New derivatives of 10,11-dihydro-10-oxo-5h-dibenz[b,f] azepin-5-carboxamide, processes for their preparation, pharmaceutical composition, method of treatment of convulsive states

 

(57) Abstract:

The invention relates to new derivatives of 10,11-dihydro-10-oxo-5H-dibenz[b, f]azepin-5-carboxamide of General formula I, where R represents a hydroxy group or a group-O-CO-R', where R' represents hydrogen, an alkyl group, heteroaryl, or R represents a group-O-CO-OR', where R' is defined above, or R represents a group-O-R2where R2represents an alkyl or alkylaryl, or R is NR3R4where R3represents hydrogen, a group NH-CO-NH2, -NH-CS-NH2and R4represents hydrogen, alkyl, alkylaryl, the meaning of the terms "alkyl", "aryl", "heteroaryl" and "halogen" are disclosed in the claims. Also described methods for obtaining such compounds, pharmaceutical composition and method for the treatment of convulsive States. The invention can be used in medicine for treatment of some diseases of the Central and peripheral nervous system. 5 S. and 9 C.p. f-crystals.

The present invention relates to new derivatives of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepin-5-carboxamide, the way they are received and containing pharmaceutical compositions. These compounds possess valuable the system.

10,11-Dihydro-10-oxo-5H-dibenz[b,f]azepin-5-carboxamide (oxcarbazepine) is a well-known agent used for treatment of epilepsy, trigeminal neuralgia and affective disorders (see, for example, Drugs 43(6), 873 (1992)). However, some patients oxcarbazepine causes severe adverse reactions, such as allergic reactions, and also causes a decrease in serum sodium. Other disadvantages of oxcarbazepine associated with its rapid metabolism; as a result, this medicine should usually apply three times a day.

The aim of the present invention is to improve some of the above properties and relates to new compounds of General formula I

< / BR>
where R represents a hydroxy group, alkyl, cycloalkyl, alkylsilanes, alkylaryl or alkylether or R represents a group-O-CO-R1where R1represents hydrogen, an alkyl group, cycloalkyl, alkylsilanes, alkylaryl, aryl or heteroaryl, or R represents a group-O-CO-R1where substituent R1defined above, or R represents a group-0-R2where R2represents an alkyl group or alkylaryl, or R is a group-NR3R4, g is represents a hydrogen, the alkyl group, alkylsilanes, alkylaryl, alkylaryl or arylcarbamoyl; the term alkyl means hydrocarbon chains, straight or branched, containing from one to six carbon atoms, optionally substituted by one or more group, and alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl; the term cycloalkyl represents alicyclic group having from three to six carbon atoms; the term aryl represents phenyl or naftalina group, optionally substituted by one or more alkoxy groups, halogen or nitro; the term heteroaryl represents a five - or six-membered ring; containing an oxygen atom, sulfur or nitrogen; the term halogen represents fluorine, chlorine, bromine or iodine.

Preferred compounds of General formula I include:

1. 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]-azepin-5-carboxamid

2. 10,11-benzylamino-10,11-dihydro-5H-dibenz[b,f]-azepin-5-carboxamid

3. 10-acetylimino-10,11-dihydro-5H-dibenz[b,f]azepin-5-carboxamid

4. 10,11-dihydro-10-propionyloxy-5H-dibenz-[b,f]azepin-5-carboxamid

5. 10-butyrolacetone-10,11-dihydro-5H-dibenz-[b, f] azepin-5-carboxamid

6. 10,11-dihydro-10-pivaloyloxy-5H-dibenz[b, f] -azepin-5-carboxamid

9. 10,11-dihydro-10-succinylamino-5H-dibenz[b,f]-azepin-5-carboxamid

10. 10,11-dihydro-10-glucurolactone-5H-dibenz-[b,f]-azepin-5-carboxamid

11. 10,11-dihydro-10-isobutoxyethene-5H-dibenz[b,f]azepin-5-carboxamid

12. 10,11-dihydro-10-methoxyimino-5H-dibenz[b,f]azepin-5-carboxamid

13. 10,11-dihydro-10-(S)-(-)-campanological-5H-dibenz[b,f]azepin-5-carboxamid

14. 10,11-dihydro-10-[(3-methoxybenzylideneamino)] -5H-dibenz[b,f]azepin-5-carboxamid

15. 10,11-dihydro-10-nicotinamine-5H-dibenz-[b, f]azepin-5-carboxamid

16. 10,11-dihydro-10-ethoxycarbonylmethylene-5H-dibenz[b,f]azepin-5-carboxamid

17. 10-butoxycarbonyloxyimino-10,11-dihydro-5H-dibenz[b,f]azepin-5-carboxamid

18. 10-benzyloxycarbonylamino-10,11-dihydro-5H-di benzo[b, f] azepin-5-carboxamid

19. 10,11-dihydro-10-phenylhydrazone-5H-dibenz[b,f]azepin-5-carboxamid

20. 10,11-dihydro-10-hydrazino-5H-dibenz[b,f]azepin-5-carboxamid

21. 10,11-dihydro-10-(2,4-dinitrophenylhydrazone)-5H-dibenz[b,f]azepin-5-carboxamid

22. 10,11-dihydro-10-semicarbazone-5H-dibenz[b,f]azepin-5-carboxamid

23. 10,11-dihydro-10-thiosemicarbazone-5H-dibenz[b, f] -azepin-5-carboxamid

24. 10-(2-chlorpheniramineodeine)-5H-dibenz[b,f]-azepin-5-carboxamid who undertook the invention relates to a method for producing compounds of the formula I, where substituent R is defined above, by reacting the compounds of formula II

< / BR>
with hydroxylamine or its derivatives of the formula III

H2NOR2(III)

where substituent R2defined above,

or by reacting the compounds of formula II with semicarbazide, thiosemicarbazide or a derivative of hydrazine of formula IV

H2NNR3R4(IV)

where the substituents R3and R4defined above,

or by reacting the compounds of formula V

< / BR>
with allermuir reagent of formula VI

A-CO-R' VI

where R' is the same as specified above for General formula I; a represents a hydroxy, halogen or-O-CO-R' or-O-CO-OR', where R1represents lower alkyl (C1to C4)

or by reacting the compounds of formula V with allermuir reagent of formula VII

Cl-CO-OR1VII

where R1such as the one above for General formula I;

the acylation reaction can be carried out in the presence of a condensing agent such as, for example, dicyclohexylcarbodiimide, carbonyldiimidazole, ethyl or isobutylparaben, and/or in the presence of organic or inorganic bases, such as pyridine, triethylamine or bicarbonate Molochny solvent, or the reaction can be carried out in mixtures of the above solvents or in the absence of any solvent.

The reaction described above can be carried out at various temperatures and pressures, for example, between 0oC and the boiling temperature of the reaction mixture at a given pressure.

Compound II is known (see, for example, German patent 2 001 087), compounds of formulas III, IV, VI and VII can be obtained by experienced specialists using the methods described, for example, in the book by R. C. Larock "Comprehensive Organic Transformations", VCH Publishers, 1989.

Another aspect of the present invention includes a method of making pharmaceutical compositions, which consists in mixing the compounds of formula I with a pharmaceutically acceptable carrier.

The present invention also includes a pharmaceutical composition for treating diseases of the Central and peripheral nervous system, which contains a compound of the present invention and a pharmaceutically acceptable carrier.

The present invention also includes a method of treating diseases of the Central and peripheral nervous system, which includes the introduction of compounds according to the invention in this form, Kay I can be used for the treatment of epilepsy, neuralgia of the trigeminal nerve and affective cerebral disorders and injuries of the nervous functions in degenerative and postischemic diseases.

Epilepsy is one of the most common human diseases (frequency about 1%). Since Huqhlinqs Jackson, more than 100 years ago, it was known that epileptic seizures are "occur from time to time, sudden, excessive, rapid and local discharges of nervous tissue". Epileptic seizures are divided into two groups: local and generalized. Local seizures are those in which the discharge begins locally and often remains localized. Generalized seizures cover the whole brain, including the reticular formation, which causes abnormal electrical activity in both hemispheres and immediate loss of consciousness. Local seizures are divided into (a) simple local seizures, (b) complex local seizures, and (C) local seizures with secondary generalization. Generalized seizures include (1) tonic-clonic seizures (large, qrand TA 1), (2) absent (small, petit mal), (3) myoclonic seizures, (4) atonic seizures, (5) clonic seizures, and (6) tonic przypadkiem seizures (Gastaut, H. , Dictionary of epilepsy. The world health organization, Geneva, 1973).

There are two ways in which drugs can prevent or reduce seizures: (a) through effects on damaged neurons of epileptic focus, to prevent or reduce excessive discharge, and (b) through impact, which will limit the spread of excitation from the epileptic focus and prevent gaps in the functions of the normal neuronal aggregates. Most, if not all, of the existing antiepileptic drugs operate at least through the second mechanism, as all they alter the brain's ability to respond to different triggers fit stimuli. Often use medicines that cause seizures, such as pentylenetetrazol (metrazol), in particular when testing anticonvulsant agents; for the same purpose induce seizures by electrical stimulation of the entire brain. It was found experimentally that the activity against inhibition induced by metrazol seizures and increase the threshold of provocation induced electricity seizures are acestei reducing the duration and prevalence of induced electricity seizures correlates with efficacy in the control of other types of epilepsy, such as tonicclonic seizures.

Anticonvulsant effect of the compounds of formula I studied on the model of induced electricity convulsions, using the test of maximal electroshock (MES) and on the model of chemically induced seizures using test metrazole. The MES test allows to evaluate the ability of drugs to prevent induced electricity tonic extension of the hind limbs in rats, the effectiveness of which seems to be possible to predict the anticonvulsant efficacy against generalized tonic-clonic seizures in humans (grand mal). Meterology test predicts the ability of potential antiepileptic agents to prevent clonic seizures and demonstrate the effectiveness of seizures type absence (petit ml).

Materials and methods

Used male Wistar rats obtained from the animal facility Harlan Interfauna Iberica (Barcelona, Spain) weighing 180-280, Animals were kept in cages for two when controlling for environmental conditions (cycle light: 12 h light and dark and the temperature of the 24oC). Food and tap water, the animals received ad libitum, and all experiments were performed in daylight.

2 - Test with metrazol

Introduction compounds of the formula I is carried out for 2 h prior to the introduction of metrazol. Metrazol (75 mg/kg) was injected subcutaneously in the region of the back; it was found that this dose of metrazol convulse in 95% of the animals. The parameters for which they were originally observation concerned the duration of seizures during the 30 min observation period after the introduction of metrazol. ED50(mg/kg) was the dose that gave a 50% reduction in the duration of seizures.

Results

1 - Test MES

In the largest tested dose (30 mg/kg) of compounds of formula I provided full protection against MES 2 h after injection. After 4 and 8 h protection created by the compounds of formula I, was the same which provides a reference compound carbamazepine.

2 - Test with metrazol

The compounds of formula I are effective against seizures induced by metrazol. The most effective dose of the compounds of formula I was 30 mg/kg and reduced the total time of stroke by 44%. Carbamazepine in doses of 30 and 60 mg/kg reduced the total time of stroke by 41 and 44%, respectively. Oxcarbazepine acted not as effective as carbamazepine. Oxcarbazepine at doses of 30 and 60 mg/kg reduced the total time of spells by 3 and 32%, respectively.

Conclusions

The compounds of formula I possess valuable anti-epileptic activity, as determined in tests with metrazol and mash, and provide anticonvulsant effect greater than or equal to anticonvulsant I can be useful to treat some diseases of the Central and peripheral nervous system in humans, for example, trigeminal neuralgia, affective cerebral disorders and injuries of the nervous functions in degenerative and postischemic diseases.

For the manufacture of pharmaceutical compositions of compounds of formula I inert pharmaceutically acceptable carriers are mixed with the active compounds. Pharmaceutically acceptable carriers can be either solid or liquid. Solid dosage forms include powders, tablets, dispergirujutsja granules and capsules. A solid carrier can be one or more substances which may also act as diluents, corrigentov, solubilizing agents, lubricating agents, suspendresume agents, binding agents or loosening tablet agents; it can also be an encapsulating material.

Preferably the dosage form is presented in the form of dosing units, for example in the form of packages containing individual quantities of the drug, such as packaging of tablets, capsules, and powders in vials or ampoules.

The dosage can vary depending on the needs of the patient, the severity of the disease and the concrete used for the connection. For convenience, the total daily dose can razdelilcem.

The present invention described herein is further illustrated by the examples of manufacturing, which should not be construed as limiting the scope of the present description. Specialists will be clear of possible alternative paths and similar structures.

EXAMPLES

Example 1:

10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepin-5-carboxamid

A suspension of 4.0 g (15,86 mmol) 10, 11-dihydro-10-oxo-5H-dibenz[b,f]azepin-5-carboxamide and 3,86 g (55,40 mmol) of hydroxylamine hydrochloride in 100 ml of absolute ethanol was treated 3,76 g (47,57 mmol) of pyridine. The mixture was heated under reflux for 1 h, and then ethanol was removed by evaporation under reduced pressure. The residue was distributed between 150 ml of water and 150 ml of dichloromethane. The organic layer was separated and washed with 50 ml of 1 M aqueous Hcl, saturated solution Panso3and saturated saline, then was dried with sodium sulfate. Filtration and evaporation of the solvent under reduced pressure gave a not-quite-white solid, which was triturated with hot ethanol to give the desired compound as a white powder with so pl. 230,4-231,5oC.

Example 2:

Using the same procedure described in the previous PR is[b, f]azepin-5-carboxamide.

Example 3:

10-acetylimino-10, 11-dihydro-5H-dibenz [b, f]azepin-5-carboxamid

A suspension of 0.5 g (of 1.87 mmol) 10, 11-dihydro-10-hydroxyimino-5H-dibenz[b, f] azepin-5-carboxamide in 25 ml of dichloromethane and 0.72 g (9,16 mmol) of pyridine was treated 0,57 g (5,61 mmol) of acetic anhydride. The resulting mixture was stirred at room temperature overnight, and then diluted with 10 ml dichloromethane. The organic phase was extracted with 20 ml of 1 M aqueous Hcl, saturated solution of NaHCO3and saturated saline, then was dried with sodium sulfate. The solvent is then evaporated under reduced pressure and the crude product was led from a mixture of dichloromethane and ethyl acetate to obtain the desired product as white crystals with so pl. 175,8-176,9oC.

Examples 4-11:

Using the above methodology, but using the corresponding anhydrides, received the following connections:

10,11-dihydro-10-propionyloxy-5H-dibenz[b,f]azepin-5-carboxamid

10-butyrolacetone-10,11-dihydro-5H-dibenz[b,f]azepin-5-carboxamid

10,11-dihydro-10-pivaloyloxy-5H-dibenz[b,f]azepin-5-carboxamid

10,11-dihydro-10-[(1-naphthyloxy)imino] -5H-dibenz[b, f] -azepin-5-carboxamid

10,11-dihydro-10-glucurolactone-5H-dibenz[b,f]azepin-5-carboxamid

10,11-dihydro-10-isobutoxyethene-5H-dibenz-[b,f]azepin-5-carboxamide.

Example 12:

10,11-dihydro-10-methoxyimino-5H-dibenz[b,f]azepin-5-carboxamid

To a suspension of 0.2 g (0.75 mmol) of 10, 11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepin-5-carboxamide in 2 ml of acetone, cooled to 0oTo that solution was added 0,065 g (1,16 mmol) of potassium hydroxide in 1 ml of water, and then 0,164 g (1,16 mmol) of iodomethane. The resulting mixture was stirred at room temperature overnight, and then added 10 ml of water. The mixture was extracted with ether and the organic layer was washed with water and saturated saline, then was dried with sodium sulfate and filtered. The solvent was removed by evaporation under reduced pressure, and the residue was chromatographically on silica gel 3% mixture of methanol/dichloromethane. Chromato-graphically homogeneous fractions were combined, the solvents were removed under reduced pressure and the residue was led from toluene to obtain the product as off-white crystals with so pl. 157,9-159,4oC.

Example 13:

10,11-dihydro-10-(S)-(-)-campanological-5H-dibenz-[b, f] azepin-5-carboxamid

To a suspension of 0.15 g (0,56 mmol) of 10.1 is smetana and 0.22 g (2.8 mmol) of pyridine in parts was added 0.15 g (0.67 mmol) chloride(S)-(-)-campanulas acid. The resulting mixture was stirred for 2 h at room temperature, after which was added one part of 0.1 g (0.46 mmol) chloride(S)-(-)-campanulas acid. After stirring for 1.5 h was added 5 ml of dichloromethane and then 5 ml of a mixture of ice water. The organic layer was separated and washed with 10 ml of 2 M Hcl, a saturated solution Panso3and saturated saline, then was dried with sodium sulfate and filtered. The solvent was removed by evaporation under reduced pressure and the residue triturated with ether to obtain not quite white solid, which was led from a mixture of dichloromethane and ethyl acetate to give the desired the desired product as white crystals with so pl. 187-187,9oC.

Examples 14-15:

Using the above methodology, but using the appropriate acid halides received the following connections:

10,11-dihydro-10-[(3-methoxybenzyloxy)imino] -5H-dibenz-[b, f]azepin-5-carboxamid

10,11-dihydro-10-nicotinamine-5H-dibenz[b,f]azepin-5-carboxamid

Example 16:

10,11-dihydro-10-ethoxycarbonylmethylene-5H-dibenz[b, f] -azepin-5-carboxamid

To a suspension of 0.2 g (0,74 mmol) and 10,11-dihydro-10-hydroxyimino-5H-dibenz[b, f]azepin-5-carboxamide is 6 mmol) ethylchloride. The resulting mixture was stirred for 2 h at room temperature, then was extracted with 20 ml of 1 N. aqueous Hcl and saturated solution Panso3, then was dried with sodium sulfate and filtered. The solvent was removed by evaporation under reduced pressure, and the residue was led from a mixture of dichloromethane and ethyl acetate to obtain white crystals with so pl. 188,9-190oC.

Examples 17-18:

Using the above methodology, but using the appropriate chloroformate received the following connections:

10-butoxycarbonyloxyimino-10,11-dihydro-5H-dibenz[b, f] -azepin-5-carboxamid

10-benzyloxycarbonylamino-10,11-dihydro-5H-dibenz-[b,f]azepin-5-carboxamid

Example 19:

10,11-dihydro-10-phenylhydrazone-5H-dibenz[b,f]azepin-5-carboxamid

A mixture of 0.2 g (0.8 mmol) of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepin-5-carboxamide, 0.5 g (4.6 mmol) of phenylhydrazine and 0.5 g (6 mmol) of sodium acetate in a mixture of 5 ml water, 5 ml of ethanol and 3 drops of concentrated hydrochloric acid was heated to 60oC for 30 min, and then left to cool to room temperature. The precipitation was then filtered and washed with cold water and diluted with ethanol to give the desired product in the but using the appropriate hydrazines received the following connections:

10,11-dihydro-10-hydrazino-5H-dibenz[b,f]azepin-5-carboxamid

10,11-dihydro-10-(2,4-dinitrophenylhydrazone)-5H-dibenz-[b,f]azepin-5-carboxamid

Example 22:

10,11-dihydro-10-semicarbazone-5H-dibenz[b,f]azepin-5-carboxamid

To a stirred solution of 0.4 g (3,59 mmol) of the hydrochloride of semicarbazide and 0.6 g (to 7.32 mmol)of sodium acetate in 4 ml of water was added 0.2 g (0.8 mmol) of 10, 11-dihydro-10-oxo-5H-dibenz[b,f]azepin-5-carboxamide. The resulting mixture was heated on a water bath and was added 6 ml of ethanol to obtain a solution. This solution was heated to 60oC for 1.5 h, and then cooled to room temperature. The ethanol was removed by evaporation under reduced pressure, and the residue was cooled to 5oWith over 2 hours of Precipitated crystalline precipitate was filtered and washed with cold water to give the desired product as pale yellow crystals with so pl. of 247.2-248,6oC.

Examples 23-24:

Using the above methodology, but using the appropriate semicarbazides, received the following connections: 10,11-dihydro-10-thiosemicarbazone-5H-dibenz[b,f]azepin-5-carboxamid

10-(2-chlorpheniramineodeine)-10,11-dihydro-5H-dibenz-[b, f]azepin-5-carboxamid

Example 2 the mole) 10, 11-dihydro-10-oxo-5H-dibenz [b,f] azepin-5-carboxamide and 0.1 g (0.67 mmol) of the hydrochloride of methyl-4-aminobutyrate in 5 ml of xylene was added 0.07 g (0.49 mmol) of titlefirst of boron TRIFLUORIDE. The resulting mixture was heated at 135oC for 7 h and then left to cool to room temperature. The mixture is then filtered and the residue was extracted with toluene. The combined extracts evaporated under reduced pressure and the residue was chromatographically on silica gel using a mixture of 4:1 petroleum ether - ethyl acetate. Chromatographically homogeneous fractions were combined and the solvents were removed under reduced pressure to give the desired product as a yellow oil, which crystallized upon standing with the formation of yellow crystals, which were decomposed by heating without melting.

The list of compounds, characterized by melting point:

N example

Connection name - So pl.,oC

(1) 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepin-5-carboxamid - 230.4-231.5

(2) 10-benzylamino-10,11-dihydro-5H-dibenz[b,f]-azepin-5-carboxamid - 161-162

(3) 10-acetylimino-10,11-dihydro-5H-dibenz[b,f]-azepin-5-carboxamid - 175.8-176.9

(4) 10,11-dihydro-10-propionyloxy-5H-dibenz-[b, f]/BR> (6) 10,11-dihydro-10-pivaloyloxy-5H-dibenz[b, f]-azepin-5-carboxamid - 192-193

(7) 10,11-dihydro-10-[(1-naphthalocyanine)] -5H-dibenz-[b,f]-azepin-5-carboxamid - 188-189

(8) 10-benzoylecgonine-10,11-dihydro-5H-dibenz[b, f] -azepin-5-carboxamid - 170-171

(9) 10,11-dihydro-10-succinylamino-5H-dibenz-[b,f]-azepin-5-carboxamid - l79-180

(10) 10,11-dihydro-10-glucurolactone-5H-dibenz-[b, f]-azepin-5-carboxamid - 169-170

(11) 10,11-dihydro-10-isobutoxyethene-5H-dibenz-[b, f]-azepin-5-carboxamid - 179-180

(12) 10,11-dihydro-10-methoxyimino-5H-dibenz[b,f]azepin-5-carboxamid - 157.9-159,4.

(13) 10,11-dihydro-10-(S)-(-)-campanological-5H-dibenz-[b, f] -azepin-5-carboxamid - 187-187,9

(14) 10,11-dihydro-10-[(3-methoxybenzyloxy)imino]-5H-dibenz-[b,f]-azepin-5-carboxamid - 190-l91

(15) 10,11-dihydro-10-nicotinamine-5H-dibenz-[b,f]-azepin-5-carboxamid - 185-186

(16) 10,11-dihydro-10-ethoxycarbonylmethylene-5H-dibenz-[b, f]-azepin-5-carboxamid - 188.9-190

(17) 10-butoxycarbonyloxyimino-10,11-dihydro-5H-dibenz-[b,f] azepin-5-carboxamid - 167.168

(18) 10-benzyloxycarbonylamino-10,11-dihydro-5H-dibenz-[b, f]-azepin-5-carboxamid - 189-190

(19) 10,11-dihydro-10-phenylhydrazone-5H-dibenz-[b, f] -azepin-5-carboxamid - 220-220.8

(20) 10,11-dihydro-10-hydrazine-5-carboxamid - 244-245

(22) 10,11-dihydro-10-semicarbazone-5H-dibenz-[b,f]-azepin-5-carboxamid - 247.2-248.6

(23) 10,11-dihydro-10-thiosemicarbazone-5H-dibenz-[b,f]-azepin-5-carboxamid - 238-240

(24) 10-(2-chlorpheniramineodeine)-5H-dibenz-[b,f]-azepin-5-carboxamid - 298-300

(25) 10,11-dihydro-10-methoxycarbonylpropionyl-5H-dibenz-[b, f] -azepin-5-carboxamide.

1. Derivatives of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepin-5-carboxamide of General formula I

< / BR>
where R represents a hydroxy group or a group-O-CO-R1where R1represents hydrogen, an alkyl group, heteroaryl, or R represents a group-O-CO-OR1where substituent R1defined above, or R represents a group-O-R2where R2represents an alkyl or alkylaryl, or R represents a group NR3R4where R3represents hydrogen, a group-NH-CO-NH2, -NH-CS-NH2and R4represents hydrogen, an alkyl group, alkylaryl; the term "alkyl" means a carbon chain, a straight or branched, containing from one to six carbon atoms, optionally substituted by one or more alkoxy groups, alkoxycarbonyl; the term "aryl" represents phenyl or naftalina group, neobyzantine aromatic ring, containing a nitrogen atom; the term "halogen" represents fluorine, chlorine, bromine or iodine.

2. Connection on p. 1, which is a

(1) 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepin-5-carboxamide;

(2) 10-benzylamino-10,11-dihydro-5H-dibenz[b,f]azepin-5-carboxamide;

(3) 10-acetylimino-10,11-dihydro-5H-dibenz[b,f]azepin-5-carboxamide;

(4) 10,11-dihydro-10-propionyloxy-5H-dibenz-[b, f] azepin-5-carboxamide;

(5) 10-butyrolacetone-10,11-dihydro-5H-dibenz[b, f] azepin-5-carboxamide;

(6) 10,11-dihydro-10-pivaloyloxy-5H-dibenz[b, f] azepin-5-carboxamide;

(7) 10,11-dihydro-10-[(1-naphthalocyanine)]-5H-dibenz[b,f]azepin-5-carboxamide;

(8) 10-benzoylecgonine-10,11-dihydro-5H-dibenz[b, f]azepin-5-carboxamide;

(9) 10,11-dihydro-10-succinylamino-5H-dibenz[b, f]azepin-5-carboxamide;

(10) 10,11-dihydro-10-glucurolactone-5H-dibenz[b,f]azepin-5-carboxamide;

(11) 10,11-dihydro-10-isobutoxyethene-5H-dibenz[b, f] azepin-5-carboxamide;

(12) 10,11-dihydro-10-methoxyimino-5H-dibenz[b,f]azepin-5-carboxamide;

(13) 10,11-dihydro-10-(S)-(-)-campanological-5H-dibenz[b,f]azepin-5-carboxamide;

(14) 10,11-dihydro-10-[(3-methoxybenzyloxy)imino] -5H-dibenz[b,f]azepin-5-carboxamide;

(15) 10,11-dihydrobenzo[b, f]azepin-5-carboxamide;

(17) 10-butoxycarbonyloxyimino-10,11-dihydro-5H-dibenz[b,f]azepin-5-carboxamide;

(18) 10-benzyloxycarbonylamino-10,11-dihydro-5H-dibenz[b, f] azepin-5-carboxamide;

(19) 10,11-dihydro-10-phenylhydrazone-5H-dibenz[b,f]azepin-5-carboxamide;

(20) 10,11-dihydro-10-hydrazino-5H-dibenz[b,f]azepin-5-carboxamide;

(21) 10,11-dihydro-10-(2,4-dinitrophenylhydrazone)-5H-dibenz[b, f] azepin-5-carboxamide;

(22) 10,11-dihydro-10-semicarbazone-5H-dibenz[b,f]azepin-5-carboxamide;

(23) 10,11-dihydro-10-thiosemicarbazone-5H-dibenz[b, f] azepin-5-carboxamide;

(24) 10-(2-chlorpheniramineodeine)-5-dibenz[b,f]azepin-5-carboxamide;

(25) 10,11-dihydro-10-methoxycarbonylpropionyl-5H-dibenz[b,f]azepin-5-carboxamide.

3. The method of obtaining compounds of General formula I

< / BR>
where R represents a hydroxy group or a group-O-CO-R1where R1represents hydrogen, an alkyl group, heteroaryl, or R represents a group-O-CO-OR1where substituent R1defined above, or R represents a group-O-R2where R2represents an alkyl group or alkylaryl, or R represents a group NR3R4where R3represents hydrogen, a group-NH-CO-NH2, -NH is dnow chain, a straight or branched, containing from one to six carbon atoms, optionally substituted by one or more alkoxy groups, alkoxycarbonyl; the term "aryl" represents phenyl or naftalina group, optionally substituted by one or more alkoxy groups, halogen or nitro; the term "heteroaryl" represents a six-membered aromatic ring containing the nitrogen atom; the term "halogen" represents fluorine, chlorine, bromine or iodine,

the interaction of the compounds of formula II

< / BR>
with thiocarbamide, thiosemicarbazide or hydroxylamine derivative of the formula

NH2Q,

where Q represents a group of formula OR2, a group of the formula-NR3R4where substituent R2the substituents R3and R4defined above.

4. The method of obtaining the compounds of formula I

< / BR>
where R represents a hydroxy group or a group-O-CO-R1where R1represents hydrogen, an alkyl group, heteroaryl, or R represents a group-O-COOR1where substituent R1defined above, or R represents a group-O-R2where R2represents an alkyl group or alkylaryl, or R represents a group NR3R4where R3 alkyl, alkylsulphonyl; the term "alkyl" means a carbon chain, a straight or branched, containing from one to six carbon atoms, optionally substituted by one or more alkoxy groups, alkoxycarbonyl; the term "aryl" represents phenyl or naftalina group, optionally substituted by one or more alkoxy groups, halogen or nitro; the term "heteroaryl" represents a six-membered aromatic ring containing the nitrogen atom; the term halogen represents fluorine, chlorine, bromine or iodine,

the interaction of the compounds of formula V

< / BR>
with allermuir agent of the formula VI

A-CO-(O)nR1,

where a represents a hydroxy, halogen or the group-O-CO-R1or-O-CO-OR1where R1represents lower alkyl (C1-C4) and R1matter specified in paragraph (1, n is 0 or 1.

5. The method according to p. 3, where Q stands for a group-OR2where R2has the values listed above.

6. The method according to p. 3, where Q stands for a group of the formula-NR3R4where the values of R3and R4above.

7. The method according to p. 4, where as Alliluyeva agent use allerease agent of the formula

A-CO-(O)nR1,

where n is 0;

A and R1have EIT is B>nR1,

where n is 1;

And means C1;

R1has the values listed above.

9. The method according to p. 3, where the interaction is carried out in the presence of a condensing agent and/or the base.

10. The method according to p. 4, where the interaction is carried out in the presence of a condensing agent and/or the base.

11. Connection under item 1 or 2, showing anticonvulsant activity.

12. Pharmaceutical composition having anticonvulsant activity, containing an effective amount of the compounds of formula I, as defined in paragraph 1, and a pharmaceutically acceptable carrier.

13. The composition according to p. 12, where the join is defined in paragraph 2.

14. The method of treatment of convulsive States by introducing a connection on p. 1 or 2 or pharmaceutical compositions under item 12 or 13, in an effective dose.

 

Same patents:

The invention relates to new modifications of 2-amino-4-(4-forbindelsen)-1-etoxycarbonyl-aminobenzoyl formula I

< / BR>
methods for their preparation and their use in pharmaceutical compositions

The invention relates to compounds of formula (I)

(I)

in which R1denotes a hydroxy or an aliphatic, analiticheskii or aromatic residue; X is a divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, analiticheskii, heteroaromatics or aromatic residue; R2is hydrogen or aliphatic or analiticheskii balance; alk - (ness.)alkylidene; R3, R4and R5independently from each other hydrogen, (ness.)alkyl, halogen, trifluoromethyl, cyano or nitro, and their salts

The invention relates to the field of medicine, to a new stable pharmaceutical composition containing as active ingredient hydrochloride of tiagabine and antioxidant selected from the-tocopherol and ascorbyl palmitate

The invention relates to a new applicable in pharmaceuticals organic compounds and, more specifically, to a chemically pure compounds - monocarbonate and dicarbamate, a derivative of 2-phenyl - 1,2-ethanediol, represented by structural formulas (I) and (II), which dominates one enantiomer and in which the phenyl ring contains as substituents one to five halogen atoms selected from fluorine, chlorine, bromine and iodine, and in which each of R1-R6is selected from hydrogen and linear or branched alkyl groups containing from one to four carbon atoms, possibly substituted phenyl group

The invention relates to new substituted 1,2,3,4-tetrahydro-2-naphthalenamine formula I, where R1and R2independently represent hydrogen, C1-4alkyl, C1-4alkoxy, halogen, trifluoromethyl; R3represents hydrogen, hydroxyl, C1-4alkoxyl, cyano, carbarnoyl; R4and R5independently represent hydrogen, C1-4alkyl, hydroxy2-4alkyl, or form together with the nitrogen atom to which they are attached, piperidine; in the form of free bases or salts obtained by attaching acid

The invention relates to substituted imidazolidin-2,4-donovin compounds, method of their production and to the use of these compounds in medicine

The invention relates to pharmaceutical drug levels of lamotrigine and its pharmaceutically acceptable salts, formed by joining acid

The invention relates to acylaminocinnamic derivative of the formula (I), where R denotes phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R1is hydrogen, alkyl, R2is hydrogen, alkyl or phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R3is phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, or represents naphthyl, lH-indol-3-yl or 1-alcheringa-3-yl, R4' and R4"is hydrogen, alkyl, and one of the radicals R4' and R4"is hydrogen, and R5- cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its salt
The invention relates to the field of medicine, particularly ophthalmology, and can be used in the treatment of acute glaucoma attack

The invention relates to medicine and relates to methods of suppressing excessive secretion of tumor necrosis factor alpha and interleukin-1 beta, as well as the treatment of diseases associated with excessive synthesis of these cytokines, Alzheimer's and Parkinson's disease using the derived indolocarbazole K-252a
The invention relates to medicine, in particular to addiction
The invention relates to chemical-pharmaceutical industry, namely, creating a potent tranquilizer

The invention relates to a composition for topical application in the form of an emulsion for the treatment of inflammatory and hyperproliferative diseases of the skin and cutaneous manifestations of immunologically mediated diseases

The invention relates to medicine, in particular for therapy and for the treatment of pathological conditions in which it participates, including an excess of bradykinin
The invention relates to medicine, namely to internal medicine and psychosomatic medicine, and for the treatment of essential arterial hypertension

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

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