2-aminoindane as selective ligands for the dopamine d3

 

(57) Abstract:

The invention relates to analogs of 2-aminoindane General formula I, where R1and R2independently represent hydrogen, C1-C8alkyl; X is CH2R3or NHSO2R4; Y represents hydrogen, NHSO2R4, SO2(Ph); R3is NHSO2R4,

SO2R4, CONR1R2; R4represents C1-C8alkyl, phenyl or phenyl, substituted by-CN or-CF3; and their pharmaceutically acceptable salts, active receptor Dopamine D3. The technical result - obtaining new derivatives of 2-aminoindane. 2 c. and 5 C.p. f-crystals, 1 table.

Background of the invention

The present invention relates to analogues of 2-aminoindane that selectively bind to the receptor dopamine D3 in vitro. The dopamine receptor D3 was recently cloned Sokolov et al. (Nature, 347, 146 (1990). It is hypothesized that this receptor subtype plays an important role as antipsychotics. Interestingly, this receptor in a large number are found in areas of the brain associated with emotional and cognitive functions.

Connection with such Pro eletricista diseases, drug abuse and addiction, Parkinson's disease, anxiety, sleep disorders, disorders of biorhythms and senile dementia.

Arneric, S. P. et al., Neuropharmacol., 21, 885 (1982) discloses analogs of Indiana in comparison with other dopamine agonists. Discovered that compounds substituted in the 5,6 - position, was inactive in this model, the consumption of food.

Arneric, S. P. et al. Arch. Int. Pharmocodyn. Ther., 257, 263 (1982) discloses analogues of 2-aminotetralin and 2-aminoindane, and again it turns out that the connection with 5,6-dimethoxysilane be inactive in the analysis to estimate the reductions in vascular smooth muscle.

Bhatnagar, R. K. et al., Pharmacol., Biochem. Behav. 17 (Suppl. 1), 11 (1982) discusses SAR studies of various structures, including aminoindane, which interact with dopamine receptors. Specifies that 5,6-dimethoxyindole be inactive compounds.

Cannon, J. G. et al., J. Med.Chem., 25, 858 (1982) discloses 4,7-dimethoxy-2-aminoindane and their dopaminergic and cardiovascular effects.

Cannon, J. G. et al., J. Med.Chem., 25, 1442 (1982) discloses the synthesis of 5,6-dimethoxy - and dihydroxyindole, as well as part of the biological studies that demonstrate that they are deprived of the stage is roizvodnykh 2-amino-4,6-dihydroxyindole.

Cannon, J. G. et al., J. Med.Chem., 28, 515 (1985) discloses the allocation of 4-hydroxyadamantane.

Cannon, J. G. et al., J. Med.Chem., 29, 2016 (1986) discloses ortho-OH/methyl, hydroxymethyl, formyl or carboxy derivatives of 2-aminoindane /4,5-replacement/, aminotetraline and benzo|f|quinoline.

Hacksell, U. et al., J. Med. Chem., 24, 429 (1981) discloses obtaining monophenolic 2-aminoindane as Central stimulants of dopamine receptors.

MA, S. et al. , J. Pharmacol. Exp. Ther., 256, 751 (1991) reveals the relationship of the activity dopaminergic structures 2 - aminoindane with primary di-substitution at the 4,5-positions.

Nichols, D. E. et al., J. Med.Chem., 33, 703 (1990) discloses nenarochkina analogues of tetralin and Indonesia analogues of 3,4- (methylendioxy)-amphetamine.

In PCT patent publication N W 090/07490 disclosed 2-aminotetraline and 2-aminoindane with aromatic substitution-OCH3or-OH together with a group of Br.

In European patent application N 883025991 filed March 24, 1988, discloses an antiarrhythmic aminoindane with a bicyclic structure and the methyl group of the amine, which are not disclosed in this invention.

In U.S. patent 4132737 disclosed substituted by trifluoromethyl 1-aminoindane, whereas the subject of the present invention I is comprised of compounds and their pharmaceutically acceptable salts of formula 1:

< / BR>
where R1and R2independently represent H, C1-8alkyl;

X represents CH2R3or NHSO2R4;

Y represents hydrogen, NHSO2R4, SO2(Ph);

R3is NHSO2R4, SO2R4, CONR1R2;

R4represents C2-C8is alkyl, aryl or C1-C8alkylaryl.

The object of the present invention are also the compounds and their pharmaceutically acceptable salts of formula 1, including a racemic mixture of both enantiomers. The preferred structure of formula 1, where R2and R2independently represent H or lower alkyl (C1-8alkyl);

Y is SO2(Ph).

In addition, an object of the present invention is a method of treating schizophrenia by introducing a therapeutically effective amount of the compounds of formula 1 to a patient suffering from schizophrenia.

The present invention also provides a method of treating Central nervous system diseases associated with the activity of the dopamine receptor D3 in a patient in need of such treatment, which comprises administration to the patient a therapeutically effective amount of the compounds of formula 1 for allercremecosmetics acceptable carrier or diluent.

The object of the present invention are pharmaceutical compositions for the treatment of diseases of the Central nervous system associated with the activity of D3 dopamine receptors comprising an effective amount of the compounds of formula 1 with a pharmaceutically acceptable carrier and diluent.

The present invention relates to compounds or pharmaceutically acceptable salts of formula 1, as previously submitted, either in racemic or pure enantiomeric forms, and X, Y, R1, R2, R3and R4independently selected in accordance with previously specified.

"Alkyl contains from one to eight carbon atoms, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomeric forms.

"Aryl" includes phenyl or phenyl substituted by CN or CF3.

Pharmaceutically acceptable salts include salts of organic and inorganic acids. Preferred pharmaceutically acceptable salts include salts of the following acids: methanesulfonic, hydrochloric, Hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric or maleic.

The compounds of formula 1 are active both in oral and in parenteral the entrances or capsules, or liquid dose forms, such as elixirs, syrups or suspensions, as known in the art. Preferably the compounds of formula 1 in solid dose form, and it is desirable in the form of tablets.

Usually the compounds of formula 1 can be entered in the amount of from about 0.25 mg to about 100 mg/person from one to three times a day. Preferably, from about 10 to about 50 mg/day in divided doses.

The exact dosage and frequency of administration depends on the particular compounds of formula 1, which is used, on the particular condition of the person in need of treatment, severity of disease, age, weight, General physical condition of the particular patient, other drug therapy, which can be done for this patient, and, as should be known to experts, should be more accurately determined by measuring the blood level or concentration of the active compound in the patient's blood and/or the patient's response to a particular condition to be treated.

Thus, the compounds being considered, together with a pharmaceutically acceptable carrier, diluent or buffer, you can type in a therapeutically or pharmaceutically effective amount to facilitate zabolevanija be administered intravenously, intramuscularly, superficially, through the skin, for example, by transdermal patch, buccal or oral human or other vertebrate.

Compositions of the present invention may be presented for administration to humans or other vertebrate in unit dose forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, solutions for oral administration or suspensions, emulsions of the type oil-in-water or water-in-oil, containing suitable quantities of the compounds, suppositories and liquid suspensions or solutions.

For oral administration can be prepared either solid or fluid unit dose forms. To obtain such solid compositions such as tablets, the compound can be mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium-aluminum-silicate, calcium sulfate, starch, lactose, Arabian gum, methylcellulose, or functionally close pharmaceutical diluent or carrier. Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture in hard gelatin capsules of appropriate size. Soft gelatin callnum oil, bright liquid petroleum butter or other inert oil.

You can make liquid unit dose forms, such as syrups, elixirs and suspensions. Such forms can be dissolved in an aqueous medium together with sugar, flavoring agents and preservatives to obtain syrup. Suspension can be obtained in aqueous media using a suspending agent, such as the Arabian gum, tragakant, methylcellulose, etc.

For parenteral administration can be prepared liquid unit dose form, using the connection and sterile media. In preparing solutions the compound can be dissolved in water for injection and sterilized through a filter, filling in the appropriate tubes or vials and seal them. Such an adjuvant, as local anesthetic agents, preservatives and buferiruemoi agents can be dissolved in the carrier. The composition can be frozen after filling into the vial and the water removed under vacuum. Lyophilized powders can be sold in capsules and restore the dosage form prior to use.

Chemical synthesis of

Commercially available 4-bromobenzylamine 1 alkylate lithium enolate of tert-butyl acetate (scheme 1) and then deterimining thionyl chloride, and subsequent cyclization Friedel-by aluminofluoride get indanan 3. 6-Bromo-1-indanone 3 get in four stages with 89% yield. 6-Bromo-1-indanone 3 carboxylic using sodium hydride and dimethylcarbonate to obtain-cetomacrogol ether 5. This method achieves high yield (97%) on a large scale (of 0.67 mol).

-Ketoester restore the sodium borohydride and methanol, getting hydroxyether 5.

As a result of dehydration-hydroxyether polyphosphoric acid polyunsaturated ester 6 with high output for 60 minutes (Vebrel, J., Carrie, R. Synthesis of methoxycarbonylamino, dihydro-1,2-naftalina and benzocyclobutene, Bull. Soc. Chim. Fr., 1982, pt.II, 116-24). Demethylation of ester administer water methanesulfonic acid and formic acid (Loev, B. acid Catalyzed hydrolysis of esters, Chem. and Ind., 1964, 193-94) to obtain 7 with high yield. Similar results were obtained using trichromacy Bor.

Asymmetric hydrogenation in the presence of (S) - BJNAP-ruthenium (II)diacetate (Ohta, T. et al. Asymmetric hydrogenation of unsaturated carboxylic acids. . ., J.Org. Chem., 1987, 52, 3174-76 and Kitamura, M., et al. Practical synthesis BJNAP romanizirovannyh complexes, J. Org.Chem. (R) - (+) - methylbenzylamine/indianboy acid from a mixture of diethyl ether/methanol to obtain optically pure acid. The enantiomeric ratio estimate by separation using chiral HPLC recovered acid/alcohol.

At this stage carboxylic acid 8 is subjected to the Curtius rearrangement due diphenylphosphinite (K. Ninomiya et al., A new convenient reagent for the modified Curtius reaction, Tetrah ed., 1974, 30, 2154-57) to obtain tert-BUTYLCARBAMATE 9, which in turn primary amine 10 by boiling under reflux with triperoxonane acid.

In the result of dialkylamide bromopropane receive tertiary amine 11. Total synthesis of (S)-(+)-5-bromo-2-N,N-di-propylaminoethyl includes 10 stages, with the full release of 9%.

(S)-(+)-5-Bromo-2-N, N-dipropylamine (11I) is used as an intermediate connection for some enantiomerically pure counterparts. Metallogeny exchange with tert-butyllithium results lithium anion, which process trimethylsilylcyanation to obtain 5 - carboxamide analogue 12. Restore it to the primary amine 14 borane-metilsulfate. In a separate series of the reaction, the lithium anion of 11 treated with paraformaldehyde (Rec. Trav. Pays-Bays, 1965, 1200) to obtain 5-hydroxymethylene analogue 13, which in turn mesilate 15 using methanesulfonyl also turn in the ndimethylacetamide 17 through acetonitrile, obtained by processing nelfinavir 15 sodium cyanide. The combined acetonitrile intermediate connection hydratious using sodium hydroxide and hydrogen peroxide to obtain 17 (Cacchi, S., et al. Obtaining amides from NITRILES at the expense of basic hydrogen peroxide under the conditions catalyzed by phase transfer, Synthesis, 1980, 243-44).

Figure 3 presents the formation of compounds 18-22 based on 5-hydroxymethylene analogue 13. This analog is obtained from 6-bromo-2 - ind-(1-ene)OIC acid (7), and its asymmetrically hydronaut, using (R)-BJNAP-ruthenium(II)diacetate to obtain (R)-(-)-5 - braindrool acid (8). Carboxylic acid 8 is subjected to a Curtius rearrangement in the presence of diphenylphosphinite to obtain tert-butyl-carbamate 9, which in turn primary amine 10 by boiling under reflux with triperoxonane acid. In the result of dialkylamide bromopropane receive tertiary amine 11. Metallogeny exchange with tert-butyllithium gives the lithium anion, which is treated with paraformaldehyde to obtain 5-hydroxymethylene analogue 13.

(R) - (-) -5-hydroxymethyl-2-N,N-dipropylamine (13) turn 96% yield, in his CHLOROTHALONIL similar 18, using thionyl chloride in tetrahydrofuran (Chem. Rev. 1963 noindent (19) with 93% yield. This sulfide is oxidized with 79% yield, using peracetic acid to obtain the sulfone 20. The accession (in the presence of palladium) formaldehyde to arilbred network (R) -(2)-5- (4-carboxybenzoyl) sulfanilyl-2-N,N-dipropylamine (21). As a result of dehydration of carboxamide in the presence of titanium tetrachloride and triethylamine (Tetrahedr. Lett., 1971, 1501) get canoening 22 with 78% yield.

Figure 4 presents the formation of compounds 24-39, on the basis of (R)-(-)-5-bromo-2-N, N-dipropylamine (11), which siteroot metal/halide exchange in the 5-position and is treated with diphenylphosphorylacetate. The obtained azide restore in the same reactor sociallyengaged (Chem. Pharm. Bull, 1986, 1524) to obtain (R)-(-)-5-amino-2-N,N - dipropylamine (23) 41% yield. This primary amine sulfonylureas benzosulphochloride or 4-chlorobenzenesulfonamide to obtain 24 and 25, respectively.

(R)-(-)-5-bromo-2-N, N-dipropylamine (11) literat metal/halide exchange with tert-butyllithium, and then treated trimethylsilylcyanation to obtain 5-carboxamide analogue 12. Restore it to the primary amine 14 borane - metilsulfate. This primary amine 14 sulfonium different sulphonylchloride to p is, which dalkilic propargyl-bromide under conditions of phase transfer before receiving diapir 40, which decarboxylase (A. P. Krapcho and A. J. Lovey, Tetrahed. Lett. , 1973, 957; A. P. Krapcho, J. F. Weimaster, J. M. Eldridge, E. G. So Jahngen Jr. A. J. Lovey and W. P. Stepheus, J. Org.Chem., 1978, 43, 138) to obtain complex monoether (41). As a result of hydrolysis of ester aqueous sodium hydroxide receive acid (42), which in turn tert-BUTYLCARBAMATE (43) by a modified Curtius rearrangement by diphenylphosphorylacetate (K. Nihomyia, T. Shioiri and S. Yamada, Tetrahed. , 1974, 30, 2151). Tert-BUTYLCARBAMATE hydrolyzing to 4-amino-1,6-heptadiene (44) triperoxonane acid and the resulting amine protect as triptorelin (45), using triperoxonane anhydride and triethylamine in tetrahydrofuran.

Diin (45) cyclist 2-Butin-1,4-diacetate, using the catalyst of Wilkinson (P. Magnus and D. Witty, Tetrahed. Lett. 1993, 34, 23) in ethanol to obtain indana (47). Triptoreline and acetate fragments hydrolyzing potassium hydroxide in aqueous methanol to obtain a crude amine (48), which dalkilic 1-bromopropane in acetonitrile to obtain dipropylamine (49) with 81% of the total output of 46. Diol (49) converted into 5,6-bis(chloromethyl)indan (50) by treatment with thionyl chloride.

5,5-bis(chloromethyl)indan (50) turn the t-butyl ether and restore sociallyengaged. Response indicates a partial recovery, and therefore, the product is treated with magnesium in methanol recovery (S. N. Maiti, P. Spevak and A. V. Narender Reddy, Syn. Comm. , 1988, 18, 1201) to obtain the crude diamine (52). This diamine restoring various sulphonylchloride in pyridine to obtain the bis(sulfonamide) 53, 54 and 55.

5,8-bis(chloromethyl)indan (56) is transformed into bis (methylphenylsulfonyl) benzosulfimide sodium dimethylformamide.

Examples

The procedure shown in chemical formula schemes 1 to 5. Compounds are numbered and presented in the diagrams.

Example 1

3-(4-Bromophenyl)propionic acid 2.

Tert-butyl acetate (159 ml, 1180 mmole) are added to sitedisability (941 mmol) in tetrahydrofuran at -78oC, and then 4-bromobenzylamine (200 g, 784 mmole). The bath temperature support at -15oC for 4 hours, then the reaction quenched by ammoniacloridegas. The resulting mixture was extracted with diethyl ether, and the organic layer was washed with diluted hydrochloric acid, water and brine, dried over sodium sulfate to obtain a pale oil. It is refluxed with triperoxonane acid (150 ml, 1960 mmole) for 1 hour. Triperoxonane acid UD is Aut of concentrated hydrochloric acid at 0oC and extracted with diethyl ether. The organic layer was washed with water and brine and dried over magnesium sulfate to obtain a solid white color after removal under vacuum of the solvent (167 g, 93%) 132-134oC so pl.

Example 2

6-Bromo-1-indanone. 3

3-(4-Bromophenyl)propionic acid (162 g, 706 mmol) and thionyl chloride (155 ml, 2120 mmole) is refluxed for 90 minutes. Then thionyl chloride is removed in vacuum, obtaining the oil is amber in color. This oil, aluminum-chloride (109 g, 816 mmole) and 1000 ml of dichloromethane is refluxed for 90 minutes and then poured on ice, add diluted hydrochloric acid, and the mixture was extracted with diethyl ether. The organic layer was washed with 2 n hydrochloric acid, water, aqueous sodium bicarbonate solution, water and brine. The resulting product is treated using flash chromatography on a column of silica gel (25 x 7 cm), elwira a mixture of ethyl acetate/dichloromethane (5:95) to obtain a solid pale brown color after removal of the solvent in vacuo (142 g, 95%). So melting point 107-109oC.

Example 3

6-Bromo-2-carboxymethyl-1-indanone. 4

6-Bromo-1-indanone (142 g, 672 mmole) in 1200 ml of tetrahydrofuran is g, 2020 mmole, 60% in oil, washed with pentane after weighing) and tetrahydrofuran (1200 ml). After boiling under reflux for 2.5 hours to the mixture was added dropwise acetic acid (240 ml) at 0oC, and then allowed to warm to room temperature. The resulting mixture is divided between a mixture of diethyl ether/dichloromethane and dilute aqueous hydrochloric acid. The organic layer was washed with 2 n hydrochloric acid, water, aqueous sodium bicarbonate and brine, and then dried over sodium sulfate to obtain a solid brown color after removal of the solvent in vacuo (176 g, 97%, crude). So melting 124,5-uniforms, 127.6oC1H NMR (300 MHz, CDCl3) (ratio about 3:1 enol:the ketone tautomers) to $ 7.91 (d, 0,27 N), to 7.77 (d, 0,73 H, J=1,8), 7,73 (DD, 0,27 N), 7,54 (DD, 0,73 H, J = 8,1, 1,8), 7,39 (d, 0,27 N), 7,34 (d, 0,73 H, J = 7,9), 3,86 (s, 2, 19H), 3,83 (m, 0,27 N), 3,80 (0,81 N), to 3.50 (m, 0,27 N), 3,47(s, 1,46 N), of 3.32 (m, 0,27 N).

Example 4

6-Bromo-2-carboxymethyl-1-hydroxyine. 5

6-Bromo-2-carboxymethyl-1-indan (139 g, 650 mmole), methanol (1100 ml) and 200 ml of tetrahydrofuran was stirred at 0oC. Batch add sodium borohydride (of 9.30 g, 245 mmole) in 45 minutes, and stirred for further 45 minutes, add sodium borohydride (12.4 g, 326 mmole) in portions during the course is the remainder divided between diethyl ether and water. The organic layer was washed with water and brine, then dried over sodium sulfate. As a result of processing flash chromatography on a column of 30 x 7 cm silica gel, elwira a mixture of dichloromethane/ethyl acetate/hexane 1:2:5, get orange wax (99,6 g, 57%).

1H NMR (300 MHz, CDCl3) (the ratio of CIS:TRANS diastereoisomers about 1: 1) of 7.55 (s, 0,43 N), 7,51 (0,057 N), 7,39 (t, 0,57 H, J = 8,1), 7,39 (t, 0,43 H, J = 8,1), 7,13 (d, 0,43 H, J = 8,1), was 7.08 (d, 0,57 H, J = 8,1), 5,44 (d, 0,57 H, J= 6,9), and 5.30 (d, 0,43 H, J = 6,0), 3.79(s, 1,7 1H), of 3.77 (s, 1,29 H, 3,45-2,95 (m, 3H), 2,87 (c, 1H).

Example 5

6-Bromo-2-carboxymethyl-1-inden. 6

6-Bromo-2-carboxymethyl-1-hydroxyine (99,4 g, 367 mmole) is heated with polyphosphoric acid (475 g) for 60 minutes (oil bath, 70oC, exothermic increasing the reaction temperature up to 80oC). Then the reaction mixture was poured into water and extracted with diethyl ether and hexane. The organic layer is washed with water and dilute aqueous sodium bicarbonate solution and brine, dried over sodium sulfate to obtain, after removal of the solvent in vacuo, the solids brown. (81,0 g, 87%). So melting 93,5-95,0oC.

1H NMR (300 MHz, CDCl3) to 7.64 (m, 2H), 7,45 (DD, 1H, J = 1,8), 7,37 (d, 1H, J = 8,0), 3,85 (s, 3H), of 3.64 (d, 2H, J = 1,7).

Approx acid (19.3 ml, 293 mmole), formic acid (286 ml, 95%) and 15 ml of water is stirred mechanically at boiling under reflux for 6 hours. Add diethyl ether, tetrahydrofuran and water, and the resulting solution extracted as a very dilute solution. The organic layer is washed with water and brine. It is stirred with activated charcoal for 5 minutes, and then filtered through diatomaceous earth. The filtrate is dried over sodium sulfate, and the solvent is removed in vacuo to obtain a solid pale yellow color (62,7 g, 89%). So melting 227,5 - 228,5oC.

1H NMR (300 MHz, d6acetone) 7,81 (s, 1H), 7,71 (m, 1H), 7,52 (s, 2H), to 3.67 (d, 2H, J = 2,0).

Example 7

(S)-(+)-5-Bromo-2-andonova acid.8

6-Bromo-2-ind-(1-ene)OIC acid (29,4 g, 123,0 mmole) of crude [(S)-2,2'-bis(diphenylphosphino)-1,1' -binaphthyl] ruthenium(II)diacetate (0.67 mmole), degassed methanol (350 ml) and tetrahydrofuran (35 ml) is shaken in an atmosphere of nitrogen (48 psi = 3,375 kg/cm2) for 63 hours. The suspension is filtered through diatomaceous earth and the solvent is removed in vacuum. The remainder is divided between diethyl ether and water. The organic layer is alkalinized 15% aqueous sodium hydroxide. The aqueous layer was acidified with concentrated hydrochloric KIS is I, dried over sodium sulfate. The solvent is removed in vacuo to obtain a solid green color, which is triturated with tetrahydrofuran and petroleum ether. The liquid is decanted, and the solvent is distilled off in vacuo to obtain a solid brown color, which is recrystallized from toluene and petroleum ether, receiving solid brown (23,2 g, 78%). So melting point 110-111,5oC. //25589= +23 (C = 0,97 MeOH).1H NMR (300 MHz, CDCl3) to 7.35 (s, 1H), 7,29 (d, 1H, J = 8,1): was 7.08 (d, 1H, J = 8,0), 3,37 (m, 1H), 3,24 (m, 2H), 3,19 (m, 2H). The optical purity determined by restoring the carboxylic acid to alcohol (borane-dimethylsulfide complex) analysis of data acquired on ChiracelOD-H column and elwira a mixture of isopropanol/hexane (1: 20) at a rate of 1 ml/min Acid can crystallize to an optical purity of (R)- (+) -- methylbenzylamine salt from methanol and diethyl ether to obtain white crystals. So melting 155oC.

Example 8

(S) - (+) -5-Bromo-2-[(2-methyl-(2-propoxy) carbylamine] indan.9

(S)-(+)-5-Bromo-2-indianabuy acid (18,9 g, 78,4 mmole) diphenylphosphinite (21,6 g, 78,4 mmole), tert-butanol (80 ml), 1,4-dioxane (80 ml) and triethylamine (10.9 ml, 78,4 t between diethyl ether and water. The organic layer was washed with 2 n hydrochloric acid, aqueous sodium bicarbonate solution and brine. The resulting solution was dried over sodium sulfate, and the solvent is removed in vacuum to obtain a transparent solid substance. It is treated using flash chromatography on a column of silica gel 29 x 5, elwira a mixture of tetrahydrofuran:hexane = 1:10. The solvent is removed in vacuo to obtain a solid white color (8,3 g, 34%). So melting point 125-126oC.

//25589= +10o(C = 0,95 MeOH).

Example 9

(S) - (+) -5-Bromo-2-aminoindan. 10.

(S) - (+) -5-Bromo-2-[(2-methyl- (2-propoxy) carbylamine]indan (7,3 g, 23.4 mmole) and triperoxonane acid (9 ml, 117 mmole) and refluxed for 60 minutes. Triperoxonane acid is removed in vacuo and the residue is divided between a mixture of diethyl ether/tetrahydrofuran and diluted with sodium hydroxide. The organic layer was washed with water and brine, dried over sodium sulfate. The solvent is removed in vacuum, obtaining a clear oil (4.9 g, 98%).

//25589= +17o(C = 1,15, MeOH).

1H NMR (300 MHz, CDCl3) 7,37 (s, 1H), 7,27 (d, 1H, J = 8,2), 7,07 (d, 1H, J = 7,9), a-3.84 (m, 1H), 3,13 (m, 2H), 2,64 (m, 2H), 1,40 (c, 2H).

pan (10.4 ml, 113 mmole), potassium carbonate (6.3 g, 45,3 mmole) and acetonitrile (50 ml) is refluxed for 22 hours. The solvent is removed in vacuum and the residue is divided between diethyl ether and water. The organic layer was washed with water and brine and dried over magnesium sulfate. Dark oil is treated using flash chromatography on a column of silica gel (24 x 2 cm), elwira a mixture of ethyl acetate/hexane (3:20). The solvent is removed in vacuo to obtain a clear oil (5.9 g, 88%).

//25589= +7o(C = 1,06 MeOH).

Cleaners containing hydrochloride salt crystallized from methanol and diethyl ether. So melting 220,5-221,5oC.

Example 11

(S)-(+)-5-Carboxamido-2,N,N-dipropylamino.12

Tert-utility (12,4 ml, 1.7 M solution of 6-pentane, 21,06 mmole) are added to (S)-(+) -5-bromo-2-N,N-dipropylamine (3.1 g, 10,53 mmole) in 20 ml of tetrahydrofuran. After 7 minutes, add trimethylsilyltriflate, and the cold bath removed. After 55 minutes, water is added, and the mixture was extracted with diethyl ether and aqueous sodium hydroxide. The ether layer is washed with water and brine and dried over sodium sulfate. The solvent is removed in vacuo to obtain a solid pale yellow color. So pravilova ether, getting solid pale yellow color. (2,19 g, 80%) So pl. 283 - 285oC.

Example 12

(S)-(+)-5-Hydroxymethyl-2-N,N-dipropylamino.13

Tert-utility (8,9 ml of 1.7 M solution in pentane, 15,18 mmole) are added to (S)-(+)-5-bromo-2-N, N-dipropylamine (2.25 g, to 7.59 mmole) in tetrahydrofuran (12 ml) at -78oC. After 5 minutes the reaction mixture was added to paraformaldehyde (0.27 g, at 8.36 mmole) and tetrahydrofuran (12 ml) at -78oC. After 60 minutes, water is added, and the mixture was extracted with diethyl ether and water. The ether layer is washed with water and brine and dried over sodium sulfate. The solvent is removed in vacuo to obtain a solid dark brown color, which is treated using flash chromatography on a column of silica gel (27 x 2 cm), elwira a mixture of dichloromethane/ethyl acetate/hexane (1:4: 5) and (1:6:3) to obtain 13, the solid amber color (1.12 g, 60%). So melting 52-54oC.

Example 13

(S)-(+)-5-Aminomethyl-2-N,N-di-1-propylamino.14

Amide 13 (1.8 g, 6.9 mmole) was dissolved in 20 ml of THF and added dropwise borane-metilsulfate (2.7 ml of a 10 M solution). This solution is heated to boiling under reflux for 1 hour and then cooled. Carefully add water 2 n hydrochloric who their solution is extracted with ether. The ether layer is washed with water and brine, dried over sodium sulfate. After removal of the solvent receive amine in the form of butter.

Example 14

(S)-(+)-5-Methylsulfonylmethyl-2-N,N-dipropylamino.15.

Methanesulfonanilide (0,37 ml, 4,67 mmole) 13 (1,05 g, 4,24 mmole), triethylamine (of 0.71 ml, 5,09 mmole) and 10 ml of dichloromethane is stirred at 0oC. After 2 hours the mixture is extracted with diethyl ether and aqueous sodium bicarbonate. The ether layer is washed with brine and dried over sodium sulfate. The solvent is removed in vacuo to obtain an oil of amber (1.2 g, 87% crude).

Example 15

(S)-(+)-5-Phenylsulfonyl-2-N,N-dipropylamino-indan.16

Benzosulfimide acid, sodium salt (0.54 g, 3,23 mmole), 15 (0.35 g, a 1.08 mmole) and 5 ml of dimethylformamide was stirred at 50oC. After 24 hours, the resulting mixture was extracted with diethyl ether and aqueous sodium bicarbonate. The ether layer is washed with water and brine and dried over sodium sulfate. The solvent is removed in vacuo to obtain a dark oil, which is treated using flash chromatography on a column of silica gel (22 x 1 cm), elwira a mixture of dichloromethane/ethyl acetate/hexane (1:6:13). Sulfon 16 obtained as a pale oil is g, 9,83 mmole), 15 (0,80 g of 2.46 mmole) and 5 ml of dimethylformamide was stirred at 50oC. After 24 hours, the resulting mixture was extracted with diethyl ether, dichloromethane and aqueous sodium bicarbonate. The ether layer is washed with water and brine and dried over sodium sulfate. The solvent is removed in vacuum to obtain a dark oil color, which is treated using flash chromatography on a column of silica gel (21 x 2 cm), elwira a mixture of dichloromethane/ethyl acetate/hexane(1:3:16), (1:6:15), and then (1: 10:9). The solvent is removed in vacuo to obtain cyanomethylene adduct in the form of a dark oil (0.35 g, 55%). This oil is combined with 15% aqueous sodium hydroxide (2.1 ml), tetrahydrofuran (12 ml) and 30% hydrogen peroxide (13,7 ml). After 54 hours, add diethyl ether and water and extracted the product. The ether layer is washed with water and brine and dried over sodium sulfate. The solvent is removed in vacuum, obtaining a white wax (0,19 g, 59%).

Example 17

(R)-(-)-5-Chloromethyl-2-N,N-dipropylamino.18

Thionyl chloride (2.3 ml) is slowly added to (R)-(-)-5 - hydroxymethyl-2-N, N-dipropylamine (7.5 g in 60 ml dry THF) in a bath with ice. After 60 minutes at room temperature, add 5 ml of ethanol and heated to boiling with reverse holodilniki layer was washed with water and brine, and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is treated using flash-chromatography; elute with a mixture of ethyl acetate/dichloromethane/hexane to obtain oil.

Example 18

(R)-(-)-5- (4-Brabanthal)thiomethyl-2-N,N-dipropylamino. 19

(R)-(-)-5-Chloromethyl-2-N, N-dipropylamine (3.0 g), 4 - bromothiophene (2.4 g), sodium hydroxide (28 ml 2 n aqueous solution), 28 ml of tetrahydrofuran and a catalytic amount of tetrabutylammonium heated at 50oC for 60 minutes. Add water, and the resulting mixture extracted with ether. The ether layer is washed with water and 2 n hydrochloric acid. The acid layer is alkalinized with sodium hydroxide and extracted with a mixture of ether/dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is treated using flash chromatography, elwira a mixture of ethyl acetate/dichloromethane/ hexane to obtain a solid substance with so melting 80-82oC. cleaners containing hydrochloride salt is recrystallized from a mixture of methane/air, getting solid with tons of melting point 142-144oC.

Example 19

(R)-(-)-5-(4-Brabanthal) sulfanilyl-2-N,N-dipropylamino.20.

Peracetic acid (ledjanoi acetic acid (7.5 ml) in a bath of cold water. After 4 hours add metilsulfate (1 ml), after 30 minutes add the ammonium hydroxide (3 M), and the resulting mixture extracted with ether. The ether layer is washed with water and brine, and then dried over sodium sulfate. The solvent is removed in vacuo to obtain a solid substance with tons of melting point 132-134oC. Malata salt, recrystallized from methanol/ether gives a solid with tons of melting point 130-131oC.

Example 20

(R)-(-)-5-(4-Carboxamides) sulfanilyl-2-N, N - dipropylamino. 21

(R)-(-)-5-(4-Brabanthal)sulfanilyl-2-N, N-dipropylamine (0,94 g), palladium acetate (0.05 g), 1,3-bis (diphenylphosphino)propane (0.21 g), diisopropylethylamine (0.75 ml) in dimethylformamide (5 ml) and formamide (0,42 ml) is heated at 120oC in an atmosphere of carbon monoxide. After 7 hours the mixture is cooled to room temperature and add sodium hydroxide (5 ml, 2 n). Water is added, and the mixture was extracted with a mixture of ether/tetrahydrofuran. The ether layer is washed with water and brine and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is treated using flash chromatography, elwira mixture methane/dichloromethane to obtain solids with tons of melting point 164-165oC. Fumaric salt, re 21

(R)-(-)-5-(4-Cyanobenzoyl) sulfanilyl-2-N,N-dipropylamino.22

The titanium tetrachloride (0.15 ml in carbon tetrachloride, 3 ml) is added to (R)-(-)-5-(4-carboxamides)sulfanilyl-2 - N,N-dipropylamine (0,23 g), triethylamine (0,46 ml) and tetrahydrofuran (5 ml) in a bath with ice. After 16.5 hours add aqueous sodium carbonate, and the resulting mixture extracted with ether. It is washed with brine and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is treated using flash chromatography, elwira a mixture of ethyl acetate/dichloromethane/hexane to obtain a solid substance. An analytical sample is recrystallized from a mixture of ethyl acetate/hexane, obtaining a solid product with tons of melting point 90-91oC. cleaners containing hydrochloride salt is recrystallized from methanol/ether, getting solid with tons of melting point 175oC (decomposition).

Example 22

(R)-(-)-5-Amino-2-N,N-dipropylamino.23

Tert-utility (9,9 ml, 1.7 M in pentane) are added to (R)- (-)-5-bromo-2-N, N-dipropylamine (11) (2.5 g) in 15 ml of tetrahydrofuran at -78oC. After 5 minutes add diphenylphosphinite (2.0 ml), and dim the reactor. The cooling bath is removed and after 45 minutes return to the place. Add socialising is dnow hydrochloric acid, and the resulting mixture is extracted with a mixture of ether/tetrahydrofuran. The acid layer is alkalinized with 15% sodium hydroxide and extracted with a mixture of ether/tetrahydrofuran. The organic layer was washed with brine, filtered through diatomaceous earth and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is treated using flash chromatography, elwira mixture metadataformat to get the oil.

Example 23

(R)-(-)-5-Benzosulfimide-2-N,N-dipropylamino.24

Benzosulphochloride (0.45 ml) is added to (R)-(-)-5-amino - 2-N,N-dipropylamine (0.4 g), triethylamine (0,48 ml) and dichloromethane (5 ml). After 19 hours add ammonium hydroxide (3 M in water), and the resulting mixture extracted with ether. The ether layer is washed with brine and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is treated using flash chromatography, elwira a mixture of ethyl acetate/dichloromethane/hexane to obtain 0.51 g diphenylsulphide adduct. Add potassium hydroxide (0,19 g) in 5 ml of methanol and 0.5 ml of water. After 17 hours the solvent is removed in vacuum, and add hydrochloric acid (2 n in water), and then alkalinized water sodium bicarbonate. The resulting mixture was extracted with a mixture of ether/dihormati the chloride salt, recrystallized from methanol/ether, is a solid substance with so melting 214-215oC. (R)-(-)-5-(4-Chlorobenzene) sulphonamido-2-N,N-dipropylamino. 25

Replacing benzosulphochloride 4-chlorobenzenesulfonamide, (R)-(-)-5-amino-2-N, N-dipropylamino treated according to the method of example 23 to obtain the title compound in the form of oil. Salt of maleic acid, recrystallized from methanol/ether gives a solid with tons of melting point 167-169oC.

Example 24

(R)-(-)-5-Acanaloniidae-2-N,N-dipropylamino. 26

Acanaloniidae (0.2 ml) are added to (R)-(-)-5 - aminomethyl-2-N,N-dipropylamine (14) (0.5 g), pyridine (0.3 ml) and tetrahydrofuran (5 ml). After 2.5 hours, add ammonium hydroxide, and the resulting mixture extracted with ether. The ether layer is washed with water and brine, and then dried over sodium sulfate. The solvent is removed in vacuo, and the residue is treated using flash chromatography, elwira a mixture of ethyl acetate/dichloromethane/hexane to obtain oil. Fumaric salt, recrystallized from methanol/ether gives substance with so melting 129-130oC.

(R) - (-) -5-Benzosulfimide-2-N,N-dipropylamino.27

Sameo way of example 24 to obtain the title compound in the form of oil. Malata salt, recrystallized from methanol/ether gives a solid with tons of melting point 144 - 145oC.

(R)-(-)-5- (4-Chlorobenzene) sulfonamide-2-N,N-dipropylamino.28

Replacing acanaloniidae 4-chlorobenzenesulfonamide, (R)-(-)-5-aminomethyl-2-N, N-dipropylamino treated according to the method of example 24 to obtain the title compound in the form of a solid substance with so melting 84-87oC.

(R)-(-)-5-(3,4-Dichlorobenzene) sulfonamide-2-N, N - dipropylamino. 29

Replacing acanaloniidae 3.4-dichlorobenzenesulfonate, (R)-(-)-5-aminomethyl-2-N, N-dipropylamino treated according to the method of example 24 to obtain the title compound in the form of a solid substance. As a result of recrystallization from a mixture of toluene/hexane get solid with tons of melting 87-90oC.

(R)-(-)-5-(4-Iodobenzoyl) sulfonamide-2-N,N - dipropylamino.30

Replacing acanaloniidae 4-iodobenzenesulfonyl, (R)-(-)-5-aminomethyl-2-N, N-dipropylamino treated according to the method of example 24 to obtain the title compound in the form of a solid substance. After recrystallization from a mixture of ether/hexane get a solid substance is>/BR>Replacing acanaloniidae 4-acetamidobenzenesulfonyl, (R)-(-)-5-aminomethyl-2-N,N-dipropylamino treated according to the method of example 24 to obtain the title compound in the form of a solid substance. Cleaners containing hydrochloride salt, recrystallized from isopropanol, gives solid with tons of melting point 217-218oC.

(R)-(-)-5-(4-Acetamido-3-chlorobenzene) sulfonamide - 2-N,N-dipropylamino. 32

Replacing acanaloniidae 4-acetamido-3-chloro - benzosulphochloride, (R)-(-)-5-aminomethyl-2-N, N-dipropylamino treated according to the method of example 24 to obtain the title compound in the form of a solid substance with tons of melting point 58-60oC.

(S)-(-)-5-(4-Triptoreline) sulfonamide-2-N, N-dipropylamino.33

Replacing acanaloniidae 4-tripersonality, (R)-(-)-5-aminomethyl-2-N, N-dipropylamino treated according to the method of example 24 to obtain the title compound in the form of a solid substance with so melting 66-70oC.

(R)-(-)-5-(4-Nitrobenzene) sulfonamide-2-N,N - dipropylamino.34

Replacing acanaloniidae 4-nitrobenzenesulfonamide, (R)-(-)-5-aminomethyl-2-N, N-dipropylamino process SUP>oC. cleaners containing hydrochloride salt after a thorough trituration with ether gives a solid substance.

(R)-(-)-5-(4-Cyanobenzoyl) sulfonamide-2-N,N-dipropyl - aminoindan. 35

Replacing acanaloniidae 4-cyanobenzenesulfonyl (R)- (-)-5-aminomethyl-2-N, N-dipropylamino treated according to the method of example 24 to obtain the title compound in the form of a solid substance with so melting 104 - 106oC. Fumaric salt after recrystallization from methanol/ether gives a solid substance with so melting 174-177oC.

(R)-(-)-5-(3-Cyanobenzoyl) sulfonamide-2-N,N-dipropylamino. 36

Replacing acanaloniidae on C-cyanobenzenesulfonyl, (10-(-)-5-aminomethyl-2-N, N-dipropylamino treated according to the method of example 24 to obtain the title compound in the form of oil. Cleaners containing hydrochloride salt after a thorough trituration with ether gives a solid with tons of melting point 110oC (decomposition).

(R)-(-)-5-(2-Cyanobenzoyl) sulfonamide-2-N, N-dipropyl-aminoindan. 37

Replacing acanaloniidae 2-cyanobenzenesulfonyl, (R)-(-)-5-aminomethyl-2-N, N-dipropylamino treated according to the method of example 24 to obtain the title compound in vitvo with tons of melting point 185oC (decomposition).

(R)-(-)-5-12-(5-Cryptor) pyridine] sulfonamide-2 - N,N-dipropylamino.38

Replacing acanaloniidae 2-(5-Cryptor)pyridinesulfonamide, (R)-(-)-5-aminomethyl-2-N,N-dipropylamino treated according to the method of example 24 to obtain the title compound in the form of a solid substance with tons of melting point 125-127oC. cleaners containing hydrochloride salt as a result of recrystallization from methanol/ether gives a solid with tons of melting point 207-209oC.

(R)-(-)-5-[3-(2,5-Dichloro)thiophenyl]sulfonamide-2 - N,N-dipropylamino. 39

Replacing acanaloniidae 2.5-dichlorothiophene-3 - sulphonylchloride, (R)-(-)-5-aminomethyl-2-N,N-dipropylamino treated according to the method of example 24 to obtain the title compound as a clear oil. After crystallization from a mixture of ether/hexane get solid with tons of melting 79-80oC. cleaners containing hydrochloride salt after recrystallization from methanol/ether gives a solid with tons of melting point 106oC (decomposition).

Example 25

Dimethyl-2, 2-di (2-PROPYNYL) malonate.40

Aqueous sodium hydroxide (1500 ml 12 n solution) is placed in a flask equipped top of the agitator. Add benzyltri solution diethylmalonate (79,3 g) and propylbromide (3 EQ., 214 g) via addition funnel over 25 minutes, maintaining the temperature below 25oC (R. K. Singh, Synthesis, 1985, 54). Then, the suspension is left under stirring for 3 hours at 25oC. the Suspension is cooled in an ice bath, and then carefully added to a mixture of ice/water. All of this is extracted with tert-butylmethylamine ether, washing the organic layer with water (twice), and then brine. After drying over sodium sulfate and remove solvent receive specified in the title compound as crystalline solid (92% yield).

Example 26

Methyl-2-(2-PROPYNYL)-4-pentynoate. 41

Dimethyl-2,2-di(2-PROPYNYL)malonate (71 g) is treated according to the method Krapcho decarboxylation by heating at 170oC with sodium chloride (25 g) and water (23 ml) in 341 ml dimethyl-sulfoxide. After 15 hours the solution is cooled and diluted with water and tert-butylmethylamine ether and extracted. The organic layer was washed with water (4×), brine, and then dried over sodium sulfate. The solvent is removed in vacuum, obtaining a liquid that is distilled, collecting specified in the title compound at 109oC (28 mm RT.cent.).

Example 27

2-(2-PROPYNYL)-4-pontenova acid. 42

Methyl-2-(2-PROPYNYL)-4-pentynoate (27.5 g) omelet hydro is irout tert-butylmethylamine ether. The organic layer was washed with brine and dried over sodium sulfate. The solvent is removed, getting mentioned in the title compound.

Example 28

4-(Tert-butoxycarbonylamino) hepta-1,6-Dien.43

To a solution of 2-(2-PROPYNYL)-4-pentenovoi acid 42 (25,0 g, 0,184 mmole in toluene (200 ml), add triethylamine (19.5 g, rate of 0.193 mol) under cooling. Add diphenylphosphinite (50.5 g, 0,184 mol) and the resulting mixture was stirred at room temperature for 15 minutes. The resulting mixture is heated on the steam bath until then, until the reaction becomes exothermic. As a reaction, the heating is continued for another 10 minutes, and at this time there is an allocation of gas. Add dry tert-butanol (150 ml) and the resulting mixture is heated at boiling under reflux on the steam bath for 24 hours. The solvent is removed in vacuo and the residue diluted with water and twice extracted with diethyl ether. The combined aqueous extracts washed with water (2x), 10% sodium carbonate solution C brine. The resulting solution was dried over magnesium sulfate, and the solvent is removed in vacuum, getting 43 in the form of a red-brown solid (35,35 g). Sample (3.2 g) is cleaned by flash chromatograph is stallization from hexane get mentioned in the title compound (43) in the form of colorless crystals, (so melting 64-67oC).

Example 29

4-Aminogatan-1,6-Dien. 44

4-(Tert-butoxycarbonylamino)hepta-1,6-Dien 43 (30,28 g, 0,146 mole) cooled in ice and with stirring, add triperoxonane acid (90 ml). The resulting mixture was stirred for 20 minutes and the excess triperoxonane acetic acid removed in vacuo. The resulting mixture was separated between water and diethyl ether, and the ether solution is extracted twice with 5% hydrochloric acid solution. The combined aqueous extracts washed with diethyl ether, cooled in ice, and alkalinized with solid sodium hydroxide. The resulting mixture was saturated with sodium chloride and extracted three times with diethyl ether. The combined extracts washed with brine and dried over magnesium sulfate. The solvent is removed in vacuo to obtain specified in the title - compound (44) in the form of oil of amber (13,2 g, 84%). Sample (0,526 g) combined with fumaric acid (0,570 g), and the mixture was crystallized from methanol/diethyl ether to obtain the salt of fumaric acid 44 in the form of light yellow crystals (0,694 g, so melting 178-179oC).

Example 30

4-(Triptorelin) hepta-1,6-Dien.45

A solution of 4-aminogatan-1,6-Diana 44 (14,63 g, 0,137 mol) and Tigrid (37,5 g, 0,178 mol) via syringe over 30 minutes. The resulting mixture was stirred at 0oC for 1 hour and left to stand at 15oC during the night. The resulting mixture was cooled on ice, and added dropwise to 100 ml of water. The resulting mixture was extracted twice with diethyl ether. The combined organic extracts are washed with 10% hydrochloric acid, saturated sodium bicarbonate solution twice and brine. The solution is dried over magnesium sulfate, and the solvent is removed in vacuum, obtaining of 29.6 g of solid substance. After crystallization from hexane containing a little ethyl acetate, get 45 in the form of yellowish crystals (21,5 g, so melting 55 - 57oC).

Example 31

2-(Triptorelin)-5,6-bis (acetoxymethyl) indan.47

A solution of 2-butyn-1,4-diacetate 46 (34,03 g, 0,200 mmol) and Tris/triphenylphosphine/radioid (2,78 g, 3,00 mmole, 3 mol%) in degassed with argon ethanol (100 ml) is heated to 80oC, and using a syringe add a solution of 4-(triptorelin) hepta-1,6-Diana (20,32 g, 0,100 mol) in degassed with argon ethanol (70 ml) for 2.5 hours. The resulting mixture was stirred at 75-80oC for 8 hours and at room temperature for 10 hours. The solvent is removed in vacuum, obtaining a dark oil. Polvo amber (24.5 g). As a result of crystallization from a mixture of ethyl acetate/hexane get mentioned in the title compound as yellow crystals brown (22,0 g, 59%. So melting 98 - 100oC).

Example 32 and 33

2-(N,N-Dipropylamino)-5,6-bis (hydroxymethyl)indan.49

A solution of potassium hydroxide (10,10 g, 0,180 mole) in 35 ml of water are added to a solution of 2-(triptorelin)-5,6-bis (acetoxymethyl)-Indiana 47 (20,1 g, 53,8 mmole) in 200 ml of methanol at room temperature, and the resulting mixture is heated to boiling under reflux for 2.5 hours. The solvent is removed in vacuum, obtaining 2-amino-5,6-bis(hydroxymethyl)indan (48) in the form of semi-solid substances. The crude product is mixed with 1 - bromopropane (27,1 g, 0,220 mol) and potassium carbonate (22,32 g rate £ 0.162 mole) in 100 ml of acetonitrile, and the resulting mixture was mechanically stirred at the boil under reflux on the steam bath for 17 hours. 1-Bromopropane (6.8 g, by 0.055 mole) is added and the boiling continued for 4 hours. The resulting mixture was diluted with water and extracted twice with ethyl acetate. The extracts washed with brine and dried over magnesium sulfate. The solvent is removed in vacuum, obtaining a brown oil (of 15.75 g). Purification using flash chromatography (silica gel 230 - 400 is about substance (12.1 g, 81%). A sample (0.50 g) is crystallized from a mixture of ethyl acetate/hexane to obtain white crystals (0,48 g).

Example 34

2-(N,N-Dipropylamino)-5,6-bis(chloromethyl) indan.50

2-(N, N-Dipropylamino)-5,6-bis/hydroxymethyl) indan 49 (2,78 g, 10.0 mmole) is cooled in ice and slowly add 8.0 ml of thionyl chloride. The resulting mixture is heated to boiling under reflux on the steam bath for 1.25 hours. The excess thionyl chloride removed in vacuo. The residue is dissolved in chloroform, and the solvent is removed in vacuum. This is a repeat, getting a solid amber color. The connection is stirred with a mixture of 10% solution of sodium carbonate and tetrahydrofuran to dissolve all solids. The resulting mixture was twice extracted with diethyl ether, and the combined extracts washed with brine and dried over magnesium sulfate. The solvent is removed in vacuum, obtaining mentioned in the title compound (50) in the form of oil (3.46").

Example 35 and 36

2-(N,N-Dipropylamino)-5,6-bis (aminomethyl) indan. 52

Sodium azide (3,30 g, or 50.8 mmole) are added to a solution of 2- (N,N-dipropylamino)-5,6-bis(chloromethyl)indane 50 (2.85 g, 9,07 mmole) in 35 ml of dimethylformamide at room temperature, and the mixture was stirred at 80who yedinenye extracts washed twice with water and once with brine. The resulting solution was dried over magnesium sulfate and filtered. A solution containing 2-(N,N-dipropylamino)-5,6 - bis(azidomethyl)indan 51, cooled in ice and slowly add sociallyengaged (1.0 M in tetrahydrofuran (THF, 13 ml, 13 mmol) and the resulting reaction mixture was stirred at room temperature for 2 hours. Successively added water (0.5 ml) and 15% sodium hydroxide (0.5 ml) and water (1.5 ml). The resulting mixture was stirred for 30 minutes and filtered. Aluminum salt is washed with tetrahydrofuran and the combined filtrate is evaporated, getting oil amber color of 2.27 g). The compound was dissolved in methanol (100 ml), and add magnesium metal. The resulting mixture is heated on the steam bath until then, until the reaction becomes exothermic. Magnesium is depleted, the solvent is distilled in vacuum, obtaining a solid substance. The resulting mixture was suspended in water and extracted several times with a mixture of 1:1 tetrahydrofuran/diethyl ether (emulsion). The combined extracts washed with brine and dried over magnesium sulfate. The solvent is removed in vacuum, obtaining mentioned in the title compound (52) as a brown oil (0,92 g).

Example 37

2-(N, N-Dipropylamino) -5,6-bis (4-chlorvinyls the pyridine is cooled in an ice and add 4-chlorobenzenesulfonamide (0,53 g of 2.51 mmole). The resulting mixture was stirred at 0oC for 40 minutes and at room temperature for 18 hours. Water is added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with 10% sodium carbonate solution, and extracted twice with diethyl ether and once with ethyl acetate. The combined extracts washed with brine and dried over magnesium sulfate. The solvent is removed in vacuum, obtaining oil red-brown color (0.34 g). In the purification using flash chromatography (silica gel 230-400 mesh mesh, 60% ethyl acetate/hexane) get a solid orange color. As a result of crystallization from a mixture of diethyl ether/hexane get mentioned in the title compound (53) in the form Orangevale crystals (0,090 g, so the melting point 140-141oC).

Example 38

2-(N, N-Dipropylamino)-5,6-bis(4-cyanobenzylidene)-indan. 54.

A solution of 2-(N, N-dipropylamino)-5,6-bis (aminomethyl) indan 52 (0,276 g, 1.00 mmole) in 4.0 ml of pyridine is cooled on ice, and add 4-cyanobenzenesulfonyl (and 0.61 g, 3.0 mmole). The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture is jut brine and dried over magnesium sulfate. The solvent is removed in vacuum, obtaining a dark oil. In the purification using flash chromatography (silica gel 230 - 400 mesh) 60-80% ethyl acetate/hexane) receive specified in the title compound (54) in the form of oil. This compound was dissolved in ethyl acetate and an excess of ethereal hydrochloric acid is added. The resulting mixture was diluted with diethyl ether and filtered. The precipitate was washed with diethyl ether and dried in vacuum, obtaining cleaners containing hydrochloride salt of compound 54 as a yellow-brown solid (0,143 g).

Example 39

2-(N,N-Dipropylamino) -5,6-bis (S-propylsulfonyl)indan.55

A solution of 2-(N, N-dipropylamino) -5,6-bis(aminomethyl) Indiana 52 (0.36 g, 1.3 mmole) in 5.0 ml of pyridine is cooled on ice, and add 1-propanesulfonate (0.64 g, 4.5 mmole). The resulting mixture was stirred at 0oC for 30 minutes and at room temperature for 3 hours. Add water (15 ml) and the resulting mixture was stirred at room temperature for 15 minutes. The resulting mixture was diluted with 10% sodium carbonate solution and extracted three times with diethyl ether. The combined extracts washed with brine and dried over magnesium sulfate. The solvent is removed in vacuum, obtaining a brown oil (0,51 logo color (0,131 g). As a result of crystallization from a mixture of diethyl ether/hexane get mentioned in the title compound (55) as off-white crystals (0,092 g, so melting 120-121oC).

Example 40

2-(N,N-Dipropylamino) -5,6-bis (phenylsulfonyl) indan. 56

Specified in the title compound (56) is obtained from 2-(N,N - dipropylamino)-5,6-bis(chloromethyl)indane and nitrobenzenesulfonate in dimethylformamide at 100oC. the Free base is converted into the salt of fumaric acid (i.e. melting point 160 - 168oC).

Methods of binding receptors

The affinity of the test compounds to these receptors was determined by measuring the displacement radiometric ligands from receptors expressed in native tissues or membranes of mammalian cells stably transfected with cDNA encoding the receptor. In the experiments, competitive binding, used 11 concentrations of the studied compounds and their was performed twice. Here is 1C50was determined by fitting the data to a single-site model by minimizing a nonlinear least squares. The binding constants were calculated using the equation of Cheng-Prahova and expressed in the Table as the value of Ki in nm. The affinity of compounds to the receptor SS="ptx2">

Cheng, Y. C. and Prushoff (1973), Biochem. Pharmacol.22, 3099 - 3108.

Research mitogenesis

It is a cellular test used to measure the inherent connection activity (power) (agonist vs. antagonist). Activation of the receptor (heterological expressed in the ovary cells of Chinese hamsters) agonist stimulates cell growth, which is measured as absorption3H - thymidine. In contrast, the antagonist to the receptor can block the stimulation of the known agonist. Compounds were tested at a dose that allows you to get an answer to a concentration of 10,000 nm. (The highest investigated dose may be lower if the effects observed in the control cells). Recorded values EC50(nm) for agonistic action. This concentration, which reached half of the maximum effect, the higher the potency of the compound, the lower EU50. Compounds which show no effect up to the highest investigated dose was recorded as > 10.000 (nm) (or any higher tested dose). The maximum effect of the compounds were compared with the maximum effect of the full agonist (dopamine). The obtained data were expressed as % response full AGU, close to 100%, was seen as full agonists. Connection with the inner activity of less than 50% was considered as partial agonists. The connection was further investigated in the presence of a full agonist on their ability to reduce or block the agonistic action. They were studied at two concentrations, 1 μm and 10 μm, and was registered as active ("A") or inactive ("ON").

Lajiness, V. E. , Chio.C.L. and Huff, R. M. (1993), J. of Pharm. and Experimental Therapeutics, 267 (3), 1573-81.

1. Adapted movement: HABLOC (% CTR.)

This test determines the influence of the studied drugs on the activity of rats moving horizontally (measured in square box photosensors) after getting used to the camera for one hour. Was measured cumulated activity for 60 min and it was expressed in % of controls, treated with solvent (solvent = 100%). In this study, some D3antagonists increase locomotor activity. The dose was administered subcutaneously.

2. Neurochemistry

Animals from the above studies 1. were scored immediately after the cessation of activity, then removed the brain. Froze striate and measured the levels of nanoperiodic NE,DA,5-HT + met = 100%). Compounds that increase the turnover of dopamine will increase the levels of DOPAC, HVA, 3-MT.

1. 2-Aminoindane General formula I

< / BR>
R1and R2independently represent hydrogen, C1-8alkyl;

X represents CH3R3or NHSO2R4;

Y represents hydrogen, NHSO2R4, SO2(Ph),

R3represents the SO2R4, NHSO2R4, CONR1R2,

R4represents a C1-8alkyl, phenyl or phenyl, substituted by-CN or-CF3,

and its pharmaceutically acceptable salts are active in the recipes Dopamine D3.

2. Connection on p. 1, in which Y represents NHSO2R4H.

3. Connection on p. 2, in which R1and R2independently represent hydrogen or C1-8alkyl.

4. Connection PP.1 to 3, in which R4represents C1-8alkyl.

5. A connection on p..1 - 4, in which X represents CH2R3.

6. Connection on p. 5, in which R3is a CONR1R2.

7. 2-Aminoindane General formula I

< / BR>
where R1and R2independently represent hydrogen or C1-rod, NHSO2R4, SO2(phenyl);

R3represents the SO2R4, NHSO2R4, CONR1R2;

R4represents a C1-8alkyl, phenyl or phenyl, substituted by-CN or-CF3,

and their pharmaceutically acceptable salts, provided that when R1and Y each represents hydrogen, and R2is CH3X is not NHSO2(C1-4)alkyl.

 

Same patents:

The invention relates to a new class of sulfonamides which are inhibitors of aspartyl-protease formula I

The invention relates to a new method of obtaining sulfur-containing imidazole derivatives of the formula I

R4-C6H4-C6H4-CH2NC4R, R2R3,

characterized in that the compound of formula (A)

Hal-C6H4-C6H4R'4< / BR>
enter into reaction with the oxidizing agent to obtain a compound of the formula (B)

CHO-C6H4-C6H4-R41,

which is then injected into the reaction with the compound of the formula (II)

H2N-CH(CN)-R31,

where possible functional groups can be protected to obtain a compound of formula (C)

R31-CH(CN)-NH-CH2-C6H4-C6H4-R41,

which enter into reaction with the compound of the formula (III)

R11-CO-Hal

to obtain the compounds of formula (D)

R31-CH(CN)-N(COR1CH2-C6H4C6H4-R41,

which undergoes the reactions proceed on the CN radical with a reagent able to enter the substituent R21where possible functional groups can be protected to obtain a compound of formula (E)


,

after which the compound of formula (E) and the compound of formula (L) is subjected to cyclization reaction to obtain compounds of formula (I)

The invention relates to compounds belonging to the group consisting of compounds of the General formula [I] or their optical isomers, or suitable for pharmacological use of salts

The invention relates to a new amidon unsaturated acids having insecticidal activity, and intermediate products for their production

The invention relates to the field of organic chemistry, and in particular to a method for producing amides of unsaturated acids of the General formula 1

Q Q1CR2= CR3CR4= CR5C(X) OTHER1(1) or their salts, where Q denotes phenyl, pyridyl, naphthyl, degloving, each of which may be substituted by 1-3 substituents selected from the group:1-C6alkyl, C1-C6alkoxy, CF3, halogen, Q1-1,2-cyclopropyl ring, possibly substituted C1-C4the alkyl, R2, R3, R4and R5denote identical or different groups, including hydrogen, C1-6alkyl group, or C1-6 haloalkyl group; one of the radicals necessarily mean hydrogen, X denotes an oxygen atom, R1denotes hydrogen or C1-6the alkyl may contain as substituents DIOXOLANYL group, cyclo(C3-C6)alkyl, possessing insecticidal activity

The invention relates to new 8-carbonylation 2-aminotetraline, their enantiomers and salts, processes for their preparation, pharmaceutical preparations on their basis and use of such compounds in therapy

The invention relates to new derivatives of 1,2,3,4-tetrahydro-2-naphtylamine, as well as their pharmaceutically acceptable salts, having the properties to affect 5-HTIAmammals and humans, as well as subclass of dopamine D2receptors, and may find application in the pharmaceutical industry
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