The use of 5-[2-chloro-1-hydroxyethyl]-4-methylthiazole to reduce the destruction of neurons, suppression of convulsions and reduced motor activity

 

(57) Abstract:

Usage: in medicine, to reduce the destruction of neurons caused by ischemia, suppression of convulsions and reduced motor activity in the recipient. The essence of the invention: enter 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole or its optical isomers or MES, or a pharmaceutically acceptable salt, selected from atendimento and hydrochloride, at a dose of 1-3000 mg/kg of body weight of the recipient. 2 C. p. F.-ly, 2 tab.

The invention relates to 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole for use in therapy and pharmaceutical compositions comprising the specified connection. The invention also concerns the use of the compounds for the manufacture of a medicinal product. Additionally the invention concerns a method for prevention or treatment of neurovirology or to achieve a sedative (calming) or anticonvulsive effect in the appointment of such compounds in sufficient quantity. Another aspect of the invention is a pharmaceutical composition for use in the prevention or treatment of neurovirology, or to achieve a sedative or anticonvulsive effect, including the specified connection as activetabchanged special interest such metabolites, as 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole having the formula:

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and its optical isomers, or pharmaceutically acceptable salt, or MES. In the literature mentioned connection is specified as the metabolite, originally identified by mass-spectrometry. For simplicity, these connections in the following are listed as 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole.

Ende. V. Spiteller G. G. Remberg in Arznlim Forsch./Drug.Res. 29 (11), No. 11 (1979), S. 1655-1658 reported that one of the metabolites hlormetiazola in human urine is 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole (substance 9 on page 1658).

Pal R. and Spiteller G. Xenobiotica, 1982, T. 12, N 12, S. 813-820 used 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole to compare metabolites hlormetiazola using mass spectrometry.

C. P. Offen Freacson M. J. Wilson K. and Burnett D. in Xenobiotica, 1985, I. 15, No. 6, S. 503 511 reveal six major metabolic peaks hlormetiazola in the urine. Peak 4 was identified as 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole.

Published data in the above-mentioned documents are mainly in the structural identification, and not to the pharmacological properties of its metabolites. Thus, at the previous level of technology is not disclosed to any farmakologicznie hlormetiazola, namely, 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole, its optical isomers, or pharmaceutically acceptable salt or MES. In the scope of the invention includes two optical isomers (+ and -) and racemic form ().

Various aspects of the invention:

pharmaceutical composition comprising 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole or its optical isomers, pharmaceutically acceptable salt, or MES, as an active ingredient;

5-(2-chloro-1-hydroxyethyl)-4-methylthiazole and its optical isomers, or pharmaceutically acceptable salt, or MES for use in therapy, especially as a means to prevent or treat neuromyasthenia, or as anticonvulsive or sedative;

the use of 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole, and its optical isomers or pharmaceutically acceptable salt, or MES for production of medicines for the prevention or treatment of neurovirology, especially in relation to conditions such as seizures, cerebral ischemia, hypoxia, epilepsy, and disease neuromyasthenia, such as Alzheimer's disease, multi-infarction dementia and Huntington's disease; or for the production of lekarstvennoj is jravirginia, especially in connection with conditions such as seizures, cerebral ischemia, hypoxia, epilepsy and diseases neuromyasthenia, such as Alzheimer's disease, multi-infarction dementia and Huntington's disease, or to achieve a sedative or anticonvulsive effect in the recipient when the need for such treatment by assigning a sufficient number of 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole or optical isomers, or pharmaceutically acceptable salt, or MES;

pharmaceutical composition for use in the prevention or treatment of neurovirology, especially in relation to conditions such as seizures, cerebral ischemia, hypoxia, epilepsy, and disease neuromyasthenia, such as Alzheimer's disease, multi-infarction dementia and Huntington's disease, or for use in achieving a sedative or anticonvulsive effect in the recipient, if necessary, of such treatment, comprising 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole or optical isomers, or pharmaceutically acceptable salt, or MES as an active ingredient.

Pharmaceutically acceptable salts are new and include the hydrochloride salt, salt with ethicolegal acid, with the ü with ethicolegal acid and the hydrochloride salt are preferred salts.

The racemate 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole can be separated using standard techniques, such as HPLC (high performance liquid chromatography, or crystallization of salts.

Considered the most clinically important field of use, namely the prevention and/or treatment of neuromyasthenia in connection with the seizure, cerebral ischemia, multi-infarction dementia and hypoxia, and receive sedative or anticonvulsive effect in the recipient if necessary such treatment.

The effectiveness of 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole for use according to the invention in the prevention or treatment of neurovirology can be demonstrated the ability to reduce the defeat of the CA1/CA2 pyramidal neurons of the hippocampus in gerbil caused by ischemia, induced by the period of occlusion of the carotid artery followed by reperfusion. The detailed mechanisms that underlie induced by ischemia, degeneration of hippocampal neurons, needed to be clarified, but the above test system on gerbil was widely used as a predictive model neuroprotective activity (see for example, B. J. Alps, C. Calder, W. K. Hass and A. D. Wilson, Brit.J.Pharmacol. 1988, 93, 877-883; P. G. 11, A. C. Foster, and G. N. Woodruff, J. Neu in the prevention and/or treatment of neurovirology, even if appointed solely after ischemic stroke, even a few hours after ischemic stroke. It should be expected that the efficiency in the appointment after the induction of ischemia would be especially appropriate when the likely clinical use.

The effectiveness of 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole for use according to the present invention in achieving the sedative effect can be demonstrated by the ability of compounds to inhibit locomotor activity, as described below (S. O. Ogren, Acta psychiatr. Scand. Suppl. 329, T. 73, 1986, c.13-29).

The effectiveness of 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole for use according to the present invention in achieving the anticonvulsive effect is described below.

In the claimed method of treatment assignment medicines can be depending on the facilities orally, rectally, or parenterally in doses, for example, about 1-3000 mg/kg, preferably about 10-1000 mg/kg, particularly preferably about 25-250 mg/kg and may be administered in the mode 1-4 hours a day. The dose depends on the mode of appointment, particularly preferred method is intravenous infusion of an aqueous solution containing 5-(2-chloro-1-hydroxyapol atendimento 8 mg/ml It should be noted that the severity of the disease, the patient's age and other factors, usually considered supervising physician, will affect the individual and the dose most suitable for a particular patient.

Medicines, including pharmaceutical compositions according to the invention may be tablets, pills, capsules, syrups, powders or granules for oral use; sterile parenteral solutions or suspensions for parenteral use; or in the form of suppositories for rectal destination.

For the production of pharmaceutical compositions containing a compound in accordance with the present invention in the form of uniform doses for oral administration can be used, for example, lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, etc., and then pressoffice in tablets. If you require coated tablets, cores, prepared as described above, can be covered by the con is on, and so p. the Tablet may be coated with a polymer known to the specialist, dissolved in a readily volatile organic solvent or mixture of organic solvents. These coatings can be added dyes, in order to easily distinguish between tablets containing different active substances or different number of active connections.

To obtain soft gelatin capsules, the active substance can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active substance, using either the above-mentioned diluents for tablets, for example, lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Hard gelatin capsules can also be filled with liquid or semi-liquid drug.

Standardized doses for rectal application can be solutions or suspensions, or they can be obtained in the form of suppositories comprising the active substance in a mixture with a neutral fat base, or gelatin rectal capsules comprising the active substance in a mixture with vegetable oil or paraffin m the example, solutions containing about 0.2-20 wt. the active substances described here, and the balance is sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other diluents known to the specialist.

Solutions for parenteral applications by injection can be obtained in the form of an aqueous solution of water-soluble pharmaceutically acceptable salt of the active substance, preferably at a concentration of about 0.5-10 wt. These solutions may also contain stabilizers and/or buffer substances, can be represented in the form of ampoules of different single doses.

Methods of obtaining 5-/2-chloro-1-hydroxyethyl/-methylthiazole and its salts.

5-(2-chloro-1-hydroxyethyl)-4-methylthiazole etandisulfonat.

To a suspension of 4-methyl-5-vinylthiazole (8,76 g, 70 mmol) in 80 ml of water and 8 ml of acetic acid was added tert.butyl hypochlorite (7,8 g, 72 mmol) for 45 min at ambient temperature. After stirring for 1 h at room temperature was added 100 ml of diethyl ether and the phases were separated. The solvent was removed from orhaneli 3.5 ml isopropanol, 3 ml of water and concentrated sulfuric acid (0.5 g). After adding atendimento calcium (1,15 g) and the mixture was stirred at 40oC for 3 hours the Precipitate was filtered, and the filtrate evaporated three successful additions isopropanol. The residue was recrystallized from a solution of 20 ml of diisopropyl ether, 30 ml of ethanol and 15 ml of methanol to yield 1.35 g of white crystalline product. The melting point 165-168oC.

1H NMR spectrum atendimento (in DMSO) 2.5 (ZN, S), 2.85 (2H, S), 3.85 (2H, d), 4.8 (broad), 5.25 (1H, t), 9.25 (1H, S) M. D.

Salt 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole hydrochloride.

The free base of 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole was treated with a solution of hydrogen chloride in ethanol. Added diethyl ether, and the resulting precipitate was collected and recrystallized from methanol-diethyl ether to yield hydrochloride salt, melting point 136-136.5oC.

1H NMR spectrum (in DMSO) 2.5 (3H, S), 3.85 (2H, d), 5.25 (1H, t), 8.4 (2H, broad) and 9.45 (1H, S) M. D.13The NMR spectrum (in DMSO) 13.9, 49.4, 65.8, 135.9, 145.0 and 153.5 M. D.

The optical resolution 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole.

(a) 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole (2 g) in dry dichloromethane (200 ml) is the atur within two hours. The reaction mixture was washed with 1N-sodium hydroxide solution and then with water. The organic layer was separated, dried and evaporated under reduced pressure to yield an oil. This oil was purified by thin-layer chromatography on silica gel to yield (1S)-(-)-campanato ester 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole (diastereomer mixture) in the form of oil, which is easily solidified.

1H NMR spectrum of this material in CDCl3shows, in particular, the peaks at 0.89 and 0.94 (combined integral 3H), 1.04 and 1.06 (combined integral 3H) and 1.10 3H(broad S) M. D.

(b) Diastereomers the mixture of esters obtained as described in (a), divided into separate diastereoisomeric method HPLC (high performance liquid chromatography) using polygonal silicon dioxide, 7 um, 225 cm column, diluent 70% hexane; 30% ethyl acetate; flow rate 20 ml/min; UV detector.

The diastereoisomer 1: the melting point of 127-128oC.1H NMR spectrum (CDCL3) 0.94, 1.04 and 1.10 (each 3H, S) M. D.

The diastereoisomer 2: the melting point of 120-121oC. 1H NMR spectrum (CDCL3) 0.89, 1.06 and 1.10 (each 3H, S) M. D.

C) Diastereomers the mixture of esters obtained as described in (a), (5 g) in acetone (100 foul temperature, then vykristallizovyvalas more solid. This solid was collected by filtration, washed and dried with the release of a substance with a melting point of 178-179oC, which, as shown by NMR spectroscopy, is the optically pure [0.88, 1.0, 1.07, 1.08 and 1.14 (each 3H, S) m D. This salt was converted back to the free base with the release of (1S)-(-)-campanato ester 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole of diastereoisomer 1(1H NMR 0.94, 1.04 and 1.1 (each 3H, S), Menshikov Palace). HPLC showed that this substance is optically pure and identical to diastereoisomer 1 obtained in (b) preparative HPLC separation.

(d) Diastereomer the mixture of esters obtained as described in (a), (200 mg) in a minimal volume of acetone was treated with a solution of (1S)-(-)-campanulas acid (117 mg) in a minimum volume of acetone. The resulting solution was left overnight at -20oC. a White solid, which separated, was collected, washed and dried with the release of a substance, as shown by NMR spectroscopy, is the optically pure(0.90, 1.02, 1.08, 1.105, 1.115 and 1.14 (each 3H,S), Menshikov Palace). This salt was converted back to the free base with the release of (1S)-(-)-campanato ester 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole of diastereoisomer 2(1H NMR measure 2, obtained in (b) preparative HPLC separation.

(e) (1S)-(-)-compentancy ester 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole diastereoisomer 1, obtained as in (b) or (C), or diastereoisomer 2, obtained as in (b) or (d), hydrolyzed separately, using an excess of 5M hydrochloric acid in methanol at 60oC output (+)- and (-)-isomers of 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole in the form of oils.

1H NMR (CDCl3) 2.5 (3H, S), 3.7 (2H), 5.1 (1H) M. D. and 8.7 (1H) M. D.

Analytical HPLC on a chiral AGP column using phosphate buffer pH 7,3 showed that each isomer was within detection of optically pure.

Pharmacological tests.

Used animals were rats of Wistar male (140-170 g) and mouse THAT male (18-30 g).

All drugs were dissolved in isotonic. Weight refers to the free base.

Research neurotoxity.

Induced ischemia in gerbil occlusion of the carotid arteries with subsequent routine procedure (see, for example, in EP 230370 and R. Gill, A. C. Foster, and G. N. Woodruff, J. Neuroscience, 1987, 7, 3343-3349).

Typical procedures and the results are illustrated as follows.

The purpose of the test soybean is the major arteries. Body temperature was maintained at 37oC during the whole experiment. Restoration of blood flow after occlusion was checked visually, and the animals were allowed to survive for 4 days. Then evaluated the degree of neural degeneration in the hippocampus. The test compound was administered (i.p. - intraperitoneally in a single dose after 60 min after occlusion. Typical results are shown in table. 1. Prior to occlusion of the assignment is not done. As can be seen from the table. 1, 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole hydrochloride salt was effective in reducing lesions of the CA1/CA2 hippocampal neurons.

As illustrated by the above results, the effectiveness of 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole in reducing defeat to CA1/CA2 hippocampal neurons in gerbil after ischemic stroke illustrates the usefulness of this compound in the prevention of neurovirology. Therefore, it is assumed that the compound is useful for preventing and/or treating neuromyasthenia, especially in relation to conditions such as seizures, cerebral ischemia, hypoxia, epilepsy, and disease neuromyasthenia, such as Alzheimer's disease, multi-infarction dementia and Huntington's disease.

As shown will VicePresident sedative/hypnotic properties, demonstration for potential clinical use as a sedative.

Research sedative effect.

The test drug was administered to mice after 20 min was recorded locomotor activity during the 30-minute period. Activity was monitored using the system interrupts the beam of infrared light in boxes 4040 see Data were expressed as the dose required to reduce motor activity by 50% (ED50). A typical result is shown in table. 2.

Research anticonvulsive effect.

Pentylenetetrazole /PTZ/ seizures.

Evaluated the seizure threshold in rats by measuring the dose of PTZ required to evoke seizure under injection through the tail vein, PTZ (10 mg/ml) was injected into the tail vein at a speed of 2.6 ml/min and measured the time until the first clonic convulsions. The seizure threshold was calculated as described by Murray Green, J. Pharmacol. 1989, 41: 879-880. Medication was administered 15 min prior to PTZ. Data were expressed as the dose required to increase the seizure threshold by 50% (TI50).

S-methyl-D-asparate /NMDA/seizures.

Groups of eight mice were injected NMDA (300 mg/kg i.p.) and recorded the number of mice exhibiting tonic seizures in required to reduce the frequency of tonic convulsions in 50% (ED50). Typical results of the fit are shown in table. 2.

1. The way to reduce destruction of neurons caused by ischemia, suppression of convulsions and reduced motor activity in the body by injecting 5-(2-chloro-1-hydroxyethyl)-4-methylthiazole, or optical isomers, or MES, or a pharmaceutically acceptable salt, selected from atendimento and hydrochloride, at a dose of 1 to 3000 mg/kg of body weight of the recipient.

2. The method according to p. 1 by implementing these compounds at a dose of 10 to 1000 mg/kg of body weight of the recipient.

3. The method according to p. 2 by implementing these compounds at a dose of 25 to 250 mg/kg of body weight of the recipient.

 

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