WO2009008769A1 - Oxalate n,n-dimethyl-2-n,n-dimethylaminomethylpyridyl-3-carbomate exhibiting anti-cholinesterase activity and improving cognitive functions - Google Patents

Oxalate n,n-dimethyl-2-n,n-dimethylaminomethylpyridyl-3-carbomate exhibiting anti-cholinesterase activity and improving cognitive functions Download PDF

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WO2009008769A1
WO2009008769A1 PCT/RU2008/000393 RU2008000393W WO2009008769A1 WO 2009008769 A1 WO2009008769 A1 WO 2009008769A1 RU 2008000393 W RU2008000393 W RU 2008000393W WO 2009008769 A1 WO2009008769 A1 WO 2009008769A1
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dimethyl
exelon
oxalate
rivastigmine
dimethylaminomethylpyridyl
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PCT/RU2008/000393
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French (fr)
Russian (ru)
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Robert Georgievich Glushkov
Sergei Danilovich Juzhakov
Nataliya Ivanovna Andreeva
Evgeny Nikolaevich Salin
Larisa Nikolaevna Dronova
Svetlana Ivanovna Gavrilova
Valentina Vasilievna Asnina
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Obschestvo S Ogranishennoi Otvetstvennostu 'farmving'
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/63One oxygen atom
    • C07D213/65One oxygen atom attached in position 3 or 5

Abstract

The invention relates to chemistry and medicine, in particular to producing pharmaceutically acceptable oxalate n,n-dimethyl-2-n,n-dimethylaminomethylpyridyl-3-carbomate which exhibits anticholinesterase and antiamnestic action and which, as opposed to the other salts of said structure, is not a hygroscopic compound. The fact that the inventive compound exhibits the anticholinesterase action which is higher that the action of rivastigmin (exelon), enables to consider it as a potential medicinal agent for treating different mental disabilities.

Description

Oxalate, N, N-dimethyl-2-N, N- dimetilaminometilpipidil-3 - carbamate possessing anticholinesterase activity and the ability to improve cognitive function

The invention relates to chemistry and medicine relates to the preparation and pharmaceutically acceptable oxalate N, N-dimethyl-2- N, N-dimetilaminometilpipidil-kapbamata having anticholinesterase and antiamnesic properties.

Previously dihydrochloride this structure called aminostigmin described as compound obladayuscheee anticholinesterase activity / Prozorovsky VB, Pavlova L.B., PA PANOVA and Dr.-Chem-Pharm. Journal 1991, Nl, 87-881 /, as well as a drug used in injectable dosage form as antidote for poisoning anticholinergic compounds / Mashkovsky M. D. Medicinal agents. Moscow, "Hovaya Bolna". 2005, p. 202 /, but has not been used for the treatment of various dementias. A significant drawback aminostigmin is hygroscopic, which significantly hampers its standardization and complicates the production of dosage forms.

The present invention aims to provide a pharmaceutically acceptable number of potential drug 3-oxypyridine derivatives having anticholinesterase activity and the ability to improve cognitive function. It should be emphasized that the solutions for this problem has been synthesized by a large group of salts of the base N, N-dimethyl-2-N, N-3-dimetilaminometilpipidil kapbamata with various inorganic and organic acids and only 2 oxalate N, N- dimethyl-N-2 , N-3-dimetilaminometilpipidil kapbamata (I) showed no hygroscopic properties.

Figure imgf000003_0001
min)

Compound I is prepared by reacting a base N, N-dimethyl-2-N, N-3-dimetilaminometilpipidil kapbamata / Johp A., Aesshlimarm, Arthur Stemrel, Rat.US 2,512,732, Jupe 27.1950; Chem.Abstr., V.44, N 19-20, p. 8961-8962 (1950) / with oxalic acid in an organic solvent, e.g., acetone. The structure of I is confirmed by elemental analysis, PMR and mass spectra. Example.

Preparation of oxalate N, N-dimethyl-2-N, N- dimetilaminometilpipidil-3-kapbamata (I, amistigmin).

To a solution of 1, 89 g (0.02 mol) of oxalic acid in 1 5 ml of acetone at 20 ° C was gradually added a solution of 4.47 g (0.02 mol) N, N- dimethyl-2-N, N-3-ddmetilaminometilpipidil -kapbamata in 15 ml of acetone. The mixture was stirred for 30 min, the precipitate was filtered off, washed with 5 ml of acetone and cyshat, polychayut 5.23 g (83.55%), m.p 155-157 DC (from izo-C 3 H 7 OH)

Haydeno,%: c 49.7; H 6.40; N 13,42.C 0 H 19 N 3 O 6. Bychicleno,%: C 49,83; H 6,11; N 13,42.

Study amistigmina pharmacological activity was compared with an analogue action of rivastigmine (Exelon), which is used as a means of enhancing cognitive function in patients with various dementias, particularly Alzheimer's disease / Gavrilova SI. Pharmacotherapy of Alzheimer's disease. Moscow, "Pylc", 2003, p. 115 /. In our country, rivastigmine (Exelon) a limited use due to high costs.

In vitro conditions using commercial preparations of human erythrocyte acetylcholinesterase and butyrylcholinesterase horse serum amistigmin by anticholinesterase activity constants determined by the values ​​of inhibition (KJ) significantly (by 2 orders against acetylcholinesterase and butyrylcholinesterase procedure 1) exceeds rivastigmine (Table. 1 ). Thus, if amistigmin effectively inhibits both enzymes, the rivastigmine (Exelon) inhibit butyrylcholinesterase 1 order of magnitude stronger than acetylcholinesterase.

In ex vivo conditions (in isolated preparations brain acetylcholinesterase and rat blood, 10 min of incubation time) amistigmin by anticholinesterase activity determined from the values of ki and IC 50 are also substantially (about 3) exceeds rivastigmine (Exelon) (tabl.2 and 3).

In experiments on rats we studied the effect of a single oral administration amistigmina and rivastigmine (Exelon) in ekvitoksicheskih doses on learning and memory disorders induced by scopolamine, using the method of the passive avoidance / Andreeva H.I., Lenin BB, MA Kalinkina and others-Chem-Pharm. magazine, 2005, N 1, p. 6-9 /. It is established that under the effect of scopolamine is the number of animals preserved skill passive avoidance response decreases (tab. 4). Amistigmin causes little dose-dependent attenuation of amnestic effect of scopolamine. In general, similar results were obtained when studying rivastirmina (Exelon). Thus it is not found significant differences in the antiamnestic effect of the test drugs. In experiments on rats we studied the effect of a single oral administration and amistigmina rivastirmina (Exelon) in ekvitoksicheskih doses on memory and learning disorders caused by electric shock using the method of passive avoidance response. It is found that this amnesia model (as opposed to the above data, obtained on skopolaminovoy model) as the amistigmin and rivastigmine (Exelon) provided slight (not statistically significant) antiamnesic action (tabl.5).

In experiments on mice we studied the effect of a single oral administration and amistigmina rivastirmina (Exelon) in ekvitoksicheskih doses on memory and learning disorders caused by electric shock using the method of passive avoidance response given in the above source. It was established that in the intact animals amistigmin causes a dose-dependent, significant improvement of learning (there is a significant increase in the latent period of entry into the dark compartment of the chamber). In general, a similar effect is observed under the influence rivastirmina (Exelon) in ekvitoksicheskih doses (middle column of Table. 6). Mice treated with electroshock after training (without administration of test drug) there is a significant deterioration in the conditioned reflex activity, which is manifested 3 -fold decrease of the latent period of entry into dark compartment chamber. Introduction amistigmina, as well as rivastigmine (Exelon), immediately after the training (up shock) results in a dose-dependent significant weakening amnestic effect electroshock (latency is increased more than 2-fold) (tabl.6 right column).

In experiments on rats examined the effects of repeated (5 days) oral administration amistigmina and rivastigmine (Exelon) in ekvitoksicheskih at doses impaired memory and learning, in multiple (5 days) administration of scopolamine method using active avoidance conditioned response / Bures Ya Bureshova O ., Houston DP Techniques and basic experiments for the study of brain and behavior. Moscow, "Bycshaya shkola" 1991, 399 /. Found that the administration of scopolamine for 30-60 min before training significantly penalized session information storing process (tabl.7). Amistigmin starting from 2 days of training, as opposed to rivastigmine, significantly reduces training violation caused by scopolamine (Table 8).

Thus, the claimed compound (amistigmin) of anticholinesterase activity and ability to improve cognitive function exceeds used in clinical practice for the treatment of dementia drug rivastigmine (Exelon), in connection with which it is of interest as a potential antiamnesic agent. Table 1

Amistigmina anticholinesterase activity and rivastigmine (Exelon) under Ip vitgo (commercial preparations of human erythrocyte acetylcholinesterase and butyrylcholinesterase horse serum)

Figure imgf000007_0001

table 2

Amistigmina anticholinesterase activity and rivastigmine (Exelon) in ex vivo conditions (in isolated preparations and erythrocyte acetylcholinesterase golovnogomozga rats)

Figure imgf000007_0002

TABLE 3

Amistigmina anticholinesterase activity and rivastigmine (Exelon) in ex vivo conditions (in isolated preparations of brain and erythrocyte acetylcholinesterase rats)

Figure imgf000007_0003
TABLE 4

Antiamnesic action amistigmina and rivastigmine (Exelon) in the amnesia caused by scopolamine in rats by the method of passive avoidance

Figure imgf000008_0001

* P <0,05 compared with control

Table 5

Antiamnesic action of compounds amistigmina and rivastigmine (Exelon) in rats at amnezii, vyzyvaemoy elektposhokom, Po procedure of passive avoidance

Drug Dose Number latent period, s (mg / kg orally) conditioned avoidances

Control 12/16 (75%) 151 ± 11,9

Electroshock 8/22 (36.4%) 83 ± 4,6

Amistigmin 0.05 (1/15 by 7/13 (53.8%) 108 ± ll, 3 8/15 (53.3% 0120 ± 9,8 * LDso) 0.016 (1/50)

Rivastigmine 1.27 (1/15 of the LDso) 5/11 (45.5%) 123 ± 10,6 * (exelon) 0.19 (1/100) 7.13 (53.8%) 88 ± 9,4

* P <0,05 compared to electroshock Table 6

Antiamnesic action amistigmina and rivastigmine (Exelon) in mice amnesia induced by electric shock, according to the method of the passive avoidance

Drug Dose latent period of stay in mice

(Mg / kg orally) light chamber (s) 24 h after:

training and subsequent electric shock (amnesia)

Control - 92,4 ± 13

(N = 12)

0.01 ± Amistigmin ΙZO Yu

(N = 16)

Control - 99.2 ± 20 (n = 7) Amistigmin 0.03 177 ± 3 *

(N = 9)

Control - 72,5 ± 4

(N = 7)

Rivastigmine 0,14 88,8 ± 20

(Exelon)

(N-9)

Control -

(N = 8) 94,3 ± 19

Rivastigmine 0,45 175,8 ± 4 *

(Exelon)

(N = 6)

Control - 28,2 ± 4,8

(N = 14) 69,5 ± 13 *

Amistigmin 0,01 79,6 ± 12 *

(N = 23) 0.03

Control 30,9 ± 4,9

(N-11)

Rivastigmine 0,14 69,2 ± 19

(Exelon)

(N = 22) 0,45 82,7 ± 13 *

* P <0,05 compared to control Table 7

Amistigmina antiamnesic action in rats with amnesia induced by scopolamine, in the conventional method, the reaction of active avoidance (hopping camera)

Day 2 Control Scopolamine Amistigmin 0.05 mg / kg obuchemg / kg / b inside Nia for 5 days in 5 days

Number -During Number of Number of Number of Number of Number of animals animals conditional conditional animals conditional avoidance avoidance avoidances

January 31 0,35 ± 0,17 20 0,25 ± 0,1 June 10 0,4 ± 0,22

February 31 20 2,16 ± 0,49 1,0 ± 0,47 .. 10 2,9 ± 1,08 *

March 31 20 3,54 ± 0,6 1,4 ± 0,56 * 10 3,6 ± 1,3 *

April 31 4,97 ± 0,6 20 2,95 ± 0,66 * 10 5,3 ± 1,26 *

31 May 20 6,45 ± 0,6 3,5 ± 0,74 * 5,4 ± 1 10 0

P <0,05 compared with control

Table 8

Antiamnesic action rivastigmine (ekselbna) in rats with amnesia induced by scopolamine, in the conventional technique of active avoidance response (hopping camera)

Figure imgf000010_0001

Number of Number of Number of Number of Number of Number of conditional zhivotuslovnyh zhivotuslovnyh zhivotizbegany GOVERNMENTAL avoidance avoidances GOVERNMENTAL GOVERNMENTAL

January 11 10 2,6 ± 0,7 0,6 ± 0,27 * 0,7 ± 0,4 10

February 11 10 5,5 ± 0,8 2,0 ± 0,9 * 1,6 ± 0,7 10

March 11 10 7,3 ± 0,8 3,6 ± 1,2 * 4,0 ± 0,9 10

4 AND 10 7,9 ± 0,7 5,1 ± 1,2 * 5,8 ± 0,9 10

May 11 10 8,8 ± 0,4 6,5 ± 0,8 * 5,9 ± 1,1 10

P <0,05 compared with control

SUBSTITUTE SHEET (RULE 26)

Claims

Claim
Oxalate, N, N-dimethyl-2-N, N-carbamate-3- dimetilaminometilpipidil different from other salts, such as dihydrochloride, lack of hygroscopicity, having anticholinesterase activity and improves cognitive function
PCT/RU2008/000393 2007-07-09 2008-06-25 Oxalate n,n-dimethyl-2-n,n-dimethylaminomethylpyridyl-3-carbomate exhibiting anti-cholinesterase activity and improving cognitive functions WO2009008769A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011100373A1 (en) 2010-02-09 2011-08-18 The Johns Hopkins University Methods and compositions for improving cognitive function

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2451513C1 (en) * 2010-12-27 2012-05-27 Федеральное государственное унитарное предприятие Научно-производственный центр "Фармзащита" Федерального медико-биологического агентства" Method for production of n,n-dimethyl-(2-n1,n1-dimethylaminomethylpyridil-3)carbamate or salts thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2512732A (en) * 1948-05-14 1950-06-27 Hoffmann La Roche Carbamic acid esters of (3-hydroxy-2-pyridylmethyl) amines and salts thereof
RU1767843C (en) * 1990-06-15 1995-05-27 Научно-исследовательский институт военной медицины Method of synthesis of biologically active substance on the basis of n,n-dimethyl- (2-n',n'- dimethylaminomethylpyridyl-3)-carbamate salt and styrenevinylbenzene sulfocationite showing inhibition effect on choline esterases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2512732A (en) * 1948-05-14 1950-06-27 Hoffmann La Roche Carbamic acid esters of (3-hydroxy-2-pyridylmethyl) amines and salts thereof
RU1767843C (en) * 1990-06-15 1995-05-27 Научно-исследовательский институт военной медицины Method of synthesis of biologically active substance on the basis of n,n-dimethyl- (2-n',n'- dimethylaminomethylpyridyl-3)-carbamate salt and styrenevinylbenzene sulfocationite showing inhibition effect on choline esterases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011100373A1 (en) 2010-02-09 2011-08-18 The Johns Hopkins University Methods and compositions for improving cognitive function

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