TECHNICAL FIELD

The present invention relates to compounds for treating neurodegenerative diseases.

BACKGROUND OF THE INVENTION

Dopaminergic receptor systems have been targeted for the development of pharmacotherapeutic agents for a number of CNS related disorders, including drug addiction, schizophrenia, depression, and Parkinson's disease (PD). Dopamine (DA) receptor agonists have been employed more extensively in the treatment of Parkinson's disease than any other type of pharmacotherapy. Levodopa (L-dopa), the immediate precursor to endogenous DA, is the current gold-standard treatment option for PD. DA receptors belong to the family of transmembrane proteins known as G-protein-coupled receptors (GPCRs). DA receptors are widely distributed in the CNS, are also present in the periphery, and are divided into five subtypes. On the basis of the stimulatory action on adenylyl cyclase, D1 and D5 are grouped together as D1 type. D2-D4 receptors are classified as D2 type because of their inhibitory action on adenylyl cyclase activity. Interestingly, the D3 receptor was found to have a distribution in the brain that is somewhat different from that of the D2 receptor. The highest levels of D3 receptor expression were found to be in the limbic region of the brain, while D2 receptor expression is most dense in the striatum of the midbrain. D2 and D3 receptor subtypes occur post- and presynaptically. In the latter location they function as autoreceptors that regulate DA synthesis, metabolism, and release. It is noteworthy that D2 and D3 receptor subtypes share 50% overall amino acid sequence homology and 75-80% in their agonist binding sites. As a result, development of ligands selective for either subtype is a challenging task.

Parkinson's disease (PD) is a progressive, neurodegenerative disorder that results from the death of DA-producing cells in the substantia nigra region of the midbrain. Common symptoms include resting tremor, muscular rigidity, bradykinesia, postural instability, and cognitive psychiatric complications. Although the etiology of PD is not yet clear and may be multifactorial, oxidative stress and mitochondrial dysfunction are thought to play a central role in the pathology of the disease. Recent studies on various genetic mutations have provided new insights into the disease process. Oxidative stress has been strongly implicated in midbrain dopaminergic cell death. Toxicity from endogenous and exogenous origins, caused by oxidative mechanisms, has been implicated as a fundamental process in progressive nigral cell loss. Along with motor fluctuations and wearing off after long-term treatment, side effects associated with L-dopa treatment and the eventual oxidation of DA derived from L-dopa have been speculated to produce further oxidative stress.

In addition, α-synuclein, a presynaptic protein involved in fibrillization, has been implicated in the pathogenesis of PD. A recent report demonstrated that in cultured human dopaminergic neurons, accumulation of α-synuclein induces apoptosis in the presence of DA and reactive oxygen species. Furthermore, an interaction between calcium, cytosolic DA, and α-synuclein has been implicated in the loss of DA neurons in the substantia nigra. In this case, DA dependent neurotoxicity is mediated by a soluble protein complex containing α-synuclein. Therefore, α-synuclein, together with oxidized DA, could have synergistic effects in terms of disease susceptibility and progression.

Accordingly, there is a need for dopamine improved D2/D3 agonist molecules, and in particular, for improved D2/D3 agonist molecules with a capacity to bind to iron.

SUMMARY OF THE INVENTION

In at least one embodiment, the present invention solves one or more problems of the prior art by providing a compound having formula I for treating a neurodegenerative disease:


wherein:

R1is H, C1-8alkyl, C2-8alkenyl, C4-8cycloalkyl, C4-8cycloalkenyl, C6-10aryl, C1-10alkyl C6-10aryl, or



R2, R3, R4, R5are each independently H or OH wherein at least 2 of R2, R3, R4, R5are OH;

R6is an optionally substituted C1-8alkyl, C1-8alkoxyl, C2-8alkenyl, C2-8alkynyl, C4-8cycloalkyl, C4-8cycloalkenyl, C6-10aryl,



R7is an optionally substituted C1-8alkyl, C1-8alkoxyl, C2-8alkenyl, C2-8alkynyl, C4-8cycloalkyl, C4-9cycloalkenyl, or C6-10aryl;

R8are each independently hydroxyl, C1-4alkyl, C1-4alkoxyl, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C4-8cycloalkyl, C4-8cycloalkenyl; C6-10aryl, —NR3qor C1-10hydrocarbon groups optionally containing one or more O, N, S, or Se heteroatoms where R3individually are H or organyl groups (e.g., C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C4-8cycloalkyl, C4-8cycloalkenyl, or C6-10aryl) and q is 2 or 3, with the proviso that when q is 3, the group bears a positive formal charge (with an appropriate counter ion (e.g., halide) being present);

Zmis absent or a divalent linking moiety in which Z is repeated m times;

o is 0, 1, 2, 3, or 4; and

m is 0, 1, 2, 3, 4, or 5.

In another embodiment, a compound having formula II for treating a neurodegenerative disease is provided:


or a pharmaceutically acceptable salt or ester thereof,
wherein:

A is an optionally substituted C6-12aryl or C6-12heteroaryl;

R14, R15are each independently H, C1-8alkyl, C1-8alkyl, C2-4alkenyl, C4-8cycloalkyl, C4-8cycloalkenyl, C6-10aryl, or C1-10alkyl, or C6-10aryl;

B1and B2are each independently:


and

o is 0, 1, 2, 3, or 4; and

R16is an optional substituent.

