Spiroheterocyclic heterocyclic compounds, methods for their preparation, intermediate compounds and pharmaceutical composition

 

The invention relates to new biologically active compounds, namely spiroheterocyclic heterocyclic compounds of the formula Iwhere n is 0 or 1; m is 0 or 1; p is 0; X represents oxygen or sulfur; Y represents CH, N or NO; W represents an oxygen or H2; Represents N or C(R2); G represents N or C(R3);
D represents N or C(R4),
provided that not more than one of A, G and D represents nitrogen, but at least one of Y, a, G, and D represents nitrogen or NO;
R1represents hydrogen or C1-C4-alkyl;
R2, R3and R4are independently hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, heteroaryl, including five - or six-membered aromatic ring with 1 or 2 nitrogen atoms, as well as furyl or morpholyl, HE OS1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6or R2and R3or R3and R4accordingly, together with part a and G or G and D, respectively, to form another six-membered aromatic ring;
R5, SO2R10, -NR5R6, (CH3)3Si and phenyl, or may together represent (CH2)jQ(CH2)kwhere Q represents a bond; j is 2 and k is 0 to 2;
R7, R8, R9, R10and R11are independently C1-C4-alkyl, NH2, aryl or its enantiomer,
and their pharmaceutically acceptable salts, and methods for their preparation, intermediate compounds and pharmaceutical compositions, which has an activating effect against nicotine7-acetylcholine receptors and can be used for the treatment and prevention of psychotic disorders and disturbances such reduction of intellectual activity. The technical result is to provide new compounds having valuable biologically active properties. 7 C. and 10 C.p. f-crystals.

The technical field
The invention relates to new spiroheterocyclic heterocyclic amines or their pharmaceutically acceptable salts, processes for their preparation, containing their pharmaceutical compositions and their use in therapy. The next objective is the provision of active compounds, which are particularly Using joins, which bind nicotinic acetylcholine receptors in the treatment of several diseases, including decreased cholinergic function such as Alzheimer's disease, disorders of cognitive abilities or attention, anxiety, depression, Smoking cessation, neuroprotection, schizophrenia, analgesia, disease, Tourette's and Parkinson's disease, discussed in the work of McDonald et al. (1995) "Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry and Pharmacology", Chapter 5, Annual Reports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc., San Diego, CA, and Williams et al. (1994), "Neuronal Nicotinic Acetylcholine Receptors", Drug News and Perspectives, vol. 7, pp. 205-223.

In U.S. patent 5468875 describes 1-azabicyclo[2.2.1]hept-3-silt esters of N-alkylcarboxylic acids, which are active muscarinic agents Central nervous system, which can be used in the treatment of Alzheimer's disease and other diseases.

1-Azabicyclo[2.2.2] Octan-3-silt esters of N-(2-alkoxyphenyl)karbinovykh acids described in Pharmazie, vol. 48, 465-466 (1933), as well as their local an anaesthetic activity. 1-Azabicyclo [2.2.2]Octan-3-silt esters of N-phenylcarbamate acids, substituted in the ortho-position of the phenyl ring, described as local anaesthetics in Acta Pharm. Suecica, 7, 239-246 (1970).

Properidine that can ispolzovaniem was detected, the compound of the formula I

where n is 0 or 1;
m is 0 or 1;
p is 0 or 1;
Y represents CH, N or NO;
X represents oxygen or sulfur;
W represents oxygen, N2or F2;
A represents N or C(R2);
G represents N or C(R3);
D represents N or C(R4),
provided that not more than one of A, G and D is nitrogen, but at least one of Y, a, G, and D represents nitrogen or NO;
R1represents hydrogen or C1-C4-alkyl;
R2, R3and R4are independently hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, heteroaryl, HE OS1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6, -CF3, -OSO2CF3or R2and R3or R3and R4thus together with part a and G or G and D, respectively, to form another six-membered aromatic or heteroaromatic ring containing from zero to two nitrogen atoms and substituted independently one or two of the following substituents: hydrogen, halogen, C1-C4-alkyl, C2-C4-alkenyl,2-C4
, -CF3, -S2CF3;
R5and R6independently represent hydrogen, C1-C4-alkyl, C(O)R7C(O)other8With (O) OR9, SO2R10or may together represent (CH2)jQ(CH2)kwhere Q is O, S, NR11or communication;
j is 2-7;
k is 0-2;
R7, R8, R9, R10and R11are independently C1-C4is alkyl, aryl or heteroaryl,
or its enantiomer and its pharmaceutically acceptable salt is a strong ligand for nicotinic acetylcholine receptors.

Unless otherwise noted, With1-C4-alkyl groups mentioned herein, such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, can be unbranched or branched chain, and C3-C4is an alkyl group may be cyclic, for example cyclopropyl, cyclobutyl.

Unless otherwise noted, C1-C6-alkyl groups mentioned herein, such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl or isohexyl, can be unbranched or branched chain, and C3-C6-alkyl does not specifically mentioned, With1-C4-alkoxygroup, shown here, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, can be unbranched or branched chain.

Unless otherwise noted, With1-C4-alkeline groups specified herein may contain one or two double bonds, such as ethynyl, Isopropenyl, n-butenyl, Isobutanol, allyl, 1,3-butadienyl.

Unless otherwise noted, With1-C4-alkyline group mentioned herein contain one triple bond, such as ethinyl, PROPYNYL, 1 - or 2-butynyl.

Halogen listed here may be fluorine, chlorine, bromine or iodine.

Unless otherwise noted, aryl refers to a phenyl ring, optionally substituted by the following substituents are from one to three of: hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, HE OS1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6, -CF3.

Unless otherwise noted, heteroaryl refers to the five - or six-membered aromatic ring containing one or two nitrogen atom, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl or pyrazolyl, the atoms ug>-C4-alkyl, C2-C4alkenyl,2-C4-quinil, HE OS1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6, -CF3; R5and R6may together be (CH2)jQ(CH2)kwhere Q is O, S, NR11or Association, and where j is 2 to 7, preferably 2-3, and k is the number from 0 to 2, so as to form a 3-7-membered ring, preferably a 5 - or 6-membered ring, such as pyrrolidinyl, imidazolidinyl, piperazinil, piperidyl, morpholinyl or thiomorpholine.

R2and R3together, with the participation of a and G, to form another six-membered aromatic or heteroaromatic ring containing from zero to two atoms of nitrogen and related groups such as quinoline, 1,5-, 1,6-, 1,7 - or 1,8-diazonaphthalene.

R3and R4together, with the participation of a and G, to form another six-membered aromatic or heteroaromatic ring containing from zero to two atoms of nitrogen and related groups such as isoquinoline, 2,5-, 2,6-, 2,7 - or 2,8-diazonaphthalene.

Preferred compounds of the invention are compounds of formula I where m is 1; n is 0; p is 0; X is oxygen; W is H2; A represents C(R2 Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-bromospiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-perspire[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-nitrospira[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
1'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]isoquinoline];
5'-(phenylcarbonylamino)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(phenylenecarbonyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(phenylcarbonylamino)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-aminosterol[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N-methylaminophenol[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N,N-dimethylaminophenol[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-N, N-diethylaminophenol[1-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b] pyridine];
5'-N-acylaminoacyl[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-N-benzylaminopurine[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine;
5'-N-formimidoyl[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-N-acetamidophenol[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
Spiro[1-azabicyclo[2.2,2]octane-3,2'-(3 N)-furo[2,3-b]isoquinoline];
Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-fu is bicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(4-morpholino)Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(1-azetidine)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-(E)-(2-(4-pyridyl)ethynyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(E)-(2-(2-pyridyl)ethynyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(2-trimethylsilylethynyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-edenilson[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(2-furyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-(3-pyridyl)Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-methylspiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)-furo[2,3-b] pyridine-5'-carbonitrile];
Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine-5'-carboxamide];
5'-N'-(3-chlorophenyl)aminocarbonylmethyl[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N'-(2-nitrophenyl)aminocarbonylmethyl[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
4'-methoxamine[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
4'-phenylthieno[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
4'-(N-2-amino-ethyl)aminosterol[l-azabicyclo[2.2,2] is luminophore[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
4'-(4-N-methylpiperazin-1-yl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[3,2-C]pyridine];
Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[3,2-C]pyridine];
Spiro(1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine-7'-oxide];
Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine-6'-carbonitrile];
6'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
6'-perspire[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine]
and their enantiomers and pharmaceutically acceptable salts.

Particularly preferred compounds of the invention are compounds of formula I where m is 1; n is 0; p is 0; X = oxygen; W is H2; A=CH, D=SN and G=C(R3), which includes the following connections:
Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine-7'-oxide];
5'-bromospiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-perspire[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-nitrospira[1-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(phenylcarbonylamino)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N) -furo[2,3-b]pyridine];
5'-(phenylenecarbonyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-('is'-(3 N)-furo[2,3-b]pyridine];
5'-N-methylaminophenol[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N,N-dimethylaminophenol[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-N, N-diethylaminophenol[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-N-acylaminoacyl[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-N-benzylaminopurine[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N-formimidoyl[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-N-acetamidophenol[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-ethaniser[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(E)-(phenylethenyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(4-morpholino)Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(1-azetidine)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-(E)-(2-(4-pyridyl)ethynyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(E)-(2-(2-pyridyl)ethynyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(2-trimethylsilylethynyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-edenilson[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(2-furyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-(3-pyridyl)Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridi,3-b] pyridine-5'-carbonitrile];
Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine-5'-carboxamide];
5'-N'-(3-chlorophenyl)aminocarbonylmethyl[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N'-(2-nitrophenyl)aminocarbonylmethyl[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-5-furo[2,3-b]pyridine].

Ways to get
In the schemes of reactions and the text that follows it, A, G, D, X, W, Y, Z, m, n and p, unless otherwise noted, such as defined above for formula I.

(A) Compounds where R is 0 and Y is N
The compounds of formula I, where R is 0 and Y is N, can be obtained by the methods depicted in scheme I, is given at the end of the description.

The compounds of formula I, where W=N2and p is 0, can be obtained by removing the protective group from compounds of formula IIA using acid in a suitable solvent. Suitable acids include mineral, organic acids and Lewis acid, such as hydrochloric and Hydrobromic acid, sulfuric acid, triftormetilfullerenov acid, methanesulfonate acid and athirat of boron TRIFLUORIDE. The preferred acid is a Hydrobromic acid. Suitable solvents include acetone, butanone, alanon and pinacolone. The preferred solvent is about 0oWith up to 60oC. Alternative, removing the protective group can be carried out by heating boranova complex in alcohol solvents. The preferred method is a boiling solution of the complex in ethanol under reflux.

The compounds of formula I, where W=O (oxygen), and p is 0, can be obtained by oxidation of compounds of formula IIA, for example, with selenium dioxide or by reaction first with N-bromosuccinimide, then with sodium bicarbonate and methylsulfoxide with subsequent removal of boranova group, as described above.

The compounds of formula I, where W=F2and p is 0, can be obtained from compounds of the formula I, where W=O, by reaction with a fluorinating agent, such as the TRIFLUORIDE diethylaminoethyl.

Compounds of formula IIA can be obtained by cyclization of the compounds of formula III, where L represents fluorine, chlorine, bromine, iodine, -och3, -SPh, -S3, -SO2Ph or-SO2CH3in the presence of a base in an inert solvent. Suitable bases include sodium hydride, sodium amide, potassium hydride, tert-adalat potassium tert-piperonyl and potassium bis(trimethylsilyl)amide and potassium. The preferred base is sodium hydride. Suitable inert Rast is drofuran and 1,4-dioxane, and dimethylsulfoxide. The preferred inert solvent is N,N-dimethylformamide. The reaction is usually carried out at a temperature of from about 10oC to about 100oC, preferably from about 20oWith up to about 66oC.

The compound of formula III, where L represents fluorine, chlorine, bromine, iodine, -och3, -SPh, -S3, -SO2Ph or-SO2CH3,can be obtained by reaction of the compound of formula IV with the compound of the formula V, where L is such as defined yours, in an inert solvent. Suitable inert solvents include diethyl simple ether, tetrahydrofuran and 1,4-dioxane. The preferred inert solvent is a tetrahydrofuran. The reaction is usually carried out at a temperature of from about -100oC to about 0oC, preferably from about -78oC to about -25oC.

The compounds of formula V, where L is as defined above, can be obtained from compounds of formula VIII, where L is as defined above, with the lithium base agent and the transfer of protons in an inert solvent. Suitable lithium base include diisopropylamide lithium, n-utility, second-utility, tert-utility and finality. Preferred lithium base AVSEC Diisopropylamine and 2,2,6,6-tetramethylpiperidine. The preferred agent of the transfer of protons is Diisopropylamine. Suitable inert solvents include diethyl simple ether, tetrahydrofuran, and 1, 4-dioxane. The preferred inert solvent is a tetrahydrofuran. The reaction is usually carried out at a temperature of from about -100oC to about 0oC, preferably from about -78oC to about -25oC. the compounds of formula V are generally consumed in the reaction with compounds of formula IV directly, without purification.

The compounds of formula IV can be obtained by reaction of the compound of formula VI with borane (BH3or B2H6) in an inert solvent. Preferred borane in tetrahydrofuran. Suitable inert solvents include diethyl simple ether, tetrahydrofuran and 1,4-dioxane. The preferred inert solvent is a tetrahydrofuran. The reaction is usually carried out at a temperature of from about -10oWith up to about 66oC, preferably from about 0oWith up to about 20oC.

The compounds of formula VIII are known, for example, they are either commercially available or can be obtained by methods known to the person skilled in the art (see , for example, The Chemistry of Heterocyclic Compounds, Pyridine and Its Derivatives, Part 1, E. Klingsb well-known specialist in this field. For example, the compounds of formula VI where X is oxygen, can be obtained from the corresponding compounds of formula VII where X represents a ketonic oxygen, using one of the reagents that are well known in this area for receiving oxiranes of ketones (see , for example, the reactions listed in J. March, "Advanced Organic Chemistry" (1985) 3rdEdition, page 1161). The compounds of formula VI where X is sulfur, can be obtained from the corresponding compounds of formula VII where X is either oxygen or sulfur, using one of the methods well known in the field to obtain epislides of ketones or thioketones (see, for example, the reactions listed in J. March, "Advanced Organic Chemistry" (1985) 3rdEdition, pages 866-867).

The compounds of formula VII are known, for example, they are either commercially available or can be obtained by methods known to the person skilled in the art (see,for example, The Chemistry of Heterocyclic Compounds, Heterocyclic Systems with Bridgehead Nitrogen Atoms, Part 2, W. L. Mosby, Ed., Interscience Publishers, Inc, NY, 1961).

(C) Compounds where R is 1 and Y is N
The compounds of formula I (R=1) can be obtained according to the methods described below in scheme II and scheme III, listed at the end of the description.

The compounds of formula I, where W is H2Adamem solvent. Suitable acids include mineral, organic acids and Lewis acid, such as hydrochloric and Hydrobromic acid, sulfuric acid, triptorelin-sulfonic acid, methanesulfonate acid and athirat of boron TRIFLUORIDE. The preferred acid is Hydrobromic acid. Suitable solvents include acetone, butanone, alanon and pinacolone. The preferred solvent is acetone. The reaction is usually carried out at a temperature of from about -10oC to about 100oC, preferably from about 0oWith up to 60oC. Alternative, removing the protective group can be carried out by heating boranova complex in alcohol solvents. The preferred method is a boiling solution of the complex in ethanol under reflux.

The compounds of formula I, where W=O and p is 1, can be obtained by oxidation of compounds of formula I, where W is H2and p is 1, with the use of selenium dioxide or by reaction first with N-bromosuccinimide, then with sodium bicarbonate and methylsulfoxide with subsequent removal of boranova group, as described above.

The compounds of formula I, where W=F2and p is 1, can be obtained from the ut can be obtained by cyclization of the compounds of formula X, where L represents fluorine, chlorine, bromine, iodine, -och3, -SPh, -S3, -SO2Ph or-SO2CH3in the presence of a base in an inert solvent. Suitable bases include sodium hydride, sodium amide, potassium hydride, tert-adalat potassium tert-piperonyl and potassium bis(trimethylsilyl)amide and potassium. The preferred base is sodium hydride. Suitable inert solvents include N, N-dimethylformamide, N-methylpyrrolidine-2-he, ethers, such as diethyl ether, tetrahydrofuran and 1,4-dioxane, and dimethylsulfoxide. The preferred inert solvent is N,N-dimethylformamide. The reaction is usually carried out at a temperature of from about -10oC to about 100oC, preferably from about 20oWith up to about 66oC.

The compounds of formula X, where L represents fluorine, chlorine, bromine, iodine, -och3, -SPh, -S3, -SO2Ph or-SO2CH3can be obtained by reaction of the compound of formula XI with the compound of the formula V, where L is as defined above, in an inert solvent. Suitable inert solvents include diethyl simple ether, tetrahydrofuran and 1,4-dioxane. The preferred inert solvent is a tetrahydrofuran. The reaction is usually carried out when the

Compounds XI, where R represents-SO2RH, -SO2Ph3-4, -SO2CH3or-SO2CF3can be obtained from compounds XII by reaction with this reagent, as toluensulfonate, methanesulfonate or triftormetilfullerenov, in the presence of an amine base, such as triethylamine, dimethylaminopyridine or diazabicyclo[4.3.0]nonan, in an inert solvent. Suitable inert solvent may be dichloromethane, chloroform, tetrahydrofuran, diethyl simple ether or dioxane. The preferred inert solvent is dichloromethane. The reaction is usually carried out at a temperature of from about -10oWith up to about 66oC, preferably from about 0oWith up to about 20oC.

Compound XII may be obtained from compounds of formula XIII by restoring such reagents as sociallyengaged, sodium bis-(2-methoxyethoxy)aluminiumhydride, teeterboard sodium or lithium tri-sec-butylbromide lithium tri-sec-butylbromide potassium tri-sec-butyl-borohydride sodium or borohydride lithium. The preferred reagent is borohydride sodium. Suitable inert solvents include diethyl simple ether, tetrahydrofuran and 1,4-dioxane from about -78oWith up to about 66oC, preferably from about -10oWith up to about 20oC.

The compounds of formula XIII, where R represents a C1-C6-alkyl, -CH2-AG or AG, where AG represents phenyl, optionally substituted by the following substituents are from one to three: halogen, C1-C4-alkyl or C1-C4-alkoxy, can be prepared by the reaction of the compound of formula XIV with borane (BH3or2H6) in an inert solvent. Preferred borane in tetrahydrofuran. Suitable inert solvents include simple ether, tetrahydrofuran and 1,4-dioxane. The preferred inert solvent is a tetrahydrofuran. The reaction is usually carried out at a temperature of from about -10oWith up to about 66oC, preferably from about 0oWith up to about 20oC.

The compounds of formula XIV are known, for example, they are either commercially available or can be obtained from compounds of formula VII by methods known to the person skilled in the art to produce complex-hydroxyamino reaction of esters and ketones (see , for example, the reactions listed in J. March, "Advanced Organic Chemistry" (1985) 3rdEdition, page 439).

The compounds of formula I, where W is H23, -SPh, -S3, -SO2Ph or-SO2CH3in the presence of a base in an inert solvent. Suitable bases include sodium hydride, sodium amide, potassium hydride, tert-adalat potassium tert-piperonyl and potassium bis(trimethylsilyl)amide and potassium. The preferred base is sodium hydride. Suitable inert solvents include N,N-dimethylformamide, N-methylpyrrolidine-2-he, ethers, such as diethyl ether, tetrahydrofuran and 1,4-dioxane, and dimethylsulfoxide. The preferred inert solvent is N,N-dimethylformamide. The reaction is usually carried out at a temperature of from about -10oC to about 100oC, preferably from about 20oWith up to about 66oC.

The compounds of formula XVIII, where L is as defined above, can be obtained by the catalytic hydrogenation of compounds of formula XVII using catalysts such as palladium on charcoal, palladium hydroxide on charcoal, palladium oxide, platinum on charcoal, platinum oxide, Raney Nickel or rhenium coal in an inert solvent. Suitable inert solvents include methanol, ethanol, aqueous methanol or ethanol and ethyl acetate. The preferred solvent is ethanol. The reaction is usually carried out at a temperature of from ormula XVII, where L is as defined above, can be obtained by reaction of the compound of formula XV with a compound of formula XVI with a palladium catalyst together with a suitable ligand, base and solvent. Suitable palladium catalysts include palladium acetate. Suitable ligands include phosphine ligands such as triphenylphosphine or tri-o-tolylphosphino. Suitable bases include amines and inorganic bases, such as triethylamine, diisopropylethylamine, sodium carbonate or tetrabutylammonium acetate. Suitable solvents include dimethylformamide or acetonitrile. The reaction is usually carried out at a temperature of from about 0oWith up to about 140oC, preferably from about 20oWith up to about 85oC.

The compounds of formula XVI, where L is as defined above, and R2represents chlorine, bromine, iodine, fluorine, trifloromethyl, toluensulfonyl or methylsulphonyl, can be obtained by literature methods from commercially available materials.

The compounds of formula XV can be obtained from compounds of formula VII by methods known to the person skilled in the art to obtain allyl alcohols from ketones using salts vinylmation, such as WinImage dstanley halogen, can be obtained from compounds of the formula I, where appropriate Deputy represents hydrogen, by reaction with a suitable halogenation agent such as bromine in acetic acid. For transformation may require the addition of an acid catalyst, such as an appropriate trihalogen iron.

The compounds of formula I, where R2, R3or R4represents C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, heteroaryl, can be obtained from compounds of the formula I, where appropriate Deputy represents halogen or S2CF3by reaction with a suitable reagent, alkyl-, alkenyl-, quinil-, aryl - or heteroarylboronic, in the presence of a suitable ORGANOMETALLIC catalyst, for example tetrakis(triphenylphosphine)palladium(0), in a suitable solvent, for example 1,2-dimethoxyethane.

The compounds of formula I, where R2, R3or R4represents aryl, heteroaryl, can be obtained from compounds of the formula I, where appropriate Deputy represents halogen or OSO2CF3reaction with an aryl - or heteroarylboronic acid in the presence of a suitable ORGANOMETALLIC catalyst, for example tetrakis(three R2, R3or R4is NO2can be obtained from compounds of the formula I, where appropriate Deputy represents hydrogen, nitration using a suitable nitrouse agent, such as nitric acid in concentrated sulfuric acid.

The compounds of formula I, where R2, R3or R4represents NH2can be obtained from compounds of the formula I, where the Deputy is NO2, restore using suitable methods, such as hydrogenation. The hydrogenation can be carried out by reaction of the compound dissolved in a suitable solvent with gaseous hydrogen in the presence of a suitable catalyst. Suitable solvents include methanol, ethanol and acetic acid. Suitable catalysts include palladium, for example 10% palladium on coal.

The compounds of formula I, where R2, R3or R4is NR5R6where R6is alkyl, can be obtained from compounds of the formula I, where appropriate Deputy is other5suitable methods of alkylation. In addition, the compounds of formula I, where R2, R3or R4is NR5R62)jQ(CH2)kcan be obtained from compounds of the formula I, where appropriate Deputy represents NH2suitable methods of alkylation. Suitable methods of alkylation may include processing the appropriate alkylhalogenide or sulphonate ester and a base such as sodium hydride, in a suitable solvent, for example DMF, or treatment with a suitable aldehyde or ketone in the presence of an acid catalyst such as zinc chloride, a reducing agent, such as cyanoborohydride sodium, and solvent, for example ethanol.

The compounds of formula I, where R2, R3or R4is OSO2CF3can be obtained from compounds of the formula I, where appropriate Deputy is HE, by reaction with triftormetilfullerenov anhydride in the presence of a suitable base, such as 2,6-di-tert-butylpyridinium, in a suitable solvent, for example dichloromethane.

The compounds of formula I, where R2, R3or R4is NR5R6can also be obtained from compounds of the formula I, where appropriate Deputy represents a halide or S2CF3by substitution of the appropriate amine with other5

The compounds of formula I, where R2, R3or R4is NR5C(O)R7can be obtained from compounds of the formula I, where appropriate Deputy represents NH2suitable methods of acylation. Suitable methods of acylation include processing the acid chloride of the carboxylic acid R6C(O)C1 in the presence optional nucleophilic catalyst such as 4-(N, N-dimethylamino)pyridine, bases, for example pyridine or triethylamine, and a suitable solvent, such as tetrahydrofuran, or, alternatively, the processing carboxylic acid R6C(O)OH blending agent, such as 1,3-dicyclohexylcarbodiimide, in a suitable solvent, for example tetrahydrofuran.

The compounds of formula I, where R2, R3or R4is NR5C(O)other8can be obtained from compounds of the formula I, where appropriate Deputy is what it is.

The compounds of formula I, where R2, R3or R4is NR5C(O)OR9can be obtained from compounds of the formula I, where appropriate Deputy is other5processing appropriate oxychloride or carbonate in the presence optional nucleophilic catalyst such as 4-(N,N-dimethylamino)pyridine, bases, for example pyridine or triethylamine, and a suitable solvent, such as tetrahydrofuran.

The compounds of formula I, where R2, R3or R4is NR5SO2R10can be obtained from compounds of the formula I, where appropriate Deputy is other5processing appropriate sulphonylchloride in a suitable solvent, such as pyridine.

The compounds of formula I, where R2, R3or R4is CN can be obtained from compounds of the formula I, where appropriate Deputy represents a halide or OSO2CF3by reaction with a cyanide salt in a suitable solvent with the addition may also desired a suitable catalyst. Suitable cyanide salts include copper cyanide(I), sodium cyanide, dictionarypath sodium or potassium cyanide and suitable solvents include the less copper oxide(I), tetrakis(triphenylphosphine)palladium(0) or complexes of Nickel(0) generated in situ from dibromobis(triphenylphosphine)Nickel(II), zinc and triphenylphosphine.

The compounds of formula I, where R2, R3or R4is IT OS1-C4-alkyl, can be obtained from the corresponding substituted 2-chloropyridine, or by chemical transformation of another substituent, for example, IT is derived can be obtained from the NH2is derived through dataproperty product.

When necessary, hydroxy, amino or other reactive groups can be protected with a protective group, as described in the standard manual "Protecting Groups in Organic Synthesis, 2ndEdition (1991) by Greene and Wuts.

The compounds of formula I can be obtained from other compounds of formula I using General methods known to the person skilled in the art for mutual transformations of functional groups (see, for example, the reactions listed in J. March, "Advanced Organic Chemistry (1985) 3rdEdition).

In addition, several of the substituted compounds of the formula I can be obtained using correspondingly substituted compounds of formula VIII, namely, 2-chloro-5-triptorelin will give the connection, where R3is CF3.

Compounds of the invention and of the intermediates can be isolated from their reaction mixtures by standard techniques.

Acid additive salts of compounds of formula I that may be mentioned include the salts of mineral acids, such as cleaners containing hydrochloride and hydrobromide salts, and salts formed with organic acids such as formiate, acetate, maleate, benzoate, tartrate and fumaric salt.

Acid additive salts of compounds of formula I can be formed by reaction of the free base or salt,
enantiomer or its protected derivative, with one or more equivalents of the appropriate acid. The reaction can be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is insoluble, such as water, dioxane, ethanol, tetrahydrofuran or diethyl simple ether, or a mixture of solvents that can be removed under vacuum or freeze-drying. The reaction can be carried out Metallichesky way (exchange reaction), or it mogh forms, all of which are included in the scope of this invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example by fractional crystallization or chiral HPLC. Alternative individual enantiomers may be obtained by reaction of the appropriate optically active starting materials under conditions of reactions, which cannot cause racemization.

(D) Compound where Y is NO
The compounds of formula I, where Y represents NO, X represents oxygen, a represents C(R2), G is C(R3) and D is C(R4), can be obtained from compounds of formula XIX where X represents oxygen, a represents C(R2), G is C(R3) and D is C(R4), restoration of suitable regenerating agent in suitable conditions, for example by sulphur dioxide in ethanol at room temperature.


The compounds of formula XIX can be obtained from compounds of the formula I, where Y is N, X is oxygen, a is C(R2), G is C(R3) and D is C(R4), by oxidation with a suitable oxidizing agent in a suitable s is s I, where Y is N, X is oxygen, a is C(R2), G is C(R3) and D is C(R4) can be obtained similarly to the above sections (A), (b) and (C).

The compounds of formula I, where Y represents N, a represents C(R2), where R2is hydroxyl, can be obtained from compounds of the formula I, where Y represents NO regrouping using carboxylic acid anhydride in a suitable solvent, for example triperoxonane anhydride in DMF.

The compounds of formula I, where Y represents N, a represents C(R2), where R2is halogen, can be obtained from compounds of the formula I, where Y represents NO and a is C(R2), where R2represents hydrogen, by reaction with a halide or oxyhalogenation phosphorus, either undiluted or with a suitable co-solvent, for example neat phosphorus oxychloride.

The compounds of formula I, where Y represents N, a represents C(R2), where R2is CN can be obtained from compounds of the formula I, where Y represents NO and a is C(R2), where R2represents hydrogen, by reaction with a suitable source of cyanide, such as trimethylsilylacetamide in PR is

Intermediate products
Another aspect of the invention relates to new intermediate products. Particularly interesting among these new intermediate products are borsoderzhashhie connections, especially the compound of formula II in scheme I and the compound of formula XIII in scheme II. These intermediate products can be used in the synthesis of compounds of the formula I, but their use is not limited to the synthesis of the above compounds.

So, for example, compounds of formula II

where n is 0 or 1;
m is 0 or 1;
p is 0 or 1;
X represents oxygen or sulfur;
W represents oxygen, N or F2;
A represents N or C(R2);
G represents N or C(R3);
D represents N or C(R4);
provided that not more than one of A, G and D is nitrogen;
R1represents hydrogen or C1-C4-alkyl;
R2, R3and R4are independently hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, heteroaryl, HE OC1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6, -CF3, -S2CF3or R2and R3or R3and R1definition or heteroaromatic ring, containing from zero to two nitrogen atoms and substituted independently one or two of the following substituents: hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, heteroaryl, HE OC1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6, -CF3, -S2CF3;
R5and R6independently represent hydrogen, C1-C4-alkyl, C(O)R7C(O)other8With(O)OR9, SO2R10or may together be (CH2)jQ(CH2)kwhere Q is O, S, NR11or communication;
j is equal to the number from 2 to 7;
k is the number from 0 to 2;
R7, R8, R9, R10and R11are independently1-C4is alkyl, aryl or heteroaryl,
or their enantiomers.

The compounds of formula XIII

where n is 0 or 1;
m is 0 or 1;
X represents oxygen or sulfur;
R1represents hydrogen or C1-C4-alkyl;
R represents a C1-C6-alkyl, -CH2-Ar or AG;
AG represents phenyl, optionally substituted by the following substituents are from one to three: halogen, C1-C4-alkyl or C1-C4-alkoxy,
or as purified enantiomers, the racemates or mixtures.

The use of compounds IV, III, II, XIII, X, and IX as intermediates in the synthesis of the ligand for nicotinic acetylcholine receptors is another aspect of the present invention.

Another aspect of the invention relates to the use of compounds of formula I, where Y is NO, as intermediate products. These intermediate products can be used in the synthesis of compounds of formula I, where Y represents N, but their use is not limited to the synthesis of the above compounds.

Pharmaceutical compositions
Another aspect of the invention relates to pharmaceutical compositions for the treatment or prophylaxis of conditions or disorders as described in the examples below, resulting from dysfunction of neuropterida nicotinic acetylcholine receptors in a mammal, preferably a human, comprising an amount of the compounds of formula I, its enantiomers or its pharmaceutically acceptable salt, is effective for treatment or prevention of such violation or condition, and an inert pharmaceutically acceptable carrier.

For the above uses the entered dose will, of course, vary depending on the connection method to briteney injected with a daily dose of from about 0.1 to about 20 mg per 1 kg of body weight of the mammal, preferably, in the form of separate doses 1 to 4 times a day or in a form with prolonged action. For a human, the total daily dose is in the range from 5 to 1400 mg, more preferably from 10 to 100 mg, and a standard dosage forms suitable for oral administration comprise from 2 to 1400 mg of the compound mixed with solid or liquid pharmaceutical carrier or diluent.

The compounds of formula I or their enantiomers and their pharmaceutically acceptable salts can be used as such or in the form of appropriate medicinal preparations for enteral or parenteral administration. In accordance with the following aspect of the present invention proposed a pharmaceutical composition comprising preferably less than 80% and more preferably less than 50% by weight of compounds according to the invention in a mixture with an inert pharmaceutically acceptable diluent or carrier.

Examples of diluents and carriers are:
- for tablets and coated tablets: lactose, starch, talc, stearic acid; for capsules: tartaric acid or lactose;
for injectable solutions; water, alcohol, glycerin, vegetable oils; for suppositories: natural or hydrogenated oils or waxes.

The proposal is>Utility
The next aspect of the invention is the use of compounds according to this invention, its enantiomers or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prophylaxis of any one of the aforementioned diseases or conditions; and a method of treatment or prophylaxis of any one of the aforementioned diseases or conditions, which includes an introduction to the patient a therapeutically effective amount of the compounds according to the invention, its enantiomers or its pharmaceutically acceptable salt.

The compounds of this invention are agonists of nicotinic acetylcholine receptors. Without going into theory, believe that the subtype agonists7 nACnR (nicotinic acetylcholine receptor) should be useful for the treatment or prophylaxis of psychotic disorders and disorders of the type of lower intellectual and have advantages compared with compounds that are agonists subtype4 nAChR. Therefore, compounds that are selective for subtype7 nAChR, preferred. Compounds according to the invention is shown as pharmaceuticals, particularly for the treatment or oticheskih disorders include schizophrenia, mania and manic depression, and anxiety. Examples of violations type of lower intellectual include Alzheimer's disease, learning deficit, impaired cognitive ability, attention deficit, memory loss and violation type hyperactivity disorder, manifested in the attention deficit. Compounds according to the invention can also be used as analgesics in the treatment of pain (including chronic pain) and in the treatment or prophylaxis of Parkinson's disease, Huntington's disease, disease, Tourette's and neurodegenerative disorders in which there is loss of cholinergic synapses. These compounds can be further indicated for the treatment or prevention of disorders of the normal circadian rhythm, for use in inducing Smoking cessation and for the treatment or prevention of nicotine addiction (including addiction resulting from exposure to products containing nicotine).

It is also believed that the compounds of this invention can be used for the treatment and prevention of ulcerative colitis.

Pharmacology
The pharmacological activity of the compounds of the invention can be evaluated in the tests presented below.

Tested -bungarotoxin (VTH) with membranes in the hippocampus of rats. Hippocampi of rats were homogenized in 20 volumes of cold buffer for homogenization (HB: concentration of component (mm): Tris(hydroxymethyl)aminomethan 50; MgCl21; NaCl, 120; KCN 5; pH 7.4). The homogenate was centrifuged for 5 minutes at 1000 x g, the supernatant was retained and the residue was extracted again. The collected supernatant centrifuged for 20 minutes at 12000 x g, washed again and suspended in HB. Membrane (30-80 μg) were incubated with 5 nm [125I]-BTX, 1 mg/ml BSA (bovine serum albumin), test drug, and either 2 mm SAS2or 0.5 mm EGTA [bis(-aminoacylase ether)etilenglikola] for 2 hours at 21oC and then filtered and washed 4 times on the filter of glass fiber Whatman (density) using the collector cells Brandel. Pre-processing filters for 3 hours with 1% (BSA/0.01% of PEI (polyethylenimine) in water was required (critical) to obtain a low control filters (0,07% of the total counts per minute). Nonspecific binding was described with application of 100 μm (-)-nicotine, and specific binding was typically 75%.

Test Century Analysis affin is representing a modified technique Martino-Barrows and Kellar (Mol Pharm (1987) 31: 169-174), the brain of rats (kartex, and the hippocampus was homogenized as in the analysis of [125I]-WITH-binding centrifugation for 20 minutes at 12000 x g, washed twice, and then again suspended in HB containing 100 μm of diisopropylfluorophosphate. After 20 minutes at 4oWith the membrane (approximately 0.5 mg) were incubated with 3 nm [3H]-(-)-nicotine, the test drug, 1 μm atropine and either 2 mm CaCl2or 0.5 mm EGTA for 1 h at 4oC and then filtered on a filter of glass fiber Whatman (density) (pre-treated for 1 hour with 0.5% PEI) using a collector cells Brandel. Nonspecific binding was determined using 10 μm carbachol and specific binding typically was 84%.

Analysis of the data binding for tests a and b
The value of the IC50and pseudodeficiency hill (nn) were calculated using the nonlinear fitting curves ALLFIT (DeLean A, Munson, P. J. and Rodbard D (1977) Am. J. Physiol., 235:E97-E102). Curves of saturation were adjusted for the one-factor model using a nonlinear regression program ENZFITTER (Leatherbarrow, R. J. (1987)), which gives the value KDto 1.67 and 1.70 nm125I--VTH and [3H]-(-)-nicotine Li-[IC50]/((2+([ligand]/[CD])n)1/n-1),
where was used the value n=1 whenever nn<1.5, was used the value n= 2, when nn1,5. The samples were analyzed in the triple repetition, values were typically5%. Values of Kiwere determined using 6 or more concentrations of the drug. Compounds of the invention are compounds with affiniscape binding (Ki) lower than 1000 nm, or in test A, or test, this indicates that they, as expected, have useful therapeutic activity.

Compounds of the invention have the advantage that they may be less toxic, can be more efficient, can operate for a long period, can have a broader range of activity, can be more potent may cause a weaker side effects, are more easily absorbed or have other useful pharmacological properties.

EXAMPLES
Commercial reagents were used without further purification. Mass spectra were recorded using a mass spectrometer or Hewlett Packard A or MicroMass Quattro-1 and represented the 20-25oC.

Getting 1
Complex Spiro[1-azabicyclo[2.2.2]octane-3,2'-oxiran]-N-borane
A mixture of iodide trimethylsulfoxonium (16,10 g, and 73.2 mmol) and dispersion of sodium hydride (60% in oil, 3.00 g, 75,0 mmol) in anhydrous dimethyl sulfoxide was stirred at room temperature under nitrogen atmosphere for 30 minutes. Then in the solid state in parts add Hinkley-3-one (7,05 g, 56,3 mmol) and the resulting mixture was stirred at 65-70oC in nitrogen atmosphere for 1 hour. The reaction mixture is cooled, add water (200 ml) and the resulting solution extracted with chloroform (3 x 200 ml). Extracts in chloroform are combined and back extracted with water (4 x 200 ml). The chloroform layer dried (MgS4), filtered and evaporated under reduced pressure, getting Spiro[1-azabicyclo[2.2.2] octane-3,2'-oxiran] (6,51 g, 46.8 mmol, 83%) as a clear, colorless liquid. To a stirred solution of Spiro[1-azabicyclo[2.2.2] octane-3,2'-oxirane] (5.3g, 38,1 mmol) in anhydrous tetrahydrofuran (100 ml) at 0oWith added dropwise a solution of borane in tetrahydrofuran (1.0 M, 38,1 ml of 38.1 mmol) and the resulting solution stirred at 0oC in nitrogen atmosphere for 30 minutes. Carefully to the reaction solution was added saturated salt solution (100MgS4), filtered and evaporated under reduced pressure, obtaining mentioned in the title compound (4.3 g, 28.1 mmol, 74%) as a white solid: MS elektrorazpredelenie 152 ([M-H]+, 15).

Getting 2
Complex of 3-(2-chloropyridin-3-ylmethyl)-3-hydroxy-1-azabicyclo[2.2.2]octane-N-borane
The solution finelite (1.8 M) in a mixture of cyclohexane/simple ether [7:3], 167 ml, 0.3 mol, 3 EQ.) add the cannula in anhydrous tetrahydrofuran (350 ml) at -60oC in nitrogen atmosphere. Then added dropwise to Diisopropylamine (0.7 ml, 5 mmol), followed by adding dropwise 2-chloropyridine (28.4 ml, 0.3 mol, 3 copies) within ten minutes. The resulting solution was stirred at -40oC in an atmosphere of nitrogen for 1.5 hours. The solution is then cooled to -60oC and added dropwise to the solution of complex Spiro[1-azabicyclo[2.2.2] octane-3,2'-oxiran] -N-borane (15.3 g, 0.1 mol) in tetrahydrofuran (75 ml). The resulting reaction mixture is then stirred at -40oC in nitrogen atmosphere. After 3 hours, slowly add a saturated solution of sodium bicarbonate (150 ml), then water (400 ml) and the resulting aqueous mixture is left to warm to room temperature. The layers are separated and the aqueous phase extracted with ethyl acetate (3 x 100 ml). The organic layers ubytovanie silica gel and elution with a mixture of ethyl acetate/hexane [3:2] gives specified in the title compound in the form of reddish-brown product (17.5 g, 65,6 mmol, 66%): MS elektrorazpredelenie 269 ([MN]+with37Cl, 10), 267 ([MN]+with35Cl, 26).

Getting 2(b)
Complex of 3-(2, 4-dichloropyridine-3-ylmethyl)-3-hydroxy-1-azabicyclo[2.2.2] octane-N-borane is obtained from 2.64 g (17.8 mmol) of 2,4-dichloropyridine and of 1.37 g (of 8.95 mmol) of Spiro[1-azabicyclo [2.2.2] octane-3,2'-oxirane] number 2,42 g (90%), so pl. 178-179oWith (ethyl acetate-hexane, 1:1).

Getting 3
Complex Spiro[3-azabicyclo[2.2.2] octane-3,2'-(3'H)-furo[2,3-b]pyridine] -N-borane
Complex of 3-(2-chloropyridin-3-ylmethyl)-3-hydroxy-1-azabicyclo[2.2.2] octane-N-borane (17,4 g, 65.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (500 ml), the resulting solution is cooled to 0oC in nitrogen atmosphere and in parts add a dispersion of sodium hydride (60% in oil, 6,55 g, 163 mmol, 2.5 EQ. ). The resulting solution was stirred at room temperature under nitrogen atmosphere for 16 hours. Then at 0oTo add a saturated solution of ammonium chloride (50 ml), then ice water (500 ml) and the resulting aqueous mixture is extracted with chloroform (4 x 125 ml). The organic extracts are combined, dried (MgSO4) and evaporated under reduced pressure, obtaining an orange solid product. Purification through a short column of silica gel with elution with a mixture of chloroform/acetone [mmol, 84%) indicated in the title compound: MS elektrorazpredelenie 231 ([MN]+, 65).

Getting 4
Complex of 3-(2-methanesulfonylaminoethyl)-3-trimethylsilyloxy-1-azabicyclo[2.2.2]octane-N-borane
(a) tert-Butyl ether 2-(3-hydroxy-1-azabicyclo[2.2.2] Oct-3-yl)acetic acid.

To a solution of Diisopropylamine (6,7 ml) in tetrahydrofuran (THF) (20 ml) at 0oWith add n-utility (2.3 M in hexano; 20 ml). The reaction mixture is stirred for 40 minutes and then cooled to -78oC. To this mixture is added dropwise a solution of tert-butyl acetate (6.4 ml) in THF (10 ml) and stirring is continued for an additional 15 minutes. To the mixture are added dropwise Hinkley-3-one (5 g) in THF (15 ml) and the mixture is left to warm to 0oC for 1 hour. To this solution was added water (100 ml), the solution is extracted twice with chloroform and the combined extracts washed once with saturated salt solution. The resulting solution is dried over MgSO4, filtered and evaporated in vacuum, obtaining at 9.53 g specified in the subtitle compound as not quite white solid product.

(b) Methyl ester of 2-(3-hydroxy-1-azabicyclo[2.2.2]-Oct-3-yl)acetic acid.

Triperoxonane acid (40 ml) is added dropwise over ω dichloromethane (40 ml) at 0oC. the Mixture is stirred for 24 hours at room temperature, then the solvent is evaporated under reduced pressure. The residue is dissolved in methanol (90 ml) and cooled in an ice bath. Dropwise within 10 minutes add concentrated sulfuric acid, then the reaction mixture was stirred at room temperature. After 3 hours the solution is poured into 10 ml of ice-cold water, do basic to pH 10 with saturated aqueous solution of sodium carbonate and extracted with chloroform (4 x 100 ml). The extracts are dried (MgSO4), filtered and evaporated in vacuum, obtaining a solid product. Recrystallization from ethyl acetate gives 6.3 g of reddish-brown crystalline specified in the subtitle compound.

(C) a Complex of methyl ester of 2-(3-hydroxy-1-azabicyclo[2.2.2]Oct-3-yl)acetic acid-N-borane
Borane in GTP (1 M, the 5.25 ml) is added dropwise during 20 minutes to a solution of methyl ester of 2-(3-hydroxy-1-azabicyclo[2.2.2]Oct-3-yl)acetic acid (1 g) in anhydrous tetrahydrofuran (THF) (20 ml), stir at 0oC. After 30 minutes, add 20 ml of saturated salt solution, stirring is continued for an additional 30 minutes and the layers are then separated. The aqueous layer was extracted with ethyl acetate (2 x 20 ml), the organization will gorhaut flash chromatography on silicates (elution with a mixture of chloroform/acetone, 95:5), receiving specified in the title compound (900 mg) in the form of not quite white solid product.

(g) Complex of 3-hydroxy-3-(2-hydroxyethyl)-1-azabicyclo[ 2.2.2]octane-N-borane.

In an argon atmosphere of borohydride lithium (2 M in tetrahydrofuran, and 2.6 ml, 5.2 mmol) is added during 5 minutes to a solution of the complex of methyl ester of 2-(3-hydroxy-1-azabicyclo[2.2.2] Oct-3-yl)acetic acid-N-borane (1 g, 4.7 mmol) in anhydrous tetrahydrofuran (20 ml) and heated to boiling under reflux for 1 hour. The reaction mixture was cooled (ice bath), quenched with water (5 ml) and saturated aqueous sodium bicarbonate (5 ml), stirred for 45 minutes at a temperature of from 0oWith up to room temperature and extracted four times with ethyl acetate. The combined organic layers are dried (MgSO4), evaporated under reduced pressure and triturated with ethyl simple ether, getting mentioned in the title compound (830 mg, 4.5 mmol, 95%) as a white solid product.

(d) Complex 3-trimethylsilyloxy-3-(2-trimethylsilyloxy)-1-azabicyclo[2.2.2]octane-N-borane.

In the atmosphere of argon chlorotrimethylsilane (0,255 ml, 2 mmol) is added via syringe over 5 minutes to the complex 3-hydroxy-3-(2-hydroxyethyl)-1-azabicyclo[2.2.2] octane-N-borane (185 is (262 mg, 2 mmol), the reaction mixture is stirred for 16 hours at room temperature and heated at 55-60oC for 3 hours. The mixture is cooled, poured into a mixture of ice/water (5 g) and extracted four times a simple ether. The combined organic layers washed four times with saturated salt solution, dried (MgSO4), evaporated under reduced, pressure and purified flash chromatography (elution with hexane/ethyl acetate 3:2), getting mentioned in the title compound (210 mg, 0.64 mmol, 64%).

(e) Complex of 3-(2-hydroxyethyl)-3-trimethylsilyloxy-1-azabicyclo[2.2.2] octane-N-borane
In the atmosphere of argon complex 3-trimethylsilyloxy-3-(2-trimethylsilyloxy)-1-azabicyclo[2.2.2] octane-N-borane (190 mg, of 0.58 mmol) in anhydrous methanol (1 ml) containing 0,032 M potassium carbonate in methanol (0.25 ml), stirred at room temperature for 84 hours, acidified to pH 7 with acetic acid and evaporated under reduced pressure. Purification with flash chromatography (elution with hexane/ethyl acetate 3:2) gives specified in the title compound (94 mg, and 0.37 mmol, 63%).

(g) Complex of 3-(2-methanesulfonylaminoethyl)-3-trimethylsilyloxy-1-azabicyclo[2.2.2]octane-N-borane
In the atmosphere of argon methanesulfonanilide (0,086 ml, 1.1 mmol) in betwedn is metilcellulose-1-azabicyclo[2.2,2]octane-N-borane (257 mg, 1 mmol) in anhydrous pyridine (4 ml), stirred at 0oC for 20 minutes and at room temperature for 2 hours. Pour into ice (15 g), extracted four times with ethyl acetate, the combined organic layers are washed successively 1 N. aqueous hydrochloric acid (three times), water and saturated aqueous sodium bicarbonate. The extracts are dried (MgSO4), evaporated under reduced pressure and purified flash chromatography (elution with a mixture of chloroform, ethyl acetate, 97:3), getting mentioned in the title compound (263 mg, 0.78 mmol, 78%).

Getting 5
(a) 3-Ethynyl-3-hydroxy-1-azabicyclo [2.2.2] octane
In an argon atmosphere a solution of 3-binucleation (1.25 g, 10 mmol) in anhydrous tetrahydrofuran (10 ml) added dropwise within 15 minutes to 1 M solution of vinylmania in tetrahydrofuran (20 ml, 20 mmol) at a temperature of from 0oWith up to 5oC, stirred at room temperature for 24 hours, cooled to 0oC and acidified to pH 1 6 M hydrochloric acid. The mixture is stirred for 15 minutes, doing basic to pH 10 with 25% aqueous sodium hydroxide, extracted with chloroform (4 x 50 ml) and a mixture of chloroform/methanol (4: 1, 50 ml), combine the organic layers, dried (MgS4), evaporated at the 5: 15), getting listed in the title compound (830 mg, 5.4 mmol, 54%).

(b) 3-Bromo-2-hydroxypyridine
A solution of bromine (9.6 g, 60 mmol) in 1 M aqueous potassium bromide (120 ml) is added during 5 minutes to a solution of 2-hydroxypyridine (5.7 g, 60 mmol) in 1 M aqueous potassium bromide (60 ml) and stirred for 24 hours. The solid precipitate was separated by filtration, the aqueous phase is saturated with chloride. sodium and extracted with chloroform (4 x 20 ml), the combined extracts dried (MgSO4), evaporated under reduced pressure and combined with the original precipitate. Purification with flash chromatography (elution with a mixture of saturated ammonia chloroform/methanol, 95: 5) and recrystallization from acetonitrile gives specified in the title compound (3.62 in) to 20.8 mmol, 35%).

(b) 3-Bromo-2-methoxypyridine
In an argon atmosphere a mixture of 3-bromo-2-hydroxypyridine (3,49 g, 20 mmol), silver carbonate (3,67 g, 13,31 mmol) and iodomethane (1.5 ml, 24,1 mmol) in benzene (30 ml) is stirred in the dark at a temperature of from 40oWith up to 50oC for 24 hours, cooled in an ice bath and filtered. The filtrate is washed once with 2% aqueous sodium carbonate and twice with water, dried (MgSO4), the benzene evaporated at atmospheric pressure and the residue purified flash chromatography (elution with a mixture of GE is cyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]-pyridine]
Complex 5'-Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b] pyridine] -N-borane (12.2 g, 53 mmol) is dissolved in 150 ml of acetone, the solution is cooled tooAnd add an aqueous solution of HBr (24%, 50 ml). The resulting solution was stirred at room temperature under nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and the aqueous residue is treated with saturated aqueous solution of sodium carbonate (50 ml). Solution make basic to pH>10 with solid sodium carbonate and the resulting solution extracted with chloroform (3 x 100 ml). The organic extracts are combined, dried (gS4), filtered and evaporated under reduced pressure, obtaining mentioned in the title compound (11.2 g, to 51.8 mmol, 98%, the total yield 54%) as not quite white solid: MS elektrorazpredelenie 217 ([MN]+, 72).

Specified in the header of the connection is divided into its (R)- and (S)-enantiomers of any of the following methods.

Method A. 250 mg specified in the connection header is shared by chiral HPLC using a column 2 cm x 25 cm CHIRALCEL-OD in the system of preparative chromatography Waters Delta Prep 3000, elwira mixture of 2,2,4-trimethylpentane/ethanol (92: 8 to 9:1) at a flow rate of 20 ml/min This gives 111 mg (S)-enantiomer ([

Method C. 1 g (4,62 mmol) specified in the connection header is treated with L-(+)-tartaric acid (694 mg, to 4.62 mmol) in 15% aqueous ethanol (10 ml) and recrystallized three times, receiving L-(+)-tartrate (S)-enantiomer (650 mg; 1.77 mmol; ([]23= +57,7o(C=2, H2O)). The filtrates are concentrated under reduced pressure and the aqueous solution do basic to pH>10 using solid sodium carbonate. The resulting mixture is extracted with chloroform (3 x 25 ml) and the combined extracts dried (gS4) and evaporated under reduced pressure. The residue (650 mg; 3 mmol) is treated with D-(-)-tartaric acid (452 mg; 3 mmol) and recrystallized as described above, receiving D-(-)-tartrate of (R)-enantiomer (775 mg; 2,11 mmol; []23= -58,2o(C=2, N2O)).

Example 2A
5'-Bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine]
A solution of Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo-[2,3-b]pyridine] (100 mg, 0,462 mmol) and sodium acetate (410 mg, 5 mmol) in 50% aqueous acetic acid (4 ml) heated to 60oC. Via syringe over 10 minutes add bromine (0.100 ml, 1.94 mmol), and the solution is then heated to boiling under reflux for 1 hour. The mixture is left to cool United extracts dried (MgSO4), filtered and evaporated under reduced pressure, obtaining mentioned in the title compound (110 mg, of 0.37 mmol, 81%) as not quite white solid: MS elektrorazpredelenie 295 ([MN]+with79Br, 100), 297 ([MN]+with81Br, 98).

Example 2B
(R)-(-5-5'-Bromospiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo-[2,3-b] pyridine]
The enantiomer, (R)-(-)Spiro[1-azabicyclo[2.2.2] -octane-3,2'(3 N)-furo-[2,3-b] pyridine] (1,95 g, 9 mmol), treated in the same manner as described in example 2A, gives specified in the title compound (1.77 g, 6 mmol, 67%) ([]23= -45,5o(C=1, Meon)).

Example 3
5'-Perspire[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine]
In nitrogen atmosphere 5'-bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo-[2,3-b]pyridine] (118 mg, 0.4 mmol), phenylboronic acid (54 mg, 0,443 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 2,3 mol.%) stirred solution of 1,2-dimethoxyethane (3 ml) and ethanol (0.75 ml) containing 2 M aqueous sodium carbonate (to 0.65 ml, 1.3 mmol). The mixture is heated at the boil under reflux for 18 hours. The reaction mixture was then evaporated under reduced pressure, the residue is dissolved in chloroform (15 ml) and the extract washed with saturated aqueous sodium carbonate (5 ml). The aqueous layer E. the reduced pressure. Purification with flash chromatography over silica gel with elution with a mixture of saturated ammonia chloroform/methanol (95:5 to 9:1) gives specified in the title compound (80 mg, 0,274 mmol, 68%) as a tan solid: MS elektrorazpredelenie 293 ([MN]+, 100).

Example 4A
5'-Nitrospira[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine]
A mixture of Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo-[2,3-b] pyridine] (325 mg, 1.5 mmol) and fuming nitric acid (0,27 ml 5,74 mmol) in sulfuric acid (0.75 ml) is heated at a temperature of from 70oWith up to 80oWith in 24 hours. The resulting viscous solution was poured onto 15 g of ice and make basic to pH>10 with solid sodium carbonate. The resulting mixture is extracted with chloroform (4 x 15 ml), dried (MgSO4), filtered and evaporated under reduced pressure. Purification with flash chromatography over silica gel with elution with a mixture of saturated ammonia chloroform/methanol (95:5) gives specified in the title compound (200 mg, 0,765 mmol, 51%) as a pale yellow solid: MS elektrorazpredelenie 262 ([MN]+, 100).

Example 4B
(R)-(-)-5'-Nitrospira[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine]
(R)-(-)-Spiro[1-azabicyclo[2.2.2. ] octane-3,2'(3 M]-furo-[2,3-b]pyridine] (3.03 g, 14 mmol) dissolved in conc is,2 mmol), the mixture is stirred for 1 hour and heated at 65-70oWith in 24 hours. Cooled, poured on ice (200 mg), add 300 ml of water, do basic to pH 10 with solid potassium carbonate, stirred for 1 hour, filtered and dried solid is listed in the title compound (3.6 g, of 13.8 mmol, 98%): MS elektrorazpredelenie (m/z, relative intensity) 262 ([MN]+, 100).

Example 4C
(S)-(+)-5'-Nitrospira[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine]
The enantiomer, (S)-(+)-Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo-[2,3-b] pyridine] (6.5 g, 30 mmol), treated in the same manner as described in example 4B, network specified in the header of the connection (of 7.75 g, 29.7 mmol, 99%): MS elektrorazpredelenie (m/z, relative intensity) 262 ([MN]+, 100).

Example 5
Spiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]quinoline]
Specified in the title compound is obtained by methods analogous to the methods described in example 1 from 2-chlorhydrin (0,99 g, the 6.06 mmol) and complex Spiro[1-azabicyclo[2.2.2] octane-3,2'-oxiran] -N-borane (0.31 g, 2.0 mmol), receiving specified in the header of the connection (is 0.135 g) as a white powder, MS elektrorazpredelenie 267 [MN]+.

These two enantiomers separated on a Chiral column OD by elution with a gradient mixture 8-10"https://img.russianpatents.com/chr/945.gif">]Dat the 23oWith in EtOH= +47,9o. The second enantiomer: 99,4% chiral purity, Rt=17,84 minutes []D= -48,5o.

Example 6
2'-Chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]isoquinoline]
Specified in the title compound is obtained by methods analogous to the methods described in example 1 from 1,3-dichlorethylene (2,41 g, 12.2 mmol) and complex Spiro-[1-azabicyclo[2,2.2] octane-3,2'-oxiran] -N-borane (0,62 g of 4.05 mmol), receiving 0,86 g of the complex of 2'-chlorpro[1-azabicyclo[2.2.2]octane-3,2' (3 N)-furo-[2,3-b] isoquinoline]-N-borane, MS elektrorazpredelenie 314 [MN]+. Remove boranova group 65 mg of N-Baranovka complex network 30 mg specified in the title compound, MS elektrorazpredelenie 301 [MN]+.

Example 7
Spiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]-isoquinoline]
Protected borane chloride of example 6 (0.3 g or 0.96 mmol) is suspended in a mixture of glacial acetic acid (6.0 ml) and water (0.5 ml). The suspension is placed in a nitrogen atmosphere and add zinc dust (150 mg). The reaction mixture was stirred at 70oC for 5 hours. The reaction mixture is left to cool and then poured into saturated Panso3. Add enough water Panso3to achieve dry (gSO4), filtered and evaporated in vacuum. The products of the two experiments unite for purification on a column of silica gel using a gradient from 2:1 mixture of hexane/ethyl acetate to 100% ethyl acetate. Faster suiryudan connection is a complex Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo-[2,3-b] isoquinoline]-N-borane and slower suiryudan a join is specified in the header connection. Output 100%: MS with chemical ionization 279 [MN]+-N2for N-Baranovka complex and 267 [MN]+specified in the connection header. Remove boranova groups in the conditions of example 1 with subsequent flash chromatography gives specified in the title compound as a brown semi-solid product: MS with chemical ionization 267 [MN]+.

Example 8A
5'-Aminosterol[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine]
A mixture of 5'-nitrospira[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine] (1.4 g, are 5.36 mmol) and 10% palladium on coal (48% moisture, 270 mg) in methanol (90 ml) hydronaut for 1 hour at a pressure of 50 psi of hydrogen. The catalyst is separated by filtration through a pillow celite and the solvent evaporated under reduced pressure, obtaining the amine (1.2 g, a 5.25 mmol, 98%) as a tan solid: MS electrahot (R)- and (S)-enantiomers in the following way.

150 mg specified in the connection header is shared by chiral HPLC using a column 2 cm x 25 cm CHIRALCEL-OD in the system of preparative chromatography Waters Delta Prep 4000 [hexane/ethanol (85:15 to 8:2)] at a flow rate of 20 ml/min. This provides 52 mg of (S)-epimer ([]22= +62o(C=1, ethanol) and 52 mg (R) - epimer ([]23= -64o(C=1, ethanol).

Example 8B
(R)-(-)-5'-Aminosterol[1-azabicyclo[2.2.2] octane-3,2'(3'H-furo-[2,3-b] pyridine]
The enantiomer, (R)-(-)-5'-nitrospira[1-azabicyclo[2.2.2]-octane-3,2'(3 N)-furo-[2,3-b] pyridine] (3.8 g, 13.3 mmol), treated in the same manner as described in example 8A, and purified flash chromatography (elution with a mixture of saturated ammonia chloroform/methanol, 95:5 to 85:15), gives specified in the title compound (2.5 g, about 10.8 mmol, 81%): MS elektrorazpredelenie (m/z, relative intensity) 232 ([MN]+, 100).

Example 8C
(S)-(+)-5'-Aminosterol[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo-[2,3-b] pyridine]
The enantiomer, (S)-(+)-5'-nitrospira[1-azabicyclo[2.2.2]-octane-3,2'(3 N)-furo-[2, 3-b]pyridine] (6.85 g, to 26.2 mmol), treated in the same manner as described in example 8A, in a saturated ammonia methanol gives specified in the header of the connection (of 5.55 g, 24 mmol, 92%): MS elektrorazpredelenie (m/z, consider the)-furo-[2,3-b]pyridine]
In nitrogen atmosphere benzoic acid (67 mg, 0.55 mmol), tetrafluoroborate O-(1H-benzotriazol-1-yl)-N, N, N', N'-tetramethylurea ("TBTU", 176 mg, 0.55 mmol), hydrate of 1-hydroxybenzotriazole ("NOT", 78 mg, 0.55 mmol) and diisopropylethylamine (0,193 ml, 1.1 mmol) are mixed in anhydrous N,N-dimethylformamide (8 ml) and stirred for 10 minutes. 5'-Aminosterol[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine] (115 mg, 0.5 mmol) is added in solid form in one portion and stirring is continued for 3 days. The solvent is evaporated under high vacuum and heated to 55oWith and the residue partitioned between saturated aqueous sodium carbonate (2 ml) and dichloromethane (10 ml). After separation the aqueous phase is extracted with dichloromethane (2 x 5 ml). The organic layers are combined, dried (gSO4) and evaporated under reduced pressure. Purification with flash chromatography over silica gel with elution with a mixture of saturated ammonia chloroform/methanol (9:1) gives specified in the title compound (125 mg, 0,372 mmol, 75%) as a yellow solid: MS elektrorazpredelenie (m/z, relative intensity) 336 ([MN]+, 100).

Example 10
5'-Phenylaminopyrimidine[1-azabicyclo[2.2.2] -octane-3,2'(3 N)-furo-[2,3-b]pyridine]
In nitrogen atmosphere finalization mmol) in anhydrous tetrahydrofuran (5 ml) and stirred for 12 hours. The solvent is evaporated under reduced pressure and the residue purified flash chromatography over silica gel with elution with a mixture of saturated ammonia chloroform/methanol (92,5:7,5), getting mentioned in the title compound (155 mg, 0,442 mmol, 86%) as not quite white solid: MS elektrorazpredelenie (m/z, relative intensity) 351 ([MN]+, 100).

Example 11
5'-Vinylsulfonylacetamido[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo-[2,3-b]pyridine]
In the atmosphere of nitrogen benzosulphochloride (0,07 ml, 0.55 mmol) are added to a solution of 5'-aminosterol[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine] (115 mg, 0.5 mmol) in anhydrous pyridine (5 ml) and stirred for 4 hours. The solvent is evaporated under high vacuum, the residue partitioned between saturated aqueous sodium carbonate (2 ml) and chloroform (10 ml), separated and the aqueous phase is extracted with chloroform (2 x 5 ml). The combined organic layers are dried (MgSO4), the solvent evaporated under reduced pressure and the residue is again evaporated from ethanol (3 x 10 ml) under reduced pressure. This gives specified in the title compound (179 mg, 0.5 mmol, 100%) as a yellow solid: MS elektrorazpredelenie (m/z,
relative intensity) 372 ([MN]+, 100).

PG, 2,11 mmol) is added slowly (exothermic reaction) to methanol (1 ml) and stirred for 1 hour. Add 5'-aminosterol[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b] pyridine] (115 mg, 0.5 mmol) and paraformaldehyde (35 mg, at 1.17 mmol) and stirred for 16 hours. The reaction mixture is heated at 50oC for 4 hours, add borohydride sodium (53 mg, 1.4 mmol) and heated to boiling under reflux for 1 hour. Then add 1 N. aqueous potassium hydroxide (0.4 ml) and boiled under reflux continued for more than 2 hours. The solvent is evaporated under reduced pressure, the residue partitioned between water (1 ml) and chloroform (4 ml), separated and the aqueous phase is extracted with chloroform (2 x 4 ml). The combined organic layers washed with saturated salt solution (1 ml), dried (gS4), evaporated under reduced pressure and purified flash chromatography through silica gel (elution with a mixture of saturated ammonia chloroform/methanol, 95:5), receiving specified in the title compound (78 mg, 0.32 mmol, 64%) as not quite white solid: MS elektrorazpredelenie (m/z, relative intensity) 246 ([MN]+, 100).

Example 13A
5'-(N, N-Dimethylamino)Spiro[1-azabicyclo[2.2.2] Octan-the hydrated zinc chloride (69 mg, 0.5 mmol), stirred for 30 minutes, the resulting solution is added to a solution of 5'-aminosterol[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b] pyridine] (115 mg, 0.5 mmol) and 37% aqueous formaldehyde (approximately 0.12 ml, 1.6 mmol) in methanol (2.5 ml) and stirred for 20 hours. Poured into 1N. aqueous potassium hydroxide (10 ml), stirred for 1 hour, evaporated under reduced pressure and extracted with aqueous residue with chloroform (4 x 10 ml). The combined extracts dried (MgS4), evaporated under reduced pressure and purified flash chromatography through silica gel (elution with a mixture of saturated ammonia chloroform/methanol, 97,5:2,5), getting mentioned in the title compound (85 mg, 0.33 mmol, 66%) as not quite white solid: MS elektrorazpredelenie (m/z, relative intensity) 260 ([MN]+, 100).

Example 13B
(R)-(-)-5'-(N, N-Dimethylamino)Spiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine]
The enantiomer, (R)-(-)-5'-aminosterol[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b] pyridine] (231 mg, 1 mmol), treated in the same manner as described in example 13A, gives specified in the title compound (178 mg, 0.69 mmol, 69%): MS elektrorazpredelenie [m/z, relative intensity) 260 ([MN]+, 100).

Example 14A
(S)-(+)-5'-((E)-(Phenylethenyl)Spiro[1-the pyridine] (150 mg, 0.51 mmol), styrene (0,07 ml, 0.61 mmol), palladium(II) acetate (1.2 mg, 0,0053 mmol), tri-o-tolylphosphino (6.4 mg, 0,021 mmol) and triethylamine (0.5 ml, 3.6 mmol) in anhydrous acetonitrile (0.5 ml) in a thick-walled threaded glass tube containing a magnetic stirring rod, rinsed with argon and sealed with Teflon stopper and FETFE O-ring. The mixture is stirred and heated at 100oC for 2 hours, cooled to room temperature, dissolved in chloroform (10 ml), washed with saturated aqueous sodium carbonate (1 ml), dried (MgS4) and evaporated under reduced pressure. Recrystallization from ethyl acetate gives specified in the title compound (90 mg, 0.28 mmol, 55%) as a light tan solid: MS elektrorazpredelenie (m/z, relative intensity) 319 ([MN]+, 100).

Example 14C
(R)-(-)-5'-((E)-(Phenylethenyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
Processing enantiomer, (R)-(-)-5'-bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine] (295 mg, 1 mmol) in the same way as described in example 14A, and purification with flash chromatography (elution with a mixture of saturated ammonia chloroform/methanol, 98:2 to 96:4) is specified in the title compound (132 mg, 0.41 mmol, 41%): MS El is sabillo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
tert-Piperonyl sodium (56.6 mg, 0.59 mmol), Tris(dibenzylideneacetone)dipalladium (15,4 mg of 0.017 mmol) and 2,2'-bis(diphenylphosphino)-1,1-dinaphthyl (21 mg, 0,034 mmol) are mixed in a thick-walled threaded glass tube containing a magnetic stirring rod, and rinsed with argon. Add (S)-(+)-5'-bromospiro[1-azabicyclo[2.2.2] octane-3,2'(3'H)-furo[2,3-b]pyridine] (130 mg, 0.44 mmol), morpholine (of 0.066 ml, from 0.76 mmol) and anhydrous tetrahydrofuran (3 ml), sealed with Teflon stopper and FETFE O-ring, is stirred and heated at 100oWith within 72 hours. The mixture is cooled to room temperature, dissolved in chloroform (25 ml), washed with saturated brine (3 x 2 ml), dried (MgSO4), evaporated under reduced pressure, and purified flash chromatography through silica gel (elution with a mixture of saturated ammonium simple ether/methanol, 4: 1) and recrystallized from ethyl acetate, getting mentioned in the title compound (35 mg, 0.12 mmol, 26%) as a tan solid: MS elektrorazpredelenie (m/z, relative intensity) 302 ([MN]+, 100).

Example 15V
(R)-(-)-5'-(4-Morpholino)Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
Processing enantiomer, (R)-(-)-5'-bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridi mmol, 32%): MS elektrorazpredelenie (m/z, relative intensity) 302 ([MN]+, 100).

Example 16
(R)-(-)-5'-(1-Azetidine)Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
(R)-(-)-5'-Bromospiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine] (295 mg, 1 mmol), azetidin (0,101 ml, 1.5 mmol), tert-piperonyl sodium (135 mg, 1.4 mmol), Tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (62 mg, 0.1 mmol) and anhydrous tetrahydrofuran (9 ml) are mixed in a thick-walled threaded glass tube containing a magnetic stirring rod, rinsed with argon and sealed with Teflon stopper and FETFE O-ring. The mixture is stirred and heated at 75oC for 4 hours, cooled to room temperature, dissolved in chloroform (20 ml), washed with saturated brine (3 x 10 ml), dried (gS4), evaporated under reduced pressure and purified flash chromatography through silica gel (elution with a mixture of saturated ammonia chloroform/methanol, 95:5), receiving specified in the title compound (230 mg, of 0.085 mmol, 85%) as a light tan solid: MS with chemical ionization (m/z, relative intensity) 272 ([MN]+, 56).

Example 17
(R)-(-)-5'-(2-(4-Pyridyl)ethynyl)spin] (295 mg, 1 mmol), 4-vinylpyridine (is 0.135 ml, 1.25 mmol), palladium(II) acetate (7.2 mg, to 0.032 mmol), tri-o-tolylphosphino (38,7 mg, to 0.127 mmol) and triethylamine (0.5 ml, 3.6 mmol) in anhydrous acetonitrile (0.5 ml) are mixed in a thick-walled threaded glass tube containing a magnetic stirring rod, rinsed with argon and sealed with Teflon stopper and FETFE O-ring. The mixture is stirred and heated at a temperature of from 100 to 105oC for 48 hours, cooled to room temperature, dissolved in chloroform (25 ml), washed with saturated aqueous sodium carbonate (2 ml), dried (MgSO4) and evaporated under reduced pressure. Purification with flash chromatography through silica gel (elution with a mixture of saturated ammonia chloroform/methanol, 95:5) followed by recrystallization from acetone gives specified in the title compound (230 mg, to 0.72 mmol, 72%): MS elektrorazpredelenie (m/z, relative intensity) 320 ([MN]+, 100).

Example 18
(R)-(-)-5'-(2-(2-Pyridyl)ethynyl)Spiro[1-azabicyclo-2.2.2] octane-3,2' (3 N)-furo[2,3-b]pyridine]
(R)-(-)-5'-Bromospiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b] pyridine] (150 mg, 0.5 mmol) is treated with 2-vinylpyridine (0,070 ml of 0.65 mmol) in the same manner as described in example 16. Purification with flash chromatography through silica gel (the C acetonitrile gives specified in the title compound (37 mg, 0.12 mmol, 23%): MS elektrorazpredelenie (m/z, relative intensity) 320 ([MN]+, 100).

Example 19
(R)-(-)-5'-(2-Trimethylsilylethynyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
(R)-(-)-5'-Bromospiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b] pyridine] (295 mg, 1 mmol), trimethylsilylacetamide (0,355 ml, 2.5 mmol), tetrakis(triphenylphosphine)palladium (230 mg, 0.2 mmol), triethylamine (2 ml) and anhydrous acetonitrile (2 ml) are mixed in a thick-walled threaded glass tube containing a magnetic stirring rod, purge with argon and sealed with Teflon stopper and FETFE O-ring. The mixture is stirred and heated at 100oC for 4 hours, cooled to room temperature, dissolved in chloroform (25 ml), washed with saturated aqueous sodium carbonate (2 ml), dried (MgS4) and evaporated under reduced pressure. Purification with flash chromatography through silica gel (elution with a mixture of saturated ammonium simple ether/methanol, 9: 1) gives specified in the title compound (280 mg, 0.90 mmol, 90%): MS elektrorazpredelenie (m/z, relative intensity) 313 ([MN]+, 30).

Example 20
(R)-(-)-5'-Edenilson[1-azabicyclo[2.2.2] octane-3,2'(3'H)-furo[2,3-b] pyridine]
In an argon atmosphere of 1 M solution of fluoride tetrabutylammonium[2.2.2] octane-3,2'(3'H)-furo[2,3-b] pyridine] (265 mg, 0.85 mmol) in anhydrous tetrahydrofuran (5 ml) and stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (2 ml), extracted with simple ether (5 x 15 ml), dried (MgS4), evaporated under reduced pressure and purified flash chromatography through silica gel (elution with a mixture of saturated ammonia chloroform/methanol, 95:5), receiving specified in the title compound (121 mg, 0.50 mmol, 59%): MS with chemical ionization (m/z, relative intensity) 241 ([MN]+, 19).

Example 21
5'-(2-Furyl)Spiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine]
A solution containing 5'-bromospiro[1-azabicyclo[2.2.2]-octane-3,2'(3 N)-furo[2,3-b]pyridine] (to 103.5 mg, 0.351 mmol), Tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.015 mmol), tri-(o-tolyl)phosphine (44,4 mg, 0,146 mmol), lithium chloride (62 mg, of 1.46 mmol) and 2-(tri-n-butylstannyl)furan (0.17 g, 0,476 mmol) in 1,2-dimethoxyethane (1 ml), heated to boiling with reverse, a refrigerator for 2 hours the Solution is evaporated and the residue is dissolved in chloroform and filtered. The filtrate is evaporated, then purified HPLC using a gradient of 0-25% of a mixture of 1:1:2 7 M solution of ammonia in methanol:methanol:chloroform and chloroform, getting mentioned in the title compound (89 mg[MN]+, 100).

Example 22
5'-(3-Pyridyl)Spiro[1'-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine]
A solution containing 5'-bromospiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine] (158 mg, 0,535 mmol), Tris(dibenzylideneacetone)dipalladium(0) (23 mg, of 0.025 mmol), tri-(o-tolyl)phosphine (66 mg, 0,217 mmol), lithium chloride (99 mg, 2.34 mmol) and 3-(tri-n-butylstannyl)pyridine (0.3 ml, about 0.3 g, approximately 0.82 mmol) in 1,2-dimethoxyethane (2 ml), heated to boiling under reflux for 6 hours the Solution is evaporated and the residue is dissolved in chloroform and filtered. The filtrate is evaporated, then purified HPLC using a gradient of 0-20% of a mixture of 1:1:2 7 M solution of ammonia in methanol:methanol:chloroform and chloroform, getting mentioned in the title compound (58 mg, 0,198 mmol, 37%) as a yellow solid: MS elektrorazpredelenie (m/z, relative intensity) 294 ([MN]+, 80), 273 (100).

Example 23
5'-Methylspiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine]
A solution containing 5'-bromospiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine] (203 mg, 0,687 mmol), Tris(dibenzylideneacetone)dipalladium(0) (33 mg, being 0.036 mmol), tri-(o-tolyl)phosphine (95 mg, 0,312 mmol), lithium chloride (241 mg, 5,69 mmol) and tetramethylsilane (1.0 ml, 1.3 g, 7.2 mmol) 2-methoxyethyl of tetramethylsilane (1 ml, 1.3 g, 7.2 mmol) and heating continued turning of the night. The solution is filtered and subjected to HPLC purification using a gradient of 0-20% of a mixture of 1:1:2 7 M solution of ammonia in methanol:methanol: chloroform and chloroform, getting mentioned in the title compound (120 mg, 0,519 mmol, 76%) as a yellow solid: MS elektrorazpredelenie (m/z, relative intensity) 231 ([MN]+, 100).

Example 24
Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b] pyridine-5'-carbonitrile] and Spiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine-5'-carboxamide]
A solution containing 5'-bromospiro[1-azabicyclo[2.2.2]-octane-3,2'(3 N)-furo[2,3-b] pyridine] (165 mg, 0,558 mmol) and copper cyanide(I) (600 mg, 1.3 g, approximately 7.2 mmol) in 1-methyl-2-pyrrolidinone (5 ml), heated in a bath maintained during 180oSince, during the night and then leave to cool. The solution is then partitioned between aqueous ammonia and chloroform and the organic layer is separated, dried (magnesium sulfate), filtered and evaporated. The residue was subjected to HPLC purification using a gradient of 0-20% of a mixture of 1: 1:2 7 M solution of ammonia in methanol:methanol:chloroform and chloroform, getting Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo-[2,3-b] pyridine-5'-carbonitrile] (52 mg, 0,216 mmol, 39%) as a pale-yellow solid p is iridin-5'-carboxamide] (71 mg, 0,274 mmol, 49%) as a pale-yellow solid product: MC with elektrorazpredelenie (m/z, relative intensity) 260 ([MN]+, 100).

Example 25
5'-Ethaniser[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine]
A solution containing 5'-bromospiro[1-azabicyclo[2.2.2]-octane-3,2'(3 N)-furo[2,3-b]pyridine] (150 mg, 0.508 mmol), Tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0,024 mmol), tri-(o-tolyl)phosphine (63 mg, 0,206 mmol), lithium chloride (103 mg, 2,43 mmol) and tri-n-butylaniline (188 mg, 0,592 mmol) in 1,2-dimethoxyethane (10 ml), heated to boiling under reflux overnight. The solution is evaporated and the residue is dissolved in chloroform and filtered. The filtrate is evaporated, then purified HPLC using a gradient of 0-25% of a mixture of 1:1:2 7 M solution of ammonia in methanol: methanol: chloroform and chloroform, getting mentioned in the title compound (93 mg, 0,385 mmol, 76%) as a yellow solid: MS elektrorazpredelenie (m/z, relative intensity) 243 ([MN]+, 100).

Example 26
(R)-(-)-5'-N'-(3-Chlorophenyl)aminocarbonylmethyl[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
(R)-(-)-5'-Aminosterol[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b] pyridine] (65 mg or 0.28 mmol) is suspended in 2.7 ml of anhydrous tetrahydrofuran under nitrogen atmosphere. Type 3 is an removed in vacuum and the crude product was purified flash chromatography. Elution of 20-40% solution of methanol/chloroform (containing NH4OH) gives the target product. The solvents are removed in vacuo and the residue is dissolved in chloroform and dried (MgSO4). Evaporation with the displacement of the two portions of a simple broadcast network 100 mg (92%) of white solid product. MS elektrorazpredelenie 385 and 387 [MN]+.

Example 27
(R)-(-)-5'-N'-(2-Nitrophenyl)aminocarbonylmethyl-[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
Using the same method as in example 27, but substituting 3-chloronicotinate 2 nitrophenylhydrazine get mentioned in the title compound; yield 97 mg (88%) of yellow powder. MS elektrorazpredelenie 396 [MN]+.

Example 28
(R)-(-)-5'-N, N-Diethylaminophenol[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
Cyanoborohydride sodium (190 mg, or 3.0 mmol) and zinc chloride (206 mg, 1.5 mmol) are added to 3.0 ml of anhydrous methanol under nitrogen atmosphere. Stirring for 5 minutes leads to complete dissolution. Add (R)-(-)-5'-amino-Spiro[1-azabicyclo[2.2.2] octane-3,2'(3'H)-furo[2,3-b] pyridine] (230 mg or 1.0 mmol), followed by acetaldehyde (0,335 ml or 6.0 mmol). The suspension is stirred at room temperature for 16 hours. The methanol was concentrated in vacuo and the suspension is poured into 20 ml of 0.1 N. the, dried (MgSO4) and evaporated in vacuo. The crude product was purified flash chromatography, starting elution with a mixture 6/3/1/0,1 ethyl acetate/methanol/water (containing NH4IT) and then the mixture 3/6/1/0,1. The solvents are removed in vacuo and the residue is dissolved in chloroform and dried (MgSO4). Get 0,227 g (79%) of a light brown syrup. MS elektrorazpredelenie 288 [MN]+.

Example 29
(R)-(-)-5'-N-Acylaminoacyl[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
(R)-(-)-5'-Aminosterol[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine] (230 mg or 1.0 mmol) and cyanoborohydride sodium suspended 6.2 ml of anhydrous methanol. Add acetaldehyde (90 µl or 1.1 mmol) and the solution stirred at room temperature for 16 hours. The methanol is removed in vacuo and the residue is dissolved in 2 ml of water and 8 ml of chloroform. The layers are separated and the aqueous layer was extracted 3 more times. The combined organic layers are dried (MgSO4) and evaporated in vacuo. The crude product was purified flash chromatography using a gradient from 3 to 15% methanol/chloroform (saturated with ammonia). The solvents are evaporated in vacuum and displace two simple portions of ether. The residue is suspended in a simple ether and collected by filtration. After simple washing with ether and drying in wisconsinensis[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
Receive by way of example 12. Of 1.0 mmol obtain 247 mg (77%) of white powder. MS elektrorazpredelenie 322 [MH]+.

Example 31
(R)-(-)-5'-N-Formimidoyl[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine]
98% formic acid (2.1 ml) and acetic anhydride (0.7 ml) are mixed in a nitrogen atmosphere and cooled in the ice bath. Add (R)-(-)-5'-aminosterol[1-azabicyclo[2.2.2] -octane-3,2'(3 N)-furo[2,3-b] pyridine] (230 mg or 1.0 mmol) and the reaction mixture is left to warm to room temperature. The reaction mixture is stirred for 26 hours and then poured with stirring saturated sodium carbonate. Solid PA2CO3add up until the pH goes back to main, and then the aqueous layer was extracted with four portions of chloroform. These chloroform layers are combined, dried (gS4) and evaporated in vacuo. The crude product was purified flash chromatography, elwira with a gradient of 2-10% of a mixture of saturated ammonia methanol/chloroform. The solvents are removed in vacuo and the residue is dissolved in chloroform, dried (MgS4) and evaporated in vacuo. The solvent displace two simple portions of ether, receiving 0.2 g (77%) of white solid product. MS elektrorazpredelenie 260 [MN]+.

Example 32
(R)-(-)-5'-N-Acetaminophen] (230 mg or 1.0 mmol) dissolved in 3 ml of anhydrous pyridine under nitrogen atmosphere. Add acetic anhydride (0.1 ml or 1.1 mmol) and the solution heated at 100oWith over 40 hours. The pyridine is removed in vacuo and the residue is dissolved in 8 ml of chloroform and washed with 4 ml saturated sodium bicarbonate. The aqueous layer was extracted two more times with chloroform and the combined organic layers dried (MgS4) and evaporated in vacuo. Purification with flash chromatography using a gradient of 3 to 20% of a mixture of saturated ammonia methanol/chloroform gives the target product. The solvents are removed in vacuo and displace two simple portions of ether. Obtain 154 mg (56%) of white solid product. MS with chemical ionization 274 [MN]+.

Example 33
4'-Chlorpro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo-[2,3-b] pyridine] and 4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[3,2-C]pyridine]
Complex of 4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine] -borane and a complex of 2'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[3,2-C] pyridine] -borane get out of 2.36 g (to 7.84 mmol) of complex 3-(2,4-dichloropyridine-3-ylmethyl)-3-hydroxy] -azabicyclo[2.2.2] octane-N-borane and 319 mg (of 7.97 mmol) of sodium hydride in dimethylformamide, as in getting 2. This mixture is treated with aqueous Hydrobromic acid in acetone, getting after flash chromatography on neutral is lo[2.2.2] octane-3,2'(3 N)-furo[2,3-b]pyridine], so pl. 109-110oWith (ethyl simple ether), and 463 mg of 4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[3,2-C]pyridine], so pl. 113-115oC.

Example 34
Spiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[3,2-C]pyridine]
4'-Chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[3,2-C]pyridine]
125 mg (or 5.0 mmol) of the compound from example 33 was dissolved in 50 ml of anhydrous methanol and add 25 mg of 10% palladium on coal. The vessel was placed on a Parr apparatus in an atmosphere of hydrogen and shaken for 2.5 hours. Pd/C is removed by filtration and washed with methanol. The solvent is removed in vacuum and the residue is dissolved in chloroform and methanol and transferred into a test tube. The solvent is removed in vacuum and displace two simple portions of ether. After drying in high vacuum to obtain 112 mg not quite white powder (104% with a residual solvent). MS elektrorazpredelenie 217 [MN]+.

Example 35
4'-Methoxamine[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine]
Sodium hydride (241 mg, 6.0 mmol) are added to a solution of 76 mg (0.30 mmol) of 4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine] in 25 ml ice methanol in a nitrogen atmosphere. The resulting solution is heated to boiling under reflux and stirred for 4 days, then cooled extract is dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue flash chromatographic on neutral silica gel using a mixture of 9:1 saturated with ammonia in chloroform/methanol, receiving 50 mg (67%) indicated in the title compound as a white solid: MS elektrorazpredelenie (m/z, relative intensity) 247 [MN]+.

Example 36
4'-Phenylthieno[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine]
Sodium hydride (151 mg, of 3.77 mmol) are added to a solution of 97 mg (0,387 mmol) 4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine], and 0.40 ml (3,91 mmol) thiophenol and 10 ml of methanol in 15 ml of dioxane in a nitrogen atmosphere. The reaction mixture is refluxed for 4 days, cooled to room temperature, diluted with 30 ml of water and extracted with chloroform (3 x 30 ml). The combined organic extract is dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue flash chromatographic on neutral silica gel using a mixture of 98:2 saturated with ammonia in chloroform/methanol getting 65 mg (52%) indicated in the title compound as a colourless oil; MS elektrorazpredelenie (m/z, relative intensity) 325 ([MN]+).

Example 37
4'-(N-2-amino-ethyl)aminosterol[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3 the amine is heated to boiling under reflux in a nitrogen atmosphere and stirred for 4 days. After cooling to room temperature the solvent is removed in vacuum. The residue is dissolved in 20 ml saturated aqueous sodium carbonate and extracted with chloroform (3 x 25 ml). The combined organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo, obtaining mentioned in the title compound as a dark oil, 80 mg (100%): MS elektrorazpredelenie (m/z, relative intensity) 275 ([MN]+).

Example 38
4'-(4-N-Methylpiperazin-1-yl)Spiro[1-azabicyclo[2.2.2] -octane-3,2' (3 N)-furo[2,3-b]pyridine]
A solution of 97 mg (0,387 mmol) 4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b] pyridine] in 1 ml of 1-methylpiperazine heated to boiling under reflux in a nitrogen atmosphere and stirred for 18 hours. After cooling to room temperature, diluted with 40 ml of water, make the main 2 ml of saturated aqueous sodium carbonate and extracted with chloroform (3 x 25 ml). The combined organic extract is dried over anhydrous magnesium sulfate, concentrated in vacuo and flash chromatographic on neutral silica gel using a mixture of 4:1 saturated with ammonia in chloroform/methanol, receiving 59 mg (48%) indicated in the title compound as an amber oil: MS elektrorazpredelenie (m/is n-3,2'(3 N)-furo[2,3-b] pyridine]
A solution of 97 mg (0,387 mmol) 4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b] pyridine] in 5 ml of benzylamine heated to boiling under reflux in a nitrogen atmosphere and stirred for 18 hours. After cooling to room temperature, diluted with 40 ml of water, make the main 2 ml of saturated aqueous sodium carbonate and extracted with chloroform (3 x 25 ml). The combined organic extract is dried over anhydrous magnesium sulfate, concentrated in vacuo and flash chromatographic on neutral silica gel using a mixture of 9:1 saturated with ammonia in chloroform/methanol, receiving 42 mg (34%) indicated in the title compound as a white solid: MS elektrorazpredelenie (m/z, relative intensity) 322 ([MN]+).

Example 40
4'-(Methylamino)Spiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine]
A solution of 151 mg (0,60 mmol) 4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3'H] -furo[2,3-b] pyridine] in 25 ml of 40% aqueous methylamine is heated to 175oWith in a steel autoclave for 18 hours, then cooled to room temperature and concentrated in vacuo. The residue is dissolved in 10 ml of ethanol containing 0.4 ml of concentrated hydrochloric acid and the solution allowed to stand for nockatunga the title compound as a white solid: MS elektrorazpredelenie (m/z, relative intensity) 246 ([MH])+.

Example 41
Spiro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine-7'-oxide]
A solution of Spiro[1-azabicyclo[2.2.2]octane-3,2' (3 N)-furo-[2,3-b]pyridine] (2,88 g, 13.3 mmol) and aqueous hydrogen peroxide (30%, 5 ml) in acetic acid (20 ml) is heated at the boil under reflux. After 16 and 24 h add additional portions of hydrogen peroxide and heating continued for a total of 48 hours the Solution is then evaporated, then the residue is again dissolved in ethanol (40 ml), which was saturated with sulfur dioxide. After 4 h, the solution evaporated and the residue purified HPLC on silica gel, using as eluent a gradient of 0-50% solvent mixture (7 M solution of ammonia in methanol (25%) /methanol (25%)/chloroform (50%) and chloroform. Specified in the header connection (934 mg, 4.0 mmol, 30%) is a solid product: MS DCI 233 ([MH]+).

Example 42
Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b] -pyridine-6'-carbonitrile]
A solution of Spiro[1-azabicyclo[2.2.2] octane-3,2'(3'H)-furo-[2,3-b]pyridine-7'-oxide] (95 mg, 0.41 mmol) was dissolved in acetonitrile (2 ml). Add triethylamine (0,12 ml, 87 mg, 0.86 mmol) and then trimethylsilylacetamide (0.2 ml, 149 mg, 1.5 mmol). The solution was stirred at room temperature overnight, C is (0.2 ml). After heating at boiling under reflux overnight the solution is kept for cooling. Add an excess of methanol and the solution incubated at room temperature for 4 h, then evaporated. The residue is purified HPLC on silica gel, using as eluent a gradient of 0-25% of a mixture of solvents (7M solution of ammonia in methanol (25%)/ methanol (25%)/ chloroform (50%) and chloroform. Specified in the title compound (50 mg, 0.21 mmol, 51%) is a solid product: MS elektrorazpredelenie 242 ([MN]+).

Example 43
6'-Chlorpro[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo-[2,3-b]pyridine]
A solution of Spiro[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo-[2,3-b]pyridine-7'-oxide] [98 mg, 0.42 mmol) in phosphorus oxychloride (2 ml) are heated at the boil under reflux for 2 hours the Solution is evaporated, the residue partitioned between aqueous potassium carbonate and chloroform, then the organic layer is dried (magnesium sulfate), filtered and evaporated. The residue is purified HPLC on silica gel, using as eluent a gradient of 0-25% solvent mixture (7 M solution of ammonia in methanol (25%)/ methanol (25%)/ chloroform (50%) and chloroform. Specified in the title compound (26 mg, 0.10 mmol, 25%) is a solid product: MS electroreception-3,2'(3 N)-furo-[2,3-b]pyridine]
(a) Complex 6'-perspire[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b] pyridine]-N-borane
The solution finelite (1.8 M in cyclohexane, 13,5 ml) are added to THF (15 ml) in an argon atmosphere. Add Diisopropylamine (0.5 ml) and the solution cooled to -78oC (bath temperature dry ice/acetone). To the resulting solution added dropwise 2,6-diporphyrin (1.23 ml, 1.56 g, to 13.6 mmol), then after 1 h added dropwise a solution of complex Spiro[1-azabicyclo[2.2.2] octane-3,2'-oxiran] -N-borane (765 mg, 5.0 mmol) in tetrahydrofuran. The solution was stirred at -78oC for 1 h and found the cooling bath is then replaced by a bath of dry ice/acetonitrile. The solution is then stirred overnight, warmed to room temperature. Add saturated aqueous sodium bicarbonate and the solution is then extracted with chloroform. The extract is then dried (gS4), filtered and evaporated. The residue is dissolved in DMF (20 ml) and then added to the suspension washed with hexane sodium hydride (60% mixture with mineral oil, 507 mg, 12.7 mmol) in DMF (20 ml), stir at 0oC. the Solution is stirred overnight, warmed to room temperature. To the solution was added saturated aqueous sodium bicarbonate and then extracted with chloroform. Extract for the a and hexane, getting listed in the subtitle compound (102 mg, 8%, 0.41 mmol): MS elektrorazpredelenie (m/z 247 [M-N]+.

(b) 6'-Perspire[1-azabicyclo[2.2.2]octane-3,2'(3 N)-furo[2,3-b]pyridine]
Complex 6'-perspire[1-azabicyclo[2.2.2] octane-3,2'(3 N)-furo[2,3-b] pyridine]-N-borane (98 mg, 0.40 mmol) dissolved in acetone (5 ml). 48% aqueous Hydrobromic acid (2 ml), diluted with water (2 ml) and then added to the solution. The resulting mixture was stirred at room temperature overnight. The solution is then evaporated and partitioned between aqueous sodium carbonate and chloroform. The organic extract was then dried (MgSO4), filtered, evaporated and the residue purified HPLC using a gradient of 0-25% of a mixture of 1:1: 2 7 M solution of ammonia in methanol:methanol:chloroform and chloroform, getting mentioned in the title compound (39 mg, has 0.168 mmol, 43%) as a solid: MS elektrorazpredelenie (m/z, relative intensity) 235 ([MN]+, 100).


Claims

1. Spiroheterocyclic heterocyclic compounds of the formula I

where n is 0 or 1;
m is 0 or 1;
p is 0;
X represents oxygen or sulfur;
Y represents CH, N or NO;
W standing
);
D represents N or C(R4),
provided that not more than one of A, G and D represents nitrogen, but at least one of Y, a, C, and D represents nitrogen or NO;
R1represents hydrogen or C1-C4-alkyl;
R2, R3and R4are independently hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, heteroaryl, including five - or six-membered aromatic ring with 1 or 2 nitrogen atoms, as well as furyl or morpholyl, HE OS1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6or R2and R3or R3and R4thus together with part a and G or G and D, respectively, to form another six-membered aromatic ring;
R5and R6independently represent hydrogen, C1-C4-alkyl, C(O)R7C(O)other8With(O)OR9, SO2R10-NR5R6, (CH3)3Si and phenyl, or may together represent (CH2)jQ(CH2)kwhere Q represents a bond, j is 2 and k is 0 to 2;
R7, R8, R9and R10represent, independently, C1-C4-alkyl, NH

3. The compound according to any one of paragraphs.1 and 2, where n is equal to 0.

4. The compound according to any one of paragraphs.1-3, where p is equal to 0.

5. The compound according to any one of paragraphs.1-4, where X represents oxygen.

6. The compound according to any one of paragraphs.1-5, where a represents C(R2); G represents C(R3and D represents C(R4).

7. The compound according to any one of paragraphs.1-6, where m is 1; n is 0; p is 0; X represents oxygen; a is a C(R2); G represents C(R3); D represents C(R4).

8. Connection on p. 1, where the specified connection is:
Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]-pyridine];
5'-bromospiro[1-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo-[2,3-b]pyridine];
5'-perspire[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-nitrospira[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
1'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo-[2,3-b]isoquinoline] ;
5'-(phenylcarbonylamino)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(phenylenecarbonyl)Spiro[1-azabicyclo[2.2.2] -octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(phenylcarbonylamino)Spiro[1-azabicyclo[2.2.2] -octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-aminosterol[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N-methylamino[2,3-b] pyridine];
5'-N, N-diethylaminophenol[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-N-acylaminoacyl[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N-benzylaminopurine[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N-formimidoyl[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N-acetamidophenol[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]-isoquinoline];
Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]-quinoline];
5'-ethaniser[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(E)-(phenylethenyl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(4-morpholino)Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(1-azetidine)Spiro[1-azabicyclo[2.2-2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
5'-(E)-(2-(4-pyridyl)ethynyl)Spiro[1-azabicyclo[2.2.2] -octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(E)-(2-(2-pyridyl)ethynyl)Spiro[1-azabicyclo[2.2.2] -octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(2-trimethylsilylethynyl)Spiro[1-azabicyclo[2.2.2] -octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-edenilson[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-(2-furyl)Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)furo[2,3-b]pyridine] ;
5'-(3-pyridyl)Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-methylspiro[1-azabicyclo the Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] -pyridine-5'-carboxamide];
5'-N'-(3-chlorophenyl)oregonensis[1-azabicyclo-[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
5'-N'-(2-nitrophenyl)oregonensis[1-azabicyclo-[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
4'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine];
4'-methoxamine[1-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
4'-phenylthieno[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[2,3-b]pyridine] ;
4'-(N-2-amino-ethyl)aminosterol[1-azabicyclo[2.2.2] -octane-3,2'-(3'H)-furo[2,3-b]pyridine];
4'-Veniaminovich[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
4'-methylaminophenol[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b] pyridine];
4'-(4-N-methylpiperazin-1-yl)Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3 N)-furo[2,3-b]pyridine];
4 harsper[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo-[3,2-C]pyridine];
Spiro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo[3,2-C]-pyridine];
6'-perspire[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo-[2,3-b]pyridine];
Spiro[1-azabicyclo[2.2,2] octane-3,2'-(3'H)-furo[2,3-b] -pyridine-6'-carbonitrile];
6'-chlorpro[1-azabicyclo[2.2.2]octane-3,2'-(3 N)-furo-[2,3-b]pyridine];
or its enantiomer or a pharmaceutically acceptable salt.

9. The compound according to any one of paragraphs.1-7, where Y is a NO.

10. Connection on p. 9 representing Spiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)-furo[2,3-b]pyridine-7'-oxide] or virouses action against nicotine7-acetylcholine receptors, for use in the treatment of diseases in which the action is effective.

12. Pharmaceutical composition having an activating action on the nicotinic7-acetylcholine receptors containing the compound according to any one of paragraphs.1-10 in a mixture with an inert pharmaceutically acceptable diluent or carrier.

13. The method of obtaining the compounds of formula I according to any one of paragraphs.1-8, where Y represents N, its enantiomer or a pharmaceutically acceptable salt, which comprises: removing boranova complex in the compound of formula II with an acid in a suitable solvent or by heating the complex in an alcohol solvent

where it is desirable or necessary converting the resulting compounds of formula 1, or its enantiomer, or its acid salt additive in its pharmaceutically acceptable acid additive salt, or converting the resulting racemic mixture of compounds of formula I in its enantiomer.

14. The method of obtaining the compounds of formula I on p. 1, where R2represents hydroxyl and Y is N, rearrangement of the connection form is a suitable solvent.

15. The method of obtaining the compounds of formula I on p. 1, where R2represents chlorine and Y is N, rearrangement of compounds of formula I on p. 1, where Y is a NO, using glorieuses source, such as phosphorus oxychloride, in a suitable solvent.

16. The method of obtaining the compounds of formula I on p. 1, where R2represents cyano and Y is N, rearrangement of compounds of formula I on p. 1, where Y represents NO source of cyanide, such as trimethylsilyl-cyanide, in a suitable solvent.

17. The compound of formula II

where n is 0 or 1;
m is 0 or 1;
p is 0;
X represents oxygen;
W represents oxygen or H2;
And represents N or C(R2);
G represents N or C(R3);
D represents N or C(R4),
provided that not more than one of A, G and D represents nitrogen;
R1represents hydrogen or C1-C4-alkyl;
R2, R3and R4represent, independently, hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, getarea, OS1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6or R2and R3or R3and R4accordingly, together with part a and G or G and D, respectively, to form another six-membered aromatic ring;
R5and R6independently represent hydrogen, C1-C4-alkyl, C(O)R7C(O)other8With(O)OR9, SO2R10or may together be (CH2)jQ(CH2)kwhere Q represents a bond, j is 2, k is from 0 to 2;
R7, R8, R9and R10represent, independently, C1-C4is alkyl or aryl,
or its enantiomer.

Priority items:
18.07.1997 - PP.1-17;
24.03.1998 on PP.1-17 (varieties radicals).

 

Same patents:

The invention relates to new triazinyl compounds of formulas Ia and Ib:

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or their salts, where in the formula Ia W represents N or C-CO-R, where R denotes HE OC1-C6alkyl or NR3R4where R3and R4- N or C1-C6alkyl, or formula Ib Az denotes imidazopyridine and in both formulas Ia and Ib R1represents C1-C4alkyl, R2denotes phenyl fragment or 2,5-cyclohexadiene-3,4-ridin-1 silt fragment

-olefin (options)" target="_blank">

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R6- H, C1-C6alkyl, benzyl, possibly substituted, substituted benzoyl, substituted C1-C6alkyl, and when NH2the group is disubstituted, the substituents may be combined to form heterocyclic ring containing 5-7 carbon atoms and 1 or 2 nitrogen atoms and optionally oxygen

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and n is 1-4, and their salts, stereoisomers and mixtures of stereoisomers; two methods of producing these compounds, and to a medicinal product which is able to inhibit the growth of tumors or slow their growth

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< / BR>
where a represents hydrogen and b is a group of the formula

< / BR>
either a and b taken together form a cyclic group

< / BR>
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< / BR>
or its salts, where R2, R4X1X2, Y1, Y2identical or different and denote hydrogen, fluorine, chlorine, bromine, iodine, hydroxy - or alkoxygroup; lowest, if necessary, branched and, if necessary, replaced, for example, at least one halogen alkyl group, a lower, if necessary branched alkenylphenol group; lower, if necessary branched alkylamino group; if necessary, substituted aryl, aracelio or aryloxyalkyl group, the alkyl chain of which, if necessary, branched and aromatic nucleus which, if necessary substituted; formyl, and unsubstituted or substituted by one or more halogen, linear or branched alkylaryl, arylcarbamoyl, aralkylamines, allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, aralkylamines, arylsulfonyl, or Y1and Y2together represent =O and where A stands for a benzene nucleus, in the case neobmennoe alkyl group; at least one lower, if necessary, the branched alkinoos group; at least one lower, if necessary branched alkyne group; at least one lower if need extensive alkoxygroup; fluorine, chlorine, bromine, iodine or more identical or different halogen, at least one substituted with one halogen or two or more identical or different halogen alkyl group, such as chlorochilon and trifluoromethyl; at least one, if necessary substituted aranceles group and/or at least one hydroxy-group; primary, secondary or tertiary amino group, the nitro-group, a nitrile group, alkylaminocarbonyl, killingray, aldehyde group, carboxyl group, all derivatives of carboxyl groups, for example esters, inorganic salts, halides
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