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US-12622895-B2 - Anti-neurodegenerative combinations and use for treatment of neurodegenerative diseases

US12622895B2US 12622895 B2US12622895 B2US 12622895B2US-12622895-B2

Abstract

The present invention provides a combination of a 5HT3-antagonist and/or a NK-1 antagonist with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine and with fluoxetine or a pharmaceutically acceptable salt or solvate thereof, zonisamide or a pharmaceutically acceptable salt or solvate thereof, or a statin or a pharmaceutically acceptable salt or solvate thereof, for use for treating a protein misfolding neurodegenerative disease such as Alzheimer's disease, Lewy body disease, Parkinson's disease, or Huntington's disease.

Inventors

  • Thomas N. Chase
  • Kathleen E. Clarence-Smith

Assignees

  • ALTO NEUROSCIENCE, INC.

Dates

Publication Date
20260512
Application Date
20190925

Claims (17)

  1. 1 . A method for treating a protein misfolding neurodegenerative disease (“PMND”) in a patient by administering to said patient in need of said treatment a pharmaceutical combination comprising active ingredients consisting of 5HT3-antagonist and/or a NK-1 antagonist, in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine and with fluoxetine, zonisamide, or a statin.
  2. 2 . The method of claim 1 , wherein said 5HT3-antagonist is selected from the group consisting of ondansetron or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 4 mg to 32 mg of ondansetron base, and dolasetron or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 75 mg to 200 mg of dolasetron mesylate; said NK1-antagonist is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt, solvate or prodrug thereof, at daily dose equivalent to from 10 mg to 250 mg of aprepitant; netupitant or a pharmaceutically acceptable salt, solvate or prodrug thereof, at daily dose equivalent to from 150 mg to 600 mg of netupitant; and rolapitant or a pharmaceutically acceptable salt, solvate or prodrug thereof, at daily dose equivalent to from 15 mg to 270 mg of rolapitant; said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is pramipexole or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride; and said fluoxetine is fluoxetine base or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 4 mg to 90 mg of fluoxetine base; or said zonisamide is selected from the group consisting of zonisamide base or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 25 mg to 600 mg of zonisamide free acid, and zonisamide free acid, at a daily dose of from 25 mg to 600 mg; or said statin is selected from the group consisting of rosuvastatin or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 2.5 mg to 40 mg of rosuvastatin calcium, and lovastatin, at a daily dose of from 2.5 mg to 80 mg.
  3. 3 . The method of claim 2 , wherein said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from more than 20 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  4. 4 . The method of claim 1 , wherein said fluoxetine is in the specific 90 mg ER-weekly preparation.
  5. 5 . The method of claim 1 , wherein said 5HT3-antagonist and/or NK-1 antagonist and said fluoxetine are administered to said patient in a fixed dose combination.
  6. 6 . The method of claim 1 , wherein said 5HT3-antagonist and/or NK1-antagonist and said zonisamide are administered to said patient in a fixed dose combination.
  7. 7 . The method of claim 1 , wherein said 5HT3-antagonist and/or NK1-antagonist and said statin are administered to said patient in a fixed dose combination.
  8. 8 . The method of claim 1 , wherein said PMND is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Lewy body dementia, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, multiple system atrophy, neurodegeneration with brain iron accumulation, Parkinsonian disorders associated with glucocerebrosidase mutations, Huntington's Disease, corticobasal degeneration, frontotemporal dementia with parkinsonism-linked to chromosome 17, Pick's Disease, Multiple Tauopathies, Amyotrophic Lateral Sclerosis, Spongiform encephalopathies, and Familial Amyloidotic Polyneuropathy.
  9. 9 . The method of claim 1 , wherein said NK1-antagonist is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt, solvate or prodrug thereof, at daily dose equivalent to from 10 mg to 250 mg of aprepitant; netupitant or a pharmaceutically acceptable salt, solvate or prodrug thereof, at daily dose equivalent to from 150 mg to 600 mg of netupitant; and rolapitant or a pharmaceutically acceptable salt, solvate or prodrug thereof, at daily dose equivalent to from 15 mg to 270 mg of rolapitant; said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; and said fluoxetine is fluoxetine base or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 4 mg to 90 mg of fluoxetine base; or said zonisamide is zonisamide base or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 25 mg to 600 mg of zonisamide free acid, and zonisamide free acid, at a daily dose of from 25 mg to 600 mg; or said statin is selected from the group consisting of rosuvastatin or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 2.5 mg to 40 mg of rosuvastatin calcium, and lovastatin, at a daily dose of from 2.5 mg to 80 mg.
  10. 10 . The method of claim 9 , wherein said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from more than 20 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  11. 11 . A pharmaceutical composition comprising: (A) active ingredients consisting of: (a) a 5HT3-antagonist and/or a NK-1 antagonist; (b) a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine or a pharmaceutically acceptable salt or solvate thereof; and (c) fluoxetine or a pharmaceutically acceptable salt or solvate thereof, zonisamide or a pharmaceutically acceptable salt or solvate thereof, or a statin; in admixture with (B) a pharmaceutical carrier or vehicle.
  12. 12 . The pharmaceutical composition of claim 11 , wherein said pharmaceutical composition is in a dosage unit form wherein (a) said 5HT3-antagonist is in an amount per unit form of from 1 μg to 300 mg and/or said NK1-antagonist is an amount of from 1 μg to 600 mg; (b) said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is selected from the group consisting of (i) the racemate or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from 0.25 mg to 90 mg of pramipexole dihydrochloride monohydrate, (ii) pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount equivalent to from 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, and (iii) a (R)/(S)-mixture or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form of from 50 mg to 3000 mg, inclusive of a(S)-enantiomer or a pharmaceutically acceptable salt or solvate thereof amount per unit form equivalent to from 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate; and (c) said fluoxetine is in an amount per unit form of from 2 mg to 90 mg, said zonisamide is in an amount per unit form of from 25 mg to 600 mg, or said statin is in an amount of from 2.5 mg to 80 mg.
  13. 13 . The pharmaceutical composition of claim 12 , wherein said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form selected from the group consisting of an amount per unit form equivalent to from more than 4.5 mg to 45 mg of pramipexole dihydrochloride monohydrate, an amount per unit form equivalent to from more than 6 mg to 45 mg of pramipexole dihydrochloride monohydrate, an amount per unit form equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate, an amount per unit form equivalent to from 7.5 mg to 25 mg of pramipexole dihydrochloride monohydrate, an amount per unit form equivalent to from 15 mg to 25 mg of pramipexole dihydrochloride monohydrate, and an amount per unit form equivalent to from 20.25 mg to 25 mg of pramipexole dihydrochloride monohydrate.
  14. 14 . The pharmaceutical composition of claim 12 , wherein said 5HT3-antagonist is ondansetron hydrochloride dihydrate, in an amount per unit form equivalent to from 2 mg to 32 mg of ondansetron base and said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is pramipexole dihydrochloride monohydrate, in an amount per unit form of from 0.125 mg to 45 mg.
  15. 15 . The pharmaceutical composition of claim 12 , wherein said NK1-antagonist is aprepitant, in an amount per unit of from 10 mg to 250 mg; and said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is pramipexole dihydrochloride monohydrate, in an amount per unit form of from 0.125 mg to 45 mg.
  16. 16 . A fixed-dose combination consisting of the pharmaceutical composition of claim 11 .
  17. 17 . A kit comprising the pharmaceutical composition according to claim 11 , and instructions for use for the treatment of a PMND in a patient in need of said treatment.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a National Stage of International Application No. PCT/US2019/052849, filed Sep. 25, 2019, which claims the benefit of U.S. Provisional Patent Application Ser. No. 62/736,190, filed Sep. 25, 2018, U.S. Provisional Patent Application Ser. No. 62/735,947, filed Sep. 25, 2018, U.S. Provisional Patent Application Ser. No. 62/736,137, filed Sep. 25, 2018, U.S. Provisional Patent Application Ser. No. 62/735,959, filed Sep. 25, 2018, U.S. Provisional Patent Application Ser. No. 62/743,690, filed Oct. 10, 2018, U.S. Provisional Patent Application Ser. No. 62/743,800, filed Oct. 10, 2018, U.S. Provisional Patent Application Ser. No. 62/770,234, filed Nov. 21, 2018, U.S. Provisional Patent Application Ser. No. 62/770,245, filed Nov. 21, 2018, U.S. Provisional Patent Application Ser. No. 62/785,996, filed Dec. 28, 2018, U.S. Provisional Patent Application Ser. No. 62/785,990, filed Dec. 28, 2018, U.S. Provisional Patent Application Ser. No. 62/884,314, filed Aug. 8, 2019, U.S. Provisional Patent Application Ser. No. 62/884,311, filed Aug. 8, 2019, and U.S. Provisional Patent Application Ser. No. 62/896,088, filed Sep. 5, 2019, the disclosures of which are incorporated herein in their entirety by reference. FIELD OF THE INVENTION The present invention pertains to the field of the treatment of neurodegenerative diseases, and in particular, of the treatment of neurotoxic processes due to protein misfolding in neurodegenerative diseases. OBJECT OF THE INVENTION The present invention concerns a pharmaceutical combination comprising a 5HT3-antagonist and/or NK-1 antagonist, 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, and fluoxetine, zonisamide or a statin, and its use for the treatment of protein misfolding neurodegenerative diseases (or disorders) in humans. A preferred embodiment of the present invention includes the use of a 5HT3-antagonist and/or NK-1 antagonist and fluoxetine, zonisamide or a statin combination for augmenting the synucleinopathy-modifying potential of pramipexole in humans, thus allowing at least a slowing of disease progression at doses that are both safe and tolerable. Definitions “CNS”: Central Nervous System.“IR”: Immediate Release of the active ingredient from a composition.“ER”: Extended Release of the active ingredient from a composition.“GI”: Gastro-Intestinal.“AE(s)”: Adverse Effect(s).“SNCA gene”: Synuclein-alpha or alpha-synuclein gene.“α-Syn”: α-Synuclein or alpha-synuclein.“A-β”. Amyloid-β.“TauP”: Tau protein.“PMND”: Protein Misfolding Neurodegenerative Disease.“AD”: Alzheimer's Disease.“PD”: Parkinson's Disease.“LBD”: Lewy Body Dementia.“DLB”: Dementia with Lewy Bodies.“HD”: Huntington's Disease.“CBD”: Corticobasal degeneration.“FTD-PD17”: frontotemporal dementia with parkinsonism-linked to chromosome 17.“FTLD”: Frontotemporal Lobe Dementia.“PSP”: Progressive Supranuclear Palsy.“PickD”: Pick's Disease.“GBA”: Mutations in the glucocerebrosidase gene.“MSA”: Multiple System Atrophy.“MT”: Multiple Tauopathies.“ALS”: Amyotrophic Lateral Sclerosis.“SEP”: Spongiform encephalopathies.“FAP”: Familial amyloidotic polyneuropathy.“TDDS”: Transdermal Drug Delivery System.“mers”: this term, preceded by a number-range, is a neologism indicating the number of protein monomers in an oligomer formed in the oligomerization of said protein, as described in the Sengupta et al. 2016 reference, which is incorporated herein by reference in its entirety.“Dyslipidemia”: a disorder of lipoprotein metabolism, including lipoprotein overproduction or deficiency, as may be manifested by elevation of the total cholesterol, the low-density lipoprotein (LDL) cholesterol and the triglyceride concentrations, and a decrease in the high-density lipoprotein (HDL) cholesterol concentration in the blood, and other blood disorders the statins are indicated for.“Effective daily dose of 5HT3-antagonist”: This expression, as used herein, refers to a dose of said 5HT3-antagonist that is at least as high as that for preventing or treating nausea and vomiting in pediatric or adult patients under cancer chemotherapy according to the current protocols for said treatment. Said dose normally is from 1 μg to 600 mg per unit form and from 1 μg to 600 mg daily; preferably, from 1 μg to 300 mg per unit form and from 1 μg to 300 mg daily.“Effective daily dose of NK1-antagonist”: This expression, as used herein, refers to a dose of said NK1-antagonist that is at least as high as that for preventing or treating nausea and vomiting in pediatric or adult patients under cancer chemotherapy according to the current protocols for said treatment. Said daily dose normally is from 1 μg to 600 mg.“6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine”: A chiral chemical compound that is available as racemate, chemically (R,S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, as (R)-stereoisomer, chemically (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amin