Classifications

• • 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
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4816—Wall or shell material
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds
• • 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
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/235—Saturated compounds containing more than one carboxyl group
  • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
  • C07C59/255—Tartaric acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • 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 invention relates to a crystalline form of 3-((lR,3R)-l-(2,6-difluoro-4-((l-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-l,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2- yl)-2,2-difluoropropan-l-ol tartrate, to pharmaceutical compositions comprising the same, as well as processes for its preparation and its use as a medicament for the treatment of cancer.
• the estrogen receptor (ER) is a ligand-activated transcriptional regulatory protein that mediates induction of a variety of biological effects through its interaction with endogenous estrogens.
• Endogenous estrogens include 17p (beta) -estradiol and estrones.
• ER has been found to have two isoforms, ER-a (alpha) and ER-P (beta).
• Estrogens and estrogen receptors are implicated in a number of diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, as well as other diseases or conditions.
• ER-a targeting agents have particular activity in the setting of metastatic disease and acquired resistance.
• WO2019245974 discloses a tartrate salt of giredestrant having Formula (I), as well as certain crystalline forms thereof.
• Form B One of the crystalline forms of the tartrate of Formula (I) described WO2019245974 is Form B (hereinafter “Form B”). It has been found that said Form B exhibits a unique mechanical behavior that makes its processing by mechanical compression very difficult. Thus, mechanical compression as applied during tableting of conventional pharmaceutical compositions regularly leads to partial decomposition of the API (see Examples 7 and 8), color changes and lump formation. One way to avoid the detrimental compression forces applied during tableting is to fill the API, or a pharmaceutical composition comprising it, directly into capsules (“direct encapsulation”). However, it has been found that Form B is not well suited for capsule formulations, because it exhibits an inhomogeneous particle size distribution that varies from batch-to-batch - as shown in Figs. 8 a)-c) - with low bulk density, as well as poor flowability (see Example 9), which hampers processing on an industrial scale.
• Form B is not well suited to provide tablet and capsule formulations on an industrial scale.
• crystalline Form B of giredestrant tartrate has improved flow properties and bulk density (see Example 9) compared to crystalline Form B prepared according to the procedures described in WO2019245974, and is very well suited for providing capsule formulations, overcoming the issues outlined above.
• Capsule formulations comprising the improved drug substance can conveniently be prepared without a granulation step, and without using a binder as an excipient.
• the capsule formulation of the invention has a lower variability in its dissolution profile than formulations comprising previously known forms of giredestrant, while showing a similar release profile.
• the present invention provides crystalline 3-((lR,3R)-l-(2,6-difluoro-4- (( 1 -(3 -fluoropropyl)azetidin-3 -yl)amino)phenyl)-3 -methyl- 1,3,4, 9-tetrahydro-2H-pyrido [3 ,4- b]indol-2-yl)-2,2-difluoropropan-l-ol tartrate of formula (I) having:
• the present invention provides processes for manufacturing the crystalline form of the invention, formulations comprising the same, and methods of using the same in medical therapy.
• Figure 1 depicts the particle size distribution (PSD) for the crystalline compound of formula (I) according to the present invention.
• Figure 2 depicts a flow chart of the process for manufacturing the pharmaceutical composition according to the invention.
• Figure 3 depicts the API content in sieve fractions of final blends containing the crystalline compound of formula (I) according to the present invention as API (“GPV0137”) or containing the compound of formula (I) in the quality disclosed in WO2019245974 (“GMP0492”) as API.
• Figure 8 a depicts the particle size distribution of API lot “A” obtained by the process described in WO2019245974 (compare with Fig. 9C of WO2019245974).
• Figure 8 b depicts the particle size distribution of API lot “B” obtained by recrystallization of API lot “A”.
• Figure 8 c depicts the particle size distribution of API lot “C” obtained by recrystallization of API lot “A”.
• Form B relates to crystalline Form B of giredestrant tartrate (Formula (I)) as described in WO2019245974, i.a. having an X-ray powder diffraction pattern comprising peaks at 11.49, 12.54, 19.16, 19.42, or 24.67 [° 2 Theta ⁇ 0. 1° 2 Theta, Cu Ka radiation].
• said crystalline Form B has an X-ray powder diffraction pattern comprising the peaks outlined in Table 1 :
• Table 1 Representative XRPD Peaks for Form B of giredestrant tartrate
• hypothalamic fluid As used herein, the terms “hypromellose”, “HPMC” and “hydroxypropyl methylcellulose” refer to cellulose, 2-hydroxypropyl methyl ether (CAS 9004-65-3), and are used interchangeably.
• HDPE high density polyethylene
• filler refers to a substance added to a pharmaceutical composition to increase the weight and/or size of the pharmaceutical composition.
• Pharmaceutically acceptable fillers are described in Remington’s Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017.
• Non-limiting examples of fillers are starch (e.g., pregelatinized starch), cellulose (e.g., microcrystalline cellulose) and lactose (e.g., lactose monohydrate).
• Preferred, yet non-limiting examples of fillers are cellulose and lactose.
• disintegrant refers to a substance added to a pharmaceutical composition to help break apart (disintegrate), e.g., after administration, and release the active ingredient, such as Form B described herein.
• Pharmaceutically acceptable disintegrants are described in Remington’ s Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of disintegrants are low substituted hydroxypropyl cellulose and croscarmellose sodium. A preferred, yet non-limiting example of a disintegrant is croscarmellose sodium.
• lubricant refers to a substance added to a pharmaceutical composition to help reduce the adherence of a granule of powder to equipment surfaces.
• Pharmaceutically acceptable lubricants are described in Remington’s Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017.
• Non-limiting examples of lubricants are sodium stearyl fumarate and magnesium stearate.
• a preferred, yet non-limiting example of a lubricant is magnesium stearate.
• the term “treating” means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
• the disorder is a cancer.
• the term “effective amount” refers to an amount of a compound described herein capable of treating a disorder, disease or condition, or symptoms thereof, disclosed herein.
• the term “patient” refers to animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quails, or guinea pigs and the like, in one embodiment a mammal, in another embodiment a human.
• a subject is a human having or at risk for cancer.
• the present invention provides crystalline 3-((lR,3R)-l-(2,6-difluoro-4- (( 1 -(3 -fluoropropyl)azetidin-3 -yl)amino)phenyl)-3 -methyl- 1,3,4, 9-tetrahydro-2H-pyrido [3 ,4- b]indol-2-yl)-2,2-difluoropropan-l-ol tartrate of formula (I) having:
• crystalline form B of giredestrant tartrate having a favourable particle size distribution is formed when said crystalline form is prepared by a particular process.
• the present invention provides a process for manufacturing the crystalline form of giredestrant tartrate described herein, said process comprising the steps of a) providing a solution of 3-((lR,3R)-l-(2,6-difluoro-4-((l-(3-fluoropropyl)azetidin-3- yl)amino)phenyl)-3 -methyl- 1,3,4, 9-tetrahydro-2H-pyrido[3 ,4-b]indol-2-yl)-2,2- difluoro-propan-l-ol (“free base”) in an organic solvent; bl) adding the solution of step a) to a solution of tartaric acid in an organic solvent at 15- 30 °C; or b2) adding a solution of tartaric acid in an organic solvent to the solution of step a) at 15- 30 °C.
• said organic solvent used in the process of the invention is ethanol.
• the process of the invention further comprises: c) stirring the suspension obtained from bl) or b2) at 15-30 °C for at least 8 hours.
• the temperature in steps bl), b2) and c) of the process of the invention is maintained at 20-25 °C.
• the temperature in steps bl), b2) and c) of the process of the invention is maintained at 20 °C.
• the concentration of the free base in the solution provided in step a) of the process of the invention is about 13 to 19%-w/w. In one embodiment, the concentration of tartaric acid in the solution used in step bl) or b2) of the process of the invention is about 8 to 12%-w/w.
• step bl) comprises: bl a) adding a first portion of the solution of step a) to a solution of tartaric acid in an organic solvent; bib) seeding the solution of step bl a) with the crystalline compound of formula (I) according to claim 1 ; and blc) adding the remainder of the solution of step a) to the mixture of step bib); and step b2) comprises: b2a) adding a first portion of a solution of tartaric acid in an organic solvent to the solution of step a); b2b) seeding the solution of step b2a) with the crystalline compound of formula (I) according to claim 1 ; and b2c) adding a second portion of a solution of tartaric acid in an organic solvent to the mixture of step b2b).
• step bl a) amounts to about 10-30% of the total amount of solution of step a);
• step b2a said first portion of a solution of tartaric acid in an organic solvent in step b2a) amounts to about 20-30% of the total amount of solution of tartaric acid in an organic solvent that is used in step b2).
• the present invention provides a crystalline compound of formula (I) as described herein, when obtained by the processes described herein.
• the present invention provides a pharmaceutical composition for oral administration comprising the crystalline compound of formula (I) as described herein and one or more pharmaceutically acceptable excipients selected from fillers, disintegrants and lubricants.
• the pharmaceutical composition according to the invention comprises the crystalline compound of formula (I) as described herein and one or more fillers, a disintegrant and a lubricant.
• the pharmaceutical composition according to the invention comprises the crystalline compound of formula (I) as described herein, and:
• said first filler is microcrystalline cellulose
• said second filler is lactose monohydrate
• said disintegrant is croscarmellose sodium
• said lubricant is magnesium stearate.
• the weight of said first filler represents 33 ⁇ 1% of the total weight of the composition
• the weight of said second filler represents 10 ⁇ l% of the total weight of the composition
• the weight of said disintegrant represents 5 ⁇ 1% of the total weight of the composition
• the weight of said lubricant represents 0.5 ⁇ l% of the total weight of the composition
• the weight of said crystalline compound of formula (I) represents 51 ,5 ⁇ 1% of the total weight of the composition.
• the pharmaceutical composition according to the invention comprises said compound of formula (I) in an amount of 38.62 mg (equivalent to 30 mg of the “free base”).
• the present invention provides a capsule for oral administration containing the pharmaceutical compositions described herein.
• said capsule is made of hypromellose.
• the pharmaceutical composition according to the invention is:
• Present invention further provides a process for the manufacture of pharmaceutical compositions as described herein.
• the present invention provides a process for the manufacture of pharmaceutical compositions according to Figure 2.
• the present invention provides a process for making the pharmaceutical compositions described herein, comprising: a) combining and blending the crystalline compound of formula (I) described herein and a first filler; b) sieving the blend obtained in step a); c) adding a second filler and a disintegrant to the blend obtained in step b); d) sieving the blend obtained in step c); e) sieving a lubricant; f) adding the sieved lubricant from step e) to the blend obtained in step d); and g) blending the mixture obtained in step f).
• said sieving in steps b) and d) is performed using a conical mill.
• said sieving in step e) is performed using a sieve with a mesh size of 0.5-1.0 mm.
• the process for making the pharmaceutical compositions of the invention further comprises:
• step g) transferring the final blend obtained in step g) into capsules.
• a particular aspect of the present invention relates to crystalline Form B as defined above for use as a medicament.
• a further aspect of the invention relates to crystalline Form B as defined herein, as well as to pharmaceutical compositions comprising the same, for use in the treatment of cancer.
• the present invention provides a method for treating cancer in a patient having said cancer, said method comprising administering an effective amount of crystalline Form B described herein, or a pharmaceutical composition described herein to the cancer patient.
• the present invention provides the use of crystalline Form B as defined herein, as well as of pharmaceutical compositions described herein, in a method for treating cancer in a patient having said cancer.
• the present invention provides the use of crystalline Form B as defined herein in the manufacture of a medicament for treating cancer in a patient having said cancer.
• said cancer is selected from lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer.
• said cancer is breast cancer.
• said cancer is breast cancer selected from hormone receptor positive breast cancer, HER2-positive breast cancer, and triple negative breast cancer.
• said cancer is breast cancer selected from HER2-negative, HER2- positive breast cancer, and triple negative breast cancer.
• said cancer is metastatic breast cancer.
• the compound or pharmaceutical composition of the invention is administered as a component of adjuvant therapy. In one embodiment, the compound or pharmaceutical composition of the invention is administered as a component of neoadjuvant therapy.
• said cancer is breast cancer which is stage 0, 1, II, III, or IV.
• the patient has had previous treatment with one or more anti-cancer agents or radiation therapy.
• the patient has had surgery prior to treatment with Form B of the invention.
• Form B of the invention is administered in combination with one or more of radiation therapy, hormone therapy, or an anti-cancer agent.
• Form B of the invention is administered in combination with one or more anti-cancer agents.
• said anti-cancer agents are selected from doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5- fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxy tamoxifen, raloxifene, droloxifene, trioxifene, keoxifene, ftutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprolide, pegfilgrastim, filgrastim, and venetocla
• said anti-cancer agents are selected from an AKT inhibitor, a CDK4/6 inhibitor, a PARP inhibitor, and an aromatase inhibitor.
• said anti-cancer agent is abemaciclib, ribociclib, or palbociclib.
• said anti-cancer agent is abemaciclib.
• said anti-cancer agent is ribociclib.
• said anti-cancer agent is palbociclib.
• said anti-cancer agent is ipatasertib. In one embodiment, said anti-cancer agent is everolimus or fulvestrant.
• said anti-cancer agent is ado-trastuzumab emtansine, trastuzumab, pertuzumab, or atezolizumab.
• said anti-cancer agent is alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, tositumomab, or a combination thereof.
• aqueous sodium hydroxide solution (22.4 kg, 28 mol NaOH, 2.1 eq) was added at ambient temperature to afford a solution of3-((lR,3R)-l-(2,6-difluoro-4-((l-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-l,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2- yl)-2,2-difluoro-propan-l-ol (hereinafter “free base”).
• the aqueous phase was discarded; the organic phase was washed with water to remove salts and filtered via charcoal.
• aqueous sodium hydroxide solution (2.1 eq, 13.8 kg, 17.2 mol NaOH,) was added at ambient temperature to afford a solution of3-((lR,3R)-l-(2,6-difluoro-4-((l-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-l,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2- yl)-2,2-difluoro-propan-l-ol (hereinafter “free base”).
• the aqueous phase was discarded; the organic phase was washed two times with water and filtered via charcoal. Subsequently, a solvent swap from TBME to EtOH was performed by vacuum distillation. The final concentration of the free-base in EtOH at the end of the solvent exchange was adjusted to 16 %- w/w.
• a Malvern MasterSizer 3000 device from Malvern, UK, coupled with a liquid dispersion unit Hydro MV®, Malvern, UK was used.
• the crystalline Giredestrant tartrate as obtained from Example 1 or 2 was dispersed in dispersion medium consisting in technical grade n-heptane with 0.2% w/w.-% Span 85 (Sorbitane trioleate, e.g. Fluka / Sigma Cat. Nr. 85549 or equivalent) non- saturated.
• the test dispersion was measured and the cumulative volume dispersion was determined using the laser diffraction instrument mentioned above in accordance with the instruction manual. Measurements were performed after 2 minutes stirring time. The Fraunhofer approximation was used for the particle diameters calculations, Opaque Particle was used for the Particle type and General purpose was used for the Analysis model. The background and the measuring duration were set at 30 seconds.
• Capsule formulations comprising the crystalline compound of formula (I) according to the invention were prepared as described in the flow diagram of Figure 2 and following the detailed procedure below.
• Step la Giredestrant tartrate and microcrystalline cellulose were combined in one container and blended.
• Step lb Blend la was sieved using a conical mill.
• Step 1c Lactose monohydrate and croscarmellose sodium were added to the blend lb and blended.
• Step Id Blend 1c was sieved using a conical mill.
• Step 2 Magnesium stearate was sieved through a sieve having a mesh size of 0.5 mm (0.5- 1.0mm), added to the blend from step Id and blended.
• Step 3 The final blend was transferred into empty size 3 HPMC capsules.
• Step 4 The capsules were packaged in HDPE bottles with desiccant.
• Example 5 30 mg Capsule Formulation
• Reference Example 6 Alternative Capsule Formulation Also provided is a capsule formulation for oral administration consisting of the same ingredients as the capsule formulation of Example 5, with the exception of hypromellose. All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade. The dose strength of the capsule formulation is preferably 30 mg (free base equivalent).
• Reference Example 6 Immediate Release Tablet Formulation
• an immediate release tablet formulation for oral administration consisting of giredestrant tartrate, microcrystalline cellulose, lactose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade.
• the dose strength of the capsule formulation is preferably 50 mg or 10 mg (free base equivalent).
• Example 7 Stability Data for API

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