Salt and polymorphic forms of (3R,4S)-L-((4-amino-5H-pyrrolo[3,2,-d]pyrimidin-7-yl)methyl)-4(methylthiomethyl)pyrodin-3-ol(MTDIA)

Patent metadata

Field	Value
Publication number	US-9994574-B2
Application number	US-201314441690-A
Country	US
Kind code	B2
Filing date	Nov 12, 2013
Priority date	Nov 12, 2012
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

The invention relates to salt forms of (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methyl-thiomethyl)pyrrolidin-3-ol, as well as polymorphic forms of the salts. The invention further relates to processes for preparing the salt forms and to the use of the salt forms in the treatment of diseases and disorders where it is desirable to inhibit 5′-methylthioadenosine phosphorylase (MTAP).

First claim

The invention claimed is:

1. A crystalline salt form of (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol, selected from the group consisting of (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol phosphate, (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol formate, (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol oxalate and (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl) pyrrolidin-3-ol sulfate,
wherein the crystalline salt form of (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol is a crystalline phosphate salt form, and the crystalline salt form of (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol phosphate is Form D, E or F;
or wherein the crystalline salt form of (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol is a crystalline formate salt form characterized by X-ray powder diffraction peaks at the following 2 theta angles: 8.11, 16.30, 20.68, 24.85, 25.70, 26.03, 28.00, 32.23 and 33.02 degrees 2 theta±0.05 degrees 2 theta: or
wherein the crystalline salt form of (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol is a crystalline oxalate salt form characterized by X-ray powder diffraction peaks at the following 2 theta angles: 6.22, 12.35, 13.54, 18.23, 20.47, 21.94, 24.22 and 29.44 degrees 2 theta±0.05 degrees 2 theta; or
wherein the crystalline salt form of (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol is a crystalline sulfate salt form characterized by X-ray powder diffraction peaks at the following 2 theta angles: 5.75, 10.33, 13.14, 15.41, 15.90, 17.61, 18.32, 21.43, 24.30, 26.15, 26.76, 27.67, 30.28, 30.97, 31.52 and 32.27 degrees 2 theta±0.05 degrees 2 theta.

2. A crystalline salt form as claimed in claim 1 which is crystalline (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol phosphate of Form D characterized by X-ray powder diffraction peaks at the following 2 theta angles: 5.38, 7.10, 8.93, 10.87, 13.06, 14.31, 15.81, 17.59, 17.92, 19.97, 21.53, 22.76, 26.00, 27.06, 27.79, 28.95 and 29.97 degrees 2 theta±0.05 degrees 2 theta.

3. A crystalline salt form as claimed in claim 2 which is further characterized by one or more additional X-ray powder diffraction peaks at the following 2 theta angles: 14.57, 15.32, 16.50, 19.07, 20.17, 20.77, 21.78, 22.22, 23.12, 24.84, 25.75, 26.31, 28.14, 28.57, 29.35, 30.50, 30.91, 31.35, 32.64, 32.09, 34.17 and 33.33 degrees 2 theta±0.05 degrees 2 theta.

4. A crystalline salt form as claimed in claim 1 which is crystalline (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol phosphate of Form E characterized by X-ray powder diffraction peaks at the following 2 theta angles: 5.26, 7.01, 8.69, 10.58, 15.95, 17.26, 17.57, 21.27, 21.60, 22.75, 25.64, 26.88, 28.86, 29.99 and 30.75 degrees 2 theta±0.05 degrees 2 theta.

5. A crystalline salt form as claimed in claim 4 which is further characterized by one or more additional X-ray powder diffraction peaks at the following 2 theta angles: 8.91, 12.56, 16.76, 17.84, 19.36, 20.14, 20.86, 22.09, 22.53, 23.03, 24.14, 25.95, 26.16, 26.63, 27.72, 29.35, 30.22, 31.11, 31.57, 32.38, 33.04, 33.38 and 33.93 degrees 2 theta±0.05 degrees 2 theta.

6. A crystalline salt form as claimed in claim 1 which is crystalline (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol phosphate of Form F characterized by X-ray powder diffraction peaks at the following 2 theta angles: 5.25, 7.00, 8.73, 10.67, 15.82, 16.04, 17.52, 17.75, 20.13, 20.77, 21.36, 21.72, 22.79, 25.70, 26.10, 28.55, 29.56, 30.52, 31.43 and 32.42 degrees 2 theta±0.05 degrees 2 theta.

7. A crystalline salt form as claimed in claim 6 which is further characterized by one or more additional X-ray powder diffraction peaks at the following 2 theta angles: 8.92, 12.69, 14.19, 15.14, 16.68, 19.21, 22.09, 23.60, 24.35, 24.80, 26.81, 27.00, 27.81, 29.01, 29.88, 32.12, 32.95, 33.68, 34.08, 35.08, 35.84, 36.58, 37.32, 39.18, 40.37, 40.79, 41.84, 42.56, 43.62, 44.51, 46.14, 46.52, 47.00, 48.24, 49.02 and 49.54 degrees 2 theta+0.05 degrees 2 theta.

8. A crystalline oxalate salt form as claimed in claim 1 which is further characterized by one or more additional X-ray powder diffraction peaks at the following 2 theta angles: 14.94, 15.72, 19.11, 22.54, 30.07, 31.11, 32.06, 32.71 and 33.90 degrees 2 theta±0.05 degrees 2 theta.

9. A crystalline formate salt form as claimed in claim 1 which is further characterized by one or more additional X-ray powder diffraction peaks at the following 2 theta angles: 10.34, 13.66, 17.54, 17.95, 18.83, 21.32, 21.71, 23.17, 24.63, 27.13, 27.57, 28.51, 28.77, 30.33, 31.05, 31.24, 33.45, 34.24, 34.52, 35.57, 35.99, 36.66, 36.93, 38.15, 38.91, 39.94, 40.47, 41.45, 42.17, 42.75, 44.36, 45.15, 46.27, 46.50, 47.36, 48.49, 49.20 and 50.12 degrees 2 theta±0.05 degrees 2 theta.

10. A pharmaceutical composition comprising a salt form as claimed in claim 1 and at least one pharmaceutically acceptable excipient.

11. A pharmaceutical composition as claimed in claim 10 , wherein the salt form is (3R,4S)-1-((4-amino-SH-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol phosphate.

12. A crystalline sulfate salt form as claimed in claim 1 , which is further characterized by one or more additional X-ray powder diffraction peaks at the following 2 theta angles: 19.14, 20.28, 20.87, 22.26, 24.64, 29.37 and 33.24 degrees 2 theta 0.05 degrees 2 theta.

13. A crystalline salt form as claimed in claim 1 , which is (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol phosphate which exhibits an endotherm at a range of 165° C. to 185° C. as measured by differential scanning calorimetry.

14. A crystalline salt form as claimed in claim 1 , which is (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol oxalate which exhibits an endotherm at 137.04° C. as measured by differential scanning calorimetry.

15. A crystalline salt form as claimed in claim 1 , which is (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol formate which exhibits an endotherm at 179.54° C. as measured by differential scanning calorimetry.

Assignees

• Victoria Link Ltd

Inventors

• Evans Gary Brian
• Kelly Peter Michael
• Tyler Peter Charles

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D207/50

  Nitrogen atoms · CPC title

• C07D207/12

  Oxygen or sulfur atoms · CPC title