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

1. Compound of the 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, 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, and nitro;

R 1 is selected from the group consisting of 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 or heteroaryl, a heterocycle, 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, 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 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 – 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, and a substituent of the formula II:

wherein

R 3 and R 4 an 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 and n are each an integer from 0 to 3;

Q 1 and Q 2 are each independently selected from the group consisting of oxygen, sulfur, and the 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 – 7 alkanoyl, C 1 –C 7 alkoxycarbonyl, arylalkyloxycarbonyl, aroyl, arylalkyl, C 1 –C 7 alkylsilyl, and C 1 –C 7 alkylsilyl-alkoxy-alkyl;

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 is H and Z is H or Cl.

4. The compound of claim 3 , wherein R 1 is H, CHO, or CH 2 OH, and R 2 is H or (CH 3 ) 3 Si(CH 2 ) 2 OCH 2 .

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

6. The compound of claim 5 , wherein m is 1, Q 1 is O, n is 1 or 2, Q 2 is CH 2 , R 2 is H or (CH 3 ) 3 Si(CH 2 ) 2 OCH 2 , and R 3 and R 4 are each independently H or CH 3 .

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

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-1-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; and

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

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

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;

[2-11-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-(11-chloro-IH-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;

and pharmaceutically acceptable salts thereof.

9. Process for the preparation of a compound of the formula I:

wherein

X is O, S, S(═O), or S(═O)2;

Y and Z are each independently selected from the group consisting of hydrogen, halogen, C 1 – 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, 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 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 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 and n represent 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 the substituents

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, 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, C 1 –C 7 alkylsilyl, and C 1 –C 7 alkylsilyl-alkoxy-alkyl; and

pharmacologically acceptable salts and solvates thereof,

the process comprising:

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

b) for compounds 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 L 1 is a leaving group,

c) for compounds 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 2 is a leaving group, with a compound of the formula Va:

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

10. 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 5 .

11. The compound of claim 1 , and pharmaceutically acceptable salts and solvates thereof, wherein R 2 is (CH 3 ) 3 Si(CH 2 ) 2 OCH 2.

12. The process of claim 9 , wherein R 2 is (CH 3 ) 3 Si(CH 2 ) 2 OCH 2.