Pyrido [2,1-a] isoquinoline derivatives

1. A compound of formula (I)

wherein

R 1 is —C(O)—N(R 5 )R 6 or —N(R 5 )R 6 ;

R 2 , R 3 and R 4 are each independently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkenyl, substituted lower alkyl, substituted lower alkoxy, or substituted lower alkenyl, wherein substituted lower alkyl, substituted lower alkoxy and substituted lower alkenyl are lower alkyl, lower alkoxy and lower alkenyl, respectively, which are independently substituted by a group selected from the group consisting of lower alkoxycarbonyl, aryl and heterocyclyl;

R 5 is hydrogen, lower alkyl, halogenated lower alkyl or cycloalkyl;

R 6 is lower alkylsulfonyl, halogenated lower alkylsulfonyl, cycloalkylsulfonyl, lower alkylcarbonyl, halogenated lower alkylcarbonyl, or cycloalkylcarbonyl; or

R 5 and R 6 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or unsaturated non-aromatic heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally mono-, di-, or tri-substituted, independently, with a group selected from the group consisting of lower alkyl, halogenated lower alkyl, oxo, dioxo and cyano;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 is —C(O)—N(R 5 )R 6 .

3. The compound according to claim 1 , wherein R 1 is —N(R 5 )R 6 .

4. The compound according to claim 1 , wherein R 2 , R 3 and R 4 are each independently hydrogen, hydroxy or lower alkoxy.

5. The compound according to claim 4 , wherein R 2 is lower alkoxy.

6. The compound according to claim 4 , wherein R 3 is lower alkoxy.

7. The compound according to claim 4 , wherein R 4 is hydrogen.

8. The compound according to claim 1 , wherein R 5 is hydrogen, lower alkyl or halogenated lower alkyl.

9. The compound according to claim 1 , wherein R 6 is lower alkylsulfonyl, lower alkylcarbonyl or cycloalkylcarbonyl.

10. The compound according to claim 1 , wherein R 5 and R 6 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or unsaturated non-aromatic heterocyclic ring optionally containing a further heteroatom selected from a sulfur and oxygen, said heterocyclic ring being optionally mono- or di-substituted, independently, with a group selected from the group consisting of lower alkyl, halogenated lower alkyl, oxo, dioxo and cyano.

11. The compound according to claim 10 , wherein R 5 and R 6 together with the nitrogen atom to which they are attached are selected from the group consisting of pyrrolidine, pyrrolidin-2-one, 4-methyl-pyrrolidin-2-one, 4-ethyl-pyrrolidin-2-one, 3-methyl-pyrrolidin-2-one, 5-methyl-pyrrolidin-2-one, 4-fluoro-methyl-pyrrolidin-2-one, pyrrolidine-2-carbonitrile, piperidine, piperidin-2-one, 4-methyl-piperidin-2-one, 5-methyl-piperidin-2-one, 5,6-dihydro-1H-pyridin-2-one, thiazolidin-3-yl, 1,1-dioxo-1,2-thiazolidin-2-yl, 1,1-dioxo [1,2]thiazinan-2-yl, azetidine, azepan-2-one, oxazolidin-2-one, 5-methyl-oxazolidin-2-one, 5-fluoromethyl-oxazolidin-2-one, and [1,3]oxazinan-2-one.

12. The compound according to claim 1 , selected from the group consisting of:

(RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-pyrrolidin-1-yl-methanone;

(RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-thiazolidin-3-yl-methanone;

(RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-azetidin-1-yl-methanone;

(SS)-1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinoline-3-carbonyl)-pyrrolidine-2-carbonitrile;

1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-piperidin-2-one;

(−)-(S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-piperidin-2-one;

(+)-(R,R,R)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one;

1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-methyl-piperidin-2-one;

(RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-pyrrolidin-2-one; and

1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 , selected from the group consisting of:

1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-ethyl-pyrrolidin-2-one;

(RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5,6-dihydro-1H-pyridin-2-one;

1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azepan-2-one;

(RS,RS,RS)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-ylamine;

(RS,RS,RS)-3-(1,1-dioxo[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine;

(S,S,S)-3-(1,1-dioxo-[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-ylamine;

(SR)-1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;

(RS,RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;

(R)-1-((S,S,S)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one and

(S)-1-((R,R,R)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 , selected from the group consisting of:

(S,S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;

(R,R,R,R)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;

1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one;

1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-piperidin-2-one;

(RS,RS,RS)-N-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-propionamide;

(RS,RS,RS)-N-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-butyramide;

cydopropanecarboxylic acid ((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-amide;

(SR)-1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one;

(RS,RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one and

(S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one;

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 , selected from the group consisting of:

(R)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one;

3-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-oxazolidin-2-one;

3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-[1,3]oxazinan-2-one;

1-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-5-methyl-pyrrolidin-2-one;

3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-5-fluoromethyl-oxazolidin-2-one;

1-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-3-methyl-pyrrolidin-2-one; and

3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-5-methyl-oxazolidin-2-one;

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 12 , selected from the group consisting of:

(RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-thiazolidin-3-yl-methanone;

(−)-(S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one; and

1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 13 , selected from the group consisting of:

(RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5,6-dihydro-1H-pyridin-2-one;

(S,S,S)-3-(1,1-dioxo-[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine; and

(R)-1-((S,S,S)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;

or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 14 , wherein said compound is (S,S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;

or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 15 , selected from the group consisting of:

(R)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one; and

3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-5-methyl-oxazolidin-2-one;

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

21. A method for the treatment of non-insulin dependent diabetes mellitus in a patient in need thereof, comprising administering to said patient a compound according to claim 1 in an amount of from about 1 to 1000 mg per day.

22. The method according to claim 21 , wherein the amount is from about 1 to 100 mg per day.

23. The compound according to claim 14 , wherein said compound is 1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-piperdin-2-one, or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 14 , wherein said compound is (S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.