WO1999035115A1

WO1999035115A1 - Benzyl and benzylidene tetralins and derivatives

Info

Publication number: WO1999035115A1
Application number: PCT/GB1998/003868
Authority: WO
Inventors: Paul Joseph Nicholls; Harold John Smith; Masoud Ahmadi; Farshid Hassanzadeh Maharlouie
Original assignee: University College Cardiff Consultants Limited
Priority date: 1998-01-02
Filing date: 1998-12-21
Publication date: 1999-07-15
Also published as: GB9800039D0; AU1772599A; ZA9811938B; EP1044181A1

Abstract

A benzyl or benzylidene tetralin or a pharmaceutically acceptable salt of benzyl or benzylidene tetralin represented by general formula (I) in which: a) R1 completes a carbon-carbon double bond with the carbon at position 2, when x is two and R2 is hydroxyl or an oxyalkenyl, oxyalkynyl or oxyaryl group; b) R2 is hydroxyl or an oxyalkenyl, oxyalkynyl or oxyaryl group when x is one and the substituent at position 2 is bonded via a double bond; or c) R?1 and R2¿ together comprise = O (in which case the substituent at position 2 is bonded via a single bond, x is two and X is not halogen); X is halogen, amino or nitro; and Y is hydroxyl or an alkoxy or aryloxy group.

Description

BENZYL AND BENZYLIDENE TETRALINS AND DERTVATTVES

The present invention is concerned with benzyl and benzylidene tetralins, and derivatives thereof useful as inhibitors of retinoic acid metabolism.

Retinoic acid (RA) supports cellular growth and differentiation and has been shown to attenuate or completely reverse the malignant phenotype for many cell lines. 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. Retinoids have also been used topically and orally for the treatment of skin diseases, i.e. actinic keratoses (precursors to squamous cell carcinoma), nonmelanoma skin cancer, acne vulgaris, psoriasis and disorders of keratinisation. 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 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 and is considered to account for its biological action. RA has a short half life (c. 1 hour) and therefore the potency of RA is reduced when it is 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. The specific P450s (P450-RA) responsible for 4-hydroxylation of RA in the human liver have not been characterised, but several reconstituted P450s CYP1A2/2B6/2C8/2D6/2E1/3A4, can catalyse the reaction. Repeated exogenous administration of RA leads to a lowering of RA levels due to induction of the metabolising enzymes. A drug which can prolong and intensify the action of endogenous RA on the epidermal cell by inhibiting P450-RA metabolising enzymes would have potential as a clinical agent in the treatment of certain skin conditions. The imidazoles, ketoconazole and liarozole, were reported as inhibitors of RA- metabolising enzymes whilst being studied as inhibitors of 17α-hydroxylase: 17,20-lyase (P450 17α) as agents for the treatment of androgen-dependent prostatic cancer by lowering testosterone levels. Ketoconazole lacks specificity towards P450 17 and inhibits several other cytochrome P450 enzymes on the steroidogenic pathway of androgen synthesis and has a poor pharmacokinetic profile.

Liarozole (R75251), a related compound, also inhibits testicular (but not adrenal) P450 17α 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 (ketoconazole is also an inhibitor of this enzyme). This view has been confirmed by experiments showing that RA metabolism in epidermal cells is inhibited (IC₅₀-2μM) and also that endogenous RA levels are increased and the elimination rate from the plasma of injected RA is reduced. 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.

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 17α, 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.

There is still therefore the need for a more potent inhibitor of retinoic acid metabolism with fewer side effects than the inhibitors of the prior art.

According to the present invention there is provided a class of benzyl and benzylidene tetralins represented by the general formula (I):

(I) in which: a) R¹ completes a carbon-carbon double bond with the carbon at position 2, when x is two and R² is hydroxyl or an oxyalkenyl, oxyalkynyl or oxyaryl group; b) R² is hydroxyl or an oxyalkenyl, oxyalkynyl or oxyaryl group when x is one and the substituent at position 2 is bonded via a double bond; or c) R¹ and R² together comprise = O (in which case the substituent at position 2 is bonded via a single bond, x is two and X is not halogen);

X is halogen, amino or nitro; and

Y is hydroxy or an alkoxy or aryloxy group.

It is preferred that Y is an alkoxy group containing not more than four carbon atoms; a particularly preferred variant is methoxy.

It is preferred that X is chloro or amino.

It is preferred that R¹ and R² together comprise = O, or that R¹ completes a carbon-carbon double bond with the carbon at position 2, and R² is an oxyalkynyl group, such as an oxypropargyl group.

It is preferred that Y is hydroxyl at position 6, x is two and X is an amino group at position 4.

Ketoconazole has an inhibition value of 31% and an IC₅₀ value of 18.8 μM. It is therefore evident that the compounds according to the present invention, represented by general formula (I), are much more potent inhibitors of retinoic acid metabolism than ketoconazole, as can be seen below.

Furthermore, a lower concentration of the compounds according to the present invention is required to achieve 50% inhibition compared with ketoconazole IC₅₀.

It might be expected that one of the enantiomers of A and B would possess most of the biological activity of the racemate and that B would have the E-configuration (as shown in the following formula), as determined for the corresponding phenolic ketone.

Preferred benzyl and benzylidene tetralins according to the invention are as follows: Compound % Inhibition (lOOμM) I£₅₀

A 78.0 l-5μM

B 60.07 5-10μM

68 ND

Such benzyl or benzylidene tetralins are suitable for use in medical therapy and more specifically as retinoic acid metabolism inhibitors. Pharmaceutically acceptable salts of the benzyl or benzylidene tetralins (such as citrates, chlorides or sulphates) may also be suitable for use as retinoic acid metabolism inhibitors. The present invention therefore preferably further comprises a pharmaceutical formulation containing such a benzyl or benzylidene tetralin together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

According to the present invention, the preferred route of administration of the formulation is topical. The formulation suitable for topical use may comprise the free base of a benzyl or benzylidene tetralin according to the invention. Furthermore, it is preferred that the formulation suitable for topical use comprises a pharmaceutically acceptable carrier, diluent or excipient which is substantially non-aqueous in nature. The formulation may be in the form of a gel, foam, salve, emollient, cream or ointment, and may, in some cases, contain paraffin wax. Alternatively, the pharmaceutical formulation according to the invention may be in a form suitable for oral administration. A formulation suitable for oral use may contain a hydrochloride salt (or other pharmaceutically acceptable salt such as a sulphate or citrate) or a free base of a basic benzyl or benzylidene tetralin according to the invention. In this case, the diluent, carrier or excipient may be lactose, microcrystalline cellulose and/or calcium phosphate dihydrate.

The benzyl or benzylidene tetralin or pharmaceutically acceptable salt thereof can be used for the treatment of dermatological conditions in (i) a dose form designed for topical administration in a dose range of 0.5-10% (w/v) with a concentration of 1 to 3% being preferred, and (ii) a dose form designed for oral administration in a dose range of 50-500mg daily with a daily dose of 150 to 250mg being preferred.

The benzyl or benzylidene tetralins (or pharmaceutically acceptable salt thereof) of the present invention may also be used in the treatment of certain dermatological conditions. These dermatological conditions may include ichthyosis, acne, psoriasis, wrinkles or photodamaged skin. Furthermore, the benzyl or benzylidene tetralins of the present invention may be used in anti-ageing preparations and in preparations to protect the skin from the effects of radiation damage caused, for example, by radiation therapy of tumours and to alleviate such damage.

METHODS

In Vitro Assessment of Inhibitory Activity of Synthesised Compounds against P450-RA

Sets of tubes in triplicate with a total volume of 400μl containing (11, 12-³H) retinoic acid (lOμl of 400nM stock), unlabelled retinoic acid in methanol (10μl of 120μM stock to give 3μM), inhibitor (8μl of 5mM ethanol stock to give lOOμM concentration in final assay volume), phosphate buffer 50mM (pH=7.4, 312μl), co-factor (NADPH) solution (50μl of 16mg/ml) were prepared, and the tubes vortexed and preheated in a water bath for 4 min.

The enzyme reaction was initiated by addition of rat liver microsomes (lOμl of lOmg/ml) and the mixture incubated at 37°C for 25 min. The enzyme action was arrested by addition of lOOμl of 1% formic acid and the tubes were placed in ice for 5 min. Then 3ml of ethyl acetate containing 0.02% butylated hydroxy anisole was added and the tubes vortexed for 10s. The tubes were then left for another 5 min 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 lOOμl of absolute ethanol and 50μl was injected into aHPLC machine equipped with a lOμm C18 μBonda pack column (3.9 x 300mm 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. The IC₅₀ values were determined from a plot of % inhibition versus log inhibitor concentration.

Example 1 - Method for the Preparation of Compound A

Synthesis

6-Hydroxy-3, 4-dihydronaphthalen-l (2H) -one ( 1 )

A solution of 6-methoxy-3,4-dihydronaphthalen-l(2H)-one (17.6g, lOOmmol) in 47% aqueous HBr was heated under reflux for 5h and cooled in an ice bath. The precipitate was collected, washed with water and finally recrystallised from water to yield the phenol as yellow crystals (9.5g, 57%), m.p. 156-157°C. v,,^ 3311 (O-H), 1661 (C=O), 1578 (C=C, Ar) cm^"1; δ_H (SOOMHzj DMSO , 10.4 (IH, s, O-H), 7.74 (IH, d, J=8.55Hz, 8-H), 6.72 (IH, dd, J=8.58Hz and J=2.04Hz, 7-H), 6.65 (IH, br s, 5-H), 2.8 (2H, t, J=5.8Hz, CH₂-CH₂-£H₂-C=O), 2.5 (2H, t, J=6.75, CH₂-CH₂-CH₂-C=O), 2 (2H, qi, J=6.21Hz, CH₂-CH₂-CH₂-C=O).

6-(Tetrahydropyranyl-2 '-oxy)-3, 4-dihydronaphthalen-l (2H)~one (2)

A mixture of 6-hydroxy-3,4-dihydronaphthalen-l(2H)-one (5g, 30mmol), 2,3- dihydropyran (6.0g, 71mmol), acetic anhydride (1 cm³) and p-toluensulfonic acid (50mg) in ether was stirred at room temperature for 3h. The resulting brown clear solution was washed with 2% KOH (2x20cm³) and water (20cm³), dried (MgSO₄) and concentrated under reduced pressure at 30°C. The crystalline residue was recrystallised from ethanol to give the ketone as pale yellow crystals (6.6g, 86.8%), m.p. 89.8-91.7°C. Found: C, 72.97; H, 7.38. C₁₅H_lgO₃ requires C, 73.14; H, 7.37%); v.^2960-2880 (C-H), 1670 (C=O), 1600 (C=C, Ar) cm^'1; δ_H (300 MHz; CDCl_j), 8.06 (IH, d, J=8.7Hz, 8-H), 7.1 (IH, dd, J=8.7Hz and J=2.4, 7-H), 6.93 (IH, d, J=2.3Hz, 5-H), 5.57 (IH, t, J=3Hz, -O-CH-O), 3.9 (IH, m, 6'-H_AH_B), 3.69 (IH, m, 6'-H_AH_B), 2.95 (2H, t, J=6.1Hz, CH₂.-CH₂-CH₂-C=O), 2.6 (2H, t, J=6.1 Hz CH₂-CH₂-CH₂-C=O), 2.16 (2H, quintet, J=6.4Hz, CH₂-£H₂-CH₂-C=O), 2.05 (IH, m, 3'-H_AH_B), 1.9 (2H, quintet, J=3.6Hz, 5'-QH₂), 1.8-1.6 (3H, m, 4'-CH₂, 3'-H_AH_B).

2-(4-Nitrophenylmet ylene)-6(tetrahydropyranyl-2 ' >yy)-3,4-dihydron φhthalen-l-one(3)

4- trobenzaldehyde (3g, 20 mmol) was added in portions over 15 min to a stirred solution of 6-(tetrahydropyranyl-2-oxy)-3,4-dihydro-napthalen-l(2H)-one (4.8 g, 19.5 mmol) in 0.7% ethanolic KOH (100 cm³) under nitrogen and the mixture was stirred at room temperature for lh. The resulting precipitate was collected, washed with cold water (3x10cm³) and crystallised from a solution of ethyl acetate - chloroform (1:1) to give the ketone as yellow crystals (2.2gm, 29.7%), m.p. 188.6-189.6°C.

(Found: C, 68.01; H, 5.81; N, 3.37. C₂₂H₂₁NO₅.1/2 H₂O require C, 68.01; H, 5.71; N, 3.60%); v^, 2925 (C-H), 1662 (C=O), 1616 (C=C), 1594 (C=C, Ar), 1513, and 1343 (NO) cm^"1. δ_H (300 Hz; CDC1₃) 8.35 (2H, d, J=8.7 Hz, 3'-, 5'-H), 8.15 (IH, d, J=8.7Hz, 8-H), 7.85 (IH, m, CO-C=CH-Ph), 7.6 (2H, d, J=8.5Hz, 2'-,6'-H), 7.1 (IH, dd, J=2.4 Hz and J=8.7Hz, 7-H), 6.95 (IH, d, J=2.7 Hz, 5-H), 5.6 (IH, t, J=3 Hz, O-£E-O), 3.9 (IH, m, 6"-CH_AH_B), 3.7 (IH, m, 6"- CH^), 3.15 (2H, m, C^-C^-^C)), 3.0 (2H, m, Ci -CH -(C=C)), 2.05 (IH, m, 3"-CIJ,Ii ), 1.9 (2H, m, 5"-CH₂), 1.6-1.8 (3H, m, 4"-£H₂, 3"-CH_AH_B).

2-(4-Nitrophenylmethylene)-6-hydroxy-3,4-dihydronaphthalen-l-one (4)

Hydrochloric acid (5%, 10 cm³) was added dropwise to a stirred solution of 2-(4- nitrophenylmethylene)-6-(tetrahydropyranyl-2 ' -oxy)-3 ,4-dihydronaphthalen- 1 -one (2.5g, 6.7 mmol) in ethyl acetate (20 cm³) and 2-butanone (10 cm³). The mixture was stirred at room temperature for lh and at 60°C for lh. Cold water (20 cm³) was then added and the resulting mixture concentrated at room temperature under reduced pressure. The resulting precipitate was collected, washed with water (2x10 cm³) and dried to give the phenolic ketone (1.4 gm, 73%) as a yellow crystalline powder, m.p. 253.2-257°C. (Found: C, 68.85; H, 4.57; N, 4.67. C₁₇H₁₃NO₄ requires C, 69.13; H, 4.44; N, 4.75%); v_max 3341 (OH), 2939.5 and 2842 (C-H), 1669.5 (C=O), 1613 (C=C), 1593, 1571 (C=C, Ar), 1512 and 1342.8 (N=O) cm^"1; δ_H (300 MHz; DMSO_d6) 10.2-10.8 (IH, br s, O-H), 8.3 (2H, d, J=8.74 Hz, 3'-,5'-H), 7.9 (IH, d, J=8.6 Hz, 8-H), 7.75 (2h, d, J=8.74 Hz, 2'-,6'-H), 7.7 (IH, s, C=O-C=CH-), 6.8 (IH, dd, J=8.6 and J=2.3 Hz, 7-H), 6.7 (IH, d, J=2.19 Hz, 5-H), 3.05 (2H, t, J=6 Hz, CH₂-CH₂-(C=C)), 2.85 (2H, t, J=6Hz, CH₂-£H₂-(C=C)).

2-(4-Aminophenylmethyl)-6-hydroxy-3.4-dihydroncφhthalen-l(2H)-one (A)

Am xture of2-(4-nitrophenylmethylene)-6-hydroxy-3,4-dihydronaphthalen-l-one (3.2 gm, 10.84 mmol), and 10% palladium charcoal (320 mg) in methanol (100 cm³) was shaken in an atmosphere of hydrogen at room temperature until 912 cm³ of gas was absorbed (theory 915 cm³). The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue was crystallised from ether to give the amino ketone (2.2 gm, 75.6%) as a white crystalline powder, m.p. 194.5-196.2°C.

(Found: C, 76.68; H, 6.49; N, 5.05%. (M+H)⁺ 268.1338. C₁₇H₁₇NO₂ requires C, 76.37; H, 6.41, 5.24%. (M+H)⁺ 268.1338). v^ 3364 & 3298 (NH₂, 1667 (C=O), 1594 (C=C,Ar) cm^"1; δ_H (300Mhz; DMSO_d6) 10.1-10.6 (IH, s, OH), 7.8 (IH, J=8.6 Hz, 8-H), 6.88 (2H, d, J=8.2 Hz, 3'-,5'-H or 2',6'-H), 6.73 (IH, dd, J=2.2 Hz and J=8.6 Hz, 7-H), 6.6 (IH, d, J=2.01 Hz, 5-H), 6.5 (2H, d, J=8.3 Hz, 2'-,6'-H or 3'- ,5'-H), 4.9 (2H, s, NH₂), 3.05 (IH, dd, J=13.5 Hz and J=3.8 Hz, (C=O)-CH_x-CI H_b-Ph), 2.8 (2H, m, CH.-CH_AH_S-CH_X-^O)) 2.6 (IH, m, CJ^-CIilJ ), 2.4 (IH, dd, ϊ_b =9.7 Hz and =13.5 Hz, (C=O)-CH_x-CH^₎-Ph)_> 1-9 (IH, m, CH₂-CH_AH_B-CH_x-(C=O)), 1.6 (IH, m, CH₂-CH_AH_B- CH_x-C=O).

Example 2 - Method for the Preparation of Compound B

2-(4-Chlorophenylmethylene)-6-methoxy-3,4-dihydronaphthalen-l-one (5)

4-Chlorobenzaldehyde (8.4 g, 60 mmol) was added to a stirred solution of commercially available 6-methoxy-3,4-dihydronaphthalene-l-(2H)-one ( (7.1 g, 40 mmol) in 4% ethanolic KOH (100 cm³) and the mixture stirred under nitrogen at room temperature for 2h. The resulting precipitate was collected, washed with cold ethanol (2x10 cm³) and water (3x15 cm³) and finally crystallized from acetone to give the ketone as yellow needle-shaped crystals, m.p. 126.3-127.4°C. v.,^ 2934 - 2842(C-H), 1653 (C=O), 1604(C=C, Ar) cm¹; δ_H (300MHz; CDC1₃) 8.2 (IH, d, J=8.72Hz, 8-H), 7.8 (IH, s, CH₂-CH₂-C=CH-Ph), 7.4 (4H, m, Ph-H), 6.95 (IH, d, J=8.72Hz, 7-H), 6.75 (IH, s, 5-H), 3.9 (3H, s, OCH₃), 3.15(2H, t, J=6.3 Hz, CH₂-CH₂- C=CH=Ph), 2.95(2H, t, J=6.3 Hz, CH₂-CH₂-C=CH-Ph).

2-(4-Chlorophenylmethylene)-6-methoxy-l, 2, 3, 4-tetrahydronaphthalen-l-ol (B)

To a stirred solution of the ketone (5), (9 gm, 30 mmol) in THF was added sodium borohydride (1.1 gm, 30 mmol) portionwise over 10 min. This mixture was stirred under reflux for 40 min, a mixture of water-ether (1:2, 30 cm³) added and the organic phase extracted with ether (2x20 cm³). The combined ether extracts were dried (MgSO₄) and concentrated under reduced pressure to give a yellow oil (8 gm) which was fractionated on a column of dry silica using petroleum ether (60-80°C)-ethyl acetate (5:1) as eluent. Evaporation of the solvent from the first fraction gave 2-(4-chlorophenylmethyl)-6-methoxy-3 ,4-dihydronaphthalen- 1 (2H)-one as a white crystalline powder (1.9 gm, 21%), m.p. 75.1-77°C.

(Found: C, 71.85; H, 5.64%. M⁺ 300.0917. C₁₈H₁₇ClO₂ requires; C, 71.86; H, 5.70%.

v^ 2942.4 and 2866 (C-H), 1669.9 (C=O), 1598.5 (C=C,Ar) cm^"1, δ_H(300 MHz, CDC1₃), 8.1 (IH, d, J=8.77, 8-H), 7.35 (2H, m, 3'-5'-H), 7.2 (2H, m, 2'-,6'-H), 6.9 (IH, dd, J=8.75 Hz and J=2.5Hz, 7-H), 6.7 (IH, d, J = 2.43 Hz, 5-H), 3.9 (3H, s, O-CH₃), 3.5 (IH, m, CH₂-CH_AH_B-CH_X- CHJVPh), 2.95 (2H, dd, J=7.46 and J=4.44, CH₂-CH_AH_B-CH_x-(C=O)), 2.7 (2H, m, CH₂- CH^-CI^-CH Ϊ-Ph ll (IH, m, C^ -CH^ -CH^CO)), 1.8 (IH, m, CII -CH_ΛS -CIL. - (C=O)).

The second main fraction was concentrated at room temperature under reduced pressure to give 2-(4-chlorophenylmethyleneV6-methoxy-1.2_r3,4-tetrahydronaphthalen-l-ol (B) as a white fluffy powder (2.5 g, 27.6%), m.p. 88.7-90.2°C (Found: C 71.99; H, 5.71%. M⁺ 300.0917). C_lgH₁₇ClO ₂ requires C, 71.86; H, 5.70%. M⁺ 300.0917). v_max 3260 (OH), 2916.2-2837.0 (C-H) 1610.2 (C=C, Ar) cm^'1; δ_H (300MHz; CD₃OD) 7.2-7.4 (5H, m, 8-H, 2',3',5',6'-Ph), 6.8(lh, dd, J=8.4 and J=2.5Hz, 7-H), 6.7(1H, d, J=2.5Hz, 5-H), 6.65(1H, s, CH₂-CH_ACH_B-C=CH)Ph, 5.1(1H, s, CHOH), 3.8(3H, s, O-CH₃), 3.0(1H, m, CH₂- CH_AH_B-(C=CH)), 2.6-2.9(3H, m, CH₂-CH_AH_B-(C=CH)).

Example 3 - Method for the Preparation of Compound C

BrCH ₂C CH KOH

CH

(C) l-(Propyn-2-yl-l-oxy)-2(4-chlorophenylmethyl)-6-methoxy-3,4-dihydronaphthalene (C)

Propargyl bromide (0.8g, 6.7mmol) was added to a stirred solution of 2-(4- chlorophenylmethylene)-6-methoxy-l,2,3,4-tetrahydronaphthalen-l-ol (B) (lg, 3.3mmol) and potasium hydroxide (2g) in acetone under nitrogen and stirring was continued at room temperature for 3h. The mixture was then filtered and water (20cm³) was added to the filtrate to form a milky emulsion. The emulsion was extracted with ether (3x20cm³) and the combined ethereal extracts washed with water (10cm³) and dried (MgSO₄). Silicagel 60 (4g) was added to the filtered solution which was evaporated to dryness at room temperature. The mbcture was then fractionated on a column of dry silica (30g, 0.04-0.063mm) with petroleum ether-ether (3:1) to give the propargyl ether (C) (0.32g, 28%) as a colourless oil on evaporation of the main fraction, (Found: C, 74.33; H, 5.84. C₂₁H₁₉C10₂ requires: C, 74.43; H, 5.65%). v_max (neat) 3294 (C=C-H), 2932.2-2835.8 (C-H), 2100 (C=C), 1608.3 (C=C, Ar^αn ¹; δ_H (300MHz; CDC1₃), 7.35(1H, d, J=8.41, 8-H), 7.3-7.2(4H, m, 2',3',5',6'-H), 6.8(1H, dd, J=8.42Hz and J=2.5Hz, 7-H), 6.75(1H, d, J=2.4Hz, 5-H), 4.5(2H, d, J=2.4Hz, CH₂-CH₂-C=C), 3.85(3H, s, OCH₃), 3.75(2H, s, -£H₂-Ph), 2.8(2H, t, J=8Hz, CH₂-CH₂-C=C), 2.5(1H, t, J=2.3Hz, -CH₂-C=£H), 2.2(2H, t, J=8.1Hz, CH₂-CH₂-C=C).

Claims

Claims:

1. A benzyl or benzylidene tetralin represented by the general formula (I)

X is halogen, amino or nitro; and

Y is hydroxyl or an alkoxy or aryloxy group; or a pharmaceutically acceptable salt of said benzyl or benzylidene tetralin.

2. A benzyl or benzylidene tetralin according to claim 1 , wherein Y is hydroxy or an alkoxy group containing not more than four carbon atoms.

3. A benzyl or benzylidene tetralin according to claim 2, wherein Y is methoxy.

4. A benzyl or benzylidene tetralin according to any of claims 1 to 3, wherein X is chloro or amino.

5. A benzyl or benzylidene tetralin according to any of claims 1 to 4, wherein R¹ and R² together comprise =O, or R¹ completes a carbon-carbon double bond with the carbon at position 2 and R² is an oxyalkynyl group.

6. A benzyl or benzylidene tetralin according to claim 1, wherein Y is hydroxyl at position 6, x is two and X is an amino group at position 4.

7. A benzyl or benzylidene tetralin according to any of claims 1 to 5 for use in medical therapy.

8. A benzyl or benzylidene tetralin according to any of claims 1 to 7, for use as a medicament for inhibition of retinoic acid metabolism.

9. A pharmaceutical formulation suitable for use in the treatment of a skin condition or cancer, which formulation comprises a benzyl or benzylidene tetralin according to any of claims 1 to 6, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

10. A pharmaceutical formulation according to claim 9, which is suitable for topical use.

11. A pharmaceutical formulation according to claim 10, which is a gel, foam, cream, salve, emollient or ointment.

12. A pharmaceutical formulation according to claim 10 or 11, wherein said benzyl or benzylidene tetralin is in the form of a free base.

13. A pharmaceutical formulation according to any of claims 9 to 12, in which the pharmaceutically acceptable carrier, diluent or excipient is substantially non-aqueous.

14. A pharmaceutical formulation according to claim 13, which contains paraffin wax.

15. A pharmaceutical formulation according to any of claims 10 to 14, which contains said benzyl or benzylidene tetralin or pharmaceutically acceptable salt thereof in an amount of 1 to 3%.

16. A pharmaceutical formulation according to claim 9, which is suitable for oral use.

17. A pharmaceutical formulation according to claim 16, wherein said benzyl or benzylidene tetralin is in the form of a hydrochloride salt or a free base.

18. A pharmaceutical formulation according to claim 16 or 17, in which the pharmaceutically acceptable carrier, diluent or excipient comprises lactose, microcrystalline cellulose and/or calcium phosphate dihydrate.

19. A pharmaceutical formulation according to any of claims 16 to 18, which is in the form of a unit dose such that said formulation can be administered in an amount of 150 to 250mg daily.

20. A benzyl or benzylidene tetralin according to any of claims 1 to 8, for use in the treatment of a dermatological condition.

21. A benzyl or benzylidene tetralin according to claim 20, wherein said dermatological condition comprises ichthyosis, acne, psoriasis, wrinkles or photodamaged skin.

22. Use of a benzyl or benzylidene tetralin according to any of claims 1 to 8 in the preparation of a medicament for use in the treatment of a dermatological condition.