Derivatives of spiro[isoquinoline-4(1h),3-pyrrolidine]-1,2',3, 5'[2n]tetron, the method of production thereof and pharmaceutical composition for the prevention or treatment of complications associated with diabetes

 

(57) Abstract:

Derivatives of Spiro (isoquinoline-4(1H), 3-pyrrolidin)- 1,2', 3,5'(2H) tetron obtained by the interaction of esters of 1,2,3,4-tetrahydro-1,3-dioxo-4-ethanolicus acid with hydrazinehydrate have pharmaceutical properties which enable their use for the prevention or treatment of complications associated with diabetes. 3 S. and 6 C.p. f-crystals, 1 table.

The invention describes 1'-aminosterol[isoquinoline-4(1H)3'-pyrrolidin] - 1,2', 3,5'(2H)-tetany and pharmaceutically acceptable salts of these compounds, methods for their preparation, their use and pharmaceutical preparations of these compounds. These compounds have pharmaceutical properties which enable their use for the prevention or treatment of complications associated with diabetes.

The use of insulin and/or hypoglycemic agents for oral administration in the treatment of diabetes mellitus was able to prolong the lives of many patients suffering from this disease. However, the use of these drugs do not exert any appreciable influence on the development of complications caused by diabetes, such as neuropathy, nephropathy, retinopathy, cataract and Coudenhove Genesis of these complications of chronic hyperglycemia and that full normalization of glucose in the blood will prevent if not all, at least most of these complications. However, for a number of reasons using therapeutic methods used at the present time, it is not possible to achieve a constant normalization of glucose in the blood.

Complications of chronic character as a result of diabetes developing in those tissues where glucose uptake is dependent on insulin. In these tissues, including the lens, retina, kidney and peripheral nervous system, systematic hyperglycemia as a result of diabetes quickly leads to increased concentrations of glucose in tissues. In all of these tissues such excess glucose undergoes metabolism by sorbitol. Caused by diabetes intensive flow of glucose, going this way, causes a cascade of biochemical changes that are slowly progressing, Scion to cellular dysfunction and structural abnormalities. Aldozoreduktaza, a key enzyme in the metabolism by sorbitol, restores glucose to sorbitol by cofactor NADP. Animals used for modeling of diabetes, compounds inhibiting alsoreported, prevented the biochemical, functional and morphological changes caused by hyperglycemia. The early works of J. X.Kinoshita who recently gave undeniable proof, what aldozoreduktaza also plays a significant role in the development of diabetic nephropathy, retinopathy and neuropathy (see McCaleb etc., g.Diab. Comp. , 2, 16, 1989; Robinson and others, Invest. Ophthalmol.Vis.Sci., 30,2285, 1989; NatWest, Inserra, Diabetes, 36, 500, 1987).

The closest prototype is U.S. Patent No. 4 927831 in the name of Malamas, issued March 22, 1991, which describes steroidogenesis-pyrrolidin-tetany formula

< / BR>
(R1is hydrogen or fluorine)

useful as inhibitors alsoreported for the treatment of complications due to diabetes and galactosemia.

1'-aminosterol[isoquinoline-4(1H), 3'-pyrrolidin]- 1,2',3,5'(2H)-tetany of the present invention expressed by formula (1):

< / BR>
where R1and R2independently represent hydrogen, alkyl group with 1-6 carbon atoms, halogen, lower CNS group with 1-6 carbon atoms, trifloromethyl group, a nitrogroup, aryl or aryl(lower alkyl)auxillou group, where the aryl contains from 6 to 10 carbon atoms and lower alkyl contains from 1 to 6 carbon atoms; R3lower alkyl containing from 1 to 6 carbon atoms, aryl, aryl(lower alkyl) - or dihalogen-substituted aryl(lower alkyl)-group, where the aryl contains from 6 to 10 carbon atoms,alkyl group with 1-6 carbon atoms, aryl group or aryl(lower alkyl)-group, where the aryl contains 6 to 10 carbon atoms and lower alkyl contains 1 to 6 carbon atoms, lanoil with 2-5 carbon atoms, carbalkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfonyl, triftormetilfullerenov, arylsulfonyl group, or R4and R5connected in a heterocyclic ring of 5-7 ring atoms including the nitrogen atom to which they are attached, as well as pharmaceutically acceptable salts of these compounds, where R4and R5is hydrogen, alkyl or aryl group.

A more preferred group of compounds of the present invention includes compounds of formula (1)

< / BR>
where R1and R3represent hydrogen or halogen, R3- dihalogen-substituted benzyl, R4and R5represent hydrogen, acyl, carboxyl or trifloromethyl group.

The most preferred compounds of the present invention are the following:

1'-amino-2-[(4-bromo-2-(forfinal)methyl] Spiro[isoquinoline - 4(1H), 3 pyrrolidine]-1,2',3,5'(2H)-tetron;

1'-amino-2-[(4-bromo-2-forfinal)methyl] -6-perspire [isoquinoline-4(1H), 3'-pyrrolidine]-1,2',3,5'(2H)-tetron;

complex dimethyl Olney acid;

N-[2-[(4-bromo-2-forfinal)methyl] -2,3-dihydro-1,2', 3,5'-tetraoxaspiro[isoquinoline-4(1H),3'-pyrrolidin]-1'-yl]ndimethylacetamide;

N-[2-[(4-bromo-2-forfinal)methyl] -2,3-dihydro-1,2', 3,5'-tetraoxaspiro[isoquinoline-4(1H),3'-pyrrolidin]-1 yl]-1,1,1-triftormetilfullerenov.

All the compounds of formula (1) have at least one asymmetric carbon atom, namely the Spiro-carbon atom in position 3' pyrolidine ring. Therefore, the compounds of formula (1) exist (and can be selected in two or more stereoisomeric forms. The present invention includes compounds of formula (1) in racemic form or in any other optically active form.

1'-aminosterol[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetany can be obtained using the method described below.

The present invention also provides a method of preventing or reducing complications due to diabetes in mammals by assigning the specified mammal compounds of formula (1) preventive or facilitate complications quantities. Such complications include neuropathy, nephropathy, retinopathy, keratopathy diabetic uveitis, cataract, and limited joint mobility.

The compounds of formula (1) applicable in accordance with the above method of application.

1 aminosterol-[isoquinoline-4(1H), 3'-pyrrolidine] -1,2',3,5'(2H)-tetany of the present invention can assign a mammal, for example, man, cattle or rabbits, either in pure form or in dosage forms, i.e., capsules or tablets, mixed with pharmacologically acceptable excipients.

Compounds of the present invention can be assigned for oral administration. However, the method of application of the active ingredients of the present invention is not limited in one way or another injection. For example, these compounds can be entered directly in the eye drops containing these compounds in a sterile ophthalmic solution with a buffer additive, preferably with a pH of 7.2 and 7.6. These compounds can be assigned for oral administration in solid form; in this case, these compounds are mixed with fillers, such as starch, lactose, certain types of clay, etc., These compounds can also be assigned for oral administration in the form of solutions or to enter them parenteral. For parenteral administration, these compounds can be used in the form of a sterile solution, preferably with a pH of 7.2 and 7.6, containing pharmaceutically acceptable buffer.

Dosage 1'-aminosterol[iletnego connection. In addition, the dosage will also depend on the status of a particular patient. Treatment usually start with smaller dosages that are less than the optimum dose of the compound. Then the dosage is gradually increased until reaching the efficacy of the drug. In General, compounds of the present invention, it is desirable to appoint, in such concentrations that achieve effective results without causing harmful or unwanted side effects. For local applications use eye drops, representing 0,05-1,0% solution. The frequency of instillation may be different from one drop every two or three days until one drops a day. For oral or parentline applications it is preferable to use a dose of from about 1.0 mg to 10.0 mg per kilogram of body weight per day, although these doses may be different. However, the dosage range is from about 1.0 mg to about 10.0 mg per kilogram of body weight per day give the most satisfactory results.

Dosage forms, such as capsules, tablets, pills, etc. can contain from about 5.0 mg to about 25.0 mg of the active ingredients of the present invention in combination with a pharmaceutical carrier. So, for oral use is meniu in combination with a pharmaceutical diluent, or without it. Tablets (foaming or newsprivacy) can contain from about 5.0 to 25.0 mg of the active ingredients according to the invention together with conventional pharmaceutical carriers. Thus tablets, which may have a shell and which can be expandable or newspanasonic, you can prepare one of the known methods. Inert diluents or carriers, for example, magnesium carbonate or lactose, can be used in conjunction with conventional dispersing agents, for example magnesium stearate,

1'-aminosterol[isoquinoline-4(1H), 3'-pyrrolidin] - 1,2', 3,5'(2H)-tetany can also be used in combination with insulin or hypoglycemic agents for oral administration, to achieve a favorable effect in the treatment of diabetes. In this case, suitable drugs are promyshlennosti insulin, or oral hypoglycemic agents, examples of which are prepaid, tolazamide, tolbutamide, phenformin. Compounds of the present invention may be administered sequentially or simultaneously with insulin or hypoglycemic agents for oral administration. Suitable routes of administration of the composition and doses of insulin ven Physicians Desk Reference, the 42nd edition of the "medical Economics company, Oradell, new Jersey, USA, 1988.

The use of the compounds of the present invention to prevent, reduce and mitigate diabetic complications can be demonstrated in experiments on galactosamine rats (see Porter and other Science", 182, 1146(1973)). Examples of such experiments are given below after some General remarks apply to all of these examples:

(a) Use four or more groups of six male rats weighing 50 to 70 g of breed "sprag-Dole". The first control group fed with a mixture of laboratory diet (Laboratory food for rodents, "Purine") and glucose at a concentration of 20% (percentage of weight). Galactosamine group, not being treated, fed the same food, in which glucose is replaced by galactose. The third group fed with a mixture consisting of a certain number of the test compounds and feed containing galactose. In the stern for the group being treated, the concentration of galactose was equal to the concentration of galactose in the diet to groups that are not being treated.

(b) four days later the animals death. The nerve of the lens and sciatic nerve removed, weighed and stored in frozen or dry is using a modified procedure M. Kraml and L. Cosenza, "Clin. Biochem." , 2, 373, (1969). Changes due to the replacement of two reagents: (a) washing the mixture consisted of 5% (m/o) aqueous solution of trichloroacetic acid and (b) a basic solution prepared by dissolving 25 mg of dulcita in 100 ml of an aqueous solution of trichloroacetic acid. (Note: to determine what amount of polyol accumulated in the tissues, in each experiment the average number of polyol found in the tissues of rats fed food containing glucose, subtracted from the amount of polyol found in the tissues of each rat from those fed feed containing galactose). The ability of compounds of the formula (I) to inhibit aldozoredouktazu set using the test in vitro, similar to the test described S. Heyman and J. X.Kinoshita, J. Biol. Chem. 240, 877 (1965). In procedure C. Humana and j.Kinoshita made the change, which is that in the preparation of the enzyme from bovine lens in the last step is not conducted chromatography.

The results in the table show, the hundred I'-aminosterol[isoquinoline-4-(IH), 3'-pyrrolidin] - 1,2',3,5'(2H)- tetany of the present invention have the ability to be active in vivo and to reduce the accumulation of Golfito who have a percentage increase in the accumulation of dulcita in the nerve tissues of the lens, the sciatic nerve and diaphragm, respectively, in rats subjected to treatment compared with rats that were not subjected to treatment.

The present invention also provides methods for making compounds of formula (I) or their salts. In particular, the compounds of formula (I) can be prepared by one of the following ways:

a) acylation of a compound of the formula:

R4R5NNH2(XIII)

where R4and R5have the above meanings, with a compound of the formula

(XIV)

or an activated form of this compound, where CO2R6carries out the function of ester, for example Olkiluoto ether such as methyl ether, and R1, R2and R3have the above values, to obtain the corresponding compound of formula (I), and if desired, to highlight the salt of this compound (where possible);

b) acylation of compounds of formula (I) where one of the radicals R4and R5represent hydrogen, and the second is chosen from the group comprising hydrogen, lower alkyl, aryl or aryl (lower alkyl) - azetiliruet substance (including sulfurous and alfileria substance) containing the group

R8CO-, R8OCO -, or R9S(O)n-

where R8sootvetstvuyuschego the compounds of formula (I), where R4is hydrogen, alkyl, aryl or aryl(lower alkoxy), and R5- alkanoyl, carbalkoxy, alkylsulfate, arylsulfonic, alkylsulfonyl, arylsulfonyl or trifloromethyl, or R4and R5both represent alkoxycarbonyl, alkanoyl, alkylsulfate, arylsulfonic, alkylsulfonyl, arylsulfonyl or trifloromethyl.

In method (a) the acylation can be conducted using the carboxylic acid of formula XIV and a binder, such as carbodiimide, for example, dicyclohexylcarbodiimide. In another case, the carboxylic acid group may be in an activated form, for example, gelegenheid, such as chloride or bromide or anhydride, such as a mixed anhydride. Methods for obtaining compounds of formula (III) described in the Publication N GB 2224734 and Europatent N 365324.

In method b) as examples acetylurea substances, as well as halides and anhydrides, you can specify, for example, compounds of formula R8COGal, (R8CO)2O, R9S(O)nGal, (R9SO2)2O and halogenfree, such as ClCOOR8.

You can conduct multiple acylation using stoichiometric excess quantity is Oia compounds according to the invention is shown in the following way.

Method: I'-aminosterol[isoquinoline-4(IH),3'-pyrrolidine]-1,2',3,5'-(2H)-tetany of the present invention are obtained by reaction carried out according to the scheme given in the end of the text, where R1is halogen or hydrogen, and R3- disubstituted aralkyl

Stage a) carry out the reaction either 2-bromobenzoyl acid, or 2-chlorbenzoyl acid of formula (III), where R1have the above meanings, with diethylmalonate and NaH in the presence of catalytic amount of CuBr to dimethyl ether by propandiol acid of formula (IV), where R1have the above values.

2-brabantia or 2-chlorbenzene acid of formula (III) as required by the present invention are produced by the industry or can be prepared by known methods.

Stage b) Dimethyl ether by propandiol acid of formula (IV) can interact with thionyl chloride under reflux to obtain the appropriate acid chloride, which after processing Et3N in a conventional solvent which does not adversely influence the reaction, for example, tetrahydrofuran, can give the compound of formula (V), where R1have the above meaning.

Stage c) is carried out, the reaction is UB>N in a conventional solvent which does not adversely influence on the reaction, for example, N,N-dimethylformamide to obtain a compound of formula (VI), where R1and R3have the above values.

Stage d) Conducting the reaction of the compound of formula (VI), where R1and R3have the above significance, with an inorganic base such as potassium carbonate, in a conventional solvent which does not adversely influence on the reaction, for example, N,N-dimethylformamide and then added tert-butylbromide to obtain the compounds of formula (VII), where R1and R3have the above values.

Stage e) Can be the reaction of the compound of formula (VII), where R1and R3have the above significance, with an organic acid, such as triperoxonane acid, in a conventional solvent that do not have a negative effect on the reaction, for example, in methylene chloride, to obtain the compounds of formula (VIII), where R1and R3have the above values.

Stage f) it is Possible to carry out the reaction of the compound of formula (VIII), where1NMR DMCO - d6, 400 MHz): 3,68 [c, 6H,(-CO2Me2], 5,79 [C, 1H, Ar-CH(CO2Me)2], for 7.12 (DD, J= 10,06 Hz, 2,61 Hz, 1H, Ar-H), 7,33 (dt, J = 8,48 G The/P> Mass spectrometry (m/e): 270 (M+), 238 (M+-CH3OH), 210 (M+-CH3OH, -CO), 151(M+-CH3OH, -CO, -CO2CH3).

Calculated,%: C 53,34; H 4,10.

Found,%: C 53,36; H 3,93.

Melting point: 121,5-123,0oC.

Dimethyl ether (2-carboxy-6-chlorophenyl)propandiol acid1NMR DMCO - d6, 200 MHz): 3,69 [c, 6H,(-CO2Me2], 5,78 [c, 1H, Ar-CH(CO2Me)2], 7,38 (d, J= 1,8 Hz , 1H, Ar-H), 7,58 (DD, J = 7.8 Hz, 1.8 Hz, 1H, Ar-H), of 7.96 (d, J=8,2 Hz, 1H, Ar - H), and 13.5 (Shir.with. 1H, -CO2H)

X (KBR, cm-1): 3200-2700 (CO2H), 1760(CO), 1740(CO), 1690(CO).

Mass spectrometry (m/e): 286 (20M+), 254 (64,M+-CH3OH), 222 (60,M+-2 x CH3OH)

Calculated,%: C 50,28; H A 3.87.

Found,%: C 50,40; H A 3.87.

Melting point: 125-127oC.

Dimethyl ether (2-carboxy-6-bromophenyl)propandiol acid 1NMR DMCO - d6, 400 MHz): 3,68 [c, 6H,(-CO2CH3)2], 5,74 [c, 1H, Ar-CH), 7.5 (d, J= 2,02 Hz, 1H, Ar-H), of 7.70 (DD, J = 8,4 Hz, to 1.98 Hz, 1H, Ar-H), 7,87 (d, J = to 8.41 Hz, 1H, Ar-H)

X (KBR, cm-1): 3400-2300(CO2H), 1745(CO), 1720(CO), 1695(CO).

Mass spectrometry (m/e): 330(M+) 298(M+-CH3OH)

Calculated%: C 43,53; H 3,35.

Found,%: C 43,56; H 3,23.

Temperature ptx2">

A mixture of dimethyl ether (2-carboxyphenyl)propandiol acid (10.0 g, 39,68 mmol) and SOCl2(100 g) is heated under reflux for 2 hours, Volatile components are removed under vacuum and the crude product (acid chloride) was dissolved in tetrahydrofuran (200 ml). Add triethylamine (27,64 ml, 198,4 mmol) and the mixture is stirred for 30 minutes, the Suspension is yellowish poured into HCl (1H, 1000 ml), extracted with EtOAc, and the organic extracts dried over MgSO4. After evaporation and crystallization from acetone/ether/hexane (after cooling to -20oC) get a solid white color (87,6 g, 94,4%, the melting point of 129-130oC).

1H NMR (DMCO - d6, 400 MHz): 3,82 (c, 3H, -CH2Me), a 4.03 (c, 3H, -ome), 7,42 (t, J = 7,26 Hz, 1H, Ar-H), 7,8 (t, J = 8,2 Hz, 1H, Ar-H); 7.9 (d, J = 8,3 Hz, 1H, Ar-H) and 8.1 (d, J = 7,26 Hz, 1H, Ar-H).

X (KBR, cm-1): 1740(CO), 1685(CO).

Mass spectrometry (m/e): 234 (15M+), 206 (38,5 M+-CO), 203(12, M+-OMe)

Calculated,%: C 61,59; H 4,30.

Found,%: C 61,82; H 4,29.

The following compounds are prepared in practical as in example 1, stage b):

Methylene ether of 6-fluoro-3-methoxy-1-oxo-1H-2-benzopyran-4-carboxylic acid.

R1and R3have above is eazol (HOBT) in a conventional solvent, which has no adverse effect on the reaction, for example, N,N-dimethylformamide, and then add the hydrazine and Et3N to obtain the compounds of formula (IX), where R1and R3have the above values.

Stage g) to carry out the reaction of the compound of formula (IX), where R1and R3have the above meanings, with methylchloroform in the presence of Et3N in a conventional solvent which does not adversely influence on the reaction, for example in tetrahydrofuran, to obtain the compounds of formula (X), where R1and R3have the above values.

Stage h) Compound of formula (IX), where R1and R3have the above values, you can interact with acetic anhydride at 70oC to obtain the compounds of formula (XI), where R1and R3have the above values.

Stage i), it is Possible to carry out the reaction of the compound of formula (IX), where R1and R3have the above significance, with the anhydride triftormetilfullerenov acid in the presence of Et3N in a conventional solvent which does not adversely influence on the reaction, for example, in methylene chloride, to obtain the compounds of formula (XII), where R1and R3and the tx2">

Example 1.

1'-amino-2-[(4-bromo-2-ferminal)methyl]Spiro[isoquinoline-4-(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetron.

Stage a) Dimethyl ether (2-carboxyphenyl)propandiol acid.

In a vigorous stir the suspension (0oC) 2-bromobenzoyl acid (30.0 g, 149,32 mmol), copper bromide (2.14 g, 14,98 mmol), and dimethyl ester of malonic acid (300 ml) is added NaH (80% in mineral oil, of 10.75 g, 358,37 mmol) for 30 min, with a flow of dry N2passed over the mixture. After the addition of NaH was completed, the mixture is stirred for 10 min at room temperature and once for 30 min at 70oC (the temperature of an external oil bath). At this time, the suspension turns into a solid mass which was dissolved in H2O (1000 ml). The aqueous layer was extracted with diethyl ether (3 x 500 ml) and acidified with 2 N. HCl. The mixture is extracted with Et SLA and dried over MgSO4. After evaporation get a completely white solid, which is recrystallized from Et2O/hexane (after cooling to 20oC) to obtain a solid white color (34,2 g, 90,9%, melting point 119 - 120oC)

1H NMR (DMCO - d6, 400 MHz): 3,67 (c, 6H, -CH(CO2CH3)2], 5,72 [c, 1H, -CH(CO2,33 Hz, 1H, Ar-H), 13.2 (c, 1H-CO2H).

X (KBR, cm-1): 3300-2700(CO2H), 1750(CO), 1730(CO), 1680 (CO).

Mass spectrometry: (m/e): 252(M+), 220(M+-CH3OH), 188(M+-2 x CH3OH)

Calculated,%: C 57,14; H 4,80.

Found,%: C 57,05; H 4,78.

The following compounds are prepared in almost the same way as in example 1, stage a):

dimethyl ether (2-carboxy-6-forfinal)propandiol acid

1H NMR (DMCO - d6, 400 MHz): 3,81 (c, 3H, -CO2CH3), 4,06 (c, 3H,-OCH3-), 7,27 (dt, J= 8,3 Hz, 1H, Ar-H), and 7.8 (DD, J = 11,83 Hz, 2,49 Hz, 1H, Ar-H), 8,16 (DD, J = 8,92 Hz, 6.2 Hz, 1H, Ar - H).

X (KBR, cm-1): 1750 (CO), 1685 (CO).

Mass spectrometry (m/e): 252 (24,M+), 224 (54,M+-CO).

Calculated,%: C 57,15; H 3,60.

Found,%: C 57,19; H 3,57.

Melting point: 142-143oC.

Methyl ester of 6-chloro-3-methoxy-1-oxo-1H-2-benzopyran-4-carboxylic acid.

1H NMR (DMCO - d6, 400 MHz): 3,81 (c, 3H, -CO2CH3), 4,05 [c, 3H, OCH3), 7,44 (DD, J = 8,56 Hz, 1,99 Hz, 1H, Ar-H), of 8.06 (m, 2H, Ar-H).

X (KBR, cm-1): 1750(CO), 1690(CO).

Mass spectrometry (m/e): 268 (34,M+), 240 (86,M+-CO)

Calculated,%: C 53,65; H 3,38.

Found,%: C 53,59; H 3,35.

Tempera is the notes.

1H NMR DMCO - d6, 400 MHz): 3,81 (c, 3H, -CO2CH3), 4,05 (c, 3H, -OCH2), and 7.6 (DD, J = scored 8.38 Hz, 1.77 Hz, 1H, AR-H), and 8.0 (d, J = 8,39 Hz, 1H, Ar-H), 8,23 (d, J = 1,95 Hz, 1H, Ar-H).

X (KBR, cm-1): 1740(CO), 1680(CO)

Mass spectrometry (m/e): 312(17M+), 284(45,M1-CO)

Calculated,%: C 46,03; H 2,90.

Found,%: C 46,12; H 2,62.

Melting point 200 - 201oC.

Stage C): methyl ester of 2-[(4-bromo-2-ferminal)methyl]-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinoline-carboxylic acid.

To a solution of methyl ester of 3-methoxy-1-oxo-1H-2-benzopyran-4-carboxylic acid (5.0 g, 21,37 mmol) in N, N-dimethyformamide (100 ml) is added 4-bromo-2-forbindelsen (4,36 g, 21,37 mmol) and Et3N (5,96 ml, 42,74 mmol). The mixture was stirred at 80oC for 30 min, poured into H2O (1500 ml), acidified with HCl(2H) and extracted with Et SLA. The organic extracts are dried over MgSO4. After evaporation and crystallization from acetone/hexane (after cooling to -20oC) get a solid white color (7.6 g, 87.7 per cent. melting point 149 - 150oC).

1H NMR (DMCO - d6, 400 MHz): [3,67 c, 4,0 (C), 3H, -CO2Me, tautomery] , [5,06 (kV), J = 15,4 Hz, 5,30 (s), 2H, -NCH2, tautomeric], 5,4 (C), 1H, CH-CO2Me, tautomeric], 7,07-8,43 (m, 7H, Ar-374(40,M+-OCH3)

Calculated,%: 53,22; H 3,23; N 3,45.

Found,%: C 53,19; H 2,98; N 3,40.

The following compounds are prepared in essentially the same way as in example 1, stage C).

Methyl ester 2-[(4-bromo-2-forfinal)methyl]-6-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-4-ethinlestradiol acid

1H NMR (DMCO - d6, 400 MHz): 3,98 (c, 3H, -CO2CH3), 5,27 (c, 2H, -NCH2-), was 7.08 (t, J = 7,95 Hz, 2H, Ar-H), 7,2 (m, 1H, Ar-H), 7,34 (m, 2H, Ar-H, -OH), 7,54 (m, 1H, Ar-H), 8,1 compared to 8.26 (m, 2H, Ar-H).

X (KBR, cm-1): 1680(CO), 1660(CO), 1610(CO)

Mass spectrometry (m/e): 423(M+), 391(M+-CH3OH).

Calculated, %: C 50,97; H 2,85; N 3,30.

Found, %: C 50,86; H 2,86; N 3,33.

Melting point 157-158oC.

Methyl ester of 6-chloro-1,2,3,4-tetrahydro-2-methyl-1,3-dioxo-4-ethinlestradiol acid

1H NMR (DMCO-d6, 200 MHz): [3,23 (c), 3,44 (c), tautomeric, 3h, -NCH3] , [3,71 (c), a 4.03 (c), tautomeric, 3H, -CO2CH3, 7,3-8,4 (tautomeric, Ar-H, -OH, 4H)

X (KBr, cm-1): 3440(OH), 1680(CO), 1600(CO)

Mass spectrometry (m/e): 267(M+-OMe), 235 (M+-OMe)

Calculated, %: C 53,85; H Of 3.77; N 5,23.

Found, %: C 53,66; H 3,63; N 5,14.

Melting point 166-167oC.

Methyl ester of 6-bromo-1,2,3,4-tetrahydro-2-omery, N-CH3] , [3,7 (c) to 4.01 (c), 3H, tautomeric, -CO2CH3], [5,33 (C), 1H, tautomeric, Ar-CH -] key to 7.5 (DD), and 7.8 (DD), tautomeric, 1H, Ar-H, 8,0 (d), 8,08 (d), tautomeric, 1H, Ar-H], [8,51 (d), 7,63 (d), tautomeric, 1H, Ar-H)

X (KBr, cm-1): 1665 (CO), 605 (CO)

Mass spectrometry (m/e):311(M+)

Calculated, %: C 46,18; H 3,23; N 4,49.

Found, %: C 45,83; H 2,77; N Of 4.38.

Melting point 190-191oC.

Stage d) 1,1-dimethylethylene ester 2-[(4-bromo-2-forfinal)methyl] -1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinoline acetic acid.

To a suspension of methyl ester 2-[(4-bromo-2-forfinal)methyl]-1,2,3,4-tetrahydro-1,3-dioxo-4-ethinlestradiol acid (4,79 g, 11,58 mmol), K2CO3(3,19 g, 23,16 mmol) in N, N-dimethylformamide (100 ml) is added tert-butyl-bromoacetate (2,81 ml, 17,37 mmol). After stirring at 75oC for 1 h the mixture was poured into H2O, extracted with EtOAc and dried over MgSO4. After evaporation and purification using fast chromatography (hexane/EtOAc 4/1) to obtain a clear oil (5,69 g, 94.5% of).

1H NMR (DMCO-d6, 400 MHz): 1,04 [s, 9H, - C(CH3)3], 3,53 c, 3H, -CO2CH3, 3,60 [DD, J = 17.7 and Hz, 2H, -CH2CO2(CH3)3], 5,14 (s, 2H, [NCH 7,17 ( t , J = of 8.25 Hz, 1H, Ar-H), was 7.36 (DD, J = At 8.36 G(CO), 1675(CO)

Mass spectrometry (m/e): 520(M + H)+, 464 M+-C(CH3)3.

The following compounds are prepared in much the same way as in example 1, step d):

1,1-dimethylethylene ester 2-[(4-bromo-2-forfinal)methyl] -6-fluoro-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4 - isoquinoline acetic acid.

1H NMR (DMCO - d6, 200 MHz): 1,10 (s, 9H, -CMe3), 3,55 (s, 3H, -CO2CH3), 3,62 (d, J = 17.5 Hz, 1H, -CH2CO2CMe3in ), 3.75 (d, J = 17.5 Hz, 1H, -CH2CO2CMe3), of 5.15 (s, 2H, -NCH2-), to 7.15 (t, J = 8,2 Hz, 1H, Ar-H), 7,35 (d, J = 8,2 Hz, 1H, Ar-H), 7,45-of 7.70 (m, 3H, Ar-H), scored 8.38 (DD, J = 8,16 Hz, 5,70 Hz, 1H, Ar-H)>

X (KBr, cm-1): 1750(CO), 1720(CO), 1675(CO)

Mass spectrometry (m/e): 538(M + H)+, 481(M++ H-CMe3)

Calculated, %: C 53,55; H 4,12; N 2,60.

Found, %: C 53,49; H 4,00; N 2,63.

1,1-dimethylethylene ester of 6-chloro-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-2-methyl-1,3-dioxo-4-ethanolicus acid.

1H NMR (DMCO-d6, 200 MHz): of 1.06 (s, 9H, -CO2CMe3), and 3.3 (s, 3H, -NCH3), and 3.6 (s, 3H, -CO2CH3), to 3.67 (q, J = 17.5 Hz, 2H, -CH2CO2CMe3to 7.68 (DD, J = 9,0 Hz, 1.6 Hz, 1H, Ar-H), to 7.77 (d, J = 2.0 Hz, 1H, Ar-H), 8,21 (d, J = 8,2 Hz, 1H, Ar-H)

X (KBr, cm-1): 1740(CO), 1720(CO), 1680(CO)

Mass spectrometry (m/e)compliance 135-136oC.

1,1-dimethylethylene ester of 6-bromo-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-2-methyl-1,3-dioxo-4-ethanolicus acid.

1H NMR (DMCO-d6, 200 MHz): 1,05 [s, 9H, -C(CH3)3], or 3.28 (s, 3H, NCH3) and 3.59 (s, 3H, -CO2CH3), to 3.58 (d, J = 17,03 Hz, 1H, -CH2CO2-), to 3.67 (d, J = 17,03 Hz, 1H, - CH2CO2-), 7,81 (DD, J = 8,4 Hz, of 1.85 Hz, 1H, Ar-H), 7,88 (d, J = 1,81 Hz, 1H, Ar-H), 8,08 (d, J = 8,4 Hz, 1H, Ar-H).

X(KBr, cm-1): 1740(CO), 1710(CO), 1670(CO)

Mass spectrometry (m/e): 425(M+), 370(M+- C4H7), 352 (M+-C4H9O)

Calculated, %: C 50,72; H To 4.73; N 3,29.

Found, %: C 50,47; H To 4.68; N 3,12.

Melting point 152-153oC.

Stage e). 2-[(4-bromo-2-forfinal)methyl] -1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-ethanolicus acid.

A mixture of 1,1-dimethylethylene ester 2-[(4-bromo-2-forfinal) methyl] -1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4 - ethanolicus acid (5,19 g, 9,81 mmol), CH2Cl2(100 ml) and CF3CO2H (20 ml) was stirred at room temperature for 5 hours, Volatile components are removed under vacuum and the residue is purified instant chromatography on silica gel, acid washed (5% H3PO4in MeOH) to obtain begc): 3,54 (s, 3H, CO2CH3), to 3.64 (q, J = 17,67 Hz, 2H, CH2CO2H), 5,12 (sq J = 15,34 Hz, 2H, -NCH2-), 7,14 (t, J = by 8.22 Hz, 1H, Ar-H), and 7.3 (d, J = *,3 Hz, 1H, Ar-H), and 7.5 and 7.6 (m, 3H, Ar-H), 7,76 (d, J = 7,4 Hz, 1H, Ar-H), 8,16 (d, J = 7.8 Hz, 1H, Ar-H), 12,35 (s, 1H, -CO2H)

X(KBr, cm-1): 3280(OH), 3200-2700(CO2H), 1750(CO), 1675(CO).

Mass spectrometry (m/e): 463(M+), 445(M+-H, -OH)

Calculated, %: C 51,28; H 3,30; N, 2,99.

Found, %: C 51,26; H 3,48; N 2,95.

The following connection will get almost the same way as in example 1, step e):

2-[(4-bromo-2-forfinal)methyl]-6-fluoro-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-ethanolicus acid.

1H NMR (DMCO-d6, 400 MHz): of 3.56 (s, 3H, -CO2CH3), and 3.6 (d, J = 17,9 Hz, -CH2CO2H), and 3.8 (d, J = and 17.9 Hz, 1H, -CH2CO2H) a 5.1 (DD, J = 15,5 Hz, 2H, -NCH2-), 7,12 (s, J = 8,23 Hz, 1H, Ar-H), 7,31( DD, J = 8,28 Hz, 1,68 Hz, 1H, Ar-H); was 7.45 (dt, J = 8,56 Hz, 2.5 Hz, 1H, Ar-H), 7,54 (DD, J = 9,77 Hz, 1.89 Hz: 1H, Ar-H), to 7.64 (DD, J = being 9.61 Hz, 2,46 Hz, 1H, Ar-H), 8,23 (DD, J = 8,79 Hz, of 5.81 Hz, 1H, Ar-H), 12,67 (Shir.with. 1H, -CO2H).

X(KBr, cm-1): 3400-2700(CO2H), 1745(CO), 1710(CO), 1670(CO)

Mass spectrometry (m/e): 481(M+), 405(M+- CO2, -CH3OH)

Calculated, %: C 49,81; H 2,93; H 2,90.

Found, % C 49,94; H 3,03; H 2,84.

Melting point 132 - 133,5oC.

SUP>1H NMR (DMCO - d6, 200 MHz): 3,27 (C. 3H, -CH3) and 3.59 (C. 3H, -CO2CH3), to 3.64 (q, J = 17.5 Hz, 2H, -CH2CO2H), the 7.65 (DD, J = 8.6 Hz, 2.0 Hz, 1H, Ar-H), 7,78 (d, J = 2.0 Hz, 1H, Ar-H), 8,18 (d, J = 8.0 Hz, 1H, Ar-H)

ISS (KBR, cm-1): 3440(OH), 3200 - 2700(CO2H), 1750(CO), 1710(CO), 1675(CO)

Mass spectrometry (m/e): 325(M1)

Calculated,%: C 51,63; H 3,71; N 4,30.

Found, %: C 51,73; H 2,70; N 4,28.

Melting point 195 - 196oC.

6-bromo-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-2-methyl-1,3-dioxo-4-ethanolicus acid

1H NMR (DMCO - d6, 200 MHz): 3,26 (s, 3H, N-CH3), 3,53 (d, J = and 17.2 Hz, 1H, -CH2H) to 3.58 (s, 3H, -CO2CH3), 3,74 (d, J = and 17.2 Hz, 1H, -CH2CO2H) to 7.77 (DD, J = 8,2 Hz, 2.2 Hz, 1H, Ar-H), 7,87 (d, J = 2.2 Hz, 1H, Ar-H), and 8.0 (d, J = 8,2 Hz, 1H, Ar-H), 12,64 (s, 1H, -CO2H)

X (KBR, cm-1): 3450-2600(CO2H), 1735(CO), 1700(CO), 1660(CO)

Mass spectrometry (m/e): 369(M+), 324(M+-CO2H)

Calculated,%: C 45,43; H 3,27; H 3,78.

Found,%: C For 45.04; H 3,16; H 3,62.

Melting point 194 - 195oC.

Stage f). 1'-amino-2-[(4-bromo-2-forfinal)methyl] Spiro[isoquinoline-4(1H), 3'-pyrrolidine]-1,2', 3,5'(2H)-tetron

To a solution of 2-[(4-bromo-2-tortenelemmel] -1, 2, 3, 4-tetrahydro 4-(methoxycarbonyl)1,3-dioxo-4-ethanolicus acid (2.5 g,, of 1.34 g, 7.0 mmol) and hydrate-1-hydroxybenzotriazole (HOBT, 1,09 g, 8,08 mmol). After stirring for 2 h drop added anhydrous hydrazine (0,22 ml, 7.0 mmol), and then Et3N (1.5 ml, 10,77 mmol). The mixture is stirred for 30 min, poured into H2O, neutralized with HCl(2H) and extracted with EtOAc. The organic extracts are dried over MgSO4. After evaporation and purification by the method of the instant chromatography (hexane/EtOAc 1:1) and subsequent crystallization from ether/hexane (after cooling to -20oC) receive a white solid (1.68 g, 70.0% of the melting point of 95 - 97oC).

1H NMR (DMCO - d6, 400 MHz): to 3.33 (d, J = 18.2 Hz, 1H, -HCHCO), 3,51 (d, J = 18.2 Hz, 1H, -HCHCO-), 5,07 (s, 2H, -NCH2-), 5,23 (s, 2H, -NH2), 7,17 (t, J = 8,3 Hz, 1H, AR-H), 7,33 (DD, J = 8,3 Hz, 1.7 Hz, 1H, Ar-H), 7,54 (m, 2H, Ar-H), 7,63 (t, J = 8,51 Hz, 1H, Ar-H), 7,79 (dt, J = 8.7 Hz, 1.25 Hz, 1H, Ar-H), 8,18 (DD, J = 7,7 Hz, 1.25 Hz, 1H, Ar-H)

X(KBR, cm-1): 3340(NH), 1720(C=O), 1670 (C=O)

Mass spectrometry (m/e): 445(4,M+)

Calculated,%: C 51,14; H 2,94; H 9,42.

Found,%: C 51,04; H 2,94; H 9: 30 A.m.

The following compound is prepared in much the same way as in example 1, step f).

1'-amino-2-[(4-bromo-2-forfinal)methyl] -6-perspire[isoquinoline - 4(1H), 3'-pyrrolidin]1,2', 3,5'(2H)-tetron

1H NMR(D(DD, J = 8,1 Hz, of 1.66 Hz, 1H, Ar-H), 7,49 (dt, J = 8,5 Hz, to 2.29 Hz, 1H, Ar-H); at 7.55 (DD, J = 9,96 Hz, 1H, Ar-H), and 7.6 (DD, J - 9.75 Hz, 2,49 Hz, 1H, Ar-H), 8,24 (DD, J = 8,9 Hz, 5.8 Hz, 1H, Ar-H).

X (KBR, cm-1): 3350(NH), 3280(NH), 1730(C=O), 1710(C=O), 1670(C=O)

Mass spectrometry (m/e): 463 (94M+)

Calculated:% C 49,16; H 2,61; N 9,05.

Found,%: C 49,19; H 2,66; N 8,96.

Melting point 232 - 234oC

Example 2.

Dimethyl ether N-[2-[(4-bromo-2-forfinal)methyl] -2,3-dihydro-1,2', 3,5'-tetraoxaspiro-[isoquinoline-4(1H), 3'-pyrrolidin]-1'-yl]-iminodiethanol acid

To a cold solution (0oC) 1'-amino-2-[(4-bromo-2-fluoro-phenyl) methyl]Spiro-[isoquinoline-4(1H),3 pyrrolidine]-1,2'3,5'-(2H)-tetron (2.0 g, 4,48 mmol) in tetrahydrofuran (50 ml) was added Et3N (3.12 ml of 22.4 mmol), and then drop by drop add methylchloroform (1,04 ml, 13,44 mmol). After stirring for 30 min the mixture was poured into H2O, acidified with HCl (2H) and extracted with EtOAc. The organic extracts are dried over MgSO4. After evaporation and purification by the method of the instant chromatography on silica gel (hexane/ EtOAc 2:1) receive a white solid (2.1 g, and 83.3%, melting point 214 - 216oC).

1H NMR (DMCO - d6, 400 MHz): 3,74 (s, 3H, -CO2CH3), 3,76 (d, J = 18,9 Hz, 1H, -HCHCO-), 3,81 (d, J = 18,9 Hz, 1H, -HCHCO-), 3,83 ( Ar-H), 7,86 (dt, H = 7,68 Hz, 1,45 Hz, 1H, Ar-H), 8,21 (DD, J = 7,88 Hz, 1.25 Hz, 1H, Ar-H)

X(KBR, cm-1): 1810(C=O), 1745(C=O), 1670(C=O)

Mass spectrometry (m/e): 561 (50, M+)

Calculated,%: C 49,13; H 3,05; N 7,47.

Found,%: C 49,33; H 3,22; N 7,26.

Example 3.

N-[2-[(4-bromo-2-forfinal)methyl] -2,3-dihydro-1,2'3,5'-tetraoxaspiro-[isoquinoline-4(1H),3'-pyrrolidin]-1'-yl]ndimethylacetamide

A mixture of 1'-amino-2-[(4-bromo-2-forfinal)methyl] Spiro[sosyalan-4(1H), 3'-pyrrolidine] -1,2'3,5'(2H)-tetron(2.0 g, 4,48 mmol) and acetic anhydride (20 ml) was stirred at 70oC for 30 min Volatile components are removed under vacuum and the residue is purified instant chromatography on silica gel (hexane/E) OAc 1:1) to a white solid (1,91 g of 87.3%, melting point 219 - 221oC).

1H NMR(DMCO - d6, 400 MHz): up to 1.98 (s, 3H, -COCH3), 3,5 (d, J = 18,9 Hz, 1H, -HCHCO-), and 3.7 (d, J = 18,9 Hz, 1H, -HCHCO-), 5,09 (DD, J = 16.2 Hz, 2H, -CH2N), 7,17 (t, J = 8,3 Hz, 1H, AR-H), 7,35 (d, J = 7.9 Hz, 1H, Ar-H), 7,56 (m, 2H, Ar-H), the 7.65 (t, J = 7.68 per Hz, 1H, Ar-H), to 7.84 (dt, J = 7.68 per Hz, 1H, Ar-H), to 7.84 (dt, J = 7.68 per Hz, 1.25 Hz, 1H, Ar-H), 8,17 (DD, J = 7,88 Hz, 1.25 Hz, 1H, Ar-H), 10,95 (s, 1H, N NHCOCH3)

X(KBR, cm-1): 3240(NH), 1740(C=O), 1700(C=O), 1660(C=O)

Mass spectrometry (m/e): 487 (54 M+), 387 (1006 M+- OONNHMOCH3)

Calculated,%: C 51,66; H 3,10; N 8,61.

Found,%: Chinolin-4(1H),3'-pyrrolidin]-1'-yl]-1,1,1-triftormetilfullerenov

In a chilled (0oC) a solution of 1'-amino-2-[(4-bromo-2-forfinal)methyl] Spiro-[isoquinoline-4(1H), 3'-pyrrolidine]-1,2',3,5'(2H)-tetron (2.0 mg, 4,48 mmol) in anhydrous CH2Cl2add Et3N (3.12 ml of 22.4 mmol), then drop by drop add (CF3SO2)2O(of 2.26 ml, 13,44 mmol). After stirring for 30 min the mixture was poured into H2O, acidified with HCl(2H) and was extracted with EtOAc. After evaporation and purification instant chromatography on silica gel, acid washed (hexane/EtOac 1:1) to obtain a yellow solid (1.1 g, 42.5%, melting point 98 - 100oC).

1H NMR (DMCO - d6, 400 MHz): 3,29 (d, J = 18.5 Hz, 1H, -HCHCO-), 3,5 (d, J = 18,4 Hz, 1H, -HCHCO-), 5,07 (s, 2H, -NCH2), 7,18 (t, J = 8,1 Hz, 1H, Ar-H), 7,32 (DD, J = 8,3 Hz, to 1.87 Hz, 1H, Ar-H), 7,38 (d, J = 7,88 Hz, 1H, Ar-H), 7,53 (DD, J = 9,96 Hz, 2,07 Hz, 1H, Ar-H), a 7.62 (t, J = 8,5 Hz, 1H, Ar-H), 7,78 (dt, J = 7.9 Hz, 1.25 Hz, 1H, Ar-H), 8,15 (DD, J = 7.9 Hz, 1.25 Hz, 1H, Ar-H),

X (KBR; cm-1): 3400(NH), 1750(C=O), 1670(C=O)

Mass spectrometry (m/e): 577( 94, M+), 387 (60, M+-CONNHSO2CF3)

Calculated,%: C 41,54; H 2,09; N 7,27.

Found,%: C 41,20; H 2,03; N 7,19.

Example 5

Capsules

Every gram of granules contains 322,6 mg of 1'-amino-2- [(4-bromo-2-forfinal)methyl] Spiro[isoquinoline-4-(1H), 3'-pyrrolidon]-1,2', 3,5' (2H)tetron as onent - 322,6

Croscarmellose sodium, NF Type A - 60,0

Microcrystalline cellulose, NF - 145, 2mm

Lactose, USP, direct compression of 450.1

Powder talc - 2,10

Magnesium stearate, NF - 20,0

The sequence of preparation

1. Mix the active ingredient, croscarmellose sodium, microcrystalline cellulose, lactose and talc powder for 30 min in PC mixer rod type to enhance mixing.

2. Add magnesium stearate and mix for 5 minutes in the mixer rod type to enhance mixing.

3. Push the mixture from stage 2, medium-hard, using 1-3/16" (30 mm) punches.

4. Let the grain of the mixture through the mill fitza using a sieve N 2, medium speed, knives forward.

5. Store this material in tightly closed containers at room temperature in the form of a granulate up until it will not be used for the manufacture of capsules.

6. Encapsulate in shell N0 weighing filling 620 mg of the granules in a capsule to obtain a capsule strength 200 mg.

Example 6

Capsules

Each capsule should contain 400 mg of the same active ingredient as in example 1.

The composition for the second cellulose, NF - 24,5

Lactose, USP, dried spray - 50,5

Calcium carboxymethylcellulose, ECG 505, NF - 12,9

Povidone, USP is 15.5

Talc, USP - of 9.30

Powder talc - 1,00

Magnesium stearate, NF - 2,60

The sequence of preparation

1. Mix the active ingredient, microcrystalline cellulose, calcium carboxymethyl cellulose, ECG 505, NF, povidone, talc powder and the lactose and PC mixer rod type to achieve uniformity.

2. Add talc and 1.30 grams of magnesium stearate to the mixture obtained in stage 1 in core PC mixer for 5 minutes

3. Pass the mixture obtained in stage 2, through a roller compactor to obtain the corresponding seals.

4. Miss compacted mixture of stage 3 slowly through the mill fitza, with plates N 2, medium speed, knives forward.

5. Mix obtained in stage 4 of the mixture into the PC mixer disabled stirrer for 3 minutes

6. Pre-mix the rest of the stearate with a part of the loaded material to achieve uniformity.

7. Add mixed at the stage portion 6 in PC mixer and mixed for 2 min with disabled agitator.

the use for the preparation of granulate:

Ingredients Quantity (mg

Active ingredient (1) - 705,0

Microcrystalline cellulose, NF - 200,0

Calcium carboxymethylcellulose, ECG 505, NF - 25,0

Povidone, USP - 30,00

Talc, USP - 20,00

Magnesium stearate, NF - 20,00

(1) is the same as in examples 1 and 2

The sequence of preparation

1. Mix the active ingredient, half of the microcrystalline cellulose, calcium carboxymethyl cellulose and povidone in a V-mixer for 15 min with running stirrer rod type to enhance mixing.

2. Add talc and 2,500 mg of magnesium stearate to the mixture of stage 1, and mixed in a V-mixer for 2 min with an operating rod stirrer to enhance mixing.

3. Pass the mixture obtained in stage 2, through a roller compactor using the appropriate conditions for the formation of a proper seal. Sift the compacted mixture through a sieve of 10 mesh. and condense the material repeatedly, passing it through a sieve.

4. Miss compacted mixture obtained in stage 3, through the mill fitza using a sieve, No. 28, medium speed, knives forward.

5. Mix obtained in stage 4 of the granules, the remaining portion of microcrystal the rods within 1 min.

6. Pass obtained at the stage 5 granulate into tablets with theoretical weight of the tablet 426 mg, using all standard tool with a concave working surface size 13/32" (10,3 mm) hardness 11-13 SCU and thickness 0,185" - 0,190" (4,7 - of 4.83 mm).

1. Derivatives of Spiro[isoquinoline-4(1H),3'- pyrrolidin]- 1,2',3,5'(2H)-tetron General formula I

< / BR>
where R1and R2is hydrogen, C1- C6-alkyl, halogen, lower-C1- C6-alkoxy, trifluoromethyl, nitro-group, phenyl, naphthyl or phenyl or naphthyl) (lower alkyl)oxygraph, in which lower alkyl contains from 1 to 6 carbon atoms;

R3lowest1- C6-alkyl, phenyl, naphthyl, (phenyl or naphthyl)lower alkyl, or dialogization (phenyl or naphthyl)lower alkyl, in which lower alkyl contains from 1 to 6 carbon atoms;

R4and R5is hydrogen, C1- C6-alkyl, phenyl, naphthyl, (phenyl or naphthyl)lower alkyl group, in which lower alkyl contains from 1 to 6 carbon atoms, WITH2- C5-alkanoyl, alkoxycarbonyl, alkylsulfonyl, trifloromethyl, phenylsulfonyl,

or their pharmaceutically acceptable salts, when R4and R5is hydrogen, alkyl, phenyl or naphthyl.

2. With jamesonii benzyl;

R4and R5is hydrogen, acyl, carbalkoxy or trifloromethyl.

3. Connection on p. 2, representing 1'-amino-2-[(4-bromo-2-forfinal)methyl] Spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetron.

4. Connection on p. 2, representing 1'-amino-2-[(4-bromo-2-forfinal)methyl]-6-perspire[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetron.

5. Connection on p. 2, representing dimethyl ether N-[2-[(4-bromo-2-forfinal)methyl] -2,3 - dihydro-1,2', 3,5'-tetraoxaspiro[isoquinoline - 4(1H), 3'-pyrrolidin]-1'-yl]iminodicarboxylic acid.

6. Connection on p. 2, representing N-[2-[(4-bromo-2-forfinal)methyl]- 2,3-dihydro-1,2', 3,5'-tetraoxaspiro[isoquinoline-4(1H),3'-pyrrolidin]-1'-yl] ndimethylacetamide.

7. Connection on p. 2, representing N-[2-[(4-bromo-2-forfinal)methyl]-2,3-dihydro-1,2',3,5'-tetraoxaspiro[isoquinoline-4(1H),3'- pyrrolidin]-1'-yl] -1,1,1-triftormetilfullerenov.

8. The method of obtaining compounds of General formula I on p. 1, characterized in that the compound of General formula XIV

< / BR>
where CO2R6- ester function;

R1, R2and R3have the meanings given in paragraph 1,

or its activated form is subjected to reaction with a hydrazine of General formula

R4R5
with subsequent isolation of the desired product in free form or in salt form, and, if necessary, by acylation one of the following reagents:

R8COHal, (R8CO)2O, R9SO2Hal (R9SO2)2O, ClCOOR8,

where R8- alkyl;

R9- alkyl, phenyl or trifluoromethyl.

9. Pharmaceutical composition for prevention or treatment of complications associated with diabetes, in a mammal, comprising an active agent and a pharmaceutically acceptable carrier, wherein the active agent contains a compound of the formula I as defined in any of paragraphs.1 - 7, in an effective amount.

 

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FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: the present innovation includes polychemotherapy and radiation therapy. Moreover, polychemotherapy should be carried out by the following scheme: on the 1st and the 8th d of the first and the third courses it is necessary to introduce doxorubicin, cyclophosphan, vincristine, and since the 1st to the 14th d - procarbazine and prednisolone; moreover, on the 1st and the 8th d of the second and the fourth courses one should introduce doxorubicin, bleomycin, vinblastine, dacarbazine. The method enables to decrease the quantity of late therapeutic complications, improves the results of relapse-free, total tumor-specific survival rate and decreases the number of polychemotherapeutic cycles.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of patients with disseminated forms of prostate cancer. Method involves administration of navelbine in the dose 30 mg/m2 on the background of anti-androgenic therapy. The course time in navelbine administration is 4 weeks and from 7-th day after the last injection of navelbine method involves administration of strontium-89 chloride in the dose 4 mKi (150 MBk), once time per 3 months, two injections. For patients with the amount of osseous metastases above 6 the dose of strontium-89 chloride is 8 mKi per one administration (300 MBk). In further courses of systemic therapy are repeated in 3 months, not early. Method shows the optimal regimen set in administration of preparations and provides the maximal effect of navelbine on osseous metastases followed by damaging effect of strontium-89 chloride on blood vessels of tumor and its cells and the absence of the potentiation toxicity on the hemopoiesis system.

EFFECT: improved and enhanced effectiveness of treatment.

3 dwg, 2 ex

FIELD: medicine, neurooncology.

SUBSTANCE: one should carry out chemotherapy and irradiation till radical dosage. Moreover, 2-3 d before the onset of radiation therapy and during the whole course of irradiation one should indicate the intake of indometacin at daily dosage being 300 mg, and 8-14 d before the end of therapy course or the stage of radiation therapy it is necessary to conduct chemotherapeutic cycle with vincristine at total dosage being 4 mG and lomustine at total dosage 160-240 mg. At performing a split course of irradiation the intake of indometacin should be indicated between the stages. The innovation enables to increase radio sensitivity of malignant tumor, suppress angiogenesis, proliferative activity and increased cytotoxic activity of chemopreparations.

EFFECT: higher efficiency of therapy.

1 cl, 3 ex

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention describes a liquid pharmaceutical composition used in treatment of cancer and comprising vinorelbin as an active component and is useful for incapsulation into soft capsules. The liquid oral pharmaceutical composition useful as a liquid filling agent composition for the dosed formulation as a soft capsule comprises vinorelbin or its pharmaceutically acceptable salt, in particular, vinorelbin tartrate, ethanol, water, glycerol and polyethylene glycol. Also, invention relates to a method for preparing cancer that involves oral administration to a patient a soft capsule comprising the pharmaceutical composition. The liquid composition containing vinorelbin proves the improved solubility and bioavailability for oral administration.

EFFECT: improved and valuable pharmaceutical and medicinal properties of pharmaceutical composition.

13 cl, 7 tbl, 6 ex

FIELD: medicine, narcology, biochemistry, pharmacy.

SUBSTANCE: invention proposes using the combination of dextromethorphan and the second medicine (quinidine, yohimbin, haloperdol, adjmaline, lobeline, pipamperon, fluoxetine, labetalol, chlorpromazine, domperidone, nortryptiline, quinine, oxyprenolol, propranolol, timolol, methaprolol, diphenhydramine, papaverine, mexiletine or their salts or isomers) for removing addiction to opiates, opioids or synthetic narcotics with exception cocaine and barbiturates (help in refusal in their using) or in case of chronic using antidepressant and corresponding treatment methods. The proposed combination of drugs reduces pain and relieves the withdrawal syndrome on the background of reducing morphine dose (antidepressant) up to the complete removing their intake.

EFFECT: enhanced effectiveness and valuable medicinal properties of medicine combinations.

54 cl, 2 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: it is necessary to carry out complex therapy including introduction of lidase, tactivin, dexason, coffeinum, nootropil, halidor, emoxipin, proserinum, actovegin, vinpocetine, cerebrum compositum, mildronate, dibasol, Magne-B6 and gliatilin at certain dosages and ways of injection, in combination with hirudotherapy, electrostimulation of optic nerve, electrophoresis with lekosym and magnetostimulation in superciliary, frontal, parietal and occipital areas. The suggested innovation improves acuity due to improved microcirculatory and metabolic processes in encephalon and optic analyzer.

EFFECT: higher efficiency of therapy.

1 ex, 3 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with generalized skin melanoma at single and multiple cerebral metastases and extracerebral lesions. The method includes systemic immunochemotherapy. For this purpose, on removing a single cerebral metastasis and melanomatous focus or at multiple cerebral lesions when operation is contraindicated it is necessary to carry out a 2-wk-long course of autohemoimmunochemotherapy, that is: 400 ml patient's autoblood should be sampled into a vial with hemoconservant and after sedimentation it should be divided into 2 equal fractions - plasma and autologous cell suspension (ACS). In separate vials it is necessary to prepare 3 media - 200 ml autoplasma (medium N1) and per 100 ml ACS (medium N2 and N3). One should incubate for 1 h in thermostat at 37° C medium N1 with 100 mg carmustine (mixture N1), medium N2 - with 25 mg metothrexate and 1 mg vincristine (mixture N2), medium N3 - with Reaferon at the dosage of 5×106 IU Reaferon (mixture N3). On the 1st d of the course one should inject mixtures intravenously by drops successively every mixture per 60 min, mixture N2 should be injected repeatedly on the 8th d of the course, mixture N3 should be injected by drops along paracetamol intake thrice weekly during the whole 2-wk-long course of therapy. Additionally, one should fulfill intravenous infusions of 150 mg carboplatin and 15 mg bleomycin upon 200 ml autoblood by drops on the 2nd and 4th d of the course, correspondingly. Totally, one should carry out 3-6 courses. The innovation provides stable regression of neurological symptoms due to decreasing the volume of cerebral metastasis and reactive perifocal cerebral edema and increasing relapse-free and metastasis-free periods and, also, life period in patients.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, neurology.

SUBSTANCE: the present innovation deals with treating cerebrasthenic syndrome (CS) due to carrying out therapy at taking into account the data of a child's complex inspection. At bioelectric cerebral activity a rest being under 40 mcV and impossibility to reconstruct its background values after functional loadings during 3 min by EEG, deviation of cerebral neuromediator supply by 10% and more, affected fermentative activity along with decreased utilization of glucose and creatine phosphate synthesis according to electromagnetic cerebral scanning (EMS) data it is possible to establish CS as a result of oxygen-dependent cerebral hypoergia to introduce amino acids, enzymes, iron preparations, vitamins, hepatoprotectors during 1-mo-long period; then - nootropes and sedative preparations and then comes transcranial micropolarizations (TCMP) along the intake of antihypoxants and vitamin and microelements complexes. Such therapeutic courses should be repeated twice or thrice at interval being not less than 2 mo at keeping soft daily schedule. In case of analogous EEG alterations, the deficiency of initial pulse circulation in carotid and vertebral-basilary (VB) basin being not less than 10%, and during carrying out functional samples - up to 55-75% against the norm, the signs of venous outflow difficulties at REG and USDG, and decreased activity of neurons by above 20% according EMS data it is possible to state upon CS at VB failure and the risk for syncopic states; also, in therapy one should additionally apply vasoactive, spasmolytic and diuretic preparations for 1 mo, and after TCMP the course of resolution therapy should be conducted. In case of instability of vertebro-motor segments and ligamentous-muscular apparatus of cervical vertebrae and rotation subluxations C1 or C2 at wave deviation being above 0.2 mm according to EMS data, and at availability of vascular abnormality of brain or neck it is necessary to fulfill MRT at vascular program. In case of pronounced instability, and/or functional blocks at the level of C1-C5, and/or shifts of disks or vertebral bodies it is important to conduct manual therapy of cervical department at "soft techniques", except those at inborn abnormality of cranio-vertebral area. The innovation provides rapid and stable effect due to differentiating complex therapy at taking into account all the links of etiopathogenesis.

EFFECT: higher efficiency of therapy.

4 cl, 3 ex

FIELD: medicine, chemical-pharmaceutical industry, chemical technology.

SUBSTANCE: invention relates to using biologically active derivatives of ajmaline possessing anti-arrhythmic effect. Method for synthesis of N4-propylajmalinium salts with carboxylic acids is carried out by neutralization of N4-propylajmalinium hydroxide with equivalent amount of carboxylic acid in homogenous phase. The end substance is isolated by distillation of solvent with the yield of salts 97-99%. Method provides preparing acetate, l-lactate, hydrooxalate, hydromalonate, hydrosuccinate, hydroglutarate, l-hydrotartrate, hydrocitrate, salicylate and p-aminobenzoate. Stable solution of N4-propylajmalinium hydromalonate in water for injection of a medicinal agent comprises sodium metabisulfite as antioxidant, 5-30 mg/ml of N4-propylajmalinium hydromalonate, ascorbic acid as antioxidant taken in the effective amounts. Preferably, stable solution of N4-propylajmalinium hydromalonate comprises 10 mg of N4-propylajmalinium hydromalonate/ml of solution, 0.20 wt.-% of sodium metabisulfite and 0.05 wt.-% of ascorbic acid as measured for solution of N4-propylajmalinium hydromalonate. Invention provides the development stable aqueous compositions of N4-propylajmalinium salts for injection of medicinal agent by selection of antioxidants.

EFFECT: improved preparing method.

7 cl, 5 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

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