WO1993012137A1 - Pharmaceutical compositions - Google Patents

Abstract

Compounds of formula (I) in which the dotted line indicates the optional presence of a double bond joining the 6 and 7 positions, A is a divalent group having a chain of at least four atoms joining the oxy group and the group BX, which group A is an aliphatic hydrocarbon group or such a group in which there is replacement by one or more groups selected from formula (1) and phenylene, wherein R is hydrogen or an alkyl group and R' and R'' are the same or different alkyl groups, of one or more carbon atoms, excluding (a) replacement of that carbon atom attached to the group B, (b) replacement of both of any two carbon atoms which are joined either directly or through a single further carbon atom, and, except in the case of the replacement groups (2) and (3), (c) replacement of that carbon atom attached to the oxy group; (B) is selected from formula (4), -COO- and -OCO-, wherein R or each R separately is hydrogen or an alkyl group, X is a sugar residue and Y is hydrogen or an alkyl, alkenyl or alkynyl group, the compound (I) optionally being in the form of a physiologically acceptable ester and/or of a physiologically acceptable salt where appropriate are of value in therapy, for example in the treatment of breast cancer.

Description

PHARMACEUTICAL COMPOSITIONS

This invention relates to novel therapeutic agents and in particular to steroid compounds suitable for use in the treatment of breast cancer.

Breast cancer is responsible for a significant percentage of deaths in women and there is a continuing need for improved agents for its treatment. A relatively recent development involves the use of anti-oestrogenic agents that block the actions of oestrogens on target tissues. Competitive oestrogen antagonists are the most specific anti-oestrogens and tamoxifen [trans-1-(p-2-dimethylamino- ethoxyphenyl)-1,2-diphenylbut-1-ene] is such an antagonist which is widely used in the treatment of breast cancer. We have now identified a group of steroid compounds showing considerable potential as competitive oestrogen antagonists.

Accordingly the present invention comprises a compound of formula (I)

(I)

in which the dotted line indicates the optional presence of a double bond joining the 6 and 7 positions, A is a divalent group having a chain of at least four atoms joining the oxy group and the group BX, which group A is an aliphatic hydrocarbon group or such a group in which there is replacement by one or more groups selected from -O-, -S-,

SO, ^SO₂, ^CO, NR, SiR'R" and phenylene,

wherein R is hydrogen or an alkyl group and R' and R" are the same or different alkyl groups, of one or more carbon atoms, but excluding (a) replacement of that carbon atom attached to the group B, (b) replacement of both of any two carbon atoms which are joined together either directly or through a single further carbon atom and, except in the case of the replacement groups

SO₂ and

CO, (c) replacement of that carbon atom attached to the oxy group,

R R R R R

B is selected from -C-N-, -CO-N-, -N-CO-, -SO₂N-, -COO- and-OCO-

R

wherein R or each R separately is hydrogen or an alkyl group, X is a sugar residue and Y is hydrogen or an alkyl, alkenyl or alkynyl group, the compound (I) optionally being in the form of a

physiologically acceptable ester, and/or of a physiologically acceptable salt where appropriate.

The standard system of numbering the steroid nucleus is used herein as shown in (A) below.

The standard method is also used for indicating stereochemistry, i.e. a thickened line represents a β bond projecting upwardly from the plane of the paper whilst a dotted line represents an α bond projecting downwardly from the plane of the paper. Although the stereochemistry of part of the molecule is as indicated in

formula (I) it will be appreciated that other opportunities for isomerism arise elsewhere in the molecule, in particular within the groups A and X, and that the invention therefore encompasses

compounds (I) in various stereochemical forms, certain of which may be of particular value by virtue of their level of therapeutic activity and/or physical properties such as greater aqueous

solubility, etc. Although, as indicated, the compound (I) may contain an additional double bond as well as its benzene ring it is preferred that the 6 and 7 positions are joined by a single bond.

The chain length of an aliphatic hydrocarbon group A between the oxy group (-O-) and the group BX of the grouping -O-A-B-X present at the 11-position of the steroid compounds of formula (I) is preferably in a range of 4 to 24 atoms, particularly 6 to 20 atoms and especially 8 to 18 or 8 to 16 atoms, for example 10 to 14 atoms (when illustrating the groups A, and also A' and A", hereinafter the left-hand end is that bonded to the oxy group attached to the 11-position of the ring and similarly for the groups B the left-hand end is that bonded to A). Similar

preferences as to chain length apply when A is an aliphatic hydrocarbon group in which one or more carbon atoms is replaced. It will be appreciated that when such replacement is in the chain joining the oxy group and the group BX all of the replacement groups except phenylene effect replacement of the carbon atom in the chain by one alternative atom.

An aliphatic hydrocarbon group A may be saturated or unsaturated and branched or unbranched. The group A may contain one or more carbon-carbon double and/or triple bonds, for example being a group -(CH₂)_m-C=C-(CH₂)_n- or especially -(CH₂)_m-CH=CH-(CH₂)_n- in which m and n are each separately an integer from 1 to 20, and m + n is 2 to 22, particularly each of m and n separately being 2 to 10 and m + n being 4 to 18, especially 8 to 12, for example each of m and n separately being 4, 5 or 6. More preferably, however, A is saturated, for example being a branched group -(CH₂)_m-CH(R')-(CH₂)_n- in which m and n are as just defined but with their total being at least 3, for example each separately being 4, 5 or 6, and R' is an alkyl group, particularly a C_1-4 alkyl group and especially methyl. However straight chain groups A are perhaps of rather greater interest, preferably being of the form -(CH₂)_p- in which p is an integer from 4 to 24, particularly 6 to 20 and especially 8 to 16, for example 10, 11, 12, 13 or 14. As indicated, however, such aliphatic hydrocarbon groups A, particularly aliphatic hydrocarbon groups A which are saturated and conveniently also unbranched, may optionally have at least one of the carbon atoms therein,, particularly those in the chain joining the oxy group and the group BX, replaced by one or more of a variety of groups subject to the exclusions indicated hereinbefore. As regards these exclusions, even in the case of the replacement groups

-CO and particularly

SO₂, it is preferred that the carbon atom attached to the oxy group is not replaced. In addition, it is preferred for replacement at the end of the carbon chain of A adjacent to the group B that the carbon atom of the chain

penultimate to B is also excluded from replacement in the case of the replacement groups -O- and -S- when B is -OCO, the replacement group -O- when B is -NRCO-, and the replacement groups

-SO,

SO₂,

^.CO and NR when B is -CONR- or -COO-, and that for replacement

at the end of the carbon chain of A adjacent to the oxy group that the carbon atom of the chain penultimate to the oxy group is also excluded from replacement in the case of the replacement groups -O-, -S- and -NR-. Moreover, even in the case of the other replacement groups it is preferred that, except for the possibility of replacement of the carbon atom attached to the oxy group by a group

-SO₂ or especially^CO, any replacement of carbon atoms in

the group A is restricted to the atoms, especially those carbon atoms in the chain, which are not attached to or penultimate to the oxy group or the group BX. In this preferred case a group A containing a replacement group in the chain will be derived from an aliphatic hydrocarbon group with a chain of at least five carbon atoms.

One type of replacement group in a group A is a phenylene group which may be bonded at the 1,2 or the 1,3 or particularly the 1,4 positions thereby contributing 1, 2 or 3 carbon atoms to the chain length as compared with the presence of a single carbon atom in A. More preferred as replacement groups, however, are the groups

-CO, NR and

SiR'R" in which R may conveniently be a C_1-6 alkyl group, for example as discussed hereinafter, or more particularly hydrogen, and R' and R" may conveniently be a C_1-4 alkyl group, such as methyl, ethyl or propyl.

Groups A of some interest containing a replacement group are those in which the carbon atom adjacent to the oxy group is replaced by

SO₂ or particularly

^CO. Particularly preferred, however, are groups A which are an aliphatic hydrocarbon group or such a group in which one or more of any of the carbon atoms, within the constraints indicated hereinbefore, are replaced by

SO or

SO₂, and particularly by -S- or especially by -O-. One example of preferred aliphatic hydrocarbon groups in which one or more of the carbon atoms are replaced by -O- has the form

-(CH₂)_h-(O)_a-(CH₂)_i-(O)_b-(CH₂)_j-(O)_c-(CH₂)_k- in which h, i and j are each separately an integer from 2 to 12, k is an integer from 1 to 12 when B is -CR₂NR-, -CONR-, -SO₂NR- or -COO-, and from 2 to 12 when B is -NRCO- or -OCO-, a, b and c are each separately 0 or 1 but with one of a, b and c being 1, and the total number of atoms in the chain is no more than 24, a specific group of this type being -(CH₂)₂-O-(CH₂)₁₁-O-(CH₂)₃-. Another example has the form [-(CH₂)₂-O-]_d-(CH₂)₂- in which d is an integer from 1 to 7, for example 2, 3 or 6 or especially 4 or 5. A third example is a specific type of the first example which is of particular interest and has the form -(CH₂)_m,-O-(CH₂)n,- in which m' is an integer from 2 to 20 and n' is an integer from 1 to 20 when B is -CR₂NR-, -CONR-, -SO₂NR- or -COO-, and from 2 to 12 when B is -NRCO- or -OCO-, with m' + n' being 3 to 23. Specific examples of such groups are those in which m' and n' are each separately an integer from 2 or 1 , respectively, to 14 with m' + n' being 7 to 15 and especially 9 to 13, such as m' = 2 and n' = 7, 8, 9, 10 or 11, or m' = 3 and n' = 6, 7, 8, 9 or 10, or vice versa, one particular group being -(CH₂)₂-O-(CH₂)₇-. In the case of all three examples, and particularly the third, other less preferred examples of groups A which are not entirely hydrocarbon in nature are the analogues thereof in which the group -O- is replaced by -S- or to a lesser extent

SO or

SO₂. The groups A containing oxygen rather than sulphur are, however, of most interest. The group B of the grouping -O-A-B-X may be one of the various, different groups indicated having a chain length of two atoms. Any alkyl groups R (when R is not hydrogen), R' and R" present in A and B may be the same or different and may conveniently be a C_1-6 branched or especially straight chain alkyl group, particularly a C_1-4 alkyl group such as propyl, ethyl and especially methyl. Where more than one group R is present in B these groups are conveniently but not necessarily the same, for example being methyl. Preferably, however, particularly as regards the ease of synthesis of the compounds, the group or groups R in B are hydrogen. Groups B of most interest are the first four of those mentioned hereinbefore, particularly the amide groups such as -NR-CO-, for example -NH-CO-, and especially -CONR-, for example -CONH-.

The group X may be the residue of a wide variety of sugars including mono-, di- and higher saccharides, although the

monosaccharide sugars are of particular interest. The saccharides are preferably either pentoses or hexoses and may be either

aldoses or ketoses although the aldopentoses and especially the aldohexoses are of particular interest. The sugars may be in the straight chain or particularly the furanose and especially the pyranose ring form. Thus, for example, the compounds (I) may contain sugar residues which derive from arabinose, ribose or other aldopentoses or glucose, galactose, mannose or other aldohexoses, and derivatives thereof. The sugar derivatives may incorporate many variations. Thus the aldopentoses may have the C₅H₁₀O₅ formula and the aldohexoses the C₆H₁₂O₆ formula as shown in (B) to (E) below which illustrate, respectively, aldopentoses in the pyranose form, aldopentoses in the furanose form, aldohexoses in the pyranose form and aldohexoses in the furanose form, the

formulae not indicating stereochemistry, the sugars being of various stereochemical forms. O

However it will be appreciated firstly that such sugars of formulae (B) to (E) are particularly adapted for use in the formation of compounds (I) containing a group B of the form -COO- with the sugar residue X consisting of the molecule shown without one of its hydroxy groups, the oxygen atom of which is incorporated into the group B. For the formation of compounds (I) containing other groups B a sugar carrying a group -NHR in which R is as described hereinbefore, in place of one of the hydroxy groups or a group -CO₂H in place of a hydroxymethyl group is suitable. The term "amino sugar" as used herein indicates a sugar containing a substituent -NHR in which R is hydrogen or an alkyl group.

Various other hydroxy group modifications may, however, also be made in the sugars, particularly the replacement of one or more thereof by hydrogen or the conversion of one or more thereof to an ester or an ether group. The ester groups may conveniently take the form described hereinafter in relation to esterified hydroxy groups present at other positions in the compounds (I) and the ether groups may also comprise either aromatic or- aliphatic groups, for example phenyl or a C_1-6 alkyl group and particularly methyl.

One or more hydroxy groups at various positions in the sugars may be modified but as regards replacement of -OH by a -NHR group or oxidation of a -CH₂OH group to a -CO₂H group, which provide a group -NR- or -CO- as part of a group B, such groups are

conveniently at the 2- or 3-position and, indeed, there is a general preference for the sugar residue to be linked at one of these positions. As regards ether formation, this most usually occurs at the 1-position to give a glycoside, for example a methyl glycoside.

Thus, although the group X may be derived from a wide variety of sugars, in many cases the sugar will have one of the formulae (B), (C), (D) and (E) as indicated hereinbefore, optionally modified by one or more of (a) conversion of one or more, but usually one, hydroxy group to a group -NHR or a hydroxymethyl group to a group -CO₂H; (b) conversion of one or more hydroxy groups to hydrogen to provide a deoxy sugar; (c) conversion of one or more hydroxy groups to a group -OR' in which R' is an alkyl or an acyl group; and (d) replacement of the hydroxy group at the 1-position by a second ring (B), (C), (D) or (E) attached via a hydroxy group thereof with the formation of a linkage -O-, the second ring itself optionally being modified by one or more of (a), (b), (c) and (d), although in the case of (d) disaccharides and especially

monosaccharides are of particular interest.

The wide diversity of sugars providing a group X-B- of the form X-NH- is exemplified by the following list of amino sugars from which compound (I) of the present invention may be derived:

D(+)-galactosamine, D-galactopyranosylamine, D(+)-glucosamine, lactosamine, β-mannosamine, neuraminic acid, L-fucosylamine,

2,3-isopropylidene-β-ribofuranosylamine, D(-)-lyxosylamine, methyl L-acosaminide, N-methyl-D-glucamine and methyl-β-L-daunosaminide, such amino sugars being commercially available from suppliers such as the Sigma Chemical Company Ltd.

Preferred sugar residues are derived from a hexapyranose and the last mentioned amino sugar in the above list, which is of particular interest, provides a sugar residue derived from a hexopyranose having the formula (II)

In formula (II) the free valency at the 3-position indicates the point of attachment to the rest of the molecule, conveniently through a group B which is of the form -CRR-NR-, particularly -SO₂NR- or especially -CONR-, wherein R is preferably hydrogen (as indicated on page 2 the right-hand end of the group B is that attached to the sugar residue X). Alternative sugar residues which are also of some interest involve a variation of formula (II) in which one or more of the following changes are present: (a) the 5-methyl group is replaced by another alkyl group as described hereinbefore, for example ethyl, or by a hydroxymethyl group;

(b) the 1-methoxy group is replaced by another alkoxy group OR' in which R' is as described hereinbefore, for example ethoxy, or by a hydroxy group; and (c) a hydrogen atom at the 2-position is replaced by a hydroxy group or, particularly, the free valency at the 3-position is instead located at the 2-position.

Sugar residues of this formula may exist in a wide number of stereoisomeric forms but are of particular interest when having the stereochemistry in which each of the methoxy, hydroxy and methyl groups at the 1, 4 and 5-positions, respectively (or a replacement thereof), and the free valency at the 3- or 2-position are disposed in the same direction (as shown in formula (Ila) below and also for compound 10 on page 64).

There is, however, also interest in sugar residues in which the stereochemistry is varied, in particular so that the 4-hydroxy group is oppositely disposed to the free valency at the 3- or 2-position and the methyl group (or a replacement thereof) at the 5-position (i.e. the groups being in an arabino rather than a lyxo configuration), and, optionally, either alternatively or in addition the 1-alkoxy group is oppositely disposed to the free valency at the 3- or 2-position and the methyl group (or a replacement thereof) at the 5-position (i.e. the glycoside grouping is of the α rather than the β configuration). These variations at the 4- and the 1-positions provide four stereoisomeric forms of the residue of formula (II) which are of particular interest.

Moreover, there is particular interest in a sugar residue of the L-configuration, although it may alternatively be in the DL- or the D-configuration.

As regards the alkyl, alkenyl and alkynyl groups Y, these may be branched or especially straight chain and are conveniently of 1 to 8 carbon atoms but preferably of 1 to 6 carbon atoms. The alkyl groups may conveniently be as described hereinbefore for R', for example being a C_1-3 alkyl group such as propyl, methyl and especially ethyl, and the alkenyl and alkynyl groups may

conveniently be of the form -CH=CHR or -C≡CR wherein R is as defined hereinbefore, particularly being hydrogen or a C_1-3 alkyl group such as propyl, ethyl and especially methyl, examples of such groups being vinyl, ethynyl and prop-1-ynyl. Preferably, however, Y is either hydrogen or an alkynyl group.

The compounds (I) may be used in the form of a physiologically acceptable salt, particularly an acid addition salt when the compound contains one or more basic groups. Such salts may be formed with various suitable inorganic and organic acids. Examples of such inorganic acids are phosphoric acid, nitric acid, sulphuric acid and particularly the hydrohalic acids hydrochloric acid, hydrobromic acid and hydroiodic acid. Examples of such organic acids are citric acid, oxalic acid, fumaric acid, maleic acid, lactic acid, succinic acid, malic acid, tartaric acid and methane sulphonic acid. Alternatively the compounds may be used in the form of a physiologically acceptable ester formed at the 3- and/or 17-positions and optionally also at any hydroxy group in the sugar residue. Such esters may be formed with various forms of organic acid. Thus the acid may be an aromatic acid but is more preferably an aliphatic acid. Examples of aliphatic acids are those carboxylic acids of 1 to 18 carbon atoms which may be saturated or unsaturated. Specific examples are the straight chain alkanoic acids formic, acetic and propionic up to palmitic and stearic, the branched chain alkanoic acids isobutyric, isovaleric and pivalic, and the alkenoic acid oleic acid. Acids containing more than one carboxy group may also be used such as succinic or glutamic acid which may, for example, be used in half ester/half salt form to enhance

solubility. The use of inorganic esters, for example sulphates or phosphates, may also be considered.

Specific compounds (I) according to the invention have both the 6 and 7 positions joined by single bonds; a group A which is -(CH₂)_p- wherein 0 is an integer from 8 to 16, for example 10, 11, 12, 13 or 14, or -(CH₂)_m,-O-(CH₂)_n,- wherein m' and n' are each separately an integer from 2 or 1, respectively, to 14 with m' + n' being 7 to 15, for example 9 to 13, such as m' = 2 and n' = 7, 8, 9, 10 or 11, or in' = 3 and n' = 6, 7, 8, 9 or 10, or vice versa, especially a group -(CH₂)₂-O-(CH₂)7- and also -(CH₂)₂-O-(CH₂)₈-, -(CH₂)₂-O-(CH₂)₉-, -(CH₂)₂-O-(CH₂)₁₀-, -O(CH₂)₁₀-O-(CH₂)₂-,

-O(CH₂)₁₀-O-(CH₂)₃-, -O(CH₂)₁₁-O-(CH₂)₂- or -O-(CH₂)₁₁-O-(CH₂₎₃-; a group B which is -NR-CO-, -SO₂NR- or especially -CONR- wherein R is hydrogen or C_1-3 alkyl, for example a group -CONH-; a group X which is of formula (II) as shown hereinbefore, especially one of α-L-arabino or especially α-L-lyxo form; and a group Y which is hydrogen or -C≡CR wherein R is hydrogen or C_1-3 alkyl, especially a group -C≡CH or a group -C≡CCH₃; such compounds optionally being in the form of a physiologically acceptable mono-, di- or tri-ester.

Preferred compounds according to the invention are thus

11β-{2-[7-(N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo-hexopyranos- 3-yl)-carbamoyl)heptoxy]ethoxy}-17α-ethynyloestra-1,3,5(10)-triene- 3,17β-diol, i.e. the compound in which 11β-[2-(7-carboxyheptoxy)- ethoxy-17α-ethynyloestra-1,3,5(10)-triene-3,17β-diol is linked to methyl-β-L-daunosaminide through the formation of an amide bond between the carboxy group of the steroid and the amino group of the sugar, and the corresponding 17α-prop-1-ynyl compound, both of which may optionally be in the form of a physiologically acceptable mono-, di- or tri-ester. Other specific compounds which may be mentioned, each of which may again optionally be in the form of a physiologically acceptable mono-, di- or tri-ester are:

11β-{9-[N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo-hexopyranos-3-yl)- carbamoyl]nonoxy}-17α-ethynyloestra-1,3,5(10)-trien-3,17β-diol,

11β-{9-[N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo-hexopyranos-3-yl)- carbamoyl]nonoxy}-17α-(prop-1-ynyl)oestra-1,3,5(10)-trien-3,17β- diol,

11β-{2-[10-(N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo-hexopyranos- 3-yl)carbamoyl)decanoxy]ethoxy}-17α-ethynyloestra-1,3,5(10)- trien-3,17β-diol, or

11β-{2-[10-(N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo-hexopyranos- 3-yl)carbamoyl)decanoxy]ethoxy}-17α-(prop-1-ynyl)oestra-1,3,5(10)- trien-3,17β-diol.

The compounds (I) according to the present invention may conveniently be prepared using a process which comprises reacting a compound of formula (III) with a compound of formula (IV),

in which the dotted line indicates the optional presence of a double bond at the 6 and 7 positions, A' is as defined for the group A of the compound of formula (I) or is a group convertible thereto, R₁ is a protected hydroxy group and R₂ is Y as defined for the compound of formula (I) or R₁ and R₂ are separately groups or together a group convertible to a hydroxy group and the group Y, R₃ is a protected hydroxy group, X' is as defined for the compound of formula (I) or is a group convertible thereto, and Z and V are groups reactive with each other, or which can be activated to be reactive with each other, to form a linkage B between A' and X', and, in any order, converting the group R₃ to a hydroxy group and one or more of the groups A', R₁, R₂ and X' to those present in the compound of formula (I) and where appropriate forming a

physiologically acceptable ester and/or salt of the compound of formula (I).

The compounds (III) and their analogues in which R₁ and/or R₃ is a hydroxy group or any ester thereof, which analogues are of value for the preparation of the compounds (III), are believed to be novel compounds and are included within the scope of the present invention. The group A' will often correspond to the group A of the compound (I), the most usual case where this is not true being when A' contains a group -S- which is subsequently converted to a group

SO or

SO₂. When R ₁ and/or R₂ are groups converti bl e to a hydroxy group R ₁ and a group Y as in (I), most usually either R₁ is a hydroxy group in protected form and R₂ is Y or R₁ and R₂ together are an oxo group which may optionally be in protected form, for example as an ethylenedioxy group, but it is possible for R₁ to be hydroxy or a protected hydroxy group and for R₂ to be an ethynyl group which is subsequently converted to a group C≡CR in which R is alkyl. When X' is a group other than the group X in (I) it is usually a group corresponding to X but in which hydroxy substituents in the sugar are in protected form. The nature of hydroxy and oxo protecting groups (i.e. groups which are removable to regenerate the hydroxy or oxo group) is discussed hereinafter but it will be appreciated that apart from the use of ester formation to protect a hydroxy group, analogues of the compounds (III) in which R₁ and/or R₃ is a hydroxy group may in general be in ester or salt form.

Such esters and salts may be physiologically acceptable but do not necessarily have to be so when they are present in an intermediate compound (IIIa) rather than a compound (I). By way of contrast, many of the compounds (IV) will be known compounds or alternatively are readily obtainable by procedures known in the art. The invention thus includes a compound of formula ( IIIa)

I in which the dotted line indicates the optional presence of a double bond joining the 6 and 7 positions, A' is a divalent group having a chain of at least four atoms joining the oxy group and the group Z, which group A is an aliphatic hydrocarbon group or such a group in which there is replacement by one or more groups selected from -O-, -S-,

SO, SO₂,^CO, ^NR, rSiR'R' and phenylene,

wherein R is hydrogen or an alkyl group and R' and R" are the same or different alkyl groups, of one or more carbon atoms, excluding (a) replacement of that carbon atom attached to the group Z,

(b) replacement of both of any two carbon atoms which are joined together either directly or through a single further carbon atom, and, except in the case of the replacement groups

SO₂ and

CO,

(c) replacement of that carbon atom attached to the oxy group, R₁ is hydroxy and R₂ is hydrogen or an alkyl, alkenyl or alkynyl group, or R₁ and R₂ together are an oxo group, and Z is selected from carboxy and sulpho and activated derivatives thereof, amino, mono-alkyl substituted amino, hydroxy and halogeno, halogenomethyl and mono- and di-alkyl substituted halogenomethyl, and other such groups in which the halogeno is replaced by an alternative leaving group, the hydroxy group at the 3-position and/or a hydroxy group R₁ or an oxo group R₁ R₂ optionally being in protected form, the compound optionally being in the form of an ester, and/or a salt where appropriate. The preferred nature of the groups Z and Z' in the

compounds (IlIa) and (IV) respectively, as discussed hereinafter, will depend upon which type of group B is present in the

compound (I). Thus, when B is -CRR-NR-, Z is a halogenomethyl group or a mono- or di-alkyl substituted halogenomethyl group, for example one containing a chloro, bromo or iodo group, or such a group in which the halogeno group is replaced by an alternative leaving group such as an alkyl or aryl sulphonyloxy group, for example a methane sulphonyloxy or toluene p-sulphonyloxy group, and V is a group -NHR. When B is -CONR-, Z is a carboxy group or more particularly an activated derivative thereof, and Z' is a group -NHR whilst the opposite situation pertains when B is -NRCO-.

Similarly, when B is -COO-, Z is a carboxy group or more

particularly an activated derivative thereof and V is a hydroxy group and the opposite situation pertains when B is -OCO-. When B is -SO₂NR-, Z is a sulpho group or more particularly an activated derivative thereof, and Z' is a group -NHR.

Most conveniently an activated carboxy or sulpho group derivative will be used in the reaction rather than a free carboxy or sulpho group, i.e. a derivative which is more reactive with an amine or an alcohol in amide or ester formation than the carboxy or sulpho group itself, for example an anhydride, acid halide or ester, where appropriate in the presence of a suitable condensing agent. Compounds (IlIa) containing a group Z which is a halogeno group or an alternative leaving group, for example an alkyl or aryl sulphonyloxy group as described hereinbefore, are of value for the preparation of other compounds (III) in which Z is a group -NHR or -SO₃H, such halogeno compounds themselves being obtained, for example, from a compound (IlIa) in which Z is a hydroxy group.

It will be appreciated, therefore, that A' in the compound of formula (IIIa) is usually, although not always, of the same chain length as A in the compound of formula (I) which is being prepared from the compound of formula (IlIa) and that in many cases the two groups are identical. The preferences as regards A' are therefore in general as discussed hereinbefore for A. It will be seen that in some cases the group Z in the compound of formula (IlIa) is a hydroxy group and a group of intermediates of particular interest has the formula (V),

in which the dotted line indicates the optional presence of a double bond at the 6 and 7 positions, A" is a divalent group having a chain of at least two atoms joining the oxy and hydroxy groups, which group A" is an aliphatic hydrocarbon group or such a group in which there- is replacement by one or more groups selected from -O-,

-S-,

-SO, SO₂,

-CO,

-"NR,

SiR'R" and phenylene, wherein R is hydrogen or an alkyl group and R' and R" are the same or different alkyl groups, of one or more carbon atoms, excluding (a) replacement of that carbon atom attached to the group OH, (b) replacement of both of any two carbon atoms which are joined together either directly or through a single further carbon atom, and, except in the case of the replacement groups

SO₂ and CO, (c) replacement

of that carbon atom attached to the oxy group, R₁ is hydroxy and R₂ is hydrogen or an alkyl, alkenyl or alkynyl group, or R ₁ and R₂ together are an oxo group, the hydroxy group at the 3-position and/or that attached to A" and/or a hydroxy group R₁ or an oxo group R₁R₂ optionally being in protected form, the compound (V) optionally being in the form of an ester, and/or a salt where appropriate.

Such compounds of formula (V) are novel and are included within the scope of the application. The nature of the hydroxy and oxo protecting groups is discussed hereinafter but it will be

appreciated that, apart from the use of ester formation to protect a hydroxy group, the compounds may also be in the form of an ester where the ester group is not simply a protecting group. Such esters, and also the salts may be physiologically acceptable but do not necessarily have to be so when they are present in an

intermediate compound (V) rather than a compound (I).

It will be seen that the scope of formula (V) overlaps with that of formula (IIIa) when Z = OH in the latter formula although it should be noted that the size of A" has a lower minimum in formula (V) than that of A' in formula (IIIa). Indeed, the preferred range of size for A" is somewhat greater than that which applies generally for A' in the compounds of formula (IIIa). Thus, as indicated hereinbefore. A' is usually of the same chain length as A and is often identical therewith. However, although A" in formula (V) may sometimes be of the same chain length as A and also identical therewith, there will be other instances when this is not the case and A" may sometimes be longer or shorter than A, as will be appreciated from the following discussion. As regards the optional replacement of carbon atoms in an aliphatic hydrocarbon group A" it is preferred that the carbon atom penultimate to the oxy or hydroxy group is also excluded from replacment in the case of the replacement groups -O-, -S- and -NR-. Conveniently this preference may be extended to other replacement groups. It will be appreciated that, where this is present in the chain joining the oxy and hydroxy groups as is preferred, the original limitations on replacement mean that for replacement groups other than SO₂ and

CO the group A will be derived from an aliphatic hydrocarbon

group with a chain of at least 3 carbon atoms and this minimum will be 5 carbon atoms where replacement of the penultimate carbon atoms is also excluded.

The synthesis of one particular compound of formula (I) from a compound of formula (IIIa) via three previous compounds of

formula (V) is illustrated in the reaction scheme which appears on pages 63 and 64, in which the individual compounds are numbered from 1 to 10, and in the Examples. (Examples 1, 5, 10, 11 and 28 describe the preparation of compounds 2, 4, 8, 9 and 10,

respectively.) This synthesis illustrates the situation where the group Z in the compound of formula (IIIa) is a carboxy group (compound 9) [providing a group B which is -COO- or in this case -CONR- in the compound of formula (I)]. It will be seen that one compound of formula (V) (compound 2), in which the group -O-A"-OH is -O-(CH₂)₂-OH, R₁ and R₂ are a protected oxo group and the hydroxy group at the 3-position is also protected, is converted by reaction with sodium hydride and 1-chloro-6-(tetrahydropyran-2-yl)- oxyhexane to a second compound of formula (V) (compound 3) in which the group -O-A"-OH is -O-(CH₂)₂-O-(CH₂)₆-OH and the 3-hydroxy group is again protected but the oxo group R₁ R₂ is not, this procedure removing the oxo protecting group in the compound 2. The oxo protecting group is replaced to provide a third compound of formula (V) (compound 4) which is then converted by the series of reactions -OH → -OTosyl → CH(CO₂C₂H₅)₂ → -CO₂H to a compound of formula (IIIa) (compound 8), in which the group -O-A-Z is

-O-(CH₂)₂-O-(CH₂)₇-CO₂H and neither the hydroxy group at the

3-position nor the oxo group R₁ R₂ are protected. The compound 8 is then reacted to convert the oxo group R₁ R₂ to a group R ₁ which is hydroxy and a group R₂ which is -C≡CH thus providing the compound of formula (IIIa), compound 9, which is the immediate precursor to the compound of formula (I) (compound 10).

In this case, therefore, the second and third compounds of formula (V) (compounds 3 and 4) contain a group A" which is one carbon atom shorter in chain length than the group A' which is present in the compounds of formula (IIIa) and the group A which is present in the compound of formula (I) (compounds 8 and 9,

and 10). In the case of the other types of group B discussed hereinafter the compounds of formula (V) corresponding to

compounds 3 and 4 which are preferred for use in the preparation of the compounds of formulae (IIIa) and (I) contain a group A" which, as compared with the group A' or A present in the compounds (IIIa) and (I), is either one carbon atom longer in chain length

(providing compounds (IIIa) in which Z = -CRRHal wherein Hal represents a halogeno group and compounds (I) in which B = -CRRNR-) or the same chain length (providing compounds (IIIa) in which Z = -NHR, -OH or SO₃H and compounds (I) in which B = -NRCO-, -OCO- or -SO₂NR). Moreover, it will be seen that compounds of formula (V) containing a much smaller group A" than the group A' or A, as in the compound 2, may be used with advantage for the preparation of various compounds of formulae (IIIa) and (V).

The preferred range of size for the chain length of the group A" will therefore vary more widely than for A'. Thus, the chain length of A" between the oxy group and the hydroxy group is preferably in a range from 2 to 25 atoms, particularly 2 to 21 atoms and especially 2 to 17 atoms, for example 2, 3 or 10 to 14 atoms, but preferences as to the nature of A" are generally similar to those expressed hereinbefore for A. Thus one preference is for A" to be a branched or unbranched saturated or unsaturated

aliphatic hydrocarbon group, for example of the type

-(CH₂)_m-C≡C-(CH₂)_n-, -(CH₂)_m-CH=CH-(CH₂)_n-, -(CH₂)_m-CH(R')-(CH₂)_n- or -(CH₂)_p- as described hereinbefore for A but with m + n being 2 to 23 and p being an integer from 2 to 25. Such groups are of value in the preparation of compounds of formula (I) containing groups A which are either totally aliphatic hydrocarbon in nature or not, although in the latter case the size of the groups will generally not be at the uppermost end of the ranges given. Other compounds, which are preferred for the preparation of compounds of formula (I) containing groups A which are not totally aliphatic hydrocarbon in nature, are those of formula (V) containing groups A" which are a branched or unbranched, saturated or unsaturated al i phati c hydrocarbon group i n whi ch one or more of the carbon atoms in the chain are replaced by groups selected from -O- and -S-. Examples of such groups are those of the form

-(CH₂)_h-(O)_a-(CH₂)_i-(O)_b-(CH₂)_j-(O)_c-(CH₂)_k-, [-(CH₂)₂-O-]_d-(CH₂)₂- and especially -(CH₂)_m,-O-(CH₂)_n,- in which the symbols are as defined in relation to A but with the total number of atoms in the chain of the first group indicated being no more than 25 and with each of m' and n' separately being an integer from 2 to 22 so that the range for m' + n, is 4 to 24, and analogues thereof in which -O- is replaced by -S-, SO or -SO₂ as discussed for A. Groups A" of particular interest are those of formula -(CH₂)_p- in which p is 2 or 3 or 7 to 17 and -(CH₂)_m,-O-(CH₂)_n,- in which m' is 2 or 3 and n' is 5, 6, 7, 8 or 9 when m' is 2 and 4, 5, 6, 7 or 8 when m' is 3 or vice versa. Specific groups -O-A"-OH of especial interest are -O(CH₂)₂O(CH₂)₂OH, -O(CH₂)₁₀OH, -O(CH₂)₁₁OH and particularly -O-(CH₂)₂-OH and -O-(CH₂)₂-O-(CH₂)₆-OH.

It will be appreciated that the reaction scheme shown on pages 63 and 64 can be widely varied. Thus it will be seen that in this reaction scheme the compound 8 is converted to the compound 9 in which R ₁ is hydroxy and R₂ is ethynyl. The corresponding compound in which R₁ is hydroxy and R₂ is hydrogen can of course be prepared through simply reducing the oxo group R₁ R₂ or,

alternatively, to produce a compound 9 in which R₂ is -C≡CR where R' is alkyl, for example methyl, LiC≡CR can be used in the second step of the reaction with the compound 8. It is also possible for a -C≡CR group R₂ where R is hydrogen or alkyl to be introduced at a different stage in the synthesis.

Where a compound is required in which R₂ is an alkyl or alkenyl group rather than an alkynyl group this may be obtained through the use of two further variations of the reaction scheme. Thus, fi rstly the oxo group of the compound 8 may be reacted with a

Grignard reagent R'MgX, wherin R' is an alkyl group as described hereinbefore and X is chloro, bromo or iodo, to provide a compound in which R₂ is alkyl. Secondly, a compound 9 in which R₂ is -C≡CH or an analogue thereof in which R₂ is -C≡CR' may be reduced

stepwise with hydrogen and a suitable catalyst to give the

corresponding compound in which R₂ is an alkenyl group -CH=CHR or an alkyl group -CH₂-CH₂R wherein R is hydrogen or an alkyl group as described hereinbefore. This latter method will provide alkenyl and alkyl groups of two carbon atoms or more. It may be appropriate simultaneously to effect hydrogenolysis of a benzyloxy group to a hydroxy group.

It will be seen that in the reaction scheme the oxo group is protected by conversion to an ethylenedioxy group and the 3-hydroxy group is protected by conversion to a benzyloxy group, the former being removed under mildly acidic conditions and the latter under mildly reducing conditions. However, a variety of alternative protecting procedures may of course be used, for example conversion to a substituted ethylenedioxy group or a substituted or

unsubstituted trimethylenedioxy group to protect an oxo group and conversion to a substituted benzyloxy group, for example a

p-tolylmethoxy group, to protect a hydroxy group. Moreover, it is possible to use different protecting groups elsewhere in the synthesis. Thus the acidic hydrolysis used to remove the

tetrahydropyranyl protecting group when proceeding from compound 2 to compound 3 also effects removal of the ethylenedioxy group which is protecting the oxo group at the 17-position. If an alternative to the tetrahydropyranyl group is used, for example a

t-butyldimethylsilyl group which can be removed with fluoride ion, then the protecting group on the side chain at the 11-position may be removed without simultaneously removing the oxo protecting group.

The earlier stages of the synthesis may also be modified, for example by reacting the compound 2 with sodium hydride or an equivalent strong base and then with a compound of formula

Hal-(CH₂)_qOG in which Hal is a halogeno group such as chloro, bromo or iodo, q is an integer and G is a suitable protecting group for a hydroxy group, for example a tetrahydropyranyl group. Moreover, by selecting an alternative protecting group G which can be removed without simultaneously removing the protecting groups on the hydroxy group at the 3-position and the oxo group at the

17-position it is possible to prepare the compound 4 or an analogue thereof containing a group A" of the form -(CH₂)_m,-O-(CH₂)_n,- in which m' and n' are as described hereinbefore in two steps

(reaction of compound 1 + Hal-(CH₂)_qOG and removal of G). Suitable protecting groups G for this purpose are, for example, a

t-butyldimethylsilyl group, this being removable selectively with fluoride ion. It will be appreciated that such a procedure can be repeated one or more times, reacting the new group

-O-(CH₂)₂-O-(CH₂)_q-OH at the 11-position with a further compound of formula Hal-(CH₂)_qOG in which Hal, q and G are as defined previously. Such a repetition of the procedure will provide a compound of formula (I) having a group A which contains two or more groups -O-.

In a further variation the compound 1 is reacted with a compound of formula Hal-(CH₂)_qCH=CH₂ in which Hal and q are as defined previously. The terminal -CH=CH₂ group of the group

-O-(CH₂)_qCH=CH₂ at the 11-position in the product so formed may then be converted to a group -CH₂-CH₂OH, for example by reaction with diborane, or a similar hydroborattng agent, followed by alkaline hydrogen peroxide. In a modification of this procedure the product of the hydroboration is treated with NH₂OSO₃H or NH₂Cl to provide a group -O-(CH₂)_q+2NH₂ at the 11-position. Such a procedure adds the chain A of the 11-substituent in one step but without the need to use a reagent containing a protected terminal hydroxy group since this hydroxy group is formed after addition of the chain.

In yet another variation the compound 1 is reacted with a compound of formula Hal-(CH₂)_m,-O-(CH₂)_n,-OG in which Hal, m', n' and G are as defined previously. This allows compound 1 to be converted directly to compound 4 or an analogue thereof.

Three variations in the reaction scheme, all starting from the same compound (1) are described in Examples 2, 3 and 4 in which the reagent 2-bromo-1-(t-butyldimethylsilyloxy)ethane used in

Example 1(1) is replaced by 1 -(t-butyldimethylsilyloxy)-2- (2-chloroethoxy)ethane, 10-bromo-1-(t-butyldimethylsilyloxy)decane and 11-bromo-1-(t-butyldimethylsilyloxy)undecane, respectively, the first mentioned reagent introducing a group containing an oxy function in the chain directly. It will be seen that Example 8 utilizes an alternative procedure employing 4-bromo-1,1,1- trimethoxybutane for extending the chain and providing a functional group convertible to a carboxy group [-O-(CH₂)₁₁OH →

-O-(CH₂)₁₁-O-(CH₂)₃C(OCH₃)₃→ -O-(CH₂)₁₁-O-(CH₂)₃CO₂CH₃ →

-O-(CH₂)₁₁-O-(CH₂)₃CO₂H] whilst Example 9 illustrates the

conversion of a hydroxymethylene group to a carboxy group using the Jones reagent [-O-(CH₂)₁₁OH → -O-(CH₂)₁₀-CO₂H]. Other variations of the procedure indicated in the reaction scheme which will be apparent to those skilled in the art may be used to produce the alternative forms of A described hereinbefore.

Compounds of formula (I) containing different groups B may be produced using alternative forms of the intermediate compounds of formulae (IIIa) and (IV) described hereinbefore. The case when B is -CONR- is that illustrated by the reaction scheme and compounds in which B is -COO- may be prepared from a similar compound of formula (IIIa) by reaction with an alternative form of compound of formula (IV) than methyl-β-L-daunosaminide having a group V which is hydroxy rather than -NHR. Compounds of formula (I) in which B is -0C0- are most conveniently prepared from a compound of formula (IIIa) which corresponds to a compound of formula (V), Z being a hydroxy group. Thus a compound containing a group -A"-OH such as compound 4 of the reaction scheme may be reacted directly with a compound of formula (IV) in which Z' is a carboxy group or a derivative thereof to provide the desired compound of formula (I). Compounds of formula (I) in which B is -CRR-NR- may conveniently be prepared starting from a compound containing a group -A"-OH such as compound 4 and converting the terminal -CRR-OH group, for example a hydroxymethyl group, to a -CRRHal group in which Hal is a halogeno group as described hereinbefore, for example a halogenomethyl group, for example by reaction with a phosphorus halide or with triphenylphosphine and a carbon tetrahalide such as carbon tetrabromide, and then reacting the halogeno group with a compound of formula (IV) in which Z' is -NHR. Alternatively, other leaving groups than a halogeno group may be used, the hydroxymethyl group instead being converted, for example, to a methyl group substituted by a sulphonyl ester group, particularly one such as is described hereinbefore.

Compounds containing a group -A'-Hal or an alternative leaving group to a halogeno group may also be used in the preparation of compounds in which B is -SO₂NR-. Thus, such a compound may be reacted with sulphite ion to provide a group -A'-SO₃- which is then treated under aqueous acidic conditions to provide a group -A'-SO₃H (as reviewed by Gilbert in "Sulphonation and related reactions", Interscience, New York, 1965, 136 and 161). Alternatively, it may be treated either with NaSH or with (NH₂)₂CS followed by NaOH to provide a group -A'-SH which is then treated, for example with Ba(MnO₄)₂, to oxidize the mercapto group to provide a group

-A'-SO₃H. The former method is preferred although the latter is of particular interest when constructing a reactant L-A-Z or L-A-B-X as discussed hereinafter. The group -A'-SO3H or an activated derivative thereof such as the sulphonyl chloride may then be reacted with a compound of formula (IV) in which Z is -NHR to provide the desired compound in which B is -SO₂NR-.

Alternatively, the hydroxy group of a compound containing a group -A"-OH may similarly be converted to a halogeno group or other leaving group and then to a group -NHR to provide a precursor for compounds of formula (I) in which B is -NR-CO-. Such a primary amine precursor may conveniently be obtained from the halogeno compound using the Gabriel synthesis in which the halogeno compound is reacted with potassium phthalimide to give an N-substituted phthalimide which is then hydrolysed to give the amine.

Alternatively, the halogeno compound may be converted to a compound containing a group -A"-N₃ by the use of a reagent such as NaN₃ in dimethylformamide, the azide function then being reduced to the primary amine by various known procedures, for example by catalytic hydrogenolysis (H₂/Pd) or using SnCl₂. Other conventional

procedures may be used for the preparation of compounds (IIIa) containing a secondary amine group. Reaction of the amine

precursor with a compound of formula (IV) in which Z' is -CO₂H or particularly an activated derivative thereof, for example using standard procedures of peptide synthesis, will yield the desired compounds (I) in which B is -NR-CO-.

As indicated hereinbefore, therefore, it will be seen that the compounds of formula (V) are of particular value as intermediates for the preparation of each of the various forms of compound of formula (I). As an alternative to the procedures for the preparation of compounds of formula (IIIa) used in the reaction scheme and the modifications thereof already described, it is possible to use a first reactant in which the group A', or at least a part thereof, is pre-formed but which does not contain the steroid ring system of the compound and to react this with a second reactant which contains the ring system in order to form a compound ( I I Ia ) containing the group -A-Z at the 11 -position in one step, or at least a small number of steps. The advantage of such an approach is that a larger part of the synthetic chemistry can be carried out before the more expensive synthetic precursor containing the steroid ring system is introduced into the synthesis. An example of such an approach is the use of a compound L-A-Z as the first reactant, in which A and Z are as defined hereinbefore and L is a suitable leaving group, and of the compound 1 as the second reactant thus forming a group -O-A-Z at the 11-position in one step (Z being in protected form where necessary). Alternatively, the first reactant may be a compound in which only a part of A' is present, such as a compound L-(CH₂)_n'-Z in which L and n' are as defined hereinebefore and the second reactant may be the compound 2 or an alternative compound containing another group -(C_H2)_m,-OH at the 11-position, the group -O-A-Z at the 11-position again being formed in one step (Z again being protected where necessary).

Following the synthesis of the compound (IIIa) the synthesis of the compound (I) may then be effected as described previously.

It is possible, however, to vary the procedure further by using a first reactant not containing the steroid ring system of the compound which already contains the group X or a group convertible thereto as well as the groups A and B. In general, such a process for the preparation of a compound of formula (I) comprises reacting a compound of formula (VI) with a compound of formula (VII)

in which the dotted bond indicates the optional presence of a double bond at the 6 and 7 positoins, R₁ is a protected hydroxy group and R₂ is Y as defined for the compound of formula (I) or R₁ and R₂ are groups convertible to a hydroxy group and the group Y, R₃ is a protected hydroxy group, W is a group -B-X or a group convertible thereto and OV and V are groups reactive with each other, or which can be activated to be reactive with each other, to form a linkage -O-A'- between the 11-position of the ring system of the compound of formula (VI) and the group W in which A' is as defined for the group A of the compound of formula (I) or is a group convertible thereto, and, in any order converting the group R₃ to a hydroxy group and one or more of the groups A', R₁, R₂ and W to those present in the compound of formula (I) and where appropriate forming a physiologically acceptable ester and/or salt of the compound of formula (I).

Examples of such a procedure are similar to those described hereinbefore using a compound L-A-Z or L-(CH₂)_n,-Z as the first reactant but with the first reactant instead taking the form

L-A-B-X (or L-A-B-X', X' being a group convertible to X) or

L-(CH₂)_n,-B-X (or L-(CH₂)_n,-B-X'). Procedures suitable for the synthesis of the compounds of formulae (VI) and (VII) will be readily apparent to those skilled in the art in the light of the discussion herein. In many cases the compound (VI) will be a compound of formula (V) as discussed hereinbefore or the compound 1 or a similar compound but with different protecting groups on the 3-hydroxy group and the 17-oxo group. The compounds of formula (I) may be formulated with a

physiologically acceptable diluent or carrier for use as

pharmaceuticals for veterinary, for example in an avian or especially a mammalian context, and particularly for human use by a variety of methods. For instance, they may be applied as a composition incorporating a liquid diluent or carrier, for example an aqueous or oily solution, suspension or emulsion, which may often be employed in injectable form for parenteral administration and therefore may conveniently be sterile and pyrogen free. Oral administration may also be used, particularly in the case of the free bases and their acid addition salts, and indeed is preferred. Although compositions for this purpose may incorporate a liquid diluent or carrier, it is more usual to use a solid, for example a conventional solid carrier material such as starch, lactose, dextrin or magnesium stearate. Such solid compositions may conveniently be of a formed type, for example as tablets, capsules (including spansules), etc.

Other forms of administration than by injection or through the oral route may also be considered in both human and veterinary contexts, for example the use of suppositories or pessaries.,

Thus, the invention further includes a pharmaceutical

composition comprising a compound of formula (I) as defined hereinbefore together with a physiologically acceptable diluent or carrier.

The compounds of formula (I) of the present invention are of particular interest for use in the treatment of breast cancer or prophylactically in women who are at high risk of contracting breast cancer for preventing or slowing the onset of the disease, the compounds being used in a broadly similar manner to the compound tamoxifen. However there are other areas in which the compounds have potential, for example in the treatment of benign breast disease and of carcinoma of the corpus uteri, and also in the treatment of infertility. Compositions may be formulated in unit dosage form, i.e. in the form of discrete portions each comprising a unit dose, or a multiple or sub-multiple of a unit dose. Whilst the dosage of active compound given will depend on various factors, including the particular compound which is employed in the composition and the condition treated, it may be stated by way of guidance that a satisfactory effect will often be achieved using a dosage in the range of 0.1 to 1 mg/kg, repeated daily for as long as is deemed appropriate, possibly for as long as 3 to 4 years. However, it will be appreciated that it may be appropriate under certain circumstances to give daily dosages either below or above these levels. Where desired, more than one compound of formula (I) may be administered in the pharmaceutical composition, or, indeed, other active compounds may be included in the composition.

The present invention therefore includes a method for aiding the regression and palliation of breast cancer, of benign breast disease, or of carcinoma of the corpus uteri, for preventing or slowing the onset of breast cancer, or for treating an ovulatory infertility, in a patient which comprises administering to that patient a therapeutically effective amount of a compound of

formula (I) as defined herein.

The invention is illustrated by the following Examples which relate both to intermediates of formulae (IIIa) and (V) and to biologically active compounds of formula (I) as summarised in the following Table.

The procedures of Examples 1, 5, 10, 11 and 28 are illustrated in Scheme 1 on pages 63 and 64 (the usual convention being followed of representing the methyl group at position 13 as a straight line), in which the compounds illustrated are numbered from (1) to (10), a similar system of numbering therefore being used to identify the same compounds in these Examples. The procedures of Examples 2, 3, 4, 6, 7, 8, 9, 12 to 27, 29 and 30 are additional to those

illustrated in Scheme 1. In the Examples and Scheme the following abbreviations are used: THF (tetrahydrofuran), EtOAc (ethyl acetate), DMF (dimethyl formamide), TBDMSO (t-butyldimethyl- silyloxy), EDTA (ethylenediamine tetra-acetic acid), EEDQ (N-ethoxy- carbonyl-2-ethoxy-1,2-dihydroquinoline), pTSA and pTSCl (p-toluene sulphonic acid and sulphonyl chloride), TLC (thin layer

chromatography), HPLC (high pressure liquid chromatography). The term 'light petroleum' indicates the fraction of b.p. 40-60°C.

Flash chromatography was carried out using S0RBSIL C60 (40/60 flash silica) with mean pore diamter 6.0 nm. Infrared spectra were obtained with KBr discs and the 1H n.m.r. spectra are given on the 6 scale (tetramethylsilane, δ 0.00 pm) using tetramethylsilane as an internal standard. Mass spectral data were obtained by electron impact which provides high resolution, where an M⁺ figure is quoted, or by fast atom bombardment which does not, where an M⁺+1 figure is quoted (with the exception of Example 28 where the M⁺ figure is quoted for the fast atom bombardment mass spectrum).

EXAMPLES

Example 1 : 3-Benzyloxy-17,17-ethylenedioxy-11β-(2-hydroxyethoxy)- oestra-1,3,5(10)-triene (2)

(1) 3-Benzyloxy-17 , 17-ethyl enedioxy- 11β-[2-(t-butyldimethyl- silyloxy)ethoxy]oestra-1,3,5(10)-triene

Sodium hydride (80% dispersion in mineral oil, 50 mg, 2.1 mmrnol) was stirred in THF (2 ml) for 10 minutes, then the supernatant solvent was removed and fresh THF (2 ml) was added and mixed well by magnetic stirring. 3-Benzyloxy-17,17-ethylenedioxyoestra-1,3,5(10)- triene-11β-ol (1) (Baran et al., Tetrahedron, 1977, 33, 609)

(500 mg, 1.2 mmol) in dry THF (1 ml) was added dropwise and the resulting mixture was stirred and heated under reflux for 6 hours. Thereafter the reaction mixture was cooled to room temperature and 2-bromo-1-(t-butyldimethylsilyloxy)ethane (300 mg, 1.3 mmol) was added dropwise over 15 to 20 minutes. The temperature of the reaction mixture was then raised to 50-65°C and stirring was continued at this temperature overnight. More NaH (50 mg, 2.1 mmol) and 2-bromo-1-(t-butyldimethylsilyloxy)ethane (300 mg, 1.3 mmol) in dry THF (2 ml) were then added, and the reaction was stirred for a further 12 hours between 50-65°C.

The reaction mixture was then cooled in an ice-bath and cold aqueous THF (1:1 v/v) was added dropwise to destroy any excess

NaH. When the effervescence had subsided the reaction mixture was diluted with dichloromethane (10 ml) which was washed with brine. The aqueous layer was separated and further extracted with fresh dichloromethane (3 x 10 ml). The combined organic extracts were dried over sodium sulphate, filtered and taken to dryness under reduced pressure to give a yellow oil. Flash chromatography

(eluting solvent:20% EtOAc in light petroleum) gave the title compound as a colourless oil (500 mg, 59.7%), ν_max 2975 and

1610 cm^-1; δ(CDCl₃) 0.00 (6H, complex), 0.90 (9H, complex),

1.15 (3H, s), 3.50-3.80 (4H, complex), 3.90 (4H, m, W_1/2 = 4 Hz), 4.30 (1H, td, J = 3.7, 2.5 and 2.5 Hz), 5.00 (2H, s), 6.80 (1H, d, J = 2.5 Hz), 6.90 (1H, dd, J = 8.7 and 2.5 Hz), 7.10 (1H, d,

J = 8.7 Hz) and 7.50 (5H, m, W_1/2 = 6 Hz). Further elution gave the starting material (200 mg recovered).

(2) 3-Benzyloxy-17,17-ethylenedioxy-11β-(2-hydroxyethoxy)oestra- 1,3,5(10)-triene

3-Benzyloxy-17,17-ethylenedioxy-11β-[2-(t-butyldimethyl- silyloxy)ethoxy]oestra-1,3,5(10)-triene (160 mg, 0.26 mmol)

dissolved in freshly dried THF (2 ml) was mixed with

tetra-n-butylammonium fluoride (1.0M solution in THF, 1 ml , 1 mmol). The mixture was stirred in the dark at room temperature overnight. T.l.c. showed a more polar spot with respect to the starting material. Thereafter the reaction mixture was diluted with water (10 ml) and the organic material was extracted into ethyl acetate (3 x 20 ml). The combined organic extracts were dried over sodium sulphate, filtered and taken to dryness under reduced pressure. The final product was chromatographed through a column of silica gel (30% EtOAc in light petroleum) and the solvent removed to give white crystals. Recrystallisation from acetone and light petroleum gave the title compound (2) as white needle-shaped crystals (120 mg, 93.4%), m.p. 143-145°C; ν_max 3500 and 1610 cm^-1; δ(CDCl₃)

1.10 (3H, s), 2.79-2.88 (2H, complex), 3.32-3.75 (4H, complex), 3.90 (4H, m, W_1/2 = 33.75 Hz), 4.34 (1H, td, J = 3.75, 2.5 and 2.5 Hz), 5.01 (2H, s), 6.71 (1H, d, J = 2.5 Hz), 6.78 (1H, dd,

J = 8.75 and 2.5 Hz), 7.10 (1H, d, J = 8.75 Hz) and 7.34 (5H, m, W_1/2 = 37.5 Hz); M⁺ 464.2576 (C₂₉H₃₆O₅ requires 464.2563).

Example 2 : 3-Benzyloxy-17,17-ethylenedioxy-11β-[2-(2-hydroxy- ethoxy)ethoxy]oestra-1,3,5(10)-triene

(1) 3-Benzyloxy-17,17-ethylenedioxy-11β-{2-[2-(1-butyldimethylsilyloxy)ethoxy]ethoxy}oestra-1,3,5(10)-triene

The procedure of Example 1(1) was followed using 1-(t-butyl- dimethylsilyloxy)-2-(2-chloroethoxy)ethane (0.6, 2.7 mmol; added in two equal portions) instead of the 2-bromo-1-(t-butyldimethyl- silyloxy)ethane. The flash chromatography gave the title compound as a colourless oil (350 mg, 48.5%), v_max 1615 cm^-1;

δ(CDCl₃) 0.00 (6H, complex), 0.90 (9H, complex), 1.90 (3H, s), 2.42 (1H, dd, J = 8.75 and 2.5 Hz), 2.76-2.88 (2H, complex),

3.40-3.70 (8H, complex), 3.90 (4H, m, W_1/2 = 31.25 Hz),

4.36 (1H, td, J = 3.75, 2.5 and 2.5 Hz), 5.02 (2H, s),

6.68 (1H, d, J = 2.5 Hz), 6.76 (1H, dd, J = 8.75 and 2.5 Hz),

7.14 (1H, d, J = 8.75 Hz) and 7.38 (5H, m, W_1/2 = 37.5 Hz).

Starting material (210 mg) was also recovered.

(2) 3-Benzyloxy-17,17-ethylenedioxy-11β-[2-(2-hydroxyethoxy)- ethoxy)oestra-1,3,5(10)-triene

The procedure of Example 1(2) was employed for the reaction of 3-benzyloxy-17,17-ethylenedioxy-11β-{2-[2-(t-buytyldimethyl- silyloxy)ethoxy]ethoxy}oestra-1,3,5(10)-triene with tetra-n-butyl- ammonium fluoride. The flash chromatography gave the title compound as a colourless oil (250 mg, 94.4%), v_max 3500, 2975 and 1610 cm^-1; δ(CDCl₃) 1.80 (3H, s), 2.43 (1H, dd, J = 8.75 and 2.5 Hz),

2.78-2.88 (2H, complex), 3.35-3.75 (8H, complex), 3.91 (4H, m, W_1/2 = 28.75 Hz, 4.36 (1H, td, J = 3.75, 2.5 and 2.5 Hz),

5.02 (2H, s), 6.68 (1H, d, J = 2.5 Hz), 6.77 (1H, dd, J = 8.75 and 2.5 Hz), 7.14 (1H, d, J = 8.75 Hz) and 7.40 (5H, m,

W_1/2 = 40 Hz). M⁺+1 509 (C₃₁H₄₀O₆ requires 508.2825).

Example 3 : 3-Benzyloxy-17,17-ethylenedioxy-11β-(10-hydroxy- decanoχy)oestra-1,3,5(10)-triene

(1) 3-Benzyloxy-17,17-ethylenedioxy-11β-[10-(t-butyldimethylsilyloxy)decanoxyloestra-1,3,5(10)-triene

The procedure of Example 1(1) was followed using 10-bromo-1- (t-butyldimethylsilyloxy)decane (1.0 g, 2.8 mmol; added in two equal portions) instead of 2-bromo-1-(t-butyldimethylsilyloxy)- ethane. The flash chromatography gave the title compound as a colourless oil (459 mg, 55.9%), v_max 2970 and 1610 cm^-1;

δ(CDCl₃) 0.00 (6H, complex), 0.90 (9H, complex), 1.09 (3H, s), 2.75-2.88 (2H, complex), 3.16 (1H, td, J = 10, 6.25 and 5 Hz),

3.57 (1H, td, J = 10, 6.25 and 5 Hz), 3.60 (2H, t, J = 6.25 Hz), 3.90 (4H, m, W_1/2 = 16.25 Hz), 4.26 (1H, td, J = 3.75, 2.5 and 2.5 Hz), 5.01 (2H, s), 6.70 (1H, d, 3 = 2.5 Hz), 6.78 (1H, dd, J = 8.75 and 2.5 Hz), 7.05 (1H, d, J = 8.75 Hz) and 7.40 (5H, m, W_1/2 = 20 Hz). Starting material (190 mg) was also recovered. (2) 3-Benzyloxy-17,17-ethylenedioxy-11β-(10-hydroxydecanoxy)- oestra-1,3,5(10)-triene

The procedure of Example 1(2) was employed for the reaction of 3-benzyloxy-17,17-ethylenedioxy-11β-[10-(t-butyldimethylsilyloxy)- decanoxy]oestra-1,3,5(10)-triene with tetra-n-butylammonium fluoride. The flash chromatography gave the title compound as a colourless oil (290 mg, 86.8%), v_max 3500, 2957 and 1605 cm^-1; δ(CDCl₃) 1.09 (3H, s), 2.42 (1H, dd, J = 8.7 and 2.5 Hz),

2.76-2.88 (2H, complex), 3.17 (1H, td, J_ = 10, 6.25 and 5 Hz),

3.58 (1H, td, J = 10, 6.25 and 5 Hz), 3.60 (2H, t, J - 6.25 Hz), 3.92 (4H, m, W_1/2 = 16.25 Hz), 4.23 (1H, td, J = 3.75, 2.5 and 2.5 Hz), 5.02 (2H, s,), 6.68 (1H, d, J = 2.5 Hz),

6.77 (1H, dd, J = 8.75 and 2.5 Hz), 7.06 (1H, d, J = 8.75 Hz) and 7.34 (5H, m, W_1/2 = 20 Hz). Example 4 : 3-Benzyloxy-17,17-ethylenedioxy-11β-(11-hydroxy- undecanoxy)oestra-1,3,5(10)-triene

(X) 3-Benzyloxy-17,17-ethylenedioxy-11β-[11-t-butyldimethyl- silyloxy)undecanoxyloestra-1,3,5(10)-triene

The procedure of Example 1(1) was followed using

11-bromo-1-(t-butyldimethylsilyloxy)undecane (1.0 g, 2.7 mmol; added in two equal portions) instead of 2-bromo-1-(t-butyldimethyl- silyloxy)ethane. The flash chromatography gave the title compound as a colourless oil (450 mg, 53.7%), v_max 2980 and 1607 cm^-1;

δ(CDCl₃) 0.00 (6H, complex), 0.90 (9H, complex), 1.10 (3H, s), 2.75-2.88 (2H, complex), 3.17 (1H, td, J = 10, 6.25 and 5 Hz), 3.58 (1H, td, J = 10, 6.25 and 5 Hz), 3.60 (2H, t, J = 6.25 Hz), 3.93 (4H, m, W_1/2 = 31.25 Hz), 4.24 (1H, td, J = 3.75, 2.5 and 2.5 Hz), 5.03 (2H, s,), 6.68 (1H, d, J = 2.5 Hz), 6.76 (1H, dd, J = 8.75 and 2.5 Hz), 7.06 (1H, d, J = 8.75 Hz) and 7.36 (5H, m, W_1/2 = 37.5 Hz). Starting material (200 mg) was also recovered. (2) 3-Benzyloxy-17,17-ethylenedioxy-11β-(11-hydroxyundecanoxy)- oestra-1,3,5(10)-triene

The procedure of Example 1(2) was employed for the reaction of 3-benzyloxy-17,17-ethylenedioxy-11β-[ 11-(t-butyldimethylsilyloxy)- undecanoxy]oestra-1,3,5(10)-triene with tetra-n-butylammonium fluoride. The flash chromatography gave the title compound

(300 mg, 80%), v_max 2980 and 1607 cm^-1; δ(CDCl₃) 1.10 (3H, s), 2.41 (1H, dd, J = 10 and 2.5 Hz), 2.76-2.88 (2H, complex),

3.17 (1H, td, J = 10, 6.25 and 5 Hz), 3.58 (1H, td, J = 10, 6.25 and 5 Hz), 3.61 (2H, t, J = 6.25 Hz), 3.93 (4H, m, W_1/2 = 30 Hz), 4.23 (1H, td, J = 3.75, 2.5 and 2.5 Hz), 5.02 (2H, s,), 6.68 (1H, d, J = 2.5 Hz), 6.76 (1H, dd, J = 8.75 and 2.5 Hz), 7.06 (1H, d, J = 7 Hz) and 7.35 (5H, m, W_1/2 = 37.5 Hz). Example 5 : 3-Benzyloxy-17,17-ethylenedioxy-11β-[2-(6-hydroxy- hexoxy)ethoxyloestra-1,3,5(10)-triene (4)

(1) 3-Benzyloxy-11β-[2-(6-hydroxyhexoxy)ethoxyloestra-1,3,5(10)- trien-17-one (3)

To a suspension of NaH (948 mg, 31 mmol) in DMF (2 ml) was added a solution of the compound (2) of Example 1

(733 mg, 1.58 mmol) in DMF (4 ml). The mixture was stirred at 60-80°C for 3 hours and then 1-chloro-6-(tetrahydropyran-2-yloxy)- hexane (THPO(CH₂)₆Cl) (1.54 g, 8 mmol) was added at 10°C. Stirring of the mixture was continued at ambient temperature overnight.

Di ethyl ether (100 ml) was added to dilute the mixture which was then treated with a few chips of ice to destroy the excess NaH. The organic solution was washed with water and brine, then dried with anhydrous Na₂SO₄ and evaporated to dryness under reduced pressure to obtain a residual slurry. The residual slurry was chromatographed with flash silica gel (30% EtOAc in petroleum spirit as an eluant) to obtain a clear oil.

To this clear oil was added methanol (40 ml) and p-toluene sulphonic acid (p-TSA) (50 mg). The mixture was heated under reflux for 1.5 hours and then most of the methanol was evaporated under reduced pressure . The residual s l urry was redi ssol ved i n ether ( 100 ml) and washed with water and brine. The organic extract was dried (Na₂SO₄) and taken to dryness under reduced pressure. The crude product was purified by HPLC (60% EtOAc in petroleum spirit as a mobile phase) to obtain the title compound (3) as an oil (824 mg, 91%); ν_max 3490, 1730 and 1610 cm^-1;

δ(CDCl₃) 1.12 (1H, s), 2.77-3.00 (3H, m), 3.26-3.74 (8H, m),

4.39 (1H, td. J = 4, 3 and 2 Hz), 5.04 (2H, s),

6.71 (1H, d, J = 3 Hz), 6.78 (1H, dd, J = 3 and 8 Hz) and

7.14 (1H, d, J = 8 Hz); M⁺ 520.3299 (C₃₃H₄₀O₅ requires 520.3189). (2) 3-Benzyloxy-17,17-ethylenedioxy-11β-[6-(hydroxyhexoxy)ethoxy]- oestra-1,3,5(10)-triene (4)

To a solution of the compound (3) (772 mg, 1.5 mmol) in benzene (35 ml) was added ethanediol (11 ml) and p-toluene

sulphonic acid ( 20 mg) . The mi xture was heated to ref l ux with azeotropic removal of water for 4 hours. Saturated NaHCO₃ solution (20 ml) was then added to the mixture. The organic solution was separated and washed with water and brine. The first aqueous solution was extracted further with diethyl ether which was then washed with brine. The combined organic extract was dried (Na₂SO₄) and taken to dryness under reduced pressure. The crude title compound (4) was chromatographed with flash silica gel (20%-80% of EtOAc in petroleum spirit as the eluant). The title compound (4) was collected from the first fraction as an oil (847 mg, 99%);

ν_max 3490 and 1610 cm^-1; δ(CDCl₃) 1.08 (3H, s), 2.43 (1H, dd, J = 10 and 2 Hz, 9α-H), 2.71-2.94 (2H, m, 6α and β-H),

3.27-3.73 (8H, m), 3.84-3.98 (4H, m), 4.36 (1H, td, J = 4, 3 and 2 Hz), 5.02 (2H, s), 6.68 (1H, d, J = 3 Hz), 6.76 (1H, dd, J = 3 and 8 Hz) and 7.14 (1H, d, J = 8 Hz);

M⁺ 564.3440 (C₃₅H₄₄O₆ requires 564.3451).

Example 6 : 3-Benzyloxy-17,17-ethylenedioxy-11β-(8-hydroxyoctanoxy)- oestra-1,3,5(10)-triene

The procedure of Example 1(1) was followed using 8-bromo-1- (t-butyldimethylsilyloxy)octane in place of 2-bromo-1-(t-butyl- dimethylsilyloxy)ethane to obtain the alternative intermediate 3-benzyloxy-17,17-ethylenedioxy-11β-(8-t-butyldimethylsilyloxy- octanoxy)oestra-1,3,5(10)-triene in 68% yield. This was converted by the procedure of Example 1(2) in 91.2% yield to the title compound which was purified by flash chromatography and obtained as a colourless oil, v_max 3600-3300 (broad), 1615, 1170 and

1106-1010cm^-1; δ(CDCl₃, 250 MHz) 1.09 (3H, s,), 2.42 (1H, dd,

J = 10 and 2.5 Hz), 2.75-2.89 (2H, complex), 3.17 (1H, dt, J = 10, 6.25 and 5 Hz), 3.57 (1H, dt, J = 10, 6.25 and 5 Hz), 3.60 (2H, t, J = 6.25 Hz), 3.85-3.95 (4H, m), 4.24 (1H, dt, J = 3.75, 2.5 and 2.5 Hz), 5.01 (2H, s), 6.68 (1H, d, J = 2.5 Hz), 6.76 (1H, dd,

J = 8.75 and 2.5 Hz), 7.06 (1H, d, J = 8.75 Hz) and

7.30-7.45 (5H, m); M⁺ 548.3518 (C₃₅H₄₈O₅ requires 548.3502). Example 7 : 3-Benzyloxy-17,17-ethylenedioxy-11β-[2-(11-hydroxy- undecanoxy)ethoxyloestra-1,3,5(10)-triene

(1) 3-Benzyloxy-17,17-ethylenedioxy-11β-[2-(11-t-butyldimethyl- silyloxyundecanoxy)ethoxy]oestra-1,3,5(10)-triene

Sodium hydride (80% dispersion in mineral oil, 50 mg,

1.67 mmol, 7.6 mol. eq.) was suspended in dry THF (2 ml) and stirred for 10 minutes. The supernatant was removed by a Pasteur pipette when the solid had settled down. Another lot of freshly dried THF (2 ml) was added to the slurry of sodium hydride and mixed well by stirring. A solution of the 3-benzyloxy-17,17- ethylenedioxy-11 β-(2-hydroxyethoxy)oestra-1,3,5(10)-triene

(100 mg, 0.22 mmol; prepared as described in Example 1) in dry THF (1 ml) was added to the suspension of sodium hydride using a pressure equalising 'modified' dropping funnel, and the mixture heated under gentle reflux for 1 hour. It was allowed to cool to room temperature and 1-bromo-11-(t-butyldimethylsilyloxy)undecane (500 mg, 1.37 mmol, 6.2 mol. eq.) was added dropwise. The mixture was then stirred at 55-65°C overnight.

The reaction mixture was then cooled in an ice-bath and cold aqueous THF (10 ml; 50% v/v) was added dropwise to destroy any excess sodium hydride. When the effervescence had subsided the mixture was diluted with dichloromethane (10 ml) which was washed with brine. The aqueous layer was separated and further extracted with fresh dichloromethane (3 x 10 ml). The combined organic extracts were dried over sodium sulphate, filtered, and taken to dryness under reduced pressure to give a yellow oil. Flash chromatography (10% ethyl acetate in light petroleum) gave the title compound as faint yellow tinted oil (130 mg, 80.6%), v_max 1610, 1275, 1170 and 1110-1010cm^-1; δ(CDCl₃, 500 MHz), 0.21 (6H, s), 0.91 (9H, s), 1.10 (3H, s), 2.42 (1H, dd, J = 10 and 2.5 Hz), 2.75-2.89 (2H, complex), 3.30 (2H, t, J = 6.25 Hz), 3.41 (2H, t, J = 6.25 Hz), 3.45 (1H, dt, J = 10, 6.25 and 5 Hz), 3.60 (2H, t, J = 6.25 Hz, 3.68 (1H, dt, J = 10, 6.25 and 5 Hz), 3.85-3.95 (4H, m) , 4.37 (1H, dt, 3_ = 3.7, 2.5 and 2.5 Hz),

5.01 (2H, s), 6.68 (1H, d, J = 2.5 Hz), 6.77 (1H, dd, J = 8.75 and 2.5 Hz), 7.14 (1H, d, J = 8.75 Hz) and 7.30-7.45 (5H, m);

M⁺ 748.5099 (C₄₆H₇₂O₆Si requires 748.5091). (2) 3-Benzyloxy-17,17-ethylenedioxy-11β-[2-(11-hydroxyundecanoxy)- ethoxyloestra-1,3,5(10)-triene

The procedure of Example 1(2) was followed to convert

3-benzyloxy-17,17-ethylenedioxy-11β-[2-(11-t-butyldimethylsilyloxy- undecanoxy)ethoxy]oestra-1,3,5(10)-triene in 90% yield to the title compound which was purified by flash chromatography (30% ethyl acetate in light petroleum) and obtained as a colourless oil, ν_max 3600-3446 (broad), 1612, 1173 and 1106-1010cm^-1;

δ(CDCl₃, 500 MHz), 1.10 (3H, s), 2.42 (1H, dd, J = 10 and 2.5 Hz), 2.75-2.89 (2H, complex), 3.30 (2H, t, J = 6.25 Hz),

3.41 (2H, t, J = 6.25 Hz), 3.45 (1H, dt, J = 10, 6.25 and 5 Hz), 3.62 (2H, t, J = 6.25 Hz), 3.68 (1H, dt, J = 8.75, 6.25 and 5 Hz), 3.85-3.95 (4H, m), 4.37 (1H, dt, J = 3.7, 2.5 and 2.5 Hz),

5.01 (2H, s), 6.68 (1H, d, J = 2.5 Hz), 6.77 (1H, dd, J = 8.75 and 2.5 Hz), 7.14 (1H, d, J = 8.75 Hz) and 7.30-7.45 (5H, m), M⁺ 634.4239 (C₄₀H₅₈O₆ requires 634.4233).

Example 8 : 3-Benzyloxy-17,17-ethylenedioxy-11β-[2-(8-hydroxy- octanoxy)ethoxyloestra-1,3,5(10)-triene

The procedure of Example 7(1) was followed using

8-bromo-1-(t-butyldimethylsilyloxy)octane in place of

1-bromo-11-(t-butyldimethylsilyloxy)undecane to obtain the

alternative intermediate 3-benzyloxy-17,17-ethylenedioxy-11β- [2-(8-t-butyldimethylsilyloxyoctanoxy)ethoxy]oestra-1,3,5(10)- triene in 91.5% yield. This was converted in 96% yield by the procedure of Example 1(2) to the title compound which was purified by flash chromatography (30% ethyl acetate in light petroleum) and obtained as a colourless oil, v_max 3600-3400 (broad), 1610, 1170 and 1106-1010cm^-1; δ(CDCl₃, 250 MHz), 1.10 (3H, s), 2.42 (1H, dd, J = 10 and 2.5 Hz), 2.75-2.89 (2H, complex), 3.30 (2H, t,

J = 6.25 Hz), 3.41 (2H, t, J = 6.25 Hz), 3.45 (1H, dt, J = 10, 6.25 and 5 Hz), 3.63 (2H, t, J = 6.25 Hz), 3.68 (2H, dt, J = 10, 6.25 and 5 Hz), 3.85-3.95 (4H, m), 4.37 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 5.01 (2H, s), 6.68 (1H, d, J = 2.5 Hz), 6.77 (1H, dd, J = 8.75 and 2.5 Hz), 7.14 (1H, d, J = 8.75 Hz) and 7.30-7.45 (5H, m);

M⁺ 592.3755 (C₃₇H₅₂O₆ requires 592.3764). Example 9 : 3-Benzyloxy-17,17-ethylenedioxy-11β-[8-(8-hydroxy octoxy)octoxyloestra-1,3,5(10)-triene

The procedure of Example 1(1) was followed using 3-benzyloxy- 17,17-ethylenedioxy-11β-(8-hydroxyoctanoxy)oestra-1,3,5(10)-triene in place of 3-benzyloxy-17,17-ethylenedioxyoestra-1,3,5(10)- trien-11β-ol and 8-bromo-l-(t-butyldimethylsilyloxy)octane in place of 2-bromo-1-(t-butyldimethylsilyloxy)ethane to obtain the

alternative intermediate 3-benzyloxy-17,17-ethylenedioxy-11β- (8-t-butyldimethylsilyloxyoctanoxy)oestra-1,3,5(10)-triene in 82.1% yield. This was converted in 89% yield by the procedure of

Example 1(2) to the title compound which was purified by flash chromatography (30% ethyl acetate in light petroleum) and obtained as a colourless oil, v_max 3600-3440 (broad), 1610, 1170 and

1106-1010cm^-1; δ(CDCl₃, 250 MHz), 1.09 (3H, s), 2.41 (1H, dd, 3 = 10 and 2.5 Hz), 2.75-2.89 (2H, complex), 3.17 (1H, dt, J = 10, 6.25 and 5 Hz), 3.36 (4H, t, J = 6.25 Hz), 3.57 (1H, dt, J = 10, 6.25 and 5 Hz), 3.62 (2H, t, J = 6.25 Hz), 3.85-3.95 (4H, m) , 4.24 (1H, dt, 3 = 3.75, 2.5 and 2.5 Hz), 5.01 (2H, s), 6.68 (1H, d, J = 2.5 Hz), 6.76 (1H, dd, J = 8.75 and 2.5 Hz), 7.06 (1H, d,

J = 8.75 Hz) and 7.30-7.45 (5H, m); M⁺ 676.4691 (C₄₃H₆₄O₆ requires 676.4703).

Example 10 : 11β-[2-(7-carboχyheptoxy)ethoxyloestra-1,3,5(10)- trien-3-ol (8)

(1) 3-Benzyloxy-17,17-ethylenedioxy-11β-{2-[6-(to!uene-p-sulphony!)- oxyhexoxylethoxy}oestra-1,3,5(10)-triene

The compound (4) of Example 5 (393 mg, 0.7 mmol) was dissolved in pyridine (3 ml) and the solution cooled in an ice-bath

for 30 minutes. Precooled p_-toluene sulphonyl chloride (330 mg) in pyridine (1 ml) was added through a syringe to the solution. The mixture was stirred at ambient temperature for 5 hours. A few chips of ice were then added and the steroids were extracted into diethyl ether (20 ml x 2). The combined organic etheral extract was washed with water and brine, dried (Na₂SO₄), and evaporated to dryness under reduced pressure. The residual slurry was purified by flash silica gel (20%-50% of EtOAc in petroleum spirit as the eluant). The title compound (5) was collected as an oil

(360 mg, 71%); v_max 1610, 1350, 1167cm^-1; δ(CDCl₃) 1.07 (3H, s), 2.43 (1H, dd, J = 10 and 2 Hz), 2.44 (3H, s), 2.71-2.88 (2H, m), 3.22-3.73 (6H, m), 3.87-4.01 (4H, m), 4.00 (2H, t, J = 7 Hz), 4.26 (1H, td, J = 4, 3 and 2 Hz), 5.02 (2H, s), 6.67 (1H, d,

J = 3 Hz), 6.75 (1H, dd, J = 3 and 8 Hz) and 7.13 (1H, d, J = 8 Hz); (M-C₇H₈O₃S)⁺ 546.3343 (product from elimination of p-toluene sulphonic acid, C₄₂H₅₀O₈ less C₇H₈O₃S = C₃₅H₄₂O₅ which

requires 546.3345).

(2) 3-Benzyloxy-17,17-ethylenedioxy-11β-{2-[7,7-bis(ethoxy- carbonyl)heptoxy]ethoxy}oestra-1,3,5(10)-triene (6)

Sodium hydride (72 mg, 2.4 mmol) was suspended in a 1:1 mixture (2 ml) of hexamethylphosphoric triamide (HMPA) and

diethyloxyethane (DME). To this solution was added

dimethylmalonate (500 μl, 2.9 mmol). The mixture was stirred at ambient temperature until all the solids were dissolved. The solution of the sodium malonate was withdrawn with a syringe and added to a solution of the compound (5) (360 mg, 0.48 mmol) in a 1:1 mixture (2 ml) of HMPA and DME. The mixture was stirred at 90°C under argon for 2.5 hours and was then cooled in an

ice-bath. A few chips of ice were added and the mixture was diluted with EtOAc (40 ml). The organic solution was washed with water and brine. The first aqueous solution was again extracted with EtOAc (40 ml). The combined organic extract was dried

(Na₂SO₄) and taken to dryness under reduced pressure. The crude product was purified by HPLC (40% EtOAc in petroleum spirit as mobile phase). The title compound (6) was collected as a

non-crystalline material (336 mg, 94%); ν_max 1725 and 1610 (weak) cm^-1; δ(CDCl₃) 1.07 (3H, s), 1.26 (6H, t, J = 7 Hz), 2.43 (1H, dd, J = 10 and 2 Hz), 2.72-2.92 (2H, m), 3.24-3.73 (7H, m), 3.84-3.98 (4H, m), 4.18 (4H, q, J = 7 Hz), 4.36 (1H, td, J = 4, 3 and 2 Hz), 5.02 (2H, s), 6.68 (1H, d, J = 3 Hz), 6.77 (1H, dd, 3 = 3

and 8 Hz) and 7.14 (1H, d, J = 8 Hz); M⁺ 706.4081 (C₄₂H₅₄O₉

requires 706.4081). (3) 17,17-Ethyl enedioxy-11β-{2-[7,7-bis(ethoxycarbonyl)- heptoxylethoxy}oestra-1,3.5(10)-trien-3-ol (7)

To a solution of the compound (6) (309 mg, 0.44 mmol) in EtOAc (20 ml) was added palladium (10% on charcoal, 330 mg). The mixture was stirred under a hydrogen atmosphere at ambient temperature for 3 hours and then filtered with Celite and more EtOAc was used to wash through the catalyst. The combined filtrate was taken to dryness under reduced pressure. The crude product was purified by flash silica gel (40%-50% EtOAc in petroleum spirit as the eluant) to give the title compound (7) as an oil (251 mg, 93%); v_max 3490, 1725 and 1601 cm^-1; δ(CDCl₃) 1.08 (3H, s, 18-H₃), 1.28 (6H,t J= 7 Hz), 2.42 (1H, dd, J = 10 and 2 Hz),

2.68-2.90 (2H, m), 3.21-3.75 (7H, m), 3.85-3.98 (4H, m),

4.21 (4H, q, J = 7 Hz), 4.35 (1H, td, J = 4, 3 and 2 Hz),

6.45 (1H, d, J = 3 Hz), 6.62 (1H, dd, J = 3 and 8 Hz) and

7.09 (1H, d, J = 8 Hz); M⁺ 616.3668 (C₃₅H₄₈O₉ requires 616.3611). (4) 11β-[2-(7-Carboxyheptoxy)ethoxyl-3-hydroxyoestra- 1,3,5(10)-trien-17-one (8)

To a solution of the compound (7) (240 mg, 0.4 mmol) in dioxane (4 ml) was added a solution of potassium hydroxide

(2% w/w in H₂O) (8 ml). The mixture was heated under reflux at 105-110°C for 3 hours, then cooled to room temperature and acidified with dilute hydrochloric acid. The steroids were extracted into CH₂Cl₂ (50 ml x 2). The organic extract was washed with water and brine, then dried (Na₂SO₄) and taken to dryness under reduced pressure to obtain the crude 17,17-ethlenedioxy-11β- {2-[7,7-bis(carboxy)heptoxy]ethoxy}oestra-1,3,5(10)-triene-3-ol (400 mg).

This crude diacid was redissolved in pyridine (10 ml). The solution was heated under reflux for 2.5 hours and then the pyridine was removed under vacuum. Two drops of concentrated HCl were added to the residue slurry which was further dried under vacuum at 40°C overnight. The residue was redissolved in

THF (6 ml) and mixed with dilute HCl (1.2M, 3 ml). The mixture was heated under reflux for 1 hour and then extracted with CH₂Cl₂ (40 ml x 2). The organic extracts were washed with water, brine, dried (Na₂SO₄) and taken to dryness under reduced pressure. The crude product was freed from trace impurities by passage through a column of silica gel (70% EtOAc in petroleum spirit as an eluant) to obtain a clean mixture (197 mg) which was further purifed by base-extraction.

The mixture was redissolved in diethyl ether (20 ml). To this solution was added KOH (2% w/w in H₂O). The mixture was then stirred at ambient temperature for 2 hours and the ether layer was separated and discarded. Another batch of ether was used to wash the aqueous alkaline solution and was discarded again. The aqueous alkaline solution was acidified with dilute HCl and was then extracted with EtOAc (100 ml x 2). The organic extract was dried (Na₂SO₄) and taken to dryness under reduced pressure to afford the title compound (8) as an oil (140 mg, 74%); v_max 3400-3200

(broad), 1730-1700 (broad) and 1610 cm^-1; δ(CDCl₃) (1.11 (3H, s), 2.36 (2H, t, J = 1 Hz), 2.71-2.95 (2H, m), 3.24-3.75 (6H, m), 4.38 (1H, td, J = 4, 3 and 2 Hz), 6.35 (1H, d, J = 3Hz),

6.59 (1H, dd, J = 3 and 8 Hz) and 7.08 (1H, d, J = 8 Hz);

M⁺ 472.2850 (C₂₈H₄₀O₆ requires 472.2825).

Example 11 : 11β-[2-(7-Carboxyheptoxy)ethoxyl-17α-ethynyloestra- 1,3,5(10)-trien-3,17β-diol (9)

To a solution of the compound (8) of Example 10

(56 mg, 0.12 mmol) in freshly dried THF (3 ml) was added lithium carbonate (10 g, 0.14 mmol) and 18-crown-6 ether (31 mg, 0.12 mmol). The mixture was kept under argon and heated under reflux for 1 hour. The mixture was then cooled to room temperature and treated with a suspension of lithium acetylide(¹⁾ ethylenediamine complex (150 mg, 1.6 mmol) in THF (3 ml). The mixture was stirred at ambient temperature overnight, then treated with a few chips of ice and acidified with dilute HCl. It was extracted with EtOAc (50 ml x 2) and the organic extract was dried (Na₂SO₄) and taken to dryness under reduced pressure to obtain a yellow oil. This yellow oil was treated with chloroform to form a fatty white solid which was further washed with chloroform and dried under vacuum overnight to provide the title compound (9) (41 mg, 69%); m.p. 100-105°C;

ν_max 3400, 3300 and 1720 cm^-1; δ(CDCl₃) (1.09 (3H, s), 2.24 (1H, dd, J = 10 and 2 Hz), 2.38 (2H, t, J = 7 Hz), 2.67 (1H, s),

2.70-2.88 (2H, m), 3.26-3.75 (6H, m), 4.39 (1H, td, J = 4, 3 and 2 Hz), 6.35 (1H, d, J = 3 Hz), 6.62 (1H, dd, J = 3 and 8 Hz) and 7.10 (1H, d, J = 8 Hz); M⁺ 498.3000 (C₃₀H₄₂O₆ requires 498.2981). Footnote In a variation of the procedure lithium propynylide or its ethylenediamine complex may be used to produce the 17α-prop-1-ynyl analogue of the title compound.

Example 12 : 11β-[11-(3-Carboxypropoxy)undecanoxy]-3-hydroxyoestra- 1,3,5(10)-trien-17-one

(1) 3-Benzyloxy-17,17-ethyl enedioxy-11β-[11-(4,4,4-trimethoxy- butoxy)undecanoxy]oestra-1,3,5(10)-triene

Sodium hydride (80% dispersion in mineral oil, 10 mg, 0.42 mmol) was stirred in dry THF (2 ml) under a nitrogen atmosphere

for 10 minutes. Thereafter the supernatant was removed and more dry THF (2 ml) was added and mixed well by stirring. 3-Benzyloxy- 17,17-ethylenedioxy-11 β-(11-hydroxyundecanoxy)oestra-1,3,5(10)- triene (100 mg, 0.17 mmol prepared as described in Example 4) in dry THF (2 ml) was added dropwise to the sodium hydride/THF suspension. The mixture was heated under reflux for one hour to form the alkoxide. After cooling the reaction mixture to room temperature, 4-bromo-1,1,1-trimethoxybutane (50 mg, 0.22 mmol) in dry THF (1 ml) was added dropwise over one hour. The reaction mixture was stirred at 40-55°C overnight. The next day more sodium hydride (10 mg, 0.42 mmol) in dry THF (1 ml) and

4-bromo-1,1,1-trimethoxy- butane (100 mg, 0.44 mmol) in dry THF (1 ml) were added in that order and the reaction mixture was stirred at 40-55°C for a further 24 hours until t.l.c. of a sample showed no change. The mixture was then cooled to room temperature and diluted carefully with THF/aqueous 5% K0H to destroy any unreacted sodium hydride. The organic material was extracted into dichloromethane (3 x 20 ml), the solution being dried over sodium sulphate and evaporated under reduced pressure to afford the title compound in crude form as a yellow oil, δ(CDCl₃, 100 MHz)

1.10 (3H, s), 2.75-2.88 (2H, complex), 3.30 (9H, s),

3.15-3.58 (6H, complex), 3.90 (4H, m, W_1/2 = 12.5 Hz),

4.23 (1H, td, J = 5, 2.5 and 2.5 Hz), 5.01 (2H, s), 6.68 (1H, d, J = 2.5 Hz), 6.76 (1H, dd, J = 8.75 and 2.5 Hz), 7.06 (1H, d,

J = 8.75 Hz) and 7.35 (5H, m, W_1/2 = 15.2 Hz).

(2) 3-Benzyloχy-17,17-ethylenedioxy-11β-[ 11-(3-methoxycarbonyl- propoxy)undecanoxyloestra-1,3,5(10)-triene

The crude 3-benzyloxy-17,17-ethylenedioxy-11β-[11-(4,4,4- trimethoxybutoxy)undecanoxy]oestra-1,3,5(10)-triene was taken up in ether (10 ml) and treated with 20% aqueous hydrochloric acid (5 ml), the two phase system then being stirred for 30 minutes at room temperature. The aqueous layer was neutralized with aqueous 20% potassium hydroxide and the ethereal layer was separated, dried over sodium sulphate, filtered and taken to dryness under reduced pressure to afford a crude yellow oil. Flash chromatography

(eluting solvent: 20% ethyl acetate in light petroleum) gave the title compound as a colourless oil (55 mg, 47.8%), v_max 2926 and 1737cm^-1; δ(CDCl₃, 500 MHz) 1.11 (3H, s), 1.90 (2H, m,

W_1/2 = 12 Hz), 2.41 (1H, dd, J = 10 and 2.5 Hz), 2.47 (2H, t,

J = 6.25 Hz), 2.81-2.92 (2H, m, complex), 3.21 (1H, td, J = 10, 6.25 and 6.25 Hz), 3.40 (2H, t, J = 6.25 Hz), 3.46 (2H, t,

J = 6.25 Hz), 3.58 (1H, td, J = 10, 6.25 and 6.25 Hz),

3.70 (3H, s), 3.89 (4H, m, W_1/2 = 32.5 Hz), 5.02 (2H, s,),

6.70 (1H, d, J = 2-5 Hz), 6.78 (1H, dd, J = 8.75 and 2.5 Hz),

7.07 (1H, d, J = 8.75 Hz) and 7.35 (5H, m, W_1/2 = 35.7 Hz).

Further elution gave the starting material (40 mg).

(3) 3-Benzyloxy-11β-[ 11-(3-carboxypropoxy)undecanoxyloestra- 1,3,5(10)-trien-17-one

3-Benzyloxy-17,17-ethylenedioxy-11β-[11-(3-methoxycarbonyl- propoxy)undecanoxy]oestra-1,3,5(10)-triene (50 mg, 0.072 mmol) was dissolved in a mixture of methanol (0.5 ml) and distilled water (0.1 ml). The solution was stirred at room temperature and lithium hydroxide (10 mg, 0.42 mmol) was added, the reaction mixture then being stirred overnight. The methanol was evaporated and the residue acidified to a pH of about 2 with 20% aqueous HCl, then extracted with ether (3 x 15 ml). The ethereal layer was dried over anhydrous MgSO₄, filtered and evaporated to dryness to afford a colourless oil. This crude product was taken up in ether (3 ml) and extracted wih 5% aqueous KOH. The aqueous layer was separated and further extracted with fresh ether (2 ml), then acidified to a pH of about 2 with aqueous 20% HCl. The acidic product was extracted into dichloromethane (5 x 15 ml) and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness to give the title compound as a colourless oil

(40 mg, 87.0%), v_max 3200-2600 (broad), 2926 and 1735cm^-1;

δ(CDCl₃, 500 MHz) 1.10 (3H, s), 1.90 (2H, m, W_1/2 = 12 Hz),

2.41 (1H, dd, J = 10 and 2.5 Hz), 2.47 (2H, t, J = 6-25 Hz), 2.79-2.90 (2H, complex), 3.21 (1H, td, J = 10, 6.25 and 6.25 Hz), 3.40 (2H, t, J = 6.25 Hz), 3.46 (2H, t, J = 6-25 Hz), 3.58 (1H, td, J = 10, 6.25 and 6.25 Hz), 5.01 (2H, s,), 6.70 (1H, d, J = 2.5 Hz), 6.78 (1H, dd, J = 8.75 and 2.5 Hz), 7.07 (1H, d, J = 8.75 Hz) and 7.35 (5H, m, W_1/2 = 37.5 Hz).

(4) 11β-[11-(3-Carboxypropoxy)undecanoxyl-3-hydroxyoestra- 1,3,5(10)-trien-17-one

To a solution of 3-benzyloxy-11β-[11-(3-carboxypropoxy)- undecanoxy]oestra-1,3,5(10)-triene-17-one (30 mg, 0.047 mmol) in dry methanol (5 ml) was added palladium (5% on charcoal, 50mg). The mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours and was then filtered through a small column of Celite, methanol being used to wash the catalyst. The combined filtrate was taken to dryness under reduced pressure and the residue purified by flash chromatography (eluting solvent: 50% ethyl acetate in light petroleum) to give the title compound as a colourless residue (24 mg, 92%), v_max 3400, 2926 and 1730cm^-1;

δ(CDCl₃, 500 MHz) 1.10 (3H, s), 1.90 (2H, m, W_1/2 = 12 Hz),

2.41 (1H, dd, J = 10 and 2.5 Hz), 2.47 (2H, t, J = 6.25 Hz),

2.79-2.90 (2H, complex), 3.21 (1H, td, J = 10, 6.25 and 6.25 Hz), 3.40 (2H, t, J = 6.25 Hz), 3.46 (2H, t, J = 6.25 Hz), 3.58 (1H, td, J = 10, 6.25 and 6.25 Hz), 6.70 (1H, d, J = 2.5 Hz), 6.78 (1H, dd, J = 8.75 and 2.5 Hz), 7.07 (1H, d, J = 8.75 Hz). Example 13 : 11β-(10-Carboxydecanoxy)-3-hydroxyoestra-1,3.5(10)- trien-17-one

(1) 3-Benzyloxy-11β-(10-carboxydecanoxy)oestra-1,3,5(10)- trien-17-one

3-Benzyloxy-17,17-ethylenedioxy-11β-(11-hydroxyundecanoxy)- oestra-1,3,5(10)triene (100 mg, 0.17 mmol; prepared as described in Example 4) was dissolved in ice cold acetone (2 ml) and Jones Reagent [1 ml, freshly prepared by dissolving chromium trioxide (26.27 g) in distilled water (77 ml) containing concentrated sulphuric acid (23 ml)] was added dropwise to the magnetically stirred solution over 10 minutes. The resulting mixture was then diluted with water (10 ml) and extracted with dichloromethane (5 x 10 ml). The combined organic solutions were washed with saturated sodium chloride solution (20 ml) and separated. The aqueous layer was further extracted with fresh dichloromethane

(3 x 10 ml) and the combined organic solutions were then dried over anhydrous sodium sulphate, filtered and taken to dryness under reduced presure to give a yellow oil. The oil was taken up in diethyl ether (5 ml) and extracted with 5% aqueous KOH (5 ml), the aqueous layer being separated and washed with fresh diethyl ether

(5 ml). The alkaline aqueous layer was acidified to a pH of about 2 with 10% aqueous HCl and extracted with dichloromethane (5 x 10 ml). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and taken to dryness to give the title compound as a colourless oil (76.3 mg, 80.4%), ν_max 3200-2400 (broad), 1736 and 1610cm^-1; δ(CDCl₃, 500 MHz) 1.11 (3H, s), 2.32 (2H, t,

J = 7.5 Hz), 2.79-2.93 (2H, complex), 3.20 (1H, td, J = 10, 6.25 and 6.25 Hz), 3.59 (1H, td, J = 10, 6.25 and 6.25 Hz), 4.27 (1H, td, J = 5, 2.5 and 2.5 Hz), 5.02 (2H, s), 6.70 (1H, d, J = 2.5 Hz), 6.78 (1H, dd, J = 8.75 and 2.5 Hz), 7.06 (1H, d, J = 8.75 Hz) and 7.36 (5H, W_1/2 = 37.5 Hz); M⁺+H 561 (C₃₆H₄₈O₅ requires 560.3971). (2) 11β-(10-Carboxydecanoxy)-3-hydroxyoestra-1,3,5(10)-trien-17-one

To a solution of 3-benzyloxy-11β-(10-carboxydecanoxy)oestra- 1,3,5(10)-triene-17-one (70 mg, 0.13 mmol) in dry diethyl ether (5 ml) was added palladium (5% on charcoal, 50 mg). The mixture was stirred under a hydrogen atmosphere at room temperature overnight and was then filtered through a short column of Celite, diethyl ether being used to wash the catalyst. The combined filtrate was taken to dryness under reduced pressure and the residue purified by flash chromatography (eluting solvent: 60% ethyl acetate in light petroleum) to give the title compound as a col ourl ess resi due (49.9 mg , yi eld 85%) , v_max 3400 ( broad ) and 1736cm^-1; δ(CDCl₃, 500 MHz) 1.11 (3H, s), 2.35 (2H, t, J = 7-5 Hz), 2.78-2.92 (2H, complex), 3.20 (1H, td, J = 10, 6.25 and 6.25 Hz), 3.60 (1H, td, J = 10, 6.25 and 6.25 Hz), 4.26 (1H, td, J = 5, 2.5 and 2.5 Hz), 6.55 (1H, d, J = 2.5 Hz), 6.62 (1H, dd, J = 8.75 and 2.5 Hz) and 7.01 (1H, d, J = 8.75 Hz); M⁺+1 471 (C₂₉H₄₂O₅ requires 470.3032).

Example 14 : 11β-(10-Carboxydecanoxy)-17α-ethynyloestra-1,3,5(10)- trien-3,17β-diol

To a solution of 11β-(10-carboxydecanoxy)-3-hydroxyoestra- 1,3,5(10)-triene-17-one (40 mg, 0.085 mmol; prepared as described in Example 13) in freshly dried THF (2 ml) was added dry lithium carbonate (14.8 mg, 0.2 mmol) and 18-crown-6-ether (52.8 mg,

0.2 mmol). The reaction mixture was heated under gentle reflux for one hour under an argon atmosphere. Thereafter the reaction mixture was allowed to cool to room temperature and was treated with a suspension of lithium acetylide ethylenediamine complex (80 mg, 0.87 mmol) in dry THF. The resulting mixture was stirred at 40-55°C overnight, then cooled to room temperature and treated with a few chips of ice. The mixture was acidified with dilute aqueous HCl and extracted with dichloromethane (5 x 15 ml). The combined organic extracts were dried over anhydrous sodium

sulphate, filtered, and taken to dryness under reduced pressure. .The resultant yellow oil was purified by flash chromatography

(eluting solvent: 50% EtOAC in light petroleum) to give the title compound as a white solid (32 mg, 75.8%), m.p. 145-148°C;

v_max 3400 (broad), 3200 and 1708cm^-1; δ(CDCl₃, 500 MHz)

1.11 (3H, s), 2.36 (2H, t, J = 7.5 Hz), 2.60 (1H, s),

2.78-2.92 (2H, complex), 3.19 (1H, td, J = 10, 6.25 and 6.25 Hz), 3.60 (1H, td, J = 10, 6.25 and 6.25 Hz), 4.26 (1H, td, J = 5, 2.5- and 2.5 Hz), 6.55 (1H, d, J = 2.5 Hz), 6.63 (1H, dd, J = 8.75 and 2.5 Hz) and 7.00 (1H, d, J = 8.75 Hz); M⁺+l 497 (C₃₁H₄₄O₅ requires 496.3189).

Example 15 : 3-Benzyloxy-11β-[2-(10-carboxydecanoxy)ethoxyloestra- 1,3,5(10)-trien-17-one

To a solution of 3-benzyloxy-17,17-ethylenedioxy-11β- [2-(11-hydroxyundecanoxy)ethoxy]oestra-1,3,5(10)-triene (33 mg, 0.052 mmol; prepared as described in Example 7) in ice cold acetone (2 ml) was added freshly prepared Jones' Reagent

(8N-chromic acid solution, 0.5 ml). The mixture was magnetically stirred for 5 minutes, then diluted with water (10 ml) and the product was extracted into dichloromethane (5 x 10 ml). The combined organic solutions were then washed with saturated sodium chloride solution (20 ml) and separated. The aqueous layer was further extracted with fresh dichloromethane (3 x 10 ml). The combined organic extracts were then dried over anhydrous sodium sulphate, filtered, and taken to dryness under reduced pressure to afford a crude yellow coloured oil. The crude residue was taken up in diethyl ether (5 ml) and extracted with 5% aqueous potassium hydroxide solution (5 ml), the aqueous layer being separated and washed with fresh diethyl ether (5 ml). This alkaline layer was acidified to ca. pH 2 with 10% aqueous hydrochloric acid and extracted with dichloromethane (5 x 10 ml). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and taken to dryness to afford the title compound as a colourless oil (28 mg, 80%), v_max 3500-2410 (broad), 1736, 1707, 1610, 1170 and 1120cm^-1; δ (CDCl₃, 500 MHz), 1.10 (3H, s), 2.32 (2H, t,

J = 6.25 Hz), 2.43 (1H, dd, J = 10 and 2.5 Hz), 2.75-2.89 (2H, complex), 3.30 (2H, t, J = 6.25 Hz), 3.41 (2H, t, J = 6-25 Hz), 3.45 (1H, dt, J = 10, 6.25 and 5 Hz), 3.68 (1H, dt, J = 10, 6.25 and 5 Hz), 4.37 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 5.01 (2H, s), 6.68 (1H, d, J = 2.5 Hz), 6.77 (1H, dd, J = 8.75 and 2.5 Hz),

7.14 (1H, d, J = 8.75 Hz) and 7.30-7.45 (5H, m) ; M⁺ 604.3757

(C₃₈H₅₂O₆ requires 604.3764). Example 16 : 11β-[2-(10-Carboxydecanoxy)ethoxyl-3-hydroxyoestra- 1,3,5(10)-trien-17-one

To a solution of 3-benzyloxy-11β-[2-(10-carboxydecanoxy)- ethoxy]oestra-1,3,5(10)-trien-17-one (26 mg, 0.04 mmol; prepared as described in Example 15) in dry diethyl ether (5 ml) was added palladium (5% on charcoal, 30 mg). The mixture was stirred under a hydrogen atmosphere at room temperature overnight. The mixture was then filtered through a short column of celite and more diethyl ether was used to wash the catalyst. The crude product was obtained by taking the combined filtrate to dryness under reduced pressure, and was then purified by flash chromatography (60% ethyl acetate in light petroleum) to afford the title compound as a colourless oil (20 mg, 90%), v_max 3600-3440 (broad), 1730, 1700, 1612, 1170 and 1120cm^-1; δ(CDCl₃, 500 MHz), 1.10 (3H, s),

2.32 (2H, t, J = 6.25 Hz), 2.43 (1H, dd, J = 10 and 2.5 Hz),

2.75-2.89 (2H, complex), 3.30 (2H, t, J = 6-25 Hz), 3.41 (2H, t, J = 6.25 Hz), 3.45 (1H, dt, J = 8.75, 6.25 and 5 Hz), 3.68 (1H, dt, J = 8.75, 6.25 and 5 Hz), 4.37 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 6.55 (1H, d, J = 2.5 Hz), 6.63 (1H, dd, J = 8.75 and 2.5 Hz) and 7.06 (1H, d, J = 8.75 Hz); M⁺ 514.3289 (C₃₁H₄₆O₆ requires 514.3294) Example 17 : 11β-[2-(10-Carboxydecanoxy)ethoxyl-17α-ethynyloestra- 1,3,5(10)-triene-3,17β-diol

To a solution of 11β-[2-(10-carboxydecanoxy)ethoxy]-3-hydroxy- oestra-1,3,5(10)-trien-17-one (15 mg, 0.03 mmol; prepared as described in Example 16) in freshly dried THF (2 ml) was added dry lithium carbonate (7.4 mg, 0.1 mmol, 3.3 mol. eq.) and

18-crown-6-ether (26.4 mg, 0.1 mmol, 3.3 mol. eq.). The reaction mixture was heated under gentle reflux for one hour under an argon atmosphere. Thereafter the reaction mixture was allowed to cool down to room temperature and was treated with a suspension of lithium acetylide-ethylenediamine complex (40 mg, 0.44 mmol,

14.7 mol. eq.) in dry THF. The resulting mixture was stirred at 40-55°C overnight, then cooled to room temperature and treated with a few chips of ice. The mixture was acidified with 5% aqueous hydrochloric acid and extracted with dichloromethane (5 x 15ml). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, and taken to dryness under reduced pressure to afford a yellow coloured oil. Flash chromatography (50% ethyl acetate in light petroleum) gave the title compound as a white solid (12 mg, 76.0%), which was recrystallised from acetone/light petroleum, m.p. 115-119°C; v_max 3423-3200 (broad), 2100 (weak), 1705, 1609, 1170 and 1120-1020cm^-1; δ(CDCl₃, 250 MHz),

1.10 (3H, s), 2.32 (2H, t, J = 6.25 Hz), 2.43 (1H, dd, J = 10 and 2.5 Hz), 2.60 (1H, s), 2.75-2.89 (2H, complex), 3.30 (2H, t, J = 6.25 Hz), 3.41 (2H, t, J = 6.25 Hz), 3.45 (1H, dt, J = 10;

6.25 and 5 Hz), 3.68 (1H, dt, J = 10, 6.25 and 5 Hz), 4.37 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 6.55 (1H, d, J = 2.5 Hz), 6.63 (1H, dd, J = 8.75 and 2.5 Hz) and 7.06 (1H, d, J = 8.75 Hz); M⁺ 540.3464 (C₃₃H₄₈O₆ requires 540.3451).

Example 18 : 3-Benzyloxy-11β-(9-carboxynonoxy)oestra-1,3,5(10)- trien-17-one

The procedure of Example 15 was followed using 3-benzyloxy- 17,17-ethylenedioxy-11 β-(10-hydroxydecanoxy)oestra-1,3,5(10)-triene (50 mg, 0.087 mmol; prepared as described in Example 3) in place of 3-benzyloxy-17,17-ethylenedioxy-11β-[2-(11-hydroxyundecanoxy)- ethoxy]oestra-1,3.5(10)-triene. The title compound was obtained as a colourless oil (39.4 mg, 83.1%), v_{ma x} 3500-2400m (broad), 1740, 1700, 1610, 1170 and 1105-1020cm^-1; δ(CDCl₃, 500 MHz),

1.11 (3H, s), 2.32 (2H, t, J = 6.25 Hz), 2.41 (1H, dd, J = 10 and 2.5 Hz), 2.75-2.95 (2H, complex), 3.20 (1H, dt, J = 10, 6.25 and 5 Hz), 3.59 (1H, dt, J = 10, 6.25 and 5 Hz), 4.27 (1H, dt,

J = 3.75, 2.5 and 2.5 Hz), 5.01 (2H, s), 6.70 (1H, d. J = 2.5 Hz), 6.78 (1H, dd, J = 8.75 and 2.5 Hz), 7.06 (1H, d, J = 8.75 Hz) and 7.30-7.45 (5H, m,); M⁺ 546.3358 (C₃₅H₄₆O₅ requires 546.3345).

Example 19 : 11β-(9-Carboxynonoxy)-3-hydroxyoestra-1,3,5(10)- trien-17-one

The procedure of Example 16 was followed using 3-benzyloxy-11β- (9-carboxynonoxy)oestra-1,3,5(10)-trien-17-one (32.3 mg, 0.06 mmol; prepared as described in Example 18) in place of 3-benzyloxy-11β- [2-(10-carboxydecanoxy)ethoxy]oestra-1,3,5(10)-trien-17-one. Flash chromatography (100% ethyl acetate) gave tne title compound as a colourless oil (24.9 mg, 92.3%), v_max 3600-3300 (broad), 1730, 1707, 1610, 1173 and 1105-1020cm^-1 ; δ(CDCl₃, 500 MHz),

1.11 (3H, s), 2.32 (2H, t, J = 6.25 Hz), 2.40 (1H, dd, J = 10 and 2.5 Hz), 2.75-2.95 (2H, complex), 3.20 (1H, dt, J = 10, 6.25 and 5 Hz), 3.60 (1H, dt, J = 10, 6.25 and 5 Hz), 4.26 (1H, dt, J = 3.75, 2.5 and 2.5 Hz), 6.55 (1H, d, J = 2.5 Hz), 6.62 (1H, dd, J = 8.75 and 2.5 Hz) and 7.01 (1H, d, J = 8.75 Hz); M⁺ 456.2889 (C₂₈H₄₀O₅ requires 456.2876).

Example 20 : 11β-(9-Carboxynonoxy-17α-ethynyloestra-1,3,5(10)- trien-3,17β-diol

The procedure of Example 17 was followed using

11 β-(9-carboxynonoxy)-3-hydroxyoestra-1,3,5(10)-trien-17-one (15 mg, 0.033 mmol; prepared as described in Example 19) in place of 11β-[2-(10-carboxydecanoxy)ethoxy]-3-hydroxyoestra-1,3,5(10)- trien-17-one. Flash chromatography (50% ethyl acetate in light petroleum) afforded the title compound as a white crystalline material which was recrystallised from acetone-light petroleum and dried overnight in vacuo (11.7 mg, 73.8%), m.p. 124-126°C;

v_max 3600-3300 (broad), 2100, 1705, 1615, 1170 and 1105cm^-1;

δ(CDCl₃, 500 MHz), 1.11 (3H, s), 2.32 (2H, t, J = 6.25 Hz),

2.40 (1H, dd, J = 10 and 2.5 Hz), 2.60 (1H, s), 2.75-2.95 (2H, complex), 3.20 (1H, dt, J = 10, 6.25 and 5 Hz), 3.60 (1H, dt,

J = 10, 6.25 and 5 Hz), 4.26 (1H, dt, J = 3.75, 2.5 and 2.5 Hz), 6.55 (1H, d, J = 2.5 Hz,), 6.62 (1H, dd, J = 8.75 and 2.5 Hz) and 7.01 (1H, d, J = 8.75 Hz); M⁺ 482.3036 (C_3oH₄₂O₅ requires 482.3032).

Example 21 : 11β-[11-(3-Carboxypropoxy)undecanoxyl-17α- ethynyloestra-1,3,5(10)-triene-3,17β-diol

The procedure of Example 17 was followed using

11β-[11-(3-carboxypropoxy)undecanoxy]-3-hydroxyoestra-1,3,5(10)- trien-17-one (14 mg, 0.026 mmol; prepared as described in

Example 12) in place of 11β-[2-(10-carboxydecanoxy)ethoxy]-3- hydroxyoestra-1,3,5(10)-trien-17-one. Flash chromatography afforded the title compound as a white crystalline solid, which was recrystallised from acetone/light petroleum and dried overnight in vacuo (11 mg, 75%), m.p. 110-112ºC; v_max 3600-3200 (broad), 2100, 1703, 1170 and 1105-1020cm^-1; δ(CDCl₃, 500 MHz),

1.11 (3H, s), 1.90 (2H, m, W_1/2 12 Hz), 2.41 (1H, dd, J = 10 and 2.5 Hz), 2.47 (2H, t, J = 6.75 Hz), 2.60 (1 H, s),

2.79-2.90 (2H, complex), 3.21 (1H, dt, J = 10, 6.25 and 5 Hz), 3.40 (2H, t, J = 6.25 Hz), 3.46 (2H, t, J = 6.25 Hz), 3.58 (1H, dt, J = 10, 6.25 and 6.25 Hz), 6.70 (1H, d, J 2.5 Hz), 6.78 (1H, dd, J = 8.75 and 2.5 Hz) and 7.07 (1H, d, J = 8.75 Hz);

M⁺ 568.3751 (C₃₅H₅₂O₆ requires 568.3764).

Example 22 : 3-Benzyloxy-17,17-ethylenedioxy-11β-{2-[ 11-(3-carboxy- propoxy)undecanoxylethoxy}oestra-1,3.5(10)-triene

(1) 3-Benzyloxy-17 ,17-ethylenedioxy-11β-{2-[ 11-(4,4,4-trimethoxy- butoxy)undecanoxylethoxy}oestra-1,3,5(10)-triene

The procedure of Example 12(1) was followed using 3-benzyloxy- 17,17-ethylenedioxy-11β-[2-(11-hydroxyundecanoxy)ethoxy]oestra- 1,3,5(10)-triene (100 mg, 0.158 mmol; prepared as described in Example 8) in place of 3-benzyloxy-17,17-ethylenedioxy-11β-(11- hydroxyundecanoxy)oestra-1,3,5(10)-triene to provide the title compound as a crude yellow oil (134 mg). T.l.c. showed the presence of the starting material as well as the title compound and the crude product was used directly in the procedure of Example 23, v_max 2840, 1610, 1170 and 1106-1010cm^-1; δ(CDCl₃, 100 MHz),

1.10 (3H, s), 2.40 (1H, dd, J = 10 and 2.5 Hz), 2.75-2.89 (2H, complex), 3.30 (9H, s), 3.30-3.58 (10H, complex), 3.85-3.95 (4H, m), 4.35 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 5.00 (2H, s), 6.65 (1H, d, J = 2.5 Hz), 6.75 (1H, dd, J = 8.75 and 2.5 Hz), 7.15 (1H, d,

J = 8.75 Hz) and 7.30-7.45 (5H, m).

(2) 3-Benzyloxy-17,17-ethylenedioxy-11β-{2-[11-(3-methoxycarbonyl- propoxy)undecanoxy]ethoxy}oestra-1,3,5(10)-triene

The procedure of Example 12(2) was followed using 3-benzyloxy- 17,17-ethylenedioxy-11β-{2-[11-(4,4,4-trimethoxybutoxy)undecanoxy]- ethoxy}oestra-1,3,5(10)-triene (125 mg) in place of 3-benzyloxy- 17,17-ethylenedioxy-11β-[ 11-(4,4,4-trimethoxybutoxy)undecanoxy]- oestra-1,3,5(10)-triene. Flash chromatography (20% ethyl acetate in l ight petrol eum) gave the title compound as a col ourl ess oi l (99.4 mg , 86%) . v_max 1736 , 1607 , 1 170 and 1106-1010cm^-1 ;

δ( CDCl ₃ , 80 MHz) , 1 .10 ( 3H, s ) , 2.45 ( 2H , t, J = 6.25 Hz) ,

2.75-2.89 (2H . complex) , 3.30-3.58 (10H, complex) ,

3.85-3.95 (4H , m) , 4.35 ( 1H, dt, J = 3.7 , 2.5 and 2.5 Hz) ,

5.00 ( 2H, s ) , 6.65 (1H, d , J = 2.5 Hz) , 6.75 (1 H , dd , J = 8.75 and 2.5 Hz) , 7.1 5 ( 1 H, d , 2 = 8.75 Hz) and 7.30-745 ( 5H, m) ;

M⁺ 733.4688 (C₄₅H₆₅O₈ requires 733.4679).

(3) 3-Benzyloxy-17,17-ethylenedioxy-11β-(2-[11-(3-carboxypropoxy)- undecanoxy]ethoxy}oestra-1,3,5(10)-triene

3-Benzyloxy-17,17-ethyl enedioxy-11β-{2-[11-(3-methoxy- carbonylpropoxy)undecanoxy]ethoxy}oestra-1,3,5(10)-triene

(91 mg, 0.124 mmol) was dissolved in methanol (0.5 ml) and distilled water (0.1 ml). Lithium hydroxide monohydrate (10 mg, 0.238 mmol) was added and the reaction mixture was stirred overnight (t.l.c.) at room temperature. The methanol was then evaporated, and the residue acidified to ca. pH 3 with 5% aqueous hydrochloric acid and extracted with ether (3 x 15 ml). The ethereal layer was dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to afford a colourless oil.

The crude product was taken up in ether (3 ml) and extracted with 5% aqueous potassium hydroxide solution. The aqueous layer was separated and further extracted with fresh ether (2 ml). The aqueous layer was then acidified to ca. pH 3 with aqueous 5% hydrochloric acid. The acidic product was extracted into

dichloromethane (5 x 15 ml). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and evaporated to dryness under reduced pressure to afford the title compound as a colourless oil (77.7 mg, 87%), v_max 3400-3200 (broad), 1706, 1610, 1170 and 1106-1010cm^-1; δ(CDCl₃, 80 MHz), 1.10 (3H, s), 2.45 (2H, t, J = 6.25 Hz), 2.75-2.89 (2H, complex), 3.30-3.58 (10H, complex), 3.85-3.95 (4H, m), 4.35 (1H, dt, J = 3.7, 2.5 and 2.5 Hz),

5.00 (2H, s), 6.65 (1H, d, J = 2.5 Hz), 6.75 (1H, dd, J = 8.75 and 2.5 Hz), 7.15 (1H, d, J = 8.75 Hz) and 7.30-7.45 (5H, m);

M+ 719.4507 (C₄₄H₆₃O₈ requires 719.4523). Example 23 : 3-Benzyloxy-11β-{2-[11-(3-carboxypropoxy)undecanoxy]- ethoxy}oestra-1,3,5(10)-trien-17-one

To a stirred solution of 3-benzyloxy-17,17-ethylenedioxy-11β- {2-[11-(3-carboxypropoxy)undecanoxy]ethoxy}oestra-1,3,5(10)-triene (37) (72 mg, 0.100 mmol; prepared as described in Example 22) in diethyl ether (2 ml) was added 5% aqueous hydrochloric acid (1 ml). The reaction mixture was gently heated under a water condenser between 40-50°C for 15 minutes. After cooling to room temperature, the reaction mixture was diluted with water (5 ml) and the organic product was extracted into fresh diethyl ether (5 x 10 ml), which was then washed with brine (10 ml). The aqueous layer was further extracted with diethyl ether (3 x 5 ml) which was then combined with the original diethyl ether extract. The ethereal solution. was then dried over anhydrous sodium sulphate, filtered, and evaporated to dryness under reduced pressure to afford the title compound as a colourless oil (65.6 mg, 97%), v_max 3400-3200 (broad), 1736,.1700, 1654, 1170 and 1106-1010cm^-1; δ(CDCl₃, 80 MHz), 1.10 (3H, s), 2.45 (2H, t, J = 6.25 Hz), 2.75-2.89 (2H, complex), 3.30-3.58 (10H, complex), 4.35 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 5.00 (2H, s), 6.65 (1H, d, J = 2.5 Hz), 6.75 (1H, dd, J = 8.75 and 2.5 Hz), 7.15 (1H, d, J = 8.75 Hz) and 7.30-7.45 (5H, m); M⁺ 675.4281 (C₄₂H₅₉O₇ requires 675.4261).

Example 24 : 11β-{2-[11-(3-Carboxypropoxy)undecanoxylethoxy}-3- hydroxyoestra-1,3,5(10)-trien-17-one

The procedure of Example 16 was followed using 3-benzyloxy- 11β-{2-[ 11-(3-carboxypropoxy)undecanoxy]ethoxy}oestra-1,3,5(10)- trien-17-one (59 mg, 0.087 mmol; prepared as described in

Example 23) in place of 3-benzyloxy-11β-[2-(10-carboxydecanoxy)- ethoxy]oestra-1,3,5(10)-trien-17-one. Flash chromatography

(100% ethyl acetate) gave the title compound as a colourless oil (46.5 mg, 91%), v_max 3600-3300 (broad), 1736, 1705, 1654, 1170 and 1106-1010cm^-1; δ(CDCl₃, 80 MHz), 1.10 (3H, s), 2.45 (2H, t, J = 6.25 Hz), 2.75-2.89 (2H, complex), 3.30-3.58 (10H, complex), 4.35 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 6.55 (1H, d, J = 2.5 Hz), 6.65 (1H, dd, J = 8.75 and 2.5 Hz) and 7.10 (1H, d, J = 8.75 Hz); M⁺ 585.3784 (C₃₅H₅₃O₇ requires 585.3791). Example 25 : 11β-{2-[11-(3-Carboxypropoxy)undecanoxylethoxy}-17α- ethynyloestra-1,3,5(10)-trien-3,17β-diol

The procedure of Example 17 was followed using

11 β-{2-[11-(3-carboxypropoxy)undecanoxy]ethoxy}-3-hydroxyoestra- 1,3,5(10)-trien-17-one (35 mg, 0.06 mmol; prepared as described in Example 24) in place of 11β-[2-(10-carboxydecanoxy)ethoxy]-3- hydroxyoestra-1,3,5(10)-trien-17-one. Flash chromatography afforded the title compound as a white crystalline solid, which was recrystallised from acetone/light petroleum and dried overnight in vacuo (24.9 mg, 68%), m.p. 110-114ºC, v_max 3600-3300 (broad), 1708, 1170 and 1106-1010cm^-1; δ(CDCl₃, 250 MHz), 1.09 (3H, s), 2.45 (2H, t, J = 6.25 Hz), 2.60 (1H, s), 2.75-2.89 (2H, complex), 3.30-3.58 (10H, complex), 4.37 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 6.55 (1H, d, J = 2.5 Hz, 6.65 (1H, dd, J = 8.75 and 2.5 Hz) and 7.10 (1H, d, J = 8.75); M⁺ 611.3959 (C₃₇H₅₅O₇ requires 611.3948). Example 26 : 3-Benzyloxy-11β-[2-(8-bromo-octanoxy)ethoxyloestra- 1,3,5(10)-trien-17-one

To a solution of 3-benzyloxy-17,17-ethylenedioxy-11β- [2-(8-hydroxyoctanoxy)ethoxy]oestra-1,3,5(10)-triene

(25 mg, 0.042 mmol; prepared as described in Example 8) in dry toluene (2 ml), was added triphenylphosphine (13.1 mg, 0.05 mmol, 1.2 mol. eq.) followed by tetrabromomethane (16.7 mg, 0.050 mmol, 1.2 mol. eq.). The reaction mixture was heated under gentle reflux for 1 hour, after which a further amount of tetrabromomethane (1.2 mol. eq.) and triphenylphosphine (1.2 mol. eq.) was added. After heating under reflux for another 2 hours, tetrabromomethane (1.2 mol. eq.) and triphenylphosphine (1.2 mol. eq.) were once more added and the reaction mixture was stirred at 40-50°C overnight. T.l.c. showed no sign of starting material. The reaction mixture was allowed to cool to room temperature and then diluted with distilled water (10 ml). The product was extracted into ethyl acetate (3 x 10 ml) and the combined organic layers were dried over anhydrous magnesium sulphate, filtered, and taken to dryness under reduced pressure to afford the title compound as a colourless oil (24.1 mg, 93.4%), v_max 1736, 1610, 1170 and 1106-1010cm^-1; δ(CDCl₃ , 250 MHz) , 1 .11 (3H, s) , 2.75-2.89 (2H, complex) ,

3.30 (2H, t, J = 6.25 Hz) , 3.35-3.50 ( 5H, complex) , 3.69 (1H, dt, J = 10, 6.25 and 5 Hz) , 4.39 (1 H, dt, J = 3.7, 2.5 and 2.5 Hz) , 5.02 (2H, s) , 6.70 (1H, d , J = 2.5 Hz) , 6.78 (1H, dd , 2 = 8.75 and 2.5 Hz) , 7.16 (1H, d, J = 8.75 Hz) and 7.30-7.45 (5H, m) ;

M⁺ 612.2626 (C₃₅H₄₇O₄Br requi res 612.2637) .

Example 27 : 11β-[2-(8-Amino-octanoxy)ethoxyl-3-hydroxyoestra- 1 ,3,5(10)-trien-17-one

(1) 3-Benzyloxy-1 1β-[2-(8-azido-octanoxy)ethoxyloestra-1 ,3 , 5(10)- trien-17-one

To a solution of 3-benzyloxy-11β-[2-(8-bromo-octanoxy)ethoxy]- oestra-1,3,5(10)-trien-17-one (19 mg, 0.031 mmol; prepared as described in Example 26) in aqueous acetone (60% v/v, 2 ml) was added sodium azide (5.4 mg, 0.083 mmol, 2.5 mol. eq.). The reaction mixture was heated under reflux overnight and thereafter allowed to cool to room temperature. The acetone was removed under reduced pressure and the residue was diluted with distilled water (5 ml). The organic product was then extracted from the mixture into ethyl acetate (3 x 10 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered, and taken to dryness under reduced pressure to give the title compound as a colourless oil (16.6 mg, 93%), v_max 2092, 1737, 1170 and 1106-1010cm^-1;

δ(CDCl₃, 250 MHz), 1.11 (3H, s), 2.75-2.89 (2H, complex),

3.23 (2H, t, J = 6.25 Hz), 3.30 (2H, t, J = 6.25 Hz),

3.39-3.50 (3H, t, J = 6.25 Hz), 3.68 (2H, dt, J = 10, 6.25

and 5 Hz), 4.38 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 5.02 (2H, s), 6.69 (1H, d, J = 2.5 Hz), 6.78 (1H, dd, J = 8.75 and 2.5 Hz), 7.14 (1H, d, J = 8.75 Hz) and 7.35-7.45 (5H, m); M⁺ 573.6663 (C₃₅H₄₇O₄N₃ requires 573.6657).

(2) 11β-[2-(8-Amino-octanoxy)ethoxyl-3-hydroxyoestra-1,3,5(10)- trien-17-one

To a solution of 3-benzyloxy-11β-[2-(8-azidio-octanoxy)ethoxy]- oestra-1,3,5(10)-trien-17-one (11.4 mg, 0.02 mmol) dry ethyl acetate (5 ml) was added palladium (5% on charcoal, 30 mg). The mixture was then stirred under a hydrogen atmosphere at room temperature overnight. It was then filtered and more ethyl acetate was used to wash the catalyst. The crude product was obtained by taking the combined filtrate and washings to dryness under reduced pressure and then dissolved in diethyl ether (5 ml). 5% Aqueous hydrochloric acid (5 ml) was added to the organic layer and the resulting two phase system was stirred for one hour at room temperature. The aqueous layer was separated, washed with fresh diethyl ether (2 x 3 ml), separated, and neutraiised with 5% aqueous sodium hydroxide solution. The required product was then extracted into dichloromethane (5 x 5 ml) and the combined extracts were dried over anhydrous sodium sulphate, filtered, and taken to dryness under reduced pressure, to afford the title compound as an oil (7 mg, 77%), v_max 3600-3300 (broad), 1737, 1170 and

1106-1010cm^-1; δ(CDCl₃, 250 MHz), 1.11 (3H, s), 2.75-2.89 (2H, complex), 2.46 (2H, t, J = 6.25 Hz), 3.30 (2H, t, J = 6.25 Hz), 3.39-3.50 (3H, t, J = 6.25 Hz), 3.68 (2H, dt, J = 10, 6.25

and 5 Hz), 4.38 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 6.69 (1H, d,

J = 2.5 Hz), 6.78 (1H, dd, J = 8.75 and 2.5 Hz) and 7.14 (1H, d, J = 8.75 Hz); M⁺ 457.3182 (C₂₈H₄₃O₄N requires 457.3192).

Example 28 : 11β-{2-[7-(N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo- hexopyranos-3-yl)carbamoyl)heptoxylethoxy}-17α-ethynyloestra- 1,3,5(10)-trien-3,17β-diol (10)

To a solution of the compound (9) of Example 11 (18 mg, 36 μmol) in DMF (0.5 ml) was added methyl-β-L-daunosaminide hydrochloride (7.5 mg, 38 μmol). The mixture was treated with a drop of pyridine and then a solution of N-ethoxycarbonyl-2-ethoxy-1,2-dihydro- quinoline (EEDQ) (11 mg, 72 μmol) in DMF (0.5 ml). The mixture was stirred at ambient temperature overnight and then diluted with water. The steroids were extracted into EtOAc (30 ml). The organic extract was washed with brine, dried (Na₂SO₄) and taken to dryness under reduced pressure. The crude product was chromatographed on silica gel (EtOAc as an eluant). The title compound (11) was collected from the second fraction as an oil (7.4 mg, 30% from methyl-β-L-daunosaminide); v_max 3540, 3410, 1640 and 1605 cm^-1; δ(CDCl₃) 1.09 (3H, s), 1.29 (3H, d, J = 6 Hz), 2.23 (2H, t,

J = 7 Hz), 2.61 (1H, s), 2.67-2.86 (2H, m), 3.23 (2H, t, J = 7 Hz), 3.39-3.50 (3H, m), 3.51 (3H, s), 3.48-3.64 (2H, m), 3.69 (1H, m), 4.14 (1H, m), 4.38 (1H, dt, J = 3, 3 and 3 Hz), 4.41 (1H, dd, J = 3 and 10 Hz), 5.30 (1H, s), 6.12 (1H, d, J = 8 Hz), 6.55 (1H, d,

J = 3 Hz), 6.65 (1H, dd, 3 = 3 and 8 Hz), and 7.10 (1H, d,

J = 8 Hz); M⁺ 624.3932 and 623.3830 which are both fragments (C₃₇H₅₅NO₈ - OH requires 624.3900 and C ₃₇H₅₅NO₈ - H₂O requires 623.3822); M⁺ 641.

Footnote The compounds 11β-(10-carboxydecanoxy)-17α-ethynyl- oestra-1,3,5(10)-trien-3,17β-diol (Example 14), 11β-[ 11-(3-carboxypropoxy)undecanoxy]-17α-ethynyloestra- 1,3,5(10)-trien-3,17β-diol (Example 21) and 11β-{2-[11- (3-carboxypropoxy)undecanoxy]ethoxy}-17α-ethynyloestra- 1,3,5(10)-trien-3,17β-diol (Example 25) may be treated by the procedure of Example 28 to produce 11β-{1.0-[N- (1 -methoxy-1,2,3,6-tetradeoxy-β-L-lyxohexopyranos-3-yl)- carbamoyl]decanoxy}-17α-ethynyloestra-1,3,5(10)-trien3,17β-diol, 11β-{n-[3-(N-(1-methoxy-1,2,3,6-tetradeoxy- β-L-lyxohexopyranos-3-yl)carbamoyl)propoxy]undecanoxy}-

17α-ethynyloestra-1,3,5(10)-trien-3,17β-diol and 11β-{2-[11-(3-(N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo- hexopyranos-3-yl)carbamoyl)propoxy)undecanoxy]ethoxy}- 17α-ethynyloestra-1,3,5(10)-trien-3,17β-diol,

respectively.

Example 29 : 11β-{2-[10-(N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo- hexopyranos-3-yl)carbamoyl)decanoxylethoxy}-17α-ethynyloestra- 1,3,5(10)-trien-3,17β-diol

To a solution of 11β-[2-(10-carboxydecanoxy)ethoxy]-17α- ethynyloestra]-1,3,5(10)-trien-3,17β-diol (7.0 mg, 0.013 mmol;

prepared as described in Example 17) in dry N,N-dimethylformamide (0.5 ml) was added methyl-β-L-daunosaminide hydrochloride (4.0 mg, 0.02 mmol, 1.5 mol. eq.). The mixture was treated with pyridine (0.5 ml) and then a solution of 2-ethoxycarbonyl-1-ethoxy-1,2- dihydroquinoline (10 mg, 0.04 mmol, 3.0 mol. eq.) in DMF (0.5 ml) was added dropwise. The mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate (5 x 10 ml). The combined extracts were washed with brine, dried over anhydrous sodium sulphate, filtered, and taken to dryness under reduced pressure. Flash chromatography (100% ethyl acetate) gave the title compound as a colourless oil. This was crystallised from ethyl acetate-light petroleum to give clusters of white crystals (7.1 mg, 80.2%), m.p. 85-88°C, ν_max 3600-3446 (broad), 2835, 2140, 1684, 1610, 1170 and 1120-1015cm^-1;

δ(CDCl₃, 250 MHz) 1.10 (3H, s), 1.29 (3H, d, J = 6.25 Hz),

2.24 (2H, t, J = 6.25 Hz), 2.42 (1H, dd, J = 10 and 2.5 Hz), 2.60 (1H, s), 2.75-2.89 (211, complex), 3.30 (2H, t, J = 6.25 Hz), 3.41 (2H, t, J = 6.25 Hz), 3.45 (1H, dt, J = 10, 6.25 and 5 Hz), 3.48 (1H, complex), 3.62 (1H, complex), 3.68 (1H, dt, J = 10, 6.25 and 5 Hz), 4.14 (1H, complex), 4.37 (1H, dt, J = 3.7, 2.5 and 2.5 Hz), 4.40 (1H, dd, J = 10 and 2.5 Hz), 6.08 (1H, d,

J = 8.75 Hz), 6.55 (1H, d, J = 2.5 Hz), 6.67 (1H, dd, J = 8.75 and 2.5 Hz) and 7.10 (1H, d, J = 8.75 Hz); M⁺ 683.4398 (C₄₀H₆₁O₈N requires 683.4397); M⁺+1 684.

Example 30 : 11β-{9-[N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo- hexopyranos-3-yl)carbamoynnonoxy}-17α-ethynyloestra-1,3,5(10)- trien-3,17β-diol

The procedure of Example 29 is followed using

11β-(9-carboxynonoxy)-17α-ethynyloestra-1,3,5(10)-trien-3,17β-diol (8.2 mg, 0.017 mmol; prepared as described in Example 20) in place of 11β-[2-(10-carboxydecanoxy)ethoxy]-17α-ethynyloestra]-1,3,5(10)- trien-3,17β-diol. Flash chromatography (100% ethyl acetate) gave the title compound as a colourless residue. This was crystallised from ethyl acetate-light petroleum to give a white crystalline solid (8.8 mg, 82.7%), m.p. 84-86°C, v_max 3600-3300 (broad),

2835, 2100, 1684, 1610, 1170 and 1105-1020cm^-1;

δ(CDCl₃, 250 MHz), 1.10 (3H, s), 1.30 (3H, d, J = 6.25 Hz),

2.23 (2H, t, J = 6.25 Hz), 2.40 (1H, dd, J = 10 and 2.5 Hz),

2.60 (1H, s). 2.75-2.95 (2H, complex), 3.17 (1H, dt, J = 10, 6.25 and 5 Hz), 3.50 (3H, s), 3.57 (1H, dt, J = 10, 6.25 and 5 Hz), 3.62 (1H, complex), 4.14 (1H, complex), 4.26 (1H, dt, J = 3.75, 2.5 and 2.5 Hz), 4.41 (1H, dd, J = 10 and 2.5 Hz), 6.08 (1H, d, J = 8.75 Hz), 6.56 (1H, d, J = 2.5 Hz), 6.64 (1H, dd, J = 8.75 and 2.5 Hz) and 7.00 (1H, d, J = 8.75 Hz); M⁺ 625.3981 (C₃₇H₅₅O₇N requires 625.3979); M⁺+1626.

Example 31 : Tests of Physiological Activity

(1) Oestrogen Receptor Binding

The activity of the compound 11β-{2-[7-(N-(1-methoxy-1,2,3,6- tetradeoxy-β-L-lyxo-hexopyranos-3-yl)carbamoyl)heptoxy]ethoxy}- 17α-ethynyloestra-1,3,5(10)-trien-3,17β-diol of Example 28 was compared with that of tamoxifen and of oestradiol in a competitive binding assay to measure the relative affinity of anti-oestrogens for rat uterine ER based upon the method of Wakeling. All stocks of anti-oestrogens were prepared in absolute ethanol and ten-fold dilutions were made in 10 mM phosphate buffer, pH 7.4, containing 1.5 mM EDTA, 2.0 mM 2-beta-mercaptoethanol and 0.1% bovine serum albumin. Cytosol was prepared from mature rat uterii by

homogenization in the 10 mM phosphate buffer, pH 7.4, described above and centrifuged at 100,000 g for 1 hour at 4°C. Aliquots of cytosol (100 μl) were incubated with 50 μl of a solution of tritiated oestradiol ([2,4,6,7- H]oestradiol-17β,

85-110 curies/mmol, Amersham, England), in the absence or presence of a solution of increasing concentration of the drug (50 μl) for 16 hours at 4°C. After incubation, a. suspension (200 μl) of dextran-coated charcoal (0.5% dextran T-70, 5% Norit A charcoal, w/v, in the 10 mM phosphate buffer, pH 7.4, described above but without the 0.1% bovine serum albumin) was added and incubation was continued for 15 minutes at 4°C. After removal of the charcoal by centrifugation, the protein-bound tritiated oestradiol in the supernatant (200 μl) was measured by liquid scintillation counting.

The results are shown in Figure 1 where the mean DPM (decays per minute) is plotted against the logarithm of the drug

concentration (the larger the negative value of the logarithm, the smaller the amount of drug required to produce the particular mean DPM). The log of the drug concentration required to produce any mean DPM level can be read off for the different drugs and it will be seen that the compound of Example 28 exhibits a higher level of oestrogen receptor binding activity as compared with tamoxifen over the entire concentration. range, i.e. less compound is required to produce any particular DPM level.

The receptor binding affinity (RBA) of the compound of

Example 28 and of tamoxifen were calculated relative to that of oestradiol as 100. The greater affinity for the oestrogen receptor for the compound of Example 11 was reflected by an RBA of 2 as compared with that for tamoxifen of 0.44.

(2.) Effect on Breast Cancer Cells

(a) In a first experiment the wells contained 3 x 10⁴ per well of the oestrogen receptor-positive MCF-7 cells in DMEM (Dulbecco's Modification of Eagle's Minimum Essential Medium) without phenol red plus 5% SSFCS (steroid stripped foetal calf serum). The medium contained 1 x 10^-8M E₂ (oestradiol) and 1 x 10^-6M of the compound of Example 28 or of tamoxifen. Controls were treated either with 0.1% ethanol or 1 x 10^-8M E₂. The cells were cultured for 7 days, cell counts being made at 3 and 7 days. All determinations were carried out in triplicate.

(b) In a second experiment the procedure was similar to that of (a) with the exception that the 1 x 10^-8M E₂ was omitted from the experiments conducted with the compound of Example 28 and with tamoxifen.

(c) In a third experiment the procedure was similar to that of (a) with the exception that the cells were 2 x 10⁴ per well of the oestrogen receptor-negative MDA-MB-231 cells.

The results for experiments (a), (b) and (c) are shown, respectively, in Figures 2, 3 and 4 from which it will be seen that in Figure 2, when oestrogen receptor-positive MCF-7 cells are used in the presence of oestradiol, the compound of Example 28 prevents proliferation compared to the E₂ treated controls both at 3 and at 7 days (p≤ 0.001 in each case). When compared to tamoxifen the results are superior in terms of the suppression which is achieved (p ≤ 0.01), a result which has been confirmed in further

experiments. When the experiment was repeated without the addition of oestradiol so that the cells were more quiescent, it will be seen from Figure 3 that there is still a significant suppression of proliferation at 3 and 7 days as compared to the E₂ treated controls but in quiescent cells the level of suppression is more similar to that shown by tamoxifen. Moreover, it should be noted that there is no stimulation of growth over and above the level shown by the ethanol containing controls for the compound of Example 28 so it does not act as an oestrogen.

When the experiment was repeated with oestrogen

receptor-negative cells, it will be seen from Figure 4 that the compound of Example 28 shows no effect indicating that the effects observed in (a) and (b) are mediated via the oestrogen receptor.

Claims

1. A compound of formula (I)

in which the dotted line indicates the optional presence of a double bond joining the 6 and 7 positions, A is a divalent group having a chain of at least four atoms joining the oxy group and the group BX, which group A is an aliphatic hydrocarbon group or such a group in which there is replacement by one or more groups selected from -0-, -S-,

SO,

^SO₂,

CO,

NR,

SiR'R' and phenylene, wherein R is hydrogen or an alkyl group and R' and R" are the same or different alkyl groups, of one or more carbon atoms, excluding (a) replacement of that carbon atom attached to the group B,

(b) replacement of both of any two carbon atoms which are joined together either directly or through a single further carbon atom, and, except in the case of the replacement groups

-SO₂ and

CO,

(c) replacement of that carbon atom attached to the oxy group,

R R R R R I I I I I

B is selected from -C-N-, -CO-N-, -N-CO-, -SO₂-N-, -COO- and -OCO- |

R

wherein R or each R separately is hydrogen or an alkyl group, X is a sugar residue and Y is hydrogen or an alkyl, alkenyl or alkynyl group, the compound (I) optionally being in the form of a

physiologically acceptable ester, and/or of a physiologically acceptable salt where appropriate.

2. A compound according to Claim 1, in which the 6 and 7 positions are joined by a single bond.

3. A compound according to Claim 1 or 2, in which the length of the chain in the group A is from 4 to 24 atoms.

4. A compound according to Claim 1, 2 or 3, in which the group A is a branched or unbranched saturated aliphatic hydrocarbon group or such a group in which one or more of the carbon atoms in the chain are replaced by one or more groups selected from -O- and -S-.

5. A compound according to Claim 4, in which A is -(CH₂)_p- or -(CH₂)_m,-O-(CH₂)_n,- wherein p is an integer from 4 to 24, m' is an integer from 2 to 20, n' is an integer from 1 to 20 and m' + n' is 3 to 23.

6. A compound according to Claim 5, in which A is

-(CH₂)₂-O-(CH₂)₇-.

7. A compound according to any of the preceding claims in which the group B is -CONR-, -NRCO- or -SO₂NR-.

8. A compound according to Claim 7, in which B is -CONH-.

9. A compound according to Claim 7 or 8, in which the group X together with the adjacent atom of the group B is the residue of an amino sugar or a carboxy sugar, the group B being attached at the 2- or 3-position of the sugar residue X.

10. A compound according to Claim 9, in which X is a

1-methoxy-1,2,3,6-tetradeoxyhexopyranos-3-yl group.

11. A compound according to any of the preceding claims, in which Y is hydrogen or a group -C≡CR in which R is hydrogen or methyl.

12. A compound according to Claim 1 being

11β-{9-[N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo-hexopyranos-3-yl)- carbamoyl]nonoxy}-17α-ethynyloestra-1,3,5(10)-trien-3,17β-diol,

11β-{9-[N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo-hexopyranos-3-yl)- carbamoyl]nonoxy}-l7α-(prop-1-ynyl)oestra-1,3,5(10)-trien-3,17β- diol,

11β-{2-[10-(N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo-hexopyranos-

3-yl)carbamoyl)decanoxy]ethoxy}-17α-ethynyloestra-1,3,5(10)- trien-3,17β-diol, or

11β-{2-[10-(N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo-hexopyranos- 3-yl)carbamoyl)decanoxy]ethoxy}-17e-(prop-1-ynyl)oestra-1,3,5(10)- trien-3,17β-diol, or a physiologically acceptable ester thereof.

13. A compound according to Claim 1 being 11β-{2-[7-(N-(1-methoxy- 1,2,3, 6-tetradeoxy-β-L-lyxb-hexopyranos-3-yl)carbamoyl)heptoxy]- ethoxy}-17α-ethynyloestra-1,3,5(10)-trien-3,17β-diol or

11β-{2-[7-(N-(1-methoxy-1,2,3,6-tetradeoxy-β-L-lyxo-hexopyranos- 3-yl)carbamoyl)heptoxy]ethoxy}-17α-(prop-1-ynyl)oestra-1,3,5(10)- trien-3,17β-diol, or a physiologically acceptable ester thereof.

14. A compound of formula (IIIa)

in which the dotted line indicates the optional presence of a double bond joining the 6 and 7 positions, A' is a divalent group having a chain of at least four atoms joining the oxy group or the group Z, which group A is an aliphatic hydrocarbon group or such a group in which there is replacement by one or more groups selected from -O-, -S-,

^SO, ^SO₂, -CO, NR,^SiR'R' and phenylene,

wherein R is hydrogen or an alkyl group and R' and R" are the same or different alkyl groups, of one or more carbon atoms, excluding

(a) replacement of that carbon atom attached to the group Z,

(b) replacement of both of any two carbon atoms which are joined together either directly or through a single further carbon atom, and, except in the case of the replacement groups

SO₂ and CO,

(c) replacement of that carbon atom attached to the oxy group, R₁ is hydroxy and R₂ is hydrogen or an alkyl, alkenyl or alkynyl group, or R₁ and R₂ together are an oxo group, and Z is selected from carboxy and sulpho and activated derivatives thereof, amino, mono-alkyl substituted amino, hydroxy, and halogeno, halogenomethyl and mono- and di-alkyl substituted halogenomethyl and other such groups in which halogeno is replaced by an alternative leaving group, the hydroxy group at the 3-position and/or a hydroxy group R₁ or an oxo group R₁ R₂ optionally being in protected form, the compound optionally being in the form of an ester, and/or a salt where appropriate.

15. A compound according to Claim 14, in which the 6 and 7 positions are joined by a single bond.

16. A compound according to Claim 14 or 15, in which A' is as defined for A in any of Claims 3 to 6.

17. A compound according to Claim 14, 15 or 16, in which Z is carboxy or an activated derivative thereof.

18. A compound according to Claim 14 being 11β-[2-(7-carboxy- heptoxy)ethoxy]oestra-1,3,5(10)-trien-3-,17β-diol, 11β-[2-(7- carboxyheptoxy)ethoxy]-17α-ethynyloestra-1,3,5(10)-trien-3,17β- diol or 11β-[2-(7-carboxyheptoxy)ethoxy]-17α-(prop-1-ynyl)oestra- 1,3,5(10)-trien-3,17β-diol or a derivative thereof in which the carboxy group is in activated form or in salt form and/or one or both hydroxy groups are in protected form.

19. A compound of formula (V)

in which the dotted line indicates the optional presence of a double bond at the 6 and 7 positions, A" is a divalent group having a chain of at least two atoms joining the oxy and hydroxy groups, which group A" is an aliphatic hydrocarbon group or such a group in which there is -replacement by one or more groups selected from -O-, -S-,

SO, SO₂, CO, NR, SiR'R' and phenylene, wherein R is

hydrogen or an alkyl group and R' and R" are the same or different alkyl groups, of one or more carbon atoms, excluding (a) replacement of that carbon atom attached to the group OH, (b) replacement of both of any two carbon atoms which are joined together either directly or through a single further carbon atom, and, except in the case of the replacement groups

-SO₂ and

-CO, (c) replacement of that carbon atom attached to the oxy group, R₁ is hydroxy and R₂ is hydrogen or an alkyl, alkenyl or alkynyl group, or R₁ and R₂ together are an oxo group, the hydroxy group at the 3-position and/or that attached to A" and/or a hydroxy group R₁ or an oxo group R₁ R₂ optionally being in protected form, the compound optionally being in the form of an ester, and/or a salt where appropriate.

20. A compound according to Claim 19, in which the 6 and 7 positions are joined by a single bond.

21. A compound according to Claim 19 or 20, in which A" is a branched or unbranched saturated aliphatic hydrocarbon group with a chain length between the oxy group and the hydroxy group of 2 to 25 atoms or such a group in which one or more of the carbon atoms in the chain are replaced by one or more groups selected from -O- and -S-.

22. A compound according to Claim 21, in which A" is -(CH₂)_p- or -(CH₂)_m,-O-(CH₂)_n,- wherein p is an integer from 2 to 25, m' is an integer from 2 to 22, n' is an integer from 2 to 22 and m' + n' is 4 to 24.

23. A compound according to Claim 22, in which A" is -O-(CH₂)₂-OH or -O-(CH₂)₂-O-(CH₂)₆-OH.

24. A compound according to Claim 19 being 3-hydroxy-11β- (2-hydroxyethoxy)-17-oxo-oestra-1,3,5(10)-triene or 3-hydroxy- 11β-[2-(6-hydroxyhexoxy)ethoxy]-17-oxo-oestra-1,3,5(10)-triene or a derivative thereof in which one or both hydroxy groups and/or the oxo group are in protected form.

25. A pharmaceutical composition comprising a compound of

formula (I) as defined in any of Claims 1 to 13 together with a physiologically acceptable diluent or carrier.

26. A compound of formula (I) as defined in any of Claims 1 to 13 for use in therapy.

27. A method for aiding the regression and palliation of breast cancer, of benign breast disease, or of carcinoma of the corpus uteri, for preventing or slowing the onset of breast cancer, or for treating an ovulatory infertility, in a patient which comprises administering to that patient a therapeutically effective amount of a compound of formula (I) as defined herein.