SELECTIVE ESTROGEN RECEPTOR DOWN-REGULATORS (SERDS)

Abstract

The present disclosure relates to orally bioavailable selective estrogen receptor down-regulators (SERDs) and the synthesis of the same. Further, the present disclosure teaches the utilization of the orally bioavailable selective estrogen receptor down-regulators (SERDs) in a treatment for proliferative diseases, including cancer, particularly breast cancer, and especially ER+ breast cancer.

Claims

1. At least one compound selected from the group consisting of Formula (I) through Formula (X).

2. The at least one compound of claim 1 for use in the treatment of a proliferative disease in a mammal in need thereof.

3. The at least one compound of claim 1 for use in the treatment of a cancer in a mammal in need thereof.

4. The at least one compound of claim 1 for use in modulating an estrogen receptor in a mammal in need thereof.

5. A composition comprising the at least one compound of claim 1 for use as a medicament.

6. The at least one compound of claim 1, wherein said compound is a structure of Formula (I): ##STR00039## R.sup.2=H, OH, Me, Cl, F, CF.sub.3 R.sup.3=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00040## wherein the R.sup.3 substituent point of attachment is on the substituent boron atom of R.sup.3, R.sup.4=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00041## and wherein the R.sup.4 substituent point of attachment is on the substituent boron atom of R.sup.4.

7. The at least one compound of claim 1, wherein said compound is a structure of Formula (II): ##STR00042## X=O, S, NH, OCH.sub.2, SCH.sub.2, NHCH.sub.2, CH.sub.2O, CH.sub.2S, or CH.sub.2NH.sub.2 ##STR00043## R.sup.2=H, OH, Me, Cl, F, CF.sub.3 R.sup.3=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00044## herein the R.sup.3 substituent point of attachment is on the substituent boron atom of R.sup.3, R.sup.4=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00045## and wherein the R.sup.4 substituent point of attachment is on the substituent boron atom of R.sup.4.

8. The at least one compound of claim 1, wherein said compound is a structure of Formula (III): ##STR00046## R.sup.2=H, OH, Me, Cl, F, CF.sub.3 R.sup.3=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00047## wherein the R.sup.3 substituent point of attachment is on the substituent boron atom of R.sup.3, R.sup.4=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00048## and wherein the R.sup.4 substituent point of attachment is on the substituent boron atom of R.sup.4.

9. The at least one compound of claim 1, wherein said compound is a structure of Formula (IV): ##STR00049## R.sup.1=H, OH, OMe, Me, Cl, F, CF.sub.3 R.sup.2=H, OH, OMe, Me, Cl, F, CF.sub.3 R.sup.3=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00050## wherein the R.sup.3 substituent point of attachment is on the substituent boron atom of R.sup.3.

10. The at least one compound of claim 1, wherein said compound is a structure of Formula (V): ##STR00051## R.sup.1=H, OH, OMe, Me, Cl, F, CF.sub.3 R.sup.2=H, OH, OMe, Me, Cl, F, CF.sub.3 R.sup.3=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00052## wherein the R.sup.3 substituent point of attachment is on the substituent boron atom of R.sup.3.

11. The at least one compound of claim 1, wherein said compound is a structure of Formula (VI): ##STR00053## R.sup.1=H, OH, OMe, Me, Cl, F, CF.sub.3 R.sup.2=H, OH, OMe, Me, Cl, F, CF.sub.3 R.sup.3=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00054## wherein the R.sup.3 substituent point of attachment is on the substituent boron atom of R.sup.3.

12. The at least one compound of claim 1, wherein said compound is a structure of Formula (VII): ##STR00055## R.sup.1=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00056## wherein the R.sup.1 substituent point of attachment is on the substituent boron atom of R.sup.1, R.sup.2=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00057## and wherein the R.sup.2 substituent point of attachment is on the substituent boron atom of R.sup.2.

13. The at least one compound of claim 1, wherein said compound is a structure of Formula (VIII): ##STR00058## R.sup.1=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00059## wherein the R.sup.1 substituent point of attachment is on the substituent boron atom of R.sup.1, R.sup.2=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00060## and wherein the R.sup.2 substituent point of attachment is on the substituent boron atom of R.sup.2.

14. The at least one compound of claim 1, wherein said compound is a structure of Formula (IX): ##STR00061## R.sup.2=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00062## wherein the R.sup.2 substituent point of attachment is on the substituent boron atom of R.sup.2. R.sup.3=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00063## and wherein the R.sup.3 substituent point of attachment is on the substituent boron atom of R.sup.3.

15. The at least one compound of claim 1, wherein said compound is a structure of Formula (X): ##STR00064## R.sup.1=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00065## wherein the R.sup.1 substituent point of attachment is on the substituent boron atom of R.sup.1. R.sup.2=H, OH, OMe, F, CF.sub.3, OCF.sub.3, Cl, Br, (HO).sub.2B, KF.sub.3B, NaF.sub.3B, ##STR00066## and wherein the R.sup.2 substituent point of attachment is on the substituent boron atom of R.sup.2.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0079] For a further understanding of the nature, objects, and advantages of the present disclosure, reference should be had to the following detailed description, read in conjunction with the following drawings, wherein like reference numerals denote like elements.

[0080] FIG. 1 shows the general synthetic scheme for preparation of SERD 1.

[0081] FIG. 2 shows the general synthetic scheme for preparation of SERD 2.

[0082] FIG. 3 shows the general synthetic scheme for preparation of SERD 3.

[0083] FIG. 4 shows the general synthetic scheme for preparation of SERD 4.

[0084] FIG. 5 shows the general synthetic scheme for preparation of SERD 5.

[0085] FIG. 6 shows the general synthetic scheme for preparation of SERD 6.

[0086] FIG. 7 shows the general synthetic scheme for preparation of SERD 7.

[0087] FIG. 8 shows the general synthetic scheme for preparation of SERD 8.

[0088] FIG. 9 shows the general synthetic scheme for preparation of SERD 9.

[0089] FIG. 10 shows the general synthetic scheme for preparation of SERD 10.

[0090] FIG. 11 shows the antiestrogenic effects of representative SERDs in T47D-KBluc cells.

[0091] FIG. 12 shows the effects of representative SERDs in MCF-7 E3 proliferation assay.

[0092] FIG. 13 shows the effect of SERD 4 on estrogen receptor (ER) expression. Western blots showing ER protein expression in MCF-7 cells dramatically downregulated by GDC-810, SERD 4, and GW-7604, respectively, in a dose-dependent manner.

[0093] FIG. 14 shows the effect of SERD 9 on estrogen receptor (ER) expression. Western blots showing ER protein expression dramatically downregulated by A. Fulvestrant, B. SERD 9 in a dose-dependent manner.

[0094] FIG. 15 shows the binding of SERD 4 and SERD 9 to estrogen receptor (ER) with high affinity.

[0095] FIG. 16 shows the oral bioavailability of SERD 4 and GW7604 in rats after a single dose of 10 mg/kg per os (p.o.).

[0096] FIG. 17 shows the oral bioavailability of SERD 9 in mice after a single dose of 5 mg/kg PO

[0097] FIG. 18 shows the efficacy of SERD 9 in mice bearing breast tumor xenograft when orally administered at two doses, as compared to that of fulvestrant administered by subcutaneous injection.

DETAILED DESCRIPTION

[0098] Before the subject disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments of the disclosure described below, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting. Instead, the scope of the present disclosure will be established by the appended claims.

[0099] In this specification and the appended claims, the singular forms a, an, and the include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs.

[0100] As used herein, the term minimize or reduce, or derivatives thereof, include a complete or partial inhibition of a specified biological effect (which is apparent from the context in which the terms minimize or reduce are used).

[0101] The compounds according to the disclosure can be prepared according to the schemes shown in FIGS. 1-10,

[0102] Table 1 below shows the cytotoxicity of the representative SERDs in various breast cancer cell lines.

TABLE-US-00001 MCF-7 MCF-7/TamR T47D/PKC BT474 IC.sub.50 (M) 4-Hydroxytamoxifen 0.0033 21.1 0.54 1.43 SERD 4 1.8 1.2 Not tested Not tested SERD 6 7.73 4.53 6.54 80.5 SERD 9 0.0032 0.044 0.37 0.39

[0103] The compounds according to the disclosure are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC of compounds of the present disclosure which possess a sufficiently basic or acidic functionality, may result in the formation of a salt, such as, in the case of a compound of the present disclosure which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present disclosure which is sufficiently acidic, an ammonium salt for example. Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of compounds of the present disclosure may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognize which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g., salt, free base, solvate, inclusion complex) of a compound of the present disclosure as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

[0104] Salts of the compounds of formulas (I) through (X) according to the disclosure can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.

[0105] All references cited in this specification are herein incorporated by reference as though each reference was specifically and individually indicated to be incorporated by reference. The citation of any reference is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such reference by virtue of prior invention.

[0106] It will be understood that each of the elements described above, or two or more together may also find a useful application in other types of methods differing from the type described above. Without further analysis, the foregoing will so fully reveal the gist of the present disclosure that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this disclosure set forth in the appended claims. The foregoing embodiments are presented by way of example only; the scope of the present disclosure is to be limited only by the following claims.

REFERENCES CITED

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