Cholinergic Enhancers with Improved Blood-Brain Barrier permeability for the Treatment of Diseases Accompanied by Cognitive Impairment

• US 20080261954A1
• Filed: 09/22/2006
• Published: 10/23/2008
• Est. Priority Date: 09/22/2005
• Status: Abandoned Application

• Current Assignee: Galantos Pharma GmbH
• Original Assignee: Galantos Pharma GmbH
• Inventors: Maelicke, Alfred
• Application Number:
  US12/067,799
• Publication Number:
  US 20080261954A1
• Time in Patent Office: Days
• US Class Current: 514/215
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: C07D 307/91 Dibenzofurans; Hydrogenated dibenzofurans
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 491/06 Peri-condensed systems
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention refers to compounds that, in addition to enhancing the sensitivity to acetylcholine and choline, and their exogenous agonists, of neuronal cholinergic receptors and/or acting as cholinesterase inhibitors and/or neuroprotective agents, have enhanced blood-brain barrier permeability in comparison to their parent compounds. The compounds are derived (either formally by their chemical structure or directly by chemical synthesis) from natural compounds belonging to the class of amaryllidaceae alkaloids e.g. Galanthamine, narwedine and lycoramine, or from metabolites of said compounds.

Claims

1. Method for improvement of blood-brain barrier permeability and/or brain-to-plasma distribution ratio of a cholinergic enhancer molecule, whether a cholinergic agonist or APL and/or a cholinesterase inhibitor and/or a neuroprotective agent, by modification of at least one of the residues R1, R2, R3, R4 and/or R5 of the base structure(s) of formula (III) so as to enhance transport into the brain and compound concentration therein

2. Method according to claim 1 wherein the bond <

1>

to >

2>

is a double bond and the bond between <

3> and

R1 is a single bond and bond <

10>

to <

11>

is a single or no bond and residues are

R1=OH, OCO-(3-pyridyl)(=nicotinic acid residue), OCO—

(3-methyl-3-pyridyl), OCO-(C₁—

C₆ alkyl), OCO-(C₁-C₂₁ alkenyl), OCO—

NH—

(C₁—

C₆ alkyl), OCO-(CH₂)_x—

NH—

COO—

(C₁—

C₆ alkyl), O—

CH₂—

O-(C₁—

C₆ alkyl), O-(CH₂)_x-OCO-(C₁—

C₆ alkyl), O-(CH₂)_x-OCO-(CH₂)_x-N—

COO-( C₁-C₆ alkyl), O-(CH₂)_x-OCO-(CH₂)_y-aryl, OCOO-(C₁—

C₆ aminalkyl), OCOO-(CH₂)_x-tetrahydrofuranyl, or a sugar, preferably glucuronic acid residue, wherein x=1, 2, 3 or 4 and y=0, 1, 2, 3 or 4

R2=H, CH₃, CO-(C₁—

C₆ alkyl), CH₂-OCO-(CH₂)_x-aryl, or a sugar, preferably glucuronic acid residue

R3=H, F or Br

R4=H, C₁-C₆ alkyl, preferably CH₃, CO-(C₁—

C₆ alkyl), CO-(3-pyridyl)(=nicotinic acid residue), CO-(3-methyl-3-pyridyl), CO-(CH-mercaptoalkyl)-(CH₂)_x-aryl, (CH₂)_x-OCO-(CH₂)_x-N—

COO-(C₁-C₆ alkyl), (CH₂)_x-OCO-(CH-arylalkyl)-N—

COO-(C₁-C₆ alkyl), wherein x=1, 2, 3 or 4

R5=an electron pair or (CH₂)_x-O-(C₁—

C₆ alkyl), (CH₂)_x-OCO-(C₁—

C₆ alkyl), (CH₂)_x-OCO-(CH₂)_x-aryl, (CH₂)_x-OCO-(CH₂)_x-N—

COO-(C₁-C₆ alkyl), wherein x=1, 2, 3 or 4 ;

in case that bond <

10>

to <

11>

is a single bond the nitrogen has a positive charge and the counterion is chloride.

3. (canceled)

4. Derivatives of a base structure of the formula (III)

6. Derivative according to claim 4, whereby the derivative is selected from the group provided in table 4.

8. Pharmaceutical composition comprising a derivative according to claim 4 or 7 or a pharmaceutically acceptable salt thereof.

9. Pharmaceutical composition according to claim 8, further comprising a pharmaceutically acceptable carrier.

10. A method for the treatment of a neurodegenerative or psychiatric or neurological disease associated with a cholinergic deficit comprising administering the pharmaceutical composition of claim 8 to a patient in need thereof.

11. Derivative of claim 5 or claim 10 wherein the disease is selected from Alzheimer'"'"'s and Parkinson'"'"'s disease, other types of dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, oxygen and nutrient deficiencies in the brain after hypoxia, anoxia, asphyxia, cardiac arrest, chronic fatique syndrome, various types of poisoning, anesthesia, particularly neuroleptic anesthesia, spinal cord disorders, inflammation, particularly central inflammatory disorders, postoperative delirium and/or subsyndronal postoperative delirium, neuropathic pain, subsequences of the abuse of alcohol and drugs, addictive alcohol and nicotine craving, and subsequences of radiotherapy.

12. The method of claim 10, wherein the disease is selected from Alzheimer'"'"'s and Parkinson'"'"'s disease, other types of dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, oxygen and nutrient deficiencies in the brain after hypoxia, anoxia, asphyxia, cardiac arrest, chronic fatique syndrome, various types of poisoning, anesthesia, particularly neuroleptic anesthesia, spinal cord disorders, inflammation, particularly central inflammatory disorders, postoperative delirium and/or subsyndronal postoperative delirium, neuropathic pain, subsequences of the abuse of alcohol and drugs, addictive alcohol and nicotine craving, and subsequences of radiotherapy.

5. (canceled)

7. Derivative of the formula (III)