2-CYANO-3-CYCLOPROPYL-3-HYDROXY-N-ARYL-THIOACRYLAMIDE DERIVATIVES

Abstract

A compound of the formula (I) or a tautomeric isoform thereof wherein R1 is selected from the group consisting of halogen, nitro, lower alkyl sulfonyl, cyano, trifluromethyl lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl, perfluoro lower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, lower alkylsulfonyl lower alkyl, lower alkylsulfonyl, lower alkanoyl, aroyl, aryl, aryloxy and R2 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkylthio, and alkylcarbonyl, and their non-toxic, pharmaceutically acceptable base addition salts or pro-drugs thereof. The compounds of the invention are useful in the treatment of nervous system diseases and disorders, which are responsive to modulation of the GABA.sub.A receptor complex.

Claims

1. A compound of the formula I or a tautomeric isoform thereof ##STR00005## wherein R1 is selected from the group consisting of a halogen, a nitro, a lower alkyl sulfonyl, a cyano, a trifluromethyl lower alkyl, a lower alkoxy, s lower alkoxycarbonyl, a carboxy, a lower alkyl aminosulfonyl, a perfluoro lower alkyl, a lower alkylthio, a hydroxy lower alkyl, an alkoxy lower alkyl, a lower alkylthio lower alkyl, a lower alkylsulfinyl lower alkyl, a lower alkylsulfonyl lower alkyl, a lower alkylsulfinyl, a lower alkanoyl, an aroyl, an aryl, an aryloxy; and wherein R2 is selected from the group consisting of hydrogen, an alkyl, an alkoxy, an alkylthio, an alkylcarbonyl, and a non-toxic, pharmaceutically acceptable base addition salt or pro-drug thereof.

2. The compound according to claim 1, wherein R1 is selected from a group consisting of fluorine, chlorine, jodine, a trifluoromethyl, a cyano, a nitro, a methansulfinyl, a methansulfonyl, a trifluoromethansulfinyl and a trifluoromethansulfonyl; and wherein R2 is selected from the group consisting of hydrogen, ethyl, and methyl.

3. The compound according to claim 1, wherein the compound is selected from the group consisting of 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-trifluormethyl-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-ethyl-4-trifluormethyl-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-fluoro-3-methyl-phenyl)-3-hydroxy-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-fluoro-3-ethyl-phenyl)-3-hydroxy-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-fluoro-phenyl)-3-hydroxy-thioacrylamide 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-nitro-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-ethyl-4-nitro-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-nitro-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-trifluoromethanesulfinyl-phenyl)-thioacrylamide, 2-cyano-N-(4-cyano-3-methyl-phenyl)-3-cyclopropyl-3-hydroxy-thioacrylamide, 2-cyano-N-(4-cyano-3-ethyl-phenyl)-3-cyclopropyl-3-hydroxy-thioacrylamide, 2-cyano-N-(4-cyano-phenyl)-3-cyclopropyl-3-hydroxy-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-trifluoromethanesulfinyl-3-methyl-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-trifluoro-methanesulfonyl-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-trifluoromethanesulfonyl-3-methyl-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-((trifluoromethyl)thio)phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-((trifluoromethyl)thio)phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-chloro-3-methyl-phenyl)-3-hydroxy-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-chloro-3-ethyl-phenyl)-3-hydroxy-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-chloro-phenyl)-3-hydroxy-thioacrylamide and their tautomeric isoforms, non-toxic, pharmaceutically acceptable salts or pro-drugs thereof.

4. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to claim 1, or an tautomer thereof, or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, optionally together with at least one acceptable and inert pharmaceutical carrier, excipient or diluent.

5. The composition according to claim 4, wherein R1 is individually selected from the group consisting of fluorine, chlorine, jodine, trifluoromethyl, cyano, nitro, methansulfinyl, methansulfonyl, trifluoromethansulfinyl and trifluoromethansulfonyl, and R2 is hydrogen.

6. The composition according to claim 4, wherein R1 is individually selected from the group consisting of fluorine, chlorine, jodine, trifluoromethyl, cyano, nitro, methansulfinyl, methansulfonyl, trifluoromethansulfinyl and trifluoromethansulfonyl, and R2 is methyl or ethyl.

7. The composition according to claim 4 wherein the compound is an active compound selected from the group consisting of 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-trifluormethyl-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-ethyl-4-trifluormethyl-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-fluoro-3-methyl-phenyl)-3-hydroxy-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-fluoro-3-ethyl-phenyl)-3-hydroxy-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-fluoro-phenyl)-3-hydroxy-thioacrylamide 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-nitro-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-ethyl-4-nitro-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-nitro-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-trifluoromethanesulfinyl-phenyl)-thioacrylamide, 2-cyano-N-(4-cyano-3-methyl-phenyl)-3-cyclopropyl-3-hydroxy-thioacrylamide, 2-cyano-N-(4-cyano-3-ethyl-phenyl)-3-cyclopropyl-3-hydroxy-thioacrylamide, 2-cyano-N-(4-cyano-phenyl)-3-cyclopropyl-3-hydroxy-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-trifluoromethanesulfinyl-3-methyl-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-trifluoro-methanesulfonyl-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-trifluoromethanesulfonyl-3-methyl-phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(4-((trifluoromethyl)thio)phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-((trifluoromethyl)thio)phenyl)-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-chloro-3-methyl-phenyl)-3-hydroxy-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-chloro-3-ethyl-phenyl)-3-hydroxy-thioacrylamide, 2-cyano-3-cyclopropyl-N-(4-chloro-phenyl)-3-hydroxy-thioacrylamide, and a tautomeric isoform, non-toxic, pharmaceutically acceptable base addition salt or pro-drug thereof.

8. The compound according to claim 1 embodied as a medicine.

9. The compound according to claim 8 for the use in the treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of the GABA.sub.A receptor complex.

10. A process for preparing the compound of formula I, comprising reacting a compound of formula II with thiophosgen to form a compound of formula III, and reacting the compound of formula III with 3-cyclopropyl-3-oxopropionitril to obtain the compound of formula I; wherein formula II is ##STR00006## wherein formula II is ##STR00007## wherein R1 is selected from the group consisting of a halogen, a nitro, a lower alkyl sulfonyl, a cyano, a trifluromethyl lower alkyl, a lower alkoxy, s lower alkoxycarbonyl, a carboxy, a lower alkyl aminosulfonyl, a perfluoro lower alkyl, a lower alkylthio, a hydroxy lower alkyl, an alkoxy lower alkyl, a lower alkylthio lower alkyl, a lower alkylsulfinyl lower alkyl, a lower alkylsulfonyl lower alkyl, a lower alkylsulfinyl, a lower alkanoyl, an aroyl, an aryl, an aryloxy; and wherein R2 is selected from the group consisting of hydrogen, an alkyl, an alkoxy, an alkylthio, an alkylcarbonyl, and a non-toxic, pharmaceutically acceptable base addition salt or pro-drug thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0096] FIG. 1 (A) shows the 50% paw withdrawal threshold (g) after spinal nerve ligation (Chung model) and oral gavage of 10 mg/kg of Example 1 (2-Cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-trifluormethyl-phenyl)-thioacrylamide), Example 2 (2-Cyano-3-cyclopropyl-N-(4-fluoro-3-methyl-phenyl)-3-hydroxy-thioacrylamide) or vehicle from DPO7 (pre-treat) till DPO12. *** p<0.001

[0097] FIG. 1 (B) shows the 50% paw withdrawal threshold (g) after spinal nerve ligation (Chung model) and oral gavage of 10 mg/kg of Example 3 (2-Cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-nitro-phenyl)-thioacrylamide), Example 4 (2-Cyano-3-cyclopropyl-3-hydroxy-N-(4-nitro-phenyl)-thioacrylamide), Example 6 (2-Cyano-N-(4-cyano-3-methyl-phenyl)-3-cyclopropyl-3-hydroxy-thioacrylamide) or vehicle from DPO 14 till DPO 19. *** p<0.001

[0098] FIG. 2 (A) shows the 50% paw withdrawal threshold (g) after capsaicin induced pain and oral gavage of 1 mg/kg of Example 1 (2-Cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-trifluormethyl-phenyl)-thioacrylamide), Example 3 (2-Cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-nitro-phenyl)-thioacrylamide) or vehicle about 40 minutes after capsaicin injection. ** p<0.01

[0099] FIG. 2 (B) shows the 50% paw withdrawal threshold (g) after capsaicin induced pain and oral gavage of 10 mg/kg of Example 2 (2-Cyano-3-cyclopropyl-N-(4-fluoro-3-methyl-phenyl)-3-hydroxy-thioacrylamide), Example 6 (2-Cyano-N-(4-cyano-3-methyl-phenyl)-3-cyclopropyl-3-hydroxy-thioacrylamide) or vehicle about 40 minutes after capsaicin injection. * p<0.05

[0100] The embodiments of the disclosure described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the disclosure.

LIST OF REFERENCES

[0101] The following additional publications are incorporated herein by references: [0102] WO 00/69842 A1 [0103] EP 731 099 A1 [0104] US 2003/0229134 [0105] EP 1500643 [0106] WO2006/20358 [0107] Chaplan, S. R., et al., 1994. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 53, 55-63. [0108] Chung, J. M., et al., 2004. Segmental Spinal Nerve Ligation Model of Neuropathic Pain. Methods in Molecular Medicine, Vol. 99: Pain Research: Methods and Protocols [0109] Lewin, A. H., De Costa, B. R., Rice, K. C. and Skolnick, P. (1989). Meta- and para-isothiocyanato-t-butylbicycloorthobenzoate: irreversible ligands of the aminobutyric acid-regulated chloride ionophore. Mol. Pharmacol., 35:189.