WO1992002498A1 - Compounds having cognition enhancer activity, a process for the preparation thereof and pharmaceutical compositions containing them - Google Patents
Compounds having cognition enhancer activity, a process for the preparation thereof and pharmaceutical compositions containing them Download PDFInfo
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- WO1992002498A1 WO1992002498A1 PCT/EP1991/001298 EP9101298W WO9202498A1 WO 1992002498 A1 WO1992002498 A1 WO 1992002498A1 EP 9101298 W EP9101298 W EP 9101298W WO 9202498 A1 WO9202498 A1 WO 9202498A1
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- compounds
- formula
- pharmaceutically acceptable
- pyrrolidon
- preparation
- Prior art date
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- 0 CCCNCCN*=C Chemical compound CCCNCCN*=C 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
Definitions
- the present invention relates to compounds of general formula (I):
- R is a linear or branched C ⁇ -Cg alkyl group, and the salts with pharmaceutically acceptable acids thereof.
- the compounds of the invention can be recognized as cognition enhancers. Said compounds proved to be extremely effective in preserving and maintaining functional capacity of the brain. Therefore, according to the obtained pharmacological results, the use of the compounds of the invention is proposed for the preparation of a medicament useful for the treatment of cerebral degeneration states and of memory disorders. Kence, the invention further relates to pharmaceutical compositions capable of preserving and restoring cerebral functional capacity and containing one or more compounds of formula (I) as active ingredient, optionally combined with other active ingredients.
- the compounds (I) can also contain some asymmetric carbon atoms; therefore the related stereoisomers and the mixtures thereof are also included in the invention.
- a further object of the invention is a process for the preparation of compounds of formula (I), characterized in that an activated derivative of (2- pyrrolidon-1-yl)acetic acid of formula (II)
- X is an halogen atom, preferably a chlorine atom, or a C,-C ⁇ alkoxy group, or an alkoxycarbonyloxy group, is reacted with a N-alkylpiperazine of formula
- organic and inorganic acids are: hydracids, sulfuric, phosphoric, nitric, acetic, citric, tartaric, fumaric, maleic, benzilic acids, and the like.
- the compounds (I) can directly be prepared from (2-pyrrolidon-1-yl)acetic acid and alkylpiperazines (III) by activating the acid with dicyclohexylcarbodiimide, carbonyldiimidazole, and the like.
- T.L.C. shows two main products with R f about 0.3 and 0.5.
- the two products are separated by distilling under reduced pressure: the desired product, having f 0.3, is collected in the 146-151°C range, at 0.1 mm Hg pressure, while the side product, having R 0,5, is collected in the 100-140°C range, at 0.1 mm Hg pressure. Once distilled, the desired compound solidifies at room temperature.
- the experiment was carried out mainly according to Giurgea C. et al. (J. Pharmacol. - Paris - 3, 17; 1972).
- the rats were put at the entrance of a plexiglas labyrinth full of water, with a sloping grid, located on the opposite side to the entrance, by means of which the rat could go out from the labyrinth.
- the experimental apparatus were square dark smoke-grey plexiglas cages, sizing 30x30x30 cm.
- the floor was constituted of a stainless steel grid alternatively connected with the positive and the negative pole of a an electric discharge supplying stimulator.
- a black knurled PVC cylinder vertically hanging from the box ceiling, was located.
- a visual and acoustic stimulus which consisted of lighting a lamp and ringing a buzzer, was produced.
- the stimulus lasted 5 seconds, after which a 5 second 0.20 A electric discharge was supplied.
- the animal to avoid the discharge, had the possibility of jumping on the pole.
- the stimulus was repeated 15 times each session; the sessions were repeated once a day for the three following days.
- the rats were orally treated with carrier (tap water, as control), with PU-3021 (25-50-100 mg/kg per day) and with Piracetam (100 mg/kg per day) as reference compound.
- carrier tap water, as control
- PU-3021 25-50-100 mg/kg per day
- Piracetam 100 mg/kg per day
- mice Male rats, weighing 22-24 g, fasting for about 12 hours, were used. The animals were random distributed among groups of 10 animals each, and orally treated with carrier (control and control + ESC), with P ⁇ -3021 (50-100 mg/kg + ESC) and with Oxiracetam (100 mg/kg + ESC), which was used as the reference compound.
- carrier control and control + ESC
- P ⁇ -3021 50-100 mg/kg + ESC
- Oxiracetam 100 mg/kg + ESC
- the rats were subjected to the passive avoidance tests, which were carried out according to the method described by Lenegre et al. (Drug Develop. Res. 13, 57; 1988).
- the experimental apparatus consisted of a two compartment box: the former being smaller and illumina ⁇ ted, while the latter being larger and dark.
- the two compartments were separated by a bulkhead that could be opened, so as to let the animals pass through it.
- the animal was put in the lit compartment and after 15 seconds the bulkhead was opened.
- a current discharge was applied for 3 seconds to the metal grid floor.
- Si a second test (S2) was carried out, in order to verify if the animals memorized the punishment.
- the memorization process in the animals was alternated by means of electroconvulsive shock.
- PU-3021 administration significantly weakened the electroshock amnestic effect at the dose of 200 mg/kg.
- the protective effect resulted already evident even after administering 50 mg/kg.
- Compounds (I) can be formulated in the form of capsules, pellets, granulate sachets, vials for intramuscular and intravenous administration, drinkable solutions, according to the methods and excipients, carriers, flavourings, sweeteners and other ingredients, well known in pharmaceutical technique.
- Said formulations can contain 50 to 1500 mg, preferably 100 to 1000 mg active ingredient, each unitary dose.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
4-Alkyl-1-[(2-pyrrolidon-1yl)acetyl]piperazine of formula (I), wherein R is C1-C5 alkyl and/or the salts thereof with pharmaceutically acceptable acids, proved to be endowed with remarkable cognition enhancer activity.
Description
COMPOUNDS HAVING COGNITION ENHANCER ACTIVITY, A PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates to compounds of general formula (I):
wherein R is a linear or branched C^-Cg alkyl group, and the salts with pharmaceutically acceptable acids thereof.
Due to their peculiar pharmacological activity, the compounds of the invention can be recognized as cognition enhancers. Said compounds proved to be extremely effective in preserving and maintaining functional capacity of the brain. Therefore, according to the obtained pharmacological results, the use of the compounds of the invention is proposed for the preparation of a medicament useful for the treatment of cerebral degeneration states and of memory disorders. Kence, the invention further relates to pharmaceutical compositions capable of preserving and restoring cerebral functional capacity and containing one or more compounds of formula (I) as active ingredient, optionally combined with other active ingredients.
According to the meanings of R, the compounds (I) can also contain some asymmetric carbon atoms;
therefore the related stereoisomers and the mixtures thereof are also included in the invention.
A further object of the invention is a process for the preparation of compounds of formula (I), characterized in that an activated derivative of (2- pyrrolidon-1-yl)acetic acid of formula (II)
wherein X is an halogen atom, preferably a chlorine atom, or a C,-Cς alkoxy group, or an alkoxycarbonyloxy group, is reacted with a N-alkylpiperazine of formula
(III)
wherein R is as above defined, and that the so obtained compounds of formula (I) are salified with pharmaceutically acceptable organic or inorganic acids. Examples of organic and inorganic acids are: hydracids, sulfuric, phosphoric, nitric, acetic, citric, tartaric, fumaric, maleic, benzilic acids, and the like.
According to another method, the compounds (I) can directly be prepared from (2-pyrrolidon-1-yl)acetic acid and alkylpiperazines (III) by activating the acid
with dicyclohexylcarbodiimide, carbonyldiimidazole, and the like.
The following examples further illustrate the invention. EXAMPLE 1
4-Methyl-l-[ (2-pyrrolidon-l-yl)acetyl]piperazine
(I, R - CH3) a) Ethyl (2-pyrrolidon-l-yl)acetate
13.25 g (0.25 moles + 10% excess) 50% NaH are suspended in 85 ml dry toluene. 19.5 ml (0.25 moles) 2- pyrrolidone, dissolved in 20 ml toluene, are slowly dropped. (As the reaction is hexothermic the temperature is kept about 30CC). After the addition, the reaction mixture is allowed to stand for about 15 minutes, then 30.6 ml (0.25 moles + 10% excess) ethyl bromoacetate, dissolved in 25 ml toluene, are dropped at room temperature. After the addition, the reaction mixture is allowed to stand for 4 hours at room temperature. Sodium bromide is filtered off. The toluene solution is evaporated under reduced pressure. The liquid residue is distilled through a Vigreux's column under reduced pressure, collecting the fraction with b.p. 172-176°C, at 30 mm Hg (colourless liquid). Yield 84%. The elemental analysis and the NMR spectra agreed with the foreseen structure, b) (2-Pyrrolidon-l-yl)acetic acid
16 g (0.093 moles) the compound obtained in step a) and 5.8 g (0.093 moles + 10% excess) KOH are dissolved in 100 ml methyl alcohol. The solution is refluxed for 5 hours. The solvent is distilled off and the colourless solid residue is
dissolved in 40 ml 10% HC1, then water is evaporated. The colourless solid residue is taken up with ethyl alcohol. Insoluble potassium chloride is filtered off. The ethanolic filtrate, containing the free acid, is evaporated. 13 g crude acid are obtained as a beige solid giving a single spot in T.L.C. Yield 97%. The elemental analysis and the NMR spectra of a sample recrystallized from isopropyl ether/diethyl ether were in agreement with the foreseen structure. c) Title compound
14.4 g (0.1 moles) (2-pyrrolidon-l-yl)acetic acid are dissolved in 300 ml dioxane. 15.4 ml (0.1 moles + 10% excess) triethylamine and 10.5 ml (0.1 moles + 10% excess) ethyl chloroformate are added. Thriethylamine hydrochloride precipitates immediately. The mixture is left under stirring at room temperature for about 30 minutes. TEA-HC1 is filtered off and 22.3 ml (0.1x2 moles) N-methylpiperazine are added to the filtered dioxane solution, which contains the mixed anhydride. The mixture is refluxed for 24 hours. Dioxane is evaporated off. The orange liquid residue is dissolved in 40 ml 10% HC1. Then pH is adjusted to 9-10 with 20 ml 10% NaOH. The solution is saturated with NaHCO, and repeatedly extracted with CH2C12. The organic layers are collected, dried over Na2S04 and evaporated. 13 g an orange thick liquid are obtained. T.L.C. shows two main products with Rf about 0.3 and 0.5. The two products are separated by distilling under reduced pressure: the desired product, having f 0.3, is collected in the 146-151°C range, at 0.1 mm Hg pressure, while the side product, having R 0,5, is
collected in the 100-140°C range, at 0.1 mm Hg pressure. Once distilled, the desired compound solidifies at room temperature. The solid is taken up with diisopropyl ether and filtered. A colourless compound is obtained with a 52% yield, m.p. 89-91cC, soluble in ethyl acetate, ethyl alcohol, methyl alcohol, CHC13 slightly soluble in water.
Analytical data, IR and NMR agree with the foreseen structure. The bromide (m.p. 136-138βC) and fu arate (m.p. 114-117°C) salts are obtained by conventional means from the corresponding acids.
EXAMPLE 2 4-Isopropyl-l-[ (2-pyrrolidon-l-yl)acetyl3piperazine (I, R » CH(CH3)2) The title compound (yield 78% m.p. 74-76°C) is obtained according to the method in Example 1 c), except N-isopropylpiperazine is used. Monotartrate salt: m.p. 132-135°C. Pharmacological activities The following pharmacological tests were performed with the compound of Example 1, hereinafter named Pϋ- 3021.
1) Water labirinth test; learning and memory storage after electroshock and long lasting anoxia. Experimental istar male rats, 170-190 g, random distributed in
5 groups, 20 animals each, were orally treated with carrier (control), with Pϋ-3021 (25-50-100 mg/kg) and with Piracetam (100 mg/kg). Daily treatment was carried out for 5 consecutive days.
The experiment was carried out mainly according to
Giurgea C. et al. (J. Pharmacol. - Paris - 3, 17; 1972). Ninety minutes after the daily administration, the rats were put at the entrance of a plexiglas labyrinth full of water, with a sloping grid, located on the opposite side to the entrance, by means of which the rat could go out from the labyrinth.
The number of the errors made by the rat in reaching the exit and the time it took to find the metal grid, that was used as exit, were evaluated. The fifth day, immediately after the labyrinth test, ten animals of each group were subjected to two distinct methods to produce amnesia: a) convulsivant electroshock (ESC) b) severe hypoxia. Thirty minutes after inducing amnesia, the animals were put again in the labyrinth to evaluate their mnemonic capability by means of the two previously used memory parameters. Results a) ESC amnesia
The group of animals treated with Piroxicam showed no statistically significant differences as compared with control animals in making errors, but it showed a slightly short time in finding the labyrinth exit. PU-3021, especially in the medium and high dosage, produced an evident effect both on learning and on ESC memory loss, b) Amnesia from severe hypoxia
The animals treated with Pϋ-3021 remarkably improved their psycophysical capacities, in fact they went through the labyrinth in a shorter time and made
fewer mistakes, as compared to controls.
The animals treated with high doses of PU-3021 proved to be unaffected by hypoxia in relation to their acquired memory; on the contrary, the animals continued with learning. Even with the lowest dose of Pϋ-3021, an evident protection from memory loss was evidenced. 2) Effect on active avoidance in "Pole jumping" test in rat
Experimental Modified De Wied's test was used (Proc. Soc. Exp. Biol. Med. 122: 28-32, 1966).
Five groups, eight female Wistar rats each, weighing 125-175 g, were used. The experimental apparatus were square dark smoke-grey plexiglas cages, sizing 30x30x30 cm. The floor was constituted of a stainless steel grid alternatively connected with the positive and the negative pole of a an electric discharge supplying stimulator. In the centre of the cage, 5 cm from the bottom, a black knurled PVC cylinder vertically hanging from the box ceiling, was located.
One minute after introducing the animals in the box, a visual and acoustic stimulus, which consisted of lighting a lamp and ringing a buzzer, was produced. The stimulus lasted 5 seconds, after which a 5 second 0.20 A electric discharge was supplied.
The animal, to avoid the discharge, had the possibility of jumping on the pole. The stimulus was repeated 15 times each session; the sessions were repeated once a day for the three following days.
Avoided punishments were counted on 2 and 3
day.
The rats were orally treated with carrier (tap water, as control), with PU-3021 (25-50-100 mg/kg per day) and with Piracetam (100 mg/kg per day) as reference compound. The treatment was carried out twice a day, the second tim 1 hour before the test. Results
Only the treatment with the highest doses of Pϋ- 3021 produced a statistically significant effect. In fact, on 2n and 3 day of the experiment, the number of animals that avoided punishment (avoidance number) was remarkably higher than the one recorded in the control group.
3) Effect on the passive avoidance conditioned response: antagonism of amnesia from electroshock Experimental
Male rats, weighing 22-24 g, fasting for about 12 hours, were used. The animals were random distributed among groups of 10 animals each, and orally treated with carrier (control and control + ESC), with Pϋ-3021 (50-100 mg/kg + ESC) and with Oxiracetam (100 mg/kg + ESC), which was used as the reference compound.
After 90 minutes from the treatment, the rats were subjected to the passive avoidance tests, which were carried out according to the method described by Lenegre et al. (Drug Develop. Res. 13, 57; 1988).
The experimental apparatus consisted of a two compartment box: the former being smaller and illumina¬ ted, while the latter being larger and dark. The two compartments were separated by a bulkhead that could be opened, so as to let the animals pass through it.
The animal was put in the lit compartment and after 15 seconds the bulkhead was opened. When the animal went with all its four feet into the dark compartment, a current discharge was applied for 3 seconds to the metal grid floor. Immediately after, the animal was removed from the cage. After 24 hours from the first test, named Si, a second test (S2) was carried out, in order to verify if the animals memorized the punishment. The memorization process in the animals was alternated by means of electroconvulsive shock. Results
PU-3021 administration significantly weakened the electroshock amnestic effect at the dose of 200 mg/kg. The protective effect resulted already evident even after administering 50 mg/kg.
Compounds (I) can be formulated in the form of capsules, pellets, granulate sachets, vials for intramuscular and intravenous administration, drinkable solutions, according to the methods and excipients, carriers, flavourings, sweeteners and other ingredients, well known in pharmaceutical technique. Said formulations can contain 50 to 1500 mg, preferably 100 to 1000 mg active ingredient, each unitary dose.
Claims
1. Compounds of formula (I)
wherein R is a linear or branched C,-c5 alkyl, pure stereoisomers and related mixtures, pharmaceutically acceptable inorganic and organic acid addition salts thereof.
2. A compound according to claim 1, which is 4- methyl-l-[ (2-pyrrolidon-l-yl)acetyl]piperazine and pharmaceutically acceptable organic and inorganic addition salts thereof.
3. A process for the preparation of the compounds of formula (I), characterized in that an activated derivative of (2-pyrrolidon-l-yl)acetic acid of formula (ID
wherein X is an halogen atom, preferably a chlorine atom, or a -__--__ alkoxy residue, or an alkoxycar- bonyloxy residue, is reacted with a N-alkylpiperazine of formula (III) 
wherein R is as above defined, and the so obtained compounds of formula I are optionally salified with pharmaceutically acceptable organic or inorganic acids.
4. A process according to claim 3, characterized in that (2-pyrrolidon-l-yl)acetic acid is activated with dicyclohexylcarbodiimide or carbonyldiimidazole.
5. Pharmaceutical compositions useful for preserving and restoring cerebral functional capacity, containing a compound of claims 1 or 2 as the active ingredient, in admixture with pharmaceutically acceptable carriers.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02124090A IT1243702B (en) | 1990-08-08 | 1990-08-08 | COMPOUNDS WITH NOOTROP ACTIVITY, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS |
| IT21240A/90 | 1990-08-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992002498A1 true WO1992002498A1 (en) | 1992-02-20 |
Family
ID=11178893
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1991/001298 WO1992002498A1 (en) | 1990-08-08 | 1991-07-11 | Compounds having cognition enhancer activity, a process for the preparation thereof and pharmaceutical compositions containing them |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU8183491A (en) |
| IT (1) | IT1243702B (en) |
| WO (1) | WO1992002498A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002051836A1 (en) * | 2000-12-27 | 2002-07-04 | Kyowa Hakko Kogyo Co., Ltd. | Dipeptidyl peptidase iv inhibitor |
| US7208497B2 (en) | 2001-07-02 | 2007-04-24 | Novo Nordisk A/S | Substituted piperazines and diazepanes |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0089900A1 (en) * | 1982-03-24 | 1983-09-28 | Prodes S.A. | New N-((2-oxo-1-pyrrolidinyl)acetyl)piperazines, the methods of producing such new compounds and their salts as well as pharmaceutical preparations for therapeutic use containing these compounds or salts |
| EP0299493A2 (en) * | 1987-07-15 | 1989-01-18 | Shionogi & Co., Ltd. | N-[(2-Oxopyrrolidin-1-yl)-acetyl]piperazine derivatives and drug for senile dementia |
| EP0408524A1 (en) * | 1989-07-12 | 1991-01-16 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | (Pyrrolidin-2-on-l-yl) acetamides as enhancers of learning and memory and pharmaceutical compositions comprising same |
-
1990
- 1990-08-08 IT IT02124090A patent/IT1243702B/en active IP Right Grant
-
1991
- 1991-07-11 AU AU81834/91A patent/AU8183491A/en not_active Abandoned
- 1991-07-11 WO PCT/EP1991/001298 patent/WO1992002498A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0089900A1 (en) * | 1982-03-24 | 1983-09-28 | Prodes S.A. | New N-((2-oxo-1-pyrrolidinyl)acetyl)piperazines, the methods of producing such new compounds and their salts as well as pharmaceutical preparations for therapeutic use containing these compounds or salts |
| EP0299493A2 (en) * | 1987-07-15 | 1989-01-18 | Shionogi & Co., Ltd. | N-[(2-Oxopyrrolidin-1-yl)-acetyl]piperazine derivatives and drug for senile dementia |
| EP0408524A1 (en) * | 1989-07-12 | 1991-01-16 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | (Pyrrolidin-2-on-l-yl) acetamides as enhancers of learning and memory and pharmaceutical compositions comprising same |
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 98, 1983, page 562, abstract no. 89386z, (Columbus, Ohio, US), & CS,A,199314 (M. PROTIVA et al.) 1 October 1982, see the whole abstract; compound with R=Me, CN 84762-34-5 * |
| COLL. CZECH. CHEM. COMMUN. vol. 55, no. 6, 1990, V. VALENTA et al.: "Potential nootropic agents: synthesis of a series of (2-oxo-1-pyrrolidinyl)acetic acid piperazides", pages 1613-1629, see the whole article; compounds VI,VII on page 1615 and exp. section * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002051836A1 (en) * | 2000-12-27 | 2002-07-04 | Kyowa Hakko Kogyo Co., Ltd. | Dipeptidyl peptidase iv inhibitor |
| US7208497B2 (en) | 2001-07-02 | 2007-04-24 | Novo Nordisk A/S | Substituted piperazines and diazepanes |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1243702B (en) | 1994-06-21 |
| IT9021240A0 (en) | 1990-08-08 |
| IT9021240A1 (en) | 1992-02-08 |
| AU8183491A (en) | 1992-03-02 |
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