Imidazo[2,1-b]thiazole derivatives, their preparation and use as medicaments

1. A compound of general formula (I):

wherein

R a and R b independently represent a 5 or 6-membered aryl radical optionally substituted by a halogen or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, alkyl radical C 1-6 ; a 5 or 6-membered heteroaryl radical having at least one heteroatom selected from N, O or S as ring member, optionally substituted by a halogen or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, alkyl radical C 1-6 ; or the following moiety:

with the proviso that one of R a and R b represents this moiety and the other one represents a 5 or 6-membered aryl radical optionally substituted by a halogen or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, alkyl radical C 1-6 ;

or a 5 or 6-membered heteroaryl radical having at least one heteroatom selected from N, O or S as ring member, optionally substituted by a halogen or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, alkyl radical C 1-6 ;

A is CH 2 or O;

B is CH or N;

R 1 and R 2 together with the bridging N form a 5 to 7-membered heterocyclic ring which can have at least one additional heteroatom selected from N, O or S and which can be optionally substituted by a branched or unbranched, saturated or unsaturated, alkyl radical C 1-6 or by an aryl radical optionally substituted by an alkyl C 1-6 , a halogen or an OH group;

n is 0, 1 or 2; and

m is 0, 1, 2, 3 or 4;

with the proviso that when A is O, m is different from 0; and

with the proviso that when B represents CH and R b represents a phenyl substituted by a halogen, R a , cannot represent the moiety:

wherein R 1 and R 2 together with the bridging N form a piperazine,

or a pharmaceutically acceptable salt, tautomer, stereoisomer, geometric isomer, prodrug or solvate thereof.

2. The compound according to claim 1 , having general formula (Ia):

wherein

R a represents a 5 or 6-membered aryl radical optionally substituted by a halogen or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, alkyl radical C 1-6 ,or a 5 or 6-membered heteroaryl radical having at least one heteroatom selected from N, O or S as ring member, optionally substituted by a halogen or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, alkyl radical C 1-6 ;

A is CH 2 or O;

B is CH or N;

R 1 and R 2 together with the bridging N form a 5 to 7-membered heterocyclic ring which can have at least one additional heteroatom selected from N, O or S and which can be optionally substituted by a branched or unbranched, saturated or unsaturated, alkyl radical C 1-6 or by an aryl radical optionally substituted by an alkyl C 1-6 , a halogen or an OH group;

n is 0, 1 or 2; and

m is 0, 1, 2, 3 or 4;

with the proviso that when A is O, m is different from 0.

3. The compound according to claim 1 , having general formula (Ib):

wherein

R b represents a 5 or 6-membered aryl radical optionally substituted by a halogen or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, alkyl radical C 1-6 ,or a 5 or 6-membered heteroaryl radical having at least one heteroatom selected from N, O or S as ring member, optionally substituted by a halogen or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, alkyl radical C 1-6 ;

A is CH 2 or O;

B is CH or N;

R 1 and R 2 together with the bridging N form a 5 to 7-membered heterocyclic ring which can have at least one additional heteroatom selected from N, O or S and which can be optionally substituted by a branched or unbranched, saturated or unsaturated, alkyl radical C 1-6 or by an aryl radical optionally substituted by an alkyl C 1-6 , a halogen or an OH group;

n is 0, 1 or 2; and

m is 0, 1, 2, 3 or 4;

with the proviso that when A is O, m is different from 0; and

with the proviso that when B represents CH and R b represents a phenyl substituted by a halogen R 1 and R 2 together with the bridging N cannot form a piperazine.

4. The compound according to claim 1 , wherein R a or R b represents a group selected from:

wherein R c , represents H, a C 1-6 alkyl, or a halogen.

5. The compound according to claim 1 , wherein R 1 and R 2 together with the bridging N form a group selected from:

wherein R d represents a H, a C 1-6 alkyl or a phenyl group optionally substituted by a C 1 - 6 alkyl, a halogen or an —OH group.

6. The compound according to claim 1 , wherein A is CH 2 and m and n are both 0.

7. The compound according to claim 1 , wherein A is O, n is 1 and m is 2.

8. The compound according to claim 1 , which is selected from the group consisting of;

[1]4-((2-phenylimidazo[2,1-b]thiazol-6-yl)methyl)morpholine maleate,

[2]6-((4-methylpiperazin-1-yl)methyl)-2-(pyridin-4-yl)imidazo[2,1-b]thiazole maleate,

[3]6-(2-(4-methylpiperazin-1-yl)ethyl)-2-phenylimidazo[2,1-b]thiazole maleate,

[4]6((2-(azepan-1-yl)ethoxy)methyl)-2-phenylimidazo[2,1-b][1,3,4]thiadiazole maleate,

[5]2((4-methylpiperazin-1-yl)methyl)-6-phenylimidazo[2,1-b]thiazole maleate,

[6]6-(azepan-1-ylmethyl)-2-phenylimidazo[2,1-b]thiazole maleate,

[7]6((4-methylpiperazin-1-methyl)-2-phenylimidazo[2,1-b]thiazole maleate,

[8]4-(2-((2-phenylimidazo[2,1-b]thiazol-6-yl)methoxy)ethyl)morpholine maleate,

[9]6-((2-(azepan-1-yl)ethoxy)methyl)-2-phenylimidazo[2,1-b]thiazole maleate,

[10]2-phenyl-6-((2-(pyrrolidin-1-yl)ethoxy)methyl)imidazo[2,1-b]thiazole maleate,

[11]6-((4-methylpiperazin-1-yl)methyl)-2-phenylimidazo[2,1-b][1,3,4]thiadiazole maleate,

[12]2-(azepan-l-ylmethyl)-6-phenylimidazo[2,1-b]thiazole maleate,

[13]2-(4-fluorophenyl)-6-((4-methylpiperazin-1- yl)methyl)imidazo[2,1-b]thiazole maleate,

[14]3-(1-((2-phenylimidazo[2,1-b]thiazol-6-yl)methyl)piperidin-4-yl)phenol maleate and pharmaceutically acceptable salts, prodrugs and solvates thereof.

9. A method of treating a sigma receptor mediated disease or condition in a subject in need thereof, comprising administration of an effective amount of a compound according to claim 1 to the subject.

10. The method according to claim 9 , wherein the disease or condition is pain.

11. The method according to claim 10 , wherein the pain is neuropathic pain, inflammatory pain or other pain conditions involving allodynia and/or hyperalgesia.

12. The method according to claim 11 , wherein the neuropathic pain is hyperpathia.

13. The method according to claim 9 , wherein the disease is diarrhea; lipoprotein disorders; hyperlipidemia; hypertriglyceridemia; hypercholesterolemia; obesity; migraine; arthritis; hypertension; arrhythmia; ulcer; glaucoma; learning, memory and attention deficits; cognition disorders; neurodegenerative diseases; demyelinating diseases; addiction to drugs and chemical substances; tardive diskinesia, epilepsy, stroke, stress, cancer, psychotic conditions; inflammation or autoimmune diseases.

14. A process for the preparation of a compound of general formula (Iaa) or (Iab):

where R a , R 1 and R 2 have the same meanings as in claim 1 and n′ is 1 or 2, the process comprising:

a) the reaction between a compound of general formula (II):

wherein B is CH or N, with a sulphonide halide, and

b) the reaction of the resulting compound with a compound of general formula (III):

R 1 R 2 NH  (III)

the reactions being carried out in the presence of a base in an organic solvent.

15. A process for the preparation of a compound of general formula (Iaa) or (Iab):

wherein R a , R 1 and R 2 have the same meanings as in claim 1 and n′ is 1 or 2, the process comprising the reaction between a compound of general formula (VII):

wherein X represents a halogen and B represents CH or N, and a compound of general formula (VIII):

wherein each R group independently represents a hydrogen, a C 1-6 alkyl or both R groups together with the bridging boron form a boronic cyclic ester, in the presence of a suitable catalyst and a base in an organic solvent.

16. A process for the preparation of a compound of general formula (Iac) or (Iad):

wherein R a , R 1 , R 2 , n and m have the same meanings as in claim 1 , the process comprising the reaction between a compound of general formula (II):

wherein B is CH or N, and a compound of general formula (XII):

wherein LG is a suitable leaving group, in the presence of a base in an organic solvent.

17. A process for the preparation of a compound of general formula (Iba) or (Ibb):

wherein R b , R 1 and R 2 have the same meanings as in claim 1 and n′ is 1 or 2, the process comprising:

a) reaction between a compound of general formula (XIII):

wherein B is CH or N, with a sulphonide halide and

b) reaction of the resulting compound with a compound of general formula (III):

R 1 R 2 NH  (III)

the reactions being carried out in the presence of a base in an organic solvent.

18. A pharmaceutical composition comprising a compound according to claim 1 , and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.

19. The method of claim 11 , wherein the allodynia is mechanical allodynia or thermal allodynia.

20. The method of claim 13 , wherein the disease is addiction to cocaine, addiction to amphetamines, addiction to ethanol or addiction to nicotine.

21. The method of claim 13 , wherein the psychotic condition is depression, anxiety or schizophrenia.

22. The process of claim 15 , wherein the R groups together with the bridging boron form a boronic acid pinacol ester.

23. The process of claim 16 , wherein LG is a halogen.

24. A compound of general formula (I):

wherein

R a and R b independently represent a group selected from:

wherein R c represents H, a C 1-6 alkyl, a halogen or an —OR′ group wherein R′ represents a linear or branched C 1-6 -alkyl group; or the following moiety:

with the proviso that one of R a and R b represents this moiety and the other one represents a group selected from:

A is CH 2 or O;

B is CH or N;

R 1 and R 2 together with the bridging N form a 5 to 7-membered heterocyclic ring which can have at least one additional heteroatom selected from N, O or S and which can be optionally substituted by a branched or unbranched, saturated or unsaturated, alkyl radical C 1-6 or by an aryl radical optionally substituted by an alkyl C 1-6 , a halogen or an OH group;

n is 0, 1 or 2; and

m is 0, 1, 2, 3 or 4;

with the proviso that when A is O, m is different from 0; and

with the proviso that when B represents CH and R b represents a phenyl substituted by a halogen, R a cannot represent the moiety:

wherein R 1 and R 2 together with the bridging N form a piperazine,

or a pharmaceutically acceptable salt, tautomer, stereoisomer, geometric isomer, prodrug or solvate thereof.