Pharmaceutical Compounds

• US 20100168113A1
• Filed: 04/10/2007
• Published: 07/01/2010
• Est. Priority Date: 04/10/2006
• Status: Active Grant

• Current Assignee: BIAL Portela & Ca, SA
• Original Assignee: BIAL Portela & Ca, SA
• Inventors: Learmonth, David Alexander, Palma, Pedro Nuno Leal, Kiss, Laszlo Erno, Silva, Patricio Manuel Vieira Soares da, Ferreira, Humberto Dos Santos
• Granted Patent: US 8,536,203 B2
• Time in Patent Office: Days
• US Class Current: 514/242
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 213/26 Radicals substituted by halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/57 Nitriles
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 407/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

This invention relates to novel substituted nitrocatechol derivatives, their use in the treatment of some central and peripheral nervous system disorders and pharmaceutical compositions containing them.

Claims

1. A compound of formula I:

wherein R₁ and R₂ are independently from each other hydrogen or a group which is hydrolysable under physiological conditions, optionally substituted lower alkanoyl or aroyl;

X represents a methylene group;

Y represents an atom of oxygen, nitrogen or sulphur;

n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1;

R₃ represents a pyridine group according to the formula A, B or C, which is connected as indicated by the unmarked bond;

where R₄, R₅, R₆ and R₇ independently from each other represent hydrogen, C₁-C₆-alkyl, C₁-C₆-thioalkyl, C₁-C₆-alkoxy, C₆-C₁₂-aryloxy or a C₆-C₁₂-thioaryl group, C₁-C₆-alkanoyl or C₇-C₁₃-aroyl group, amino, C₁-C₆—

alkylamino, C₁-C₆-dialkylamino, C₃-C₁₂-cycloalkylamino, C₃-C₁₂-heterocycloalkylamino, C₁-C₆-alkylsulphonyl, C₆-C₁₂-arylsulphonyl, halogen, C₁-C₆-haloalkyl, trifluoromethyl, cyano, nitro or a heteroaryl group;

or two or more of residues R₄, R₅, R₆ and R₇ taken together represent aliphatic or heteroaliphatic rings or aromatic or hetero aromatic rings and wherein P represents a central unit, which is preferably a planar unit and which is even more preferably selected from the regioisomers of 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazin-2,4-diyl, 1,2,4-triazin-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1H-pyrrol-2,5-diyl, wherein alkyl is represented by methyl, ethyl, n-propyl and n-butyl and wherein alkoxy is represented by methoxy, ethoxy, n-propoxy and isopropoxy, 1-alkyl-1H-pyrrol-2,5-diyl, wherein alkyl is represented by methyl, ethyl, n-propyl and n-butyl, thiazol-2,4-diyl, 1-H-pyrazol-1,5-diyl, pyrimidin-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, 3-alkoxycarbonylfuran-2,4-diyl, wherein alkoxy is represented by methoxy, ethoxy, n-propoxy and isopropoxy, benzene-1,3-diyl and (Z)-1-cyanoethen-1,2-diyl;

or a pharmaceutically acceptable salt or ester of a compound of formula I.

2. A compound, salt or ester according to claim 1, wherein the compound of formula I is selected from 3-nitro-5-(3-(4-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzene-1,2-diol, 5-(3-(2-chloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 3-nitro-5-(3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzene-1,2-diol, 5-(3-(6-methyl-4-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(2,6-dimethyl-4-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(3,5-dichloropyridin-4-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(6-methyl-2-phenyl-4-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(2-bromo-4,5,6-trimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(2-chloro-4,5,6-trimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 3-nitro-5-(3-(2-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzene-1,2-diol, 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 3-nitro-5-(3-(5-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzene-1,2-diol, 5-(3-(2-fluoropyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(2-fluoropyridin-4-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(6-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(2-chloro-6-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(2-bromo-6-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 5-(3-(2-bromo-5-chloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, 3-nitro-5-(5-(4-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzene-1,2-diol, 5-(5-(2-chloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 5-(5-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 3-nitro-5-(5-(6-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzene-1,2-diol, 5-(5-(6-methyl-4-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 5-(5-(2,6-dimethyl-4-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 5-(5-(3,5-dichloropyridin-4-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 5-(5-(6-methyl-2-phenyl-4-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 5-(5-(2-bromo-4,5,6-trimethylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 5-(5-(2-chloro-4,5,6-trimethylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 3-nitro-5-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzene-1,2-diol, 5-(5-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 3-nitro-5-(5-(5-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzene-1,2-diol, 5-(5-(2-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 5-(5-(2-fluoropyridin-4-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 5-(5-(6-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl)-3-nitro benzene-1,2-diol, 5-(5-(2-chloro-6-methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 5-(5-(2-bromo-6-methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol, 5-(5-(2-bromo-5-chloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-nitrobenzene-1,2-diol.

3. A compound, salt or ester according to claim 1, wherein the compound of formula I is 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

4. A compound, salt or ester according to claim 1 for use as an active ingredient in a pharmaceutical composition.

5. A pharmaceutical composition comprising a compound, salt or ester according to any one of claims 1 to 4.

6. A pharmaceutical composition as claimed in claim 5, further comprising L-DOPA.

7. A pharmaceutical composition as claimed in claim 5 or 6, further comprising an aromatic L-amino acid decarboxylase inhibitor.

8. A pharmaceutical composition according to claim 7, wherein the DOPA decarboxylase inhibitor is a DOPA decarboxylase inhibitor selected from benserazide or carbidopa.

9. Use of a compound, salt, ester or composition according to any one of claims 1 to 4 for the preparation of a pharmaceutical composition for the treatment of a central and peripheral nervous system disorder.

10. Use of a compound, salt, ester or composition according to any one of claims 1 to 4 for the treatment of a central and peripheral nervous system disorder.

11. Use as claimed in claim 9 or 10 wherein the central and peripheral nervous system disorder is a movement disorder, a gastrointestinal disturbance, an oedema formation state or hypertension.

12. Use as claimed in claim 11 wherein the movement disorder is restless leg syndrome, Parkinson'"'"'s disease or a pathological state involving Parkinsonism.

13. Method of treatment of a central and peripheral nervous system disorder, comprising the step of administering an effective dose of a pharmaceutical composition as claimed in any of claims 5 to 8 to a subject in need thereof.

14. Method as claimed in claim 13, wherein the central and peripheral nervous system disorder is a movement disorder, a gastrointestinal disturbance, an oedema formation state or hypertension.

15. Method as claimed in claim 14, wherein the movement disorder is Parkinson'"'"'s disease or a pathological state involving Parkinsonism.

16. Method of reducing COMT activity in a subject, comprising the step of administering an effective amount of a compound, salt, ester or composition according to any one of claims 1 to 4 to a subject in need thereof.

17. Method of increasing levels of L-DOPA in the brain or plasma of a subject, comprising the step of administering an effective amount of a compound, salt, ester or composition according to any one of claims 1 to 4 to a subject in need thereof.

18. Method of increasing bio availability of L-DOPA in the brain or plasma of a subject, comprising the step of administering an effective amount of a compound, salt, ester or composition according to any one of claims 1 to 4 to a subject in need thereof.

19. Method of decreasing levels of 3-O-methyl-L-DOPA (3-OMD) in the brain or plasma of a subject, comprising the step of administering an effective amount of a compound, salt, ester or composition according to any one of claims 1 to 4 to a subject in need thereof.

20. Method as claimed in any of claims 13 to 19 wherein the pharmaceutical composition or the compound is administered from twice per day to once every other day.

21. Method as claimed in any of claims 13 to 19 wherein the pharmaceutical composition is administered once per day.

22. Method as claimed in any of claims 13 to 21 wherein the subject is also receiving therapy with L-DOPA.

23. Method as claimed in any of claims 13 to 22 wherein the subject is also receiving therapy with an aromatic L-amino acid decarboxylase inhibitor.

24. Method as claimed in claim 23 wherein the aromatic L-amino acid decarboxylase inhibitor is a DOPA decarboxylase inhibitor selected from benserazide and carbidopa.

25. Process for the preparation of compounds according to the general formula I in claim 1 wherein P represents a 1,2,4-oxadiazolyl group, said process comprising steps wherein a compound of formula VA, VB or VC,

wherein R₄, R₅, R₆ and R₇ are defined as in the general formula I in claim 1, is subjected to cyclisation with a compound of formula III under conditions suitable to produce oxadiazole derivatives of formula VIA, VIB or VIC,

optionally followed by removal of the protecting groups R₈ and/or R₉.

26. Process according to claim 25, wherein the compound of formula III is activated by reaction with thionyl chloride or 1,1-carbonyldiimidazole.

27. Process according to claim 25 or 26, wherein the cyclisation step consisting of condensation and dehydration is conducted sequentially in a one-pot reaction.

28. Process according to any one of claims 25 to 27, wherein the cyclisation step is carried out in the presence of a suitable organic base.

29. Process according to claim 28, wherein the cyclisation step is carried out in the presence of pyridine.

30. Process according to any one of claims 25 to 29 wherein the groups R₈ and R₉ are independently from each other or jointly removed and replaced with hydrogen or a group which is hydrolysable under physiological conditions.

31. Process according to any one of claims 25 to 30 wherein R₈ and R₉ of the compound of formula III independently from each other represent methyl or hydrogen.

32. Process according to claim 31, wherein the methyl group is removed by reaction with aluminium chloride and pyridine in N-methylpyrrolidinone.

33. Process according to any one of claims 25 to 32, wherein the condensation and dehydration is performed in a dipolar aprotic solvent.

34. Process according to claim 33, wherein the condensation and dehydration is performed in dimethylacetamide, N-methylpyrrolidinone or dimethylsulfoxide.

35. Process according to any one of claims 25 to 34, wherein the compound of formula VA, VB or VC is obtained by the reaction of compound VIIIA, VIIIB or VIIIC, respectively,

wherein R₄, R₅, R₄ and R₇ are defined as in the general formula I in claim 1, with hydroxylamine in the presence of a chelating agent under conditions suitable to produce amidoxime derivatives.

36. Process according to claim 35, wherein the chelating agent is selected from the group consisting of 8-hydroxyquinoline, ortho-phenanthroline and hydrates or derivatives thereof.

37. Use of a compound of formula I as defined in claim 1, or a pharmacologically acceptable salt or ester thereof, for the preparation of a medicament for administration according to a dosing regimen having a dosing periodicity ranging from about twice a day to about once every other day, for the prevention or treatment of central and peripheral nervous system associated disorders.

38. Use according to claim 37, wherein the dosing regimen is once daily.

39. Use according to claim 37, wherein the dosing regimen is once every other day.

40. Use according to any one of claims 37 to 39, wherein the central and peripheral nervous system associated disorder is a movement disorder, a gastrointestinal disturbance, an oedema formation state or hypertension.

41. Method as claimed in claim 40, wherein the movement disorder is restless leg syndrome, Parkinson'"'"'s disease or a pathological state involving Parkinsonism.

42. Use according to any one of claims 37 to 41, wherein the central and peripheral nervous system associated disorder is treatable by a L-DOPA/AADC therapy.

43. Use according to any one of claims 37 to 42, wherein the compound of formula I is 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

44. Package comprising a pharmaceutical composition comprising a compound of formula I as defined in claim 1, or a pharmacologically acceptable salt or ester thereof, in combination with instructions to administer said composition with a dosing regimen having a dosing periodicity ranging from about twice a day to about once every other day.

45. Package according to claim 44, wherein the dosing regimen is once daily.

46. Package according to claim 44, wherein the dosing regimen is once every other day.

47. Package according to any one of claims 44 to 46, wherein the central and peripheral nervous system associated disorder is a movement disorder, a gastrointestinal disturbance, an oedema formation state or hypertension.

48. Package as claimed in claim 47, wherein the movement disorder is restless leg syndrome, Parkinson'"'"'s disease or a pathological state involving Parkinsonism.

49. Package according to any one of claims 44 to 48, wherein the package further comprises a pharmaceutical composition comprising L-DOPA and/or an AADC.

50. Package according to any one of claims 44 to 49, wherein the compound of formula I is 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.