1,2-Diaza-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 or a hetero atom selected from O, S, S(═O), S(═O) 2 , and NR a , wherein R a is hydrogen or a protecting group;

Y and Z independently from each other denote one or more identical or different substituents linked to any available carbon atom, selected from H, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkinyl, 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, and nitro;

R 1 is H, halogen, an optionally substituted heteroaryl or heterocycle, hydroxy, C 1 -C 7 alkoxy, aryloxy, amino, N—(C 1 -C 7 )alkylamino, N,N-di(C 1 -C 7 -alkyl)amino, (C 1 -C 7 -alkyl)amino, amino-C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, aroyl, C 1 -C 7 alkanoyloxy, carboxy, an optionally substituted C 1 -C 7 alkyloxycarbonyl or aryloxycarbonyl, carbamoyl, N—(C 1 -C 7 -alkyl)carbamoyl, N,N-di(C 1 -C 7 -alkyl)carbamoyl, cyano, nitro,

or a substituent of the formula II:

 wherein

R 3 and R 4 simultaneously or independently from each other are selected from hydrogen, C 1 -C 4 alkyl, aryl or together with N have the meaning of an optionally substituted heterocycle and heteroaryl;

m and n represent an integer from 0 to 3;

Q 1 and Q 2 represent, independently from each other, oxygen, sulfur or groups

 wherein the substituents

Y 1 and Y 2 independently from each other are selected from 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, nitro or together form carbonyl and imino group;

R 2 has the meaning of hydrogen, optionally substituted C 1 -C 7 alkyl or aryl or a protecting group: formyl, C 1 -C 7 alkanoyl, C 1 -C 7 alkoxycarbonyl, arylalkyloxycarbonyl, aroyl, arylalkyl, C 1 -C 7 alkylsilyl; or

Dimethyl-{2-[2-(8-thia-1,2-diaza-dibenzo[e,h]azulene-1-yl)-ethoxy]-ethyl}-amine;

Dimethyl-{3-[2-(8-thia-1,2-diaza-dibenzo[e,h]azulene-1-yl)-ethoxy]-propyl}-amine;

Dimethyl-{2-[2-(8-thia-1,2-diaza-dibenzo[e,h]azulene-2-yl)-ethoxy]-ethyl}-amine;

Dimethyl-{3-[2-(8-thia-1,2-diaza-dibenzo[e,h]azulene-2-yl)-ethoxy]-propyl}-amine;

as well as pharmacologically acceptable salts thereof.

2. The compound according to claim 1 , wherein X has the meaning of S or O.

3. The compound according to claim 2 , wherein Y has the meaning of H and Z has the meaning of H or Cl.

4. The compound according to claim 3 , wherein R 1 has the meaning of CHO or CH 2 OH and R 2 has the meaning of H, (CH 3 ) 3 SiCH 2 CH 2 OCH 2 or C 6 H 5 CH 2 CH 2 .

5. The compound according to claim 3 , wherein R 1 has the meaning of formula II.

6. The compound according to claim 5 , wherein symbol m has the meaning of 1, Q 1 has the meaning of O, n has the meaning of 1 or 2, Q 2 has the meaning of CH 2 , R 2 has the meaning of H, (CH 3 ) 3 SiCH 2 CH 2 OCH 2 or C 6 H 5 CH 2 CH 2 and R 3 and R 4 have the meaning of H or CH 3 .

7. The compound of claim 4 selected from the group consisting of:

2-(8-Oxa-1,2-diaza-dibenzo[e,h]azulene-1-yl)-ethanol;

2-(8-Oxa-1,2-diaza-dibenzo[e,h]azulene-2-yl)-ethanol;

2-(8-Thia-1,2-diaza-dibenzo[e,h]azulene-1-yl)-ethanol;

2-(8-Thia-1,2-diaza-dibenzo[e,h]azulene-2-yl)-ethanol;

(2-Phenethyl-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-yl)-methanol;

(2-Phenethyl-2H-8-thia-1,2-diaza-dibenzo[e,h]azulene-3-yl)-methanol;

[2-(2-Trimethylsilyl-ethoxymethyl)-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-yl]-methanol;

[2-(2-Trimethylsilyl-ethoxymethyl)-2H-8-thia-1,2-diaza-dibenzo[e,h]azulene-3-yl]-methanol;

[11-Chloro-2-(2-trimethylsilyl-ethoxymethyl)-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-yl]-methanol,

and pharmacologically acceptable salts thereof.

8. The compound and salt of claim 6 selected from the group consisting of:

Dimethyl-{2-[2-(8-thia-1,2-diaza-dibenzo[e,h]azulene-1-yl)-ethoxy]-ethyl}-amine;

Dimethyl-{3-[2-(8-thia-1,2-diaza-dibenzo[e,h]azulene-1-yl)-ethoxy]-propyl}-amine;

Dimethyl-{2-[2-(8-thia-1,2-diaza-dibenzo[e,h]azulene-2-yl)-ethoxy]-ethyl}-amine;

Dimethyl-{3-[2-(8-thia-1,2-diaza-dibenzo[e,h]azulene-2-yl)-ethoxy]-propyl}-amine;

Dimethyl-[2-(2-phenethyl-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-ethyl]-amine;

Dimethyl-[3-(2-phenethyl-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-propyl]-amine;

Dimethyl-[2-(2-phenethyl-2H-8-thia-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-ethyl]-amine;

Dimethyl-[3-(2-phenethyl-2H-8-thia-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-propyl]-amine,

Dimethyl-{2-[2-(2-trimethylsilyl-ethoxymethyl)-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy]-ethyl}-amine;

Dimethyl-[2-(1H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-ethyl]-amine;

Dimethyl-[2-(2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-ethyl]-amine;

Dimethyl-{3-[2-(2-trimethylsilyl-ethoxymethyl)-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy]-propyl}-amine;

Dimethyl-[3-(1H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-propyl]-amine;

Dimethyl-[3-(2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-propyl]-amine;

Dimethyl-{2-[2-(2-trimethylsilyl-ethoxymethyl)-2H-8-thia-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy]-ethyl}-amine;

Dimethyl-[2-(1H-8-thia-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-ethyl]-amine;

Dimethyl-[2-(2H-8-thia-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-ethyl]-amine;

Dimethyl-{3-[2-(2-trimethylsilyl-ethoxymethyl)-2H-8-thia-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy]-propyl}-amine;

Dimethyl-[3-(1H-8-thia-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-propyl]-amine;

Dimethyl-[3-(2H-8-thia-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-propyl]-amine;

{2[11-Chloro-2-(2-trimethylsilyl-ethoxymethyl)-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy]-ethyl}-dimethyl-amine;

[2-(11-Chloro-1H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-ethyl]-dimethyl-amine;

[2-(11-Chloro-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-ethyl]-dimethyl-amine;

{3-[11-Chloro-2-(2-trimethylsilyl-ethoxymethyl)-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy]-propyl}-dimethyl-amine,

[3-(11-Chloro-1H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-propyl]-dimethyl-amine; and

[3-(11-Chloro-2H-8-oxa-1,2-diaza-dibenzo[e,h]azulene-3-ylmethoxy)-propyl]-dimethyl-amine.

9. A process for the preparation of compounds of the formula I:

 wherein

X is CH 2 or a hetero atom selected from O, S, S(═O), S(═O) 2 , and NR a , wherein R a is hydrogen or a protecting group;

Y and Z independently from each other denote one or more identical or different substituents linked to any available carbon atom, selected from H, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkinyl, 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, and nitro;

R 1 is H, halogen, an optionally substituted heteroaryl or heterocycle, hydroxy, C 1 -C 7 alkoxy, aryloxy, amino, N—(C 1 -C 7 )alkylamino, N,N-di(C 1 -C 7 -alkyl)amino, (C 1 -C 7 -alkyl)amino, amino-C 1 -C 7 alkoxy, C 1 -C 7 -, alkanoyl, aroyl, C 1 -C 7 alkanoyloxy, carboxy, an optionally substituted C 1 -C 7 alkyloxycarbonyl or aryloxycarbonyl, carbamoyl, N—(C 1 -C 7 -alkyl)carbamoyl, N,N-di(C 1 -C 7 -alkyl)carbamoyl, cyano, nitro,

or a substituent of the formula II:

 wherein

R 3 and R 4 simultaneously or independently from each other are selected from hydrogen, C 1 -C 4 alkyl, aryl or together with N have the meaning of an optionally substituted heterocycle and heteroaryl;

m and n represent an integer from 0 to 3;

Q 1 and Q 2 represent, independently from each other, oxygen, sulfur or groups

 wherein the substituents

y 1 and y 2 independently from each other are selected from 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, nitro or together form carbonyl and imino group;

R 2 has the meaning of hydrogen, optionally substituted C 1 -C 7 alkyl or aryl or a protecting group: formyl, C 1 -C 7 alkanoyl, C 1 -C 7 alkoxycarbonyl, arylalkyloxycarbonyl, aroyl, arylalkyl, C 1 -C 7 alkylsilyl;

as well as pharmacologically acceptable salts thereof, characterized in that the preparation processes comprise

a) for the compounds of the formula I, wherein R 1 has the meaning of CHO, formylation of the compounds of the formula III

b) for the compounds of the formula I, wherein Q 1 has the meaning —O—, a reaction of alcohols of the formula IV

 with compounds of the formula V

 wherein L 1 has the meaning of a leaving group,

c) for the compounds of the formula I, wherein Q 1 has the meaning of —O—, —NH—, —S— or —C≡C—,

a reaction of the compounds of the formula VI

 wherein L has the meaning of a leaving group, with compounds of the formula VII

d) for the compounds of the formula I, wherein Q 1 has a meaning of —O—, —NH— or —S—, a reaction of compounds of the formula VIII

 with compounds of the formula V, wherein L 1 has the meaning of a leaving group

e) for the compounds of the formula I, wherein Q 1 has the meaning of —C═C—, a reaction of the compounds of the formula VIII, wherein Q 1 has the meaning of carbonyl, with phosphorous ylides.

10. A method of treating inflammation associated with TNF-α comprising administering to a subject in need thereof a compound according to claim 5 .

11. The method of claim 10 , wherein the inflammation associated with TNF-α is inflammation associated with rheumatoid arthritis.