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Last Updated: March 19, 2024

Details for Patent: 9,624,204


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Title:Polymorphic forms of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl) piperazine hydrochloride
Abstract: The invention relates to new crystalline modifications of the hydrochloride of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine- , crystalline modification of the dihydrochloride of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and amorphous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride which are suitable in particular for the preparation of solid medicaments for the treatment or prevention of depressive disorders, anxiety disorders, bipolar disorders, mania, dementia, substance-related disorders, sexual dysfunctions, eating disorders, obesity, fibromyalgia, sleeping disorders, psychiatric disorders, cerebral infarct, tension, for the therapy of side-effects in the treatment of hypertension, cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome and undesired puerperal lactation.
Inventor(s): Bathe; Andreas (Darmstadt, DE), Helfert; Bernd (Ober-Ramstadt, DE), Neuenfeld; Steffen (Messel, DE), Kniel; Heike (Heppenheim, DE), Bartels; Matthias (Darmstadt, DE), Rudolph; Susanne (Dieburg, DE), Bottcher; Henning (Darmstadt, DE)
Assignee: Merck Patentgesellschaft (Darmstadt, DE)
Filing Date:Nov 21, 2014
Application Number:14/549,779
Claims:1. A compound which is 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate in its crystalline modification and having at least one group of 2Theta characteristic peak values selected from the following groups: i. Group A: at least three of the characteristic peak values corresponding to 10.40.+-.0.1, 11.19.+-.0.1, 13.39.+-.0.1, 13.54.+-.0.1, 13.79.+-.0.1, 15.84.+-.0.1, 21.09.+-.0.1, 23.64.+-.0.1, 24.49.+-.0.1 or 25.79.+-.0.1 degrees; ii. Group B: at least three of the characteristic peak values corresponding to 10.49.+-.0.1, 11.73.+-.0.1, 13.12.+-.0.1, 14.46.+-.0.1, 16.24.+-.0.1, 19.32.+-.0.1, 20.05.+-.0.1, 21.75.+-.0.1, 23.50.+-.0.1, or 26.35.+-.0.1 degrees; iii. Group C: at least three of the characteristic peak values corresponding to 5.38.+-.0.1, 9.58.+-.0.1, 10.68.+-.0.1, 13.76.+-.0.1, 15.98.+-.0.1, 22.29.+-.0.1, 23.50.+-.0.1, 24.77.+-.0.1, 26.28.+-.0.1 or 26.52.+-.0.1 degrees; iv. Group D: at least three of the characteristic peak values corresponding to 5.58.+-.0.1, 9.69.+-.0.1, 10.68.+-.0.1, 11.12.+-.0.1, 13.48.+-.0.1, 13.74.+-.0.1, 16.08.+-.0.1, 21.30.+-.0.1, 21.49.+-.0.1 or 24.88.+-.0.1 degrees; v. Group E: at least three of the characteristic peak values corresponding to 8.54.+-.0.1, 12.50.+-.0.1, 13.17.+-.0.1, 18.56.+-.0.1, 19.28.+-.0.1, 19.76.+-.0.1, 20.94.+-.0.1, 21.21.+-.0.1, 25.40.+-.0.1, or 26.26.+-.0.1 degrees; and vi. Group F: at least three of the characteristic peak values corresponding to 5.88.+-.0.1, 11.08.+-.0.1, 17.10.+-.0.1, 18.14.+-.0.1, 21.19.+-.0.1, 22.21.+-.0.1 or 25.47.+-.0.1 degrees.

2. A compound according to claim 1 as 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate in its crystalline modification and having at least three of the characteristic peak values in Group A (Form I).

3. A compound according to claim 1 as 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate in its crystalline modification and having at least three of the characteristic peak values in Group B (Form II).

4. A compound according to claim 1 as 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate in its crystalline modification and having at least three of the characteristic peak values in Group C (Form XV).

5. A compound according to claim 1 as 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate in its crystalline modification and having at least three of the characteristic peak values in Group D (Form X).

6. A compound according to claim 1 as 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate in its crystalline modification and having at least three of the characteristic peak values in Group E (Form XI).

7. A compound according to claim 1 as 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate in its crystalline modification and having at least three of the characteristic peak values in Group F.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7.

9. A compound which is 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride hydrate in its crystalline modification and having at least one group of 2Theta characteristic peak values selected from the following groups: i. Group A: at least three of the characteristic peak values corresponding to 9.34.+-.0.1, 10.83.+-.0.1, 13.00.+-.0.1, 13.47.+-.0.1, 18.70.+-.0.1, 19.44.+-.0.1, 20.09.+-.0.1, 20.98.+-.0.1, 25.41.+-.0.1 or 26.13.+-.0.1 degrees; ii. Group B: at least three of the characteristic peak values corresponding to 9.05.+-.0.1, 10.00.+-.0.1, 13.05.+-.0.1, 20.89.+-.0.1, 21.26.+-.0.1, 22.85.+-.0.1, 23.11.+-.0.1, 23.61.+-.0.1, 23.87.+-.0.1, or 24.76.+-.0.1 degrees; and iii. Group C: at least three of the characteristic peak values corresponding to 11.55.+-.0.1, 13.26.+-.0.1, 13.53.+-.0.1, 15.48.+-.0.1, 16.89.+-.0.1, 18.87.+-.0.1, 19.82.+-.0.1, 20.49.+-.0.1, 23.74.+-.0.1 or 27.50.+-.0.1 degrees.

10. A compound according to claim 9 as 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride hydrate in its crystalline modification and having at least three of the characteristic peak values in Group A (Form V).

11. A compound according to claim 9 as 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride hydrate in its crystalline modification and having at least three of the characteristic peak values in Group B.

12. A compound according to claim 9 as 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride hydrate in its crystalline modification and having at least three of the characteristic peak values in Group C.

13. A pharmaceutical composition comprising a compound according to any one of claims 9 to 12.

14. Process for preparing Form I according to claim 2, which comprises: (1) dispersing 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine in acetone; (2) converting the 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine base, by addition of 1N hydrochloric acid into the hydrochloride salt at temperatures between 30.degree. C. and the boiling point of acetone; (3) precipitation of Form I at room temperature; and (4) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride acetonate by filtration, and drying in vacuo at room temperature.

15. Process for preparing Form I according to claim 2 which comprises: (1) suspending Form III of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride in acetone; (2) stirring at room temperature between a few hours to 20 days; and (3) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride acetonate by filtration, and drying in vacuo at room temperature.

16. The process of claim 15, wherein step (2) is carried out for 10 to 20 days.

17. Process for preparing Form II according to claim 3, which comprises: (1) dispersing 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine in tetrahydrofuran; (2) converting the 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine base, by addition of 1N hydrochloric acid into the hydrochloride salt at temperatures between 10.degree. C. and 60.degree. C.; (3) precipitation of Form II at room temperature; and (4) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate with tetrahydrofuran by filtration, and drying in vacuo at room temperature.

18. Process for preparing Form II according to claim 3 which comprises: (1) suspending Form III of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride in tetrahydrofuran; (2) stirring at room temperature between a few hours to 30 days; and (3) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride tetrahydrofuran by filtration, and drying in vacuo at room temperature.

19. The process of claim 18, wherein step (2) is carried out for 15 to 30 days.

20. Process for preparing Form XV according to claim 4, which comprises: (1) dispersing 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine in tetrahydrofuran; (2) converting the 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine base, by addition of 1N hydrochloric acid into the hydrochloride salt at temperatures between -10.degree. C. and 10.degree. C.; (3) precipitation of Form XV at room temperature; and (4) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate with tetrahydrofuran by filtration, and drying in vacuo at room temperature.

21. Process for preparing Form X according to claim 5, which comprises: (1) dispersing 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine in tetrahydrofuran; (2) converting the 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine base, by addition of 1N hydrochloric acid into the hydrochloride salt at temperatures between 10.degree. C. and 40.degree. C.; (3) precipitation of Form II at room temperature; and (4) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate with tetrahydrofuran by filtration, and drying at temperatures up to 80.degree. C. maximum.

22. Process for preparing Form XI according to claim 6, which comprises: (1) suspending Form VI of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride in methanol at temperatures between 55.degree. C. and the boiling point of methanol; (2) cooling down the reaction mixture to temperatures between -40.degree. and -10.degree. C.; and (3) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride methanolate by filtration at room temperature, and drying in vacuo at room temperature.

23. Process for preparing Form V according to claim 10, which comprises: (1) dispersing 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine in tetrahydrofuran; (2) converting the 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine base, by addition of aqueous hydrochloric acid into the hydrochloride salt; (3) precipitation of Form V at room temperature; and (4) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride monohydrate by filtration, and drying in vacuo at room temperature.

24. A method of the treatment of depressive disorders, anxiety disorders, bipolar disorders, mania, dementia, substance-related disorders, sexual dysfunctions, eating disorders, obesity, fibromyalgia, sleeping disorders, psychiatric disorders, cerebral infarct, tension, for the therapy of side-effects in the treatment of hypertension, cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome and undesired puerperal lactation comprising the step of adminstering to a subject an effective amount of a compound according to any one of claims 1-7.

25. A method for the treatment of depressive disorders, anxiety disorders, bipolar disorders, mania, dementia, substance-related disorders, sexual dysfunctions, eating disorders, obesity, fibromyalgia, sleeping disorders, psychiatric disorders, cerebral infarct, tension, for the therapy of side-effects in the treatment of hypertension, cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome and undesired puerperal lactation comprising the step of administering to a subject an effective amount of a compound according to any one of claims 9-12.

26. A method for the treatment of depressive disorders comprising the step of administering to a subject an effective amount of a compound according to any one of claims 1-7.

27. A method for the treatment of depressive disorders comprising the step of administering to a subject an effective amount of a compound according to any one of claims 9-12.

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