IP Library › Granted Patent US 8,129,541
Granted Patent B2
US 8,129,541 · App. 12/640,479 · Granted Mar 6, 2012

5-phenylthiazole derivatives and use as PI3 kinase inhibitors

Assignee: Novartis AG
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Quick Facts
Patent No.
US 8,129,541
App. No.
12/640,479
Granted
Mar 6, 2012
Kind
B2
Abstract

Compounds of formula I in free or salt form, wherein R 1 , R 2 , R 3 , R 4 and R 5 have the meanings as indicated in the specification, are useful for treating diseases mediated by phosphatidylinositol 3-kinase. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.

Claims (307)

1. A compound of formula I

in free or salt form, wherein

R 1 is aminocarbonyl optionally substituted by nitrile,

or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by halogen, hydroxy, amino, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, carboxy, C 1 -C 8 -alkoxycarbonyl, nitrile, C 1 -C 8 -haloalkyl, or by C 1 -C 8 -alkyl optionally substituted by hydroxy,

or R 1 is C 1 -C 8 -alkylaminocarbonyl which is optionally substituted by C 3 -C 8 -cycloalkyl optionally substituted by hydroxy,

or R 1 is C 1 -C 8 -alkylaminocarbonyl which is optionally substituted by C 1 -C 8 -alkoxy optionally substituted by hydroxy,

or R 1 is C 1 -C 8 -alkylaminocarbonyl which is optionally substituted by phenyl substituted by hydroxy or C 1 -C 8 -alkyl,

or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by a 5-or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy,

or R 1 is —(C═O)—(NH)-Het where Het denotes a 4-, 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,

or R 1 is —(C═O)—(NH)—T where T denotes C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, or by C 1 -C 8 -alkyl substituted by hydroxy, or T denotes phenyl substituted by hydroxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, or by C 1 -C 8 -alkyl substituted by hydroxy;

R 2 is C 1 -C 3 -alkyl or halogen;

one of R 3 and R 4 is R 6 and the other is R 7 ;

R 5 is hydrogen or halogen;

R 6 is hydroxy, amino, —SOR 8 , —SO 2 R 8 , —SO 2 NH 2 , —SO 2 NR 9 R 10 , —COR 8 , —CONHR 8 , —NHSO 2 R 8 , nitrile, carboxy, —OR 8 or C 1 -C 8 -haloalkyl;

R 7 is hydrogen, R 11 , —OR 11 , halo, carboxy, —SO 2 R 8 , cyano or C 1 -C 8 -haloalkyl, or, when R 4 is R 7 ,

R 7 can also be —NR 12 R 13 ,R 14 or —OR 14 ;

R 8 and R 11 are independently C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by halogen, hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino;

either R 9 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl, and R 10 is hydrogen or C 1 -C 8 -alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl;

either R 12 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino, and R 13 is hydrogen or C 1 -C 8 -alkyl; or R 12 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl; and

R 14 is C 1 -C 8 -alkyl optionally substituted by hydroxy or —NR 12 R 13 .

2. A compound according to claim 1 wherein

R 1 is aminocarbonyl optionally substituted by nitrile,

or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by halogen, hydroxy, di(C 1 -C 8 - alkyl)amino, carboxy, C 1 -C 8 -alkoxycarbonyl, nitrile, C 1 -C 8 -haloalkyl, or by C 1 -C 8 -alkyl optionally substituted by hydroxy,

or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by C 3 -C 8 -cycloalkyl,

or R 1 is C 1 -C 8 -alkylaminocarbonyl which is optionally substituted by C 1 -C 8 -alkoxy optionally substituted by hydroxy,

or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl,

or R 1 is —(C═O)—(NH)-Het where Het denotes a 4-, 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,

or R 1 is —(C═O)—NH-T where T denotes C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkyl, or by C 1 -C 8 -alkyl substituted by hydroxy,

or T denotes phenyl substituted by hydroxy, C 1 -C 8 -alkyl, or by C 1 -C 8 -alkyl substituted by hydroxy;

R 2 is C 1 -C 3 -alkyl;

one of R 3 and R 4 is R 6 and the other is R 7 ;

R 5 is hydrogen or halogen;

R 6 is hydroxy, amino, —SO 2 R 8 , —SO 2 NH 2 , —SO 2 NR 9 R 10 , —NHSO 2 R 8 , cyano, carboxy, —OR 8 or C 1 -C 4 -haloalkyl;

R 7 is hydrogen, —OR 11 , fluorine, chlorine, bromine, nitrile or C 1 -C 4 -haloalkyl, or, when R 4 is R 7 , R 7 can also be —NR 12 R 13 or —OR 14 ;

R 8 and R 11 are independently C 1 -C 8 -alkyl;

either R 9 is C 1 -C 8 -alkyl optionally substituted by hydroxy, C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl, and R 10 is hydrogen or C 1 -C 8 -alkyl;

or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl;

either R 12 is C 1 -C 8 -alkyl optionally substituted by di(C 1 -C 8 -alkyl)amino, and R 13 is hydrogen or C 1 -C 8 -alkyl; or R 12 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl; and

R 14 is C 1 -C 8 -alkyl.

3. A compound according to claim 2 , in free or salt form, wherein R 1 is aminocarbonyl optionally substituted by nitrile,

or R 1 is C 1 -C 4 -alkylaminocarbonyl optionally substituted by halogen, hydroxy, di(C 1 -C 4 -alkyl)amino, carboxy, C 1 -C 4 -alkoxycarbonyl, nitrile, C 1 -C 4 -haloalkyl, or by C 1 -C 4 -alkyl optionally substituted by hydroxy,

or R 1 is C 1 -C 4 -alkylaminocarbonyl optionally substituted by C 3 -C 5 -cycloalkyl,

or R 1 is C 1 -C 8 -alkylaminocarbonyl which is optionally substituted by C 1 -C 4 -alkoxy optionally substituted by hydroxy,

or R 1 is C 1 -C 4 -alkylaminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 4 -alkyl,

or R 1 is —(C═O)—(NH)-Het where Het denotes a 4-, 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,

or R 1 is —(C═O)—NH-T where T denotes C 3 -C 5 -cycloalkyl optionally substituted by hydroxy, C 1 -C 4 -alkyl, or by C 1 -C 4 -alkyl substituted by hydroxy,

or T denotes phenyl substituted by hydroxy, C 1 -C 4 -alkyl, or by C 1 -C 4 -alkyl substituted by hydroxy;

R 2 is C 1 -C 3 -alkyl;

one of R 3 and R 4 is R 6 and the other is R 7 ;

R 5 is hydrogen or halogen;

R 6 is hydroxy, amino, SO 2 R 8 , SO 2 NH 2 , SO 2 NR 9 R 10 , NHSO 2 R 8 , nitrile, carboxy, OR 8 or C 1 -C 4 -haloalkyl;

R 7 is hydrogen, —OR 11 , fluorine, chlorine, bromine, cyano or C 1 -C 4 -haloalkyl, or, when R 4 is R 7 ,

R 7 can also be —NR 12 R 13 or —OR 14 ;

R 8 and R 11 are independently C 1 -C 4 -alkyl;

either R 9 is C 1 -C 4 -alkyl optionally substituted by hydroxy, C 3 -C 5 -cycloalkyl optionally substituted by hydroxy, C 1 -C 4 -alkoxy, nitrile, di(C 1 -C 4 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 4 -alkyl, and R 10 is hydrogen or C 1 -C 4 -alkyl;

or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 4 -alkyl;

either R 12 is C 1 -C 4 -alkyl optionally substituted by di(C 1 -C 4 -alkyl)amino, and R 13 is hydrogen or C 1 -C 4 -alkyl; or R 12 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 4 -alkyl; and

R 14 is C 1-4 alkyl.

4. A compound of formula I according to claim 1 in free or salt form, wherein

R 1 is aminocarbonyl,

or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by hydroxy, amino, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl(amino), carboxy, C 1 -C 8 -alkyl optionally substituted by hydroxy, or by halogen,

or R 1 is C 1 -C 8 -alkylaminocarbonyl which is optionally substituted by C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy optionally substituted by hydroxy, C 1 -C 8 -alkoxycarbonyl, nitrile, halogen, phenyl substituted by hydroxy or C 1 -C 8 -alkyl,

or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy,

or R 1 is —(C═O)—(NH)-Het where Het denotes a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy;

R 2 is C 1 -C 3 -alkyl or halogen;

one of R 3 and R 4 is R 6 and the other is R 7;

R 5 is hydrogen or halogen;

R 6 is hydroxy, amino, —SOR 8 , —SO 2 R 8 , —SO 2 NH 2 , —SO 2 NR 9 R 10 , —COR 8 , —CONHR 8 , —NHSO 2 R 8 , nitrile, carboxy, —OR or C 1 -C 8 -haloalkyl;

R 7 is hydrogen, R 11 , —OR 11 , halo, carboxy, —SO 2 R 8 , cyano or C 1 -C 8 -haloalkyl, or, when R 4 is R 7 ,

R 7 can also be —NR 12 R 13 , R R14 or —OR 14;

R 8 and R 11 are independently C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by halogen, hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino;

either R 9 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl, and R 10 is hydrogen or C 1 -C 8 -alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl;

either R 12 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino, and R 13 is hydrogen or C 1 -C 8 -alkyl; or R 12 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl; and

R 14 is C 1 -C 8 - alkyl optionally substituted by hydroxy or —NR 12 R 13 .

5. A compound according to claim 4 wherein

R 1 is aminocarbonyl,

or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by hydroxy, di(C 1 -C 8 -alkylamino), carboxy, C 1 -C 8 -alkyl optionally substituted by hydroxy, or by halogen,

or R 1 is C 1 -C 8 -alkylaminocarbonyl which is optionally substituted by C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy optionally substituted by hydroxy, C 1 -C 8 -alkoxycarbonyl, nitrile, halogen, phenyl substituted by hydroxy or C 1 -C 8 -alkyl,

or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy,

or R 1 is —(C═O)—(NH)-Het where Het denotes a 5- or 6-membered N-heterocyclic ring optionally substituted by hydroxy, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy;

R 2 is C 1 -C 3 -alkyl;

one of R 3 and R 4 is R 6 and the other is R 7 ;

R 5 is hydrogen or halogen;

R 6 is hydroxy, amino, —SO 2 R 8 , —SO 2 NH 2 , —SO 2 NR 9 R 10 , —NHSO 2 R 8 , cyano, carboxy, —OR 8 or C 1 C 4 -haloalkyl;

R 7 is hydrogen, —OR 11 , fluorine, chlorine, bromine, cyano or C 1 -C 4 -haloalkyl, or, when R 4 is R 7 ,

R 7 can also be —NR 12 R 13 or —OR 14 ;

R 8 and R 11 are independently C 1 -C 8 -alkyl;

either R 9 is C 1 -C 8 -alkyl optionally substituted by hydroxy, C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl, and R 10 is hydrogen or C 1 -C 8 -alkyl;

or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl;

either R 12 is C 1 -C 8 -alkyl optionally substituted by di(C 1 -C 8 -alkyl)amino, and R 13 is hydrogen or C 1 -C 8 -alkyl; or R 12 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl; and

R 14 is C 1 -C 8 -alkyl.

6. A compound of formula I according to claim 1 , in free or salt form, wherein

R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by amino, carboxy, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, nitrile, or by halogen,

or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl;

R 2 is C 1 - C 3 -alkyl or halogen;

one of R 3 and R 4 is R 6 and the other is R 7 ;

R 5 is hydrogen or halogen;

R 6 is hydroxy, amino, SOR 8 , SO 2 R 8 , SO 2 NH 2 , SO 2 NR 9 R 10 , COR 8 , CONHR 8 , NHSO 2 R 8 , nitrile, carboxy, OR 8 or C 1 -C 8 -haloalkyl;

R 7 is hydrogen, R 11 , OR 11 , halo, cyano, carboxy, SO 2 R 8 ′, or C 1 -C 8 -haloalkyl, or, when R 4 is R 7 ,

R 7 can also be NR 12 R 13 , R 14 or OR 14 ;

R 8 and R 11 are independently C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by halogen, hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino;

either R 9 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl, and R 10 is hydrogen or C 1 -C 8 -alkyl;

or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl;

either R 12 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino, and R 13 is hydrogen or C 1 -C 8 -alkyl; or R 12 and R 13 together with the nitrogen atom to which they are attached form a 5 or 6- membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl; and R 14 is C 1 -C 8 -alkyl optionally substituted by hydroxy or NR 12 R 13 .

7. A compound according to claim 6 wherein

R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by carboxy or C 1 -C 8 -alkoxycarbonyl;

R 2 is C 1 -C 3 -alkyl;

one of R 3 and R 4 is R 6 and the other is R 7 ;

R 5 is hydrogen or halogen;

R 6 is hydroxy, amino, SO 2 R 8 , SO 2 NH 2 , SO 2 NR 9 R 10 , NHSO 2 R 8 , cyano, carboxy, OR 8 or C 1 -C 4 - haloalkyl;

R 7 is hydrogen, OR 11 , fluorine, chlorine, bromine, cyano or C 1 -C 4 -haloalkyl, or, when R 4 is R 7 , R 7 can also be NR 12 R 13 or OR 14 ;

R 8 and R 11 are independently C 1 -C 8 -alkyl;

either R 9 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, di(C 1 -C 8 -alkyl)amino or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl, and R 10 is hydrogen or C 1 -C 8 -alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5 or 6- membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl;

either R 12 is C 1 -C 8 -alkyl optionally substituted by di(C 1 -C 8 -alkyl)amino, and R 13 is hydrogen or C 1 -C 8 -alkyl; or R 12 and R 13 together with the nitrogen atom to which they are attached form a 5 or 6- membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl; and

R 14 is C 1 -C 8 -alkyl.

8. A compound of claim 1 , that is also a compound of formula XIX

in free or salt form, wherein R a , R b , R c and R 1 are as shown in the following table:

R a

R b

R c

R 1

H

H

H

H

Cl

Cl

OCH 3

H

OCH 3

H

H

H

H

H

H

H

H

H

H

H

or

F

H

9. A compound of claim 1 , that is also a compound of formula XIX

in free or salt form, wherein R a , R b , R c and R 1 are as shown in the following table:

R a

R b

R c

R 1

H

F

H

F

H

F

H

F

H

F

H

F

H

F

H

Cl

H

H

H

Cl

H

Cl

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

H

H

H

H

H

or

H

10. A compound of claim 1 , that is also a compound of formula XIX

in free or salt form, wherein R a , R b , R c and R 1 are as shown in the following table:

R a

R b

R c

R 1

Cl

H

F

—H

F

H

—CF 3

H

—CF 3

H

H

H

Cl

H

Cl

H

F

Cl

H

H

Cl

H

H

H

F

H

F

H

F

H

F

H

or

F

H

11. A compound according to claim 1 in combination with at least one drug substance which is an anti-inflammatory, a bronchodilator or an antihistamine drug substance.

12. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 , optionally together with a pharmaceutically acceptable diluent or carrier.

13. A pharmaceutical composition comprising as active ingredient a compound according to claim 8 , optionally together with a pharmaceutically acceptable diluent or carrier.

14. A pharmaceutical composition comprising as active ingredient a compound according to claim 9 , optionally together with a pharmaceutically acceptable diluent or carrier.

15. A pharmaceutical composition comprising as active ingredient a compound according to claim 10 , optionally together with a pharmaceutically acceptable diluent or carrier.

Priority Claims (2)
GB 0204765.2 · Feb 28, 2002 · national
GB 0229626.7 · Dec 19, 2002 · national
Continuity (2)
Division 10504259
Related Publication 20100093690A1 · Apr 15, 2010