Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-07-02
2004-09-14
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C552S633000
Reexamination Certificate
active
06790843
ABSTRACT:
The invention relates to new C-19-halogen-substituted steroids of the androst-9(11)-ene series, namely 17&bgr;-hydroxy-19-halogen-androsta-4,9(11)-dien-3-ones of general formula I, and process for their production. In addition, the use of the new radiohalogen-labeled compounds of Formula I as radio-pharmaceutical agents is the subject of the invention. These compounds can be used especially preferably in diagnostic studies of the prostate.
Moreover, the invention relates to the use of non-labeled compounds of Formula I as starting products for the production of new biologically active 5&bgr;-substituted androst-9(11)-enes of general formula II and the new 6&bgr;,19-cycloandrosta-4,9(11)-dienes of Formula III as well as processes for their production and use.
The basic attempt to develop diagnostically and therapeutically usable agents by radioactive labeling of testosterone (17&bgr;-hydroxyandrost-4-en-3-one) is known in the literature (S. J. Brandes and J. E. Katzenellenbogen, Nucl. Med. Biol. 15, 53-67, 1988). The previously used testosterone derivatives have not been introduced into clinical practice, however, in particular because of insufficient tissue selectivity and metabolic instability.
The object of this invention was therefore to find new compounds that are better suited for radiodiagnostic processes.
New 17&bgr;-hydroxy-19-halogen-androsta-4,9(11)-dien-3-ones of general formula I were found that are distinguished by a surprisingly high affinity to the androgen receptor Formula I
in which
X=a halogen or radiohalogen radical, preferably Br, I,
125
I,
131
I,
82
Br or
77
Br.
The compound 17&bgr;-hydroxy-19-
125
iodo-androsta-4,9(11)-dien-3-one represents a preferred radiopharmaceutical agent. The compounds 17&bgr;-hydroxy-19-iodo-androsta-4,9(11)-dien-3-one and 19-bromo-17&bgr;-hydroxy-androsta-4,9(11)-dien-3-one also show a high affinity to the androgen receptor.
The new compounds of general formula I are suitable in particular in the form of the radiohalogen-labeled derivatives for diagnostic use, preferably for graphic visualization of the prostate and for early detection of pathophysiological changes thereof.
The compounds according to the invention are distinguished from known derivatives of testosterone (J. N. Wright et al., J. Chem. Soc. Perkin/1989, 1647-1655) by a 9(11)-double bond. This structural element opens up the possibility of introducing a functional group at C-19 by a process that is advantageously distinguished from the standard methods for functionalizing a C-19-methyl group (J. Kalvoda et al., Helv. Chim. Acta 46, 1361, 1963 and M. Akhtar and D. H. R. Barton, J. Am. Chem. Soc. 88, 1528, 1964).
The production of the 17&bgr;-hydroxy-19-halogen-androsta-4,9(11)-dien-3-ones of general formula I according to the invention is carried out according to claim
4
, and dependent claims
5
to
8
are preferred variants.
Diagram 1 below shows the synthesis methods according to the invention in the example of 17&bgr;-hydroxy-19-iodo-androsta-4,9(11)-dien-3-one.
The starting material is aldehyde 1 that is known in the literature (3,3-(2,2-dimethyl-trimethylenedioxy)-10&bgr;-formyl-androst-9(11)-ene-5&agr;,17&bgr;-diol—G. Neef et al., Tetrahedron 49, 833-840, 1993), which was used for the production of C-19-iodide 7.
Surprisingly enough, however, the known compound 7 is not suitable for the production of an end product of Formula I according to the invention. Under the conditions of the usual deketalization/dehydration as well as the subsequent ester saponification at C-17, the C-19-iodine substitution is not maintained.
Only the process that is outlined in Diagram 1 ensures the production of the end products in high yields and purity and allows for the synthesis of the target compounds of general formula I.
In a first step of the process according to the invention, first the C-17&bgr;-hydroxy group is protected by silylation with the formation of intermediate product 2. With hydride-transferring reagents, such as, e.g., with sodium borohydride or lithium aluminum hydride, compound 2 is reduced to alcohol 3 in a way that is common in the art. Under conditions described by Neef et al. (Tetrahedron 49, 833, 1993), alcohol 3 is then further reacted to form iodide 4, whereby only a slight excess of elementary iodine must be used for reaction. Especially when the process is carried out with transfer of the reaction sequence to radiolabeled end compounds, this can be regarded as a special advantage.
Although conceivable in principle, iodide 4 cannot be converted directly into end product 6 of general formula I by treatment with acid in a one-stage process. Having the process according to the invention proceed in steps is essential to the success of the process.
First, under standard conditions (e.g., with thionyl chloride/pyridine), dehydration is performed, which results in the formation of a mixture of double-bond isomers 5a and 5b. In a separate subsequent step, mixture 5a, b is then converted smoothly into target compound 6 (Formula I with X=I) without prior separation. This final synthesis step, which contains the cleavage of the 3-ketal grouping and the silyl ether cleavage at C-17&bgr;, is preferably performed with a strong protonic acid such as trifluoroacetic acid or sulfuric acid.
The synthesis that is shown in the example of iodine for radical X of general formula I is also performed analogously for the production of bromide or the radiolabeled halides.
By the use of almost stoichiometric amounts of halogens, in particular when using radiohalogens, the process according to the invention is not only economical and environmentally safe, but it also makes possible the production of end compounds with high specific activity.
The substances of general formula I bind with high affinity to the androgen receptor despite a voluminous halogen substituent at the C-19 position.
Because of their biochemical and pharmacokinetic properties, the compounds according to the invention are extremely well suited for use in diagnostic processes.
Thus, e.g., iodide 6 (Formula I, X=I) with an IC
50
value of 57 nmol/l shows a slight weakening of the binding affinity in comparison to the reference standard (
3
H-methyltrienolone R 1881), but it remains in an order of magnitude that shows a large degree of specific binding to the human androgen receptor in the prostate tissue.
The graphic visualization of the prostate requires, however, not only a large degree of specific binding, but it also requires little or almost no binding to transport proteins in the serum (S. J. Brandes and J. E. Katzenellenbogen, Nucl. Med. Biol. 15, 53-67, 1988). Decisive serum protein for the transport of androgens is SHBG (steroid hormone binding globulin). The SHBG affinity of iodide 6 compared to the standard DHT (5&agr;-dihydrotestosterone) is reduced by a factor of 197. Thus, another requirement for the contrast-rich imaging of androgen-receptor-containing tissue is met.
The subject of the invention is therefore also the use of the compounds of general formula I as a diagnostic agent according to claims
9
and
10
. A preferred use is carried out for graphic visualization of the prostate and for early detection of pathophysiological changes thereof.
In addition to the use for diagnostic purposes, the non-labeled compounds of Formula I according to the invention are also valuable starting products for the production of new, unusual substituted steroids according to claim
11
.
The silylation of the 17&bgr;-hydroxy group of the C-19-halogen-substituted steroids of the androst-9(11)-ene series according to the invention thus results in a 17&bgr;-silyl ether of general formula Ia
in which X=halogen, selected from Br, I, and which represents an important intermediate product for the further synthesis in a so-called tandem process to the new compounds of general formula II. Moreover, the intermediate products of formula Ia are used for the production of the new 6&bgr;,19-cycloandrosta-4,9(11)-dienes of general formula III.
Shown in the example of 17&bgr;-(tert-butyltri
Fritzemeier Karl-Heinrich
Golde Roland
Neef Gunter
Badio Barbara P.
Millen White Zelano & Branigan P.C.
Schering AG
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