Salts of aza-bicyclic di-aryl ethers and methods to make them or their precursors

Patent metadata

Field	Value
Publication number	US-2016145253-A1
Application number	US-201614997207-A
Country	US
Kind code	A1
Filing date	Jan 15, 2016
Priority date	Jul 15, 2011
Publication date	May 26, 2016
Grant date	—

Abstract

The present invention relates to salts of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, to methods for making them or their precursors, to pharmaceutical compositions comprising them, and to their use as medicaments.

First claim

1 . A salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane wherein said salt is the fumarate, maleate, chloride, phosphate, succinate, or malonate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane.

2 . The salt according to claim 1 , wherein the salt is the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form.

3 . The salt according to claim 2 , wherein the salt is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 1 .

4 . The salt according to claim 1 , wherein the salt is the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, wherein the mean particle size of the crystals is at least 15 μm.

5 . The salt according to claim 2 , wherein the salt is the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, and wherein the salt is in substantially pure form.

6 . The salt according to claim 2 , wherein the salt is the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, and wherein the salt has a purity greater than 90 weight %.

7 . A method for the prevention, treatment, and/or delay of progression of a disease or condition, in which nAChR α7 activation plays a role or is implicated, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a salt as defined in claim 1 .

8 . A method for the prevention, treatment, and/or delay of progression of psychiatric or neurodegenerative disorders in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a salt as defined in claim 1 .

9 . A method of preparing a mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form comprising the steps of:
(a) preparing a solution of a mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in a solvent mixture of a primary alcohol, a secondary alcohol, and water, wherein the primary alcohol: secondary alcohol volume ratio is from 9:1 to 1:1, and wherein the primary alcohol: water volume ratio is from 17:1 to 7:1; (b) heating the solution of step (a) to elevated temperature; (c) adding the solution of step (b) gradually to an ether anti solvent at a temperature ranging from ambient temperature to 55° C. until a primary alcohol:ether antisolvent volume ratio from 5:1 to 1:1 is reached; wherein after an amount of the solution of step (b) from 10% to 40% of the total amount is added, the resulting solution is seeded with seed crystals of a mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, wherein the seed crystals are suspended in a secondary alcohol; (d) cooling the seeded solution of step (c) gradually to a temperature below ambient; and (e) isolate the solids by filtration to obtain the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form.

10 . A process for the production of a compound of formula I

or a salt thereof, the process comprising:
reacting a compound of formula II

or a salt thereof, with a compound of formula V

or a salt thereof, at elevated temperature in the presence of a base and an inert dipolar aprotic solvent,
wherein the base is (M 2 )OC(R) 3 , wherein M 2 is sodium or potassium and each R independently is C 1-6 alkyl or two R together with the carbon atom they are bound to form C 4-6 cycloalkyl, or the base is a hydroxide base,
to form the compound of formula I; and
optionally converting the compound of formula I to a salt thereof.

11 . The process according to claim 10 , wherein the base is gradually added to the reaction mixture.

12 . The process according to claim 10 , wherein the base is sodium tert-butanolate or potassium tert-butanolate.

13 . The process according to claim 10 , wherein the inert dipolar aprotic solvent is dimethylsulfoxide.

14 . The process according to claim 13 , wherein the reaction mixture further comprises toluene.

15 . The process according to claim 10 , further comprising producing the compound of formula II or the salt thereof

according to a process comprising:
a) reacting a compound of formula III

with a compound of formula IV

and/or
with a compound of formula IVA

wherein M 1 is alkali and n is 1, or M 1 is earth alkali and n is 2;
in the presence of a palladium catalyst; a base selected from a carbonate base, a phosphate base, a hydroxide base, and an alcoholate base; water and an inert solvent;
to form the compound of formula II; and
b) optionally converting the compound of formula II to a salt thereof.

16 . The process according to claim 15 , wherein the reaction of the compound of formula III with the compound of formula IV and/or the compound of formula IVA is carried out at a pH from 10.5 to 13.

17 . The process according to claim 15 ,
wherein the inert solvent is a partly water soluble solvent; wherein cysteine is added to the biphasic reaction mixture after formation of the compound of formula II; the phases are separated; and the compound of formula II is isolated from the non-aqueous phase.

Assignees

• Novartis Ag

Inventors

• Marterer Wolfgang
• Prashad Mahavir
• Villhauer Edwin Bernard
• Waykole Liladhar Murlidhar
• Vivelo James Anthony
• Sutter Bertrand
• Bianchi Jean-Claude
• Wu Raeann
• Har Denis
• Karpinski Piotr H
• Pignone Massimo
• Stingelin Doris
• Buerger Eckart

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title