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1. WO2009007419 - NOVEL BRONCHODILATING ISOQUINOLINE CARBAMATES

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

Claims

1. A compound according to formula I,


wherein

Rl is selected from H and methyl;

R2 is selected from H and methyl;

R3 is selected from H, fluoro, chloro, bromo, C 1-3 alkyl and CH2 phenyl;

R4 is selected from H, fluoro, chloro, bromo, C 1-3 alkyl and CH2 phenyl;

G is a CO-2 alkylene aryl or CO-2 alkylene heteroaryl; said alkylene is optionally substituted with 1 or 2 substituent(s) independently selected from benzyl, Cl-5 alkyl and C 1-5 fluoroalkyl; said aryl or heteroaryl is optionally substituted, at any substitutable ring atom, with 1 or 2 substituent(s) independently selected from C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, C 1-5 fiuoroalkylthio,
NH(CO)C 1 -5 alkyl, NH(CO)C 1 -5 alkoxy, NHSO2C 1 -5 alkyl, (CO)C 1 -5 alkyl, COOH, (CO)C 1-5 alkoxy, (C0)NH2, (CO)NHC 1-5 alkyl, (CO)N(C 1-5 alkyl)2, cyano,
SO2NHC0-5 alkyl, nitro, aryl, heteroaryl, morpholinyl, N(C4-5 alkylene) and N3 (azido);

as a free base or a pharmaceutically acceptable addition salt, solvate or solvate of a salt thereof and as a pure stereoisomer, a racemic-, diastereomeric- or scalemic mixture;

with the provisos that

not both of Rl and R2 is methyl; and

the following compounds are excluded:


2. A compound according claim 1, wherein G is selected from Gl to G5;



(R1 1 )V


and wherein, Ll is C 1-2 alkylene, wherein said alkylene is optionally substituted with a maximum of "m" independently selected substituent(s) R5, wherein "m" represent an integer number;

the integer number "m" is 0 to 2;

R5 is selected from benzyl, C 1-5 alkyl and C 1-5 fluoroalkyl;

Xl, X2, X3, X4 and X5 are, independently of each other, selected from N and C; 0 (zero), 1 or 2 of Xl to X5 are N; Q is optionally substituted with a maximum of "n" independently selected substituent(s) R6 at any substitutable ring carbon atom, wherein "n" represent an integer number;

the integer number "n" is 0 (zero) to 2;

R6 is selected from C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, C 1-5 fiuoroalkylthio, NH(CO)C 1-5 alkyl, NH(CO)C 1-5 alkoxy, NHSO2C 1 -5 alkyl, (CO)C 1 -5 alkyl, COOH, (CO)C 1 -5 alkoxy, (C0)NH2, (CO)NHC 1 -5 alkyl, (CO)N(C 1-5 alkyl)2, cyano, SO2NHC0-5 alkyl, nitro, aryl, heteroaryl, morpholinyl, N(C4-5 alkylene) and N3 (azido);

L2 is C 1-2 alkylene, wherein said alkylene is optionally substituted with a maximum of "o" independently selected substituent(s) R7, wherein "o" represent an integer number;

the integer number "o" is 0 (zero) to 2;

R7 is selected from benzyl, C 1-5 alkyl and C 1-5 fluoroalkyl;

the condensed rings Wl and W2 together represent a bicyclic aromatic system, in which X6, X7 and X8, independently of each other, are selected from N and C; 0 (zero) or 1 of X6 to X8 is N; said bicyclic aromatic system is optionally substituted with a maximum of "p" independently selected substituent(s) R8, at any substitutable ring carbon atom(s) of any of the rings Wl and W2, wherein "p" represent an integer number;

the integer number "p" is 0 (zero) to 2;

R8 is selected from C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, C 1-5 fiuoroalkylthio, NH(CO)C 1-5 alkyl, NH(CO)C 1-5 alkoxy, NHSO2C 1 -5 alkyl, (CO)C 1 -5 alkyl, COOH, (CO)C 1 -5 alkoxy, (C0)NH2, (CO)NHC 1 -5 alkyl, (CO)N(C 1-5 alkyl)2, cyano, SO2NHC0-5 alkyl, nitro, aryl, heteroaryl, morpholinyl, N(C4-5 alkylene) and N3 (azido);

X9 and XlO are independently selected from N and C; O (zero) or 1 of X9 and XlO are N; Y is optionally substituted with one substituent R9 at any substitutable aromatic ring carbon atom.

R9 is selected from C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, C 1-5 fiuoroalkylthio, NH(CO)C 1-5 alkyl, NH(CO)C 1-5 alkoxy, NHSO2C1-5 alkyl, (CO)C 1-5 alkyl, COOH, (CO)C 1-5 alkoxy, (C0)NH2, (CO)NHCl-5 alkyl, (CO)N(C 1-5 alkyl)2, cyano, SO2NHC0-5 alkyl, nitro, aryl, heteroaryl, morpholinyl, N(C4-5 alkylene) and N3 (azido);

Z is optionally substituted with one substituent RlO at any substitutable aromatic ring carbon;

RlO is selected from C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, C 1-5 fiuoroalkylthio, NH(CO)C 1-5 alkyl, NH(CO)C 1-5 alkoxy, NHSO2C1-5 alkyl, (CO)C 1-5 alkyl, COOH, (CO)C 1-5 alkoxy, (C0)NH2, (CO)NHCl-5 alkyl, (CO)N(C 1-5 alkyl)2, cyano, SO2NHC0-5 alkyl, nitro, aryl, heteroaryl, morpholinyl, N(C4-5 alkylene) and N3 (azido);

L3 is C 1-2 alkylene, wherein said alkylene is optionally substituted with a maximum of "v" independently selected substituent(s) Rl 1, wherein "v" represent an integer number;

the integer number "v" is 0 (zero) to 2;

Rl 1 is selected from benzyl, C 1-5 alkyl and C 1-5 fluoroalkyl;

the condensed rings Tl and T2 together represent a bicyclic aromatic system, in which Xl 1, Xl 2 and Xl 3, independently of each other, are selected from N and C; 0 (zero) or 1 of said Xl 1, Xl 2 and Xl 3 is N; said bicyclic aromatic system is optionally substituted with a maximum of "s" independently selected substituent(s) R12, at any substitutable ring carbon atom(s) of any of the rings Tl and T2, wherein "s" represent an integer number;

the integer number "s" is 0 (zero) to 2;

Rl 2 is selected from C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, C 1-5 fiuoroalkylthio, NH(CO)C 1-5 alkyl, NH(CO)C 1-5 alkoxy, NHSO2C1-5 alkyl, (CO)C 1-5 alkyl, COOH, (CO)C 1-5 alkoxy, (C0)NH2, (CO)NHCl-5 alkyl, (CO)N(C 1-5 alkyl)2, cyano, SO2NHC0-5 alkyl, nitro, aryl, heteroaryl, morpholinyl, N(C4-5 alkylene) and N3 (azido);

3. The compound according to claim 1 or 2, wherein Rl and R2 is H.

4. The compound according to claim 1, 2 or 3, wherein R3 and R4, independent of each other, are selected from H, fluoro, chloro, bromo, and methyl.

5. The compound according to claim 4, wherein R3 and R4, independent of each other, are selected from H, chloro and bromo.

6. The compound according to claim 5, wherein R3 and R4 are chloro.

7. The compound according to any of the claims 2 to 6, wherein G is Gl.

8. The compound according to claim 7, wherein at least one of Xl to X5 is N.

9. The compound according to claim 8, wherein Xl or X2 is N and only one of Xl to X5 is N.

10. The compound according to any of the claims 7 to 9, wherein m is 0 (zero) and n is 1 or 2 and R6 is selected from C1-C3 alkyl, such as methyl, trifluoromethyl, halo, hydroxy, N(C4-5 alkylene), methoxy, SO2Me, cyano, thienyl, nitro, phenyl, morpholinyl and NMe2.

11. The compound according to claim 10, wherein R6 is selected from methyl, trifluoromethyl, fluoro, chloro and NMe2.

12. The compound according to any of the claims 2 to 6, wherein G is G2 and L2 is methylene or wherein G is G5 and L3 is methylene.

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


14. A compound according to claim 1, said compound being selected from the group consisting of:

15. A pharmaceutical composition comprising a compound according to any of the claims 1 to 14 and at least one pharmaceutically acceptable carrier.

16. The pharmaceutical composition according to claim 15, comprising an antiasthmatic.

17. The pharmaceutical composition according to claim 16, wherein the principal mechanism of action of the anti-asthmatic is selected from the group consisting of β2-agonist, anticholinergic and calcium antagonist, or wherein the antiasthmatic is a corticosteroid.

18. The compound according to any of the claims 1 to 14 or a composition according to any of the claims 15 to 17 for use in therapy.

19. The compound according to any of the claims 1 to 14 or a composition according to any of the claims 15 to 17 for use in the prevention and/or treatment of a disease or condition characterized by bronchoconstriction of the respiratory apparatus.

20. The compound according to any of the claims 1 to 14 or a composition according to any of the claims 15 to 17 for use in the prevention and/or treatment of a disease or condition characterized by inflammation of the respiratory apparatus.

21. The compound or composition according to claim 19 or 20, wherein said disease or condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis and bronchopulmonary dysplasia.

22. A method of prevention and/or treatment a disease or condition
characterized by bronchoconstriction and/or inflammatory conditions of the respiratory apparatus, such as of asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis and bronchopulmonary dysplasia, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound according to any of the claims 1 to 14 or a composition according to any of claim 15 to 17 comprising a therapeutically effective amount of a compound according to any of the claims 1 to 14.

23. A method of prevention and/or treatment of a disease or condition characterized by bronchoconstriction and/or inflammatory conditions of the respiratory apparatus, such as of asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis and bronchopulmonary dysplasia, comprising the simultaneous or consecutive administration therapeutically effective amounts of a compound according to any of the claims 1 to 14 and an antiasthmatic.

24. The method according to claim 23, wherein the administered dose of the anti-asthmatic is 1 to 10 times less than the established therapeutically effective dose when administered alone for prevention or treatment of the same disease or condition.

25. The method according to claim 23 or 24, wherein the administered dose of a compound according to any one of claims 1 to 14 is 1 to 10 times less than the established therapeutically effective dose when administered alone for prevention or treatment of the same disease or condition.

26. The method according to any of the claims 23 to 25, wherein the principal mechanism of action of the anti-asthmatic is selected from the group consisting of β2-agonist, anticholinergic and calcium antagonist, or wherein the anti-asthmatic is a corticosteroid.

27. The compound according to any of the claims 1 to 14 or a composition according to claim 15 for use in the prevention and/or treatment of a disease or condition characterized by systemic or respiratory vasoconstriction.

28. A method of prevention and/or treatment of a disease or condition characterized by systemic or respiratory vasoconstriction, comprising administrering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound according to any of the claims 1 to 14 or a composition according to claim 15 comprising a therapeutically effective amount of a compound according to any of the claims 1 to 14.