2-thia-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 , 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 selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, trifluoromethyl, 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, C 1 -C 4 alkylsulfonyl, 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, C 1 -C 7 alkyl optionally substituted with at least one substituent selected from the group consisting of halogen, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; C 2 -C 7 alkenyl optionally substituted with at least one halogen atom; C 2 -C 7 alkynyl: a monocyclic or bicyclic aryl group linked to the rest of the molecule via a direct bond or a C 1 -C 4 alkylene group and optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulflnyl; a monocyclic or bicyclic heteroaryl group linked via a carbon or nitrogen atom to the rest of the molecule via a direct bond or a C 1 -C 4 alkylene group and optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, 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 - 4 -alkyl)-amino, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; a five-membered or six-membered fully saturated or partly unsaturated heterocycle group linked via a carbon or nitrogen atom to the rest of the molecule via a direct bond or a C 1 -C 4 alkylene group and optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; 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 alkyl)amino, N,N-di-(C 1 -C 7 alkyl)amino, C 1 -C 7 alkylamino, 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, C 1 -C 7 alkyloxycarbonyl or C 6 -C 7 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, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylsulfinyl, 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, and aryl, or

R 3 and R 4 taken together with the nitrogen atom to which they are attached form a heterocycle or heteroaryl group selected from the group consisting of morpholine-4-yl, piperidine-1-yl, pyrrolidine-1-yl, imidazole-1-yl and piperazine-1-yl;

m and n are each independently an integer from 0 to 3;

Q 1 and Q 2 are each independently selected from the group consisting of oxygen, sulphur,

 wherein

Y 1 and y 2 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl optionally substituted with at least one substituent selected from the group consisting of halogen, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; an aryl group optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyl, thiol, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, 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 hydrogen, carboxy or alkyloxycarbonyl; and

pharmaceutically acceptable salts and solvates thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is S or O.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof wherein Y and Z are each independently H or Cl.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein R 1 is H, Br, COOH, COOMe or COOEt and R 2 is H, COOH, COOMe, or COOEt.

5. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H and R 1 is COOMe, COOEt, or CH 2 OH.

6. The compound of claim 3 or a pharmacuetically acceptable salt thereof wherein R 2 is H and R 1 is a substituent having the formula II.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein m is 1, n is 1 or 2, Q 1 is O, and Q 2 is CH 2 .

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently H or Me.

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

8-oxa-2-thia-dibenzo[e,h]azulene;

2,8-dithia-dibenzo[e,h,]azulene;

5-chloro-8-oxa-2-thia-dibenzo[e,h,]azulene;

8-oxa-2-thia-dibenzo[e,h,]azulene-1, 3-dicarboxylic acid monoethyl ester;

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

5-chloro-8-oxa-2-thia-dibenzo[e,h,]azulene-1,3-dicarboxylic acid 3-methyl ester; and

2,8-dithia-dibenzo[e,h,]azulene-1, 3-dicarboxylic acid monoethyl ester.

10. The compound of claim 5 selected from the group consisting of:

8-oxa-2-thia-dibenzo[e,h,]azulene-1-carboxylic acid ethyl ester;

5-chloro-8-oxa-2-thia-dibenzo[e,h,]azulene-1-carboxylic acid methyl ester;

11-chloro-8-oxa-2-thia-dibenzo[e,h,]azulene-1-carboxylic acid methyl ester;

2,8-dithia-dibenzo[e,h,]azulene-1-carboxylic acid ethyl ester;

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

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

(11-chloro-8-oxa-2-thia-dibenzo[e,h,]azulene-1-yl)-methanol; and

(2,8-dithia-dibenzo[e,h,]azulene-1-yl)-methanol.

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

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

dimethyl-[2-(8-oxa-2-thia-dibenzo[e,h,]azulene-1-yl methoxy)-ethyl]-amine;

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

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

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

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

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

3-11-chloro-8-oxa-2-thia-dibenzo[e,h,]azulene1-ylmethoxy)-propylamine;

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

[2,8-dithia-dibenzo[e,h,]azulene-1-ylmethoxy)-ethyl]-dimethyl-amine; and

3-(2,8-dithia-dibenzo[e,h,]azulene-1-ylmethoxy)-propylamine; and a pharmaceutically acceptable salt thereof.

12. A process for the preparation of a compound of the formula I:

wherein

X is CH 2 , O, S, S(═O), S(═O) 2 , or NR a , wherein R a a is hydrogen or a protecting group;

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, trifluoromethyl, 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, C 1 -C 4 alkylsulfonyl, 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, C 1 -C 7 alkyl optionally substituted with at least one substituent selected from the group consisting of halogen, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; C 2 -C 7 alkenyl optionally substituted with at least one halogen atom; C 2 -C 7 alkynyl; a monocyclic or bicyclic aryl group linked to the rest of the molecule via a direct bond or a C 1 -C 4 alkylene group and optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsultinyl; a monocyclic or bicyclic heteroaryl group linked via a carbon or nitrogen atom to the rest of the molecule via a direct bond or a C 1 -C 4 alkylene group and optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; a five-membered or six-membered fully saturated or partly unsaturated heterocycle group linked via a carbon or nitrogen atom to the rest of the molecule via a direct bond or a C 1 -C 4 alkylene group and optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; 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 alkyl)amino, N,N-di-(C 1 -C 7 alkyl)amino, C 1 -C 7 alkylamino, 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, C 1 -C 7 alkyloxycarbonyl or C 6 -C 7 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, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylsulfinyl, 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, and aryl, or

R 3 and R 4 taken together with the nitrogen atom to which they are attached form heterocycle or heteroaryl group selected from the group consisting of morpholine-4-yl, piperidine-1-yl, pyrrolidine-1-yl, imidazole-1-yl and piperazine-1-yl;

m and n are each independently an integer from 0 to 3;

Q 1 , and Q 2 are each independently selected from the group consisting of oxygen, sulphur,

 wherein

Y 1 and Y2 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl optionally substituted with at least one substituent selected from the group consisting of halogen, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; an aryl group optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, 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, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyl, thiol, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, cyano, and nitro; or Y 1 and Y2 taken together with the carbon atom to which they are attached form a carbonyl or imino group;

R 2 is hydrogen, carboxy or alkyloxycarbonyl; and

pharmaceutically acceptable salts and solvates thereof

which comprises one of the following steps (a) through (e):

a) for a compound of the formula I, wherein R 1 and R 2 are each independently a carboxyl group, cyclizing an α-diketone of the formula III:

 with a compound of the formula IV:

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

reacting an alcohol of the formula V:

 with a compound of the formula VI:

 wherein R 5 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 Va:

 wherein L 1 is a leaving group with a compound of the formula VIa:

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

reacting a compound of the formula Vb:

 with a compound of the formula VI, wherein R 5 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 Vb, wherein Q 1 is carbonyl, with a phosphorous ylide.

13. A method of treating inflammation associated with TNF-α comprising administering to a subject an effective amount of a compound according to claim 1 .

14. The method of claim 13 wherein the inflammation associated with TNF-α is inflammation associated with rheumatoid arthritis.