Derivatives of isatin or isfinansira, the method of obtaining derivatives isfinansira and pharmaceutical composition

 

(57) Abstract:

Describes compounds having the formula I

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where R4and R5independently represent hydrogen, halogen, CF3, CN, NO2or a group of SO2NR1R2where R1is hydrogen or C1-C6-alkyl, which may be normal, branched or cyclic, R2is hydrogen or C1-C6-alkyl, which may be normal, branched or cyclic, or where R1and R2together form a group -(CH2)n-A-(CH2)m-, where A Is O, S, CH2or NRIwhere RI- H, C1-C6-alkyl, which may be normal, branched or cyclic, n=0, 1, 2, 3, 4, 5 and m=0, 1, 2, 3, 4, 5; Q - NOH or O; Z Is O, S, N-RIIwhere RII, RIII, RIV, RVindependently represent hydrogen, benzyl, C1-C6-acyl, C1-C6-alkoxy, which may be branched or cyclic, or C1-C6-alkyl which may be branched or cyclic; X represents -(CH2)o- where=0, 1, 2 or 3; Y represents -(CH2)p- where p= 0, 1, 2 or 3; and indicate the attachment points. Described pharmaceutical composition, the manifestation is of ineni. 3 S. and 6 C. p. F.-ly.

The invention relates to new, containing condensed ring derivatives, oxime indole-2,3-dione, a treatment for these compounds, pharmaceutical compositions comprising these compounds, and the method of obtaining new compounds described in this invention.

Excessive excitation, called neurotransmitters, can cause degeneration and death of neurons. Consider that part of the intermediate stage of this degeneration is exitotoxicity excitatory amino acids (EAA) glutamate and aspartate - N-methyl-D-aspartate (NMDA) receptor, the receptor-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid (AMPA and kainite-induced receptor. This exitotoxicity action EAA causes the death of neurons in the cerebral circulation disorders, such as cerebral ischemia or infarction of the brain, caused by a number of conditions such as thromboembolic or hemorrhagic attack, spasm of blood vessels of the brain, hypoglycemia, cardiac arrest, seizures, asphyxia at birth, lack of oxygen in the blood, for example, as a result of drowning, lung and brain injury, as well as lathyrism, Alzheimer's disease the properties of antagonists of excitatory amino acids (EAA), for example in the location (site) of the AMPA binding. Six-membered cycle in these derivatives may be substituted and/or condensed with a four - semiclean carbocyclic ring. Typical compounds containing such a condensed carbocyclic ring, are the following connections:

1H-Benz[g]indole-2,3-dione-3-oxime;

5-nitro-1H-Benz[g]indole-2,3-dione-3-oxime; and

5-nitro-1H-6,7,8,9-tetrahydrobenzo[g]indole-2,3-dione-3-oxime;

such compounds are characterized by values 1C50within 10 to 100 μm, when the definition of a standard method of analysis based on the binding of AMPA described in T. Honore et al, Neuroscience Letters, 54, 27 - 32 (1985).

Active novel compounds described in the invention represent an oxime derivatives of indole-2,3-dione with condensed cycles, where a cycle is condensed with indole nucleus contains heteroatoms of oxygen, nitrogen and sulfur, as defined below. It has been found that such compounds can be used to treat diseases of mammals, including humans, and especially for the treatment of diseases that can be treated by suppressing the actions of excitatory amino acids such mammal, and typical connections have value IC50in praise, which will be described in more detail below.

Thus, the invention features:

the compound having the formula

< / BR>
where R4and R5- independently from each other hydrogen, halogen, CF3, CN, NO2or group of SO2NR1R2in which R1is hydrogen or alkyl (C1-C6that may be normal, branched or cyclic, R2is hydrogen or alkyl (C1-C6that may be normal, branched or cyclic, or where R1and R2together form a group -(CH2)n-A-(CH2)m- in which A Is O, S, CH2or NRIwhere RI- H, alkyl (C1-C6that may be normal, branched or cyclic, n= 0, 1, 2, 3, 4, 5 and m= 0, 1, 2, 3, 4, 5;

Q - NOH or O;

Z IS O, S, N-RIIwhere RII, RIII, RIVand RVis independently hydrogen, benzyl, (C=O)CF3the acyl C1-C6alkoxyl C1-C6that may be branched or cyclic, or alkyl (C1-C6that may be normal, branched or cyclic, CH2CO2RVIwhere RVIis hydrogen or alkyl (C1-C6that may be linear or branched;

X - BR>
the compound having the formula

< / BR>
where

R4, R5and RIIhave the meanings given above;

the compound having the formula

< / BR>
where R4, R5and RIIhave the meanings given above;

the compound having the formula

< / BR>
where R4, R5and RIIhave the meanings given above;

the compound having the formula

< / BR>
where R4and R5have the meanings given above, and

the compound having the formula

< / BR>
where R4and R5have the meanings given above,

the method of treatment of diseases of mammals, including humans, are affected by blockade of receptors glutamic and aspartic acids, which comprises the administration to a patient in need of such treatment, an effective amount of the compound indicated in the beginning, in the form of a standard single dose

the method described above, which treats disorders of the cerebral circulation or psychotic disorder,

and, in addition, the pharmaceutical composition comprising a therapeutically effective amount of the compounds specified above at the beginning, together with a pharmaceutically acceptable carrier,

and the way to get soedinili group SO2NR1R2where R1is hydrogen or alkyl (C1-C6that may be normal, branched or cyclic, R2is hydrogen or alkyl (C1-C6that may be normal, branched or cyclic, or where R1and R2together form a group - (CH2)n-A-(CH2)m-, where A Is O, S, CH2or NRIwhere RI- H, alkyl (C1-C6that may be normal, branched or cyclic, n= 0, 1, 2, 3, 4, 5 and m= 0, 1, 2, 3, 4, 5;

Q - NOH;

Z = O, S, N-RIIwhere RII, RIII, RIVand RVis independently hydrogen, benzyl, (C=O)CF3the acyl C1-C6alkoxyl C1-C6that may be branched or cyclic, alkyl (C1-C6that may be normal, branched or cyclic, the group CH2CO2RVIwhere RVIis hydrogen or alkyl (C1-C6that may be normal or branched,

X IS -(CH2)o- where o = 0, 1, 2 or 3;

Y IS -(CH2)p- where p = 0, 1, 2 or 3;

and the point of attachment,

which involves the reaction of the above compounds, where O is oxygen, with hydroxylamine or its reactive derivative.

For example, the compound 7-methyl-1,6,7,8-tetrahydrobenzo - [2,1-b:3,4-c'] dipyrrole-2,3-dione-3-oxime has a value IC50equal to 1 μm when tested for binding to AMPA according to the method described by T. Honore et al., Neuroscience Letters 54, 27 - 32 (1985). When the same test connection 1,2,3,6,7,8-hexahydro-3-(hydroxyimino)-N, N, 7-trimethyl-2-oksobenzo[2,1-b: 3,4-c'] dipyrrole-5-sulfon-amide has a value IC50= 0.3 ám.

The compound 5-nitro-1H, 6H-2,3,7,8,9,10-hexahydro-2,3,7 - dioxaspiro[2,3-g] indole-3-oxime in the same test conditions is the value of the IC50= 4 ám.

The compound 7-methyl-1,6,7,8-tetrahydrobenzo[2,1-b:3,4-c'] dipyrrole-2,3-dione-3-oxime has the value of the ED50= 8 mg/kg when administered intravenously to test the seizure (convulsions) caused by AMPA, as described below.

Clonic convulsions induced AMPA.

AMPA entered intracerebroventricular (icv) in an amount of 15 μg/kg to mice NMRI, causes clonic convulsions, which can be suppressed by antagonists of excitatory amino acids acting on receptors other than the NMDA receptor.

IU is the amount of 0.3 ág ten female NMRI mice (weighing 24 - 26 g) per dose. We noted the number of mice, which was observed clonic seizures over the next 5 minutes the value of the ED50was calculated as the dose, the overwhelming clonic convulsions in 50% of mice.

Pharmaceutical compositions.

Connections proposed in the invention, along with the usual auxiliary substance, the carrier or diluent can be prepared in the form of pharmaceutical compositions and unit dosages, and in this form can be used in the form of solid preparations such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with liquids - all this for oral administration (by mouth); in the form of suppositories for rectal use (through the rectum); or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit standard dose may contain conventional ingredients in conventional proportions, with the addition of additional active compounds (or effectors) or without them, and such form containing a unit dose may contain any suitable effective amount of active is rashimi single dose are tablets containing 10 mg of active ingredient or, more generally, 0.1 to 100 mg per one tablet.

Solid forms of pharmaceutical compositions for oral administration, and solutions for injection are preferred.

The method of treatment. Compounds described in the invention, are useful in the treatment of disorders of the Central nervous system associated with their biological activity. In accordance with these compounds described in the invention can be applied to entities, including man, in need of treatment, mitigation or elimination of symptoms associated with the biological activity of these compounds. Such symptoms include especially dependent excitatory amino acids psychosis-dependent excitatory amino acids hypoxia-dependent excitatory amino acids ischemia-dependent excitatory amino acids convulsions and dependent excitatory amino acid migraine. Suitable doses are in the range of 0.1 - 1000 mg / day, 10 to 500 mg per day, and especially 30 to 100 mg per day, depending, as usual, the exact method of preparation, the form in which they used the drug, indications, from the subject treatment is the treatment.

Compounds described in the invention can also be used for the treatment of schizophrenia, epilepsy, anxiety, pain, and addiction to drugs.

Example 1.

a). 5-Nitro-tetralone.

10 ml (75 mmol) of a-tetralone was added dropwise to 7.6 g (75 mmol) of potassium nitrate dissolved in 75 ml of concentrated sulfuric acid (at -10oC). The resulting mixture was poured into ice and the precipitate suspended in the air. The residue (7-nitro-isomer) was filtered, and the ether solution evaporated. The residue after evaporation was purified by the method of column chromatography on silica gel. Yield: 4.7 g of 5-nitro-tetralone, so pl. 94 - 96oC.

b). 6-Nitro-2-oxo-1-benzazepin.

The product obtained in example 1 (a), as described above, 2,43 g (35 mmol) of hydroxylamine hydrochloride and 3.7 g (35 mmol) of sodium carbonate were added to 100 ml of methanol, and the mixture is boiled under reflux for 90 min, after which it was cooled and neutralized with an aqueous solution of acetic acid. The resulting precipitated in the sediment oxime was isolated (4.3 g), so pl. 139 - 141oC. This product was heated with stirring in polyphosphoric acid (50 g) at 110oC for 30 minutes, the Reaction mixture was poured on crushed ice. Got a solid sieges. the HP 150 - 155oC.

c). 6-Amino-2-oxo-1-benzazepin.

The product obtained in example 1 (b), was first made by a standard method at 1 at on Pd/C catalyst in ethanol. Output 6-amino-2-oxo-1-benzazepine 2.0 g, so pl. 175 - 178oC.

d). 1H,6H-2,3,7,8,9,10-Hexahydro-2,3,7-trioxo-azepino - [2,3-g]indole.

The product obtained in example 1 (c), and 2 ml (13 mmol) of diethylmalonate in 20 ml of glacial acetic acid is boiled under reflux for 4 h, then the mixture was cooled and concentrated by evaporation, the residue was heated (60 - 80oC) in 25 ml of 5% NaOH in air for 2 hours the Mixture was then cooled and was added concentrated hydrochloric acid until the pH has reached the value 0. The precipitate was isolated by filtration. Yield: 0.55 g, so pl. > 300oC.

e). 1H, 6H-2,3,7,8,9,10-Hexahydro-2,3,7-trioxo-azepino [2,3-g]indole-3-oxime.

to 0.23 g of the Product obtained in example 1 (d), 0.1 g (1.3 mmol) of hydroxylamine hydrochloride and 0.14 g (1.3 mmol) of sodium carbonate was stirred in 10 ml of methanol for 6 h, after which was added water (20 ml). Precipitated precipitated product was filtered. The yield of the target compound 0.2 g, so pl. 256 - 258oC.

In a similar way we have received the following oximes of the corresponding the

6,7,9,10-tetrahydropyrrolo[2,3-g] [2,4]benzodiazepine-2,3,8(1H) Trion-3-oxime, so pl. > 300oC;

6,8-dihydro-1H-thieno[3,4-g]indole-2,3-dione-3-oxime, so pl. 192 - 195oC;

6,8-dihydro-1H-furo[3,4-g]indole-2,3-dione-3-oxime, so pl. > 300oC;

8-acetyl-1,6,7,8-tetrahydrobenzo[2,1-b: 3,4-b'] dipyrrole-2,3 - dione-3-oxime, so pl. 244 - 245oC.

Example 2.

a). 5-Nitro-1H-6H-2,3,7,8,9,10-hexahydro-2,3,7-dioxaspiro [2,3-g] indole.

0.25 g of the Product obtained in example 1 (a), was added 0.12 g (1.2 mmol) of potassium nitrate in concentrated sulfuric acid (10 ml) at -5oC; after stirring for 10 min the reaction mixture was poured on crushed ice. The resulting mixture was extracted with ethyl acetate, and the organic solvent was evaporated; got a target compound in the form of yellow crystals. Yield: 0.1 g, so pl. 277 - 278oC.

In the same way obtained by nitration 6,7,9,10-tetrahydro-6-nitro-pyrrolo[2,3-g][2,4]benzodiazepine-2,3,8- (1H)Trion, so pl. > 300oC.

b). 5-Nitro-1H, 6H-2,3,7,8,9,10-hexahydro-2,3,7-dioxaspiro [2,3-g] indole-3-oxime.

A mixture of the product obtained in example 2, a), and 35 mg (0.5 mmol) of hydroxylamine hydrochloride and 53 mg (0.5 mmol) of sodium carbonate in 6 ml of methanol was stirred for 2 h, what about the connection 0.1 g, so pl. 232 - 234oC.

Example 3.

a). 2,3-Di(methyl bromide)-nitrobenzene.

30 g of N-bromosuccinimide (NBS) was added in portions to 9 g of 2,3-dimethylnitrobenzene and 0.25 ml of tert-butylperbenzoate in 100 ml of carbon tetrachloride, and the mixture is boiled under reflux for 24 hours then the reaction mixture was cooled and was added ether. Succinimide was filtered and the filtrate evaporated. Got a 2,3-di(methyl bromide)-nitrobenzene (18 g) in the form of oil, which could be recrystallized from ethanol. So pl. 68 - 70oC.

b). N-methyl-4-nitro-2H-1,3-dihydropyrrolo[3,4]benzene.

20 g of the Product obtained in example 3 (a), was dissolved in 300 ml of methylene chloride at 10oC. After the solution was passed methylamine up until the thin layer chromatography has not been shown that the solution remained only a small amount of substance. The reaction mixture was extracted with water and then 4h. hydrochloric acid (150 ml). the pH of the aqueous phase was brought to 10 with the help of 4h. NaOH. As a result of this treatment has received the target compound in the form of crystals dull colors, which were isolated by filtration. The yield of the target compound in the form of hydrochloride 2.5 g, so pl. > 300oC.

Anal. 233 - 235oC (hydrochloride) - by reaction with tert-butylamine;

N-ethyl-4-nitro-2H-1,3-dihydropyrrolo[3,4] benzene, T. pl. 250oC (decomposition) reaction with ethylamine;

N-benzyl-4-nitro-2H-1,3-dihydropyrrolo[3,4] benzene, T. pl. 238 - 239oC (hydrochloride) - by reaction with benzylamine;

the hydrochloride of N-methoxy-4-nitro-2H-1,3-dihydropyrrolo[3,4] -benzene by reaction with hydrochloride O-methylhydroxylamine (oil).

c). 1,2,4,5-Tetrahydro-5-nitro-3-oxo-2,4-benzodiazepine.

Obtain 2,3-di-aminomethyl-nitrobenzene, so pl. 93 - 95oC.

A mixture of phthalimide potassium (11 mmol) and 2,3-dibromomethyl-nitrobenzene (5 mmol) was stirred at the boiling temperature of the solvent in a mixture of THF (30 ml) and DMF (10 ml) for 2 hours

The precipitate was filtered and treated with hydrazinehydrate (0.75 ml) in methanol (50 ml). This mixture was boiled under reflux for 3 h, cooled to room temperature and filtered. The filtrate is evaporated, and the residue was stirred in CH2Cl2. Then the filtered solution in CH2Cl2evaporated. Got 2,3-diaminophenyl-nitrobenzene as light pink crystals, so pl. 93 - 95oC.

10 mmol of the product described above was dissolved in dry DMF (Les cooling precipitated precipitated product was filtered. Got white crystals, so pl. 260 - 265oC (decomposition).

d). 2-Methyl-4-amino-2H-1,3-dihydropyrrolo[3,4]benzene hydrochloride.

of 4.2 g of the Product obtained in example 3 (b), was first made by a standard method on the catalyst Pd/C in ethanol. Yield: 3.2 g of target compound, so pl. 147 - 150oC.

The following amines were obtained similarly by hydrogenation of the corresponding nitro compounds:

hydrochloride-2-tert-butyl-4-amino-2H-1,3-dihydropyrrolo[3,4] -benzene (oil);

hydrochloride of 2-benzyl-4-amino-2H-1,3-dihydropyrrolo[3,4]-benzene (oil);

the hydrochloride of 2-methoxy-4-amino-2H-1,3-dihydropyrrolo[3,4] -benzene (oil);

1-acetyl-7-aminoindole, so pl. 156 - 158oC by hydrogenation of 1-acetyl-5-bromo-7-nitroindoline;

hydrochloride 3-amino-benzo[3,4]butyrolactone, so pl. 227 - 230oC;

hydrochloride 4-amino-1,3-dihydrobenzo[c]furan, so pl. 238 - 241oC;

1,2,4,5-tetrahydro-5-amino-3-oxo-2,4-benzodiazepine, so pl. 222 - 224oC;

4-amino-1,3-dihydrobenzo[c] thiophene (oil) was used as the catalyst of Nickel Raney;

5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline, the oil obtained by hydrogenation of methyl sulfate 2-methyl-5-nitro-isoquinoline catalyst PtO2.

oC for 30 minutes the Solution was cooled and the pH was brought to 8 by adding Na2CO3. Received a crystalline precipitate, which was filtered and washed with water. After drying, the crystals were dissolved in 20 ml of concentrated sulfuric acid and heated with stirring to 100oC 15 - 20 minutes the Mixture was cooled and added to 100 g of crushed ice, followed by addition of 15 ml of 30% sodium hydroxide solution. After this was added a saturated aqueous solution of sodium carbonate until the pH was not equal to 9. The precipitate was isolated and then recrystallized from ethanol. The yield of the target compound 1.6 g, so pl. 163 - 165oC.

Similarly, received the following connections:

7(1,1-dimethylethyl)-1,6,7,8-tetrahydrobenzo[2,1-b: 3,4-c'] dipyrrole-2,3-dione, T. pl. 178 - 180oC;

7-ethyl-1,6,7,8-tetrahydrobenzo[2,1-b: 3,4-c'] dipyrrole-2,3-dione, T. pl. 168 - 170oC;

1,6,7,8-tetrahydro-7-methoxybenzo[2,1-b:3,4-c']dipyrrole-2,3-dione, T. pl. 174 - 176oC;

1,6,7,8-tetrahydro-7-(phenylmethyl)benzo[2,1-b:3,4-c']- dipyrrole-2,3-dione, T. pl. > 300oC;

6,8-dihydro-2H-thieno[3,4-g]indole-2,3-dione, T. pl. > 300oC;

6,8-dihydro-1H-f theoC;

6,7,9,10-tetrahydropyrrolo[2,3-g][2,4]benzodiazepine-2,3,8 (1H)-Trion, so pl. > 300oC;

1H-furo[3,4-g]indole-2,3,6(8H)-Trion, so pl. > 300oC;

6,7,8,9-tetrahydro-7-methyl-1H-pyrrolo[2,3-f] isoquinoline-2,3-dione, T. pl. > 300oC;

6,7,8,9-tetrahydro-7-ethoxycarbonylmethyl-1H-pyrrolo[2,3-f] isoquinoline-2,3-dione, T. pl. 180 - 183oC;

6,7,8,9-tetrahydro-7-TRIFLUOROACETYL-1H-pyrrolo[2,3-f] isoquinoline - 2,3-dione, T. pl. 216 - 219oC;

6,7,8,9-tetrahydro-7-acetyl-1H-pyrrolo[2,3-f]isoquinoline-2,3-dione, T. pl. 248 - 250oC.

Example 4. 7-Acetyl-6,7,8,9-tetrahydro-5-nitro-1H-pyrrolo[2,3-f] isoquinoline-2,3-dione, T. pl. > 300oC, was obtained by nitration of 7-acetyl-6,7,8,9-tetrahydro-1H-pyrrolo[2,3-f] isoquinoline-2,3-dione action KNO3in 98% sulfuric acid.

Example 5. 5-Bromo-1,6,7,8-tetrahydro-7-methylbenzo[2,1-b: 3,4-c'] dipyrrole-2,3-dione.

To a stirred suspension 1,6,7,8-tetrahydro-7-methyl-benzo [2,1-b: 3,4-c'] dipyrrole-2,3-dione (0.5 g, 2.48 mmol) in water (20 ml) was added a solution of bromine (0.7 ml) in ethanol (5 ml). After stirring 5 h at room temperature the reaction was finished and the pH was brought to 8 by adding saturated solution of Na2CO3. Precipitated precipitated product was filtered and washed with water, so pl. > 300oC.

oC.

Example 6. 6,7,8,9-tetrahydro-1H-pyrrolo[2,3-f]isoquinoline-2,3 - dione.

To a cooled with ice and stirred suspension 6,7,8,9-tetrahydro-7-methyl-1H-pyrrolo[2,3-f] isoquinoline-2,3-dione (500 mg) in 1,2-dichloroethane (10 ml) was added claritinclaritin (0.25 ml). The mixture is then boiled under reflux for 1 h, then cooled it to room temperature and filtered. The filtrate is evaporated, the residue was dissolved in methanol (10 ml) and heated under reflux for 10 minutes After evaporation of the solvent obtained crude target compound in the form of dry residue. So pl. 270oC.

Example 7. 7-(1,1-Dimethylethyl)-1,2,3,6,7,8-hexahydro-3- (hydroxyimino)-N,N-dimethyl-2-oksobenzo[2,1-b:3,4-c']dipyrrole-5-sulfonamide.

1,6,7,8-Tetrahydro-7-(dimethylethyl)benzo[2,1-b:3,4-c']- dipyrrole-2,3-dione (0.5 g) was dissolved in chlorosulfonic acid (2 ml). The solution was heated to 80oC for 10 - 20 min, then cooled, and the excess chlorosulfonic acid was decomposed by the addition of pure NaCl and then adding 2 ml of water. After some time fell precipitate of the hydrochloride of 7-(dimethylethyl)-1,2,3,6,7,8-hexahydro-3,3-dichloro-2-oksobenzo- [2,1-b: 3,4-c'] dipyrrole-5-sulphonylchloride. The precipitate was filtered off, washed with 4n. HCl is Yali filtering. To a solution in THF was added dimethylamine until the reaction is completed (determined by thin-layer chromatography). The reaction mixture was filtered, and the solvent was removed by evaporation. The residue was obtained crude 7-(1,1-dimethylethyl)-1,2,3,6,7,8-hexahydro-3,3-dichloro-N, N-dimethyl-2 - oksobenzo[2,1-b:3,4-c'] dipyrrole-5-sulfonamide in the form of an oily substance, which was reacted with hydroxylamine hydrochloride (100 mg) in boiling methanol (5 ml).

After boiling under reflux for 1 h the reaction mixture was cooled to room temperature and the product (target compound) was filtered in the form of monochlorohydrin. So pl. (free base) 242 - 244oC.

In a similar way received the following connections:

7-monochlorohydrin-7-ethyl-1,2,3,6,7,8-hexahydro-3-(hydroxyimino) -N,N-dimethyl-2-oksobenzo[2,1-b:3,4-c']dipyrrole-5-sulfonamida, so pl. > 300oC;

1,2,3,6,7,8-hexahydro-3-(hydroxyimino)-N, N, 7-trimethyl-2 - oksobenzo[2,1-b:3,4-c']dipyrrole-5-sulfonamide, so pl. > 300oC;

monochlorohydrin 1,2,3,6,7,8-hexahydro-3-(hydroxyimino)-N,N,7 - trimethyl-2-oksobenzo[2,1-b:3,4-c']dipyrrole-5-sulfonamida, so pl. > 300oC;

monochlorohydrin 1,2,3,6,7,8-hexahydro-3-(hydroxyimino)-N, 7 - dimethyl-2-oksobenzo[2,1-b:3,4-c'] is-2-oksobenzo[2,1-b: 3,4-c'] dipyrrole-5-yl] sulfonyl] pyrrolidine, so pl. > 300oC;

monochlorohydrin 1,2,3,6,7,8-hexahydro-3-(hydroxyimino)-7-methyl - 2-oksobenzo[2,1-b:3,4-c']dipyrrole-5-sulfonamida, so pl. > 300oC;

monochlorohydrin 2,3,6,7,8,9-hexahydro-3-(hydroxyimino)-N, N, 7 - trimethyl-2-oxo-1H-pyrrolo[2,3-f]isoquinoline-5-sulfonamida, so pl. 268oC;

7-acetyl-5-(N,N-dimethylsulphamoyl)-6,7,8,9-tetrahydro-1H-pyrrolo [2,3-f] isoquinoline-2,3-dione-3-oxime, so pl. 260 - 261oC.

Example 8. 7-Methyl-1,6,7,8-tetrahydrobenzo[2,1-b:3,4-c']dipyrrole - 2,3-dione-3-oxime.

200 mg of the product obtained in example 3, (e), 150 mg of sodium carbonate and 100 mg of hydroxylamine hydrochloride in 20 ml of methanol was stirred 3 hours at the boiling temperature of the mixture. Then to the reaction mixture were added water and acetic acid and then added sodium bicarbonate to establish a pH of 8. The crystalline precipitate was isolated by filtration. The yield of the target product is 200 mg, so pl. > 300oC.

Similarly, there were obtained the following compounds:

7-(1,1-dimethylethyl)-1,6,7,8-tetrahydrobenzo[2,1-b: 3,4-c'] -dipyrrole - 2,3-dione-3-oxime, so pl. 242 - 244oC;

the hydrochloride of 7-ethyl-1,6,7,8-tetrahydrobenzo[2,1-b:3,4-c']-dipyrrole - 2,3-dione-3-oxime, so pl. > 300oC;

1,6,7,8-tetrahydro-7-methoxybenzo[2,1-b: 3,4-c'] -dipyrrole-2,3 - dione-3-oxime, so pl. > 300,7,8,9-tetrahydro-7-methyl-1H-pyrrolo[2,3-f] isoquinoline-2,3 - dione-3-oxime, so pl. 193 - 195oC;

hydrochloride 6,7,8,9-tetrahydro-1H-pyrrolo[2,3-f] isoquinoline 2,3-dione-3-oxime, so pl. > 300oC;

7-acetyl-6,7,8,9-tetrahydro-1H-pyrrolo[2,3-f] isoquinoline-2,3 - dione-3-oxime, so pl. 190 - 193oC;

7-acetyl-5-nitro-6,7,8,9-tetrahydro-1H-pyrrolo[2,3-f] isoquinoline-2,3-dione-3-oxime, so pl. 217 - 219oC;

6,7,8,9-tetrahydro-7-TRIFLUOROACETYL-1H-pyrrolo[2,3-f] isoquinoline-2,3-dione-3-oxime, so pl. 251 - 253oC;

7-ethoxycarbonylmethyl-6,7,8,9-tetrahydro-1H-pyrrolo-[2,3-f] isoquinoline-2,3-dione-3-oxime, so pl. 212 - 214oC.

1. Derivatives of isatin or isfinansira General formula

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where R4and R5independently is hydrogen, halogen, CF3, CN, NO2or group of SO2NR1R2where R1is hydrogen or C1- C6-alkyl, which may be normal, branched or cyclic, R2is hydrogen or C1- C6-alkyl, which may be normal, branched or cyclic,

or R1and R2together with the nitrogen atom form a heterocycle;

Q - NOH or O;

Z IS O, S, N-RIIwhere RII, RIIIindependently is hydrogen, benzyl, C1- C6-alkoxy, which may be branched or cyclic, C1- C6-alkyl, which can be- where p = 0, 1, 2 or 3;

and the attachment point.

2. Derivatives isfinansira under item 1 of General formula

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where R4, R5and RIImatter under item 1.

3. Derivatives isfinansira under item 1 of General formula

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where R4, R5and RIImatter under item 1.

4. Derivatives isfinansira under item 1 of General formula

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where R4, R5and RIImatter under item 1.

5. Derivatives isfinansira under item 1 of General formula

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where R4and R5matter under item 1.

6. Derivatives isfinansira under item 1 of General formula

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where R4and R5matter under item 1.

7. Derivatives of isatin or isfinansira under item 1, with activity related to the blockade of glutamic receptors or asparginase acid.

8. The method of obtaining derivatives isfinansira General formula

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where R4, R5X, Y, Z, and are set to p. 1;

Q - NOH,

which consists in the interaction of the compounds of General formula

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where R4, R5X, Y, Z, and are set to p. 1;

Q is oxygen,

with hydroxylamine or its reactive derivative.

9. Pharmaceutical kogasa active substance and a pharmaceutically acceptable carrier, characterized in that active compound composition comprises a derivative of isatin or isfinansira under item 1 in an effective amount.

Priority: points:

28.08.91 on PP.1 to 4 and 9;

05.02.92 on PP.1, 5, 6, and 9 when Z is - NRIIand-C (=O)-NRII.

 

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