1-or 3-thia-benznaphthoazulenes as inhibitors of tumour 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(═O) 2 , or NR 1 , wherein R a is hydrogen or a protecting group;

Y and Z independently from each other denote 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, 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, sulfonyl, C 1 -C 4 alkylsulfonyl, sulfinyl, C 1 -C 4 alkylsulfmyl, carboxy, C 1 -C 4 alkoxycarbonyl, nitro;

G A or G B :

independently from each other denote 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, 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, sulfonyl, C 1 -C 4 alkylsulfonyl, sulfinyl, C 1 -C 4 alkylsulfinyl, carboxy, C 1 -C 4 alkoxycarbonyl, nitro;

R 1 may be 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-C 1 -C 7 alkyl, 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-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 2 and R 3 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;

n represents an integer from 0 to 3;

m represents an integer from 1 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, nitro or together form carbonyl or imino group;

as well as pharmacologically acceptable salts and solvates thereof.

2 . Compound according to claim 1 , wherein X has a meaning of S or O.

3 . Compound according to claim 2 , wherein Y and Z have a meaning of H.

4 . Compound according to claim 3 , wherein G A or G B have a meaning of structures

5 . Compound according to claim 4 , wherein R 1 has a meaning of CO 2 Et, CH 2 OH.

6 . Compound according to claim 4 , wherein R 1 has a meaning of the formula II.

7 . Compound according to claim 6 , wherein the symbol m has the meaning of 1, n has the meaning of 1 or 2, Q 1 has the meaning of O and Q 2 has the meaning of CH 2 .

8 . Compound according to claim 7 , wherein R 2 and/or R 3 have the meaning of H, CH 3 or together with N the meaning of morpholine-4-yl, piperidine-1-yl or pyrrolidine-1-yl.

9 . Selected compounds according to claim 5:

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[], 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;

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

10 . Selected compounds and salts according to claim 8:

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

dimethyl-[3-(8-oxa-1-thia-benzo[elnaphtho[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.

11 . 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 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, 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, sulfonyl, C 1 -C 4 alkylsulfonyl, sulfinyl, C 1 -C 4 alkylsulfinyl, carboxy, C 1 -C 4 alkoxycarbonyl, nitro;

G A or G B :

independently from each other denote 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, 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, sulfonyl, C 1 -C 4 alkylsulfonyl, sulfinyl, C 1 -C 4 alkylsulfinyl, carboxy, C 1 -C 4 alkoxycarbonyl, nitro;

R 1 may be 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-C 1 -C 7 alkyl, 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-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 2 and R 3 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;

n represents an integer from 0 to 3;

m represents an integer from 1 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, nitro or together form carbonyl or imino group;

as well as of pharmacologically acceptable salts and solvates thereof,

characterized in that the preparation processes comprise

a) for the compounds of the formula I, wherein R 1 is alkyloxycarbonyl,

a cyclisation of a compound of the formula III

with esters of mercaptoacetic acid;

b) for the compounds of the formula I, wherein Q 1 has the meaning of —O—,

a reaction of alcohols of the formula V

with compounds of the formula IV

wherein R 4 has a meaning of a leaving group;

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

a reaction of the compounds of the formula Va

wherein L has the meaning of a leaving group,

with the compounds of the formula IVa

d) for the compounds of the formula I, wherein Q 1 has the meaning of a hetero atom —O—, —NH— or —S—,

a reaction of the compounds of the formula Vb

with the compounds of the formula IV, wherein R 4 has the meaning of a leaving group;

e) for the compounds of the formula I, wherein Q 1 has the meaning of —C═C—,

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

12 . Use of the compounds of the formula I according to claim 5 as intermediates for the preparation of novel compounds of benzonaphthoazulene class having an antiinflammatory action.

13 . Use of the compounds of the fornmula I according to claim 6 as inhibitors of 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.