New condensed isoquinolines as ligands for dopamine receptor


(57) Abstract:

The invention relates to the field of chemistry and medicine, specifically to dopamine receptor ligands of formula (I), pharmaceutical compositions of such compounds and to the method of using such compounds for the effective treatment of patients suffering from dopaminezantac dysfunction of the Central or peripheral nervous system. 3 S. and 7 C.p. f-crystals, 6 ill., table 2.

The invention was created with the support of the U.S. government and awarded (grant) under N MN-42705, awarded by the National institutes of Health. The U.S. government has certain rights in the invention.

The scope of the invention

This invention is directed to new ligands for dopamine receptors. More specifically, this invention relates to optionally substituted compounds tetrahydro-1H-naphthas[1,2,3-de]isoquinoline and their use in pharmaceutical compositions for the treatment dopaminezantac dysfunction of the Central and peripheral nervous system.

Rationale and brief description of the invention

Dopamine, a neurotransmitter in the Central nervous system involved in numerous neurological disorders. For example, vydvinut, it is recognized that either excessive or insufficient functional dopaminergic activity in the Central and/or peripheral nervous system can cause hypertension, narcolepsy, and other behavioral, neurological, physiological disorders and movement disorders, including Parkinson's disease, a chronic, progressive disease characterized by an inability to control system of voluntary movements.

Dopamine receptors are traditionally divided into two classes (D1and D2based on pharmacological and functional characteristics. D1receptors predominantly recognize vinyltetrahydrofuran and lead to stimulation of the enzyme adenylate cyclase, whereas D2the receptors recognize the butyrophenones and benzamide and negatively (or not) connected with adenylate cyclase. It is now known that there are several subclasses of dopamine receptor and at least five genetic codes for a dopamine receptor subclasses: D1D2D3D4and D5. However, continues to be used and the traditional classification, for which D1-this class includes D1(D>receptors.

Medicines for the Central nervous system, with affinity for the dopamine receptors, are usually classified not only according to their receptor selectivity, but also for their agonistic (stimulatory receptor) or antagonist (blocking receptor) activity. Although the physiological activity associated with the interaction of dopamine with different subclasses of receptors is not fully understood, it is known that ligands with selectivity for a particular subclass of receptors should give more or less predictable neuropharmaceuticals results. Study of the suitability of selective against dopamine receptor antagonistic and agonistic compounds will enable the development of experiments to better understand a variety of functional roles1receptors, and will lead to new ways to treat various disorders of the Central and peripheral nervous system.

Initially, the study of dopamine receptors were concentrated on the D2the class, however, recently it became evident the crucial role of D1the dopamine receptor in the Central nervous system. Originally arts one chemical class, vinyltetrahydrofuran, such as antagonist SCH23390 (1):

< / BR>
It was found that some of vinyltetrahydrofuran serve D1receptor agonists; however, the agonists derived from this class [including, for example, SKF38393 (+)-2], usually completely absent their own performance. Recently it was shown that even SKF 82958, which are supposed to be a full agonist, does not show full of self-efficacy in drugs with low receptor reserve. The distinction between full and partial agonists efficiency is important for researchers in the field of medicine due to the fact that these compounds have different effects on complex events, mediated by the Central nervous system. For example, dihydrexidine and full agonist, A-77636, have extraordinary effect against Parkinson's disease model MRTR-treated monkeys, whereas partial agonists do not show significant activity. Recently obtained results suggest that the full and partial agonists differ in their effects on other complex neural functions. Therefore, researchers have concentrated their efforts on the development of ligands that I have joining is dihydrexidine (3), hexahydrobenzo[a]phenanthridine formula:

< / BR>
Structure dihydrexidine unique in relation to other D1agonists, as added cyclic system, giving the relative rigidity of the molecule. Research in modeling molecules dihydrexidine (3) showed that the connection has a limited number of low energy conformations, in which all aromatic cycles are coplanar relative location. Recent elucidation of the configuration of the active enantiomer dihydrexidine (3) coincided with predicted on the basis of this model.

Unlike other closely similar, with high intrinsic activity of D1agonists, such as 3-substituted aminoethylethanolamine, dihydrexidine (3) provides a semi-rigid template to create a model of dopamine ligand. Essential features of this model include the presence trancodes - phenyldiamine group, Equatorial oriented one electron pair on the basic nitrogen atom and close coplanarity additional phenyl rings and rings pyrocatechin. A model based on dihydrexidine has transitny - phenyldiamine radical, whereas dopaminergically is drexeline, serves as a basis for creating additional 1receptor agonists. Development and synthesis of D1receptor agonist with high intrinsic activity, are important for medical research in connection with the potential application of full agonists for the treatment of complex phenomena, mediated by the Central nervous system, as well as conditions involving peripheral dopamine receptors. For example, the compositions of this invention are potentially applicable as a means to lower blood pressure.

One alternative embodiment of the present invention is a new class of dopamine receptor agonists of the General formula:

< / BR>
their pharmaceutically acceptable salts and pharmaceutical compositions of such compounds. These compounds are useful in the treatment of patients suffering from dopaminezantac dysfunction of the Central nervous system, as well as the treatment of conditions involving peripheral dopamine receptors, as evidenced by the observed neurological, psychological, physiological, or behavioral disorders.

Fig. 1 illustrates the stages of chemical reactions on schemesare, CCl4, then heated to the boiling temperature under reflux; (b) ethyl ester of sarcosine HCl, K2CO3acetone; c) i. NaOEt, EtOH, heated to the boiling temperature under reflux, ii. HCl, heated to the boiling temperature under reflux.

Fig. 2 illustrates the stages of chemical reaction according to scheme 2, the conversion of 2,3-dimethoxy-N, N'-diethylbenzamide in DiNapoli. Reagents: a) i. second-utility, TMEDA, Et2O, -78oC, ii. The connection 7, iii. TsOH, toluene, heated to the boiling temperature under reflux; b) i. 1-chloroethylphosphonic, (CH2Cl)2ii. CH3OH; c) TsCl, Et3N; d) H2/Pd-C, HOAc; (e) (BH3-THF; (f) conc. H2SO4, -40oC to -5oC; g) Na-Hg, CH3OH, Na2HPO4; (h) BBr3CH2Cl2.

Fig. 3 graphically affinity dinapala (triangles), (+)-dihydrexidine (squares) and (+)-SCH23390 (filled circles) for industrial D1the receptors. Industrial D1receptors in rats have been labelled with [3H]SCH23390 (1) and add the unlabeled DiNapoli, (+)-dihydrexidine or (+)-SCH23390 to determine specific binding of each connection D1the receptor.

Fig. 4 graphically the ability dinapala (4), (+)-Dmin.

Fig. 5 graphically the ability dinapala (4), (+)-dihydrexidine [(+)-3] and (+)-SKF38393 [(+)-2] to stimulation of cAMP accumulation in C-6 glioma cells (expressing the D1Areceptors primates) relative to dopamine.

Fig. 6 graphically affinity dinapala (triangles), (+)-dihydrexidine (squares) and (+)-SCH23390 (filled circles) for industrial D2the receptors. Industrial D2receptors in rats have been labelled with [3H]SCH23390 and add the unlabeled DiNapoli, (+)dihydrexidine or (+)-SCH23390 to determine specific binding of each connection D2the receptor.

According to this invention proposed a compound of General formula

< / BR>
and its pharmaceutically acceptable salt,

where R and R5denote hydrogen or C1-C4alkyl; R1denotes hydrogen, C1-C4alkyl or phenoxazine group; X denotes hydrogen, halogen or a group of the formula-OR6where R6denotes hydrogen, C1-C4alkyl or phenoxazine group, and R2, R3and R4independently selected from the group including hydrogen, C1-C4alkyl, phenyl, halogen or a group-OR1where R1has adopted the above values, and when X oboznachaet is S="ptx2">

The term "C1-C4alkyl", as used here, refers to a branched or linear alkyl group with 1-4 carbon atoms, including, but not right restrictions, methyl, ethyl, propyl, isopropyl, n-butyl, tertbutyl and cyclopropylmethyl.

The term "pharmaceutically acceptable salt" refers to salts obtained by the application of organic or inorganic acids, their salts suitable for use by humans or lower animals and does not cause unwanted toxic, irritating, allergic or other reactions. Acids suitable for the formation of pharmaceutically acceptable salts or biologically active compounds having amidofunctional, well known in the relevant field. Salts can be obtained in situ (in place) during the final isolation and purification of these compounds or separately, in the interaction of selected compounds in the free base form with an appropriate salt-forming acid.

The term "phenoxazine group", as used here, refers to the substituents on the phenolic oxygen, warning, adverse reactions and decomposition during synthesis, which later can be removed without at the Alenia well known in the relevant field. They include ethers, such as simple cyclopropylmethyl, cyclohexylamine, allyl esters and the like; simple alkoxyalkyl esters, such as simple methoxyethylamine or methoxyethoxymethyl esters and the like; simple allylthiourea esters, such as simple methylthiomethyl esters; simple tetrahydropyranyloxy esters; simple arylalkylamine esters, such as simple benzyl, 0-nitrobenzyloxy, p-methoxybenzyloxy, 9-antimetropia, 4-picolylamine esters and the like; simple trialkyl-Silovye esters, such as simple trimethylsilyloxy, triethylsilane, tributyltinhydride, tert-butyldiphenylsilyl esters and the like; complex alkalemia or akrilovye esters, such as acetates, propionate, n-butyrate, isobutyrate, trimethylacetate, benzoate and the like; carbonates, such as methyl, ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylmethyl, benzyl and the like; carbamates, such as methyl, isobutyl, phenyl, benzyl, dimethyl, and the like.

The term "C1-C4alkoxy", as used herein, refers to a branched or linear alkyl group of 1-4 carbon atoms attached through an oxygen atom, including, but not order the program of the present invention, these compounds may be prepared in conventional dosage forms for use in methods of treating patients suffering from dopaminezantac dysfunction of the Central or peripheral nervous system. Effective doses of these compounds depend on many factors, including requiring treatment, symptoms, route of administration and the General condition of the patient. For example, for oral administration the effective dose of these compounds is approximately in the range of from 0.1 to 50 mg/kg, more typically range from 0.5 to 25 mg/kg Effective parenteral doses may be on the order of from 0.01 to 5 mg/kg of body weight. Basically, the treatment regimen with the use of compounds according to this invention include the introduction of about 1 to 500 mg of the compounds according to this invention per day single dose or single dose.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions and syrups containing commonly used in the art, inert diluents, such as water. Such compositions can also include adjuvants such as wetting means, emulsifying and suspendresume tools, pedimental known in the relevant field of technology products by dispersing or dissolving an effective dose of the compounds in a parenterally acceptable solvent, such as water, or, more preferably, in isotonic sodium chloride. Parenteral formulations can be sterilized using known in the relevant technical field techniques microfiltration.

Compounds according to this invention can also be included in the solid dosage forms for oral administration such as capsules, tablets, powders, pills and the like. Typically, the active compound is mixed with an inert diluent or carrier, such as sugar or starch, and other excipients suitable for the dosage form. Thus, tableting compositions must include acceptable lubricants, binding and/or leavening agents. Optional powder composition containing the active compound according to this invention and, for example, a carrier in the form of sugar or starch, can be filled into gelatin capsules for oral administration. Other dosage forms of the compounds of this invention can be prepared using known in the relevant field techniques in forms adapted to the specific method of administration.

One obtained according to this invention the connection is in synthesized from 2-methyl-2,3-dihydro-4(1H)-isohedron on the way, described in Fig. 1 and 2. Bromination of the side-chain ethyl-o-toluate (5a) using NBS in the presence of benzoyl peroxide gives compound 5b. Alkylation of ethyl ether sarcosine compound 5b gives compound 6, which, after condensation, Dieckmann a, and subsequent decarboxylation during acid hydrolysis gives compound 7.

As shown in scheme 2 (Fig. 2), orthonitrophenyl licitatie 2,3-dimethoxy-N, N'-diethylbenzamide (8) using a second-utility/TMEDA in diethyl ether at -78oC, condensation containing lithium groups with the connection 7 and the subsequent heating to the boiling point under reflux with p-toluensulfonate give spirolactone 9 with moderate output. N-Demethylation of compound (9) with 1-chloroethylphosphonic and subsequent methanolysis intermediate product give compound 10, which in the processing of p-toluensulfonate and triethylamine gives compound 11.

Previous attempts of synthesis of compound (11) direct condensation of 2-p-toluensulfonyl-2,3-dihydro-4(1H)-isohedron lithium compound 8 in THF or diethyl ether and subsequent lactonization acid gave only a small amount (< 5%) of compound (11). Analizatzea 2-SS="ptx2">

Hydrogenolysis of compound (11) in glacial acetic acid in the presence of 10% palladium on carbon gives compound 12, which when restoring with DIBORANE gives intermediate connection 13. Cyclization of compound 13 with concentrated sulfuric acid at low temperature leads to the connection 14. N-Detailimage connection 14 with Na/Hg in methanol containing centripetality buffer, gives compound 15. Finally, the connection 15 is treated with borrisrandom for cleavage of the methyl ester, which leads to DiNapoli (4) in the form of Hydrobromic salt.

Comparison of spatial structures of low-energy conformations of (+)-TRANS-10,11-dihydroxy-5,6,6 a,7,8,12 b - hexahydrobenzo[a] phenanthridine [(+)-di-hydroxyzin] and 11bR-enantiomer diapason, which homochiral in respect of (+)-dihydrexidine on 12bS chiral center. It is easy to see the two main structural features. First, steric volume, provide a bridge group C(7)-C(8)etano in dihydrexidine (3) has been removed. Secondly, the angle suspended phenyl ring with respect to the plane of the loop pyrocatechin slightly changed. This is most obvious when considering the front plane, when the aroma is giving use, to attach suspended phenyl ring via a methylene group to the ring pyrocatechin: this forces suspended the phenyl ring to bend in a clockwise direction relative to dihydrexidine (3), when considered in light of the above. Amino occupy a similar position, providing a degree of conformational flexibility of the heterocycle. In addition, both molecules may represent N-H vector in the Equatorial orientation that is characteristic of pharmacophore and is important for D1receptor agonists. In accordance with these observations, the pharmacological properties of these two molecules are similar.

Experiments to determine binding dinapala in respect of D1the receptors. Found that DiNapoli has almost identical compared to dihydrexidine (3) affinity (K1= 5,9 nm) to industrial D1receptors in rats. In addition, experiments on the competition using its SCH23390 (1) as a competitor, showed that DiNapoli shows high competitive affinity, and it corresponds to less deep curve comparison that says about agonistic properties (see Fig. 3). Agonistic St is W ith the production of cAMP in the striatum of rats and C-6 mD1cells (see below experimental data). As in the striatum of rats, and C-6 mD1-cells DiNapoli has full agonistic activity with EC50about 30 nm in the synthesis stimulating cAMP by D1receptors.

Thus, pharmacological data lead to the conclusion that DiNapoli has a high affinity for the dopamine D1the receptors labeled with [3H] SCH23390, which is almost identical to the affinity of (+)-TRANS-10,11-dihydroxy-5,6,6 a, 7,8,12 b-hexahydrobenzo[a] phenanthridine (dihydrexidine). In addition, ()-8,9-dihydroxy-2,3,7,11 b-tetrahydro-1H-oil[1,2,3-de] isoquinoline (DiNapoli), as in industrial membranes of rats and cloned expressed D1Athe receptors in primates, is a full agonist in relation to dopamine, like dihydrexidine (3), but in contrast to the partial agonist (+)-SKF 38393 (see Fig. 4 and 5: (+)-SKF 38393 = (+)-2; ()-TRANS-10,11-dihydroxy-5,6,6 a, 7,8,12 b - hexahydrobenzo[a]phenanthridine = ()-3 and ()-8,9-dihydroxy-2,3,7,11 b-tetrahydro-1H-oil[1,2,3-de]isoquinoline = 4).

Based on the General model of D1pharmacophore should expect that both the affinity and intrinsic activity of racemic dinapala (and its substituted analogues) belongs to only one of eye of the racemate with the use of recognized techniques of separation will lead to a single isomer dinapala with approximately doubled relative to the racemate D1affinity, which will make its affinity for D1the receptor is the same as (+)-TRANS-10,11 - dihydroxy - 5,6,6 a,7,8,12 b-hexahydrobenzo [a] phenanthridine.

As shown by Fig. 3 and table 1, DiNapoli has a great affinity for D2-like receptors than dihydrexidine, it was expected that he would be somewhat selective for D1and not D2-like receptors. However, it is determined that dihydrexidine takes only approximately tenfold D1: D2the selectivity. In addition, dihydrexidine although it has the expected dopamine-agonistic activity, also has an unusual property, here called "functional selectivity". In particular, in rats (in vivo or in vitro) dihydrexidine acts as an agonist D2-like receptors, localized postsynaptic, but as antagonist D2-like receptors, localized pre-synaptic. It is assumed that this is due to differences in ligand-receptor-G-protein complex, localized post-synaptic differently than pre - synaptic, which is defined by the presence of specific G-proteins in a given cellular environment.

It is shown that these D2properties dihydrexidine inherent the same is and this basis it was possible to assume, as D1and D2properties dinapala also concentrated in the homochiral enantiomer. Optical isomers dinapala and related analogues are an important tool for studying the phenomenon of "functional selectivity".

Earlier it was reported that dihydrexidine has an effect against Parkinson's disease in MRTR model of Parkinson's disease, it is predicted that DiNapoli should have similar effects. Therefore, DiNapoli and its derivatives have potential clinical applicability in Parkinson's disease and other conditions where stimulation of dopamine receptors may have therapeutic effect. In addition, it is reported that appropriate modifications dihydrexidine give analogues, which can serve as a target for specific groups in the population class dopamine receptors. Similar approaches to DiNapoli should lead to compounds with a new receptor selectivity subclass and/or functional profiles.

With regard to the following described experimental methods, the melting temperature is determined by the device for measuring the melting point Thomas-Hoover'a and not correct.

1H-is (M. D.) relative to TMS (tetramethylsilane). The infrared spectrum recorded in KBr pellets or in the liquid film using Percin Elmer 1600 serial FTIR spectrometer. Chemical ionization mass spectra (CIMS) recorded on Finnigan 4000 quadrupole mass spectrometer. CI-range high-resolution recorded on a Kratos MS50 spectrometer. Data on elemental analysis obtained in the microanalytical laboratory, Purdue University, West Lafayette, IN.

THF is distilled from sodium-benzophenone under nitrogen atmosphere immediately prior to use; 1,2-dichloroethane is distilled with pjatiokisi phosphorus before use.

Example 1.

Obtaining 2-methyl-2,3-dihydro-4(1H)-isohedron

Ethyl 2-bromoethylene (5b)

A solution of ethyl-o-toluate (41,2 g, 0.25 mol) in carbon tetrachloride (200 ml) is added dropwise to a stirred mixture of benzoyl peroxide (100 mg), carbon tetrachloride (200 ml) and NBS (44,5 g, 0.25 mol) at 0oC. the Mixture is heated to boiling point under reflux for 3.5 hours under nitrogen atmosphere and allowed to cool to room temperature overnight. Besieged succinimide removed by filtration and dense precipitate on the filter was washed with carbon tetrachloride. The combined filtrates are washed sequentially 2 N. NaOH (100 ml) and water (2 x 100 MAV. Drying in a high vacuum over night gives of 60.5 g (99%) of crude compound 5b:1H-NMR spectrum of the product shows the presence of about 15% unreacted educt. Because the mixture is difficult to separate chromatographically or by vacuum distillation, it is used in the next stage without additional purification:1H-NMR (CDCl3) was 1.43 (t, J = 7 Hz, 3H, CH2CH3), to 4.41 (q, J = 7 Hz, 2H, CH2CH3), 4,96 (s, 1H, CH2Br), from 7.24 (m, 1H, ArH), 7,38 (m, 1H, ArH), of 7.48 (m, 2H, ArH).

Ethyl ester of N-(2-carboethoxy)sarcosine (6).

To a mixture of the hydrochloride of the ethyl ester sarcosine (32,2 g, 0.21 mol), potassium carbonate (325 mesh; of 86.9 g, to 0.63 mol) and acetone (800 ml) add a solution of compound 5b (60,7 g, obtained from 0.25 mol ethyl-0-toluate; 85% conversion to compound 6; calculated 0.21 mol) in acetone (100 ml) at room temperature under nitrogen atmosphere. The mixture is stirred while heating to the boiling temperature under reflux for 2 hours and then left at room temperature for 20 hours. The solid product removed by filtration (Celite) and the residue is washed with acetone. The filtrates are combined and evaporated under reduced pressure, obtaining oil. The oil is dissolved in 250 ml of 3 N. hydrochloric acid and washed with diethyl ether. The aqueous layer was alkalinized water is / establishment, which is distilled in vacuum, getting 45,33 g (77%) of compound 6: so Kip. 140-142oC (0.5 mm Hg) [so Kip. 182-183oC (10 mm Hg)];1H-NMR (CDCl3) to 1.24 (t, 3H, J = 7,1 Hz, CH3), of 1.36 (t, 3H, J = 7,1 Hz, CH3), to 2.35 (s, 3H, NCH3), with 3.27 (s, 2H, CH2Ar), of 4.00 (s, 2H, NCH2), 4,14 (q, 2H, J = 7,1 Hz, CH2CH3), 4,32 (q, 2H, J = 7,1 Hz, CH2CH3), 7,28 (t, 1H, J = 7,4 Hz, ArH), 7,42 (t, 1H, J = 7,6 Hz, ArH), 7,52 (d, 1H, J = 7.8 Hz, ArH), 7,74 (d, 1H, J = 7.7 Hz, ArH).

2-Methyl-2,3-dihydro-4(1H)isohedron (7). Freshly cut sodium (10,9 g, 0,47 g-atom) is added to absolute ethanol (110 ml) under nitrogen atmosphere and the reaction mixture is heated to boiling point under reflux. After the disappearance of metallic sodium to the reaction mixture slowly add a solution of compound 6 (35,9 g, 0,128 mol) in dry toluene (160 ml). Then the reaction mixture is heated to boiling point under reflux and the ethanol is separated by azeotropic through the nozzle Dean-stark. After cooling, the solvent is evaporated under reduced pressure. The resulting yellow semi-solid residue is dissolved in a mixture of water (50 ml), 98% ethanol (60 ml) and concentrated HCl (240 ml) and heated to boiling point under reflux for 26 hours. After cooling, the mixture was concentrated in vacuo and gently alkalinized solid the Ute, receiving a connection 7 (17.11 per bbl g, 83%): so Kip. 130-132oC (5 mm Hg) [so Kip. 81-83oC (0.4 mm Hg); so square (HCl) 250oC]; IR (nerdball.) 1694 (C=O) cm-1;1H-NMR (CDCl3) 2,48 (s, 3H, CH3), and 3.31 (s, 2H, CH3), 3,74 (s, 2H, CH2), 7,22 (d, 1H, J = 7.7 Hz, ArH), 7,34 (t, 1H, J = 7.9 Hz, ArH), to 7.50 (t, 1H, J = 7.5 Hz, ArH), 8,02 (d, 1H, J = 7.9 Hz, ArH).

Synthesis of 8,9-dihydroxy-2,3,7,11 b-tetrahydro-1H-oil[1,2,3-de]isoquinoline

To a solution of 2,3-dimethoxy-N,N'-diethylbenzamide (compound 8) (14,94 g, 63 mmol) in diethyl ether (1400 ml) at -78oC in nitrogen atmosphere consistently add, dropwise, N,N,N',N'-tetramethylenebis (TMEDA, to 9.45 ml, 63 mmol) and second-utility (53.3 per ml, 69 mmol, 1.3 M solution in hexane) through Sept rubber with a syringe. After 1 hour, to a heterogeneous mixture of freshly distilled connection 7 (10.1 g, 62,7 mmol). Remove the cooling bath and the reaction mixture allowed to warm to room temperature for 9 hours. Then add a saturated solution of NH4Cl (400 ml) and the mixture is stirred for 15 minutes. The ether layer is separated and the aqueous layer was extracted with dichloromethane (4 x 100 ml). The organic layers are combined, dried (MgSO4) and evaporated to a brown oil. The oil was dissolved in toluene (500 ml) and heated to boiling point under reflux in techine, washed with dilute aqueous NaHCO3, water and then dried (Na2SO4), filtered and evaporated, receiving resinous residue. When rubbing with ethyl acetate-hexane (50:50) is deposited solid product.

Recrystallization from ethyl acetate-hexane gives was 12.75 g (63%) of compound (9) (2',3'-dihydro-4,5-dimethoxy-2'-methylspiro[isobenzofuran - 1(3H)-4'(1'H)isoquinoline]-3-one): so pl. 193-194oC; IR (KBr) 1752 cm-1(C=O);1H-NMR (CDCl3) 2,47 (s, 3H, NCH3), is 2.88 (d, 1H, J = 11,6 Hz), to 3.02 (d, 1H, J = 11.7 Hz), 3,76 (d, 1H, J = 15,0 Hz), with 3.79 (d, 1H, J = 15.1 Hz), 3,90 (s, 3H, OCH3), 4,17 (s, 3H, OCH3), 6,83 (d, 1H, J = 8,4 Hz, ArH), 7,03 (d, 1H, J = 8,2 Hz, ArH), 7,11 (m, 3H, ArH), 7,22 (m, 1H, ArH); MS (Cl) m/z 326 (100); Anal. (C19H19NO4) C, H, n

2', 3'-Dihydro-4,5 - dimethoxy-Spiro [isobenzofuran - 1(3H),4'(1'H) isoquinoline]-3-one (10).

1-Chloro-ethylchloride (5,1 ml of 46.3 mmol) is added dropwise to a suspension of compound 9 (6,21 r, 19.2 mmol) in 100 ml of 1,2-dichloroethane at 0oC in nitrogen atmosphere. The mixture is stirred under nitrogen atmosphere for 15 minutes at 0oC and then heated to the boiling temperature under reflux for 8 hours. The mixture is allowed to cool and concentrated under reduced pressure. To the mixture is added 75 ml of methanol and the reaction mixture is heated to a temperature of Kenya, getting hydrochloric salt of compound 10 with an almost quantitative yield. The product is pure enough to be used in the next stage without additional purification:

so pl. (HCl) 220-222oC; so square (base) 208-210oC; IR (CH2Cl2, base) 1754 cm-1(C=O);1H-NMR (CDCl3, base) 3,18 (d, 1H, J = 13.5 Hz), 3,30 (d, 1H, J = 13.5 Hz), of 3.84 (s, 3H, OCH3), of 3.96 (s, 3H, OCH3), was 4.02 (s, 2H, CH2N) to 6.67 (d, 1H, J = 7.5 Hz, ArH), 7,12 (m, 2H, ArH), 7,19 (d, 1H, J = 7.5 Hz, ArH), 7,26 (t, 1H, J = 7.5 Hz, ArH), 7,41 (d, 1H, J = 8.5 Hz, ArH); MS (Cl) m/z 312 (100); HRCIMS calculated. for C18H17NO4: 312,1236; Found 312,1198; anal. (C18H17NO4) H, N; C: calculated 69,44; found, 68,01.

2', 3'-Dihydro-4,5 - dimethoxy-2'-p-toluensulfonate [isobenzofuran - 1(3H),4'(1'H)isoquinoline] -3-one (11)

7 ml of triethylamine is added dropwise to a mixture of p-toluensulfonate (3.6 g, to 18.9 mmol), compound 10 (as HCl-salt, obtained from 19.2 mmol of compound (9) and chloroform (100 ml) at 0oC in nitrogen atmosphere. After complete addition, the ice bath removed and the reaction mixture was stirred at room temperature for 1 hour. Then the reaction mixture podkalyvayut 100 ml of chilled water 0.1 N. HCl, extracted with dichloromethane (2 x 100 ml after rubbing with ethyl acetate-hexane atoC gives a solid product. Recrystallization from ethyl acetate-hexane gives a total of 8.74 g (97%, all based on connection 9) of compound (11): so pl. 208-210oC; IR (KBr) 1767 cm-1(C=O);1H-NMR (CDCl3) 2,43 (s, 1H, CH3), up 3.22 (d, 1H, J = 11 Hz), 3,88 (d, 1H, J = 11 Hz), 3,90 (s, 3H, OCH3), of 3.96 (d, 1H, J = 15 Hz), 4,17 (s, 3H, OCH3), to 4.81 (d, 1H, J = 15 Hz), 6,97 (d, 1H, J = 7.7 Hz, ArH), 7,16 (m, 3H, ArH), 7,26 (m, 1H, ArH), 7,38 (d, 2H, J = 8 Hz, ArH), 7,72 (d, 2H, J = 8 Hz, ArH); MS (Cl) m/z 466 (100); anal. (C25H23NO6S) C, H, n

3,4-Dimethoxy-6-[(2-p-toluensulfonyl-1,2,3,4 - tetrahydroisoquinoline)-4-yl]benzoic acid (12).

A solution of compound 11 (2,56 g, 5.51 mol) in glacial acetic acid (250 ml) with 10% palladium on activated carbon (6,30 g) is shaken on hydrogenator Parra at a gauge pressure of 50 psi (17,58 kg/cm2; see page 18 oripa., line 4) for 48 hours at room temperature. The catalyst was removed by filtration and the solvent evaporated, getting to 2.55 g (99%) of compound 12 with a purity sufficient for use in the next stage. An analytical sample is recrystallized from ethanol-water: so pl. 182-184oC; IR (KBr) 1717 cm-1(COOH);1H-NMR (DMSO-d6) to 2.35 (s, 3H, CH3), of 3.12 (m, 1H), 3,51 (DD, 1H, J = 5, and 11.5 Hz), 3,71 (s, 6H, OCH3), 4,10 (m, 1H, Ar225H25NO6S: 468,1481; found 468,1467; anal. (C25H25NO6S) C, H, n

2-N-p-toluensulfonyl-4-(2-hydroxymethyl-3,4-acid)-1,2,3,4 - tetrahydroisoquinoline (13).

To a solution of compound 12 (1.4 g, 2,99 mmol) in dry tetrahydrofuran (30 ml) is added 1.0 M of balancetransfer (8 ml) at 0oC in nitrogen atmosphere. Upon completion of the addition the mixture is stirred while heating to the boiling temperature under reflux overnight. Add additional DIBORANE (4 ml) and continue stirring for another 30 minutes. After cooling and evaporation under reduced pressure, carefully add the methanol and the solvent is removed under reduced pressure. The procedure was repeated three times to ensure complete methanolysis intermediate boranova complex. Evaporation of the solvent give 1.10 g (81%) of crude compound 13. Analytical samples clean flash chromatography (silica gel, EtOAc/hexane) followed by recrystallization from ethyl acetate/hexane: so pl. 162-164oC;1H-NMR (CDCl3) of 2.38 (s, 3H, CH3), 3,18 (DD, 1H, J = 7,5, to 11.9 Hz), to 3.67 (DD, 1H, J = 4,5, and 11.8 Hz), 3,81 (s, 3H, OCH3), 3,85 (s, 3H, OCH25H27NO5S) C, H, n

8,9-Dimethoxy-2-p - toluensulfonyl-2,3,7,11 b - tetrahydro-1H - naphthas [1,2,3-de]isoquinoline (14).

Powdered compound 13 (427 mg, 0.98 mmol) is added in several portions to 50 ml of the cooled concentrated sulfuric acid (50 ml) at -40oC in nitrogen atmosphere with vigorous mechanical stirring. After the addition the reaction mixture is heated to -5oC for 2 hours and then poured on crushed ice (450 g) and left to mix for 1 hour. The product is extracted with dichloromethane (2 x 150 ml), washed with water (2 x 150 ml), dried (MgSO4), filtered and evaporated, obtaining oil, which when crushed with diethyl ether at 0oC gives compound 14 (353 mg, 82%) as a white solid product, which is used in the next stage without additional purification. An analytical sample receive centrifugal rotary chromatography using 50% ethyl acetate-hexane as eluent, followed by recrystallization from EtOAc/hexane: so pl. 204-206oC;1H-NMR (CDCl3) to 2.40 (s, 3H, CH3), 2,80 (m, 1H, H-1a), a 3.50 (DD, 1H, J = 4,5, 17.5 Hz, H-1b), 3 Hz, H-7b), was 4.76 (d, 1H, J = 14,8 Hz, H-3b), 6,77 (d, 1H, J = 8,3 Hz, ArH), 6.87 in (d, 1H, J = 8,4 Hz, ArH), 6,94 (d, 1H, J = 7,6 Hz, ArH), 7,13 (t, 1H, J = 7.5 Hz, Ar H-5), 7,18 (d, 1H, J = 7.2 Hz, ArH), 7,33 (d, 2H, J = 8.1 Hz, ArH), 7,78 (d, 2H, J = 8,2 Hz, ArH); MS (Cl) m/z 436 (55), 198 (86), 157 (100); HRCIMS calculated. for C25H25NO4S: 436,1583; found 436,1570; anal. (C25H25NO4S) C, H, n

8,9-Dimethoxy-2,3,7,11 b-tetrahydro - 1H-naphthas[1,2,3-de] isoquinoline (15).

A mixture of compound 14 (440 mg, 1.01 mmol), dry methanol (10 ml), disodium hydrogen phosphate (574 mg, 4.04 mmol) was stirred in nitrogen atmosphere at room temperature. To this mixture is added in three portions 6.20 g 6% Na-Hg and the reaction mixture is heated to boiling point under reflux for 2 hours. After cooling, add water (200 ml) and the mixture extracted with diethyl ether (3 x 200 ml). Layers diethyl ether unite, dried (MgSO4), filtered (Celite) and evaporated, obtaining oil, which solidified under vacuum. After rotary chromatography receive 142 mg (50%) of compound 15 in the form of oil. The oil quickly darkening and it is immediately used in the next stage. A small portion of the oil is treated with ethereal HCl and hydrochloric salt of compound 15 is recrystallized from ethanol-diethyl ether: so square (HCl salt) 190oC (Rav>3
), 3,842 (s, 3H, OCH3), a 4.03 (DD, 1H, J = 6,12 Hz, H-7a), 4,08 (s, 2H, H-3), to 4.33 (d, 1H, J = 17,4 Hz, H-7b), is 6.78 (d, 1H, J = 8,24 Hz, ArH), 6,92 (m, 3H, ArH), 7,11 (t, 1H, J = 7.5 Hz, ArH), 7,18 (d, 1H, J = 7.5 Hz, ArH); MS (Cl) m/z 282 (100); HRCIMS calculated. for C18H19NO2: 282,1494; found 282,1497.

8,9-Dihydroxy-2,3,7,11 b - tetrahydro-1H-naphthas [1,2,3-de] isoquinoline (4).

To a solution of compound 15 (25 mg, 0,089 mmol) in dichloromethane (5 ml) at -78oC add tribromide boron (0.04 ml, 0,106 g, 0.42 mmol). After stirring at -78oC in nitrogen atmosphere for 2 hours, the cooling bath removed and the reaction mixture was allowed to mix at room temperature for 5 hours. Then the reaction mixture was cooled to -78oC and carefully add methanol (2 ml). After stirring for 15 minutes at room temperature the solvent is evaporated under reduced pressure. Add a further quantity of methanol and the procedure was repeated three times. The resulting grey solid product is recrystallized from ethanol-ethyl acetate, receiving generally 12 mg (41%) Hydrobromic salt of compound 4:

so pl. 258oC (decomp.);1H-NMR (HBr-salt CD3OD) of 3.43 (t, 1H, J = 12 Hz, H-1a), of 3.48 (DD, 1H, J = 3,5, 18 Hz, H-1b), Android 4.04 (m, 1H, H-11b), to 4.38 (DD, 2H, J = 5,5, 12 Hz, H-7), of 4.44 (s, 2H, H-3), to 6.58 (d, 1H, J = 8.5 Hz, ArH), of 6.71 (d, 1H, J = 15NO2: 254,1181; found 254,1192.

Pharmacology dinapala


Adult male Sprague Dawley rats (200-250 g) obtained from Charles River Breeding laboratories (Raleigh, NC) or Harlan laboratories (Indianapolis, IN). Rats hammer, abezglavlena, remove the entire brain and briefly cooled in ice-salt solution. Cook thin slices of the brain using the cutting block and then excised the Central striatum of two vanocni slices containing the greater part of this area. The tissue was immediately frozen using dry ice and stored at -70oC until the day of the test.

Cell culture. Cell C-6 glioma expressing D1A receptor rhesus macaques, (C-6 mD1A; Machida et al., 1992) grown in DMEM-H medium containing or 4,500 mg/l glucose, L-glutamine, 5% fetal serum cows and 600 ng/ml of G418 or 2 mg/ml puromycin. Cells are incubated in a humid incubator at 37oC with 5% CO2.

Preparation of membranes. Cells grown in 75 cm2flasks until confluence. Cells are washed and are lysed with 10 ml ice hypoosmotic buffer (NEW) (5 mm Hepes, 2.5 mm MgCl2, 1 mm EDTA; pH 7,4) for 10 minutes at 4oC. the cells are Then scraped from the flasks using a sterile cell scraper Baxter a (McGaw Park, which leaves about 14 ml. Then membranes, scraped from several flasks are pooled. The combined cell suspension homogenized (10 strokes), 14 ml at a time, using 15 ml glass homogenizer. Homogenates of cells combine and twist at 43000 rpm (Sorvall RG-5D/SS-34, Du Pont, Wilmington, DE) at 4oC 20 minutes Remove supernatant and precipitate in the test tube after centrifugation resuspended (10 strokes) in 1 ml ice HOB for each source flask homogenised cells. This homogenate was then rotated at 43000 rpm at 4oC for 20 minutes. Remove supernatant and the resulting sludge resuspended (10 strokes) in ice buffer for storing (50 mm Hepes, 6 mm MgCl2, 1 mm EDTA; pH 7,4), receiving a final concentration of about 2.0 mg protein/ml Aliquots of the final homogenate stored in test tubes for microcentrifuge at -80oC. Before applying for a test on adenylate cyclase concentration

protein for each membrane preparation determine quantified using the BCA reagent for protein tests (Pierce, Rockford, IL), adapted for use in the reader for microplasmin (Molecular Devices; Menlo Park, CA).

Tests on dopamine-receptor binding.

Frozen skipjack is adenowo ice 50 mm HEPES buffer with 4.0 mm MgCl2(pH of 7.4). The fabric is centrifuged at 27000 rpm for 10 minutes, the supernatant discarded, and the sediment in the tube after centrifugation of the homogenized (five strokes), resuspended in ice buffer and centrifuged again. The final precipitate in the test tube after centrifugation resuspended at a concentration of 2.0 mg wet weight/ml the Amount of fabric added to each tube for testing, is 1.0 mg in a final volume testing of 1.0 ml of D1receptors have been labelled with [3H] SCH23390 (0,30 nm); D2receptors have been labelled with [3H]spiperone (0.07 nm); unlabeled ketanserin (50 nm) add to disguise binding to 5-HT2the plots. Total binding is defined as the radioligand binding in the absence of any competing drugs. Nonspecific binding estimate, adding unlabeled SCH23390 (1 μm) or unlabeled chlorpromazine (1 μm) for testing on the D1and D2receptor binding, respectively. As an internal standard in each test include curve comparison for the six concentrations of unlabeled SCH23390 (D1binding) or chlorpromazine (D2binding). For each concentration of drug spend triple apreda with ice buffer for 12-cell collection cells Skatron'a (Skatron, Inc., Sterling, VA) using a filter plate made of fiberglass (Skatron N 7034). Filters allow to dry and add 0.1 ml of Optiphase HI-SAF II scintillation fluid. Radioactivity was determined on LKB Wallac 1219 RackBeta liquid scintillation counter (Wallac, Gaithersburg, MD). The protein levels in tissue determines, using the ICA reagent for protein determination (Pierce, Rockford, IL).

Data analysis for radioreceptor tests.

Data on the binding of each test analysed separately. Data normalize, expressing the average dpm for each concentration of competitor in percentage from the total binding. This data is then subjected to nonlinear regression analysis using the algorithm for sigmoidal curves in the curve-fitting program InPlot (Graphpad Inc.; San Francisco, CA) or EBDA and LIGAND standard program, adapted for the IBM-PC by McPherson to receive TO0,5and Hill coefficient a (nnfor each curve. Analysis of residual variations shows the perfect match; the values of r are about 0,99 for all curves in the experiments.

Adenylate cyclase activity in the striatum of rats. For measurement of adenylate cyclase activity by separating the cAMP from the other labeled nucleotides used method automatic is on a glass homogenizer in 5 mm HEPES buffer (pH 7.5), containing 2 mm EGTA (50 ml/g of tissue). After adding and mixing 50 ml/l of 50 mm HEPES buffer (pH 7.5) containing 2 mm EGTA, 20 µl aliquot of the tissue homogenate is added to the obtained reaction mixture (final volume 100 μl) containing 0.5 mm ATP, 0.5 mm isobutylmethylxanthine, [32P]ATP (0.5 mccoury), 1 mm cAMP, 2 mm MgCl2, 100 mm HEPES buffer, 2 mm GTP, 0-100 μm dopamine, DHX or SKF38393, 10 mm creatine phosphate and 5 units of creatine phosphokinase. For each concentration of the drugs perform a triple determination. The reaction continued for 15 minutes at 30oC and then cut by adding 100 μl of 3% sodium dodecyl sulfate (SDS). Proteins and most of the non-cyclic nucleotides precipitated by adding 300 µl of 4.5% ZnSO4and 10% Ba(OH)2each. The samples centrifuged (10,000 rpm for 8-9 min) and supernatant injected in GHUR system (water Z-module or RCM 8x10 module, equipped with a C18, 10 micron cartridge). Mobile phase is 150 mm sodium acetate (pH 5.0), with 23% of methanol. For the quantitative determination of unlabeled cAMP added to the samples as an internal standard, using a UV-detector (254 nm detection). The radioactivity of each fraction determine the radiation detector of the current thread (Inus Systems. Tampa, FL), use the s ' cAMP, calculated using RE Nelson (Cupertino, CA) Model 900 data collection modules and TurboChrom standard program. The protein levels in tissue determined using BCA reagent for protein detection (Pierce, Rockford, IL).

Analysis on adenylate cyclase in G-6mD1Acells.

Frozen membranes are thawed and added to a test tube for testing (10 mg protein/tube) containing the reaction mixture [100 mm Hepes, (pH of 7.4), 100 mm NaCl, 4 mm MgCl2, 2 mm EDTA, 500 μm isobutylmethylxanthine (IBMX), 0.01 percent ascorbic acid, 10 μm of parylene, 2 mm ATP, 5 μm GTR, 20 mm creatine phosphate, 5 units of creatine phosphokinase (CPK), 1 μm propranolol] and the selected remedy. The final reaction volume is 100 μl.

Basal cAMP activity is detected by incubation of the tissue in the reaction mixture without the addition of drugs. Tubes for testing duplicating and after 15 minutes incubation at 30oC the reaction is stopped by adding 500 μl of 0.1 G. of HCl. Tubes short handle on the vortex funnel and then in BHG HermLe Z 230 M microcentrifuge for five minutes at 15,000 rpm for deposition of microparticles.

The radioimmunoassay (RIA) at cAMP. The concentration of cAMP in each sample is determined using an RIA den. Buffer analysis is 50 mm sodium acetate buffer with 0.1% sodium azide (pH of 4.75). Standard curves cAMP receive buffer at concentrations of 2-500 fmol/tube for testing. To increase the sensitivity analysis, all samples and standards will acetimidoyl 10 μl solution of 2:1 triethylamine : acetic anhydride. Samples for duplicate analyses. Each test tube for testing (total volume 300 μl) contains 25 ál of each sample, 75 μl of buffer, 100 ál of primary antibody (sheep anti-cAMP, 1:100000 dilution with 1% BSA in buffer) and 100 μl of [125I]-cAMP (50000 dpm/100 μl of buffer). The tubes are treated in the vortex funnel and stored at 4oC overnight (about 18 hours). Bound antibodies, the radioactivity is separated by adding 25 µl of BioMag rabbit, anti-goat IgG (Advanced Magnetics, Cambridge MA), and then subjected to vortex-treated at 4oC for 1 hour. To these samples was added 1 ml of 12% of polyethylene glycol/50 mm sodium acetate buffer (pH 6.75 in) and the tubes centrifuged at 1700 rpm for 10 min Supernatant separated by aspiration and the radioactivity in the precipitate after centrifugation determined using a LKB Wallac gamma counter (Gaithersburg, MD).

Data analysis for the study of adenylate cyclase.

Data for each sample is expressed Dogo drugs. Data for each drug are expressed in relation to the stimulation produced by 100 μm DA.

The results of the binding and functional effects dinapala on the D1receptors in the striatum homogenates of rats.

As shown in Fig. 3, DiNapoli competes, showing high affinity for D1receptors in the striatum homogenates of rats with affinity, almost identical with dihydrexidine, full D1agonist. As DiNapoli and dihydrexidine corresponds to lower the steepness of the curves comparison than SCH 23390 (1), which is the prototype of the D1antagonist.

Table 1 summarizes the affinity of (+)-3 and (a)-4 to dopamine receptors in the rat brain. Study of the binding of radio-dopamine receptors conducted in the striatum homogenates in rats using 0.3 nm3H-SCH23390 (D1plots) and 0.07 nm3H-spiperone in the presence of 50 nm unlabeled ketanserina (D2the plots). Curves comparison was analyzed by the method of nonlinear regression to determine the values of K0,5and the ratio of the slope of the Hill a (nn). Presents the mean values and standard error for three identical tests in kuchikomi - 5,6,6 a, 7,8,12 b-hexahydrobenzo [a]phenanthridine = ()-3 and ()-8,9-dihydroxy - 2,3,7,11 b-tetrahydro - 1H - oil [1,2,3-de]isoquinoline = 4] to stimulate cAMP accumulation examined in the striatum homogenates of rats. With high affinity full agonist ()-3 and a partial agonist (+)-2 is included for comparison. The results of these experiments are shown in Fig. 4 as mean values SEM (average statistical error) of at least three experiments. The saturation concentration (10 μm) as dinapala and dihydrexidine cause the same degree of increased synthesis of cAMP (95,8% 4,7 for dinapala and 91.3% to 4.6 for dihydrexidine), which provides a maximally effective concentration of dopamine (100 μm). On the contrary, partial agonist (+)-2 leads to less than 50% stimulation (40,7 7,0 for SKF 38393). These actions are blocked by D1antagonist SCH23390.

Functional efficiency dinapala investigated also in the cloned D1Athe receptors of the Primate expressed in C-6 glioma cells (C-6 mD1cells). As shown in Fig. 5, the connection DiNapoli also has full effectiveness of this drug, with EC50about 30 nm (the data represent the average of two experiments performed in duplicate). ()-TRANS-10,11-dihydrox the ATA, whereas (+)-2 has only partial effectiveness.

Linking by D2the receptors. Investigated the ability dinapala to competition for D2receptors in the striatum homogenates of rats. As shown in Fig. 6 and table 1, the affinity dinapala to D2-like receptors in the striatum homogenates of rats (K0,5= 31 nm) is significantly higher than the affinity dihydrexidine to D2-like receptors (K0,5= 50 nm). As can be seen from Fig. 6, the slope of the curves comparison for dinapala and dihydrexidine less than for the prototype of the D2antagonist - chlorpromazine.

Using the same General methods that are described above in example 1, the synthesized compounds of examples 2-48 listed in table 2, using the starting compounds corresponding to the compounds shown in schemes 1 and 2 (Fig. 1 and 2), but substituted functional groups required for obtaining substituted structures corresponding condensed product of naphtohinola shown for each example. So, for example 3, 4 and/or 5-substituted analogues of compound 5a (scheme 1) gives the corresponding substituents R4, R3and R2accordingly, in formula I. Zamestitesj the compounds of formula I, where R5denotes methyl and isopropyl, respectively. The other 2, and 3 substituted benzamides (analogues of compound 8 in scheme 2) gives the corresponding substituted structure at C8 and C9 in the formula I.

The above compounds illustrate the invention but do not limit the described compounds. Understood that variations and modifications are typical compounds which can be obtained by any expert in the relevant field, are also included in the scope of the invention as described in the attached items.

The example of the pharmaceutical composition.

The example of the pharmaceutical composition is a solution of dinapala dissolved in isotonic sodium chloride, namely isotonic sodium chloride solution containing 0.35 mg/ml diapason, which is obtained, for example, by dissolving 350 mg dinapala with stirring in 1 liter of isotonic sodium chloride.

This solution is used for injecting dinapala. The composition and method of isotonic solution of sodium chloride are widely known in this technical field.

This solution diapason can be used on the PMA for oral administration, also suitable for use according to the present invention.

1. Condensed isoquinolines of the formula

< / BR>
or their pharmaceutically acceptable salt,

where R and R5is hydrogen or C1-C4alkyl;

R1is hydrogen or C1-C4alkyl;

X is hydrogen, halogen or a group of the formula-OR6where R6is hydrogen or C1-C4alkyl;

R2, R3and R4independently selected from the group including hydrogen, C1-C4alkyl, phenyl, halogen or a group-OR1where R1has adopted the above values.

2. Connection on p. 1, where X is hydroxy and R1- hydrogen.

3. Connection on p. 1, where R and R5- hydrogen.

4. Connection on p. 2, where R and R5- hydrogen.

5. Connection on p. 1, where R2- R5each hydrogen.

6. Connection on p. 1, where X and R1- hydrogen.

7. Connection on p. 1, where R5- hydrogen.

8. Connection on p. 1, where R5- C1-C4alkyl.

9. A method of treating patients suffering from dopaminezantac dysfunction of the Central or peripheral nervous system, as evidenced by the observed neurological, mental is the compounds of the formula

< / BR>
where R and R5is hydrogen or C1-C4alkyl;

R1is hydrogen or C1-C4alkyl;

X is hydrogen, halogen or a group of the formula-OR6where R6is hydrogen or C1-C4alkyl;

R2, R3and R4independently selected from the group including hydrogen, C1-C4alkyl, phenyl, halogen or a group-OR1where R1has adopted the above values,

or its pharmaceutically acceptable salt in an amount effective to alleviate the symptoms of the disorders.

10. Pharmaceutical composition for treating dopaminezantac dysfunction of the Central nervous system, where this composition includes a therapeutically effective amount of the compounds of formula

< / BR>
or its pharmaceutically acceptable salt,

where R and R5is hydrogen or C1-C4alkyl;

R1is hydrogen or C1-C4alkyl;

X is hydrogen, halogen or a group of the formula-OR6where R6is hydrogen or C1-C4alkyl;

R2, R3and R4independently selected from the group including hydrogen, C1-C4alkyl, phenyl, halogen or a group-OR1where R1has adopted the above values,<


Same patents:

The invention relates to novel condensed derivative indana formula I

< / BR>
in which A represents an optionally substituted benzene ring, naphthalene ring or benzene ring condensed with the lowest alkylenedioxy; ring B represents an optionally substituted benzene, Y = -N= CR or CR=N-

The invention relates to 6-[X-(2-hydroxyethyl)aminoalkyl]-5,11-dioxo-5,6,-dihydro-11H - indeno[1,2-C]isoquinolines of the General formula I

< / BR>
in which

X represents the number of carbon atoms equal to 0-5 in aminoalkyl group, located at the nitrogen atom in the 6 position of the canonical formulas indrosophila, to their salts with inorganic and organic acids and method of production thereof

The invention relates to medicine, namely to neurology and psychiatry

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

Anxiolytic tool // 2175229
The invention relates to medicine, in particular to pharmacology

The invention relates to pharmaceutical compositions containing as active ingredient at least one substance inhibiting NO-synthetase, and at least one substance that traps the reactive forms of oxygen, and, optionally, a pharmaceutically acceptable carrier

The invention relates to the derivatives of surinamite, glycinamide, alaninemia and phenylalaninamide formula I

< / BR>
where R is 1,2,3,4-tetrahydro-2-naphthalenyl or 2-indanyl, optionally substituted lower alkyl, alkoxy or halogen; R' is hydrogen, lower alkyl, phenyl (lower) alkyl; R1is hydrogen, C1- C4alkyl, optionally acylated C1- C4hydroxyalkyl or phenyl (lower) alkyl; R2is hydrogen, C1- C7alkyl, phenyl (lower)alkyl

The invention relates to new hydrochloridum substituted acetylene aminoalcohols of General formula I R1R2C(OH)CH2CCCH2AmHCl, which have low toxicity and have properties antagonists haloperidol, thanks to which can find application in medicine for the treatment and prevention of Parkinson's disease

The invention relates to medicine

The invention relates to new compounds of formula I, where R1- H, alkyl, aryl, R2- alkyl, R3- H, halogen, the nitro-group, R4- H, alkyl, Z is alkyl, W is alkyl, alkoxy, substituted aryl, substituted heteroaryl, where the heteroatoms may be O, N, S, and substituted amino group and substituted oxygraph, X - substituted aryl or substituted heteroaryl, where the heteroatoms may be O, N, S