, Ar C (3') H and C (5') H).

Chiral chromatography : tr 9. 32 min (49. 4%), 10. 73 min (49. 8%).

Column : Chiralpak AD (4. 6 x 250 mm, Diacel Chemical Ltd).

Mobile phase : propan-2-ol : hexane (50 : 50 v/v). Flow rat : 2 ml/min. Detection : W at 254 nm.

Example 2a 1- (2, 4-Dichlorophenyl)-2- (4'-nitrophenyl)-1, 2-ethandione The title compound of Example 2a was isolated as yellow crystals (ethanol), following oxidation of the title compound of Example 1 when the reaction proceeded beyond 1. 5 hours, m. p. 133-134°C. Found : C, 51. 86 ; H, 2. 09 ; N, 4. 19. C14H7Cl2NO4 requires C, 51. 88 ; H, 2. 18 ; N, 4. 32%. nmaX (KBr)/cm-1 1681 (C = O, a-diketone), 1529 and 1347 (NO2). dH (300 MHz ; CDC13) 7. 43 (1H, dd, J = 1. 7 Hz, J = 8. 8 Hz, Ar C (5) H), 7. 44 (1H, d, J = 1. 8Hz, Ar C (3) H), 7. 82 (1H, d, J = 8. 8 Hz, Ar C (6) H), 8. 17 (2H, d, J = 8. 9 Hz, Ar C (2') H and C (6') H), 8. 36 (2H, d, J = 8. 9 Hz, Ar C (3') H and C (5') H).

Example 2b 1- (2, 4-Dichlorophenyl)-2- (4'nitrophenyl)-1, 2-ethandione Conc. nitric acid (30 ml, S. G. 1. 42) was poured onto the title compound of Example 1 (5 g ; 0. 016 mol.) in a round- bottomed flask fitted with an air condenser. The reaction mixture was heated on a boiling water bath for 2. 5 hours until the evolution of brown fumes of nitric oxide ceased, whereupon the solution was poured onto ice and stirred. The

resulting gum obtained after decantation, gave yellow crystals after crystallization (ethanol), of the title compound of Example 2b (2. 90 g, 55. 9%), m. p. 132-134°C, with analytical data as shown in Example 2a and a mixed m. p.

132-134°C.

Example 3 2, 2-Dibromo-1-(2, 4-dichlorophensl)-2-(4'-nitrophenYl)-1- ethanone Bromine (0. 12 ml ; 0. 0025 mol.) was added to a solution of Intermediate 1 (0. 75 g ; 0. 0025 mol.) and aluminium chloride (0. 01 g) in diethyl ether (20 ml), with stirring in an ice- bath. After 30 minutes the colourless solution was extracted with water, and the organic phase dried (MgSO4) and the solvent removed under vacuum to leave a yellow oil which solidified on standing. Crystallization (ethanol) gave bright yellow crystals of the title compound of Example 3 (0. 89 g ; 76. 1%), m. p. 126-127°C. Found : C, 35. 62 ; H, 1. 70 ; N, 3. 01. C14H7Br2Cl2NO3 requires C, 35. 94 ; H, 1. 51 ; N, 2. 99%. nmaX (KBr)/cm-1 1681 (C = O), 1529 and 1347 (NO2). dH (300MHz ; CDCl3) 7. 51 (2H, m, Ar C (3) H and C (5) H), 7. 92 (1H, d, J = 8. 8 Hz, Ar C (6) H), 8. 24 (2H, d, J = 8. 7 Hz, Ar C (2') H and C (6') H, 8. 42 (2H, d, J = 8. 7 Hz, Ar C (3') H and C (5') H).

Example 4 <BR> <BR> <BR> <BR> <BR> <BR> 1- (2, 4-Dichlorophenyl)-1, 1-ethylenedioxy-2- (4'-nitrophenyl) ethane A mixture of ethylene glycol (10 ml) and p-toluene sulphonic acid (0. 4 g) was refluxed in toluene (80 ml) with a Dean- Stark trap until evolution of water ceased (24hours).

Intermediate 1 (1. 55 g ; 0. 005 mol.) was added to the reaction mixture and refluxing continued for a further 24hours. On cooling the reaction mixture was evaporated removing toulene, and the residue cooled in an ice-bath.

The resulting precipitate was filtered to give, following crystallization (ethanol), the title compound of Example 4 (0. 46 g ; 26. 0%) as pale yellow crystals, m. p. 117-118°C.

Found : C, 54. 33 ; H, 3. 78 ; N, 3. 92. C16Hl3Cl2NO4 requires C, 54. 26 ; H, 3. 70 ; N, 3. 95%. nmaX (KBr)/cm~l 1584 (C = C), 1514 and 1342 (NO2). dH (300MHz ; CDCl3) 3. 55 (2H, s, CH2), 3. 81 (2H, m, CH2 ketal), 3. 86 (2H, m, CH2 ketal), 7. 21 (1H, dd, J = 8. 4 Hz, J = 2. 1 Hz, Ar C (5) H), 7. 42 (2H, d, J = 8. 6 Hz, Ar C (2') H and C (6') H), 7. 43 (1H, d, J = 8. 4 Hz, Ar C (6) H, 7. 49 (1H, d, J = 2. 1 Hz, Ar C (3) H), 8. 13 (2H, d, J = 8. 6 Hz, Ar C (3') H and C (5') H).

Example 5 Di (1- (2, 4-dichlorophenyl)-2- (4'-nitrophenyl) ethyl) carbonate A solution of the title compound of Example 1 (1. 56 g ; 0. 005 mol.) and 1, l'-carbonyl diimidazole (3. 24 g ; 0. 01 mol.) in

anhydrous acetonitrile (50 ml) was stirred at room temperature for 6 hours, then concentrated to a small volume and the residue redissolved in dichloromethane. The organic phase was washed with brine, dried (MgSO4) and evaporated to give, following recrystallization (ethanol), the title compound of Example 5 (3. 01 g ; 92. 6%) as pale yellow crystals, m. p. 119°C. Found : C, 53. 34 ; H, 3. 36 ; N, 4. 33 C29H20Cl4N207 requires C, 53. 56 ; H, 3. 10 ; N, 4. 31%. nmax (KBr)/cm-1 1754 (C =0, carbonate), 1520 and 1344 (NO2). dH (300MHz ; CDC13) 3. 34 (4H, t, J = 7Hz, 2 xCH2CH), 6. 29 (2H, dd, J = 7. 7 Hz, J = 5. 3 Hz, 2 x CH2CH), 7. 37 (2H, dd, J = 1. 4 Hz, J = 8. 8 Hz, 2 x Ar C (5) H), 7. 42 (2H, d, J = 8. 8 Hz, 2 x Ar C (6) H), 7. 45 (4H, d, J = 8. 5 Hz, 2 x Ar C (2') H and C (6') H), 7. 52 (2H, d, J = 1. 4 Hz, 2 x Ar C (3) H), 8. 26 (4H, d, J = 8. 5 Hz, 2 x Ar C (3') H and C (5') H).

Example 6 2- (2', 4'-Dichlorophenyl-1- (4-nitrophenyl)-1-ethanol Sodium borohydride (0. 09 g ; 0. 0025 mol.) was added to a solution of Intermediate 5 (0. 78 g ; 0. 0025 mol.) in tetrahydrofuran (20 ml) and a drop of water to solubilize the sodium borohydride. A dark red colour formed. The mixture was stirred at room temperature for 1 hour, during which time the solution turned pale yellow. Water (30 ml) was added and the solution concentrated to give a residue, which was redissolved in ethyl acetate. The organic solution was washed with brine, dried (MgSO4) and evaporated

to an oil which gave, on recrystallization (ethanol), the title compound of Example 6 (0. 72 g ; 92. 3%), as clusters of beige needles, m. p. 136°C. Found : C, 53. 90 ; H, 3. 58 ; N, 4. 29, Cl4HllCl2NO3 requires C, 53. 87 ; H, 3. 55 ; N, 4. 49%. nmax (KBr)/cm-1 3502 (OH), 1601 (C = C, Ar), 1517 and 1343 (NO2). dH (300 MHz ; DMSO-d6) 3. 01 (2H, d, J = 6. 7 Hz, CH2), 4.95 (1H, q, J = 6. 0 Hz, CHOH), 5. 77 (1H, d, J = 4. 8 Hz, CHOH), 7. 33 (2H, m, Ar C (3') H and C (5') H), 7. 55 (H, d, J = 2. 0 Hz, Ar C (6') H), 7. 57 (2H, d, J = 8. 7 Hz, Ar C (2) H and C (6) H), 8. 18 (2H, d, J = 8. 7 Hz, Ar C (3) H and C (5) H).

Example 7 <BR> <BR> <BR> <BR> <BR> <BR> 2- (2', 4'-Dichlorophenyl)-1, 1-ethylenedioxy-1- (4- nitrophenyl) ethane Intermediate 5 (0. 78 g ; 0. 0025 mol.), was reacted with ethylene glycol (10 ml) in the presence of p-toluene sulphonic acid (0. 2 g) in toluene (80 ml) under reflux with a Dean-Stark trap for 24 hours. The above work-up, yielded the title compound of Example 7 (0. 29 g ; 32. 8%) as a white solid, m. p. 122°C. Found : C, 54. 50 ; H, 3. 63 ; N, 4. 04.

C16Hl3Cl2NO4 requires C, 54. 26 ; H, 3. 70 ; N, 3. 95%. nmax (KBr)/cm-1 1584 (C = C), 1519 and 1354 (N02). dH (300 MHz ; CDC13) 3. 29 (2H, s, CH2), 3. 71 (2H, m, CH2 ketal), 3. 87 (2H, m, CH2 ketal), 7. 12 (1H, dd, J = 8. 3 Hz, J = 2. 1 Hz, Ar C (5') H), 7. 24 (1H, d, J = 8. 4 Hz, Ar C (6') H), 7. 49 (1H, d, J = 2. 3 Hz, Ar C (3') H), 7. 52 (2H, d, J = 8. 8 Hz, Ar C (2) H and C (6)-H), 8. 12 (2H, d, J = 8. 8 Hz, Ar C (3) H and C (5) H).

Example 8 <BR> <BR> <BR> <BR> <BR> <BR> 2-(2', 4'-Dichlorophenol)-1-(4-dimethylaminophenyl)-2-<BR> <BR> <BR> <BR> <BR> hydroxy-l-ethanone Potassium cyanide (3 g) dissolved in water (60 ml) was added to a solution of 4-dimethylaminobenzaldehyde (14. 9 g ; 0. 1 mol.) and 2, 4-dichlorobenzaldehyde (17. 6 g, 0. 1 mol.) dissolved in 95% ethanol (80 ml). After refluxing for 1 hour, the mixture was allowed to cool, when a crystalline material (9. 6 g) separated. A further portion of potassium cyanide (1 g) was added to the filtrate and the mixture refluxed for 1 hour. After cooling a second crop of the title compound of Example 8 (2. 1 g) was collected by filtration. The two crops of crystals were combined, washed twice with water and then with a small volume of ethanol, before crystallization (ethanol) to yield the title compound of Example 8 (10. 9 g ; 33. 4%) as yellow crystals, m. p. 111°C.

Found : C, 59. 24 ; H, 4. 80 ; N 4. 38. C16H1sCl2NO2 requires C, 59. 27 ; H, 4. 66 ; N, 4. 32%. r, a, (KBr)/cm-1 3419 (OH), 2920 (N-Me), 1654 (C=O). dH (300MHz ; CDCl3) 3. 11 (6H, s, N (CH3) 2), 4. 93 (1H, d, J = 5. 1 Hz, CHOH), 6. 27 (1H, d, J = 4. 6 Hz, CHOH), 6. 62 (2H, d, J = 9. 1 Hz, Ar ( (3) Hand C (5) H), 7. 11 (1H, d, J = 8. 4 Hz, Ar C (6') H), 7. 18 (1H, dd, J = 8. 4 Hz, J = 1. 9 Hz Ar C (5') H), 7. 48 (1H, d, J = 2. 0 Hz, Ar C (3') H), 7. 84 (2H, d, J = 9. 1 Hz, Ar C (2) H and C (6) H). m/e (APCI, low resolution) 148 and 149 ((CH3)2NC6H4CO^+~) 175 and 177 (C6H3C12 CHOH+).

Example 9 1- (2, 4-Dichlorophenyl)-2- (4'-dimethylaminophenyl)-1, 2- ethandione Freshly prepared Fehling's solution (50 ml) was added to a solution of the title compound of Example 8 (0. 32 g ; 0. 01 mol.) in ethanol (30 ml), and the mixture heated for 30 minutes at 100°C. The blue solution quickly turned to a brown mixture with the precipitation of copper (I) oxide.

After cooling, the copper (I) oxide was removed by filtration through celite, and the filtrate concentrated in vacuo. The concentrate was extracted with dichloromethane, washed with water, dried (MgSO4) and the solvent removed by evaporation to give a red oil. Crystallization (ethanol) gave the title compound of Example 9 as fine orange needles, m. p. 155°C. Found : C, 59. 39 ; H, 4. 27 ; N 4. 09.

C16Hl3Cl2NO2 requires C, 59. 65 ; H, 4. 07 ; N, 4. 35%. nmax (KBr)/cm-1 1683 (C=O), 1601 (C=C). dH (300 MHz ; CDCl3) 3. 11 (6H, s, N (CH3) 2), 6. 76 (2H, d, J = 9. 1 Hz, Ar C (3') H and C (5') H), 7. 44 (1H, dd, J = 8. 4 Hz, J = 1. 9 Hz, Ar C (5) H), 7. 49 (1H, d, J = 1. 9, Ar C (3) H), 7. 87 (1H, d, J = 8. 4 Hz, Ar C (6) H), 7. 96 (2H, d, J = 9. 0 Hz, Ar C (2') H and C (6') H).

Example 10 2- (4'-Aminophenyl)-1- (2, 4-dichlorophenyl)-1, 2-ethandione Intermediate 7] (0. 38 g ; 0. 001 mol.) was refluxed in conc. hydrochloric acid (20 ml) and methanol (10 ml) for 1 hour.

On cooling the HCl salt precipitated from solution. The mixture was concentrated to half volume and the precipitate collected. The salt was redissolved in warm methanol (30 ml) and sodium hydroxide (2M ; 10 ml) added to release the free amine. The solution was evaporated to dryness, and the residue dissolved in dichloromethane and washed with water.

The organic phase was dried (MgSO4) and evaporated to give a yellow oil. Trituration (ether) gave the title compound of Example 10 as yellow solid (0. 24 g ; 81. 6%) m. p. 92-93°C.

Found : C : 57. 04 ; H, 2. 97 ; N 4. 51. C14H9Cl2NO2 requires C, 57. 17 ; H, 3. 08 ; N, 4. 76% nmaX (KBr)/cm~1 3448 (NH), 1675 (C=O, diketone). dH (300 MHz ; CDC13) 4. 43 (2H, br, s, NH2), 6. 73 (2H, d, J = 8. 7 Hz, Ar C (3) H and C (5) H), 7. 43 (1H, dd, J = 8. 4 Hz, J = 1. 9 Hz, Ar C (5')H), 7. 49 (1H, d, J = 1. 9 Hz, Ar C (3') H), 7. 87 (1H, d, J = 8. 3 Hz, Ar C (6') H), 7.89 (2H, d, J = 8. 7 Hz, Ar C (2) H and C (6) H).

Example 11 Methyl 2-(4-nitroPhensl)-4-oxo-4-phenolbutanoate Anhydrous potassium carbonate (5. 53 g, 40 mmol) in dry acetone (100 cm3) was stirred with Intermediate 8 (1. 95 g, 9. 9 mmol) for 30 minutes at reflux and Intermediate 9 (2. 01

g, 10. 1 mmol) was added dropwise over a period of 30 minutes. The solution was refluxed for a further 3 hours, after which the resulting dark brown mixture was filtered.

The filtrate was concentrated under reduced pressure to leave a dark brown oil which crystallised when mixed with ether. The crystals were triturated with ether and filtered to give the title compound of Example 11 as pale green crystals (2. 54 g, 72%). M. P. 165. 1-165. 9°C. nmx KBr disc/ cm- 1728. 1 (CO2CH3), 1681. 4 (C=O), 1519. 0 and 1346. 7 (NO2) ; dH D3COCD3. 8. 18 (2H, d, J=8. 9 Hz, 3, 5-PhH), 8. 0 (2H, d, J=7. 1 Hz, 2', 6'-PhH) 7. 67 (2H, d, J=8. 8 Hz, 2, 6-PhH), 7. 59 (1H, t, J=7. 2 Hz, 4-Ph-H), 7. 46 (2H, t, J=7. 6 Hz3, 3, 5-PhH), 4. 40 (1H, dd, JAX=4.3, Hz JBX=10. 1 Hz CH, CHAHB), 3. 98 (1H, dd, JXB= 10. 1 Hz, JAB=18. 3 Hz, CHxCHAHB), 3. 61 (3H, s, CH3), 3. 48 (1H, dd, JXA=4.3 Hz, JBA=18.2 Hz, CHXC_AHB) ; dC 196. 15 (C=O, C-4), 172. 99 (C=O, Ac), 147. 80, 145. 81, 135. 13 and 132. 48 (3 x Ph- C), 132. 48, 130. 00, 129. 387, 129. 32, 124. 54, and 122. 673 (5 x CH, Ph-H), 53. 21 (CH, C-2), 46. 53 (CH3, Ac) and 42. 51 (CH2, C-3).

Example 12 Methyl 4- (4-bromophenvl)-2- (4-nitrophenyl)-4-oxobutanoate The title compound of Example 12 was obtained from Intermediate 8 and 2-bromo-l- (4-bromophenyl)-l-ethanone as a yellow solid (65%) M. P. 113. 9-115. 3°C. nmax KBr disc/cm-1 1725. 6 (CO2CH3), 1672 (C=O), 1516 and 1346 (NO2) ; dH 8. 23 (2H, d, J=7. 9 Hz, 3, 5-PhH), 7. 85 (2H, d, J=7. 7 Hz, 2', 6'- PhH), 7. 65 (2h, d, J=7. 8 Hz, 3'-5'-PhH), 7. 57 (2H, d, J=8. 2

Hz, 2, 6-PhH), 4. 48 (1H, dd, JAX=4. 6 Hz, JBX9. 4 Hz, CHXCHAHB), 3. 95 (1H, dd, JXB=9-4 Hz, JAB=18. 0 Hz, CHXCHA H), 3. 75 (3H, s, OCH3), 3. 34 (1H, dd, JXA=4. 6 Hz, JBA= 18. 0 Hz, CHXCHAHB) ; dC 196. 15 (C=O, C-4), 172. 99 (C=O, Ac), 160. 98, 147. 80, 145. 81 and 135. 13 (4 x Ph-C), 132. 48, 130. 00, 129. 39 and 124. 54, (4 x CH, Ph-H), 53. 21 (CH, C-2), 46. 53 (CH3, Ac) and 42. 51 (CH2, C-3).

Example 13 Methyl 4- (2-chlorophenyl)-2- (4-nitrophenyl)-4-oxobutanoate The title compound of Example 13 was obtained from Intermediates 8 and 10 as yellow crystals (22%). M. P. 85. 4- 86. 2°C. nmax KBr disc/cm-1 1727. 4 (CO2CH3), 1693. 8 (C=O), 1514. 2 and 1343. 8 (NO2) ; dH 8. 22 (2H, d, J=8. 7 Hz, 3, 5-PhH), 7. 57 (1H, d, J=7. 4 Hz, 6'-PhH), 7. 55 (2H, d, J=8. 8 Hz, 2, 6- PhH), 7. 45 (2H, d, J=3. 7 Hz, 3',5'-PhH), 7. 33 (1H, m, 4'- PhH), 4. 48 (1H, dd, JAX=4. 9 Hz, JBX=9.5, Hz, CHxCHAHB), 3.94 (1H, dd, JxB=9. 5 Hz, JAB= 18. 1 Hz, CHXCHAHB), 3. 75 (3H, s, CH3), 3. 40 (1H, dd, JXA= 4. 9 Hz, JBA= 18. 1 H z, CHXCHACHB) ; dC 199. 88 (C=O, C-4), 172. 83 (C=O, Ac), 147. 79, 145. 61, 138. 42 and 131. 56 (4 x Ph-C), 132. 78, 131. 16, 129. 83, 129. 45, 127. 50 and 124. 50 (6 x CH, Ph-H), 53. 20 (CH, C-2), 46. 89 (CH3, Ac) and 46.47 (CH2, C-3).

Example 14 Methyl 4-(3-chlorophenyl)-2-(4-nitrophenyl)-4-ozxobutanoate The title compound of Example 14 was obtained from Intermediates 8 and 10 as yellow crystals (41%). M. P. 117. 3- 118. 2°C. nmaX KBr disc/cm-1 1737. 4 (CO2CH3), 1680. 2 (C=O), 1517. 8 and 1350. 8 (NO2) ; dH 8. 23 (2H, d, J=8. 4 Hz, 3, 5-PhH), 7. 94 (1H, bs, 2'-PhH), 7. 85 (1H, d, J=7. 4 Hz, 6'-PhH), 7. 57 (3H, d, J=8. 1 Hz, 2, 6-and 4'-PhH), 7. 43 (lHz, t, J=7. 7 Hz 5'-PhH), 4.44 (1H, dd, JAX=4.5 Hz, JBX= 9. 1 Hz, CHxCH, H,), 3. 97 (1H, dd, JxB= 9. 4 Hz, JAB 18. 0HZ3, CHXHAHB), 3. 73 (3H, s, CH3), 3. 35 (1H, dd, JXA=4. 5 Hz, JBA=18. 1 Hz, CHXCHAHB). dC 195. 95 (C=O, C-4), 172. 94 (C=O, Ac), 147. 78, 145. 76, 137. 90 and 135. 45 (4 x Ph-C), 133. 95, 130. 53, 129. 34, 128. 56,'126. 60 and 124. 52 (6 x CH, Ph-H), 53. 12 (CH, C-2), 46. 45 (CH3, Ac) and 42. 62 (CH2, C-3).

Example 15 Methyl 4- (4-chlorophenvl)-2- (4-nitrophenyl)-4-oxobutanoate The title compound of Example 15 was obtained from Intermediates 8 and 12 as yellow crystals (56%). M. P. 107. 5- 108. 6°C. nm,,,. KBr disc/cm-1 1726. 1 (CO2CH3), 1673. 3 (C=O), 1517. 2 and 1346. 3 (NO20 ; dH 8. 22 (2H, d, J=8. 6 Hz, 3, 5-PhH), 7. 94 (2H, d, J=8. 4 Hz, 2', 6'-PhH), 7. 57 (2H, d, J=8. 7Hz, 2, 6-PhH), 7. 46 (2H, d, J=8. 4 Hz, 3', 5' PhH), 4. 45 (1H, dd, JAX=4.76 Hz, JBX= 9. 4 Hz, CHCHAHB), 3. 95 (1H, dd, JXB=9. 5 Hz, JAB=18.0 Hz, CHXCHAHB), 3. 75 (3H, s, CH3), 3. 35 (1H, dd, JXA=4. 8 Hz, JBA=18. 0 Hz, CHXCHAHB) ; dC 195. 94 (C=O, C-4),

173. 00 (C=O, Ac), 147. 80, 145. 84, 140. 58 and 134. 74 (4 x Ph- C), 129. 92, 129. 48, 129. 38 and 124. 52 (4 x CH, Ph-H), 53. 19 (CH, C-2), 46. 58 (CH3, Ac) and 42. 53 (CH2, C-3).

Example 16 Methyl4- (2, 4-dichlorophenyl)-2- (4-nitrophenyl)-4- oxobutanoate The title compound of Example 16 was obtained from Intermediates 8 and 13 as pale yellow crystals (71%). M. P.

118. 3-118. 8°C. nm,, x KBr disc/cm-1 1728. 1 (CO2CH3), 1691. 4 (C=O), 1519. 0 and 1346. 7 (NO20 ; d 8. 2 (2H, d, J=8. 7 Hz, 3, 5-PhH), 7. 55 (1H, d, J=8. 4 Hz, 6'-PhH), 7. 50 (2H, d, J=8. 8 Hz, 2, 6-PhH), 7. 45 (1H, d, J=1. 9 Hz, 3'-PhH) 7. 33 (1H, dd, J=8. 3 Hz, J=1. 9 Hz, 5'-Phh), 4. 44 (1H, dd, JAX=4. 8 Hz, JBX=9. 7 Hz, CHXCHAHB), 3. 86 (1H, dd, JXB=9. 7 Hz, JAB18. 1 Hz, CHXCHH 3. 70 (3H, s, CH3), 3. 32 (1H, dd, J=4. 8 Hz, JBA=18.1 Hz, CHXCHAHB ; dC 198. 59 (C=O, C-4), 172. 78 (C=O, Ac), 147. 84, 145. 43, 138. 56, 136. 53 and 132. 79 (5 x Ph-C), 131. 13, 131. 01, 129. 41, 127. 93 and 124. 56 (5 x CH, Ph-H), 53. 25 (CH, C-2), 46. 92 (CH3, Ac) and 46. 44 (CH2, C-3).

Example 17 Methyl 4- (3, 4-dichlorophenyl)-2- (4-nitrophenyl)-4- oxobutanoate The title compound of Example 17 was obtained from Intermediates 8 and 14 as yellow crystals (47%). M. P. 114. 6-

115. 7°C. nmaX KBr disc/cmw 1731. 3 (CO2CH3), 1692. 1 (C=O), 1518. 6 and 1346. 6 (NO2) ; dH 8. 22 (2H, d, J=8. 6 Hz, 3, 5-PhH), 8. 06 (1H, d, J=1. 8 Hz, 2'-PhH), 7. 82 (1H, dd, J=1. 8 Hz, J=8. 3 Hz, 6'-PhH), 7. 57 (1H, d, J=7. 8 Hz, 5'-PhH), 7. 57 (2H, d, J=8. 8 Hz, 2, 6-PhH), 4. 45 (1H, dd, JAX=4. 6 Hz, JBX=9. 5 Hz CHXCHAHB) 3. 95 (1H, dd, JXB=9. 6 Hz, JAB=18. 1 Hz CHXCHAHB), 3. 75 (3H, s, CH3), 3. 33 (1H, dd, JXA4. 7 Hz, JBA= 18. 1 Hz, CHXCHAHB) ; dC 195. 06 (C=O, C-4), 172. 87 (C=O, Ac), 147. 80, 145. 62, 138. 62, 135. 92 and 133. 83 (5 x C, Ph-C), 131. 23, 130. 48, 129. 39, 127. 53 and 124. 54 (5 x CH, Ph-H), 53. 24 (CH, C-2), 46. 47 (CH3, Ac) and 42. 51 (CH2, C-3).

Example 18 Methyl 4- (4-nitrophenyl)-2- (4-nitrophenyl)-4-oxobutanoate The title compound was obtained from Intermediate 8 and 2- bromo- (4-nitrophenyl)-1-ethanone as yellow crystals (28%).

M. P. 121. 8-123. 7°C. nmaX KBr disc/cm-1 1730. 2 (CO2CH3), 1693. 2 (C=O), 1530. 1 and 1346. 1 (NO2) ; dH 8. 32 (2H, d, J=8. 8 Hz, 3', 5'-PhH), 8. 22 (2H, d, J=8. 8 Hz, 3, 5-PhH), 8. 16 (2H, d, J=8. 8 Hz, 2', 6'-PhH), 7. 60 (2H, d, J=8. 8 Hz, 2, 6-PhH), 4. 48 (1H, dd, Jx=4. 5 Hz, JBX=9.6 Hz, CHXCHAHB), 4. 05 (1H, dd, JXB= 9. 6 Hz, JAB= 18.3 Hz, CHXCHAHB), 3. 76 (3H, s, CH3), 3. 42 (1H, dd, JXA=4.5 Hz, JBA=18. 3 Hz CHXCHAHB ; dC 195. 88 (C=O, C-4), 172. 82 (C=O, Ac), 150. 94, 147. 82, 145. 50 and 140. 79 (14 x Ph-C), 129. 62, 129. 40, 124. 58 and 124. 37 (4 x CH, Ph-H), 53. 31 (CH, C-2), 46. 48 (CH3, Ac) and 43. 04 (CH2, C-3).

Example 19 3-94-Nitrophenyl)-1-phenyl-1, 4-butanediol To a solution of the title compound of Example 11 (1. 01 g, 3. 2 mmol) in diglyme (50 cm3) was added soldium borohydride (0. 5 g, 13 mmol), and the mixture stirred overnight at room temperature. The purple solution was added to ice water (50 cm3), ethyl acetate (50 cm3) and then acidified (2M HCl).

The organic layer was separated and washed with water (2 x 50 cm3), saturated sodium bicarbonate (50 cm3), water (50 cm3), then dried (MgSO4). The organic solvent was removed to leave a brown oil which crystallised when mixed with ether to give the title compound of Example 19 as yellow crystals (0. 57 g, 62%). M. P. 142. 9-143. 9°C. (Found : C, 66. 77 ; H, 5. 99 ; N, 4. 76. C16H17NO4 requires C, 66. 88 ; H, 5. 96 ; N, 4. 87%) ; n,,,, KBr disc/cm-1 3341. 9 and 3268. 8 (OH), 1516. 8 and 1343. 0 (N02) ; dH d6-DMSO 8. 20 (2H, d, J=8. 7 Hz, 3, 5-PhH), 7. 59 (2H, d, J=8. 7 Hz, 2, 6-PhH), 7. 25 (5H, m, PhH), 5. 27 (1H, d, J=4. 5 Hz, CHOH), 4. 78 (1H, t, J=5. 4 Hz, CH2OH), 4. 18 (1H, m, CHOH) 3. 6 (2H, m, CH20H), 3. 25 (1H, dt, J=6. 3 Hz, JXB = JyB = 10. 5 Hz, CH2-CHBCHXHY), 2. 0 (1H, dt, JCX=4. 0 Hz, J8x= 10 Hz, Jyx= 14 Hz, CHBCHxHy-CHc-), 1. 85 (1H, dt, Jcy= 2. 6 Hz, JBY=10. 8 Hz, J=13. 5 Hz,-CHBCHxHy-CHc-). dC 152. 93, 147. 41 and 146. 83 (3 x Ph-C), 130. 49, 128. 83, 127. 48 126. 34 and 124. 03 (5 x CH, Ph-H), 70. 69 (CH, C-4), 66. 62 (CH2, C-1), 45. 96 (CH, C-2) and 42. 79 (CH2, C-3.

Example 20 1- (4-bromophenvl)-3- (4-nitrophenyl)-1, 4-butanediol The title compound of Example 20 was obtained from the title compound of Example 12. Column chromatography using ethyl acetate : petroleum ether (8 : 2 v : v) gave green crystals (79%). M. P. 127. 2-128. 4°C (Found : C, 53. 59 ; H, 3. 44 ; N, 3. 57. C16H17NO4 requires C, 53. 42 ; H, 3. 42 ; N, 3. 66%) ; n= E3r disc/cm-1 3518. 7 and 3395. 1 (OH), 1510. 3 and 1352. 8 (NO2) ; dH d6-DMSO 8. 20 (2H, d, J=8. 2 Hz, 3, 5-PhH), 7. 56 (2H, d, J=8. 4 Hz, 2, 6-PhH), 7. 45 (2H, d, J=8. 0 Hz, 2', 6'-PhH), 7. 20 (2H, d, J=8. 1 Hz, 3', 5'-PhH), 5. 36 (1H, d, J=4. 5 Hz, CHOH), 4. 79 (1H, t, J=5. 5 Hz, CH2OH), 4. 18 (1H, m, CH OH), 3. 59 (2H, m, CH2OH), 3. 2 (1H, dt, J=6. 1 Hz, J, @B = JYB = 10 Hz, -CH2-CHBCHXHY-F ), 1. 99 (1H, dt, JCX=3. 8 Hz, JBX = 10.2 Hz, JYX = 14.3 Hz CHBCHXHY-CHC-), 1.85 (1H, dt, JCY=2.5 Hz, JBY=10. 9 Hz, JXY=14.3 Hz,-CHBCH HY-CHc) ; dC 152. 47, 145. 83, 145. 03 and 119. 73 (4 x Ph-C), 130. 75, 129. 50, 127. 70 and 123. 10 (4 x CH, Ph-H), 69. 19 (CH, C-4), 65. 65 (CH2, C-1), 44. 94 (CH, C-2) and 41. 59 (CH2, C-3).

Example 21 1- (2-chlorophenyl)-3- (4-nitrophenvl)-1, 4-butanediol The title compound of Example 21 was obtained from the title compound of Example 13. Column chromatography with ethyl acetate : petroleum ether (6 : 4 v : v), pale yellow (35%). m. p. 123.5 - 124.7°C. Vmax KBr disc/cm-1 3341. 9 and 3268. 8 (OH), 1516. 8 and 1343. 0 (NO2) ; 5 H d6-DMSO 8. 20 (2H, d, J=8. 1 Hz, 3"-Ph-H), 7. 61 (3H, d, J=7. 8 Hz, 2"-Ph-

H, -PH-H), 7. 35 (1H, t, J=7. 3 Hz, Ph-H), 7. 30 (1H, d, J=7. 6 Hz,-Ph-H), 7. 23 (1H, t, J=7. 1Hz, Ph-H), 5. 44 (1H, d, J=4. 6 Hz, CH-OH), 4. 79 (1H, t, J=5. 1 Hz, CH2OH), 4. 48 (1H, m, CHcOH), 3. 59 (2H, t, J=5. 8 Hz, CH2OH), 3. 32 (1H, m, CH2-CHBCHXHY), 1.85 (2H, m, (CHBCHXHYCHC) ; #C 152.29, 146.95, 144. 81 and 130. 97 (4 x C, Ph-C), 130. 62, 129. 64, 129. 06, 128. 15, 128. 04 and 123. 88 (6 x CH, Ph-C), 67. 25 (CH, C-1), 66. 61 (CH2, C-4), 45. 95 (CH, C-3) and 41. 11 (CH2, C-2).

Example 22 1- (3-chlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol The title compound of Example 22 was obtained as crystals from the title compound of Example 14. (34%). m. p. 114. 4- 115. 0°C. Va, KBr disc/cm-1 3341. 9 and 3268. 8 (OH), 1516. 8 and 1343. 0 (NO2) ; 5H d6-DMSO 8. 17 (2H, d, J=8. 4Hz, 3"-Ph- H), 7. 59 (2H, d, J=8. 5 Hz, 2" - Ph-H), 7. 29 (4H, m, 2', 4', 5'and 6'-Ph-H), 5. 42 (1H, d, J=4. 7Hz, CH-OH), 4. 78 (1H, t, J=5. 2 Hz, CH2OH), 4. 18 (1H, m, CHcOH), 3. 59 (2H, m, CH2OH), 3. 23 (1H, m, CH,-CH 1. 90 (2H, m, CHBCHXHYCHC) ; #C 152. 62, 150. 01, 146. 85 and 133. 67 (4 x C, Ph-C), 130. 73, 130. 45, 127. 37, 126. 63, 125. 06 and 124. 02 (6 x CH, Ph-C), 70. 17 (CH, C-1), 66. 63 (CH2, C-4), 45. 90 (CH, C-3) and 42. 42 (CH2, C-2).

Example 23 1-(4-chlorophenyl)-3-94-nitrophenyl)-1, 4-butanediol The title compound of Example 23 was obtained as a solid from the title compound of Example 15. (79%). m. p. 124. 8 -125. 3°C. VmaX KBr disc/cm-1 3525. 9 and 3356. 8 (OH), 1506. 8 and 1352. 6 (NO2) ; #H d6 - DMSO 8. 17 (2H, d, J=8. 3 Hz, 3"- Ph-H), 7. 55 (2H, d, J=8. 3 Hz, 2"-Ph-H), 7. 33 (2H, d, J=8. 7 Hz, 2', 6'-Ph-H), 7. 26 (2H, d, J=8. 0 Hz, 3', 5'-Ph- H), 5. 37 (1H, d, J=3. 4 Hz, CH-OH), 4. 79 (1H, t, J=4. 5 Hz, CH2OH), 4. 19 (1H, m, CHCOH), 3. 59 (2H, brs, CH2OH), 3. 21 (1H, m, CH2-CHBCHXHY), 2.00 (1H, m, CHBCHXHYCHC), 1.83 (IH, m, CHHCHxHYCHc) ; bC 152. 72, 146. 83, 146. 34 and 131. 94 (4 x C, Ph-C), 130. 43, 128. 83, 128. 23 and 124. 02 (4 x CH, Ph- C), 70. 08 (CH, C-1) 66. 59 (CH2, C-4), 45. 88 (CH, C-3) and 42. 56 (CH2, C-2).

Example 24 1- (2, 4-dichlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol The title compound of Example 24 was obtained as yellow crystals from the title compound of Example 16. (86%). m. p. 126. 8-128. 5°C. (Found : C, 54. 12 ; H, 4. 23 ; N, 4. 00).

C16HlsCl2NO4 requires C, 54. 08 ; H, 4. 22 ; N, 3. 94%) ; VmaX KBr disc/cm-1 3469 and 3364 (OH), 1516 and 1347 (N02) ; 6H d6- DMSO 8. 20 (2H, d, J=8. 7 Hz, 3 " - Ph-H), 7. 58 (2H, d, J=8. 7 Hz, 2"-Ph-H), 7. 60 (1H, d, J=8. 3 Hz, 6' -Ph-H), 7. 44 (1H, d, J=2. 0 Hz, 3'-Ph-H), 7. 42 (1H, dd, J=2. 0 J=8. 4 Hz, 5'- Ph-H), 5. 51 (1H, d, J=4. 7 Hz, CH-OH), 4. 78 (1H, t, J=5. 4

Hz, CH2OH), 4. 42 (1H, m, CHCOH), 3. 57 (2H, t, J=5. 9 Hz, CH20H), 3. 3 (1H, CH2-CH 1. 84 (2H, m, CHgCHxHyCHe) ; 5C 150. 00, 144. 84, and 141, 80, 130. 5, 129. 7 (5 x Ph-C), 128. 49, 127. 52, 126. 91, 126. 17 and 121. 78 (5 x CH, Ph-H), 64. 87 (CH, C-1), 64. 39 (CH2, C-4), 43. 74 (CH, C-3) and 38. 78 (CH2, C-2).

Example 25 1- (3, 4-dichlorophenyl)-3- (4-nitrophenyl)-1, 4-butanediol The title compound of Example 25 was obtained from the title compound of Example 17. (28%). m. p. 126. 2- 126. 9°C. VmaX KBr disc/cm-l 3341. 9 and 3268. 8 (OH), 1516. 8 and 1343. 0 (NO20 ; oH d6-DMSO 8. 15 (2H, d, J=8. 3 Hz, 3"- Ph-H), 7. 55 (2H, d, J=8. 4 Hz, 2"-Ph-H), 7. 50 (1H, d, J=8. 1 Hz, 5'-Ph-H), 7. 46 (1H, d, J=1. 3 Hz, 2'-Ph-H), 7. 23 (1H, dd, J=1. 1, J=8. 2 Hz, 6' - Ph-H), 5. 47 (1H, d, J=4. 8 Hz, CH-OH), 4. 78 (1H, t, J=5. 3 Hz, CH2OH), 4. 18 (1H, m, CHcOH), 3. 55 (2H, m, CH2OH), 3. 19 (1H, m, CHZ-CH CHXHY), 1. 93 (2H, m, CHBCHYHYCHc) ; 5C 152. 47, 148. 52, 146. 81, 131. 6, 131. 5 (5 x Ph-C), 131. 02, 130. 46, 128. 45, 126. 78 and 123. 98 (5 x CH, Ph-H), 69. 69 (CH, C-1) 66. 60 (CH2, C- 4), 45. 83 (CH, C-3) and 42. 13 (CH2, C-2).

Example 26 1- (4-nitrophenyl)-3- (4-nitrophenyl)-1, 4-butanediol The title compound of Example 26 was obtained from the title compound of Example 18. m. p. 121. 8-123. 7°C.

(Found : C, 53. 59 ; H, 3. 44 ; N, 3. 57. C16H16N2O6 requires C, 53. 42 ; H, 3. 42 ; N, 3. 66%) ; Vmax KBr disc/cm-1 3518. 7 and 3395. 1 (OH), 1510. 3 and 1352. 8 (NO2).

Example 27 3- (4-nitrophenyl)-5-phenyltetrahydro-2-furanone The title compound of Example 11 (1. 38g, 4. 40mmol) in 70% ethanol/water (50 cm3) was stirred at room temperature with sodium borohydride (0. 2g, 7. 40mmol) for 8 hours. The resulting purple reaction mixture was added to ice water (50 cm3) and ethyl acetate (50 cm3) and then acidified (2M HC1). The organic layer was separated and washed with water (2 x 50 cm3), saturated sodium bicarbonate (50 cm3), water (50 cm3) and then dried (MgSO4). The volatile components were removed to leave a brown oil. The final product was purified by column chromatography with ethyl acetate : petroleum ether 3 : 7 to give a pale yellow solid (1. 06g, 85%). m. p. 96. 2-98. 3°C. (Found : C, 67. 56 ; H, 4. 78 ; N, 4. 90. C16Hl3NO4 requires C, 67. 83 ; H, 4. 62 ; N, 4. 94%) ; Vmax KBr disc/cm-1 1773 (CO2CH-), 1518 and 1347 (NO2) ; 5H 8. 24 (2H, d, J=8. 8 Hz, 3"-Ph-H), 7. 56 (2H, d, J=8. 7 Hz, 2"-Ph-H), 7. 45 (5H, m, Ph-H), 5. 62 (1H, dd, JAX=5.45 JBX=10.7 Hz, CHxCHAHB)/4. 24 (1H, dd, JAY=8. 3,

JBY=12. 8 Hz, CHAHBCHY), 3. 19 (1H, ddd, JXA=5.3, JYA=8. 2, JBA=10-8 Hz, CHXCH HBCHy), 2. 45 (1H, m, JXB=10. 7, JYB=12. 8, JAB=12. 8 Hz, CHXCHAHBCHY) ; 5C 175. 59 (Ac), 147. 79, 143. 70 and 134. 43 (3 x Ph-C), 129. 65, 129. 38, 127. 48, 126. 02 and 124. 55 (5 x CH, Ph-H), 79. 88 (CH, C-3), 47. 63 (CH, C-5) and 40. 32 (CH2, C-4).

Example 28 5- (4-Bromophenyl)-3- (4-nitrophenyl) tetrahydro-2-furanone According to the procedure described in Example 27, the title compound of Example 28 was prepared as yellow crystals from the title compound of Example 12 (25%). Vax KBr disc/cm-1 1774 (-CO2CH-), 1519 and 1350 (NO2) ; 5H 8. 16 (2H, d, J=8. 6 Hz, 3" -Ph-H), 7. 49 (4H, t, J=8. 7 Hz, 2"and 2', 6' -Ph-H), 7. 24 (2H, d, J=8. 4 Hz, 3', 5' -Ph-H), 5. 46 (1H, dd, JAX=5.46, JBX=10.7 Hz, CHXCHAHB), 4. 15 (1H, dd, JAY=8. 3, JBY=12. 8 Hz, CHAHBCHY), 3. 10 (1H, m, JXA=5. 6, JYA=7.8, JBA=12. 7 Hz, CHXCHAHBCHy), 2. 32 (1H, m, JXB=10. 7, JyB=12. 8, JA=12. 7 Hz CHXCHAHBCHY) ; #C 175. 22 (Ac), 147. 84, 143. 31, 137. 44 and 123. 36 (4 x Ph-C), 132. 54, 129. 60, 127. 66 and 124. 46 (4 x CH, Ph-H), 79. 06 (CH, C-3), 47. 90 (CH, C-5) and 40. 19 (CH2, C-4).

Example 29 5- (2, 4-dichlorophenyl)-3- (4-nitrophenyl) tetrahvdro-2- furanone The title compound of Example 16 was employed according to the procedure described in Example 27, whereby a pale yellow oil was formed. Column chromatography with ethyl acetate : petroleum ether (3 : 7) gave pale yellow crystals of the title compound of Example 29 (48%). m. p. 148. 7- 153. 9°C. (Found : C, 54. 39 ; H, 3. 32, N, 3. 71. C16HllCl2NO4 requires C, 54. 56 ; H, 3. 15 ; N, 3. 98%) ; Vmax KBr disc/cm-1 1780 (-CO2CH-), 1519 and 1347 (NO2) ; 6H 8. 28 (2H, d, J=8. 7 Hz, 3" -Ph-H), 7. 54 (1H, d, J=8. 5 Hz, 6'-Ph-H), 7. 53 (2H, d, J=8. 7 Hz, 2"-Ph-H), 7. 48 (1H, d, J=2. 0 Hz, 3'-Ph-H), 7. 40 (1H, dd, J=2. 0, J=8. 5 Hz, 5' -Ph-H), 5. 62 (1H, dd, JAX=5.6, JBX=10.3 Hz, CHXCHAHB), 4. 24 (1H, dd, JAY=-8. 6, JBY=12.3 Hz, CHXCHAHBCHY), 3. 41 (1H, m, JXA=5.70, JYA=8. 5, JBA=12.9 Hz, CHXCHAHBCHY), 2. 26 (1H, m, JXB=10. 3, JYB=12. 3, JAB=12.9 Hz, CHxCHHCHy) ; #C 174. 84 (Ac), 147. 96, 143. 03, 135. 53, 135. 24 and 132. 31 (5 x Ph-C), 130. 17, 129. 50, 128. 42, 127. 43 and 124. 67 (5 x CH, Ph-H), 76. 52 (CH, C-3), 47. 15 (CH, C-5) and 38. 81 (CH2, C-4).

Example 30 <BR> <BR> <BR> <BR> <BR> <BR> 5-(2, 4-dichlorophenyl)-3-(4-aminoPhenol)-2-pyrrolidinone A mixture of Intermediate 15 (2. 04g, 5. 14mmol), acetic acid (30cm3) and water (2cm3) was stirred with a mechanical stirrer and Zinc dust (lOg) was added carefully. The

mixture was stirred and refluxed for 1 hour. Water (lOcm3) was added and the solution was basified with NaOH (6M). The organic components were extracted with ethyl acetate (3 x 50cm3), dried (MgSO4) and concentrated to yield the title compound of Example 30 as green crystals which were recrystallised from benzene (0. lOg, 6%). m. p.

215. 0-218. 0°C. (Found : C, 61. 83 ; H, 4. 66 ; N, 7. 95.

C16Hl4Cl2N20 requires C, 59. 82 ; H, 4. 39 ; N, 8. 72%) ; VmaX disc/cm-1 3342 and 3220 (NH2), 1695 (CH2CONH-) ; 6H d6-DMSO 7. 62 (IH, d, J=1. 8 Hz, 3 ' -Ph-H), 7. 55 (1H, d, J=8. 4 Hz, 6'-Ph-H), 7. 50 (1H, dd, J=1. 9, J=8. 4 Hz, 5'-Ph-H), 6. 85 (2H, d, J=8. 4 Hz, 3" -Ph-H), 6. 49 (2H, d, J=8. 4 Hz, 2"- Ph-H), 4. 97 (3H, m, CHXCHAHB and NH2), 3. 59 (1H, dd, JBY=9.1, JAY=10.4 Hz, CHAHBCHy)/2. 98 (1H, m, JXB=7. 1, JYB=8.7, JAB=12.5 Hz, CHXCHAHBCHY), 1. 60 (1H, m, JXA=8. 7, JYA=10.7, JBA=12. 4 Hz, CHXCHHCHY) Examples 31 and 32 Methyl 4- (2, 4-dichlorophenvlamino)-4-oxo-2- (4-nitrophenyl) butanoate and Methyl 3- (2, 4-dichlorophenyloxoamino)-2- (4- nitrophenyl) propanoate Intermediate 15 (2. 67g, 6. 72mmol) was stirred with phosphorus pentachloride (3g) in ether (20 cm3) for 3 hours. The volatile components were removed and water (25 cm3) added. The mixture was boiled for 10 minutes and the water was decanted to leave a yellow paste which was purified by column chromatography with ethyl

acetate : petroleum ether (3 : 70) to give two main fractions, namely the title compounds of Examples 31 and 32.

Example 31 (0. 15g, 5. 6%). m. p. 124. 3-125. 7°C. VmaX KBr disc/cm-1 3291 (NH), 1730 CO2CH3), 1644 (C=O), 1513 and 1349 (NO2) ; 5H 8. 23 (2H, d, J=8. 7 Hz, 3"-Ph-H), 7. 59 (1H, d, J=8. 3 Hz, 6'-Ph-H), 7. 57 (2H, d, J=8. 7 Hz, 2" - Ph-H), 7. 42 (1H, d, J=1. 9 Hz, 3'-Ph-H), 7. 26 (1H, dd, J=1. 9, J=8. 3 Hz, 5'-Ph-H), 4. 27 (1H, dd, JAX-5.8, JBX=8.L7 Hz, CHxCHAHB), 3. 96 (2H, m, CHXCHAHB), 3. 70 (3H, s, OCH3) ; 6C 172. 64 (C=O, C-1), 166. 07 (C=O, C-4), 148. 00, 143. 61, 137. 55, 133. 10 and 131. 80 (5 x Ph-C), 131. 65, 130. 52, 129. 55, 128. 04 and 124. 57 (5 x CH, Ph-H), 53. 18 (OCH3), 50. 95 (CH, C-2) and 42. 87 (CH2, C-3).

Example 32 (1. 04g, 39%). m. p. 118. 6-120. 3°C. (Found : C, 51. 29 ; H, 3. 60 ; N, 7. 11. Cl7Hl4Cl2N2Os requires C, 51. 40 ; H, 3. 55 ; N, 7. 05%) ; Va, KBr disc/cm~l 3373 (NH), 1726 (CO2CH3), 1697 (C=O), 1516 and 1349 (NO2) ; 5H 8. 18 (2H, d, J=7. 0 Hz, 3 " - Ph-h), 7. 68 (1H, brs, 6' -Ph-H), 7. 47 (2H, d, J=8. 7 Hz, 2"-Ph-H), 7. 32 (1H, d, J=2. 3 Hz, 3' - Ph-H), 7. 18 (1H, dd, J=2. 3, J=8. 8 Hz, 5' -Ph-H), 4. 37 (1H, dd, JAX=5.2, JBX=9. 5 Hz, CHxCHAH,), 3. 68 (3H, s, OCH3), 3. 33 (1H, dd, JXB=9.5, JAB=15. 6 Hz, CHXCHAHB), 2. 78 (1H, dd, JXA=5. 2, JBA=15. 6 Hz, CHXCHAHB) ; #C 171. 46 (C=O, C-1), 167. 05 (C=O, C-4), 146. 48, 143. 84, 131. 87, 128. 47 and 122. 36 (5 x Ph- C), 127. 90, 127. 78, 126. 87, 123. 18 and 121. 49 (5 x CH, Ph- H), 51. 92 (OCH3), 45. 97 (CH, C-2) and 39. 51 (CH2, C-3).

BIOLOGICAL METHODS In Vitro Inhibition Studies 1. P450-RA Sets of tubes, in triplicate, with a total volume of 400AI containing (11, 12-3H) retinoic acid 10nM (10y1 of 400 nM stock), unlabelled retinoic acid in methanol (10y1 of 120AM stock to give 3AM), inhibitor (8Al of 5mM ethanol stock to give 100AM concentration in final assay volume), phosphate buffer 50mM (pH=7. 4, 312µl), NADPH solution (501 of 16mg/ml) were prepared, and the tubes vortexed and preheated in a water bath for 4 minutes.

The enzyme reaction was initiated by addition of rat liver microsomes (10y1 of 10mg/ml) and the mixture incubated at 37°C for 25 minutes. The enzyme action was arrested by addition of 1001 of 1% formic acid and the tubes were placed in ice for 5 minutes. Then 3ml of ethyl acetate containing 0. 02% butylated hydroxy anisole was added and the tubes vortexed for 10 seconds. The tubes were then left for another 5 minutes at room temperature and the organic layer (2ml) was removed from each tube and transferred to another set of tubes. The ethyl acetate extracts were evaporated using a univap centrifuge connected to a vacuum pump and a multitrap at-80°C.

After 60 minutes the tubes were removed and the residue was reconstituted in absolute ethanol (100y1) and 50y1 was injected into a HPLC machine equipped with a 10ym C18

ABonda pack column (3. 9x300mm, Millipore) using acetonitrile : water (containing 1% ammonium acetate) 75 : 25 as mobile phase and connected to a mixer (Reeve model 9702) and a radioactive detector (Reeve model 9701). The results were analysed by an on line computer system. The scintillation fluid used was a mixture of 50 : 50 Hisafe 3 and methanol.

Percentage inhibition was calculated from the conversion rate of the samples containing inhibitors to that of control samples which contained absolute ethanol instead of inhibitor solution. Ketoconazole was used as a standard.

Due to the sensitivity of retinoic acid all the above assays were carried out in a dark room equipped with yellow light.