GB2355007A - Tamoxifen analogue glycosides and use thereof - Google Patents

Abstract

Tamoxifen analogue glycosides disclosed as are methods for treating or preventing a number of conditions that may be treated with said antioestrogenic compounds.

Description

2355007 Tamoxifen and Tamoxifen Analogue Glycosides and Use Thereof

The invention is in the field of organic and medicinal chemistry. In particular, the invention relates to tarnoxifen and tanioxifen analogue glycosides and the use thereof to treat conditions that are treatable with tarnoxifen and tarnoxifen analogues.

Tarnoxifen is an antioestrogenic agent that blocks the actions of estrogens on target tissues. Tamoxifen is useful as a palliative treatment for certain patients with advanced breast cancer; it can also be used effectively as an adjuvant in the treatment of oestrogen receptorcontaining breast tumours [cf. Goodman and Gilman's "The Pharmacological Basis of Therapeutics," 80'edition, pp. 1256-1257 and 1395-1397, Gilman et aL (eds.), Pergamon Press, New York, NY (1990)].

Tarnoxifen is a triarylene derivative having the same stilbene nucleus as diethylstilbestrol. Such triarylene derivatives can display either agonist or antagonist activity depending on the orientation of the alkylaminoethoxy side chain. In the trans configuration (of tamoxifen), the compounds are antioestrogens. In the cis configuration, they are agonists. in humans, both isomers can be activated metabolically by hydroxylation at C-4 of the A ring, producing phenolic metabolites with affinities for the oestrogen receptor that are 100-fold greater than those of the parent molecules. Although the isomers of tamoxifen are relatively stable, their metabolites isomerise readily to produce mixtures. This may explain why antioestrogenic properties observed in vivo do not always agree with those detected in vitro (Goodman and Gilman, supra).

Tamoxifen and its derivatives may be used, for example, as oestrogenic, antioestrogenic and progestanic agents (US-A-4,696,949); for imaging oestrogen receptors (with,..., halo-substituted tamoxifen, US-A-5,192, 525); treating a mammal for breast cancer, treating or preventing cardiovascular disease, treating or preventing osteoporosis (IJS-A-5,877, 219); treating breast cancer (US-A-5,807,899); treating endometriosis, obesity, benign prostatic hypertrophy and prostatic carcinoma in mammals (US-A-5, 852,059); treating oestrogendependent tumours such as breast cancer tumours (US-A-5,491,173); treating osteoporosis, pre-menstrual syndrome, vasomotor spasms associated with menopause, atrophic vaginitis, Kraurosis vulvae, female hypogonadism, primary ovarian failure, excessive hair growth and prostatic cancer (US-A-5,189,212); and treating psoriasis (US- A-4,851,433).

A number of analogues of tamoxifen is known (cf. US Patent Nos. 5,877,219, 5,192,525, 5,196,435, 5,807,899 and 4,696,949).

In a first aspect, the present invention provides a compound of the Formula (1):

RI R2 M R3 wherein R' is H, --(CH2),,CR'=CR6CR; -(CH,).C(X)NR8R; R5 R6 F17 -Z-(CH2)4- WR!; or -R-COOH; (CHOP R is -(CH2)10- or -(CH2)w--; R2 is one or more halo, hydroxy, lower alkyl, or lower alkoxy, or is a buta- 1, 3 -dienyl radical which, together with the adjacent benzene ring, forms a naphthyl radical, or -OQ, wherein Q is a straight or branched chain glycosidic. residue containing 1-20 glycosidic. units per residue, or an orthoester glycoside moiety of the Formula (II):

OCA ORI) wherein A represents a glycofuranosyl or glycopyranosyl ring; Ra is hydrogen; lower CI-4 alkyl; C7-10 aralkyl; phenyl or phenyl substituted by chloro, fluoro, bromo, iodo, lower C14 alkyl or lower CI-4 alkoxy; or naphthyl; and Rb is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue; with the proviso that at least one of R is -OQ; W is H, halo, hydroxy, lower alkyl, or lower alkoxy, or is a buta- 1, 3- dienyl radical which together with the adjacent benzene ring forms a naphthyl. radical; R is -CN, -N02, lower alkyl, lower alkyl substituted by Y, or -Y; R5 and R6 are independently H, -CI-4 alkyl, --C24 alkenyl, --C2-4 alkynyl, -X-CI-3 alkyl, -X-C24 alkenyl, -X-C2-4 alkynyl or -Y; R7 is -CN, -C 1 -4alkyl-OH, -C(O)NR'0R'1, -C(O)NR'2R", --C 1 4alkyl-NWOR", -C(O)F, -C(O)OR 12, __C(O)NRI2 OR", --C(O)NHC(O)RI2, --C(O)NHCH2R,2, - C(NH2)(NOR 12), -S(O)R 12, -S(O)(0)(OR 12), -S(O)(O)(NCH02R'2), P03R 12, - P(O)-(NR 12R13)(NR 12 R13), _p(O)(NR12RI3)(OR 14), _CONRI2 (CH2OCH3, - CONR 12 (CH2),NR8R9 or oxadiazole substituted with methyl; R8 and R? are independently hydrogen, --CI-7akl, --C3-7CYClOalkYl, -0-CI- 7alkYl, C-1-7alkyl-Y or phenyl; R10 and R1 1 are independently methyl or ethyl or, taken together, form a morpholino group bonded via its nitrogen atom; R 12 and R 13 are independently H, --Cl.12alkYl, --C2-12a&enYl, --C2- 12alkYnYl, The invention ftniher provides pharmaceutical compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable carriers therefor.

Also envisaged are methods for the treatment and/or prophylaxis of conditions wherein tamoxifen may be indicated, especially which are selected from cardiovascular disease, osteoporosis, endometriosis, obesity, benign prostatic hypertrophy, prostatic carcinoma, oestrogendependent turnours, oestrogen independent tumours, breast cancer, metastatic breast cancer, pre-menstrual syndrome, vasomotor spasms associated with menopause, atrophic vaginitis, Kraurosis vulvae, female hypogonadism, primary ovarian failure, excessive hair growth, and psoriasis, said method comprising administering to an animal having the condition an effective amount of a compound of the present invention.

The present invention further provides the use of a compound of formula (I), or salt thereof, in the manufacture of a medicament for the treatment or prophlyxis of a condition wherein tamoxifen may be indicated, especially wherein said condition is selected from cardiovascular disease, osteoporosis, endometriosis, obesity, benign prostatic hypertrophy.prostatic carcinoma, oestrogen- dependent tumours, oestrogen independent tumours, breast cancer, metastatic breast cancer, pre-menstrual syndrome, vasomotor spasms associated with menopause, atrophic vaginitis, Kraurosis vulvae, temale hypogonaaism, pnmary ovarian failure, excessive hair growth, and psoriasis.

The above method and use are generally applicable to cardiovascular disease, osteoporosis, endometriosis, obesity, benign prostatic hypertrophy, prostatic, carcinoma, oestrogen-dependent tumours, oestrogen independent turnours, breast cancer, metastatic breast cancer, premenstrual syndrome, vasomotor spasms associated with menopause, atrophic vaginitis, Kraurosis vulvae, female hypogonadism, primary ovarian failure and excessive hair growth.

Preferred are treating or preventing oestrogen-dependent turnours, each of these, individually, being more preferred. Such turnours are, preferably, breast tumours.

The preferred route of administration is per os.

As provided herein, the term "alkyl," alone or in combination, refers to a straight or branched chain saturated C, to C7 hydrocarbon group, unless otherwise preceded by some other chain length designator. The term "lower alkyl" is used herein to indicate C, to C4 unless otherwise preceded by some other chain length designator. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, isobutyl, -butyl, n-hexyl, and the like.

The term "haloalkyl" is defined herein as an alkyl substituted with one or more halogens. The term "cycloalkyl" is defined herein to include cyclic. hydrocarbon radicals from C3-C7- Some exemplary cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclobutyl, and cyclopentyl- The term "aryl," alone or in combination, is defined herein as a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group, e.g., phenyl or naphthyl, which can be unsubstituted or substituted, for example, with one or more and, in particular, one to three substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino,, acylamino (alkanoyl), alkylthio, alkylsulphinyl and alkylsulphonyl. Some exemplary aryl groups include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4chlorophenyl, 2-methylphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 4nitrophenyl, and the like.

The tenn "heteroaryl" is defined herein as a 5- or 6-membered heterocyclic aromatic group which can optionally carry a fused benzene ring and which can be unsubstituted or substituted, for example, with one or more and, in particular, one to three substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl and alkylsulphonyl.

The term "halogen" is defined herein to include fluorine, chlorine, bromine and iodine.

The term "linear and cyclic heteroalkyl" are defined in accordance with the term "alkyl" with the suitable replacement of carbon atoms with some other atom, such as nitrogen or sulphur, which would render a chemically stable species.

Additionally, the functional groups mentioned above have been set forth with parenthetical designations surrounding certain atoms or groups of atoms where it is desirable to elucidate molecular structure or bonding schemes. It will be appreciated that, in the absence of any indication to the contrary, any such use of parentheses is entirely in accordance with the IUPAC Rules. Illustratively, and without being bound, for example, a single atom such as "0" or a group of atoms such as "NH2" may be presented in parentheses within the formula of one of the functional groups set forth above [see, for example, when R7 is. -C(O)R 12, -C(O)OR 12, _C(O)NRI2 OR", - C(NH2)(NOR"), etc.]. In such a situation, the parentheses are intended to illustrate that the atom or groups of atoms contained therein are bonded to the nearest preceding chemically suitable atom which is not surrounded by parentheses.

More particularly, for example, -C(O)R 12 is intended to r epresent a functional group wherein the oxygen is bonded to the carbon, the nearest preceding atom which is not surrounded by parentheses and is chemically suited for bonding according to classical orbital electron bonding theory. Alternatively, -C(NI-12)(NOR 12) is intended to represent a fimctional group wherein the nitrogen present in both N112 and NOR 12 is bonded to the carbon, the nearest preceding atom which is not surrounded by parentheses. These examples are illustrated in (a) and (b) below. Those skilled in the art will recognise that the appropriate bonding schemes (e. g. single, double, etc.) are evident from the rules of orbital bonding.

C-R 12 (a) -C= NOR12 NH2 (b) Additionally, some of the fimctional groups mentioned above have been set forth with parenthetical designations "() " surrounding certain atoms or groups of atoms wherein the parentheses are immediately followed with an alphabetical or numerical subscript [see, for example, where R7 is...- CONR 12 (CH2)KOCH3)1- In such a situation, it is intended that the atom or groups of atoms contained therein are present within the functional group as multiples of the sub. script. For example, if r-2 When R7 is _C0NR12(CH2)'OCH3' then k7 _CONR12CH,CH20CH3.

Those skilled in the art will recognise that stereocentres exist in compounds of Formula (1). Accordingly, the present invention includes all possible stereoisorners and geometric isomers of Formula (1) and includes not only racernic: mixtures but also the optically active isomers. When a compound of Formula (1) is desired as a single enantiorner, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate.. Resolution of the final product, any intermediate, or a starting material, may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E.L. Eliel (Mcgraw Hill, 1962) and Tables ofResolving Agents by S. H. Wilen. Additionally, in situations where tautomers of the compounds of Formula (1) are possible, the present invention is intended to include all tautomeric forms of the compounds.

In preferred compounds of the invention: R' is -Z-(CH2)q-NRR9, where q is 2, Z is oxygen, R 8 is H or a lower alkyl radical and R9 is a lower alkyl radical, or R 8 and R?, together with the adjacent nitrogen atom, form a heterocyclic radical; R4 is H or lower alkyl; R2 is -OQ; and R3 is H or OH.

More preferably, R8 and R9 are both the same lower alkyl radical, especially methyl; R is a lower alkyl radical, especially ethyl; R2 is -0glucosyl; and W is OH.

Especially preferred compounds of Formula (1) include, individually, without limitation: 1-[4'-(2-dimethylaminoethoxy)phenyl]-I-(4'-0-0-1'glucopyranosylphenyl)-2-p henylbut-l-ene, 1-[4'-(2dimethylaminoethoxy)phenyl]-I-(3'-O-P-I'-glucopyranosylphenyl)-2-p henylbut-l-ene, and 4-chloro-l-[4'-(dimethylaminoethoxy)phenyl]-I -(4'-OP-I'-glucopyranosylphenyl)-2phenylbut- 1 -ene; and the pharmaceutically acceptable salts thereof.

Other preferred compounds include the glycosides and orthoester glycosides of the hydroxy metabolites, derivatives and analogs of chlomiphene, naloxifene, trioxifene, idoxifene, raloxifene, droloxifene, GW 5638, levormeloxifene and centchroman, Particular examples include (E)l-(4-iodophenyl)-2-(4-0-0-l'-glucopyranosylphenyl)-l[4(pyrrolidinoethoxy)phenyl] -but- I -ene (the glucoside of a hydroxy derivative of idoxifene), 1 {4-[2-(diethylamino)ethoxy]phenyl)-2-(4-0-pl'-glueopyranosylphenyl)-l-pheny l-2chloroethylene (the glucoside of a hydroxy derivative of clomiphene), 3,4-dihydro-2-[(4-0-pitglucopyranosylphenyl)-l-naphthalenyl]-I-{4-[2-(l-pyr rolidinyl)ethoxy]phenyl)methanone (the glucoside of a dihydroxy derivative related to trioxifene, see Jones, C.D. et aL, J Med Chem. 35:931-938 (1992)); 1 1-f4-[2-(l-piperdinyl)ethoxy]phenyl}-l 1H -3-(0-1'P'glucopyranosyl)benzo[a]fluorene-9-oI and I 1-{4-[2-(Ipiperdinyl)ethoxylphenyl)-I IHbenzo[a]fluorene-3-ol-9-0-p'glucopyranoside; and trans- I - f 2-[4-(7-0- I'-b-glucopyranosyl2,2dimethyl-3-phenyl-3,4-dihydro-2H-1-benzopyran-4-yl)ph enoxy]ethyllpyrrolidine (centchroman-7-0-glucoside).

A further group of preferred compounds are triphenylethylenes of the Formula (III):

R-(CH2) 0 =C (-C2H4-E) am G F wherein v is an integer from I to 10, R! is a group'of formula -A--S(O)w--B-R wherein A is either a direct bond or an amino bridge -NR'- or (CH2)r-, wherein Rc is a hydrogen atom or a straight-chain or branched alkyl group with up to 6 carbon atoms, I is an integer from 1-5, w is 05 1 or 2, B is either a direct bond or a saturated or unsaturated, aliphatic, linear or branched chain alkyl with up to 6 carbon atoms, and R d is a hydrogen atom; a partially or completely fluorinated, saturated, aliphatic, linear or branched C I -3-alkyl group; phenyl, or I- or 2-naphthyl; an amide radical of formula C(O)NR'R? where R' and R' are identical or different and are a hydrogen atom, a linear or branched CI-8-alkyl radical, optionally substituted by one or more aryl, alkyl- and dialkylamino groups, hydroxy, halogen or esterified carboxyl, R2 is a hydrogen atom, an iodine atom or a hydroxy group, is a hydrogen atom, is one or more halo, hydroxy, lower alkyl, or lower alkoxy, or is a buta-1,3-dienyl radical which together with the adjacent benzene ring forms a naphthyl. radical, or a methylene bridge with E when G is in the ortho position of the ring, or -OQ, wherein Q is a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or an orthoester glycoside moiety of the Formula (II):

CA-."11 ORb wherein A represents a glycofuranosyl or glycopyranosyl. ring; is hydrogen; lower C1.4 alkyl; C7-1o aralkyl; phenyl. or phenyl substituted by chloro, fluoro, bromo, iodo, lower C14 alkyl or lower Cj_4 alkoxy; or naphthyl; and Rb is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, with the proviso that at least one G is -OQ; or a pharmaceutically acceptable salt thereof Useful pharmaceutically acceptable salts include acid addition salts, e.g. inorganic acids such as HCI, HBr, sulphuric, sodium hydrogen sulphate, phosphoric acid, sodium dihydrogen phosphate, and disodium hydrogen phosphate, as well as organic acids such as formic, acetic, benzoic, carbonic and the like. Where the compound is substituted by a carboxy group, pharmaceutically acceptable salts may be obtained with an inorganic base such as an alkali or alkaline earth metal hydroxide [e.g. LiOH, NaOH, KOH, or Ca(OH)21 Or an organic base such as choline hydroxide, spermidine, spermine, glucamine and the like.

The compounds of the present invention may be used according to wellknown methods of using tarnoxifen and derivatives thereof, e.g. for use as oestrogenic, antioestrogenic and progestanic agents; for imaging oestrogen receptors (with halo-substituted derivatives); treating or preventing cardiovascular disease, treating or preventing osteoporosis; treating endometriosis, obesity, benign prostatic hypertrophy and prostatic carcinoma in mammals; treating oestrogen-dependent turnours such as breast cancer turnours; treating premenstrual syndrome, vasomotor spasms associated with menopause, atrophic vaginitis, Kraurosis vulvae, female hypogonadism, primary ovarian failure, excessive hair growth and prostatic cancer; and treating psoriasis. The compounds may be used to treat any one of these conditions or may be used prophylactically to'prevent them.

The compounds of the invention may be co-administered together with other compounds, e.g., 9-cis-retinoic acid and derivatives thereof, to treat cancer, in particular, breast cancer (US-A-5,821,254); interferon to treat breast cancer (US-A-5,024,833); epinephrine, norepinephrine or dopamine to modify vasoconstrictive activity (US-A5,470,883); melatonin and derivatives thereof to treat breast cancer (US-A-5,196,435); a platinum anti-neoplastic compound to treat non-melanoma cancers (IJS-A-5, 844,001); a bone growth factor to stimulate new bone formation (US-A-5, 118,667); ONCONASETm to treat human pancreatic adenocareinoma and human lung carcinoma (US-A-5,540,925); Raloxifene and derivatives thereof to treat mammary cancers and other conditions (US Patent no's 4,656,187, 5,567,820, 5,512,296, 5,508,292, 5,496,851, 5,496,828, 5,492, 927, 5,447,941, 5,534,526, 5,530,010, 5,525,624, 5,521,214, 5,521,198, 5, 641,790, 5,622,975, 5,610,168, 5,610,167, 5,610,166, 5,591,753, 5,552,417, 5,552,416, 5,550,123, 5,545,641, 5,646,137, 5,663,184, 5,672,610, 5,686, 467, 5,686,476, 5,688,812, 5,698,572, 5,700,815, 5,708,010, 5,770,612, 5, 494,920, 5,686,468, 5,843,962, 5,5 78,614, 5,446,053, 5,693,656, 5,843, 964, 5,593,987, 5,843,984, 5,510,358, 5,484,797, 5,610,167, 5,578,614, 5, 843,914, 5,770,612, 5,698,572, 5,693,656, 5,552,416, 5,502,074, 5,492,927, 5,447,941, 5,441,964, 5,439,93 1, 5,418,252, 5,726,168, 5,843,984, 5,827, 844, 5,808,061), an androstene derivative to treat an androgen responsive condition (US-A-5,846,976); a tissue factor pathway inhibitor to induce or augment tissue factor expression or release in a turnour tissue (US-A5,902,582); a progesterone antagonist for hormone substitution therapy for perimenopausal and postmenopausal women (IJS-A-5,719,136); a non-steroidal antioestrogen compound for inhibiting hormone-dependent breast carcinoma in a mammal (US-A-5,658,83 1); a compound having antiprogestational activity to induce labour, terminate pregnancy, or treat gynaecological disorders (US-A-4,888,33 1); arninoalkyl ethers of phenols to treat breast or colon cancer in humans (US-A-4,803,227); and an anti- androgen for prophylaxis and therapy of prostate hypoplasia (US-A4,310, 523).

By glycosidic units are meant glycopyranosyl or glycofuranosyl, as well as their amino sugar derivatives. The residues may be homopolymers, random or alternating, or block copolymers thereof. The glycosidic units have free hydroxy groups, or hydroxy groups acylated with a group R]5- (C=O)-, wherein Ris is hydrogen, lower CI_6 alkyl, C6_10 substituted or unsubstituted aryl or C7-16 aralkyl. Preferably, the acyl groups are acetyl or propipnyl. Other preferred R15 groups are phenyl, nitrophenyl, halophenyl, lower alkyl substituted phenyl, lower alkoxy substituted phenyl and the like or benzyl, lower alkoxy substituted benzyl and the like.

The compounds particularly useful in the practice of the invention contain at least one glydoside or orthoester glycoside residue on the A ring of A compound according to Formula IL Preferably, the glycoside or orthoester glycoside is linked through the I -carbon to the 4hydroxy group on tamoxifen.

Any such glycoside can comprise up to 20 glycosidic units. Preferred, however, are those having less than 10, most preferred, those having 3 or less glycosidic units.. Specific examples are those containing I or 2 glycosidic units in the glycoside residue.

The glycopyranose or glycofuranose ring, or amino derivative thereof, may be fully or partially acylated or completely deacylated. The completely or partially acylated glycoside is useful as a defined intermediate for the synthesis of the deacylated material.

Among the possible glycopyranosyl structures are glucose, mannose, galactose, gulose, allose, altrose, idose, or talose. Among the furanosyl structures, the preferred ones are derived from fructose, arabinose or xylose. Among preferred diglycosides are sucrose, cellobiose, maltose, lactose, trehalose, gentiobiose, and melibiose. Among the triglycosides, the preferred ones may be raffinose or gentianose. The preferred amino derivatives are N-acetylD-galactosamine, N-acetyl-D-glucosarnine, Nacetyl-D-mannosamine, N-acety1neuraminic acid, D-glucosamine, lyxosylamine, D-galactosamine, and the like.

When more than one glycosidic unit is present on a single hydroxy group, i.e., di or polyglycosidic residues, the individual glycosidic rings may be bonded by 1- 1, 1-2, 1-3, 14, 1-5 or 1-6 bonds, most preferably 1-2, 14 and 1-6. The linkages between individual glycosidic rings may be a or b.

The water soluble glycosidic derivatives of the aforementioned compounds may be obtained according to the general methods disclosed by Holick in US-A4,410,515. Ihe glycosyl orthoester compounds may be obtained according to US-A-4,521,41 0.

A number of hydroxy-substituted analogues of tamoxifen are known and can be glycosylated according to the present invention. See US Patent No's. 5, 877,219, 5,192,525, 5,196,435, 5,807,899 and 4,696,949. See Scheme I for a general method of preparing the 4glycosyl derivatives of tamoxifen.

Scheme I 0 0 OH OAc Br AcO OAc OAc NaOH Acetone 0,_^N Dowex-110-01-1 Methanol 0 0 0 0 0 OH 0 0 c %0 OH %0 OAc OH ClAc 4-[O]-Tamoxifen-p-glucopyFranoside OH OAc Any animal which may benefit from the compounds of Formula 1, may be treated according to the present invention. Preferred animals are mammals, e.g. humans, although the invention is not intended to be so limited.

The compounds of the invention can be administered in any appropriate pharmaceutically acceptable carrier for oral administration, especially as the tamoxifen glycosides and derivatives thereof are biologically active upon oral administration. The compounds of the invention may also be administered in any appropriate pharmaceutical carrier for parenteral, intramuscular or topical administration. They can be administered by any means that achieve their intended purpose.

The dosage administered will depend on the age, health and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. An exemplary systemic daily dosage is about 0.00 1 to about 100.0 mg/kg of body weight. Normally, from about 0. 0 1 to about 10. 0 mg/kg of body weight of the glycoside or orthoester glycoside, in one or more dosages per day, is effective to obtain the desired results. One of ordinary skill in the art can determine the optimal dosages and concentrations of the glycoside and orthoester glycoside compounds of the invention with only routine experimentation.

The compounds can be employed in dosage forms such as tablets, capsules or powder packets, or liquid solutions, suspensions or elixirs for oral administration, as well as sterile liquid for formulations such as solutions or suspensions for parenteral use. A lipid vehicle can be used in parenteral administration. The compounds may also be administered via topical patches, ointments, gels or other transdermal applications. In such compositions, the active ingredient will ordinarily be present in an amount of at least 0. 1 % by weight based on the total weight of the composition, and not more than 90% by weight. An inert pharmaceutically acceptable carrier is preferable such as 95% ethanol, vegetable oils, propylene glycols, saline buffers, sesame oil, etc. Reference is made to Remington's Pharmaceutical Sciences, 18 th Edition, Gennaro et al (eds.), 1990, for methods of preparing pharmaceutical compositions.

The compounds administered are substantially pure. The phrase "substantially pure" encompasses compounds created by chemical synthesis and/or compounds substantially free of chemicals which may accompany the compounds in the natural state, as evidenced by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).

Having now generally described this invention, the same will be understood by reference to the following Example, which are provided herein for purposes of illustration only and are not intended to be limiting.

Example I Organic Synthesis of 2 ',314'V6 -Tetra-0-acetyl--Zbglucopyranosyl-4-0-Tamoxifen: (Yetra 0-acetyl-4-0-fi-I -glucopyranoside) Acetobromoglucose was bought from Sigma and used without purification. 4Hydroxy tamoxifen (minimum 70% Z isomer) supplied by Sigma was used as such as a mixture of Z and E isomers.

4-Hydroxy tamoxifen (50 mg, 0. 129 nmol) in isopropanol free acetone (1.5 ml) was cooled to OIC under argon and stirred efficiently. Two solutions of acetobromoglucose (100 mg; 2.3-fold excess) in acetone (500 RI and 13. 3% NaOH in water (w/W %) were prepared freshly and kept cold. Five equal volumes of nearly 100 [LI of acetobromoglucose was injected in cold 4hydroxy tamoxifen during 4 hours in equal intervals. Each of the bromoglucose injections were accompanied by 20 gI of 13.3% sodium hydroxide. After all the bromoglucose has been added, the mixture was warmed to room temperature and stirred for 30 minutes. Acetone and water were removed by pump at low temperature. The mixture was separated on a silica gel column. Ether and triethylamine (10: 1) mixture was used as eluent. The less polar tetraacetate was removed from column and crystallised from diethyl ether. It afforded 37 mg of crystalline white solid. The NMR spectra showed the presence of nearly 10- 15 % of E isomer -b-glucoside was present along with desired -Z-isomer-bglucoside.

NMR: d (4.95; doublet, J--9.2Hz, E isomer, -10- 15% of I H); d (5.12; doublet, J=8.9Hz, Z isomer, 85-90% of I H); d (6.5-7.2; aromatic-H, 13 H); d (5.3 to 3.5; glucosyl-H, 9H); d (2.35-2.45; multiplet, 4H); d (2 to 2. 2; overlapping singlets of N-CH3 and acetate, 18H); and d 0.9 (triplet 3 H, CH3)- The crude product obtained by recrystallisation was used as such without purifying E and Z isomers.

4-[O,l -fi-Glucopyranosyljtamoxifen To a solution of 2',3',4',6'-tetra-0-acetyl-l'-p-glucopyranosyl-4-0- tamoxifen (20 mg) in methanol (3 ml) was added Dowex- I I O-OH resin (100 mg). The mixture was refluxed for 4 hours in an inert atmosphere in the absence of light. After cooling and filtering the resin, the solvent was evaporated to a gum. Trituration with acetonitrile gave (14.9 mg) crystals.

38 mg of the crude glucoside obtained as above was crystallised from acetonitrile (0.5 ml). Crystals were collected by centrifuging and washing with fresh cold acetonitrile (2 x 500 pl). The white powder was dried under vacuum, which yielded (23 mg) of homogeneous white powder. The structure of this material was consistent with the spectral data.

UV. maxima at 243 nm and 279 run. Mass Spectra: Molecular formula C32H39NO7- (Gave molecular ion at 550.30 in formic acid consistent with structure.) NMR: (DMSO-d6,250C), d (0.9, triplet; CH3); d (2.2 & 2.65, N(CH3)2, singlets); d (2.4, quartet CH2); d (3.0-4. 1, multiplets; 9 H); d (4.5-5. 1, multiplets, 6 H); d (5.27, doublet, J=9Hz, E isomer, anomericH, and 5.35 doublet, J=8.8 Hz -90% of Z isomer); d (6.6 to 7.3, multiplet, Aromatic-H, 13H).

Claims (11)

1. A compound of the Formula (1):

R1 R2 (V R3 wherein R' is H, 4CH2),,CR'=CRCR; 4CH2).. C(X)NRR?; R5 R6 (CH2)p R is -(CH2)tO- or -(CH2),r-; is one or more halo, hydroxy, lower alkyl, or lower alkoxy, or is a buta- 1, 3 -dienyl. radical which, together with the adjacent benzene ring, forms a naphthyl radical, or -OQ, wherein Q is a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or an orthoester glycoside moiety of the Formula (H):

0:] A ORb UP Ray wherein A represents a glycofuranosyl or glycopyranosyl ring; R,, is hydrogen; lower C14 alkyl; C7-Io aralkyl; phenyl or phenyl substituted by chloro, fluoro, bromo, iodo, lower C1.4 alkyl or lower CI4 alkoxy; or naphthyl; and Rb is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue; with the proviso that at least one of R2is -OQ; R3 is H, halo, hydroxy, lower alkyl, or lower alkoxy, or is a buta-1, 3- dienyl radical which together with the adjacent benzene ring fonns a naphthyl radical; R4 is -CN, -N02, lower alkyl, lower alkyl substituted by Y, or -Y; R 5 and R6 are independently H, -C 1.4 alkyl, -C2-4 alkenyl, --C2.4 alkynyl, -X-C 1 -3 alkyl, -X-C24 alkenyl, -X--C2-4 alkynyl or -Y; R 7 is -CN, -C,4alkyl-OH, -C(O)NR'OR", --C(O)NR 12 R 13, -Cl4alkyl-NR"R", -C(O)R, -C(O)OR 12, __C(O)NRI2 OR 13, -C(O)NHC(O)R'2, -C(O)NHCH2R", - C(NH2)(NOR'), -S(O)R 12, -S(O)(0)(OR 12), -S(O)(0)(NCH02R 12), P03R 12, - P(O)-(NR 12 R 13)(NRI2 R13), _p(o)(NR12R13)(OR 14), _CONRI2 (CHAOCH3, - CONR 12(CH2)'NRIkI or oxadiazole substituted with methyl; R 8 and R9 are independently hydrogen, --CI-7alkyl, --C-3-7cycloalkyl, -0- CI-7alkyl, -C1.7alkyl-Y or phenyl; R10 and R' 1 are independently methyl or ethyl or, taken together, form a morpholino group bonded via its nitrogen atom; R 12 and R 13 are independently H, -Cl.12alkYl, --C2-12alkenYl, -C2- ]2alkynyl, -0--cl-12alkYl, -O-C2-12alkenYl, -4D-C2-12alkynyl, -C3-7 cycloalkyl; -C3-7cycloalkenyl, linear and cyclic het.eroalkyl, aryl, heteroaryl or -Y; R 14 is H, --CI-12akl, --C2-12alkenYl, --C-242alkynyl,--C-3-7 CYClOalkyl; -C3-7cycloalkenyl, linear and cyclic heteroalkyl, aryl, heteroaryl or -Y; X is oxygen or sulphur; Y is halogen, H, alkylcarbonyloxy, fonnyloxy or formyl; Z is oxygen or sulphur; n is an integer selected from 0, 1 or 2; m is the integer I or 2; p is an integer selected from I to 4; q is the integer I or 2; r is an integer 1-12; t is an integer selected from 1 to 4; and u is an integer selected from 1 to 4; or a pharmaceutically acceptable salt thereof

2. A compound according to claim 1, wherein: R' is -Z-(CH,),-NRR, wherein q is 2, Z is oxygen, R8 is H or a lower allgi radical and R9 is a lower alkyl radical, or R' and R?, together with the adjacent nitrogen atom, form a heterocyclic radical; le is H or lower alkyl; R is -OQ; and is H or OH.

3. A compound according to claim 2, wherein: R8 and R9 are both the same lower alkyl radical; W is a lower alkyl radical; A2 is -0-glucosyl; and is H.

4. A compound according to claim 2 or 3, wherein: R' and R? are both methyl; and R is ethyl.

5. A compound according to claim I which is:!-[4'-(2diinethylaminoethoxy)phenyl]-I-(4'-O-P-I'-glucopyranosylphenyl)-2-p henylbut-l-ene, 1-[4'-(2-dimethylaminoethoxy)phenyl]-I -(3'-O-P-I'-glueopyranosylphenyl)- 2-phenylbut- I -ene, or 4-chloro-1 -[4'-(dimethylatninoethoxy)phenyl]-I - (4'-O-PF-glucopyranosylphenyl)-2phenylbut-l-ene.

6. A pharmaceutical composition comprising a compound according to any preceding claim, together with a pharmaceutically acceptable carrier therefor.

7. Use of a compound according to claim 1, in the manufacture of a medicament for the treatment or prophlyxis of a condition wherein tamoxifen may be indicated.

8. Use according to claim 7, wherein said condition is selected from cardiovascular disease, osteoporosis, endometriosis, obesity, benign prostatic hypertrophy, prostatic carcinoma, oestrogen-dependent turnours, oestrogen independent tumours, breast cancer, metastatic breast cancer, pre-menstrual syndrome, vasomotor spasms associated with menopause, atrophic vaginitis, Kraurosis vulvae, female hypogonadism, primary ovarian failure, excessive hair growth, and psoriasis.

9. Use according to claim 8, wherein said condition is an oestrogendependent tumour.

10. Use according to claim 8, wherein said oestrogen-dependent turnour is a breast tumour.

11. Use according to any of claims 7 to 9, wherein said medicament is for oral administration.