United States Patent
`Barrie et al.
`
`1191
`
`[11] Patent Number:
`
`5,604,213
`
`[45] Date of Patent:
`
`Feb. 18, 1997
`
`l|I||||||||l||||||||||ll||I||||||||||||1|||l||1|l|||l|||l||||||||||||||
`US005604213A
`
`[54]
`
`17-SUBSTITUTED STEROIDS USEFUL IN
`CANCER TREATMENT
`
`[75]
`
`Inventors: Susan E. Barrie, Kent; Michael
`Jarman, London; Gerard A. Potter,
`Cheshire; Ian R. Hardcastle, Sutton,
`all of Great Britain
`
`[73] Assignee: British Technology Group Limited,
`London, England
`
`[21] Appl. No.: 315,882
`
`[22] Filed:
`
`Sep. 30, 1994
`
`Related U.S. Application Data
`
`[63] Continuation-in-part of PC1‘IGB93l00531 May. 15, 1993.
`
`[30]
`
`Foreign Application Priority Data
`
`Mar. 31, 1992
`Nov. 27, 1992
`Sep. 30, 1993
`1111. 14, 1994
`
`[on]
`[GB]
`[on]
`[GB]
`
`United Kingdom ................... 9207057
`United Kingdom ..
`9224880
`
`United Kingdom ..
`9320132
`United Kingdom ................... 9414192
`
`[51]
`Int. Cl.‘ ............................. A6lK 31/58; C071 43/00
`
`[52] U.s. Cl. ................................. 514/176; 540/95
`[58] Field of Search ................................ 540/95; 514/176
`
`[56]
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`288053 10/1988 European Pat. Ofl’.
`413270
`2/1991 European PaL Ofl’.
`
`.
`.
`
`OTHER PUBLICATIONS
`
`M—J. Shiao,.“New synthesis of Azabufalin from C-17
`Steroidal Ketones”, J. Org. Chem. 47, 5189-5191 (1982).
`B. F. 1-lofirnan. ‘The pharmacology of cardiac glycosides” in
`Cardiac therapy, ed. M. R. Rosen and B.‘ F. Hoffman,
`Martinus Nijhoif Publishers
`(1983), Chapter 11, pp.
`387-412.
`
`R. Thomas et al., "Synthesis and Biological Activity of
`Sernisynthetic Digitalis Analogs”,
`J. Pharm. Sci. 63,
`1649-1683 (1974).
`'1‘. Shigei and S. Mineshita, “Cardiotonic activities of four
`new compounds .
`.
`. ”, Experientia 24, 466-467 (1968).
`T. Shigei et al., “Structure—Activity Relationship of the
`Cardenolide .
`.
`. ”, Experientia 29, 449-450 (1973).
`3
`of
`M.
`Okada
`and
`Y.
`Saito,
`“Synthesis
`enolide
`B-1-lydroxy-5a-card—20
`(22)
`(14-Deoxy-14|3-uzarigenin)”, Chem. Pharm. Bull. 16,
`2223-2227 (1968).
`B. K. Naidoo et al., “Cardiotonic Steroids 1: Importance of
`14B—Hydroxy Group in Digitoxigenin" J. Pharm. Sci. 63,
`1391-1394 (1974).
`W. Schbnfeld and K. R. H. Repke, “A Free-Wilson Analysis
`of SB, l4B—Androstane Derivatives Inhibiting the NalK—AT—
`Pase from Human Heart", Quant. Struct.—Act. Relat. 7,
`160-165 (1988).
`T. Hashimoto et al., “Studies on Digitalis Glyeosides XXXV
`. . . ”, Chem. Pharm. Bull. 27, 2975-2979 (1979).
`K-O. Haustein et al., “Structure-Activity Relationships of
`Natural and Semi-Synthetic Genius and Glycosides .
`.
`. ”,
`Pharmacology 10, 65-75 (1973).
`
`Th. W. Gitntert and H. H. A. Linde, “Cardiac glycosides:
`Prerequisites for the developmt of new caniiotonic com-
`pounds", Experientia, 33, 698-703 (1977).
`J. Wicha et
`:11.
`‘Synthesis of
`l7.beta.-Pyridyl—and
`17.beta—Pyridyl—androstane Derivatives’. Heterocycles. vol.
`16, No. 4, 1981, pp. 521-524.
`J. Wicha et al. ‘Synthesis and Molecular Biological Activity
`of the Pyridine Analog of Cardiotonic Steroids’. Hetero-
`cycles. vol. 20, No. 2, 1983, pp. 231-234.
`G. A. Potter eta1., “Discovery of Highly Potent and Selec-
`tive Enzyme Inhibitors .
`.
`. " Poster presented at
`the
`Smithliline Beechani Research Symposium. Robinson Col-
`lege, Cambridge, England, 25-26 Mar. 1993.
`S. E. Barrie et al., “Highly Potent Inhibitors of Human
`Cytochrome P-450 (1701) .
`.
`. " Poster presented at the
`British Association for Cancer Research meeting in Shef-
`field, England, 28-31 Mar. 1993.
`G. A. Potter et al., “Highly Potent Inhibitors of Human
`Cytrochrome P—450 (1701) . . . ”,Poster presented at the third
`Drug Discovery and Development Symposium, San Diego,
`California. USA. 22-24 Jul. 1993.
`l7—Iodids Und-
`B. Schweder et al., “Synthesis des A1‘,
`Triflats von Androsta—4—en—3, 17-dion .
`.
`. ", J. Prakt.
`Chem. 335, 201-204 (1993).
`D. H. R. Barton et al., “An Improved Preparation of Vinyl
`lodides", Tetrahedron letters 24, 1605-1608 (1983).
`
`(List continued on next page.)
`
`Pn'mary Examiner—Mukund J. Shah
`Assistant Examiner—Anthony Bottino
`Attorney, Agent, or Firm—Nixon & Vanderhye
`
`[57]
`
`ABSTRACT
`
`Compounds of the general formula (1)
`
`
`
`wherein X represents the residue of the A, B and C rings of
`a steroid, R represents a hydrogen atom or an alkyl group of
`1 to 4 carbon atoms, R1‘ represents a hydrogen atom and R"
`represents a hydrogen atom or an alkyl or alkoxy group of
`1-4 carbon atoms. or a hydroxy or allrylcarbonyloxy group
`of 2 to 5 carbon atoms or R” and R" together represent a
`double bond, and R“ represents a hydrogen atom or an alkyl
`group ofl to4carbonatoms,intheforn-1ofthefreebases
`or phannaceutically acceptable acid addition salts. are useful
`for treatment of androgen-dependent disorders, especially
`prostatic cancer, and also oestrogen-dependent disorders
`such as breast cancer.
`
`22 Claims, No Drawings
`
`ARGENTUM EX1005
`ARGENTUM EX1005
`Page 1
`
`Page 1
`
`

`
`
`
`
`
`
`
`
`
`emy of Sciences. Chemistry. vol. 33, No. 1-2, 1985, pp.
`
`1947'
`h"
`"
`'d.P..
`a1.‘Cdi
`J.W'h
`
`
`
`
`
`
`
`ar °t°m° Sm.°1 .3
`1° 3 ct.
`7 Syi“ 6513 °
`
`
`
`
`17.beta—Pyridy1—androstane Derivatives. Bulletin of the
`
`
`
`
`
`
`
`Polish Academy Of SCie11CeS- Ch5mi3tTY- V01- 32’ N°- 1"2a
`
`
`
`1984, pp. 75-83.
`
`f
`
`
`
`
`
`
`
`5,604,213
`Page 2
`
`
`
`
`OTHER PUBLICATIONS
`
`
`D. H. R. Barton et al., “Studies on the oxidation of Hydra-
`
`
`
`
`
`
`
`zones with iodide .
`. ”, Tetrahedron 44, 147-162 (1988).
`.
`
`
`
`
`
`
`
`
`
`
`J. Wicha et a1. ‘Cardiotonic Steroids. Part 8. Synthesis of
`
`
`
`
`
`
`
`
`nbeta
`
`
`
`from
`(3'pyridy1)—14.beta.—Androst—4—ene—3.beta.14—dio1
`
`
`
`
`
`
`17—Oxoandrostane Derivatives’ Bulletin of the Polish Acad-
`
`Page 2
`
`Page 2
`
`

`
`5,604,213
`
`
`
`1
`
`17-SUBSTITUTED STEROIDS USEFUL IN
`
`
`
`CANCER TREATMENT
`
`
`
`
`
`
`
`
`This specification is a continuation-in-part of PCT Appli-
`cation PCT/GB93/00531, filed Mar. 15, 1993 and which
`
`
`
`
`
`
`
`
`designated the United States of America.
`
`
`
`
`
`
`
`
`
`THE INVENTION
`
`
`BACKGROUND
`
`1. Field of the Invention
`
`
`
`
`This invention relates to l7-substituted steroids and their
`
`
`
`
`
`
`
`use in the treatment of androgen-dependent and oestrogen-
`
`
`
`
`
`
`
`
`
`
`
`
`
`dependent disorders, especially prostatic cancer and breast
`cancer respectively.
`
`
`2. Description of the Related Art
`
`
`
`
`
`
`
`
`
`
`The
`l7ot-hydroxylase/C1120 lyase enzyme complex
`(hereinafter “hydroxylase/lyase”) is known to be essential
`
`
`
`
`
`for the biosynthesis of androgens and oestrogens. In the
`
`
`
`
`
`
`
`
`
`treatment of androgen-dependent disorders, especially pro-
`
`
`
`
`
`static cancer, there is a need for strong inhibitors of hydroxy-
`
`
`
`
`
`
`
`
`lase/lyase. Certain anti-androgenic steroids are well known,
`
`
`
`
`
`
`
`
`
`
`
`
`for example Cyproterone acetate (17ot-acetoxy-6-chloro-1oz,
`
`
`
`2ot-methylene-4,6-pregnadiene-3,20-dione). Many
`other
`steroids have been tested as hydroxylase/lyase inhibitors.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`See, for example, PCT Specification WO 92/00992 (Scher-
`
`
`
`
`
`
`
`ing AG) which describes anti-androgenic steroids having a
`
`
`
`
`
`
`
`
`
`pyrazole or triazole ring fused to the A ring at the 2,3-
`
`
`
`
`
`
`
`position, or European Specifications EP-A 288053 and EP-A
`
`
`
`
`
`
`413270 (Merrell Dow) which propose l7[3-cyclopropy-
`larnino androst-5-en-3|3-ol or -4-en-3-one and their deriva-
`
`
`
`
`
`
`tives.
`
`
`SUMMARY OF THE INVENTION
`
`
`
`
`It has now surprisingly been found that steroids lacking a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`C20 side chain and having a 17-(3-pyridyl) ring in its place,
`together with a 16,17-double bond, are powerful hydroxy-
`
`
`
`
`
`
`
`lase/lyase inhibitors, useful for the above-stated purposes.
`
`
`
`
`
`
`
`According to -the invention,
`there are provided com-
`
`
`
`
`
`
`
`
`
`
`
`pounds of the general formula
`
`R
`
`
`
`(1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`wherein X represents the residue of the A, B and C rings
`
`
`
`
`
`
`of asteroid, R represents a hydrogen atom or an alkyl
`
`
`
`
`
`
`
`
`
`
`
`
`
`group of 1-4 carbon atoms, R14 represents a hydrogen
`atom, a halogen atom or an alkyl group of 1 to 4 carbon
`
`
`
`
`
`
`
`atoms and each of the R15 substituents independently
`
`
`
`
`
`
`
`represents a hydrogen atom or an alkyl or alkoxy group
`
`
`
`
`
`
`of 1-4 carbon atoms, a hydroxy group or an alkylcar-
`
`
`
`
`
`
`
`bonyloxy group of 2 to 5 carbon atoms or together
`
`
`
`
`
`
`represent an oxo or methylene group or R14 and one of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the R15 groups together represent a double bond and the
`other R15 group represents a hydrogen atom or an alkyl
`
`
`
`
`
`
`
`group of l
`to 4 carbon atoms, and R15 represents a
`
`
`
`
`
`
`
`hydrogen atom, halogen atom, or an alkyl group of 1 to
`
`
`
`
`
`
`
`
`10
`
`
`
`
`
`20
`
`25
`
`
`
`30
`
`35
`
`
`
`40
`
`
`
`45
`
`
`
`50
`
`55
`
`
`
`60
`
`
`
`65
`
`
`
`
`
`2
`
`in the form of the free bases or
`4 carbon atoms,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutically acceptable acid addition salts.
`The term “steroid” herein includes any compound having
`
`
`
`
`
`
`
`
`the steroidal B and C rings, but in which all or part of the A
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ring is missing e.g. ring not closed (lacking the 2- or
`3-position C-atom or both) or takes the form of a cyclopen—
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`tane ring. It also includes azasteroids having a ring nitrogen
`
`
`
`
`
`
`
`
`atom in place of a ring carbon atom, especially in the A—ring
`such as in 4-azasteroids.
`
`
`In general, the compounds of formula (1) are new and
`
`
`
`
`
`
`
`
`
`such compounds per se are included in the invention.
`
`
`
`
`
`
`
`
`
`However, certain of them have been disclosed as interme-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`diates in the synthesis of certain steroids having a 3-pyridyl
`
`
`
`
`
`
`
`
`or 3-pyridonyl group in the 17B-position, see J. Wicha and
`
`
`
`
`
`
`
`
`M. Masnyk, Bulletin of the Polish Academy of Sciences:
`Chemistry 33 (1-2), 19-27 and 29-37 (1985). The first of
`
`
`
`
`
`
`
`
`these papers says that a 17B-side chain of the form
`
`
`
`
`
`
`
`
`
`—C=C—C=O or —C=C—C=N favours cardiotonic
`
`
`
`
`
`
`
`
`
`
`
`properties and describes the synthesis of 17B-(3-pyridyl)-
`14B-androst-4-ene-3B,14-diol, while the second uses this
`
`
`
`
`
`
`
`
`
`
`compound to prepare 17B-[3-pyrid-2(lH)onyl]-14[3-an-
`drost-4-ene-3B,l4-diol. Those final compounds diifer from
`
`
`
`
`
`
`
`
`
`
`
`
`
`those of the present invention by having a saturated D-ting
`and the paper contains no test results. Insofar as certain
`
`
`
`
`
`
`
`
`
`
`compounds within formula (1) are known as intermediates
`
`
`
`
`
`
`
`in these syntheses, the invention extends to the compounds
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`only for use in therapy. These are 3B-acetoxy-17-(3-pyridy-
`
`
`
`
`
`l)androsta-5,14,l6-triene and 3[3,15oc- and 3B,l5[5-diac-
`
`
`
`
`etoxy-17-(3-pyridyl)androsta-5,l6-diene. See also J. Wicha.
`et. al., Heterocycles 20, 231-234 (1983 ) which is a pre-
`
`
`
`
`
`
`
`
`liminary communication of the first of the above two papers.
`
`
`
`
`
`
`
`
`J. Wicha et. al., Bulletin of the Polish Academy of
`
`
`
`
`
`
`
`
`Sciences, Chemistry 32 (1-2), 75-83 (1984) have also
`
`
`
`
`
`
`
`
`
`
`
`
`described the preparation of 3B-methoxy-17[3-(3-pyridyl)an-
`
`
`
`
`
`
`
`
`drostane and pyridone analogues thereof via the intermedi-
`
`
`
`ate 3B-methoxy-17-(3-pyridyl)-5ot-androst-16-ene. Accord-
`
`
`
`
`
`
`
`
`
`ingly, the invention extends to the latter compound only for
`use in therapy. A preliminary communication of this paper,
`
`
`
`
`
`
`
`
`
`
`
`
`
`by J. Wicha and M. Masynk, appeared in Heterocycles 16,
`521-524 (1981).
`
`
`The invention also includes pharmaceutical compositions
`
`
`
`
`
`
`comprising a compound of formula (1) in association with a
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutically acceptable diluent or carrier. The termi-
`
`
`
`
`
`“pharmaceutical
`compositions”
`implies
`that
`nology
`
`
`
`
`
`
`
`injectible formulations are sterile and pyrogen-free and
`
`
`
`
`
`
`
`thereby excludes any compositions comprising the com-
`
`
`
`
`
`
`
`pound of formula (1) and a non-sterile organic solvent, such
`as may be encountered in the context of the final stages of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`preparing these above-mentioned compounds of formula (1)
`which have been described in the literature but without any
`
`
`
`
`
`
`
`
`
`
`
`
`
`therapeutic use being mentioned.
`
`DESCRIPTION OF THE PREFERRED
`
`
`EMBODIMENTS
`
`
`
`
`
`In the compounds of the invention the essential structural
`
`
`
`
`
`
`
`features comprise all of:
`
`
`
`
`
`
`
`
`a 3-pyridyl ring in the 17-position
`
`
`
`
`
`
`
`a ring double bond in the 16,17-position of the D-ring
`
`
`
`
`the 18-position methyl group
`It is critical that the pyridine nitrogen atom be in the
`
`
`
`
`
`
`
`
`3-position, not the 2- or 4-position. It is also critical that the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pyridine ring be joined directly to the 17-carbon atom. This
`
`
`
`
`
`
`
`criticality is demonstrated by tests of inhibiting activity
`
`
`
`
`
`
`
`against hydroxylase and lyase (Table 1). The concentration
`of test compound required to achieve 50% inhibition of the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 3
`
`Page 3
`
`

`
`5,604,213
`
`
`
`4
`
`
`
`
`
`
`in the above-cited Specification WO 92/00992, or oxazole
`
`
`
`
`
`ring fused in the same positions.
`
`
`
`
`
`By way of example, X can represent the residue of
`
`
`
`
`
`
`androstan-3ot- or 3B—ol,
`
`
`androst-5-en-30+ or 3B-ol,
`
`
`androst-4-en-3-one,
`
`androst~2-ene,
`androst-4-ene,
`androst-5-ene,
`
`
`
`
`
`androsta-5,7-dien-30¢ or 3B-ol,
`
`androsta-1,4-dien-3-one,
`
`androsta-3,5-diene,
`
`estra-l,3,5[l0]-triene, -
`
`estra-1,3,5[l0]-trien-3-ol,
`Sot-androstan-3~one,
`
`androst-4-ene-3,11-dione,
`
`6-fluoroandrost-4-ene-3-one or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`androstan-4-ene-3,6-dione
`
`each of which, where structurally permissible, can be further
`
`
`
`
`
`
`derivatised in one or more of the following ways:
`
`
`
`
`
`
`to form 3-esters, especially 3-alkanoates and —benzoates,
`
`
`
`
`
`
`
`to have one or more carbon to carbon ring double bonds
`
`
`
`
`
`
`
`
`
`in any of the 5,6-, 6,7-7,8-, 9,ll- and 11,12-positions
`
`
`
`
`
`
`
`
`as 3-oximes
`
`
`as 3-methylenes
`
`
`as 3-carboxylates
`
`as 3-nitriles
`
`as 3-nitros
`
`
`as 3-desoxy derivatives
`
`
`
`to have one or more hydroxy, halo, C1_4-alkyl, trifluo-
`
`
`
`
`
`
`
`
`
`
`
`
`romethyl, CM-alkoxy, CM-alkanoyloxy, benzoyloxy,
`oxo, methylene or alkenyl substituents in the A, B or
`
`
`
`
`
`
`
`C-ring
`to be 19-nor.
`
`
`Preferred CM-alkyl and alkoxy groups are methyl and
`
`
`
`
`
`
`
`
`ethoxy.
`Preferred C1_,,~alkanoyloxy groups are acetoxy and pro-
`
`
`
`
`
`
`
`
`panoyloxy.
`Preferred halo groups are fluoro, bromo and chloro and
`
`
`
`
`
`
`
`
`the preferred substitution position is the 6-position.
`
`
`
`
`
`
`The substituents include, for instance, 2-fluoro, 4-fluoro,
`
`
`
`
`
`
`
`
`
`
`
`
`6-fluoro, 9-fluoro, 3-trifluoromethyl, 6-methyl, 7-methyl,
`
`
`
`
`
`
`6-oxo, 7—oxo, 11-oxo, 6-methylene, 11-methylene, 4-hy-
`droxy, 7-hydroxy, ll-hydroxy or 12-hydroxy, each in any
`
`
`
`
`
`
`appropriate epimeric form, and, subject to structural com-
`
`
`
`
`
`
`
`patibility (well known in general steroid chemistry), in any
`
`
`
`
`
`
`
`combination of two or more such groups.
`
`
`
`
`
`Compounds which are likely to be unstable are considered
`
`
`
`
`
`
`excluded from consideration. Such compounds will be evi-
`
`
`
`
`
`
`
`dent to steroid chemists. Compounds having esoteric sub-
`
`
`
`
`
`
`
`stituents likely to interfere with the stereochemical align-
`
`
`
`
`
`
`
`
`ment of the steroid molecule with the enzymes to be
`
`
`
`
`
`
`
`
`
`inhibited, by virtue of steric or electronic distribution effects,
`
`
`
`
`
`
`are to be avoided. For example, a 2,3,5,6-tetrafluoro-4-
`
`
`
`
`
`
`
`trifluoromethylphenoxy substituent in the 3-position is not
`
`
`
`
`
`recommended. Androst-5-en-3B-ol having such an ether
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`substituent in place of the 3B-hydroxy group has been shown
`to be a very poor inhibitor for lyase and hydroxylase.
`
`
`
`
`
`
`
`
`The currently preferred compounds of formula (1) include
`
`
`
`
`
`
`those which are saturated and unsubstituted at the 11- and
`
`
`
`
`
`
`
`
`
`12-positions and which therefore are of the general formula
`
`
`
`
`
`
`
`
`(3)1
`
`
`Page 4
`
`3
`
`enzyme is far greater for the 2-pyridyl, 4-pyridyl and 2-py-
`
`
`
`
`
`
`
`
`
`ridylmethyl compounds tested than for the 3-pyridyl. The
`
`
`
`
`
`
`
`
`methods of determination were as described in the Examples
`
`
`
`
`
`
`hereinafter.
`
`
`TABLE 1
`
`Effect of variations in the 17-substitutent on inhibition of
`
`
`
`
`
`hydroxylasc and lyase, demonstrating the criticality of the
`
`
`
`
`
`
`
`
`17-substituent in this invention.
`
`
`
`R17
`17
`
`
`16
`
`
`10
`
`
`
`(2)
`
`
`
`H0
`
`
`
`R”
`
`
`
`l \
`“ N
`
`
`
`Type
`
`2-Pyridyl
`
`
`
`(for comparison)
`
`Lyase
`
`
`0.13
`
`
`
`1Cso (HM)
`
`
`I-lydroylase
`
`
`0.32
`
`
`
`f
`
`\
`
`
`
`N
`
`
`3-pyridyl
`
`
`
`(present invention)
`
`
`
`0.003
`
`
`
`0.004
`
`
`
`4—pyridyl
`
`(for comparison)
`
`
`
`
`2.0
`
`
`
`5.0
`
`
`
`
`
`2—picolyl
`
`
`/ \ (for comparison)
`
`
`
`>10
`
`
`>10
`
`
`
`
`Note:
`
`all the compounds of formula (2) tested were poor inhibitors of aromatase:
`
`
`
`
`
`
`
`
`
`
`ICSO >20 M.
`
`
`
`Our modelling of the geometry of the putative transition
`
`
`
`
`
`
`
`
`
`state of the lyase component of the hydroxylase-lyase
`
`
`
`
`
`
`
`
`enzyme complex, in the putative mechanism of action of the
`
`
`
`
`
`
`
`lyase component, suggests that the l6,17—double bond is
`
`
`
`
`
`
`
`essential to allow the 3-pyridine ring to adopt the orientation
`
`
`
`
`
`
`
`
`required for co-ordination to the haem group of the hydroxy-
`
`
`
`
`
`
`
`
`
`
`lase-lyase complex.
`Elsewhere, the D-ring can have any other simple substitu-
`
`
`
`
`
`
`
`
`
`ent. Certain simple substituents are defined in connection
`
`
`
`
`
`
`
`with the preferred general formula (1), but it will be appre-
`
`
`
`
`
`
`
`
`
`ciated that others could be substituted for those of formula
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(1). In the compounds of formula (1), R15 is preferably
`hydrogen or alkyl of 1 to 3 carbon atoms, R15 hydrogen,
`
`
`
`
`
`
`
`
`alkyl of l to 3 carbon atoms, fluorine, chlorine, bromine or
`
`
`
`
`
`
`
`iodine, and R hydrogen or methyl, in the 5-position of the
`
`
`
`
`
`
`
`
`
`pyridine ring.
`The remainder of the molecule, designated “X” in formula
`
`
`
`
`
`
`
`(1), can be of any kind conventional in steroid chemistry or
`
`
`
`
`
`
`
`have any other feature known in steroids having anti-
`
`
`
`
`
`
`
`
`androgenic activity, for example the pyrazole or triazole
`
`
`
`
`
`
`
`
`ring, fused to the A ring at the 2- and 3- positions, disclosed
`
`
`
`
`
`
`
`
`20
`
`25
`
`
`
`30
`
`
`
`35
`
`
`
`40
`
`
`
`45
`
`
`
`50
`
`
`
`55
`
`
`
`60
`
`65
`
`
`
`Page 4
`
`

`
`5,604,213
`
`
`
`(3)
`
`
`
`l0
`
`6
`
`
`
`
`
`
`
`
`
`carbon atoms, most preferably ethyl or methoxy, or Z‘ and
`
`
`
`
`
`
`
`Z2 together represent an alkylenedioxy group of 2 or 3
`
`
`
`
`
`
`
`
`
`carbon atoms and R is as defined above and carrying out said
`cross-coupling reaction.
`
`
`
`
`
`
`
`The palladium complex-catalysed cross-coupling reaction
`
`
`
`
`
`
`
`
`of the l7-substituted steroid with the boron compound is
`
`
`
`
`
`
`
`
`
`believed to involve the steps indicated in the following
`
`
`
`
`
`
`illustrative reaction scheme 1 (Py=3-pyridyl). The pyridyl
`
`
`
`
`
`
`anionic species is provided by the boron compound.
`Schemel
`
`OSOZCF3
`
`0so2c1=3
`
`Ph3P
`
`/
`\‘Pd
`
`5
`
`\PPh3
`5
` “Pye”
`
`uPd(PPh3)2n
`
`GOSOZCF3
`
`Py
`
`Ph3P
`
`/
`\Pd
`
`for
`The replacement of the 17-enol group can be,
`
`
`
`
`
`
`
`
`
`
`
`example, to form a 16,17-ene trifluoromethanesulphonate
`(“triflate”) of formula (6):
`
`
`
`
`
`
`
`
`O- SO2CF3
`
`
`
`
`(6)
`
`
`
`
`
`
`
`15
`R14
`
`R
`R15
`
`
`or a 17-iodo or bromo-16,[17]-ene (a “vinyl halide”) of
`
`
`
`
`
`
`formula (7):
`
`
`
`
`
`
`
`(7)
`
`
`
`
`
`
`
`
`
`(Hal=I or Br)
`
`
`
`
`
`
`
`
`Compounds of formula (6) can be prepared by reacting
`the 17-oxo compound of formula (4) with an enol ester-
`
`
`
`
`
`
`
`
`
`forming trifluoromethanesulphonic acid derivative such as
`
`
`
`
`
`the anhydride, see S. Cacchi, E. Morera and G. Ortar,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Tetrahedron Letters, 25, 4821 (1984). The 17-oxo compound
`can be considered notionally to exist in the enol form, the
`
`
`
`
`
`
`
`
`reaction being one of esterification of the enol.
`
`
`
`
`
`
`For the preparation of the 17-position derivatives of
`
`
`
`
`
`
`
`
`formula (6) or (7) any necessary protection of other groups
`
`
`
`
`
`
`
`
`
`in the molecule may be first carried out. For example in the
`
`
`
`
`
`
`
`
`
`
`triflate route hydroxyl groups are conveniently protected as
`
`
`
`
`
`
`
`their acetates, whilst in the vinyl halide route the 3-oxo
`
`
`
`
`
`
`
`
`
`
`group of steroids can be selectively protected as their
`
`
`
`
`
`
`
`
`
`perfluorotolyl enol ethers, see M. Jarman and R. McCague,
`
`
`
`
`
`
`
`J.Chem. Soc. Perkin Trans. 1, 1129 (1987).
`
`
`
`
`
`
`
`Page 5
`
`15
`
`
`
`20
`
`25
`
`
`
`
`30
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`wherein Q represents the residue of A, B and C rings of
`asteroid, and R is a hydrogen atom or an alkyl group of 1-4
`
`
`
`
`
`
`
`carbon atoms.
`
`
`However, 11- and/or 12-substituted compounds are also
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`active. Particularly preferred are ll-oxo and 1113-hydroxy
`
`
`
`
`derivatives of compounds of formula (3).
`
`
`
`
`
`
`Specifically preferred compounds of the invention com-
`prise
`
`
`l7-(3-pyridyl)androsta-5,16-dien-3B-ol,
`
`17-(3-pyridyl)androsta-3,5,16-triene,
`
`17-(3-pyridyI)androsta-4,16-dien-3-one,
`l7-(3-pyridyl)estra-1,3,5[l0],l6-tetraen-3-ol,
`
`17-(3-pyridyl)-Sot-androsb16-en-30:-ol
`and their acid addition salts and 3-esters.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Other notable compounds of the invention comprise
`
`l7-(3-pyridyl)-Soc-androsvl6-en-3-one,
`17- (3 -pyridyl)-androsta-4, 1 6-diene-3, 1 l -dione,
`
`
`
`
`17-(3-pyridyl)-androsta-3,5,16-trien-3-ol,
`
`
`
`6ot- and 6[3—fluoro-l7-(3-pyridyl)androsta-4,16-dien-3-one
`
`17-(3-pyridyl)androsta-4,l6-dien-3,6-dione,
`
`
`
`17-[3-(5-methyl pyridy1)]androsta-5,16 dien-3B-ol
`3oL-trifluoromethyl-l7-(3-pyridyl)androsta-16-en-313-ol
`and their acid addition salts and 3-esters.
`
`
`
`
`
`
`
`Insofar as certain compounds within formula (1) are 35
`
`
`
`
`
`
`
`
`
`known per se and these are compounds which are less easy
`
`
`
`
`
`
`
`
`
`to prepare than many of the others, a preferred class of
`
`
`
`
`
`
`
`
`
`compounds of formula (1) is those which do not have a
`
`
`
`
`
`
`
`
`3B-alkoxy group, a 14,15-double bond or a 15-ester group.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The compounds of formula (1) can be prepared by a 40
`
`method which is in itself novel and inventive. Starting from
`
`
`
`
`
`
`
`
`a 17-oxo compound of general formula (4):
`
`
`
`
`
`
`
`
`0
`
`(4)
`
`
`45
`
`
`
`
`R14
`
`R15
`
`R15
`
`\
`
`
`
`
`
`
`
`
`
`
`
`wherein X, R”, R15 and R15 are as defined above and any
`other oxo groups and hydroxy groups in the molecule are
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`first appropriately protected, the method comprises replac-
`ing the 17-hydroxy group of compound (4) in its enol form
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`by a leaving group (L) which is capable of being replaced by
`a 3-pyridyl group in a palladium complex-catalysed cross-
`
`
`
`
`
`
`coupling reaction with a pyridyl ring-substituted boron
`
`
`
`
`
`
`compound of formula (5):
`
`
`
`R
`
`(5)
`
`
`
`
`
`50
`
`
`55
`
`
`z \ N
`
`B2121
`
`
`
`
`
`
`
`
`wherein Z1 and Z2 independently represent hydroxy or
`alkoxy or alkyl of 1-4 carbon atoms each, preferably 1-3
`
`
`
`
`
`
`
`
`
`
`65
`
`
`
`Page 5
`
`

`
`5,604,213
`
`
`
`
`8
`-continued
`Scheme 2
`
`
`
`
`7
`
`
`
`
`
`
`
`
`
`Compounds of formula (7) can be prepared by first
`hydrazinating the 17-oxo compounds of formula (4) by a
`
`
`
`
`
`
`
`standard method to form the 17-hydrazone, which is then
`
`
`
`
`
`
`
`reacted with bromine or iodine in the presence of an amine
`
`
`
`
`
`
`
`or guanidine base, see D. Barton, G. Bashiardes and J.
`
`
`
`
`
`
`
`
`
`Fourrny, Tetrahedron Letters, 24, 1605 (1983).
`
`
`
`
`
`
`The 17-position derivative (whether triflate or vinyl
`
`
`
`
`
`
`
`halide) is then reacted with the boron compound of formula
`
`
`
`
`
`
`
`
`(5) using as catalyst a pa11adium(0) phosphine complex, for
`
`
`
`
`
`
`
`example tetrakis(triphenylphosphine)palladium(0), or a pal-
`
`
`
`ladium (II) phosphine complex which is reducible in situ to
`
`
`
`
`
`
`
`
`
`
`
`
`
`a palladium(0) phosphine species, especially bis(triph-
`
`
`
`enylphosphine)palladium (II) chloride.
`
`
`
`
`
`
`
`
`Palladium (O) —
`
`
`Ph3P complex
`
`
`e.g. from PdC12(Ph3P)2
`
`
`
`
`
`Hal
`
`
`
`
`
`R14
`
`R15
`(Hal = I or Br)
`
`
`
`
`
`
`
`R15
`
`
`
`
`SUMMARY OF THE INVENTION
`
`
`
`
`
`The vinyl halide route, via a compound of formula (7), is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`particularly well suited to the preparation of 3B-acyloxy-16,
`
`
`
`
`
`17-ene-17-(3-pyridyl)
`steroids, especially the preferred
`
`
`compound, 3B-acetoxy-17-(3-pyridyl)androsta-5,16-diene,
`of formula (8):
`
`
`
`
`20
`
`
`
`25
`
`
`
`
`Z \ N
`
`
`
`30
`
`
`(8)
`
`AcO
`
`
`
`
`
`
`
`
`
`
`but using the unprotected 313-hydroxy compound as starting
`material. By—products can be reduced either (a) by keeping
`
`
`
`
`
`
`
`
`the proportion of organoboron compound (borane) used in
`
`
`
`
`
`
`the cross-coupling reaction within the range 1.0 to 1.2
`
`
`
`
`
`
`
`
`
`equivalents per equivalent of steroid or (b) by crystallising
`
`
`
`
`
`
`
`the reaction product of the cross-coupling reaction from a
`
`
`
`
`
`
`
`mixture of acetonitrile and methanol. This route via the vinyl
`
`
`
`
`
`
`
`
`
`iodide intermediate is therefore amenable to large scale
`
`
`
`
`
`
`synthesis, and is shown in Scheme 2 below.
`
`
`
`
`
`Scheme 2
`
`
`35
`
`
`
`40
`
`45
`
`
`
`S0
`
`
`
`
`
`/ N—NI-I2
`/ O
`
`
`is4X { R Standardmethod
`X [
`R16
`
`
`
`
`
`
`
`
`R
`‘
`15
`(unspecified)
`14
`
`
`
`R15
`R
`
`
`I2 or Brgl
`a.rr1ine or
`
`
`
`guanidine base
`
`
`(lit. ref. given)
`
`
`
`
`15
`
`
`
`
`R
`
`R
`M
`
`R15
`
`
`
`
`
`55
`
`
`
`60
`
`
`
`65
`
`
`
`The principle of this aspect of the invention may be
`
`
`
`
`
`
`
`
`
`expressed as a method of preparing a 3B-hydroxy- or
`
`
`
`
`
`
`
`
`
`3B-(lower
`acyloxy)-16,17-ene-17-(3-pyridyl)-substituted
`steroid, wherein the 3B-(lower acyloxy) group of the steroid
`
`
`
`
`
`
`
`
`has from 2 to 4 carbon atoms, which comprises subjecting
`
`
`
`
`
`
`
`a 3B-hydroxy-16,17-ene-17-iodo or-bromo steroid to a pal-
`
`
`
`
`
`ladium complex-catalysed cross-coupling reaction with a
`
`
`
`
`
`
`
`
`
`
`
`(3-pyridyl)-substituted borane, in which the pyridine ring is
`substituted at the 5-position by an alkyl group of 1
`to 4
`
`
`
`
`
`
`
`carbon atoms or is unsubstituted thereat, especially with a
`
`
`
`
`
`
`said borane of formula (5), wherein R is a hydrogen atom or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`an alkyl group of 1-4 carbon atoms and Z‘ and Z2 inde-
`pendently represent hydroxy or alkoxy or alkyl or 1-3
`
`
`
`
`
`
`
`
`
`carbon atoms each or Z‘ and Z2 together represent an
`
`
`
`
`
`
`
`
`
`
`alkylenedioxy group of 2 or 3 carbon atoms, in a proportion
`
`
`
`
`
`of at least 1.0 equivalent of boron compound per equivalent
`
`
`
`
`
`
`
`
`of steroid, in an organic liquid, which is a solvent for the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3B-hydroxy steroidal reaction product, and optionally esteri-
`
`
`
`
`
`
`
`fying the 3B-hydroxy reaction product to the 3B-acyloxy
`ester, which method comprises feature (a) or (b) above.
`
`
`
`
`
`
`
`
`
`Preferably the vinyl iodide or bromide is unsubstituted in
`
`
`
`
`
`
`the 14, 15 and 16-positions, in which case it can be prepared
`
`
`
`
`
`
`
`
`
`from dehydroepiandrosterone (DHEA). In the hydrazination
`
`
`
`
`
`it is preferable to use hydrazine hydrate together with a
`
`
`
`
`
`
`
`
`
`catalytic amount of a proton provider which is most pref-
`
`
`
`
`
`
`
`
`
`
`erably hydrazine sulfate.
`The hydrazone is preferably iodinated with iodine or
`
`
`
`
`
`
`
`brorninated with bromine in the presence of a strong base
`
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`such as a tetraalkylguanidine, especially tetrarnethylguand-
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`me which is cheaply and readily available.
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`In the cross-coupling reaction, the boron compound is
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`preferably a diethylborane or a dimethoxyborane (Z1=Z2=Et
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`or OMe). Other boranes include those in which the boron
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`atom is part of a cyclic ether ring e.g. as in Z‘, Z2=l,2-
`ethylenedioxy or 1,3-propylenedioxy. In embodiment (a) of
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`this aspect of the invention the proportion of borane added
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`is at least 1.0, but no more than 1.2 equivalents of boron per
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`equivalent of steroid, preferably about 1.1, but
`in the
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`embodiment (b) a higher proportion is preferred, e.g. from
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`1.2:1 to 1.5 :1 equivalents of boron compound to steroid. The
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`higher proportion will give the better yield of product but
`also more of the contaminating boron, phosphine and/or
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`palladium compounds. According to embodiment (b), how-
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`ever, these are removed with the acetonitrile solvent. In
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`either embodiment, the palladium compound is a palladium
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`(O) phosphine complex such as tetrakis(triphenylphosphine)
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`palladium (0) or a compound reducible to a palladium (0)
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`Page 6
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`Page 6
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`5,604,213
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`9
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`phosphine species, especially bis(triphenylphosphine) pal-
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`ladium (II) chloride. The reaction vessel is preferably purged
`with an inert gas, especially argon or nitrogen, to minimise
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`the possibility of oxidation with a corresponding redox
`reduction of palladium to the metallic state.
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`The cross-coupling reaction is preferably carried out in
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`two phases, one aqueous, one organic. The organic phase
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`comprises an organic solvent for the 3B-hydroxy steroidal
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`reaction product, especially tetrahydrofuran (THF). Other
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`cyclic ethers such as dioxane could be used in place of THF.
`Preferably, a nucleophilic activator, such as sodium carbon-
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`ate, is used, in which case it is normally present in the
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`aqueous phase.
`After the reaction, inorganic salts can be removed by first
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`adding another organic solvent, preferably diethyl ether,
`which is a solvent for the organoboron contaminants pro-
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`duced in the reaction product, and miscible with the first-
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`mentioned organic solvent (e.g. THF), but immiscible with
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`water, whereafter the organic, e.g. THF-diethyl ether, phase
`and water (aqueous phase) can be separated. After this
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`separation, various work-up procedures are operable. In one
`procedure, particularly suited to embodiment (a), the THF
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`and diethyl ether are removed, e.g. evaporated as a mixture,
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`and the remaining reaction product is washed with a third
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`organic solvent, which can be diethyl ether, preferably
`cooled to below room temperature, most especially to 10° C.
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`or lower. The third organic solvent is one in which the
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`3B-hydroxy steroid reaction product has a low solubility and
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`which, importantly, removes the organoboron compound/s
`(and also the contaminating phosphine and palladium com-
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`pound/s). Diethyl ether is preferred.
`A different work-up procedure, used in embodiment (b),
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`comprises crystallisation from acetonitrile/methanol. Aceto-
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`nitrile is a preferred crystallisation solvent to keep boron
`compound as well as palladium compound in solution and is
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`therefore used in an excess over methanol e.g. an excess of
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`at least 5:1 and preferably about 8:1 by volume.
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`To prepare the 3B-acyloxy (alkylcarbonyloxy) com-
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`pounds, of which the acetoxy compound is preferred, stan-
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`dard acylating (acyl-esterification) agents such as acetyl,
`propionyl or butyryl chloride or anhydride can be used. The
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`final esterification product may be crystallised direct from
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`hexane, rather than from ethanol/water followed by hexane.
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`Preferably, the work-up procedure comprises reverse phase
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`chromatography,
`i.e. using a relatively lip