1- or 3-thia-benzonaphthoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof

1. A compound of the formula I

wherein

X is selected from the group consisting of CH 2 , O, S, S(═O), S(═O) 2 , and 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, and nitro;

one of

is present and is selected from the group consisting of

R 1 is a C 1 -C 7 alkyl group 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 -alkyl)amino, N,N-di(C 1 -C 4 -alkyl)amino, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; a C 1 -C 7 alkyloxycarbonyl or a substituent of the formula II

wherein

R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and aryl or

R 2 and R 3 taken together with the nitrogen atom to which they are attached form a heterocycle or heteroaryl group which is optionally substituted with one or two substituents selected from the group consisting of halogen, 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 -alkyl)amino, N,N-di(C 1 -C 4 -alkyl)amino, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl;

n is an integer from 0 to 3;

m is an integer from 1 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, 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, nitro; a C 1 -C 4 alkyl optionally substituted with at least one substituent selected from the group consisting of halogen atom, hydroxy, C 1 -C 4 alkoxy, thiol, C 1 -C 4 alkylthio, amino, N-(C 1 -C 4 -alkyl)amino, N,N-di(C 1 -C 4 -alkyl)amino, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; and an aryl group optionally substituted with one or two substituents selected from the group consisting of halogen, 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 -alkyl)amino, N,N-di(C 1 -C 4 -alkyl)amino, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; or

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

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 H.

4. The compound of claim 3 , wherein R 1 is CO 2 Et, or CH 2 OH.

5. The compound of claim 3 , wherein R 1 is a substituent of formula II.

6. The compound of claim 5 , wherein m is 1, n is 1 or 2, Q 1 is O and Q 2 is CH 2 .

7. The compound of claim 6 , wherein R 2 and R 3 are each independently H or CH 3 or R 2 and R 3 taken together with the nitrogen atom to which they are attached are morpholine-4-yl, piperidine-1-yl or pyrrolidine-1-yl.

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

8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-carboxylic acid ethyl ester;

1,8-dithia-benzo[e]naphtho[3,2-h]azulene-2-carboxylic acid ethyl ester;

3,10-dithia-benzo[e]naphtho[1,2-h]azulene-2-carboxylic acid ethyl ester;

10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-carboxylic acid ethyl ester;

11-methoxy-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-carboxylic acid ethyl ester;

6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-carboxylic acid ethyl ester;

10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-carboxylic acid ethyl ester;

(8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-yl)-methanol;

(1,8-dithia-benzo[e]naphtho[3,2-h]azulene-2-yl)-methanol;

(3,10-dithia-benzo[e]naphtho[1,2-h]azulene-2-yl)-methanol;

(10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-yl)-methanol;

(11-methoxy-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-yl)-methanol;

(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-yl)-methanol; and

(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-yl)-methanol.

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

dimethyl-[2-(8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-ethyl]-amine;

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

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

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

dimethyl-[2-(3,10-dithia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-ethyl]-amine;

dimethyl-[3-(3,10-dithia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-propyl]-amine;

dimethyl-[2-(10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-ethyl]-amine;

dimethyl-[3-(10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-propyl]-amine;

dimethyl-[3-(11-methoxy-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-propyl]-amine;

dimethyl-[2-(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-ethyl]-amine;

dimethyl-[3-(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-propyl]-amine;

3-(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-propylamine;

methyl-[3-(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-propyl]-amine;

dimethyl-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-ethyl]-amine;

dimethyl-[3-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-propyl]-amine;

4-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-ethyl]-morpholine;

1-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-ethyl]-piperidine;

1-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine;

dimethyl-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-propyl]-amine;

dimethyl-[1-methyl-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-ethyl]-amine; and

pharmaceutically acceptable salts and solvates thereof.

10. A process for the preparation of a compound of the formula I

wherein

X is selected from the group consisting of CH 2 , O, S, S(═O), S(═O) 2 , and 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 alkinyl, 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,N-di(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, and nitro;

one of

and is selected from the group consisting of

R 1 is a C 1 -C 7 alkyl group 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 -alkyl)amino, N,N-di(C 1 -C-alkyl)amino, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; a C 1 -C 7 alkyloxycarbonyl or a substituent of the formula II

wherein

R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and aryl or

R 2 and R 3 taken together with the nitrogen atom to which they are attached form a heterocycle or heteroaryl group which is optionally substituted which is optionally substituted with one or two substituents selected from the group consisting of halogen, 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 -alkyl)amino, N,N-di(C 1 -C 4 -alkyl)amino, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl;

n is an integer from 0 to 3;

m is an integer from 1 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, 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, nitro; a C 1 -C 4 alkyl optionally substituted with at least one substituent selected from the group consisting of halogen atom, hydroxy, C 1 -C 4 alkoxy, thiol, C 1 -C 4 alkylthio, amino, N-(C 1 -C 4 -alkyl)amino, N,N-di(C 1 -C 4 -alkyl)amino, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; and an aryl group optionally substituted with one or two substituents selected from the group consisting of halogen, 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 -alkyl)amino, N,N-di(C 1 -C 4 -alkyl)amino, C 1 -C 4 alkylsulfonyl, and C 1 -C 4 alkylsulfinyl; or

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

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 is alkyloxycarbonyl, cyclizing a compound of the formula III

 with an ester of mercaptoacetic acid;

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 IV

wherein R 4 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 is a leaving group, with a compound of the formula IVa

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

 reacting a compound of the formula Vb

 with a compound of the formula IV, wherein R 4 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.

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

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