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CN-122003228-A - Stable 4- (aminomethyl) -6- (phenylpyrazolyl) phthalazinone compositions and methods for preparing same

CN122003228ACN 122003228 ACN122003228 ACN 122003228ACN-122003228-A

Abstract

A granular composition of 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1 h-pyrazol-5-yl) -4-chloro-6-cyclopropoxy-3-fluorobenzonitrile comprising a crystalline form of said compound comprising a first chiral crystalline form present in an amount of at least 85 wt% by weight of said crystalline form, and a filler. A process for preparing the composition comprises providing a crystalline form of 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropoxy-3-fluorobenzonitrile comprising at least 95 wt% of a first chiral crystalline form, providing a filler, mixing the crystalline form and the filler in a weight ratio of at least 1:10, subjecting the mixture to a granulation process selected from the group consisting of fluid bed granulation, high or low shear granulation and dry granulation to obtain a granular composition, wherein the granular composition has no more than 10 wt% of the amorphous form of 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropoxy-3-fluorobenzonitrile, and wherein the granular composition has no more than 5.5 wt% of the second hand form of 2- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl-3-fluorobenzonitrile.

Inventors

  • N. Loka
  • M. Kailipur
  • S. Shanulai
  • C. Nunes

Assignees

  • 米拉蒂治疗公司

Dates

Publication Date
20260508
Application Date
20240912
Priority Date
20230919

Claims (20)

  1. A granular composition of 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1 h-pyrazol-5-yl) -4-chloro-6-cyclopropoxy-3-fluorobenzonitrile comprising: A crystalline form of 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1 h-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile comprising: a first chiral crystalline form present in an amount of at least 85 wt% by weight of the crystalline form; an optional second chiral form present in an amount of no more than 5wt% by weight of the crystalline form, and An optional amorphous form present in an amount of no more than 10 wt% by weight of the crystalline form; Filler, and Optionally an organic acid.
  2. 2. The particulate composition of claim 1, wherein the crystalline form is a hydrochloride salt.
  3. 3. The particulate composition of claim 1, wherein the crystalline composition is a free base.
  4. 4. A granular composition according to any one of claims 1 to 3 wherein the crystalline form is present in an amount of at least 10 wt% (e.g. at least 20 wt%, at least 30 wt%, at least 40 wt% or at least 50 wt%) by weight of the granular composition.
  5. 5. The particulate composition of any one of claims 1-4, wherein the crystalline form is present in an amount ranging from 10-90 wt% (e.g., ranging from 10-70 wt% or 10-50 wt% or 30-90 wt% or 30-70 wt% or 30-50 wt%) based on the weight of the particulate composition.
  6. 6. The particulate composition of any one of claims 1-5, wherein the filler is selected from the group consisting of colloidal silica, croscarmellose sodium, polyvinylpyrrolidone, dibasic calcium phosphate, sodium lauryl sulfate, hydroxypropyl cellulose (e.g., hydroxypropyl methylcellulose), lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, sodium stearyl fumarate, or a combination thereof.
  7. 7. The particulate composition of any one of claims 1-6, wherein the filler comprises microcrystalline cellulose, mannitol, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
  8. 8. The particulate composition of claim 7, wherein microcrystalline cellulose is present in an amount of at least 20 wt% (e.g., at least 30 wt%, at least 40wt%, or at least 50 wt%) by weight of the particulate composition.
  9. 9. The particulate composition of claim 7 or claim 8, wherein mannitol is present in an amount of at least 10wt% (e.g., at least 15 wt% or at least 20 wt%) by weight of the particulate composition.
  10. 10. The particulate composition of any one of claims 7-91, wherein the croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide and magnesium stearate are present in an amount of no more than 15 wt% (e.g., no more than 12 wt% or no more than 10 wt% or no more than 8 wt%) based on the weight of the particulate composition.
  11. 11. The particulate composition of any one of claims 1-6, wherein the filler comprises microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate.
  12. 12. The particulate composition of claim 11, wherein microcrystalline cellulose is present in an amount of at least 5 wt% (e.g., at least 10 wt%, at least 15 wt%, at least 20 wt%, or at least 25 wt%) by weight of the particulate composition.
  13. 13. A granular composition according to claim 11 or claim 12 wherein the croscarmellose sodium is present in an amount of at least 4 wt% (e.g. at least 6 wt% or at least 8 wt%) by weight of the granular composition.
  14. 14. A granular composition according to any one of claims 11 to 13 wherein the hydroxypropyl methylcellulose and magnesium stearate are present in an amount of no more than 10 wt% (e.g. no more than 5 wt%).
  15. 15. The particulate composition of any one of claims 1-6, wherein the filler comprises microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, and magnesium stearate.
  16. 16. The particulate composition of claim 15, wherein microcrystalline cellulose is present in an amount of at least 5 wt% (e.g., at least 10 wt%, at least 15 wt%, at least 20 wt%, or at least 25 wt%) by weight of the particulate composition.
  17. 17. A granular composition according to claim 15 or claim 16 wherein the croscarmellose sodium is present in an amount of at least 4 wt% (e.g. at least 6 wt% or at least 8 wt%) by weight of the granular composition.
  18. 18. The particulate composition according to any one of claims 15-17, wherein polyvinylpyrrolidone and magnesium stearate are present in an amount of no more than 10 wt% (e.g. no more than 5 wt%) by weight of the particulate composition.
  19. 19. The particulate composition of any one of claims 1-18, wherein the filler is present in an amount of at least 10 wt% (e.g., at least 20 wt%, at least 30 wt%, at least 40 wt%, or at least 50 wt%) by weight of the particulate composition.
  20. 20. The particulate composition according to any one of claims 1-19, wherein the filler is present in an amount ranging from 10-90 wt% (e.g. ranging from 10-70 wt% or 10-50 wt% or 30-90 wt% or 30-70 wt% or 30-50 wt%) based on the weight of the particulate composition.

Description

Stable 4- (aminomethyl) -6- (phenylpyrazolyl) phthalazinone compositions and methods for preparing same Cross Reference to Related Applications The present application claims priority from U.S. provisional patent application No. 63/583,775 filed on 9/2023, 19, the disclosure of which is incorporated herein by reference in its entirety. Technical Field The present invention relates to a granular composition of 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1 h-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile, a pharmaceutical composition comprising the granular composition and a process for the preparation thereof. The particulate compositions are useful for the treatment and/or prevention of diseases and/or conditions involving cell proliferation, such as cancer. In particular, the granular composition provides therapeutic benefits as an MTA-synergistic inhibitor of the protein arginine N-methyltransferase 5 (PRMT 5). Background The protein arginine N-methyltransferase (PRMT 5) is an arginine methyltransferase type II that catalyzes the transfer of the methyl group of S-adenosyl-L-methionine (SAM) to the ω -nitrogen of the guanidino function of the protein L-arginine residue (ω -monomethylation) and transfers the second methyl group to another ω -nitrogen, producing symmetrical dimethylarginine (sDMA). PRMT5 forms a complex with MEP50 (methyosin 50) that is necessary for substrate recognition and targeting and is also necessary for PRMT 5-catalyzed histone 2A and histone 4 methyltransferase activity (see, e.g., ho et al, (2013) PLOS ONE (8): 10.1371/animation/e 6b5348e-9052-44ab-8f06-90d01dc88fc 2). Homozygous deletions of p16/CDKN2a are prevalent in cancer, and these mutations typically involve co-deletions of adjacent genes, including the gene encoding methylthioadenosine phosphatase (MTAP). It is estimated that about 15% of all human cancers have homozygous deletions of the MTAP gene (see e.g. Firestone & schram (2017) j. Am. Chem soc 139 (39): 13754-13760. Doi: 10.1021/jacs.7b05803. Electronic edition, 2017, 9, 20). Cells lacking MTAP activity have elevated levels of MTAP substrate Methylthioadenosine (MTA), which is a potent inhibitor of PRMT 5. Inhibition of PRMT5 activity results in reduced methylation activity and increased sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Thus, loss of MTAP activity reduces the methylation activity of PRMT5, making cells selectively dependent on PRMT5 activity. Thus, MTA-synergistic inhibition of PRMT5 activity in MTAP-deficient cancers may provide therapeutic benefits for a variety of cancers. The compounds of the present invention provide such therapeutic benefits as MTA-synergistic inhibitors of PRMT5, which negatively regulate the activity of MTA-bound PRMT5 in cells, particularly MTAP-deficient cells, or are useful in the treatment of various forms of MTAP-associated cancers. In particular, 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1 h-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile is a potent and selective inhibitor of PRMT5, and has been found to have pharmacological activity. Thus, it has been found that a granular composition of 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1 h-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile is suitable for use in a pharmaceutical composition. Summary of The Invention In one aspect, the present disclosure provides a granular composition of 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1 h-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile of compound 1 as shown below and below. Accordingly, in one aspect, the present disclosure provides a particulate composition of compound 1 comprising: A crystalline or solid form of 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1 h-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile comprising: A first chiral crystalline form present in an amount of at least 85 wt% based on the weight of the crystalline form or solid form; optionally a second chiral form (e.g. crystalline or amorphous) present in an amount of no more than 5wt% by weight of the crystalline form or solid form, and An optional amorphous form present in an amount of no more than 10 wt% by weight of the crystalline or solid form; Filler, and Optionally an organic acid. In certain embodiments, the first chiral crystalline form is a crystalline form of a compound of formula (I): 。 in certain embodiments, the second chiral form is a crystalline or amorphous form of a compound of formula (II): 。 In another aspect, the present disclosure provides a pharmaceutical composition comprising a particulate composition as described herein. In another aspect, the present disclosure provides a method of preparing a particulate composition as described herein. The method comprises the following steps: providing a crystalline