Amine salts of laquinimod

• US 8,975,279 B2
• Filed: 10/31/2013
• Issued: 03/10/2015
• Est. Priority Date: 11/07/2012
• Status: Active Grant

• Current Assignee: Teva Pharmaceutical Industries Limited
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Frenkel, Anton, Laxer, Avital, Aronheim, Judith
• Primary Examiner(s): Hui, San-Ming
• Assistant Examiner(s): CALVILLO, Y JEANMARIE Z
• Application Number:
  US14/068,599
• Publication Number:
  US 20140128430A1
• Time in Patent Office: 495 Days
• Field of Search: None
• US Class Current: 514/312
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 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 Class Codes: C07C 215/08 with only one hydroxy group and one amino group bound to the carbon skeleton
• CPC Class Codes: C07C 215/10 with one amino group and at least two hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 215/40 with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 229/26 having more than one amino group bound to the carbon skeleton, e.g. lysine
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4

Abstract

The subject invention provides a Laquinimod amine salt, which is laquinimod meglumine, laquinimod choline hydroxide, laquinimod L-lysine or laquinimod monoethanolamine.

Claims

1. Laquinimod amine salt, which is laquinimod meglumine, laquinimod choline hydroxide, laquinimod L-lysine or laquinimod monoethanolamine.

2. The laquinimod amine salt of claim 1 which is laquinimod meglumine.

3. The laquinimod meglumine of claim 2 which is isolated.

4. The laquinimod meglumine according to claim 2, wherein the laquinimod meglumine is characterized by

a) a DSC thermogram as shown in FIGS. 4A, B and C;

b) a solid-state ¹³C NMR spectrum with broad peak at 60-77, broad peak at 122-134, peak at 142.2 and 171.3±

0.2 ppm; and

/or

c) a solid state ¹³C as shown in FIGS. 5A and 5B.

5. The laquinimod amine salt of claim 1 which is laquinimod choline hydroxide.

6. The laquinimod choline hydroxide of claim 5 which is isolated.

7. The laquinimod choline hydroxide according to claim 5, wherein the laquinimod choline hydroxide is characterized by

a) a DSC thermogram as shown in FIGS. 6A, B, C, D and E;

b) a powder XRD pattern with characteristic peaks at 10.1°

, 11.8°

, 13.4°

, 14.4° and

16.1°

2-theta±

0.2;

c) a powder XRD pattern with characteristic peaks at 19.3°

, 21.2°

, 22.7°

, 24.8° and

27.6°

2-theta±

0.2;

d) a powder XRD pattern as shown in FIGS. 7 and 8;

e) a solid-state ¹³C NMR spectrum with peaks at about 122.1, 127.2, 142.7 and 169.7±

0.2 ppm;

f) a solid-state ¹³C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift in the 100 to 180 ppm range and another signal in that same chemical shift range of 100 to 180 ppm of about 12.6, 17.7, 33.2, 60.2 and ±

0.1 ppm; and

/or

g) a solid state ¹³C NMR as shown in FIGS. 9A and B.

8. The laquinimod choline hydroxide according to any one of claims 5-7, wherein the laquinimod choline hydroxide is in crystalline form or in amorphous form.

9. The laquinimod amine salt of claim 1 which is laquinimod L-lysine.

10. The laquinimod L-lysine of claim 9 which is isolated.

11. The laquinimod L-lysine according to claim 9, wherein the laquinimod L-lysine is characterized by a) the DSC thermogram as shown in FIGS. 10A, B and C;

b) a powder XRD pattern with characteristic peaks at 5.6°

, 9.0°

, 11.7°

, 13.0° and

15.9°

2-theta±

0.2;

c) a powder XRD pattern with characteristic peaks at 17.9°

, 18.9°

, 21.1°

, 22.5° and

23.0°

degrees 2-theta±

0.2; and

/or

d) a powder XRD pattern as shown in FIG. 11.

12. The laquinimod L-lysine according to any one of claims 9-11, wherein the laquinimod L-lysine is in crystalline form or in amorphous form.

13. The laquinimod amine salt of claim 1 which is laquinimod monoethanolamine.

14. The laquinimod monoethanolamine of claim 13 which is isolated.

15. The laquinimod monoethanolamine of claim 13, wherein the laquinimod monoethanolamine is characterized by

a) a DSC thermogram as shown in FIG. 12A;

b) a powder XRD pattern with characteristic peaks at 6.5°

, 14.4°

, 17.9°

, 18.7° and

20.6°

2-theta±

0.2;

c) a powder XRD pattern with characteristic peaks at 17.1°

, 19.4°

, 22.3°

, 23.3° and

24.8°

degrees 2-theta±

0.2;

d) a powder XRD pattern as shown in FIG. 13;

e) a DSC thermogram as shown in FIG. 12B;

f) a powder XRD pattern with characteristic peaks at 8.2°

, 9.8°

, 11.2°

, 13.2° and

17.9°

2-theta±

0.2;

g) a powder XRD pattern with characteristic peaks at 18.6°

, 20.4°

, 22.9°

, 24.3° and

26.2°

2-theta±

0.2; and

/or

h) a powder XRD pattern as shown in FIG. 14.

16. The laquinimod monoethanolamine according to any one of claims 13-15, wherein the laquinimod monoethanolamine is in crystalline form or in amorphous form.

17. A pharmaceutical composition comprising the laquinimod amine salt of any one of claim 1-4, 5-7, 9, 11, or 13-15 and at least one pharmaceutical acceptable excipient.

18. A process for manufacture of laquinimod amine salt according to any one of claim 1-4, 5-7, or 9-11, or 13, comprising:

a) combining a solution of amine with laquinimod acid to form a first mixture;

b) adding a solvent to the first mixture to form a second mixture;

c) removing liquid from the second mixture; and

d) recovering the laquinimod amine.

19. A process for manufacture of the pharmaceutical composition according to claim 17, comprising:

a) obtaining laquinimod amine salt; and

b) admixing the laquinimod amine salt with at least one pharmaceutical acceptable excipient.

20. A method for treating a subject afflicted with a form of multiple sclerosis or clinical isolated syndrome, or for alleviating a symptom of multiple sclerosis in a subject afflicted with a form of multiple sclerosis, comprising administering to the subject the pharmaceutical composition according to claim 17 so as to thereby treat the subject or alleviate the symptom of multiple sclerosis in the subject.