Dimeric compounds 4-phenylpiperidine, 4-phenyl-1,2,3,6 - tetrahydropyridine or 4-phenylpiperazine or dimeric compounds spirocycles of piperidino and pharmaceutical composition

 

(57) Abstract:

The proposed dimer compounds 4-phenylpiperidine, 4-phenyl-1,2,3,6-tetrahydropyridine or 4-phenylpiperazine or dimers spirocycles piperidine derivatives of General formula (I), where n has values from 1 to 5; R1-R4represent hydrogen, halogen, trifluoromethyl, C1-6-alkyl; R5and R6each represent hydrogen or are linked together form an ethylene bridge; X is O, S, SO2, CO or (CH2)mwhere m is 0 or 1, or X represents NR7where R7represents C1-6alkyl, cycloalkyl, phenyl, or X is CR8R9where R8and R9chosen from hydroxyl, or optionally substituted by halogen atom phenyl and (1) Z1is a hydrogen atom, and Z2represents (CH2)p, where p = 0; Y represents N, C or CH and the dotted line indicates an optional bond, i.e., if Y = C, represents the relationship; (2) Z1and Y are linked together by a simple relationship, forming spirocyclic structure, and in this case, Y is C and the dotted line indicates the lack of communication, Z1represents O, S, (CH2)gwhere q = 1, 2, or 3, or Z1is CH2O, CH2S, CH2CH2O, THE2)p, where p = 0 or 1, which have the ability to be used as ligands of Sigma receptors. The pharmaceutical composition, the binding of Sigma receptors. 3 S. and 7 C.p. f-crystals, 1 PL.

The invention relates to a derivative of a new class of dimers of the piperidine, 1,2,3,6-tetrahydropyridine and piperazine where the nitrogen atoms of the basic six-membered rings connected by a spatial chain with the formation of symmetric dimeric bis/1-piperidyl/, bis/1,2,3,6-tetrahydro-1-pyridyl/ or bis/1-piperazinil/ connections. These dimers effectively communicate with Sigma receptors and therefore can be used in the treatment of certain physical and neurological disorders.

Piperidine, 1,2,3,6-tetrahydropyridine or piperazines substituted 4-phenyl groups or derivatives of piperidine may be Spiro-structure in position 4 to hetero - or carbocyclic ring system.

Were described derivatives of 4-phenylpiperidine, 4-phenyl-1,2,3,6-tetrahydropyridine, 4-phenylpiperazine and spirocycles of piperidine.

In the international patent application N WO 91/09594 there is a General description of a wide class of ligands of Sigma receptor, some of which are soedineniya - alkyl, -alkenyl, quinil-alkoxyl or-alkoxyalkyl, which, in turn, can be substituted.

The terms "aryl" or "heteroaryl" is defined by enumerating the number of such substituents.

In European patent publication N EP 0414289 A1 disclosed a class of derivatives of 1,2,3,4-tetrahydro-Spiro (naphthalene-1,4'-piperidine) and 1,4-dihydro-Spiro(naphthalene-1,4'-piperidine), substituted on the N atom of the piperidine "hydrocarbon" group, about which we know that it has a selective antagonistic activity towards the Sigma receptor. The term "hydrocarbon" in this patent includes all possible linear, branched, cyclic, heterocyclic, etc. groups. However, the specifically disclosed only connection with such "hydrocarbon" substituents at the nitrogen atom of the piperidine as benzyl, phenetyl, cycloalkylation, furyl - or thienylmethyl or lower alkyl or alkenyl.

Indicated that these compounds displace labeled with tritium ditolyl-guanidine (DTG) Sigma-sites with higher efficiency than 200 nm.

As the most preferred compounds specified 1'-benzyl-1,2,3,4-tetrahydro-Spiro(naphthalene-1,4'-piperidine).

In European patent publication N EP 0445974 A2 described with Asano, these compounds replace the tritium-labeled detailhandel (DTG) Sigma-sites with efficiency higher than 200 nm.

EP application N EP-A2-0431943 applies to a wider class of spiroperidol, substituted on the nitrogen atom of the piperidine, and stated that they are suitable for use as antiarrhythmic agents and to improve krovoobrasheniya function of the heart. In this application example shows several compounds, most of which contain oxo - and/or sulfonylamino-substituents in spiritlessly ring system.

The rest of the compounds contains another polar Deputy attached to the Spiro-core and/or they have some polar substituents on the nitrogen atom of the piperidine.

Not given any instructions on the action of these compounds on Sigma receptors.

Based on the research of the biology and function of Sigma receptors presents evidence that the ligands of Sigma receptors may be useful in the treatment of psychosis and movement disorders like dystonia and retarded dyskinesia, disorders of motility-related chorea Huntington or syndrome Tourette, and Parkinson's disease (Walker, J. M. et al. Pharmac is such trials in the treatment of psychosis (Snyder, S. H. Largent, B. Z. J. Neuropsychiatry, 1989, 1, 7) and that the group of ligands of Sigma receptors demonstrates antipollution activity in model experiments on animals (international patent publication N WO 9103243). Moreover, it was found that some of the ligands of Sigma receptors included in the modulation of processes, including NMDA receptors in the brain and act as anti-ischemic agents in tests in vivo (Rao, T. S. et al. Molecular Pharmacology, 1990, 37, 978 and Pao T. S., et al. Life Sciences, 1990, 47, PLI-PK5).

In addition to ischemia can be used in the treatment of other diseases such as epilepsy and convulsions.

In addition, as was found, some ligands of Sigma receptor demonstrate anti-amnesiascope action in model experiments on animals (Early et al. Brain Research 1991, 546, 281-286).

As shown, the Sigma ligands affect Central levels of acetylcholine in animal experiments (Matsuno et al., Brain Researh, 1992, 575, 315-319; Junien et al. Eur. J. Pharm., 1991, 200, 343-345) and therefore may be effective in the treatment of senile dementia, for example, A type of Alzheimer's disease.

Finally, some guanidine derivatives having activity towards the Sigma receptor, can be used as anxiolytics (international patent pulsetrain nervous system, can be useful in the treatment of such conditions.

It was found that the compounds of a new class of dimers of the piperidine, 1,2,3,6-tetrahydropyridine and piperazine are effective ligands of Sigma receptors.

In the present invention proposed new derivatives of dimers of 4-phenylpiperidine, 4-phenyl-1,2,3,6-tetrahydropyridine or 4-phenylpiperazine or dimers spirocycles piperidine derivatives of General formula I:

< / BR>
where n has a value from 1 to 5;

R1- R4independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, lower alkylthio, lower alkylsulfonyl, lower alkyl or dialkylamino, cyano, trifloromethyl, nitro; triptoreline or tripterocalyx;

R5and R6independently represent hydrogen, lower alkyl, or may be linked together to form ethylene or propylene bridge.

X represents O, S, SO, SO2, CO or (CH2)mwhere m = 0 or 1;

X is NR7where R7means H, lower alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl, or X is CR8R9TO8and R9independently selected from the group consisting of hydroxyl and substituents defined for R1-R4and Z2means (CH2)pwhere p = 0; and Y represents N, CH or C; and the dotted line indicates an optional bond, that is, means of communication, if Y means C; or

2) Z1and Y are linked together by a simple relationship, forming spirocyclic structure; and in this case Y means C, and the dotted line does not mean communication; and

Z1means O, S, (CH2)qand q = 1,2 or 3, or

Z1means CH2O, CH2S, CH2CH2O, CH2CH2S, CH=CH, CH=CHCH2CH2OCH2CH2SCH2CH=CH-O or CH=CH-S; and

Z2means O, S, or (CH2)pwhere p = 0 or 1, provided that Z1may not be O, S or (CH2)qwhere q = 1, where Z2means (CH2)pwhere p = 0;

or their salts accession acids or their predecessors dosage forms.

Some compounds of General formula I can exist as optical isomers; and the optical isomers are also included within the scope of the invention.

Definitions of General formula I, halogen means fluorine, chlorine, bromine or iodine.

The terms "lower alkyl", "lower alkoxy", "lower alkylthio" and "lower alkylsulfonyl", etc. denote a branched or unbranched group, with the l, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, methylthio, ethylthio, 1 propylthio, 2-propylthio, methylsulphonyl, ethylsulfonyl or etc. Similarly, the terms "lower alkyl or dialkylamino" refers to the group containing the previously defined lower alkyl, and "lower alkenyl" refers to alkenylphenol group (branched or unbranched, containing from two to six carbon atoms, such as ethynyl, 1-propenyl, 2-propenyl, 3-propenyl, 2-butyl-1-yl, etc.

The term "cycloalkyl" refers to cyclic hydrocarbon containing 3-8 carbon atoms, inclusive.

Optional substituents at the phenyl groups can be independently selected from halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkyl or dialkylamino, cyano, trifloromethyl or triptoreline.

Each phenyl group may have one or more substituents.

In the definition of the Z1listed in paragraph (2) group can be oriented in both directions, that is, for example, a group of CH2O may be associated with a "y"-a group or through a C atom or via an atom O.

Salt accession acids of this AI with non-toxic acids. Examples of such organic salts can serve as salts of maleic, fumaric, benzoic, ascorbic, monowai (embonic), succinic, oxalic, bis-methylanilinium, methansulfonate, ethicolegal, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, almond, cinnamon, tarakanovas, aspartic, stearic, palmitic, takenaway, glycolic, p-aminobenzoic, glutamic acid, benzosulfimide and theophyllinate acid, and salt of 8-halodefinitely acid, for example, 8-Romeoville. Examples of inorganic acids can serve as hydrochloric, Hydrobromic, sulfuric, sulfamine, phosphoric and nitric acid.

It was found that the compounds of the present invention are potential ligands of Sigma receptors, replacing labeled with tritium di-tolylguanidine (DTG) for Sigma sites in vitro with high efficiency, for example, for many compounds with IR50values below 1 nm. Moreover, it was shown that many of the compounds of the present invention are highly selective ligands for Sigma receptors. For example, it was found that in relation to1the adrenergic receptors and receptors for dopamine D-2) is>Sigma and 5-HT2/Sigma, respectively) are 100 -> 1000.

Compounds of the present invention have the added advantage that their salts are easily dissolved in water.

In addition, due to the fact that they are symmetric dimers of these compounds there are certain benefits.

The dimers of the piperidine, 1,2,3,6-tetrahydropyridine and piperazine of the present invention is suitable for treatment of the occupation, psychosis, seizures, epilepsy, movement disorders, disorders of motor functions, amnesia, vascular diseases of the brain, senile dementia, for example Alzheimer's type and Parkinson's disease.

One preferred subgroup of the compounds of the present invention includes compounds of formula 1 where Z1and Z2not connected together, and Z2represents (CH2)p, where p = 0, i.e., compounds 4-phenyl-piperidine-1,2,3,6-tetrahydropyridine-piperazine.

Another preferred group includes the compounds of formula 1 in which Z1and Y are linked together, forming spirocyclic system. Preferred meanings of the following formula 1:

n = 1, 2, or 3;

X represents (CH2)mwhere miles X is S, On or CR8R9where R8means hydroxyl or optionally substituted phenyl, and R9means hydrogen:

R2-R4independently selected from hydrogen, halogen, lower alkyl and trifloromethyl;

R5and R6means hydrogen;

and if Z1and Y are connected to each other to form spiritlessly system, Z1means (CH2)qwhere q = 1, 2, or 3, CH2O, (CH2)2O, CH=CH, O, S, or CH2S; and

Z2means (CH2)pwhere p = 0 or 1, or Acting

The most preferred spropertyname formula 1 are those in which Z2means (CH2)pwhere p = 0, Z1means (CH2)qwhere q = 1, 2, or 3, CH2O, (CH2)2O, CH = CH, O, S, or CH2S, especially CH2O, CH2S or (CH2)2O.

The most preferred compounds are:

1,4-bis[Spiro[isobenzofuran-1-(3H),4'-piperidine]-1'-yl]butene;

1,4-bis[4-(4-forfinal)piperidine-1-yl]butane;

1,4-bis[4-(4-forfinal)piperazine-1-yl]butane;

1,6-bis[Spiro[isobenzofuran-1-(3H), 4'-piperidine]-1'-yl]hexane;

1,4-bis[6-fluoro-Spiro[isobenzofuran-1(3H), 4'-piperidine]-1'- yl]-butane;

1,5-bis[Spiro[isobenzofuran-1(3H),4'-piperidine]-1'-yl]PE is -1'-yl]butane;

1,4-bis[Spiro[1-benzopyran-4,4'-piperidine)-1'-yl]butane;

1,3-bis[Spiro/isobenzofuran-1(3H),4'-piperidin[-1'-yl]propane;

1,3-bis[4-(4-forfinal)piperidine-1-yl]propane;

1,2-bis[Spiro/isobenzofuran-1(3H),4'-piperidine]-1'-yl]ethane;

1,2-bis[4-(4-forfinal)piperidine-1-yl]ethane;

N,N-bis[2-Spiro[isobenzofuran-1(3H),4'-piperidine]-1'-yl]ethyl/ N-cyclopentylamine;

1,4-bis[4-(4-forfinal)-1,2,3,6-tetrahydropyridine-1-yl]butane;

N,N-bis[2-[4-(4-forfinal)piperidine-1-yl]ethyl]aniline;

1,5-bis[Spiro[isobenzofuran-1(3H), 4'-piperidine] -1'-yl] -3- (4-forfinal)pentan;

Bis[2-Spiro[isobenzofuran-1(3H), 4'-piperidine] -1'-ileti]sulfide difumarat.

Another object of the present invention relates to pharmaceutical compositions containing an effective amount of at least one new derived dimer of the piperidine, 1,2,3,6-tetrahydropyridine for piperazine above formula I, or its pharmaceutically acceptable salt accession acid, or its predecessor dosage forms in combination with one or more pharmaceutically acceptable carriers or diluents.

The pharmaceutical compositions of the present invention can be used in any suitable way, for example, orally in the form of t is for drinking, preparing such compositions can be used known in the art methods, and any pharmaceutically acceptable carriers, diluents, excipients or other additives known in the art.

Typically, compounds of the present invention is administered in unit dosage forms containing the specified compound in an amount of from about 0.01 to 50 mg

Full daily dose usually ranges from about 0.05 to 100 mg, preferably from about 0.1 to 50 mg of active compound of the invention.

Thus, according to the invention using derivatives of dimers of the piperidine, 1,2,3,6-tetrahydropyridine and piperazine above formula 1 or their salts accession acids or precursors of drugs for the preparation of pharmaceutical preparations for the treatment of anxiety, psychosis, epilepsy, convulsion, movement disorders, disorders of motor functions, amnesia, vascular diseases of the brain, senile dementia type Alzheimer's or Parkinson's disease.

Musculoskeletal disorders or motility disorders that can be treated with drugs with the use of compounds of the present invention include dystonia and slower dyskinesia and motility disorders associated with chorea Huntington or syndrome Tourette. Dystonia may be acute or long and can be caused by neurolaeninae, caused by cerebral infarction, cerebral bleeding, cerebral atherosclerosis, subarachnoid hemorrhage, cerebral thrombus, cerebral embolism, or so forth, for example, ischemia.

The compounds of formula I can be obtained:

a) restoration of the amide carbonyl groups of the compounds of formula II

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where n is from 0 to 4, X, Y, R1-R6, Z1, Z2and the dotted line have the above meanings;

b) restoration of the amide carbonyl groups of the compounds of formula III:

< / BR>
where n' is n-1 and n, X, Y, R1-R6, Z1, Z2and the dotted line have the above meanings;

the alkylation of compounds of formula IV:

< / BR>
where Y, R1-R6, Z1, Z2and the dotted line have the above significance,

the epichlorohydrin or alkylating agent of formula Y:

A - (CH2)n- X - (CH2)n- A (V)

where X and n have the previously indicated meanings, and A suitable means tsepliaeva group, for example halogen, mesilate or toilet:

g) recovering the alkylation of an amine of the formula IV a dialdehyde of the formula VI or a carboxylic acid of formula VII

OHC - (CH2)n'- X - (CH2)n'- CHO, (VI; or

d) recovery of double bonds in the compound of formula 1 to obtain the corresponding saturated compounds of formula 1. Such double bonds are present, if the dotted line represents the relationship and/or if Z1and Y are linked together to form spirobiindane and Z1means a double bond, then the resulting compound of formula 1 is isolated in the form of free base or its pharmaceutically acceptable salt.

Restoration by the method (a) can preferably conducted in an inert solvent, such as diethyl ether or tetrahydrofuran, thereby regenerating agent, as, for example, sociallyengaged, ia I3or DIBORANE at an appropriate temperature (usually from room temperature up to the boiling temperature under reflux). The restoration of the amides according to the method b) perform similarly.

The alkylation of compounds of formula IV according to the way in) convenient to make such an inert organic solvent, such as alcohol or ketone with a suitable boiling point, preferably in the presence of a base (potassium carbonate or triethylamine) at the boiling point under reflux. The epichlorohydrin is the preferred re the de n=1; and X is CHOH.

Reductive alkylation according to method d) carry out the standard literature methods. Aldehydes VI and carboxylic acid VII are either commercially available, or get them in standard ways.

Restoration of double bonds according to the method d) is usually carried out by catalytic hydrogenation using catalysts of Pd and Pt in proton solvents, such as ethanol or methanol in acidic conditions.

Alkylating reagents Y either commercially available or they can be well-known methods, or by oxidizing the corresponding alcohols, or restoring carboxylic acid or their respective derivatives.

The diamines of formula II is conveniently receive the processing of 1-unsubstituted derivatives IV so appropriate derived activated dicarboxylic acid as the corresponding chlorides or anhydrides of carboxylic acids by known methods.

Derivatives of carboxylic acids are either commercially available or can be obtained by standard methods.

Intermediate mono-amides III similarly receive as a result of interaction Alojamientos carboxylic acid via its activated the stage: first interacting portion of the activated acid with one mol of the compounds IV, and then by the interaction of the halide portion of stereography with another moth IV. These reactions lead to the standard conditions of acylation/alkylation.

4-phenylpiperidine formula IV (Y = C, and the dotted line indicates the absence of a relationship) either commercially available or obtained by the method of U.S. patent 2891066; McElvain et al. J. Amer. Chem. Soc., 1950, 72, 3134; Bally et al. Chem. Ber., 1987, 20. The corresponding 4-phenyl-1,2,3,6-tetrahydropyridine formula IV (Y = C, and the dotted line represents an additional bond) is obtained from N-protected 4-piperidinol, by adding an appropriately substituted finality or fenermine-halides with the subsequent removal of water, acid catalyzed. N-protective group of carbamate, benzyl, sulfonyl, acetyl) at the end is removed in the usual way.

Derivatives of 3-phenyl-8-azabicyclo[3,2,1] Oct-2-ene receive appropriately N-protected 8-azabicyclo[3,2,1]Octan-3-ones. 4-phenylpiperidine also conveniently be obtained by the catalytic hydrogenation of the corresponding 4-phenyl-1,2,3,6-tetrahydropyridine using Pt catalyst.

4-phenylpiperazine formula IV (Y = N, and the dotted line indicates the absence of a relationship) either commercially available or obtainable according to the method of Martin et al. J. Med. Chem. , 1989, 32, 1052-1056. Ethyl) - amine (sometimes N-protected) by boiling under reflux in a high boiling solvent, for example, chloro-benzene, usually within a few days (2-3), sometimes with the subsequent removal of the protection (if there was N-protected group) in the usual way.

Derivatives spirobiindane formula IV where Z1and Y are linked together, and Y represents a carbon atom, obtained as follows:

Spiro[isobenzofuran-1-/3H/, 4'-piperidine] according to the method described by Marxer et al. J. Org. Chem. 1975, 40, 1427.

Accordingly receive Spiro[isobenzofuran-1-(3H), 3'-8'-azabicyclo-[3', 2',1']octane N-methyl-8-azabicyclo[3,2,1]Octan-3-ones; 2,3-dihydro-Spiro[1H-inden-1,4'-piperidine and 3,4-dihydro-speronato-1-(2H), 4'-piperidine] get modifying the method of J. Med. Chem., 1992, 35/11/, 2033-2039 and French patent N 1335831;

1'-methyl-Spiro[benzo[c] thiophene-1(3H), 4'-piperidine] get in the way Parham et al., J. Org. Chem/., 1975, 41, 2628. Appropriate demetilirovanie derived receiving, processing etelcharge.com with subsequent alkaline hydrolysis of the intermediate ethylcarbamate.

1'-phenylmethyl-Spiro[1H-2-benzopyran-4(3H), 4'-piperidine] get in the way Jamamoto et al. J. Med. Chem., 1981, 24, 194. Appropriate dibenzylamino get derived by hydrogenation in the presence of a palladium catalyst; 3,4-dihydro-1'-phenylmethyl-Spiro[2H-2-benzop the Pharm. Bull., 1981, 23, 3494. Appropriate dibenzylamino get derived by processing etelcharge.com with subsequent alkaline hydrolysis of the intermediate ethylcarbamate;

1'-phenylmethyl-Spiro[2H-1-benzopyran-2,4'-piperidine] get in the way Jamamoto et al. Chem. Pharm. Bull., 1981, 29, 3494. Appropriate dibenzylamino get derived by hydrogenation in the presence of a palladium catalyst;

1'-phenylmethyl-Spiro[3H-2-benzopyran-3,4'-piperidine]-1(4H)-it get in the way Jamamoto et al. J. Med. Chem., 1981, 24, 194.

Recovery sociallyengaged followed by treatment with phosphoric acid according to the method Marxer et al. J. Org. Chem., 1975, 41, 1427 results in 1,4-dihydro-1'-phenylmethyl-Spiro-[3H-2 - benzopyran-3,4'-piperidine, which dibenzyline by hydrogenation in the presence of a palladium catalyst;

1'-benzyl-Spiro[4H-1-benzopyran-4,4'-piperidine] get a way similar to that described in EP-A1-0414289 for the synthesis of 1'-benzyl-1,4'-dihydrospiro[naphthalene-1,4'-piperidine].

In the hydrogenation in the presence of Pd catalyst receive 2,3-dihydrospiro[4H-1-benzopyran-4,4'-piperidine];

Spiro[1,3-benzodioxole-2,4'-piperidine] is obtained by boiling under reflux for 1-etoxycarbonyl-4-the removal of water and subsequent removal of the benzyl group by hydrogenation in the presence of palladium catalyst.

The substituents R1-R6enter processing appropriately substituted starting compound indicated earlier ways.

Further, the present invention is illustrated by some examples, which, however, should not be considered as limiting.

So melting is determined at the device Buchi SMP-20, the amendments do not contribute. Spectra1H NMR obtained on a spectrometer Bruker AC 250 (250 Mhgc). As solvents using deuterated chloroform (99.8% of D), D2O (99,9% D) or dimethylsulfoxide (99.9%of D).

As an internal standard using TMS. Chemical shifts are expressed in million shares. Used the following abbreviations: s = singlet, d = doublet, t = triplet, square = Quartet, p = Pente, DD = double doublet, dt = double triplet, TT = triple triplet, m = multiplet.

Example 1 (method a)

1,4-bis[Spiro[isobenzofuran-1(3H),4'-piperidine]-1'-yl]butane 1a

To a solution of Spiro[isobenzofuran-1(3H),4'-piperidine] (3 g) in 25 ml dichloromethane add 3 ml of triethylamine. The resulting mixture is cooled to 5oC, and add a solution of 1 g of succinic acid dichloride in 10 ml of dichloromethane dropwise over 1/2 hour. Stirring is continued at room temperature for chasm it is extracted with a mixture of ethyl acetate and THF (1: 1). The solvent is evaporated in vacuum and the remaining solid product is recrystallized from diethyl ether. Output: 2,8, So pl. 212oC. To a suspension of LiAlH4(3 g) in 150 ml dry THF add small portions of the entire diamid (2.8 g) obtained previously. The temperature is slowly increased up to the boiling temperature under reflux and maintained for 2 hours. After cooling to a temperature below 10oC excess LiAlH4decompose, carefully adding concentrated aqueous NaOH solution (3 ml) and 15 ml of water. The inorganic salt is filtered off and the solvent is evaporated in vacuum. The remaining solid product was stirred with diethyl ether, and is listed in the title compound 1a in the form of crystals is filtered off and dried. The output of 1.4, So pl. 128oC.

1H NMR (CDCl3) :: 1,55-1, 65 (m, 4H), 1,80 (d, 4H), 2,0 (dt, 4H), of 2.45 (t, 4H), 2,45 is 2.55 (m, 4H), 2.95 and (Shir.D., 4H), of 5.05 (s, 4H), 7,10-7,30 (m, 8H).

Similarly receive the following connections:

1,4-bis[4-(4-forfinal)piperidine-1-yl]butane 1b, so pl. 124oC.

1H NMR (CDCl3) : 1,55-1,60 (m, 4H), 1.70 to of 1.85 (m, 6H), was 2.05 (dt, 4H), 2.40 a (Shir.T., 4H), 2,45 (T. T., 2H), 6,95 (t, 4H), 7,20 (DD, 4H).

1,4-bis[1,4-dihydro-Spiro(2-benzopyran-3,4'-piperidine)-1'-yl]- butane-1c, so pl. 147-148oC.


1,5-bis[4-(4-forfinal)piperidine-1-yl] pentane, 2,5 fumarate 1d, So pl. 176oC.1H NMR (DMSO-d6) : 1,35 (Shir.p, 2H), 1,65 (Shir.p, 4H), 1,80-1,90 (m, 8H), 2,50-2,70 (m, 6H), to 2.75 (t, 4H), 3,30 (d, 4H), 6,55 (c, 5H), 7,10 (t, 4H), 7,25 (DD, 4H);

1,4-bis[4-(4-forfinal)piperazine-1-yl]butane 1e, So pl. 156-158oC.

1H NMR (CDCl3) : 1,60 (Shir.p, 4H), 2,45 (Shir.T., 4H), 2,60 (t, 8H), 3.15 in (t, 8H), 6,85-7,00 (m, 8H);

1,6-bis[Spiro[isobenzofuran-1(3H), 4'-piperidine]-1'-yl] hexane, 1f So pl. 99-102oC.1H NMR (CDCl3) 1,35 (Shir.p, 4H), 1,60 (Shir.p, 4H), 1,80 (d, 4H), from 2.00 (dt, 4 H), 2,35 is 2.55 (m, 9H), 2,85 (Shir.D., 4H), of 5.05 (s, 4H), 7,15-7,30 (m, 8H);

1,4-bis[6-fluoro-Spiro[isobenzofuran-1(3H), 4'-piperidine] -1'-yl] - butane 1g, So pl. 134-135oC.

1H NMR (CDCl3) : 1,55-1,65 (m, 4H), of 1.75 (d, 4H), from 2.00 (dt, 4H), 2.40 a (dt, 4H), 2.40 a-2,50 (m, 4H), 2,90 (Shir.d, 4H), of 5.05 (s, 4H), to 6.80 (DD, 2H), 6,95 (dt, 2H), 7,15 (DD, 2H)

1,5-bis[Spiro[isobenzofuran-1(3H), 4'-piperidine] -1'-yl] pentanitrate 1h. So pl. 156-157oC.

1H NMR (DMSO-d6), :: 1,35 (Shir.p., 2H), 1,60-1,80 (m, 8H), of 2.25 (dt, 4H) 2,80-2,95 (m, 8H), 3,25 (Shir.D., 4H), of 5.05 (s, 4H), 7,20-7,35 (m, 8H);

1,4-bis[Spiro(1,3-benzodioxole-2,4'-piperidine)-1'-yl] butane 1i So pl. 164-167oC1H NMR (CDCl3) 1,60 (Shir.p., 4H), 2,15 (t, 8H), of 2.50 (t, 4H), 2,70 (t, 8H), 6,85 (s, 8H).

1,4-bis[6-(trifluoromethyl)-Spiro[isobenzofuran-1(3H), 4'-piperidine]-1'-yl] butane, DIAC is with, 4H), 7,45 (Shir.s, 2H), 7,65 (d, 2H), of 7.75 (d, 2H)

1,4-bis[1,3-dihydro-Spiro[2-benzopyran-4,4'-piperidine]-1'-yl]- butane 1k. So pl. 173-176oC.

1H NMR (CDCl3) 1,55 (p, 4H), of 1.75 (d, 4 H), 2.05 is-of 2.20 (m, 8H), of 2.45 (t, 4H), 2,90 (d, 4H), 3,90 (s, 4H), 4,80 (s, 4H), to 6.95 (d, 2H), 7,15 (t, 2H), 7,25 (m,2H), 7,50 (d, 2H).

1,4-bis[5-methyl-Spiro[isobenzofuran-1(3H), 4'-piperidine] -1'-yl]- butane 1l. So pl. 149-151oC1H NMR (CDCl3) :: 1.55V (p, 4H), of 1.75 (d, 4H), of 1.95 (dt, 4H), 2,90 (s, 6H), 2,35-of 2.50 (m, 8H), 2,85 (d, 4H), of 5.05 (s, 4H), 6,95-7,10 (m, 6H).

1,4-bis[7-fluoro-Spiro[isobenzofuran-1(3H), 4'-piperidine] -1'-yl] - butane 1m. So pl. 175-179oC.

1H NMR (CDCl3) 1,55-1,65 (m, 4H), 1,80 (d, 4H), from 2.00 (dt, 4H), 2,30-of 2.50 (m, 16H), 2,90 (Shir.d, 4H), of 5.05 (s, 4H), 6.90 to-7,00 (m, 4H), 7,20-7,25 (m, 2H);

1,4-bis[Spiro[isobenzofuran-1(3H), 3'-8'-azabicyclo[3', 2',1']- Octan] 8'-yl]butane 1n, So pl. 175-179oC.

1H NMR (CDCl3) : 1,65 (p, 4H), 1,90 (d, 4H), 1,95-of 1.05 (m, 4H), of 2.15 (DD, 4H), 2,15-of 2.30 (m, 4H), 2,50 (Shir.S., 4H), 3,30 (Shir.S., 4H), of 5.05 (s, 4H), 7,10-7,30 (m, 8H);

1,4-bis[3-(4-forfinal)-8-azabicyclo[3,2,1] Oct-2-EN-8-yl] butane 1o, So pl. 163-165oC1H NMR (CDCl3) : 1,55-of 1.56 (m, 6H), 1,90 (dt, 2H), 1,95 was 2.25 (m, 6H), 2,55 (Shir.T., 4H), 2,80 (DD, 2H), 3,50 (Shir.t, 4H), of 6.20 (d, 2H), 7,00 (t, 4H), 7,30 (DD, 4H);

1,4-bis[Spiro(1-benzopyran-2,4'-piperidine)-1'-yl]butane, difumarat 1p, So pl. 192-198oC.

1H NMR (DMSO-d6) : 1,55-1,65 (m, naftalin-1(2H), 4'-phenyl]-1'-yl]- butane 1g, So pl. 167-175oC.

1H NMR (CDCl3) : 1,55-1,70 (m, 8H), 1,70-1,90 (m, 8H), of 2.20 (dt, 4H), of 2.20 to 2.35 (m, 4H), 2,45 (Shir.t, 4H), of 2,75 2,90 (m, 8H), 7,00-7,20 (m, 6H), at 7.55 (d, 2H):

1,4-bis[3,4-dihydro-Spiro(1-benzopyran-2,4'-piperidine)-1'-yl] butane, difumarat 1r, So pl. 202-204oC.

1H NMR (DMSO-d6) : 1,50-1,60 (m, 4H), 1,70-1,90 (m, 12H), 2,60 is 2.80 (m,12H), 2,80-2,95 (m,4H), 6,55 (s,4H), 6,70-of 6.90 (m,4H), 7,05-7,20 (m,4H);

1,4-bis[Spiro[isobenzofuran-1(3H), 4'-piperidine] -1'-yl] butane 1S So pl. 155-160oC;1H NMR (CDCl3) : 1,55-1,65 (m,4H), 1,90-2,00 (m,4H), 2,15-of 2.30 (m,8H), 2,45 (Shir. t,4H), 3.00 and-3,10-to 2.55 (m,4H), to 4.15 (s,4H), 7,25 (s,8H);

1,4-bis[Spiro(1-benzopyran-2,4'-piperidine)-1'-yl]butane, fumarate 1.25 1t, So pl. 226-230oC;

1H NMR (D2) : 1,90 (Shir.s,4H), of 2.15-2.45 (m,8H), 2,90 (t,4H), 3,20-the 3.65 (m,12H), of 3.95 (t,4H), of 6.65 (s,2,5 H), 7,15-7,40 (m,8H);

1,4-bis[Spiro[1-benzopyran-4,4'-piperidine] -1'-yl] butane 1, and So pl. 163-165oC;1H NMR (CDCl3) : 1,50-of 1.65 (m,8H), 1,95 (t,4H), 2,10-of 2.25 (m,8H), 2.40 a (t, 4H), of 2,75 2,90 (m,4H), 4,10 (t,4H), to 6.80 (DD, 2H), 6.90 to (dt, 2H), 7,05 (dt, 2H), 7,40 (DD,2H).

Example 2 (method b)

1,3-bis[Spiro[isobenzofuran-1(3H),4'-piperidine]-1'-yl]propanefueled 2a

To a solution of Spiro[isobenzofuran-1(3H),4'-piperidine](1.9 g) in dichloromethane (40 ml) is added to 2.3 ml of triethylamine. After cooling to 10oC was added dropwise a solution of acid chloride Toi temperature for another 1 hour. 1'-(3-chloropropanol)-Spiro[isobenzofuran-1(3H),4'-piperidine] and clean, treating the reaction mixture in a chromatographic column with silica gel (eluent: a mixture of ethyl acetate and heptane 60:40). Get 1.8 g in the form of oil. After removal of the hydrogen chloride allocate 1'-(2-propenyl)-Spiro(isobenzofuran-1(3H), 4'-piperidine) as a by-product. Obtain 0.7 g in the form of oil. Amide 3-chloro-propanoic acid and amitrofanova acid are dissolved in isobutyl ketone (MIBK) (40 ml). To this solution add K2CO3(1.5 g) and Spiro[isobenzofuran-1(3H),4'-piperidine] (1.8 g).

The resulting mixture was refluxed over night. The inorganic salt is filtered off and MIBK is evaporated in vacuum. The obtained amide 1,3-bis[Spiro[isobenzofuran-1(3H), 4'-piperidine)-1'-yl] propanoic acid purified through column chromatography with silica gel (eluent: ethyl acetate containing 4% triethylamine). Yield 2.2 g of a viscous oil. To a suspension of LiAlH4(0.8 g) in dry tetrahydrofuran add the selected mono-amide (2.2 g) in solution in THF (25 ml). The resulting mixture was refluxed for 2 hours. The excess LiAlH4destroy, carefully adding concentrated aqueous NaOH (1 ml) in 10oC, with the oil is dissolved in 15 ml of ethanol, and add 1.1 g of fumaric acid. After heating to 60oC salt fumaric acid specified in the title compound 2a crystallized. The output of 2.2, So pl. 232 - 233oC.

1H NMR (DMCO-d6) : 1,70 (d, 4H), 1,95 (Shir.p, 2H), 2,10 (dt, 4H), to 2.65 (t, 4H), 2.70 height is 2.80 (m, 4H), 3.15 in (Shir.d, 4H), to 5.00 (s,4H), 6,55 (C. 4H), 7,20-7,35 (m,8H).

In a similar way we obtain the following connections:

1,3-bis[4-[4-forfinal]piperidine-1-yl]propane 2b, So pl. 59-61oC.

1H NMR (CDCl3) : 1,75-1,90 (m, 10H), was 2.05 (dt, 4H), of 2.45 (t, 4H), 2,45 is 2.55 (m, 2H), 3,05 (Shir. d, 4H), to 6.95 (t, 4H), 7,20 (DD, 4H);

1,2-bis[Spiro[isobenzofuran-1(3H), 4'-piperidine] -1'-yl] ethane 2c, So pl. 152-153oC.1H NMR (CDCl3) : 1,80 (d, 4H), from 2.00 (dt, 4H), 2,50 (dt. 4H), to 2.65 (s, 4H), 2,90 (Shir.D., 4H), of 5.05 (s, 4H), 7,10-7,30 (m, 8H);

1,2-bis[4-(4-forfinal)piperidine-1-yl]ethane 2d, So pl. 151-154oC

1H NMR (CDCl3) : 1,70-of 1.85 (m, 8H), 2,10 (dt, 4H), 2,45 is 2.55 (m, 2H), 2,60 (s, 4H), 3,05 (Shir.d, 4H), to 6.95 (t, 4H), to 7.15 (DD, 4H).

Example 3 (method a)

N,N-bis[2-Spiro[isobenzofuran-1(3(H),4'-piperidine]-1'-ileti] -N-cyclopentylamine of trihydrochloride 3A.

To a solution of Spiro[isobenzofuran-1(3H),4'-piperidine] (14 g) in 160 ml of dichloromethane added 11 ml of triethylamine. After cooling to 10oC was added dropwise a solution of 8 ml of chloroacetanilide in 10 ml dichloro the ect is filtered through silica gel (eluent: ethyl acetate/n-heptane 60: 40), resulting in a gain of 12 g-chloracetamide derived. The mixture obtained is chloroacetamide derivative (1.4 g) and cyclopentylamine in MIBK (25 ml) is refluxed for 2 hours. The solvent is evaporated in vacuo, and cyclopentylamine derivative extracted from alkaline (pH above 9) aqueous solution with ethyl acetate. The organic phase is treated as indicated previously, obtaining 2.0 g (cyclopentylamine)-acetamide derivative in the form of a viscous oil. To a solution of (cyclopentylamine)acetamide derivative (2 g) in MIBK add 1'-chloracetamide[isobenzofuran-1(3H), 4'-piperidine] (1.4 g) and potassium carbonate (1 g). The resulting mixture is refluxed for 3 hours. After cooling to room temperature the mixture is filtered through silica gel (eluent: 4% triethylamine in ethyl acetate). After evaporation of the solvents to obtain 2.4 g of diamide that restore LiAlH4according to the method of example 1. Specified in the title 3A compound is crystallized from a mixture of ethanol-acetone (1:4). The output of 1.3, So pl. 258-260oC.

1H NMR (DMCO-d6) 1,50 at 2.45 (m,16H), 3,25-of 3.80 (m,17H), of 5.05 (s,4H), 7,10-7,40 (m, 8H).

In a similar way we obtain the following connection:

N, N-bis[2-Spiro - NMR (DMC-d6) :: 1,90 (d, 4H), 2,50-2,90 (m, 7H), of 3.25 (t, 4H), 3,50-3,90 (m, 12H), of 5.05 (s, 4H), 7,15-7,40 (m, 8H)

Example 4 (method a)

1,4-bis[Spiro(ind-2-EN-1,4'-piperidine)-1'-yl]butane 4A

The following method is a modification of the method in J. Med. Chem., 1992, 35(11), 2033-2039. A solution of 18 ml of indene in 75 ml of dry THF cooled to 0oC was added dropwise and letibit(trimethylsilyl)amide (300 ml) for 20 minutes.

After stirring for 0.5 h at 0oC, add a solution of N-tert. -butyloxycarbonyl-N, N-bis(2-chloroethyl) amine (36 g) in 100 ml dry THF in a half hour while cooling with ice. After 2 h stirring at 0oC the solvent is evaporated in vacuum. The remaining oil is treated through column chromatography (eluent: heptane/diethyl ether 80:20), resulting in a gain of 19 g of tert.-butyloxycarbonyl derived in the form of pure oil. Protection of spirobiindane removed, adding it (14 g) carefully to triperoxonane acid (75 ml) at room temperature. Excess triperoxonane acid is evaporated in a vacuum. The remaining viscous oil is dissolved in 150 ml of dichloromethane and 30 ml of triethylamine. At 0-5oC was added dropwise 3.1 g of succinic acid dichloride in 15 ml of dichloromethane. Then the resulting mixture premise process, getting diamid in the form of oil (11,6). The solution diamide (11 g) in dry THF (100 ml) was added dropwise to a suspension of LiAlH4in dry THF (100 ml) for 0.5 h at 40 - 50oC. After boiling for 2 hours the mixture is cooled to 10oC and carefully add concentrated aqueous NaOH solution (5 ml) and 15 ml of water. The inorganic salt is filtered off and the solvent is evaporated in vacuum. Specified in the title compound 4A purified through column chromatography with silica gel (elute with a mixture of ethyl acetate/ethanol/triethylamine 90:10:4) and finally crystallized from ethyl acetate. Yield 4.3 g So pl. 121 - 122oC.1H NMR (CDCl3) 1,40 (Shir. d, 4H), 1,65 (Shir. p, 4H), of 2.25 (dt, 4H), to 2.35 (t, 4H), 2,55 (Shir. t, 4H), 3,05 (Shir.d, 4H), 6.75 in (d, 2H), 6,85 (d, 2H), 7,15 - 7,40 (m, 8H).

Example 5 (method e)

1,4-bis[Spiro[indan-1,4'-piperidine)-1'-yl]-butane 5A

To a solution of 1,4-bis-Spiro[ind-2-EN-1,4'-piperidine-1'-yl]butane (compound 4A) (3 g) in 90 ml of ethanol is added 5 ml of acetic acid and 5% palladium on coal (0.9 g). The resulting mixture hydronaut in a Parr apparatus for 2 hours at a pressure of 3 ATM. The catalyst is filtered off and the solvent is evaporated. The remaining oil is dissolved in dilute aqueous NH4OH (200 ml, pH above 9). Specified in the title compound 5A extracted utilize the P>oC.

1H NMR (CDCl3) :: 1,55 - 1,65 (m, 8H), 1,95 is 2.10 (m, 8H), 2,15 (t, 4H), 2,45 (Shir. s, 4H), 2.95 and (t, 8H), 7,10 - 7,30 (m, 8H).

Example 6 1,4-bis[4-(4-forfinal)-1,2,3,6-tetrahydropyridine-1-yl]butane 6A

To a solution of piperidine-4-atelectasia (7 g) (commercially available) and triethylamine in 50 ml dichloromethane was added dropwise dichloro-succinic acid anhydride (3.1 g) in 25 ml of dichloromethane at 10oC for 15 minutes. After stirring for 1 hour at room temperature, add 200 ml of water, and the organic phase is then treated. The crude crystalline diamid (7,4 g) melts at 120oC. To a suspension of LiAlH4(20 g) in dry THF (400 ml) was added dropwise a solution of diamide (70 g) in dry THF (700 ml) at 40oC for 45 minutes. After boiling under reflux for 2 hours, the reaction mixture is cooled to 10oC and carefully add concentrated NaOH solution (10 ml) and water (30 ml). The inorganic salt is filtered off and the solvent is evaporated in vacuum, obtaining 1,4-bis-(1-piperidino)butane derivative (62 g) as oil. Protection of the ketone groups are removed by adding perchlorate (240 ml) to the solution derived 1,4-bis(1-piperidino)butane (40 g) in dichloromethane at -10oC. the resulting mixture was stirred is consistent aqueous solution of NaOH. The organic phase is isolated and then treated, receiving 1,4-bis(4-oxopiperidin-1-yl)butane (26 g) in the form of oil, which is used without further purification. A solution of n-utility in 200 ml of hexane (1.6 M) is added to the dry diethyl ether (200 ml) under cooling. The resulting solution was cooled to -50oC, and add a solution of 1-bromo-4-fervently in dry diethyl ether (200 ml) for half an hour at -45oC. After stirring for another half an hour was added dropwise a solution of 1,4-bis(4-oxopiperidin-1-yl)butane (24 g) in dry diethyl ether for 40 minutes. The temperature is allowed to rise to 0oC. the resulting mixture was poured on ice (1.5 kg). To bring the pH to below 1 carefully add diluted hydrochloric acid. The organic phase is isolated and drained. To the acidic aqueous solution was added NH4OH to pH over 9.

1,4-bis[4-(4-forfinal)-4-hydroxypiperidine-1-yl] butane (10 g) and extracted with ethyl acetate (2 50 ml) and isolated in the form of oil. Removal of water is carried out by dissolving derived piperidine-4-ol (10 g) in 50 ml triperoxonane acid by boiling under reflux for 1 hour. After cooling to room temperature, the mixture was poured on ice (2 kg) and ethyl acetate (500 ml). On the t series, as indicated previously. Specified in the title compound 6A is crystallized from ethyl acetate. The output of 6.1, So pl. 165 - 167oC.1H NMR (CDCl3) 1,65 (Shir. p, 4H), 2,45 is 2.55 (m, 8H), to 2.75 (t, 4H), 3,15 (4H square), 6,00 (Shir. S., 2H), 7,00 (t, 4H), 7,35 (DD, 4H).

Example 7 (method a)

N,N-bis 2-[4-(4-forfinal)piperidine-1-yl]ethyl]aniline 7a

To a solution of aniline (49 g) in 400 ml of ethanol is added 130 g of sodium acetate and 250 g of ethylbromoacetate. The resulting mixture was refluxed overnight and then filtered. The solvent is evaporated in vacuum and the remaining oil is distilled under reduced pressure (12 mm RT. Art.). Thus distilled off unreacted ethylbromoacetate and monoalkylamines aniline, receiving the crude diethyl-N,N-onlinediazepam (31 g), which is used without further purification. To a solution of this diapir (31 g) in 200 ml of ethanol is added KOH (20 g) and 30 ml of water. The hydrolysis is carried out by boiling under reflux for 2 hours. Ethanol and water is evaporated in vacuo, and the remaining di-potassium salt is dissolved in water (500 ml). Add concentrated hydrochloric acid to pH below 1. N,N-bis(carboxymethyl)-aniline is extracted twice with ethyl acetate portions of 100 ml. of the Crude product (24 g) obtained after processing of the-forfinal)piperidine (6 g), dicyclohexylcarbodiimide (8.5 g), para-toluenesulfonic acid (150 mg) in anhydrous pyridine (50 ml) is stirred overnight at 25 - 30oC. Add 500 ml of water and 300 ml of ethyl acetate, and carefully add concentrated hydrochloric acid to pH = 3. The organic phase is treated as described previously. The crude diamide purified through column chromatography with silica gel (eluent : ethyl acetate). The output of 4.2, So pl. 167 - 168oC. In the recovery diamide (4,2 g) processing LiAlH4according to the method of example 1 are as specified in the title compound 7a. Yield 0.9, So pl. 104 - 105oC (crystallized from diethyl ether).

1H NMR (CDCl3) :: 1,75 - 2,00 (m, 8H), of 2.20 (dt, 4H), 2,60 (t, 4H), 2,45 is 2.55 (m, 2H), 3.15 in (Shir. d, 4H), 3,55 (t, 4H), 6,70 - to 6.80 (m, 3H), 7,05 (t, 4H), 7,20 - 7,30 (m, 6H).

Accordingly from the dichloride 3-(4-forfinal)of glutaric acid and Spiro[isobenzofuran-1(3H),4'-piperidine] get

1,5-bis[Spiro[isobenzofuran-1(3H), 4'-piperidine] -1'-yl] -3- (4-forfinal)pentane difumarat 7b, So pl. 175 - 177oC.

1H NMR (DMSO-d6) to 1.70 (d, 4H), 1,80 - 2,20 (m, 8H), 2.40 a - 2,50 (m, 1H), 2,60 is 2.80 (m, 8H), 3,10 (Shir. s, 4H), to 5.00 (s, 4H), 6,55 (s, 4H), 7,05 - 7,35 (m, 12H).

Example 8 (method a)

Bis[2-Spiro(isobenzofuran-1(3H), 4'-piperidine)-1'-ileti] Loretan, cooled to 10oC, was added dropwise over 15 minutes a solution of bromoacetamide (7 ml) in 25 ml dichloromethane. The resulting mixture is stirred further at room temperature for 45 minutes. The crude reaction mixture was purified further by silica gel, and bromoacetamide Spiro[isobenzofuran-1(3H), 4'-piperidine]and elute with a mixture of ethyl acetate/heptane 3 : 2. The output of 5.6, 2.4 g of ethyldiglycol in 40 ml ethanol add small portions of solid tert.-piperonyl potassium (2.3 g). To the obtained ethyldiglycol potassium added 3.8 g of bromoacetamide of videolooking. This mixture is stirred overnight and 1'-ethoxycarbonylmethylene-Spiro [isobenzofuran-1(3H)-4'-piperidine] (3.8 g) handle, extragere diethyl ether from the water. 3.8 g of a complex of ethyl ether hydrolized to the corresponding 1'-karboksimetoksimetilguanina-Spiro[isobenzofuran-1-(3H) 4'-piperidine] (3.2 g) by boiling under reflux with KOH in aqueous ethanol according to the method of example 7. Carboxylic acid (3.1 g) is refluxed with thionyl chloride (1.5 ml) and a drop of DMF in dichloromethane (50 ml) for 1 hour. The excess thionyl chloride is carefully evaporated twice with n-heptane in a vacuum. To a cooled to 10oC to a solution of Spiro[isobenzofuran-1 is the ID of the carboxylic acid (3 g) in 25 ml dichloromethane. After stirring for a further one hour at room temperature, diamid (2.9 g) allocate, treating the crude reaction mixture on a chromatographic column with silica gel (eluent: ethyl acetate). The total number of diamide restore LiAlH4according to the method of example 1. The output of 2.2, Difumarat specified in the title compound 8A is crystallized from a mixture of ethanol/acetate 1:1.

So pl. 92 - 94oC.1H NMR (DMSO-d6) :: 1,65 (d, 4H), of 2.05 (dt, 4H), 2.05 is (t, 4H), 2,85 (s, 8H), 3,05 (d, 4H), to 5.00 (s, 4H), 6,60 (s, 4H), 7,20 - 7,35 (m, 8H).

Example 9

Bis[2-Spiro[isobenzofuran-1(3H),4'-piperidine]-1'-ileti sulfon 9a

Bis[2-Spiro[isobenzofuran-1(3H), 4'-piperidine-1'-yl] ethylsulfate (0.8 g) from example 8 was dissolved in 10 ml triperoxonane acid and cooled to 0oC. was added dropwise a cold solution of 35% H2O2(1 ml) in 4 ml triperoxonane acid (4 ml) for 5 minutes. After heating for 1 hour at 50oC, the reaction mixture was poured into 200 ml ethyl acetate and 500 ml of dilute aqueous NH4OH (chilled on ice). The organic phase is isolated and treated as described previously. The crude product is purified on a chromatographic column with silica gel (eluent: ethyl acetate/triethylamine 100:4). Specified in the title UP>H NMR (CDCl3) : 1,80 (d, 4H), of 1.95 (dt, 4H), to 2.55 (dt, 4H), 2,85 (Shir. d, 4H), of 3.00 (t, 4H), to 3.35 (t, 4H), of 5.05 (s, 4H), 7,10 - 7,30 (m, 8H).

Example 10 (method b)

Bis[2-Spiro-[isobenzofuran-1-(3H), 4'-piperidine] -1'-ileti]ester, dihydrochloride 10A

To Spiro[isobenzofuran-1(3H), 4'-piperidine] (15 g) in 150 ml ethanol add finely ground powder of potassium carbonate. At 25 - 30oC was added dropwise 10 ml of ethylbromoacetate. The resulting mixture was stirred at 50 - 55oC for one hour. The inorganic salt is filtered off and the ethanol evaporated in vacuo. The crude 1'-ethoxycarbonylmethyl-Spiro-[isobenzofuran-1(3H),4'-piperidine] is extracted from the water and diethyl ether and treated as described previously. A yield of 20 g of butter.

20 g of ester restore LiAlH4according to the method of example 1, obtaining 1'-(2-hydroxyethyl)-Spiro[isobenzofuran-1(3H), 4'-piperidine] (12 g) as oil. To a suspension of NaH (1.4 g 50% in oil) in 40 ml of dry THF was added dropwise at room temperature a solution of 1'-(2-hydroxyethyl)- Spiro[isobenzofuran-1(3H), 4'-piperidine] (6 g) in dry THF (25 ml). Allocated hydrogen. After stirring for a further 20 minutes at 25 - 30oC, was added dropwise a solution of 1'-chloroacetyl - Spiro[isobenzofuran-1(3H),4'-piperidine] (4 g) (obtained as the corresponding bromine is souran-1(3H), 4'-piperidine]-1'-yl-ethyl - Spiro[isobenzofuran-1(3H), 4'-piperidine] -1'-incorporeality simple ether (6 g) by extraction with ethyl acetate from the water and cleaned at the end of the chromatographic column with silica gel (eluent: a mixture of ethyl acetate/ethanol/triethylamine 80:20:4). Selected so monoamide (4,5) restore LiAlH4according to the method of example 2, obtaining mentioned in the title compound 10A. The dihydrochloride crystallized from acetone. The output of 2.2, So pl. 141 - 143oC.

1H NMR (DMSO-d6) of 1.85 (d, 4H), 2,50 - 2,75 (m, 4H), 3,10 - 3,70 (m, 12H), 3,85 (Shir. s, 4H), of 5.05 (s, 4H), 7,16 - 7,40 (m, 8H), or 10.60 (Shir. s, 2H).

Example 11 (method b)

1,6-bis[5-methyl-Spiro[isobenzofuran-1(3H), 4'-piperidine)-1'-yl] - hexane 11a

A solution of 5-methyl-Spiro[isobenzofuran-1(3H),4'-piperidine] (4 grams) of 1,6-dibromohexane (2.2 g), finely ground powder of potassium carbonate (2.7 g) and a crystal of potassium iodide in MILK (150 ml) is refluxed for 4 hours. Inorganic salts are filtered off, and MILK is evaporated. After chromatographic purification on silica gel (eluent: ethyl acetate/ethanol/triethylamine 75:25:4) receive a net specified in the title compound 11a. The output of 1.0, So pl. 113 - 116oC (recrystallized from 2-propyl ether).1H NMR (CDCl3): what measures 12 (method b)

1,3-bis[4-(4-forfinal)piperidine-1-yl]-2-propanol 12A

A mixture of 4-(4-forfinal)piperidine (2,63 g), epichlorohydrin (1.1 ml), potassium carbonate (2.0 g) in MIBK stirred over night at room temperature. Inorganic salts are filtered off, and the resulting solution is boiled and then under reflux for 3 hours. After adding 1 ml of triethylamine, the crude reaction mixture was injected into the chromatographic column with silica gel (eluent ethyl acetate/triethylamine 100:4). Specified in the title compound 12A is crystallized from 2-propyl ether. The output of 1.2, So pl. 79 - 80oC.

1H NMR (CDCl3) : 1,65 - 1,90 (m, 8H), of 2.15 (dt, 2H), 2,35 (dt, 2H), 2.40 a (D. 4H), 2,45 - 2,60 (m, 2H), 3,10 (t, 4H), 3,95 (p, 1H), 6,95 (t, 4H), to 7.15 (DD, 4H).

Example 13 (method b)

1,3-bis[4-(4-forfinal)piperazine-1-yl]-2-propanol 13 and

To a solution of 1-(4-forfinal)piperazine (12 g) in 40 ml of acetone at boiling under reflux is added dropwise a solution of 1,3-dichloroacetone (1.3 g) in 10 ml of acetone. The resulting mixture was refluxed for another 2 hours. The acetone is evaporated in vacuum. The remaining viscous oil is processed through column chromatography with silica gel (eluent : ethyl acetate/ethanol/triethylamine 80: 20: 4). Specified in the title Cl3) 2,70 (t, 8H), 3.15 in (t, 8H), of 3.45 (s, 4H), 6,85 - 7,00 (m, 8H).

Pharmacology

Compounds of the present invention are testing a well known reliable ways as follows:

Inhibition of binding 3H-DTG with the Sigma receptors in the rat brain in vitro

This way determine the inhibition by drugs of the binding of 2 nm3H-DTG (1,3-di-ortho-tolylguanidine) with Sigma receptors in membrane homogenates from rat brain without mouchka in vitro according to the method of Weber et al. Proc. Natl. Acad. Sci. 1986, 83, 8784.

Drugs fabrics:

The homogenate: Rats (150 - 250g) decapitate, and the brain (without mouchka) just extract and put on ice, weighed and homogenized in 100 volumes (0oC) 50 mm Tris buffer (pH 7,7) washed with ethanol the homogenizer of Teflon glass at 0oC and stored on ice until use.

P2-membrane: the Brain is homogenized in 10 volumes of 0.32 M sucrose in rinsed with ethanol the homogenizer of Teflon glass, shaking up and down 10 times. The homogenate was centrifuged for 10 minutes at 900 gm at 4oC. the Supernatant is decanted and centrifuged for 20 minutes at 50000 gm at 4oC. the precipitate again suspension in 10 volumes of ice 50 nm Tris-BU 50000 g at 4oC. the Precipitate is again suspended in 50 volumes of ice-cold Tris-buffer and used immediately.

Analysis of the binding:

0.5 ml of 50 mm Tris buffer (pH 7,7), 0.25 ml of the sample (6 to 100 μm DTG, 6 (test connection), or Tris buffer) and 0.25 ml 6 2 nm3H DTG mixed in a 5 ml plastic test vials and incubated at 4oC before use. The binding reaction initiated by mixing 0.5 ml of the tissue suspension in the solution and incubated at 25oC for 20 minutes. The fiberglass filters (Whatman GF/B) is placed in the filtration organism, which is then tightly closed. Immediately before filtering generate a vacuum, and the filters washed with 0.1% solution of polyethylenimine (PAYS), and then once with Tris-buffer. The binding reaction is stopped by filtering the analyzed mixture under reduced pressure (750 mbar), and then another 3 times washing in 5 ml ice-cold Tris-buffer.

The filters are placed in vials counter and add 4 ml of scintillation solution. Ampoules process in Bemanos.com scintillation counter.

Buffers and solutions:

59 mm Tris-buffer pH 7,7: 7,38 g Trizma-7,7 plus distilled water to 1 liter.

100 ml of 10% polyethylenimine (PAYS): 100 ml distilled H2O add about 20 g of 50% is nm3H-DTG: the Exact amount depends on the actual concentration portion, but he was picked up as close as possible to 12 nm. Containers for radioactive solution was washed with 96% ethanol before use.

6 x 100 ám DTG: 14,36 mg/100 ml should be stored frozen in 10 ml of aliquot.

3H-DTG get from NEN Research Products, Du Pont Denmark.

The specific activity of 62.3 Curie/mmol.

For comparison, the tests included the known ligands of Sigma receptors VMF 14802 and rimcazole.

From the table it is seen that the compounds of the present invention are very effective ligands for Sigma receptors compared with compounds that are known to specialists as ligands for Sigma receptors. As you can see, many of the tested compounds have U50values below 1 nm.

Further, the ability of the compounds of the present invention to inhibit binding3H-Prazosin with - adrenergic receptors in the membranes of the rat brain determined in vitro according to the method Hyttel et al. J. Neurochem, 1985, 44, 1615; Skarsfeldt T. et al. Eur. Pharmacol. 1986, 125, 323.

Additionally, some compounds of the present invention are tested in relation to the activity of binding of the dopamine D2receptor according to the method of Van der Welde et al. Drug. Dev. Res. 1988, 15, 389 - 404, and in relation to the activity of binding of serotonin 5-HT2receptor according to the method Hyttel, Pharmacology and Toxicology, 1987, 61, 126 - 129.

For most compounds epinasty for 1adrenergic receptors and D2, 5-HT1Aand 5-HT2receptors were significantly lower compared with the efficiency of binding of Sigma receptors. Thus, it appears that many of the compounds are highly selective ligands for Sigma receptors. So, for example, for a 1adrenergic receptors and receptors of dopamine D2, serotonin 5-HT1Aand 5-HT2relationship values IR50binding (alpha/Sigma, dopamine/Sigma, 5-HT1A/Sigma and 5-HT2Sigma, respectively, were from 100 to more than 1000.

Examples of compositions

The pharmaceutical compositions of the present invention can be obtained by conventional means, well known to the experts. So, for example, tablets can be obtained by mixing the active ingredient with ordinary adjuvants and/or diluents, and then extruding the mixture in a conventional machine for tableting. Examples of adjuvants or diluents include: corn starch, lactose, talc, magnesium stearate, gelatine, lactose, gums, etc. you Can use other and the so on, provided that they are compatible with the active ingredients. Injectable solutions can be obtained by dissolving the active ingredient and possible additives in a part of the carrier, preferably in sterile water, bringing the solution to the desired volume, sterilizing the solution and filling them suitable vials or test tubes. You can add any of the commonly used additives, such as agents, giving toychest, preservatives, antioxidants, etc.

Typical examples of compositions of the present invention:

1) Tablets containing 5.0 mg of compound 1b in the calculation of the free base:

Compound 1b - 5.0 mg

Lactose 60 mg

Corn starch 30 mg

Hydroxypropylcellulose - 2.4 mg

Microcrystalline cellulose is 19.2 mg

Croscarmellose, type A (Croscarmellose) - 2.4 mg

Magnesium stearate - 0.84 mg

2) Tablets containing 1.0 mg of compound 1e in the calculation of the free base:

Compound 1e - 1.0 mg

Lactose - 23,5 mg

Corn starch - 46,9 mg

Povidone - 1.8 mg

Microcrystalline cellulose is 14.4 mg

Croscarmellose, type A - 1.8 mg

Magnesium stearate - 0,63 mg

3) Syrup containing per milliliter:

The connection 1s 2.5 mg

Sorbitol 500 mg

Ganol - 0,005 ml

Flavoring agent 0.05 mg

Nachrichten 0.5 mg

Water up to 1 ml

4) Solution for injection containing per milliliter:

Compound 2b 0.5 mg

Sorbitol - 5.1 mg

Glacial acetic acid - 0.08 mg

Water for injection to 1 ml

1. Dimeric compounds 4-phenylpiperidine, 4-phenyl-1,2,3,6-tetrahydropyridine or 4-phenylpiperazine or dimeric compounds spirocycles of piperidino General formula I

< / BR>
where n = 1 to 5;

R1-R4independently selected from hydrogen, halogen, trifloromethyl,1-6of alkyl;

R5and R6independently mean hydrogen, or they can be linked together with the formation of the ethylene bridge;

X is O, S, SO2, CO or (CH2)mwhere m = 0 or 1; X is NR7where R7means1-6alkyl, cycloalkyl, phenyl, or X is CR8R9where R8and R9independently selected from the group consisting of hydroxyl and phenyl, each phenyl group is optionally substituted by one or more substituents selected from halogen;

1) Z1determine how hydrogen and Z2represents (CH2)pwhere p = 0;

Y represents N, CH or C;

dotted lenny together a simple link, forming spirocyclic structure, and in this case, Y is C and the dotted line indicates no connection;

Z1represents O, S (CH2)qand q = 1,2 or 3, or Z1is CH2O, CH2S, CH2CH2O, CH2CH2S, CH = CH, CH = CHCH2CH2OCH2CH2SCH2;

Z2represents O, S or (CH2)pwhere p = 0 or 1, provided that Z1there can be O, S or (CH2)qwhere q = 1, if Z2represents (CH2)pwhere p = 0,

and their salts accession acids.

2. Connection on p. 1, in which Z1and Y are not connected together, and Z2means (CH2)pwhere p = 0.

3. Connection on p. 1, in which Z1and Y are linked together with the formation of spiritlessly system.

4. Connection on p. 1, in which n = 1, 2, or 3.

5. Connection on p. 1, in which X is (CH2)mwhere m = 0 or 1; X is NR7where R7means1-6alkyl, cycloalkyl, phenyl or phenyl substituted by halogen, or X is S, O or CR8R9where R8means hydroxyl, phenyl or phenyl substituted by halogen, and R9means hydrogen.

6. Connection on p. 1, cat is R6mean hydrogen.

7. Connection on p. 3, in which Z1means (CH2)qwhere q = 1, 2, or 3, or Z1means CH2OH, (CH2)2Oh, CH = CH, O, S, or CH2S and Z2means 0 or (CH2)pwhere p = 0 or 1.

8. Connection on p. 7, in which Z2means (CH2)pwhere p = 0, and Z1means CH2O, CH2S or (CH2)2O.

9. Dimeric 4-phenylpiperidine, 4-phenyl-1,2,3,6-tetrahydropyridine or 4-phenylpiperazin according to any one of paragraphs.1 - 8, with the ability to be used as ligands of Sigma receptors.

10. The pharmaceutical composition, the binding of Sigma receptors, characterized in that it comprises an effective amount of at least one dimeric 4-phenylpiperidine, 4-phenyl-1,2,3,6-tetrahydropyridine or 4-phenylpiperazine according to any one of paragraphs.1 - 8, or its pharmaceutically acceptable salt accession acid in combination with one or more of pharmaceutically acceptable carriers or diluents, preferably in the form of a unit dose containing specified compound in an amount of 0.01 - 50 mg

 

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< / BR>
where

A represents a group of the formula

-CH2-R (V)

where

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< / BR>
where

R1denotes hydrogen, methyl or ethyl group,

or

A and B form a group of the formula

< / BR>
where

R2denotes a methyl or ethyl group,

A and B form a group of the formula

< / BR>
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