Aqueous solution comprising 3-quinuclidinones for the treatment hyperproliferative, autoimmune and heart disease

1. A liquid composition, comprising an aqueous solution of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, and

a pH regulating agent,

wherein:

R 1 is selected from H, —CH 2 —O—R 3 , —CH 2 —S—R 3 , and —CH 2 —NR 3 R 4 ;

R 2 is selected from —CH 2 —O—R 3 , —CH 2 —S—R 3 , and —CH 2 —NR 3 R 4 ; and

R 3 and R 4 are the same or different and are independently selected from H; substituted or non-substituted, unbranched or branched, saturated or unsaturated C3-C12 cycloalkyl or C1-C10 alkyl; substituted or non-substituted benzyl; substituted or non-substituted mono- or bicyclic aryl; substituted or non-substituted mono-, bi- or tricyclic C2-C10 heteroaryl or non-aromatic C2-C10 heterocyclyl containing one or several heteroatoms independently selected from N, O and S; or

R 3 and R 4 in —CH 2 —NR 3 R 4 are bonded together and form, together with the nitrogen atom to which they are bonded, a substituted or non-substituted non-aromatic C2-C10 mono- or bicyclic heterocyclyl optionally containing one or more further heteroatoms independently selected from N, O and S and optionally comprising one or more cyclic keto groups;

wherein the substituents of the substituted groups are independently selected from unbranched or branched, saturated or unsaturated C3-C12 cycloalkyl or C1-C10 alkyl; halogen; halogen-substituted C1-C10 alkyl, mono- or bicyclic aryl; mono-, bi- or tricyclic C2-C10 heteroaryl or non-aromatic C2-C10 heterocyclyl containing one or several heteroatoms independently selected from N, O and S; C1-C10 alkoxy; amino; and C1-C10 alkylamino;

wherein the aqueous solution has a pH from 3.0 to 5.0.

2. The liquid composition according to claim 1 , wherein

R 1 is selected from H and —CH 2 —O—R 3 ; and

R 2 is —CH 2 —O—R 3 .

3. The liquid composition according to claim 1 , wherein each R 3 is independently H or substituted or non-substituted, unbranched or branched, saturated or unsaturated C1-C6 alkyl.

4. The liquid composition according to claim 3 , wherein each R 3 is independently H or methyl.

5. The liquid composition according to claim 4 , wherein the compound is 2-(hydroxymethyl)-2-(methoxymethyl)quinuclidin-3-one or 2,2-bis(hydroxymethyl)-quinuclidin-3-one.

6. The liquid composition according to claim 1 , further comprising at least one additional therapeutically active agent.

7. The liquid composition according to claim 1 , wherein the aqueous solution has a pH between 3.0 and 4.5.

8. The liquid composition according to claim 1 , wherein the compound of formula (I) is present in the aqueous solution at a concentration of from 10 mg/mL to 250 mg/mL.

9. The liquid composition according to claim 1 , wherein the aqueous solution comprises NaCl at a concentration of between 0% to 3% weight by volume.

10. The liquid composition according to claim 1 , for use in the treatment of a disorder selected from hyperproliferative diseases, autoimmune diseases and heart diseases.

11. A method for preparing the liquid composition according to claim 1 , comprising adding, to an aqueous phase,

the compound of formula (I), or a pharmaceutically acceptable salt thereof;

optionally, at least one further therapeutically active agent; and

a pH regulating agent in an amount so as to provide a pH in the composition of from 3.0 to 5.0.

12. The method according to claim 11 , wherein the pH regulating agent is added in an amount so as to provide a pH in the composition of from 3.0 to 4.5.

13. The method according to claim 11 , wherein NaCl is added to the aqueous phase in an amount so as to provide a concentration of NaCl in the liquid composition of up to 3% weight by volume.

14. The method according to claim 11 , wherein the compound of formula (I), or the pharmaceutically acceptable salt thereof, is added to the aqueous phase in an amount so as to provide a concentration of the compound of formula (I) in the liquid composition of from 10 mg/mL to 250 mg/mL.

15. The liquid composition according to claim 1 , wherein the compound is 2-(hydroxymethyl)-2-(methoxymethyl)quinuclidin-3-one.

16. The liquid composition according to claim 1 , wherein the compound is selected from the group consisting of:

2-[(benzyloxy)methyl]quinuclidin-3-one;

2-(butoxymethyl)quinuclidin-3-one;

2-(propoxymethyl)quinuclidin-3-one;

2-[(phenylthio)methyl]quinuclidin-3-one;

2-[(7H-purin-6-ylthio)methyl]quinuclidin-3-one;

2-(2,3-dihydro-1H-indol-1-ylmethyl)quinuclidin-3-one;

2-({[2-amino-3-chloro-5-(trifluoromethyl)phenyl]-amino}methyl)quinuclidin-3-one;

2-(morpholin-4-ylmethyl)quinuclidin-3-one;

2-[(4-methylpiperazin-1-yl)methyl]quinuclidin-3-one;

2-{[ethyl(pyridin-4-ylmethyl)amino]methyl}quinuclidin-3-one;

2-[(3,5-dimethylpiperazin-1-yl)methyl]quinuclidin-3-one;

2-[(5,6-dimethyl-1H-benzimidazol-1-yl)methyl]-quinuclidin-3-one;

2-[(7-amino-1H-[1,2,3]triazolo[4,5-d]pyrimidin-1-yl)methyl]quinuclidin-3-one;

1,3-dimethyl-7-[(3-oxo-1-azabicyclo[2.2.2]oct-2-yl)-methyl]tetrahydro-1H-purine-2,6,8(3H)-trione;

2-[(2,6-dichloro-9H-purin-9-yl)methyl]quinuclidin-3-one; and

2-[(6-methoxy-9H-purin-9-yl)methyl]quinuclidin-3-one

17. A concentrated stock solution, comprising an aqueous solution of a compound of formula (I)

or a pharmaceutically acceptable salt thereof,

and a pH regulating agent,

the compound of formula (I) being present in the stock solution at a concentration of 75 mg/mL to 250 mg/mL, and the stock solution having a pH of from 3.8 to 4.2,

wherein:

R 1 is selected from H, —CH 2 —O—R 3 , —CH 2 —S—R 3 , and —CH 2 —NR 3 R 4 ;

R 2 is selected from —CH 2 —O—R 3 , —CH 2 —S—R 3 , and —CH 2 —NR 3 R 4 ; and

R 3 and R 4 are the same or different and are independently selected from H; substituted or non-substituted, unbranched or branched, saturated or unsaturated C3-C12 cycloalkyl or C1-C10 alkyl; substituted or non-substituted benzyl; substituted or non-substituted mono- or bicyclic aryl; substituted or non-substituted mono-, bi- or tricyclic C2-C10 heteroaryl or non-aromatic C2-C10 heterocyclyl containing one or several heteroatoms independently selected from N, O and S; or

R 3 and R 4 in —CH 2 —NR 3 R 4 are bonded together and form, together with the nitrogen atom to which they are bonded, a substituted or non-substituted non-aromatic C2-C10 mono- or bicyclic heterocyclyl optionally containing one or more further heteroatoms independently selected from N, O and S and optionally comprising one or more cyclic keto groups;

wherein the substituents of the substituted groups are independently selected from unbranched or branched, saturated or unsaturated C3-C12 cycloalkyl or C1-C10 alkyl; halogen; halogen-substituted C1-C10 alkyl, mono- or bicyclic aryl; mono-, bi- or tricyclic C2-C10 heteroaryl or non-aromatic C2-C10 heterocyclyl containing one or several heteroatoms independently selected from N, O and S; C1-C10 alkoxy; amino; and C1-C10 alkylamino,

and wherein the stock solution is storage stable.

18. The concentrated stock solution according to claim 17 , wherein the stock solution further comprises NaCl at a concentration of between 0.5% to 1.5% weight by volume.

19. The concentrated stock solution according to claim 17 , wherein said pH regulating agent comprises a pharmaceutically acceptable organic acid or inorganic mineral acid, a pharmaceutically acceptable acid buffer, or any mixture thereof.