Nitrocatechol Derivatives as Comt Inhibitors

• US 20090054437A1
• Filed: 07/26/2006
• Published: 02/26/2009
• Est. Priority Date: 07/26/2005
• Status: Active Grant

• Current Assignee: BIAL Portela & Ca, SA
• Original Assignee: BIAL Portela & Ca, SA
• Inventors: Silva, Patricio Manuel Vieira Araujo Soares da, Learmonth, David Alexander, Palma, Pedro Nuno Leal, Kiss, Laszlo Erno, Ferreira, Humberto Dos Santos
• Granted Patent: US 8,168,793 B2
• Time in Patent Office: Days
• US Class Current: 514/236.200
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• 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 27/02 Ophthalmic agents
• 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 213/89 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 215/60 N-oxides
• CPC Class Codes: C07D 271/06 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 271/107 with two aryl or substituted aryl radicals attached in positions 2 and 5
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 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 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond

Abstract

New compounds of formula I are described. The compounds have potentially valuable pharmaceutical properties in the treatment of some central and peripheral nervous system disorders.

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 N-oxide 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 or C₃-C₁₂-heterocycloalkylamino, C₁-C₆-alkylsulphonyl or C₆-C₁₂-arylsulphonyl, halogen, C₁-C₆-haloalkyl, trifluoromethyl, cyano, nitro or a heteroaryl group;

or

where

two or more of residues R₄, R₅, R₆ and R₇ taken together represent aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings; and

wherein

P represents a central unit 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 the alkyl is methyl, ethyl, n-propyl or n-butyl and wherein the alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

1-alkyl-1H-pyrrol-2,5-diyl, wherein the alkyl is methyl, ethyl, n-propyl or 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 the alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

benzene-1,3-diyl; and

(Z)-1-cyanoethen-1,2-diyl, wherein the regioisomers of the central unit include both regioisomers realizable by exchange of the nitrocatechol moiety and the —

(X)_n—

(Y)_m—

R₃ moiety.

2. A compound according to claim 1, selected from the group consisting of 5-[3-(3,5-dichloro-1-oxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-chloro-1-oxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-morpholin-4-yl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 3-nitro-5-[3-(1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, 5-[3-(4-bromo-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-chloro-6-methyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-morpholin-4-yl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 3-nitro-5-[3-(1-oxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, 5-[3-(2-methyl-1-oxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(6-methyl-1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2,6-dimethyl-1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-methyl-1-oxy-6-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(6-methyl-1-oxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-6-methyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-chloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-4,5,6-trimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2-chloro-4,5,6-trimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2-bromo-5-chloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol and 3-nitro-5-[3-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol.

3. A method of treating a subject afflicted by a central or peripheral nervous system disorder, where a reduction in the O-methylation of catecholamines may be of therapeutical benefit, comprising administering to the subject an amount of a compound according to claim 1 effective to treat said disorder of the subject.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

6. The method of claim 1 wherein the disorder is selected from a mood disorder, Parkinson'"'"'s disease, a parkinsonian disorder, restless legs syndrome, a gastrointestinal disturbance, an edema formation state and hypertension.

7. The use of a compound according to claim 1 in therapy.

8. A method of treating a disorder or a disease for which a therapy with a COMT inhibitor is indicated comprising administering an effective amount of a compound according to claim 1.

9. A method of preparing a compound according to formula I in claim 1, comprising the step of subjecting a compound of formula IIA, IIB or IIC,

wherein R₄, R₅, R₆ and R₇ are defined as in the general formula I in claim 1 to cyclisation with a compound of formula III,

wherein R₈ and R₉ independently from each other represent hydrogen or suitable protective groups for aromatic hydroxyl groups, under conditions suitable to produce oxadiazole derivatives of formula IVA, IVB or IVC,

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

10. A method of preparing a compound according to formula I in claim 1, comprising the steps of:

a) subjecting 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 to cyclisation with a compound of formula III under conditions suitable to produce oxadiazole derivatives of formula VIA, VIB or VIC,

b) oxidizing the pyridyl nitrogen atom to give a compound according to formula IVA, IVB or IVC, optionally followed by removal of the protecting groups R₈ and/or R₉.

11. The method of claim 9, wherein the compound of formula III is activated by reaction with thionyl chloride or 1,1-carbonyldiimidazole.

12. The method of claim 9, wherein the cyclisation step consisting of condensation and dehydration is conducted sequentially in a one-pot reaction.

13. The method of claim 9, wherein the cyclisation step is carried out in the presence of a suitable organic base.

14. The method of claim 13, wherein the cyclisation step is carried out in the presence of pyridine.

15. The method of claim 9, 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.

18. The method of claim 9, wherein the condensation and dehydration is performed in a dipolar aprotic solvent.

19. The method of claim 18, wherein the condensation and dehydration is performed in dimethylacetamide, N-methylpyrrolidinone or dimethylsulfoxide.

20. The method of claim 10, wherein the pyridyl nitrogen atom of the oxadiazolyl compound of formula VIA, VIB or VIC is oxidised by hydrogen peroxide, peracetic acid, trifluoroperacetic acid or urea-hydrogen peroxide complex and trifluoroacetic anhydride.

21. The method of claim 9, wherein the compound of formula IIA, IIB or IIC is obtained by the reaction of compound VIIA, VIIB or VIIC, respectively,

wherein R₄, R₅, R₆ 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.

22. The method of claim 10, wherein the compound of formula VA, VB or VC is obtained by the reaction of compound VIIIA, VIIIB or VIIIC, respectively,

wherein R₄, R₅, R₆ 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.

23. The method according to claim 19, wherein the chelating agent is selected from the group consisting of 8-hydroxyquinoline, ortho-phenanthroline and hydrates or derivatives thereof.

24. A method of preparing a compound according to formula I in claim 1, comprising oxidizing a pyridine compound to a pyridine N-oxide compound.

5. (canceled)

16. The method of 9, wherein R₈ and R₉ of the compound of formula III independently from each other represent methyl or hydrogen.

17. The method of claim 16, wherein the methyl group is removed by reaction with aluminium chloride and pyridine in N-methylpyrrolidinone.