Analogs of pridopidine, their preparation and use

Patent metadata

Field	Value
Publication number	US-10130621-B2
Application number	US-201514754339-A
Country	US
Kind code	B2
Filing date	Jun 29, 2015
Priority date	Jun 30, 2014
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

This invention also provides an impurity or a salt thereof for use, as a reference standard to detect trace amounts of the impurity in a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof. This invention further provides a process for producing a pridopidine drug product comprising obtaining a pridopidine drug substance and mixing the pridopidine drug substance with suitable excipients so as to produce the pridopidine drug product. This invention also provides a process for producing a pridopidine drug product. This invention also provides a process of distributing a pridopidine drug product.

First claim

What is claimed is:

1. An isolated compound having the structure:

(3R,4S)-4-(3-(methylsulfonyl)phenyl)-1-propylpiperidin-3-ol (hereinafter Compound 4), or a salt thereof.

2. A composition comprising pridopidine and a compound which has the structure:

(3R,4S)-4-(3-(methylsulfonyl)phenyl)-1-propylpiperidin-3-ol (hereinafter Compound 4), or

4-(3-(methylsulfonyl)phenyl)-1-propylpiperidin-4-ol (hereinafter Compound 1), or a salt thereof.

3. The composition of claim 2 , wherein the composition is a pharmaceutical composition comprising an amount of pridopidine and at least one of Compound 1 and Compound 4 wherein
a) Compound 1 is present in the pharmaceutical composition in an amount not more than 10 area-% relative to the concentration of pridopidine, based on a determination by an HPLC method, or
b) Compound 4 is present in the pharmaceutical composition in an amount not more than 10 area-% relative to the concentration of pridopidine, based on a determination by an HPLC method.

4. The pharmaceutical composition of claim 3 , comprising pridopidine hydrochloride salt.

5. The pharmaceutical composition of claim 3 , in an oral dosage unit form.

6. The pharmaceutical composition of claim 5 , wherein the oral dosage unit form comprises about 22.5 mg, about 45 mg, about 67.5 mg, about 90 mg, about 100 mg, about 112.5 mg, about 125 mg, about 135 mg, about 150 mg, or about 180 mg pridopidine.

7. A process for producing a pridopidine drug product comprising obtaining a pridopidine drug substance and mixing the pridopidine drug substance with suitable excipients so as to produce the pridopidine drug product, wherein the pridopidine drug substance comprises the composition of claim 2 , and wherein the pridopidine drug substance comprises:
i) an amount of Compound 1 in the pridopidine drug substance that is not more than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) an amount of Compound 4 in the pridopidine drug substance that is not more than 0.15 area-% Compound 4, relative to the concentration of pridopidine.

8. The process of claim 7 , wherein the process further comprises subjecting a sample of the pridopidine drug substance to stability testing before the step of determining the amount of at least one of Compound 1 and Compound 4 in the pridopidine drug substance.

9. A process for producing a pridopidine drug product for commercial sale comprising obtaining a batch of pridopidine drug product that comprises:
i) an amount of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidin-4-ol (hereinafter Compound 1) in the batch of pridopidine drug product that is not more than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) an amount of (3R,4S)-4-(3-(methysulfonyl)phenyl)-1-propylpiperidin-3-ol (hereinafter Compound 4) in the batch of pridopidine drug product that is not more than 0.15 area-% Compound 4, relative to the concentration of pridopidine, and

preparing the batch of pridopidine drug product for commercial sale.

10. The process of claim 9 , wherein the process further comprises determining the amount of at least one of Compound 1 and Compound 4 in the batch of pridopidine drug product.

11. The process of claim 10 , wherein the process further comprises subjecting a sample of the batch of pridopidine drug product to stability testing before determining the amount of at least one of Compound 1 and Compound 4 in the sample of the batch of pridopidine drug product.

12. A process of distributing a pridopidine drug product comprising a pridopidine drug substance comprising,
a) obtaining the pridopidine drug product wherein the pridopidine drug substance comprises the composition of claim 2 , and wherein the pridopidine drug substance comprises:
i) an amount of Compound 1 in the pridopidine drug substance that is not more than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) an amount of Compound 4 in the pridopidine drug substance that is not more than 0.15 area-% Compound 4, relative to the concentration of pridopidine; and

b) distributing the pridopidine drug product comprising the pridopidine drug substance.

13. A process of distributing a pridopidine drug product comprising,
a) obtaining the pridopidine drug product that comprises the composition of claim 2 , and wherein the pridopidine drug product comprises:
i) an amount of Compound 1 in the pridopidine drug product that is not more than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) an amount of Compound 4 in the pridopidine drug product that is not more than 0.15 area-% Compound 4, relative to the concentration of pridopidine; and

b) distributing the pridopidine drug product.

14. An impurity or a salt thereof for use as a reference standard to detect trace amounts of the impurity in a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof, wherein the impurity is selected from the group consisting of the compound of claim 1 or 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidin-4-ol (hereinafter Compound 1).

15. A process for validating a batch of a pharmaceutical product containing pridopidine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for distribution comprising:
a) determining the amount of at least one of the compound according to claim 1 , or 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidin-4-ol (hereinafter Compound 1); and
b) validating the batch for distribution only if
i) the batch is determined to have not more than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) the batch is determined to have not more than 0.15 area-% Compound 4, relative to the concentration of pridopidine.

16. The pharmaceutical composition of claim 3 , wherein the composition comprises at least one or more of 1-(3,3-bis(3-(methylsulfonyl)phenyl)propyl)-4-(3-(methylsulfonyl)phenyl)piperidone (hereinafter Compound 2), 1,4-bis((3-(1-propylpiperidin-4-yl)phenyl)sulfonyl)butane (hereinafter Compound 3), 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine 1-oxide (hereinafter Compound 5), 1-(2-methylpentyl)-4-(3-(methysulfonyl)phenyl)piperidine (hereinafter Compound 6), and 4-(3-(methylsulfinyl)phenyl)-1-propyl-1,2,3,6-tetrahydropyridine (hereinafter Compound 7) wherein
a) Compound 1 is present in the pharmaceutical composition in an amount not more than 0.15 area-% relative to the concentration of pridopidine, based on a determination by an HPLC method, or
b) Compound 2 is present in the pharmaceutical composition in an amount not more than 0.15 area-% relative to the concentration of pridopidine, based on a determination by an HPLC method, or
c) Compound 3 is present in the pharmaceutical composition in an amount not more than 0.15 area-% relative to the concentration of pridopidine, based on a determination by an HPLC method, or
d) Compound 4 is present in the pharmaceutical composition in an amount not more than 0.15 area-% relative to the concentration of pridopidine, based on a determination by an HPLC method, or
e) Compound 5 is present in the pharmaceutical composition in an amount not more than 0.15 area-% relative to the concentration of pridopidine, based on a determination by an HPLC method, or

Assignees

• Schmidt Malle
• Paeri Malle
• Laos Marit
• Maasalu Ants
• Kaljuste Kalle
• Teva Pharma

Inventors

• Schmidt Malle
• Päri Malle
• Laos Marit
• Maasalu Ants
• Kaljuste Kalle

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• G01N30/88

  Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 · CPC title

• G01N2030/8872

  impurities · CPC title