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WO2024188999A1 - Forme cristalline - Google Patents

Forme cristalline Download PDF

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Publication number
WO2024188999A1
WO2024188999A1 PCT/EP2024/056495 EP2024056495W WO2024188999A1 WO 2024188999 A1 WO2024188999 A1 WO 2024188999A1 EP 2024056495 W EP2024056495 W EP 2024056495W WO 2024188999 A1 WO2024188999 A1 WO 2024188999A1
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WIPO (PCT)
Prior art keywords
compound
crystalline form
fluoro
mmol
ray powder
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PCT/EP2024/056495
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English (en)
Inventor
Philip Anthony CORNER
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AstraZeneca AB
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AstraZeneca AB
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Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to CN202480017739.5A priority Critical patent/CN120917029A/zh
Priority to AU2024236796A priority patent/AU2024236796A1/en
Priority to KR1020257033631A priority patent/KR20250155619A/ko
Publication of WO2024188999A1 publication Critical patent/WO2024188999A1/fr
Priority to IL323224A priority patent/IL323224A/en
Priority to MX2025010674A priority patent/MX2025010674A/es
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present specification relates to a crystalline form of (3S)-2-[(5-amino-6-fluoro-1 H- pyrrolo[3,2-b]pyridin-2-yl)methyl]-1'-but-2-ynyl-6-fluoro-spiro[isoindoline-3,3'-pyrrolidine]-1 ,2'- dione, and to compositions and uses thereof.
  • Protein arginine methyltransferase 5 is a member of the PRMT family of arginine methyltransferase enzymes that catalyse the addition of methyl groups to the guanidine motif of arginine residues, using S-adenosyl-L-methionine (SAM) as a methyl donor.
  • SAM S-adenosyl-L-methionine
  • PRMT5 is a type II arginine methyltransferase that symmetrically dimethylates the guanidine group of arginine residues thus converting a guanidine NH2 group of arginine to a NMe2 group.
  • PRMT5 methylates a number of diverse substrates including histone and non-histone proteins, and in so doing regulates processes such as RNA splicing, cellular proliferation and DNA repair.
  • PRMT5 is overexpressed in a number of cancer types and has been identified as a candidate for therapeutic intervention through the development of small molecules that inhibit PRMT5 methyltransferase activity (see e.g. Kim et al., (2020) Cell Stress 4(8) 199-2151).
  • Cyclin dependent kinase inhibitor 2A is a tumour suppressor gene that is homozygously deleted in approximately 15% of cancers. Loss of the 9p21 chromosome locus results in the co-deletion of a number of additional genes including the gene encoding methylthioadenosine phosphorylase (MTAP).
  • MTAP is a metabolic enzyme involved in methionine salvage and loss of MTAP results in increased concentrations of the MTAP substrate methylthioadenosine (MTA) in CDKN2A/MTAP deleted cancer cells.
  • MTA itself acts as a weak PRMT5 inhibitor and MTA accumulation in CDKN2A/MTAP deleted cancer cell lines accordingly leads to a partial inhibition of PRMT5 activity.
  • Compromised PRMT5 activity renders CDKN2A/MTAP deleted cancer cells susceptible to further targeting of PRMT5, for example using short hairpin RNA (shRNA).
  • short hairpin RNA shRNA
  • MTA-synergistic PRMT5 inhibitors (i.e.
  • MTA-synergistic PRMT5 inhibitors should possess a high therapeutic index (and low off target toxicity) as their anti-proliferative activity will selectively manifest in the targeted, CDKN2A/MTAP deleted, tumour cells.
  • MTA-synergistic PRMT5 inhibitors have entered clinical trials, such as MRTX-1719 (NCT05245500); TNG-908 (NCT05275478); TNG-462 (NCT05732831); AMG-193 (NCT05094336, NCT05094336); and AZD3470 (NCT06130553; NCT06137144).
  • MRTX-1719 NCT05245500
  • TNG-908 NCT05275478
  • TNG-462 NCT05732831
  • AMG-193 NCT05094336, NCT05094336
  • AZD3470 NCT06130553; NCT06137144
  • PCT/EP2022/075248 discloses PRMT5 inhibitors, particularly MTA-synergistic PRMT5 inhibitors, including the compound (3S)-2-[(5-amino-6-fluoro-1 H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-T-but-2-ynyl-6-fluoro- spiro[isoindoline-3,3'-pyrrolidine]-1 ,2'-dione (herein referred to as Compound (I)): Compound (I), alongside its activity as an inhibitor of PRMT5 enzyme in MTA present (IC50 0.006 pM) and MTA absent (IC50 0.027 pM) assays, its activity in HCT116 wild type cells (IC50 0.2 pM) and HCT116 MTAP knock-out cells (IC50 0.0059 pM), and its activity against cell proliferation in HCT116 wild type cells (IC50 6.1
  • the drug substance In the formulation of drug substances, it is important for the drug substance (active compound) to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the of view of obtaining a commercially-viable manufacturing process for the drug substance itself, but also from the point of view of subsequent manufacture of pharmaceutical formulations comprising the active compound and suitable excipients.
  • the chemical stability and the physical stability of the active compound are important factors in determining the suitability of a solid form for use in the development of pharmaceutical formulations.
  • the active compound, and formulations containing it should be capable of being effectively stored over appreciable periods of time, without exhibiting any significant change in the physico-chemical characteristics (e.g. chemical composition, density, hygroscopicity and solubility) of the active compound.
  • the specification provides a crystalline form which is a co-crystal of (3S)-2-[(5- amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-1'-but-2-ynyl-6-fluoro-spiro[isoindoline-3,3'- pyrrol idine]- 1 ,2'-dione:
  • Compound (I) Form A Compound (I), and adipic acid in a 2:1 ratio (herein referred to as “Compound (I) Form A”).
  • the specification also provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient.
  • the specification also provides Compound (I) Form A for use as a medicament, for example in the prophylaxis or treatment of a disorder mediated by PRMT5.
  • the specification also provides the use of Compound (I) Form A in the manufacture of a medicament, for example for the prophylaxis or treatment of a disorder mediated by PRMT5.
  • the specification also provides a method of prevention or treatment, for example preventing or treating a disorder mediated by PRMT5, which comprises administering Compound (I) Form A.
  • Reference Form 1 a crystalline form of Compound (I) (herein referred to as “Reference Form 1”).
  • Reference Form 1 displays characteristics which may be deleterious for pharmaceutical development. For example, at ambient conditions Reference Form 1 exists as a hemi-hydrate which can reversibly be converted to the anhydrous form or mono-hydrate upon changes in temperature and/or relative humidity.
  • Reference Form 1 The reversible (de)hydration behaviour of Reference Form 1 may result in unpredictable changes in physical properties due to interconversion between the discrete forms, consequently affecting storage and manufacture, and may also create variability in analytical assaying which could complicate its development and use as a pharmaceutical active.
  • Compound (I) Form A as described herein possesses a distinct crystal structure (as determined by XRPD) and surprisingly displays a combination of characteristics which are attractive in the context of pharmaceutical development.
  • Compound (I) may exist in other solid forms with alternative counter-ions such as acetic acid, 1,5-naphthalenedisulfonic acid, glutaric acid, oxalic acid, propionic acid, camphoric acid, 5- nitroisophthalic acid, 5-chlorosalicylic acid, 3,5-dinitrobenzoic acid, benzoic acid, fumaric acid, sulphuric acid, 2-mesitylenesulfonic acid, gallic acid, 3,5-dihydroxybenzoic acid, or 2,4- dihydroxybenzoic acid.
  • These may exist in crystalline forms which are i) co-crystals of Compound (I) and the counter-ion; ii) salts of Compound (I); or mixtures thereof.
  • Compound (I) Form A is a crystalline form which appears to be particularly suitable for pharmaceutical development.
  • Figure 1 X-ray powder diffraction pattern of Compound (I) Form A, a physical form of (3S)-2- [(5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-1'-but-2-ynyl-6-fluoro-spiro[isoindoline- 3,3'-pyrrolidine]-1,2'-dione and adipic acid in a 2:1 ratio.
  • Figure 2 Differential scanning calorimetry and thermogravimetric analysis overlay thermogram of Reference Form 1.
  • Figure 3 Differential scanning calorimetry and thermogravimetric analysis overlay thermogram of Compound (I) Form A.
  • X-ray powder diffraction analysis may be performed according to standard methods, examples of which can be found in e.g. Kitaigorodsky, A. I. (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L.E. (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York.
  • an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used).
  • intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation.
  • persons skilled in the art of X-ray powder diffraction will realise that the relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used.
  • the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer.
  • the surface planarity of the sample may also have a small effect.
  • the relative intensity of peaks can be affected by, for example, grains above approximately 30 micrometer in size and non-unitary aspect ratios which may affect analysis of samples. Furthermore, it should be understood that intensities may fluctuate depending on experimental conditions and sample preparation such as preferred orientation of the particles in the sample. The use of automatic or fixed divergence slits will also influence the relative intensity calculations. A person skilled in the art can handle such effects when comparing diffraction patterns. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a power diffraction pattern substantially identical to those disclosed herein fall within the scope of the present specification (for further information see Jenkins, R & Snyder, R.L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons, 1996).
  • a measurement error of a diffraction angle in an X-ray powder diffractogram is about 5% or less, in particular plus or minus 0.2° 2-theta, and such degree of a measurement error should be taken into account when considering the X-ray powder diffraction pattern in Figure 1, and when reading Tables 2 and Table 3. Furthermore, it should be understood that intensities may fluctuate depending on experimental conditions and sample preparation (preferred orientation). Definition of relative intensity is described in Table 1:
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least one specific peak at ( ⁇ 0.2) 8.9 degrees 2-theta when measured using CuKa radiation. In one embodiment the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least one specific peak at about 8.9 degrees 2-theta when measured using CuKa radiation. In one embodiment the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least one specific peak at ( ⁇ 0.2) 19.1 degrees 2-theta when measured using CuKa radiation. In one embodiment the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least one specific peak at about 19.1 degrees 2-theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least two specific peaks at ( ⁇ 0.2) 8.9 and 19.1 degrees 2-theta when measured using CuKa radiation. In one embodiment the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least two specific peaks at about 8.9 and 19.1 degrees 2-theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least one specific peak selected from ( ⁇ 0.2) 8.9, 19.1, 19.7 and 22.9 degrees 2-theta when measured using CuKa radiation. In one embodiment the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least one specific peak selected from about 8.9, 19.1 , 19.7 and 22.9 degrees 2- theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least two specific peaks selected from ( ⁇ 0.2) 8.9, 19.1 , 19.7 and 22.9 degrees 2-theta when measured using CuKa radiation. In one embodiment the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least two specific peaks selected from about 8.9, 19.1, 19.7 and 22.9 degrees 2- theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least three specific peaks selected from ( ⁇ 0.2) 8.9, 19.1 , 19.7 and 22.9 degrees 2-theta when measured using CuKa radiation. In one embodiment the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least three specific peaks selected from about 8.9, 19.1, 19.7 and 22.9 degrees 2- theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing specific peaks at ( ⁇ 0.2) 8.9, 19.1, 19.7 and 22.9 degrees 2-theta when measured using CuKa radiation. In one embodiment the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing specific peaks at about 8.9, 19.1, 19.7 and 22.9 degrees 2-theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing specific peaks at ( ⁇ 0.2) 8.9, 19.1, 19.7 and 22.9 degrees 2-theta when measured using CuKa radiation, and one, two, three, four, five or six specific peaks selected from ( ⁇ 0.2) 14.5, 16.9, 17.4, 21.2, 23.7 and 25.8 degrees 2-theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing specific peaks at about 8.9, 19.1, 19.7 and 22.9 degrees 2-theta when measured using CuKa radiation, and one, two, three, four, five or six specific peaks selected from about 14.5, 16.9, 17.4, 21.2, 23.7 and 25.8 degrees 2-theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least two peaks selected from ( ⁇ 0.2) 8.9, 14.5, 16.9, 17.4, 19.1, 19.7, 21.2, 22.9, 23.7 and 25.8 degrees 2-theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing at least two peaks selected from about 8.9, 14.5, 16.9, 17.4, 19.1, 19.7, 21.2, 22.9, 23.7 and 25.8 degrees 2-theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing specific peaks at ( ⁇ 0.2) 8.9, 14.5, 16.9, 17.4, 19.1, 19.7, 21.2, 22.9, 23.7 and 25.8 degrees 2-theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing specific peaks at about 8.9, 14.5, 16.9, 17.4, 19.1 , 19.7, 21.2, 22.9, 23.7 and 25.8 degrees 2-theta when measured using CuKa radiation.
  • the complete list of XRPD pattern peaks for Compound (I) Form A is shown in Table 3.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing the specific peaks substantially as shown in Table 3 when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing specific peaks at ( ⁇ 0.2) 8.9, 14.5, 16.9, 17.4, 19.1, 19.7, 21.2, 22.9, 23.7 and 25.8 degrees 2-theta when measured using CuKa radiation, and one, two or three specific peaks selected from ( ⁇ 0.2) 27.0, 28.1 and 29.2 degrees 2-theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern containing specific peaks at about 8.9, 14.5, 16.9, 17.4, 19.1, 19.7, 21.2, 22.9, 23.7 and 25.8 degrees 2-theta when measured using CuKa radiation, and one, two or three specific peaks selected from about 27.0, 28.1 and 29.2 degrees 2-theta when measured using CuKa radiation.
  • the specification provides Compound (I) Form A which has an X-ray powder diffraction pattern substantially as shown in Figure 1 when measured using CuKa radiation.
  • the XRPD of the crystalline form may contain one or more of the 2-theta values listed, for example one or more of the 2-theta values, 2 or more of the 2-theta values or 3 or more of the 2-theta values listed. Similar descriptions with reference to different numbers of peaks (such as “... containing at least two specific peaks...” etc) are to be interpreted in the same manner.
  • DSC differential scanning calorimetry
  • a measurement error of a diffraction angle in DSC thermal events is approximately plus or minus 5°C, and such degree of a measurement error should be taken into account when considering the DSC data included herein, such as for Figure 3.
  • Compound (I) Form A When heated in a differential scanning calorimeter (conditions as described in the Examples section), Compound (I) Form A exhibits a melting with an onset temperature at about 216.6°C, and a peak temperature at about 217.7°C as illustrated in Figure 3.
  • the specification provides Compound (I) Form A which has a DSC thermogram with an onset melting at 216.6°C plus or minus 5°C and a peak at 217.7°C plus or minus 5°C. In one embodiment the specification provides Compound (I) Form A which has a DSC thermogram with an onset melting at about 216.6°C and a peak at about 217.7°C. In one embodiment the specification provides Compound (I) Form A which has a DSC thermogram substantially as shown in Figure 3.
  • TGA Thermogravimetric analysis
  • the specification provides a crystalline form which is a co-crystal of (3S)-2- [(5-amino-6-fluoro-1 H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-T-but-2-ynyl-6-fluoro-spiro[isoindoline- 3,3'-pyrrolidine]-1 ,2'-dione:
  • Compound (I), and adipic acid in a 2: 1 ratio having at least one of the following: a) an X-ray powder diffraction pattern containing specific peaks at ( ⁇ 0.2) 8.9, 19.1 , 19.7 and 22.9 degrees 2-theta when measured using CuKa radiation; b) an X-ray powder diffraction pattern containing specific peaks at ( ⁇ 0.2) 8.9, 14.5, 16.9, 17.4, 19.1 , 19.7, 21.2, 22.9, 23.7 and 25.8 degrees 2-theta when measured using CuKa radiation; c) an X-ray powder diffraction pattern substantially as shown in Figure 1 ; d) a DSC thermogram with an onset melting at 216.6°C plus or minus 5°C and a peak at 217.7°C plus or minus 5°C; e) a DSC thermogram and optionally a TGA thermogram substantially as shown in Figure 3.
  • the degree of crystallinity is greater than about 60%. In one embodiment, the degree of crystallinity is greater than about 80%. In one embodiment, the degree of crystallinity is greater than about 90%. In one embodiment, the degree of crystallinity is greater than about 95%. In one embodiment, the degree of crystallinity is greater than about 98%.
  • the crystalline form is substantially free from other crystalline forms of Compound (I) (i.e. a crystalline form or forms other than Compound (I) Form A). Therefore, in one embodiment, the crystalline form contains less than 20%, 15%, 10%, 5%, 3% or 1% by weight of other crystalline forms of Compound (I). In one embodiment, the crystalline form contains more than 80%, 85%, 90%, 95%, 97% or 99% by weight of Compound (I) Form A.
  • Compound (I) Form A is believed to be a co-crystal of (3S)-2-[(5-amino-6-fluoro-1 H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-1'-but-2-ynyl-6-fluoro- spiro[isoindoline-3,3'-pyrrolidine]-1 ,2'-dione and adipic acid in a 2:1 ratio i.e.
  • Compound (I) Form A may also be referred to as Compound (l):hemi-adipic acid co-crystal.
  • co-crystal formation results from situations whereby an acid or base “co-former” is a solid at room temperature and there is no or only partial proton transfer between the free compound and such an acid or base co-former. Consequently, a cocrystal of the co-former and free compound results rather than a salt.
  • the definition of the coformer acid or base being a solid at room temperature is intended to distinguish co-crystals from solvates. It is accepted that the proton transfer is in fact a continuum, and can change with temperature, and therefore the point at which a co-crystal is better described as a salt can be somewhat subjective. However, as noted above, based on all present experimental evidence Compound (I) Form A is believed to be a co-crystal.
  • Compound (I) Form A obtainable by any of the methods disclosed herein. In one embodiment, there is provided Compound (I) Form A obtainable by the method of Example 1 , Method A. In one embodiment, there is provided Compound (I) Form A obtainable by the method of Example 1 , Method B. In one embodiment, there is provided Compound (I) Form A obtainable by the method of Example 1 , Method C.
  • Compound (I) Form A may be further characterised by additional techniques well known to the skilled person, such as single crystal X-ray diffraction (for example to evaluate proton position, bond lengths or bond angles), solid state 1 H-NMR, (to evaluate for example, C or N chemical shifts) or spectroscopic techniques (to measure for example, O-H or N-H signals and IR peak shifts resulting from hydrogen bonding).
  • additional techniques well known to the skilled person such as single crystal X-ray diffraction (for example to evaluate proton position, bond lengths or bond angles), solid state 1 H-NMR, (to evaluate for example, C or N chemical shifts) or spectroscopic techniques (to measure for example, O-H or N-H signals and IR peak shifts resulting from hydrogen bonding).
  • Compound (I) Form A may be prepared as described in the Examples herein. Crystallisation of the desired Compound (I) Form A may be aided by seeding with crystals of the desired form. The seed crystals may be obtained using one of the methods described in the Examples, such as Method B. The use of seeding is particularly advantageous in larger-scale manufacture.
  • Compound (I) is an inhibitor of PRMT5, and in particular Compound (I) is a MTA-synergistic PRMT5 inhibitor. Therefore, Compound (I) Form A is expected to be useful as a medicament, such as in the prophylaxis or treatment of a disorder mediated by PRMT5 i.e. a disorder wherein inhibition of PRMT5 provides a prophylactic or therapeutic effect.
  • prophylaxis is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease or condition and secondary prophylaxis whereby the disease or condition has already developed and the subject is temporarily or permanently protected against exacerbation or worsening of the disease or condition, or the development of new symptoms associated with the disease or condition.
  • prophylactic prevents and preventions are used synonymously with “prophylaxis”.
  • treatment is intended to have its normal meaning of dealing with a disease or condition in order to entirely or partially relieve one, some or all of its symptoms in a subject, or to correct or compensate for the underlying pathology.
  • treatment and treating are used synonymously with “therapy”.
  • a subject will typically be a subject in need of prophylaxis or treatment according to the specification.
  • the subject is a human.
  • the specification provides Compound (I) Form A for use as a medicament.
  • the specification provides Compound (I) Form A for use in the prophylaxis or treatment of a disorder mediated by PRMT5 (e.g. cancer). In one embodiment, the specification provides Compound (I) Form A for use in the prophylaxis of a disorder mediated by PRMT5 (e.g. cancer). In one embodiment, the specification provides Compound (I) Form A for use in the treatment of a disorder mediated by PRMT5 (e.g. cancer).
  • the specification provides the use of Compound (I) Form A in the manufacture of a medicament.
  • the specification provides the use of Compound (I) Form A in the manufacture of a medicament for the prophylaxis or treatment of a disorder mediated by PRMT5 (e.g. cancer). In one embodiment, the specification provides the use of Compound (I) Form A in the manufacture of a medicament for the prophylaxis of a disorder mediated by PRMT5 (e.g. cancer). In one embodiment, the specification provides the use of Compound (I) Form A in the manufacture of a medicament for the treatment of a disorder mediated by PRMT5 (e.g. cancer). In one embodiment, the specification provides a method of preventing or treating a disorder mediated by PRMT5 (e.g. cancer), which comprises administering Compound (I) Form A.
  • PRMT5 e.g. cancer
  • the specification provides a method of preventing a disorder mediated by PRMT5 (e.g. cancer), which comprises administering Compound (I) Form A. In one embodiment, the specification provides a method of treating a disorder mediated by PRMT5 (e.g. cancer).
  • the disorder mediated by PRMT5 is cancer.
  • the cancer is a MTAP deleted cancer i.e. a cancer in which the MTAP gene has been deleted.
  • the cancer is a CDKN2A deleted and MTAP deleted cancer i.e. a cancer in which the CDKN2A and MTAP genes are deleted.
  • the cancer is selected from gastric, pancreatic, colorectal, uterine, bile duct, stomach, bladder, cervical, testicular germ cell, lung (e.g. non-small cell lung cancer), multiple myeloma, lymphoma (e.g. diffuse large B cell lymphoma or Hodgkin’s lymphoma), rhabdomyosarcoma and cutaneous squamous cell carcinoma.
  • lung e.g. non-small cell lung cancer
  • multiple myeloma e.g. diffuse large B cell lymphoma or Hodgkin’s lymphoma
  • rhabdomyosarcoma e.g. diffuse large B cell lymphoma or Hodgkin’s lymphoma
  • cutaneous squamous cell carcinoma e.g., cutaneous squamous cell carcinoma.
  • the cancer is selected from gastric, lung (e.g. non-small cell lung cancer) and lymphoma (e.g. diffuse large B cell lymphoma or Hodgkin’s lymphoma).
  • lung e.g. non-small cell lung cancer
  • lymphoma e.g. diffuse large B cell lymphoma or Hodgkin’s lymphoma
  • the cancer is non-small cell lung cancer. In one embodiment, the cancer is diffuse large B cell lymphoma. In one embodiment, the cancer is Hodgkin’s lymphoma.
  • Compound (I) Form A may be administered in conjunction with other compounds used for the treatment of the above conditions.
  • a combination therapy comprising Compound (I) Form A and a second active ingredient.
  • Compound (I) Form A and a second active ingredient may be administered concurrently, sequentially or in admixture, for the treatment of one or more of the conditions listed above. Such a combination may be used in combination with one or more further active ingredients.
  • Compound (I) Form A will typically be administered as a pharmaceutical composition. Therefore, in one embodiment the specification provides a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient. In one embodiment, the specification provides a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient for use as a medicament.
  • the specification provides a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient for use in the prophylaxis or treatment of a disorder mediated by PRMT5, such as the disorders disclosed herein (e.g. cancer).
  • the specification provides a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient for use in the prophylaxis of a disorder mediated by PRMT5, such as the disorders disclosed herein (e.g. cancer).
  • the specification provides a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient for use in the treatment of a disorder mediated by PRMT5, such as the disorders disclosed herein (e.g. cancer).
  • the specification provides the use of a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament.
  • the specification provides the use of a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for the prophylaxis or treatment of a disorder mediated by PRMT5, such as the disorders disclosed herein (e.g. cancer).
  • the specification provides the use of a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for the prophylaxis of a disorder mediated by PRMT5, such as the disorders disclosed herein (e.g. cancer).
  • the specification provides the use of a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for the treatment of a disorder mediated by PRMT5, such as the disorders disclosed herein (e.g. cancer).
  • a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for the treatment of a disorder mediated by PRMT5, such as the disorders disclosed herein (e.g. cancer).
  • the specification provides a method of preventing or treating a disorder mediated by PRMT5, such as the disorders disclosed herein (e.g. cancer), which comprises administering a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient.
  • the specification provides a method of preventing a disorder mediated by PRMT5, such as the disorders disclosed herein (e.g. cancer), which comprises administering a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient.
  • the specification provides a method of treating a disorder mediated by PRMT5, such as the disorders disclosed herein (e.g. cancer), which comprises administering a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient.
  • Compound (I) Form A will normally be administered in the form of a pharmaceutical composition comprising Compound (I) Form A in a pharmaceutically acceptable dosage form via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses. In one embodiment, Compound (I) Form A or a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient are administered orally.
  • the specification provides a solid oral dosage form comprising Compound (I) Form A or a pharmaceutical composition comprising Compound (I) Form A and at least one pharmaceutically acceptable excipient.
  • the solid oral dosage form is a tablet.
  • compositions of the specification may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents; granulating and disintegrating agents; binding agents; and lubricating agents. Tablet formulations may be uncoated or coated using conventional coating agents and procedures well known in the art.
  • the amount of active ingredient (i.e. Compound (I) Form A) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. Suitable daily doses of Compound (I) Form A in prophylactic or therapeutic treatment of humans are about 0.0001-100 mg/kg body weight.
  • NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Bruker Avance 400 (400 MHz) instrument]; measurements were taken at ambient temperature unless otherwise specified; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; bs, broad signal; (vii) in general, compounds were also characterized by mass spectrometry following liquid chromatography (LCMS or LIPLC); reverse-phase C18 silica was used with a flow rate of 1 mL/min and detection was by Electrospray Mass Spectrometry and by UV absorbance recording a wavelength range of 220-320 nm.
  • LCMS liquid chromatography
  • Analytical LIPLC was performed on CSH C18 reverse-phase silica, using a Waters Acquity LIPLC CSH C18 column with dimensions 2.1 x 50 mm and particle size 1.7 micron) Gradient analysis was employed using decreasingly polar mixtures as eluent, for example decreasingly polar mixtures of water (containing 0.1% formic acid or 0.1 % ammonia) as solvent A and acetonitrile as solvent B.
  • a typical 2 minute analytical LIPLC method would employ a solvent gradient over 1.3 min, at approximately 1 mL/min, from a 97:3 mixture of solvents A and B respectively to a 3:97 mixture of solvents A and B.
  • the reported molecular ion corresponds to the [M+H]+ unless otherwise specified; for molecules with multiple isotopic patterns (Br, Cl etc.) the reported value is the one obtained for the lowest isotope mass unless otherwise specified;
  • Diisobutylaluminum hydride (1M in toluene) (170 mL, 170.42 mmol) was added dropwise to a stirred solution of methyl 5-chloro-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1/7-pyrrolo[3,2- b]pyridine-2-carboxylate (27.80 g, 77.47 mmol) in DCM (333 mL) at 5 °C over 15 minutes. The reaction mixture was stirred at rt for 30 minutes. The reaction mixture was carefully poured into 2M NaOH (500 mL), diluted with DCM (500 mL) and stirred for 1 hour.
  • Methyl 2-(2-bromo-4-fluorophenyl)acetate (45.0 g, 182.14 mmol) and triethylamine (27.90 mL, 200.35 mmol) were placed in a steel pressure vessel with MeOH (300 mL).
  • MeOH 300 mL
  • [1 ,T- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (complex with dichloromethane) (4.46 g, 5.46 mmol) was added and the vessel was sealed.
  • the vessel was purged with carbon monoxide and then charged to 7 bar with carbon monoxide.
  • the pressure vessel was heated to 100 °C and stirred for 2 hours.
  • the reaction mixture was allowed to cool, vented and filtered to remove catalyst.
  • the aqueous phase was re-extracted with EtOAc (100 mL), the organics were combined and washed with brine (50 mL).
  • the organic phase was passed through a phase separating filter paper and the solvent was removed in vacuo.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford the title compound (45.3 g, 96%) as a pale yellow oil.
  • 1,1 ,3,3-tetramethylguanidine (13.7 mL, 109 mmol) was then added dropwise.
  • the reaction mixture was stirred at 5 °C for 5 minutes.
  • the THF was removed in vacuo.
  • the reaction mixture was partitioned between EtOAc (400 mL) and water (400 mL) and the organic phase was passed through a phase separating filter paper. The solvent was removed in vacuo to afford an orange oil.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford the title compound (25.8 g, 96%) as a cream solid.
  • Methyl (S)-1-allyl-5-fluoro-2-(4-methoxybenzyl)-3-oxoisoindoline-1-carboxylate (20.0 g, 54.1 mmol) was placed in a flask with MeCN (200 mL) and water (100 mL). Ammonium cerium(IV) nitrate (74.2 g, 135 mmol) was added and the reaction mixture was stirred at rt for 30 minutes. The MeCN was removed in vacuo and the reaction mixture was partitioned between DCM (400 mL) and water (250 mL). The aqueous phase was extracted with DCM (200 mL).
  • the reaction mixture was cooled and partitioned between water (300 mL) and EtOAc (300 mL). The aqueous phase was re-extracted with EtOAc (200 mL). The organic phases were combined, washed with water (3 x 200 mL), brine (200 mL), passed through a phase separating filter paper and the solvent was removed in vacuo.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford the title compound (22.2 g, 83%) as a yellow gum which slowly solidified/crystallised to give a yellow solid.
  • the reaction mixture was stirred at rt for 18 hours.
  • the reaction mixture was partitioned between DCM (200 mL) and water (100 mL).
  • the aqueous phase was re-extracted with DCM (100 mL) and the organic phases were combined, passed through a phase separating filter paper and the solvent was removed in vacuo.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford the title compound (8.70 g, 75%) as a beige foam.
  • Triethylamine (3.08 mL, 22.10 mmol) was added and the reaction mixture was stirred at rt for 30 minutes.
  • Sodium triacetoxyborohydride (6.25 g, 29.47 mmol) was added and the reaction mixture was stirred at rt overnight.
  • the reaction mixture was diluted with DCM (250 mL) and washed with saturated NaHCOs (100 mL), water (100 mL) and brine (100 mL). The organic phase was passed through a phase separating filter paper and the solvent was removed in vacuo to afford the title compound.
  • the crude compound was used without further purification in the next reaction assuming 100% yield, m/z MH + 666.
  • Method B Anti-solvent/coolinq co-crystallisation (not seeded)
  • Reference Form 1 (501.51 mg, 1.0942 mmol, 95 mass%) was charged into a 8 mL vial, adipic acid (166.13 mg, 1.1368 mmol, 100 mass%) and dimethyl sulfoxide (3.54 g, 45.3 mmol, 100 mass%) were charged and the contents agitated using a doubly 3-pitched blade impeller at 600 rpm, heated to 25°C and held at this temperature for 5 minutes. The contents of the vial were then heated at a rate of 5°C/minute to 80°C and the temperature held for 20 minutes.
  • Method C Coolinq/anti-solvent co-crystallisation (seeded)
  • Reference Form 1 (8.01 g, 18.2 mmol, 99 mass%) was charged into a 100 mL vessel, adipic acid (2.57 g, 17.6 mmol, 100 mass%) and dimethyl sulfoxide (54.88 g, 702.4 mmol, 100 mass%) were charged and the contents agitated using a 4-pitched blade impeller at 400 rpm, heated to 25°C and held at this temperature for 30 minutes. The contents of the vessel were then heated at a rate of 5°C/minute to 80°C and the temperature held for 20 minutes.
  • the anti-solvent, water (12 mL, 666.119 mmol, 100 mass%) was charged to the vessel at 20°C over 6 hours and the temperature held for a further 6 hours. The contents of the vessel were then discharged to a filter (63 mm diameter) under ambient conditions and deliquored under vacuum resulting in a cake height of 8 mm. Pre-mixed dimethyl sulfoxide (7.2 mL, 100 mmol, 100 mass%) and water (4.8 mL, 270 mmol, 100 mass%) were charged to the vessel under ambient conditions for washing. The contents of the vessel were agitated at 20°C then discharged to the filter under ambient conditions and deliquored under vacuum.
  • the powder X-ray diffractogram was recorded with a two theta scan axis and in one dimensional scan with a Rigaku SmartLab (wavelength of X-rays 1.5418 A nickel-Filtered Cu Ka radiation, 40 kV, 50 mA) equipped with a D/tex Ultra 250 detector and CBO-E optic.
  • the sample was rotated at 30 revolutions per minute during measurement.
  • the sample was scanned from 3-40° 2-theta using a 0.01° and 0.1 min step width and scan speed, respectively.
  • the powder sample was packed in a long glass capillary with 0.9 mm outer diameter.
  • Relative intensity refers to integrated peak size normalised to that of the largest peak with the categories defined as in Table 1.
  • Thermal events were analysed by standard mode differential scanning calorimetry on a TA Discovery DSC instrument. Approximately 1.5-2.0 mg of material contained in a standard closed aluminium pan was measured over the temperature range 25°C to 300°C at a constant heating rate of 10°C/minute. Nitrogen was used as a purge gas at a flow rate of 50 mL/minute.
  • TGA of Reference Form 1 shows weight loss of 1.617% to 100°C due to de-solvation, indicating an initial hydrated form ( Figure 2).
  • TGA of Compound (I) Form A showed no significant weight loss prior to the melting point, indicating an anhydrous form ( Figure 3).
  • DVS analysis shows that Reference Form 1 undergoes reversible hydration from the hemihydrate to the mono-hydrate at high relative humidity, and reversible dehydration from the hemihydrate to the an-hydrate at low relative humidity (Figure 4). DVS analysis also reveals that Reference Form 1 has a moisture uptake of 3.37% at 80% relative humidity ( Figure 4).
  • Compound (I) Form A has very low hygroscopicity, with a moisture uptake of 0.50% at 80% relative humidity ( Figure 5).
  • SGF simulated gastric fluid
  • FaSSIF fasted state simulated intestinal fluid
  • FeSSIF fed state simulated intestinal fluid
  • Compound (I) Form A Physical stability of Compound (I) Form A was assessed by a water slurry method. Approximately 15 mg of Compound (I) Form A was weighed into a vial and 250 pL water added. This was stirred using a magnetic stirrer bar at ambient temperature for 10 days, then filtered using a 0.45 pm centrifuge filter (13,000 rpm for 5 minutes) and analysed by XRPD, which showed no form change in the Compound (I) Form A material, indicating that Compound (I) Form A appears to be physically stable.

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Abstract

La présente invention concerne une forme cristalline de (3S)-2-[(5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)méthyl]-1'-but-2-ynyl-6-fluoro-spiro[isoindoline-3,3'-pyrrolidine]-1,2'-dione, et des compositions à base de celle-ci et des utilisations associées.
PCT/EP2024/056495 2023-03-13 2024-03-12 Forme cristalline Pending WO2024188999A1 (fr)

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CN202480017739.5A CN120917029A (zh) 2023-03-13 2024-03-12 结晶形式
AU2024236796A AU2024236796A1 (en) 2023-03-13 2024-03-12 Crystalline form
KR1020257033631A KR20250155619A (ko) 2023-03-13 2024-03-12 결정질 형태
IL323224A IL323224A (en) 2023-03-13 2025-09-08 Crystalline form
MX2025010674A MX2025010674A (es) 2023-03-13 2025-09-10 Forma cristalina

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448388B2 (en) 2023-04-21 2025-10-21 Gilead Sciences, Inc. PRMT5 inhibitors and uses thereof

Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2022192745A1 (fr) * 2021-03-11 2022-09-15 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 coopératif à base de mta
WO2023278564A1 (fr) * 2021-07-02 2023-01-05 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 à coopération avec la mta à base d'aminopyridine
WO2023036974A1 (fr) 2021-09-13 2023-03-16 Astrazeneca Ab Composés spirocycliques

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2022192745A1 (fr) * 2021-03-11 2022-09-15 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 coopératif à base de mta
WO2023278564A1 (fr) * 2021-07-02 2023-01-05 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 à coopération avec la mta à base d'aminopyridine
WO2023036974A1 (fr) 2021-09-13 2023-03-16 Astrazeneca Ab Composés spirocycliques

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BUNN, C.W.: "Chemical Crystallography", 1948, CLARENDON PRESS
JENKINS, RSNYDER, R. L.: "Introduction to X-Ray Powder Diffractometry", 1996, JOHN WILEY & SONS
KIM ET AL., CELL STRESS, vol. 4, no. 8, 2020, pages 199 - 2151
KITAIGORODSKY, A.I.: "Molecular Crystals and Molecules", 1973, ACADEMIC PRESS
KLUG, H.P.ALEXANDER, L.E.: "X-ray Diffraction Procedures", 1974, JOHN WILEY & SONS
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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US12448388B2 (en) 2023-04-21 2025-10-21 Gilead Sciences, Inc. PRMT5 inhibitors and uses thereof

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