DIMETHYLAMINOETHANOL SALT OF A GLP-1 RECEPTOR MODULATOR

• US 20200131164A1
• Filed: 09/29/2017
• Published: 04/30/2020
• Est. Priority Date: 09/30/2016
• Status: Active Grant

• Current Assignee: Receptos LLC (Bristol-Myers Squibb Company)
• Original Assignee: Celgene International II SARL (Bristol-Myers Squibb Company)
• Inventors: Vidal, Ephraim, Bakale, Roger, Turnbull, Philip, Moser, David, Robbins, Andrew, Grant, Craig
• Granted Patent: US 11,066,395 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

Crystalline 2-hydroxy-N,N-dimethylethanaminium 1-(2-(5-(tert-butyl)-thiophene-2-carboxamido)-3-(4-(5-(4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate salt, and methods related to synthesis and therapeutic use of the same.

Claims

1. A compound having the following structure:

2. The compound of claim 1 having the following structure:

3. The compound of claim 1 having the following structure:

4. The compound of claim 1 having the following structure:

5. A racemic mixture of the compounds of claims 3 and 4.

13. The compound of any one of claims 1, 2 or 6 having a purity in excess of 95% by weight.

14. The compound of any one of claims 1, 2 or 6 having a purity in excess of 98% by weight.

15. A pharmaceutical composition comprising a compound of any one of claims 1, 2 or 6 together with at least one pharmaceutically acceptable carrier, diluent or excipient.

16. A method of treatment of a disease or malcondition in a patient for which activation, potentiation, modulation or agonism of a glucagon-like peptide 1 receptor is medically indicated, comprising administering an effective amount of a compound of any one of claims 1, 2 or 6 to the patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient.

17. The method of claim 16 wherein the disease or malcondition is type I diabetes, type II diabetes, gestational diabetes, obesity, excessive appetite, insufficient satiety, metabolic disorder, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.

18. The method of claim 16 wherein the disease or malcondition is type II diabetes.

19. The method of claim 16, wherein the disease or malcondition is non-alcoholic fatty liver disease.

20. The method of claim 16, wherein the disease or malcondition is non-alcoholic steatohepatitis.

6. Crystalline 2-hydroxy-N,N-dimethylethanaminium 1-(2-(5-(tert-butyl)-thiophene-2-carboxamido)-3-(4-(5-(4′

-ethyl-[1,1′

-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate salt.

7. Crystalline 2-hydroxy-N,N-dimethylethanaminium 1-(2-(5-(tert-butyl)-thiophene-2-carboxamido)-3-(4-(5-(4′

-ethyl-[1,1′

-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate salt having an XRPD pattern as shown in FIG. 1A.

8. Crystalline 2-hydroxy-N,N-dimethylethanaminium 1-(2-(5-(tert-butyl)-thiophene-2-carboxamido)-3-(4-(5-(4′

-ethyl-[1,1′

-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate salt having an XRPD pattern as shown in FIG. 2A.

9. Crystalline 2-hydroxy-N,N-dimethylethanaminium 1-(2-(5-(tert-butyl)-thiophene-2-carboxamido)-3-(4-(5-(4′

-ethyl-[1,1′

-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate salt having an XRPD pattern as shown in FIG. 3A.

10. Crystalline 2-hydroxy-N,N-dimethylethanaminium 1-(2-(5-(tert-butyl)-thiophene-2-carboxamido)-3-(4-(5-(4′

-ethyl-[1,1′

-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate salt which exhibits an XRPD pattern having characteristic peaks expressed in distances (d-spacing) in degrees 2θ

(+/−

0.2°

θ

) as listed in Table 1A.

11. Crystalline 2-hydroxy-N,N-dimethylethanaminium 1-(2-(5-(tert-butyl)-thiophene-2-carboxamido)-3-(4-(5-(4′

-ethyl-[1,1′

-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate salt which exhibits an XRPD pattern having characteristic peaks expressed in distances (d-spacing) in degrees 2θ

(+/−

0.2°

θ

) as listed in Table 1B.

12. Crystalline 2-hydroxy-N,N-dimethylethanaminium 1-(2-(5-(tert-butyl)-thiophene-2-carboxamido)-3-(4-(5-(4′

-ethyl-[1,1′

-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate salt which exhibits an XRPD pattern having characteristic peaks expressed in distances (d-spacing) in degrees 2θ

(+/−

0.2°

θ

) as listed in Table 1C.