WO1993021145A1 - Composes non steroidiens a activite agoniste et antagoniste par rapport au recepteur de progesterone, et procedes d'utilisation - Google Patents

Composes non steroidiens a activite agoniste et antagoniste par rapport au recepteur de progesterone, et procedes d'utilisation Download PDF

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WO1993021145A1
WO1993021145A1 PCT/US1993/003909 US9303909W WO9321145A1 WO 1993021145 A1 WO1993021145 A1 WO 1993021145A1 US 9303909 W US9303909 W US 9303909W WO 9321145 A1 WO9321145 A1 WO 9321145A1
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cyclocymopol
compound
monomethyl ether
progesterone
methylidene
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PCT/US1993/003909
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English (en)
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I. Charles Pathirana
Tina S. Berger
Robert S. Stein
William Fenical
Todd K. Jones
Lawrence G. Hamann
Luc Farmer
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Ligand Pharmaceuticals Inc.
The Regents Of The University Of California
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Priority to EP93910811A priority Critical patent/EP0637296A4/fr
Publication of WO1993021145A1 publication Critical patent/WO1993021145A1/fr

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Definitions

  • This invention relates to intracellular receptors and ligands therefor. More specifically, this invention relates to compounds which are non-steroidal progesterone receptor antagonists or agonists, and methods for use of such compounds or ligands.
  • hormones certain small molecule, non-peptide hormones and similarly acting vitamins and vitamin metabolites (collectively hereinafter called “hormones”) modulate gene transcription by acting in concert with intracellular components, including intracellular receptors and discrete DNA promoter enhancer sequences known as hormone response elements (HREs).
  • hormone response elements HREs
  • ligands are synthesized in the body or may be taken in as a component of food. It has also been shown that compounds other than the natural ligands can act upon intracellular receptors to regulate hormone-responsive genes. For example, some natural product derivatives and synthetic compounds also function as ligands for these receptors.
  • Intracellular receptors form a class of structurally-related genetic regulators scientists have named "ligand dependent transcription factors.” Regulation of a gene by such factors requires both the intracellular receptor itself and a corresponding ligand which has the ability to selectively bind to the intracellular receptor in a way that affects gene activity. Until bound by a ligand, the intracellular receptor is unable to exert an effect on the gene. Hormone or other ligand molecules in the fluid surrounding a cell pass through the outer cell membrane by passive diffusion. Once inside the cell, the ligand binds to specific intracellular receptor proteins, creating a ligand/receptor complex. The binding of the ligand to its receptor induces a change in the shape of the intracellular receptor. This conformational change is believed to expose regions of the intracellular receptor that permit the intracellular receptor/1igand complex to bind to a specific subset of genes present in the cell' s DNA in the cell nucleus.
  • the blueprint to build specific proteins is encoded in the DNA sequence of each gene. This blueprint is copied in a process referred to as "transcription,” to give rise to the actual template for the production of specific proteins, messenger RNA or "mRNA". The mRNA then moves from the cell's nucleus into the cytoplasm and is translated, which results in the production of proteins encoded in the mRNA. Accordingly, a reduction in the transcription of mRNA reduces the production of the specific proteins.
  • the intracellular receptor/ligand complex binds to the specific site on the DNA, it alters the amount of the protein encoded by the gene that the cell is directed to produce, by altering the amount of mRNA transcribed by that gene.
  • a ligand which binds an intracellular receptor and mimics the effect of the natural ligand is referred to as an "agonist” ligand.
  • a ligand that inhibits the effect of the hormone is called an "antagonist.”
  • Intracellular receptors are referred to as "ligand-dependent transcription factors" because their activity is dependent upon the binding of their hormonal or other ligands, which are necessary to drive the intracellular receptor into its active conformation.
  • the intracellular receptors form a large family of proteins that are closely related in structure. They are important drug targets, and many drugs currently on the market are ligands for these receptors. Not surprisingly, the structural similarity of the receptors often results in cross-reactivity between a drug and receptors other than its target. It is apparent, therefore, that there is a need to find alternative ligands (agonists and antagonists) which are readily available for therapeutic administration, have added specificity for particular receptors, and have increased activity.
  • Ligands to the progesterone receptor are known to play an important role in gynecological medicine, cancer, and other health care problems of women. Its natural ligand, the female steroid progesterone, and synthetic analogues are, for example, used in birth control formulations. Antagonists to progesterone are useful in treating chronic disorders such as certain forms of hormone dependent cancer of the breast, ovaries, and endometrium (the lining of the uterus), and in treating uterine fibroids. Endometriosis, a leading cause of infertility in women, currently treated in early stage development by surgery, is also amenable to treatment with progesterone.
  • cymopol A group of prenylated bromohydroquinones, called collectively cymopols, has been isolated and identified by several investigators using as a starting material the green marine alga Cymopolia barbata (L.) Lamouroux (Dasycladaceae).
  • cymopol C 16 H 21 BrO 2
  • cymopol is a crystalline phenol which has a bromogeranyl-hydroquinone or brominated monoterpene-quinol structure.
  • Cyclocymopol [1-bromo-3-(4-bromo-2,5-dihydroxybenzyl)-2,2-dimethyl-4 methylene cyclohexane] and its monomethyl ether have also been obtained from C. barbata. See Högberg et al., supra. As described in McConnell et al., Phytochemistry, Vol. 21, No. 8, pp. 2139-41 (1982), C. barbata contains a mixture of optically active diastereomers of cyclocymopol, C 16 H 20 Br 2 O 2 , and cyclocymopol monomethyl ether, C 17 H 22 Br 2 O 2 , having the following structures:
  • Wall et al. J. Nat. Prod., Vol. 52, No. 5, pp. 1092-99 (1989), described additional diastereomeric cymopol compounds (cymobarbatol and 4-isocymobarbatol) which were determined to be highly active antimutagens.
  • Wall et al. reported obtaining pure cymobarbatol compounds, but were unable to obtain stable cyclocymopol fractions.
  • the forms of cyclocympol and cyclocymopol monomethyl ether obtained by Högberg et al., supra, were pure forms of formulae lb and 2b above.
  • the present invention is directed to compounds, compositions, and methods for modulating processes mediated by progesterone receptors. More particularly, the invention relates to non-steroidal compounds which are high affinity, high specificity ligands for progesterone receptors. These compounds exhibit progesterone receptor agonist or progesterone receptor antagonist activity, and modulate processes mediated by progesterone receptors. Accordingly, the invention also relates to methods for modulating processes mediated by progesterone receptors employing the compounds disclosed. Examples of compounds used in and forming part of the invention include cyclocymopol derivatives and purified diastereomers thereof, synthetic cyclocymopol analogs, and semisynthetic derivatives of natural cyclocymopols. Pharmaceutical compositions containing the compounds disclosed are also within the scope of this invention. Also included are methods for identifying or purifying progesterone receptors by use of the compounds of this invention.
  • Figure 1 presents the proton NMR spectrum for the individual pure 3R (panel a) and 3S (panel b) diastereomeric acetates of cyclocymopol monomethyl ether.
  • Figure 2 presents activation profiles for analysis of progesterone receptor activation by a cyclocymopol monomethyl ether diastereomeric mixture (compound SO-44), by a pure 3S diastereomeric acetate (compound SO-51), and by a pure 3R diastereomeric acetate (compound SO-52).
  • agonist dose response is shown in panel a
  • antagonist dose response in panel b.
  • Figure 3 presents activation profiles for analysis of progesterone receptor activation by (3R)-cyclocymopol monomethyl ether (compound SO-53).
  • 3R 3R-cyclocymopol monomethyl ether
  • agonist dose response is shown in panel a
  • antagonist dose response is shown in panel b.
  • Figure 4 presents activation profiles for analysis of progesterone receptor activation by (35)-cyclocymopol monomethyl ether (compound SO-54) and its acetate (compound SO-51).
  • agonist dose response is shown in panel a
  • antagonist dose response is shown in panel b.
  • Figure 5 presents activation profiles for analysis of progesterone receptor activation by (3R)-cyclocymopol monomethyl ether (compound SO-9).
  • 3R 3R-cyclocymopol monomethyl ether
  • FIG. 5 presents activation profiles for analysis of progesterone receptor activation by (3R)-cyclocymopol monomethyl ether (compound SO-9).
  • compound SO-9 3R-cyclocymopol monomethyl ether
  • Figure 6 presents activation profiles for analysis of glucocorticoid receptor activation by (3R)-cyclocymopol monomethyl ether (compound SO-09).
  • 3R glucocorticoid receptor activation by (3R)-cyclocymopol monomethyl ether
  • agonist dose response is shown in panel a
  • antagonist dose response is shown in panel b.
  • Figure 7 presents profiles of displacement of 3 H-labeled progesterone by cyclocymopol monomethyl ether diastereomers (panels a and b), and of the 3 H-labeled progesterone agonist R5020 by RU486 and by a (3R)-cyclocymopol monomethyl ether compound (SO-9).
  • Figure 8 presents profiles for analysis of progestrone binding for RU486 and (3R)-cyclocymopol monomethyl ether (compound SO-9).
  • Figure 9 presents profiles of the displacement of 3 H-labeled dexamethasone from glucocorticoid receptor for several compounds.
  • Figure 10 presents profiles showing the functional activities of cyclocymopol analogues in T47D cells.
  • Panel a shows ligand dependent induction of alkaline phosphatase in T47D cells by RTJ486 and cyclocymopol monomethyl ether diastereomers.
  • Inhibition by (3R)-cyclocymopol monomethyl ether (SO-53) of progesterone-stimulated induction of alkaline phosphatase is shown in panel b, and of R5020 stimulated induction in panel c.
  • Figure 11 presents profiles showing the inhibition by RU486 of induction of alkaline phosphatase in T47D cells by (35)-cyclocymopol monomethyl ether (SO-54) in panel a and by its acetate (SO-51) in panel b.
  • Cyclocymopols useful in this invention are defined as those having the formulae:
  • X is carbon, oxygen, or nitrogen
  • R 1 is R 17 , -OR 17 , -N(R 17 ) (R 17 ,), -SR 17 , fluorine, chlorine, bromine, or -NO 2 ;
  • R 17 and (R 17 ,), each independently, are hydrogen, saturated or unsaturated C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 5 -C 7 aryl, or C 7 aralkyl, said alkyl groups being branched or straight-chain;
  • R 3 is R 17 or -OR 17 ;
  • R 4 is hydrogen, -OR 17 , -OC (O) R 17 , -OC (O) OR 17 ,
  • R 5 is hydrogen or OR 17 ;
  • R 6 is R 17 ;
  • R 7 and R 8 are R 18 , or R 7 and R 8 together are a carbocyclic 3-8 member ring;
  • R 13 and R 14 are -OR 17 or R 18 , except when R 13 is attached to an sp 2 carbon atom in the ring, then R 14 is not present and R 13 is -OR 17 or R 18 ;
  • R 15 and R 16 are R 18 or OR 17 , or R 15 and R 16 together are -CH 2 -O- forming an epoxide, or R 15 and
  • alkyl refers to straight-chain, branched-chain, cyclic structures, and combinations thereof.
  • aryl refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted, being preferably phenyl or phenyl substituted by one to three substituents, such substituents being advantageously lower alkyl, hydroxy, lower alkoxy, lower acyloxy, halogen, cyano, trihalomethyl, lower alcylamino, or lower alkoxycarbonyl.
  • Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are carbon atoms.
  • Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and optionally substituted naphthyl groups.
  • Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and suitable heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
  • aralkyl refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl and the like, and may be optionally substituted.
  • the cyclocymopol compounds of this invention bind selectively to the progesterone receptor.
  • the non-synthetic cyclocymopol compounds have agonist or antagonist activity depending on their stereoisomeric form.
  • the 3 ⁇ or 3R diastereomer of cyclocymopol monomethyl ether has progesterone receptor antagonist activity
  • the 3 ⁇ or 3Sdiastereomer of cyclocymopol monomethyl ether has progesterone receptor agonist activity.
  • other cyclocymopol analogs or derivatives have been found to predominently exhibit progesterone receptor antagonist activity regardless of their stereoisomeric form.
  • the co-transfection assay provides a method for identifying functional ligands (either agonists which mimic, or antagonists which inhibit, the effect of hormones) for ligand-responsive receptor proteins.
  • the co-transfection assay provides a mechanism to evaluate ability of a compound to function as an agonist or antagonist of the activity modulated by an intracellular receptor.
  • the co-transfection assay mimics an in vivo system in the laboratory.
  • a cloned gene for an intracellular receptor is introduced by transfection (a procedure to induce cells to take up foreign genes) into a background cell substantially devoid of endogenous intracellular receptors. This introduced gene directs the recipient cells to make the intracellular receptor protein.
  • a second gene is also introduced (co-transfected) into the same cells in conjunction with the intracellular receptor gene. This second gene functions as a reporter for the transcription-modulating activity of the target intracellular receptor.
  • the reporter acts as a surrogate for the products normally expressed by a gene under control of the target receptor and its natural hormone.
  • a preferred reporter gene is one which expresses the firefly enzyme luciferase.
  • the co-transfection assay can detect small molecule agonists or antagonists of target intracellular receptors. Exposing the cells to an agonist ligand increases reporter activity in the transfeeted cells that can be conveniently measured, reflecting ligand-dependent, intracellular receptor-mediated increases in reporter transcription. To detect antagonists, the co-transfection assay is carried out in the presence of a constant concentration of an agonist known to induce a defined reporter signal. Increasing concentrations of a test antagonist will decrease the reporter signal. The co-transfection assay is therefore useful to detect both agonists and antagonists of specific intracellular receptors. It determines not only whether a compound interacts with a particular intracellular receptor, but also whether this interaction mimics (agonizes) or blocks (antagonizes) the effects of the natural regulatory molecules on target gene expression.
  • Co-transfected cells are exposed to a medium to which is added the potential ligand that is being evaluated. If the candidate ligand diffuses into the cell and binds to the receptor and the resulting complex functions as an agonist, it binds to the co-transfected reporter gene and initiates transcription.
  • that gene is one that expresses, for example, luciferase
  • luciferase is produced which catalyzes a light-emitting reaction with its substrate luciferin.
  • the amount of light produced relative to the concentration of candidate ligand used in the assay provides a measure of the potency and efficacy of the compound tested.
  • Antagonist activity is evaluated by adding the candidate ligand and a known agonist to the co-transfected cells. Suppression of agonist-induced luciferase production by the candidate compound, and hence the amount of light produced, indicates the candidate ligand is an antagonist.
  • CV-1's Cultured monkey kidney cells
  • the receptor cDNA was introduced in a mammalian expression vector under the control of the Rous Sarcoma virus LTR. These vectors provide for the efficient production of the progesterone receptor in these cells, which do not normally express this receptor gene.
  • a reporter vector was also transfected, containing a firefly luciferase gene under the control of the hormone-responsive promoter. Addition of control hormone
  • the cyclocymopol compounds were tested at eight concentrations (10 -4 to 10 -11 M) for the generation of a full dose response curve, and were compared to the progesterone control hormone response. A total of three replicates per concentration point were tested for each compound, and the EC 50 was calculated for each positive response. Both agonist and antagonist activity for each test compound was determined in parallel. In the antagonist assay, 10 -8 M progesterone was added to the media immediately prior to the addition of the cyclocymopol test compounds at the eight concentrations.
  • the assays showed a 3R (3 ⁇ ) and 3S (3 ⁇ ) diastereomer mixture of cyclocymopol monomethyl ether (designated compound SO-44) to have progesterone receptor antagonist activity, as shown in Figure 2.
  • agonist dose response is shown in panel a, and antagonist dose response in panel b.
  • the corresponding purified 3R diastereomeric acetate designated SO-52
  • a purified 3S diastereomeric acetate designated SO-51
  • Compound SO-9 and the identical compound from a separate preparation, compound SO-53 exhibit progesterone receptor antagonist activity (see Figure 5), and were tested for cross reactivity with the other known intracellular receptor classes, e.g., glucocorticoid, mineralocorticoid, androgen, estrogen, and retinoic acid.
  • Compound SO-9 was also tested with orphan receptors (which are receptors whose natural ligand is unknown). The compound was found not to cross-react with any of the other receptors, which demonstrates that activity was limited to the progesterone receptor.
  • Figure 6 is illustrative, and shows that compound SO-9 demonstrated neither agonist nor antagonist activity with the glucocorticoid receptor, dexamethasone.
  • the 3R and 3S diastereomeric acetates of cyclocymopol monomethyl ether were also individually tested for cross reactivity with the other known intracellular receptor classes. This testing showed the 3R diastereomer to have slight agonist activity with the glucocorticoid receptor. No antagonist activity was detected with either compound.
  • a plasmid which expresses progesterone receptor was transfected into CV-1 cells by the method of calcium phosphate precipitation. After six hours, the cells were washed and incubated at 37°C with 95% O 2 /5% CO 2 for 40 hours prior to harvest.
  • Progesterone receptor antagonists such as RU486, can increase the specific binding of progesterone to its ligand binding site. This enigma was also observed upon performing binding studies with 3 H-progesterone in the presence of compound SO-9. As shown in Figure 8, this compound significantly increased the apparent Bmax of 3 H-progesterone.
  • T47D cells have proven to be a particularly useful model to investigate the molecular actions of sex steroids because they contain endogenous functional receptors for, and respond to, progestins, and their respective antagonists. Moreover, these cells contain exceptionally high titers of progesterone receptors and are exceptionally sensitive to the actions of progestins in a manner quite similar to their actions in normal and neoplastic mammary epithelial cells.
  • progestins induce de novo synthesis of a plasma-associated alkaline phosphatase, which has been reported to be similar, if not identical, to the alkaline phosphatase present in the normal breast and human milk.
  • T47D cells were cultured in RPMI 1640 medium fortified with 10% fetal bovine serum, 2 mM glutamine, 0.2 ug/ml bovine insulin and, 0.05 mg/ml gentamicin. Cells were plated in 100-mm plates in medium; 48 hours later they were changed to medium containing 2% charcoal-treated serum with or without test compounds in a final ethanol concentration of 0.1%. For routine induction of alkaline phosphatase, cells were treated for three days with two media changes and harvested as described below.
  • cytosol Cells were collected with a rubber policeman into phosphate-buffered saline, pelleted, and lysed with TPSG buffer (0.2% Triton X-100 containing 10 mM sodium phosphate pH-7.4, 0.1 M sucrose, and 10% glycerol) at 0° C for 30 min with vigorous vortex mixing every 5 min. Nuclei were sedimented at 2500 rpm, and the supernatant was saved as cytosol. The protein content of the cytosol was assayed by the method of Bradford.
  • (3R)-cyclocymopol monomethyl ether could function as a progesterone receptor antagonist, the effects of increasing concentrations of this compound on R5020-induced alkaline phosphatase activity were quantified in T47D cells.
  • 3R)-cyclocymopol monomethyl ether (compound SO-53) is an effective antagonist of the progesterone mimic.
  • 3R)-cyclocymopol monomethyl ether compound SO-53 attenuated this induction in a concentration-dependent manner.
  • progesterone agonist (35)-cyclocymopol monomethyl ether (compound SO-54), and its acetate (SO-51)
  • progesterone antagonist RU486, as shown in Figure 11.
  • 3R- cyclocymopol monomethyl ether (compound SO-53) functioned as a progesterone receptor antagonist and attenuated the effects of progesterone in a concentration- dependant manner.
  • Synthetic and semisynthetic cyclocymopol analogs have been prepared which also have activity for the intracellular receptor for progesterone.
  • Representative analogs of the present invention are prepared according to the following illustrative synthetic schemes and illustrative examples.
  • reaction mixture was allowed to stir at 0°C for 60 min, at which time TLC analysis indicated complete consumption of starting material, and the formation of a less polar product (Rf 0.81, 2:1 hexanes/ethyl acetate).
  • Hexane 100 mL was then added, and the contents of the flask were transferred to a separatory funnel containing 50 mL of saturated aqueous NH 4 Cl, rinsing with an additional 50 mL hexane and 10 mL water.
  • the layers were separated, and the organic phase was washed with 20 mL 10% Na 2 S 2 O 3 , dried over Na 2 SO 4 , and concentrated under diminished pressure.
  • the reaction mixture was then cooled to 0°C before the cautious addition of 50 mL water, and the contents of the flask were then poured into a 500 mL Erlenmeyer flask containing 150 mL ice-cold 10% H 2 SO 4 .
  • the mixture was then extracted with ether (2 ⁇ 200 mL), and the combined organics were washed successively with water (100 mL), and saturated aqueous NaHCO 3 (100 mL), dried over Na 2 SO 4 , and concentrated under diminished pressure to give 6.05 g (quantitative) of the dimethylenone (Rf 0.55, 2:1 hexane/ethyl acetate).
  • This compound was prepared from 3-ethoxy-6, 5,5-trimethylcyclohex-2-en-1-one (9) (1.60 g, 8.80 mmol) in the manner previously described for enone 8, yielding 1.03 g (85%) of the methylated enone as a colorless oil.
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ 0.90 and 1.07 (2s, 2 ⁇ 3H, geminal- CH 3 's), 1.10 (d, 3H, CHCH 3 ), 5.96 (dd, 1H, 2-H), 6.16 ppm (dd, 1H, 3-H).
  • This compound was prepared from 6-[2'-(tert-butyl)dimethylsilyloxy-4'-bromo-5'-methoxyphenyl]methyl-5,5-dimethylcyclohex-2-en-1-one (11) (0.075 g, 0.166 mmol) in the manner previously described for olefin (13), with the following procedural changes necessitated by the incompatibility of structural features particular to this substrate and the typical synthetic methodology.
  • Tetra-n-butylammonium fluoride (0.20 mL of a 1.0 M solution in THF, 0.20 mmol, 1.20 equiv) was added, and the mixture was allowed to warm to room temperature. The contents of the flask were then poured into a separatory funnel containing 30 mL ethyl acetate and 10 mL 1.0 M NaHSO 4 , the layers were separated, and the organic phase was washed with 10 mL brine, dried over Na 2 SO 4 , and concentrated under diminished pressure.
  • the crude material thus obtained was immediately carried on to the next step by transferring to a 10 mL nalgene vial containing 2-3 mL THF, and 0.3 mL premade HF/pyridine complex was added. After stirring overnight at room temperature, the reaction mixture was worked up in the usual manner, and purification by flash column chromatography (silica gel, hexane/ethyl acetate, gradient elution) afforded 38.3 mg (64%) of the desired acetoxydiene as a colorless, oily solid.
  • This compound was prepared from 1-methylidene-6-(2'-acetoxy-4'-bromo-5'-methoxyphenyl)methyl-3,5,5-trimethylcyclohex-2-ene (17) (6.8 mg, 0.017 mmol) in the manner previously described for phenolic diene 15, affording 5.8 mg (96%) of the phenolic diene as a colorless, oily solid.
  • This compound was prepared from 4,5,5-trimethylcyclohex-2-en-1-one (10) (169 mg, 1.22 mmol) in the manner previously described for benzylated enone 11, affording 0.337 g (59%) of the less polar trans diastereomer as a colorless, oily solid, along with 22 mg (4%) of the more polar cis diastereomer as a colorless, oily solid, separable by flash column chromatography. The relative stereochemistry of each respective diastereomer was confirmed by nOe NMR experiments.
  • This compound was prepared from trans-6-[2'-(tert-butyl)dimethylsilyloxy-4'-bromo-5'-methoxyphenyl]methyl-4,5,5-trimethylcyclohex-2-en-1-one (19) (150 mg, 0.321 mmol) in the manner previously described for benzylated ketone 12, affording 0.149 g (99%) of the trans ketone as a colorless, oily solid.
  • This compound was prepared from trans-6-[2'-(tert-butyl)dimethylsilyloxy-4'-bromo-5'-methoxyphenyl]methyl-4,5,5-trimethylcyclohex-2-en-1-one (19) (70.0 mg, 0.15 mmol) in the manner previously described for acetoxy-diene 14, affording 46.8 mg (79%) of the acetoxy-diene as a colorless oil.
  • This compound was prepared from 5,5-dimethyleyelohex-2-en-1-one (8) (0.600 g, 4.83 mmol) and p-nitrobenzyl bromide (1.581 g, 7.32 mmol) in the manner described for the synthesis of enone 11, affording 627 mg (50%) of the nitro-enone as a pale yellow oil.
  • This compound was prepared from 6-(4'-nitrophenyl)methyl-5,5-dimethylcyclohex-2-en-1-one (24) (133 mg, 0.514 mmol) in the manner previously described for the synthesis of olefin 13, with the following procedural changes. Three equivalents of (trimethyl) silylmethyllithium were used, and the subsequent elimination step required 48 h to go to completion, affording 120 mg (86%) of the nitrodiene as a colorless oil.
  • This compound was prepared in three steps from cyclohexanone and 2-(tert-butyl)dimethylsilyloxy-4-bromo-5-methoxybenzyl bromide (6) as previously described for the synthesis of olefin 13, to give the desired olefin in three steps in 13.5% overall yield as a colorless oil.
  • This compound was prepared from (35)-2'-(tert-butyl)dimethylsilyloxycyclocymopol monomethyl ether (25.0 mg, 0.047 mmol) in the manner described for the synthesis of the cyclocymopol derivative 27, affording 5.5 mg (35%) of the debromophenol as a colorless oil, along with the remainder of the mass balance as deprotected starting material.
  • the 400 MHz 1 H NMR spectrum and TLC elution properties of this compound were identical to those reported for the racemic analog 13. (This compound is also designated Compound "G" below.)
  • N-methyl-N-(2-pyridyl) formamide (28.5 mg, 25 ⁇ L, 0.21 mmol, 2.1 equiv) was added as a solution in 1 mL THF, and the reaction mixture was allowed to stir for 30 min before quenching with 1 mL 1:4 acetic acid/methanol. The reaction mixture was then partitioned between hexane and 1.0 M NaHSO 4 , washed with pH 7 buffer, and the resultant organic phase was dried over Na 2 SO 4 and concentrated under diminished pressure.
  • This compound was prepared from (3R)-2'-(tert-butyl)dimethylsilyloxycyclocymopol monomethyl ether (15.2 mg, 0.029 mmol) and iodine (300 ⁇ L of a 0.25 M solution in benzene, 0.075 mmol, 2.6 equiv) in the manner previously described for cyclocymopol derivative 29, affording 9.2 mg (70%) of the iodocyclocymopol derivative as a colorless oily solid.
  • Efficacy is reported as the % maximal response observed for each compound relative to RU-486, a compound known to exhibit progesterone receptor antagonist activity. Also reported in Tables 1 and 2 for each compound is its potency or IC 50 (which is the concentration (nM), required to reduce the maximal response by 50%), and its binding activity for the progesterone receptor.
  • the synthetic cyclocymopol compounds were also individually tested for cross-reactivity with the other known intracellular receptor classes. This testing showed the compounds not to have activity with the glucocorticoid receptor, in contrast to RU-486 which shows significant activity for that receptor. Some derivative compounds were found to exhibit slight activity for the androgen receptor.
  • the co-transfection assay provides a functional assessment of the ligand being tested as either an agonist or antagonist of the specific genetic process sought to be affected, and mimics an in vivo system in the laboratory.
  • Ligands which do not react with other intracellular receptors, as determined by the co-transfection assay, can be expected to result in fewer pharmacological side effects. Because the co-transfection assay is conducted in living cells, the evaluation of a ligand provides an early indicator of the potential toxicity of the candidate ligand at concentrations where a therapeutic benefit would be expected.
  • non-steroid progesterone receptor antagonist and agonist compounds disclosed can be readily utilized in pharmacological applications where progesterone receptor antagonist or agonist activity is desired, and where it is desired to minimize cross reactivities with other related intracellular receptors.
  • In vivo applications of the invention include administration of the disclosed compounds to mammalian subjects, and in particular to humans.
  • the compounds of the present invention are small molecules which are relatively fat soluble or lipophilic and enter the cell by passive diffusion across the plasma membrane. Consequently, these ligands are well suited for administration orally as well as by injection. Upon administration, these ligands can selectively activate progesterone receptors and thereby modulate processes mediated by these receptors.
  • compositions of this invention are prepared in conventional dosage unit forms by incorporating an active compound of the invention, or a mixture of such compounds, with a nontoxic pharmaceutical carrier according to accepted procedures in a nontoxic amount sufficient to produce the desired pharmacodynamic activity in a mammalian and in particular a human subject.
  • the composition contains the active ingredient in an active, but nontoxic, amount selected from about 5 mg to about 500 mg of active ingredient per dosage unit. This quantity depends on the specific biological activity desired and the condition of the patient.
  • the pharmaceutical carrier or vehicle employed may be, for example, a solid or liquid.
  • a variety of pharmaceutical forms can be employed.
  • the preparation when using a solid carrier, can be plain milled micronized in oil, tableted, placed in a hard gelatin or enteric-coated capsule in micronized powder or pellet form, or in the form of a troche, lozenge, or suppository.
  • the preparation when using a liquid carrier, can be in the form of a liquid, such as an ampule, or as an aqueous or nonaqueous liquid suspension.
  • the following examples provide illustrative pharmacological composition formulations: Example 23
  • Hard gelatin capsules are prepared using the following ingredients:
  • the above ingredients are mixed and filled into hard gelatin capsules in 250 mg quantities.
  • a tablet is prepared using the ingredients below:
  • Tablets each containing 60 mg of active ingredient, are made as follows:
  • the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of PVP is mixed with the resultant powders, which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at
  • SCMS magnesium stearate
  • talc previously passed through a No. 60 mesh U.S. sieve, and then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Suppositories each containing 225 mg of active ingredient, may be made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of normal 2g capacity and allowed to cool.
  • An intravenous formulation may be prepared as follows:
  • the compound is dissolved in the glycerol and then the solution is slowly diluted with isotonic saline.
  • the solution of the above ingredients is then administered intravenously at a rate of 1 ml per minute to a patient.
  • the compounds of this invention also have utility when labeled as ligands for use in assays to determine the presence of progesterone receptors. They are particularly useful due to their ability to selectively activate progesterone receptors, and can therefore be used to determine the presence of such receptors in the presence of other related receptors.
  • these compounds can be used to purify samples of progesterone receptors in vitro .
  • Such purification can be carried out by mixing samples containing progesterone receptors with one or more of the cyclocymopol and derivative compounds disclosed so that the compound (ligand) binds to the receptor, and then separating out the bound ligand/receptor combination by separation techniques which are known to those of skill in the art. These techniques include column separation, filtration, centrifugation, tagging and physical separation, and antibody complexing, among others.

Abstract

Des composés non stéroïdiens constituant des ligands à haute affinité et à haute spécificité pour les récepteurs de progestérone sont décrits. Ces composés comprennent des dérivés synthétiques de cyclocymopol et de ses diastéréomères, un éther de (3R)-cyclocymopol monométhyle pur du point de vue spectroscopique et chromatographique, qui agit comme un antagoniste de récepteur de progestérone, et un éther de (3S)-cyclocymopol monométhyle pur du point de vue spectroscopique et chromatographique qui agit comme un agoniste de récepteur de progestérone. L'invention se rapporte également à des procédés d'utilisation des composés décrits pour moduler des processus induits par des récepteurs de progestérone et pour traiter des patients nécessitant une thérapie par un agoniste ou un antagoniste de récepteur de progestérone.
PCT/US1993/003909 1992-04-21 1993-04-21 Composes non steroidiens a activite agoniste et antagoniste par rapport au recepteur de progesterone, et procedes d'utilisation WO1993021145A1 (fr)

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WO1995011215A1 (fr) * 1993-10-21 1995-04-27 Ligand Pharmaceuticals Incorporated Antagonistes non steroides pour le recepteur de l'androgene
LT4291B (lt) 1994-12-23 1998-02-25 Schering Aktiengesellschaft Junginiai, veikiantys prieš progesteroną ir estrogeną, skirti bendrai moterų kontracepcijai
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011215A1 (fr) * 1993-10-21 1995-04-27 Ligand Pharmaceuticals Incorporated Antagonistes non steroides pour le recepteur de l'androgene
US5677336A (en) * 1993-10-21 1997-10-14 Ligand Pharmaceuticals Incorporated Non-steroid androgen receptor antagonist compounds and methods
LT4291B (lt) 1994-12-23 1998-02-25 Schering Aktiengesellschaft Junginiai, veikiantys prieš progesteroną ir estrogeną, skirti bendrai moterų kontracepcijai
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

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AU4117093A (en) 1993-11-18
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MX9302312A (es) 1994-06-30
CA2133325A1 (fr) 1993-10-28

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