SALTS OF AZA-BICYCLIC DI-ARYL ETHERS AND METHODS TO MAKE THEM OR THEIR PRECURSORS

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.

Claims

1. A salt of (R)-3-(6-(4-methylphenyI)-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.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0435] FIG. 1 shows the XRPD pattern for the mono-fumarate salt of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form

[0436] FIG. 2 shows the XRPD pattern for the mono-maleate salt of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form

[0437] FIG. 3 shows the XRPD pattern for the mono-hydrochloride salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form

[0438] FIGS. 4A, 4B and 4C show the XRPD patterns for Form A, B and C of the phosphate salt of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form

[0439] FIGS. 5A and 5B show the XRPD patterns for Form A and B of the mono-succinate salt of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form

[0440] FIG. 6 shows the XRPD pattern for the mono-malonate salt of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form

[0441] FIG. 7A and 7B show the XRPD patterns for Form A and B of the free base of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form

[0442] Thus, in addition to other illustrative embodiments, this invention can be seen to comprise one or more of the following illustrative embodiments:

[0443] 1. A salt of (R)-3-(6-(4-methylphenyI)-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.

[0444] 2. The salt according to embodiment 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.

[0445] 3. The salt according to embodiment 2, wherein the salt is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 1.

[0446] 4. The salt according to embodiment 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.

[0447] 5. The salt according to any one of embodiments 2 to 4, wherein the salt is the mono-fumarate salt of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, and wherein the salt is in substantially pure form.

[0448] 6. The salt according to any one of embodiments 2 to 4, wherein the salt is the mono-fumarate salt of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, and wherein the salt has a purity greater than 90 weight %.

[0449] 7. A pharmaceutical composition, which comprises a salt as defined in any one of embodiments 1 to 6 as active ingredient and at least one pharmaceutically acceptable carrier.

[0450] 8. A pharmaceutical composition, which comprises a salt as defined in any one of embodiments 1 to 6 in combination with one or more further therapeutic agent as active ingredients and at least one pharmaceutically acceptable carrier.

[0451] 9. A pharmaceutical composition comprising mono-fumarate of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane according to any one of embodiments 2 to 6 as active ingredient and at least one pharmaceutically acceptable carrier, wherein the composition is in the form of a tablet.

[0452] 10. A pharmaceutical composition in the form of a tablet comprising

[0453] (a) mono-fumarate of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane according to any one of embodiments 2 to 6 as active ingredient;

[0454] (b) a filler;

[0455] (c) a disintegrant;

[0456] (d) a lubricant; and

[0457] (e) a gliding agent;

[0458] wherein the only lubricant present is a lubricant selected from sodium stearyl fumarate, sodium lauryl sulfate, glyceryl behenates, hydrogenated vegetable oils, wax cetyl esters and talc.

[0459] 11. A pharmaceutical composition in the form of a tablet comprising

[0460] (a) up to 10% by weight mono-fumarate of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane according to any one of embodiments 2 to 6 as active ingredient;

[0461] (b) from 1 to 20% by weight maize starch; from 15 to 35% by weight microcrystalline cellulose; and from 40 to 75% by weight sprayed lactose;

[0462] (c) from 0.5 to 5% by weight sodium carboxymethylcellulose XL;

[0463] (d) from 0.5 to 3% by weight sodium stearyl fumarate; and

[0464] (e) from 0.1 to 1% by weight Aerosil.

[0465] 12. A pharmaceutical composition in the form of a tablet comprising from 1 to 10% by weight mono-fumarate of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane according to any one of embodiments 2 to 6 as active ingredient and at least one pharmaceutically acceptable carrier;

[0466] wherein the composition comprises an active ingredient layer comprising the mono-fumarate and an auxialiary layer being devoid of the mono-fumarate;

[0467] wherein the weight ratio of the active ingredient layer to the auxialiary layer is from 10:90 to 90:10.

[0468] 13. A pharmaceutical composition in the form of a tablet comprising from 1 to 10% by weight mono-fumarate of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane according to any one of embodiments 2 to 6 as active;

[0469] wherein the composition comprises an active ingredient layer comprising the mono-fumarate and an auxialiary layer being devoid of the mono-fumarate;

[0470] wherein the weight ratio of the active ingredient layer to the auxialiary layer is from 10:90 to 90:10; [0471] wherein the active ingredient layer comprises

[0472] (1a) from 11 to 25% by weight of the active ingredient layer the mono-fumarate of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;

[0473] (1b) from 15 to 35% by weight of the active ingredient layer microcrystalline cellulose; and from 40 to 70% by weight of the active ingredient layer sprayed lactose;

[0474] (1c) from 1 to 5% by weight of the active ingredient layer sodium carboxymethylcellulose XL;

[0475] (1d) from 1 to 5% by weight of the active ingredient layer sodium stearyl fumarate; and

[0476] (1e) from 0.1 to 1% by weight of the active ingredient layer Aerosil; and

[0477] wherein the auxiliary layer comprises

[0478] (2a) from 10 to 35% by weight of the auxiliary layer microcrystalline cellulose; and from 50 to 75% by weight of the auxiliary layer sprayed lactose;

[0479] (2b) from 1 to 3% by weight of the auxiliary layer sodium carboxymethylcellulose XL;

[0480] (2c) from 1 to 5% by weight of the auxiliary layer sodium stearyl fumarate; and

[0481] (2d) from 0.1 to 1% by weight of the auxiliary layer Aerosil.

[0482] 14. 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 any one of embodiments 1 to 6.

[0483] 15. A method for the prevention, treatment and/or delay of progression of 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 any one of embodiments 1 to 6.

[0484] 16. A composition comprising at least 90 weight % of salt according to any one of embodiments 1 to 4, based on the weight of the composition.

[0485] 17. A method of preparing a mono-fumarate salt of (R)-3-(6-(4-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form comprising the steps of

[0486] (a) preparing a solution of a mono-fumarate salt of (R)-3-(6-(4-methylphenyI)-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;

[0487] (b) heating the solution of step (a) to elevated temperature;

[0488] (c) adding the solution of step (b) gradually to an ether antisolvent 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-methylphenyI)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, wherein the seed crystals are suspended in a secondary alcohol;

[0489] (d) cooling the seeded solution of step (c) gradually to a temperature below ambient; and

[0490] (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.

[0491] 18. A process for the production of a compound of formula II or a salt thereof

##STR00013##

[0492] comprising

[0493] a) reacting a compound of formula III

##STR00014##

[0494] with a compound of formula IV

##STR00015##

and/or

[0495] with a compound of formula IVA

##STR00016##

[0496] wherein M.sub.1 is alkali and n is 1 or M.sub.1 is earth alkali and n is 2;

[0497] 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;

[0498] to form the compound of formula II; and

[0499] b) optionally converting the compound of formula II to a salt thereof.

[0500] 19. The process according to embodiment 18, wherein the reaction is carried out at a pH from 10.5 to 13.

[0501] 20. The process according to embodiment 18 or 19,

[0502] wherein the inert solvent is a partly water soluble solvent;

[0503] 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.

[0504] 21. A process for the production of a compound of formula I

##STR00017##

[0505] or a salt thereof comprising

[0506] c) reacting a compound of formula II

##STR00018##

[0507] or a salt thereof;

[0508] with a compound of formula V

##STR00019##

[0509] or a salt thereof;

[0510] at elevated temperature in the presence of a base and an inert dipolar aprotic solvent;

[0511] wherein the base is (M.sub.2)OC(R).sub.3, wherein M.sub.2 is sodium or potassium and each R independently is C.sub.1-6alkyl or two R together with the carbon atom they are bound to form C.sub.4-6cycloalkyl, or the base is a hydroxide base;

[0512] to form the compound of formula I; and

[0513] d) optionally converting the compound of formula I to a salt thereof.

[0514] 22. The process according to embodiment 21, wherein the base is gradually added to the reaction mixture.

[0515] 23. The process according to embodiment 21 or 22, wherein the base is sodium tert-butanolate or potassium tert-butanolate.

[0516] 24. The process according to any one of embodiments 21 to 23, wherein the inert dipolar aprotic solvent is dimethylsulfoxide.

[0517] 25. The process according to embodiment 24, wherein the reaction mixture further comprises toluene.