Steroid bisphosphonates

Details Steroid bisphosphonates Steroid bisphosphonates

1999-04-08

2000-10-31

Badio, Barbara

Organic compounds -- part of the class 532-570 series

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

514169, 514178, 514182, A61K 3156, C07J 5100

Patent

active

061405183

DESCRIPTION:

BRIEF SUMMARY
This invention concerns steroid derivatives and in particular bisphosphonate derivatives of hydroxy steroids for use in the prevention or treatment of osteoporosis and related bone disorders.
Hydroxy steroids such as oestradiol 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 disodium etidronate and 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 carbonate group, and EP-A-0548884 describes steroid bisphosphate ethers.
We have now found a new group of bisphosphonate derivatives of such steroids which are linked by a carboxyl group and, by virtue of the affinity of the bisphosphonate groups for bone, have the potential to target the active steroid selectively on 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 metastases and malignant hypercalcaemia.
The compounds of the invention are derivatives of hydroxy steroids which are themselves bone resorption inhibitors or bone formation stimulators and thus useful in the prevention or treatment of osteoporosis, the derivatives having at least one group A in place of a hydroxy group on the steroid molecule, where A is a group of the formula ##STR2## where X is: (i) St--O--CO-- where St is the residue of the hydroxy steroid given by removal of an OH group, aralkyl or aryl group, any of which may optionally be substituted, or these compounds.
The compounds of the invention may thus have the formula St-A where St and A are as defined above. Particular groups of compounds of interest are those of the formulae: replaced by a group A, but the invention includes derivatives of such compounds in which two or more hydroxy groups are replaced by A groups.
The structural variety of the compounds of the invention allows their hydrolysis properties to be modulated as required. For example, most known steroid-bisphosphonate conjugates, particularly oestradiol-biphosphonates, hydrolyse very rapidly whereas slower hydrolysis and hence slower release of the steroid is often desirable. Compounds of formula (1) above such as the compound (4) below which contains two steroid units are resistant to hydrolysis and thus advantageous when a slower rate of steroid release is required. On the other hand, compounds containing only one steroid unit are less resistant to hydrolysis and thus more suitable when rapid steroid release is required. The compounds of formula (1) also enable two different steroid units to be included in the same molecule, and this allows steroids of different activities to be delivered at the same time.
The parent hydroxy steroid may be an oestrogen, androgen, anabolic steroid, glucocorticoid or progestagen which inhibits bone resorption or stimulates bone formation, such as for example 17.beta.-oestradiol, oestrone, testosterone, norethindrone, androsterone, norethandrolone and nandrolone. These compounds generally have a hydroxy group at the 3- or 17- position or both, and further examples of hydroxy steroids which may be used are listed in EP-A 0496520.
In the group X, R.sup.1 may be a C.sub.1-6 alkyl (e.g. methyl, ethyl, isopropyl or t-butyl), C.sub.2-6 alkenyl (e.g. allyl), C.sub.3-8 cycloalkyl (e.g. cyclopentyl or cyclohexyl), phenyl (C.sub.1-6)alkyl or a mono- or bicyclic aryl group (e.g. phenyl or naphthyl). The alkyl and alkenyl groups may for example be substituted by one or more halogen atoms (e.g. chlorine) and the cycloalkyl groups by one or more C.sub.1-4 alkyl groups or halogen atoms (e.g. chlorine). The aryl groups may be substituted by one or more hydroxy groups, as in naphthol.
The compounds of the invention

REFERENCES:
patent: 5391776 (1995-02-01), Ueno et al.
Guervenou et al., Phosphorus, Sulfur and Silicon and the Related Elements, 88(1-4):1-13 (1995).

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