Thienodibenzoazulene compounds as tumor necrosis factor inhibitors

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16 . A method for the treatment of inflammatory diseases and conditions induced by or associated with excessive production of TNF-α and/or IL-1, which comprises administering to a subject a therapeutically effective amount of a compound of formula I or a pharmacologically acceptable salt or hydrate thereof:

wherein

x represents CH 2 , or a heteroatom selected from the group consisting of O, S, S(═O), S(═O) 2 or NR 13

wherein R 13 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, arylcarbonyl, C 1-6 alkylsulfonyl, or arylsulfonyl;

each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 independently represents hydrogen, fluoro, chloro, bromo; or C 1 -C 7 alkyl, C 2 -C 7 alkenyl; monocyclic or bicyclic aryl group having from 6 to 10 carbon atoms and alternating double bonds between carbon atoms and said aryl group can be unsubstituted or substituted with fluoro, chloro, bromo, hydroxy, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, aryloxy, wherein aryl has the meaning as defined above, C 1 -C 7 alkylthio, arylthio wherein aryl has the meaning as defined above, C 1 -C 7 alkylsulfonyl, cyano, or amino; C 1 -C 7 mono or di-C 1 -C 7 substituted amino, heteroaryl which is a monocyclic or bicyclic aromatic hydrocarbon containing at least one heteroatom selected from O, S or N optionally said heteroaryl can be unsubstituted or substituted with fluoro, chloro, bromo, CF 3 , methyl, ethyl or propyl; or halomethyl, hydroxy, C 1 -C 7 alkoxy, aryloxy wherein aryl has the meaning as defined above, C 1 -C 7 alkylthio, arylthio wherein aryl has the meaning as defined above, C 1 -C 7 alkylsulfonyl, cyano, amino, C 1 -C 7 mono- or di-C 1 -C 7 substituted amino, C 1 -C 7 hydroxycarbonyl, C 1 -C 7 alkanoyloxycarbonyl, carbamoyl, mono-N-(C 1 -C 7 )alkylcarbamoyl, di-N,N-(C 1 -C 7 )alkylcarbamoyl, C 1 -C 7 alkyloxycarbonyl, aryloxycarbonyl, C 1 -C 7 alkylcarbonyl, arylcarbonyl;

R 10 represents C 2 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl, aryl or heteroaryl wherein aryl and heteroaryl have the meaning as defined above, C 1 -C 15 haloalkyl, C 1 -C 15 hydroxyalkyl, C 1 -C 15 alkyloxy, C 1 -C 15 alkylthio, C 3 -C 15 alkylcarbonyl, C 2 -C 15 hydroxycarbonyl, C 3 -C 15 alkyloxycarbonyl, C 1 -C 15 alkylsulfonyl, arylsulfonyl or C 1 -C 15 alkylarylsulfonyl wherein aryl has the meaning as defined above, CH═CHCH 2 OH, CH═CHCH 2 O(CH 2 ) n -A, or C 1 -C 15 alkylamino represented by the formula

(CH 2 )n-A

wherein

n is an integer from 1 to 15, optionally one or more methylene groups can be substituted with an oxygen or sulphur atom A represents saturated or unsaturated a five- or six-membered ring having from one to three heteroatoms selected from the group consisting of O, S, N or combinations thereof, or a group of the formula

wherein

R 11 and R 12 independently represent hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, aryl or heteroaryl wherein aryl and heteroaryl have the meaning as defined above, or a saturated or unsaturated five- or six-membered ring having from one to three heteroatoms selected from the group consisting of O, S, N or combinations thereof.

17 . The method of claim 16 wherein R 10 represents CH 2 OH, CH═CHCH 2 OH or CH 2 CH 2 CH 2 OH.

18 . The method of claim 16 wherein R 10 represents (CH 2 ) n A, CH 2 O(CH 2 ) n -A, CH═CHCH 2 O(CH 2 ) n -A or CH 2 CH 2 CH 2 O(CH 2 ) n -A.

19 . The method of claim 16 wherein A represents morpholine-4-yl, piperidine-1-yl or pyrrolidine-1-yl.

20 . The method of claim 16 wherein A represents

wherein R 11 and R 12 are as defined in claim 16 .

21 . The method of claim 16 wherein R 11 and R 12 represent H, —CH 3 or —CH 2 CH 3 .

22 . The method of claim 16 wherein R 2 represents H, SCH 3 , F, Cl, Br or CH 3 .

23 . The method of claim 16 wherein R 3 represents H, OCH 3 , F, Cl, Br, CF 3 or CH 3 .

24 . The method of claim 16 wherein R 4 represents H, F, Cl or CH 3 .

25 . The method of claim 16 wherein R 6 represents H, F or Cl.

26 . The method according to claim 16 wherein R 10 represents C 1 -C 15 hydroxyalkyl, or C 2 -C 15 alkylamino represented by the formula

(CH 2 ) n -A.

27 . The method of claim 26 wherein said heteroaryl group is selected from the group consisting of thiophene, pyrrole, imidazole, pyridine, oxazole, thiazole, pyrazole, tetrazole, pyrimidine, pyrazine and triazine.

28 . The method of claim 16 wherein said heteroaryl group is selected from the group consisting of thiophene, pyrrole, imidazole, pyridine, oxazole, thiazole, pyrazole, tetrazole, pyrimidine, pyrazine and triazine.

29 . The method of claim 16 wherein the compound of formula I is selected from the group consisting of:

dimethyl-[3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine hydrochloride,

dimethyl-[2-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine hydrochloride,

4-[2-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,

1-[2-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,

1-[2-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,

[3-(9-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine,

[2-(9-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine,

4-[2-(9-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine,

1-[2-(9-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine,

1-[2-(9-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,

[3-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine,

[2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine,

4-[2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine,

1-[2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine,

1-[2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,

[3-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,

[2-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,

4-[2-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,

1-[2-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,

1-[2-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,

[3-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,

[2-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,

4-[2-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,

1-[2-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,

1-[2-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,

[3-(11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,

[2-(11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,

4-[2-(11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,

1-[2-(11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,

1-[2-(11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,

[3-(11-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,

[2-(11-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,

4-[2-(11-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,

1-[2-(11-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,

1-[2-(11-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,

[3-(11-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,

[2-(11-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,

4-[2-(11-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine,

1-[2-(11-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine,

1-[2-(11-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,

[3-(10-trifluoromethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine, dimethyl-[2-(10-trifluoromethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine hydrochloride,

4-[2-(10-trifluoromethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine,

1-[2-(10-trifluoromethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,

1-[2-(10-trifluoromethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,

[3-(10-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine,

[2-(10-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,

1-[2-(10-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,

1-[2-(10-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,

[3-(10-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,

[2-(10-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,

1-[2-(10-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,

1-[2-(10-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,

[2-(10-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,

[3-(9,11-dimethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,

[2-(9,11-dimethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,

1-[2-(9,11-dimethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,

[3-(10,11-dichloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,

[2-(10,11-dichloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,

4-[2-(10,11-dichloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,

1-[2-(10,11-dichloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,

1-[2-(10,11-dichloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,

[3-(9-chloro-11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,

[2-(9-chloro-11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,

4-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-but-3-ene-2-one,

4-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-but-3-ene-2-one,

3-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-acrylic acid,

3-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-propionic acid,

3-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine,

3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine,

N,N-dimethyl-[3-(11-methylsulfanyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

N,N-dimethyl-[2-(11-methylsulfanyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,

N,N-dimethyl-[3-(10-methyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

N,N-dimethyl-[2-(10-methyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,

N,N-dimethyl-[3-(11-methyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

N,N-dimethyl-[2-(11-methyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,

N,N-dimethyl-[3-(10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

N,N-dimethyl-[2-(10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,

1-(2-(10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine,

1-(2-(10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,

3-(10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine,

N,N-dimethyl-[3-(6-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

N,N-dimethyl-[2-(6-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,

3-(6-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

N,N-dimethyl-[3-(10-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

N,N-dimethyl-[2-(10-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,

[2-(3-dimethylamino-propoxymethyl)-1-thia-8-aza-dibenzo[e,h]azulene-8-yl)-phenyl-methanon,

[2-(2-dimethylamino-ethoxymethyl)-1-thia-8-aza-dibenzo[e,h]azulene-8-yl)-phenyl-methanon,

N,N-dimethyl-[3-(8H-1-thia-8-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

N,N-dimethyl-[2-(8H-1-thia-8-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,

[3-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine hydrochloride,

[3-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy]-propylamine,

N,N-dimethyl-{3-[3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-propyloxy]-propyl}-amine,

N,N-dimethyl-{2-[3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-propyloxy]-ethyl}-amine,

N,N-dimethyl-{3-[3-(1,8-dithia-dibenzo[e,h]azulene-2-yl)-propyloxy]-propyl}-amine,

N,N-dimethyl-{2-[3-(1,8-dithia-dibenzo[e,h]azulene-2-yl)-propyloxy]-ethyl}-amine,

N,N-dimethyl-{3-(8H-1-thia-dibenzo[e,h]azulene-2-yl)-methoxy]-propyl}-amine,

N,N-dimethyl-{2-(8H-1-thia-dibenzo[e,h]azulene-2-yl)-methoxy]-ethyl}-amine,

N,N-dimethyl-{3-[3-(1,8-dithia-dibenzo[e,h]azulene-2-yl)-allyloxy]-propyl}-amine,

N,N-dimethyl-{2-[3-(1,8-dithia-dibenzo[e,h]azulene-2-yl)-allyloxy]-ethyl}-amine,

N-methyl-[3-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

N-methyl-[2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,

N-methyl-[3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

N-methyl-[3-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,

2-bromomethyl-1,8-dithia-dibenzo[e,h]azulene, and

2-(1,8-dithia-dibenzo[e,h]azulene-2-yl)-ethylamine, and salts and hydrates thereof.

30 . The method of claim 16 wherein the compound of formula I is [2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine.