A method of obtaining a pharmaceutical composition for the treatment of restlessness, derivatives, piperidine derivatives, pharmaceutical composition for the treatment of states of anxiety or epilepsy

 

(57) Abstract:

Describes a method of obtaining a pharmaceutical composition for the treatment of States of anxiety and epilepsy, including mixing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient is used as a compound piperidine derivatives of General formula (I), where the values of R1- R7, Z1- Z3specified in paragraph 1 of the formula. Describes a pharmaceutical composition for the treatment of States of anxiety or epilepsy. 3 S. and 18 C.p. f-crystals, 1 PL.

The present invention relates to the class been the analogs of piperidine compounds with anxiolytic effect and the ability of binding to the Sigma receptor and therefore are useful for the treatment of mental and neurological disorders.

The prior art various related compounds.

So, in the U.S. patents NN 3 686 186 and 3 745 165 described Spiro[phthalan-1,4'-piperidine] and Spiro[isochroman-3,4'-piperidine] new connection, optional with benzyl Deputy at the N-atom of the piperidine. Indicates that Talanova compounds are useful as antidepressants, as shown through their ability the EIT as hypotriglyceridemic agents.

In open display patent application Germany N 2 458 176 and the corresponding U.S. patent N 3 985 889 described 1,3-dihydrospiro[isobenzofuran-1,4'-piperidine] or 1,3-dihydrospiro[isobenzofuran-1,3'-pyrolidine] compounds substituted at the N atom of the ring is lower alkyl, cycloalkyl or phenyl (C2-4)-alkyl and optionally having oxoprop attached to the furan ring, which are useful as tranquilizers, as shown by their ability to influence the behavior and depressive reflex and muscle relaxation, and they also claimed as useful for the treatment of pain, as shown in the experiment on mice with induced 2-phenyl-1,4-quinone writing spasm. However, the pharmacological data presented for only one such connection without the carbonyl group in the furan ring, namely 1,3-dihydro-1'-methylspiro[isobenzofuran-1,4'- piperidines] connection, and specifically described only four such compounds with other Deputy than methyl at N-atom of the piperidine, namely 1'-cyclopropylmethyl-, 1'-[3-(4-perbenzoic)propyl] -, 1'-[4,4-bis(4-forfinal)butyl] - and 1'-acetyl-1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]. There are no indications about their effect on Sigma receptors.

In Japanese patent is entrusted substituted N-atom of the piperidine-alkyl, cycloalkyl, allyl, aryl, aralkyl or arylcyclohexylamine and optionally substituted in Romanova ring exography. However, with regard to such spiroxamine compounds not having oxazolidine in Romanova ring specifically described only methyl, phenyl or benzyl group at the N-atom piperidino rings. These compounds are stated as having anti-allergic activity and there are no data on the effects on the Central nervous system.

Known also European patent EP N 0 414 289 A1, describes derivatives of 1,2,3,4-tetrahydro-Spiro[naphthalene-1,4'- piperidine] and 1,4-dihydro-Spiro[naphthalene-1,4'-piperidine], substituted N-atom of the piperidine "hydrocarbon", and stated that they have selective activity of antagonists of the Sigma receptors. The term "hydrocarbon" as defined in the specified patent covers all possible group with a straight chain, cyclic, heterocyclic, etc; however, the specifically disclosed only compounds having benzyl, phenylethyl, cycloalkylation, furyl - or thienylmethyl or lower alkyl or alkenyl as "hydrocarbon" Deputy. It was found that the compounds displace tretirovanie detailhandel (DTG) from Sigma-centers with Spiro[naphthalene-1,4-piperidine]. In European patent publication describes the corresponding derivatives of Spiro[indan-1,4'-piperidine] and Spiro[benzocycloheptene-5,4'-piperidine]. Also found that only connections replace tretirovanie detailheader (DTG) from Sigma-centres with capacity of more than 200 nm.

ER N application EP-A2-0 431 943 belongs to another, a very broad class spiroheterocyclic compounds substituted at the N-atom of the piperidine. These compounds are indicated as useful anti-arrhythmic agents and to improve the function of the heart pump.

In this application confirmed by the examples of several compounds, most of which contains oxo - and/or sulfonylamine Deputy in spiritlessly ring system. The remaining compounds the most part has a different polar Deputy, such as nitro, amino, condensed imidazolium, etc. attached to the Spiro-core, and/or have some polar substituents, such as sulfonylamino, nitro, amino, etc., the substituent at N-atom of the piperidine. In addition, some compounds have heteroarylboronic Deputy at the N-atom of the piperidine, whereas only very few confirmed examples of compounds do not have such deputies, and they are the few Spiro[3H-1-benzopyran-3,4'-piperidine] , having benzyl, finitely, sexily or Gately Deputy at the N-atom of the piperidine, and there are no data on the effect of compounds on Sigma receptors.

In U.S. patent No. 4 420 485 described 1'-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-Spiro[benzofuran-2(H),4'- piperidine], optionally having one or two substituent benzofuranol ring. Compounds claimed as useful as antihypertensive agents on the treatment of their mental or neurological disorders.

In open display patent application Germany N 28 27 874, corresponding to U.S. patent No. 4 251 538, in General, describes a class of 3-[4-(4-phenylpiperazin-1-yl)butyl] indole derivatives, optionally substituted in the indole piperidinol or tetrahydropyridine and/or phenyl groups. Indicated that the compounds have a dopamine antagonistic action and inhibiting re-increase serotonin effect on the Central nervous system, and, therefore, are useful for the treatment of Parkinson's disease and depression. However, this documentary is not confirmed, there are no pharmacological data and definitely does not assume or indicate inhibitory Sigma-receptor action.

In addition, ballico, are tetrahydropyridine compounds and/or they have oxazolidine in butilkoi chain. Mentioned only a few been the analogs of piperidine compounds without oxazolidine in butilkoi chain, namely 3-[4-(4-phenyl-1-piperidyl)butyl]-indole and 1-methyl-, 1-phenyl - 2-methylpropane them, and their derivatives substituted by halogen, stands or trifluoromethyl in the 4-phenyl substituent in piperidino group. In relation to the physical data are given only the melting point for one such connection.

International patent application N WO 91/09594, published July 11, 1991, applies, incidentally, to 4-phenylpiperidine compounds which are Sigma-receptor ligands, and having optionally substituted "heteroaryl"-alkyl, -alkanniny, -alkynylaryl, -alkoxy or-alkoxyalkyl Deputy at the N-atom of the piperidine. The term "heteroaryl"-alkyl is determined by reference to a very wide class of such substituents. However, the specifically disclosed only four N-substituted 4-phenylpiperidine connections, all of which are 1-(phenyl-lower alkyl)-4 - phenylpiperidine and only four compounds having heteroaryl"-alkyl substituent, specifically mentioned, they are all piperazinonyl CLASS="ptx2">

When studying the biology and function of Sigma receptors were presented proof that the Sigma-receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and retarded dyskinesia and motor disorders associated with chorea Huntington's or Tourette's syndrome, and Parkinson's disease (Walker F. M. et al., Pharmacological Reviews, 1990, 42, 355). Known Sigma receptor ligand rimcazole clinically demonstrated efficacy in the treatment of psychosis (Snyder S. H., B. L. Largent J. Neuropsychiatry 1989, 1, 7) and was described by the group of Sigma receptor ligands, showing antipollution activity in animal models (international patent application N WO 9103243).

In addition, it was reported that Sigma receptor ligands have been involved in the modulation of cases, mediasound the NMDA receptor in the brain and act as anti-ischemic agents in tests in vitro (Rao T. S. et al., Molecular Pharmacology, 1990, 37, 978). In addition to ischemia, they can also be useful in the treatment of other such cases, mediasound the NMDA receptor, for example, epilepsy and convulsions.

It was also found that some of the Sigma-receptor ligands are anti-ischemic effect on animal models (Early et al., Brain Research 1991, 546, 281-286). Been shown to influence the et al., Eur.J. Pharm. 1991, 200, 343-345) and, therefore, may have power in the treatment of senile dementia of the Alzheimer's type.

Also described some of guanidine derivatives having Sigma receptor activity, which is useful as anxiolytics (international patent application N WO 9014067).

Therefore, suppose that the agents, powerfully acting on the Sigma receptors in the Central nervous system, can be potentially useful in the treatment of such conditions.

Discovered that a certain class been the analogs of piperidine compounds binds to the Sigma receptors with the capacity, which usually have a size by 2-3 orders of magnitude greater than the maximum capacity indicated in the European patent publication EP 0 414 289 A1. In addition, it was found that the compounds of the specified class show anxiolytic effects in animal models.

This class of compounds includes compounds of General formula I

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where R1is:

a) group-D-B-A-R,

in which spacer elements is a group having up to 19 members selected from alkylene, Alcanena and akinlana, which can be branched or straight chain and optionally substituted by hydroxyl, which again erode inclusive,

A is a bond or a divalent group selected from O, S, SO, SO2and

W is O or S, and the dotted line indicates an optional bond;

R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl, cycloalkylation, cycloalkylation, phenylalkyl, diphenylalkanes, any alkyl group optionally substituted by one or two hydroxyl groups, which again can be optional tarifitsirovana aliphatic carboxylic acid having from two to twenty-four carbon atoms, inclusive, and any phenyl group is optionally substituted by one or more substituents in the phenyl ring; and

D is CR5R7where R5and R7independently selected from the substituents defined below for R4-R7or cycloalkanones group; or

b) a group having the General formula II

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where X is CHR10, O, S, SO, SO2or NR10, R10is hydrogen, lower alkyl or alkenyl, cycloalkyl or cycloalkylation, cycloalkenyl or cycloalkenyl, acyl, aminoalkyl, mono - or dialkylaminoalkyl, sulfonium or aralkyl or phenyl, optionally substituted by one or two for>0is a heteroaromatic group, preferably 2-tanila, 3-tanila, 2-TuranAlem, 3-TuranAlem, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridium, 3-pyridium or 4-pyridium;

one or two dotted lines can be communication;

when the dashed line emanating from Y indicates a bond, Y is N or CH; or

when specified as a dotted line is not a bond, Y is CH2; NH, C=O or C=S;

Ra-Rdindependently selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl, lower alkylthio, lower alkylsulfonyl, lower alkyl or dialkylamino, cyano, trifloromethyl or triptoreline;

U is CH2, O or S; or

when one of the dashed lines extending from the U indicates the bond, U is CH; the relationship between U and Q1or Q2respectively can also be a triple bond and in this case U is "C";

Q1selected among communication, alkylene or Alcanena, a Q2is alkylene having at least two C-atoms, Alcanena or group of Q2'D, where Q2'has the same meaning as Q2, a D has the values given above, Q1and Q2have together from 2 to 20 carbon atoms and optional zametayuschii carboxylic acid, having 2-24 carbon atoms, inclusive; and

R2and R3independently are hydrogen, lower alkyl or they may be associated with the formation of the ethylene or propylene bridge;

R4-R7independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl, lower alkylthio, lower alkyl or dialkylamino, cyano, trifloromethyl or triptoreline; and

i) Z1and Z2linked together, in this case, Z1is CH2, O or S;

Z2and Z3independently are (CH2)nn is 0 or 1, O or S, provided that Z1cannot be S or O when Z2is S or O, and Z2and Z3both can be (CH2)nwhen n = 0:

or Z1and Z2together can be a group-CH=CH-;

or when Z3is (CH2)nwhere n is 0, Z1and Z2may together represent a three-membered divalent group, optionally containing one unsaturated bond, and optionally containing one O or S heteroatom; or

ii) when R1is a group as defined in b), Z1and Z2can also be unbound, in this case, Z12)nwhere n is 0;

provided that when Z1-Z3have the meanings defined in i), where Z3is (CH2)nwhere n is 0 and Z1and Z2together are 2 - or 3-membered divalent hydrocarbon group, optionally containing one unsaturated bond, and R1is a group defined in a), then D-B-A-R cannot be phenyl-C1-3-alkyl, lower-alkyl or lower alkenyl;

and salts accession acids or precursors of drugs.

According to the present invention are also piperidine compounds having the above General formula I or their salts accession acids or precursors of drugs for pharmaceutical formulations for the treatment of States of anxiety, psychosis, epilepsy, convulsion, movement disorders, motor disturbances, amnesia, cardiovascular diseases, senile of dementia type of Alzheimer's disease or Parkinson's disease.

Some of the compounds of General formula I can exist as optical isomers, and such optical isomers are also the subject of invention.

The term alkyl means C1-C20is an alkyl group with straight or did what, having one or more unsaturated bonds in the chain. The term cycloalkyl means carbocyclic ring having 3-8 carbon atoms, inclusive, or a bicyclic or tricyclic carbonyl, such as substituted.

The terms lower alkyl, lower alkoxy, lower alkylthio, etc. mean such a branched or unbranched group, having from one to six atoms, inclusive. Examples of such groups are methyl, ethyl, 1-propyl, 2-propyl, 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.

Halogen means fluorine, chlorine, bromine or iodine.

The term "sulfonyl" is used when referring to alkyl - or aryl-substituted sulfonyl, similarly "acyl" is used to denote alkyl - or arylcarboxylic.

The term "one or two dotted lines can be a relationship means that each of the dotted lines may or may not be a connection, namely, that cycle and lateral communication, respectively, may or may not have a double bond in the positions of the dotted lines in formula II, provided that only two simultaneously indicate the relationship and that nearby is edelenyi R can independently be selected from among halogen, lower alkyl, lower alkoxy, hydroxyl, lower alkylthio, lower alkylsulfonyl, lower alkyl or dialkylamino, cyano, trifloromethyl or triptoreline. Each phenyl group may bear one or more substituents.

Salt accession acids are pharmaceutically acceptable salts of the compounds of formula I formed with non-toxic acids. Examples of such organic salts 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, asparginase, stearic, palmitic, takenaway, glycolic, p-aminobenzoic, glutamic, benzosulfimide and theophyllinate acid, and 8-valuevillage, for example, 8-Romeoville. Examples of such inorganic salts are the salts of hydrochloric, (Hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

Disorders of movement and motor disorders that can be cured product according to the invention are, for example, dystonia and slow dyskinesias or delayed and may be caused by neuroleptics or have another reason.

Cerebralischemia diseases are those diseases caused by cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoidal hemorrhage, cerebral thrombosis, cerebral embolism, or similar, for example, ischemia, hypoxia, anoxia.

It was found that the compounds according to the invention replaces tretirovanie detailhandel (DTG) from Sigma-centres in vitro with power above about 40 nm, and mostly above 1 nm, i.e., they bind to Sigma receptors are much more strongly than the ligands of Sigma receptors, such as, for example, VMF 14802 and rimcazole. In addition, it was shown that a large part of these compounds is very selective ligands for Sigma receptors. For example, compared with1- adrenoceptors and receptors of dopamine D2it was found that the majority of these compounds has a relationship of affinity (IC50alpha/Sigma and dopamine/Sigma, respectively) 30-10000. In addition, the compounds show a very potent anxiolytic effects in animal behavior in the test at very low doses, namely the values of EC50in the range of ng-µg/kg

When Z1and Z2related vmesnika Z3is (CH2)nwhere n is 0, and Z2is "O" or "S" and Z1is CH2or Z1and Z2together are CH2-O-CH2. Other preferred groups are those when Z1is CH2, Z2is O and Z3is CH2; or Z3is O and Z1-Z2is CH=CH; or Z1is OH, Z3is O and Z2is (CH2)nwhere n=0.

Particularly preferred compounds are:

1'-(3-adamantane-1-propyl)Spiro[3H-2-benzofuran-3,4'- piperidine];

1'-[4-(1-benzyl-3-indole)-1-butyl] -Spiro[isobenzofuran-1(3H),4'- piperidine];

1'-(3-(3-phenylimidazoline-2-on-1-yl)-1-propyl) Spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-[1-(4-forfinal)-3-indolyl] -1-butyl] -Spiro [isobenzofuran-1(3H), 4'-piperidine];

1,4-dihydro-1'-[4-[1-(4-forfinal)-3-indolyl]-1 - butyl]Spiro[3H-2-benzopyran-3,4'-piperidine];

1'-(4-(1-p-toluensulfonyl-3-indolyl)-1-butyl) Spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-[5-fluoro-1-(4-forfinal)-3-indolyl] -1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine];

6-fluoro-1'-[4-[1-(4-forfinal)-3-indolyl] -1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-[1-(4-were)-3-indolyl]-1-butyl]Spiro[1H - 2-benzoindole)-1 - butyl] Spiro[isobenzofuran-1(3H), 4'-piperidine];

1'-[3-(5-perbendaharaan-3-yl)-1 - propyl] Spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-(5-perbendaharaan-3-yl)-1-butyl] -Spiro[isobenzofuran - 1(3H),4'-piperidine];

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

4-forfinal-3-[4-(4-(4-forfinal)-1-piperidyl)-1-butyl] -5 - cryptomaterial;

1'-(4-(1,2-benzisoxazol-3-yl)-1-butyl) Spiro[isobenzofuran-1(3H),4'-piperidine]; and

1'-[3-(benzo[B] thiophene-3-ylthio)-1 - propyl]Spiro[isobenzofuran-1(3H),4'-piperidine].

Some of the compounds used in accordance with the invention, are new and therefore in another aspect the present invention relates to new piperidine derivative having the formula I, as defined above, provided that, if R1is a group of formula II, as defined above in (b), Z1, Z2and Z3have the values listed previously in ii), X is NH, Y is CH and the dotted line emanating from Y is a bond, then Q1-U-Q2- cannot be an alkyl having less than 5 carbon atoms;

if R1is a group of formula II, as defined above, where Z3is OH, Z1is CH2, Z2is (CH2)nn R -(CH2)3then Rccannot be fluorine;

if Z3is OH, Z2and Z1both are CH2and D-B-A-R is optionally substituted by Venetian, then R6may not be methoxy; and

if Z1is OH, Z2and Z3both are CH2then D-B-A-R cannot be Venetian, or optionally hydroxyl-substituted hexyl or heptyl.

The present invention also includes a pharmaceutical composition consisting of at least one new piperidinol compounds according to the invention, as defined above, or pharmaceutically acceptable salts thereof accession acid or predecessor medication in combination with one or more pharmaceutically acceptable carriers or diluents.

The pharmaceutical composition according to the present invention or those, which are obtained in accordance with the present invention, can be introduced by any suitable means, for example, orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For the preparation of such compositions can be used in methods known in the prior art, and can be used any f is applied to a given level of technology.

Usually the proposed compound is administered in unit dosage form containing the specified connection number in the range of about 0.01 to 50 mg

The total daily dose is usually in the range of about 0.05 to 100 mg, and more preferably from about 0.1 to 20 mg of active compound of the invention.

The compounds of formula I can be obtained:

a) when recovering the amide carbonyl compounds of the formula III

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where R2-R7and Z1-Z3are these values a R11is this group that CH2-R11is a group that includes the definition of R1;

b) by alkylation of compounds of formula IV

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where R2-R7and Z1-Z3have the previously indicated meanings, of alkylating agent of the formula R1-V, where R1has these values, and V is a suitable tsepliaeva group, such as halogen, mesilate or toilet;

C) the reductive alkylation of amines of formula IV with an aldehyde of the formula R11-CHO or carboxylic acids of the formula R11-COOH or ketones of the formula R12-CO-R13where R2-R7, R11and Z1-Z3are these values a R1;

g) when restoring C=Y1the double bond in the compound of formula V

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where Ra-RdX U, Q1, Q2, R2-R7and Z1-Z3have these values, a Y1is CH or N;

d) by the oxidation of compounds of formula VI in oxoniensia formula VII:

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where Ra-RdX U, Q1, Q2, R2-R7and Z1-Z3have the previously indicated meanings;

f) by the alkylation of compounds of formula VIII to obtain compounds of General formula I, where X= NR10', R10'is lower alkyl, alkenyl, cycloalkyl, cycloalkylation, cycloalkenyl or cycloalkenyl,

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where Ra-Rd, Y, U, Q1, Q2, R2-R7and Z1-Z3have the previously indicated meanings, of alkylating agent of the formula R10'-V1where R10'has these values, a V1is appropriate adsenseboy group, for example, halogen, mesilate or tosylate; or acylation of compounds of formula VIII allermuir agent having the formula, R10"-CO-Hal, where Hal is halogen and R10"is a group which together with the CH2forms the group R10'and subsequent restore is soedineniya General formula I, where X=NR10"', R10"'is optionally substituted by phenyl or heteroaryl, alleroisk agent of the formula Ar-V1where Ar is optionally substituted phenyl or heteroaryl, a V1has the previously indicated meaning;

C) to obtain compounds of General formula I, where X=NCO-R10'or N-CO-Ar, where R10'and Ar have the previously indicated meanings, acelerou compound of formula VIII allermuir agent of the formula R10'-CO-Hal or Ar-CO-Hal, where Hal have the previously indicated meanings;

and) to obtain compounds of General formula I, where X=NSO2R10'or NSO2Ar, where R10'and Ar have the previously indicated meanings, sulfonylureas the compounds of formula VIII sulfonylureas agent of the formula R10'SO2Hal or ArSO2Hal, where Hal have the previously indicated meanings;

K) reductive alkylation of compounds of formula VIII carbonyl compounds of the formula R14-CO-R15where R14and R15are such groups that R14-CH-R15is the group R10as defined previously;

l) if the reaction circuit cycle hydrazone IX indazol derived X

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< / BR>
where Ra-Rd, U, Q1, Q2, R2-R7, R10and Z1
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in which R1-R7, Z1and V1have the previously indicated meanings;

then allocate the compound of formula I in free base or its pharmaceutically acceptable salt accession acid.

Restoration by the method (a) may preferably be carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran, in the presence of sociallyengaged at the boiling point under reflux.

Amides of formula III is conveniently get in the processing of piperidine derivatives of the formula IV suitable carboxylic acid anhydrides of the formula R11-COCl in the presence of a base (potassium carbonate or triethylamine). When R11-CH2means a group of formula-D-B-A-R, the corresponding carboxylic acid anhydrides of the formula R11-COCl are either commercially available or obtained by standard methods.

When R11-CH2means a group of formula II, the corresponding carboxylic acid anhydrides of the formula XII

< / BR>
where Ra-RdX, Y, U and Q1have these values, a Q2'is this group that Q2'-CH2is the group of Q2as opreparation formula IV, where Z1and Z2linked together are as follows:

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

2,3-dihydro-Spiro[1H-inden-1,4'-piperidine] and 3,4-dihydro - Spiro[naphthalen-1(2H),4'-piperidine] - according to the method described in the French patent N 1 335 831.

1'-methyl-Spiro[benzo[c]thiophene-1(3H),4'-piperidine] - according to the method described by Parham et al., J. Org.Chem. 1976, 41, 2628. Appropriate demetilirovanie derivative is obtained by processing etelcharge.com with subsequent alkaline hydrolysis of the intermediate ethylcarbamate.

1'-phenylmethyl-Spiro[1H-2-benzopyran-4(3H),4'-piperidine] - according to the method described by Yamamoto et al, J. Med.Chem., 1981, 24, 194. Appropriate dibenzylidene derivative obtained when the hydrogenation in the presence of palladium catalyst.

3,4-dihydro-1'-phenylmethyl-Spiro[2H-1-benzopyran-2,4'- piperidine] - according to the method described by Yamamoto et al, Chem.Pharm. Bull. 1981, 29, 3494. Appropriate dibenzylidene derivative is obtained by processing etelcharge.com with subsequent alkaline hydrolysis of the intermediate ethylcarbamate.

1'-phenylmethyl-Spiro[2H-1-benzopyran-2,4'-piperidine] get the procedure described Yamamoto et al, Chem.Pharm.Bull, 1981, 29, 3494. Rubbish.

1'-phenylmethyl-Spiro[3H-2-benzopyran-3,4'-piperidine] -1(4H)-he - according to the method described by Yamamoto et al, Y. Med.Chem. 1981, 24, 194. Recovery sociallyengaged followed by treatment with phosphoric acid according to the method described Marxer et al, J. Org.Chem. 1975, 40, 1427, receive 1,4-dihydro-1'-phenylmethyl - Spiro[3H-2-benzopyran-3,4'-piperidine] , which dibenzyline by hydrogenation in the presence of palladium catalyst.

1'-benseler[4H-1-benzopyran-4,4'-piperidine] get in the way similar to the method described in EP 0 414 289 A1 for the synthesis of 1'-benzyl-1,4-dihydrospiro[naphthalene-1,4'-piperidine] . Hydrogenation in the presence of a palladium catalyst gives 2,3-dihydrospiro[4H-1-benzopyran-4,4'-piperidine].

Spiro[1,3-benzodioxole-2,4'-piperidine] get boiling under reflux for 1-etoxycarbonyl-4-piperidine and catechol in toluene solution in the presence of p-toluensulfonate acid with continuous removal of water and subsequent removal of the benzyl group under hydrogenation in the presence of palladium catalyst.

The substituents R-R injected, using appropriately substituted starting compound and a technique similar to that described above.

Derivatives of piperidine of formula IV where Z1and Z

Alkylation of compounds of formula IV according to the method b) is convenient to carry out in an inert organic solvent, such as a suitably boiling alcohol or ketone, preferably in the presence of a base (potassium carbonate or triethylamine) at boiling point with the inverse solvent.

Alkylating reagents of formula R1-V, where R1mean-D-B-A-R, where A is O, S or a bond, and D, b and R have the previously indicated meanings, receive a standard literary techniques. Appropriate sulfoxidov and sulfones obtained when the oxidation of sulfides by methods known in the prior art.

Such alkylating agents, in which A is a group where W is O or S, get the method described in DE-OS N 2035370.

Receiving alkylating agents of the formula R1-V, where R1means the group having the General formula II, illustrated by examples in the following reaction schemes. In formulas reaction schemes, Ra-Rd, V, and Ar have the previously indicated meanings, and E is 1-piperidino group of General formula IV. Indene formula II is conveniently be obtained according to scheme 1, in which Ra-Rdand V have the above values.

Circuit 1

The deletion of method 3 is preferably carried out in a suitable alcohol, for example methanol, in the presence of a strong mineral acid, for example concentrated hydrochloric acid. Preferably the method 4 is a processing methanesulfonamido in the presence of triethylamine in dichloromethane, thereby obtaining the corresponding methanesulfonate, but the alternative can be carried out the conversion of the hydroxyl to the halogen using a suitable reagent, such as thionyl chloride.

Indāni formula II get in scheme 2, in which Ra-Rdand V have the above values

Scheme 2

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< / BR>
Method 1a is similar to method 1 with the modification that the removal of water is carried out directly on the crude product using concentrated hydrochloric acid. The resulting mixture of isomers restore method 2. One of the obtained isomers produce, whereas the remaining mixture hydronaut traditional Parr apparatus (method 5) in presumabaly II is the most convenient to get to or from indolinone acid, for example, innovatieve acid, as described in European patent application N 376607, or according to scheme 3, in which Ra-Rd, And V Ar have the previously indicated meanings.

Scheme 3

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Source indexedby ether get in the way described in U.S. patent No. 4 710 500. Alkylation in method 5 is carried out in an inert, convenient boiling organic solvent, such as alcohol or ketone, preferably in the presence of a base (potassium carbonate or triethylamine). Decarboxylation in method 6 is preferably carried out thermally, after hydrolysis of diapir in decollato, in a suitable inert solvent, for example, quinoline, dimethylformamide, or N-methyl-2-pyrrolidone (NRM) in the presence of copper.

Indole-3-roxypropyl derivatives can also be obtained by heating a mixture of 3-acetoxybenzoic and 1,3-propylene glycol in the presence of sulfuric acid, resulting in a gain of 3-(indol-3 - yloxy)-1-propanamine derivatives, which are converted into the corresponding methanesulfonate or halide compounds by method 4.

Benzofuran and 2,3-dihydrobenzofuran formula II get in schemes 4 and 5, in which Ra-Rdand E have the above values.

Scheme 5

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Method 12 is in the traditional transformation of the carboxylic acid amide via the acid chloride of carboxylic acid. Lengthening the side chain is carried out at the transformation of the hydroxyl group in the chloride during processing, preferably with thionyl chloride in dichloromethane in the presence of a few drops of dimethylformamide (method 13) followed by treatment of the cyanide salt, such as potassium cyanide, in a suitable dipolar aprotic solvent, preferably dimethyl sulfoxide, at 100-200oC (method 14). Hydrolysis of ceanography carry out mineral acid at elevated temperature (method 15).

Benzo[b]tiophene and 2,3-dihydrobenzo[b]tiophene form proizvodnye receive from methylbenzo[b]thiophene-3-carboxylate when restoring in methanol derived by sociallyengaged with subsequent alkylation of ethylbromoacetate and a recovery benzo[b] thiophene-3-eletronically derivatives, which in turn target connection mode 4. Benzofuran-3 - eletronically derivative gain in the same way.

Benzo[b]thiophene-5,5-dioxide derivative is produced by oxidation of the corresponding derivatives of benzo[b] thiophene according to standard literature methods. 2,3-dioxindole formula II get methods similar to method g). The indoles of formula II get methods similar to method d). Indazols formula II get methods similar to method K).

Reductive alkylation of amines of formula IV according to the way in) is done according to standard literature methods. Aldehydes, carboxylic acids and ketones of the formula R11-CHO, R11-COOH and R12-COR13, respectively, are either commercially available or obtained by standard methods, or by methods analogous to methods described in schemes 1-5.

Recovery C=Y1the double bond according to method g) it is convenient to carry out the catalytic hydrogenation in ethanol on platinum catalyst or by hydrogenation with DIBORANE or a precursor of DIBORANE, such as triethylamine or dimethylsulfoxide complex, tetrahydrofuran or dioxane from 0oC to the boiling temperature tx2">

Alternatively, the double bond can be restored by sodium borohydride in methanol in the presence of triperoxonane acid (see, for example, Berger et al, J. Med.Chem., 1977, 20, 600).

Oxidation of compounds of formula VI according to the method d) are carried out by Szabo-Pustay et al, Synthesis, 1979, 276.

Alkylation, acylation or sulfonylurea compounds of formula VIII by means (e), h) and I), respectively, is carried out in an inert solvent, such as a suitably boiling alcohol or ketone, preferably in the presence of a base (potassium carbonate or triethylamine). Alkylating reagents R10'-V1, alleluya agents R10"-CO-V1, R10'-CO-V1and Ar-CO-V1and sulfonylurea agents R10'-SO2-V1and Ar-SO2-V1respectively, are commercially available or obtained by standard methods.

Atilirovanie the compounds of formula VIII according to the method f) it is most convenient to carry out when using the well-known reaction Willmann. Allerease reagents Ar-V1are commercially available.

Reductive alkylation of compounds of formula VIII by the way) is done according to standard literature methods.

Zamykanie is suitable inert organic solvent, such as dimethylformamide, in the presence of a base, preferably tert.butoxide potassium.

The hydrazones of formula IX receive under the scheme 6, in which Ra-Rd, R10and Hal have the previously indicated meanings.

Scheme 6

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Way 16 is to add the Grignard reagent 4-chloro-1-butanol to about-gelbeseiten under standard conditions for Grignard reactions. Turning to the hydrazone (method 17) is carried out at boiling under reflux in ethanol in the presence of hydrazine. Alternatively, hydroxyl derivative, obtained by the method of 16, can be converted to amine via a corresponding mutility similar to method 4, and (a) before turning ketogroup.

Restoration by the method m) is most conveniently be accomplished by catalytic hydrogenation in alcohol on a palladium catalyst. Compounds of formulas V, VI and VIII of the get methods a), b), K), l) or m). The compounds of formula XI are treated as compound of formula R1-V14-arylpyrimidines in alcohol with a suitable boiling point.

Further, the invention is illustrated in the examples which do not limit the invention.

Example 1.

1'-bouterse is ethylbromide, 5 g of potassium carbonate and 0.2 g of potassium iodide in 100 ml of 4-methyl-2-pentanone refluxed for 16 hours. After cooling, the reaction mixture was washed with 100 ml of water and concentrated in vacuo. The target compound is crystallized in the form of the oxalate salt from acetone by adding oxalic acid. Recrystallized from a mixture of ethanol/ether. Output 1.2 g, so pl. 171-173oC.

Similarly also get:

1'-interspiro[isobenzofuran-1(3H), 4'-piperidine] , oxalate, 1b, so pl. 170-172oC.

Example 2

1'-(4-phenyl-1-butyl)Spiro[isobenzofuran-1(3H),4'-piperidine], fumarate, 2A

It chilled with ice to a solution of 20 g of 4-phenyl-1-butanol and 15 g of triethylamine in 200 ml of dichloromethane was added dropwise a solution of 12 ml of methanesulfonamide in 50 ml of dichloromethane. After stirring for 1 hour at 10oC, the reaction mixture was diluted with water. The aqueous phase is extracted with dichloromethane, the combined organic phases are dried over magnesium sulfate, evaporated volatile components under vacuum, to obtain 29 g of a light yellow oil, 4-phenyl-1 - butylmalonate, which is sufficiently pure for use in the next stage. A mixture of 2 g of Spiro[isobenzofuran - 1(3H),4'-piperidine], 6 g of 4-phenyl-1-butyl-met. After cooling the reaction mixture, it is filtered and concentrated in vacuo. The remaining viscous oil is applied on a column of silica gel (eluent: ether/methanol/triethylamine = 93: 5: 2), receive a colorless oil, which crystallizes in the form of fumaric salt, 2A, from acetone adding fumaric acid. Yield 0.7 g, so pl. 197-199oC.

Similarly also get:

1'-(4-cyclohexyl-1-butyl)Spiro[isobenzofuran-1(3H), 4'- piperidine], oxalate, 2B, so pl. 139-142oC;

2,3-dihydro-1'-(4-phenyl-1-butyl)Spiro[1H-inden-1,4'- piperidine] , fumarate, 2B, so pl. 207-211oC;

1'-(4-phenyl-1-butyl)Spiro[benzo[c] thiophene-1(3H), 4'- piperidine], maleate, 2G, so pl. 176-177oC;

3,4-dihydro-1'-(4-phenyl-1-butyl)Spiro[naphthalene-1(2H),4'- piperidine], fumarate, 2D, T. pl. 191-193oC;

1'-(4-phenyl-1-butyl)Spiro[1H-2-benzopyran-4(3H), 4'- piperidine], maleate, 2E, so pl. 169-170oC;

1,4-dihydro-1'-(4-phenyl-1-butyl)Spiro[3H-2-benzopyran-3,4' -piperidine], maleate, 2ZH, so pl. 152-153oC;

3,4-dihydro-1'-(4-phenyl-1-butyl)Spiro[2H-1-benzopyran-2,4' -piperidine], oxalate, 2H, T. pl. 155-157oC;

1'-(4-phenyl-1-butyl)Spiro[2H-1-benzopyran-2,4'- piperidine], fumarate, 2i, so pl. 184-185oC;

1'-(3-cyclohexyloxy-1-propyl)Spiro[isobenzofuran-1(3H),4' -piperidine], fumarate, 2K, so pl. 15 is hydroxy-1-propyl)Spiro[3H-2-benzopyran-3,4'- piperidine] , maleate, 2m, so pl. 171-173oC;

1'-(3-adamantane-1-propyl)Spiro[3H-2-benzopyran-3,4'- piperidine] , maleate, 2H, T. pl. 221-224oC;

1'-(3-methylthio-1-propyl)Spiro[isobenzofuran-1(3H), 4'- piperidine] , oxalate, 2O, so pl. 126-127oC;

1'-(3-cyclohexylthio-1-propyl)Spiro[isobenzofuran-1(3H), 4'- piperidine], oxalate, 2P, so pl. 170-174oC;

1'-(3-phenylthio-1-propyl)Spiro[isobenzofuran-1(3H), 4'- piperidine] , oxalate, 2P, so pl. 152-155oC;

1'-(3-methylsulphonyl-1-propyl)Spiro[isobenzofuran-1(3H), 4'- piperidine], 2C, T. pl. 163-164oC;

1'-(3-cyclohexanesulfonyl-1-propyl)Spiro[isobenzofuran-1 (3H), 4'-piperidine], 2T, so pl. 118-120oC;

1'-(3-phenylsulfonyl-1-propyl)Spiro[isobenzofuran-1(3H)4'- piperidine] , 2U, so pl. 197-202oC;

8'-(4-phenyl-1-butyl)Spiro[isobenzofuran-1(3H), 3'-8 - azabicyclo[3,2,1] Octan], maleate, 2F, so pl. 180-181oC;

1'-[4-(3-indolyl-1-butyl] -Spiro[isobenzofuran-1(3H),4'- piperidine], 2, I. pl. 150-155oC;

1'-[4-(3-indolyl)-1-butyl] -Spiro[1H-2-benzopyran-4(3H), 4'- piperidine], oxalate, C, so pl. 222-225oC;

1'-[5-(3-indolyl)-1-pentyl] -Spiro[1H-2-benzopyran-4(3H),4'- piperidine], oxalate, 2H, T. pl. 145-146oC;

1'-[6-(3-indolyl)-1-hexyl] -Spiro[1H-2-benzopyran-4(3H),4'- piperidine], oxalate, 2sh, so pl. 117-118oC;

1'-[4-(5,6-dichloro-3-endolysosomes-1(3H), 4'- piperidine], 2A, so pl. 185-187oC;

1'-[4-(1-methyl-3-indolyl)-1-butyl] -Spiro[isobenzofuran-1(3H), 4'- piperidine], BB, so pl. 101-102oC;

3-[4-(4-phenyl-1-piperidyl)-1-butyl]indole, VW, so pl. 131-132oC;

3-[4-(4-(3,4-dichlorophenyl)-1-piperidyl)-1-butyl] indole, gg, so pl. 118-119oC;

5,6-dichloro-3-[4-(4-(4-forfinal)-1-piperidyl)-1-butyl] indole, d, so pl. 120-121oC;

3-[6-(4-(4-forfinal)-1-piperidyl)-1-hexyl]indole, EE, so pl. 90-91oC;

3-[4-(4-(2-methoxyphenyl)-1-piperidyl)-1-butyl]indole, oxalate, JJ, so pl. 183-188oC;

1'-[4-(1-benzyl-3-indolyl)-1-butyl] -Spiro[isobenzofuran-1(3H), 4'- piperidine], SS, so pl. 166-168oC;

3-[4-(4-(4-forfinal)-1-piperidyl)-1-butyl] indole-2-it, EE, so pl. 108-110oC;

6-fluoro-1'-(4-(3-indolyl)-1-butyl)Spiro[isobenzofuran-1(3H), 4'- piperidine], ck, so pl. 189-191oC.

Example 3.

1'-(4-(3-cyclohexylpiperidine-2-on-1-yl)-1-butyl) Spiro[isobenzofuran-1(3H),4'-piperidine] hydrochloride, 3A

A mixture of 2.0 g of 1-cyclohexyl-3-(4-chloro-1-butyl)-2 - imidazolidinone, (obtained by the method described in open display patent application Germany 2035370), 1.5 g of Spiro[isobenzofuran - 1(3H),4'-piperidine], 4.4 g of potassium carbonate and 0.1 g of potassium iodide in 60 ml of isobutyl ketone is refluxed for 17 casolo purified by chromatography on a column (silica gel, eluent: ethyl acetate/heptane/triethylamine = 9: 1: 1). The target compound crystallizes as the hydrochloride from a mixture of acetone/ether with ethereal HCl solution. The output of 1.9 g, so pl. 203-207oC>

Similarly also get:

1'-(2-(3-phenylimidazoline-2-on-1-yl)-1-ethyl) Spiro[isobenzofuran-1(3H), 4'-piperidine] hydrochloride, 3b, so pl. 151-154oC;

1'-(3-(3-phenylimidazoline-2-on-1-yl)-1-propyl) Spiro[isobenzofuran-1(3H),4'-piperidine] hydrochloride, 3V, so pl. 232-250oC;

1'-(2-(3-cyclohexylpiperidine-2-on-1-yl)-1-ethyl) Spiro[isobenzofuran-1(3H),4'-piperidine] hydrochloride, 3G, so pl. 160-161oC.

Example 4

1'-propyl-Spiro[isobenzofuran-1(3H),4'-piperidine], maleate, 4A

To a mixture of 3 g of Spiro[isobenzofuran-1(3H),4'-piperidine], 5 g of potassium carbonate and 100 ml of water in 100 ml of toluene are added dropwise to 3 g of propionitrile. After 3 hours stirring at room temperature, separated toluene phase is washed with water and concentrated in vacuo. The remaining oil is dissolved in 100 ml of tetrahydrofuran and added 1 g of sociallyengaged. After 3 hours of boiling the reaction mixture under reflux the mixture is cooled and successively add 2 ml of water, 1 ml of 9 N NaOH and 5 ml of water. The mixture is filtered and kristallizatsiya from a mixture of acetone/ether. Yield 0.7 g, so pl. 107-109oC.

Similarly also get:

1'-(5-methyl-1-hexyl)-Spiro[isobenzofuran-1(3H),4'- piperidine], oxalate, 4B, so pl. 162-164oC;

1'-(2-phenyl-1-ethyl)-Spiro[isobenzofuran-1(3H), 4'- piperidine] , maleate, 4V, so pl. 161-163oC;

1'-(3-phenyl-1-propyl)-Spiro[isobenzofuran-1(3H), 4'- piperidine], maleate, 4G, so pl. 142-144oC;

1'-(5-phenyl-1-pentyl)-Spiro[isobenzofuran-1(3H), 4'-piperidine], oxalate, 4D, so pl. 115-117oC;

1'-(6-phenyl-1-hexyl)-Spiro[isobenzofuran-1(3H),4'- piperidine], oxalate, 4E, so pl. 156-157oC;

1'-octadecenyl-Spiro[isobenzofuran-1(3H), 4'-piperidine], oxalate, j, so pl. 208-210oC.

Example 5

1'-[4-[1-(4-forfinal)-3-indolyl] -1-butyl] - Spiro[isobenzofuran-1(3H), 4'-piperidine], 5A

A mixture of 3 g of 2, 5 g of 1-fluoro-4-yogashala, 0.5 g of copper powder and 2 g of potassium carbonate in 50 ml of NRM allowed to stand 5 hours at 160-170oC. After filtering, add water, then extracted with ether. Removal of solvent in vacuo gives a red oil, which is applied on a column of silica gel (eluent: ethyl acetate). The target connection, 5A, crystallizes in the form of the oxalate salt from acetone by adding oxalic acid. Output 1.3 g, so pl. 169-170oC.

Similarly also receive the 142-143oC;

1'-[4-[1-(3-thienyl)-3-indolyl] -1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine], 5V, so pl. 182-183oC;

1'-[4-[1-(2-thienyl)-3-indolyl] -1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine], 5g, so pl. 198-202oC;

1'-[4-[1-(3-furanyl)-3-indolyl] -1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine], 5D, so pl. 141-142oC;

1-(4-forfinal)-3-[4-(4-phenyl-1-piperidyl)-1-butyl] indole, oxalate, 5e, so pl. 171-173oC;

1'-[4-[1-(4-pyridyl)-3-indolyl] -1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, j, so pl. 127-129oC.

Example 6

1'-(4-(1-methanesulfonyl-3-indolyl)-1-butyl) Spiro[isobenzofuran-1(3H), 4'-piperidine], oxalate, 6A

A solution of 20 g of NaOH in 20 ml of water cooled to 10oC and add a solution of 4 g of 4-(3-indolyl)-1-butanol in 60 ml of methylene chloride together with 0.8 g of acid tetrabutylammonium sulfate. Added dropwise 2.5 ml of methanesulfonamide in 25 ml of methylene chloride at 15oC, then stirred for 20 minutes at room temperature. Share phase and the organic phase is washed with water. Dried over magnesium sulfate and remove the solvent in vacuo, get the oil, which is purified by chromatography on a column (silica gel, eluent: ether/methylene chloride/heptane = 1:1:1) obtain 1.8 g of heavy oil, 4-(1-methanesulfonyl-3-indolyl)-1-butalbitalyour from acetone by adding oxalic acid. Yield 1.0 g, so pl. 83-85oC.

Similarly also receive:

1'-(4-(1-p-toluensulfonyl-3-indolyl)-1-butyl) Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 6b, so pl. 201-204oC;

6-fluoro-1'-(4-(1-(2-thienyl)sulfonyl-3-indolyl)-1-butyl) Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 6V, so pl. 184-186oC.

Example 7

1'-(4-(1-acetyl-3-indolyl)-1-butyl)Spiro[isobenzofuran - 1(3H),4'-piperidine], oxalate, 7

A solution of 0.8 ml of acetylchloride in 10 ml of methylene chloride are added dropwise at 15oC to a mixture of 1.8 g 2, 1 g of sodium hydroxide and 0.2 g of acid tetrabutylammonium sulfate in 40 ml of methylene chloride. After one hour of stirring at room temperature, add water, separate the organic phase and dried over magnesium sulfate, filter and remove the solvent in vacuo, get a viscous oil, which was purified by chromatography on a column (silica gel, eluent: heptane/ethyl acetate/triethylamine = 60:40:4). The target compound is crystallized in the form of the oxalate salt from acetone by adding oxalic acid. Yield 0.45 g, so pl. 139-140oC.

Example 8

1'-[3-[1-(4-forfinal)-3-indolinone] -1 - propyl] Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 8A

A mixture of 24 g of 3-atomic charges of-1-phenylindole, 240 ml of 1,3-dioxin the shape ether. The ether phase is dried over magnesium sulfate, and then remove the solvent in vacuo, the obtained 3-(1-phenyl-3-indolinone)-1 - propanol, sufficiently pure for use in the next stage.

The target connection receive according to the method described in example 2, using Spiro[isobenzofuran-1(3H),4'-piperidine], and crystallized in the form of the oxalate salt from acetone by adding oxalic acid. Output 2 g, so pl. 151-154oC.

In a similar manner were also obtained:

1'-[3-[6-chloro-1-(4-forfinal)-3-indolinone]-1 - propyl]Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 8b, so pl. 180-181oC;

1'-[3-[5-chloro-1-(4-forfinal)-3-indolinone]-1-butyl] Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 8V, so pl. 115-118oC;

5-chloro-1-(4-forfinal)-3-[3-(4-(4-were)-1 - piperidinyl)-1-propyloxy]indole, 8D, so pl. 111-112oC.

Example 9

1'-[4-[1-(4-forfinal)-3-indolyl] -1-butyl]Spiro[1H-2 - benzopyran-4(3H), 4'-piperidine], maleate, 9a

Added dropwise to 500 ml of tertrahydrofuran ring solution of 103 g of methyl-4(3-indolyl)-butyrate to a suspension of 25 g of sociallyengaged in 1000 ml of tetrahydrofuran at 40oC, followed by stirring for one hour at room temperature. Normal processing network 96 g of 4-(3-indolyl)-1 - butanol which is converted into the target compound 9a by the method, described in example 2, using Spiro[1H-2-benzopyran-4(3H), 4'-piperidine] . Maleato salt crystallized from acetone with the addition of maleic acid. Output 1.5 g, so pl. 189-190oC.

Similarly also get:

1'-[4-[5-fluoro-1-(4-forfinal)-3-indolyl] -1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 9b, so pl. 164-165oC;

1'-[4-[1-(4-forfinal)-3-indolyl] -1 - butyl]Spiro[benzo[c]thiophene-1(3H), 4'-piperidine], maleate, 9V, so pl. 179-180oC;

8'-[4-[1-(4-forfinal)-3-indolyl] -1 - butyl] Spiro[isobenzofuran-1(3H), 3'-8-azabicyclo[3,2,1]Octan], maleate, 9g, so pl. 161-162oC;

6-fluoro-1'-[4-[1-(4-forfinal)-3-indolyl] -1-butyl]Spiro [isobenzofuran-1(3H),4'-piperidine] hydrochloride, 9D, so pl. 227-231oC;

1'-[4-[1-(4-forfinal)-3-indolyl]-1-butyl]-6 - isopropyl]Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 9F, so pl. 129-144oC;

7-fluoro-1'-[4-[1-(4-forfinal)-3-indolyl] -1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, j, so pl. 186-189oC;

1'-[4-[1-(4-forfinal)-3-indolyl]-1-butyl]-5 - methyl]Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, s, so pl. 154-156oC;

1'-[4-[1-(4-were)-3-indolyl]-1-butyl]Spiro[1H - 2-benzopyran-4(3H), 4'-piperidine], fumarate, 9, so pl. 186-188oC;

1'-[4-[5-fluoro-1-(3-thienyl)-3-indolyl] -1-butyl] -Spiro [isobenzo the h-4(3H), 4'-piperidine], fumarate, 9L, so pl. 185-187oC;

1-(4-forfinal)-3-[4-(4-(4-forfinal)-1-piperidyl)-1 - butyl]indole, oxalate, 9M, so pl. 190-191oC;

1-(4-forfinal)-3-[4-(4-(4-were)-1-piperidine)-1 - butyl]indole maleate, n, so pl. 130-132oC;

1-(4-forfinal)-3-[4-(4-(4-isopropylphenyl)-1-piperidyl) -1-butyl]indole maleate, o, so pl. 160-162oC;

1-(4-forfinal)-3-[4-(4-(4-dimethylaminophenyl)-1 - piperidyl)-1-butyl]indole fumarate, 9P, so pl. 180-182oC;

1-phenyl-3-[4-(4-(4-forfinal)-1-piperidyl)-1-butyl] indole, oxalate, 9R, so pl. 174-176oC;

1'-[4-(1-(2-thiazolyl)-3-indolyl)-1 - butyl] Spiro[isobenzofuran-1(3H), 4'-piperidine], fumarate, 9s, so pl. 165-167oC;

6-trifluoromethyl-1'-[4-[1-(4-forfinal)-3-indolyl]-1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine], fumarate, 9T, so pl. 100-105oC;

4-fluoro-1'-[4-[1-(4-forfinal)-3-indolyl] -1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 9U, so pl. 160-163oC;

1-(4-forfinal)-3-[4-(4-(3-triptoreline)-1 - piperidyl)-1-butyl]indole maleate, 9F, so pl. 112-113oC;

2,3-dihydro-1'-[4-[1-(4-forfinal)-3-indolyl]-1 - butyl]Spiro[4H-1-benzopyran-4,4'-piperidine], oxalate, 9ץ, so pl. 187-192oC;

6-fluoro-1'-[4-[5-fluoro-1-(4-forfinal)-3-indolyl]- 1-butyl]Spiro[isobenzofuran-1(H),4'-piperidine], oxalate, C, so pl. 144-146oC.

g methyl-benzol[b]thiophene-3-racette in 100 ml of dry tetrahydrofuran are added dropwise to a suspension of 10 g of sociallyengaged in 500 ml of dry tetrahydrofuran at room temperature, then boiled for 1 hour under reflux. Hydrolyzing water, filter and remove the solvent to obtain the oil, which is applied on a column of silica gel (eluent: methylene chloride), get to 34.5 g of benzo[b]thiophene-3-retinol in the form of butter.

The product is dissolved in 200 ml of methylene chloride, was added 20 ml of thionyl chloride, and then boiled for 5 hours under reflux. Remove the solvent and excess thionyl chloride in vacuo, get 45 grams of 3-(2-chloro-1-ethyl)-benzo[b] thiophene in the form of butter.

Chloride is converted into 4-benzo[b] thiophene-3-yl-1-butanol by processing diethylmalonate followed by hydrolysis, decarboxylation restoration by the method described in example 11.

The target connection 10A is obtained from 4-benzo[b]thiophene-3-yl - 1-butanol and Spiro[isobenzofuran-1(3H),4'-piperidine] according to the method described in example 2. Output 2.2 g, so pl. 144-145oC.

Similarly also get:

1,4-dihydro-1'-(4-(benzo[b] thiophene-3-yl)-1-butyl) Spiro[3H-2-benzopyran-3,4'-piperidine], maleate, 10B, so pl. 172-173oC;

1'-(4-(5-methylbenzo[b] thiophene-3-yl)-1-butyl) Spiro[isobenzofuran-1(3H), 4'-piperidine], maleate, 10V, so pl. 164-165oC.

Example 11

2,3-dihydro-5-fluoro-3-[3-(4-(4-forfinal)-1-piperidyl)-1 - propyl] benzo is melhorada and 1 ml of dimethylformamide. After 3 hours boiling under reflux, the reaction mixture was concentrated in vacuo and the remaining oil is dissolved in 800 ml of dichloromethane. Slowly add 1.5 l of methanol and stirred the mixture for 1 hour. After removal of solvent in vacuo remains 125 g methyl-5-perbendaharaan-3-carboxylate in the form of butter.

The oil is dissolved in 1.8 l of methanol and add 7 g of magnesium shavings. After start of the reaction add an additional 80 g of magnesium portions over 1.5 hours, maintaining the reaction temperature 30-40oC. the Reaction mixture is stirred for 1 hour, then add aqueous ammonium chloride. Extracted with ether, the ether phase is dried over sodium sulfate, then remove the solvent in vacuo, is a viscous oil, methyl-2,3-dihydro-5-perbendaharaan-3-carboxylate (120 g).

The oil is dissolved in 500 ml of dry ether and added dropwise to a suspension of 32 g of sociallyengaged in 600 ml of dry ether. The mixture is boiled for 3 hours under reflux, then hydrolyzing with water. Filtration and removal of solvent in vacuo to give 95 g of 2,3-dihydro - 5-fluoro-3-oxidativestress, which in turn 155 g of 2,3-dihydro-5-perbendaharaan-3-ylmethylphosphonate according to the method described in example 2.

Dissolve
C. the Mixture is heated at 60oC and added dropwise a solution of 155 g of 2,3-dihydro-5-perbendaharaan-3-ylmethylphosphonate in 150 ml of NRM. The mixture is stirred for 4 hours at 70-75oC, then add cold water. Extracted with ether, the ether phase is dried over magnesium sulfate, and then remove the solvent in vacuo, obtain 160 g of 2-(2,3-dihydro-5-perbendaharaan-3-ylmethyl)malonate in the form of oil, which is pure enough for further synthesis.

The oil is dissolved in 2 l of ethanol and add a mixture of 120 g of solid potassium hydroxide and 200 ml of water, then 2 hours and refluxed. The reaction mixture was concentrated in vacuo, added water, then extracted with ether. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is distilled off in vacuum, get a viscous oil, which was dissolved in 1 l of NRM and incubated for 2 hours at 150oC. Add water and extracted with ether, obtained after drying over magnesium sulfate and removal under vacuum of the solvent 77 g of 3-(2,3-dihydro-5 - perbendaharaan-3-yl)-propionic acid. Recovery sociallyengaged by the above method gives 51 g of 3-(2,3-dihydro-5-forbe the soba, described in example 2.

The target connection 11a receive from 4.2 g of 3-(2,3-dihydro-5 - perbendaharaan-3-yl)-1-propylaminosulfonyl and 5.5 g of 4-(4-forfinal)piperidine according to the method described in example 2. Yield 1.8 g, so pl. 83-85oC.

Similarly also get:

1'-[3-(2,3-dihydro-5-perbendaharaan-3-yl)-1 - propyl]Spiro[isobenzofuran-1(3H),4'-piperidine], 11b, so pl. 62-63oC;

Example 12

1'-[4-(2,3-dihydro-5-perbendaharaan-3-yl)-1-butyl]- Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 12

3-(2,3-dihydro-5-perbendaharaan-3-yl)-1-propanol obtained by the method of example 11 (51 g) is dissolved in 300 ml of dichloromethane was added 0.5 ml of dimethylformamide. Added dropwise 50 ml of thionyl chloride for 20 minutes, then stirred for 3 hours. Add ice water, the organic phase is separated, dried over magnesium sulfate and concentrated in vacuo, to obtain 46 g of 3-(3-chloro-1-propyl)-2,3-dihydro-5-perbendaharaan in the form of butter.

Suspended 12 g of potassium cyanide in 180 ml of dimethyl sulfoxide is heated to 80oC. was Added dropwise a solution of 42 g of 3-(3-chloro-1 - propyl)-2,3-dihydro-5-perbendaharaan in 40 ml of dimethyl sulfoxide and then 15 minutes heated at 140oC. After cooling, add ether and water, separate the scoe oil, which is applied on a column of silica gel, get 20 g of 4-(2,3-dihydro-5-perbendaharaan-3-yl)butyronitrile in the form of butter.

Cyanide is dissolved in 100 ml of glacial acetic acid, then add 200 ml of concentrated hydrochloric acid. After 5 hours boiling under reflux, water is added, then extracted with ethyl acetate. Drying the organic phase over magnesium sulfate and removal of solvent in vacuo gives 20 g of 4-(2,3-dihydro-5 - perbendaharaan)butyric acid.

Dissolve 8 g of acid in 50 ml of dichloromethane and add 0.5 ml of dimethylformamide. Add 20 ml of thionyl chloride, and then refluxed for 1.5 hours. The reaction mixture is twice concentrated in vacuo with heptane, to obtain 7 g of acid chloride of 4-(2,3-dihydro-5-perbendaharaan-3-yl)butyric acid in the form of butter.

Cooled to 5oC a solution of 2 g of Spiro[isobenzofuran-1(3H)4'- piperidine] and 3 ml of triethylamine in 50 ml dichloromethane and added dropwise a solution of 3 g of acid chloride of 4-(2,3-dihydro-5 - perbendaharaan-3-yl)butyric acid in 25 ml of dichloromethane. After 1 hour stirring at room temperature the reaction mixture is washed with salt water and dried over magnesium sulfate. Upon removal of solvent in vacuum and 2.6 g of sociallyengaged in 60 ml of dry tetrahydrofuran. The reaction mixture is refluxed for 2 hours and hydrolyzing water. Filtration and removal of solvent in vacuo to give a viscous oil, which is applied on a column of silica gel (eluent: heptane/ethyl acetate/triethylamine = 70:25:5), obtain 2.9 g of target compound 12, which crystallized in the form of the oxalate salt from acetone by adding oxalic acid. Output 2.2 g so pl. 102-103oC.

Example 13

1'-[4-(2,3-dihydro-3-indolyl)-1-butyl] Spiro[1,3 - benzodioxole-2,4'-piperidine], oxalate, 13A

To a solution of 4 g 25B and 10 g BH3-NMe3; in 100 ml of dioxane, was added 12 ml of concentrated hydrochloric acid. After 0.5 hour of stirring the mixture for 2 hours, refluxed. The mixture is cooled to room temperature and add 40 ml of 6N hydrochloric acid, then 1 hour and refluxed. Alkalinized reaction mixture of aqueous sodium hydroxide and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and the solvent is distilled off in vacuum. Get orange oil, which is applied on a column of silica gel (eluent: ethyl acetate/heptane/triethylamine = 70:28:2). The target connection 13A crystallized in the form of the oxalate salt from acetone by adding oxalic KIS is a Lil)-1 - butyl] Spiro[isobenzofuran-1(3H), 4'-piperidine], oxalate, 13B, so pl. 161-164oC;

1'-[4-(2,3-dihydro-3-indolyl)-1-butyl] Spiro[1H-2 - benzopyran-4(3H),4'-piperidine], oxalate, 13B, so pl. 105-107oC;

2,3-dihydro-3-[4-(4-(2-methoxyphenyl)-1-piperidinyl)-1 - butyl]indole, oxalate, 13 g, so pl. 160-162oC.

Example 14

1'-[2-[5-chloro-1-(4-forfinal)-3-indolinone]-1 - ethyl]Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 14a

To a solution of 50 g of methyl 5-chloro-1-(4-forfinal)-3-indole-2 - carboxylate and 40 g of potassium carbonate in 500 ml of acetone are added dropwise while boiling under reflux 35 g ethylbromoacetate in 100 ml of acetone. After 6 hours boiling under reflux, the mixture is filtered and distilled in a vacuum solvent. The addition of water and extraction with ether to give after drying over magnesium sulfate and removal of the solvent in vacuum, 62 g of a viscous oil methyl-5 - chloro-3-ethoxycarbonylmethoxy-1-(4-forfinal)-indole-2-carboxylate.

The oil is dissolved in 800 ml of ethanol and added 30 g of potassium hydroxide. Boiled for 4 hours under reflux, was added 4 g of crushed ice, then acidified with hydrochloric acid to obtain a colorless solid, which was dissolved in 250 ml of NRM. Add 5 g of copper bronze and the mixture is kept for 4 hours at 200oC. Adding to the EOS-1-(4 - forfinal)-3-indoleacetate acid.

The acid is dissolved in 500 ml of tetrahydrofuran and added 4 g of sociallyengaged. After 3 hours boiling under reflux, the reaction mixture was hydrolized with water, filtered and concentrated in vacuo, to obtain 18 g of 5-chloro-1-(4-forfinal)- 3-(2-acetyloxy)-indole in the form of butter.

The oil is dissolved in 250 ml dichloromethane and added 10 ml of triethylamine. Added dropwise 10 ml of methanesulfonanilide at 0-5oC, then stirred for 4 hours. The reaction mixture is washed with water, dried over magnesium sulfate and concentrated in vacuo, get 21 g of 5-chloro-1-(4-forfinal)-3-indolealkylamine in the form of a viscous oil.

1'-[2-[5-chloro-1-(4-forfinal)-3-indolinone]-1 - ethyl]Spiro[isobenzofuran-1(3H),4'-piperidine], 14a, obtained from 3 g of 5-chloro-1-(4-forfinal)-3-indolocarbazoles and Spiro[isobenzofuran-1(3H),4'-piperidine] according to the method of example 2, followed by purification by chromatography on a column (silica gel, eluent: ethyl acetate). The target compound is crystallized in the form of the oxalate salt from acetone. Yield 0.8 g, so pl. 216-217oC.

Similarly also receive;

5-chloro-1-(4-forfinal)-3-[2-(4-(4-forfinal)-1 - piperidinyl)-1-teletaxi]indole, 14b, so pl. 102-105oC.

Example 15

1'-(3 is the group of 3 g of 3-(5-perbendaharaan-3-yl)- propionic acid and 2 g of Spiro[isobenzofuran-1(3H),4'- piperidine] according to the method, described in example 12. Get 3-(5-perbendaharaan-3-yl)-propionic acid according to the method similar to the method of preparation of 3-(2,3-dihydro-5-perbendaharaan-3-yl)-propionic acid of example 11, but omitting the recovery of magnesium shavings. The target compound 8 is crystallized in the form of the oxalate salt from acetone by adding oxalic acid. Yield 2.6 g, so pl. 157-159oC.

Example 16

1'-[4-(5-perbendaharaan-3-yl)-1-butyl] -Spiro[isobenzofuran - 1(3H),4'-piperidine], oxalate, 16

Get the target connection from 3.5 g of 4-(5-perbendaharaan-3 - yl)butyric acid and 3 g of Spiro[isobenzofuran-1(3H),4'-piperidine] according to the method described in example 12. Receive a 4-(5-perbendaharaan - 3-yl)butyric acid by the method analogous to obtain 4-(2,3-dihydro-5-perbendaharaan-3-yl)butyric acid as described in example 12 using 3-(5-perbendaharaan-3-yl)-1-propanol instead of the corresponding dihydro-analogue. 3-(5-perbendaharaan-3-yl)-1 - propanol receive according to the method described in example 11, but omitting the recovery of magnesium shavings. The target connection 16 is crystallized in the form of the oxalate salt of acetate by adding oxalic acid. Yield 4.8 g, so pl. 154-156oC.

Example 17

1'-[4-[1-(4-forfinal)-5-cryptometrics-3-yl] the of hydrofuran slowly added 140 g of ethylbromide, dissolved in 500 ml of dry tetrahydrofuran, then 20 minutes is refluxed. Add dropwise a solution of 274 g of 4-chloro-1-butanol in 500 ml of tetrahydrofuran at the boiling point under reflux. After 20 minutes of stirring Grigorovici the solution is filtered and added in portions to a solution of 200 g of 2-chloro-4 - triftormetilfosfinov in 600 ml of dry tetrahydrofuran. The reaction mixture is stirred 16 hours at room temperature, then added 2N hydrochloric acid and ice. Extracted with ether, the ether phase is dried over magnesium sulfate and remove the solvent in vacuo, get a viscous oil, which is applied on a column of silica gel (eluent: dichloromethane/ether = 3:1) obtain 101 g of 4-(2-chloro-5-trifloromethyl)-1-butanol in the form of butter.

Dissolve 80 g of oil in 800 ml of ethanol and added to 160 ml of hydrazine hydrate is added, and then boiled for 20 hours under reflux. The reaction mixture is cooled and concentrated in vacuo. Add the water, then extracted with ether. The ether phase is dried over magnesium sulfate and remove the solvent in vacuo, obtain 79 g of the hydrazone of 4-(2-chloro-5-trifloromethyl)-1-butanol in the form of oil. Dissolve 20 g of the hydrazone in dimethylformamide and added 10 g of tert. extravert with ethyl acetate, dried an ethyl acetate phase over magnesium sulfate and remove the solvent in vacuo, get a viscous oil, which is applied on a column of silica gel (eluent: ethyl acetate), to obtain 2.7 g of crystalline 4-(5-trifluoromethyl-3-indazole)-1-butanol, T. pl. 177-179oC. Arriraw 2.7 g of indazole 5 g of 1-fluoro-4-yogashala according to the method described in example 5, to obtain 2.7 g of 4-[1-(4-forfinal)-5 - trifluoromethyl-3-indazole] -1-butanol, T. pl. 77-79oC, which is converted into the corresponding methanesulfonate by the method described in example 2. Get the target connection 17A of 2 g methanesulfonate and 2 g of Spiro[isobenzofuran-1(3H), 4'- piperidine] according to the method described in example 2. Yield 1.7 g, so pl. 74-76oC.

Similarly also get:

4-forfinal-3-[4-(4-(4-forfinal)-1-piperidinyl)- 1-butyl]-5-cryptomaterial, 17B, so pl. 124-125oC.

Example 18

1'-[4-(3-cryptomaterial-3-yl)-1-(butyl]-Spiro [isobenzofuran-1(3H), 4'-piperidine], 18

Receive a 4-(2-chloro-5-trifloromethyl)-1-butanol according to the method of example 17 and transform it to the corresponding methanesulfonate by the method described in example 2. Processing Spiro[isobenzofuran-1(3H),4'-piperidine] according to the method described in example 2, get 1'-[4-(2-chloro-5-triptoreline is on the way described in example 17 gives the target connection 18, so pl. 146-147oC.

Example 19

1'-(4-(1,2-benzisoxazol-3-yl)-1-butyl)Spiro[isobenzofuran - 1(3H),4'-piperidine], oxalate, 19a, so pl. 164-165oC

A solution of 18 g of 1,2-benzisoxazol-3-acetic acid (obtained by G. Casini et al, J. Het.Chem.6, 1969, 279), 150 ml of ether saturated with dry HCl and 200 ml of methanol is stirred for 2 hours at room temperature. Remove the volatiles in vacuo, obtain 17 g of methyl-1,2-benzisoxazol-3-acetate in the form of oil. The oil is dissolved in 100 ml of tetrahydrofuran and added dropwise to a suspension of 6 g of sociallyengaged in 200 ml of tetrahydrofuran at 0 to 10oC, then stirred for 30 minutes at 15oC. Normal processing gives 13 g of 2-(1,2-benzisoxazol-3-yl)ethanol in the form of butter.

Turn 13 g of ethanol derived in the corresponding methanesulfonate by the method described in example 2 (yield 20 g). A solution of 20 g of methansulfonate in 20 ml of dimethyl sulfoxide was added to a suspension of 15 g of sodium cyanide in 40 ml of dimethyl sulfoxide at 70oC, then 30 minutes, stirred at 70-80oC. Add water and ether, the separated phase and the ether phase is dried over magnesium sulfate. After removal of solvent in vacuo obtain 13 g of 3-(1,2-benzisoxazol-3-yl)propionitrile Ifira, then stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, added water and ether and separated phases. The ether phase is dried over magnesium sulfate and the solvent is distilled off in vacuum, 13 g of methyl-3-(1,2-benzisoxazol-3-yl)propionate in the form of butter.

By repeating the above stages turn 3-(1,2-benzisoxazol-3-yl)propenal in methyl-4-(1,2-benzisoxazol-2 - yl)butyrate, which restores sociallyengaged by the procedure described above, 4-(1,2-benzisoxazol-3-yl)-1 - butanol. According to the method described in example 2, to obtain 4-(1,2-benzisoxazol-3-yl)-1-butylmalonate.

Get the target connection 19a of 3.4 g of 4-(1,2-benzisoxazol - 3-yl)-1-butylmalonate and 2 g of Spiro[benzofuran-1(3H), 4'- piperidine] according to the method described in example 2. Oxalate salt crystallized from acetone by adding oxalic acid. Output 2.4 g so pl. 164-165oC.

Similarly also receive:

3-[4-(4-(4-forfinal)-1-piperidyl)-1-butyl]-1,2 - benzisoxazol, oxalate, 19b, so pl. 174-175oC;

1-(4-(1,2-benzisoxazol-3-yl)-1-butyl)Spiro[3H-2 - benzopyran-3,4'-piperidine], oxalate 19c, so pl. 162-163oC;

3-[4-(4-(2,6-dichlorophenyl)-1-piperidyl)-1-butyl]-1,2 - benzisoxazol, fumarate, 19 Eridan], oxalate, 20, so pl. 131-132oC.

Get the target connection 20 of 3.2 g of 3-(1,2-benzisoxazol-3-yl)-1-propanol (obtained as described in example 19) and 2 g of Spiro[isobenzofuran-1(3H), 4'-piperidine] according to the method of example 2. The product is crystallized from acetone in the form of the oxalate salt by adding oxalic acid. Output 2.3 g, so pl. 131-132oC.

Example 21

3-[3-(4-(4-forfinal)-piperidine-1-yl)-1-propyloxy] -1,2 - benzisothiazol, 21

A mixture of 15 g of 4-(4-ftoheia)-piperidine, 20 g of ethyl-3-bromopropionate and 14 g of potassium carbonate in the mixture is refluxed for 16 hours. After filtration and removal of solvent in vacuo obtain 26 g of crude ethyl-3-(4-(4 - forfinal)-1-piperidyl)propionate in the form of oil, which is used directly in the next stage.

The oil was dissolved in 70 ml of dry tetrahydrofuran and added dropwise to a suspension of 6.5 g of sociallyengaged in 250 ml of dry tetrahydrofuran under 15oC in nitrogen atmosphere. After 30 minutes stirring at room temperature was added to 6.5 ml of water, 7 ml of 10 N sodium hydroxide and 30 ml of water successively. After filtration and removal of solvent to obtain 20 g of crude 3-(4-(4-forfinal)-1-piperidyl)-1-propanol in the form of oil to the propanol in 150 ml of dry toluene is treated with portions of 50% suspension of 3 g of sodium hydride in xylene. A solution of 3.6 g of 3-chloro-1,2-benzisothiazole in 30 ml of dry toluene are added dropwise at room temperature, then stirred for 1.5 hours at room temperature. Add ice, split phase and the aqueous phase is extracted with ether.

Drying of the combined organic phases over magnesium sulfate and removal of solvent in vacuo gives an oil which is applied to the chromatographic column (silica gel, eluent: ethyl acetate/heptane/triethylamine = 50:50:4). The target connection 21 is crystallized from isopropyl ether/heptane. Output 1.5 g, so pl. 91-92oC.

Example 22

1'-(4-(1,2-benzisothiazol-3-yl)-1-butyl)- Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 22

Dissolve 17 g of 4-(1,2-benzisothiazol-3-yl)butyric acid (C. Branca et al, Phytochemistry, 14, 1975, 2545) in 500 ml dry toluene and cooled to -10oC. are Added dropwise to 120 ml of 1 M solution of di-tert.butylaminoethyl in toluene at -10oC, then stirred for 2 hours at room temperature. Add 300 ml of 2 M diluted sulfuric acid, separate the phases, the aqueous phase is extracted with ether and the combined organic phases are dried over magnesium sulfate. The solvent is distilled off in vacuum, get a viscous oil, which was purified through column chromatography left join 22 from 4-(1,2-benzisothiazol-3-yl)- 1-butanol and Spiro[isobenzofuran-1(3H),4'-piperidine] according to the method, described in example 2. Oxalate salt crystallized from acetone by adding oxalic acid. Output 2 g, so pl. 151-152oC.

Example 23

1-(4-forfinal)-3-[4-[3-(4-forfinal)-8 - azabicyclo[3,2,1]-Oct-2-EN-8-yl]-1-butyl]-indole, 23

A mixture of 600 ml of dry ether and 500 ml of 15%, utility in hexane cooled to -45oC. was Added dropwise a solution of 145 g of 4-bromo-1-fervently in 350 ml of dry ether at -45oC, then stirred for 1 hour. Add dropwise a solution of 85 g of 8-methyl - 8-azabicyclo[3,2,1]Octan-3-one in 400 ml of dry ether at -50oC, then stirred for 30 minutes, raising the temperature to -20oC. the Reaction mixture was poured into 2 M hydrochloric acid and is divided into phases. The ether phase is extracted with 2 M hydrochloric acid and alkalinized combined aqueous phase aqueous sodium hydroxide. Extraction acetylaceton, drying the organic phase over magnesium sulfate and removal of solvent in vacuo gives 96 g of 3-(4-forfinal)-3-hydroxy-8-methyl-8-azabicyclo[3,2,1]octane in the form of a solid product, so pl. 169oC.

The product is dissolved in 500 ml triperoxonane acid, then 1 hour and refluxed. The reaction mixture was concentrated in vacuo, water is added and the mixture is alkalinized water hydroxide intothree is the Aquum give 3-(4-forfinal)-8-methyl-8 - azabicyclo[3,2,1]Oct-2-ene in the form of a solid product (91 g, so pl. 62-63oC).

The product is dissolved in 550 ml of 1,1,1-trichloroethane and heated at 70oC. was Added dropwise a solution of 14 ml of 2,2,2-trichlorethylphosphate in 25 ml of 1,1,1-trichloroethane at 70oC, then 1 hour and refluxed. Add additional 24 ml of 2,2,2-trichlorethylphosphate, then boiled for 5 hours under reflux. Removal of volatiles in vacuo and purification by chromatography on a column (silica gel, eluent: methylene chloride) to give 3-(4-forfinal)-8-(2,2,2-Trichloroisocyanuric)-8-azabicyclo[3,2,1] Oct-2-ene (59 g) in the form of butter.

Dissolve 17 g of (4-forfinal)-8- (2,2,2-Trichloroisocyanuric)-8-azabicyclo[3,2,1]Oct-2-ene in 170 ml of glacial acetic acid, then add 20 ml of water. The mixture is heated to 50oC and add 40 g of zinc powder portions. After 2 hours of stirring at 50oC the mixture is filtered and concentrated in vacuo. Add water and alkalinized a mixture of aqueous sodium hydroxide. Extraction with ethyl acetate, drying the organic phase over magnesium sulfate and removal of solvent in vacuo gives 7 g of 3-(4-forfinal)-8-azabicyclo[3,2,1]Oct-2-ene in the form of butter.

Get the target connection 23 from 3-(4-forfinal)-8 - azabicyclo[3,2,1] Oct-2-ene according to the method described in the example is-benzisoxazol, oxalate, 24, so pl. 169-170oC

A solution of 10 g of 3-(4-forfinal)-8-azabicyclo[3,2,1]Oct-2-ene are dissolved in 150 ml of glacial acetic acid. Add 0.5 g of platinum oxide, and then treated with gaseous hydrogen at a pressure of 3 atmospheres in the conventional apparatus Parra. Filtration and removal of solvent in vacuo gives a viscous oil. Add water and the mixture is alkalinized (pH > 9) water sodium hydroxide. Extracted with ethyl acetate, the organic phase is dried over magnesium sulfate and remove the solvent in vacuo, obtain 9 g of 3-(4-forfinal)-8-azabicyclo[3,2,1]octane in the form of oil. Get the target connection 24 from 3-(4-forfinal)-8 - azabicyclo[3,2,1]octane and 4-(1,2-benzisoxazol-3-yl)-1 - butylmalonate (obtained as described in example 19) by the method described in example 2. Oxalate salt crystallized from acetone by adding oxalic acid. Output 1.1 g, so pl. 169-170oC.

Example 25

1'-(4-phenyl-1-butyl)-Spiro[1,3-benzodioxole - 2,4'-piperidine] , maleate, 25A

A mixture of 17 g of 1-etoxycarbonyl-4-piperidinol, 13 g of pyrocatechol and 2.5 g of p-toluensulfonate acid in 250 ml of dry toluene is refluxed with continuous removal of water. After 3 hours the reaction mixture was concentrated in vacuo, add 200 ml of 2% n is Italia in vacuum the remaining red oil is applied on a column of silica gel (eluent: ethyl acetate/heptane = 1:1), get 22 g of light yellow oil, 1'-etoxycarbonyl-Spiro[1,3-benzodioxole-2,4'- piperidine].

The oil is dissolved in 250 ml of ethanol is added 10 g of sodium hydroxide and 20 ml of water, the mixture is refluxed for 20 hours. Removal of solvent in vacuo, add salted water and subsequent extraction with dichloromethane gives after drying the organic phase over magnesium sulfate and removal of solvent in vacuo red oil, which is applied on a column of silica gel (eluent: ethyl acetate/methanol/triethylamine = 4:5:1) obtain 10 g of colorless crystals Spiro[1,3-benzodioxole-2,4'- piperidine], so pl. 108-110oC.

The target compound 25A was obtained from 2.3 g of 4-phenyl-1-butyl - methansulfonate and 1.9 g of Spiro[1,3-benzodioxole-2,4'-piperidine] according to the method described in example 2, crystallized in the form of maleate salt from acetone by addition of maleic acid. Yield 1.6 g, so pl. 156-157oC.

Similarly also get:

1'-[4-(3-indolyl)-1-butyl]-Spiro[1,3-benzodioxole-2,4'- piperidine], 25B, so pl. 144-149oC.

Example 26

1'-[4-(4-forfinal)-4-hydroxy-1-butyl] -Spiro[isobenzofuran - 1(3H), 4'-piperidine], oxalate, 26a

Dissolve 2 g of 1'-(3-(4-perbenzoic)-1-propyl)- Spiro[isobenzofuran-1(3H), 4 according to the method described in example 1, in 100 ml of ethanol. Add 0.1 g of palladium oxide and the mixture hydronaut in a Parr apparatus under hydrogen pressure of 3 ATM for 16 hours. Filtration and concentration in vacuo to give after adding a mixture of ethyl acetate/acetone crystalline 26a. Output 1.5 g, so pl. 75-80oC.

Similarly also get:

1'-(4-phenyl-4-hydroxy-1-butyl)- Spiro[isobenzofuran-1(3H), 4'-piperidine] , 26B, so pl. 139-140oC;

1'-(4-cyclohexyl-4-hydroxy-1-butyl)-Spiro[isobenzofuran - 1(3H), 4'-piperidine], oxalate, 26V, so pl. 87-89oC.

Example 27

1'-(4-(1H-inden-3-yl)-1-butyl-Spiro[isobenzofuran-1(3H), 4'- piperidine], 27

A suspension of 80 g of activated zinc in 200 ml of dry tetrahydrofuran is refluxed and add a few crystals of iodine. Add dropwise a solution of 100 g of 1-indanone and 200 g of methyl-4-bromocrotonate in 500 ml of dry tetrahydrofuran, then refluxed for 1 hour. After cooling, add ice and aqueous ammonium chloride, then extracted with dichloromethane. Removal of solvent in vacuo gives a viscous oil which is purified on a column of silica gel (eluent: dichloromethane/ether = 1:1) obtain 78 g of methyl-4(1-aksiondan-1-yl)-crotonate. Dissolve 20 g crotonate in 200 ml of dry apacheria under reflux, the reaction mixture was hydrolized with water. Filtering, drying the ether phase over magnesium sulfate and removal of solvent in vacuo gives 18 g of 4-(1-aksiondan-1-yl)-1-butanol in the form of butter.

Dissolve 16 g of alcohol in 250 ml of methanol and added 40 ml of concentrated hydrochloric acid. After 30 minutes stirring at room temperature the reaction mixture was concentrated in vacuo, added water and extracted with a mixture of ether. Drying of the ether phase over magnesium sulfate and removal of solvent in vacuo to give a viscous oil, which is applied on a column of silica gel (eluent: dichloromethane/ether = 9:1) obtain 1.8 g of 4-((1H)inden-3-yl)-1 - butanol.

According to the method described in example 2, the alcohol is transformed into the corresponding methanesulfonate and get the target compound 27 using Spiro[isobenzofuran-1(3H),4'-piperidine], so pl. 79-80oC.

Example 28

1'-[4-(indan-1-yl)-1-butyl] -Spiro[isobenzofuran - 1(3H)4'-piperidine] , oxalate, 28

A suspension of 40 g of activated zinc in 150 ml of dry tetrahydrofuran is refluxed and add a few crystals of iodine. A solution of 50 g of 1-indanone and 100 g methyl-4-bromocrotonate in 400 ml of dry tetrahydrofuran are added dropwise, then 1 hour and refluxed. After cooling primav is the formation of the organic phase gives a viscous oil, which is dissolved in 400 ml of methanol. Add 100 ml of concentrated hydrochloric acid and the mixture is stirred for 30 minutes. Removal of solvent in vacuo, addition of water and extraction with ether to give after drying over magnesium sulfate and removal of solvent in vacuo 34 g of oil. The oil is dissolved in 300 ml of dry ether and added dropwise to a suspension of 21 g of sociallyengaged. After 2 hours boiling under reflux, the reaction mixture was hydrolized with water. Filtration and removal of solvent in vacuo gives a mixture of isomers, which can be allocated 6 g of 4-(1-indanyl)-but-3 - EN-1-ol by chromatography on a column (silica gel, eluent: dichloromethane/ether = 9:1). The remaining mixture of isomers (9 g) was dissolved in 150 ml of methanol and hydronaut when the hydrogen pressure of 3 ATM in normal Parr apparatus in the presence of 5% palladium on coal for 12 hours. Filtration and removal of solvent in vacuo gives 6 g of 4-(1-indanyl)-1-butanol.

Turn the alcohol into the target connection 28 through the corresponding methanesulfonate by the method described in example 2, using Spiro[isobenzofuran-1(3H),4'-piperidine], so pl. 114-115oC.

Example 29

1'-[4-(1-indanyl)-but-3-EN-1-yl] -Spiro[isobenzofuran - 1(3H),4'-piperidine], oxalate, 29

the technique of example 2. The target connection receive according to the method of example 2, using Spiro[isobenzofuran-1(3H), 4'-piperidine], so pl. 108-109oC.

Example 30

1'-(4-(2,3-dihydro-1-(4-forfinal)-3-indolyl)-1-butyl)- Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 30

Added dropwise to a solution of 5 g 5A 30 ml triperoxonane acid, 0.5 g of tianpingjia of sodium in 25 ml of methanol. After 2 hours stirring at room temperature the mixture was concentrated in vacuo, add 50 ml of ethyl acetate, then washed with 2 x 50 ml 2 N sodium hydroxide. Drying the organic phase over sodium sulfate and remove solvent in vacuo to give the target base, which crystallized in the form of oxalate from acetone by adding oxalic acid. Yield 0.7 g, so pl. 172-173oC.

Example 31

1'-[3-(benzo[b] thiophene-3-ylthio)-1 - propyl]Spiro[isobenzofuran-1(3H),4'-piperidine], maleate, 31A

Refluxed for 18 hours, a solution of 20 g of benzo[b]thiophene-3-one, 25 g of 3-mercaptopropionic acid, 3 ml of 2 N hydrochloric acid in 80 ml of xylene. Add 100 ml of water and 300 ml of ether and separated phases. The ether phase is extracted with 150 ml of 2 N sodium hydroxide, then alkaline phase is acidified with concentrated hydrochloric acid.

Extraction of EPS is-ylthio)-propionic acid.

The acid is dissolved in 100 ml of tetrahydrofuran and added dropwise to a suspension of 4 g of sociallyengaged in 150 ml of tetrahydrofuran. After 3 hours boiling under reflux, the reaction mixture was quenched with water, then during normal processing gain of 12.7 g of 3-(benzo[b]thiophene-3-ylthio)-1-propanol in the form of butter.

The target connection 31A receive by way of example 2, using Spiro[isobenzofuran-1(3H),4'-piperidine], and crystallized as the maleate from acetone by addition of maleic acid. Yield 0.9 g, so pl. 154-155oC.

Similarly also get:

1'-[3-(benzo[b] thiophene-3-ylthio)-1-propyl] Spiro[3H-2 - benzopyran-3,4'-piperidine], maleate, 31B, so pl. 169-170oC.

Example 32

1'-[4-(2,3-dihydrobenzo[b]thiophene-3-ilidene)-1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine]-S,S-dioxide, maleate, 32

A solution of 4.4 g of 4-(3-benzo[b]thiophene-3-yl)-1 - butylmalonate, obtained as described in examples 10 and 2, in 12 ml of glacial acetic acid is treated dropwise a 30% aqueous hydrogen peroxide at room temperature, then 20 minutes, heated at 80oC. Upon cooling, the crystallized product, 4-(3-benzo[b]thiophene-S,S-dioxide-3-yl)-1-butylmalonate. Yield 3.7 g, so pl. 100-101oC.

The process is to obtain the target compound 32, which crystallized as the maleate from acetone adding maleic acid. Output 1 g, so pl. 186-187oC.

Example 33

1'-[4-(2,3-dihydro-benzo[b] thiophene-3-yl)-1-butyl] Spiro[isobenzofuran-1(3H),4'-piperidine]-S,S-dioxide, maleate, 33

Oxidation of 8.5 g of 4-(benzo[b]thiophene-3-yl)butyric acid by the method described in example 32, gives 9.2 grams of the corresponding S,S-dioxide. A solution of 4 g of acid in 25 ml of tetrahydrofuran are added dropwise to a suspension of 1.3 g of sociallyengaged in 50 ml of tetrahydrofuran at 0oC, then stirred for 2 hours at room temperature. The usual treatment is given 3 g of 4-(2,3-dihydro - benzo[b] thiophene-S, S-dioxide-3-yl)-1-butanol, which is converted into the target compound in the processing of Spiro[isobenzofuran-1(3H),4'- piperidine] according to the method of example 2. The product crystallized in the form of fumarata from a mixture of acetone/ethanol with the addition of fumaric acid. Output 1.5 g, so pl. 197-198oC.

Example 34

1'-[3-(benzo[b] thiophene-3-yloxy)-1 - propyl] Spiro[isobenzofuran-1(3H), 4'-piperidine], maleate, 34

A mixture of 30 g of benzo[b]thiophene-3-she, 73 g of ethyl-3-bromopropionate, 55 g of potassium carbonate, 1.3 g of potassium iodide and 600 ml of acetone is refluxed for 18 hours. Filtration and removal of solvent in vacuum to drop to a suspension of 5 g of sociallyengaged in 100 ml of ether, then 1 hour and refluxed. Normal processing gives a viscous oil, which is applied on a column of silica gel (eluent: isopropyl ether), receive 3-(benzo[b]thiophene-3-yloxy)-1-propanol (0.54 g) as oil.

Get the target compound by the method described in example 2, using Spiro[isobenzofuran-1(3H),4'-piperidine], and crystallized in the form of maleate salt from a mixture of acetone/ether adding maleic acid. Yield 0.34 g, so pl. 116-117oC.

Example 35

1'-[2-(benzo[b] thiophene-3-ylethoxy)-1 - ethyl] Spiro[isobenzofuran-1(3H), 4'-piperidine], fumarate, 35A

A solution of 15 g methylbenzo[b]thiophene-3-carboxylate in 50 ml of ether are added dropwise to a suspension of 3.5 g of sociallyengaged in 100 ml of ether, then 2 hours and refluxed. Normal processing gives 13.5 g of benzo[b] thiophene-3-ylmethanol in the form of butter.

The oil is dissolved in 50 ml of tetrahydrofuran and added dropwise to a suspension of sodium hydride (5 g of 80% paraffin suspensions) in 100 ml of tetrahydrofuran, then 1 hour and refluxed. Add 35 g of ethylbromoacetate in 50 ml of tetrahydrofuran at 60oC, then 1 hour and refluxed. Add an additional 20 g of ethylbromoacetate, flow the oil is applied on a column of silica gel (eluent: ethyl acetate/heptane 2:8), get 5 g ethylbenzo[b]thiophene-3-immediatedata in the form of oil. Recovery sociallyengaged, as described above, gives 3.8 g of 2-(benzo[b]thiophene-3-ylmethylene)ethanol in the form of butter.

The target connection 35A receive according to the method described in example 2, using Spiro[isobenzofuran-1(3H),4'-piperidine], and crystallized in the form of fumaric salt from a mixture of acetone/ethanol with the addition of fumaric acid. Yield 0.55 g, so pl. 149-150oC.

Similarly also get:

1'-[2-(5-perbendaharaan-3-ylmethylene)-1 - ethyl] Spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 35B, so pl. 148-149oC;

1'-[2-(benzofuran-3-ylmethylene)-1-ethyl] - 4-perspire[isobenzofuran-1(3H),4'-piperidine], oxalate, 35V, so pl. 120-122oC.

Example 36

1'-[4-(1-(2-dimethylamino-1-ethyl)-3-indolyl)-1 - butyl]Spiro[isobenzofuran-1(3H),4'-piperidine], dihydrochlor, 36

A solution of 5 g of 4-(3-indolyl)-1-butanol in 50 ml of dry DMF is cooled to 10oC, then treated with 3 g of tert.butoxide potassium. After stirring for 5 minutes, added dropwise to 3.5 g of 2-chloro-N,N-dimethylacetamide, dissolved in 10 ml of dry DMF, at 10-15oC. After one hour stirring at room temperature, add water, then extracted with ethyl acetate. Sustainbility-3 - indolyl)-1-butanol, (7 g), which in turn 1'-[4-(1-dimethylaminocarbonylmethyl-3-indolyl)-1-butyl] Spiro[isobenzofuran-1(3H), 4'-piperidine] according to the method described in example 2, using Spiro[isobenzofuran-1(3H),4'-piperidine]. Yield 5.7 g of a viscous oil. Normal recovery sociallyengaged gives the target connection 36, which crystallized as the dihydrochloride from acetone by adding hydrochloric acid. Output 2.4 g, so pl. 244-245oC.

Pharmacology

Representatives of the compounds of formula I were tested in accordance with established and reliable pharmacological test as follows.

Inhibition of3H-DTG binding to Sigma receptors in the brain of rats in vitro.

By this method the inhibition by the drug binding of 2 nm3H-DTG (1,3-di-o-tolylguanidine) with Sigma receptors in homogenates or membranes of rat brain without cerebellum was determined in vitro, as modified Weber et al, Proc,Natl.Acad.Sci.l986, 83, 8784.

Drugs cloth

The homogenate: Decapitate rats (150-152 g) and quickly remove the brain (without cerebellum) and placed on ice, weighed and homogenized in 100 volumes of ice (0oC) 50 gr Tris-buffer (pH 7,7) washed in ethanol glass/Teflon homogenizer at 0o, washed with ethanol glass/Teflon homogenizer (10 strokes up and down. The homogenate was centrifuged for 10 minutes at 900 gmat 4oC. the Decanted supernatant and centrifuged for 20 minutes at 50,000 gmat 4oC. the resulting ball re-suspended in 10 volumes of ice 50 PM Tris-buffer (pH of 7.7) and incubated for 30 minutes at 37oC. Suspension of membranes then centrifuged for an additional 20 minutes at 50,000 gmat 4oC. the Ball is re-suspended in 50 volumes of ice Tris-buffer and used immediately.

Analysis of the binding.

Mix 0.5 ml of 50 mM Tris buffer (pH 7,7), 0.25 ml of displacer (6 x 100 mm, 6 x [test connection] or Tris buffer) and 0.25 ml 6 x 2 nm3H-DTG in plastic test tubes for testing capacity of 5 ml and incubated at 4oC before use. The binding reaction occurs immediately upon mixing 0.5 ml of the suspension cloth with this solution and incubation at 25oC for 20 minutes. The glass fiber filter (GF(B) is placed on the filter machine, which is then hermetically closed. Directly before filtering impose a vacuum and the filters washed with 0.1% solution PEl from the spray bottle, then once washed with Tris-buffer.

Buffers and solutions.

50 ml of Tris-buffer pH 7,7: 7,38 g Lockjaw - 7,7 plus distilled water to 1 l

100 ml of 10% polyethylenimine (PEl): 100 ml of distilled water was added to about 20 g of 50%. PEl, which solubilizers under stirring and heating. Diluted (1+99) before use.

6 x 2 nm3H-DTG: the exact amount depends on the actual concentration of the bath, but it is prepared as close to 12 nm. Containers for radioactive solution was washed with 96% ethanol before use.

6 x 100 ám DTG: 14,36 mg/100 ml store frozen aliquot in 10 ml.

3H-DTG HEH obtained from research products, DuPont demaru. The specific activity of 62.3 Kyu/mmol.

Known Sigma receptor ligands VMF 14802 and rimcazole included in the test for comparison purposes.

The table shows that the compounds used in the present invention are very potent Sigma receptor ligands in comparison with standard compounds, which are known in the prior art Sigma-the deposits of better than 1 nm.

In addition, it was determined the ability of these compounds to inhibit the binding3H-Prazosin1adrenoceptors in membranes of rat brain in vitro by Hyttel et al, J. Neurochem, 1985, 44, 1615; Skarsfeldt T. et al, J. Pharmacol, 1986, 125, 323.

Additionally, compounds of the invention were tested in relation to the activity of binding to the dopamine D2receptor van der Welde et al, Eur.J.Pharmacol, 1987, 134, 211.

For most of the compounds have an affinity for1adrenoceptors and D2receptors were weak compared to the strong binding to the Sigma receptor. Consequently, many of the compounds are highly selective Sigma receptor ligands that have binding abilities (IR50alpha/IR50Sigma and IR50dopamine/IR50Sigma, respectively) 30-10000.

The discrimination test light/dark on rats.

The test was performed in accordance with F. C. Colpaert et al, Psychpharmacology (1985) 86:45-54, In the test was used Wistar rats WU.

The test is carried out using a box with two compartments activity, which can be easily defined action of anxiolytic compounds to reduce aversion to bright ambient light. The box is designed as an experimental boym light. The rest of the box is painted white and brightly lit. The floor of each site is divided into squares. Registers a behavior change. Data collected from groups doses analyzed using univariate analysis of variance and test Dunnett. Compound was administered intraperitoneally 45 minutes before testing.

In this model test was tested several compounds showed a significant anxiolytic activity at values ED50in the range of ng-µg/kg

Examples of formulations

Pharmaceutical formulations of the invention can be prepared are known at this level of development methods.

For example: tablets can be obtained by mixing the active ingredient with conventional excipients and/or diluents and further compressing the mixture in the usual teletrauma car. Examples of excipients or diluents include corn starch, potato starch, talc, magnesium stearate, gelatine, lactose, gums, etc. Any other excipients or additives commonly used for such purposes, such as colorants, perfumes, preservatives, etc. may be used provided that they are compatible with Acadiana and possible additives in a part of the solvent for injection, preferably sterile water, establishing the desired volume, sterilization of the solution and filling in suitable vials or bottles. Any suitable additives conventionally used in this art, may be added, such as toning agents, preservatives, antioxidants, etc.

Typical examples of formulations of the invention are the following:

1) Tablets containing 0.5 mg of Compound 3b, calculated on a free base:

Compound 3b - 0.5 mg

Lactose - 18 mg

Potato starch - 27 mg

Sucrose - 58 mg

Sorbitol - 3 mg

Talc 5 mg

Gelatin 2 mg

Povidone - 1 mg

Magnesium stearate 0.5 mg

2) Tablets containing 5 mg of Compound 2H, calculated on a free base:

Compound 2H - 5 mg

Lactose - 16 mg

Potato starch - 45 mg

Sucrose - 106 mg

Sorbitol - 6 mg

Talc - 9 mg

Gelatin - 4 mg

Povidone - 3 mg

Magnesium stearate is 0.60 mg

3) Syrup containing per milliliter:

Compound 6b - 2.5 mg

Sorbitol 500 mg

Tragakant - 7 mg

Glycerin 50 mg

Methyl paraben 1 mg

Propyl-paraben 0.1 mg

Ethanol - 0,005 ml

Water up to 1 ml

4) Solution for injection containing mil on the La injection, containing per milliliter:

Compound 17B - 0.1 mg

Sorbitol - 42.9 mg

Acetic acid - 0,63 mg

Sodium hydroxide - 22 mg

Sterile water up to 1 MDR

1. A method of obtaining a pharmaceutical composition for the treatment of States of anxiety and epilepsy, including mixing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient is used as a compound piperidine derivatives of General formula I

< / BR>
where R1is

a) group-D-B-A-R, where In is up to 19-membered alkalinous group, branched or straight chain, possibly substituted by hydroxyl;

A is a bond or a divalent group selected from O, S, SO, SO2and

< / BR>
where W is O or S and the dashed line indicates an optional bond;

R represents a C1-C20-alkyl, C3-C8-cycloalkyl, substituted, phenyl, C4-C20-cycloalkenyl, or phenyl(C1-C20)-alkyl, any phenyl group is optionally substituted by one or more substituents selected from halogen, C1-C6-alkyl, C1-C6-alkoxy, hydroxy, trifloromethyl;

D represents CR8R
or C) a group of the General formula II

< / BR>
where X represents CHR10, O, S, SO, SO2or NR10and R10is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, adamantium or3-C8-cycloalkyl(C1-C6)-alkyl, acyl, amino(C1-C6)alkyl, mono - or di(C1-C6)alkylamino(C1-C6)-alkyl, alkylsulfonyl, phenylsulfonyl, phenyl(C1-C6)alkyl or phenyl, optionally substituted by one or more substituents, independently selected from halogen, C1-C6-alkyl, C1-C6-alkoxyl, hydroxyl, trifloromethyl, and cyano, or R10is a 2-tanila, 3-tanila, 2-TuranAlem, 3-TuranAlem, 2-thiazolyl, 2-pyridium, 3-pyridium, 4-pyridium;

one or two dotted lines can be communication;

when the dashed line emanating from Y indicates a bond, Y is N or CH, or when the dotted line does not indicate a relationship, Y is CH2or NH;

Ra-Rdindependently selected from hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxyl,1-C6-alkylthio,1-C6-alkylsulfonyl and trifloromethyl;

BR> the relationship between Q1and Q2respectively, and U can also be a triple bond, and in this case U is S;

Q1selected from communication, alkylene or Alcanena and Q2is alkylene having at least two atoms, or Alcanena, Q1and Q2have together 2 to 20 carbon atoms:

R2and R3independently are hydrogen, C1-C6the alkyl or they may be connected together to form ethylene or propylene bridge;

R4- R7independently selected from hydrogen, halogen, C1-C6-alkyl, hydroxyl, C1-C6-alkyl or di(C1-C6)alkylamine, and triptorelin;

i) Z1and Z2linked together, in this case, Z1is CH2, O or S; Z2and Z3independently are a bond, CH2, O or S, provided that Z1cannot be S or O when Z2is S or O, and Z2and Z3can't be a bond, or Z1and Z2may together represent a group-CH=CH -, provided that at least one of the Z1, Z2, Z3are O or S; or when Z3is a bond, Z1and Z2together can represent a three-membered divalent group, with>
can also be unbound, in this case, Z1is a group defined for R4-R7, Z2is hydrogen and Z3is a bond; provided that D-B-A-R can't be WITH1-C6-alkyl or C1-C6-alkenyl, cycloalkyl-C1-3the alkyl and optionally substituted phenyl-C1-4-alkyl; when Z2is a relationship and one of the Z1and Z3is On, then the other Z1and Z3can't be CH2,

or salts of its accession acid.

2. The method according to under item 1, characterized in that the compound of General formula I is a compound in which, when Z1and Z2linked together, at least one of the Z1, Z2and Z3means O or S.

3. The method according to p. 2, characterized in that the compound of General formula I is a compound in which Z3is a bond and Z2is O or S, Z1is CH2or Z1and Z2together represent CH2-O-CH2.

4. The method according to p. 2, characterized in that the compound of General formula I is a compound in which Z1is CH2, Z2is About what I'm About, Z3is O and Z2is the link.

5. The method according to p. 1, characterized in that the compound of General formula I is a compound in which Z1and Z2not connected and Z3is the link.

6. The method according to p. 1, characterized in that the compound of General formula I is selected among the following:

1'-(3-adamantane-1-propyl)Spiro[3H-2-benzopyran-3,4'-piperidine];

1'-[4-(1-benzyl-3-indolyl)-1-butyl] -Spiro[isobenzofuran-1(3H), 4'-piperidine];

1'(3-(3-phenylimidazoline-2-on-1-yl)-1-propyl)Spiro[isobenzofuran-1-(3H), 4'-piperidine];

1'-[4-[1-(4-forfinal)-3-indolyl] -1-butyl] -Spiro[isobenzofuran-1-(3H), 4'-piperidine];

1,4-dihydro-1'-[4-[1-(4-forfinal)-3-indolyl] -1-butyl]Spiro[3H-2-benzopyran-3,4-'piperidine];

1'-[4-[1-R-toluensulfonyl-3-indolyl)-1-butyl)Spiro[isobenzofuran-1(3H), 4'-piperidine];

1'-[4-[5-fluoro-1-(4-forfinal)-3-indolyl] -1-butyl] Spiro[isobenzofuran-1(3H), 4'-piperidine];

6-fluoro-1'-[4-[1-(4-forfinal)-3-indolyl] -1-butyl] Spiro[isobenzofuran-1(3H), 4'-piperidine];

1'-[4-[1-(4-were)-3-indolyl]-1-butyl]Spiro[1H-2-benzopyran-4-(3H), 4'-piperidine];

1-(4-forfinal)-3-[4-(4-(4-forfinal)-1-piperidyl)-1-butyl]indole;

1'-[4-(1-2-triazolyl)-3-indolyl)-1-butyl] Spiro[isobenzofuran-3-yl)-1-butyl] -Spiro[isobenzofuran-1(3H), 4'-piperidine];

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

4-forfinal-3-[4-(4-(4-forfinal)-1-piperidinyl)-1-butyl]-5-cryptomaterial;

1'-(4-(1,2-benzisoxazol-3-yl)-1-butyl)Spiro[isobenzofuran-1(3H), 4'-piperidine];

1'-[3-(benzo[b] thiophene-3-ylthio)-1-propyl]Spiro[isobenzofuran-1(3H), 4'-piperidine].

7. Derivatives of piperidine derivatives of General formula I

< / BR>
where R1is

a) group-D-B-A-R, where In is up to 19-membered alkalinous group, branched or straight chain, possibly substituted by hydroxyl;

A is a bond or a divalent group selected from 0, S, SO, SO2and

< / BR>
where W is O or S and the dashed line indicates an optional bond;

R represents a C1-C20-alkyl, C3-C8-cycloalkyl, substituted, phenyl, C4-C20-cycloalkenyl, or phenyl(C1-C20)alkyl, any phenyl group is optionally substituted by one or more substituents selected from halogen, C1-C6-alkyl, C1-C6-alkoxy, hydroxytryptamine;

D represents CR8R9where R8and R9independently selected for zamestitelyami CHR10, O, S, SO, SO2or NR10and R10is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, adamantium or3-C8-cycloalkyl(C1-C6)-alkyl, acyl, amino(C1-C6)-alkyl, mono - or di(C1-C6)-alkylamino(C1-C6)-alkyl, alkylsulfonyl, phenylsulfonyl, phenyl(C1-C6)alkyl or phenyl, optionally substituted by one or more substituents, independently selected from halogen, C1-C6-alkyl, C1-C6-alkoxyl, hydroxyl, trifloromethyl, and cyano, or R10is a 2-tanila, 3-tanila, 2-TuranAlem, 3-TuranAlem, 2-thiazolyl, 2-pyridium, 3-pyridium, 4-pyridium;

one or two dotted lines can be communication;

when the dashed line emanating from Y indicates a bond, Y is N or CH; or when the dashed line does not indicate a bond, Y is CH2or NH;

Ra-Rdindependently selected from hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxyl,1-C6-alkylthio,1-C6-alkylsulfonyl and trifloromethyl;

U is CH2, O, and S; or when one of the dashed lines, the emergent and oinoi communication, and in this case U is S;

Q1selected from communication, alkylene or Alcanena and Q2is alkylene having at least two atoms, or Alcanena, Q1and Q2have together 2 to 20 carbon atoms;

R2and R3independently are hydrogen, C1-C6the alkyl or they may be linked together to form ethylene or propylene bridge;

R4- R7independently selected from hydrogen, halogen, C1-C6-alkyl, hydroxyl, C1-C6-alkyl or di(C1-C6)alkylamine and trifloromethyl;

i) Z1and Z2linked together, in this case, Z1is CH2, O or S; Z2and Z3independently are a bond, CH2, O or S, provided that Z1cannot be S or O when Z2is S or O, and Z2and Z3can't be a bond, or Z1and Z2may together represent a group-CH=CH-, provided that at least one of the Z1, Z2, Z3are O or S; or when Z3is a bond, Z1and Z2together can represent a three-membered divalent group containing one O or S heteroatom; and optionally containing an unsaturated bond; the mi, in this case, Z1is a group defined for R4-R7; Z2is hydrogen and Z3is a bond, provided that when R1is a group of formula II, as defined under b), Z1, Z2and Z3defined under (ii),

X is O;

Y is N;

the dashed line emanating from Y indicates the connection;

-Q1-U-Q2specifies - (CH2)3then Rwithcannot be fluorine;

if R1is a group of formula II, as defined under b), Z1, Z2and Z3defined under (ii),

X is NH;

Y is CH;

the dashed line emanating from Y indicates a bond, then Q1-U-Q2cannot be an alkyl having less than 5 carbon atoms;

if Z2is a relationship and one of the Z1and Z3is On, then the other Z1and Z3can't be CH2;

D-B-A-R can't be WITH1-6-alkyl or C1-C6-alkenyl, cycloalkyl-C1-C3the alkyl and optionally substituted phenyl-C1-C4-alkyl;

if Z1is O and Z2and Z3are both CH2then D-B-A-R may not be optional, hexyl or heptyl, substituted hydroxy is the group D-B-A-R and Z1and Z2are as defined under (i).

9. Connection on p. 7, characterized in that it R1represents a group of General formula II and Z1and Z2defined under (i).

10. Connection on p. 7, characterized in that it R1represents a group of General formula II and Z1and Z2defined under (ii).

11. Connection on p. 7, characterized in that it is a compound in which Z1and Z2linked together.

12. Connection PP.7 - 9, 11, characterized in that it is a compound in which Z3is a bond, and Z2is O or S and Z1is CH2or Z1and Z2are CH2-O-CH2.

13. Connection PP.7 to 9, characterized in that it is a compound in which Z1is CH2, Z2is O and Z3is CH2or Z3is O and Z1- Z2is CH=CH, or Z1is OH, Z3is O and Z2is the link.

14. Connection on p. 7, characterized in that it is a compound in which Z1and Z2not connected and Z3the hydroxy-1-propyl)Spiro[3H-2-benzopyran-3,4'-piperidine];

1'[4-1-benzyl-3-indolyl)-1-butyl] -Spiro[isobenzofuran-1(3H), 4'-piperidine];

1'-(3-(3-phenylimidazoline-2-on-1-yl)-1-propyl)Spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-[1-(4-forfinal)-3-indolyl] -1-butyl] -Spiro[isobenzofuran-1(3H), 4'-piperidine];

1,4-dihydro-1'-[4-[1-(4-forfinal)-3-indolyl] -1-butyl] Spiro[3H-2-benzopyran-3,4'-piperidine];

1'-(4-(1-p-toluensulfonyl-3-indolyl)-1-butyl)Spiro[isobenzofuran-1(3H), 4'-piperidine];

1'-[4-[5-fluoro-1-(4-forfinal)-3-indolyl/-1-butyl] Spiro[isobenzofuran-1(3H),4'-piperidine];

6-fluoro-1'-[4-[1-(4-forfinal)-3-indolyl] -1-butyl] Spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-[1-(4-were)-3-indolyl]-1-butyl]-Spiro[1H,2-benzopyran-4(3H), 4'-piperidine];

1-(4-forfinal)-3-[4-(4-(4-forfinal)-1-piperidyl)-1-butyl]indole;

1'-[4-(1-(2-thiazolyl)-3-indolyl)-1-butyl] Spiro[isobenzofuran-1(3H), 4'-piperidine];

1'-[3-(5-perbendaharaan-3-yl)-1-propyl] Spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-(5-perbendaharaan-3-yl)-1-butyl]Spiro[isobenzofuran-1(3H),4'-piperidine];

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

4-forfinal-3-[4-(4-(4-forfinal)-1-piperidinyl]-1-butyl]-5-cryptomaterial;

1'-(4-(1,2-benzisoxazol-3-yl)-1-butyl] Spiro[isobenzofuran-1(3H), 4'-piperidine composition for treating a state of anxiety or epilepsy, characterized in that it includes at least one piperidine connection PP.7 - 10 or its pharmaceutically acceptable salt in an effective amount together with one or more pharmaceutically acceptable carrier or diluent.

17. Connection PP.11 and 12, characterized in that it is a compound in which Z3is a bond, Z2is O and Z3is CH2.

18. Connection on p. 17, characterized in that it R1is a compound of formula II in which X is NR10, Y is CH and the dotted line emanating from Y is a bond.

19. Connection on p. 18, characterized in that it R10possibly substituted phenyl.

20. Connection on p. 15, characterized in that it is a 1'-[4-[1-(4-forfinal)-3-indolyl]-1-butyl]Spiro[isobenzofuran-1(3H),4'-piperidine] or its pharmaceutically acceptable salt.

21. The pharmaceutical composition according to p. 16, characterized in that as the active ingredient using an effective amount of at least one compound of piperidine in PP.17 - 20 or its pharmaceutically acceptable salt.

Priority points:

13.06.91 - all>or

< / BR>
where W is O and S, and the dotted line indicates an optional bond, R - substituted, D represents CR8R9where R8and R9independently selected from the substituents defined for R4- R7, R10- substituted, phenyl(C1-C6)alkyl, amino(C1-C6)alkyl, mono - or di(C1-C6)alkylamino(C1-C6)alkyl, the relationship between Q1and Q2, respectively, and U can be by a triple bond and in this case U is S;

10.02.92 - a is a divalent group selected from O, S, SO, SO2or

< / BR>
where W is O and S, and the dotted line indicates an optional bond, R - substituted, D represents CR8R9where R8and R9independently selected from the substituents defined for R4- R7, R10- substituted, phenyl(C1-C6)alkyl, amino(C1-C6)alkyl, mono - or di(C1-C6)alkylamino(C1-C6)alkyl, the relationship between Q1and Q2, respectively, and U can be by a triple bond and in this case U is S.

 

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