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

1 . Compound of the formula I:

wherein

X may be CH 2 or a hetero atom such as O, S, S(═O), S(A) 2 , or NR a , wherein R a is hydrogen or a protecting group;

Y and Z independently from each other denote hydrogen, one or more identical or different substituents linked to any available carbon atom, and may be 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, trifluoromiethoxy, C 1 -C 4 alkanoyl, amino, amino-C 1 -C 4 alkyl, C 1 -C 4 alkylamino, 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, nitro;

R 1 may be hydrogen, halogen, an optionally substituted C 1 -C 7 alkyl or C 2 -C 7 alkenyl C 2 -C 7 alkinyl, an optionally substituted aryl or heteroaryl and a heterocycle, hydroxy, hydroxy-C 2 -C 7 alkenyl, hydroxy-C 2 -C 7 alkinyl, C 1 -C 7 alkoxy, thiol, thio-C 2 -C 7 alkenyl, thio-C 2 -C 7 alkinyl, C 1 -C 7 alkylthio, amino, N—(C 1 -C 7 )alkylamino, N,N-di(C 1 -C 7 -alkyl)amino, (C 1 -C 7 -alkyl)amino, amino-C 2 -C 7 alkenyl, amino-C 2 -C 7 alkinyl, 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 aloxycarbonyl, 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 A:

wherein

R 3 and R 4 simultaneously or independently from each other may be hydrogen, C 1 -C 4 alkyl, aryl or together with N have the meaning of an optionally substituted heterocycle or 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 may be 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 or 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 and solvates thereof.

2 . Compound according to claim 1 , characterized in that X has the meaning of S or O.

3 . Compound according to claim 2 , characterized in that Y has the meaning of H and Z has the meaning of H or Cl.

4 . Compound according to claim 3 , characterized in that kW has the meaning of H, CHO, CH 2 OH, and R 2 has the meaning of H or (CH 3 ) 3 Si(CH 2 ) 2 OCH 2 .

5 . Compound and salt according to claim 3 , characterized in that R 1 has the meaning of the formula A.

6 . Compound and salt according to claim 5 , characterized in that the 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 or (CH 3 ) 3 Si(CH 2 ) 2 OCH 2 , and R 3 and R 4 have the meaning of H or CH 3 .

7 . Selected compounds according to claim 4:

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

11-chloro-1H-8-oxa-1-aza-dibenzo[e,h]azulene;

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

1H-8-oxa-11-aza-dibenzo[e,h]azulene-2-carbaldehyde;

11-chloro-1H-8-oxa-1-aza-dibenzo[e h]azulene-2-carbaldehyde,

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

1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-carbaldehyde;

11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-carbaldehyde;

1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2 carbaldehyde:

[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-yl]-methanol;

[11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-yl]-methanol;

[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-yl]-methanol.

8 . Selected compounds and salts according to claim 6:

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

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

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

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

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

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

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

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

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

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

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

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

3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propylamine;

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

9 . Process for the preparation of the compounds of the formula I:

wherein

X may be CH 2 or a hetero atom such as O, S, S(═O), S(═O) 2 , or NR a wherein R a is hydrogen or a protecting group;

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

R 1 may be hydrogen, halogen, an optionally substituted C 1 -C 7 alkyl or C 2 -C 7 alkenyl, C 2 -C 7 alkinyl, an optionally substituted aryl or heteroaryl and a heterocycle, hydroxy, hydroxy-C 2 -C 7 alkenyl, hydroxy-C 1 -C 7 alkynyl, C 1 -C 7 alkoxy, thiol, thio-C 1 -C 7 alkenyl, thio-C 2 -C 7 alkinyl, C 1 -C 7 alkylthio, amino, N—(C 1 -C 7 )alkylamino, N,N-di(C 1 -C 7 -alkyl)amino, (C 1 -C 7 alkyl)amino, amino-C 2 -C 7 alkenyl, amino-C 2 -C 7 alkinyl, 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 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 A:

wherein

R 3 and R 4 simultaneously or independently from each other may be hydrogen, C 1 -C 4 alkyl, aryl or together with N have the meaning of an optionally substituted heterocycle or 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 may be 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 or 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 and solvates thereof, characterized in that processes for the preparation comprise

a) for compounds of the formula I wherein R 1 is hydrogen a cyclization of compounds of the formula III:

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

a reaction of compounds of the formula IVa:

wherein L 2 has the meaning of a leaving group, with compounds of the formula Va:

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

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

e) for compounds wherein Q 1 has a meaning of —C═C—,

a reaction of compounds of the formule IVb, wherein Q 1 has the meaning of carbonyl, with phosphorous ylides.

10 . Use of compounds of the formula I according to claim 4 as intermediates for preparing novel compounds of 1-aza-dibenzoazulene class having an antiinflammatory action.

11 . Use of compounds of the formula I according to claim 5 as inhibitors of the production of cytokins or inflammation mediators in the treatment and prophylaxis of any pathological condition or disease induced by excessive unregulated production of cytokins or inflammation mediators in such a way that a non-toxic dose of appropriate pharmaceutical preparations may be administered per os, parenterally or locally.