FIELD OF THE INVENTION

The present invention relates to pharmacologically active 2-substituted 4,5-dihydroxyisophthalonitriles, or pharmaceutically acceptable salts and esters thereof, as well as to pharmaceutical compositions containing them and to their use as inhibitors of the catechol O-methyltransferase (COMT) enzyme.

BACKGROUND OF THE INVENTION

Dopamine is deficient in the brain of patients suffering from Parkinson's disease. Levodopa is used orally in the treatment of Parkinson's disease. Levodopa is a dopamine precursor, which is converted to dopamine in the brain. However, only a small portion of orally administered levodopa reaches the brain, because levodopa is metabolized in the peripheral system by COMT as well as by dopa decarboxylase (DDC). COMT metabolizes levodopa by converting it to 3-O-methyldopa, which is therapeutically ineffective and detrimental when competing with levodopa. COMT inhibitors have been shown to be effective in clinical use for the treatment of Parkinson's disease as an adjunct to levodopa therapy.

It is generally thought that the levodopa concentration in plasma reflects the levodopa levels in the brain. It is thus desirable to achieve a high levodopa concentration in plasma. However, optimal levodopa concentration in plasma is not achieved, for example, with the currently used COMT inhibitor entacapone.

COMT inhibitors have also been indicated to be useful in the treatment of, for example, hypertension, heart failure and depression (U.S. Pat. No. 5,446,194) as well as inhibitors for the prevention of diabetic vascular dysfunctions (WO 98/27973). COMT inhibitors have also been disclosed as being useful for treating or controlling pain (WO 01/68083) as well as for treating restless legs syndrome (RLS), which is also known as Ekbom's syndrome (WO 2006/051154). RLS is characterized by an irresistible urge to move the legs accompanied by other unpleasant sensations deep within the legs.

Some compounds with COMT inhibiting activity are known in the art. Isoflavone derivatives as COMT inhibitors have been disclosed in U.S. Pat. No. 3,974,184 and CN 101643465 A. Catechol derivatives as COMT inhibitors have been disclosed in U.S. Pat. Nos. 5,236,952, 5,446,194, WO 96/37456, WO 00/37423, WO 01/98250, WO 01/98251, WO 02/02548, WO 02/22551, WO 2004/112729, WO 2005/058228, WO 2007/010085, WO 2007/013830, WO 2007/063789, WO 2007/117165, JP 2008308493, JP 2008308494, JP 2008308495, EP 2246338 A1, WO 2009/081892, EP 2305633 A1, JP 2011021010, JP 2012051884, and JP 2012051885. 3-Hydroxypyridin-4(1H)-one derivatives, 3-hydroxypyridin-2(1H)-one derivatives, and 5-hydroxypyrimidin-4(3H)-one derivatives as COMT inhibitors have been disclosed in WO 2011/109254, WO 2011/109261, and WO 2011/109267, respectively. Flavone derivatives as COMT inhibitors have been disclosed in CN 102755312 A.

SUMMARY OF THE INVENTION

An object of the present invention is to provide further inhibitors of the catechol O-methyltransferase enzyme that can be used for the treatment of diseases or conditions wherein inhibition of COMT is indicated to be useful. Accordingly, an object of the present invention is to provide further compounds to be used as COMT inhibiting agents in the treatment of mammals, including humans and animals. Furthermore, pharmaceutical compositions containing the present compounds are provided.

The COMT inhibitors of the invention provide in levodopa therapy an improved levodopa concentration in plasma.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds having the general formula I,

[Image Omitted]

wherein

R₁is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, (C₄-C₁₀)cycloalkenyl, aryl, (R₂)₂C═C—, halogen, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl-S—, (C₄-C₁₀)cycloalkenyloxy, (C₄-C₁₀)cycloalkenyl-S—, aryloxy, aryl-S—, heteroaryloxy, heteroaryl-S—, (R₃)₂N—, (R₄)₂C═N—, heterocyclyl, heteroaryl, aryl(C₁-C₆)alkyl, (1-amino-1-carboxymethyl)-(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-S—(C₁-C₆)alkyl, (R₃)₂N—(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, carboxy(C₂-C₆)alkenyl, (C₃-C₇)cycloalkyl(C₂-C₆)alkenyl, aryl(C₂-C₆)alkenyl, (C₁-C₆)alkoxy(C₂-C₆)alkenyl, heterocyclyl(C₂-C₆)alkenyl, heteroaryl(C₂-C₆)alkenyl, carboxy(C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl(C₂-C₆)alkynyl, aryl(C₂-C₆)alkynyl, (C₁-C₆)alkoxy(C₂-C₆)alkynyl, heterocyclyl(C₂-C₆)alkynyl, heteroaryl(C₂-C₆)alkynyl, halo(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—O—, R₅—(S═O)—, R₅—(O═S═O)—, hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy-(C═O)—(C₂-C₆)alkenyl or (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, wherein said (C₄-C₁₀)cycloalkenyl, aryl, heterocyclyl, heteroaryl or (C₃-C₇)cycloalkyl as such or as part of another group is unsubstituted or substituted with 1, 2 or 3 substituents(s) R₆;

R₂is, independently at each occurrence, carboxy or aryl, wherein said aryl is, independently at each occurrence, unsubstituted or substituted with 1, 2 or 3 substituent(s) R₆;

R₃is, independently at each occurrence, H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, (C₃-C₇)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl or (C₁-C₆)alkoxy(C₁-C₆)alkyl, wherein said (C₃-C₇)cycloalkyl or aryl as such or as part of another group is, independently at each occurrence, unsubstituted or substituted with 1 substituent being (C₁-C₆)alkyl, halogen, hydroxy, (C₁-C₆)alkoxy or hydroxy(C₁-C₆)alkyl;

R₄is, independently at each occurrence, H or aryl, wherein said aryl is, independently at each occurrence, unsubstituted or substituted with 1 substituent being (C₁-C₆)alkyl, halogen or (C₁-C₆)alkoxy;

R₅is (C₁-C₆)alkyl, aryl, hydroxy or (C₁-C₆)alkoxy, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 substituent(s) R₆;

R₆is, independently at each occurrence, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, carboxy, cyano, aryl, halogen, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl-S—, (C₄-C₁₀)cycloalkenyloxy, (C₄-C₁₀)cycloalkenyl-S—, aryloxy, aryl-S—, heteroaryloxy, heteroaryl-S—, (R₇)₂N—, heteroaryl, carboxy(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkoxy-(C═O)—, heterocyclyl-(C═O)—, (R₇)₂N—(C═O)—, halo(C₁-C₆)alkoxy, R₈—(S═O)—, R₈—(O═S═O)—, (C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl, (R₇)₂N—(C═O)—(C₁-C₆)alkyl or (C₁-C₆)alkoxy(C₁-C₆)alkoxy-(C═O)—, wherein said aryl, heteroaryl or heterocyclyl as such or as part of another group is, independently at each occurrence, unsubstituted or substituted with 1 substituent being (C₁-C₆)alkyl;

or R₆and R₆both attached to the same carbon ring atom form, together with the carbon ring atom to which they are attached, a —(C═O)— group;

R₇is, independently at each occurrence, H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl or carboxy(C₁-C₆)alkyl, wherein said (C₃-C₇)cycloalkyl is, independently at each occurrence, unsubstituted or substituted with 1 substituent being (C₁-C₆)alkyl;

R₈is, independently at each occurrence, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy or (R₉)₂N—;

R₉is, independently at each occurrence, (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt or ester thereof.