WO2011008675A2 - Catecholamine compounds, compositions, and formulations, and methods of using the same - Google Patents

Catecholamine compounds, compositions, and formulations, and methods of using the same Download PDF

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WO2011008675A2
WO2011008675A2 PCT/US2010/041666 US2010041666W WO2011008675A2 WO 2011008675 A2 WO2011008675 A2 WO 2011008675A2 US 2010041666 W US2010041666 W US 2010041666W WO 2011008675 A2 WO2011008675 A2 WO 2011008675A2
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substituted
compound
pharmaceutical composition
formula
cycloheteroalkyl
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PCT/US2010/041666
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French (fr)
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WO2011008675A3 (en
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Andrew R. Chadeayne
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Chadeayne Andrew R
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • C07D321/02—Seven-membered rings
    • C07D321/10—Seven-membered rings condensed with carbocyclic rings or ring systems

Definitions

  • the invention relates to catecholamine compounds, compositions, and
  • formulations comprising them, and methods of treating Parkinson's disease with those compounds, compositions, and formulations.
  • Parkinson's disease also known as Parkinson disease or "PD” is a degenerative disease of the brain (central nervous system) that often impairs motor skills, speech, and other functions. See Jankovic J., 2008, “Parkinson's disease: clinical features and diagnosis”, J. Neurol. Neurosurg. Psychiatr., 2008, 79(4): 368-76.
  • Parkinson's disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement
  • bradykinesia and, in extreme cases, a loss of physical movement (akinesia).
  • the primary symptoms result from decreased stimulation of the motor cortex by the basal ganglia. This decreased stimulation is often caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain.
  • PD is both chronic and progressive.
  • PD is the most common cause of chronic progressive parkinsonism, a term which refers to the syndrome of tremor, rigidity, bradykinesia, and postural instability.
  • PD is also called "primary parkinsonism” or "idiopathic PD” (classically meaning having no known cause, although many genetic mutations associated with PD have now been discovered). While many forms of parkinsonism are idiopathic, secondary cases may result from toxicity (most notably of drugs), head trauma, or other medical disorders.
  • PD is not considered to be a fatal disease by itself, but it progresses over time and leads to other complications.
  • the average life expectancy of a PD patient is generally lower than for people who do not have the disease.
  • PD may cause complications such as choking, pneumonia, and falls that can lead to death.
  • the progression of symptoms in PD may take 20 years or more to be fatal. In some people, however, the disease progresses more quickly. There is no way to predict with certainty what course the disease will take for an individual person. With appropriate treatment, most people with PD can live productive lives for many years after diagnosis.
  • Parkinson's disease is synonymous with "primary parkinsonism", i.e., isolated parkinsonism due to a neurodegenerative process without any secondary systemic cause. In some cases, it would be inaccurate to say that the cause is "unknown” because a small proportion is caused by genetic mutations. It is possible for a patient to be initially diagnosed with Parkinson's disease but then to develop additional features, requiring revising the diagnosis. See National Institute for Health and Clinical Excellence, Clinical guideline 35: Parkinson's disease, London, June 2006.
  • Parkinson's disease The most prominent symptoms of Parkinson's disease include: Tremor, Rigidity (i.e., stiffness; increased muscle tone), Akinesia/bradykinesia (i.e., the absence of movement and slowness, respectively, and Postural instability (i.e., failure of postural reflexes, often leading to impaired balance).
  • PD also causes cognitive and mood disturbances, which may be related.
  • Cognitive disturbances associated with Parkinson's disease may include slowed reaction time and executive dysfunction. These disturbances may be characterized by difficulties in differential allocation of attention, impulse control, set shifting, prioritizing, evaluating the salience of ambient data, interpreting social cues, and subjective time awareness. This complex is present to some degree in most Parkinson's patients. With time it may progress to dementia, hallucinations, delusions, and/or paranoia.
  • short term memory loss may occur, often impairing procedural memory more than declarative memory.
  • Parkinson's disease has also been observed to affect an afflicted person's sleep. Symptoms include excessive daytime somnolence, initial, intermediate, and terminal insomnia, and disturbances in REM sleep, disturbingly vivid dreams, and REM Sleep Disorder. The latter is characterized by the afflicted person's acting out his or her dream content, which can present years prior to diagnosing a person with Parkinson's disease.
  • Parkinson's disease has also been correlated with an impairment of perceptual abilities.
  • Symptoms of decreased perception include: impaired visual contrast sensitivity, impaired spatial reasoning, impaired color discrimination, impaired
  • hyposmia or anosmia can present years prior to diagnosing a person with Parkinson's disease.
  • Parkinson's disease reports pain, such as neuropathic pain, muscle pain, joint pain, and tendon pain. Such pain is often attributable to tension, dystonia, rigidity, joint stiffness, and injuries associated with attempts at
  • Some persons afflicted with Parkinson's disease experience oily skin, seborrheic dermatitis, urinary incontinence, nocturia, constipation, and/or gastric dysmotility.
  • Parkinson's disease Some persons afflicted with Parkinson's disease experience altered sexual function, characterized by profound impairment of sexual arousal, behavior, orgasm, and drive. Such sexual symptoms are usually noted in the mid and late stages of Parkinson's disease.
  • Parkinson's disease which means “having no specific known cause”.
  • Other far less common causes of Parkinson's disease including genetic mutations, toxins, head trauma, cerebral anoxia, and drug-induced Parkinson's disease.
  • Parkinson's disease is more likely to have relatives that also have Parkinson's disease. However, this does not mean that the disorder has been passed on genetically.
  • Another theory for the cause of Parkinson's disease is that it is caused by exposure to toxins.
  • Parkinson's disease Another theory for the cause of Parkinson's disease suggests that it is linked to head trauma.
  • the risk of developing Parkinson's increases eightfold for patients who have had head trauma requiring hospitalization and the risk increases 1 1 -fold for patients who had experienced severe head injury.
  • Neurochemical ⁇ the symptoms of Parkinson's disease result from the loss of pigmented dopamine-secreting (dopaminergic) cells in the pars compacta region of the substantia nigra of the brain. These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the direct pathway and excitation of the indirect pathway.
  • the direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder.
  • the lack of dopamine results in increased inhibition of the ventral anterior nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia.
  • the nigrostriatal pathway mediates movement and is the most conspicuously affected in early Parkinson's disease.
  • the other pathways include the mesocortical, the mesolimbic, and the tuberoinfundibular. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson's disease.
  • Diagnosing Parkinson's disease typically relies on analyzing a person's medical history and performing a neurological examination. Such an examination may be conducted by interviewing and observing the patient in person, using the Unified
  • Parkinson's Disease Rating Scale A physician may also use a radiotracer for SPECT scanning machines called DaTSCAN (General Electric), which is specialized for diagnosing Parkinson's disease. Early signs and symptoms of PD may sometimes be dismissed as the effects of normal aging. The physician may need to observe the person for some time until it is apparent that the symptoms are consistently present. Usually doctors look for shuffling of feet and lack of swing in the arms. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases. However, CT and MRI brain scans of people with PD often appear normal.
  • DaTSCAN General Electric
  • the UPDRS has multiple ratings that measure motor function, and also mental functioning, behavior, mood, and activities of daily living. Both the Hoehn and Yahr scale and the UPDRS are used to measure how individuals are faring and how much a given course of treatment is helping them. It should be noted that neither scale is specific to Parkinson's disease; patients with other illnesses can score in the Parkinson's range.
  • Treating Parkinson's disease requires broad-based management including patient and family education, support group services, general wellness maintenance, physiotherapy, exercise, and nutrition. National Institute for Health and Clinical Excellence, Clinical guideline 35: Parkinson's disease, London, June 2006. Presently, there is no cure for PD. However, medications can provide at least some relief from the symptoms. These medications generally target the dopamine pathways. Levodopa (also known as "L-dopa”) is the most widely used drug for treating Parkinson's disease. L-dopa is transformed into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known by its former name dopa- decarboxylase).
  • L-dopa is often administered with one or more other drugs. These drugs are designed to balance the metabolism of L-dopa and dopamine in order to provide the patient with an effective (but not adversely high) amount.
  • Dopamine agonists such as, for example, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and lisuride have been shown moderately effective in treating the symptoms of Parkinson's disease.
  • Dopamine agonists often have side effects including but not limited to somnolence, hallucinations and/or insomnia.
  • Dopamine agonists initially act by stimulating some of the dopamine receptors. However, these dopamine agonists often cause the dopamine receptors to become progressively less sensitive, thereby eventually increasing the symptoms of Parkinson's disease. Accordingly, chronic treatment with dopamine agonists may be undesirable but dopamine agonists can still be useful for patients experiencing on-off fluctuations and dyskinesias as a result of high doses of L-dopa.
  • Monoamine oxidase-B inhibitors inhibit the enzyme monoamine oxidase-B (MAO-B). Such inhibition slows down the breakdown of dopamine secreted by the dopaminergic neurons.
  • Selegiline and rasagiline reduce the symptoms by inhibiting monoamine oxidase-B (MAO-B), thereby inhibiting the breakdown of dopamine secreted by the dopaminergic neurons. Metabolites of selegiline include
  • Carbidopa and benserazide are dopa decarboxylase inhibitors. They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are generally given as combination preparations of carbidopa/levodopa (co-careldopa) (e.g. Sinemet, Parcopa) and benserazide/levodopa (co-beneldopa) (e.g. Madopar). There are also controlled release versions of Sinemet and Madopar that spread out the effect of the L-dopa.
  • Duodopa is a combination of levodopa and carbidopa, dispersed as a viscous gel.
  • L-dopa may also be administered with one or more drugs that inhibit the COMT enzyme.
  • Tolcapone inhibits the Catechol-O-methyl transferase (COMT) enzyme.
  • COMT is one of several enzymes that degrade catecholamines such as, e.g., dopamine.
  • COMT inhibitors are often used to complement L-dopa.
  • entacapone When administered in conjunction with dopaminergic agents such as L-dopa, entacapone prevents COMT from metabolizing L-dopa into 3-methoxy-4-hydroxy-L- phenylalanine (3-OMD) in the periphery, which does not easily cross the blood brain barrier (BBB).
  • BBB blood brain barrier
  • entacapone is somewhat similar to carbidopa or benserazide, in that it is an inhibitor of an enzyme that converts L-dopa into a
  • Carbidopa and benserazide inhibit aromatic L- amino acid decarboxylase, which converts L-dopa into dopamine, which cannot cross the BBB.
  • Entacapone is a member of the class of drugs known as nitrocatechols.
  • entacapone The most frequent undesirable effects caused by entacapone relate to the increased effects of L-dopa, such as involuntary movements (dyskinesias). These occur most frequently at the beginning of entacapone treatment. Others common side effects are gastrointestinal problems, including diarrhea, nausea, and abdominal pains. The substance may also cause urine to turn reddish-brown. This is a harmless side effect and is not a cause for concern. In studies with entacapone, some people have reported experiencing a dry mouth.
  • Entacapone is marketed under the trade name Comtan® in the United States. Entacapone is also sold as part of a 3-component formulation additionally comprising carbidopa and levodopa (marketed by Novartis under the trade name Stalevo®.
  • Catecholamine compounds e.g., entacapone, L-Dopa, and carbidopa are vicinal aromatic diol compounds.
  • Such compounds can be oxidized chemically or electrochemically to their analogous oquinone compounds. When this conversion to the oquinone form occurs, further degradative reactions become likely because the o- quinone compounds are relatively highly reactive. See Scheme 1. In particular, they are reactive towards nucleophiles, for example, undergoing a Michael addition reaction.
  • a catecholamine e.g., entacapone, L-Dopa, and carbidopa
  • entacapone entacapone
  • L-Dopa L-Dopa
  • carbidopa nucleophilic reagents
  • entacapone is oxidized into its analogous o-quinone form, which is then susceptible to attack by a nucleophile (Nu:) at any one of three positions, resulting in a Michael addition product.
  • nucleophile could be any group present in that formulation that is capable of reacting with the o-quinone form.
  • Catecholamines include, as part of their chemical structure, an amino group. This amino group can act as a nucleophile. Accordingly, where a catecholamine is oxidized into its analogous o-quinone form, that form may be susceptible to attack by an amine group of another catecholamine. As a result, under oxidizing conditions, catecholamines may degrade via intermolecular reactions (such as the amine of one catechol attacks the o-quinone form of an oxidized catecholamine).
  • the substituent group(s) on a particular catecholamine affect that compound's susceptibility to degradative oxidation reactions because those substituent groups affect the electronic properties of the molecule. Additionally, the substituent group(s) on a given catecholamine's amino group affect that amino group's ability to serve as a nucleophile. For example, the amino group in entacapone is substituted with two ethyl groups, thereby hindering entacapone's amino group and making it a less effective nucleophile in some circumstances than, for example, its unsubstituted analog.
  • the compounds in the mixture may either react with like compounds or cross-react with different catecholamines in the mixture.
  • catecholamines may serve as better nucleophiles and some may be more susceptible to oxidative degradation, including more than one catecholamine in a single formulation may increase the possibility that the components of that formulation will degrade.
  • Parkinson's drugs e.g., L-dopa
  • pharmaceutical formulation comprising all of the therapeutically active substances in one dosage form.
  • Providing all of the active substances in one dosage form increases patient compliance and decreases the possibility that a patient will mistakenly take one drug without concurrently taking another.
  • combinations of drugs for Parkinson's disease are intended to be used in concert to achieve synergistic effects, mistakenly omitting one drug could potentially lead to severe unwanted effects.
  • a Parkinson's disease patient with two or more catecholamine compounds in a single pharmaceutical formulation.
  • combining two or more catecholamines can increase the possibility that the drugs in that formulation degrade, either during formulating, or while the formulation is stored prior to administering it to the patient.
  • Parkinson's disease patient with a medication that is stable under ambient conditions and stable in the presence of other Parkinson's drugs.
  • compounds of formula (I) that is resistant to the degradative pathways that lead to the deterioration of other Parkinson's drugs. This compound liberates a catecholamine in vivo, while preventing the degradative pathways that may destroy such a catecholamine under ambient conditions (e.g., storage).
  • the compound of formula (I) may be combined in a single formulation with other Parkinson's drugs (e.g., L-dopa, carbidopa) without reacting with the other drugs present in the formulation.
  • Parkinson's drugs e.g., L-dopa, carbidopa
  • each of R 1 and R 2 is independently chosen from H or a catechol-oxidation- inhibiting pro-moiety, provided that R 1 and R 2 are not both H;
  • each of E 1 and E 2 is independently chosen from an electron withdrawing group; each of R 3 and R 4 is independently chosen from a C 1 -6 alkyl group;
  • compositions comprising compounds of formula (I) and at least one pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical compositions of the invention may include additional pharmaceutically active compounds in addition to the compound of formula (I).
  • the pharmaceutical compositions of this invention may include one, two, three, or more additional pharmaceutically active compounds in addition to the compound of formula (I).
  • pharmaceutical formulations comprising the compound of formula (I) or a composition comprising the compound of formula (I).
  • the pharmaceutical formulations may include additional pharmaceutically active compounds in addition to the compound of formula (I).
  • the pharmaceutical formulations of this invention may include one, two, three, or more additional pharmaceutically active compounds in addition to the compounds of formula (I).
  • the pharmaceutical formulations are present as solid formulations, such as, by way of example only, a tablet, pill, powder, or granule.
  • the pharmaceutical formulations of the invention are liquid formulations.
  • the liquid formulations In some exemplary embodiments the liquid
  • formulation is a buffered solution, which is buffered at a pH appropriate to avoid cleavage of either or both of the groups R 1 and/or R 2 .
  • Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (I).
  • Parkinson's disease comprising administering a pharmaceutical composition
  • Parkinson's disease comprising administering a pharmaceutical formulation comprising at least one compound of formula (I).
  • each of the groups R 1 and R 2 may independently be chosen from H or a "catechol-oxidation-inhibiting pro-moiety", provided that R 1 and R 2 are not both H. This means that one or both of R 1 and R 2 is a "catechol-oxidation- inhibiting pro-moiety.”
  • a “catechol-oxidation-inhibiting pro-moiety” is a group that, when attached to a phenolic position of a catechol compound, prevents the formation of a ketone from the corresponding phenol.
  • a “catechol-oxidation-inhibiting pro-moiety” is also a group that may be liberated from the compound of formula (I), providing the free phenol when exposed to physiological conditions.
  • a particular catechol compound is susceptible to oxidative degradation at one or more of the phenolic position(s)
  • using a compound that replaces the hydrogen of the phenol with a "catechol-oxidation-inhibiting pro-moiety” may prevent oxidative degradation, while allowing delivery of the active drug upon administering the compound to the patient.
  • each of the groups E 1 and E 2 is independently chosen from an electron withdrawing group.
  • independently chosen from as used herein, it is meant that the groups may be chosen to be the same or may be chosen to be different.
  • E 1 and E 2 may either be the same or different electron withdrawing groups.
  • An electron withdrawing group is a group that draws electrons away from other (e.g., adjacent) portions of the molecule.
  • Some examples of electron withdrawing groups include, by way of example only, a nitrile group (CN), a nitro group (NO 2 ), a carboxylic acid group (COOH), a halogen group (F, Cl, Br, I), a carbonyl group, etc.
  • each of the "catechol-oxidation-inhibiting pro-moiety" groups, R 1 and R 2 is independently chosen from alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,— C(O)OR 5 , -C(O)R 5 ,— (CR 6 R 7 )OC(O)R 8 ,
  • R 5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • R 6 , R 7 , R 8 , R 9 , and R 10 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6 and R 7 together with the carbon atom to which R 6 and R 7 are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
  • each substituent group is independently chosen from F, Cl, Br, I, CN,
  • each of the groups E 1 and E 2 is independently chosen from NO 2 , CN, SO 3 , and CF 3 in a compound of formula (I).
  • the group E 1 is NO 2 and the group E 2 is CN, providing a compound of the following formula (Ia):
  • each of the groups R 3 and R 4 in a compound of formula (I) is independently chosen from a C 1-6 saturated alkyl group.
  • each of the groups R 3 and R 4 in a compound of formula (I) is ethyl, providing a compound of formula (Ib):
  • a compound of formula (I) is disclosed, wherein each of the groups R 3 and R 4 is ethyl in the compound of formula (I), the group E 1 is NO 2 , and the group E 2 is CN in the compound of formula (I), providing a compound of the following formula (Ic):
  • R 1 and R 2 are as described for compounds of formula (I) herein.
  • a compound of formula (I) is disclosed, wherein each of R 1 and R 2 is independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,— C(O)OR 5 , -C(O)R 5 ,— (CR 6 R 7 )OC(O)R 8 ,
  • R 5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • R 6 , R 7 , R 8 , R 9 , and R 10 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6 and R 7 , together with the carbon atom to which R 6 and R 7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
  • each substituent group is independently chosen from F, Cl, Br, I, CN,
  • R 5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • R 6 and R 7 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6 and R 7 together with the carbon atom to which R 6 and R 7 are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
  • R 8 is chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • each substituent group is independently chosen from F, Cl, Br, I, CN,
  • a compound of formula (I) is disclosed, wherein E 1 is NO 2 , E 2 is CN, R 3 is ethyl, and R 4 is ethyl, providing a compound of the following formula (Id):
  • a compound of formula (I) is disclosed, wherein E 1 is NO 2 , E 2 is CN, R 3 is ethyl, R 4 is ethyl, and each of R 1 and R 2 is independently chosen from— C(O)OR 5 , -C(O)R 5 ,— (CR 6 R 7 )OC(O)R 8 ,
  • R 5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • R 6 , R 7 , R 8 , R 9 , and R 10 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6 and R 7 , together with the carbon atom to which R 6 and R 7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
  • each substituent group is independently chosen from F, Cl, Br, I, CN,
  • a compound of formula (I) is disclosed, wherein E 1 is NO 2 , E 2 is CN, R 3 is ethyl, R 4 is ethyl, and each of R 1 and R 2 is independently chosen from -C(O)OR 5 , -C(O)R 5 , and— (CR 6 R 7 )OC(O)R 8 ,
  • R 5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • R 6 , R 7 , and R 8 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6 and R 7 , together with the carbon atom to which R 6 and R 7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
  • each substituent group is independently chosen from F, Cl, Br, I,— CN, -NO 2 ,—OH, C 1 -6 alkyl, and C 1 -6 alkoxy.
  • a compound of formula (I) is disclosed, wherein E 1 is NO 2 , E 2 is CN, R 3 is ethyl, and R 4 is ethyl, providing a compound of the following formula (Ie):
  • each of the groups R 1 and R 2 is independently chosen from— C(O)OR 5 and -C(O)R 5 ,
  • R 5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.
  • a compound of formula (I) is disclosed, wherein E 1 is NO 2 , E 2 is CN, R 3 is ethyl, and R 4 is ethyl, providing a compound of the following formula (If):
  • each of the groups R 1 and R 2 is independently chosen from— C(O)OR 5 and -C(O)R 5 ,
  • R 5 is chosen from alkyl or substituted alkyl.
  • compositions comprising at least one compound of formula (I), disclosed herein.
  • a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier and/or excipient is disclosed.
  • composition comprising a compound of the formula (Ia) and at least one
  • composition comprising a compound of the formula (Ib) and at least one
  • composition comprising a compound of the formula (Ic) and at least one
  • composition comprising a compound of the formula (Id) and at least one
  • composition comprising a compound of the formula (Ie) and at least one
  • a pharmaceutical composition comprising a compound of the formula (If) and at least one
  • a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier and/or excipient, wherein each of the "catechol- oxidation-inhibiting pro-moiety" groups, R 1 and R 2 in the compounds of formula (I), is independently chosen from alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl, substituted cycloalkyl, substituted cycloalkyl,
  • cycloheteroalkyl substituted cycloheteroalkyl, -C(O)OR 5 , -C(O)R 5 ,—
  • R 5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • R 6 , R 7 , R 8 , R 9 and R 10 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6 and R 7 , together with the carbon atom to which R 6 and R 7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
  • each substituent group is independently chosen from F, Cl, Br, I,— CN, -NO 2 ,—OH, C 1 -6 alkyl, and C 1 -6 alkoxy.
  • composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier and/or excipient is disclosed, wherein each of R 1 and R 2 is independently chosen from -C(O)OR 5 , -C(O)R 5 , and— (CR 6 R 7 )OC(O)R 8 , wherein
  • R 5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • R 6 and R 7 are independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6 and
  • R 7 together with the carbon atom to which R 6 and R 7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
  • R 8 is chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • each substituent group is independently chosen from F, Cl, Br, I,— CN, -NO 2 ,—OH, C 1 -6 alkyl, and C 1 -6 alkoxy.
  • composition comprising at least one compound of formula (I) and at least one
  • each of E 1 and E 2 is independently chosen from NO 2 , CN, SO 3 , or CF 3 .
  • composition comprising at least one compound of formula (I) and at least one
  • E 1 is NO 2 and E 2 is CN.
  • composition comprising at least one compound of formula (I) and at least one
  • each of R 3 and R 4 is independently chosen from a C 1-6 saturated alkyl group.
  • a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier and/or excipient is disclosed, wherein each of R 3 and R 4 is ethyl.
  • compositions comprising at least one compound of formula (I) and at least one additional pharmaceutically active compound, such as, for example, at least one first additional pharmaceutically active compound and at least one second additional pharmaceutically active compound.
  • a pharmaceutical composition comprising at least one compound of formula (I) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
  • Prodrugs of carbidopa may be obtained, for example, as described in U.S. Patent No. 7,101 ,912, which is incorporated by reference in its entirety.
  • Prodrugs of levodopa may be obtained, for example, as described in U.S. Patent No. 7,323,585, which is incorporated by reference in its entirety.
  • one embodiment of the invention contemplates a
  • composition comprising at least one compound of formula (I) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • a pharmaceutical composition comprising at least one compound of formula (I), levodopa, and carbidopa is disclosed.
  • a pharmaceutical composition comprising at least one compound of formula (Ia) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
  • one embodiment of the invention contemplates a
  • composition comprising at least one compound of formula (Ia) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • a pharmaceutical composition comprising at least one compound of formula (Ia), levodopa, and carbidopa is disclosed.
  • a pharmaceutical composition comprising at least one compound of formula (Ib) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
  • one embodiment of the invention contemplates a
  • composition comprising at least one compound of formula (Ib) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • a pharmaceutical composition comprising at least one compound of formula (Ib), levodopa, and carbidopa is disclosed.
  • a pharmaceutical composition comprising at least one compound of formula (Ic) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
  • one embodiment of this invention contemplates a
  • composition comprising at least one compound of formula (Ic) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • a pharmaceutical composition comprising at least one compound of formula (Ic), levodopa, and carbidopa is disclosed.
  • a pharmaceutical composition comprising at least one compound of formula (Id) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • one embodiment of this invention contemplates a
  • composition comprising at least one compound of formula (Id) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • a pharmaceutical composition comprising at least one compound of formula (Id), levodopa, and carbidopa is disclosed.
  • a pharmaceutical composition comprising at least one compound of formula (Ie) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
  • one embodiment of this invention contemplates a
  • composition comprising at least one compound of formula (Ie) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • a pharmaceutical composition comprising at least one compound of formula (Ie), levodopa, and carbidopa is disclosed.
  • a pharmaceutical composition comprising at least one compound of formula (If) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
  • one embodiment of this invention contemplates a
  • composition comprising at least one compound of formula (If) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • a pharmaceutical composition comprising at least one compound of formula (If), levodopa, and carbidopa is disclosed.
  • Also disclosed herein are methods for treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (I) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (Ia) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (Ib) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (Ic) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (Id) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (Ie) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (If) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • Also disclosed herein are methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (I) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (Ia) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (Ib) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (Ic) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (Id) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (Ie) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (If) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • Parkinson's disease comprising administering at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional pharmaceutically active compound, to a patient in need thereof.
  • Also disclosed herein are methods of treating Parkinson's disease comprising administering a pharmaceutical composition comprising at least one compound of formula (I) or a salt thereof and at least one additional pharmaceutically active compound, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (I) and at least one additional pharmaceutically active compounds independently chosen from COMT inhibitors, dopamine agonists, and MAO-B inhibitors.
  • a pharmaceutical composition comprising at least one compound of formula (I) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (I) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (I) and at least two additional pharmaceutically active compounds independently chosen from COMT inhibitors, dopamine agonists, and MAO-B inhibitors.
  • a pharmaceutical composition comprising at least one compound of formula (I) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I), levodopa, and carbidopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ia) and at least one additional pharmaceutically active chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • additional pharmaceutically active chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ia) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ia) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient
  • a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ia), levodopa, and carbidopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ib) and at least one additional pharmaceutically active chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • additional pharmaceutically active chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ib) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ib), levodopa, and carbidopa, to a patient in need thereof.
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ic) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ic) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ic) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ic) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ic), levodopa, and carbidopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ic), levodopa, and carbidopa
  • a pharmaceutical composition comprising at least one compound of formula (Id) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Id) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Id) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient
  • methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Id), levodopa, and carbidopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Id), levodopa, and carbidopa
  • a pharmaceutical composition comprising at least one compound of formula (Ie) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ie) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need
  • a pharmaceutical composition comprising at least one compound of formula (Ie) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (Ie) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient
  • a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ie), levodopa, and carbidopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (If) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (If) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (If) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
  • a pharmaceutical composition comprising at least one compound of formula (If), levodopa, and carbidopa, to a patient in need thereof.
  • pharmaceutical formulations comprising at least one compound of formula (I).
  • Appropriate formulations comprising at least one compound of formula (I) are within the ability of those skilled in the art to determine, and may include, for example, pharmaceutically acceptable carriers and/or excipients known to those of skill in the art.
  • the formulation comprising at least one
  • administration may include, for example, capsules, tablets, pills, powders, and granules.
  • the at least one compound of formula (I) may be contained in a solid dosage form formulation that provides quick release, sustained release, or delayed release after administration to the patient.
  • the at least one compound of formula (I) may be mixed with at least one inert, pharmaceutically acceptable carrier and/or excipient, including, for example: fillers or extenders; binders; humectants;
  • the solid dosage forms may also comprise buffering and/or opacifying agents, as well as any other excipient known to those of skill in the art.
  • the formulation comprising at least one compound of formula (I) is a liquid formulation, such as a liquid oral formulation or a liquid formulation for injection.
  • the formulation comprising at least one compound of formula (I) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R 1 and R 2 from cleaving.
  • Guidance for what pH "is appropriate" could be attained, for example in references describing the stability of different groups under different conditions, such as, for example, Greene's Protective Groups in Organic Synthesis. Fourth Edition by Peter G. M. Wuts and Theodora W. Greene, John Wiley & Sons, Inc., Hoboken, NJ, 2006.
  • a pharmaceutical formulation comprising at least one compound of formula (Ia) is disclosed.
  • the formulation comprising at least one compound of formula (Ia) is a solid formulation.
  • the formulation comprising at least one compound of formula (Ia) is a liquid formulation.
  • the formulation comprising at least one compound of formula (Ia) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R 1 and R 2 from cleaving.
  • a pharmaceutical formulation comprising at least one compound of formula (Ib) is disclosed.
  • the formulation comprising at least one compound of formula (Ib) is a solid formulation.
  • the formulation comprising at least one compound of formula (Ib) is a liquid formulation.
  • the formulation comprising at least one compound of formula (Ib) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R 1 and R 2 from cleaving.
  • a pharmaceutical formulation comprising at least one compound of formula (Ic) is disclosed.
  • the formulation comprising at least one compound of formula (Ic) is a solid formulation.
  • the formulation comprising at least one compound of formula (Ic) is a liquid formulation.
  • the formulation comprising at least one compound of formula (Ic) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R 1 and R 2 from cleaving.
  • a pharmaceutical formulation comprising at least one compound of formula (Id) is disclosed.
  • the formulation comprising at least one compound of formula (Id) is a solid formulation.
  • the formulation comprising at least one compound of formula (Id) is a liquid formulation.
  • the formulation comprising at least one compound of formula (Id) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R 1 and R 2 from cleaving.
  • a pharmaceutical formulation comprising at least one compound of formula (Ie) is disclosed.
  • the formulation comprising at least one compound of formula (Ie) is a solid formulation.
  • the formulation comprising at least one compound of formula (Ie) is a liquid formulation.
  • the formulation comprising at least one compound of formula (Ie) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R 1 and R 2 from cleaving.
  • a pharmaceutical formulation comprising at least one compound of formula (If) is disclosed.
  • the formulation comprising at least one compound of formula (If) is a solid formulation.
  • the formulation comprising at least one compound of formula (If) is a liquid formulation.
  • the formulation comprising at least one compound of formula (If) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R 1 and R 2 from cleaving.
  • compositions comprising at least one compound of formula (I) and at least one additional compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
  • a pharmaceutical formulation comprising at least one compound of formula (I), levodopa, and carbidopa is disclosed.
  • the pharmaceutical formulation comprising at least one compound of formula (I) and at least one additional compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is a solid formulation.
  • the formulation comprising at least one compound of formula (I) and at least one additional compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is a liquid formulation.
  • the liquid formulation comprising at least one compound of formula (I) and at least one additional compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is a buffered solution, maintaining a pH that is appropriate to prevent the groups R 1 and R 2 from cleaving.
  • the phrase "compound of formula (I)" (which is meant to include compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If), is meant to include pharmaceutically acceptable salts thereof, whether or not so stated.
  • the at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is also meant to include pharmaceutically acceptable salts thereof, whether or not so stated.
  • treating Parkinson's disease is meant to include treating the condition itself or treating and/or alleviating the symptoms associated therewith, in any degree.
  • the phrase "therapeutically effective amount” is meant to include an amount of a therapeutic agent (or combination of agents) sufficient to treat and/or alleviate a condition treatable by administration of a compound, composition, or formulation of the invention, in any degree, and may include a therapeutically effective amount of at least one compound of formula (I) alone, in combination with additional compounds of formula (I), or in combination with other pharmaceutically active compounds. That amount can be, for example, an amount sufficient to exhibit a detectable therapeutic or ameliorative effect, and can be determined by routine experimentation by those of skill in the art. The effect may include, for example, treatment and/or alleviation of Parkinson's disease or the symptoms associated therewith. The actual amount required, e.g.
  • any drugs used in combination or coincidental with the specific compound employed will depend upon a variety of factors including, for example, the severity of the condition, the specific pharmaceutical composition employed, the age, body weight, general health, gender, and diet of the patient, the mode of administration, the time of administration, the route of administration, the duration of the treatment, any drugs used in combination or coincidental with the specific compound employed, and other such factors well known in the medical arts. These factors are discussed in Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman, J.Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001.
  • the at least one compound of formula (I) may be administered at dosage levels ranging from about 0.5 mg/kg to about 500 mg/kg, such as from about 1 mg/kg to about 200 mg/kg, or from about 5 mg/kg to about 50 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than about 0.5 mg/kg or greater than about 500 mg/kg (for example, ranging from about 500 mg/kg to about 1000 mg/kg) can also be administered to a subject in certain embodiments of the invention.
  • the at least one compound of formula (I) may be administered at dosage levels ranging from about 0.01 mmol per day to about 100 mmol per day, such as from about 0.1 mmol per day to about 50 mmol per day, or 0.25 mmol per day to about 20 mmol per day. It will also be appreciated that dosages smaller than about 0.1 mmol per day or greater than about 100 mmol per day (for example, ranging from about 100 mmol per day to about 1000 mmol per day) can also be administered to a subject in certain embodiments of the invention. As discussed above, the amount required for a particular patient will depend upon a variety of factors well known to those of skill in the art.
  • the amount of the at least one additional pharmaceutically active compound may easily be determined by those of skill in the art, for example the at least one additional pharmaceutically active compound may be administered at dosage levels currently known to have a therapeutic effect. As a further example, the at least one additional pharmaceutically active compound may be administered at dosage levels ranging from about 0.5 mg/kg to about 500 mg/kg, such as from about 1 mg/kg to about 200 mg/kg, or from about 5 mg/kg to about 50 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dosages smaller than about 0.5 mg/kg or greater than about 500 mg/kg can also be administered to a subject in certain embodiments of the invention.
  • the amount required for a particular patient will depend upon a variety of factors well known to those of skill in the art.
  • a patient in need thereof is meant to include a person who has Parkinson's disease, who is experiencing parkinsonism or Parkinson- like symptoms, or who otherwise has been identified as one who may potentially benefit from the treatment indicated.
  • grammatical variants are intended to be non-limiting, such that recitation of an item or items is not to the exclusion of other like items that can be substituted or added to the recited item(s).
  • the compounds of the invention can be synthesized by following the synthetic methods disclosed herein, along with the generally available knowledge and techniques available to a synthetic chemist, such as at least those provided in undergraduate organic chemistry textbooks and organic chemistry laboratory textbooks.
  • a compound of formula (I) can be synthesized by performing an aldol condensation reaction between an aromatic aldehyde (e.g., S1 ) with the alpha carbon of an amide.
  • an aromatic aldehyde e.g., S1
  • compounds of formula (I) may be synthesized by first generating entacapone and thereafter treating entacapone with reagents appropriate for generating the—OR 1 and—OR 2 groups present in the compounds of formula (I). The following reaction may be used to generate entacapone:
  • Entacapone is also commercially available. With entacapone as a starting material, each of the phenol groups may be modified to generate a group of—OR 1 and—OR 2 by treating entacapone with a reagent capable of adding either or both of the groups R 1 and/or R 2 . R 1 and R 2 may either be added in concert or in sequential reactions.
  • General guidance for converting a phenol group (i.e., Ph-OH) into a— OR 1 and/or— OR 2 group can be found, for example, in Greene's Protective Groups in Organic Synthesis, Fourth Edition by Peter G. M. Wuts and Theodora W.
  • the compounds of formula (I) can be synthesized by first synthesizing a compound of formula (S1 ) and then using said compound of formula (S1 ) as a reagent in an aldol reaction with a compound of formula (S2). This generally applicable synthesis is depicted below. Additionally, for each step, exemplary reaction conditions are provided. Also, 1 H-NMR and 13 C-NMR data are provided for some exemplary compounds which may be synthesized by following the scheme below.
  • the compound of formula (S2) may be the compound (S2-A).
  • the compound of formula (S1 ) may be synthesized from 5- nitrovanillin.
  • 5-nitrovanillin is commercially available, for example from Sigma Aldrich, Inc.
  • 5-nitrovanillin can be readily used to synthesize an exemplary compound of the formula (S1 ).
  • 5- nitrovanillin can be treated with a reagent that is appropriate for introducing the group R 2 .
  • the resulting compound can then be treated with a reagent suitable for cleaving the 3-methoxy group, while leaving the R 2 group in place, as indicated by the arrow labeled "3" in Scheme 2, above.
  • the resulting compound can thereafter be treated with a reagent capable of introducing the R 1 group in order to generate a compound of formula (S1 ), wherein the group E 1 is a nitro group.
  • 5-nitrovanillin can be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R 2 group:
  • R 5 is as described herein for the compound of formula (I).
  • Other groups can be readily introduced to the alcohol (i.e., phenol) position of 5-nitrovanillin by following the guidance in the prior art, such as Greene's Protecting Groups in Organic Synthesis.
  • 5-nitrovanillin can be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R 2 group:
  • R 5 is as described herein for the compound of formula (I).
  • 5-nitrovanillin can be treated with a reagent that is
  • 5-nitrovanillin can be treated with a haloacid or equivalent thereof (such as, for example, HBr) in order to cleave the methyl of the 3-methoxy group to afford the di-hydroxy compound, as exemplified by the reaction labeled "1 " in Scheme 2.
  • a haloacid or equivalent thereof such as, for example, HBr
  • Other methods for cleaving a methyl group to generate a phenol are described in Greene's Protecting Groups in Organic Synthesis.
  • the di-hydroxy compound may be treated with a reagent such as, for example, an acid chloride or an equivalent thereof in order to introduce at least one of the groups R 1 and/or R 2 , as depicted by the reaction arrow labeled "6" in Scheme 2.
  • a reagent such as, for example, an acid chloride or an equivalent thereof in order to introduce at least one of the groups R 1 and/or R 2 , as depicted by the reaction arrow labeled "6" in Scheme 2.
  • a reagent such as, for example, an acid chloride or an equivalent thereof in order to introduce at least one of the groups R 1 and/or R 2 , as depicted by the reaction arrow labeled "6" in Scheme 2.
  • Such an acid chloride may include, for example, wherein R 5 is as described herein for the compound of formula (I).
  • Other suitable groups for R 1 and/or R 2 may be introduced by following the guidance in the prior art for adding groups to phenols, such as Greene's Protecting Groups in
  • the groups R 1 and R 2 may be the same and a compound of formula (S1 ) may be synthesized from 5-nitrovanillin by following the path marked by arrows "1 " and “6" of Scheme 2.
  • the groups R 1 and R 2 may be different and the compound of formula (S1 ) may be synthesized from 5-nitrovanillin by following the path marked by arrows "2," “3,” and “4" in Scheme 2.
  • the groups R 1 and R 2 may be the same and the compound of formula (S1 ) may be synthesized from 5-nitrovanillin by following the path marked by arrows "2,” “3,” and “4" in Scheme 2.
  • 5-nitrovanillin can be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R 2 group:
  • R 5 is as described herein for the compound of formula (I).
  • Other groups can be readily introduced to the alcohol (i.e., phenol) position of 5-nitrovanillin by following the guidance in the prior art, such as Greene's Protecting Groups in Organic Synthesis.
  • 5-nitrovanillin can be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R 2 group:
  • the product of the reaction labeled "2" in Scheme 2 may be subsequently treated with a reagent appropriate for cleaving the methyl group of the 3-methoxy group.
  • a reagent appropriate for cleaving the methyl group of the 3-methoxy group for example, the product of the reaction labeled "2" in Scheme 2 may be treated with a haloacid or equivalent thereof (such as, for example, HBr) in order to cleave the methyl of the 3-methoxy group to afford the di-hydroxy compound, as exemplified by the reaction labeled "3" in Scheme 2.
  • the product of the reaction labeled "3" in Scheme 2 may be treated with a reagent appropriate for introducing an R 1 group.
  • the product of the reaction labeled "3" in Scheme 2 may be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R 1 group:
  • R 5 is as described herein for the compound of formula (I).
  • Other groups can be readily introduced to the alcohol (i.e., phenol) position of the product of the reaction labeled "3" in Scheme 2 by following the guidance in the prior art, such as Greene's Protecting Groups in Organic Synthesis.
  • the product of the reaction labeled "3" in Scheme 2 may be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R 2 group:
  • R 5 is as described herein for the compound of formula (I).
  • the groups R 1 and R 2 are different and the compound of formula (S1 ) may be subsequently treated with a reagent that selectively cleaves one of these groups (R 1 or R 2 ) and does not cleave the other, as indicated by the arrow labeled "5" in Scheme 2.
  • a reagent that selectively cleaves one of these groups (R 1 or R 2 ) and does not cleave the other, as indicated by the arrow labeled "5" in Scheme 2.
  • Such selective cleavage may be accomplished by following the guidance provided in Protecting Groups in Organic Synthesis, previously cited above.

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Abstract

The invention relates to catecholamine compounds, compositions, and formulations comprising those compounds, and methods of treating Parkinson's disease with those compounds, compositions, and/or formulations.

Description

CATECHOLAMINE COMPOUNDS, COMPOSITIONS, AND FORMULATIONS,
AND METHODS OF USING THE SAME
Cross- Reference to Related Applications
This application claims priority under 35 U. S. C. § 119 to U.S. Provisional
Application 61/225,81 1 , filed July 15, 2009, which is incorporated herein by
reference.
Technical Field
The invention relates to catecholamine compounds, compositions, and
formulations comprising them, and methods of treating Parkinson's disease with those compounds, compositions, and formulations.
Background
Parkinson's disease (also known as Parkinson disease or "PD") is a degenerative disease of the brain (central nervous system) that often impairs motor skills, speech, and other functions. See Jankovic J., 2008, "Parkinson's disease: clinical features and diagnosis", J. Neurol. Neurosurg. Psychiatr., 2008, 79(4): 368-76.
Parkinson's disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement
(bradykinesia), and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms result from decreased stimulation of the motor cortex by the basal ganglia. This decreased stimulation is often caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain.
Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive. PD is the most common cause of chronic progressive parkinsonism, a term which refers to the syndrome of tremor, rigidity, bradykinesia, and postural instability. PD is also called "primary parkinsonism" or "idiopathic PD" (classically meaning having no known cause, although many genetic mutations associated with PD have now been discovered). While many forms of parkinsonism are idiopathic, secondary cases may result from toxicity (most notably of drugs), head trauma, or other medical disorders.
PD is not considered to be a fatal disease by itself, but it progresses over time and leads to other complications. The average life expectancy of a PD patient is generally lower than for people who do not have the disease. "Parkinson's Disease", Mayo Clinic: College of Medicine:
http://cancercenter.mayo.edu/mayo/research/parkinsons/, retrieved on 2006-1 1 -04. In the late stages of the disease, PD may cause complications such as choking, pneumonia, and falls that can lead to death. The progression of symptoms in PD may take 20 years or more to be fatal. In some people, however, the disease progresses more quickly. There is no way to predict with certainty what course the disease will take for an individual person. With appropriate treatment, most people with PD can live productive lives for many years after diagnosis.
"Parkinson's disease" is synonymous with "primary parkinsonism", i.e., isolated parkinsonism due to a neurodegenerative process without any secondary systemic cause. In some cases, it would be inaccurate to say that the cause is "unknown" because a small proportion is caused by genetic mutations. It is possible for a patient to be initially diagnosed with Parkinson's disease but then to develop additional features, requiring revising the diagnosis. See National Institute for Health and Clinical Excellence, Clinical guideline 35: Parkinson's disease, London, June 2006.
The most prominent symptoms of Parkinson's disease include: Tremor, Rigidity (i.e., stiffness; increased muscle tone), Akinesia/bradykinesia (i.e., the absence of movement and slowness, respectively, and Postural instability (i.e., failure of postural reflexes, often leading to impaired balance).
PD also causes cognitive and mood disturbances, which may be related.
Estimated prevalence rates of depression vary widely according to the population sampled and methodology used. Reviews of depression estimate its occurrence in anywhere from 20-80% of cases. Lieberman A., 2006, "Depression in Parkinson's disease— a review," Acta Neurol Scand 1 13(1 ): 1-8. Estimates from community samples tend to find lower rates than from specialist centers. Most studies use self- report questionnaires such as the Beck Depression Inventory, which may over inflate scores due to physical symptoms. Studies using diagnostic interviews by trained psychiatrists also report lower rates of depression. More generally, there is an increased risk for any individual with depression to go on to develop Parkinson's disease at a later date, lshihara L, Brayne C, 2006, "A systematic review of depression and mental illness preceding Parkinson's disease," Acta Neurol Scand., 1 13(4): 21 1-20. Seventy percent of individuals with Parkinson's disease diagnosed with pre-existing depression go on to develop anxiety. Ninety percent of Parkinson's disease patients with pre-existing anxiety subsequently develop depression, apathy, or abulia.
Cognitive disturbances associated with Parkinson's disease may include slowed reaction time and executive dysfunction. These disturbances may be characterized by difficulties in differential allocation of attention, impulse control, set shifting, prioritizing, evaluating the salience of ambient data, interpreting social cues, and subjective time awareness. This complex is present to some degree in most Parkinson's patients. With time it may progress to dementia, hallucinations, delusions, and/or paranoia.
Additionally, short term memory loss may occur, often impairing procedural memory more than declarative memory.
Parkinson's disease has also been observed to affect an afflicted person's sleep. Symptoms include excessive daytime somnolence, initial, intermediate, and terminal insomnia, and disturbances in REM sleep, disturbingly vivid dreams, and REM Sleep Disorder. The latter is characterized by the afflicted person's acting out his or her dream content, which can present years prior to diagnosing a person with Parkinson's disease.
Parkinson's disease has also been correlated with an impairment of perceptual abilities. Symptoms of decreased perception include: impaired visual contrast sensitivity, impaired spatial reasoning, impaired color discrimination, impaired
convergence insufficiency (characterized by double vision), and/or impaired oculomotor control. Additionally, some patients report dizziness and fainting, which is often attributed to orthostatic hypotension, which is a failure of the autonomic nervous system to adjust blood pressure in response to changes in body position. Some patients experience impaired proprioception, which is an impairment in a person's awareness of bodily position in three-dimensional space. Some patients may experience reduced or loss of sense of smell (hyposmia or anosmia). As in the case of the above-mentioned REM Sleep Disorder, hyposmia or anosmia can present years prior to diagnosing a person with Parkinson's disease.
Some person's with Parkinson's disease report pain, such as neuropathic pain, muscle pain, joint pain, and tendon pain. Such pain is often attributable to tension, dystonia, rigidity, joint stiffness, and injuries associated with attempts at
accommodation.
Some persons afflicted with Parkinson's disease experience oily skin, seborrheic dermatitis, urinary incontinence, nocturia, constipation, and/or gastric dysmotility.
Some persons afflicted with Parkinson's disease experience altered sexual function, characterized by profound impairment of sexual arousal, behavior, orgasm, and drive. Such sexual symptoms are usually noted in the mid and late stages of Parkinson's disease.
Many persons afflicted with Parkinson's disease experience weight loss, which becomes significant over a period of about ten years.
Most people with Parkinson's disease are described as having idiopathic
Parkinson's disease, which means "having no specific known cause". Other far less common causes of Parkinson's disease including genetic mutations, toxins, head trauma, cerebral anoxia, and drug-induced Parkinson's disease.
In recent years, a number of specific genetic mutations causing Parkinson's disease have been discovered, including in certain populations (Contursi, Italy). These account for only a minority of Parkinson's disease cases. Someone who has
Parkinson's disease is more likely to have relatives that also have Parkinson's disease. However, this does not mean that the disorder has been passed on genetically. Another theory for the cause of Parkinson's disease is that it is caused by exposure to toxins. One theory holds that the disease may result in many or even most cases from the combination of a genetically determined vulnerability to environmental toxins along with exposure to those toxins. Di Monte DA, Lavasani M, Manning-Bog AB., 2002, "Environmental factors in Parkinson's disease," Neurotoxicology. 23 (4-5): 487-502. Excessive accumulations of iron, which are toxic to nerve cells, are also typically observed in conjunction with the protein inclusions. Iron and other transition metals such as copper bind to neuromelanin in the affected neurons of the substantia nigra. Neuromelanin may be acting as a protective agent. The most likely mechanism is generation of reactive oxygen species. Jenner P., 1998, "Oxidative mechanisms in nigral cell death in Parkinson's disease", Mov. Disord. 13 Suppl 1 : 24-34. Iron also induces aggregation of synuclein by oxidative mechanism. Kaur D, Andersen J., 2002, "Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility?" Aging Cell 1 (1 ): 17-21.
Another theory for the cause of Parkinson's disease suggests that it is linked to head trauma. A recent methodologically strong retrospective study found that those who have experienced a head injury are four times more likely to develop Parkinson's disease than those who have never suffered a head injury. Bower JH, Maraganore DM, Peterson BJ, McDonnell SK, Ahlskog JE, Rocca WA., 2003, "Head trauma preceding PD: a case-control study" (abstract page), Neurology 60(10): 1610-5. The risk of developing Parkinson's increases eightfold for patients who have had head trauma requiring hospitalization and the risk increases 1 1 -fold for patients who had experienced severe head injury. Neurochemical^, the symptoms of Parkinson's disease result from the loss of pigmented dopamine-secreting (dopaminergic) cells in the pars compacta region of the substantia nigra of the brain. These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the direct pathway and excitation of the indirect pathway.
The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder. The lack of dopamine results in increased inhibition of the ventral anterior nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia.
There are four major dopamine pathways in the brain. The nigrostriatal pathway, referred to above, mediates movement and is the most conspicuously affected in early Parkinson's disease. The other pathways include the mesocortical, the mesolimbic, and the tuberoinfundibular. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson's disease.
Diagnosing Parkinson's disease typically relies on analyzing a person's medical history and performing a neurological examination. Such an examination may be conducted by interviewing and observing the patient in person, using the Unified
Parkinson's Disease Rating Scale. A physician may also use a radiotracer for SPECT scanning machines called DaTSCAN (General Electric), which is specialized for diagnosing Parkinson's disease. Early signs and symptoms of PD may sometimes be dismissed as the effects of normal aging. The physician may need to observe the person for some time until it is apparent that the symptoms are consistently present. Usually doctors look for shuffling of feet and lack of swing in the arms. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases. However, CT and MRI brain scans of people with PD often appear normal.
Clinical practice guidelines introduced in the UK in 2006 state that the diagnosis and follow-up of Parkinson's disease should be done by a specialist in the disease, usually a neurologist or geriatrician with an interest in movement disorders. National Institute for Health and Clinical Excellence, Clinical guideline 35: Parkinson's disease, London, June 2006.
One commonly used system for describing how the symptoms of PD progress is called the Hoehn and Yahr scale. Another commonly used scale is the Unified
Parkinson's Disease Rating Scale (UPDRS). The UPDRS has multiple ratings that measure motor function, and also mental functioning, behavior, mood, and activities of daily living. Both the Hoehn and Yahr scale and the UPDRS are used to measure how individuals are faring and how much a given course of treatment is helping them. It should be noted that neither scale is specific to Parkinson's disease; patients with other illnesses can score in the Parkinson's range.
Treating Parkinson's disease requires broad-based management including patient and family education, support group services, general wellness maintenance, physiotherapy, exercise, and nutrition. National Institute for Health and Clinical Excellence, Clinical guideline 35: Parkinson's disease, London, June 2006. Presently, there is no cure for PD. However, medications can provide at least some relief from the symptoms. These medications generally target the dopamine pathways. Levodopa (also known as "L-dopa") is the most widely used drug for treating Parkinson's disease. L-dopa is transformed into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known by its former name dopa- decarboxylase). However, only 1 - 5% of L-dopa enters the dopaminergic neurons. The remaining L-dopa is often metabolised to dopamine elsewhere in the patient's body, causing a wide variety of side effects. Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa. Accordingly, administering L-dopa eventually becomes counterproductive. In order to mediate some of the adverse side- effects of L-dopa administration, L-dopa is often administered with one or more other drugs. These drugs are designed to balance the metabolism of L-dopa and dopamine in order to provide the patient with an effective (but not adversely high) amount.
Dopamine agonists such as, for example, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and lisuride have been shown moderately effective in treating the symptoms of Parkinson's disease. Dopamine agonists often have side effects including but not limited to somnolence, hallucinations and/or insomnia. Dopamine agonists initially act by stimulating some of the dopamine receptors. However, these dopamine agonists often cause the dopamine receptors to become progressively less sensitive, thereby eventually increasing the symptoms of Parkinson's disease. Accordingly, chronic treatment with dopamine agonists may be undesirable but dopamine agonists can still be useful for patients experiencing on-off fluctuations and dyskinesias as a result of high doses of L-dopa.
Monoamine oxidase-B inhibitors inhibit the enzyme monoamine oxidase-B (MAO-B). Such inhibition slows down the breakdown of dopamine secreted by the dopaminergic neurons. Selegiline and rasagiline reduce the symptoms by inhibiting monoamine oxidase-B (MAO-B), thereby inhibiting the breakdown of dopamine secreted by the dopaminergic neurons. Metabolites of selegiline include
levoamphetamine and levomethamphetamine. Accumulation of these metabolites might result in side effects such as insomnia. One potential side effect of selegiline in conjunction with L-dopa can be stomatitis. One report raised concern about increased mortality when MAO-B inhibitors were combined with L-dopa. R. Cilia et al., 2006, "Long-term Efficacy of Entacapone in Patients with Parkinson's Disease and Motor Fluctuations - A Six- Year Clinical Follow-Up Study". However subsequent studies have not confirmed this finding. Thorogood M, Armstrong B, Nichols T, Hollowell J., 1998, "Mortality in people taking selegiline: observational study", BMJ 317 (7153): 252-4. In contrast to non-selective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.
Carbidopa and benserazide are dopa decarboxylase inhibitors. They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are generally given as combination preparations of carbidopa/levodopa (co-careldopa) (e.g. Sinemet, Parcopa) and benserazide/levodopa (co-beneldopa) (e.g. Madopar). There are also controlled release versions of Sinemet and Madopar that spread out the effect of the L-dopa. Duodopa is a combination of levodopa and carbidopa, dispersed as a viscous gel. Using a patient-operated portable pump, the drug is continuously delivered via a tube directly into the upper small intestine, where it is rapidly absorbed. In addition to administering L-dopa along with a decarboxylase inhibitor, L-dopa may also be administered with one or more drugs that inhibit the COMT enzyme. Tolcapone inhibits the Catechol-O-methyl transferase (COMT) enzyme. COMT is one of several enzymes that degrade catecholamines such as, e.g., dopamine. By inhibiting COMT, a drug slows the degradation of catecholamines by COMT, thereby prolonging the effects of L-dopa. Accordingly, COMT inhibitors are often used to complement L-dopa. Unfortunately, due to its possible side effects such as liver failure, Tolcapone is limited in its availability. A similar drug— another COMT inhibitor— entacapone has not been shown to cause significant alterations of liver function and maintains adequate inhibition of COMT over time. R. Cilia et al., 2006, "Long-term Efficacy of Entacapone in Patients with Parkinson's Disease and Motor Fluctuations - A Six-Year Clinical Follow-Up Study".
When administered in conjunction with dopaminergic agents such as L-dopa, entacapone prevents COMT from metabolizing L-dopa into 3-methoxy-4-hydroxy-L- phenylalanine (3-OMD) in the periphery, which does not easily cross the blood brain barrier (BBB). Pharmacologically, entacapone is somewhat similar to carbidopa or benserazide, in that it is an inhibitor of an enzyme that converts L-dopa into a
compound that cannot cross the BBB. Carbidopa and benserazide inhibit aromatic L- amino acid decarboxylase, which converts L-dopa into dopamine, which cannot cross the BBB.
Entacapone is a member of the class of drugs known as nitrocatechols.
The most frequent undesirable effects caused by entacapone relate to the increased effects of L-dopa, such as involuntary movements (dyskinesias). These occur most frequently at the beginning of entacapone treatment. Others common side effects are gastrointestinal problems, including diarrhea, nausea, and abdominal pains. The substance may also cause urine to turn reddish-brown. This is a harmless side effect and is not a cause for concern. In studies with entacapone, some people have reported experiencing a dry mouth.
Entacapone is marketed under the trade name Comtan® in the United States. Entacapone is also sold as part of a 3-component formulation additionally comprising carbidopa and levodopa (marketed by Novartis under the trade name Stalevo®.
Providing entacapone to a patient concurrently with L-dopa and/or carbidopa is a promising combination drug therapy for treating the symptoms of Parkinson's disease. Unfortunately, studies have shown that one or more of the components in 3-component formulations, such as Stalevo®, may degrade under ambient conditions. Because many of the drugs used to treat Parkinson's disease have dose-dependent side-effects and also affect the properties of other drugs used to treat Parkinson's diseases, it is important to carefully control the quantity of each drug administered. Degradation of a given drug prior to administering it may affect the quantity that is administered to the patient. Accordingly, wherever possible, degradation of the drug to be administered should be avoided.
Although it has not been identified within the context of 2- or 3-component Parkinson's formulations until now, studies published in the scientific literature have indicated that certain catechol compounds, such as carbidopa and levodopa are susceptible to degradative oxidative pathways. See Madriakian, T. et al., Chem. Pharm Bull., 2007, 55(6), 865-70.
Catecholamine compounds, e.g., entacapone, L-Dopa, and carbidopa are vicinal aromatic diol compounds. Such compounds can be oxidized chemically or electrochemically to their analogous oquinone compounds. When this conversion to the oquinone form occurs, further degradative reactions become likely because the o- quinone compounds are relatively highly reactive. See Scheme 1. In particular, they are reactive towards nucleophiles, for example, undergoing a Michael addition reaction.
For example, when a catecholamine e.g., entacapone, L-Dopa, and carbidopa, is converted to its analogous oquinone form, that form may be readily attacked by a wide variety of nucleophilic reagents, such as amines.
Figure imgf000014_0001
Scheme 1: One possibility of oxidative degradation through o-quinone form of entacapone.
For example, in Scheme 1, entacapone is oxidized into its analogous o-quinone form, which is then susceptible to attack by a nucleophile (Nu:) at any one of three positions, resulting in a Michael addition product. Such degradation, through the o quinone form, is possible for any catecholamine present in a formulation and the nucleophile could be any group present in that formulation that is capable of reacting with the o-quinone form. Catecholamines include, as part of their chemical structure, an amino group. This amino group can act as a nucleophile. Accordingly, where a catecholamine is oxidized into its analogous o-quinone form, that form may be susceptible to attack by an amine group of another catecholamine. As a result, under oxidizing conditions, catecholamines may degrade via intermolecular reactions (such as the amine of one catechol attacks the o-quinone form of an oxidized catecholamine).
The substituent group(s) on a particular catecholamine affect that compound's susceptibility to degradative oxidation reactions because those substituent groups affect the electronic properties of the molecule. Additionally, the substituent group(s) on a given catecholamine's amino group affect that amino group's ability to serve as a nucleophile. For example, the amino group in entacapone is substituted with two ethyl groups, thereby hindering entacapone's amino group and making it a less effective nucleophile in some circumstances than, for example, its unsubstituted analog.
Accordingly, different catecholamines have different nucleophilic properties and different susceptibilities to oxidative degradation.
When more than one catecholamine is formulated together with one or more different catecholamine(s), the compounds in the mixture may either react with like compounds or cross-react with different catecholamines in the mixture. As some catecholamines may serve as better nucleophiles and some may be more susceptible to oxidative degradation, including more than one catecholamine in a single formulation may increase the possibility that the components of that formulation will degrade.
Because of the side-effects of Parkinson's drugs (e.g., L-dopa) it is extremely important to deliver an accurate amount of the drug to the patient. While formulating the active catecholamines together may make them more susceptible to degradation, it is nevertheless highly desirable to provide a Parkinson's disease patient with a
pharmaceutical formulation comprising all of the therapeutically active substances in one dosage form. Providing all of the active substances in one dosage form increases patient compliance and decreases the possibility that a patient will mistakenly take one drug without concurrently taking another. As the combinations of drugs for Parkinson's disease are intended to be used in concert to achieve synergistic effects, mistakenly omitting one drug could potentially lead to severe unwanted effects.
Accordingly, it is desirable to provide a Parkinson's disease patient with two or more catecholamine compounds in a single pharmaceutical formulation. However, combining two or more catecholamines can increase the possibility that the drugs in that formulation degrade, either during formulating, or while the formulation is stored prior to administering it to the patient.
Thus, it remains necessary to provide a Parkinson's disease patient with a medication that is stable under ambient conditions and stable in the presence of other Parkinson's drugs. Disclosed herein are compounds of formula (I) that is resistant to the degradative pathways that lead to the deterioration of other Parkinson's drugs. This compound liberates a catecholamine in vivo, while preventing the degradative pathways that may destroy such a catecholamine under ambient conditions (e.g., storage).
Additionally, the compound of formula (I) may be combined in a single formulation with other Parkinson's drugs (e.g., L-dopa, carbidopa) without reacting with the other drugs present in the formulation. Summary
Disclosed herein are compounds of the following formula (I):
Figure imgf000017_0001
wherein
each of R1 and R2 is independently chosen from H or a catechol-oxidation- inhibiting pro-moiety, provided that R1 and R2 are not both H;
each of E1 and E2 is independently chosen from an electron withdrawing group; each of R3 and R4 is independently chosen from a C1 -6 alkyl group;
and pharmaceutically acceptable salts thereof.
Also disclosed are pharmaceutical compositions comprising compounds of formula (I) and at least one pharmaceutically acceptable carrier and/or excipient. In some embodiments, the pharmaceutical compositions of the invention may include additional pharmaceutically active compounds in addition to the compound of formula (I). For example, the pharmaceutical compositions of this invention may include one, two, three, or more additional pharmaceutically active compounds in addition to the compound of formula (I). Also disclosed are pharmaceutical formulations comprising the compound of formula (I) or a composition comprising the compound of formula (I). In some exemplary embodiments, the pharmaceutical formulations may include additional pharmaceutically active compounds in addition to the compound of formula (I). For example, the pharmaceutical formulations of this invention may include one, two, three, or more additional pharmaceutically active compounds in addition to the compounds of formula (I). In some exemplary embodiments, the pharmaceutical formulations are present as solid formulations, such as, by way of example only, a tablet, pill, powder, or granule. In other exemplary embodiments, the pharmaceutical formulations of the invention are liquid formulations. In some exemplary embodiments the liquid
formulation is a buffered solution, which is buffered at a pH appropriate to avoid cleavage of either or both of the groups R1 and/or R2.
Also disclosed are methods of treating diseases or conditions, such as
Parkinson's disease, comprising administering a therapeutically effective amount of at least one compound of formula (I).
Also disclosed are methods of treating diseases or conditions, such as
Parkinson's disease, comprising administering a pharmaceutical composition
comprising at least one compound of formula (I).
Also disclosed are methods of treating diseases or conditions, such as
Parkinson's disease, comprising administering a pharmaceutical formulation comprising at least one compound of formula (I).
In the compound of formula (I), each of the groups R1 and R2 may independently be chosen from H or a "catechol-oxidation-inhibiting pro-moiety", provided that R1 and R2 are not both H. This means that one or both of R1 and R2 is a "catechol-oxidation- inhibiting pro-moiety."
A "catechol-oxidation-inhibiting pro-moiety" is a group that, when attached to a phenolic position of a catechol compound, prevents the formation of a ketone from the corresponding phenol. A "catechol-oxidation-inhibiting pro-moiety" is also a group that may be liberated from the compound of formula (I), providing the free phenol when exposed to physiological conditions. Thus, where a particular catechol compound is susceptible to oxidative degradation at one or more of the phenolic position(s), using a compound that replaces the hydrogen of the phenol with a "catechol-oxidation-inhibiting pro-moiety" may prevent oxidative degradation, while allowing delivery of the active drug upon administering the compound to the patient.
In the compound of formula (I), each of the groups E1 and E2 is independently chosen from an electron withdrawing group. By "independently chosen from" as used herein, it is meant that the groups may be chosen to be the same or may be chosen to be different. Thus, E1 and E2 may either be the same or different electron withdrawing groups. An electron withdrawing group is a group that draws electrons away from other (e.g., adjacent) portions of the molecule. Some examples of electron withdrawing groups include, by way of example only, a nitrile group (CN), a nitro group (NO2), a carboxylic acid group (COOH), a halogen group (F, Cl, Br, I), a carbonyl group, etc.
Description of Exemplary Embodiments
In one exemplary embodiment of the compound of formula (I), each of the "catechol-oxidation-inhibiting pro-moiety" groups, R1 and R2, is independently chosen from alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,— C(O)OR5, -C(O)R5,— (CR6R7)OC(O)R8,
Figure imgf000020_0001
and
Figure imgf000020_0002
wherein
R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R6, R7, R8, R9, and R10 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7 together with the carbon atom to which R6 and R7 are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
wherein each substituent group is independently chosen from F, Cl, Br, I, CN,
NO2,—OH, C1 -6 alkyl, and C1 -6 alkoxy.
In one exemplary embodiment of the invention each of the groups E1 and E2 is independently chosen from NO2, CN, SO3, and CF3 in a compound of formula (I).
In one exemplary embodiment of the invention, the group E1 is NO2 and the group E2 is CN, providing a compound of the following formula (Ia):
Figure imgf000021_0001
wherein the groups R1, R2, R3, and R4 are as described for compounds of formula (I) herein.
In one exemplary embodiment of the invention, each of the groups R3 and R4 in a compound of formula (I) is independently chosen from a C1-6 saturated alkyl group.
In one exemplary embodiment of the invention, each of the groups R3 and R4 in a compound of formula (I) is ethyl, providing a compound of formula (Ib):
Figure imgf000022_0001
wherein the groups R1, R2, E1, and E2 are as described for compounds of formula (I) herein.
In another exemplary embodiment of the invention, a compound of formula (I) is disclosed, wherein each of the groups R3 and R4 is ethyl in the compound of formula (I), the group E1 is NO2, and the group E2 is CN in the compound of formula (I), providing a compound of the following formula (Ic):
Figure imgf000022_0002
wherein the groups R1 and R2 are as described for compounds of formula (I) herein. In another exemplary embodiment of the invention a compound of formula (I) is disclosed, wherein each of R1 and R2 is independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,— C(O)OR5, -C(O)R5,— (CR6R7)OC(O)R8,
Figure imgf000023_0001
and
Figure imgf000023_0002
wherein
R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R6, R7, R8, R9, and R10 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7, together with the carbon atom to which R6 and R7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
wherein each substituent group is independently chosen from F, Cl, Br, I, CN,
NO2, OH, C1 -6 alkyl, and C1 -6 alkoxy.
In another exemplary embodiment of the invention, a compound of formula (I) is disclosed, wherein each of R1 and R2 is independently chosen from— C(O)OR5,
-C(O)R5, and— (CR6R7)OC(O)R8,
wherein
R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R6 and R7 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7 together with the carbon atom to which R6 and R7 are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
R8 is chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
wherein each substituent group is independently chosen from F, Cl, Br, I, CN,
NO2, OH, C1 -6 alkyl, and C1 -6 alkoxy.
In another exemplary embodiment of the invention, a compound of formula (I) is disclosed, wherein E1 is NO2, E2 is CN, R3 is ethyl, and R4 is ethyl, providing a compound of the following formula (Id):
Figure imgf000025_0001
wherein each of the groups R1 and R2 is as described herein for the compound of formula (I).
In another exemplary embodiment of the invention, a compound of formula (I) is disclosed, wherein E1 is NO2, E2 is CN, R3 is ethyl, R4 is ethyl, and each of R1 and R2 is independently chosen from— C(O)OR5, -C(O)R5,— (CR6R7)OC(O)R8,
Figure imgf000026_0001
and
Figure imgf000026_0002
wherein
R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R6, R7, R8, R9, and R10 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7, together with the carbon atom to which R6 and R7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
wherein each substituent group is independently chosen from F, Cl, Br, I, CN,
NO2, OH, C1-6 alkyl, and C1-6 alkoxy. In another exemplary embodiment of the invention, a compound of formula (I) is disclosed, wherein E1 is NO2, E2 is CN, R3 is ethyl, R4 is ethyl, and each of R1 and R2 is independently chosen from -C(O)OR5, -C(O)R5, and— (CR6R7)OC(O)R8,
wherein
R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R6, R7, and R8 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7, together with the carbon atom to which R6 and R7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
wherein each substituent group is independently chosen from F, Cl, Br, I,— CN, -NO2,—OH, C1 -6 alkyl, and C1 -6 alkoxy.
In another exemplary embodiment of the invention, a compound of formula (I) is disclosed, wherein E1 is NO2, E2 is CN, R3 is ethyl, and R4 is ethyl, providing a compound of the following formula (Ie):
Figure imgf000028_0001
wherein each of the groups R1 and R2 is independently chosen from— C(O)OR5 and -C(O)R5,
wherein R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.
In another exemplary embodiment of the invention, a compound of formula (I) is disclosed, wherein E1 is NO2, E2 is CN, R3 is ethyl, and R4 is ethyl, providing a compound of the following formula (If):
Figure imgf000028_0002
wherein each of the groups R1 and R2 is independently chosen from— C(O)OR5 and -C(O)R5,
wherein R5 is chosen from alkyl or substituted alkyl.
Also disclosed herein are pharmaceutical compositions comprising at least one compound of formula (I), disclosed herein.
In one embodiment of the invention, a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier and/or excipient is disclosed.
In another exemplary embodiment of the invention, a pharmaceutical
composition comprising a compound of the formula (Ia) and at least one
pharmaceutically acceptable carrier and/or excipient is disclosed.
In another exemplary embodiment of the invention, a pharmaceutical
composition comprising a compound of the formula (Ib) and at least one
pharmaceutically acceptable carrier and/or excipient is disclosed.
In another exemplary embodiment of the invention, a pharmaceutical
composition comprising a compound of the formula (Ic) and at least one
pharmaceutically acceptable carrier and/or excipient is disclosed.
In another exemplary embodiment of the invention, a pharmaceutical
composition comprising a compound of the formula (Id) and at least one
pharmaceutically acceptable carrier and/or excipient is disclosed.
In another exemplary embodiment of the invention, a pharmaceutical
composition comprising a compound of the formula (Ie) and at least one
pharmaceutically acceptable carrier and/or excipient is disclosed. In another exemplary embodiment of the invention, a pharmaceutical composition comprising a compound of the formula (If) and at least one
pharmaceutically acceptable carrier and/or excipient is disclosed.
In one exemplary embodiment of the invention, a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier and/or excipient is disclosed, wherein each of the "catechol- oxidation-inhibiting pro-moiety" groups, R1 and R2 in the compounds of formula (I), is independently chosen from alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, -C(O)OR5, -C(O)R5,—
(CR6R7)OC(O)R8,
Figure imgf000030_0001
and
Figure imgf000030_0002
wherein
R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R6, R7, R8, R9 and R10 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7, together with the carbon atom to which R6 and R7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
wherein each substituent group is independently chosen from F, Cl, Br, I,— CN, -NO2,—OH, C1 -6 alkyl, and C1 -6 alkoxy.
In another exemplary embodiment of the invention, a pharmaceutical
composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier and/or excipient is disclosed, wherein each of R1 and R2 is independently chosen from -C(O)OR5, -C(O)R5, and— (CR6R7)OC(O)R8, wherein
R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R6 and R7 are independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and
R7, together with the carbon atom to which R6 and R7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
R8 is chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
wherein each substituent group is independently chosen from F, Cl, Br, I,— CN, -NO2,—OH, C1 -6 alkyl, and C1 -6 alkoxy.
In another exemplary embodiment of the invention, a pharmaceutical
composition comprising at least one compound of formula (I) and at least one
pharmaceutically acceptable carrier and/or excipient is disclosed, wherein each of E1 and E2 is independently chosen from NO2, CN, SO3, or CF3.
In another exemplary embodiment of the invention, a pharmaceutical
composition comprising at least one compound of formula (I) and at least one
pharmaceutically acceptable carrier and/or excipient is disclosed, wherein E1 is NO2 and E2 is CN.
In another exemplary embodiment of the invention, a pharmaceutical
composition comprising at least one compound of formula (I) and at least one
pharmaceutically acceptable carrier and/or excipient is disclosed, wherein each of R3 and R4 is independently chosen from a C1-6 saturated alkyl group. In another exemplary embodiment of the invention, a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier and/or excipient is disclosed, wherein each of R3 and R4 is ethyl.
Also disclosed herein are pharmaceutical compositions comprising at least one compound of formula (I) and at least one additional pharmaceutically active compound, such as, for example, at least one first additional pharmaceutically active compound and at least one second additional pharmaceutically active compound.
In one embodiment of the invention, a pharmaceutical composition comprising at least one compound of formula (I) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed. Prodrugs of carbidopa may be obtained, for example, as described in U.S. Patent No. 7,101 ,912, which is incorporated by reference in its entirety. Prodrugs of levodopa may be obtained, for example, as described in U.S. Patent No. 7,323,585, which is incorporated by reference in its entirety.
By way of example, one embodiment of the invention contemplates a
pharmaceutical composition comprising at least one compound of formula (I) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa. For example, a pharmaceutical composition comprising at least one compound of formula (I), levodopa, and carbidopa is disclosed.
In one embodiment of the invention, a pharmaceutical composition comprising at least one compound of formula (Ia) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
By way of example, one embodiment of the invention contemplates a
pharmaceutical composition comprising at least one compound of formula (Ia) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa. For example, a pharmaceutical composition comprising at least one compound of formula (Ia), levodopa, and carbidopa is disclosed.
In one embodiment of the invention, a pharmaceutical composition comprising at least one compound of formula (Ib) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
By way of example, one embodiment of the invention contemplates a
pharmaceutical composition comprising at least one compound of formula (Ib) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa. For example, a pharmaceutical composition comprising at least one compound of formula (Ib), levodopa, and carbidopa is disclosed.
In one embodiment of the invention, a pharmaceutical composition comprising at least one compound of formula (Ic) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
By way of example, one embodiment of this invention contemplates a
pharmaceutical composition comprising at least one compound of formula (Ic) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa. For example, a pharmaceutical composition comprising at least one compound of formula (Ic), levodopa, and carbidopa is disclosed.
In one embodiment of the invention, a pharmaceutical composition comprising at least one compound of formula (Id) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa.
By way of example, one embodiment of this invention contemplates a
pharmaceutical composition comprising at least one compound of formula (Id) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa. For example, a pharmaceutical composition comprising at least one compound of formula (Id), levodopa, and carbidopa is disclosed.
In one embodiment of the invention, a pharmaceutical composition comprising at least one compound of formula (Ie) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
By way of example, one embodiment of this invention contemplates a
pharmaceutical composition comprising at least one compound of formula (Ie) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa. For example, a pharmaceutical composition comprising at least one compound of formula (Ie), levodopa, and carbidopa is disclosed.
In one embodiment of the invention, a pharmaceutical composition comprising at least one compound of formula (If) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is disclosed.
By way of example, one embodiment of this invention contemplates a
pharmaceutical composition comprising at least one compound of formula (If) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa. For example, a pharmaceutical composition comprising at least one compound of formula (If), levodopa, and carbidopa is disclosed.
Also disclosed herein are methods for treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (I) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (Ia) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (Ib) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (Ic) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (Id) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (Ie) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one compound of formula (If) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
Also disclosed herein are methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (I) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (Ia) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (Ib) or pharmaceutically acceptable salt thereof, to a patient in need thereof. In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (Ic) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (Id) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (Ie) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of at least one pharmaceutical composition comprising at least one compound of formula (If) or pharmaceutically acceptable salt thereof, to a patient in need thereof.
Further disclosed herein are methods of treating Parkinson's disease comprising administering at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional pharmaceutically active compound, to a patient in need thereof.
Also disclosed herein are methods of treating Parkinson's disease comprising administering a pharmaceutical composition comprising at least one compound of formula (I) or a salt thereof and at least one additional pharmaceutically active compound, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I) and at least one additional pharmaceutically active compounds independently chosen from COMT inhibitors, dopamine agonists, and MAO-B inhibitors.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I) and at least two additional pharmaceutically active compounds independently chosen from COMT inhibitors, dopamine agonists, and MAO-B inhibitors.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I), levodopa, and carbidopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ia) and at least one additional pharmaceutically active chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ia) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ia), levodopa, and carbidopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ib) and at least one additional pharmaceutically active chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ib) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ib), levodopa, and carbidopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ic) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ic) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ic), levodopa, and carbidopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Id) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Id) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Id), levodopa, and carbidopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ie) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ie) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof. In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (Ie), levodopa, and carbidopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (If) and at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (If) and at least two additional pharmaceutically active compounds independently chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa, to a patient in need thereof.
In various embodiments of the invention are disclosed methods of treating Parkinson's disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (If), levodopa, and carbidopa, to a patient in need thereof. Also disclosed herein are pharmaceutical formulations comprising at least one compound of formula (I). Appropriate formulations comprising at least one compound of formula (I) are within the ability of those skilled in the art to determine, and may include, for example, pharmaceutically acceptable carriers and/or excipients known to those of skill in the art.
In one exemplary embodiment, the formulation comprising at least one
compound of formula (I) is a solid formulation. Solid dosage forms for oral
administration may include, for example, capsules, tablets, pills, powders, and granules. The at least one compound of formula (I) may be contained in a solid dosage form formulation that provides quick release, sustained release, or delayed release after administration to the patient. In such solid dosage forms, the at least one compound of formula (I) may be mixed with at least one inert, pharmaceutically acceptable carrier and/or excipient, including, for example: fillers or extenders; binders; humectants;
disintegrating agents; dissolution retarding agents; absorption accelerators; wetting agents; absorbents; and lubricants. The solid dosage forms may also comprise buffering and/or opacifying agents, as well as any other excipient known to those of skill in the art.
In another exemplary embodiment, the formulation comprising at least one compound of formula (I) is a liquid formulation, such as a liquid oral formulation or a liquid formulation for injection. In one embodiment, the formulation comprising at least one compound of formula (I) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R1 and R2 from cleaving. Guidance for what pH "is appropriate" could be attained, for example in references describing the stability of different groups under different conditions, such as, for example, Greene's Protective Groups in Organic Synthesis. Fourth Edition by Peter G. M. Wuts and Theodora W. Greene, John Wiley & Sons, Inc., Hoboken, NJ, 2006.
In one exemplary embodiment, a pharmaceutical formulation comprising at least one compound of formula (Ia) is disclosed. In one exemplary embodiment, the formulation comprising at least one compound of formula (Ia) is a solid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (Ia) is a liquid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (Ia) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R1 and R2 from cleaving.
In one exemplary embodiment, a pharmaceutical formulation comprising at least one compound of formula (Ib) is disclosed. In one exemplary embodiment, the formulation comprising at least one compound of formula (Ib) is a solid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (Ib) is a liquid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (Ib) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R1 and R2 from cleaving.
In one exemplary embodiment, a pharmaceutical formulation comprising at least one compound of formula (Ic) is disclosed. In one exemplary embodiment, the formulation comprising at least one compound of formula (Ic) is a solid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (Ic) is a liquid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (Ic) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R1 and R2 from cleaving.
In one exemplary embodiment, a pharmaceutical formulation comprising at least one compound of formula (Id) is disclosed. In one exemplary embodiment, the formulation comprising at least one compound of formula (Id) is a solid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (Id) is a liquid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (Id) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R1 and R2 from cleaving.
In one exemplary embodiment, a pharmaceutical formulation comprising at least one compound of formula (Ie) is disclosed. In one exemplary embodiment, the formulation comprising at least one compound of formula (Ie) is a solid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (Ie) is a liquid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (Ie) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R1 and R2 from cleaving.
In one exemplary embodiment, a pharmaceutical formulation comprising at least one compound of formula (If) is disclosed. In one exemplary embodiment, the formulation comprising at least one compound of formula (If) is a solid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (If) is a liquid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (If) is a buffered solution, maintaining a pH that is appropriate to prevent the groups R1 and R2 from cleaving. Also disclosed herein are pharmaceutical formulations comprising at least one compound of formula (I) and at least one additional compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa. In one exemplary embodiment, a pharmaceutical formulation comprising at least one compound of formula (I), levodopa, and carbidopa is disclosed.
In one exemplary embodiment, the pharmaceutical formulation comprising at least one compound of formula (I) and at least one additional compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is a solid formulation. In another exemplary embodiment, the formulation comprising at least one compound of formula (I) and at least one additional compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is a liquid formulation. In another exemplary embodiment, the liquid formulation comprising at least one compound of formula (I) and at least one additional compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is a buffered solution, maintaining a pH that is appropriate to prevent the groups R1 and R2 from cleaving.
As used herein, the phrase "compound of formula (I)" (which is meant to include compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If), is meant to include pharmaceutically acceptable salts thereof, whether or not so stated. Likewise, the at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, and prodrugs of levodopa is also meant to include pharmaceutically acceptable salts thereof, whether or not so stated.
As used herein, the phrase "treating Parkinson's disease" is meant to include treating the condition itself or treating and/or alleviating the symptoms associated therewith, in any degree.
As used herein, the phrase "therapeutically effective amount" is meant to include an amount of a therapeutic agent (or combination of agents) sufficient to treat and/or alleviate a condition treatable by administration of a compound, composition, or formulation of the invention, in any degree, and may include a therapeutically effective amount of at least one compound of formula (I) alone, in combination with additional compounds of formula (I), or in combination with other pharmaceutically active compounds. That amount can be, for example, an amount sufficient to exhibit a detectable therapeutic or ameliorative effect, and can be determined by routine experimentation by those of skill in the art. The effect may include, for example, treatment and/or alleviation of Parkinson's disease or the symptoms associated therewith. The actual amount required, e.g. for treatment of any particular patient, will depend upon a variety of factors including, for example, the severity of the condition, the specific pharmaceutical composition employed, the age, body weight, general health, gender, and diet of the patient, the mode of administration, the time of administration, the route of administration, the duration of the treatment, any drugs used in combination or coincidental with the specific compound employed, and other such factors well known in the medical arts. These factors are discussed in Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman, J.Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001.
By way of example only, the at least one compound of formula (I) may be administered at dosage levels ranging from about 0.5 mg/kg to about 500 mg/kg, such as from about 1 mg/kg to about 200 mg/kg, or from about 5 mg/kg to about 50 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than about 0.5 mg/kg or greater than about 500 mg/kg (for example, ranging from about 500 mg/kg to about 1000 mg/kg) can also be administered to a subject in certain embodiments of the invention.
For example, the at least one compound of formula (I) may be administered at dosage levels ranging from about 0.01 mmol per day to about 100 mmol per day, such as from about 0.1 mmol per day to about 50 mmol per day, or 0.25 mmol per day to about 20 mmol per day. It will also be appreciated that dosages smaller than about 0.1 mmol per day or greater than about 100 mmol per day (for example, ranging from about 100 mmol per day to about 1000 mmol per day) can also be administered to a subject in certain embodiments of the invention. As discussed above, the amount required for a particular patient will depend upon a variety of factors well known to those of skill in the art.
The amount of the at least one additional pharmaceutically active compound may easily be determined by those of skill in the art, for example the at least one additional pharmaceutically active compound may be administered at dosage levels currently known to have a therapeutic effect. As a further example, the at least one additional pharmaceutically active compound may be administered at dosage levels ranging from about 0.5 mg/kg to about 500 mg/kg, such as from about 1 mg/kg to about 200 mg/kg, or from about 5 mg/kg to about 50 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than about 0.5 mg/kg or greater than about 500 mg/kg (for example, ranging from about 500 mg/kg to about 1000 mg/kg) can also be administered to a subject in certain embodiments of the invention. As discussed above, the amount required for a particular patient will depend upon a variety of factors well known to those of skill in the art.
As used herein, the phrase "a patient in need thereof" is meant to include a person who has Parkinson's disease, who is experiencing parkinsonism or Parkinson- like symptoms, or who otherwise has been identified as one who may potentially benefit from the treatment indicated.
Although the present invention herein has been described with reference to various exemplary embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. Those having skill in the art would recognize that various modifications to the exemplary embodiments may be made, without departing from the scope of the invention.
Moreover, it should be understood that various features and/or characteristics of differing embodiments herein may be combined with one another. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the scope of the invention.
Furthermore, other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a scope and spirit being indicated by the claims.
Finally, it is noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the," include plural referents unless expressly and unequivocally limited to one referent, and vice versa. Thus, by way of example only, reference to "a compound of formula (I)" can refer to one or more compounds of formula (I), and reference to "a pharmaceutically acceptable salt" can refer to one or more pharmaceutically acceptable salts. As used herein, the term "include" and its
grammatical variants are intended to be non-limiting, such that recitation of an item or items is not to the exclusion of other like items that can be substituted or added to the recited item(s).
Examples
The compounds of the invention can be synthesized by following the synthetic methods disclosed herein, along with the generally available knowledge and techniques available to a synthetic chemist, such as at least those provided in undergraduate organic chemistry textbooks and organic chemistry laboratory textbooks.
In one example, a compound of formula (I) can be synthesized by performing an aldol condensation reaction between an aromatic aldehyde (e.g., S1 ) with the alpha carbon of an amide.
Figure imgf000054_0001
In the above general example, the groups R1, R2, E1, E2, R3, and R4 are as described herein for compounds of the formula (I).
In another example, compounds of formula (I) may be synthesized by first generating entacapone and thereafter treating entacapone with reagents appropriate for generating the—OR1 and—OR2 groups present in the compounds of formula (I). The following reaction may be used to generate entacapone:
Figure imgf000054_0002
This reaction, generating entacapone, is described in U.S. Patent App. Pub. No.
2008/0146829, which is incorporated by reference in its entirety. Entacapone is also commercially available. With entacapone as a starting material, each of the phenol groups may be modified to generate a group of—OR1 and—OR2 by treating entacapone with a reagent capable of adding either or both of the groups R1 and/or R2. R1 and R2 may either be added in concert or in sequential reactions. General guidance for converting a phenol group (i.e., Ph-OH) into a— OR1 and/or— OR2 group can be found, for example, in Greene's Protective Groups in Organic Synthesis, Fourth Edition by Peter G. M. Wuts and Theodora W. Greene, John Wiley & Sons, Inc., Hoboken, NJ, 2006, which is incorporated by reference in its entirety. Other reactions of alcohols (i.e., phenols) through which a—OR1 and/or—OR2 group can be formed are described in Jones, M. Jr., Organic Chemistry, 1997, WW Norton: New York. See, e.g., c. 17, p. 817 et seq. ("...Glycols, Ethers, and Related Sulfur Compounds...").
In one embodiment, the compounds of formula (I) can be synthesized by first synthesizing a compound of formula (S1 ) and then using said compound of formula (S1 ) as a reagent in an aldol reaction with a compound of formula (S2). This generally applicable synthesis is depicted below. Additionally, for each step, exemplary reaction conditions are provided. Also, 1H-NMR and 13C-NMR data are provided for some exemplary compounds which may be synthesized by following the scheme below.
Although only some of the compounds of the invention are specifically exemplified, the syntheses described herein could be routinely modified to provide other compounds of the invention, not specifically exemplified. See, e.g., Gilbert, J. C. and Martin, S. F., Experimental Organic Chemistry, 2nd Ed. ,1994, Saunders College Publishing: New York; Priva, D. L. et al., Organic Laboratory Techniques, 1988, Saunders College
Publishing: New York.
In one embodiment, the compound of formula (S2) may be the compound (S2-A).
In one embodiment, the compound of formula (S1 ) may be synthesized from 5- nitrovanillin. 5-nitrovanillin is commercially available, for example from Sigma Aldrich, Inc.
As shown in Scheme 2 below, 5-nitrovanillin can be readily used to synthesize an exemplary compound of the formula (S1 ).
Figure imgf000056_0001
Scheme 2
In one embodiment, as indicated by the arrow labeled "2" in Scheme 2, 5- nitrovanillin can be treated with a reagent that is appropriate for introducing the group R2. The resulting compound can then be treated with a reagent suitable for cleaving the 3-methoxy group, while leaving the R2 group in place, as indicated by the arrow labeled "3" in Scheme 2, above. As indicated by the arrow labeled "4" in Scheme 2, the resulting compound can thereafter be treated with a reagent capable of introducing the R1 group in order to generate a compound of formula (S1 ), wherein the group E1 is a nitro group.
In one example, 5-nitrovanillin can be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R2 group:
Figure imgf000057_0001
wherein R5 is as described herein for the compound of formula (I). Other groups can be readily introduced to the alcohol (i.e., phenol) position of 5-nitrovanillin by following the guidance in the prior art, such as Greene's Protecting Groups in Organic Synthesis. For example, 5-nitrovanillin can be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R2 group:
Figure imgf000057_0002
wherein R5 is as described herein for the compound of formula (I).
In one embodiment, 5-nitrovanillin can be treated with a reagent that is
appropriate for removing the 3-methoxy group in order to generate a di-hydroxy compound, as indicated by the arrow labeled "1 " in Scheme 2, above. The resulting compound can then be treated with at least two equivalents of a reagent appropriate for adding the group R1 and R2, as indicated by the arrow labeled "6" in Scheme 2, above. In one example, 5-nitrovanillin can be treated with a haloacid or equivalent thereof (such as, for example, HBr) in order to cleave the methyl of the 3-methoxy group to afford the di-hydroxy compound, as exemplified by the reaction labeled "1 " in Scheme 2. Other methods for cleaving a methyl group to generate a phenol are described in Greene's Protecting Groups in Organic Synthesis.
After generating a di-hydroxy compound, for example by following the reaction labeled "1 " in Scheme 2, the di-hydroxy compound may be treated with a reagent such as, for example, an acid chloride or an equivalent thereof in order to introduce at least one of the groups R1 and/or R2, as depicted by the reaction arrow labeled "6" in Scheme 2. Such an acid chloride may include, for example,
Figure imgf000058_0001
wherein R5 is as described herein for the compound of formula (I). Other suitable groups for R1 and/or R2 may be introduced by following the guidance in the prior art for adding groups to phenols, such as Greene's Protecting Groups in Organic Synthesis or Maitland Jones's Organic Chemistry.
In one embodiment, the groups R1 and R2 may be the same and a compound of formula (S1 ) may be synthesized from 5-nitrovanillin by following the path marked by arrows "1 " and "6" of Scheme 2. In another embodiment, the groups R1 and R2 may be different and the compound of formula (S1 ) may be synthesized from 5-nitrovanillin by following the path marked by arrows "2," "3," and "4" in Scheme 2. In one embodiment, the groups R1 and R2 may be the same and the compound of formula (S1 ) may be synthesized from 5-nitrovanillin by following the path marked by arrows "2," "3," and "4" in Scheme 2. For example, 5-nitrovanillin can be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R2 group:
Figure imgf000059_0001
wherein R5 is as described herein for the compound of formula (I). Other groups can be readily introduced to the alcohol (i.e., phenol) position of 5-nitrovanillin by following the guidance in the prior art, such as Greene's Protecting Groups in Organic Synthesis. For example, 5-nitrovanillin can be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R2 group:
Figure imgf000059_0002
wherein R5 is as described herein for the compound of formula (I). Thereafter, the product of the reaction labeled "2" in Scheme 2 may be subsequently treated with a reagent appropriate for cleaving the methyl group of the 3-methoxy group. For example, the product of the reaction labeled "2" in Scheme 2 may be treated with a haloacid or equivalent thereof (such as, for example, HBr) in order to cleave the methyl of the 3-methoxy group to afford the di-hydroxy compound, as exemplified by the reaction labeled "3" in Scheme 2. Other methods for cleaving a methyl group to generate a phenol are described in Greene's Protecting Groups in Organic Synthesis, which also provides conditions for selectively cleaving a methyl group without altering another group in the molecule, such as the group R2.
In one example, the product of the reaction labeled "3" in Scheme 2 may be treated with a reagent appropriate for introducing an R1 group. For example, the product of the reaction labeled "3" in Scheme 2 may be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R1 group:
Figure imgf000060_0001
wherein R5 is as described herein for the compound of formula (I). Other groups can be readily introduced to the alcohol (i.e., phenol) position of the product of the reaction labeled "3" in Scheme 2 by following the guidance in the prior art, such as Greene's Protecting Groups in Organic Synthesis. For example, the product of the reaction labeled "3" in Scheme 2 may be treated with an acid chloride of the following formula under basic conditions (such as, for example, anhydrous methylene chloride) in order to introduce an R2 group:
Figure imgf000060_0002
wherein R5 is as described herein for the compound of formula (I).
In one embodiment , the groups R1 and R2 are different and the compound of formula (S1 ) may be subsequently treated with a reagent that selectively cleaves one of these groups (R1 or R2) and does not cleave the other, as indicated by the arrow labeled "5" in Scheme 2. Such selective cleavage may be accomplished by following the guidance provided in Protecting Groups in Organic Synthesis, previously cited above.
Some exemplary compounds of formula (I) are depicted below in the following Table 1 , along with NMR data that would allow a chemist to identify the compound spectroscopically. The NMR shifts disclosed in the table are in parts per million from TMS. The proton shift for the phenol group (where present) can be a broad peak around 5 ppm or not observed, presumably due to its exchanging on the NMR timescale. Accordingly, the phenol resonance(s) is/are omitted from the table.
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001

Claims

CLAIMS claim:
1. A compound of the following formula (I):
Figure imgf000074_0001
wherein
each of R1 and R2 is independently chosen from a catechol-oxidation-inhibiting pro-moiety;
each of E1 and E2 is independently chosen from an electron withdrawing group; each of R3 and R4 is independently chosen from a C-ι-6 alkyl group;
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , wherein each of E1 and E2 is independently chosen from NO2, CN, SO3, and CF3.
3. The compound of claim 2, wherein E1 is NO2 and E2 is CN.
4. The compound of claim 1 , wherein each of R3 and R4 is independently chosen from a C1-6 saturated alkyl group.
5. The compound of claim 3, wherein each of R3 and R4 is ethyl.
6. The compound of claim 4, wherein each of R3 and R4 is ethyl.
7. The compound of claim 1 , wherein each of R1 and R2 is independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, -C(O)OR5, -C(O)R5,
— (CR6R7)OC(O)R8,
Figure imgf000075_0001
and
Figure imgf000075_0002
wherein R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R6, R7, R8, R9, and R10are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7, together with the carbon atom to which R6 and R7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
wherein each substituent group is independently chosen from F, Cl, Br, I,— CN,
-NO2,—OH, C1 -6 alkyl, and C1 -6 alkoxy.
8. The compound of claim 7, wherein each of R1 and R2 is independently chosen from -C(O)OR5, -C(O)R5, and— (CR6R7)OC(O)R8,
wherein
R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R6 and R7 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7, together with the carbon atom to which R6 and R7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
R8 is chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
wherein each substituent group is independently chosen from F, Cl, Br, I,— CN,
-NO2,—OH, C1 -6 alkyl, and C1 -6 alkoxy.
9. The compound of claim 7, wherein E1 is NO2, E2 is CN, R3 is ethyl, and R4 is ethyl.
10. The compound of claim 9, wherein each of R1 and R2 are independently chosen from— C(O)OR5 and— C(O)R5, wherein R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.
1 1. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 , and at least one pharmaceutically acceptable carrier and/or excipient.
12. The pharmaceutical composition of claim 1 1 , wherein in formula (I), each of R1 and R2 is independently chosen from -C(O)OR5, -C(O)R5, and
— (CR6R7)OC(O)R8,
wherein
R5 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R6, R7, and R8 are each independently chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7, together with the carbon atom to which R6 and R7 are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
wherein each substituent group is independently chosen from F, Cl, Br, I,— CN, -NO2,—OH, C1 -6 alkyl, and C1 -6 alkoxy.
13. The pharmaceutical composition of claim 12, wherein in formula (I), each of E1 and E2 is independently chosen from NO2, CN, SO3, and CF3.
14. The pharmaceutical composition of claim 13, wherein in formula (I), E1 is NO2 and E2 is CN.
15. The pharmaceutical composition of claim 14, wherein in formula (I), each of R3 and R4 is independently chosen from a C1^ saturated alkyl group.
16. The pharmaceutical composition of claim 15, wherein in formula (I), each of R3 and R4 is ethyl.
17. The pharmaceutical composition of claim 1 1 , additionally comprising at least one additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, prodrugs of levodopa, and pharmaceutically acceptable salts thereof.
18. The pharmaceutical composition of claim 16, additionally comprising at least one first additional pharmaceutically active compound chosen from levodopa, carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, prodrugs of levodopa, and pharmaceutically acceptable salts thereof.
19. The pharmaceutical composition of claim 17 wherein said at least one additional compound is chosen from levodopa and pharmaceutically acceptable salts thereof.
20. The pharmaceutical composition of claim 19, additionally comprising at least one second additional pharmaceutically active compound chosen from carbidopa, benserazide, entacapone, tolcapone, bromocriptine, pergolide pramipexole, ropinirole, cabergoline, apomorphine, lisuride, prodrugs of carbidopa, prodrugs of levodopa, and pharmaceutically acceptable salts thereof.
21. A method of treating Parkinson's disease comprising administering a therapeutically effective amount of a compound chosen from compounds of formula (I) according to any one of claims 1 -10 and pharmaceutically acceptable salts thereof, to a patient in need thereof.
22. The method of claim 21 , wherein said compound is chosen from compounds of claim 2 and pharmaceutically acceptable salts thereof.
23. The method of claim 21 , wherein said compound is chosen from compounds of claim 3 and pharmaceutically acceptable salts thereof.
24. The method of claim 21 , wherein said compound is chosen from compounds of claim 6 and pharmaceutically acceptable salts thereof.
25. The method of claim 21 , wherein said compound is chosen from compounds of claim 8 and pharmaceutically acceptable salts thereof.
26. The method of claim 21 , wherein said compound is chosen from compounds of claim 10 and pharmaceutically acceptable salts thereof.
27. A method of treating Parkinson's disease comprising administering a pharmaceutical composition according to any one of claims 1 1 -20 to a patient in need thereof.
28. The method of claim 27, wherein said pharmaceutical composition is a pharmaceutical composition according to claim 12.
29. The method of claim 27, wherein said pharmaceutical composition is a pharmaceutical composition according to claim 13.
30. The method of claim 27, wherein said pharmaceutical composition is a pharmaceutical composition according to claim 14.
31. The method of claim 27, wherein said pharmaceutical composition is a pharmaceutical composition according to claim 15.
32. The method of claim 27, wherein said pharmaceutical composition is a pharmaceutical composition according to claim 16.
33. The method of claim 27, wherein said pharmaceutical composition is a pharmaceutical composition according to claim 17.
34. The method of claim 27, wherein said pharmaceutical composition is a pharmaceutical composition according to claim 18.
35. The method of claim 27, wherein said pharmaceutical composition is a pharmaceutical composition according to claim 19.
36. The method of claim 27, wherein said pharmaceutical composition is a pharmaceutical composition according to claim 20.
37. A pharmaceutical formulation comprising a pharmaceutical composition according to any one of claims 1 1 -20.
38. The pharmaceutical formulation of claim 37, wherein said formulation is a solid formulation.
39. The solid pharmaceutical formulation of claim 38, wherein said solid pharmaceutical formulation comprises the pharmaceutical composition according to claim 19.
40. The solid pharmaceutical formulation of claim 38, wherein said solid pharmaceutical formulation comprises the pharmaceutical composition according to claim 20.
41. A pharmaceutical composition comprising at least one compound chosen from compounds of formula (I), carbidopa, levodopa, and pharmaceutically acceptable salts thereof.
42. A pharmaceutical formulation comprising the pharmaceutical composition of claim 41 , wherein said formulation is a solid formulation.
43. A pharmaceutical formulation comprising the pharmaceutical composition of claim 41 , wherein said formulation is a liquid formulation.
44. A pharmaceutical formulation according to claim 43 wherein the liquid formulation is a buffered liquid formulation.
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