WO2020190780A1 - Inhibiting cyclic amp-responsive element-binding protein (creb) - Google Patents
Inhibiting cyclic amp-responsive element-binding protein (creb) Download PDFInfo
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- WO2020190780A1 WO2020190780A1 PCT/US2020/022783 US2020022783W WO2020190780A1 WO 2020190780 A1 WO2020190780 A1 WO 2020190780A1 US 2020022783 W US2020022783 W US 2020022783W WO 2020190780 A1 WO2020190780 A1 WO 2020190780A1
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- NOUKMOKAEKAWKS-FSEQIFNCSA-N C[C@@H](CC1)N(C(OC)=O)c(cc2)c1c1c2[n]([C@H](CCC2)C[C@@H]2C(O)=O)c([C@@H](c2cc(F)ccc2OC)O)n1 Chemical compound C[C@@H](CC1)N(C(OC)=O)c(cc2)c1c1c2[n]([C@H](CCC2)C[C@@H]2C(O)=O)c([C@@H](c2cc(F)ccc2OC)O)n1 NOUKMOKAEKAWKS-FSEQIFNCSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
Definitions
- the present disclosure relates to solid and salt forms of compounds and methods for the inhibition of p300 (also known as EP300 and KAT3B) binding protein of adenovirus El A protein, and/or cyclic AMP- responsive element-binding protein (CREB) (CBP, also known as KAT3A), a cellular paralog of p300.
- p300 also known as EP300 and KAT3B
- CBP cyclic AMP- responsive element-binding protein
- KAT3A cyclic AMP- responsive element-binding protein
- CBP/p300 are lysine acetyltransferases that catalyze the attachment of an acetyl group to a lysine side chain of histones and other protein substrates.
- p300 also known as EP300 and KAT3B
- CREB cyclic AMP-responsive element-binding protein binding protein
- CBP also known as KAT3A
- CBP/p300 share extensive sequence identity and functional similarity and are often referred to as CBP/p300.
- CBP/p300-catalyzed acetylation of histones and other proteins is pivotal to gene activation. Heightened p300 expression and activities have been observed in advanced human cancers such as prostate and in human primary breast cancer specimens. Chemical inhibition of CBP/p300 that possesses intrinsic acetyltransferase enzymatic activity is more feasible than blocking transcription factors with small molecules, as discovery of chemical inhibitors of transcription factors has proven extremely challenging.
- the salt is an acid addition salt selected from hydrochloric acid, p- toluenesulfonic acid, benzenesulfonic acid, and sulfuric acid.
- Figure 1.A is a table of the parameters used for X-ray powder diffraction analysis of the solid forms disclosed herein.
- Figure l.B is a table of the parameters used for thermogravimetric and differential scanning calorimetry analysis of the solid forms disclosed herein.
- Figure l.C is a table of the parameters used for dynamic vapor sorption analysis of the solid forms disclosed herein.
- Figure l.D is a table of the parameters used for the HPLC analysis of the amorphous free base compound disclosed herein.
- Figure 2 is a table of the X-ray powder diffraction peaks with a greater than 5% relative intensity of the type A, B, and C hydrochloric acid addition salt forms disclosed herein.
- Figure 3 is a table of the X-ray powder diffraction peaks with a greater than 5% relative intensity of the type A and B p-toluenesulfonic acid addition slat forms disclosed herein.
- Figure 4 is a table of the X-ray powder diffraction peaks with a greater than 5% relative intensity of the type A benzenesulfonic acid addition salt form disclosed herein.
- Figure 5 is a table of the X-ray powder diffraction peaks with a greater than 5% relative intensity of the type A sulfuric acid addition salt form disclosed herein.
- Figure 6 is a table of the X-ray powder diffraction peaks with a greater than 5% relative intensity of the crystalline freeform type A solid form disclosed herein.
- Figure 7 is a table of the kinetic solubility assessments of the type A hydrochloric acid addition salt form, type B p-toluenesulfonic acid addition salt form, and crystalline freeform type A solid form disclosed herein.
- the present disclosure relates to salts and solid forms of compounds and compositions that are capable of modulating the activity of the CBP/p300 family bromodomains.
- the disclosure features methods of treating, preventing or ameliorating a disease or disorder in which CBP/p300 bromodomains play a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), (II), or Group A, or a pharmaceutically acceptable salt thereof.
- the methods of the present disclosure can be used in the treatment of a variety of CBP/p300 bromodomain dependent diseases and disorders by inhibiting the activity of a CBP/p300 bromodomains. Inhibition of CBP/p300 bromodomains provides a novel approach to the treatment of diseases including, but not limited to, cancer.
- Salt and crystalline solid forms of drug compounds can confer several distinct advantages over amorphous or non-solid forms, including: 1) increased solubility, dissolution rates, and bioavailability for poorly soluble compounds, 2) decreased solubility for use in extended release formulations, diminished Ostwald ripening, or to accomplish taste masking for particularly soluble compounds, 3) improved physical properties such as melting temperature, hygroscopicity, and mechanical properties, 4) improved chemical stability and compatibility with pharmaceutical excipients, and 5) improved compound purity, chiral resolution of distinct stereoisomers, and filterability.
- novel CBP Inhibitor Compounds are provided. Unless otherwise indicated, “CBP Inhibitor Compound” as used herein refers to a compound having a detectable CBP IC50 value of 1 micromolar or lower when tested according to the HTRF biochemical Assay Protocol of Example 3.
- the compounds of Formula (I), (II), and Group A may contain one or more stereocenters, and, therefore, exist in different stereoisomeric forms. It is intended that unless otherwise indicated all stereoisomeric forms of the compounds of Formula (I), (II), and Group A, as well as mixtures thereof, including racemic mixtures, form part of the present disclosure.
- the present disclosure embraces all geometric and positional isomers. For example, if a compound of Formula (I), (II), or Group A incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure.
- Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound.
- the compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry.
- the assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.
- Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
- Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. , chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g. , hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
- an appropriate optically active compound e.g. , chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
- some of the compounds of Formula (I), (II), or Group A may be atropisomers (e.g. , substituted biaryls) and are considered as part of this disclosure. Enantiomers can also be separated by use of a chiral HPFC column.
- the compounds of Formula (I), (II), or Group A may form acid addition salts, which may be pharmaceutically acceptable salts.
- the disclosure also includes pharmaceutical compositions comprising one or more compounds as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- pharmaceutical compositions reported herein can be provided in a unit dosage form (e.g., capsule, tablet or the like).
- pharmaceutical compositions reported herein can be provided in an oral dosage form.
- an oral dosage form of a compound of Formula (I), (II), or Group A can be a capsule.
- an oral dosage form of a compound of Formula (I), (II), or Group A is a tablet.
- an oral dosage form comprises one or more fillers, disintigrants, lubricants, glidants, anti-adherents and/or anti-statics.
- an oral dosage form is prepared via dry blending.
- an oral dosage form is a tablet and is prepared via dry granulation.
- a CBP Inhibitor compound of the present disclosure can be dosed at a therapeutically effective level.
- the present disclosure relates to solid forms of compounds, or pharmaceutically acceptable salts or isomers thereof, capable of modulating CBP/p300 family bromodomains which are useful for the treatment of diseases and disorders associated with modulation of CBP/p300 family bromodomains.
- the disclosure further relates to solid forms of compounds, or pharmaceutically acceptable salts or isomers thereof, which are useful for inhibiting CBP/p300 family bromodomains.
- the disclosure relates to a solid form of a compound of Formula (I)
- the disclosure relates to a solid and salt forms selected from one or more of Group A: and enantiomers, hydrates, solvates, and tautomers thereof and acid addition salts of the foregoing.
- the present disclosure relates to solid and salt forms of Formula (II):
- the acid addition salts of the foregoing may originate from the addition of hydrochloric acid (HC1), p-tolunesulfonic acid, benzenesulfonic acid, and sulfuric acid (H2SO4). In the absence of an acid addition salt, the compounds are referred to as a free base form.
- the acid addition salts and free base forms may be crystalline.
- the free base form may not be amorphous in some embodiments.
- the amorphous, free base form is accessed through a synthesis provided in Example 1. This chemical synthesis produces the compound of formula (II) with substantial purity. Only trace amounts of the stereoisomeric contaminants of Group A are present in the end synthetic product, with the exception of compound A6, which is present in quantifiable amounts.
- the amorphous, free base form is produced with purities in excess of 99%, as determined by HPLC analysis as outlined in the examples below.
- types A, B, and C three crystalline forms (hereafter referred to as types A, B, and C), two crystalline forms of a p-toluenesulfonic acid addition salt (hereafter referred to as types A and B), one crystalline form of a benzenesulfonic acid addition salt (hereafter referred to as type A), one form of a sulfuric acid addition salt (hereafter referred to as type A), and a free base crystalline form (hereafter referred to as freeform type A) of the compounds of Formula (I).
- Crystalline type A of the hydrochloric acid addition salt is characterized by an X-ray powder diffraction pattern (XRPD) having at least three approximate peak positions (degrees 2Q ⁇ 0.2) when measured using Cu K a radiation, selected from the group consisting of: 7.27, 8.98, 10.60, 15.60, and 23.93, when the XRPD is collected from about 3 to about 40 degrees 2Q.
- Figure 2 contains a list of peaks from the X-ray powder diffraction pattern of the type A hydrochloric acid addition salt having a relative intensity greater than or equal to 5%.
- the HC1 type A salt is also characterized by a weight loss of approximately 1.1% at temperatures up to 170 °C, as measured by thermogravimetric analysis.
- the HC1 type A salt is also characterized as hygroscopic, evidenced by the water uptake of 6.3% at relative humidity of up to 80%, as measured by dynamic vapor sorption isotherm plots.
- the type A hydrochloric acid addition salt is characterized by the kinetic solubility data shown below in Example 2.
- the type A hydrochloric acid addition salt can be stable for at least two weeks at temperatures up to 40 °C and relative humidity of up to 75%.
- Crystalline type A of the hydrochloric acid addition salt is an anhydrate (anhydrous).
- the crystalline type A of the hydrochloric acid addition salt can be prepared by dissolving the free base form in an organic solvent, adding hydrochloric acid, heating the resulting solution followed by cooling, as provided in Example l.b.
- Crystalline type B of the hydrochloric acid addition salt is characterized by an X-ray powder diffraction pattern (XRPD) having at least three approximate peak positions (degrees 2Q ⁇ 0.2) when measured using Cu K a radiation, selected from the group consisting of: 10.23, 18.72, 23.03, 24.77, and 28.03, when the XRPD is collected from about 3 to about 40 degrees 2Q.
- Figure 2 contains a list of peaks from the X-ray powder diffraction pattern of the type B hydrochloric acid addition salt having a relative intensity greater than or equal to 5%.
- HC1 type B salt is also characterized by a weight loss of approximately 20% at temperatures up to 200 °C, as measured by thermogravimetric analysis.
- crystalline type B of the hydrochloric acid addition salt is a hydrate or solvate.
- the crystalline type B of the hydrochloric acid addition salt can be prepared by dissolving the type A hydrochloric acid addition salt in a mixture of organic solvents, and then heating the resulting solution, followed by cooling and slow evaporation at room temperature as provided in Example l.c.
- Crystalline type C of the hydrochloric acid addition salt is characterized by an X-ray powder diffraction pattern (XRPD) having at least three approximate peak positions (degrees 2Q ⁇ 0.2) when measured using Cu K a radiation, selected from the group consisting of: 7.05, 19.84, 21.09, 24.98, and 31.44, when the XRPD is collected from about 3 to about 40 degrees 2Q.
- Figure 2 contains a list of peaks from the X-ray powder diffraction pattern of the type B hydrochloric acid addition salt having a relative intensity greater than or equal to 5%.
- HC1 type C salt is also characterized by a weight loss of approximately 9.4% at temperatures up to 180 °C, as measured by thermogravimetric analysis.
- crystalline type C of the hydrochloric acid addition salt is a hydrate or solvate.
- the crystalline type B of the hydrochloric acid addition salt can be prepared by dissolving the type A hydrochloric acid addition salt in a mixture of organic solvents, and then heating the resulting solution, followed by cooling and slow evaporation at room temperature as provided in Example 1.d.
- Crystalline type A of the p-toluenesulfonic acid addition salt is characterized by an X-ray powder diffraction pattern (XRPD) having at least three approximate peak positions (degrees 2Q ⁇ 0.2) when measured using Cu K a radiation, selected from the group consisting of: 6.59, 13.20, 14.46, 18.00, and 21.74, when the XRPD is collected from about 3 to about 40 degrees 2Q.
- Figure 3 contains a list of peaks from the X-ray powder diffraction pattern of type A p-toluenesulfonic acid addition salt having a relative intensity greater than or equal to 5%.
- the type A p-toluenesulfonic acid addition salt is also characterized by a weight loss of approximately 1.0% at temperatures up to 180 °C, as measured by thermogravimetric analysis.
- the crystalline type A p-toluenesulfonic acid addition salt can be prepared by dissolving the free base form in an organic solvent, adding p-toluenesulfonic acid, and heating the resulting solution followed by cooling, as provided in Example l.e.
- Crystalline type B of the p-toluenesulfonic acid addition salt is characterized by an X-ray powder diffraction pattern (XRPD) having at least three approximate peak positions (degrees 2Q ⁇ 0.2) when measured using Cu K a radiation, selected from the group consisting of: 7.10, 9.15, 15.08, 16.19, 17.25, 18.31, and 21.13, when the XRPD is collected from about 3 to about 40 degrees 2Q.
- Figure 3 contains a list of peaks from the X-ray powder diffraction pattern of type B p-toluenesulfonic acid addition salt having a relative intensity greater than or equal to 5%.
- the type B p-toluenesulfonic acid addition salt is also characterized by a weight loss of approximately 1.3% at temperatures up to 180 °C, as measured by thermogravimetric analysis.
- the type B p-toluenesulfonic acid addition salt is also characterized as hygroscopic, evidenced by the water uptake of 2.1 % at relative humidity of up to 80%, as measured by dynamic vapor sorption isotherm plots.
- the type B p-toluenesulfonic acid addition salt is characterized by the kinetic solubility data shown below in Example 2.
- the type B p-toluenesulfonic acid addition salt is stable for at least two weeks at temperatures up to 40 °C and relative humidity of up to 75%.
- the crystalline type B p-toluenesulfonic acid addition salt can be prepared by dissolving the free base form in an organic solvent, adding p-toluenesulfonic acid, heating the resulting solution followed by cooling, as provided in Example 1.f.
- Crystalline type B of the p-toluenesulfonic acid addition salt is an anhydrate (anhydrous).
- Crystalline type A of the benzenesulfonic acid addition salt is characterized by an X-ray powder diffraction pattern (XRPD) having at least three approximate peak positions (degrees 2Q ⁇ 0.2) when measured using Cu K a radiation, selected from the group consisting of: 5.84, 7.48, 9.45, 16.84, 18.90, 19.61, 20.70, and 25.14, when the XRPD is collected from about 3 to about 40 degrees 2Q.
- Figure 4 contains a list of peaks from the X-ray powder diffraction pattern of type A benzenesulfonic acid addition salt having a relative intensity greater than or equal to 5%.
- the crystalline type A benzenesulfonic acid addition salt can be prepared by dissolving the free base form in an organic solvent, adding benzenesulfonic acid, heating the resulting solution followed by cooling, as provided in Example 1.g.
- Crystalline type A of the sulfuric acid addition salt is characterized by an X-ray powder diffraction pattern (XRPD) having at least three approximate peak positions (degrees 2Q ⁇ 0.2) when measured using Cu K a radiation, selected from the group consisting of: 8.24, 9.98, 13.58, 16.87, 18.78, 20.00, and 25.52, when the XRPD is collected from about 3 to about 40 degrees 2Q.
- Figure 5 contains a list of peaks from the X-ray powder diffraction pattern of type A sulfuric acid addition salt having a relative intensity greater than or equal to 5%.
- the crystalline type A sulfuric acid addition salt can be prepared by dissolving the free base form in an organic solvent, adding sulfuric acid, heating the resulting solution followed by cooling, as provided in Example 1.h.
- Crystalline type A free base form is characterized by an X-ray powder diffraction pattern (XRPD) having at least three approximate peak positions (degrees 2Q ⁇ 0.2) when measured using Cu K a radiation, selected from the group consisting of: 11.11, 14.11 , 18.21, 20.48, and 26.24, when the XRPD is collected from about 3 to about 40 degrees 2Q.
- Figure 6 contains a list of peaks from the X-ray powder diffraction pattern of type A free base form having a relative intensity greater than or equal to 5%.
- the type A free base form is also characterized by negligible weight loss at temperatures up to 210 °C, as measured by thermogravimetric analysis.
- the type A free base from is characterized by the kinetic solubility data shown below in Example 2.
- the crystalline type A free base form can be prepared by dissolving the free base form in an organic solvent at reflux and subsequently cooling the resulting solution, as provided in Example 1.i.
- the salt and crystalline forms used in the preparation of the pharmaceutical compositions are at least 95% pure, as assessed by HPLC analysis.
- the compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the examples given below.
- the compounds of the present disclosure i.e. , compounds of Formula (I), (II), or Group A or a pharmaceutically acceptable salt thereof, may be prepared by methods known in the art of organic synthesis as set forth in part by the synthetic schemes depicted in the examples. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula (I), (II), or Group A.
- stereocenters exist in the compounds of Formula (I), (II), or Group A. Accordingly, the present disclosure includes both possible stereoisomers (unless otherwise indicated and/or specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. Unless otherwise indicated, when a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
- the present disclosure relates to a method of inhibiting one or more of CBP/p300-family bromodomains, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), (II), or Group A.
- CBP Inhibitor Compounds are useful in the development of pharmaceutical compositions suitable for treatment of certain related forms of cancer. CBP Inhibitor Compounds are useful for treating disease states that are responsive to the inhibition of CBP.
- CBP and EP300 are closely related multi-domain proteins that function as transcriptional co-activators. They carry acetyl-lysine binding bromodomains which impart a scaffolding or positioning function on these proteins and have proven to be suitable for the design of small molecule inhibitors of their biological function. These paralogs are highly homologous at the amino acid level and share many overlapping functions.
- HATs histone acetyl transferases
- AHTs histone acetyl transferases
- CBP/p300 consist of numerous transcription factors including nuclear hormone receptors such as the androgen receptor (AR).
- AR nuclear hormone receptor
- CBP/p300 function as co-activators of AR-signaling by acetylation of the AR which activates its transcriptional activity and promotes its protein stability.
- they acetylate histone H3 at lysine 27 (Ac-H3K27) to provide a docking site for the bromodomain thus providing a scaffold to bridge the nuclear receptor to the basal transcriptional machinery.
- Acetylation of histone leads to the generation of a transcriptionally permissive environment on chromatin.
- the localization of CBP/p300 to AR dependent super-enhancers thus leads to increased localized Ac-H3K27 which further increases transcription at these loci.
- X-Ray Powder Diffraction was performed with a Panalytical X’Pert 3 Powder XRPD on a Si zero-background holder.
- the 2Q position was calibrated against a Panalytical Si reference standard disc.
- the XRPD parameters used are listed in Figure 1A.
- TGA Thermogravimetric Analysis
- CBP cyclic AMP-responsive element binding protein also known as KAT3A
- p300 EP300 also known as KAT3B
- organic solvent will be readily known those skilled in the art, but may include chemical solvents such as acetone, acetonitrile, benzene, chloroform, 1 ,4-dioxane, diethyl ether, dichloromethane, dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, ethanol, ethyl acetate, hexanes, isopropanol, methanol, N-methylpyrolidone, pyridine, tetrahydrofuran, toluene, water, in addition to those not explicitly named.
- chemical solvents such as acetone, acetonitrile, benzene, chloroform, 1 ,4-dioxane, diethyl ether, dichloromethane, dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, ethanol, ethyl acetate, hexanes, isopropanol,
- the crude product was purified by reverse phase chromatography (Column: C18; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (5% to 20% over 30 min); Detector, UV 254 nm) to afford 2-(5-fluoro-2- methoxyphenyl)-2-hydroxyacetic acid as a white solid (1.10 g, 93%).
- the resulting mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1 : 1 ethyl acetate/petroleum ether) to afford the crude product (35.0 g).
- the crude product was dissolved in ethyl acetate (230 mL), followed by the addition of D -Camphor sulfonic acid (36.9 g, 0.158 mol).
- the resulting solution was stirred for 1 h at 60 °C and then cooled to room temperature.
- the solids were collected by filtration, and rinsed with ethyl acetate (120 mL).
- the solids were dissolved in water (50 mL).
- Step 7 methyl (2S)-5-amino-6-[[(lR,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-l,2,3,4- tetrahydroquinoline- 1 -carboxylate
- Step 8 methyl (2S)-5-[2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetamido]-6-[[(lR,3R)-3- (methoxycarbonyl)cyclohexyl]amino]-2-methyl-l,2,3,4-tetrahydroquinoline-l-carboxylate
- Step 9 methyl (7S)-2-[(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-3-[(lR,3R)-3- (methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate.
- the crude product was purified by Prep-HPLC (Column, XBridge Prep C18 OBD Column, 19x150 mm, 5um; Mobile phase, A: water (containing 10 rnmol/L NH4HCO3) and B: ACN (15.0% to 29.0% over 14 min); Detector, UV 220/254nm).
- the product was separated by Chiral-Prep-HPLC (Column, CHIRALPAK IE, 2x25cm, 5 um; Mobile phase, A: Hex (containing 0.1%FA) and B: ethanol (hold 50.0% ethanol over 12 min); Detector, UV 220/254 nm).
- the solution was then warmed to room temperature and a precipitate was observed following the slow, unassisted evaporation of a portion of the solvent.
- the precipitate was collected via centrifugation, dried at 40 °C under vacuum, and subsequently characterized by XRPD, DSC, and TGA. The results indicated that the sample is crystalline via XRPD and conformed to the type B hydrochloric acid addition salt.
- the solution was then warmed to room temperature and a precipitate was observed following the slow, unassisted evaporation of a portion of the solvent.
- the precipitate was collected via centrifugation, dried at 40 °C under vacuum, and subsequently characterized by XRPD, DSC, and TGA. The results indicated that the sample is crystalline via XRPD and conformed to the type C hydrochloric acid addition salt.
- the resulting solid was collected via centrifugation, dried at 40 °C under vacuum, and subsequently characterized by XRPD, DSC, TGA, and 'H NMR. The results indicated that the sample is crystalline via XRPD and conformed to the type A benzenesulfonic acid addition salt.
- the resulting solid was collected via centrifugation, dried at 40 °C under vacuum, and subsequently characterized by XRPD, DSC, and TGA. The results indicated that the sample is crystalline via XRPD and conformed to the type A sulfuric acid addition salt.
- Solubility of HC1 salt Type A, tosylate Type B, and freeform type A was measured in water, SGF, FaSSIF and FeSSIF at 37 °C with solid loading of ⁇ 10 mg/mL calculated as freebase. All solubility samples were kept rolling at 25 rpm at 37 °C, and sampled at 1 , 4, and 24 h, respectively. Supernatant was extracted via centrifugation before filtration, and used for solubility and pH measurement. Residual solids were collected for XRPD characterization. The results are summari ed in Figure 7.
- the assay was performed in a final volume of 6 pL in assay buffer containing 50 mM Hepes (pH 7.5, (0.5M Hepes, pH 7.5 solution; Teknova H1575)), 0.5 mM GSH, 0.01% BGG (0.22 mM filtered, Sigma, G7516-25G), 0.005% BSA (0.22 pM filtered, EMD Millipore Corporation, 126575) and 0.01% Triton X- 100 (Sigma, T9284-10L).
- Hepes pH 7.5, (0.5M Hepes, pH 7.5 solution; Teknova H1575)
- BGG 0.22 mM filtered, Sigma, G7516-25G
- BSA 0.22 pM filtered, EMD Millipore Corporation, 126575
- Triton X- 100 Sigma, T9284-10L
- Nanoliter quantities of 10-point, 3-fold serial dilution in DMSO were pre dispensed into 1536 assay plates (Corning, #3724BC) for a final test concentration of 33 pM to 1.7 nM, top to lowest dose, respectively.
- 3 pL of 2x Protein and 3 pL of 2 x Peptide Ligand were added to assay plates (pre-stamped with compound). Plates were incubated for varying times at room temperature prior to measuring the signal.
- TR-FRET Time -Resolved Fluorescence Resonance Energy Transfer
- IC50 values were determined by curve fitting of the standard 4 parameter logistic fitting algorithm included in the Activity Base software package: IDBS XE Designer Model205. Data is fitted using the Levenburg Marquardt algorithm.
- IC50 values were determined by curve fitting of the standard 4 parameter logistic fitting algorithm included in the Activity Base software package: IDBS XE Designer Model205. Data is fitted using the Levenburg Marquardt algorithm.
- CBP inhibitors were pre -dispensed into 1536 assay plates for a final test concentration of 33 pM to 1.7 nM. Protein and Ligands were added to the compound to a final concentration of 2.5nM CBP or BRD4 (N-terminal GST-CREBBP (1081-1197), BRD4 tandem domains) and 25 nM Tetra-Acetylated H3 peptide Plates and incubated for 4h. Data were reported as percent inhibition compared with control wells. IC50 values were determined by curve fitting of the standard 4 parameter logistic fitting algorithm.
- an X-ray powder diffraction pattern comprising at least three peak positions (degrees 2 Q+0.2) when measured using Cu Ka radiation, selected from the group consisting of: 7.27, 8.98, 10.60, 15.60, and 23.93.
- an X-ray powder diffraction pattern comprising at least three peak positions (degrees 2 Q+0.2) when measured using Cu Ka radiation, selected from the group consisting of: 10.23, 18.72, 23.03, 24.77, and 28.03.
- an X-ray powder diffraction pattern comprising at least three peak positions (degrees 2 Q+0.2) when measured using Cu Ka radiation, selected from the group consisting of: 7.05, 19.84, 21.09, 24.98, and 31.44.
- a pharmaceutical composition comprising the solid form of any one of clauses 1-15 and one or more of a pharmaceutically acceptable carrier, adjuvant, and vehicle.
- a method of inhibiting one or more of CBP/p300-family bromodomains in a patient comprising administering to the patient in need thereof an effective amount of the solid form of any one of clause 1- 15, or the pharmaceutical composition of clause 18.
- a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with the activity of one or more CBP/p300-family bromodomains in a patient comprising: administering to the patient in need thereof a therapeutically effective amount of the solid form of any one of clause 1-15 or a composition of clause 18.
- the solid form is a hydrochloric acid addition salt
- the hydrochloric acid addition salt is Type A hydrochloric acid addition salt
- the solid form is a hydrochloric acid addition salt
- the hydrochloric acid addition salt is Type A hydrochloric acid addition salt
- a pharmaceutical composition comprising the solid form of any one of clauses 1-7 and one or more of a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- a method of inhibiting one or more CBP/p300-family bromodomains in a patient comprising administering to the patient in need thereof a therapeutically effective amount of the solid form of any one of clauses 1-7 or the pharmaceutical composition of clause 13.
- a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with the activity of one or more CBP/p300-family bromodomains in a patient comprising administering to the patient in need thereof a therapeutically effective amount of the solid form of any one of clauses 1-7 or the pharmaceutical composition of clause 13.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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AU2020239990A AU2020239990A1 (en) | 2019-03-15 | 2020-03-13 | Inhibiting cyclic AMP-responsive element-binding protein (CREB) |
EP20773477.3A EP3937936A4 (en) | 2019-03-15 | 2020-03-13 | Inhibiting cyclic amp-responsive element-binding protein (creb) |
BR112021016921A BR112021016921A2 (en) | 2019-03-15 | 2020-03-13 | Inhibition of cyclic amp-responsive element binding protein (creb) |
CA3132628A CA3132628A1 (en) | 2019-03-15 | 2020-03-13 | Inhibiting cyclic amp-responsive element-binding protein (creb) |
CN202080028527.9A CN113874017A (en) | 2019-03-15 | 2020-03-13 | Inhibiting cyclic AMP-response element binding protein (CREB) |
MX2021010829A MX2021010829A (en) | 2019-03-15 | 2020-03-13 | Inhibiting cyclic amp-responsive element-binding protein (creb). |
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US201962819482P | 2019-03-15 | 2019-03-15 | |
US62/819,482 | 2019-03-15 |
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WO2020190780A1 true WO2020190780A1 (en) | 2020-09-24 |
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PCT/US2020/022783 WO2020190780A1 (en) | 2019-03-15 | 2020-03-13 | Inhibiting cyclic amp-responsive element-binding protein (creb) |
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EP (1) | EP3937936A4 (en) |
CN (1) | CN113874017A (en) |
AU (1) | AU2020239990A1 (en) |
BR (1) | BR112021016921A2 (en) |
CA (1) | CA3132628A1 (en) |
MX (1) | MX2021010829A (en) |
WO (1) | WO2020190780A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US11795168B2 (en) * | 2020-09-23 | 2023-10-24 | Forma Therapeutics, Inc. | Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP) |
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US20040214825A1 (en) * | 1999-01-06 | 2004-10-28 | Pharmacia & Upjohn Company | Method of treating sexual disturbances |
US20080255110A1 (en) * | 2002-11-15 | 2008-10-16 | Sanofi-Aventis | Imidazoquinoline derivatives as adenosine a3 receptor ligands |
WO2019055869A1 (en) * | 2017-09-15 | 2019-03-21 | Forma Therapeutics, Inc. | Tetrahydro-imidazo quinoline compositions as cbp/p300 inhibitors |
Family Cites Families (2)
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GB201504689D0 (en) * | 2015-03-19 | 2015-05-06 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
GB201617630D0 (en) * | 2016-10-18 | 2016-11-30 | Cellcentric Ltd | Pharmaceutical compounds |
-
2020
- 2020-03-13 CN CN202080028527.9A patent/CN113874017A/en active Pending
- 2020-03-13 AU AU2020239990A patent/AU2020239990A1/en active Pending
- 2020-03-13 WO PCT/US2020/022783 patent/WO2020190780A1/en active Search and Examination
- 2020-03-13 CA CA3132628A patent/CA3132628A1/en active Pending
- 2020-03-13 MX MX2021010829A patent/MX2021010829A/en unknown
- 2020-03-13 EP EP20773477.3A patent/EP3937936A4/en active Pending
- 2020-03-13 BR BR112021016921A patent/BR112021016921A2/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040214825A1 (en) * | 1999-01-06 | 2004-10-28 | Pharmacia & Upjohn Company | Method of treating sexual disturbances |
US20080255110A1 (en) * | 2002-11-15 | 2008-10-16 | Sanofi-Aventis | Imidazoquinoline derivatives as adenosine a3 receptor ligands |
WO2019055869A1 (en) * | 2017-09-15 | 2019-03-21 | Forma Therapeutics, Inc. | Tetrahydro-imidazo quinoline compositions as cbp/p300 inhibitors |
Non-Patent Citations (2)
Title |
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DATABASE PubChem 20 August 2019 (2019-08-20), Database accession no. 138472436 * |
See also references of EP3937936A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11795168B2 (en) * | 2020-09-23 | 2023-10-24 | Forma Therapeutics, Inc. | Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP) |
Also Published As
Publication number | Publication date |
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EP3937936A4 (en) | 2022-12-28 |
EP3937936A1 (en) | 2022-01-19 |
CA3132628A1 (en) | 2020-09-24 |
BR112021016921A2 (en) | 2021-11-03 |
CN113874017A (en) | 2021-12-31 |
AU2020239990A1 (en) | 2021-11-04 |
MX2021010829A (en) | 2021-12-10 |
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