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

1. A compound of formula I:

wherein

X is O, S, S(═O), or S(═O2);

Y and Z are each independently selected from the group consisting of 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, and nitro;

R 1 is selected from the group consisting of halogen, hydroxy, C 1 –C 7 -alkoxy, aryloxy, amino, N-(C 1 –C, alkyl)amino, 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, and a substituent of the formula II:

wherein

R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1 –C 4 alkyl, aryl or 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 selected from the group consisting of oxygen, sulfur,

wherein

y 1 and y 2 are each independently selected from the group consisting of 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, and nitro or

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

R 2 is selected from the group consisting of hydrogen, optionally substituted C 1 –C 7 alkyl or aryl, and a protecting group selected from the group consisting of formyl, C 1 –C 7 alkanoyl, C 1 –C 7 alkoxycarbonyl, arylalkyloxycarbonyl, aroyl, arylalkyl, and C 1 –C 7 alkylsilyl;

and pharmaceutically acceptable salts and solvates thereof.

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

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

4. The compound of claim 3 , wherein R 1 is CHO or CH 3 OCOCH═CH and R 2 is H, CH 3, C 6 H 5 CH 2 CH 2 or (CH 3 ) 3 SiCH 2 CH 2 OCH 2 .

5. The compound of claim 3 , wherein R 1 is (CH 2 ) m OH and R 2 is H, CH 3, C 6 H 5 CH 2 CH 2 or (CH 3 ) 3 SiCH 2 CH 2 OCH 2 .

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

7. The compound of claim 3 , wherein R 1 is

8. The compound of claim 7 , wherein m is 1 or 3, Q 1 is O, n is 1 or 2, Q 2 is CH 2, R 2 is H, CH 3, C 6 H 5 CH 2 CH 2 or (CH 3 ) 3 SiCH 2 CH 2 OCH 2 , and R 3 and are each independently H or CH 3 .

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

1-methyl-1H-8-oxa-1,3-diaza-dibenzo[e,h]azulene-2-carbaldehyde;

1-methyl-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-carbaldehyde;

1-phenethyl-1H-8-oxa-1,3-diaza-dibenzo[e,h]azulene-2-carbaldehyde;

1-phenethyl-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-carbaldehyde;

1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1,3-diaza-dibenzo[e,h]azulene-2-carbaldehyde;

1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-carbaldehyde;

5-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1,3-diaza-dibenzo[e,h]azulene-2-carbaldehyde;

11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1,3-diaza-dibenzo[e,h]azulene-2-carbaldehyde;

5-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-carbaldehyde;

11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-carbaldehyde; and

3-(1-phenethyl-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-yl)-acrylic acid methyl ester.

10. The compound of claim 6 selected from the group consisting of:

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

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

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

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

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

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

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

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

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

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

3-(1-phenethyl-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-yl)-propan-1-ol.

11. The compound of claim 8 selected from the group consisting of:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

dimethyl-[3-(1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl)-amine {3-[5-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-dimethyl-amine;

3-(5-chloro-1H-8-oxa-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine;

3-[5-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy]-propylamine;

3-(5-chloro-1H-8-oxa-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine;

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

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

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

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

{2-[5-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-dimethyl-amine;

[2-(5-chloro-1H-8-thia-1,3-diaza-dibenzo[e, h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine;

{3-[5-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-dimethyl-amine;

[3-(5-chloro-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine;

dimethyl-{3-[3-(1-phenethyl-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-yl)-propoxy]-propyl}-amine;

and pharmaceutically acceptable salts thereof.

12. Process for the preparation of compounds of the formula

wherein

X is O, S, S (═O), or S (═O2);

Y and Z are each independently selected from the group consisting of hydrogen 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, nitro;

R 1 is selected from the group consisting of halogen, hydroxy, C 1 –C 7 alkoxy, aryloxy, amino, N-(C 1 –C 7 alkyl) amino, 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, and a substituent of the formula II

wherein

R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1 –C 4 -alkyl, aryl or, 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 selected from the group consisting of, oxygen, sulfur or groups:

wherein

y 1 , and y 2 are each independently selected from the group consisting of 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, and nitro or y 1 and y 2 taken together with the carbon atom to which they are attached form a carbonyl or imino group;

R 2 is selected from the group consisting of hydrogen, optionally substituted C 1 –C 7 alkyl or aryl, and a protecting group selected from the group consisting of: formyl, C 1 –C 7 alkanoyl, C 1 –C 7 alkoxycarbonyl, arylalkyloxycarbonyl, aroyl, arylalkyl and C 1 –C 7 alkylsilyl ; and

pharmacologically acceptable salts and solvates thereof, . . . the process comprising:

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

with N,N-dimethylformamide;

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

with a compound of the formula V

wherein L1 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 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—, a reaction of a compound of the formula IVb:

with a compound of the formula V, wherein L 1 is a leaving group;

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

13. A method for treating inflammation associated with TNF-α comprising administering to a subject in need of treatment an effective amount of a compound according to claim 7 .