Derivatives of trans-isomers of 1-piperazine-1,2-dihydroindeno

 

(57) Abstract:

The invention can be used in the chemistry of heterocyclic compounds and medicine. Describes derivatives of TRANS-1-piperazine-1,2-dihydroindeno General formula I given in the text description. Compounds according to the invention can be used in the treatment of diseases of the Central nervous system, have low toxicity. These compounds may be obtained, for example, by reacting the corresponding indene with the appropriate piperazine derivatives. 1 S. and 2 C.p., table 1.

The invention relates to new derivatives of 1-piperazine-1,2-dihydroindeno and their acid additive salts which are active in relation to dopamine receptors in the Central nervous system, in particular are potential antagonists of dopamine receptors D, medicinal products containing these derivatives as active ingredients, and to the use of these derivatives in the treatment of diseases of the Central nervous system.

New derivatives of 1-piperazine-1,2-dihydroindeno according to the invention are TRANS-isomers (with respect to indenbom cycle), represented by the following formula I:

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where X is selected from the hydrated or substituted by halogen, or titillation;

R1is hydrogen, lower alkyl, lower alkyl substituted by hydroxyl;

R2- lower alkyl, or R1and R2together with atoms of nitrogen and carbon to which they are attached, form piperidino ring, optionally substituted hydroxyl group;

R3is hydrogen or lower alkyl, or R2and R3together with the carbon atom to which they are attached, form a 3 - to 7-membered carbocycle, condensed type seroprevalence with piperazinyl ring;

R4is hydrogen or lower alkyl, provided that R2and R3can't form a ring when the ring together form a group R1and R2.

The term "lower alkyl" means an alkyl group with straight or branched chain, containing from one to four carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, terbutyl etc.

Similar 1-piperazine-3-phenylindane, substituted on the carbon atoms piperidino ring and with potential antipsychotic activity, previously described in U.S. patent 4 443 448. It was also discovered that some compounds act as inhibitors bind to. ed. Chem., 1983, Vol. 26, 935-947), which indicate a high affinity to the D2- receptors. Moreover it is reported that the affinity to the receptors of dopamine D1determined by inhibition of binding3H-pegloticase for one of the compounds of this series, namely refludan, significantly weaker than the affinity to the D2, which was assessed by the inhibition of binding of H-spiperone (O. Svendsen et al., Drug. Dev. Res., 1986, Vol. 7, 35-47).

Other 1-piperazine-3-phenylindane described in U.S. patent 4 684 650. It was shown that the compound is a selective 5-HT2antagonists that are inactive or weak antagonists of dopamine in vivo (antagonism towards methylphenidate). Data on the affinity for D2the receptor for this series are reported in the work of K. P. Bgeso et al., J Med. Chem., 1988, Vol. 31, 2247-2256 and as expected, they have a significantly lower affinity to the D2receptors than for 5-HT2the receptors. The affinity to the D1for one of the compounds, irindalone (as measured by the inhibition of binding 3H - SCH 23390), was even less than the affinity to the D2(Hyttel et al., Drug Dev. Res., 1988, Vol. 15, 389-404).

Neojidan the receptors, and that in General they have a greater affinity for D1receptors than for D2the receptors. Moreover, it was shown that they have high affinity for 5-HT2receptors and can cause catalepsy in rats only at relatively high doses.

Above relating to the effect of compounds with a mixture of D1/D2the profile indicates that these compounds are useful as neuroleptic funds in psychosis, including positive symptoms of schizophrenia. Next, antagonistic activity against 5-HT2receptors suggests that the risk of uniparametric effects when using these connection minimum (which is also evidenced by the relatively weak cataleptic effects). Antagonism against 5-HT2and activity as an inhibitor of dopamine uptake indicates that these compounds may have a beneficial effect on negative symptoms of schizophrenia). Thus, it is shown that these compounds are promising antipsychotic means, the likelihood of uniparametric side effects when using them is low. Moreover antagonistic activity against 5-HT2is depressio, sleep disorders, migraine and Parkinson's disease (Parkinson's disease), while inhibition of dopamine uptake, accompanied or not accompanied antagonistic activity towards dopamine, suggests that they may be effective in the treatment of cocaine abuse. Further, the inhibition of dopamine uptake suggests that these compounds may be useful in the treatment of Parkinson's disease and depression.

Only the TRANS derivatives of 1-piperazineethanol formula I are active, and cisisomer not have appreciable activity.

Thus, the aim of the invention are TRANS-isomers, compounds having the General formula I above and their precursors, as well as their pharmaceutically acceptable acid additive salt.

TRANS relative to indenbom ring are in the form of a pair of optical isomers, and these isomers are included in the scope of the claims in this invention. It is now known that the antagonistic activity towards D1(and 5-HT2is primarily a property of one of the optical isomers, while the properties associated with the inhibition of dopamine uptake, Pris is oralny carbon atom. The resulting stereometry also included in the scope of claims of the invention.

Predecessors of medicines according to the invention are, inter alia, esters containing hydroxyl groups. Such esters are decomposed accordingly, highlighting the connection according to the invention in a specific moment in time, when parenteral purpose in the form of compositions in a suitable oil, such as coconut oil, in particular viscoleopeanut oil, sesame oil, cottonseed oil, corn oil, soy oil, olive oil, etc. or synthetic esters of fatty acids and of glycerol or propylene glycol.

Pharmaceutically acceptable acid additive salts of the compounds according to the invention are salts formed non-toxic organic and inorganic acids. Examples of such salts with organic acids are salts of maleic, fumaric, benzoic, ascorbic, monowai, succinic, oxalic, bis-methylanilinium, methansulfonate, ethicolegal, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, almond, cinnamon, tarakanovas, aspartic, STE and theophyllinate acid, and 8-valuevillage, such as 8-bromo-theophylline. Examples of these inorganic salts are the salts of hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

Preferred compounds of formula I are the compounds listed above.

The invention relates also to a method for producing new derivatives of the formula I, which includes

a) interaction of the compounds of the following formula II:

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with piperazine derivatives of the formula III:

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where in the above formulas, the values of X, Y, Ar, R1, R2, R3and R4stated previously and Z represents a halogen atom or a group-OSO2R6in which R6denotes alkyl, such as methyl, or aryl, such as p-tolyl;

(b) coordination compounds of the following formula IV:

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where the value of X, Y, Ar, R2, R3and R4earlier, with a compound of formula R1- Z, in which R1and Z - indicated previously, except that R1cannot be a hydrogen atom, or with an epoxide of the formula where R' denotes a hydrogen atom, methyl, ethyl, ethynyl, cycloalkyl or cycloalkenyl;

c) interaction of the compounds of formula IV with a compound R '-- CHO, where R" denotes timedata the compounds of formula IV with HCHO/HCOOH with the formation of derivatives of the compounds of formula I, in which R1denotes methyl (methylation by Eschweiler-Clarke);

e) recovering the compounds of formula V:

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where the values of X, Y, Ar, R2, R3and R4stated previously, and R' denotes a hydrogen atom, a lower alkoxy group, Cl - C3-alkyl, C2 - C3 - alkenyl, cycloalkyl or cycloalkenyl;

f) recovering the compound of formula VI:

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where the values of X, Y, and Ar are indicated previously, one of the substituents R'1, R'2, R'3and R'4contains one or more ester, ketone or aldehyde groups with a suitable reducing agent with formation of the corresponding compounds containing one or more hydroxyl groups.

The reaction according to method (a) is preferably carried out by boiling under reflux in an inert solvent, such as acetone or methyl-isobutylketone using either an excess of the original piperazine or using equimolar amounts of reactants, in the presence of a carbonate of an alkali metal such as potassium carbonate, or other derivative of an alkali metal.

The reaction according to method (b) is preferably carried out by boiling under reflux in an inert solvent, such as ethanol or methyl-image is knogo metal.

The reaction according to method (c) is preferably carried out in an inert solvent such as an alcohol (particularly methanol) or a simple ether (particularly tetrahydrofuran) by hydrogenation in the presence of a suitable catalyst such as platinum dioxide or palladium, or using a borohydride, such as cyanoborohydride sodium at pH in the range 5-6.

The reaction according to method (d) is preferably carried out in an excess of formaldehyde in formic acid by boiling under reflux.

The reaction according to method (e) is preferably carried out in an inert solvent, such as diethyl ether or tetrahydrofuran, using a suitable reducing agent, such as socialogical.

The reaction according to method (f) is preferably carried out in an inert solvent, such as diethyl ether or tetrahydrofuran, using a suitable reducing agent, such as socialogical or borohydride, in particular sodium borohydride.

Acid additive salts according to the invention is easily obtained by methods known in the art. The Foundation interacts with either the calculated amount of organic or inorganic acid in a solvent, able to mix with water, such that it is unable to mix with water solvent, such as ethyl ether or chloroform, with the desired salt is allocated immediately. These salts can be obtained by classical methods of decomposition of suitable salts.

Separation of the compounds of the formula I into the individual isomers can be accomplished by methods known in the art.

The compounds of formula I can be obtained from the corresponding 2,3-dihydroindol-1-ones by the method similar to the method described in U.S. patent 4 443 448, U.S. patent 4 684 650 and article J. Med. Chem, 1983, Vol. 26, 935-947. Indanone get either by cyclization of the corresponding diphenylpropionic acids, or, more conveniently, as described for the synthesis of similar compounds in U.S. patent 4 873 344 and article J. Org. Chem., 1990, 5 4822, from an appropriately substituted esters of 1-amino-3-cyano-1-inden-2-carboxylic acid, which in turn can be obtained, as described in U.S. patent 4 873 344.

Some piperazine derivatives of the formula III are available on the market (2-methylpiperazine, 2,5-dimethylpiperazine and 2,6-dimethylpiperazine), and other piperazines be made by methods described in the literature: 2-isopropylpiperazine (Beylshtein, 3 and 4 Additions, T. 23, S. 430 and are there links); octahedrite [1,2-a]pyrazin, IIIa (Peck, R. L. the districts in the literature (Granger R. al., Trav. Soc. Pharm. Montpellier, 1965, 25, 313-317), but as 5,8-diazaspiro [3,5] nonan, IIId, were obtained by the method described below for the synthesis of 2,2-dimethylpiperazine and 2,2-diethylpiperazine.

It is obvious that the compounds of formula IV can be obtained by the method (a). Compounds of formulas V and VI can be obtained from the compounds of formula IV by methods known in the art.

The invention is further illustrated by examples, which in no case should not be considered as limiting it.

Example 1 2,2-Dimethylpiperazine.

To a mixture of Isobutyraldehyde (790 g, 10, 95 mol) and dioxane (39.5 g, of 0.45 mol) in dry ether (4 l) at room temperature type II ml of bromine. The mixture is cooled to 5oC with 5-10oC add 509 ml (1588, to 9.93 mol) of bromine. Pour the reaction mixture into 4 l of ice water and with stirring, gradually add sodium carbonate (600 g). The organic phase is separated, dried (over magnesium sulfate) and redistilled, getting 1150 g (69.6 per cent) of 2-bromo-Isobutyraldehyde with so Kip. 70 - 77oC (170 mm RT.cent.).

2-Bromo-Isobutyraldehyde (1070 g, 7,09 mol) is added with vigorous stirring to a mixture of Ethylenediamine (2.2 kg, 36,6 mol) and toluene with 5 - 10oC. the Reaction mixture was stirred PR is th separated, and the lower layer is extracted twice with 500 ml of toluene. The organic extracts are combined and evaporated in vacuo, and the residue is distilled, getting 450 g (56,6 %) of crude 2,2-dimethyl-1,2,5,6 - tetrahydropyrazin with so Kip. 80 - 120oC (170 mm RT.cent.).

To a solution of crude 2,2-demenil-1,2,5,6-tetrahydropyrazin (450 g) in I l of ethanol is added 5% palladium on coal (20 g) and the reaction mixture hydronaut in the Parr apparatus under a pressure of 3.5 at until, until there is no further absorption of hydrogen. After filtering the reaction mixture is distilled at atmospheric pressure. Collect fractions with so Kip. 140 - 180oC, which is again distilled, getting 159 g (19.8 per cent, counting by 2-bromo-Isobutyraldehyde) 2,2-dimethylpiperazine, so Kip. 150 - 170oC (760 mm RT.cent.).

Range PMR (250 MHz, chloroform - d) : 1,12 (singlet, 6H), 1,33 (broadened singlet, 2H, NH), 2,60 (singlet, 2H).

The product solidifies upon standing (so pl. below 35oC).

Similarly receive 2,2-diethylpiperazine and piperazine derivatives IIIa - d.

Example 2.

(+)-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-IH-inden-I-yl] -2,2-dimethylpiperazine, hemifumarate, I.

A mixture of 1,6-dichloro-3-(4-forfinal)-2,3-dihydro-IH-indene (28 g of 0.1 mol), 2,2-dimethylpiperazine (15 g, of 0.13 mol) and potassium carbonate (30 g) in Aut ether and water. The ether layer is separated and extracted with IM methanesulfonic acid. Base distinguish the action of 10M solution of potassium hydroxide, extracted with ether and dried (over magnesium sulfate). After filtration and evaporation in vacuo the residue is dissolved in acetone and treated with fumaric acid. Salt of fumaric acid is filtered off and obtain 27 g of compound I in the form hemifumarate salt so pl. 240 - 241oC. a Sample recrystallized from ethanol, has so pl. 242 - 244oC.

Isomeric purity (TCX): 95% transisomer (racemate).

Elemental analysis:

Calculated %: C 66,25; H 6,30; N 6,72

Found %: C 66,05, H Of 6.49; N 6,44.

Example 3.

(+)-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-IH-inden-I-yl] -1,2,2-trimethylpyrazine, maleate, 2

Mix hemifumarate of compound I (23 g, by 0.055 mol, see example I), 37% formaldehyde solution (100 ml) and formic acid (100 ml). A clear solution is heated on a steam bath for 2 h, and then evaporated in vacuum. The balance in the usual way turn into the base. The base is dissolved in ethyl acetate and treated with maleic acid. Maleate is recrystallized from ethyl acetate and obtain 13.5 g (50%) of compound 2 in the form of maleate with so pl. 143 - 156oC.

Some the CLASS="ptx2">

Found, %: C 63,77; H 6,27; N 5,65.

The methods described in examples 2 and 3 (N-methyl derivative), is used to produce the following compounds:

(+)-TRANS-4-[3-phenyl-2,3-dihydro-IH-inden-I-yl] -1,2,2-trimethylpyrazine, dioleate; so pl. 162 - 165oC.

Connection 3.

(+)-TRANS-2,2-dimethyl-4-[6-methyl-3-(4-forfinal) -2,3-dihydro-IH-inden-I-yl] piperazine; so pl. 108 - 110oC.

Connection 4.

(+)-TRANS-4-[6-methyl-3-(4-forfinal)-2,3-dihydro-IH-inden-I-yl] -1,2,2-trimethylpyrazine; so pl. 119 - 121oC. Connection 5.

(+)-TRANS-2,2-dimethyl-4-[trifloromethyl-3-(4-forfinal)-2,3-dihydro-IH-inden-I-yl]piperazine; so pl. 94 - 95oC. Connection 6.

(+)-TRANS-4-[6-trifluoromethyl-3-(4-forfinal)-2,3-dihydro-IH-inden-I-yl] -1,2,2-trimethylpyrazine; so pl. 112 - 114oC. Connection 7.

(+)-TRANS-4-[6-bromo-3-(4-forfinal)-2,3-dihydro-IH-inden-I-yl] -1,2,2-trimethylpyrazine, 1.5 fumarate; so pl. 142 - 145oC. Connection 8.

()-TRANS-4-[5,6-dichloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -1,2,2-trimethylpyrazine, 1.5 fumarate;

so pl. 182 - 184oC. Connection 9.

()-TRANS-4-[6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl] -1,2,2, -trimethylpyrazine, 1.5 maleate; so pl. 170 - 171oC. Connection 10.

()-TRANS-4-[6-chloro-3-(2-

()-TRANS-4-[6-chloro-3(3-forfinal)-2,3-dihydro-1H-inden-1-yl] -1,2,2-trimethylpyrazine, demolet; so pl. 140 - 142oC. Connection 12.

()-TRANS-4-[6-chloro-3-(3-thienyl)-2,3-dihydro-1H-inden-1-yl] -2,2-dimethylpiperazine, demolet; so pl. 163 - 165oC. Connection 13.

()-TRANS-4-[6-chloro-3-(3-thienyl)-2,3-dihydro-1H-inden-1-yl] -1,2,2-trimethylpyrazine, dihydrochloride ; so pl. 173 - 176oC. Connection 14.

()-TRANS-4-[4-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -1,2,2-trimethylpyrazine, dioxalate; so pl. 120 - 125oC. Connection 15.

()-TRANS-4-[5-chloro-3-(4-forfinal)-2,3--dihydro-1H-inden-1-yl] -1,2,2-trimethylpyrazine; so pl. 126 - 128oC. Connection 16.

()-TRANS-4-[7-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -1,2,2-trimethylpyrazine; 1,3-oxalate; so pl. 153 - 155oC. Connection 17.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl]- 1,2-dimethylpiperazine, demolet; so pl. 181 - 183oC. Connection 18.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -2-(2-propyl)piperazine, demolet; so pl. 135 - 137oC. 1 Pair of diastereoisomeric TRANS. Connection 19.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -2-(2-propyl)piperazine, maleate; so pl. 156 - 159oC. a Pair of 2 diastereoisomeric TRANS. With the eat; so pl. 119 - 122oC. 1 Pair of diastereoisomeric TRANS. Connection 21.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -1-methyl-2-(2-propyl)piperazine, demolet; so pl. 160 - 162oC. 1 Pair of diastereoisomeric TRANS. The connection 22.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H - inden-1-yl] -2,2-diethylpiperazine, fumarate; so pl. 231 - 233oC. Connection 23.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1 - yl] -2,2-diethyl-1-methylpiperazin, oxalate; so pl. 144 - 146oC. Connection 24.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H - inden-1-yl]-(1-TRANS-2,5-trimethyl)piperazine, maleate; so pl. 166 - 169oC. Connection 25.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -(1-CIS-2,6-trimethyl)piperazine, dioxalate; so pl. 158 - 160oC. Connection 26.

()-TRANS-4-[6-trifluoromethyl-3-(4-forfinal)-2,3-dihydro - 1H-inden-1-yl] -CIS-2,6-dimethylpiperazine, dihydrochloride; so pl. 255 - 260oC. Connection 27.

()-TRANS-8-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H - inden-1-yl]-5-methyl-5,8-diazaspiro[3,5] nonan, dihydrochloride; so pl. 188 - 190oC. connection 28.

()-TRANS-9-[6-chloro-3-(4-forfinal)2,3-dihydro-1H-inden - 1-yl] -6-methyl-6,9-diazaspiro[4,5]decane, fumarate; so pl. 144 - 147oC. Connection 29.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -1,4-diazaspiro[5,5]undecane, fumarate; so pl. 241 - 243oC. Connection 31.

()-TRANS-4-[6-chloro-3-(4-forfinal)2,3-dihydro-1H-inden-1-yl] -1-methyl-1,4-diazaspiro[5,5]undecane, dihydrochloride; so pl. 205 - 207oC. Connection 32.

2-[6-fluoro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] octahedrite[1,2-a] pyrazin, dihydrochloride; so pl. 225 - 227oC. a Mixture of 1:1 CIS - and TRANS-isomers. The connection 33.

()-TRANS-2-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl]- octahedrite[1,2-a]pyrazin, demolet; so pl. 172 and 174oC. Connection 34.

2-[6-Fluoro-3-(4-Forfinal)-2,3-dihydro-1H-inden-1-yl] -octahedrite [1,2-a]pyrazin-8-ol, hydrochloride; so pl. 223 - 225oC. a Mixture of 1:1 CIS - and TRANS-isomers. Connection 35.

()-TRANS-4-[7-fluoro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -1,2,2 - trimethylpyrazine, oxalate; so pl. 133 - 135oC. Connection 36.

()-TRANS-4-[3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -1,2.2 - trimethylpyrazine, demolet; so pl. 135 - 137oC. Connection 37.

()-TRANS-4-[6-fluoro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -1,2,2 - trimethylpyrazine, demolet; so pl. 154 - 156oC. Connection 38.

Example 4.

()-TRANS-4-[6-fluoro-3-(4-forfang, of 0.017 mol), 3-chloro-1-propanol (1.9 grams, at 0.020 mol) and potassium carbonate (3 g, 0,021 mol) in ethanol (250 ml), left overnight to boil under reflux. The selection of the target product from the reaction mixture were carried out as described in example 2 and get 6 g of crude base. The base is converted into the ethyl acetate salt of maleic acid and recrystallized twice from a mixture of aceton-ether, obtaining 2.5 g of the maleate of compound 39 with so pl. 177 - 178oC.

Isomeric purity (TLC): 92% transisomer (racemate).

Elemental analysis:

Calculated,%: C 63,08; H 6,44; N 5,26.

Found,%; C 63,28; H X 6.15; N 5,62.

The methodology described in example 4 is used for the following connections:

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -2,2 - dimethyl-1-(2-propyl)piperazine, dioxalate; so pl. 157 - 159oC. Connection 40.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -2-methyl-1-(2-propyl)piperazine, demolet; so pl. 89 - 92oC. Connection 41.

()-TRANS-9-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -6- (2-propyl)-6,9-diazaspiro[4,5]decane, dihydrochloride; so pl. 227 - 238oC. Connection 42.

Example 5.

()-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -2,2-dimethyl-1-piperazinecarboxamide potassium (3 g, 0,021 mol) in methyl-isobutylketone refluxed for 4 hours, the Reaction mixture was evaporated in vacuo to add ether and water. The ether layer is separated, dried (over magnesium sulfate) and evaporated, receiving 7 g of crude ester. The ether is dissolved in dry ether, add socialogical (2 g) and boil the mixture under reflux for 3 hours the Excess lydialydia decompose water, the organic layer is separated by decantation and the product is extracted from the ether phase through IN solution methansulfonate. Base distinguish the action of 10N sodium hydroxide solution, extracted with ether, dried and evaporated in vacuum. The base is recrystallized from petroleum ether, obtaining 1.1 g of product with so pl. 79 - 81oC.

Isomeric purity (TLC): 99% transisomer (racemate).

Elemental analysis:

Calculated,%: C 68,55; H 7,02; N 6,95.

Found,%; C 68,77; H 7,32; N Is 6.78.

The methodology described in example 5 is used for the following connections:

()-TRANS-9-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl]-6-(2 - hydroxyethyl)-6,9-diazaspiro[4,5] decane, dihydrochloride; so pl. 167 - 169oC. Connection 44.

()-TRANS-4-[6-chloro-3-(3-thienyl)-2,3-dihydro-1H-inden-1-yl]-2,2 - dimethyl-1-piperazino the hydro-1H-inden-1-yl]-1,2,2-trimethylpyrazine, maleate, (+)-2 and (-)-2.

To a solution of compound 2 (base, 70 g, 0,187 mol) in 1 l of ethyl acetate add hydrate (+)-O, O'-Dibenzoyl-D-tartaric acid ( (+)- DBT, 70,6 g, 0,189 mol). The obtained clear solution is left overnight at room temperature. The crude salt (+) - DBT filtered off, dried (yield 53 g) and recrystallized from a mixture of ethyl acetate-methanol. Salt (+)-DBT (so pl. 123 - 128oC) turn into the base, which was dissolved in acetone and converted into the hydrochloride. Output dihydrochloride (-)-2 is 13 grams, so pl. 201 - 202oC; []2D2- 23,4o(C = 0,5, MeOH).

The first filtrate from the salts of (+)-DBT evaporated in vacuum and transferred to the base (38 g), which was dissolved in ethyl acetate and treated with hydrate of (-)-DBT (38,3 g), getting salt of (-)-DBT. It is transformed into the hydrochloride analogously to (-)-enantiomer. Output dihydrochloride (+)-2 is 14.8 g, so pl. 206 - 208oC; []2D2+24,5o(C = 0,5, MeOH).

Elemental analysis:

Calculated,%: C 59,26; H 6,34; N 6,28.

Found,%: C 59,33; H 6,64; N 6,46 ((-)-2-)

Found,%: C 59,05; H 6,47; N 6,04 ((+)-2).

Connection 29, 37, 40 and 44 separated into their enantiomers using a methodology similar to that shown in example 6:

(-)-TRANS-9-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-Jn (s = 1, DMF). Connection (-)-29.

(+)-TRANS-9-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -6-methyl-6,9-diazaspiro [4,5] decane, dihydrochloride; so pl. 205 - 207oC; []2D2+10,5o(C = 1, DMF). Connection (+)-29.

(-)-TRANS-4-[3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -1,2,2-trimethylpyrazine, demolet; so pl. 197 - 199oC; []2D2-2,7o(C = 0,5, MeOH). Connection (-)-37,

(+)-TRANS-4-[3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -1,2,2-trimethylpyrazine, demolet; so pl. 198 - 199oC; []2D2+2,5o(C = 0,5, MeOH). Connection (+)-37.

(-)-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -2,2-dimethyl-1-(2-propyl)piperazine, dioxalate; so pl. 169 - 171oC; []2D2-18,4o(C = 1, MeOH). Connection (-)-40.

(+)-TRANS-4-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -2,2-dimethyl-1-(2-propyl)piperazine, dioxalate; so pl. 171 - 172oC; []2D2+18,2o(C = 1, MeOH), Connection (+)-40.

(-)-TRANS-9-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -6-(2-hydroxyethyl)-6,9-diazaspiro [4,5] - decane, dihydrochloride; so pl. 197 - 199oC; []2D2-10,2o(C = 1, MeOH). Connection (-)-44.

(+)-TRANS-9-[6-chloro-3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl] -6-(2-hydroxic inania (+)-44.

Pharmacology

These compounds were tested following well-known and reliable pharmacological tests.

Study of the binding of the receptor

Receptors of dopamine D1. Study of the inhibition of binding3H-SCH 23390 with receptors of dopamine D1in veins membranes of rats were carried out as described in Hyttel, J and Arnt, J/ J/ Neurol Transm., 1987, Vol. 68, 171.

Receptors of dopamine D2. Study of the inhibition of binding3H-spiperone with receptors of dopamine D2in veins membranes of rats were carried out as described in Hyttel, J. Acta. Pharmacol. Toxicol., 1986, Vol. 59, 387.

Receptors 5-HT2. Study of the inhibition of binding3H-ketanserina with receptors 5-HT2in membranes derived from the cortical substance of rats were carried out as described in Hyttel, J. Acta. Pharmacol. Toxicol., 1987, Vol. 61, 126.

Data affinity to receptors D1D2and 5-HT2compounds described in the examples presented in the table. For comparison, the data for reference compounds chelodina, irindalone and clozapine.

The results presented in the table show that the compounds in General have a very high tool for receptor D12significantly weaker. For this reason, the relation of D1/D2above, and in some cases significantly higher than clozapine, taken as reference compounds. Moreover, the compounds have affinity to the receptors 5-HT2and the data is provided for optically split compounds, show that this tool basically has one enantiomer.

Inhibition of dopamine uptake

Study of the inhibition of dopamine uptake in vitro lead as described in K. P. Bages, J. Med. Chem., 1983, Vol 26, 935 - 947.

For racemic compounds of magnitude 1C50to inhibit the uptake of dopamine, as a rule, are < 1 mkmol. Some compounds active in the low nanomolar range. So, the values of 1C50be 16 nm (compound (+)-2), 14 nm (compound 10), 36 nm (compound 37) and 9 nm (compound 38); for the corresponding described in the literature compounds with unsubstituted piperazinyl ring size 1C50is 180 nm, see K. P. , J. Med. Chem., 1983, Vol. 26, 935 - 947). To split the connection property of suppressing the inhibition of dopamine uptake mainly attributable to the enantiomer, opposite to that which is active in the above F 38393 cyclic behavior in rats with unilateral lesion 6-OHDA

This test is similar to test the inhibitory effect on receptor dopamine D1in vivo

The experiments were carried out as described in J. Arnt and J. Hyttel, J. Neural. Transm. , 1986, Vol. 67, 225 - 240. Tests carried out after 2 to 9 months after injury, when detected sustainable opposite cyclic feedback on the action hydrochloride 2,3,4,5-tetrahydro-7,6-dihydroxy-1-phenyl-1H-3 - benzazepine (SK&F 38393) (4,3 mmol/kg = 1.4 mg/kg). Compound is administered by injection for 2 hours before the administration of SK&F 38393. Antagonistic effect for each rat assessed as the percentage of inhibition of the control response. For each dose use from four to eight animals.

1. Derivatives of TRANS-isomers of 1-piperazine-1,2-dihydroindeno General formula

< / BR>
where X is hydrogen, halogen, trifluoromethyl, lower alkyl or nitro-group;

Y is hydrogen or halogen;

Ar is phenyl, unsubstituted or substituted by halogen, or titillation;

R1is hydrogen, lower alkyl, lower alkyl substituted by hydroxyl;

R2- lower alkyl, or R1and R2together with atoms of nitrogen and carbon to which they are attached, form piperidino ring, optionally substituted hydroxyl GI attached, form a 3 - to 7-membered carbocycle, condensed type seroprevalence with piperazinyl ring;

R4is hydrogen or lower alkyl, provided that R2and R3can't form a ring when the ring together form the group R1and R2.

2. Connection on p. 1, wherein X is hydrogen, halogen, lower alkyl, trifluoromethyl or nitro-group, Y is hydrogen, halogen, Ar is phenyl, unsubstituted or substituted by halogen, or thienyl, R1is hydrogen, lower alkyl or lower alkyl substituted by hydroxyl, R2- lower alkyl, or R1and R2together with atoms of nitrogen and carbon to which they are attached, form piperidino ring, optionally substituted hydroxyl group, R3is hydrogen or lower alkyl, or R2and R3together with the carbon atom to which they are attached, form a 3 - to 7-membered carbocycle, condensed type seroprevalence with piperazinone ring, R4is hydrogen or methyl.

3. Connection on p. 1, wherein X is a hydrogen atom, chlorine atom, bromine atom, fluorine atom, methyl, trifluoromethyl or nitro-group, Y is hydrogen, Ar is phenyl, forfinal or thienyl, R1is a hydrogen atom, marked methyl, or R2and R3together with the carbon atom to which they are attached, form spiroloculina or spirocyclopentane ring, and R4- hydrogen.

 

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