Compositions and Methods of Using (R)- Pramipexole

• US 20110190356A1
• Filed: 08/19/2009
• Published: 08/04/2011
• Est. Priority Date: 08/19/2008
• Status: Abandoned Application

• Current Assignee: Knopp Biosciences LLC
• Original Assignee: Knopp Neurosciences Inc. (Knopp Biosciences LLC)
• Inventors: Gribkoff, Valentin, Bozik, Michael E.
• Application Number:
  US13/059,713
• Publication Number:
  US 20110190356A1
• Time in Patent Office: Days
• US Class Current: 514/367
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Pharmaceutical compositions of (R)-pramipexole and one or more secondary therapeutic agents such as, for example dopamine agonists, dopaminergic agonists, COMT inhibitors, MOA inhibitors, excitatory amino acid antagonists, growth factors, neurotrophic factors, antioxidants, anti-inflammatory agents, immunomodulators, anti-glutamatergics, ion channel blockers, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, heat shock protein inducers/protein disaggregators and downregulators, monoamine oxidase type B (MOAB) inhibitors, multi-target agents, kinase inhibitors, Bcl inducers, histone deacetylase (HDAC) mediators, glial modulators, mitochondrial energy promoting agents, myostatin inhibitors, caspase inhibitors and combinations thereof or those related to mitochondrial dysfunction or increased oxidative stress are disclosed.

Claims

1-89. -89. (canceled)

90. A multi-component therapeutic comprising:

a first component comprising a therapeutically effective amount of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or a pharmaceutically acceptable salt thereof; and

a second component comprising a therapeutically effective amount of one or more secondary therapeutic agents, wherein the secondary therapeutic agents are selected from a dopamine agonist, dopaminergic agonist, COMT inhibitors, MOA inhibitors, excitatory amino acid antagonists, growth factors, neurotrophic factors, antioxidants, anti-inflammatory agents, immunomodulators, anti-glutamatergics, ion channel blockers, α

-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, heat shock protein inducers/protein disaggregators and downregulators, monoamine oxidase type B (MOAB) inhibitors, multi-target agents, kinase inhibitors, Bcl protein inducers, histone deacetylase (HDAC) mediators, glial modulators, mitochondrial energy promoting agents, myostatin inhibitors, caspase inhibitors and combinations thereof.

91. The multi-component therapeutic of claim 90, wherein the first component and each of the second component are provided in individual unit doses.

92. The multi-component therapeutic of claim 90, wherein the first component and the second component is provided in a single unit dose.

93. The multi-component therapeutic of claim 90, wherein each individual dose or the single unit dose is formulated to be administered orally.

94. The multi-component therapeutic of claim 90, wherein the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine, or pharmaceutically acceptable salt thereof, has a 99.90% or greater chiral purity.

95. The multi-component therapeutic of claim 90, wherein the therapeutically effective of amount of any one of the first component and the second component in the multi-component therapeutic is an amount less than a therapeutically effective amount when that component is administered alone.

96. The multi-component therapeutic of claim 90, wherein the therapeutically effective amount of the first component comprises from about 50 mgs to about 5,000 mgs of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or a pharmaceutically acceptable salt thereof.

97. The multi-component therapeutic of claim 90, wherein the multi-component therapeutic comprises less than about 1.5 dopaminergic activity equivalents.

98. The multi-component therapeutic of claim 90, wherein the multi-component therapeutic comprises less than about 0.05 dopaminergic activity equivalents.

99. The multi-component therapeutic of claim 90, wherein the multi-component pharmaceutical composition results in a neuroprotective activity equivalent of about 50 to about 5,000.

100. The multi-component therapeutic of claim 90, wherein the dopamine agonists are selected from apomorphine, carbidopa, levodopa, bromocriptine, lisuride, cabergoline, piribedel, and combinations thereof;

the dopaminergic agonists are selected from ropinirole, rotigotine, pergolide, amantadine, and combinations thereof;

the COMT inhibitors are selected from entacapone, tolcapone, and combinations thereof;

the MOA inhibitors are selected from selegiline, rasagiline moclobemide, isocarboxazid, phenelzine, tranylcypromine, nialamide, iproniazid, iproclozide, toloxatone, linezolid, dextroamphetamine, EVT 302, Ro 19-6491, Ro 19-6327, deprenyl, pargyline, ladostigil, and combinations thereof;

the excitatory amino acid antagonists is talampanel;

the growth factors and/or neurotrophic factors are selected from insulin-like growth factor-1 (IGF-1), IGF-1 adenoviral-associated virus (IGF-1 AAV), mecasermin rinfabate (IPLEX), glial cell line-derived neurotrophic factor (GDNF), hepatocyte growth factor (HGF), granulocyte colony stimulating factor (G-CSF), and combinations thereof;

the antioxidants, anti-inflammatories, and immunomodulators are selected from AEOL 10150, cefriaxone, celastrol, coenzyme Q10, copaxone, cox-2 inhibitors, nimesulide, cyclosporin, ebselen, edaravone, radicut, promethazine, tamoxifen, thalidomide, vitamin E, VP025, and combinations thereof;

the anti-glutamatergics and ion channel blockers are selected from FP-0011, memantine, N-acetylated-a-linked acidic dipeptidease (NAALADase) inhibitors, nimodipine, riluzole, and combinations thereof;

the AMPA receptor antagonists are selected from 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), talampanel, and combinations thereof;

the heat shock protein inducers, protein disaggregators or protein down regulators are selected from arimoclomol, ISIS 333611, lithium, misfolded SOD-1 antibodies, rhHSP70, TDP-43 antagonists, trehalose, and combinations thereof;

the MOAB inhibitors is rasagiline [R(+)N-propargyl-1-aminoindan];

the multi-target agents is 4-[2(aminomethyl)-1,3-thiazol-4-yl]-2,6 di-tert-butylphenol;

the kinase inhibitors are selected from olomoucine, quinolin-2(1H)-one derivatives, roscovitine, tamoxifen, and combinations thereof;

the Bcl protein inducers are selected from ginsenoside Rb1 and Rg1, G3139, oblimersen, and combinations thereof;

the HDAC mediators are selected from phenylbutyrate, scriptaid, valproic acid, and combinations thereof;

the glial modulators is ONO-2506;

the mitochondrial energy promoters are selected from resveratrol, creatine, erythropoietin, cholest-4-en-3-One, oxime (TRO-19622), and combinations thereof;

the myostatin inhibitors are selected from ACE-031, MYO-029, and combinations thereof;

the caspase inhibitors are selected from ESPA-1002, IDN-6556, pralnacasan, and combinations thereof; and

the therapeutically effective amount of each of the one or more secondary therapeutic agents independently comprises from about 2 mgs to about 5,000 mgs of a secondary therapeutic agent.

101. The multi-component therapeutic of claim 90, wherein the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine is a pharmaceutically acceptable salt of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

102. The multi-component therapeutic of claim 101, wherein the pharmaceutically acceptable salt is (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride monohydrate.

103. A method of treating a neurodegenerative disease in a patient comprising:

administering to the patient a first component comprising a therapeutically effective amount of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or a pharmaceutically acceptable salt thereof; and

administering adjunctively to the patient a second component comprising a therapeutically effective amount of one or more secondary therapeutic agents;

wherein

the one or more secondary therapeutic agents are selected from dopamine agonists, dopaminergic agonists, COMT inhibitors, MOA inhibitors, excitatory amino acid antagonists, growth factors, neurotrophic factors, antioxidants, anti-inflammatory agents, immunomodulators, anti-glutamatergics, ion channel blockers, α

-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, heat shock protein inducers/protein disaggregators and downregulators, monoamine oxidase type B (MOAB) inhibitors, multi-target agents, kinase inhibitors, Bcl protein inducers, histone deacetylase (HDAC) mediators, glial modulators, mitochondrial energy promoting agents, myostatin inhibitors, caspase inhibitors and combinations thereof.

104. The method of claim 103, wherein the steps of administering the first component and administering the one or more second component occurs concurrently.

105. The method of claim 103, wherein the steps of administering the first component and administering the second component occurs separately.

106. The method of claim 103, wherein the steps of administering the first component and administering the second component each individually occur one or more times in a 24-hour period.

107. The method of claim 103, wherein the neurodegenerative disease is selected from stroke, neurotrauma, acute metabolic dysfunction, sequelae from cerebral seizure, status epilepticus, acute encephalitis, Huntington'"'"'s Chorea, metabolically induced neurological damage, senile dementia of Alzheimer'"'"'s type, age associated cognitive dysfunction, vascular dementia, multi-infarct dementia, Lewy body dementia, neurodegenerative dementia, neurodegenerative movement disorder, ataxia, Friedreich'"'"'s ataxia, multiple sclerosis, spinal muscular atrophy, primary lateral sclerosis, seizure disorders, motor neuron disorder or disease, inflammatory demyelinating disorder, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, hepatic encephalopathy, and chronic encephalitis.

108. The method of claim 103, wherein the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine, or pharmaceutically acceptable salt thereof, has a 99.90% or greater chiral purity.

109. The method of claim 103, wherein the therapeutically effective amount of the first component comprises from about 50 mgs to about 5,000 mgs of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or a pharmaceutically acceptable salt thereof.

110. The method of claim 103, wherein the therapeutically effective amount of the first component comprises from about 50 mgs to about 750 mgs of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or a pharmaceutically acceptable salt thereof.

111. The method of claim 103, wherein the therapeutically effective amount of the first component further comprises less than about 1.0 mg of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or a pharmaceutically acceptable salt thereof.

112. The method of claim 103, wherein the dopamine agonists are selected from apomorphine, carbidopa, levodopa, bromocriptine, lisuride, cabergoline, piribedel, and combinations thereof;

wherein

the dopaminergic agonists are selected from ropinirole, rotigotine, pergolide, amantadine, and combinations thereof;

the COMT inhibitors are selected from entacapone, tolcapone, and combinations thereof;

the MOA inhibitors are selected from selegiline, rasagiline moclobemide, isocarboxazid, phenelzine, tranylcypromine, nialamide, iproniazid, iproclozide, toloxatone, linezolid, dextroamphetamine, EVT 302, Ro 19-6491, Ro 19-6327, deprenyl, pargyline, ladostigil, and combinations thereof;

the excitatory amino acid antagonists is talampanel;

the growth factors and/or neurotrophic factors are selected from insulin-like growth factor-1 (IGF-1), IGF-1 adenoviral-associated virus (IGF-1 AAV), mecasermin rinfabate (IPLEX), glial cell line-derived neurotrophic factor (GDNF), hepatocyte growth factor (HGF), granulocyte colony stimulating factor (G-CSF), and combinations thereof;

the antioxidants, anti-inflammatories, and immunomodulators are selected from AEOL 10150, cefriaxone, celastrol, coenzyme Q10, copaxone, cox-2 inhibitors, nimesulide, cyclosporin, ebselen, edaravone, radicut, promethazine, tamoxifen, thalidomide, vitamin E, VP025, and combinations thereof;

the anti-glutamatergics and ion channel blockers are selected from FP-0011, memantine, N-acetylated-a-linked acidic dipeptidease (NAALADase) inhibitors, nimodipine, riluzole, and combinations thereof;

the AMPA receptor antagonists are selected from 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), talampanel, and combinations thereof;

the heat shock protein inducers, protein disaggregators or protein down regulators are selected from arimoclomol, ISIS 333611, lithium, misfolded SOD-1 antibodies, rhHSP70, TDP-43 antagonists, trehalose, and combinations thereof;

the MOAB inhibitors is rasagiline [R(+)N-propargyl-1-aminoindan];

the multi-target agents is 4-[2(aminomethyl)-1,3-thiazol-4-yl]-2,6 di-tert-butylphenol;

the kinase inhibitors are selected from olomoucine, quinolin-2(1H)-one derivatives, roscovitine, tamoxifen, and combinations thereof;

the Bcl protein inducers are selected from ginsenoside Rb1 and Rg1, G3139, oblimersen, and combinations thereof;

the HDAC mediators are selected from phenylbutyrate, scriptaid, valproic acid, and combinations thereof;

the glial modulators is ONO-2506;

the mitochondrial energy promoters are selected from resveratrol, creatine, erythropoietin, cholest-4-en-3-One, oxime (TRO-19622), and combinations thereof;

the myostatin inhibitors are selected from ACE-031, MYO-029, and combinations thereof;

the caspase inhibitors are selected from ESPA-1002, IDN-6556, pralnacasan, and combinations thereof; and

the therapeutically effective amount each of the one or more secondary therapeutic agents, independently, comprises from about 2 mgs to about 5,000 mgs of a secondary therapeutic agent.

113. The method of claim 103, comprising a course of treatment wherein the steps of administering the first component and administering the second component is repeated one or more times in a 24-hour period for 5 days to one or more years.

114. The method of claim 103, wherein the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine is a pharmaceutically acceptable salt of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

115. The method of claim 114, wherein the pharmaceutically acceptable salt is (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride monohydrate.