1-thia-3-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof

1. A compound of the formula I

wherein

X is CH 2 , O, S, S(=O), S(=O) 2 , or NR a , wherein R a is hydrogen or a protecting group;

Y and Z are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo-C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, trifluoromethoxy, C 1 -C 4 alkanoyl, amino, amino-C 1 -C 4 alkyl, N-(C 1 -C 4 -alkyl)amino, N,N-di(C 1 -C 4 -alkyl)amino, thiol, C 1 -C 4 alkylthio, sulfonyl, C 1 -C 4 alkylsulfonyl, sulfinyl, C 1 -C 4 alkylsulfinyl, carboxy, C 1 -C 4 alkoxycarbonyl, cyano, or nitro;

R 1 is hydrogen, halogen, an optionally substituted C 1 -C 7 alkyl or C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, an optionally substituted aryl, heteroaryl or heterocycle, C 1 -C 2 alcohol, hydroxy, hydroxy-C 2 -C 7 alkenyl, hydroxy-C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, thiol, thio-C 2 -C 7 alkenyl, thio-C 2 -C 7 alkynyl, C 1 -C 7 alkylthio, amino-C 2 -C 7 alkenyl, amino-C 2 -C 7 alkynyl, amino-C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, aroyl, oxo-C 1 -C 7 alkyl, C 1 -C 7 alkanoyloxy, carboxy, an optionally substituted C 1 -C 7 alkyloxycarbonyl or C 1 -C 7 aryloxycarbonyl, carbamoyl, N-(C 1 -C 7 -alkyl)carbamoyl, N,N-di(C 1 -C 7 -alkyl)carbamoyl, cyano, cyano-C 1 -C 7 alkyl, sulfonyl, C 1 -C 7 alkylsutfonyl, sulfinyl, C 1 -C 7 alkylsulfinyl, nitro, or a substituent of the formula II

wherein

R 2 and R 3 are each independently hydrogen, C 1 -C 4 alkyl, or aryl or R 2 and R 3 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle or heteroaryl;

m is an integer from 1 to 3;

n is an integer from 0 to 3;

Q 1 and Q 2 are each independently oxygen, sulfur,

wherein

y 1 and y 2 are each independently hydrogen, halogen, an optionally substituted C 1 -C 4 alkyl or aryl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyl, thiol, C 1 -C 4 alkylthio, sulfonyl, C 1 -C 4 alkylsulfonyl, sulfinyl, C 1 -C 4 alkylsulfinyl, cyano, or nitro or

y 1 and y 2 taken together with the carbon atom to which they are attached form a carbonyl or imino group;

and pharmacologically acceptable salts and solvates thereof.

2. The compound according to claim 1 , wherein Y and Z are each independently H, F, Cl, Br, CF 3 , or OCH 3 .

3. The compound according to claim 2 , wherein R 1 is H, CH 3 , CH 2 CN, CHO, CH═CH 2 , CH 2 COOC 2 H 5 , COOC 2 H 5 , or CH 2 OCOCH 3 .

4. The compound according to claim 1 , wherein R 1 is an optionally substituted aryl or heteroaryl.

5. The compound according to claim 2 , wherein R 1 is a C 1 -C 2 alcohol.

6. The compound according to claim 1 , wherein R 1 is a substituent of the formula II.

7. The compound according to claim 6 , wherein m is 1 or 2, n is 1 or 2 or 3, Q 1 is O, Q 2 is CH 2 , and R 2 and R 3 are each independently hydrogen or methyl.

8. The compound selected from the group consisting of:

8-oxa-1-thia-3-aza-dibenzo[e,h]azulene,

5-fluoro-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene,

5-chloro-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene;

1,8-dithia-3-aza-dibenzo[e,h]azulene;

5-chloro-2-methyl-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene;

5-fluoro-2-methyl-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene;

6-chloro-2-methyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-methyl-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

6-bromo-2-methyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

5-bromo-2-methyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

5-chloro-2-methyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-methyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-methyl-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene;

(6-chloro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-acetonitrile;

8-oxa-1-thia-3-aza-dibenzo[e,h]azulene-2-carbaldehyde;

5-fluoro-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene-2-carbaldehyde;

5-chloro-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene-2-carbaldehyde;

1,8-dithia-3-aza-dibenzo[e,h]azulene-2-carbaldehyde;

6-chloro-2-vinyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

(6-chloro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-acetic acid ethyl ester;

6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester;

5-fluoro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester;

5-fluoro-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene-2-yl-acetic acid methyl ester; and

5-chloro-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene-2-yl-acetic acid methyl ester.

9. The compound selected from the group consisting of:

2-phenyl-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(4-chloro-phenyl )-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-pyridine-3-yl-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-pyridine-4-yl-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-thiophene-3-yl-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene,

2-(3-pyrrole-1-yl-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(3-chloro-4-fluoro-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(4-tert-butyl-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-pyrazine-2-yl-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

6-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-1,8-dithia3-aza-dibenzo[e,h]azulene;

2-(4-[1,3]dioxolane-2-yl-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

(6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-(3,4,5-trimethoxy-phenyl)amine;

(3-methoxy-phenyl)-(6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-amine;

2-(3,5-dibromo-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(3-fluoro-4-methyl-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(2,3-dihydro-benzofuran-5-yl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-p-toluyl-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(4-[1,2,3]thiadiazole-4-yl-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-isoxazole-5-yl-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(2-methyl-thiazole-4-yl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(6-methyl-pyridine-3-yl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene, 2-(6-methoxy-pyridine-3-yl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(3-chloro-5-trifluoromethyl-pyridine-2-yl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(2,6-dichloro-benzyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene; 6-trifluoromethyl-2-(4-trifluoromethyl-pyridine-3-yl )-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(2,6-dichloro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(2,4-dichloro-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

6-trifluoromethyl-2-(3-trifluoromethyl-phenyl)-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(5-methyl-isoxazole-3-yl)-6-trifluoromethyl-1,8-dithia3-aza-dibenzo[e,h]azulene;

2-(2-chloro-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(2,6-dichloro-pyridine-4-yl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

6-trifluoromethyl-2-(6-trifluoromethyl-pyridine-2-yl)-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-(2,4-dichloro-phenyl)-6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-pyridine-4-yl-6-trifluoromethyl-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene;

5,6-dichloro-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

2-pyridine-4-yl-8H-1-thia-3-aza-dibenzo[e,h]azulene;

5-methoxy-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

5-fluoro-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

7-chloro-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

7-bromo-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

6-chloro-2-pyridine-4-yl-1,8-dithia-3-aza-di benzo[e,h]azulene;

5-bromo-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

7-chloro-5-fluoro-2-pyridine4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

5-methyl-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

7-methyl-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

5-chloro-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

6-methyl-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene;

6-chloro-5-fluoro-2-pyridine-4-yl-1,8-dithia-3-aza-dibenzo[e,h]azulene; and

1-(2-pyridine-4-yl-1-thia-3,8-diaza-dibenzo[e,h]azulene-8-yl)-ethanone.

10. The compound according to claim 5 selected from the group consisting of:

(8-oxa-1-thia-3-aza-dibenzo[e,h]azulene-2-yl)-methanol;

(5-fluoro-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene-2-yl)-methanol;

(5-chloro-8oxa-1-thia-3-aza-dibenzo[e,h]azulene-2-yl)-methanol;

(1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-methanol;

2-(6-chloro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-ethanol,

(6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-methanol; and

(5-fluoro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-methanol.

11. The compound according to claim 7 selected from the group consisting of:

dimethyl-[2-(8-oxa-1-thia-3-aza-dibenzo[e, h]azulene-2-ylmethoxy)-ethyl]-amine;

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

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

[2-(5-fluoro-8-oxa-1-thia-3-aza-dibenzo[e, h]azulene-2-ylmethoxy)-ethyl]-dimethylamine;

[3-(5-fluoro-8-oxa-1-thia-3-aza-dibenzo[e, h]azulene-2-ylmethoxy)-propyl]-dimethylamine;

[2-(5-chloro-8-oxa-1-thia-3-aza-dibenzo[e, h]azulene-2-ylmethoxy)-ethyl]-dimethylamine;

[3-(5-chloro-8-oxa-1-thia-3-aza-dibenzo[e, h]azulene-2-ylmethoxy)-propyl]-dimethylamine;

[2-(1,8-dithia-3-aza-dibenzo[e, h]azulene-2-ylmethoxy)-ethyl]-dimethylamine;

[3-(1,8-dithia-3-aza-dibenzo[e, h]azulene-2-ylmethoxy)-propyl]-dimethylamine;

{3-[2-(6-chloro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-ethoxy]-propyl}-dimethylamine;

dimethyl-[2-(6-trifluoromethyl-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine;

[2-(5-fluoro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethylamine;

dimethyl-[3-(6-trifluoromethyl-1,8-dithia3aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine; and

[3-(5-fluoro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethylamine.

12. A process for the preparation of a compound of the formula I

wherein

X is CH 2 , O, S, S(═O), S(═O) 2 , or NR a , wherein R a is hydrogen or a protecting group;

Y and Z are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo-C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, trifluoromethoxy, C 1 -C 4 alkanoyl, amino, amino-C 1 -C 4 alkyl, N-(C 1 -C 4 -alkyl)amino N,N-di(C 1 -C 4 -alkyl)amino, thiol, C 1 -C 4 alkylthio, sulfonyl, C 1 -C 4 alkylsulfonyl, sulfinyl, C 1 -C 4 alkylsulfinyl, carboxy, C 1 -C 4 alkoxycarbonyl, cyano, or nitro;

R 1 is hydrogen, halogen, an optionally substituted C 1 -C 7 alkyl or C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, an optionally substituted aryl, heteroaryl or heterocycle, C 1 -C 2 alcohol, hydroxy, hydroxy-C 2 -C 7 alkenyl, hydroxy-C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, thiol, thio-C 2 -C 7 alkenyl, thio-C 2 -C 7 alkynyl, C 1 -C 7 alkylthio, amino-C 2 -C 7 alkenyl, amino-C 2 -C 7 alkynyl, amino-C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, aroyl, oxo-C 1 -C 7 alkyl, C 1 -C 7 alkanoyloxy, carboxy, an optionally substituted C 1 -C 7 alkyloxycarbonyl or C 1 -C 7 aryloxycarbonyl, carbamoyl, N-(C 1 -C 7 -alkyl)carbamoyl, N,N-di(C 1 -C 7 -alkyl)carbamoyl, cyano, cyano-C 1 -C 7 alkyl, sulfonyl, C 1 -C 7 alkylsulfonyl, sulfinyl, C 1 -C 7 alkylsulfinyl, nitro, or a substituent of the formula II

wherein

R 2 and R 3 are each independently hydrogen, C 1 -C 4 alkyl, or aryl or

R 2 and R 3 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle or heteroaryl;

m is an integer from 1 to 3;

n is an integer from 0 to 3;

Q 1 and Q 2 are each independently oxygen, sulfur,

wherein

y 1 and y 2 are each independently hydrogen, halogen, an optionally substituted C 1 -C 4 alkyl or aryl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyl, thiol, C 1 -C 4 alkylthio, sulfonyl, C 1 -C 4 alkylsulfonyl, sulfinyl, C 1 -C 4 alkylsulfinyl, cyano, or nitro or

y 1 and y 2 taken together with the carbon atom to which they are attached form a carbonyl or imino group;

and pharmacologically acceptable salts and solvates thereof,

which comprises one of the following steps (a) through (e):

a) a cyclization of an α-bromoketone of the formula III:

with a compound of the formula IV:

b) for a compound of the formula I, wherein Q 1 is —O—,

a reaction of an alcohol of the formula V:

with a compound of the formula VI:

wherein R 4 is a leaving group;

c) for a compound of the formula I, wherein Q 1 is —O—, —NH—, —S— or —C≡C—, a reaction of a compound of the formula Va:

wherein L is a leaving group, with a compound of the formula VIa:

d) for a compound of the formula I, wherein Q 1 is —O—, —NH— or —S—, a reaction of a compound of the formula Vb:

with a compound of the formula VI, wherein R 4 is a leaving group;

e) for a compound of the formula I, wherein Q 1 is —C═C—, a reaction of a compound of the formula Va, wherein Q 1 is carbonyl, with a phosphorous ylide.

13. A method of treating inflammation associated with TNF-α comprising administering to a subject in need thereof a an effective amount of a compound according to claim 6 .

14. The method of claim 13 wherein the inflammation associated with TNF-α is inflammation associated with rheumatoid arthritis.