Details for Patent: 5,618,807
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Title: | Method for preparing 17-substituted steroids useful in cancer treatment |
Abstract: | Compounds of the general formula (1) ##STR1## wherein X represents the residue of the A, B and C rings of a asteroid, R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R.sup.14 represents a hydrogen atom and R.sup.15 represents a hydrogen atom or an alkyl or alkoxy group of 1-4 carbon atoms, or a hydroxy or alkylcarbonyloxy group of 2 to 5 carbon atoms or R.sup.14 and R.sup.15 together represent a double bond, and R.sup.16 represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, in the form of the free bases or pharmaceutically acceptable acid addition salts, are used for treatment of androgen-dependent disorders, especially prostatic cancer, and also oestrogen-dependent disorders such as breast cancer. |
Inventor(s): | Barrie; Susan E. (Kent, GB3), Jarman; Michael (London, GB3), Potter; Gerard A. (Cheshire, GB3), Hardcastle; Ian R. (Sutton, GB3) |
Assignee: | British Technology Group Limited (London, GB2) |
Filing Date: | Feb 22, 1995 |
Application Number: | 08/392,178 |
Claims: | 1. A method of preparing a 3.beta.]-hydroxy- or 3.beta.- (lower acyloxy) 16,17-ene-17-(3-pyridyl)-substituted steroid, wherein the 3.beta.-(lower acyloxy) group of steroid has from 2 to 4 carbon atoms, which comprises: cross-coupling a 3.beta.-hydroxy-16,17-ene-17-iodo or -bromo steroid with a (3-pyridyl)-substituted borane using a palladium complex catalyst, wherein the pyridine ring in said borane is unsubstituted or substituted at the 5-position by an alkyl group of 1 to 4 carbon atoms, in a proportion of at least 1.0 equivalent of borane per equivalent of steroid, in an organic liquid which is a solvent for the 3.beta.-hydroxy steroidal reaction product, and, where the 3.beta.-(lower acyloxy) ester is to be prepared, reacting the resulting 3.beta.-hydroxy steroidal reaction product with an esterifying agent effective to replace the hydroxy group by a said lower acyloxy group, wherein (a) the reaction is carried out with 1.0 to 1.2 equivalents of borane per equivalent of steroid or (b) the product of the cross-coupling reaction is crystallized from a mixture of acetonitrile and methanol. 2. A method according to claim 1, wherein the 3.beta.-hydroxy steroidal reaction product, with or without isolation, is reacted with an acetyl-esterifying agent to give the corresponding 3.beta.-acetoxy- 16,17-ene-17-(3-pyridyl) steroid. 3. A method according to claim 1, wherein the starting steroid has a D-ring of the following partial formula ##STR27## wherein Hal is I or Br, X represents the residue of the A, B and C rings of the steroid, the A ring being substituted by a 3.beta.-hydroxy group, R.sup.14 represents a hydrogen atom, a halogen atom or an alkyl group of 1 to 4 carbon atoms, each of the R.sup.15 substituents independently represents a hydrogen atom or an alkyl or alkoxy group of 1 to 4 carbon atoms, a hydroxy group or an alkylcarbonyloxy group of 2 to 5 carbon atoms or together represent an oxo or methylene group or R.sup.14 and one of the R.sup.15 groups together represent a double bond and the other R.sup.15 group represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, and R.sup.16 represents a hydrogen atom, halogen atom, or an alkyl group of 1 to 4 carbon atoms. 4. A method according to claim 3, wherein the starting steroid is 3.beta.-hydroxyandrost-5-en-17 one. 5. A method according to claim 3, wherein the (3-pyridyl)-substituted borane is of formula: ##STR28## wherein R represents a hydrogen atom or an alkyl group of 1-4 carbon atoms and Z.sup.1 and Z.sup.2 independently represent hydroxy or alkoxy or alkyl of 1-3 carbon atoms each or Z.sup.1 and Z.sup.2 together represent an alkylenedioxy group of 2 or 3 carbon atoms. 6. A method according to claim 1, in which the cross-coupling reaction is carried out in two phases, one of which is aqueous and the other of which comprises the said organic liquid. 7. A method according to claim 1, wherein feature (b) of claim 26 is employed and the volumetric ratio of acetonitrile to methanol is at least 5:1. 8. A method according to claim 1, wherein feature (a) of claim 26 is employed and the proportion of borane per equivalent of steroid is from 1.2:1 to 1.5:1. 9. A method according to claim 1, wherein the ester is prepared and after esterification the product is subjected to reverse phase chromatography. |