# US 11,306,058 B2 · Crystalline form of N-butyldeoxygalactonojirimycin

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- Number: US 11,306,058 B2
- Document ID: US11306058B2
- Status: Granted
- Kind: B2
- Application number: 16/618,036
- Filed: 2018-05-31
- Published: 2020-05-07
- Granted: 2022-04-19
- Earliest claimed: 2017-06-01
- Assignees: Idorsia Pharmaceuticals Ltd
- Applicants: Idorsia Pharmaceuticals Ltd
- Inventors: Vitor Oliveira; Ivan Pogorelic; Jean-Paul Roduit
- Web page: https://patentgrep.com/patent/US11306058B2

## CPC

- C07D 211/40: Oxygen atoms
- C07D 211/46: having a hydrogen atom as the second substituent in position 4
- A61K 9/4858: {Organic compounds}
- A61P 3/06: Antihyperlipidemics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The invention relates to a crystalline form of [(2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)-piperidine-3,4,5-triol, processes for the preparation thereof, pharmaceutical compositions containing such a crystalline form, and its use as a medicament, especially as glycolipid biosynthesis inhibitor.

## Claims

### Claim 1

A crystalline form of the compound f(2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol:
characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.6°, 17.7°, and 21.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.

### Claim 2 (depends on 1)

A crystalline form of the compound according to claim 1, characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.6° 12.4°, 14.8°, 17.7°, and 21.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.

### Claim 3 (depends on 1)

A crystalline form of the compound according to claim 1, characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.6° 12.4°, 13.4°, 14.8°, 16.8°, 17.7°, 19.4°, 21.5°, 22.1°, and 24.2°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.

### Claim 4 (depends on 1)

A crystalline form of the compound according to claim 1, which essentially shows the X-ray powder diffraction pattern as depicted in FIG. 1.

### Claim 5 (depends on 1)

A crystalline form of the compound according to claim 1, wherein said crystalline form shows endothermal melting with a peak at about 130° C. as determined by differential scanning calorimetry.

### Claim 6 (depends on 1)

A crystalline form of the compound according to claim 1, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is equal or greater than about 50 μm.

### Claim 7 (depends on 1)

A crystalline form of the compound according to claim 1, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein
D50 is from about 50 μm to about 150 μm; and
D90 is from about 100 μm to about 400 μm.

### Claim 8 (depends on 1)

A process for the preparation of the crystalline form of the compound according to claim 1, wherein said process comprises:
I) Step 1 comprising:
i. Preparing a solution of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol in isopropanol, wherein preferably about 100 ww % to 140 ww % of isopropanol with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol is used;
ii. Warming up the solution to about 45° C. to 60° C.;
iii. Adding anhydrous acetone, wherein about 450 ww % to 550 ww % with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol is added, and wherein said acetone is added during about 30 min;
iv. Cooling the obtained solution to about −5° C. to +5° C. at a constant rate;
v. Agitating at about 0° C. for 1 to 3 hours;
vi. Isolating the product by solid-liquid separation;
vii. Washing the solid with anhydrous acetone, wherein about 250 ww % to 300 ww % of acetone with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol is used; and
viii. Drying; and
II) Step 2 comprising:
i. Dissolving the product of the first crystallization step at about 45° C. in about 200 ww % to 250 ww % methanol with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol;
ii. Filtering over activated carbon;
iii. Washing the activated carbon with about 90 ww % of methanol with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol;
iv. Concentrating the solution under vacuum;
v. Dissolving the distillation residue of the previous step in about 60 ww % to 65 ww % methanol and about 4 ww % to 8 ww % water with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol;
vi. Warming up the solution to about 55° C. to 58° C.
vii. Adding about 200 ww % to 220 ww % ethyl acetate during about 25 min to 45 min while keeping the temperature between about 55° C. to 58° C.;
viii. Cooling the resulting suspension down to about −5 to +5° C. at a constant rate;
ix. Agitating at about 0° C. for 1.5 to 3 hours;
x. Isolating the product by solid-liquid separation;
xi. Washing the solid twice with ethyl acetate; and
xii. Drying.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 1; and
from about 24 ww % to about 44 ww % of one or more diluents selected from a group consisting of lactose anhydrous, silicified microcrystalline cellulose, microcrystalline cellulose, calcium hydrogen phosphate and isomalt;
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof;
where the total ww % of said pharmaceutical composition is 100.

### Claim 10 (depends on 1, 9)

A pharmaceutical composition according to claim 9, comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 1;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof,
where the total ww % of said pharmaceutical composition is 100.

### Claim 11 (depends on 9)

A capsule comprising the pharmaceutical composition according to claim 9.

### Claim 12 (depends on 1)

A method of reducing or eliminating symptoms of Niemann-Pick type C disease; Gaucher disease types 1, 2 and 3; Tay-Sachs disease, Sandhoff disease, GM2 gangliosidosis AB variant; GM1 gangliosidosis; Fabry disease; Schindler disease; Smith-Lemly-Opitz syndrome; Tangier disease; mucolipidosis IV; mucopolysaccharidoses; GbA1-synucleopathies and syndromes thereof; Huntington's disease; polycystic kidney disease; Darier's disease; or Guillain-Barré syndrome the method comprising administering to a patient in need thereof a pharmaceutically effective amount of the crystalline form of the compound according to claim 1.

### Claim 13 (depends on 1)

A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound according to claim 1.

### Claim 14 (depends on 1)

A crystalline form of the compound according to claim 1, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is from about 50 μm to about 300 μm.

### Claim 15 (depends on 1)

A crystalline form of the compound according to claim 1, wherein said crystalline form has a total impurity amount of less than about 0.5%.

### Claim 16 (depends on 2)

A crystalline form of the compound according to claim 2, wherein said crystalline form shows endothermal melting with a peak at about 130° C. as determined by differential scanning calorimetry.

### Claim 17 (depends on 2)

A crystalline form of the compound according to claim 2, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is equal or greater than about 50 μm.

### Claim 18 (depends on 2)

A crystalline form of the compound according to claim 2, wherein said crystalline form consists essentially of particles having a particle size distribution wherein D50 is equal or greater than about 70 μm.

### Claim 19 (depends on 2)

A crystalline form of the compound according to claim 2, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is from about 50 μm to about 300 μm.

### Claim 20 (depends on 2)

A crystalline form of the compound according to claim 2, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is from about 70 μm to about 250 μm.

### Claim 21 (depends on 2)

A crystalline form of the compound according to claim 2, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein
D50 is from about 50 μm to about 300 μm; and
D90 is from about 100 μm to about 400 μm.

### Claim 22 (depends on 2)

A crystalline form of the compound according to claim 2, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein
D50 is from about 50 μm to about 300 μm; and
D90 is from about 100 μm to about 400 μm;
and D10 is from about 3 μm to about 12 μm.

### Claim 23 (depends on 3)

A crystalline form of the compound according to claim 3, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is equal or greater than about 50 μm.

### Claim 24 (depends on 3)

A crystalline form of the compound according to claim 3, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is from about 50 μm to about 300 μm.

### Claim 25 (depends on 3)

A crystalline form of the compound according to claim 3, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is from about 70 μm to about 250 μm.

### Claim 26 (depends on 3)

A crystalline form of the compound according to claim 3, wherein said crystalline form consists essentially of particles having a particle size distribution, wherein
D50 is from about 50 μm to about 300 μm; and
D90 is from about 100 μm to about 400 μm.

### Claim 27 (depends on 10)

A pharmaceutical composition according to claim 10, wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.

### Claim 28 (depends on 2)

A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 2; and
from about 24 ww % to about 44 ww % of one or more diluents selected from a group consisting of lactose anhydrous, silicified microcrystalline cellulose, microcrystalline cellulose, calcium hydrogen phosphate and isomalt; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof;
where the total ww % of said pharmaceutical composition is 100.

### Claim 29 (depends on 28)

A pharmaceutical composition according to claim 28, wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.

### Claim 30 (depends on 2)

A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 2;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.

### Claim 31 (depends on 30)

A pharmaceutical composition according to claim 30, wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.

### Claim 32 (depends on 17)

A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 17; and
from about 24 ww % to about 44 ww % of one or more diluents selected from a group consisting of lactose anhydrous, silicified microcrystalline cellulose, microcrystalline cellulose, calcium hydrogen phosphate and isomalt; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof;
where the total ww % of said pharmaceutical composition is 100.

### Claim 33 (depends on 32)

A pharmaceutical composition according to claim 32, wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.

### Claim 34 (depends on 17)

A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 17;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.

### Claim 35 (depends on 34)

A pharmaceutical composition according to claim 34, wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.

### Claim 36 (depends on 19)

A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 19;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.

### Claim 37 (depends on 21)

A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 21;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.

### Claim 38 (depends on 37)

A pharmaceutical composition according to claim 37, wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.

### Claim 39 (depends on 23)

A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 23;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.

### Claim 40 (depends on 24)

A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 24;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.

### Claim 41 (depends on 28)

A capsule comprising the pharmaceutical composition according to claim 28.

### Claim 42 (depends on 29)

A capsule comprising the pharmaceutical composition according to claim 29.

### Claim 43 (depends on 30)

A capsule comprising the pharmaceutical composition according to claim 30.

### Claim 44 (depends on 31)

A capsule comprising the pharmaceutical composition according to claim 31.

### Claim 45 (depends on 44)

A capsule according to claim 44, wherein said capsule comprises said compound in an amount of about 250 mg of active ingredient per capsule.

### Claim 46 (depends on 45)

A capsule according to claim 45, wherein said capsule is a size 0 capsule.

### Claim 47 (depends on 32)

A capsule comprising the pharmaceutical composition according to claim 32.

### Claim 48 (depends on 33)

A capsule comprising the pharmaceutical composition according to claim 33.

### Claim 49 (depends on 48)

A capsule according to claim 48, wherein said capsule comprises said compound in an amount of about 250 mg of active ingredient per capsule.

### Claim 50 (depends on 49)

A capsule according to claim 49, wherein said capsule is a size 0 capsule.

### Claim 51 (depends on 34)

A capsule comprising the pharmaceutical composition according to claim 34.

### Claim 52 (depends on 51)

A capsule according to claim 51, wherein said capsule comprises said compound in an amount of about 250 mg of active ingredient per capsule.

### Claim 53 (depends on 52)

A capsule according to claim 52, wherein said capsule is a size 0 capsule.

### Claim 54 (depends on 35)

A capsule comprising the pharmaceutical composition according to claim 35.

### Claim 55 (depends on 54)

A capsule according to claim 54, wherein said capsule comprises said compound in an amount of about 250 mg of active ingredient per capsule.

### Claim 56 (depends on 55)

A capsule according to claim 55, wherein said capsule is a size 0 capsule.

### Claim 57 (depends on 42)

A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 42.

### Claim 58 (depends on 43)

A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 43.

### Claim 59 (depends on 44)

A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 44.

### Claim 60 (depends on 48)

A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 48.

### Claim 61 (depends on 51)

A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 51.

### Claim 62 (depends on 54)

A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 54.