Back to results
US 2006/0069149 A1Published application
Thiadibenzoazulene derivatives for the treatment of inflammatory diseases
AssigneePliva-Istrazivacki Institut d.o.o.
InventorsMladen Mercep, Milan Mesic, Dijana Pesic, Iva Benko
Life of this patent
Estimating the term…
Abstract
The present invention relates to (a) novel 1-thiadibenzoazulene derivatives of the formula (I), (b) to their pharmacologically acceptable esters, salts and solvates, (c) to processes and intermediates for the preparation thereof, (d) to a process for preparing pharmaceutical formulations for the treatment of inflammatory diseases and conditions and (e) to the use thereof in the treatment of inflammatory diseases and conditions in humans and animals. These compounds inhibit tumour necrosis factor-α (TNF-α) production and interleukin-1 (IL-1) production and exhibit an analgetic action.
Claims17
Compound of the formula I
- wherein
- X denotes a hetero atom —O— or —S—;
- Y is H;
- Z is a fragment of the formula II
- —O—(CH2)m-A II
- wherein
- A denotes hydrogen, an C1-C7 alkyl which is unsubstituted or substituted by 1 to 3 groups selected from halo, hydroxy, C1-C4 alkoxy, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- C2-C7 alkenylwhich is unsubstituted or substituted by 1 to 3 halo atoms;
- C2-C7 alkinyl;
- monocyclic or bicyclic aryl group having from 6 to 10 carbon atoms and alternating double bonds between carbon atoms, wherein the monocyclic or bicyclic aryl group is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- C4-C12 monocyclic or bicyclic heteroaryl ring system which is aromatic or partially aromatic containing at least one heteroatom selected from oxygen, sulphur and nitrogen, wherein C4-C12 monocyclic or bicyclic heteroaryl ring system is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- 5-6 membered heterocyclic group containing at least 1 heteroatom selected from oxygen, sulphur and nitrogen, wherein the 5-6 membered heterocyclic group is fully saturated or partially unsaturated and is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- amino;
- N—(C1-C7-alkyl)amino;
- or N,N-di(C1-C7-alkyl)amino group;
- m denotes an integer from 0 to 4;
- R1 denotes hydrogen, halo, C1-C7 alkyl which is unsubstituted or substituted by 1 to 3 groups selected from halo, hydroxy, C1-C4 alkoxy, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- C2-C7 alkenyl which is unsubstituted or substituted by 1 to 3 halo atoms;
- C2-C7 alkinyl;
- C1-C4 alkyloxycarbonyl, monocyclic or bicyclic aryl group having from 6 to 10 carbon atoms and alternating double bonds between carbon atoms, wherein the monocyclic or bicyclic aryl group is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- C4-C12 mocyclic or bicyclic heteroaryl ring system which is aromatic or partially aromatic containing at least one heteroatom selected from oxygen, sulphur and nitrogen, wherein C4-C12 monocyclic or bicyclic heteroaryl ring system is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- 5-6 membered heterocyclic group containing at least 1 heteroatom selected from oxygen, sulphur and nitrogen, wherein the 5-6 membered heterocyclic group is fully saturated or partially unsaturated and is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- hydroxy;
- hydroxy-C2-C7 alkenyl;
- hydroxy-C2-C7 alkinyl;
- C1-C7 alkoxy;
- thiol;
- thio-C2C7 alkenyl;
- thio-C2C7 alkinyl;
- C1-C7 alkylthiol;
- amino;
- N—(C1-C7-alkyl)amino;
- N,N-di(C1-C7-alkyl)amino;
- C1-C7 alkylamino;
- amino-C2-C7 alkenyl;
- amino-C2-C7 alkinyl;
- amino-C1-C7 alkoxy;
- C1-C7 alkanoyl;
- aroyl, oxo-C1-C7 alkyl;
- C1-C7 alkanoyloxy;
- carboxy;
- C1-C7 alkyloxycarbonyl wherein alkyl has the meaning as defined above, aryloxycarbonyl, wherein aryl has the meaning as defined above;
- carbamoyl;
- N—(C1-C7-alkyl)carbamoyl;
- N,N-di(C1-C7-alkyl)carbamoyl;
- cyano;
- cyano-C1-C7 alkyl;
- sulfonyl;
- C1-C7 alkylsulfonyl;
- sulfinyl;
- C1-C7 alkylsulfinyl;
- nitro ;or a substituent of the formula II, wherein the symbols A and m have the meaning as defined above;
- and pharmacologically acceptable esters, salts and solvates thereof.
50 more elements
A process for the preparation of a compound of the formula I
- wherein
- X denotes a hetero atom —O— or —S—;
- Y is H;
- Z is a fragment of the formula II
- —O—(CH2)m-A II
- wherein
- A denotes hydrogen, an C1-C7 alkyl which is unsubstituted or substituted by 1 to 3 groups selected from halo, hydroxy, C1-C4 alkoxy, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- C2-C4 alkenyl which is unsubstituted or substituted by 1 to 3 halo atoms;
- C2-C7 alkinyl;
- monocyclic or bicyclic aryl group having from 6 to 10 carbon atoms and alternating double bonds between carbon atoms, wherein the monocyclic or bicyclic aryl group is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- C4-C12 monocyclic or bicyclic heteroaryl ring system which is aromatic or partially aromatic containing at least one heteroatom selected from oxygen, sulphur and nitrogen, wherein C4-C12 monocyclic or bicyclic heteroaryl ring system is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- 5-6 membered heterocyclic group containing at least 1 heteroatom selected from oxygen, sulphur and nitrogen, wherein the 5-6 membered heterocyclic group is fully saturated or partially unsaturated and is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- amino;
- N—(C1-C7-alkyl)amino;
- or N,N-di(C1-C7-alkyl)amino group;
- m denotes an integer from 1 to 4;
- R1 denotes hydrogen, halo, C1-C7 alkyl which is unsubstituted or substituted by 1 to 3 groups selected from halo, hydroxy, C1-C4 alkoxy, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- C2-C7 alkenyl which is unsubstituted or substituted by 1 to 3 halo atoms;
- C2-C7 alkinyl;
- C1-C4 alkyloxycarbonyl, monocyclic or bicyclic aryl group having from 6 to 10 carbon atoms and alternating double bonds between carbon atoms, wherein the monocyclic or bicyclic aryl group is unsubstituted or is substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- C4-C12 monocyclic or bicyclic heteroaryl ring system which is aromatic or partially aromatic containing at least one heteroatom selected from oxygen, sulphur and nitrogen, wherein C4-C12 monocyclic or bicyclic heteroaryl ring system is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- 5-6 membered heterocyclic group containing at least 1 heteroatom selected from oxygen, sulphur and nitrogen, wherein the 5-6 membered heterocyclic group is fully saturated or partially unsaturated and is unsubstituted or substituted by 1 or 2 substituents selected from halo, C1-C4 alkyl, trifluoromethyl, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyloxycarbonyl, thiol, C1-C4 alkylthio, amino, N—(C1-C4) alkylamino, N,N-di(C1-C4-alkyl)-amino, sulfonyl, C1-C4 alkylsulfonyl, sulfinyl and C1-C4 alkylsulfinyl;
- hydroxy;
- hydroxy-C2-C7 alkenyl;
- hydroxy-C2-C7 alkinyl;
- C1-C7 alkoxy;
- thiol;
- thio-C2C7 alkenyl;
- thio-C2C7 alkinyl;
- C1-C7 alkylthiol;
- amino;
- N—(C1-C7-alkyl)amino;
- N,N-di(C1-C7-alkyl)amino;
- C1-C7 alkylamino;
- amino-C2-C7 alkenyl;
- amino-C2-C7 alkinyl;
- amino-C1-C7 alkoxy;
- C1-C7 alkanoyl;
- aroyl;
- oxo-C1-C7 alkyl;
- C1-C7 alkanoyloxy;
- carboxy;
- C1-C7 alkyloxycarbonyl, wherein alkyl has the meaning as defined above;
- aryloxycarbonyl, wherein aryl has the meaning as defined above;
- carbamoyl;
- N—(C1-C7-alkyl)carbamoyl;
- N,N-di(C1-C7-alkyl)carbamoyl;
- cyano;
- cyano-C1-C7 alkyl;
- sulfonyl;
- C1-C7 alkylsulfonyl;
- sulfinyl;
- C1-C7 alkylsulfinyl;
- nitro ;
- or a substituent of the formula II, wherein the symbols A and m have the meaning as defined above;
- and pharmacologically acceptable esters, salts and solvates thereof,
- characterized in that the preparation processes comprises:
- a) a condensation reaction of an alcohol of the formula Illa
- wherein at least one of the radicals R2 and R3 individually denotes hydrogen and the other one a protecting group, whereas R1 has the meaning as defined above;
- or a condensation of a compound of the formula IIIb
- wherein B denotes a —C(O)— or —CH2— group and Y and Z have the meaning as defined above,
- with a compound of the formula IVa
- L1-(CH2)m-A IVa
- wherein L1 is a leaving group and m and A have the meaning as defined above;
- b) a condensation reaction of a compound of the formula IlIc
- wherein B denotes a —C(O)— or —CH2— group, L2 has the individual meaning of a leaving group and Y and Z have a meaning as defined above,
- with a compound of the formula IVb
- HO—(CH2)m-A IVb
- wherein A and m have the meaning as defined above.
66 more elements
Dependencies are inferred from the claim text.