Spiro-azabicyclic compounds, methods for their preparation and intermediates

 

(57) Abstract:

Spiro-azabicycles the compounds of formula I where R is hydrogen or methyl and n = 1 or 2, or their pharmaceutically acceptable salts are useful in the treatment or prophylaxis of psychotic disorders and disorders associated with reduced intelligence. 6 C. and 7 C.p. f-crystals.

The invention relates to new compounds, methods for their preparation, containing compositions and their use in the treatment.

As you know, Spiro-azabicyclic compounds have therapeutic activity in a number of disorders of the Central nervous system. Taiwanese patent application 201312, European patent application 452101 (both from the Institute of biological research Israel), international patent application WO 95/03303 (Institute of biological research of Israel, published after the earliest priority date of this application) and European patent application 350118 (Merck Sharpe and Dohme) reveal a Spiro-linked 5-membered rings azabicyclic compounds, including derivatives of azabicyclo(2.2.2) octane and/or azabicyclo(2.2.1)heptane, which have the activity of muscarinic agonists and are indicated for the treatment of diseases, due nedostate the o-linked 5-membered rings azabicycles connection which are antagonists of the receptors 5-HT3and which is indicated for the treatment of schizophrenia, nausea, migraine and Alzheimer's disease.

Currently, we have identified a new group of Spiro-azabicyclic compounds which have useful pharmacological properties.

Thus, in accordance with the invention we present compounds of the formula:

< / BR>
in which R represents hydrogen or methyl; and

n = 1 or 2;

and its pharmaceutically acceptable salts accession acids (acid additive salt).

We prefer compounds of formula I in which R represents hydrogen. We prefer compounds of formula I in which n = 2.

As another aspect of the invention we provide a process of producing compounds of the formula I or their pharmaceutically acceptable salts accession acids, which includes: (a) obtaining the compounds of formula I in which R represents hydrogen, by cyclization of the corresponding compounds of formula II;

< / BR>
in which n corresponds to the above definition; (b) obtaining the compounds of formula I by reaction of the corresponding compounds of formula III:

< / BR>
in which n and R sauveli I, in which R is methyl, by alkylation of the corresponding compounds of formula I in which R represents hydrogen;

(d) obtaining a single enantiomer of compounds of formula I by allocating a given enantiomer from a mixture of enantiomers;

and when it is desirable or necessary, converting the resulting compounds of formula I or its salts accession acid, its pharmaceutically acceptable salt accession acid, or Vice versa.

According to the method of (a) the reaction is carried out by heating the compounds of formula II in proton polar solvent, for example water.

In process (b) examples carbonilla compounds include carbonyldiimidazole, carbonylchloride (phosgene) and triphosgene. The reaction ring closure occurs when heating or boiling under reflux the compounds of formula III with a carbonyl-diimidazole in a polar organic solvent such as tetrahydrofuran, within 1-4 hours or until completion of the reaction. Alternative phosgene can barbotirovaniya through a solution of the compounds of formula III in an organic solvent, such as tetrahydrofuran or toluene, at elevated temperature for 1-4 hours or until the reaction is not zaverdinos region, for example, by processing the compounds of formula 1 in which R represents hydrogen, a strong base followed by treatment with methylglucamide, such as methyliodide.

The compounds of formula II can be obtained by rearrangements Curtius the compounds of formula IV:

< / BR>
where n corresponds to the above definition.

Typical reaction conditions rearrangement of Curtius discussed in the work of I. March, "Advanced Organic Chemistry" (1985) 3rd Edition page 984-5, however, we prefer to conduct the reaction by processing the compounds of formula IV in water with sodium nitrite and heat to approximately 85oC for about 1 hour. The compound of formula IV is not allocated, and the cyclization reaction described in method (a), flows directly in situ.

The compounds of formula IV can be obtained by treatment of compounds of formula V:

< / BR>
where n corresponds to the above definition, a R' represents an alkyl or aryl group, anhydrous hydrazine.

The reaction may be conducted in proton polar solvent at ambient temperature for 4-12 hours. We prefer that R' represented alkyl, typically methyl, ethyl or tert-butyl.
with ether acetic acid in the presence of n-utillity. Ether acetic acid (for example, tert-butyl or ethyl ester) is first treated with n-butyllithium at -78oC, and the reaction proceeds by adding the compounds of formula VI and warming to room temperature. The product is obtained in the quench the reaction with water.

The compounds of formula VI are either known or can be obtained using known methods.

The compounds of formula III can be obtained by reaction of compounds of formula VII:

< / BR>
where n corresponds to the above definition,

with ammonia or methylamine.

This reaction can be conducted under standard conditions, for example, by combining the reagents in a polar proton solvent at ambient temperature or elevated temperature.

The compounds of formula III can also be obtained through the reaction of compounds of formula VI trimethylsilylcyanation (Me3SiCN), followed by reduction, for example by sociallyengaged or Nickel Rene. Reaction conditions known to specialists in this field.

The compounds of formula VII can be obtained from corresponding compounds of formula VI with the use of the and, referenced in the work of I. March, "Advanced Organic Chemistry" (1985) 3rd Edition, page 1161). We found that trimethylsulfoxonium is a suitable reagent, and the reaction can be carried out in DMSO at a temperature between room temperature and 80oC over a period of time up to 2 hours or until the reaction is complete.

Salt accession acid compounds of formula I that may be mentioned include the salts of mineral acids such as hydrochloric and Hydrobromic salt; and salts formed with organic acids such as salts of formic, acetic, malic, benzoic acid and fumaric acid.

Salt accession acid compounds of the formula I can be formed by the reaction of the free base or a salt, enantiomer or a protected derivative, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, such as water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents that can be removed under vacuum or by freeze-drying. The reaction can be Metallichesky process or may aukcionnyh mixtures using standard techniques.

The compounds of formula I exist in tautomeric or enantiomeric forms, all of which are included in the scope of the invention. The various optical isomers may be isolated by separation of the racemic mixture of the compounds using conventional techniques such as fractional crystallization or chiral HPLC. Alternative individual enantiomers may be obtained by reaction of the appropriate optically active starting materials under the reaction conditions that do not cause racemization.

Intermediate compounds also exist in enantiomeric forms and can be used as purified enantiomers, racemates or mixtures.

Compounds of the invention are shown as pharmaceuticals, in particular in the treatment or prophylaxis of psychotic disorders and disorders associated with reduced intelligence. Examples of psychotic disorders include schizophrenia, manic psychosis and manic-depressive syndrome. Examples of disorders or diseases associated with intellectual disorders that include Alzheimer's disease, reduced ability to learn, lack of cognitive functions and disorders characterized by hyperactivity and defibillator Parkinson's disease and Hartington, neurodegenerative disorders in which there is loss of cholinergic synapses, Tourette syndrome, depression and anxiety, or fear. In addition, compounds may be indicated for the treatment or prevention of disorders associated with flights over long distances, and for the purpose of Smoking cessation.

In accordance with another aspect of the invention we present compounds of the invention for use as pharmaceutical agents, especially for the treatment and prophylaxis of the aforementioned diseases or conditions.

For the above use, the dose assigned to the reception, of course use depending on the connection method of the destination and the desired treatment. However, in General, satisfactory results are obtained when the compounds of the invention is administered in a daily dose of approximately 0.1 mg to 20 mg per kg animal body weight, preferably in the appointment of fractional doses 1 to 4 times per day in the form of means of prolonged action. For human total daily dose is in the range from 5 mg to 1400 mg, more preferably from 10 mg to 100 mg, and single doses suitable for oral administration comprise from 2 connecting formula I and their pharmaceutically acceptable salts, can be used by themselves or in the form of appropriate medicinal preparations for enteral or parenteral destination. In accordance with another aspect of the invention provides a pharmaceutical composition comprising preferably less than 80% and more than 50% by weight of compounds of the invention in a mixture with a pharmaceutically acceptable diluent or carrier.

Examples of diluents and carriers include:

for tablets and coated tablets: lactose, starch, talc, stearic acid;

for capsules: tartaric acid or lactose;

for injectable solutions: water, alcohols, glycerol, vegetable oils;

for candles: natural or hardened oils or waxes.

Also provided is a method of obtaining such a pharmaceutical composition, which comprises mixing the ingredients.

In accordance with another aspect of the invention provides the use of compounds of formula I or its pharmaceutically acceptable salts in the manufacture of medicaments for the treatment or prevention of one of the above diseases or conditions; and a method of treatment or prophylaxis of any of the aforementioned diseases or conditions, which includes nasnavi salt.

The compound of formula IV and compounds of formula III in which R is methyl, are a new useful intermediate products. Thus, according to another aspect of the invention we provide compounds of formula IV or their salts. We also provide the compounds of formula III in which R represents methyl or their salts.

The compounds of formula I are agonists of nicotinic acetylcholine receptors. Without limitation to any theory it is believed that agonists of receptor subtype 7 nAChR (nicotinic acetylcholine receptors) should be useful in the treatment or prophylaxis of psychotic disorders and disorders with intellectual disabilities and have advantages over the compounds, which are compounds subtype or are agonists compounds subtype 4 nAChR. Therefore, preferred are compounds that are selective against subtype 7 nAChR. The pharmacological activity of the compounds of the invention can be measured using the following tests or tests.

TEST AND

Analysis of affinity with subtype 7 nAChR

The binding of the I125- - Bungarotoxin (VTH) with membranes in the hippocampus of rats

Hippocampi of rats homogenized in 20 volumes of cold 1; NaCl, 120; KCl 5; pH 7,4). The homogenate was centrifuged for 5 minutes at 1000g, the supernatant retain, and the residue is subjected to re-extraction. The supernatant collected from all test tubes, centrifuged for 20 minutes at 12000g, washed and re-suspended in GB. Membrane (30-80 μg) incubated with 5 nm [1125]-BTX, 1 mg/ml BSA (bovine serum albumin) test drug, and/or 2 mm CaCl2or 0.5 mm EGTA ethylene glycol-bis (- aminoacylase ether for 2 hours at 21oC, and then filtered and washed 4 times through fiberglass filters Whatman (thickness C) using the collector cells Brandel. To ensure a minimum number of inconclusive definitions (0,07% of the total number of definitions per minute) is essential pre-processing filters for 3 hours with a mixture of 1% BSA/0.01% of PE1 (polyethylenimine) in water. Nonspecific binding was described as 100 μm (-)-nicotine, and specific binding was usually 75%.

TEST B

Analysis of affinity with subtype 4 nAChR

Binding of [H3]-(-)-nicotine

Using modified procedures Martino-Barrows and Kellar (Mol Pharm 31:169-174; 1987), the head of the rat brain (cortex and hippocampus) homogenized as in appendrow in GB, containing 100 μm of diisopropylfluorophosphate. After 20 minutes at 4oC membrane (~0.5 mg) incubated with 3 nm [H3]-(-)-nicotine drug test, 1 μm atropine and/or 2 mm CaCl2or 0.5 mm EGTA for 1 h at 4oC, and then filtered through glass fiber filters Whathman (thickness C) (after pretreatment for 1 hour with 0.5% PE1) using the collector cells Brandel. Nonspecific binding was described 100 μm carbachol, and specific binding typically was 84%.

Analysis of the data binding for tests a and B

The values of the IC50and pseudoelastic coefficients (nH) were calculated using the program to construct nonlinear curve ALLFIT (DeLean, A., Manson P. I. and Rodbard D. (1977) Am.J. Physiol., 235:E97-E102). Curves of saturation were adjusted to a single-site model using the nonlinear regression program ENZFITTER (Leatherbarrow. R. J. (1987)), obtaining the values of KDto 1.67 and 1.70 nm for ligands [1125]-BTX and [H3]-(-)-nicotine, respectively. Values of Kiwas assessed using the General equation of Cheng-Prusoff:

Ki= [IC50]/((2+([ligand]/ [KD])n)1n-1),

where the value of n = 1 was used when nH<1.5, and n=2 was used when nH1,5. the ispolzovaniem 6 or more concentrations of the drug.

Compared with the compounds of the prior art compounds of the invention have the advantage that they may be less toxic, more efficient, long acting, have a broader spectrum of activity, to have a stronger effect, to cause fewer side effects, be more easily absorbed or have other useful pharmacological properties.

The invention is illustrated by the following examples:

EXAMPLE 1

Monohydrochloride Spiro[1-azabicyclo[2.2.2]Octan-3,5'- oxazolidin]-2'-it

(a)TRButyl ether of 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 0oC add 2.3 M BuLi (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 10 ml THF and stirring is continued for additional 15 minutes. To the mixture are added dropwise Hinkley-3-one (free base) (5.0 g) in THF (15 ml), and the mixture is allowed to warmed to 0oC for 1 hour. To this solution was added water (100 ml), the solution is twice extracted with chloroform, and the combined extracts about aluca at 9.53 g specified in the subtitle compound as not quite white solid.

(b) Hydrazide 2-(3-hydroxy-1-azabicyclo[2.2.2]Oct-3-yl)acetic acid

To a solution of 3.5 g of the compound of stage (a) in 15 ml of methylene-chloride type triperoxonane acid (39 ml) and the mixture stirred at ambient temperature for three hours. The mixture is then concentrated in vacuo. The residue is dissolved in methanol (30 ml) and add 18M H2SO4(3 ml), and the mixture is stirred over night. The mixture is then poured into a solution of sodium carbonate in water, extracted three times with chloroform, dried over MgSO4, filtered and concentrated in vacuo, receiving a yellow solid. The solid is dissolved in methanol (10 ml) and to this solution was added hydrazine (2 ml), and the mixture is then heated to boiling under reflux for one hour. The mixture is then concentrated in vacuo. The obtained solid is suspended in toluene (50 ml) for two hours, heated to reflux distilled in an apparatus with a trap Dean-Stark. Then the reaction mixture is allowed to cool and the product is filtered, getting 1,82 g specified in the subtitle compound as a tan solid.1NMR (500 MHz; CD3OD): 1.3-1.9 (m,4H), 2.1 (m,1H), 2.45 (DD., J=15 Hz, 2H), 2.6-2.9(m,6H). MC (m/z): 200 [MN]+.

oC and add the 0oC solution of sodium nitrate (0.33 g) in 5 ml of water. The solution was stirred at 0oC for twenty minutes and then for another twenty minutes, heated to 70oC. the Reaction mixture was cooled to ambient temperature, alkalinized 50% NaOH/H2O. the Solution is saturated with NaCl and extracted with chloroform 4x20 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in methanol, and after the mixture was bubbled gaseous HCl up until the pH is not below 2. To the solution was added diethyl ether, and the resulting white solid is filtered off, getting 0.73 g specified in the connection header in the form of not-quite-white solid, so pl. 289-291oC.1H NMR (500 MHz, DMSO): 1.7 to 1.9 (m, 3H), of 2.05 (m, 1H), 2,25 (Shir.S., 1H), 3.15 in (m, 3H), of 3.2 to 3.5 (m, 1H), 3,4-3,6 (m, 3H), 3,6 (D., 1H), 7,75 (S., 1H), 10,95 (Shir.S., 1H).

EXAMPLE 2

Monohydrochloride (+)- and (-)-Spiro[1-azabicyclo[2.2.2]Octan - 3,5'-oxazolidin]-2'-it

To a solution of compound of example 1 (3.8 g) in absolute ethanol is added a solution Dibenzoyl-L-tartaric acid (7,474 g) in absolute ethanol, and to this mixture a small portion of ethyl acetate. After standing for one hour was formed to sodium, extracted with chloroform h ml, dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in methanol, and after the mixture was bubbled gaseous HCl up until the pH is not below 2. To the solution was added diethyl ether, and the resulting white solid is filtered off, getting to 0.63 g of (+)-enantiomer, melting point >250oC. []D= +57,978 (C = 0,6570, CH3OH).

Left above the filtrate is converted into the free base by concentrating the solution, and then dissolving the residue in 20% NaOH/H2O, extracted with chloroform, dried over MgSO4, filtered and concentrated in vacuo, getting to 1.21 g of residue. The residue is dissolved in absolute ethanol and combined with a solution of 2.38 g Dibenzoyl-D-tartaric acid in absolute ethanol. The mixture is stirred and add a small portion of ethyl acetate, resulting after stirring for one hour produces white solid. The precipitate is filtered off and dissolved in 20% NaOH/H2O, extracted with chloroform, dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in methanol, and after the mixture was bubbled gaseous HCl up until the pH is not below 2. To the solution add dietro is t;250oC. []D= 61,473 (c=0,7727, CH3OH).

EXAMPLE 3

Monohydrochloride Spiro[1-azabicyclo[2.2.1] heptane-3,5'- oxazolidin-2']

(a) Ethyl ester of 3-hydroxy-1-azabicyclo[2.2.1]hept-3-yl acetic acid

To a cooled (-78oC) the solution Diisopropylamine (2.65 ml, 0,0203 mol) in tetrahydrofuran (150 ml) over one minute added dropwise 2.5 M BuLi in hexano (8.1 ml, 0,0203 mol). Ten minutes in one minute added dropwise ethyl acetate (1.97 ml, 0,0203 mol). After another ten minutes within five minutes added dropwise 1-azabicyclo[2.2.1] heptane-3-one (1.5 g, 0,0135 mol, obtained by the method described in I. Chem. Soc. Chem. Commun. 1618, 1988) in tetrahydrofuran (25 ml). Twenty-five minutes, the cold bath removed, and the mixture is left to be reheated to ambient temperature. To the mixture is added water (100 ml), and then chloroform (250 ml). The organic layer is separated and the aqueous layer extracted with chloroform (100 ml). The combined organic extracts dried over MgSO4, filtered and concentrated in vacuo, obtaining mentioned in the subtitle compound (1.12 g).

b) Hydrazide 3-hydroxy-1-azabicyclo[2.2.1]hept-3-yl acetic acid

To a solution of the product of stage (a) (1.12 g, 0,0056 mol) in methanol (20 ml) of Pres concentrated in vacuo and double azeotrope is distilled off with toluene (100 ml) with heating to reflux distilled in the apparatus, equipped with a trap Dean-stark obtaining specified in the subtitle compound (1,11 g).

b) Monohydrochloride Spiro[1-azabicyclo[2.2.1] heptane-3,5' oxazolidin-2']

To a cooled (0oC) a solution of the product of stage (b) (1,11 g 0,006 mol) in water (50 ml) with pH was brought to 1 with concentrated HCl, within two minutes added dropwise an aqueous solution of NaNO2(0,455 g, 0,0066 mol). After complete addition, the cold bath removed and the mixture for one hour, heated to 85oC. the Mixture is allowed to cool to ambient temperature and alkalinized to pH 10 with a mixture of 50% NaOH/H2O. the Mixture was extracted three times with chloroform (150 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue is subjected to flash chromatography on silica gel using methanol/ethyl acetate [1:1]. The appropriate fractions are collected and concentrated. The residue is then dissolved in chloroform, filtered and concentrated in vacuo. The residue is dissolved in a mixture of ethyl acetate/methanol and treated with a saturated solution of HCl/ethyl acetate to until the pH of the solution will not be < 6. The solution is concentrated and receiving 120 mg of residue. This residue is dissolved in hot methanol and precipitated with ether, receiving specified in the header soy is 1H), 10,6 (Shir.S., 1H).

EXAMPLE 4

Monohydrochloride 3'-methyl-Spiro[1-azabicyclo[2.2.2] Octan - 3,5'-oxazolidin-2']

(A) Spiro-1-azabicyclo[2.2.2]Octan-3-oxiran

To a suspension of sodium hydride (11.6 g of 60% oil dispersion, washed three times with hexane: 0,35 mol) in 600 ml of DMSO in parts add 101,4 (0,35 mol) trimethylsulfoxonium iodide. After reduction of the deposition gas mixture is stirred at room temperature for 30 minutes. During the 30-minute period added dropwise a solution Hinkley-3-one (44 g to 0.35 mol) in 200 ml of THF, and the mixture for 1 hour, heated to 70-80oC. the Reaction mixture is cooled to room temperature, poured into 1 l of ice water, and the aqueous solution extracted with CHCl3(4x300 ml). The organic extracts are washed with H2O (g ml), saturated brine (CH ml), dried over MgSO4and the solution evaporated, receiving specified in subheading in the form of a yellow oil (37.6 g, 77%).

(b) 3-Hydroxy-1-azabicyclo[2.2.2]Oct-3-yl methylaminomethyl

To a solution of 25 ml (to 0.72 mole) of condensed methylamine in 75 ml of methanol is added 10.2 g (0,073 mole) of the product of stage (a) and the solution stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced dawlance connection in the form of oil.

(c) Monohydrochloride 3'-methyl-Spiro[1-azabicyclo[2.2.2] Octan-3,5'- oxazolidin-2']

To a solution of the product of stage (b) (8.0 g, of 0.47 mol) in 100 ml THF added to 9.15 g (0,056 mole) of carbonyldiimidazole, and the mixture is heated under reflux for 3 hours. Then the reaction mixture is cooled to room temperature and concentrated in vacuo. The residual oil is dissolved in 200 Il CH2Cl2the solution was washed with H2O (g ml), brine (CH ml), dried over MgSO4and evaporated, receiving a yellow solid. This substance is dissolved in 50 ml of methanol/isopropanol 1:1, acidified with HCl in methanol, and the precipitate is collected, washed with cold methanol and dried, obtaining 5.6 g (51%) of target compound as a colourless solid, so pl. 305-307oC.1H NMR (500 MHz, DMSO): 1,8 (m, 3H), of 2.05 (m, 1H) 2,25 (Shir.S., 1H), 2,75 (C., 3H), 3,1-3,2 (m, 3H), of 3.25 to 3.35 (m, 1H), 3,4-3,5 (m, 1H), 3,5-3,6 (m, 2H), 3,7 (D., 1H), 10,9 (Shir. S., 1H).

EXAMPLE 5

Connection monohydrochloride Spiro[1-azabicyclo[2.2.2]Octan - 3,5'-oxazolidin]-2'-it,

monohydrochloride (+)-Spiro[1-azabicyclo[2.2.2]Octan-3,5'- oxazolidin]-2'-it,

monohydrochloride (-)-Spiro[1-azabicyclo[2.2.2]Octan - 3,5'-oxazolidin]-2'-it,

monochloride Spiro[1-azabicyclo[2.2.1]heptane-3,5'-oxazolidin - 2'-about the accordance with the above-described test and A given value of the affinity binding (Kiless than 10 μm, which indicates their expected useful therapeutic activity.

Connection monohydrochloride Spiro[1-azabicyclo[2.2.2]Octan-3,5'- oxazolidin]-2'-it,

monohydrochloride (+)-Spiro[1-azabicyclo[2.2.2] Octan-3,5'-oxazolidin] - 2'-she,

monohydrochloride (-)-Spiro[1-azabicyclo[2.2.2]Octan-3,5'- oxazolidin]-2'-it,

monohydrochloride Spiro[1-azabicyclo[2.2.1]heptane-3,5'-oxazolidin - 2'] and

monohydrochloride 3'-methyl Spiro[1-azabicyclo[2.2.2]Octan-3,5'- oxazolidin-2']

tested in accordance with the above-described test B and given values of Kiat least 1.6 times greater than the values given in the test A, which indicates that they have the desired selectivity.

1. Spiro-azabicycles the compounds of formula I

< / BR>
in which R represents hydrogen or methyl;

n = 1 or 2

or their pharmaceutically acceptable salts accession acid or enantiomers.

2. Connection on p. 1, in which R represents hydrogen, or its pharmaceutically acceptable salt accession acid or enantiomer.

3. Connection on p. 1 representing Spiro[1-azabicyclo[2,2,2]Octan-3,5'-oxazolidin] -2'-one or its pharmaceutically acceptable salt in the EN-3,5'-oxazolidin] -2'-one or its pharmaceutically acceptable salt accession acid.

5. Connection on p. 1, representing the (-)-Spiro[1-azabicyclo[2,2,2]Octan-3,5'-oxazolidin] -2'-one or its pharmaceutically acceptable salt accession acid.

6. Connection on p. 1 representing Spiro[1-azabicyclo[2,2,1]heptane-3,5'-oxazolidin-2'-he] or its pharmaceutically acceptable salt accession acid or enantiomer.

7. Connection on p. 1, representing the 3'-methyl Spiro[1-azabicyclo[2,2,2] Octan-3,5'-oxazolidin-2'-he] or its pharmaceutically acceptable salt accession acid or enantiomer.

8. The compound according to any one of paragraphs. 1-7 or its pharmaceutically acceptable salt accession acid or an enantiomer having the properties of agonists of nicotinic acetylcholine receptors.

9. The pharmaceutical composition exhibiting the properties of nicotinic acetylcholine receptors comprising an effective amount of the compound described in any of paragraphs.1-8, or its pharmaceutically acceptable salt accession acid or an enantiomer, a mixture with a pharmaceutically acceptable diluent or carrier.

10. The method of obtaining the compounds of formula I, as described in paragraph 1, or its pharmaceutically acceptable salt accession acid or Anant is specified in paragraph 1,

subjected to cyclization and if desired, the compound obtained of the formula I, in which R is hydrogen, is converted into a compound in which R is methyl, by alkylation or get one enantiomer of the compounds of formula I by separating it from the mixture of enantiomers and, if desired or necessary, transform the resulting compound of formula I or its salt accession acid or an enantiomer into its pharmaceutically acceptable salt accession acid or an enantiomer or Vice versa.

11. The method of obtaining the compounds of formula I, as described in paragraph 1, or its pharmaceutically acceptable salt accession acid or an enantiomer, characterized in that the compound of formula III

< / BR>
in which n and R have the meanings given in paragraph 1,

subjected to reaction with the compound, giving a carbonyl, optionally, the compound of formula I in which R is hydrogen, is converted into a compound in which R is methyl, by alkylation or get one enantiomer of the compounds of formula I by separating it from the mixture of enantiomers and, if desired or necessary, transform the resulting compound of formula I or its salt to recognize the Vice versa.

12. The compound of formula IV

< / BR>
in which n has the meaning as defined in paragraph 1,

or its salt or enantiomer.

13. The compound of formula III

< / BR>
in which n has the meaning as defined in paragraph 1;

R represents methyl,

or its salt or enantiomer.

Priority points:

24.08.94 - PP.1-4 and 8-13;

08.03.95 - PP.5 and 6;

22.08.95 - p. 7.

 

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