Treatment of androgen deprivation therapy associated symptoms

Patent metadata

Field	Value
Publication number	US-2019111039-A1
Application number	US-201816216256-A
Country	US
Kind code	A1
Filing date	Dec 11, 2018
Priority date	Sep 11, 2014
Publication date	Apr 18, 2019
Grant date	—

Abstract

or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1 . A process for the preparation of the compound of Formula I

comprising the steps of:
reacting Zn(CN) 2 with the compound of Formula II, thereby forming the compound of Formula III

and
forming the compound of Formula I by reacting the compound of Formula III with the compound of Formula IV

2 . The process of claim 1 , wherein the reaction of the compound of Formula II with Zn(CN) 2 to form a compound of Formula III comprises:
(i) reacting the compound of Formula II with Zn(CN) 2 , Zn(OAc) 2 , Zn, and Pd(dppf) 2 Cl 2 .CH 2 Cl 2 in DMAc to form a compound of Formula III in solution;
(ii) adding water to precipitate and isolate the compound of Formula III from the solution;
(iii) dissolving the precipitated isolate of the compound of Formula III in a mixture of MTBE and acetone to form a slurry;
(iv) filtering the slurry to form a filtrate having a compound of Formula III; and
(v) treating the filtrate having a compound of Formula III with charcoal, MgSO 4 , and FLORISIL™.

3 . The process of claim 2 , wherein the compound of Formula III is crystallized in the heptane.

4 . The process of claim 1 , wherein a substantially pure form of a compound of Formula I is produced by a process which comprises the steps of:
(i) reacting the compound of Formula III with 2-picolyl chloride hydrochloride and K 2 CO 3 in DMAC to give a compound of Formula I in solution; and (ii) isolating the compound of Formula I by adding water to the solution formed in step (i) and filtering.

5 . The process of claim 4 , additionally comprising the further step of:
(iii) recrystallizing the filtered isolate in EtOH to produce a substantially pure crystalline form of a compound of Formula I.

6 . The process of claim 5 , wherein the filtered isolate is recrystallized at least three times in EtOH to produce a substantially pure crystalline form of a compound of Formula I.

7 . The process of claim 6 , wherein said substantially pure crystalline form of a compound of Formula I comprises less than 15% by weight of impurities.

8 . A pharmaceutical composition comprising a substantially pure form of (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester or a pharmaceutically acceptable salt thereof.

9 . The pharmaceutical composition form according to claim 8 , wherein the composition comprises less than 15% by weight of impurities.

10 . The pharmaceutical composition form according to claim 8 , for the treatment of the symptoms of secondary hypogonadism induced by androgen deprivation therapy.

11 . The pharmaceutical composition according to claim 8 , wherein said pharmaceutical composition is in the form of a capsule.

12 . A technical grade form of (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester or a pharmaceutically acceptable salt thereof.

Assignees

• Lilly Co Eli

Inventors

• Benson Charles Thomas
• Richey Rachel Nicole
• Yu Hannah

Classifications

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D209/60

  Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles · CPC title

• A61K31/403 Primary

  condensed with carbocyclic rings, e.g. carbazole · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title