USE OF PIPERINE AND DERIVATIVES THEREOF FOR THE THERAPY OF NEUROLOGICAL CONDITIONS

• US 20100179130A1
• Filed: 07/03/2008
• Published: 07/15/2010
• Est. Priority Date: 07/03/2007
• Status: Abandoned Application

• Current Assignee: Sygnis Bioscience GmbH & Co. KG
• Original Assignee: Syngis Bioscience GmbH & Company KG
• Inventors: Laage, Rico, Schneider, Armin, Pitzer, Claudia, Krüger, Carola, Moraru, Anja
• Application Number:
  US12/667,459
• Publication Number:
  US 20100179130A1
• Time in Patent Office: Days
• US Class Current: 514/217.30
• CPC Class Codes: A61K 31/015 carbocyclic
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/36 Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/4465 only substituted in position 4
• CPC Class Codes: A61K 31/45 having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
• CPC Class Codes: A61K 31/4525 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 36/67 Piperaceae (Pepper family), e.g. Jamaican pepper or kava
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention relates to the use of piperine and derivatives thereof for the preparation of a pharmaceutical composition for treating and/or preventing a neuronal condition where there is a need of neuroprotection and/or neuroregeneration. The invention furthermore relates to the use of piperine and derivatives thereof for the in vitro differentiation of neural stem cells and the use of such pre-treated cells for stem cell therapy von neurological conditions.

Claims

1-13. -13. (canceled)

14. A Method of treating and/or preventing a neuronal condition in a subject suffering therefrom comprising administering to the said subject in a therapeutically effective amount a compound having the general formula (III)

wherein

R⁶ represents a pyrrolidino, piperidino, azepano, 4-methylpiperidino, morpholino, 4,5-dihydro-2-thiazolamino, 2-tetrahydrofurfurylamino, 2-tetrahydrofuranylamino, N-monoalkylamino group of 4 to 6 carbon atoms, N-monocycloalkylamino group of 4 to 8 carbon atoms, bicyclo[2.2.1]heptylamino group, 3′

,4′

-methylenedioxy-substituted benzylamino group, 2-phenethylamino group, and

m=0, 1, 2, or 3, provided that

when m=1, R¹ represents an alkoxy group having from 1 to 3 carbon atoms or a halogen atom;

when m=2, each R¹ independently represents an alkoxy group having from 1 to 3 carbon atoms or the two R¹ together represent a 3′

,4′

-methylenedioxy group, a 3′

,4′

-ethylenedioxy group, or a 3′

,4′

-propylenedioxy group;

when m=3, two R¹ together represent a 3′

,4′

-methylenedioxy group, a 3′

,4′

-ethylenedioxy group, or a 3′

,4′

-propylenedioxy group and the other R¹ represents an alkoxy group having from 1 to 3 carbon atoms or a halogen atom.

15. The method of claim 14, wherein the compound is selected from the group consisting of:

Antiepilepsirine, 1-(3-trans-benzo-1,3-dioxol-5-ylacryloyl)cyclohexylamine, 1-(3-trans-benzo-1,3-dioxol-5-ylacryloyl)cycloheptylamine, 1-(3-trans-benzo-1,3-dioxol-5-ylacryloyl)cyclopenylamine, 1-(3-trans-benzo-1,3-dioxol-5-ylacryloyl)pyrrolidine, 1-(3-trans-benzo-1,3-dioxol-5-ylacryloyl)morpholine, 3-(1,3-benzodioxol-5-yl)-N-cyclooctylacrylamide, 1-[3-(1,3-benzodioxol-5-yl)acryloyl]-4-methylpiperidine, 3-Benzol[1,3]dioxol-5-yl-N-(4,5-dihydro-thiazol-2-yl)-acrylamide, 3-(1,3-benzodioxol-5-yl)-N-(tetrahydro-2-furanylmethyl)acrylamide, 3-(1,3-benzodioxol-5-yl)-N-bicyclo[2.2.1]hept-2-ylacrylamide, 1-Azepan-1-yl-3-(8-chloro-2,3-dihydro-benzol[1,4]dioxin-6-yl)-propenone, 1-Azepan-1-yl-3-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-propenone, 1-Azepan-1-yl-3-(9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-propenone, 3-(Chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)N-cyclohexyl-acrylamide, N-cyclooctyl-3-(4-methoxyphenyl)acrylamide, 3-(4-ethoxyphenyl)-N-(tetrahydro-2-furanyl)acrylamide, N-cyclohexyl-3-(4-ethoxyphenyl)acrylamide, N-cyclopentyl-3-(4-propoxyphenyl)acrylamide, N-cycloheptyl-3-(4-propoxyphenyl)acrylamide, 1-[3-(4-propoxyphenyl)acryloyl]piperidine, 1-[3-(4-propoxyphenyl)acryloyl]azepane, (2E)-3-(4-chlorophenyl)-1-piperidylprop-2-en-1-one, 1-(4-methoxy-cinnamoyl)piperidine, 1-(3-methoxy-cinnamoyl)piperidine, 1-(2-methoxy-cinnamoyl)piperidine, 1-cinnamoyl-piperidine, 1-(3,4-dimethoxy-cinnamoyl)piperidine,

16. The method of claim 14, wherein the neurological condition is at least one condition selected from the group consisting of cerebral ischemia, amyotrophic lateral sclerosis, glaucoma, Alzheimer'"'"'s disease, neurodegenerative trinucleotide repeat disorders, neurodegenerative lysosomal storage diseases, multiple sclerosis, spinal cord injury, spinal cord trauma, dementia, schizophrenia, and peripheral neuropathy.

17. The method of claim 14, wherein the neurological condition is a neurological disease with a pathophysiological mechanism involving ischemia and/or hypoxia selected from the group consisting of stroke, traumatic brain injury, cerebral ischemia due to cardiocirculatory arrest, glaucoma, spinal cord injury, and spinal cord trauma.

18. A method for enhancing learning and memory comprising administering to a subject in need thereof an effective amount of a compound having the general formula (III) as defined in claim 14.

19. The method of claim 18, wherein said compound is selected from the group consisting of:

Antiepilepsirine, 1-(3-trans-benzo-1,3-dioxol-5-ylacryloyl)cyclohexylamine, 1-(3-trans-benzo-1,3-dioxol-5-ylacryloyl)cycloheptylamine, 1-(3-trans-benzo-1,3-dioxol-5-ylacryloyl)cyclopenylamine, 1-(3-trans-benzo-1,3-dioxol-5-ylacryloyl)pyrrolidine, 1-(3-trans-benzo-1,3-dioxol-5-ylacryloyl)morpholine, 3-(1,3-benzodioxol-5-yl)-N-cyclooctylacrylamide, 1-[3-(1,3-benzodioxol-5-yl)acryloyl]-4-methylpiperidine, 3-Benzol[1,3]dioxol-5-yl-N-(4,5-dihydro-thiazol-2-yl)-acrylamide, 3-(1,3-benzodioxol-5-yl)-N-(tetrahydro-2-furanylmethyl)acrylamide, 3-(1,3-benzodioxol-5-yl)-N-bicyclo[2.2.1]hept-2-ylacrylamide, 1-Azepan-1-yl-3-(8-chloro-2,3-dihydro-benzol[1,4]dioxin-6-yl)-propenone, 1-Azepan-1-yl-3-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-propenone, 1-Azepan-1-yl-3-(9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-propenone, 3-(Chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)N-cyclohexyl-acrylamide, N-cyclooctyl-3-(4-methoxyphenyl)acrylamide, 3-(4-ethoxyphenyl)-N-(tetrahydro-2-furanyl)acrylamide, N-cyclohexyl-3-(4-ethoxyphenyl)acylamide, N-cyclopentyl-3-(4-propoxyphenyl)acrylamide, N-cycloheptyl-3-(4-propoxyphenyl)acrylamide, 1-[3-(4-propoxyphenyl)acryloyl]piperidine, 1-[3-(4-propoxyphenyl)acryloyl]azepane, (2E)-3-(4-chlorophenyl)-1-piperidylprop-2-en-1-one, 1-(4-methoxy-cinnamoyl)piperidine, 1-(3-methoxy-cinnamoyl)piperidine, 1-(2-methoxy-cinnamoyl)piperidine, 1-cinnamoyl-piperidine, dimethoxy-cinnamoyl)piperidine,

20. A method of treating and/or preventing a neuronal condition in a subject suffering therefrom comprising administering to the said subject a therapeutically effective amount of a compound with the general formula (I)

wherein

n=0, 1, or 2, provided that

when n=0, R² and R³ represent hydrogen atoms or together represent a carbon to carbon double bond, either in E or in Z geometric configuration;

when n=1, or 2, R² and R³ represent hydrogen atoms or together represent a carbon to carbon double bond, either in E or in Z geometric configuration, and R⁴ and R⁵ represent hydrogen atoms or together represent a carbon to carbon double bond, either in E or in Z geometric configuration;

m=0, 1, 2, or 3, provided that

when m=1, R¹ represents an alkoxy group having from 1 to 3 carbon atoms, a hydroxy group, or a halogen atom

when m=2, each R¹ independently represents an alkoxy group having from 1 to 3 carbon atoms or the two R¹ together represent a 3′

,4′

-methylenedioxy group, a 3′

,4′

-ethylenedioxy group, or a 3′

,4′

-propylenedioxy group;

when m=3, two R¹ together represent a 3′

,4′

-methylenedioxy group, a 3′

,4′

-ethylenedioxy group, or a 3′

,4′

-propylenedioxy group and the other R¹ represents an alkoxy group having from 1 to 3 carbon atoms, a hydroxy group, or a halogen atom;

R⁶ represents a pyrrolidino, piperidino, azepano, 4-methylpiperidino, morpholino, 4,5-dihydro-2-thiazolamino, 2-tetrahydrofurfurylamino, 2-tetrahydrofuranylamino, N-monoalkylamino group of 4 to 6 carbon atoms, N-monocycloalkylamino group of 4 to 8 carbon atoms, bicyclo[2.2.1]heptylamino group, 3′

,4′

-methylenedioxy-substituted benzylamino group, 2-phenethylamino group, or an alkoxy group having from 1 to 6 carbon atoms.

21. The method of claim 20, wherein said compound is to be provided in a dosage of 2 to 200 mg/kg body weight.

22. The method of claim 20, wherein said neuronal condition is neuronal loss accompanying late stage acute neurological conditions.

23. The method of claim 20, wherein said neuronal condition is rehabilitation from acute neurological conditions.