WO2002092100A1 - 17-(c(ch3) (ch2) o-3c (r4, r5) n (r6, r7))-substituted 19-nor-pregna-1, 3, 5(10)-triene derivatives and their medical use - Google Patents

Abstract

Compounds of formula (I) in which: R1 represents a hydrogen atom or an o-protecting group; R2 represents a hydroxyl, lower alkoxy, carboxaldehyde, lower alk-1-enyl or hydroxy- or lower alkoxy-substituted lower alkyl group; R3 represents a methyl group having α- or β- configuration; X represents a C¿1-3? alkylene group or a valence bond; Y represents a group of formula -C(R?4) (R5)NR6R7¿ where R?4 and R5¿, which may be the same or different, are each selected from hydrogen atoms, alkyl, alkenyl and alkynyl groups such that the total carbon content of R?4 and R5¿ does not exceed three atoms; R6 represents a hydrogen atom, an aliphatic or araliphatic organic group, or an acyl group comprising an aliphatic, araliphatic or aryl organic group linked to the nitrogen atom by way of a carbonyl group; and R7 is a hydrogen atom or a lower alkyl group; and the dotted line signifies that a double bond may optionally be present at the 16(17)-position exhibit potent cell modulating activity, including antiproliferative and antiangiogenic effects.

Description

7- (C ( CH3 ) ( CH2 ) 0-3 C (R4 , R5 ) N (R6 , R7 ) ) -SUBSTITUTED 19-NOR-PREGNA-l , 3 , 5 ( 10 ) TRIENE DERIVATIVES AND THEIR MEDICAL USE

This invention relates to novel sterol derivatives, more particularly to 2-substituted ring A aromatic sterol derivatives having a comparatively short Imposition hydrocarbyl side chain which terminates in an optionally substituted amino group. Such compounds have been found to have cell modulating activity and may exhibit valuable antiproliferative and antiangiogenic effects .

WO-A-0068246 discloses a range of 3-sterols and O- protected derivatives having an aromatic A-ring and a 17-position side chain which terminates with an amine, amide or hydroxyl group attached to a tertiary carbon atom. These compounds exhibit potent effects on the modulation of cell growth and differentiation, for example as demonstrated by their ability to inhibit growth of cancer cells in vi tro and in vivo, while possessing an advantageous therapeutic ratio by virtue of their low levels of calcaemic activity, for example as determined by their effects on serum calcium and phosphorus levels in rats. In this respect the activity of the compounds resembles that of various vitamin D analogues despite the fact that they have an intact tetracyclic nucleus and lack both the seco steroid triene system of vitamin D analogues and the ability to mimic a conjugated conformational isomer thereof.

It is also known that 2-methoxyoestradiol, which like 2-methoxyoestrone is a natural metabolite of oestradiol, prevents proliferation and promotes the death of cancer cells in vivo . Studies have suggested that these effects are at least in part mediated by inhibition or misdirection of tubulin polymerisation in a manner similar to that exhibited by colchicine; thus the metabolite has been observed to bind to the colchicine binding site of tubulin. As noted by Cushman et al . in J^". Med. Chem . 38 (12 ) , pp. 2041-2049 [1995] , 2-methoxyoestradiol has also been found to inhibit angiogenesis (the creation of new blood vessels) ; this is potentially an extremely valuable property in cancer treatment, since angiogenesis is required for the growth of solid tumours . Both Cushman et al . ( op. ci t . ) and Lovely et al . in J^". Med. Chem. 39 (9) , pp. 1917-1923 [1996] report the synthesis and evaluation for cytotoxicity of various 2- methoxyoestradiol analogues; all the compounds investigated w'ere 17-ones or optionally substituted 17- ols .

The antiproliferative and antiangiogenic effects of 2-methoxyoestradiol are discussed by Pribluda et al . in Cancer and Metastatic Reviews 19 (1 -2 ) , pp. 173-179

[2000] , where it is stated that it targets both tumour cell and endothelial cell compartments by inducing apoptosis in rapidly proliferating cells and inhibiting blood vessel formation at several stages in the angiogenic cascade. It is also said to inhibit metastatic spread in several models.

Dubey et al . in Biochem . Biophys . Comm . 278 (1 ) , pp. 27-33 [2000] report that endogenous methoxyoestradiols mediate the antimitogenic effects of oestradiol on vascular smooth muscle cells via oestrogen receptor- independent mechanisms .

WO-A-9933859 discloses a variety of 1,3,5- oestratrienes having heteroatom-containing hydrocarbyl side chains at the 17-position. The compounds are said to be oestrogen antagonists and there is no suggestion that they may exhibit antiproliferative or antiangiogenic effects or colchicine-like interference with tubulin polymerisation.

WO-A-9933858 discloses 3-sulphamoyloxy-l, 3 , 5- oestratrienes which contain relatively short hydrocarbyl side chains at the 17-position and which are said to act as inhibitors of steroidal sulphatase enzymes . Again there is no suggestion that they may exhibit antiproliferative or antiangiogenic effects or colchicine-like interference with tubulin polymerisation . The present invention- is based on the unexpected finding that a range of 2-substituted ring A aromatic sterol derivatives having a comparatively short 17- position hydrocarbyl side chain which terminates in an optionally N- and/or C-substituted aminomethyl group exhibit potent cell modulating activity. Tissue culture assays show such compounds to exhibit dose response curves characteristic of colchicine, suggesting that their antiproliferative activity derives at least in part from colchicine-like interference with tubulin polymerisation. Compounds of the invention may therefore inhibit angiogenesis in analogous but more potent manner compared to compounds such as 2- methoxyoestradiol .

According to one embodiment of the invention there are provided compounds of formula (I)

in which:

R¹ represents a hydrogen atom or an O-protecting group;

R² represents a hydroxyl, lower alkoxy, carboxaldehyde, lower alk-l-enyl or hydroxy- or lower alkoxy-substituted lower alkyl group;

R³ represents a methyl group having α- or β- configuration; X represents a C^ alkylene group or a valence bond;

Y represents a group of formula -C(R⁴) (R⁵)NR⁶R⁷ where R⁴ and R⁵, which may be the same or different, are each selected from hydrogen atoms, alkyl, alkenyl and alkynyl groups such that the total carbon content of R⁴ and R⁵ does not exceed three atoms; R⁶ represents a hydrogen atom, an aliphatic or araliphatic organic group, or an acyl group comprising an aliphatic, araliphatic or aryl organic group linked to the nitrogen atom by way of a carbonyl group<; and R⁷ is a hydrogen atom or a lower alkyl group; and the dotted line signifies that a double bond may optionally be present at the 16 (17) -position. O-protecting groups present as R¹ groups may, for example, comprise any suitable cleavable O-protecting group such as is known in the art. Representative groups include (i) etherifying groups such as silyl groups (e.g. tri (lower alkyl) silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl or t- butyldimethylsilyl; tri (aryl) silyl groups, e.g. tri (C₆_₁₂ aryl) silyl groups such as triphenylsilyl; and mixed alkyl-arylsilyl groups), lower (e.g. Cι_₆) alkyl groups optionally interrupted by an oxygen atom (e.g. such as methyl, ethyl, methoxymethyl or methoxyethoxymethyl) or substituted by a lower (e.g. C₃_₈) cycloalkyl group (e.g. as in cyclopentylmethyl) or by an acyloxy group (e.g. by a lower alkanoyloxy group, for example as in pivaloyloxymethyl) , and cyclic ether groups (e.g. containing up to 6 carbon atoms, as in tetrahydropyranyl) , and (ii) esterifying groups such as lower (e.g. χ_₆) alkanoyl (e.g. such as acetyl, propionyl, isobutyryl, pivaloyl or hemisuccinyl) , aroyl (e.g. containing 7-15 carbon atoms, such as benzoyl or 4-phenylazobenzoyl) , lower (e.g. C_τ_₆) alkane sulphonyl (e.g. such as methane sulphonyl or a halogenated group such as methane sulphonyl), arene sulphonyl (e.g. a C₆_ι₂ group such as p-toluene sulphonyl) , and sulphamoyl, for example groups of formula (R⁸) (R⁹)N.S0₂- where R⁸ and R⁹ are each independently selected from hydrogen atoms and lower (e.g. Cχ.₆) alkyl groups or together form a lower (e.g. C₃_₁₀) alkylene chain optionally interrupted by one or more heteroatoms selected from 0, N and S.

Where R² represents a lower alkoxy group, this may for example be a straight chain or branched C_x_₆ alkoxy group such as a methoxy, ethoxy or propoxy group. Lower alk-l-enyl groups may, for example, contain 2-6 carbon atoms, e.g. as in vinyl, prop-1-enyl and but-1-enyl groups . Representative hydroxy- and lower alkoxy- substituted lower alkyl groups include hydroxymethyl , 1- and 2 -hydroxyethyl, 1-, 2- and 3-hydroxypropyl and corresponding methoxy- and ethoxy-substituted groups. Lower alkoxy-substituted lower alkyl groups preferably contain up to 6 carbon atoms in total .

Where R³ in formula (I) is a methyl group in the a- configuration, the compounds have the 20R configuration characteristic of natural sterols such as cholesterol; where R³ is in the β-configuration the compounds have the 20S con iguration of the corresponding epi-derivatives . It will be appreciated that the invention also embraces mixtures of the two isomers. Where X is an alkylene group this may, for example, be a methylene, ethylene or trimethylene group. In compounds in which both R⁴ and R⁵ are other than hydrogen, X is preferably a valence bond.

Y may, for example, be an optionally N-substituted aminomethyl group in which R⁴ and R⁵ both represent hydrogen atoms, a group in which one of R⁴ and R⁵ is methyl, ethyl, vinyl, ethynyl or propargyl and the other is hydrogen, or a group in which R⁴ and R⁵ are both methyl . Where R⁶ represents an aliphatic group this may, for example, be a lower alkyl group, e.g. a straight chain or branched Cι_₆ alkyl group such as a methyl, ethyl, propyl or butyl group. Araliphatic groups R⁶ may, for example, include C₆_₁₂ carbocyclic aryl C^ alkyl groups such as benzyl or phenethyl . Where R⁶ represents an acyl group this may, for example, be a lower (e.g. C^g) alkanoyl group such as formyl, acetyl or propionyl; a C₆_₁₂ carbocyclic aryl C₂-₅ alkanoyl group such as phenylacetyl ; or a C₇_₁₃ carbocyclic aroyl group such as benzoyl . The group R⁶ may optionally carry one or more substituents, for example selected from halo (e.g. chloro or bromo) , lower alkyl such as methyl, lower alkoxy (e.g. methoxy), lower alkanoyl (e.g. acetyl), lower alkylamino (e.g. methylamino) , di (lower alkyl) amino (e.g. dimethylamino) , nitro, carbamoyl and lower alkanoylamino (e.g. acetamido) ; in such substituents the qualification "lower" preferably denotes groups containing no more than four carbon atoms .

When R⁷ represents a lower alkyl group this may, for example, be a straight chain or branched C_x_₆ alkyl group such as a methyl, ethyl, propyl or butyl group.

Compounds of formula (I) in which R¹ is hydrogen, a metabolically labile O-protecting group (e.g. a lower alkanoyl group such as acetyl or hemisuccinyl ; an acyloxymethyl group, for example a lower alkanoyloxymethyl group such as pivaloyloxymethyl; or a sulphonyl group, for example as in a sulphate or sulphamate group) or a lower alkyl etherifying 0- protecting group such as methyl, ethyl or isobutyl may be useful directly in therapy. The use of compounds in which R¹ is a biolabile sulphamoyl group may be advantageous, since such groups will tend to inhibit steroid sulphatases which may otherwise degrade steroid- 3-ols formed upon removal of such a protecting group from the 3 -position. Compounds (I) containing non- metabolically labile O-protecting groups (e.g. bulky silyl ether groups such as triisopropyl, t- butyldimethylsilyl or triphenylsilyl) are principally of use as synthetic intermediates.

The cell modulating activity of active compounds according to the invention, combined with their substantial lack of adverse side effects, render them of interest both alone and as adjuncts in the management of diseases associated with abnormal cell proliferation, such as neoplastic disease, particularly myelogenous leukemias as well as neoplastic disease of the brain, breast, stomach, gastrointestinal tract, prostate, pancreas, uro-genital tract (male and female) and pulmonary neoplasia.

Their cell modulating activity suggests that active compounds of the invention may, like other oestrogen response modulators, have additional utilities either alone or as adjuncts in the chemotherapy of infection and in other therapeutic modalities in which mononuclear phagocytes are involved, for example in treatment of bone disease (especially osteoporosis, osteopenia and osteodystrophy as in rickets or renal osteodystrophy) , autoimmune disease, host-graft reaction, transplant rejection, inflammatory diseases (including modulation of immunoinflammatory reactions) , neoplasias and hyperplasias, their potential utility in treatment of neoplasias and hyperplasias being evidenced by their ability to inhibit growth of a variety of human cancer cells. Additionally, they may be useful in treatment of dermatological diseases (for example including acne, alopecia, eczema, pruritus, psoriasis and skin aging, including photoaging) , hypertension, rheumatoid arthritis, psoriatic arthritis, asthma, cognitive impairment and senile dementia (including Alzheimer's disease) , in fertility control in both human and animal subjects, in lowering elevated serum cholesterol, and in management of disorders involving blood clotting (e.g. by dissolution of existing clots and/or by prevention of clotting) . The invention embraces use of these compounds in the therapy or prophylaxis of such conditions and in the manufacture of medicaments for use in such treatment or prophylaxis.

Active compounds according to the invention may be formulated for administration by any convenient route, e.g. orally (including sublingually) , parenterally, rectally or by inhalation; pharmaceutical compositions so formulated comprise a feature of the invention.

Orally administrable compositions may, if desired, contain one or more physiologically compatible carriers and/or excipients and may be solid or liquid. The compositions may take any convenient form including, for example, tablets, coated tablets, capsules, lozenges, aqueous or oily suspensions, solutions, emulsions, syrups, elixirs and dry products suitable for reconstitution with water or another suitable liquid vehicle before use. The compositions may advantageously be prepared in dosage unit form. Tablets and capsules according to "the invention may, if desired, contain conventional ingredients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl-pyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. Tablets may be coated according to methods well known in the art .

Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles, which may include edible oils, for example vegetable oils such as arachis oil, almond oil, fractionated coconut oil, fish- liver oils, oily esters such as polysorbate 80, propylene glycol, or ethyl alcohol; and preservatives, for example methyl or propyl -hydroxybenzoates or sorbic acid. Liquid compositions may conveniently be encapsulated in, for example, gelatin to give a product in dosage unit form.

Compositions for parenteral administration may be formulated using an injectable liquid carrier such as sterile pyrogen-free water, sterile peroxide-free ethyl oleate, dehydrated alcohol or propylene glycol or a dehydrated alcohol/propylene glycol mixture, and may be injected intravenously, intraperitoneally or intramuscularly.

Compositions for rectal administration may be formulated using a conventional suppository base such as cocoa butter or another glyceride .

Compositions for administration by inhalation are conveniently formulated for self-propelled delivery, e.g. in metered dose form, for example as a suspension in a propellant such as a halogenated hydrocarbon filled into an aerosol container provided with a metering dispense valve.

It may be advantageous to incorporate an antioxidant, for example ascorbic acid, butylated hydroxyanisole or hydroquinone in the compositions of the invention to enhance their storage life.

Where any of the above compositions are prepared in dosage unit form these may for example contain 2 μg - 100 mg of active compound according to the invention per unit dosage form; such dosage units may for example be administered 1-4 times per day. The compositions may if desired incorporate one or more further active ingredients .

A suitable daily dose of an active compound according to the invention may for example be in the range 2 μg - 400 mg per day, depending on factors such as the severity of the condition being treated and the age, weight and condition of the subject. Compounds according to the invention may be prepared by any convenient method, for example by reaction of a compound containing a precursor for the desired 17-position side chain in one or more stages and with one or more reactants serving to form the desired 17-position side chain, followed if necessary and/or desired by removal of any O-protecting group.

Appropriate techniques for formation of a desired side chain include those described in WO-A- 9516672 and WO-A-0068246.

Thus, for example, compounds of the invention may be prepared from appropriately 2-substituted, e.g. 2 - hydroxylated or 2-alkoxylated, derivatives of oestrone by, for example, Wit ig reaction with an ethylidene phosphorane to convert the 17-one to the corresponding 17 (20) -ethylidene compound, following the procedure described by Krubiner and Oliveto, J^". Org . Chem. 31 , pp. 24-26 [1965] . Alternatively, the corresponding E-isomer may be obtained following the procedure of Midland and Kwon, Tetrahedron Lett . 23 (20) , pp. 2077-2080 [1982]. The thus-obtained alkenes may be subjected to conventional stereospecific hydroboration reactions followed by oxidative work-up with alkaline hydrogen peroxide solution (Krubiner, op . ci t . ) to afford the corresponding 20-ols, which may be oxidised to 20-ones with chromium trioxide (Krubiner, op. ci t . ) . Wittig reaction with methoxymethylenetriphenyl-phosphorane followed by hydrolysis of the enol ether with aqueous acid gives a non-stereospecific compound (I) in which X is a valence bond and Y is an aldehyde group. Reduction with sodium borohydride gives a corresponding compound of formula (I) wherein X is a valence bond and Y is hydroxymethyl .

Compounds of the invention having a double bond at the 16 (17) -position may, for example, be prepared stereospecifically by subjecting the appropriate E- or Z-17(20) ethylidene compound prepared as described above to a stereospecific ene reaction. For example, such ene reactions include treatment with ormaldehyde, boron trifluoride and optionally acetic anhydride (Batcho et al . , Helv. Chi . Acta 64 , pp. 1682-1687 [1981]) to form compounds of formula (I) in which X is a valence bond and Y is hydroxymethyl or acetoxymethyl . In an alternative ene reaction, treatment with ethyl propiolate/diethyl aluminium chloride (Dauben and Brookhart, J^". Am . Chem . Soc . 103 , pp. 237-238 [1980]) affords ethyl esters of Δl6,17 acids which may be reduced to give compounds in which Y is hydroxymethyl . Where appropriate the Δl6,17 compounds described above may be stereospecifically hydrogenated, e.g. catalytically, to form a single bond at the 16 (17) - position.

The acetyl group in compounds in which Y is acetoxymethyl may be removed by hydrolysis and replaced by a leaving group such as tosyloxy. Homologation reactions may then be performed to increase the size of X, these including (i) treatment with a metal cyanide, hydrolysing the cyano group to yield a carboxy group or reducing the cyano group (e.g. with a metal hydride reducing agent such as diisobutyl aluminium hydride) to yield a carboxaldehyde group, and where appropriate reducing the carboxy or carboxaldehyde group (e.g. using sodium borohydride or lithium aluminium hydride) to yield a hydroxymethyl group which may in turn be subjected to tosylation and, if desired, further nucleophilic displacement; and (ii) treatment with a metallated derivative of an ester or thioester of acetic acid, with a derivative containing another carbanionic equivalent of acetic acid (e.g. a metallated derivative of acetonitrile) , or with a metallated malonate ester (in which last instance the reaction product is partially hydrolysed to yield a monoester which may be decarboxylated by heating to yield a carboxylate ester) , reducing the resulting ester or thioester product to an alcohol (e.g. using lithium aluminium hydride), and converting the resulting hydroxyl group to a leaving group, such as a tosylate group or a halogen atom, e.g. as hereinbefore described. Alternatively, compounds in which Y is a carboxaldehyde group may be homologated by Wittig reaction with methoxymethylenetriphenyl- phosphorane followed by hydrolysis of the resulting enol ether, e.g. with aqueous acid.

It will be appreciated that such procedures may be repeated as needed to yield compounds (I) in which X is a desired alkylene group.

Hydroxy-terminated compounds in which R⁴ and/or R⁵ are other than hydrogen may be prepared by conventional means, for instance from a corresponding aldehyde or ketone by reaction with an appropriate organometallic reagent, for example a Grignard reagent, metal acetylide, alkyl lithium or alkyl silane.

Terminal hydroxyl groups in the side chains of compounds as described above may be converted to leaving groups, for example sulphonate ester groups (e.g. lower alkyl sulphonyloxy groups such as mesyloxy, lower fluoroalkyl sulphonyloxy groups such as trifluoromethane sulphonyloxy or aryl sulphonyloxy groups such as tosyloxy) or halogen atoms (e.g. chlorine, bromine or iodine) , and thence to amine precursor functional groups such as cyano or azido (e.g. by reaction with an appropriate alkali metal salt) ; the thus-obtained compounds may be reduced to yield amine group-terminated products . Compounds of formula (I) in which R⁶ represents a lower alkanoyl, aralkanoyl or aroyl group and R⁷ represents a hydrogen atom may be prepared by acylation of a corresponding compound (I) in which R⁶ is hydrogen, for example by reaction with an appropriate acyl halide or acid anhydride, preferably in the presence of water or a lower alcohol as may typically be incorporated to suppress acylation of groups other than the amino group, or with an appropriate acid in the presence of a coupling agent such as N,N' -carbonyldiimidazole or dicyclohexylcarbodiimide. It will be appreciated that if the acylation is carried out in the absence of components such as water or lower alcohols which suppress the acylation of hydroxyl groups, then any hydroxyl groups present in the molecule, e.g. at the 2- or 3- position, should desirably be in O-protected form during such an acylation reaction. Compounds of formula (I) in which R⁶ represents an aliphatic or araliphatic group and R⁷ represents a hydrogen atom may, for example, be prepared by reducing a corresponding compound (I) in which R⁶ is an aliphatic, araliphatic or aryl acyl group, e.g. using a metal hydride reducing agent such as lithium aluminium hydride .

Compounds of formula (I) in which at least one of R⁶ and R⁷ represents a hydrogen atom may be subjected to appropriate substitution reactions to introduce desired R⁶ and/or R⁷ groups, for example to direct alkylation

(e.g. by reaction with an alkyl halide) or to reductive amination (e.g. by reaction with an appropriate aldehyde and a reducing agent such as sodium cyanoborohydride) . Compounds according to the invention may also be prepared from a 2-unsubstituted oestrogen by building up the desired 17-position side chain and then introducing the desired 2-substituent as a later step, for instance by following the procedures of Cushman et al . {op . ci t . ) . The key 2-formyl compounds used in such procedures are conveniently prepared by formation of a 3 -methoxymethyl ether, selective lithiation at the 2- position and formylation with dimethylformamide according to the procedure of Lovely et al . { op. ci t . ) . Sulphamoyl R¹ groups may be introduced by conventional methods such as reaction with an appropriate sulphamoyl chloride in the presence of a mild base, e.g. as described by Schwartz et al . in Steroids 61 , pp. 710-717 [1996] or as described in WO-A- 9933858.

In general, O-protecting groups may, for example, be removed by conventional methods such as are well documented in the literature. Thus esterifying acyl groups may be removed by basic hydrolysis, e.g. using an alkali metal alkoxide in an alkanol . Etherifying groups such as silyl groups may be removed by acid hydrolysis or treatment with a fluoride salt, e.g. a tetraalkyl ammonium fluoride. The use of such acid-labile but base-stable protecting groups may be of particular advantage during homologation steps to build up a desired side chain, in view of the strongly basic conditions normally employed for such reactions. The contents of all documents referred to in this specification are incorporated herein by reference. The following non-limitative examples serve to illustrate the invention. All temperatures are in °C.

Preparation 1

2 - βthoxy- 3 - triisopropylsilyloxy- 19 -nor-prβqn- 1 , 3 , 5 (10 ) . 17 (20 ) Z- tetraene

Sodium hydride (294 mg, 50%) in dimethylsulphoxide (6 ml) was stirred at 70° for 1 hour, then cooled to room temperature. Ethyltriphenylphosphonium iodide (2.75 g) in dimethylsulphoxide (10 ml) was added dropwise and the mixture was stirred for 30 minutes. A solution of 2-methoxy-oestrone-3-triisopropylsilyl ether (600 mg, prepared by silylation of the 3 -OH compound with triisopropylsilyl chloride and imidazole in dichloromethane overnight at room temperature) in dimethylsulphoxide (10 ml) was added dropwise. The resulting solution was stirred for 30 minutes, whereafter the temperature was raised to 70° and stirring was continued overnight. The reaction mixture was then cooled and worked up. Separation and purification of the products by chromatography gave the title compound (125 mg, see below) and the 3 -OH analogue (300 mg) : IR (CDC1₃) v_max 1590, 3520 cm^"1; NMR (CDC1₃)- δ 0.9 (s, 18-H's), 1.67 (d, =CH-CH's), 3.8 (s, OCH's), 4.7-5.2 (q, =CHMe) , 6.5, 6.7 (s, 1,4-H's).

Silylation of this 3-OH compound (300 mg) as above and purification of the product by chromatography gave the title compound (370 mg) : IR (CDC1₃) v_max 1600 cm^"1; NMR (CDC1₃) δ 0.9 (s, 18-H's), 1.68 (d, =CH-CH's), 3.7 (s, OCH's), 4.7-5.3 (q, =CH-Me) , 6.4, 6.6 (s-, 1,4-H's). Preparation 2

2 -Methoxy-3-triisopropylsilyloxy-2Oce-acetoxymethyl-19- nor-pregna-1, 3 , 5 (10) .16-tetraβne [Formula (I): R¹ = (i- Pr)₃Si. R² = CH₃Q, R³ = α-CH₃. X = valence bond. Y = CH,OCOCH₃. Δ16 double bond!

A mixture of boron trifluoride etherate (6 μl) and acetic anhydride (0.66 ml) in dichloromethane (0.3 ml) was added dropwise to a solution of 2-methoxy-3-triiso- propylsilyloxy-19-nor-pregn-l, 3 , 5 (10) , 17 (20) Z-tetraene from Preparation 1 (0.20 g) in dichloromethane (1 ml) containing acetic anhydride (0.1 ml) and paraformaldehyde (13 mg) . The mixture was stirred for 2 hours, whereafter saturated sodium hydrogen carbonate was added and stirring was continued for 3 hours. The product was isolated by extraction into dichloromethane and purified by chromatography to give the title compound (205 mg) : IR (CDC1₃) v_max 1605, 1725 cm^"1; NMR (CDC1₃) δ 0.73 (s, 18-H's), 1.97 (s, OCOCH's), 3.6 (s,

OCH's), 3.7-4.3 (b, 22-H's), 5.2-5.5 (bs, 16-H's), 6.4, 6.57 (s, 1,4-H's) .

Preparation 3

2-Methoxy-3 -triisopropylsilyloxy-2Oα-hydroxymethyl-19- nor-pregn-1,3.5, (10) -triene [Formula (I): R¹ = (i-Pr₃)Si, R² = CH₃0, R³ = α-CH₃. X = valence bond. Y = CHOHl

The 20α-acetoxymethyl product from Preparation 2 (360 mg) was first deacetylated by treatment with lithium aluminium hydride (1.2 ml, 2.5 eq.) in ether (7 ml) for 30 minutes at room temperature. The thus-obtained crude 20c.-hydroxymeth.yl compound (200 mg) was then hydrogenated over 5% platinum on carbon (40 mg) in ethanol (10 ml) . Filtration and removal of the solvent gave the title compound (175 mg) : IR (CDC1₃) v_raax 1600, 3300-3640 cm^"1; NMR (CDC1₃) δ 0.73 (s, 18-Me) , 3.1-3.5 (m, 22-H; s, OMe) , 6.43, 6.6(ea s, 1,4-H's) .

Preparation 4 >

2 -Methoxy- 3- riisopropylsilyloxy- 2 Oα-p- toluenβsulphonyl - oxymβthyl-19-nor-pregn-1.3.5 (10) -triene [Formula (I) : R^{1 ■}= (i-Pr)₃Si. R² = CH₃Q. R³ = α-CH₃, X = valence bond, Y = CHgO.tosyll

The 20-hydroxymethyl compound from Preparation 3 (140 mg) in methylene chloride (2 ml) containing tosyl chloride (135 mg) and pyridine (0.3 ml) was stirred overnight at room temperature, treated with saturated aqueous sodium bicarbonate and stirred for a further 2.5 hours. Work up and purification by preparative thin layer chromatography gave the title compound (180 mg) : IR (CDC1₃) v_max 1590 cm^-1; NMR (CDC1₃) δ 0.67 (s, 18-Me), 2.36 (s, tosyl-Me) , 3.67 (s, OMe), 6.35, 6.53 (ea s, 1,4-H's), 6.8-7.8 (q, tosyl Ar-H ' s) .

Preparation 5

2 -Methoxy-3 -triisopropylsilyloxy-2Oα-bromomethyl-19-nor- pregn-1.3,5 (10) -triene [Formula (I); R¹ = (i-Pr)₃Si, R² = CH₃Q. R³ = α-CH₃, X = valence bond. Y = CH₂Br]

The tosylate from Preparation 4 (180 mg) in acetonitrile (5 ml) and dichloroethane (5 ml) containing lithium bromide (313 mg, 10 equiv) was heated under reflux overnight . Work up and purification by preparative thin layer chromatography gave the title compound (125 mg) : NMR (CDC1₃) δ 0.7 (s, 18-Me), 3.0-3.9 (m, 22-H's; s, OMe), 6.36, 6.53 (ea s, 1,4-H's). Example 1

a) 2-Me hoxy-3-triisopropylsilyloxy-20Q:-azidomethyl- 19-nor-pregn-l,3.5 (10) -triene [Formula (I): R¹ = (i- Pr)₃Si, R² = CH₃Q. R³ == -CH₃. X = valence bond. Y = CH₂N₃1

The 20-bromomethyl compound from Preparation 5 (125 mg) in methylene chloride (3 ml) and water (3 ml) containing sodium azide (728 mg) and tetrabutylammonium bromide (15 mg) was stirred overnight at 80°, whereafter the product was extracted /into ethyl acetate . Work up and purification by preparative thin layer chromatography gave the title compound (115 mg) : IR (CDC1₃) v_raax 1590, 2100 cm^"1; NMR (CDC1₃) δ 0.67 (s, 18-Me), 3.63 (s, OMe), 6.37, 6.53 (ea s, 1,4-H's).

b) 2 -Methoxy- 3 - triisopropylsilyloxy- 2 Oo - aminomethyl- 19 -nor-prβgn- 1 . 3 . 5 ( 10 ) - triene [Formula ( I) ; R¹ = ( i - Pr) ₃Si . R² = CH₃Q , R³ = α-CH₃. X = valence bond. Y = CH₂NH₂1

Lithium aluminium hydride (0.55 ml, 1M in ether) was added dropwise to a solution of the 20-azidomethyl compound from (a) above (115 mg) in ether (2.2 ml) and the resulting mixture was stirred for 1 hour. Work up gave crude title compound (110 mg) : IR (CDC1₃) v_max 1600 cm^-1; NMR (CDC1₃) δ 0.73 (s, 18-Me), 3.7 (s, OMe), 6.4, 6.63 (ea s, 1,4-H's) .

c 2-Methoxy-3-hydroxy-20α-aminomβthyl-19-nor-pregn- 1.3.5(10) -triene [Formula (I): R¹ = H. R² = CH₃Q. R³ = α- CH₃. X = valence bond. Y = CH,NH₂]

The silyl ether from (b) above (50 mg) was desilylated by treatment with tetrabutylammonium fluoride (0.3 ml) in tetrahydrofuran (0.3 ml) for 4 hours at room temperature. Work up and purification by preparative thin layer chromatography gave the title compound (20 mg) : NMR (CDCl₃) δ 0.77 (s, 18-Me), 3.77 (s, OMe), 6.43, 6.63 (ea s, 1,4-H's) .

Example 2

a) 2 -Methoxy-3 -triisopropylsilyloxy-20α- acetamidomethyl-19-nor-pregn-l, 3 , 5 (10) -triene [Formula (I); R¹ = (i-Pr)₃Si. R² = CH₃Q. R³ = α-CH₃. X = valence bond. Y = CH .NH.CO.CH₃1

The silyl ether from Example 1(b) (60 mg) in methylene chloride (1 ml) containing acetic anhydride (100 μl) and pyridine (100 μl) was stirred overnight at room temperature. Work up gave crude title compound (70 mg) : IR (CDC1₃) v_max 1600, 1660, 3650 cm^"1; NMR (CDCl₃) δ 0.7 (s, 18-Me), 1.95 (s, acetyl), 3.67 (s, OMe), 5.3-5.7 (m, NH) , 6.4, 6.6 (ea s, 1,4-H's).

h∑ 2 -Methoxy-3 -hydroxy-20c.-acetamidometh.yl-19-nor- pregn-1,3, 5 (10) -triene [Formula (I): R¹ = H, R² = CH₃Q, R³ = α-CH₃, X = valence bond. Y = CH .NH.CO.CH₃1

The silyl ether from (a) above (70 mg) was desilylated by treatment with tetrabutylammonium fluoride (0.3 ml) in tetrahydrofuran (0.3 ml) overnight at room temperature. Work up and purification by preparative thin layer chromatography gave the title compound (20 mg) : IR (CDC1₃) v_raax 1600, 1665, 3200-3600 cm^"1; NMR (CDC1₃) δ 0.73 (s, 18-Me), 1.0 (d, 21-Me) , 1.93 (s, acetyl), 3.77 (s, OMe), 6.47, 6.63 (ea s, 1,4-H's).

Claims

Claims

1. Compounds of formula (I)

in which:

R¹ represents a hydrogen atom or an O-protecting group;

R² represents a hydroxyl, lower alkoxy, .carboxaldehyde, lower alk-l-enyl or hydroxy- or lower alkoxy-substituted lower alkyl group;

R³ represents a methyl group having α- or β- configuration;

X represents a C^ alkylene group or a valence bond;

Y represents a group of formula -C(R⁴) (R⁵)NR⁶R⁷ where R⁴ and R⁵, which may be the same or different, are each selected from hydrogen atoms, alkyl, alkenyl and alkynyl groups such that the total carbon content of R⁴ and R⁵ does not exceed three atoms; R⁶ represents a hydrogen atom, an aliphatic or araliphatic organic group, or an acyl group comprising an aliphatic, araliphatic or aryl organic group linked to the nitrogen atom by way of a — ^* carbonyl group; and R⁷ is a hydrogen atom or a lower alkyl group; and the dotted line signifies that a double bond may optionally be present at the 16 (17) -position.

2. Compounds as claimed in claim 1 wherein R¹ is a hydrogen atom, a lower alkyl group or a metabolically labile O-protecting group.

3. Compounds as claimed in claim 1 or claim 2 wherein R² is a hydroxy group or a lower alkoxy group.

4. Compounds as claimed in any of the preceding claims wherein X is a valence bond.

5. Compounds as claimed in claim 4 wherein R⁴ and R⁵ are both other than hydrogen.

6. Compounds as claimed in any of claims 1 to 4 wherein R⁴ is a hydrogen atom and R^s is selected from hydrogen, methyl, ethyl, vinyl, ethynyl and propargyl, or wherein R⁴ and R⁵ are both methyl groups .

7. Compounds as claimed in any of the preceding claims wherein R⁶ is a hydrogen atom, a lower alkyl group or a lower alkanoyl group.

8. Compounds as claimed in any of the preceding claims wherein R⁷ is a hydrogen atom.

9. The compounds : 2-methoxy-3-hydroxy-20α-aminomethyl-19-nor-pregn- 1, 3, 5 (10) -triene and

2-methoxy-3-hydroxy-20α-acetamidomethyl-19-nor- pregn-1, 3,5 (10) -triene .

10. Active compounds of formula (I) as claimed in any of the preceding claims for use in management of neoplastic disease; in treatment of bone diseases, autoimmune disease, host-graft reaction, transplant rejection, inflammatory diseases, neoplasias or hyperplasias, dermatological diseases, hypertension, rheumatoid arthritis, psoriatic arthritis, asthma, cognitive impairment or senile dementia; in fertility control in human or animal subjects; in lowering elevated serum cholesterol or in management of disorders involving blood clotting.

11. Active compounds of formula (I) as claimed in any of claims 1 to 9 for use as antiangiogenics or for the manufacture of a medicament for use as an antiangiogenic .

12. The use of an active compound of formula (I) as claimed in any of claims 1 to 9 for the manufacture of a medicament for use in management of neoplastic disease; in treatment of bone diseases, autoimmune disease, host- graft reaction, transplant rejection, inflammatory diseases, neoplasias or hyperplasias, dermatological diseases, hypertension, rheumatoid arthritis, psoriatic arthritis, asthma, cognitive impairment or senile dementia; in fertility control in human or animal subjects; in lowering elevated serum cholesterol or in management of disorders involving blood clotting.

13. Pharmaceutical compositions comprising an active compound of formula (I) as claimed in any of claims 1 to 9 in admixture with one or more physiologically acceptable carriers or excipients.

14. A method of treatment of a human or non-human animal subject in management of neoplastic disease; in treatment of bone diseases, autoimmune disease, host- graft reaction, transplant rejection, inflammatory ._ _ . . diseases, neoplasias or hyperplasias, dermatological diseases, hypertension, rheumatoid arthritis, psoriatic arthritis, asthma, cognitive impairment or senile dementia; in fertility control in human or animal subjects; in lowering elevated serum cholesterol or in management of disorders involving blood clotting, which method comprises administering to said subject a therapeutically effective amount of an active compound of formula (I) as claimed in any of claims 1 to 9.

15. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises reacting a compound containing a precursor for the desired 17-position side chain in one or more stages and with one or more reactants serving to form the desired 17-position side chain, followed if necessary and/or desired by reaction to introduce a desired 2-substituent and/or to remove any O-protecting group.