WO2009022932A1 - Pharmaceutical compositions comprising monocholine succinate salts - Google Patents
Pharmaceutical compositions comprising monocholine succinate salts Download PDFInfo
- Publication number
- WO2009022932A1 WO2009022932A1 PCT/RU2007/000419 RU2007000419W WO2009022932A1 WO 2009022932 A1 WO2009022932 A1 WO 2009022932A1 RU 2007000419 W RU2007000419 W RU 2007000419W WO 2009022932 A1 WO2009022932 A1 WO 2009022932A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- pharmaceutically acceptable
- monocholine
- pharmaceutical compositions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- 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
- A61P25/28—Drugs for disorders of the nervous system 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
Definitions
- the invention relates to the use of monocholine salts of succinic acid in pharmaceutical compositions, particularly in compositions with a neuroprotective activity.
- Monocholine salt of succinic acid is known from the prior art and is disclosed, for example, by published US patent 5,124,061 as a component of compositions for increasing the resistance of plants to damage by freezing conditions.
- monocholine salts of succinic acid manifest a pronounced effect on brain function and can be used as an active component in pharmaceutical compositions.
- It is an object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of monocholine salts of succinic acid.
- the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I)
- the term pharmaceutically acceptable salt refers to non-toxic base addition salts.
- the pharmaceutically acceptable salts of the invention are prepared by a reaction of compound of formula (I) with a pharmaceutically acceptable base by methods well-known from the art.
- bases include, but are not limited to, ammonia; sodium base; potassium base; thiamine base; organic amines like as triethylamine, ethanolamine, dimethylethanolamine, diethanolamine, and triethanolamine; 2-ethyl-6-methyl-3-hydroxypiridine; and basic amino acids like arginine, ornithine, and lysine.
- the pharmaceutically acceptable salt of the invention is selected from the group consisting of sodium salt (compound of formula II), potassium salt (compound of formula III), and thiamine salt (compound of formula IV).
- the term "therapeutically effective amount” refers to a nontoxic but sufficient amount of an active agent to provide the desired therapeutic effect.
- the therapeutically effective amount of compounds of formula (I) through (V) is from 0.01 to 30 mg per a unit dosage form of compositions of the present invention. More preferably, from 5 to 15 mg per a unit dosage form.
- pharmaceutically acceptable carrier refers to a one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to any portion of the body of a mammal, preferably a human.
- the carrier may be a liquid, solution, suspension, gel, ointment, lotion, powder, or combinations thereof.
- the carrier is a pharmaceutically acceptable aqueous carrier.
- compositions of the invention are prepared by methods well-known from the art in accordance with accepted pharmaceutical procedures, for example, as described in Remington's Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pa.,
- compositions of the invention can be prepared in a variety of unit dosage forms. Such forms are include, but are not limited to, eye drops, spray, gel, ointment, tablet, capsule, and powder.
- the content of compounds of formula (I) is in the range from 0.1 to 99 %, preferably 0.5 to 10 % by the weight of the composition.
- composition of the present invention can be used for treating a disease.
- diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebral ischemia and neurological damage due to stroke, diabetic polyneuropathy, glaucoma, retinopathy, and amyotrophic lateral sclerosis.
- treating a disease means treating, controlling, preventing and/or reducing one or more clinical signs (i.e., symptoms) of the disease in a mammal in need thereof.
- Nonexclusive examples of mammals of the invention include humans and companion animals such as cats and dogs.
- the mammal is a human.
- Example 1 The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
- Example 1 The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
- Example 1 The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way. Example 1.
- a compound of formula (I) is prepared by mixing 12.1 g choline base with 11.8 g succinic acid at room temperature without of a solvent. Resulting mixture is dissolved in acetone at ambient temperature; and the solution is filtered through a filter. Compound (I) is recovered as ionic liquid by evaporating of acetone from the solution.
- 1 H NMR in D 2 O 2.41(9H, s), 3.19(4H, s), 3.49(2H, t), 4.10(2H, t).
- a compound of formula (II) is prepared by mixing of 2.2 g of the compound of formula (I) with 0.04 g of sodium hydroxide at ambient temperature without of a solvent. The mixture is dried under vacuum and re- crystallized from isopropanol-acetone. Compound (II) is recovered as a white powder.
- 1 H NMR in D 2 O 2.35(9H, s), 3.15(4H, s), 3.46(2H, t), 4.00(2H, t).
- a compound of formula (III) is prepared by mixing of 2.2 g of the compound of formula (I) with 0.056 g of potassium hydroxide at ambient temperature without of a solvent. The mixture is dried under vacuum and re- crystallized from isopropanol-acetone. Compound (III) is recovered as a white powder.
- 1 H NMR in D 2 O 2.31(9H, s), 3.10(4H, s), 3.45(2H, t), 4.02(2H, t).
- a compound of formula (IV) is prepared by mixing of 2.2 g of the compound of formula (I) with 2.82 g of thiamine base at ambient temperature without of a solvent. The mixture is dried under vacuum and re-crystallized from isopropanol-acetone. Compound (IV) is recovered as a white powder.
- Example 2 This example demonstrates injection formulation comprising compound of formula (I).
- This example demonstrates injection formulation comprising compound of formula (II).
- This example demonstrates injection formulation comprising compound of formula (III).
- This example demonstrates injection formulation comprising compound of formula (IV).
- compositions of the invention for the treatment Alzheimer's disease.
- Beta-amyloid was administered bilaterally into NBM of male Wistar rats in dose of 2 ⁇ g per each side.
- rats received intraperitoneally compositions comprising a water solution of compounds of formula (I), (II), (III), or (IV), once-a-day for 7 days in dose of 10 mg/kg.
- Control rats received saline intraperitoneally.
- a two-compartment, step-through, passive avoidance apparatus consisting of illuminated (25 x 40 x 25 cm) and dark (25 x 40 x 25 cm) compartments attached to an electrified grid floor and separated by a guillotine door (8 x 8 cm) was used.
- the rat was placed in the illuminated compartment in a position its tail directed to the closed door for 2 min to habituate to the apparatus.
- the guillotine door was opened and time to enter to dark compartment was recorded.
- the rat When the rat entered to dark compartment completely (four foots in dark compartment), the guillotine door was closed and the rat was delivered an electrical shock of 0.8 niA for 3 sec through the grid floor. After the shock, the rat was immediately placed in home cage.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
The present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salts thereof. Preferably, the pharmaceutically acceptable salt is selected from the group consisting of sodium salt, potassium salt, and thiamine salt.
Description
PHARMACEUTICAL COMPOSITIONS COMPRISING MONOCHOLINE
SUCCINATE SALTS
Field of the Invention
The invention relates to the use of monocholine salts of succinic acid in pharmaceutical compositions, particularly in compositions with a neuroprotective activity.
Background of the invention
Monocholine salt of succinic acid is known from the prior art and is disclosed, for example, by published US patent 5,124,061 as a component of compositions for increasing the resistance of plants to damage by freezing conditions.
However, there are no data in the art on the use of monocholine salt of succinic acid as an active component in pharmaceutical compositions.
Surprisingly, it is demonstrated in the present invention that monocholine salts of succinic acid manifest a pronounced effect on brain function and can be used as an active component in pharmaceutical compositions.
It is an object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of monocholine salts of succinic acid.
Detailed Description of the Invention
The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I)
The term "therapeutically effective amount" refers to a nontoxic but sufficient amount of an active agent to provide the desired therapeutic effect. Preferably, the therapeutically effective amount of compounds of formula (I) through (V) is from 0.01 to 30 mg per a unit dosage form of compositions of the present invention. More preferably, from 5 to 15 mg per a unit dosage form.
The term «pharmaceutically acceptable carrier" refers to a one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to any portion of the body of a mammal, preferably a
human. Typically, the carrier may be a liquid, solution, suspension, gel, ointment, lotion, powder, or combinations thereof. Preferably, the carrier is a pharmaceutically acceptable aqueous carrier.
The compositions of the invention are prepared by methods well-known from the art in accordance with accepted pharmaceutical procedures, for example, as described in Remington's Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pa.,
Eighteenth edition (1990).
The compositions of the invention can be prepared in a variety of unit dosage forms. Such forms are include, but are not limited to, eye drops, spray, gel, ointment, tablet, capsule, and powder. The content of compounds of formula (I) is in the range from 0.1 to 99 %, preferably 0.5 to 10 % by the weight of the composition.
The composition of the present invention can be used for treating a disease. Such diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebral ischemia and neurological damage due to stroke, diabetic polyneuropathy, glaucoma, retinopathy, and amyotrophic lateral sclerosis.
As used herein, the term "treating a disease" means treating, controlling, preventing and/or reducing one or more clinical signs (i.e., symptoms) of the disease in a mammal in need thereof.
Nonexclusive examples of mammals of the invention include humans and companion animals such as cats and dogs. Preferably, the mammal is a human.
The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
Example 1.
This example demonstrates preparation of compounds of formula (I). A compound of formula (I) is prepared by mixing 12.1 g choline base with 11.8 g succinic acid at room temperature without of a solvent. Resulting mixture is dissolved in acetone at ambient temperature; and the solution is filtered through a filter. Compound (I) is recovered as ionic liquid by evaporating of acetone from the solution. 1H NMR in D2O: 2.41(9H, s), 3.19(4H, s), 3.49(2H, t), 4.10(2H, t). Formula: C9H19NO5. Found: C 48.82%, H 8.69%, and N 6.30%. Calculated: C 48.86%, H 8.66%, and N 6.33 %. A compound of formula (II) is prepared by mixing of 2.2 g of the compound of formula (I) with 0.04 g of sodium hydroxide at ambient temperature without of a solvent. The mixture is dried under vacuum and re- crystallized from isopropanol-acetone. Compound (II) is recovered as a white powder. 1H NMR in D2O: 2.35(9H, s), 3.15(4H, s), 3.46(2H, t), 4.00(2H, t). Formula: C9H18NO5Na. Found: C 44.40%, H 7.49%, and N 5.72%. Calculated: C 44.44%, H 7.46%, and N 5.76%.
A compound of formula (III) is prepared by mixing of 2.2 g of the compound of formula (I) with 0.056 g of potassium hydroxide at ambient temperature without of a solvent. The mixture is dried under vacuum and re- crystallized from isopropanol-acetone. Compound (III) is recovered as a white powder. 1H NMR in D2O: 2.31(9H, s), 3.10(4H, s), 3.45(2H, t), 4.02(2H, t). Formula: C9H18NO5K. Found: C 41.63%, H 7.02%, and N 5.34%. Calculated: C 41.68%, H 6.99%, and N 5.40%.
A compound of formula (IV) is prepared by mixing of 2.2 g of the compound of formula (I) with 2.82 g of thiamine base at ambient temperature without of a solvent. The mixture is dried under vacuum and re-crystallized
from isopropanol-acetone. Compound (IV) is recovered as a white powder. Formula: C21H35N5O6S. Found: C 51.90%, H 7.31%, and N 14.39%. Calculated: C 51.94%, H 7.27%, and N 14.42%.
Example 2. This example demonstrates injection formulation comprising compound of formula (I).
Compound of formula (I) is dissolved in water for injection to the desired volume, 0.4M disodium phosphate is added to pH 5.0. In this manner, solution with concentration of compound of formula (I) of 5% is prepared. The solution is filtered through a sterilizing grade filter (0.2 μm), and filled into ampoules.
Example 3.
This example demonstrates injection formulation comprising compound of formula (II).
Compound of formula (II) is dissolved in water for injection to the desired volume, 0.4M disodium phosphate is added to pH 5.0. In this manner, solution
with concentration of compound of formula (II) of 5% is prepared. The solution is filtered through a sterilizing grade filter (0.2 μm), and filled into ampoules.
Example 4.
This example demonstrates injection formulation comprising compound of formula (III).
Compound of formula (III) is dissolved in water for injection to the desired volume, 0.4M disodium phosphate is added to pH 5.0. In this manner, solution with concentration of compound of formula (III) of 5% is prepared. The solution is filtered through a sterilizing grade filter (0.2 μm), and filled into ampoules.
Example 5.
This example demonstrates injection formulation comprising compound of formula (IV).
Compound of formula (IV) is dissolved in water for injection to the desired volume, 0.4M disodium phosphate is added to pH 5.0. In this manner, solution with concentration of compound of formula (IV) of 5% is prepared. The
solution is filtered through a sterilizing grade filter (0.2 μm), and filled into ampoules.
Example 6.
This example demonstrates efficacy of compositions of the invention for the treatment Alzheimer's disease.
A disease relevant to human Alzheimer's disease was induced by injection of beta-amyloid peptide 25-35 (beta-amyloid) into nucleus basalis magnocellularis (NBM) of rat brains as described by Harkany T et al. in Behav Brain Res. 1998 90(2^:133-45. Beta-amyloid was administered bilaterally into NBM of male Wistar rats in dose of 2 μg per each side. On day 16th after the amyloid injection, rats received intraperitoneally compositions comprising a water solution of compounds of formula (I), (II), (III), or (IV), once-a-day for 7 days in dose of 10 mg/kg. Control rats received saline intraperitoneally. Ony week after the last day of the treatment, passive avoidance performance in rats was tested for two consecutive days. A two-compartment, step-through, passive avoidance apparatus consisting of illuminated (25 x 40 x 25 cm) and dark (25 x 40 x 25 cm) compartments attached to an electrified grid floor and separated by a guillotine door (8 x 8 cm) was used. In the acquisition trial, the rat was placed in the illuminated compartment in a position its tail directed to the closed door for 2 min to habituate to the apparatus. The guillotine door was opened and time to enter to dark compartment was recorded. When the rat entered to dark compartment completely (four foots in dark compartment), the guillotine door was closed and the rat was delivered an electrical shock of 0.8 niA for 3 sec through the grid floor. After the shock, the rat was immediately placed in home cage. In the retention trial, conducted 24 h after the acquisition trial, the rat was placed in the illuminated compartment and the retention latency to enter into the
dark compartment was recorded until 180 s had elapsed. The latency was accepted for 180 s, if the rat did not enter the dark compartment for 180 s. Data are presented as retention latency mean ± SD (n=10).
*Differs significantly of control (P<0.05).
Claims
1. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I)
2. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (II)
Formula (II) 
and a pharmaceutically acceptable carrier.
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (III)
CH3
\ + CH2 C0OK T. i ,τm
CH, — N — CH2 — CH-> — OH • I _ Formula (III) ά s " CH2 COO
CH3 χ
and a pharmaceutically acceptable carrier.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (IV) Formula (IV)
and a pharmaceutically acceptable carrier.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/RU2007/000419 WO2009022932A1 (en) | 2007-08-02 | 2007-08-02 | Pharmaceutical compositions comprising monocholine succinate salts |
| EA201000119A EA201000119A1 (en) | 2007-08-02 | 2007-08-02 | PHARMACEUTICAL COMPOSITIONS CONTAINING MONOCHOLINE SALTS OF AMBER ACID |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/RU2007/000419 WO2009022932A1 (en) | 2007-08-02 | 2007-08-02 | Pharmaceutical compositions comprising monocholine succinate salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2009022932A1 true WO2009022932A1 (en) | 2009-02-19 |
Family
ID=39423025
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/RU2007/000419 Ceased WO2009022932A1 (en) | 2007-08-02 | 2007-08-02 | Pharmaceutical compositions comprising monocholine succinate salts |
Country Status (2)
| Country | Link |
|---|---|
| EA (1) | EA201000119A1 (en) |
| WO (1) | WO2009022932A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010033045A1 (en) * | 2008-09-16 | 2010-03-25 | Igor Anatolievich Pomytkin | Compositions and methods for prevention or treatment of beta amyloid deposition |
| US9634868B2 (en) | 2009-04-10 | 2017-04-25 | Sun Patent Trust | Wireless base station apparatus, wireless terminal apparatus, frequency resource allocation method, and method of forming transmission signal |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124061A (en) * | 1991-04-01 | 1992-06-23 | Geary Sr Robert J | Systemic plant cryoprotection with choline salts |
| US20060199862A1 (en) * | 2005-03-04 | 2006-09-07 | Pomytkin Igor A | Method for enhancing cognitive function |
-
2007
- 2007-08-02 WO PCT/RU2007/000419 patent/WO2009022932A1/en not_active Ceased
- 2007-08-02 EA EA201000119A patent/EA201000119A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124061A (en) * | 1991-04-01 | 1992-06-23 | Geary Sr Robert J | Systemic plant cryoprotection with choline salts |
| US20060199862A1 (en) * | 2005-03-04 | 2006-09-07 | Pomytkin Igor A | Method for enhancing cognitive function |
Non-Patent Citations (2)
| Title |
|---|
| POMYTKIN I A ET AL: "Study of the effect of preconditioning with succinic acid salt of choline (1:2) on the disturbances of energy metabolism in the brain during ischemia by 31P NMR in vivo.", DOKLADY. BIOCHEMISTRY AND BIOPHYSICS 2005 JUL-AUG, vol. 403, July 2005 (2005-07-01), pages 289 - 292, XP002482049, ISSN: 1607-6729 * |
| POMYTKIN N A ET AL: "Neuroprotective effect of choline succinate in rats with experimental chronic cerebral ischemia evaluated by cognitive ability tests", BIOLOGY BULLETIN, vol. 34, no. 2, March 2007 (2007-03-01), pages 144 - 147, XP002482048, ISSN: 1062-3590 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010033045A1 (en) * | 2008-09-16 | 2010-03-25 | Igor Anatolievich Pomytkin | Compositions and methods for prevention or treatment of beta amyloid deposition |
| US9634868B2 (en) | 2009-04-10 | 2017-04-25 | Sun Patent Trust | Wireless base station apparatus, wireless terminal apparatus, frequency resource allocation method, and method of forming transmission signal |
Also Published As
| Publication number | Publication date |
|---|---|
| EA201000119A1 (en) | 2010-06-30 |
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