Therapeutic applications of the derivative tamilchelvan

 

(57) Abstract:

The invention can be used in pharmacy and medicine for the preparation and use of tools and products designed to restrict or inhibit the effects caused by neurotoxic substances (neurotoxins). The stated use of 2-methyl-1-(piperidinyl)-1-(2-thienyl)cyclohexane in racemic form, in the form of practically pure diastereoisomers or enantiomers as the beginning of the current drugs. Medications are designed to limit or inhibiting effects caused by exposure to exogenous neurotoxic substances or neurotoxins. The proposed composition having the specified action, and a combination product containing 2-methyl-1-(piperidinyl)-1-(2-thienyl)cyclohexane. If this composition contains at least one pharmaceutical substance actions, and the product is at least one substance selected from the anticholinergic, antispasmodic substances and reaktivatory of cholinesterase. Introduction components of the combined product may be simultaneous, separate or dispersed in time. The use of the invention allows to restore the normal condition of the organisms is correspondingly applied tamilchelvan, one or in combination with other pharmaceutically active substances for the preparation of medicines intended to limit or inhibit the effects caused by neurotoxic substances, i.e. neurotoxins. The invention also concerns a product containing tamilchelvan and at least one anticholinergic, anticonvulsive substance or reactivator of cholinesterase, as well as pharmaceutical compositions based on it. The specified product is particularly interesting because it restricts or inhibits the effects of neurotoxic substances.

In the family of neurotoxic agents, neurotoxins are substances such as organophosphorus compounds, which are found, for example, insecticides or pesticides, domestic or industrial applications, as well as in combat gases, such as soman, sarin, Tabun or VX. Among the existing therapeutic premedication methods aimed at combating intoxication named substances, there is no method that could prevent neuropathologically complications.

The object of the invention is the use of tamilchelvan, otvechajuwego the Chennai for limiting or inhibiting effects, caused by the use of neurotoxic and neurotoxin substances in primates and especially humans. This connection can be used individually or together with other substances, the pharmaceutical activity of which consists in the restriction or inhibition effects of neurotoxic substances.

Tamilchelvan above, described in the patent EP 396734. Tamilchelvan 2 asymmetric carbon atoms, the connection may be in racemic form, in the form of practically pure diastereoisomers or enantiomers.

Getting diastereoisomers 1-tamilchelvan consists in the interaction of 2-patientline with 2 methylcyclohexanol obtained 2-methyl-1-(2-thienyl)cyclohexanol process by NaN3to obtain the corresponding azide, restore this azide and finally treated with 1,5-halogenation. Diastereoisomer CIS and TRANS share preparative chromatography on silica gel, using a mixture of hexane/simple ether (95/5 by volume): the first fraction of the form, TRANS crystallized at 40-41oWith; the second fraction of the form CIS, crystallized at 80-81

More specifically, an object of the invention is the use of tamilchelvan defined above, together with at least one substance selected from the anticholinergic substances, anticonvulsant substances and reaktivatory of cholinesterase.

More specifically, an object of the invention is the use of teenycinema mentioned above, together with at least one anticholinergic agent, at least one anticonvulsant substance and at least one reactivation of cholinesterase.

Pharmacological terms used in the text of the description, are the classical value, known to specialists in this field. Thus, as anticholinergic substances include the following ingredients: atropine, scopolamine, N-oxide atropine, digoxigenin and methyl sulfate of tiemonium. As anticonvulsive substances include, for example, the following substances: phenobarbital, primidone, carbamazepine, ethosuximide, phenytoin, sodium valproate, progabid, gabapentin, vigabatrin, loprazolam, benzodiazepines, such as clonazepam, clobazam, diazepam and prodiesel. As reaktivatory of cholinesterase can be called pralidoxime, oligotrichida fact, that tamilchelvan used in conjunction with a reversible cholinesterase inhibitor that is designed to receive up to exposure to neurotoxic substances, or neurotoxins. Among the reversible cholinesterase inhibitors can be called pyridostigmine, physostigmine.

The object of the invention is a product, as a medicinal product containing teenagersteen described above, in combination with at least one pharmaceutically active substance, which is able to restrict or inhibit the effects produced by neurotoxic substances or neurotoxins, and pharmaceutical composition containing this product. In particular, the invention relates to a product as a medicinal product containing tamilchelvan described above, in racemic form or in the form of practically pure diastereoisomers or enantiomers in combination with at least one substance selected from the anticholinergic, antispasmodic substances and reaktivatory cholinesterase. Preferably, the specified product contains tamilchelvan and at least one anticholinergic agent, one anticonvulsant substance and one reactivator choline one substance, selected from anticholinergic, antispasmodic substances and reagents cholinesterase as a combination product for simultaneous, separate or dispersed in time use and intended for limiting or inhibiting effects of neurotoxic substances or neurotoxins.

The invention also concerns the product mentioned above, characterized in that it additionally contains a cholinesterase inhibitor that is designed to receive prior to exposure to neurotoxic substances, or neurotoxins. Tamilchelvan defined above, can be introduced in a dose containing from 0.001 to 10 mg/kg, preferably from 0.01 to 0.1 mg/kg of a Substance, which if necessary, connect, such as anticholinergics, anticonvulsants substances or reaktivatory of cholinesterase known in pharmacology, administered in doses that are usually recommended in the relevant pharmacological fields.

Tamilchelvan according to the invention, as well as substances with pharmaceutical activity, which if necessary is used, can be introduced classical ways: by mouth, intramuscularly, intraperitoneally, enter doctitle, cyanocyclohexyl injected, and substances with pharmaceutical activity, which if necessary use, such as anticholinergics, anticonvulsants substances and reaktivatory cholinesterase, intramuscularly or intravenously. When tamilchelvan used together with at least one pharmaceutical substance actions, as defined above, the method of introduction of tamilchelvan may differ from the methods of introduction of these other substances.

Enter tamilchelvan you from the moment of intoxication to a few hours after it. It is preferable to enter within 2 h after intoxication, even more preferably, it was entered during the period from 10 to 45 minutes after intoxication.

The results, shown below in the experimental part, show greater efficiency additional intake of CIS-tamilchelvan in the period from 10 to 45 minutes after intoxication.

Thus, the invention relates to the use described above, characterized in that 2-methyl-1-(1-piperidinyl)-1-(2-thienyl)cyclohexane, in racemic form or in the form of practically pure diastereoisomers or enantiomers.

The following examples are given to illustrate the above and should not limit the scope of the invention.

Experimental part

Pharmacological research

1) the First series of experiments:

The study Protocol:

Nine monkeys species Cynomolgus were treated for 1 h to intoxication mestinon (0.2 mg/kg; B. T. intramuscularly). This dose mestinon inhibits 30% plasma cholinesterase that meets the standards of protection, which adhere to the NATO countries. Then animals injected dose 5DI50toxic substances soman, organophosphorus compounds at the rate of 30 µg/kg (C. M.), then treated with a 1 min after intoxication "therapeutic cocktail" that contains: atropine sulphate (0.5 mg/kg; B. m )+valium (0.2 mg/kg; VM)+pralidoxime (30 mg/kg: C. M.). This mixture 3 drugs corresponds emergency treatment performed at the staff level autodiscovery syringes.

After 10 min of intoxication animals took CIS-tamilchelvan intravenous (of 0.01, 0.03 and 0.1 mg/kg 3 animals per dose).

Animals (not fixed) then examined, signs of acute toxicity and recovery note 17 times during the periods of observation the Ute, remove the brain, immerse it at 1 month in formalin, and then make a histological sections (10 μm), stained with the dye (Luxol Fast Blue HE) for possible detection neuropathologically complications.

Were carried out similar experiments with the control animals did not receive CIS-tamilchelvan. Thus, it is possible to see the influence of this compound on clinical signs of poisoned animals and neuropathologically complications.

The results:

Control animals (n=4):

These animals showed significant signs of intoxication (muscle fasiculation, tremors, sluggish pozhevyvanie), which appeared after 1-2 min after injection of soman, then the animals see tonusa-clonic seizures associated with opistotonus. Then all the animals quickly fell into a coma, for approximately 5 minutes Coma animals lasted from 20 to 40 minutes After this phase coma animals slowly recovered within 6 h after intoxication, shaking gradually ceased. The day after intoxication all animals were able to walk, grab and climb, but their normal activity was recovered only 4 days after intoxicatie number of neurons recorded in the second layer prednamerennoe part of the cerebral cortex in all primates.

Animals treated with tamilsexcinema (n=3 per dose):

Was carried out by intravenous administration of CIS-tamilchelvan, as specified in the study Protocol for phase coma animals. Observation of clinical status is summarised in table.1.

Three weeks after intoxication histological examination of brain tissue of animals treated with tamilsexcinema shows the normal density of neurons in layer II of the fronto-parietal cortex independent of dose CIS-tamilchelvan. The calculation made in this area of the brain indicates a significant difference between the density of neurons observed in control animals and in animals treated with tamilsexcinema. Thus, there is the effect of neurotoxity produced by tamilsexcinema which is shown starting with the lowest dose.

Conclusion:

In the experiment, emergency treatment was assigned a 1 min after intoxication. Under these conditions, a painful condition caused by soman, lasted only 3 to 5 minutes However, m is lamina in addition to emergency politicamente treatment allows the dose of 0.01 mg/kg intravenously significantly improve recovery intoxicating animals 48 h after soman and prevent depression of neurons, observed in fronto-parietal cortex of control animals.

2) the Second series of experiment

The series of experiments described below, closer to the real situation.

The Protocol of the experiment is as follows:

Animals poisoned by a dose 8DL50after 1 min after intoxication, did one injection Autodiscover syringe containing atropine sulphate valium, pralidoxime. CIS-tamilchelvan was introduced after 45 min intravenously, this a period of 45 minutes is the time required to pick up the wounded, and then to deliver it to the point of care, where a special team will be held decontamination his service and the introduction of intravenous injection of the medical staff.

The study Protocol:

One month prior to the experiment 6 Cynomolgus monkeys operate to be implanted cortical electrodes for recording EEG according to the standardised Protocol (Mestries et al., Sci. Tech. Anim. Lab., 1984, 9, 35-46). Provided appropriate post-operative care (antibiotherapy General plan within 10 days and the local application of antiseptics during 5 days).

Before the experiment the animals were anestesiol (Inalgan, 3 mg/kg, B. M. ), ZAT is I Kalhana more than 99%) of primates is connected to the device, recording EEG (ALVAR 16 channels). The values of the EEG; animals recorded continuously for 6 h and analyze the energy distribution of the frequency bands after FFT analysis (lane Delta of 0.5-5 Hz, theta band of 5-10 Hz band alpha 10-16 Hz beta band 16-48 Hz), to give the possibility to calculate the index of the EEG (% Delta+%theta/% beta). Animals pre-treated with mestinon (0.2 mg/kg C m) for 1 h before intoxication with soman. This dose mestinon inhibits 30% plasma cholinesterase that meets the standards of protection, which adhere to the NATO countries. Then animals are intoxication dose 8DL50soman, organophosphorus compound (30 mg/kg C m), then after 1 min after intoxication treated with a mixture of sulphate of atropine (0.25 mg C m)=valium (0.1 mg/kg C m )+pralidoxime (15 mg/kg, B. M.). These doses for primates equivalent dose, administered to one person Autodiscover syringe. Then the animal should be observed and the presence or absence of each animal 5 signs of acute toxicity (tremors, clonic convulsions) or tonic-clonic stroke, coma, respiratory disorders, hyperactivity when loud or tangible pathogens, as well as 4 sign of recovery (pupillary reflex, kostelny the 45 min 3 animals treated with CIS-tamilsexcinema, intravenous dose of 0.1 mg/kg Other 3 animals did not accept the connection. Signs of toxicity and recovery, mentioned above, is then recorded for each animal after 1 h, 1 h 15 min 1 h 30 min 1 h 45 min, 2 h, 2 h 30 min, 3 h, 3 h 30 min, 4 h, 4 h 30 min 5 h after intoxication. After 5 h after intoxication (i.e. 6 hours from the beginning of the experiment with respect to time pre-treatment with mestinon), record values EEG in animals stop, primates are removed from the chamber, where they are fixed, then move (without anesthesia) in a cell of a large size. The clinical condition of the animals is then measured through 5h, CH, 6h, then 24h, 48h, 3 days, 4 days, 1 week, 2 weeks, 3 weeks after intoxication, starting with the same signs of acute toxicity and recovery, as before mentioned, to which is added the presence or absence of prostration (characteristic of toxicity), as well as their ability to sit, walk and climb, and to feed themselves. (Sign of recovery).

Three weeks after intoxication of animals killed by intravenous injection of pentobarbital, quickly remove the brain and placed in 10% formalin solution for 1 month (change the solution every week). At the end of the implementation is>The results:

The first 45 minutes after intoxication:

(before the introduction of the CIS tamilchelvan, the Period P1)

Clinical signs:

In all animals, serious signs of intoxication (muscle fasiculation, tremors, sluggish pozhevyvanie) that appear after 2-3 min after the injection of soman. Then all animals appear tonusa-clonic convulsions, along with opistotonus. Latent period cramps for about 3-4 minutes during this acute phase animals cyanotic. Next five out of 6 animals fall into coma after about 5-8 minutes This phase of the coma lasts approximately 30 minutes Disordered breathing movements (shortness of breath) have 6 animals and note the strong selection. After 45 minutes after intoxication 1 the animal is still in a coma and one of 6 normal palpebral reflex and the ability to visual tracking. At the same time in all animals there is a constant jitter, combined with a strong disorder of the respiratory rhythm.

The EEG activity:

The appearance of tonic-clonic crises noted above, is accompanied by painful condition (epileptic), characteristic of poisoning by organophosphorous compound. It is a painful Sosin after intoxication). Analysis of the bands shows an increase in the energy distribution of EEG in the beta band with a simultaneous decline in the relative energy in the band Delta, not only on the temporal branches, but also on the parietal. This increase in the relative energy at high frequencies is typical for injection diazepam animals (Lipp, Arch. Int. Pharmacodyn., 1973, 202, 244-251). The index calculation EEG (Delta+theta/beta) within the first 45 minutes after intoxication shows a very strong reduction relative to the period prior to the injection of soman. This means, according to the literature, increased arousal level of the brain (Nagymajtenyi et al., Neurotox. Teratology, 1988, 10, 429-434).

45 minutes after intoxication until the end of recording EEG:

(5 h after intoxication, the Period P2)

Clinical signs:

3 animals not receiving tamilchelvan show constant jitter, combined with clonic convulsions for several hours, as well as disorders of the respiratory rhythm in combination with disorderly abdominal movements. Their recovery is very slow as only one animal 3 has kostelny and grasping reflexes, and the ability to visual tracking through 6 h after intoxication. animals dying from respiratory disorders after 4 h after intoxication.

In animals treated with CIS-tamilchelvan, say 5-10 min after the intravenous product, termination clonic seizures or tonic-clonic crises, as well as the complete disappearance of respiratory disorders. In animals, regular breathing. After the initial stage of coma, 3 animals treated with CIS-tamilsexcinema, restore the ability to bite, grab and keep look for from 2 hours to 2 hours and 30 minutes after intoxication. None of the 3 animals treated with CIS-tamilsexcinema not die within 5 h after injection of soman.

The EEG activity:

In animals not treated with CIS-tamilchelvan, note the preservation of the epileptic state during the period from 2 h 30 min to 3 h after intoxication. The EEG activity then gradually subsides with a relative predominance of energy at low frequencies (band Delta) in combination with (b) with decreasing relative energy at high frequencies (beta band). The index of the EEG during the period P2shows, relative to the period prior to the injection of soman, a big increase last and temporal branches, and parietal. This increase in the index associated with increasing relative to the n et al., Pharmacol. Biochem. Behav., 1992 42, 711-719).

In animals treated with CIS-tamilchelvan, mark the termination of epileptic status during the period from 8 to 10 min after intravenous injection of this product. Picture high-frequency (high-energy) EEG gives way to the low frequency (2-4 Hz), characteristic of the CIS-tamilchelvan, for approximately 1 hour Then EEG gradually returned to normal without causing parasitically activity. Analysis using the frequency band in period P2shows the energy distribution of EEG equivalent recorded in the period prior to intoxication. Calculated during this period the index of the EEG is identical to the index period to intoxication.

From 5 h after intoxication to killing animals:

(3 weeks after the experiment)

Two control surviving animals recovered very slowly after returning to the cage. One of the 2 animals die within 48 h after experimenting in a state of extreme exhaustion (the animal is unable to move independently to feed). The only animal survivors of the control series, has recovered quite well since the 5th h after into is the food.

In 3 animals treated with CIS-tamilsexcinema, mark complete clinical recovery after 5 h after intoxication, except for the ability to walk and carbonio returned to normal in these animals the next day after the experiment. None of the 3 animals treated with CIS-tamilsexcinema not die within 3 weeks of observations and clinical recovery is quite satisfactory.

Histopathological examination of brain surviving animals:

Histopathological examination of the brain is the only surviving animal of the control group not treated with CIS-tamilsexcinema shows neuropathological complications in hippocampi and prednamerennoe part of the brain. In hippocampe note foci reduction of neurons in the pyramidal layer of the sector, CA1and a severe defeat granular layer timing Girona. In prednamerennoe part of the brain celebrate neural vacuum layer II-III.

In animals treated with CIS-tamilsexcinema not find any pathological damage.

The findings are presented in table.2.

Conclusion: In the second series of the experimental is hexylamine, added to Autodiscover syringe:

a) very definitely improves survival intoxicating animals;

b) contributes to their clinical recovery;

C) quickly normalizes the EEG activity;

d) completely prevents neuropathologically complications.

The obtained results clearly demonstrate therapeutic benefit associated with the introduction of CIS-tamilchelvan much intoxicatingly patient who could afford to enter only one syringe with three components, even with the introduction of CIS-tamilchelvan later, 45 minutes after first aid.

Example

Preparation for injectable solution of CIS-tamilchelvan

The lyophilisate of the CIS tamilchelvan 0.5 mg

Mannitol 25 mg

Sodium chloride - to 85.5 mg

Water for the preparation of injection: Up to 10.0 ml

Substances which may optionally be used together with tamilsexcinema, are in their usual form used in the appropriate pharmacological field.

1. The use of 2-methyl-1-(piperidinyl)-1-(2-thienyl)cyclohexane in racemic form, in the form of almost pure diastereoisomer the project effects, caused by exposure to exogenous neurotoxic substances or neurotoxins.

2. Application under item 1, in which drugs additionally contain one or more other pharmaceutical substances that can restrict or inhibit the effects caused by neurotoxic or neurotoxine substances.

3. Application under item 2, in which drugs additionally contain at least one substance selected among anticholinergic, antispasmodic substances or reaktivatory cholinesterase.

4. Use one of the p. 2 or 3, in which drugs additionally contain at least one anticholinergic agent, at least one anticonvulsant substance or at least one reactivator cholinesterase.

5. Use one of the p. 3 or 4, wherein the anticholinergic substance selected from the atropine, scopolamine, N-oxide atropine, digoxigenin and methyl sulfate of tiemonium.

6. Use one of the p. 3 or 4, in which anticonvulsant substance selected from the group consisting of phenobarbital, primidone, benzodiazepines, carbamazepine, ethosuximide, phenytoin, sodium valproate, progabid, gabapentin, Vihavainen, selected from clonazepam, clobazam, diazepam and prodiazepam.

8. Use one of the p. 3 or 4, in which reactivates cholinesterase selected from pralidoxime, obidoxime or Hl6.

9. Use one of the PP.1-8, in which drugs additionally contain a reversible cholinesterase inhibitor that is designed to receive up to exposure to neurotoxic substances or neurotoxins.

10. Use one of the PP.1-9, in which a reversible cholinesterase inhibitor is selected among mestinon, physostigmine.

11. Use one of the PP.1-10, in which 2-methyl-1-(1-piperidinyl)-1-(2-thienyl)cyclohexane is in the drug in racemic form, in the form of practically pure diastereoisomers or enantiomers, and medicines are designed for insertion through two hours and preferably one hour after intoxication neurotoxic substances or neurotoxins.

12. Composition which is able to restrict or inhibit the effects caused by neurotoxic or neurotoxine substances containing as an active start 2-methyl-1-(1-piperidinyl)-1-(2-thienyl)cyclohexane in racemic form, in the form of practically pure diastereoisomers is ICICI or to inhibit the effects caused neurotoxic or neurotoxine substances.

13. The composition according to p. 12, containing 2-methyl-1-(1-piperidinyl)-1-(2-thienyl)cyclohexane in combination, at least one substance selected from the anticholinergic, antispasmodic substances and reaktivatory of cholinesterase.

14. Composition according to one of paragraphs.12 and 13, containing 2-methyl-1-(1-piperidinyl)-1-(2-thienyl)-cyclohexane, in combination, at least one anticholinergic agent, at least one anticonvulsant or at least one reactivation of cholinesterase.

15. Composition according to one of paragraphs.13 and 14, in which an anticholinergic substance selected from the atropine, scopolamine, N-oxide atropine, digoxigenin and methyl sulfate tamania.

16. Composition according to one of paragraphs.13 and 14, in which anticonvulsant substance selected from the group consisting of phenobarbital, primidone, carbamazepine, ethosuximide, phenytoin, sodium valproate, progabid, gabapentin, vigabatrin, loprazolam and benzodiazepines, such as clonazepam, clobazam, diazepam and prodiesel.

17. Composition according to one of paragraphs.13 and 14, in which reactivator of cholinesterase selected from pralidoxime, obidoxime, H16.

18. Kombinierten, containing 2-methyl-1-(1-piperidinyl)-1-(2-thienyl)-cyclohexane and at least one substance selected from the anticholinergic, antispasmodic substances and reaktivatory of cholinesterase, for simultaneous, separate or dispersed in time use.

19. The combined product under item 18, additionally containing a cholinesterase inhibitor for administration to exposure to neurotoxic substances or neurotoxin.

20. The combined product under item 19, in which the reversible cholinesterase inhibitor selected from mestinon and physostigmine.

Priority points:

06.12.1996 on PP.1-10, 12-20;

l3.06.1997-p. 11.

 

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