1-oxa-3-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the production thereof

1. A compound of the formula I

wherein

X is 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, trifluoromethyl, 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, C 1 –C 7 alkyl, CHO, (CH 2 ) 2 COOH, (CH 2 ) 2 CO 2 Et, (CH 2 ) m L, wherein m is 1 or 3 and L is OH or Br;

or a substituent of the formula II

 wherein

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

m is integer from 1 to 3;

n is integer from 0 to 3;

Q 1 and Q 2 are each independently oxygen, sulphur

 wherein

y 1 and y 2 are each independently hydrogen, halogen, 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, nitro or y 1 and y 2 taken together with the carbon or nitrogen atom to which they are attached form a carbonyl group or an imino group;

and a pharmacologically acceptable salt or solvate salt thereof,

wherein an optionally substituted heteroaryl or heterocycle is a heteroaryl or heterocyclic group, which is substituted with one or two substituents, selected from the group consisting of halogen, C 1 –C 4 alkyl, cyano, nitro, hydroxy, C 1 –C 4 alkoxy, thiol, C 1 –C 4 alkylthio, amino, N—(C 1 –C 4 ) alkylamino, N,N-di(C 1 –C 4 -alkyl)-amino, sulfonyl, C 1 –C 4 alkylsulfonyl, sulfinyl, and C 1 –C 4 alkylsulfinyl.

2. The compound according to claim 1 , wherein X is S or O.

3. The compound according to claim 2 , wherein Y and Z are each independently H, or Cl.

4. The compound according to claim 3 , wherein R 1 is H, CH 3 , CHO, (CH 2 ) 2 COOH, or (CH 2 ) 2 CO 2 Et.

5. The compound according to claim 3 , wherein R 1 is (CH 2 ) m L.

6. The compound according to claim 5 , wherein m is 1 or 3.

7. The compound according to claim 6 , wherein L is OH or Br.

8. The compound according to claim 3 , wherein R 1 is a substituent of the formula II.

9. The compound according to claim 8 , wherein m 1 or 3 n is 1 or 2, Q 1 is O, Q 2 is CH 2 and R 1 and R 2 are each CH 3 .

10. The compound according to claim 4 selected from the group consisting of:

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

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

3-(1-oxa-8-thia-3-aza-dibenzo[e,h]azulene-2-yl)-propionic acid ethyl ester;

3-(1,8-dioxa-3-aza-dibenzo[e,h]azulene-2-yl)-propionic acid ethyl ester;

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

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

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

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

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

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

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

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

3-(1,8-dioxa-3-aza-dibenzo[e,h]azulene-2-yl)-propionic acid.

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

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

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

3-(1,8-dioxa-3-aza-dibenzo[e,h]azulene-2-yl)-propane-1-ol;

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

2-bromomethyl-1,8-dioxa-3-aza-dibenzo[e,h]azulene;

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

2-bromomethyl-11-chloro-1-oxa-8-thia-3-aza-dibenzo [e,h]azulene;

2-bromomethyl-5-chloro-1,8-dioxa-3-aza-dibenzo[e,h]azulene; and

2-bromomethyl-11-chloro-1,8-dioxa-3-aza-dibenzo[e,h]azulene.

12. The compound according to claim 9 selected from the group consisting of:

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

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

dimethyl-{2-[3-(1-oxa-8-thia-3-aza-dibenzo[e,h]azulene-2-yl)-propoxy]-ethyl}-amine; dimethyl-{3-[3-(1-oxa-8-thia-3-aza-dibenzo[e,h]azulene-2-yl)-propoxy]-propyl}-amine;

{2-[3-(1,8-dioxa-3-aza-dibenzo[e,h]azulene-2-yl)-propoxy]-ethyl}-dimethylamine;

{3-[3-(1,8-dioxa-3-aza-dibenzo[e,h]azulene-2-yl)-propoxy]-propyl}-dimethylamine;

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

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

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

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

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

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

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

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

[2-(11-chloro-1,8-dioxa-3-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethylamine;

[3-(11-chloro-1,8-dioxa-3-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethylamine; and a

pharmacologically acceptable salt thereof.

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

wherein

X is 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, trifluoromethyl, 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, C 1 –C 7 alkyl, CHO, (CH 2 ) 2 COOH, (CH 2 ) 2 CO 2 Et, (CH 2 ) m L, wherein m is 1 or 3 and L at is OH or Br;

or a sub substituent of the formula II

 wherein

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

m is integer from 1 to 3;

n is integer from 0 to 3,

Q 1 and Q 2 represent, independently from each other, are each independently oxygen, sulphur,

 wherein the substituents

y 1 and y 2 are each independently hydrogen, halogen, 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, nitro or y 1 and y 2 taken together with the carbon or nitrogen atom to which they are attached form a carbonyl group or an imino group;

and a pharmacologically acceptable salt or solvate thereof,

wherein an optionally substituted heteroaryl or heterocycle is a heteroaryl or heterocyclic group, which is substituted with one or two substituents, selected from the group consisting of halogen, C 1 –C 4 alkyl, cyano, nitro, hydroxy, C 1 –C 4 alkoxy, thiol, C 1 –C 4 alkylthio, amino, N-(C 1 –C 4 ) alkylamino, N,N-di(C 1 –C 4 -alkyl)-amino, sulfonyl, C 1 –C 4 alkylsulfonyl, sulfinyl, and C 1 –C 4 alkylsulfinyl comprising one of the following steps a) through e)

a) for a compound of the formula I, cyclizing a compound of the formula III

 wherein A of is —O— or —NH—;

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

—O—, reacting an alcohol of the formula IV:

 with a compound of the formula V:

 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—,

reacting a compound of the formula IVa

 wherein L is a leaving group,

with a compound of the formula Va

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

reacting a compound of the formula IVb

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

e) for a compound of the formula I, wherein Q 1 is —C═C—,

reacting a compound of the formula IVb, wherein Q 1 is a carbonyl, with a phosphorous ylide.

14. A method of treating a pathological condition or disease induced by an excessive unregulated production of a cytokine or inflammation mediator comprising administering to a subject an effective amount of a compound according to claim 8 perorally, parenterally or locally.