THIADIAZOLE DERIVATIVES FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES

• US 20090054410A1
• Filed: 08/06/2008
• Published: 02/26/2009
• Est. Priority Date: 02/07/2006
• Status: Active Grant

• Current Assignee: Nv Remynd
• Original Assignee: Nv Remynd
• Inventors: VAN DAMME, Nele, COUPET, Kristel Marie Edith, GOMME, Ellen, WERA, Stefaan, VAN DER AUWERA, Ingrid, LOX, Marleen, GRIFFIOEN, Gerard, DECRUY, Tine, VAN DOOREN, Tom, DUHAMEL, Hein Roger
• Granted Patent: US 8,541,406 B2
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

This invention provides specifically substituted 1,2,4-thiadiazole derivatives for use in the treatment of an α-synucleopathy such as Parkinson'"'"'s disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, multiple system atrophy and Alzheimer'"'"'s disease. This invention also provides various methods for producing such substituted 1,2,4-thiadiazole derivatives.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of a 1,2,4-thiadiazole derivative according to the structural formula (A)

wherein the divalent group schematically represented by the structural formula (A′

)

includes an optionally mono-substituted or poly-substituted, saturated or partly unsaturated heterocyclic ring with at least two nitrogen atoms in the said heterocyclic ring and with a total of 5 to 7 atoms in the said heterocyclic ring, and further wherein;

R₆ is a substituent independently selected from the group consisting of oxo and C_1-4 alkyl;

n is selected from the group consisting of 0, 1, 2 and 3;

R₁, R₂, R₃, R₄ and R₅ are each independently selected from the group consisting of hydrogen, C_1-4 alkyl, C_1-4 alkoxy, aryl, aryloxy, aryl-C_1-4 alkyloxy, heteroaryloxy, benzenesulfonate, amino, hydroxy, nitro, trifluoromethyl, trifluoromethoxy and halogen, or any two adjacent substituents selected from the group consisting of R₁, R₂, R₃, R₄ and R₅ form, together with the phenyl ring carbon atoms to which they are attached, a saturated or unsaturated ring fused to said phenyl ring and having from 5 to 7 ring members, said saturated or unsaturated ring optionally comprising one or two oxygen atoms and being optionally substituted with one or more halogen atoms;

R₇, R₈, R₉, R₁₀ and R₁₁ are each independently selected from the group consisting of hydrogen, C_1-10 alkyl, C_1-6 alkoxy, C_1-4 alkylthio, C_2-4 alkenyl, C_3-8 cycloalkyl, aryl, hydroxy, acetyl, nitro, trifluoromethyl and halogen;

or any two adjacent substituents selected from the group consisting of R₇, R₈, R₉, R₁₀ and R₁₁ form, together with the phenyl ring carbon atoms to which they are attached, a saturated or unsaturated ring fused to said phenyl ring and having from 5 to 7 ring members, said saturated or unsaturated ring optionally comprising one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; and

each of said C_1-6 alkyl, C_1-6 alkoxy, aryl or fused ring is optionally substituted with one or more halogen atoms;

R₁₂ and R₁₃ are each independently selected from the group consisting of hydrogen, C_1-6 alkyl, aryl-C_1-4 alkyl, aryl and N-containing heterocyclic rings, or R₁₂ and R₁₃ together form a C_3-6 cycloalkyl or heterocyclic group; and

X is a linking moiety selected from the group consisting of a single bond;

—

C(═

O)—

;

—

S(═

O)₂—

;

divalent saturated or unsaturated non-cyclic hydrocarbon groups comprising from 1 to 6 atoms in the main chain, each of said atoms in the main chain being independently selected from the group consisting of carbon, nitrogen and sulfur, each of said carbon atoms in the main chain being optionally substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, C_1-4 alkyl and halogen, and each of said sulfur atoms in the main chain being optionally substituted with oxo, provided that the number of heteroatoms in the main chain of said divalent saturated or unsaturated non-cyclic hydrocarbon group is 0, 1 or 2; and

divalent saturated or unsaturated heterocyclic groups comprising from 2 to 6 carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen in the said heterocyclic group;

or X together with one of R₇ and R₁₁ forms a saturated or unsaturated ring having from 5 to 7 ring members and being fused to the phenyl ring bearing said one of R₇ and R₁₁, said saturated or unsaturated ring optionally comprising one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, and said saturated or unsaturated ring optionally comprising one or more substituents independently selected from the group consisting of C_1-4 alkyl and trifluoromethyl;

or a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.

2. A pharmaceutical composition according to claim 1, wherein the divalent group represented by the structural formula (A′

) includes one or more further heteroatoms in the heterocyclic ring or attached to one or more carbon atoms of the heterocyclic ring.

3. A pharmaceutical composition according to claim 1, wherein the divalent group represented by the structural formula (A′

) is selected from the group consisting of piperazinyl, 2,3-dioxopiperazinyl, 2,5-dioxopiperazinyl, 2-methylpiperazinyl, trans-2,5-dimethylpiperazinyl, 3,6-dimethyl-2,5-dioxopiperazinyl, 3-isopropyl-2,5-dioxopiperazinyl, 3-tert-butyl-2,5-dioxopiperazinyl, 2,4-dioxoimidazolidinyl, 2,4,5-trioxoimidazolidinyl and homopiperazinyl.

4. A pharmaceutical composition according to claim 1, wherein the 1,2,4-thiadiazole derivative is represented by the structural formula (A₁)

wherein X, R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₁ are as defined in claim 1, R₆ is hydrogen or is as defined in claim 1, or a stereoisomer or a solvate thereof, or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition according to claim 1, wherein X is a divalent saturated or unsaturated non-cyclic hydrocarbon group comprising from 1 to 3 carbon atoms but no heteroatom in the main chain, and wherein each of said carbon atoms in the main chain is optionally substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, C_1-4 alkyl and halogen.

6. A pharmaceutical composition according to claim 1, wherein X is selected from the group consisting of C_1-6 alkylene, —

CO—

CH₂—

, —

CO—

(CH₂)₂—

, —

CO—

CH═

CH—

, —

CO—

CHR₁₄—

, —

CH₂—

CH═

CH— and

—

CO—

CHX′

—

, wherein R₁₄ is C_1-4 alkyl and wherein X′

is halogen.

7. A pharmaceutical composition according to claim 1, wherein X is a divalent saturated or unsaturated non-cyclic hydrocarbon group comprising from 1 to 5 carbon atoms and one single nitrogen, oxygen or sulfur atom in the main chain, wherein each of said carbon atoms in the main chain is optionally substituted with one or more substituents independently selected from the group consisting of oxo, thioxo and C_1-4 alkyl, and wherein a sulfur atom in the main chain is optionally substituted with oxo.

8. A pharmaceutical composition according to claim 7, wherein X is selected from the group consisting of —

CO—

NH—

, —

(CH₂)₂—

NH—

CO—

, —

(CH₂)₂—

NH—

CO—

CH₂—

, —

(CH₂)₂—

NH—

CO—

(CH₂)₂—

, —

(CH₂)₂—

NH—

CO—

CHR₁₄—

, —

SO₂—

CH═

CH— and

—

SO₂—

CH₂—

, wherein R₁₄ is C_1-4 alkyl.

9. A pharmaceutical composition according to claim 1, wherein X is a divalent saturated or unsaturated non-cyclic hydrocarbon group comprising from 1 to 5 carbon atoms and one single oxygen atom in the main chain, wherein said oxygen atom is not adjacent to the nitrogen atom of the divalent group (A′

).

10. A pharmaceutical composition according to claim 9, wherein X is —

C(═

O)—

O—

CH₂—

.

11. A pharmaceutical composition according to claim 1, wherein X is a divalent saturated or unsaturated non-cyclic hydrocarbon group comprising from 1 to 4 carbon atoms and two non-adjacent nitrogen atoms in the main chain, wherein none of said nitrogen atoms is adjacent to the nitrogen atom of the divalent group (A′

).

12. A pharmaceutical composition according to claim 11, wherein X is —

(CH₂)₂—

NH—

CO—

NH—

CH₂—

.

13. A pharmaceutical composition according to claim 1, wherein X is 1,2,4-thiadiazolyl.

14. A pharmaceutical composition according to claim 1, wherein each of R₁, R₂, R₃, R₄ and R₅ is fluoro.

15. A pharmaceutical composition according to claim 1, wherein at least two of R₁, R₂, R₃, R₄ and R₅ are hydrogen.

16. A pharmaceutical composition according to claim 1, wherein three of R₁, R₂, R₃, R₄ and R₅ are methoxy.

17. A pharmaceutical composition according to claim 1, wherein three of R₁, R₂, R₃, R₄ and R₅ are hydrogen, and wherein two of R₁, R₂, R₃, R₄ and R₅ are identical and are selected from the group consisting of halogen, C_1-4 alkoxy and trifluoromethyl.

18. A pharmaceutical composition according to claim 1, wherein three of R₁, R₂, R₃, R₄ and R₅ are hydrogen, and wherein two of R₁, R₂, R₃, R₄ and R₅ are halogen and are independently selected from the group consisting of fluoro, chloro and bromo.

19. A pharmaceutical composition according to claim 1, wherein three of R₁, R₂, R₃, R₄ and R₅ are hydrogen, and wherein two adjacent substituents selected from the group consisting of R₁, R₂, R₃, R₄ and R₅ form, together with the phenyl ring carbon atoms to which they are attached, a phenyl or methylenedioxy ring fused to said phenyl ring.

20. A pharmaceutical composition according to claim 1, wherein four of R₁, R₂, R₃, R₄ and R₅ are hydrogen, and wherein one of R₁, R₂, R₃, R₄ and R₅ is selected from the group consisting of C_1-4 alkyl, C_1-4 alkoxy, aryl, aryloxy, aryl-C_1-4 alkyloxy, heteroaryloxy, benzenesulfonate, amino, hydroxy, nitro, trifluoromethyl, trifluoromethoxy and halogen.

21. A pharmaceutical composition according to claim 1, wherein R₁₂ and R₁₃ together form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and piperidinyl.

22. A pharmaceutical composition according to claim 1, wherein R₁₂ is hydrogen and R₁₃ is selected from the group consisting of piperidinyl and morpholinyl.

23. A pharmaceutical composition according to claim 1, wherein two adjacent substituents selected from the group consisting of R₇, R₈, R₉, R₁₀ and R₁₁ form, together with the phenyl ring carbon atoms to which they are attached, a methylenedioxy group fused to said phenyl ring.

24. A pharmaceutical composition according to claim 1, wherein at least three of R₇, R₈, R₉, R₁₀ and R₁₁ are hydrogen, and wherein at most two of R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from the group consisting of C_1-6 alkyl, C_1-6 alkoxy, phenyl, hydroxy, acetyl, nitro, trifluoromethyl and halogen.

25. A pharmaceutical composition according to claim 1, wherein said 1,2,4-thiadiazole derivative is selected from the group consisting of:

4-phenylacetyl-1-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

4-(4-fluorophenylacetyl), 1-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-fluorophenylacetyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-methoxyphenylacetyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-phenylacetyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine

1-(4-fluorophenylacetyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[chloro(phenyl)acetyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(2-phenylbutanoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

N-(3-fluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,

N-(2-methylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(4-ethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(2-ethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-phenyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,

N-(4-ethoxyphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(2-methylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,

N-(2-fluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,

N-(2-trifluoromethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,

N-(2-trifluoromethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(2,6-dimethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(2,4-dimethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(2,6-dichlorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(3-cyanophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(2,4-difluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(2,6-dimethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,

N-1-naphtyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(3,4-difluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

N-(2,4-dimethoxyphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,

N-(3,4-difluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,

N-(3,5-dimethoxyphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,

1-[4-tert-butylphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-methoxyphenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-methoxyphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-fluorophenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-chlorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[1-naphtylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[2,5-dichlorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[2,4,6-trimethylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,

1-[2-naphtylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[2,5-dichlorophenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,

1-[4-bromophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-3-methylpiperazine,

1-[1-naphtylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-3-methylpiperazine,

1-[4-tert-butylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[1-naphtylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[3-methoxyphenysulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[2,4,6-trimethylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[3-trifluorophenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-phenylsulfonyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[4-acetamidophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[4-acetamidophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,

1-[4-methylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[4-methoxyphenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[2-naphtylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-methoxyphenylsulfonyl]-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-tert-butylphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[4-acetamidophenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[3-trifluoromethylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[4-fluorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-fluorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[4-fluorophenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[4-methoxyphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[4-ter-butylphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[3-trifluoromethylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,

1-[4-methylphenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-bromophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[2-naphtylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-chlorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-tert-butylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,

1-[4-methoxyphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine

1-[4-tert-butylphenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine

1-[quinoline-8-sulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[4-nitrophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[3-nitro-4-chlorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[4-nitrophenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[4-methoxyphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[3-nitro-4-chlorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-piperazine

1-(benzylsulfonyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(benzylsulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(phenylprop-2-ensulfonyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(phenylprop-2-ensulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine

1-(phenylprop-2-ensulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(butylsulfonyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(octylsulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(butylsulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(ethylsulfonyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(isopropylsulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[(2E)-3-phenylprop-2-enoyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-[(2E)-3-phenylprop-2-enoyl]-4-B103-2-methylpiperazine,

1-[(2E)-3-phenylprop-2-enoyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,

1-(3-phenylpropanoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(3-phenylpropanoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[3-phenylprop-2-enyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[3-phenylprop-2-enyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-[3-phenylprop-2-enyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

4-pentyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

4-butyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

4-hexyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

4-chloro-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

3,5-dichloro-N-[2-{4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

2-methyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

3-fluoro-N-{2-[4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

4-methyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

4-fluoro-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

4-ethyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}benzamide,

3-fluoro-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,

3-fluoro-N-{2-[4-[3-benzyl-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}benzamide,

2-(4-fluorophenyl)-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}acetamide,

2-phenyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-acetamide,

2-(4-fluorophenyl)-N-{2-[4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}acetamide,

N-benzyl-N′

-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl urea

2-phenyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-butanamide,

3-phenyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-propanamide,

1-benzyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(1,3-benzodioxol-5-ylmethyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,

1-(2-fluorobenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-ethylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-butylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-methoxybenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(1,3-benzodioxol-5-ylcarbonyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-butylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-hexylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(3-chlorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine

1-(4-fluorobenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-methylbenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(3-fluorobenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine

1-benzoyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-fluorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-tert-butylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(1,1′

-biphenyl-4-ylcarbonyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-methoxybenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-ethylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(2-naphthoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(2-methoxybenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-pentylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-bromobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine

1-(2,4-dimethoxybenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(3,5-dichlorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(3-chlorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(2-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(3-bromobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine

1-(4-ethylbenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(3-methylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(3-trifluoromethylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-tert-butylbenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-ethylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(2-bromobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine

1-(2-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(3-fluorobenzoyl)-4-[3-benzyl-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(2-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-fluorobenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-fluorobenzoyl)-4-[3-benzyl-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-chlorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(3-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(3-fluorobenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-benzoyl-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(2-fluorobenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(1,3-benzodioxol-5-ylcarbonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(3-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-fluorobenzoyl)-4-[3-benzyl-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-bromobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-ethylbenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(2-chlorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine

1-(2-fluorobenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine

1-(4-trifluoromethylbenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-benzoyl-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-bromobenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-trifluoromethylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(3-nitro-4-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-benzoyl-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-chlorobenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(2-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-hexylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(2-chloro-4-nitrobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(1,3-benzodioxol-5-ylcarbonyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine

1-(3-fluorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(4-tert-butylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-benzoyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-butylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-tert-butylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-nitrobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,

1-(2-methylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(2-ethoxyphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(2-fluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(3-trifluoromethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,

1-(4-chlorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-1,4-diazepane,

1-(4-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-1,4-diazepane,

1-(1,3-benzodioxol-5-ylcarbonyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-1,4-diazepane,

1-[4-methoxyphenylsulfonyl]-4-[3-(3-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(2-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[2-methoxyphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-ethoxyphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-ethylphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-phenylsulfonyl-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-(4-propionyloxy)benzene-sulfonyl-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]-piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(3-methyl-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(2-methyl-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(2-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(3-methyl-4-fluoro-benzyl-1,2,4-thiadiazol-5-yl]-piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(4-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-bromophenylsulfonyl]-4-[3-(3-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(3-methoxybenzyl)-1,2,4-thia-diazol-5-yl]-2-methylpiperazine; and

1-(4-hydroxybenzenesulfonyl)-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine.

27. A pharmaceutical composition according to claim 1, further comprising a therapeutic amount of one or more drugs selected from the group consisting of neuro-protective agents and α

-synuclein deposition inhibitors.

28. A method of preventing or treating an α

-synucleopathy, comprising the administration of a therapeutic effective amount of a 1,2,4-thiadiazole derivative as defined in claim 1 to a patient in need thereof, optionally in combination with one or more pharmaceutically acceptable carriers, and optionally in combination with a therapeutic amount of one or more drugs selected from the group consisting of neuro-protective agents and α

-synuclein deposition inhibitors.

29. A method of prevention or treatment according to claim 28, wherein said α

-synucleopathy is selected from the group consisting of Parkinson'"'"'s disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, multiple system atrophy and Alzheimer'"'"'s disease.

26. A 1,2,4-thiadiazole derivative selected from the group consisting of:

1-[3-methoxyphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(3-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(2-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[2-methoxyphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-ethoxyphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-ethylphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-phenylsulfonyl-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-(4-propionyloxy)benzene-sulfonyl-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]-piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(3-methyl-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(2-methyl-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(2-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(3-methyl-4-fluoro-benzyl-1,2,4-thiadiazol-5-yl]-piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(4-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-bromophenylsulfonyl]-4-[3-(3-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;

1-[4-methoxyphenylsulfonyl]-4-[3-(3-methoxybenzyl)-1,2,4-thia-diazol-5-yl]-2-methylpiperazine; and

1-(4-hydroxybenzenesulfonyl)-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine.