MXPA99000232A - Esteroi bisphosphonates - Google Patents

Abstract

The bisphosphonate derivatives of the hydroxy steroids which are inhibitors of bone resorption or stimulators of bone formation, the derivatives have at least one group A instead of a hydroxy group on the steroid molecule, where A is a group of the formula (A) where X is: (i) St-O-Co- where St is the residue of the hydroxy asteroid given by the removal of an OH group, (ii) R1-0-CO- where R1 is an alkyl group, alkenyl, cycloalkyl, aralkyl or aryl, any of which may be optionally substituted, or (iii) a hydrogen atom, and the salts and solvents of these compounds. The steroid is typically 17α-oestradiol, oestrone, testosterone, norethindrone, androsterone, noretandrolone or nandrolone. The derivatives can be used in the treatment of bone disorders such as osteoporos

Description

STEROID BISPHOSPHONATES Field of Invention The present invention involves the steroid derivatives and in particular the bisphosphonate derivatives of the hydroxy steroids for use in the prevention or treatment of osteoporosis and bone related disorders.

Background of the Invention, Hydroxy steroids such as Oest, Adiol and Testosterone have been proposed for use in the treatment of osteoporosis, either by inhibition of bone resorption or stimulation of bone formation, and bisphosphonates such as etidronate and disodium clodronate are also known as bone resorption inhibitors. Certain bisphosphonate derivatives of steroids have also recently been proposed for these purposes in EP-A-0496520 and EP-A-0548884. In the compounds of EP-A-0496520 the steroidal group is linked to the bisphosphonate group by a carbamate or a group REF .: 29175 carbonate, and EP-A-0548884 describes steroids of the bisphosphate ethers.

We have now found a new group of bisphosphonate derivatives such as steroids which are linked by a carboxyl group and, by virtue of the affinity of the bisphosphonate groups to the bones, have the potential to target the steroid selectively active in the bone and then release the active material in situ by hydrolysis. The compounds of the invention are thus of interest in the prevention or treatment of osteoporosis and other bone disorders such as Paget's disease, bone metastasis and malignant hypercalcaemia.

Description of the invention.

The compounds of the invention are derivatives of hydroxy steroids which are inhibitors reabsorbed by the bones themselves or stimulators for the formation of bones and thus useful for the prevention or treatment of osteoporosis, the derivatives have at least one group A instead of a hydroxy group in the steroid molecule, where A is a group of the formula. where X is: (i) St-O-CO- where St is a residue of the hydroxy steroid given by the removal of an OH group, (ii) R1-0-CO- wherein R1 is an alkyl, alkenyl, cycloalkyl, aralkyl or aryl group, any of which may be optionally substituted; or (iii) a hydrogen atom. The invention also includes salts and solvents of these compounds.

Therefore, the compounds of the invention can have the formula St-A where St and A are as defined above. The particular groups of the compounds of interest are then of the formulas: (D (St-0-CO) 2CHCH2CH (PO (OH)) 2) 2 (2) (St-O-CO) (R1-0-CO) CHCH2CH (PO (OH)) 2) 2 (3) (St-O-CO) CH2CH2CH (PO (OH) 2) 2 Where steroids contain more than one hydroxy group, only one is generally substituted by a group A, but the invention includes derivatives of said compounds in which two or more hydroxy groups are substituted by groups A.

The structural variety of the compounds of the invention allows their hydrolysis properties to be modulated as required. For example, the best-known steroid-bisphosphonate conjugates, particularly oestradiol-bisphosphonates, hydrolyze very rapidly while delayed hydrolysis and therefore slow release of the steroid is often desired. The compounds of the above formula (1) such as the later compound (4) which contain two steroid units are resistant to hydrolysis and therefore advantageous when a low rate of steroid release is required. On the other hand, compounds containing a single unit of the steroid are less resistant to hydrolysis and therefore more suitable when a rapid release of the steroid is required. The compounds of formula (1) also allow two different steroid units to be included in the same molecule, and this allows steroids of different activities to be released at the same time.

The main hydroxy steroid may be an oestrogen, androgen, anabolic steroid, glucocorticoid or progestagen which inhibit the bone reabsorption or stimulate its formation, such as for example 17β-oestradiol, oestrone, testosterone, noret indrona, androst erona, noretandrolone and nandrolone. These compounds generally have a hydroxy group in the 3- or 17- position or both, and additional examples of hydroxy steroids which may be used are listed in EP-A 0496520.

In the group X, R 1 can be a C 5 -alkyl (eg methyl, ethyl, isopropyl or t-butyl), C 2-6 alkenyl (eg allyl), C 3-8 cycloalkyl (e.g. . cyclopentyl or cyclohexyl), phenyl-alkyl (C? -6) or a mono- or bicyclic aryl group (eg phenyl or naphthyl). The alkyl and alkenyl groups for example can be substituted by one or more halogen atoms (eg chlorine) and the cycloalkyl groups by one or more of the C? -4 -4 alkyl groups or halogen atoms (eg chlorine) ). The aryl groups can be substituted by one more hydroxy groups, such as a naphthol.

The compounds of the invention are capable of forming salts with bases and examples of such salts are the alkali metal salts (eg sodium) and alkaline earth metal salts (eg calcium). Some compounds of the invention exist in enantiometric forms and all their similar forms are included.

The particular compounds of importance have the following formula: (4) The compounds of the invention are useful in the prevention or treatment of osteoporosis and the other disorders referred to above in men and animals and they can be formulated for these purposes as pharmaceutical compositions together with one or more pharmaceutically accepted carrier vehicles, excipients or diluents. For example, the active ingredient in these compositions can be a compound (4), (5) or (6) shown above.

The pharmaceutical compositions of the invention may be available for administration in oral, buccal, parenteral or local form.

For example, for oral administration, the compositions may be in the form of tablets, troches or capsules containing pharmaceutically acceptable excipients such as binders, fillers, lubricants, wetting or disintegrating agents. The tablets can also be coated by known methods. Liquid preparations for oral administration may be in the form of solutions, syrups or suspensions and may contain pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives.

The compositions may also be formulated for use in injections and may be presented in unit dosage form, eg in ampoules. The compositions for injections may be in the form of suspensions, solutions or emulsions, in oil or aqueous vehicles, and may contain formulatory agents such as suspension, stabilizers, solubilizers and / or dispersing agents.

The compositions may also be available for administration locally, eg, transdermal patches, ointments, creams and lotions.

The compounds of the invention can be administered in combination with other pharmaceutically active ingredients.

The total daily dose of the compounds of the invention used in medicine, suitably vary in the range of 0.001-10.0 mg / kg per body weight and these can be given in divided doses, eg. 1-4 times per day.

The compounds of the invention in which X is a group (i), for example the compounds of the formula (1) above, can be prepared by transesterification of the carboxylic ester groups of a compound of the formula (7). (where R2 and R3 are C? -S alkyl groups, eg ethyl, and can be the same or different) with the hydroxy steroid (StOH), to give a phosphonate ester (8) of the formula (St-O- CO) 2CHCH2CH (PO (OR3) 2) 2, followed by hydrolysis of the phosphonate ester group to give the desired bisphosphonic acid.

The transesterification of (7) can be effected in the presence of a catalytic base such as DMAP (dimethylaminopyridine), for example in a hydrocarbon solvent at any temperature suitable for reflux.

When the major hydroxy steroid contains an additional hydroxy group which remains in the final product, it should be protected during the transesterification reaction (for example as a benzyl ether) and the protection group subsequently removed.

The hydrolysis of ester (8) can be carried out with a tri (C? -6 alkyl) silyl halide such as trimethylsilyl bromide, for example in a halogenated hydrocarbon solvent.

Bisphosphonates (7) can be prepared by the first reaction of a methylene bisphosphonate (9) with paraformaldehyde (eg in the presence of a catalytic base such as a diethylamine) followed by removal of methanol to give a methylidene compound (10) which is then reacted with a dialkylmalonate (in which the alkyl group is R 2 as defined above) in the presence of a catalytic base (e.g., sodium ethoxide).

Compounds wherein X is a group (iii), for example the compounds of formula (3) above can be prepared by the esterification of the hydroxy steroid (StOH) with the acid (11) The reaction can be carried out in the presence of a base and an activating agent such as EDCI (N- (3-ethyl-dimylaminopropyl) -N'-ethylcarbodiimide hydrochloride). The phosphonate ester groups can then be removed by hydrolysis as described above to give the required bisphosphonic acid.

In addition, when the hydroxy steroid contains an additional hydroxy group which is retained, it must be protected during the reaction and subsequently eliminated.

The acids (11) can be prepared from the above methylidene compound (10) by the addition of a dibenzyl malonate, in the presence of a non-nucleophilic catalyst base, to give the ester (12). followed by hydrolysis (eg on palladium on carbon) and a subsequent decarboxylation (eg by heating).

Compounds in which x is a group (ii), for example the compounds of formula (2) above can be prepared from a malonate (13) of the hydroxy steroid.

Rx0C0. CH2 CO.OSt (13) by reaction with a methylidene compound (10) in the presence of a non-nucleophilic base to give the addition product (14) followed by removal of the phosphonate ester group by hydrolysis as described above to give the desired bisphosphonic acid.

The following examples illustrate the invention.

Synthesis of Tetraethyl ethylidene bisphosphonate (16) (i) Tetraethyl methylene bisphosphonate (47.4 g, 0.165 mol, 1.0 equiv.), Paraformaldehyde (24.75 g, 0.825 mol, 5.0 equiv.), Diethylamine (17.1 ml, 12.1 g, 0.165 mol, 1.0 equiv.) Were added to methanol (470). ml). The reaction mixture was heated to 60 ° C until the mixture was converted to a colorless solution (30 minutes), and stirred for 15 hours at room temperature. The mixture was concentrated under reduced pressure, and adding toluene (150 ml). The solvent was removed under reduced pressure. The addition of toluene followed by a second concentration process aided by the removal of methanol from the crude viscous intermediate product 15. dH (CDCL3) 1.29 (12H, t, J = 8, P-OCH2CH3), 2. 67 (1H, tt, JH-P = 24, JH-H = 5, P2CHCH20CH3), 3.32 (3H, s, -0CH3), 3.86 (2H, td, JH.P = 17, JH-H = 5, P2CHCH2OCH3), and 4.15 (8H, m, P-OCH2CH3). (or) Toluene-p-sulfonic acid (0.15 g, catalytic) was added to the solution of the crude tetraethyl (2-methoxy) ethylidene bisphosphonate 15 in toluene (250 ml). The reaction mixture was heated overnight, under reflux conditions, after this period of time of elimination had passed to completion. The reaction mixture was washed with water (3 x 100 ml), and the solvent removed under reduced pressure for yield 16 as an oil (43.16 g, 88% for 2 steps); Vmax 3020, 2960, 1485, 1452, 1402, 1270 (b), and 1050 (b); dH (CDCL3) 1.30 (12H, t, J = 8.0, P-OCH2CH3), 4.0-4.2 (8H, m, P-OCH2CH3), and 6.94 (2H, dd, trans JP_H = 40.0, cis JP.H = 36.4 , 2C = CH2), dc (CDCL3) 16.15 (4C, t, J = 3.4, P-OCH2CH3), 63.08 (4C, d, J = 3.4, P-OCH2CH3), 132.58 (C, t, J = 127, PCP) and 149.11 (IC, s, -P2C = CH2); m.s. (Cl) m / z 301 (M + + H).

Synthesis of Hexa ethyl - [3,3 bis (oxycarbonyl)] propylidene bis [phosphonate] (17) Sodium (0.23 g, 10 mmol, 0.1 equiv.) Was dissolved in ethanol (100 ml) and stirred at 0 ° C under a nitrogen atmosphere. The mixture was allowed to warm to room temperature until all the sodium had dissolved. The sodium ethoxide solution prepared in situ was transferred via a cannula to a solution of 16 (30.0 g, 100 mmol, 1.0 equiv.) And diethyl malonate (15.20 ml, 16.02 g, 100 mmol, 1.0 equiv.) In ethanol (50ml) The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. The reaction mixture was washed with 1M aqueous HCl (3 x 100 ml) and extracted into CHCl2 (200 ml). The organic fraction was collected and dried with anhydrous MgSO, the solvent was removed under a very small amount of the final reduced pressure of the solvent was removed under high vacuum. The desired product 17 was isolated as an oil in excellent yield (43.8 g / 95.1%). (Foundation: C 43.97 H 7.55, C17H34O10 2 provides: C 44.35 H 7.44); Vmax 3010, 1749, 1732, 1270 (b), and 1045 (b) cm "1; dH (CDCL3) 1.28 (6H, t, J = 7.16, C02CH2CH3), 1.35 (12H, t, J = 7.12, P02CH2CH3) , 2.33 - 2.75 (3H, m), 3.97 (1H, t, J = 7.68, -CH (C02Et) 2), and 4.12 - 4.27 (12H, m); dc (CDCL3) 14.48 (2C, s, -C02CH2CH3 ), 16.71 (4C, d, -CHCH2CH-), 34.71 (C, t, JCP = 132, PCP), 50.51 (C, t, JCP = 8, -CH2CH (C02Et) 2 / 61.97 (2C, s, - C02CH2CH3), 63.22 (4C, t, JCp = P02CH2CH3), and 169.31 (2C, s, C02Et); dP (CDCL3) 22.33; m / z (Cl) 461 (M + + H).

Use 3 Synthesis of Tetraethyl [3, 3-bis - [3-benzyloxy-tetra-1,3,5-triene-17β-yloxycarbonyl] propylidene "bis [phosphonate] (18) 4 - (N, N- dimethylamino) pyridine (0.013 g, 0.11 mmol, 0.1 equiv.) and 3-benzyl-17β-oestradiol (0.861 g, 2.39 mmol, 2.2 equiv.) were added to a solution of 17 (0.50 g, 1.09 mmol, 1.0 equiv.) in toluene (10 ml) The reaction mixture was heated under reflux for 11 days under a nitrogen atmosphere.The solvent was removed under reduced pressure and the crude product absorbed on silica gel.The product was purified by the flash of silica gel in the chromatographic column, the eluent used was 1-3% methanol in CH2CL2, the desired product was obtained as a viscous oil (0.80 g, 67%), Vmax 3017, 2936, 1724, 1605, 1498, 1203 (b), and 929; dH (CDCL3) 0.84 (3H, s, 18'-CH3), 0.88 (3H, s, 18'-CH3), 1.23-1.97 (21H, m), 1.35 (12H , t, J = 7), 2.15 - 2.36 (13H, m), 4.72 - 4.81 (2H, m, 17'H), 5.0 5 (4H, s, -0CH2Ph), 6.74 (2H, s, 4'H), 6.80 (d, 2H, J = 9, 2'H), 7.23 (d, 2H, J = 9, l'H) , and 7.30 -7.47 (m, 10H); dc (CDCL3) 13.09, 13.20, 17.43, 17.51, 24.35, 26.19, 27.24, 28.29, 28.53, 30.82, 35.51 (t, JCP = 132, PCP), 37.95, 44.15, 44.31, 44.84, 50.80, 51.38 (t, JCP = 7.3, -CHCH2CH (C02R) 2), 63.83 (t, JCp = 6.9, - CH2CH (C02R) 2), 71.00, 85.02 (d, JCP = 10.4, P02CH2CH3), 113.39, 115.92, 127.42, 128. 49, 128.89, 129.59, 133.73, 138.39, 138.95, 157.84, and 169.96 (d, JCP = 3.5, -CH (C02R) 2); dP (CDCL3) 20.4: m / z (+ ve ion FAB) 1094 (M ++ H 100).

In the 4 Synthesis of Tetraethyl, "{3, 3-bis [estra-1, 3, 5-triene-3-hydroxy-17β-yloxycarbonyl] propyl iden bis [phosphonate] (19) For a solution containing 18 (692 mg, 0.633 mmol, 1.0 equiv.) In teahydrofuran / methanol 1: 1 (10 ml) was added at 10% Pd / C (140 mg). The reaction mixture was stirred under a hydrogen atmosphere (1 bar) for 6 hours. The reaction mixture was filtered, received in CH2CL2 and washed with brine. The organic layer was collected and dried with anhydrous MgSO 4 and the solvent removed under reduced pressure. In addition the product was purified by the flash of the silica gel in the chromatographic column, eluted with 3-5% methanol in CH2CL2. The solvent was once again removed and the product was produced as a foam under high vacuum (557 mg, 96.4%); (Foundation: C 64.68; H, 7.76, C49H7oO? 2P2 provides: C 64.46; H, 7.73); dH (CDCL3) 0.775 (3H, s, 18'-CH3), 0.781 (3H, s, 18 '-CH3), 1.15 - 1.87 (21H, m), 1.34 (12H, t, J = 6.8, P-OCH2CH3 ), 2.09 - 2.33 (6H, m), 2.49 (2H, heptet, J = 7.6, P2CHCH_2CH (C02R) 2), 2.66 (IH, tt, Jp-H = 24, JH-H = 7.2 P2CHCH2CH (C02R) 2 ), 2.81 (4H, m), 4.05 (H, t, J = 7.6, P2CHCH2CH (C02R) 2), 4.16 - 4.24 (8H, m, P-OCH2CH3) 4.71 (2H, q, 9.2, 17 'H) , 6.58 (2H, s, 4 'H), 6.66 (2H, d, J = 8, 2' H), and 7.08 (2H, d, J = 8.8, l 'H), dc (CDCL3) 11.93 (IC , 18 'C), 12.03 (IC, 18' C), 16.29 (4C, d, J = 5, P-OCH2CH3), 23.22 (2C), 24.95 (IC, b-P2CHCH2CH-), 26.16 (2C), 27.18 (1C), 27.37 (IC), 29.53 (2C), 34.17 (IC, t, J = 134, PCP), 36.81 (2C), 38.56 (2C), 42.98 (2C), 43.17 (IC), 43.68 ( 1C), 49.64 (2C), 50.23 (IC, t, J = 9, P2CHCH2CH (C02R) 2) 63.06 (4C, t, J = 7, P-OCH2CH3), 83.95 (IC, 17 'C), 84.09 (IC, 17'C), 112.77 (2C), 115.31 (2C), 126.22 (2C), 131.48 (2C), 131.53 (2C), 137.79 (2C), 154.23 (2C), and 168.84 (2C, -C02R); dP (CDCL3) 20.7 (s); / z (+ ve ion FAB) 913 (M ++ H, 76), 159 (100).

Example 5 Synthesis of 3, 3 -Bis - (is tra- 1, 3, 5-trien-3-hydroxy-17β-yloxycarbonyl) propylidene bis (phosphonic acid) (20) For a solution of 19 (250 mg, 0.275 mmol, 1.0 equiv.) In CCL4 / CHCL3 1: 1 (3 ml) was added trimethylsilyl bromide (1.24 ml, 1.47 g, 9.62 mmol, 35 equiv.) And the mixture stirred for 24 hours under a nitrogen atmosphere. Water (5 ml) was added and an off-white solid formed. The precipitate was filtered and washed with cold water and CH2CL2. The product was dried under high vacuum and obtained as a whitish powder (206 mg, 94%) which is decomposed at 180 ° C; dH (CD30D) 0.85 (3H, s, 18'-CH3), 0.86 (3H, s, 18 '-CH3), 1.20-2.05 (21H, m), 2.10-2.30 (5H, m), 2.38-2.50 ( 3H, m), 2.70 - 2.81 (4H, m), 4.08 (1H, t, J = 7, -CH2CH (C02H) 2), 4.72 (2H, t, J = 8, 17 'H), 6.47 (2H, d, J = 2, 4' H), 6.53 (2H , dd, J = 9, J = 2, 2 'H), and 7.05 (2H, d, J = 9, 1' H); dC (CD3OD) 12.64 (IC, 18 'C), 12.71 (IC, 18' C), 24.22 (2C), 26.37 (1C, b, -P2CHCH2CH-), 27.44 (2C), 28.45 (2C), 28.52 ( 2C), 30.63 (2C), 36.79 (1C, t, J = 127, PCP), 38.16 (2C, b), 40.18 (2C), 44.28 (IC, 13 'C), 44.40 (IC, 13' C) , 45.10 (2C), 50.94 (2C), 52.04 (IC, b, -CH (C02R) 2), 85.26 (IC, 17 'C), 85.34 (IC, 17' C), 113.79 (2C), 116.08 (2C), 127.21 (2C), 132.36 (2C) , 138.73 (2C), 155.94 (2C, 3 'C), and 170.49 (2C, -C02R); dP (CD3OD) 22.6; / z (-ve ion FAB) 799 (M "-H, 100).

Example 6 Synthesis of Tetraethyl [3, 3-bis (benzyl oxycarbonyl)] propyl ideno bis [phosphonate] (21) Tetraethyl ethylidene bisphosphonate 16 (1.00 g, 3.33 mmol, 1.0 equiv.), And dibenzyl malonate (0.83 ml, 0.946 g, 3.33 mmol, 1.0 equiv.) Were dissolved in a solution of tetrahydrofuran (15 ml). The solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1M), (0.33 ml, 0.33 mmol, 0.1 equiv.), Was added to the reaction mixture and stirred for one hour at room temperature. The saturated aqueous ammonium chloride (50 ml) was added to the reaction mixture and the product extracted into CH2CL2 (100 ml). The organic layer was collected and dried with anhydrous MgSO 4, the solvent was removed under reduced pressure. The crude product was absorbed on silica gel and purified by the flash of the silica gel in the chromatographic column, eluted with 2-3% methanol / CH2CL2. The product was isolated in a colorless oil (1.12 g, at? 58% yield); dH (CDCL3) 1.30 (6H, t, J = 7.1, -0CH2CH3), 1.31 (6H, t, J = 7.1, -0CH2CH3, 2.37-2.74 (3H, m), 4.07-4.24 (9H, m) , 5.14 (4H, s, -0CH2Ph), and 7.24-7.35 (10H, m); dc (CDCL3) 16.10 (2C, -OCH2CH3), 16.24 (2C, -OH2CH3), 24.81 (IC, m, -CH2CHP2) 34.11 (IC, t, JC.P = 132.1, PCP), 49.93 (IC, t, JC-P = 7.8, -C (O) CHRC (O)), 62.66 (4C, m, -OCH2CH3, 67.11 (2C , -OCH2Ph), 128.03 (4C, ortho C), 128.22 (2C, for C), 128.40 (4C, meta C), 135.12 (2C, 1- in Ph) and 168.41 (2C, -OC (O) CH); dP (CDCL3) 32.19; m / z (+ ve ion FAB) (M ++ H) 585 (36), 369 (7), and 91 (100); HRMS (M ++ H) (Basis: 585.20184 C27H39P2O ? or disposes: 585.20185).

E p lo 7 Synthesis of Tetraethyl 3, 3-bis (phosphono) -propylidene bis (carboxylic acid) (22) 21 (0.698 g, 1.19 mmol), was dissolved in tetrahydrofuran (10 ml), and adding palladium activated with carbon (0.10 g, cat.). The reaction mixture was stirred under a hydrogen atmosphere, overnight, at room temperature. The reaction mixture was filtered and washed with saturated aqueous ammonium chloride (50 ml). The product was extracted into CH2CL2 and dried with anhydrous MgSO4, the solvent was removed under reduced pressure, and the product dried under high vacuum as a white solid, (0.42 g, at 88% yield); dH (MeOD) 1.35 (12H, t, J = 6.6, -PO-CH2CH3), 1.74 (2H, heptet, J = 7.7, P2CHCH2CH-), 2.08 (1H, tt, Jp.H = 23.1, J = 6.6, P-CHRP), 3.18 (HH, t, J = 6.6, -CH2CH (C02H) 2), 3.48-3.63 (8H, m, PO-CH2CH3); dC (MeOD) 16.55 (2C, P-0-CH2CH3), 16.68 (2C, P-0-CH2CH3), 25.95 (IC, t, P2CHCH2CH-), 35.01 (IC, t, JP-c = 133.4, P- CHRP), 51.10 (1C, m, -CH (C02H) 2), 64.45 (4C, dd, J = 9.4, 6.7, P-0-CH2CH3), 171.84 (2C, -C02H), dP (MeOD) 22.8; m / z (+ ve ion FAB) (M ++ D) 406 (100), and (M ++ H) 405 (90) E p 8 Synthesis of Tetraethyl 4,4-bis (phosphono) -butanoic acid (23) (2. 3) 22 (0.200 g, 0.495 mmol), was heated at 130 ° C for 3 hours, under a continuous stream of nitrogen. The product was obtained as a colorless oil (0.174 g, 99%); dH (MeOD) 1.35 (12H, t J = 7.7, -OCH2CH3), 2.06-2.25 (2H, m, P2CHCH2CH-), 2.63-2.69 (H, m, -CDHC02H), 2.81 (1H, tt, JP-H = 24.2, J = 6.6, -PCHP-), 4.11-4.25 (8H, m, PO-CH2CH3); dc (MeOD) 16.57 (2C, P-0-CH2CH3), 16.71 (2C, P-O-CH2CH3), 21.82 - 22.10 (IC, m, P2CHCH2CH2-), 32.53-33.07 (IC, m P2CHCH2CH2C02H), 35.87 (1C, t, J = 133.4, P-CHR-P), 64.07-64.36 (4C, m, P-0-CH2CH3), and 175.85 (1C, -C02H); dP (MeOD) 24.95; m / z (-ve ion FAB) 361 (100) (M "-H, for a di-deuterated product); HRMS (+ ve ion FAB) (Foundation: 363.12997 C12H25D208P2 provides: 363. 13067).

Example 9 Synthesis of Tetraethyl ". {3 - [3-benzoyloxy) estra-1, 3, 5-trien-17β-yloxycarbonyl] propyl iden bis [phosphonate] (24) 23 (0.071 g, 0.20 mmol), 1.0 equiv.), 3-O-benzoyl-17β-oestradiol (0.089 g, 0.24 mmol, 1.2 equiv.), And 4 - (N, N-dimethylamine) pyridine (0.005 g, 0.04 mmol, 0.2 equiv.), Were dissolved in CH2CL (5 ml), and stirred at 0 ° C under a nitrogen atmosphere. EDCI (0.0455 g, 0.24 mmol, 1.2 equiv.), Were added to the reaction mixture, and allowed to slowly warm to room temperature while being stirred overnight. The reaction mixture was washed with water (30ml), and the product extracted in CH2CL2. The organic layer was collected, dried with anhydrous MgSO 4, and the solvent removed under reduced pressure. The crude product was absorbed on silica gel and purified by the flash of the silica gel on the chromatographic column, methanol / CH2CL at 1-3%. They were used as eluents. The product dried under high vacuum and was isolated as a colorless oil (0.048 g, 33%); Vmax 3053, 2983, 1729, 1601, 1243 and 1025; dH (CDCL3) 0.84 (3H, s, 18'-CH3), 1.25 - 1.93 (11H, m), 1.35 (12H, t, J = 7.2, P-OCH2CH3), 1.12 -2.74 (7H, m), 2.87-2.92 (2H, m), 4.12-4.28 (8H, m, P-OCH2CH3 ), 4.70 (ÍH, dd, J = 8.8, 7.1, 17 'H), 6.92 - 7.00 (2H, m), 7.33 (ÍH, d, J = 8.2, l' H), 7.46 - 7.67 (3H, m ) and 8.20 (2H, dt, J = 8.3, 1.6 ortho H 's in Ph); dc (CDCL3) 12.06 (IC, 18 '-CH3), 16.32 (2C, P-OCH2CH3), 16.43 (2C, P-0CH2CH3), 21.04 (IC, m, P2CHCH2CH2-), 23.25 (IC), 26.03 (CCI) ), 27.00 (ÍC), 27.59 (ÍC), 29.50 (ÍC), 35.68 (ÍC, t, J = 132.1, P2-CHR), 36.86 (IC), 38.18 (IC), 38.35 (C), 42.87 (C), 43.98 (C), 49.80 (C), 62.61 (4C t, J = 6.7, P-OCH2CH3), 82.74 (IC, 17'C), 118.67 (ÍC), 121.58 (ÍC), 126.43 (ÍC), 128.49 (2C), 129. 70 (ÍC), 130.10 (2C), 133.45 (ÍC), 137.84 (C), 138.19 (C), 148.68 (C), and 172.72 (C); dP (CDCL3) 23.2; m / z (+ ve ion FAB) 7.21 (M ++ H, per product containing 2D), 720 (M ++ H, per product containing ID), and 719 (M ++ H). The ethyl and benzyl groups can be eliminated by the methods of Example 4 and 5 In the Synthesis of Ethyl 17-oxostra- 1, 3, 5-trien-3-ilproprionate (25) Oestrone (0.54 g, 2.0 mmol, 1.0 equiv.), Triethylamine (0.56 ml, 0.405 g, 4.0 mmol, 2.0 equiv.), Were dissolved in tetrahydrofuran (15 ml) and stirred at 0 ° C under a nitrogen atmosphere. Ethyl malonyl chloride (0.76 ml, 0.903 g, 6.0 mmol, 3.0 equiv.) Were added slowly to the reaction mixture, which was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with water (2 x 50 ml), and the product extracted in CH 2 Cl 2, and dried with anhydrous MgSO 4. The solvent was removed under reduced pressure, the crude product absorbed on silica gel and purified by the gel flash on the chromatographic column, eluted with 0.5% methanol / CHCl2.

The product was isolated as a colorless oil (0.144 g, at 19% yield); dH (CDCL3) 0.90 (3H, s, 18'-CH3), 1.32 (3H, t, J = 7.1, -0CH2CH3), 1.36-1.75 (6H, m), 1.88-2.59 (7H, m), 2.91 ( 2H, dd, J = 8.3, 3.8), 3.59 (2H, s, malonate H), 4.26 (2H, q, 7.1, -OCH2CH3), 6.86 - 6.91 (2H, m), and 7.29 (ÍH, d, J = 8.2, 1?); dc (CDCL3) 13.65, 13.95, 21.41, 25.60, 26.13, 29.21, 31.39, 35.68, 37.83, 41.47, 43.98, 47.75, 50.26, 61.58, 118.35, 121.18, 126.30, 137.65, 138.00, 148.22 (3 'C), 165.25 (-C02Et), 166.09 (-C02Ph), and 214.04 (17'C); m / z (+ ve ion FAB) 385 (38) (M ++ H), 115 (100).

The synthesis of Tetraethyl [4-ethoxy-4-oxo-3- (17-oxostra-1,3,5-trienyloxycarbonyl) -butyl-idene] bis [phosphonate] (26) (0.112 g, 0.291 mmol, 1.0 equiv.), And 16 (0.087 g, 0.291 mmol, 1.0 equiv.), Were dissolved in tetrahydrofuran and stirred at room temperature under a nitrogen atmosphere. A solution of lithium bis (trimethylsilyl) amide (1M) in tetrahydrofuran (0.03 ml, 0.03 mmol, 0.1 equiv.) Was added to the reaction mixture and stirred for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the product extracted in CH2CL2. The organic layer was collected and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the crude product absorbed on silica gel. The product was purified by the flash of silica gel in the chromatographic column, methanol / CH2CL2 0.5-3% as eluent. The product was isolated and dried under high vacuum to give a colorless oil (0.060 g, 33%); dH (CDCL3) 0.91 (3H, S, 18 '-CH3), 1.27-1.72 (8H, m), 1.37 (12H, t, J = 7.2, P-0-CH2CH3), 1.90-2.95 (13H, m) , 4.13 -4.33 (11H, m), 6.82-6.90 (2H, m), and 7.30 (ÍH, d, J = 8.8, l'H); dc (CDCL3) 13.76 (IC, 18'C), 14.06 (IC, -C02CH2CH3), 16.24 (2C, -P02CH2CH3), 16.35 (2C, -P02CH2CH3), 21.53 (IC, P2CHCH2CH-), 24.96 (IC, m ), 25.70 (IC), 26.24 (IC), 29.32 (IC), 31.50 (1C), 34.28 (IC, t, J = 132.1, PCP), 35.76 (IC), 37.97 (1C), 44.11 (IC), 17.86 (IC), 49.93 - 50.23 (IC, m, -C (O) CHRC (O) -), 50.42 (IC), 61.77 (IC, -C02CH2CH3), 62.66-62.98 (4C, m, P-0-CH2CH3), 118. 35 (ÍC), 121.18 (1C), 126.36 (ÍC), 137.70 (ÍC), 138.08 (ÍC), 148.38 (ÍC), 167.73 (ÍC), 168. 54 (ÍC), and 214.15; dP (CDCL3) 22.34, and 22.44; m / z (+ ve ion FAB) 685 (57) (M + + H), 239 (100); HRMS (Foundation: 685.29124 C33H50O3.1P2 provides: 685. 29066). (26) can be converted to the corresponding bisphosphonic acid by the method of Example 5.

The use of tetraethylo- "3, 3-bis [androst-4-in-3-one-17ß-yloxycarbonyl] propylidene bis [phosphonate] (27) Testosterone (0.500 g, 1.73 mmol, 2.2 equiv.) 17 (0.363 g, 0.788 mmol, 1.0 equiv.) And 4 - (N, N-dimethylamine) pyridine were dissolved in toluene (7 ml) and heated under reflux, under an atmosphere of nitrogen. After 10 days of reflux, more testosterone (0.250 g, 0.86 mmol, 1.1 equiv.) Was added to the reaction mixture, and heated under reflux conditions for another 6 days. The reaction was suspended and washed with saturated aqueous ammonium chloride. The product was extracted into CH2CL2, and dried with anhydrous MgSO4. The solvent was removed under reduced pressure, and the crude product absorbed on silica gel. The product was purified by flash silica gel on the chromatographic column, 3% methanol / CH2CL2 was used as eluent. The product was isolated as a foam under high vacuum (0.61 g, 82% based on 3); dH (CDCL3), 0.76 (3H, s, 18'-CH3), 0.78 (3H, s, 18'-CH3), 080-80 (20H, m), 1.12 (6H, s, 19'-CH3), 1.28 (12H, t, J = 7.2), 1.94 - 1.98 (2H, m), 2.05 - 2.57 (13H, m), 3.94 (1H, t, J = 7.6, malonate H), 4.58 (2H, q, J = 8, 17'H), and 5.66 (2H, s, 4'H); dc (CDCL3), 11.91 (IC), 12.02 (IC), 16.31 (2C), 16.42 (2C), 17.39 (2C), 20.49 (2C), 23.45 (2C), 24.82 - 25.02 (IC, m), 27.31 (2C), 31.43 (2C), 32.67 (2C), 33.88 (2C), 34.34 (IC, t, J = 133.4), 35.34 (2C), 35.69 (2C), 36.53 (2C), 38.57 (2C), 42.56-42.72 (2C, m), 50.17 (2C). 53.61 (2C), 61.51 (ÍC), 62.61 - 62.92 (4C, m), 83.50 (ÍC), 83.64 (ÍC), 123.97 (2C), 168.80 (ÍC), 168.88 (ÍC), 170.77 (2C), and 199.37 (2C); dP (CDCL3), 22.98; m / z (+ ve ion FAB) (M ++ H) 946 (14), 703 (87), and 461 (100). (27) can be converted into the corresponding bisphosphonic acid by the method of Example 5.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (1)

Claims

1. Hydroxy steroid bisphosphonate derivatives characterized in that they are inhibitors of bone resorption or stimulators of bone formation, the derivatives have at least one group A instead of a hydroxy group in the steroid molecule, where A is a group of the formula where x is: (i) St-O-CO- where St is a residue of the hydroxy steroid given by the removal of an OH group; (ii) R1-0-CO- wherein R1 is an alkyl, alkenyl, cycloalkyl, aralkyl or aryl group, any of which may be optionally substituted; or (iii) a hydrogen atom and the salts and solvents of these compounds. Compounds according to claim 1 of the formula (1) (St-O-CO) 2CHCH2CH (PO (OH) 2) 2 Compounds according to claim 1 or claim 2, characterized in that the steroid is an oestrogen, androgen, anabolic steroid, glucocorticoid or progestogen. Compounds according to claim 1 or claim 2, characterized in that the steroid is 17β-oestradiol, oestrone, testosterone, norethindrone, androsterone, noretandrolone or nandrolone. A compound according to claim 1, said compound being: (4) A pharmaceutical composition containing one or more compounds according to any preceding claim and one or more pharmaceutically accepted carrier vehicles, excipients or diluents. A process for the preparation of a compound according to claim 1, characterized in that it comprises: in the preparation of a compound in which x is a group (i), transesterifying the carboxylic ester groups of a compound of the formula (7) (where R2 and R3 are C6 -6 alkyl groups and may be the same or different) with the hydroxy steroid (StOH), to give a phosphonate ester (8) of the formula (St -O-CO) 2CHCH 2 CH (PO (OR 3) 2) 2, followed by removal of the phosphonate ester groups by hydrolysis; (B) in the preparation of a compound in which x is a group (iii), esterifying the hydroxy steroid (StOH) with the acid (11) followed by removal of the phosphonate ester groups by hydrolysis; or (C) in the preparation of a compound in which x is a group (ii), reacting a malonate (13) of the hydroxy steroid R1CO. CH2.CO.OSt (13) with a methylidene compound (10) to give the pct addition (14) 0 0 (14) (OR OB3l2 followed by removal of the phosphonate ester groups by hydrolysis.