Substituted 3-aminoquinuclidine

 

(57) Abstract:

Describes compounds of formula (1)

< / BR>
in which W, Ar1, Ar2and Ar3have the meanings given in the description, and pharmaceutically acceptable salts of such compounds. These compounds are antagonists of substance P and are useful for the treatment of gastrointestinal disorders, inflammatory diseases and disorders of the Central nervous system and pain. 24 C.p. f-crystals, 2 tab., 25 Il.

The invention relates to new and useful derivatives of hinoklidina that are of interest in the field of medicinal chemistry. More specifically the invention relates to a new series of substituted 3-aminoquinuclidine, including their pharmaceutically acceptable salts, which are of particular interest from the point of view of their ability to act as antagonists of substance P. These compounds are useful in the treatment of gastrointestinal disorders, Central nervous system disorders, inflammation, asthma, pain, and migraines. The invention also includes a new method of therapy.

E. J. Warawa in U.S. patent N 3560510 discloses certain 3-amino-2-benzhydryl-hioliday, which are useful as diuretic agents, and match

In addition, E. J. Warawa et al. in Journal of Medicinal Chemistry, Vol. 18, p. 587 (1975) extended this work to other members of this series, in which 3-amino-fragment is ethylamino, phenylethylamine, b-isopropylamino or 2-furfurylamine group.

Substance P is found in nature undecapeptide belonging to theminimum family of peptides, the latter is called so due to its rapid stimulatory effect on smooth muscle tissue. More specifically, substance P is a pharmaceutically active neuropeptide that is produced in mammals (originally isolated from the intestine) and possesses a characteristic amino acid sequence, which is discussed in U.S. patent N 4680283 D. F. Veber et al. Broad involvement of substance P and other tachykinins in the pathophysiology of many diseases widely demonstrated in practice. For example, substance P, as has recently been shown to be involved in transmitting pain or migraine (see B. E. B. Sandberg et al. Journal of Medicinal Chemistry, Vol. 25, p. 1009, (1982), as well as in Central nervous system disorders, such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, and in the gastro-Ki is in Cluster Headache", published by F. Sicuteri et al. Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).

In the recent past, some attempts were made to obtain peptideprophet substances which are antagonists of substance P and other tachykinins peptides to more effectively treat various disorders and diseases described above. Peptideprophet nature of these substances makes them too labile with metabolic point of view, to serve as a practical therapeutic agents in the treatment of diseases. Ones antagonists of the invention, on the other hand, does not have this disadvantage, however, they are more resistant to metabolic point of view, than peptideprophet agents, known previously.

Other ones receptor antagonists substance P are described in the applications under consideration simultaneously with the present application. Derivatives of hinoklidina and related compounds that have activity as antagonists of the receptor for substance P, are referred to in PCT application PCT/US 89/05338, filed November 10, 1989, and published as WO 90/05729 may 31, 1990 and patent application U.S. N 557442, filed July 23, 1990. Other derivatives of hinoklidina and related compounds, which have activeclean" and "Derivative of hinoklidina" filed respectively on April 25, 1991 and 15 may 1991 Piperidine derivatives and related heterocyclic nitrogen-containing compounds that are useful as antagonists of substance P, are mentioned in the patent application U.S. N 619361, filed November 28, 1990, and the application of the U.S. N 590423, filed September 28, 1990 Derivative of azerbaran, which have activity as antagonists of the receptor for substance P, are mentioned in the application U.S. N 07/719884, filed June 21, 1991, Feralcode-derived nitrogen-containing heterocycles, which are active as antagonists of the receptor for substance P, are mentioned in the patent application U.S. N 07/717943, filed July 20, 1991, All of the foregoing patent applications are owned by the same applicant as the present application.

The invention relates to compounds having the formula:

< / BR>
where W represents Y or X(CH2)n,

Y represents optionally substituted C1-C6)alkyl, optionally substituted (C2-C6)alkenyl or optionally substituted C3-C8)cycloalkyl;

X is hydroxy or optionally substituted C1-C6)alkoxy, CONR1R2, CO2R1, CHR1OR2, CHR1NR2R3, COR1or, is inoline, teinila, furil, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n represents an integer from 0 to 6;

Ar1, Ar2and Ar3are each independently optionally substituted aryl, where the specified aryl selected from phenyl, naphthyl, pyridyl, chinoline, teinila, furil, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl;

and R1, R2and R3are independently selected from hydrogen, (C1-C6) alkyl, (C1-C6)alkoxy, (C3-C8), cycloalkyl, aryl, where the specified aryl selected from phenyl, naphthyl, pyridyl, chinoline, teinila, furil, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl, and optionally substituted C1-C6)heterocyclic group, where the specified heterocyclic group selected from pyrrolidino, piperidino, morpholino, piperazinil, thiomorpholine; and

where the substituents in the aforementioned substituted alkyl, alkenyl, cycloalkyl and alkoxy groups are independently selected from halogen, nitro, amino, (C1-C4)alkyl, (C1-C4)alkoxy, trifloromethyl, triptoreline;

and where the substituents on the above-mentioned selected from oxygen, di-oxygen and (C1-C4) alkyl;

and where the substituents on the above substituted aryl groups Ar1are independently selected from halogen, (C1-C6)alkyl, optionally substituted with one, two or three halogen groups, (C1-C6)alkoxy, optionally substituted with one to three halogen groups, (C1-C6)alkylsulfonyl, (C2-C6)alkenyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl, and di(C1-C6)alkylamino, in which one or both alkyl groups may be optionally substituted C1-C6)alkylsulfonyl or (C1-C6)alkylsulfonyl group;

and where the substituents on the above substituted Ar2and Ar3groups are independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfonyl, di(C1-C4)alkylamino, trifloromethyl, triptoreline;

provided that Y is unsubstituted or substituted (C1-C4)alkyl and is attached to hinoklidina ring 4 or 6 positions.

The invention also relates to farmaceuti pharmaceutically acceptable acids but the additive salts of the above-mentioned basic compounds of the invention, are acids which form non-toxic acid additive salts, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saharat, benzoate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, pamoate [i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthoate)] salts.

The term "alkyl" means radicals of branched or unbranched hydrocarbon chain, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and similar.

The term "alkenyl", as used here, refers to radicals of branched or unbranched hydrocarbon chain containing one double bond including, but not limited to, ethinyl, 1 - or 2-propenyl, 2-methyl-1-propenyl, 1 - and 2-butenyl and similar.

The term "alkoxy", as used here, means-OR (R is alkyl) including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and similar.

The term "alkylthio" ISOE is about, n-propylthio, isopropylthio, n-butylthio, isobutyric, t-butylthio and similar.

The term "cycloalkyl" shall mean cyclic radicals, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and similar.

The term "halogen" means chlorine, fluorine, bromine or iodine.

Preferred compounds of the invention are those in which Y is-COOH, Ar2and Ar3are diphenylmethyl and Ar1is a disubstituted phenyl group.

Specific preferred compounds of the invention include the following:

/3R, 4S, 5S, 6S, /-5-/5-isopropyl-2-methoxybenzylamine/-6 - diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

/3R, 4S, 5S, 6S,/-5-/2-methoxy-5-methylthiophenethylamine/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R, 4S, 5S, 6S,(-5-(2,5-dimethoxyphenethylamine(-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R, 4S, 5S, 6S,(-5-(2-methoxy-5-methylbenzylamino(-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R, 4S, 5S, 6S,(-5-(5-ethyl-2-methoxybenzylamine(-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R, 4S, 5S, 6S,(-5-(2-methoxy-5-p-propylaniline(-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

/3R, 4S, 5S, 6S, /-5-/5-methyl-methanesulfonamido-2-methoxybenzylamine/-6 - diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

/3R, 4S, 5S, 6S,/-5-/2-methoxy-5-methylsulfonylbenzoyl(-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

/3R, 4S, 5S, 6S,/-5-/2-methoxy-5-triphtalocyaninine/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

/3R, 4S, 5S, 6S,/-5-(2-methoxy-5-methylsulfonylbenzoyl/-6-diphenyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

/3R, 4S, 5S, 6S,/-5-/5-dimethylamino-2-methoxybenzylamine/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

/2S, 4S, 5S, 6S, /-5-/5-isopropyl-2-methoxy, benzylamino(-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

/2S, 4S, 5S, 6S,/-5-/2-methoxy-5-methylthiophenethylamine/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

/2S, 4S, 5S, 6S,/-5-/2,5-dimethoxyphenethylamine/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

/2S, 4S, 5S, 6S,/-5-/2-methoxy-5-methylbenzylamino/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

/2S, 4S, 5S, 6S,/-5-/5-ethyl-2-methoxybenzylamine/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

/2S, 4S, 5S, 6S,/-5-/2-methoxy-5-p-propylaniline/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

/2S, 4S, 5S, 6S, /-5-/5-methyl-methanesulfonamido-2-methoxybenzylamine(-6 - diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

/2S, 4S, 5S, 6S,/-5-/2-methoxy-5-methylsulfonylbenzoyl/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

/2S, 4S, 5S, 6S,/-5-/2-methoxy-5-triphtalocyaninine/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

/2S, 4S, 5S, 6S,/-5-/2-methoxy-5-methylsulfonylbenzoyl/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid and

/2S, 4S, 5S, 6S,/-5-/5-dimethylamino-2-methoxybenzylamine/-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid.

The invention also relates to pharmaceutical compositions for the treatment or prevention of a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammation of the digestive tract), anxiety, depression or estimatesa disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airway disease, allergic disorders, such as poisoning the ivy, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrous and collagen diseases such as scleroderma and sizing, such as alcoholism, somatica disorders, stress-related peripheral neuropathy, neuralgia, neurotic diseases disorders such as Alzheimer's disease, dementia associated with AIDS, diabetic neuropathy and multiple sclerosis, disorders related to enhancing or immune suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in mammals, including humans, containing the compound of formula (1) or its pharmaceutically acceptable salt in an amount effective in treating or preventing such condition, and a pharmaceutically acceptable carrier.

The invention relates also to a method of treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammation of the digestive tract), anxiety, depression or estimatesa disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airway disease, allergic disorders such as poison ivy, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrous and collagen diseases, such as scleral is such violations, such as alcoholism, somatic disorders, stress-related peripheral neuropathy, neuralgia, neurotic diseases disorders such as Alzheimer's disease, dementia associated with AIDS, diabetic neuropathy and multiple sclerosis, disorders related to enhancing or immune suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in mammals, including humans, comprising an introduction to the specified mammal the compounds of formula (1) or its pharmaceutically acceptable salt in an amount effective for treating or preventing such condition.

The invention also relates to pharmaceutical compositions for counteracting the effects of substance P in a mammal, including humans, contain opposing substance P, the number of the compounds of formula (1) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

The invention relates also to a method of counteracting the effects of substance P in a mammal, including humans, consisting in the introduction to the specified mammal counteracting substance P number of the compounds of formula (1) or its pharmaceutically acceptable soliste in mammals, including humans, caused by an excess of substance P containing opposing substance P, the number of the compounds of formula (1) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

The invention relates also to a method of treating or preventing disorders in mammals, including humans, caused by an excess of substance P, which includes the introduction of the specified mammal counteracting substance P number of the compounds of formula (1) or its pharmaceutically acceptable salt.

The invention also relates to pharmaceutical compositions for the treatment or prevention of a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammation of the digestive tract), anxiety, depression or estimatesa disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airway disease, allergic disorders such as poison ivy, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrous and collagen diseases such as scleroderma and tosinopally fasciolosis, reflex sympathetic of distr is the R with stress, peripheral neuropathy, neuralgia, neurotic diseases disorders such as Alzheimer's disease, dementia associated with AIDS, diabetic neuropathy and multiple sclerosis, disorders related to enhancing or immune suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in mammals, including humans, containing the compound of formula (1) or its pharmaceutically acceptable salt in an amount effective to counteract the effect of substance P at its receptor site, and a pharmaceutically acceptable carrier.

The invention relates also to a method of treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammation of the digestive tract), anxiety, depression or estimatesa disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airway disease, allergic disorders, such as plyushevoe poisoning, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrous and collagen diseases such as scleroderma and tosinopally fascioliasis, reflex centrolene, stress-related peripheral neuropathy, neuralgia, neurotic diseases disorders such as Alzheimer's disease, dementia associated with AIDS, diabetic neuropathy and multiple sclerosis, disorders related to enhancing or immune suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in mammals, including humans, containing the compound of formula (1) or its pharmaceutically acceptable salt in an amount effective to counteract the effect of substance P at its receptor site.

The invention relates also to pharmaceutical compositions for the treatment or prevention of disorders in mammals, including humans, for the treatment or prevention that is effective or easier by reducing neurotransmission, through substance P containing the compound of formula (1) or its pharmaceutically acceptable salt in an amount effective to counteract the effect of substance P at its receptor site, and a pharmaceutically acceptable carrier.

The invention relates also to a method of treating or preventing disorders in mammals, including humans, treatment or prevention, which is interested in the introduction to the specified mammal the compounds of formula (1) or its pharmaceutically acceptable salt, in a quantity effective to counteract the effect of substance P at its receptor site.

The invention relates also to pharmaceutical compositions for the treatment or prevention of disorders in mammals, including humans, for the treatment or prevention that is effective or easier by reducing neurotransmission, through substance P containing the compound of formula (1) or its pharmaceutically acceptable salt in an amount effective to treat or prevent such disorders, and a pharmaceutically acceptable carrier.

The invention relates also to a method of treating or preventing disorders in mammals, including humans, for the treatment or prevention that is effective or easier by reducing neurotransmission by substance P, which includes the introduction of the specified mammal the compounds of formula (1) or its pharmaceutically acceptable salt in an amount effective to treat or prevent such disorders.

The compounds of formula (1) have chiral centers and therefore exist in different enantiomeric forms. The invention relates to all optical isomers and all stereoisomers which the connections described, except that one or more hydrogen atoms or carbon substituted by their isotopes. Such compounds are useful as research and diagnostic tools in pharmakinetics studies of metabolism and related analyses. Specific applications in the study include the analysis of radioligand binding studies autoradiography and study of binding in vivo, with specific application in the diagnostic area include the study of the receptor for substance P in the brain when linking in vivo in the relevant tissues due to inflammation, for example, cells of the immune type or cells involved in inflammatory disorders of the digestive tract and similar. In radioactiveman forms of the compounds of formulae I and VII are included compounds labeled with isotopes tritium and C14.

The new compounds of the invention can be obtained, as described in the reaction schemes and the discussion presented in Fig.1-3. Unless otherwise stated, W, Ar1, Ar2, Ar3X, Y, R1, R2, R3and n in the reaction schemes and discussion that follow, have the meanings given above.

The compounds of formula 1 can the>have the meanings given above, each of W and W1represented by the Deputy -(CH2)nX or Y are defined as for formula 1 above, or equivalent (CH2)nX or Y in a synthetic way. P and Q represent, respectively, the nitrogen-protecting group.

Substituted Hinkley-2-ones (i) can be obtained from the correspondingly substituted of isonicotinate using the method of obtaining the unsubstituted Hinkley-3-ones described in Org. Synth. Coll. Vol.V. 989(1973). For example, 5-methyl-, 5-methoxycarbonyl - and 5-diethyl-aminocarbonyl-Hinkley-3-ones were obtained by this method (J. Chem.Soc.Perkin Trans. 1, 409 (1991().

Introduction benzhydryl group or a similar group in 2-position Hinkley-3-one (i) can be performed using the method described in J. Med. Chem. 18, 587, (1975). The compound (i) can be converted into 2-benzylidene the compound (ii) via aldol condensation with aromatic aldehyde (Ar2CHO), catalyzed by a base such as sodium hydroxide, in proton solvent (e.g. ethanol). This reaction preferably is carried out at the boiling temperature of the solvent.

The introduction of another aryl group (Ar2) can be accomplished by the reaction of the green number of the halide of copper (II), such as copper bromide or iodide, improves the yield of 1,4-addition. This reaction is usually carried out at a low temperature, -78oC 0oC. In some cases, to improve the selectivity is preferred to the method described Kuwajima (Tetrahedron, 45, 349 (1989 (a), using trimethylsilane, hexamethylphosphoramide (HMPA) and a complex of copper bromide and dimethyl sulfide (CuBr-DMS). The obtained compound (iii), if desired, can be converted into the corresponding carboxylic acid by hydrolysis catalyzed by acid. Carboxylic acid can be converted, if desired, into the corresponding amide by method well known in this field.

The compound (iii) can be converted to the claimed compounds (vi) using two independent methods. The first way involves direct introduction of arylmethylidene (Ar1CH2NH-) in the 3-position genociding rings. This conversion is done through education first imine (iii) and the corresponding benzylamine. This reaction is usually catalyzed by acid (e.g., campanulaceae (CSA) and is performed in hot toluene at digitaltechnik conditions. Then Imin restored, giving the compound (vi). It vosstanavenie, such as the reagents on the basis of aluminum, boron, borhydride or trialkylsilanes. In most cases, the reaction with trialkylborane (for example, 9-borabicyclo [3.3.1] non - (9-BB) (or triacetoxyborohydride sodium (NaBH(OAc)3) in THF at room temperature gives satisfactory results when holding it for half an hour to several days.

The second path includes a synthesis in several stages through the 3-amino compound (v), which is then alkiliruya, giving the compound (vi). The compound (iv) is derived imino-type, such as oxime, hydrazone or Imin. It can be formed by the reaction of (iii) with the corresponding Q-NH2(for example, hydroxylamine, N, N-dimethylhydrazone, ammonia or benzylamino). The resulting product (vi) can be restored using any of a variety of reducing agents. Appropriate reducing agents include sociallyengaged, (LAH), boranova reagents, catalytic hydrogenation, or a combination of the above. In the case of Iminov derived from ammonia as the reducing agent, formic acid can be used. The obtained 3-amino derivatives (v) then allmaterials the corresponding benzaldehyde (Ar24), triacetoxyborohydride sodium (NaBH(OAc)3or trialkylsilanes can also be used to perform this transformation.

Functional group W in the compound (vi) can be changed to another functionality W1. Some of the claimed compounds (ix) can be obtained this way. For example, the compound (vi), where W represents the amide can be converted into the corresponding amino derivatives by reaction with the appropriate regenerating reagent such as LAH. It can also be converted into the corresponding carboxylic acid by hydrolysis.

Carboxylic acid, thus obtained, can be converted into the corresponding ester by standard methods that are well known in this field.

Compounds (vi), where W represents the ester or carboxylic acid can be converted into the corresponding hydroxymethylene connection processing corresponding regenerating agent such as LAH.

The above conversion of one functional group W other W1are standard spoog transformation, appropriate protection of the MO group benzylamine compounds (vi). For such protection is appropriate Cbz or Boc-group (see T. W. Green, Protective Groups in Organic Synthesis, J. Wiley and Sons. (1981)). After the transformation (conversion) functional group protecting group is removed by using an appropriate standard method, receiving the proposed compound (ix).

Due to the fact that all connections of hinoklidina of the invention possess at least one asymmetric center, they can exist in various stereoisomeric forms or configurations. Therefore, the compounds can exist in separate (+) and (-)-optically active forms and racemic forms or their (a) mixtures, and in the case of compounds with two asymmetric centers, they may additionally exist as diastereomers with their respective optical isomers. The invention includes all such forms within its scope. For example, the diastereomers can be separated by methods well known to specialists in this field, for example by means of fractional crystallization and similar methods, however, optically active isomers can be obtained by using the simple techniques of separation, which is inany of the invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, often in practice it is preferable to select hinoklidina base from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert to the free base by treatment with an alkaline reagent, and then to turn the free base in a pharmaceutically acceptable salt accession acid. Salt accession acids (or acid-salt additive) hinoksalinovym bases of the invention are easily obtained by processing bases equivalent amount of the chosen mineral or organic acid in an aqueous solvent or an appropriate organic solvent, such as methanol or ethanol. After careful evaporation of the solvent easily get the desired solid salt.

Acid, which is used to obtain pharmaceutically acceptable salts accession acids above hinoksalinovym basis of the invention is an acid which forms a non-toxic salt accession acids, i.e., salts containing pharmaceutically prilly phosphate, acetate, lactate, citrate or bi-tartrate, succinate, maleate, gluconate, saharat, benzoate, methanesulfonate, benzene sulfonate, p-toluensulfonate and pamoate (i.e., 1,1-methylene-bis-2-hydroxy-3 - naphthoate) of salt.

Some hinoklidina compounds of the invention, which also have acid groups, are able to form basic salts with various pharmacologically acceptable cations. Examples of such salts are salts of alkali or alkaline earth metals, especially sodium and potassium salts. All these salts get in the usual ways. Chemical bases which are used as reagents for producing pharmaceutically acceptable basic salts of the invention are those which form non-toxic basic salts described here sour hinoksalinovym derivatives. Specific non-toxic basic salts include those who come from a pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc., These salts can be easily obtained by treating the above-mentioned acidic hinoksalinovym compounds with an aqueous solution containing the desired pharmacologically acceptable cation, and then the evaporation of the final solution to dryness, Predoctoral acidic compounds and the desired alkali metal alkoxide and then evaporation of the final solution to dryness in the same manner as the above. In any case, it is preferable to use stoichiometric amounts of reactants in order to ensure completeness of reaction and maximum outputs the desired end product.

The compounds of formula (1) and their pharmaceutically acceptable salts (hereinafter referred to as "active compounds of the invention") show significant binding activity of the receptor for substance P, and therefore are valuable in the treatment of a wide variety of clinical conditions which are characterized by excessive activity of the specified substance P. Such conditions include gastrointestinal disorders such as ulcers and colitis and other diseases of the gastrointestinal tract, disorders of the Central nervous system such as anxiety and psychosis, inflammatory diseases such as rheumatoid arthritis and inflammatory disease of the digestive tract, respiratory disease, such as asthma, as well as pain in any of the above conditions, including migraine. Therefore, these compounds are easily adapted to therapeutic use as antagonists of substance P to inhibit and/or treat any of the above clinical conditions mammals, including humans.

Active compounds of the invention can be administered by themselves or in combination with pharmaceutically acceptable carriers or diluents by any of the three previously mentioned methods, and such introduction can be carried out in single or multiple doses. More specifically, the active compounds of the invention can be introduced using a large variety of the firs in the form of tablets, capsules, pellets, pastilles, solid candles, powders, sprayable solutions, creams, ointments, suppositories, jellies, containing the drug, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc., Such carriers include solid diluents or fillers, sterile aqueous medium and various non-toxic organic solvents, etc. However, the oral pharmaceutical compositions can podkashivatsya and/or aromatizirovat. Typically a therapeutically effective compounds of this invention are present in such dosage forms at concentration levels of about 5.0 percent to 70 weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be used together with such different leavening agents, such as starch, preferably corn, potato or tapioca starch, alginic acid and certain silicate complexes, together with a binder for granulation type polyvinylpyrrolidone, sucrose, gelatin and gum acacia. In addition, for the purposes of tabletting often very useful lubricating agents is taken as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar and high molecular weight glycols. If oral administration is desirable to use aqueous suspensions and / or elixirs, the active ingredient may be combined with various sweetening or flavouring agents, colouring matter or dyes and, if desired, emulsifying or suspendresume agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

For parenteral application, to apply the solutions of the compounds of the invention in either sesame or peanut oil in an aqueous solution of propylene glycol. Aqueous solutions, if necessary, should supererogatory (preferably pH 8) and the liquid diluent first make isotonic. These aqueous solutions are suitable for intravenous injection. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. Preparation of all these solutions under sterile conditions is easily accomplished using standard pharmaceutical techniques well known to specialists in this field. Furthermore, who is this can preferably be carried out using creams, jellies, gels, pastes, ointments and similar forms in accordance with standard pharmaceutical practice.

The activity of compounds of the invention can be determined by their ability to inhibit the binding of substance P at its receptor site in the cells bullish tail tissue or IM-9 by use of radioactive ligands. Antagonistic activity described here hinoksalinovym compounds in relation to substance P is estimated using standard testing procedures described M. A. Gascieri et al. as reported in the Journal of Biological Chemistry, Vol. 258 p. 5158 (1983). This method essentially involves determining the concentration of the individual compound required to recover 50% of the number of ligands radiochango substance P at its receptor sites in these isolated cells of the tissues of the cow or IM-9, thus giving the characteristic values IC50for each tested compound. In this test some of the preferred compounds show IC50values in the range of 0.1 to 60 mm with respect to inhibition of binding at its receptor.

Anti-inflammatory activity of the compounds of the invention can be determined using standard tests in the ne, Vol. III, page 544 (1962)). In this test, anti-inflammatory activity determined as the percentage of inhibition of cancer hind legs of male albino rats (weighing 150-190 g) in response to pomodorino injection carrageenin. Carrageenin injected in a 1% aqueous solution. Then determine the formation of tumors by changing the volume of the paw after the initial injection and three hours after injection carrageenin. The increase in three hours after injection carrageenin is an individual response. Compounds are considered active if the differences in response between animals treated with medication (six rats per group) and a control group receiving only one carrier is significant compared with the results given by the standard connection type phenylbutazone oral dose of 33 mg(kg

Antipsychotic activity of the compounds of the invention as neuroleptic agents for the inhibition of various psychotic disorders may primarily be determined by examining their ability to inhibit induced by substance P hypermodernity rats. This study was conducted first by rat control seizing destination through the catheter and then measuring their individual locomotor response to a specified stimulus.

The invention is illustrated by the following examples. However, it should be clear that the invention is not limited to the specific details of these examples. Proton nuclear magnetic resonance spectrum (PMR) were measured at 270 MHz, unless otherwise specified, and the position of peaks expressed in parts per million using as a standard tetramethylsilane. The shape of the peaks are indicated as follows: s singlet, d doublet, i.e. the triplet, square Quartet, m, multiplet and br. wide.

In the reaction schemes and the procedures that are given in the examples, Me represents methyl, Et is ethyl, Ph is phenyl, TFA is triperoxonane acid and t-Boc represents tertbutoxycarbonyl.

Example 1. A. Methyl 2-chlorisondamine (2)

N-oxidecontaining acid 1 (50.0 g, 0,359 mol), Piatigorsky phosphorus (120 g, 0,576 mole) and phosphorus oxychloride (160 ml, 1,72 mole) are mixed together and stirred at room temperature. The mixture is heated at the boil under reflux for 2 hours the Excess POCl3removed by distillation (1 mm Hg (and then by evaporation in a vacuum). The resulting residue is carefully quenched with dry methanol with an exothermic reaction. The mixture is alkalinized NaHCO3and extracted with EtOAc. The extracts is isonicotinate 2 (136-144oC, 35 mm Hg, to 41.6 g). Although this substance contains a mixture (about 18% mole. specific1H-NMR), it does not affect the subsequent reaction.

1H NMR (CDCl3): 8,54 (Shir. d, J 5 Hz, 1H), 7,89 (Shir. s, 2H), to 7.77 (DD, J 5.1 Hz, 1H), of 3.97 (s, 3H).

B. Methyl 2-(2-phenylethynyl)isonicotinate (3)

Methyl 2-chlorisondamine, 2 (19,08 g, 0,111 100 mole% purity), phenylacetylene (13,6 g of 0.133 mol), copper iodide (1,00 g's, 5.25 mol) and triethylamine (30 ml) are mixed together while stirring at room temperature, and to this mixture is added bis(triphenylphosphine)palladium (II) chloride (2.0 g, to 2.85 mmole). The reaction mixture is heated to boiling under reflux for 7 hours, the Solvent is removed by evaporation and the residue is subjected to chromatographicaliy (silica gel, 10-30% EtOAc-hexane) followed by crystallization from a mixture of ether(hexane to obtain methyl 2-(2-phenylethynyl)isonicotinate (11,25 g, 43%).

1H NMR (CDCl3): 8,77 (Shir. d, J 5 Hz, 1H), 8,08 (m, 1H), 7,78 (DD, J 5.2 Hz, 1H), 7.62mm (m, 2H), 7,38 (m, 3H), 3,98 (s, 3H).

C. Methyl(N-ethoxycarbonylmethyl-2-phenethyl-piperidine and 4-carboxylate (4)

Isonicotinate, 3 (was 12.75 g, 53,8 mmole) is dissolved in acetic acid (18 ml) and subjected to catalytic hydrogenation with PtO2(459 mg) at 50 kg/cm2within 15 h, using autoaim mixture of CIS/TRANS isomers of piperidine (16,36 g, with a ratio of about 5:1). The above raw foods and ethylbromoacetate (10.8 g, 64.7 mmole) dissolved in toluene (150 ml) and suspended K2CO3(15 g, 109 mmol) obtained in solution. The mixture is heated at the boil under reflux for 5 h and the reaction quenched with aqueous solution of NH4Cl. The resulting mixture was extracted with EtOAc, washed with brine and dried over Na2SO4. Evaporation of solvent gives a mixture of CIS/TRANS isomers of 4 (18,91 g).

1H-NMR (CDCl3): 4 CIS-isomer (less polar, basic): 7,31 7,16 (m, 5H), 4,14 (sq J 7 Hz, 2H), 3,69 (s, 3H), 3,47 (d, J 17 Hz, 1H), 3,39 (d, J 17 Hz, 1H), 3,00 (m, 1H), 2.77-to of 2.53 (m, 4H), 2,38 (TT, J and 12.4 Hz, 1H), 2,03 (m, 1H), 1,96-of 1.64 (m, 3H), of 1.52 (q, J 12 Hz, 2H), 1,25 (t, J 7 Hz, 3H) (4-TRANS-isomer more polymer, min); to 3.36 (d, J 17 Hz, 1H), 3,29 (d, J 17 Hz, 1H).

D. 6-penicillinallergic-3-one(5) and (6)

To a mixture of tert-butoxide potassium and toluene (50 ml), heated to boiling under reflux, gradually add the crude mixture of 4 dissolved in toluene (100 ml). The addition is carried out for 3 h, and the resulting mixture was additionally heated for 1 h the Reaction is quenched with 6N-HCl and the solvent is removed by evaporation. To the residue add 12N-HCl (40 ml) and the mixture is heated at 120oC during the night. The concentration of the rat alkalinized with NaOH and NaHCO3to pH 8.5 and extracted with EtOAc. The extracts washed with brine and dried over Na2SO4. Evaporation of solvent gives diastereomer a mixture of 5 and 6 (at 8.36 g). Analysis 1H-NMR spectra of this substance indicates the presence of about 2:1 mixture of 5 (-phenethyl, more polar) and 6 (-isomer (less polar). A mixture of 5 and 6 are chromatographicaliy (silica gel, 50 to 70% EtOAc-hexane) obtaining a fraction enriched 5 (0.68 g, about 8:1), fraction 6 (0,58 g, about 1:10) and undivided fraction (of 5.24 g).

Data for compound 5.

1H-NMR (270 MHz, CDCl3): 7.32 7.17 (m, 5H), 3.47 (d, J 19 Hz, 1H), 3.11 (d, J 19 Hz, 1H), 3.05-2.80 (m, 3H), 2.69 (m, 2H), 2.42 (m, 1H), 2.18 (m, 1H), 1.96 (m, 2H), 1.89-1.49 (m, 3H).

13C-NMR (CDCl3): 219.0, 141.4, 127.86, 127.93, 125.3, 56.1, 53.7, 48.6, 40.2, 36.2, 32.0, 31.9, 24.6.

Data for compound 6.

1H-NMR (270 MHz, CDCl3): 7.32 7.14 (m, 5H), 3.38 (d, J 18 Hz, 1H), 3.23 (d, J 18 Hz, 1H), 2.86-2.65 (m, 4H), 2.40 (m, 1H), 2.17 (m, 1H), 2.05-1.76 (m, 4H), 1.54 (m, 1H).

13C-NMR (CDCl3): 219.1, 141.4, 127.8, 125.3, 63.8, 54.8, 40.1, 39.4, 36.2, 32.5, 32.4, 25.1.

E. (2R*, 4R*, 6R*)-2-Diphenylmethyl-6-penicillinallergic-3-one (7)

Compound 5 (577 mg, 2.52 mmole), benzaldehyde (328 mg, 3.09 mmole) and NaOH (7.6 mg, 0.19 mmole) was dissolved in EtOH (8 ml) and the resulting solution was heated to boiling with inverse x is4Cl. The organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, the oil obtained is cleaned chromatography (silica gel, 5-20% EtOAc (hexane) and get 2-benzylidene connection 5 (738 mg, 92%). To a cold suspension of CuBr (dimethyl sulfide (27 lhs, 0.13 mmole) in toluene (6 ml) at -60oC add phenylmagnesium (3.0 mmol) in ether, 1.25 ml). To this connection add a mixture of the above 2-benzylidene compound (738 mg, 2.33 mmole), chlorotrimethylsilane (0.71 ml, 5.6 mmole), NMR (0.98 ml, 5.6 mmole) and toluene (6 ml), keeping the internal temperature below-6-oC. After 1 h the reaction mixture was gradually warmed up to 0oC. the Reaction is quenched with AcOH (0.43 ml) at -60oC and add ether and water. The solution is brought to pH=4 and the organic layer washed with brine and dried over Na2SO4. The solvent is removed by evaporation and the crude substance is cleaned chromatography (silica gel, 13 50% EtOAc (hexane) and get pure product 7 (357 mg, 39%).

1H-NMR (279 MHz, CDCl3): 7.42 7.10 (m, 15H), 4.44 (d, J 9.2 Hz, 1H), 4.18 (d, J 9.2 g, 1H), 2.95 2.78 (m, 2H), 2.69-2.47 (m, 3H), 2.39 (m, 1H), 2.15 0.52 (m, 6H).

13H-NMR (CDCl3): 220.1, 143.1, 122.6, 141.7, 128.3, 128.2, 128.14, 128.07, 126.1, 125.6, 65.2, 56.1, 50.0, 44.0, 41.9, 35.6, 32.3, 31.6, 27.1.

F. /2R*2Cl2, dried over Na2SO4and concentrate. The crude substance is cleaned combined methods; chromatographytandem on column (silica gel, MeOH(CH2Cl2), preparative thin-layer chromatography (silica gel, 10% MeOH(CH2Cl2) and crystallization from MeOH, receiving a pure compound 8 (109 mg, 23%).

So pl. 107.1 107.9oC.

IR(Nujol): 1493, 1243 cm-1.

1H-NMR (CDCl3): 7.35-6.95 (m, 16H), 6.78-6.67 (m, 2H), 6.58 (DD, J 7.3, 1.5 Hz, 1H), 4.52 (d, J 12 Hz, 1H), 3.63 (DD, J 12.8 Hz, 1H), 3.58 (d, J 13 Hz, 1H), 3.53 (s, 3H), 3.38 (m, 1H), 3.27 (d, J 13 Hz, 1H), 2.81 (DD, J 8.44 Hz, 1H), 2.59-2.47 (m, 2H), 2.06 (m, 1H), 1.96 (m, 2H), 1.85 (m, 1H), 1.74 (m, 1H), 1.62-1.37 (m, 2H), 1.21 (m, 1H), 0.99 (m, 1H).

Examples 2 and 3. /2R*, 3R*, 4R*, 6R*/- /2R*, 3R*, 4R*, 6R*/-2-Diphenyl me is via 9 in the same manner, as of 5 and 8.

9 Exo-isomer (less polar).

1H-NMR (270 MHz, CDCl3): 4.4 4 (d, J 92 Hz, 1H), 3.83 (d, J 9.2 Hz, 1H).

13H-NMR (CDCl3): 219.9, 74.2, 57.3, 50.8, 41.8, 35.7, 34.3, 33, 4; 32.7, 26.0

9-endo isomer (more polar).

1H-NMR (270 MHz, CDCl3): 4.52 (d, J 7.5 Hz, 1H), 4.04 (d, J 9.2 Hz, 1H).

13C/NMR (CDCl3): 220.6, 72.6, 50.3, 49.2, 41.6, 41.4, 35.5, 32.3, 24.8.

/2R*, 3R*, 4R*, 6R*/-2-Diphenylmethyl-3-/2-methoxy benzyl/amino-6-phenethyl-1-azabicyclo[2.2.2]octane:

So pl. 110.0 114.7oC.

IR(Nujol): 1599, 1587, 1232 cm-1.

1H-NMR (CDCl3): 7.35-6.06 (m, 14H), 6.77-6.67 (m, 4H), 6.59 (DD, J 7.4, 1.6 Hz, 1H), 4.61 (d, J 12 Hz, 1H), 3.59 (d, J 13 Hz, 1H), 3.53 (s, 3H), 3.42 (m, 1H), 3.27 (d, J 13 Hz, 1H), 3.14 (m, 1H), 2.86 (DD, J 8.4 Hz, 1H), 2.68 (m, 1H), 2.50 (m, 1H), 2.42-2.20 (m, 2H), 2.04 (m, 1H), 1.88 (m, 2H), 1.63-1.42 (m, 2H), 1.25-1.09 (m, 2H).

/2R*, 3R*, 4R*, 6R*/-2-Diphenylmethyl-3-/2-methoxy benzyl/amino-6-phenethyl-1-azabicyclo[2.2.2]octane:

So pl. 122.4 125.3oC.

IR(Nujol): 1494, 1243, 1052 cm-1.

1H-NMR (CDCl3): 7.37-7.00 (m, 16H), 6.77 (t, J 7.4, 1H), 6.71 (d, J 7.9 Hz, 1H), 3.59 (d, J 14 Hz, 1H), 3.55 (s, 3H), 3.32 (d, J 14 Hz, 1H), 3.32-3.26 (m, 1H), 2.91-2.80 (m, 2H), 2.48 (m, 1H), 2.33 (t, J 8.4 Hz, 2H), 2.07 (m, 2H), 1.60-1.41 (m, 4H), 0.82 (m, 1H).

Schematic examples 1-3, see picciani(amino-6-phenethyl-1-azabicyclo[2.2.2]octane.

The compound of example 4 is produced from compound 7 and 2.5 dimethoxyphenethylamine the same way as in example 1.

So pl. 123.5 124.8oC.

IR(Nujol): 1499, 1492, 1226 cm-1.

1H-NMR (CDCl3): 7.35-6.95 (m, 15H), 6.67 (DD, J 9.3 Hz, 1H), 6, (d, J 9 Hz, 1H), 6.37 (d, J 3 Hz, 1H), 4.52 (d, J 13 Hz, 1H), 3.73 (s, 3H), 3.63 (m, 1H), 3.53 (d, J 13 Hz, 1H), 3.49 (s, 3H), 3.37 (m, 1H), 3.18 (d, J 13 Hz, 1H), 2.84 (DD, J 7.5, 4.3 Hz, 1H), 2.60-2.44 (m, 2H), 2.10-1.68 (m, 5H), 1.50 (m, 2H), 1.20 (m, 1H), 1.01 (m, 1H).

Example 5. /3R*, 4R*, 5R*, 6R*-N,N-Diethyl - 5-2,5-dimethoxyphenethylamine/-6-diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-carboxamide (17)

A. CIS-Methyl-3-(diethylcarbamoyl)-1-(methoxycarbonylmethyl)- piperidin-4-carboxylate (12)

CIS-Methyl-3-(diethylcarbamoyl)-1-(methoxycarbonylmethyl)- piperidin-4-carboxylate, 12 receive in accordance with the method described in Tetrahedron Letters, 1989, 30, P. 5795-5798 and J. Chem. Soc. Perknitrans. 1, 1991, p. 409-420.

B. /3R*, 4R*/-N,N-Diethyl-5-oxo-1-azabicyclo [2.2.2]Octan-3-carboxamide (13)

A solution of 12 (159 g, 0.503 mol) in toluene (700 ml) is added dropwise over 2.5 h to a solution of tert-butoxide potassium (169 g, 1.51 mol) in toluene (1.9 l) at 110oC in nitrogen atmosphere. The mixture is heated at the boil under reflux for 1 h and cooled to room temperature. D is. After that, the organic layer is separated, the aqueous layer was neutralized and extracted with ethyl acetate for 15 h in a continuous extraction apparatus. The combined extracts dried over MgSO4and concentrate. Recrystallization from ethanol gives 13 (34,6 g 31%) as a colorless crystal. The stereochemistry is defined according to x-ray analysis13C and NMR.

IR(KBr): 2975, 2915, 2875, 1726, 1629, 1483, 1462, 1454, 1434, 1410, 1382, 1368, 1296, 1253, 1141, 1081, 1052 cm-1.

1H-NMR (CDCl3): 3.6 (d, J 8 Hz, 1H), 3.5-3.1 (m, 8H), 3.0-2.9 (m, 2H), 2.5 (DD, J 6.3 Hz, 1H), 2.2 (DD, J 8.3 Hz, 2H), 1.2 (t, J 7 Hz, 3H), 1.1 (t, J 8 Hz, 3H).

13C-NMR (CDCl3): 215.4, 173.2, 62.5, 51.5, 45.9, 42.3, 42.0, 41.3, 40.5, 25.9, 15.0, 12.9.

C. /3R*, 4R*/-N, N-Diethyl-5-oxo-6-benzylidene - 1-azabicyclo[2.2.2]Octan-3-carboxamide (14).

A mixture of 13 (34.6 g, 154 mmole), benzaldehyde (17.4 g, 164 mmole) and NaOH (6.5 g, 164 mmole) in EtOH (400 ml) is refluxed for 3 hours After cooling the mixture to room temperature, the obtained yellow crystals are collected by filtration and washed with cold ethanol and dried in vacuum, obtaining 14 (38,4 g, 128 mmol). The filtrate is concentrated under reduced pressure, receiving the second part of (3.3 g, 11 mmol) (total 41.7 g, 139 mmol, 90%).

IR(KBr): 2990, 2930, 2975, 1706, 1640, 145H), 2.7 (DD, J 5.0, 3.0 Hz, 2H), 1.2 (t, J 7 Hz, 3H), 1.1 (t, J 8 Hz, 3H).

13C-NMR (CDCl3): 202.5, 172.9, 143.8, 134.1, 132.0, 129.3, 128.2, 125.2, 52.3, 47.7, 46.4, 43.5, 42.0, 41.9, 40.5, 25.9, 15.1, 13.1.

D. /3R*, 4R*, 6R*/-N,N-Diethyl-5-oxo-6 - diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-carboxamide and /3R*, 4R*, 6R*/-N,N-diethyl-5-oxo-6 - diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamide (15) and (16)

1 l chetyrehosnuju flask equipped with a mechanical stirrer, a thermometer, an open flame dried and rinsed with nitrogen. This flask is placed CuBr(CH3SCH33.1 g, 15 mmol), add dry THF (400 ml) and cooled to -50oC. To this suspension is added 3 mol(l (ether solution)phenylmagnesium (50 ml, 150 mmol) dropwise over 20 min and stirred for 30 min at -60oC. In this reaction, the suspension is added dropwise a solution of 14 (45 g, 150 mmol) in 400 ml of dry THF (gently heated to dissolve) in nitrogen atmosphere for 1 h After the addition the reaction mixture was stirred at 0oC for 1.5 hours Added to the reaction mixture, a saturated aqueous solution of NH4Cl (100 ml) and the organic layer was washed with saturated aqueous NH4Cl to the disappearance of the blue color. The washing water colored the4and concentrate. The crude solid product is cleaned chromatography on silica gel(hexane)EtOAc= 1: 1 -1:2 as eluent) to give 1,2 adduct (1.2 g, 3.1 mmole, 2%) and 1,4 adduct 15 and 16 (54 g, 138 mmol, 92%). The products 15(16 changing a sharp temperature drop.

1H-NMR (CDCl3): 15 isomer: 7.43 (d, J=7 Hz, 2H), 7.3-7.1(m, 8H), 4.7(d, J=7 Hz, 1H), 4.4(d, J=7 Hz, 1H), 3.4-3.1(m, 7H), 2.5-2.4(m, 3H), 1.9-1.8 (m, 2H), 1.2(t, J=3 Hz, 3H), 1.1(t, J=7.3 Hz, 3H).

16 isomer: 7.4-7.2(m, 10H), 4.8(d, J=11 Hz, 1H), 3.96 (d, J=Hz, 1H), 3.6-3.5(m, 1H), 3.4-2.8(m, 8H), 2.5-2.4(m, 1H), 1.9-1.8(m, 2H), 1.2-1.1(m, 6H).

E. /3R*, 4R*, 5R*, 6*/-N, N-Diethyl-5/2.5-dimethoxyphenethylamine/-6-diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-carboxamide (17)

Tetrachloride titanium (3.99 ml of 1 mol/l solution in CH2Cl2, 3.99 mmole? add to a mixture of 2.5-dimethoxyphenethylamine (1.31 g, 7,84 mmole) of triethylamine (2.14 ml, 15.4 mmole) and the mixture of 15 and 16 (ratio 15:16 11:8, 3.0 g, 7.68 mmole) in dry CH2Cl2(20 ml) under nitrogen atmosphere at 0oC and stirred for 4 days at room temperature. The reaction mixture was poured in aqueous NaOH solution (about 10 ml) and 5oC and extracted with CH2Cl2. After separation of the organic layer the aqueous layer was extracted with CH2Cl2. The combined organic layers with the reaction without further purification. A solution of crude imine in THF (15 ml) is added to a suspension of NaBH(OAc)3(4.9 g, 23 mmole) in a solution of acetic acid (13 ml) in THF (10 ml) at 10oC. After stirring at room temperature for 1 h the reaction mixture was poured in aqueous NaOH solution (30 ml) and 5oC and extracted with CH2Cl2(10 ml x 3). The combined organic extracts washed with brine, dried over MgSO4and concentrate. The crude oil is cleaned chromatography on silica gel (CH2Cl2:E OAc=2:1, CH2Cl2:MeOH 100:0.5 to 100:3) to give 17 (1.44 g, 2.7 mmole, 35%).

So pl. 143.7 145.6oC.

IR(KBr): 2965, 2935, 2885, 1621, 1494, 1483, 1475, 1465, 1453, 1431, 1241 cm-1.

1H-NMR (CDCl3): 7.3-6.9(m, 10H), 6.6(Shir.s, 2H), 6.4(Shir.s, 1H), 4.65(d, J= 11 Hz, 1H), 3.9-3.05(m, 8H(, 3.7(s, 3H), 3.6(s,3H(, 2.9-2.6(m, 4H(, 2.5-2.35(m, 2H), 1.75-1.45(m, 2H), 1.2(t, J=7 Hz, 3H), 1.1(t, J=7 Hz, 3H).

Example 6. /3R*, 4R*, 5S*, 6S*/-N, N-Diethyl-5- /2-methoxybenzylamine/6-diphenylmethyl-1-azabicyclo [2.2.2]Octan-3-carboxamide (18)

The connection 18 receive in accordance with the production method of compound 17 (NaBH4used for recovery of the crude imine). The stereochemistry of 18 determined according to the1H-NMR and H-H COSY NMR. So pl. 121.2 - 122.6oC.

IR(KBr): 3325, 2980 6.3(d, J=7 Hz, 1H), 4.6(d, J=12 Hz, 1H), 3.9-3.1(m, 8H), 3.6(s, 3H), 2.8-2.65(m, 4H), 2.5-2.3(m, 2H), 1.8-1.4(m, 2H), 1.2(t, J=7 Hz, 3H), 1.1(t, J=7 Hz, 3H).

Example 7. /3R*4S*, 5R*, 6R*/-N, N-Diethyl-5- /2.5-dimethoxyphenethylamine/-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamide (19)

A mixture of 17 (506 mg, 0.93 mmole) and 20% MeONa (MeOH( (140 ml) was heated to boiling under reflux in nitrogen atmosphere for 3 hours After cooling, the reaction mixture obtained white suspension was poured into crushed ice and extracted with CH2Cl2(80 ml x 3). The combined organic layers washed with brine, dried over MgSO4and concentrate. The resulting crude solid is cleaned chromatography on silica gel (CH2Cl2:MeOH 10:1) to give 19 (0.46 g, 0.8 mmole, 92%).

So pl. 168.2 167.8oC.

IR(KBr): 2980, 2940, 2800, 1632, 1503, 1463, 1451, 1431, 1268, 1048 cm-1.

Example 8. /2R*, 3R*, 5S*/-5-/N, N-diethylaminomethyl/-3-(2,5-dimethoxyphenethylamine/-2-diphenylmethyl-1-azabicyclo[2.2.2]octane (20)

A solution of 19 (300 mg, 0.55 mmole) in dry THF (2 ml) are added to a suspension of LiAIH4(105 mg, 2.75 mmole) in 4 ml of dry THF at 5oC and stirred at room temperature for 1 h Na2SO4/10 H2O (2 g) is added to the reaction mixtures is whim THF. The filtrate is concentrated under reduced pressure. The oil obtained is dissolved in 2 ml of acetone and add CH3SO3H (159 mg, 1.65 mmole) to a solution of crude oil in acetone (2 ml). The resulting precipitate is collected by filtration and dried in vacuum to obtain 20 (254 mg, 0.31 mmole, 57%).

So pl. 239.7 242.2oC (decomposition).

IR(KBr): 3455, 2980, 2950, 1504, 1466, 1227, 1203, 1196, 1059, 1051, 1044 cm1.

Schematic examples 5-8, see Fig. 6-8.

Example 9. A. /3R*, 4R*/-N, N-Diethyl-6-diphenylmethyl-5.5 - Ethylenedioxy-1-azabicyclo[2.2.2]Octan-3-carboxamide (21)

A mixture of (3R*, 4R*)(-N,N-diethyl-6-diphenylmethyl-5-oxo-1-azabicyclo-[2.2.2] octane-3-carboxamide (10 g, 26 mmol), 1,2-bis(trimethylsiloxy/ethane) 6 g, 29 mmol), trimethylsilylacetamide (20 ml) and ether (50 ml) is heated at 100oC for 3 hours After removal of by-products by distillation (93oC atmospheric pressure), the mixture was poured into a cold aqueous solution of bicarbonate (NaHCO3) (250 ml) and extracted with methylene chloride (CH2Cl2) (100 ml) three times. The combined extracts dried over sodium sulfate (Na2SO4) and concentrate. The crude product was cleaned by recrystallization from a mixture of atrocent (EtOAc) (hexane to obtain 21) 1:2 mixture , the Ara Ph2CHCH another isomer)MS(D1-E1):M/z=434 (M+).

B. (3R*4S*)-N, N-Diethyl-6-diphenylmethyl-5,5-Ethylenedioxy-1-azabicyclo[2.2.2]Octan-3-carboxamide (22).

A suspension of 21 (9.8 g, 22 mmol) in sodium methoxide (28% in MeOH, 400 g) is heated at the boil under reflux for 9 hours the resulting solution was poured onto ice (300 ml) and extracted (CH2Cl2) 150 ml three times. The combined extracts dried over sodium sulfate (Na2SO4) and concentrate. The crude product is purified by recrystallization from ethanol (EtOH) to give 22 (1:4 mixture of 6-position, and 8.4 g, 19 mmol, 87%).

1H-NMR (CDCl3): 4.40(d, J=12.1 Hz, Ph2CHCH one isomer), 4.34. 3.93, (d+d, J= 12.5 Hz, pair Ph2CHCH and Ph2CHCH another isomer, MS (D1-E1(:M(z=434 (M+).

C. (3R*4S*)-N, N-Diethyl-6-diphenylmethyl-5-oxo-1 - azabicyclo[2.2.2] Octan-3-carboxamide (23)

A solution of 22 (6.5 g, 15 mmol in 6N-HCl aq. the solution (100 ml) is heated at the boil under reflux for 10 hours To the resulting solution add sodium hydroxide (NaOH( (24 g) in water (100 ml) and extracted with CH2Cl2(100 ml) 4 times. The combined extracts dried over NaSO4and concentrate. The crude product is purified by recrystallization from ethanol to obtain 23 (1:1, see the EPA), 4.47, 4.03 (d+d, J=8.4 Hz, pair Ph2CHCH and Ph2CHCH another isomer).

D. (3R*4S*, 5S*, 6S*)-N, N-Diethyl-5-(2,5-dimethoxybenzyl)-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamide (24(

A mixture of 23 (3.9 g, 10 mmol), 2,5-dimethoxyphenethylamine (1.9 g, 11 mmol) (Acta. Chem. Scand, 25, p.2629 (1971) and camphorsulfonate (120 ml) in toluene (40 ml) is heated at the boil under reflux for 8 h with removal of water and then removing the solvent. The residue is dissolved in a small amount of THF (5 ml) and this solution added to a solution of triacetoxyborohydride sodium (5.3 g, 25 mmol) in acetic acid (100 ml) at room temperature. The mixture is stirred at room temperature for 4 h and the solvent is removed. Add water (25 ml) and the mixture is neutralized NaHCO3and extracted with EtOAc three times. The crude product was cleaned by recrystallization from EtOAc to obtain 24 (2.4 g, 4.4 mmole), 44%).

So pl. 153.1-154.1oC.

IR(KBr): 1634, 1501, 1466, 1447, 1432, 1266, 1227 cm-1.

1H-NMR (CDCl3): 7.03-7.37 (m, 1H), 6.68 (DD, J=8.8 Hz, 2.5 Hz, 1H), 6.62 (d, J= 8 Hz, 1H), 6.38 (d, J=2.5 Hz, 1H), 4.51 (d, J=12.1 Hz, 1H), 3.73 (s, 3H), 3.49 (s, 3H), 3.05-3.77 (m, 9H), 2.92 (DD, J=8.1 Hz, 4.4 Hz, 1H), 2.54-2.89 (m, 3H), 2.11 (Shir. 1H), 1.70-1.79 (m, 2H), 1.15 (t, J=7.3 Hz, 3H), 1.11 (t, J=7 Hz, 3H).

Example 10. (2Rwho lo[2.2.2]octane (25(

To a suspension of sociallyengaged (80 ml, 2.1 mmole) in THF (10 ml) add 24 (220 mg, 0.41 mmole) at room temperature. The mixture is stirred at room temperature for 2 hours Add Na2SO4/10 H2O (320 mg, 1 mmol) and the mixture is then stirred for 10 minutes After removal of the sludge solution concentrate. The residue is dissolved in hexane (20 ml), then filtered and concentrated to obtain 25 (210 mg, 0.39 mmole, 95%) as a colourless oil.

IR(KBr): 3430, 2935, 1499, 1467, 1459, 1450, 1226, 1050, 702 cm-1< / BR>
1H-NMR (CDCl3): 7.03-7.41 (m, 1H), 6.68 (DD, J=8.8, 3.0 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.43 (d, J=2.8 Hz, 1H), 4.47 (d, J=12.1 Hz, 1H), 3.74 (s, 3H), 3.68 (DD, J=12.7, 7.9 Hz, 1H), 3.58 (d, J=13.2 Hz, 1H), 3.51 (s, 3H), 3.23 (d, J=13.2 Hz. 1H), 3.10-3.25 (m, 1H), 2.85-2.95 (m, 2H), 2.35-2.60 (m, 7H), 2.29 (DD, J= 13.2, 2.5 Hz, 1H), 2.12 (Shir. 1H), 1.70-1.90 (m, 2H), 1.26-1.43 (m, 1H), 1.01 (t, J=7.1 Hz, 6H).

Schematic examples 9-10, see Fig. 9-10.

The compounds of examples 11 and 12 receive in a manner analogous to the method of obtaining the compounds of example 2 and example 3 and purified using chromatography, preparative thin-layer chromatography and recrystallization their dimesylate salt from acetone.

Example 11. (2R*, 3R*4S*, 6R*)-3-(2.5-dimethoxyphenethylamine)-2-diphenylmethyl-6-pentyl-1 sabicic the RM(CDCl3): 7.37-7.01 (m, 15H), 6.69 DD, J=8.9, 2.5 Hz, IH), 6,63 (d, J= 8.9 Hz, IH), 6.42(d, J=2.5 Hz, IH), 4.50(d, J=12.4 Hz, IH), 3.74 (C. 3H), 3.70( DD, J=12.4, 7.9 Hz, IH), 3.57-3.52(m, IH), 3,52 (c. 3H),3.31-3.21 (m, IH), 3.23(d, J=13 Hz, IH), 2.91 2.90(m, 2H), 2.48(m, IH), 2.32(m, 2H), 2.12 1.97(m, 2H), 1.59-1.30 (m, 4H), 0.81(m, IH).

Example 12. (2R*, 3R*, 4R*, 6S*)-3-(2.5-dimethoxyphenethylamine)-2-diphenylmethyl-6-phenethyl-1-azabicyclo [2.2.2] Octan dimesylate

So pl. 207.5-212.0oC.

IR(Nujol): 1502, 1163, 1039 cm-1.

-1H-Yarm (CDCl3): 7.34-7.06(m, 13H), 6.72-6.53(m, 4H(, 6,37(d, J=2.8 Hz, IH), 4.61(d, J= 11.8 Hz, IH), of 3.73(c, 3H), 3,53(d, J=13.2 Hz, IH), 3,49(c, 3H), 3.43 points(m, IH), 3.20(d, J=13.2 Hz, IH), 3.12(m, IH), 2.89(m, IH), to 2.67(m, IH), 2.50-2.26(m, 3H), 2.03(Shir. s, IH), of 1.88(m, 2H), 1,65 was 1.43(m, 2H), 1.20-1.05(m, 2H).

Schematic examples 11-12, see Fig. 11.

Example 13. (2R*4S*, 5S*, 6S*)-N, N-dimethyl-5-(2,5 dimethoxybenzyl)amino-6-diphenylmethyl-1-azabicyclo [2.2.2]Octan-2-carboxamide (35).

A. 4-methoxycarbonyl-pyridine-2-carboxylic acid (26)

The connection 26 to receive in accordance with the method proposed in J. de Pharmacie de bel Gique, 1969, 24,3-21.

B. Methyl-2-dimethylcarbamoyl-pyridine-4-carboxylate (28)

A mixture of compound 26 (73 g, 0.4 mole) and thionyl chloride (88 ml, 1.2 mol) in toluene (200 ml) heated to boiling under reflux for 3 hours ZAT is our purification. The solution of acid chloride 27 in CH2CI2(100 ml) are added to a suspension of dimethylaminohydrolase (98.6 g, 1.2 mol) and triethylamine (1.3 mole in CH2CI2(200 ml) at 0oC dropwise over 10 min and stirred for 1 h at room temperature. To the reaction mixture are added water (200 ml), the aqueous layer was extracted with CH2CI2. The combined organic layers washed with IN NaOH solution, brine, dried over MgSO4and concentrate. The crude solid is cleaned chromatography on a short column of silica gel (EtOAc used as eluent) and get a connection 28 (47 g, 226 mmol, 56%),

IH-Yarm (CDCl3): 8.74(DD, J=5.1 Hz, IH), 8.19(m, IH), 7.90(DD, J=5.2 Hz, IH), 3.97(c. 3H), 3.16(c, 3H), 3.08(c, 3H).

C. Methyl-2-dimethylcarbamoyl-1-(methoxycarbonylmethyl(piperidine( 4-carboxylate (29(

A mixture of compound 28 (55.4 g, 0.27 mmole), conc. HCL (16 ml) in MeOH (62 ml) is subjected to hydrogenation on platinum oxide (1 g) at a pressure of 8 kg/cm2within 24 hours the Catalyst was removed by filtration. The filtrate is concentrated under reduced pressure and the resulting oil is used without further purification. A mixture of crude intermediate hydrochloride, methylpropanoate (61 g, 0.4 mole) and K2CO3(73.5 g, 0.53 mol) in toluene (200 ml) EtOAc (200 ml). The combined organic extracts dried over MgSO4and concentrate. Crude oil is cleaned chromatography on silica gel using EtOAc as eluent, and receive 29 (69.8 g, 0.26 mol, 97%).

IR (pure substance) (cm-1): 3455, 2955, 1735, 1726, 1648, 1636, 1498, 1435, 1249, 1205, 1198, 1169, 1138, 1094.

D. (2R*4S*)-2-benzylidene-6-dimethylcarbamoyl-3-oxo-1-azabicyclo [2.2.2] octane and (2R*4S*)-2-benzylidene-6-dimethylcarbamoyl-3-oxo-1-azabicyclo [2.2.2]octane (32) and (33).

A solution of 29 (30 g, III mmole) in toluene (150 ml) is added dropwise over 0.5 h to a solution of t-butoxide potassium (37.4 g, 333 mmole in toluene (400 ml) at 110oC in nitrogen atmosphere. The mixture is heated at the boil under reflux for 0.5 h and cooled to room temperature. After evaporation of the solvent, water is added (200 ml) to the residue and adjusted the pH of the mixture to 7 with concentrated HCL and concentrated. The brown residue is cleaned chromatography on silica gel (EtOAc:MeOH 10:1 as eluent( and get a brown oil (11.9 g). A mixture of the obtained crude oil, brine (1 ml) in DMCO (10 ml) is heated at 100oC for 1.5 h and concentrated under reduced pressure. A mixture of the residue, benzaldehyde (11.8 g, 111 mmol) in EtOH (30 ml) is heated under cheroot CH2CI2(50 ml). The combined organic extracts dried over MgSO4and concentrate. Crude oil is cleaned chromatography on silica gel (EtOAc: hexane 1:1 as eluent) and get a connection 32 (7.65 g, 26.9 mmole, 24.2% and 33)200 mg, 0.7 mmole 0.6%).

Data connections 32:

1H-NMR (CDCl3):7.82-7.79(m, 2H), 7.37-7.29(m, 3H), 7.11(s, 1H), 3.91(DD, J= 10.6 Hz, 1H), 3.33-3.07(m, 2H), 3.03(s, 3H), 2,96-2.81(m, 1H), 2.72-2.68(m, 1H), 2.45(s, 3H), 2.11-2.04(m, 2H), 1.93-1.84(m, 1H).

13C-NMR (CDCl3): 204.2, 169.1, 141.1, 133.5, 131.4, 129.2, 127.8, 56.8, 47.8, 39.6, 35.3, 25.8, 25.4.

These compounds 33:

1H-NMR (CDCl3): 7.97-7.93(m, 2H), 7.42-7.34(m, 3H), 7.08(1H), 3.83-3.76(m, 1H), 3.31-3.20(m, 1H), 3.02-2.90(m, 2H), 3.02(s, 3H),2.97(s, 3H), 2.73-2.69(m, 1H), 2.21-2.11(m, 1H), 1.98-1.88(m, 2H).

13C-NMR (CDCl3): 205.3, 168.9, 143.7, 132.9, 131.6, 129.4, 128.0, 124.6, 56.4, 42.4, 40.1, 37.3, 35.8, 25.8, 25.0.

E.(2R*4S*, 6S*)-N,N-dimethyl-5-oxo-6 - diphenylmethyl-1-azabicyclo[2.2.2] Octan-2-carboxamide (34)

The connection 34 to receive in accordance with the same method as the compound (3R*, 4R*, 6R*)-N, N-diethyl-5 - oxo-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamide (15).

IR(KBR): 1723, 1644 cm-1.

1H-NMR (CDCl3):7.29-7.07(m, 10H), 4.29(d, J=10 Hz, 1H), 4.18(d, J=10 Hz, 1H), 3.59(m, 1H), 3.01-2.81(m, 2H), 2,97(s, 3H), 2.66-2.46(m, 2H), 36.4, 36.1, 28.9, 24.2.

F. (2R*4S*, 5S*, 6S*)-N,N-dimethyl - 5-(2.5-dimethoxybenzil(amino-6-diphenyl-methyl-1-azabicyclo[2.2.2]Octan-2-carboxamide (35(

A mixture of compound 34 (2.22 g, 6.13 mmole) of 2,5-dimethoxyphenethylamine (1.23 g of 7.36 mmole) and CSA (camphorsulfonate) (20 mg) in toluene (50 ml) heated to boiling under reflux for 24 h with water trap Dean-stark. The solvent is removed under reduced pressure. Crude Imin use for the next stage without purification. A solution of crude imine in dry THF (20 mg) are added to a solution of NaBH (OAc)3(3.9 g, 18.4 mmole) and acetic acid (3 ml) in dry THF (20 ml) at 5oC and stirred at room temperature for 15 hours the pH was adjusted to 10 by addition of 1N NaOH and extracted with EtOAc (20 ml). The combined organic extracts washed with brine, dried over MgSO4and concentrate. Crude oil is cleaned chromatography on silica gel (EtOAc hexane 1:1 as eluent) and receive a colorless oil. The oil is purified by recrystallization from MeOH to obtain compound 35 in the form of colorless crystals (2.21 g, 4.3 mmole, 70%).

So pl. 171.3-174.5oC.

IR(KBR): 2940, 2875, 2835, 2800, 1644, 1504, 1463, 1450, 1307, 1225, 1049, 825, 705 cm-1.

1H-NMR (CDCL3

Example 14. (2R*4S*, 5R*, 6R*(-N, N-dimethyl - 5-(2.5-dimethoxybenzil(amino-6 - diphenylmethyl-1-azabicyclo[2.2.2]Octan-2-carboxamide (36)

Specified in the title compound 36 receives a manner analogous to the method of example 13. The connection is obtained from the other fractions of crude oil described in stage F of example 13 as a colourless oil and purified by recrystallization from MeOH to obtain colorless crystals (244 mg, 0.5 mmole, 8%).

So pl. 176.2-178.9oC.

IR(KBR): 2945, 2860, 2835, 1635, 1597, 1493, 1459, 1281, 1220, 1053, 1027, 704 cm-1< / BR>
1H-NMR (CDCL3): 7.35-6.97(m, 10H), 6.70-6.61(m, 3H), 4.30(d, J=13 Hz, 1H), 3.85-3.67(m, 1H), 3.76 (s, 3H), 3.71(s, 3H), 3.52(d, J=14 Hz, 1H), 3.32(DD. J= 11.5 Hz, 1H), 3.25(d, J=14 Hz, 1H), 3.05-2.98(m, 1H), 2.76-2.61(m, 3H), 2.75(s, 3H), 2.15(c, 3H), 2.14(Shir.c, 1H), 1.66-1.50(m, 2H), 1.25-1.11(m, 3H).

Schematic examples 13 and 14, see Fig.12-14.

Example 15. (2R*, 4R*, 5R*, 6R*)-2-N,N-dimethyl - 5-(2.5-dimethoxybenzyl)amino-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-2-carboxamide (39)

A. (2R*, 4R*, 6S*)-N, N-dimethyl-5-oxo-6 - diphenylmethyl-1-azabicyclo[2.2.2]Octan-2-carboxamide and (2R*, 4R*, 6S*) and N,N-dimethyl-5-oxo-6 - diphenylmethyl-1-is written to obtain (3R*, 4R*, 6R*)-N,N-diethyl-5-oxo-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-2-carboxamide (15).

IR(KBR): 2935, 1733, 1726, 1634, 1493, 1452 cm-1.

B. (2R*, 4R*, 5R*, 6R*)-2-N,N-dimethyl - 5-(2.5-dimethoxybenzil(amino-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-2-carboxamide (39(

Specified in the title compound (39( receive 22% yield and isolated in the form dihydrochloride salt (2HCl).

So pl. 224.6-228.0oC (decomp.) (2HCl salt).

IR(KBR): 3435, 3175, 2960, 2925, 1663, 1575, 1510, 1235, 1040, 715 cm-1(2HCl salt).

1H-NMR(CDCl3freeform): 7.35-6.97(m, 10H), 6.67(DD, J=9,3 Hz, 1H), 6.60(d, J=9 Hz, 1H), 6.39(d, J=3 Hz, 1H), 4.52(d, J=12 Hz, 1H), 3.72(c, 3H), 3.57-3.50(m, 2H), 3.46(c, 3H), 3.36(Shir.D. J=8.4 Hz, 1H), 3.24(d, J=13 Hz, 1H), 3.19-3.30(m, 1H), 2.96(DD, J=8.4 Hz, 1H), 2.78(c, 3H), 2.67-2.59(m, 1H), 2.30-2.21(m, 1H), 2.17(c, 3H), 1.81-1.72(m, 1H), 1.45-1.36(m, 2H).

Example 16 (2R*, 4R*, 5S*, 6S*(-2-N, N-dimethyl - 5-(2.5-dimethoxybenzil(amino-6-diphenylmethyl(-1-azabicyclo[2.2.2]Octan-2-carboxamide (40)

Specified in the title compound (40) is obtained in yield of 7% in the manner described above to obtain compound (39).

IR(pure substance) (free form): 2940, 1634, 1495. 1226 cm-11H-NMR(CDCl3) (free form): 7.37-7.01(m, 10H), 6.72-6.64(m, 2H), 6.39(d, J=2 Hz, 1H), 4.52(d, J=12 Hz, 1, H), 2.84-2.72(m, 3H), 2.77(c, 3H), 2.39(c, 3H), 2.29-2.12(m, 2H), 1.78-1.71(m, 2H), 1.55-1.43(m, 1H).

Example 17. (2R*, 3R*, 4R*, 6S*)-3-(2.5 - dimethoxybenzil(amino-2 - diphenylmethyl-6-hydroxymethyl-1-azabicyclo[2.2.2]octane (41)

In the suspension sociallyengaged (LiAlH4) (92 mg, 2.4 mmole) in dry THF (10 ml) at 0oC add a solution of compound 35 (417 ml, 0.8 mmole) in dry THF (10 ml) and heated to boiling under reflux for 1 hour Add Na2SO4/10 H2O to the reaction mixture and stirred for 30 minutes After cooling, remove the solids by filtration and washed with THF. The filtrate is evaporated, add the excess 10% HCl(MeO and concentrate. The oil obtained is cleaned by recrystallization from MeOH-ether. White crystals are collected by filtration and dried in vacuum, obtaining a connection 41 2HCl (240 mg, 0.44 mmole, 55%).

So pl. 206.2-207.9oC (2HCl salt).

IR(KBR): 3490, 3430, 3210, 3130, 1505, 1450, 1229, 1047, 1040, 748, 710 cm-1(2HCl salt)

1H-NMR(CDCl3) (free form): 7.33-7.05(m, 10H), 6.67(DD, J=9.3 Hz, 1H), 6.60(d, J=9 Hz, 1H), 6.37(d, J=3 Hz, 1H), 4.51(d, J=12 Hz, 1H), 3.72(c, 3H), 3.56-3.40(m, 3H), 3.46(c, 3H), 3.27-3.18(m, 3H), 2.89-2.75(m, 2H), 2.60-2.51(m, 1H), 2.19-2.13(m, 1H), 1.96-1.88(m, 1H), 1.72-1.62(m, 1H), 1.37-1.25(m, 1H), 0.94-0.86(m, 1H).

Schematic examples 15-17, see Fig.15-16.


A. 5-isopropyl-2-methoxybenzyl amine (44)

5-isopropyl-2-methoxybenzylidene 42 receive in accordance with the method described in Japanese patent (Koto) 501127/1983.

A mixture of the obtained compound 42 (80 g, 0.37 mol( and of sodium azide (NaN3) (28.6 g, 0.44 mol) in dimethylformamide (DMF) (200 ml) was stirred at room temperature for 15 hours, the Reaction mixture was poured into water and extracted with Et2O. United Et2O extracts washed with water and brine and dried over magnesium sulfate (MgSO4). After evaporation of the solvent, the obtained azide 43 is used without further purification. The crude azide 43 hydronaut over platinum dioxide (PtO2) (1 g) at a pressure of 2 kg/cm2within three days. The catalyst is removed by filtration on calicovon filter, washed with MeOH. The combined filtrates are concentrated, the resulting crude amine cleaned vacuumed so Kip. 93-98oC 0.2 MND( and receive a colorless oil 44 (21.6 g, 0.12 mol, 33%).

These compounds 43 (azide):

IR (pure substance): 2105 cm-1.

1H-NMR (270 MHz, CDCl3): 7.18(DD, J=8.2 Hz, 1H), 7.15(d, J=2 Hz, 1H), 7.10(d, J= 8 Hz, 1H), 4.34(c, 2H), 3.84(c, 3H), 2.87(Hep, J=7 Hz, 1H), 2.22(d, J=7 Hz, 6H).

Data connection 44 (Amin):

IR (pure substance): 2960, 1498, 145 is C, 1H), 1.22(d, J=7 Hz, 6H).

B. (2R*4S*, 5S*, 6S*(-N,N-dimethyl - 5-(5-isopropyl-2-methoxybenzyl( amino-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-2-carboxamide (45)

The connection 45 receive the same manner as the connection 35. The connection 45 is isolated in the form of the dihydrochloride playdates salt.

So pl. 168.9-174.6oC (with decomposition).

IR(KBR(: 3410, 3190, 2965, 1656, 1505, 1454, 1257, 1029, 710 cm-1.

1H-NMR(CDCl3): (freeform): 7.31-6.98(m, 11H), 6.64-6.59 (m, 2H), 4.41(Shir. d, J=12 Hz, 1H), 3.36-3.18(m, 5H(, 3.49(c, 3H), 3.00-2.95(m, 1H), 2.80-2.69(c, 1H), 2.73(c, 3H), 2.60-2.51(m, 1H),2.40-2.35(m, 1H), 2.22(W, c, 1H), 2.15(c, 3H), 2.00-1.89(m, 1H), 1,60-1.50(m, 1H), 1.30-1.18(m, 7H).

Scheme to example 18, see Fig.17.

Example 19. (3R*4S*, 5S*, 6S*)-N,N-dimethyl-5-(2.5-dimethoxyphenethylamine)-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamide (49)

A. (3R*4S*)-6-diphenylmethyl-5-oxo-1 - azabicyclo[2.2.2]octane-3-carboxylic acid hydrochloride (46)

A solution of (3R*4S*)-N, N-diethyl-6-diphenylmethyl-5-Ethylenedioxy-1-azabicyclo[2.2.2] Octan-3-carboxamide (5.2 g, 12 mmol) in 6N-HCl (150 mg) is heated at the boil under reflux for 18 hours the precipitate is collected and dried, yielding 46 (1.7 g, 4.6 mmole), 38% 46: (3R*, 4R*), isomer Ph 2CHCH and Ph 2CHCH.

B. (3R*4S*) N,N-dimethyl-6-diphenylmethyl-5-oxo-1-azabicyclo[2.2.2]Octan-3-carbonamide (47)

Suspension 46 (2.1 g, 6.6 mmole) and dimethylamine hydrochloride (0.65 g, 8.80 mmole) in DMF (30 ml) is treated with triethylamine (1.3 g, 13 mmol) at room temperature. To this suspension add diethylthiophosphate (1.2 g, 7.3 mmole) followed by the addition of triethylamine (0.67 g, 6.7 mmole) at room temperature. The mixture is stirred at room temperature for 5 h, poured into an aqueous solution of NaHCO3(50 ml) and extracted with EtOAc three times. The combined extracts dried over Na2SO4and concentrate. This mixture cleans chromatography on a column of silica gel (hexane:EtOAc 1:4) and get 47 in the form of a single isomer in the 3-position (1.4 g, 3.9 mmole, 60%).

1H-NMR(CDCL3): 4.49, 4.02(d+d, J=8 Hz; a pair of Ph2CHCH and Ph2CHCH one isomer), 4.66, 3.96 (d+d, J= 8 Hz, couple, Ph2CHCH and Ph2CHCH another isomer).

A mixture of 47 (3.9 g, 10 mmol), 2.5 dimethoxyphenethylamine (1.9 g, 11 mmol), camphorsulfonate (120 mg) in toluene (40 ml) is heated at the boil under reflux with removal of water for 8 h and then remove the solvent. The residue is dissolved in a small amount of THF (5 ml) and this solution added to a solution triacetoxy atoi temperature for 4 h and the solvent is removed. Add water (25 ml) and the mixture is neutralized with sodium bicarbonate (NaHCO3) and extracted with ethyl acetate (EtOAc) three times. The combined extracts dried over sodium sulfate (Na2SO4) and concentrate. The crude product was cleaned by recrystallization from EtOAc, receiving 49(2.4 g, 4.4 mmole, 44%).

C. (3R*4S*, 5S*, 6S*)-N,N-dimethyl-5-(2.5-dimethoxyphenethylamine)-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamide (49(

So pl. 142.0-142.9oC.

IR(KBR): 1637, 1499 cm-1.

1H-NMR(CDCl3): 7.03-7.37(m, 10H), 6.69(DD. J=8.8,2.5 Hz, 1H), 6.64(d, J= 8.8 Hz, 1H), 6.39(d, J=2.5 Hz, 1H), 4.51(d, J=12.1 Hz, 1H), 3.73(c, 3H), 3.49(c, 3H), 3.05-3.82(m, 9H), 2.96(c, 6H), 2.62-2.95(m, 4H), 2.17(Shir. 1H), 1.62-1.77(m, 2H).

Example 20. (3R*4S*, 5S*, 6S*)5-(2.5 - dimethoxyphenethylamine)-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamide (50)

A. (3R*4S*)dimethyl-6-diphenylmethyl-5-oxo-1 - azabicyclo[2.2.2]Octan-3-carboxamide (48)

Suspension 47 (1.1 g, 3.3 mmole) in THF (10 ml) is treated with triethylamine (0.66 g, 6.6 mmole) at room temperature. To this suspension add ethylchloride (0.36 g, 3.3 mmole) at 0oC. After 30 minutes, add an aqueous solution of NH3(0.67 g, 6.7 mmole) at 0oC. the Mixture is stirred at room temperature in the center, receiving 48 (1.2 g: 3.0 mmole, 90% 4:1 mixture of isomers (3-position). This product is used without further purification.

H1NMR(CDCl3): 4.43, 3.98 (d+d, J=9 Hz; a pair of Ph 2CHCH and Ph 2CHCH one isomer), 4.51, 4.28 (d+d, J=8 Hz, a pair of Ph 2CHCH and Ph 2CHCH another isomer).

B. (3R*4S*, 5S*, 6S*)-5-(2.5 - dimethoxyphenethylamine(-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamide (50)

A mixture of 48 (1.2 g, 3 mmole) of 2,5 - dimethoxyphenethylamine (0.6 g, 3.3 mmole), camphorsulfonate (45 mg) in toluene (15 ml) are heated at boiling under reflux, removing water for 3 h, and then remove the solvent. The residue is dissolved in a small amount of THF (3 ml) and this solution added to a solution of aracelisbritt sodium (1.7 g, 8 mmol( in acetic acid (40 ml) at room temperature. The mixture is stirred at room temperature for 3 h and the solvent is removed. Water is added and the mixture is neutralized NaHCO3and extracted with EtOAc three times. The combined extracts dried over Na2SO4and concentrate. Recrystallization from MeOH acetone gives a byproduct. The mother liquor is concentrated and the residue is cleaned by recrystallization from MeOH(EtOAc, receiving 50 (0.7 g, of 0.56 mmole, 19%).

T. pl. 127-129oC.

H), 6,36(d, J=2.5 Hz, 1H), 4,47(d, J=12.1 Hz, 1H), 3.74(s, 3H), 3.53(s, 3H), 3.48-3.75(m, 3H), 2.95-3.26(m, 6H(, 2.11(Shir. 1H), 2.59-2.62(m, 1H), 2.37-2.50(m, 2H), 1.76-1.89(m, 1H).

Schematic examples 19-20, see Fig. 18-19.

Example 21. (3R*4S*, 5S*, 6S*)-5-(2.5 - dimethoxyphenethylamine)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid hydrochloride (51)

A solution of compound 50 (100 mg, 0.2 mmole) in concentrated HCI (2 ml) is refluxed for 15 hours After cooling to room temperature, the mixture is alkalinized with an aqueous solution of NH3and extracted with CH2Cl2twice. The combined extracts are dried and concentrated. Add 10% HCl-MEOH and evaporated. The precipitate is recrystallized from MeOH-ether, receiving 51(30 mg, 0.054 mmole, 27%).

T. pl. 230oC.

IR (KBr): 2945, 1726, 1503, 1451 cm-1.

H1H-NMR (free base, CDCl3): 6.95-7.32(m, 1OH), of 6.65(DD, J=8.8, 2.5 Hz, 1H), 6.61(d, J=8.8 Hz, 1H), of 6.49(d, J=2.5 Hz, 1H), to 4.41(d, J=12.1 Hz, 1H), 3.68(s, 3H), 3.53(s, 3H), 2.70-3.70(m, (m, 7H), 2.31-2.60(m, 3H), 1.67-1.85(m, 1H), 1.33-1.49(m, 1H).

Scheme to example 21, see Fig. 20.

Example 22. B. (3R*4S*, 5S*, 6S*)- N,N - diethyl-5-(5-isopropyl-2-methoxybenzylamine)-6 - diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-carboxamide (52)

Indicated which measures 9), and isolated in the form of cleaners containing hydrochloride salt.

IR (free amine, KBr): 3450, 1633, 1499, 1443, 1248, 700 cm-1.

1H-NMR(free amine, CDCl3): 7.37-7.04(m, 1OH), 7.01(DD, J=2.8, 6.7 Hz, 1H), 6.65(d, J=6.7 Hz, 1H), 6.60(d, J=2,8 Hz, 1H), 4.52(d, J=12.1 Hz, 1H), 3.70-3.50(m, 4H(, 3.53(s, 3H), 3.38-3.07(m, 5H(, 2.96(DD, J= 4.2, 7.9 Hz, 1H), 2.90-2.56(m, 4H(, 2.17(Shir. s, 1H), 1.84-1.73 m, 2H), 1.20(d, J= 7.3 Hz, 6H), 1.17(t, J=7.0 Hz, 3H), 1.11(t, J=7.0 Hz, 3H).

Scheme to example 22, see Fig. 21.

Example 23. CIS-4-allyl-3N-(2,5-dimethoxybenzyl(amino-2-diphenylmethyl-1-azabicyclo [2.2.2]octane(61)

A. Ethyl N-BOC-isonipecotic (54(

Ethyl isoperational 53 (25.83 g, 164 mmole), dissolved in 25 ml of THF, is slowly added to a solution of di-tert-butyl dicarbonate (37.2, 70 mmole) at room temperature. Immediately reaction takes place and experiencing the allocation of CO2. The solvent is removed by evaporation and the residue is dispersed in a vacuum. After the above removal (80-100oC) collecting the fraction with the 12oC at 1.5 mm Hg, getting 38.3 g of ethyl N-BOC-isonicotinate 54 (161 mmole, 92%).

1H-NMR(CDCl3): 4.14 (q, J=7 Hz, 2H,4.03(Shir. D. 2H),2.83(Shir. so 2H), 2.43(TT, J= 10.9, 3.9 Hz, 1H), 1.87 (m, 2H), 1.64(m, 2H), 1.46(s, 9H), 1.26(t, J=7 Hz, 3H).

Century 4-allyl-1-azabicyclo[2.2.2]Octan-3-one(57)

Ethyl N-Boc-isonipecotate 54 (33.56, 131 mmole) dissolved in 15 ml of whom, 153 mmole) and 300 ml of THF at -60oC. the Rate of addition is controlled by maintaining the internal temperature below -60oC. After the addition the reaction mixture is heated to -25oC and then cooled to -60oC. Add allylbromide (12.4 ml, 143 mmole) to a solution of atrata (<-60C) and the mixture is heated up to -5oC. After the suppression of the reaction of acetic acid (17.6 ml) at -60oC the solvent is removed by evaporation. The residue is subjected to processing in the usual way (extraction with ethyl acetate at pH=6,0, washing with brine, drying over Na2SO4, concentration by evaporation) to give the crude product (40.13 g( ethyl N-Boc-4-allyl-isonicotinate 55.

1H-NMR(CDCl3): of 5.68(m, 1H), 5.08-5,0(m, 2H), 4.17(sq J=7.1 H,2H), 3.86(Shir. d, J= 13 Hz, 2H), 2.90(m, 2H), 2.27(d, J=7.3 Hz, 2H), 2.07(m, 2H), 1.45(s, 9H(, 1.38(m, 2H), 1.26(t, J=7.1, 3H).

The resulting crude product was diluted with 20 ml ethyl acetate and mixed with 60 ml triperoxonane acid. After 4 h reaction at room temperature the mixture is concentrated by evaporation and subsequent joint evaporation with toluene, receiving ethyl-4-allyl-isonicotinate, in the form of its salt with triperoxonane acid (TFA(

1H-NMR(CDCl3): 8.60(Shir. s, 1H)8.30(Shir. s, 1H), 5.68-5.56(m, 1H), 5.15-5.06 allyl-isonicotinate and ethylbromoacetate (23 g, 141 mmole) is dissolved in toluene. To this solution was added anhydrous K2CO3(70.7 g, 512 mmol( and the resulting suspension is heated to 80oC for 15 minutes the Reaction mixture is cooled and adjusted to pH 8.0 dilute HCl. The resulting solution was processed in the usual way (extracted by ethyl acetate, washed with brine, dried over Na2SO4concentrate by evaporation (getting 37.4 crude ethyl 4-allyl-ethoxycarbonylmethyl-isonicotinate 56.

1H-NMR(CDCl3): 5.68(m, 1H), 5.06-4.99(m, 2H), 3.22(-4.12(m, 4H(, 3.19(c, 2H), 2.83(m, 2H), 2.36-2.21(m, 4H(, 2.15(d, J=13 Hz, 2H), 1.61(m, 2H), 1.264(t, J=7 Hz, 3H), 1.256(t, J=7 Hz, 3H).

Tert-piperonyl potassium suspended (35.84 g, 320 mmol) in 100 ml of toluene and capastat under reflux. To this suspension gradually add the crude ethyl 4-allyl-N-ethoxy carbonylmethyl 56, obtained above. The reaction is quenched with 120 ml of water and the mixture is heated at 80oC during the night. Add 6N-HCL (54 ml) to the mixture, which is stirred for 15 minutes, the Reaction mixture was cooled to room temperature and adjusted to pH=8.0 dilute HCI. The resulting solution is treated in the usual way (extracted with methylene chloride at pH= 13.5, washed with brine, dried over Na2SO4the conc is SUP>o
C and 15 mm Hg, receiving 4-allyl-1-azabicyclo[2.2.2]Octan-3-one 57(15.35 g, 72% from 54).

1H-NMR(CDCl3): 5.78(m, 1H), 5.08-4.98(m, 2H), 3.26(s, 2H), 3.01(m, 4H(, 2.20(d, J=7.4 Hz, 2H), 1.95-1.65(m, 4H).

13C-NMR(CDCI3(: 218.4, 133.6, 117,1, 62.0, 47.0, 37.2, 29.4.

C. 4-allyl-2-diphenylmethyl-1-azabicyclo[2.2.2]Octan-2-he (58(

4-allyl-1-azabicyclo[2.2.2]Octan-3-one (57( (17.66 g, 107 mmol(, benzaldehyde (12.49 g, 117 mmol( and sodium hydroxide (0.46 g, 11.5 mmol( dissolved in 80 ml of ethanol and the mixture refluxed for 1 h Then the mixture is cooled, collected yellow solid substance, receiving 4-allyl-2-benzylidene-1-azabicyclo[2.2.2]Octan-3-one (26.66 g, 98%).

1H-NMR(CDCl3): 8.04-8.01(m, 2H), 7.40-7.32(m, 3H), 7.03(s, 1H), 5.87(m, IH), 5.08-5.02(m, 2H), 3.24-2.96(m, 4H), 2.32(d, J=7.4 Hz, 2H), 1.97-1.74(m, 4H).

Dimethylsulfide complex copper bromide (1( (1.06 g, 5.16 mmole) and 100 ml of toluene are placed in a reaction vessel which is immersed in a bath with a mixture of dry ice and acetone. Slowly add fenermine bromide (3.0 M in ether, 42 ml, 126 mmole) to the copper catalyst, while maintaining the internal temperature below -60oC. To this yellow-white suspension is added a solution prepared from 4-allyl-2-benzylidene-1-azabicyclo[2.2.2] Octan-3-one (25.9 g, 103 mmole), tributyltinchloride (31.4 the ing the reaction mixture is heated until the 0oC. the Reaction cut of 14.5 ml of acetic acid at -60oC. Water is added to the reaction mixture, which neutralize Na2CO3(pH= 6.2. The resulting solution was processed in the usual way (extracted with ether at pH=6.5 and then at pH=8.0, washed with brine, dried over Na2SO4concentrate by evaporation) to give the crude product, which was triturated with ether to obtain 4-allyl-2-diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-one 58 (23.04 g, 68%).

1H-NMR(CDCl3): 7.39-7.15(m, 1OH(, 5.72 (m, 1H(, 5.04-4.95(m, 2H), 4.47(d, J=8.4 Hz, 1H), 3.96(d, J=8.4 Hz, 1H), 3.11(m, 2H), 2.65(m, 2H), 1.16(m, 2H), 1,94-1,6(m, 4H).

13C-NMR(CDCl3): 219.3, 143.1, 142,2, 134.3, 128.3, 126.5, 126.4, 117.5,72.3, 50.6, 50.0, 44.0, 42.4, 37.9, 31.1, 29.9.

4-allyl-2-diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-one 58( (4.00 g, 12.1 mmole) and ammonium salt of formic acid (8.00 g, 127 mmole) is dissolved in 24 ml of formamide, the resulting solution was heated at 170oC (bath temperature( within 5 hours the Solvent is removed in vacuo and water is added to the precipitate. The obtained solid is purified by recrystallization from methanol, the resulting mixture (about 1:1( CIS - and TRANS-4-allyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octane, 59 (2.03 g, 70%).

1H-NMR(CDCl3): 6.69(l, J= 11.4 Hz, 4H), 6.52(d, J=11.7 Hz, 7H) MS: 360 (F, 319).

2CO3aq. solution. The resulting solution is treated in the usual way (extracted with methylene chloride, dried over Na2SO4concentrate by evaporation) to give a mixture of CIS - and TRANS-isomers of 4-allyl-2-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-amine 60 (1.95 g). MS: 332(F(, 291, 166.

E. CIS-4-allyl-3N-(2.5-dimethoxybenzyl)amino-2-diphenylmethyl-1-azabicyclo [2.2.2]octane(61(

The result of the above crude amine 60 and 2,5-dimethoxybenzaldehyde (1.19 g, 6.99 mmol) dissolved in methanol. Add a trace of bromocresol green and laborgerate sodium (380 mg, 6.05 mmole) and the pH of the reaction mixture was adjusted to acidic with acetic acid. After reaction overnight, the reaction mixture was alkalinized Na2CO3aq. solution and treated in the usual way (extracted with CH2CI2, washed with brine, dried over Na2SO4concentrate by evaporation, receiving the mixture, which is purified by chromatography on a column (silica gel, 0-10% MeOH(CH2Cl2), getting partially separated fractions Cys (61) and TRANS (62) isomers. Recrystallization fractions from methanol enriches the more polar isomer, giving pure CIS isomer 61 (280 mg). Less polar isomer 62 turn tx2">

T. pl. 163.7-164.8oC.

IR (Nujol): 1394, 1498, 1029 cm-1.

1H-NMR (CDCl3): 7.40-7.02(m, 1OH), 6,70(m, 2H), 6.40(Shir.with. 1H), 5.77(m, 1H), 5,04-4.97(m, 4,59(d, J= 11.9 Hz, 1H), 3.77-3.68(m, 7H), including 3.77(s, 3H), 3.72(s, 3H) and 3.34(d, J=11.4 Hz, 1H), 2.98(m, 1H), 2.88-2.56(m, 4H), 2.25-2.05(m, 3H), 1.57-1.40(m, 3H), 1.25(m, 1H).

Example 24. TRANS-4-allyl-3N-(2.5-dimethoxybenzil(amino-2-diphenylmethyl-1-azabicyclo [2.2.2]octane(62)

Specified in the title compound 62 receive, as described in example 23 E above.

So pl. 245.0-246.1oC.

IR (Nujol): 1609, 1502, 1044 cm-1.

1H-NMR(CDCl3): 7.44-7.09(m, 1OH), of 6.71-6.63(m, 2H), 6.52(d, J=1.5 Hz, 1H), 5.76(m, 1H), of 5.05-4.94(m, 2H), 3,90(d, J=11.9 Hz, 1H), 3.75(s, 3H), 3.71(s, 3H), 3.31(DD, J= 11.9 Hz, 3.5 Hz, 1H), 3.00(d, J=12,4 Hz, 1H), 2.96-2.83(m, 3H), 2.25-2.40(m, 1H), 2.40(d, J=12.4 Hz, 1H), 2.24(Shir. C. 1H),2.17-2.02(m, 2H), 1.66-1.13(m, 4H).

Scheme examples 23-24, see Fig. 22-23.

These compounds are examples 25-33 receive in accordance with the method described in example 9.

Example 25. (3R*4S*, 5S*, 6S*)-N,N-diethyl-5-(5-ethyl-2-methoxybenzylamine)-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamid the dihydrochloride.

So pl. 190-193oC.

IR (KBr, free amine): 1609, 1502, 1044 cm-1.

1H-NMR(CDCl3free amine): 7.3 J=11.9,3,5 Hz, 1H), 3.00(d, J=12.4 Hz, 1H), 2.96-2.83(m, 3H), 2.52-2.40(m, 1H), 2.40(d, J= 12.4 Hz, 2,96-and 2.83(m, 3H), 2.52-2.40(m, 1H), 2.40(d, J=12.4 Hz, 1H), 2.24(Shir. s, 1H), 2,18-2,02(m, 2H), 1.66-1-13(m, 4H).

Example 26. (3R*4S*, 5S*, 6S*)-N,N-diethyl-5-(2-methoxy-5-methylthiophenethylamine)-6-diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-carboxamid the dihydrochloride.

So pl. 158-163oC.

IR (KBr, free amine): 3450, 1630, 1487, 1443, 1244, 1029, 813, 750,701, 699 cm-1< / BR>
1H-NMR(CDCl3free amine): 7,35? 7.04 baby mortality (m, 11H), 6,76 (d, J=2.2 Hz, 1H), 6,65 d, J=8,8 Hz, 1H), 4,50 (d, J=12.1 Hz, 1H), 3,68-to 3.52 (m, 4H), 3,50 (c, 3H), 3.33 and-a 3.06 (m, 5H), 2,90 (kV, 1H), 2,83-of 2.56 (m, 3H), 2,42(s, 3H), 2.11(Shir. s, 1H),1.80-1.65(m, 2H), 1.17(t, J=7.0 Hz, 3H), 1.11(t, J=7.0 Hz, 3H).

Example 27. (3R*4S*, 5S*, 6S*)-N,N-diethyl-5-(2-methoxy-5-triphtalocyaninine(-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamide.

So pl. 122-125oC.

IR (KBr, free amine): 3450, 1634, 1499, 1465, 1252, 1153, 1031; 752, 704, 604 cm-1< / BR>
1H-NMR(CDCl3free amine): 7.36-6.99(m, 10H), 6.66(d, J=9.2 Hz, 1H), 6.55(d, J= 2.6 Hz, 1H), 4.48(d, J=12.1 Hz, 1H), 3.60-3.47(m, 4H), 3.56(s, 3H), 3.33-3.05(m, 5H), 2.91(DD, J= 4, 7.9 Hz, 1H), 2.85-2.58 m, 3H), 2.11(Shir. s, 1H), 1.90-1.55(m, 2H), 1.15(t, J=7.1 Hz, 3H), 1.10(t, J=7.1 Hz, 3H).

Example 28. (3R*4S*, 5S*, 6S*)- N,N - diethyl-5-(5 - chloro-2-methylthiophenethylamine)-6-diphenylmethyl-1-azab): 3430, 1631, 1486, 1449, 1247, 1025, 821, 751, 701, 693 cm-1< / BR>
1H-NMR(CDCl3free amine) 7.58(d, J=6.9 Hz, 2H), 7.40-7.19(m, 7H), 7.14(DD, J= 2.5, 8.9 Hz, 1H), 6.63(d, J=8.9 Hz, 2H), 5.24(Shir. C. 1H), 4.49(d, J= 11.9 Hz, 1H), 3.85-3.06(m, 12H), 3.47(s, 3H), 2.24(Shir. s,IH), 2.15-1.90(m, 2H), 1.2 3(t, J=7.2 Hz, 3H), 1.02(t, J=7.2 Hz, 3H).

Example 29. (3R*4S*, 5S*, 6S*)- N,N - diethyl-5-(5-tert-butyl-2-methylthiophenethylamine)-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamid the dihydrochloride.

So pl. 180-183oC.

IR (KBr, free amine): 3450, 1630, 1500, 1457, 1450, 1250, 751, 702 cm-1.

1H-NMR(CDCl3free amine): 7.36-7.03(m, 10H), 6.89(d, J=2.6 Hz, 1H), 6.64(d, J= 8.8 Hz, 1H), 4.52(d, J=12.1 Hz, 1H), 3.71-3.48(m, 4H(, 3.52(s, 3H), 3.35-3.03(m, 5H), 2.98(DD, J= 4.0 Hz, 7.7 Hz, 1H), 2.91-2.60(m, 3H), 2.19(Shir. s, 1H), 1.87-1.75(m, 2H), 1.27(s, 9H), 1.16(t, J=7.3 Hz, 3H), 1.11(t, J=7.3 Hz, 3H).

Example 30. (3R*4S*, 5S*, 6S*)-5-(2-methoxy-5-methylthiophenethylamine)-6-diphenylmethyl - 1 - azabicyclo[2.2.2]octane-3-carboxylic acid dihydrochloride.

So pl. 170-175oC.

IR (KBr, free amine): 3420, 1725, 1490 cm-1< / BR>
1H-NMR(CDCl3free amine): 7.40(m, 11H), 6.75(Shir. C. 1H), 6.41(d, J= 8.4 Hz, 1H), 4.40(d, J=11.7 Hz, 1H), 4.05(Shir. s, 1H), 3.48(s, 3H), 3.60-3.40(m, 2H), 3.34-2.50(m, 8H), 2.38(c, 3H), 1.95 (s, 3H), 1.95-1.56(m, 2H).

Example 31. (3R*4S*, 5S*

So pl. 247oC.

IR (KBr, free amine): 3310, 1685, 1505 cm-1< / BR>
1H-NMR(CDCl3free amine): 7.35-7.00(m, 11H), 6.66(d, J= 8.4 Hz, 1H), 6.57(d, J= 2.2 Hz, 1H), 5.39(Shir. C. 2H), 4.48(t, J=12.1 Hz, 1H), 3.70-3.64(m, 1H), 3.63(d, J=12.8 Hz, 1H), 3.55(s, 3H), 3.20(d, J=12,8 Hz, 1H), 3.19-2.93(m, 4H), 2.83-2.60(m, 2H), 2.49-2.42(m, 2H), 1.95-1.81(m, 1H)1.60-1.50(m, 1H), 1.20(d, J=6.6 Hz, 3H), 1.18(d, J=6.6 Hz, 3H).

Example 32. (3R*4S*, 5S*, 6S*)-5-(5-isopropyl - 2-methylthiophenethylamine)-6-diphenylmethyl-1-azabicyclo[2.2.2] octane-3-carboxylic acid dihydrochloride.

So pl. 150-155oC.

IR (KBr, Svobodny Amin): 3400, 1730, 1510 cm-1< / BR>
-1H-Yarm (CDCl3free amine): 7.36-7.00(m, IIH), 6.63(d, J=8.8 Hz, IH), to 6.57(d, J=1.8 Hz, IH), 4.47(d, j=12.4 Hz, IIH), IH), 4.00(Shir.s, IH), 3.51(c, 3H), 3.70-3.45(m, 2H), 3.40-2.40(m, 8H(, 2.00-1.55(m, 2H), 1.19(d, J=6.9 Hz, 3H)1.18(d, J=6.9 Hz, 3H).

Example 33. (3R*4S*, 6S*)-5-(methoxy-5-methylthiophenethylamine(6-diphenyl-1-azabicyclo) [2.2.2] octane-3-carboxylic acid dihydrochloride

So pl. 220-225oC.

IR(KBr): 3300, 3200, 1685, 1495 cm-1.

-1H-Yarm(CDCl3free amine): 7.34-7.06(m, 11H), 6.72(d, J=2.6 Hz, IH), 6.67(d, J=8.4 Hz, IH), 5.48(Shir.with. 2H), 4.45(d, J=12.1 Hz, IH), 3.80-3.64(m, IH), 3.62-3.50(m, 4H(, 3,28-2.95(m, 4H(, 3.28-2.95(m, 6H), 2.63-2.76(m, IH), 2.57-2.45(m, IH), 2.42(c, 3H), 1.95-1.50(m, 2H).

Example 34. (2R*, 3RID (65)

To a suspension of ketone 63 (0.30 g, 0.77 mmole) and 4-methoxybenzylamine (0.12 mg, 0.89 mmole) in dry toluene (5.0 ml) was added D-camphorsulfonate (9.2 mg, 0.04 mmole). The resulting mixture is stirred and refluxed equipped with addition funnel with molecular sieves 4 removal isotropes water. After mixing the above conditions heating overnight, the reaction mixture was concentrated in vacuo to dryness, obtaining raw Imin 64. It is dissolved in dry THF (1.0 ml) and the solution added dropwise to a stirred solution of triacetoxyborohydride sodium (0.41 g, 1.93 mmole) in acetic acid (8.0 ml) at room temperature. After stirring at room temperature for 8 h, the reaction mixture was concentrated in vacuo. The residue is alkalinized with NaOH water solution, and extracted with chloroform (CHCl3). The combined extracts CHCl3washed with saturated NaCl solution, dried (K2CO3) and concentrated in vacuo to obtain a pale yellow viscous oil (0.52 g). This connection chromatographic on silica gel (Merck Kieselgel 60, 8.0 g). Elution with a mixture of methylene chloride-MeOH (CH2Cl2-MeOH) (100:1) gives 65, accompanied by traces of the endo isomer in the form of a colorless oil, which sa is s 65 (65.5 mg, 17%) in the form of colorless prisms.

So pl. 131-133oC (isopropanol).

IR(Nujol): 3380(m), 1645(s), 1610(m), 1510(s), 1243(s), 1030(s), 810(m), 750(m), 745(m), 710(m), 690(m) cm-1.

1H-NMR(CDCl3): 7,43-to 7.15(m, 9H(, 7.15-7.04(m, IH), 6.68(d, J=8.8 Hz, 2H), 6.50(d, J=8.8 Hz, 2H), 4.43(d, J=12.21 Hz, IH), 3.78 (c, 3H), 3.77-3-62 (m, IH), 3.56(d, J=13.0 Hz, IH), 3.56-3.44(m, IH), 3.16(d, L=13.0 Hz, IH), 3.35-3.04 (m, 6H), 2.84(DD, J=4.0, 7.7.Hz, IH), 2.80-2.65(m, IH), 2.59(DD, J= 8.6, 8.6 Hz, IH), 2.08 (Shir.with. IH), 1.86-1.68(m, 2H), 1.63(Shir. s, NH, IH), 1.15(t, J=7.1 Hz, 3H), 1.11(t, J=7.1 Hz, 3H).

Scheme to example 34, see Fig. 24.

Example 35. (3R*4S*, 5S*, 6S*)-methyl-6-diphenylmethyl-5-(2-methoxy-5-methylthiophenethylamine(-1-azabicyclo (2.2.2( Okan-3-carboxylate (66)

A solution of (3R*4S*, 5S*, 6S*)-N,N-diethyl-5-(2-methoxy-5-methylthiophenethylamine)-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid (specified in the title compound of example 30, 0.40 g, 0.65 mol) in 10% HCl/MeOH (5 ml) is refluxed for 2 hours After cooling to room temperature to remove the solvent. Add an aqueous solution of NaHCO3(pH 8), the organic layer is extracted with EtOAc (70 ml) twice. The combined extracts washed with brine, dried (MgSO4) and evaporated. The remainder chromatographic on silica gel with hexane: EtOAc 3:2 as eluent, recip (Cl3free amine): 7.30-7.05 (m, 11H), 6.72 (d, J 2.2 Hz, IH), 6.65 (d, J 8.4 Hz, IH), 4.43 (d, J 12.1 Hz, IH), 3.71 (s, 3H), 3.55(s, 3H), 3.65-3.52 (m, 3H), 3.24 (d, J 13.2 Hz, IH), 3.20 2.92 (m, 4H), 2.66 2.43 (m, 3H), 2.42 (s, 3H), 1.92 1.75 (m, IH), 1.50 1.32 (m, IH).

Example 36. (3R*4S*, 5S*, 6S*)-6-diphenylmethyl-3-hydroxymethyl-5-(2-methoxy - 5-methyl-dibenzylamino(-1-azabicyclo [2.2.2] Octan the dihydrochloride (67)

To a suspension of LiAIH4(12 mg, 0.39 mmole) in ether (5 ml) is added 66(66 mg, 0.13 mmole) at 0oC, then stirred at room temperature for 1 h Add an aqueous solution of NaHCO3(2 drops) and then EtOAc (20 ml) is stirred for 15 minutes the Organic layer is separated, dried (MgSO4) and evaporated under reduced pressure. The crude product is treated with 10% HCl/MeOH, receiving 67 (43 mg, 55%).

So pl. 178 -182oC.

IR(KBR(: 3400, 1575, 1495 cm-1< / BR>
1N-Yarm (Cl3free amine): 7.34 7.07 (m, IH), 6.73(d, J 2.2 Hz, IH), 6.64 (d, J 8.4 Hz, IH), 4.45(d, J 12.1 Hz, IH), 3.54(s, 3H), 3.76 3.52 (m, 5H), 3.20(d, J 12.8 Hz, IH), 3.21 3.20(m, IH), 2.98 2.86(m, 2H), 2.60 2.47(m, IH), 2.42(s, 3H), 2.30 2.19(m, 2H), 2.00 1.72(m, 2H), 1.39 1.30(m, IH).

Example 37. (3*, 4*, 5*, 6*)-methyl-5-(2-methoxy-5-methylthiophenethylamine)-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid dihydrochloride (68)

To a solution of 66(forms 0.141 g, 0.25 m the 50oC for 2 hours the Solvent is removed, extracted with EtAc (100 ml). The organic layer was washed with brine, dried (MgSO4) and evaporated. The remainder chromatographic on silica gel, using as eluent a mixture of hexane/EtOAc 1:1, receiving 68 (28 mg, 20%).

So pl. 144-147oC.

IR(KBR): 3420, 1730, 1495 cm-1.

1H-NMR(Cl3free amine): 7.29 7.05 (m, IIH), 6.74 (d, J 2.2 Hz, IH), 6.61(d, J 8.4 Hz, IH), 4.4 (d, J 12.1 Hz, IH), 3.84(DD, J 7.3, 12.1 Hz, IH), 3.72 3.62(m, IH), 3.68(s, 3H), 3.48(s, 3H), 3.58 3.49(m, 2H), 3.31(dt, J 2.7, 13.6 Hz, IH), 3.15(d, J 13.6 Hz, IH), 2.87 2.75 (m, 2H), 2.70 2.62(m, IH), 2.62 2.48 (m, 2H), 2.41(s, 3H), 2.11 1.97 m, IH).

Schematic examples 35-37 see Fig.25.

Example 38. (2R*, 4R*, 5R*, 6R*)-dimethyl-6-diphenylmethyl-5-(methoxy-5-methylthiophenethylamine)-1-azabicyclo [2.2.2] Octan-2-carboxamid

Specified in the title compound of example 38 is treated in the same way, which is used to obtain compound 39 (15).

So pl. 156 158oC.

IR(KBR):3450, 2920, 1645, 1495 cm-1.

1N-Yarm (Cl3free amine): 7.36 6.98 (m, IIH), 6.74(d, J 2.6 Hz, IH), 6.63(d, J 8.4 Hz, IH), 4.51(d, J 12.1 Hz, IH), 3.55 D. J 13.2 Hz, IH), 3.52 3.49 (m, 3H), 3.36(d, 8.4 Hz, IH), 3.21 (d, J 13.2 Hz, IH), 3.19 3.00(m, IH), 2.97 2.92(m, IH), 2.79(c, 3H), 2.66 - 2.59(m, IH), 2.41(s, 3H), 2.20 2.1 (m, IH), 2.17(c, 3H), 1.82 1.67(m, IH), anselmino) -1-azabicyclo [2.2.2] octane-2-carboxylic acid dihydrochloride

Specified in the title compound of example 39 is treated in the same way, which is used to obtain compound 24 (9).

So pl. 162 167oC.

IR(KBR): 3430, 1740, 1495 cm-1.

1N-Yarm (Cl3): 7.36 7.25 (m, 1OH), 7.1(DD, J 2.7, 8.4 Hz, IH) 6.71(d, J 2.6 Hz, IH), 6.67(d, J 8.4 Hz, IH), 4.65 D. J 12.1 Hz, IH), 4.26 (DD, J 8.4 12.1 Hz, IH), 3.79 3.67(m, IH), 3.53 (c, 3H), 3.50 - 3.20 (s, 3H), 3.10 2.80 (m, IH), 2.70-2.57(m, 1H), 2.42 (s, 3H), 2.33 - 2.15(m, IH), 1.72 1.60(m, IH).

Named connections 40, 41 and 42 are treated in the same way, which is used to produce compounds 49 and 50 (19 and 20).

Example 40. (3R*4S*, 5S*, 6S*)-N-methoxy-N-methyl-5-(2,5-dimethoxyaniline)-6-diphenylmethyl-1-azabicyclo [2.2.2] Okan-3-carboxamide-3-carboxamid the dihydrochloride.

So pl. 174 176oC.

IR(KBR): 3415, 2945, 1658, 1504, 1454, 1436, 1391, 1232, 1041, 711 cm-1< / BR>
1H-NMR(Cl3, free base): 7.36-7.05(m, IOH), 6.67(DD, J 2.9, 8.2 IH), 6.60(D. J 8.8 Hz, IH), 6.42(d, J 2.9 Hz, IH), 4.52(d, J 12.1 Hz, IH), 3.73(s, 3H), 3.67(s, 3H), 3.47 (c, 3H), 3.20(s, 3H), 3.83 2.80(m, 8H(, 2.71-2.60(m, IH), 2.36( W, IH), 1.85 1,25(m, 2H).

Example 41. (3R*4S*, 5*, 6*)-N-ethyl-5-(2,5-dimethoxyaniline)-6-diphenylmethyl-1-azabicyclo [2.2.2] Octan-3-carboxamid the dihydrochloride.

So Cl3, free base): 7.39 7.03 (m, IOH), 6.75 6.60(m, 2H), 6.41(D. J 2.2 Hz, IH), 5.44 (Shir. IH), 4.40(d, J 12.5 Hz, IH), 3.81 3.53 (m, 2H), 3.74 (s, 3H), 3.59 (s, 3H), 3.33 2.91(m, 8H(, 2.74 2.62(m, IH), 2.22 (Shir. IH), 1.90 1.76(m, IH), 1.42 1.25(m, IH), 1.12(t, J Hz, 3H).

Example 42. (3R*4S*, 5S*, 6*)-(3-oxa-1,5-pentalen-(5-(2,5-dimethoxyaniline)6-diphenylmethyl-1-azabicyclo [2.2.2] Octan-3-carboxamide.

So pl. 164 165oC.

IR(KBr)2935, 1645, 1498, 1450, 1432, 1268, 1232, 1112, 1048, 1023, 704 cm-1.

1H-NMR (DCl3): of 7.36 7.05 (m, IOH), of 6.68(DD, J 2.9, 8,8 Hz, (IH), 6.62 d, J 8.8 Hz, IH), 6,36(d, J 2.9 Hz, IH), 4.51(d, J 12.1 Hz, IH), 3.73((s, 3H), 3.48(s, 3H), 3.80 3.00(m, 13H), 2.99(DD, J 4.1, 7.7 Hz, IH), 2.86 2.57(m, 3H), 2.08(Shir. IH), 1.83 1.34(m, 2H).

Example 43. (2R*, 4R*, 5R*, 6*)-methyl-6-diphenylmethyl-5-(2-methoxy-5-methylthiophenethylamine) -1-azabicyclo [2.2.2] Okan-2-carboxylate the dihydrochloride.

Specified in the title compound of example 43 receive the same manner as that used for compound 66 (35).

So pl. 132 136oC.

IR(KBr): 3440, 1720, 1495 cm-1.

1H-NMR(DCl3free amine): 7.34 -7.03(m, IIH), 6.74(d, J 2.6 Hz, IH), 6.65 (d, J 8.4 Hz, IH), 4.54(d, J 11.7 Hz, IH), 3,69, 3.47 (s, 3H), 3.60(s, 3H), 3.54(s, 3H), 3.20(d, J 13.2 Hz, IH), 3.12 - 2.96(m, IH), 2.90(DD, J 4.08, 8.1 Hz, IH), 2.70 2.56(m, IH), 2.42(s, 3H), 2.23 2.10 m, 2H), 1.95 oxymethyl-5-(2-methoxy-5 - methylthiophenethylamine)-1-azabicyclo [2.2.2] Octan the dihydrochloride.

Specified in the title compound of example 44 is treated with a method similar to the production method of compound 67 (36).

So pl. 148 153oC.

IR(KBr): 3420, 3200, 1495, 1250 cm-1.

1H-NMR (DCl3free amine): 7.40 6.96(m, IIH), 6.76(d, J 2.6 Hz, IH), 6.65 (d, J 8.4 Hz, IH), 4.61(d, J 12.1 Hz, IH), 3,63, 3.37 (m, 4H), 3.51(s, 3H), 3.23(d, J 13.2 IH), 3.04 2.90(m, 3H), 2.60 2.47(m, IH), 2.41(C. 3H), 2.10 1.75(m, 3H), 2.72 2.58(m, IH), 1.12 0.98(m, 2H).

Example 45. (3R*4S*, 5S*, 6S*) -N-ethyl-5-(2.5-dimethoxyphenethylamine)-6-diphenylmethyl-1-azabicyclo [2.2.2] Octan-3-carboxamid

Specified in the title compound of example 45 is treated in the same way, which is used to obtain (3R*4S*, 5S*, 6S*)-N-methoxy-N-methyl-5-(2.5-dimethoxyphenethylamine)6-diphenylmethyl-1-azabicyclo [2.2.2] Okan-3-carboxamide (41).

IR(KBR): 2490, 1645, 1498, 1463, 1451, 1228, 703 cm-1.

1H-NMR (Cl3, free base): 7.39 7.06(m, IOH), 6.80 6.65(m, 2H), 6.38(d, J 2 Hz, IH), 5.39(Shir. IH), 4.48(d, J 12 Hz, IH), 3.74(s, 3H), 3.55(s, 3H), 3.84 2.50(m, IIH), 2.22(Shir. IH), 1.86 - 1.44(m, 2H).

Example 46. (3R*4S*, 5S*, 6S*)-N-N-(3-thia-1,5-pentile(-5-(2.5-dimethoxyphenethylamine) -6-diphenylmethyl-1-azabicyclo [2.2.2] Octan-3-carboxamide.

Specified in nazvaniyj">

So pl. 185 188oC.

IR(KBR): 2930, 1645, 1497, 1450, 1429, 1285, 1264, 1230, 1218, 1204, 1184, 1046, 1023, 802, 754, 703 cm-1.

1H-NMR (Cl3): 7.36 7.04 (m, IOH), 6.70 6.59(m, 2H), 6.36(d, J 3 Hz, IH), 4.52(D. J 12 Hz, IH), 4.18(W, 2H), 3.72(s, 3H), 3.48(c, 3H), 3.87 3.43(m, 4H), 3.35 2.47(m, IIH), 2.11(Shir. IH), 1.84 - 1.54 (m, 2H).

Example 47. (3R*4S*, 5S*, 6S*)-N-N-(3-thia-1,5 - pentile(-5-(2.5-dimethoxyphenethylamine( -6-diphenylmethyl-1-azabicyclo [2.2.2] Octan-3-carboxamide-S-oxide.

A mixture of (3R*4S*, 5S*, 6S*)- N,N-(3-thia-1,5-pentile(-5-(2,5-dimethoxyaniline)-6-diphenylmethyl-1-azabicyclo[2.2.2] octane-3-carboxamide (other 46,170 mg, 0.3 mmole), NaIO4(60 mg, 0.3 mmole) and N2O (4 ml) was stirred at room temperature for 2 hours, the Mixture is alkalinized NaHCO3, extracted with CH2CI2(20 ml)2), dried and concentrated. The crude product is cleaned chromatography on a column (silica gel 5 g, CH2Cl2:MeOH=10:1) and stirred from EtOH (10 ml) to obtain specified in the title compound (70 mg, 40%).

T. pl. 235-239oC.

IR (KBr): 3445, 2930, 1642, 1500, 1468, 1450, 1428, 1227, 1180, 1046, 1013, 748, 704 cm-1.

1H-NMR (CDCl3): 7.40-7.07(m, 1OH), 6,72-6.61(m, 2H), 6.36(d, J=3 Hz, 1H), 3.74(s, 3H), 3.51(s, 3H), 4,14-3.12(m, 4H), 3.00-2.54(m, 11H), 2.11(Shir.1H), 1.85-1.56(m, 2H).

l-1-azabicyclo[2.2.2] Octan-3-carboxamide-S, S-dioxide.

A mixture of (3R*4S*, 5S*, 6S*)-N,N-(3-thia-1,5-pentile(-5-(2,5-dimethoxyaniline)-6-diphenylmethyl-1-azabicyclo[2.2.2] octane-3-carboxamide (46, 200 mg, 0.35 mmole), peroxymonosulfate potassium (620 mg, 1 mmol), Meon (3 ml) and H2O was stirred at room temperature for 5 hours, the Mixture is alkalinized NaHCO3, extracted with CH2Cl2(20 ml), dried and concentrated. The crude product is cleaned chromatography on a column (silica gel, 5 g, CH2CI2: MeOH 10: 1) and recrystallized from EtOH (50 ml), receiving specified in the title compound (190 mg, 90%).

T. pl. 252-254oC.

IR (KBr): 3435, 1648, 1500, 1317, 1283, 1229, 1192 cm-1.

1H-NMR (CDCl3): 7.40-7.70(m, 1OH), was 6.73-6.61(m, 2H), 6.32(d, J=3 Hz, 1H), 4.52(d, J= 12 Hz, 1H), 4.48-4.30(m, 2H), 3.74(s, 3H), 3.48(s, 3H), 3.90-2.55(m, 15H(, 2.02(Shir. 1H), 1.83-1.46(m, 2H).

Example 49. (3R*4S*, 5S*, 6S*)-5-1-isopropyl-2-methoxybenzylamine)-6-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-carboxamid the dihydrochloride

Optical separation of (3R*4S*(-N,N - diethyl - 5-oxo-1-azabicyclo[2.2.2] octane-3-carboxamide. (3R*4S*(-N,N-diethyl-5-oxo-1-azabicyclo[2.2.2]octane-3-carboxamide (180 g, 0.804 mol and (-(-Dibenzoyl(L-tartaric acid (L-DWT( monohydrate (211 g, 0.5 down. The solution is quickly cooled to about 40oC in a water bath and allow to remain overnight for the formation of crystals, which are collected by filtration. It was found that the obtained crystals (100, 5 g, 21.5%) (+(- (3R, 4R(-N, N - (diethyl-5-oxo-1-azabicyclo[2.2.2] Octan-3-carboxamide L-DWT salt 97% optical purity. Add a further quantity (-( L-DWT monohydrate (90,6 g, 0.241 mol( stock solution, which is concentrated to about 3.5 l by evaporation. The resulting mixture is refluxed to obtain a clear solution, which is left at room temperature. After 2 days, the resulting crystals are collected by filtration. It was found that the crystals (117 g, 25%) are (-)-(3S, 4S)-N,N-diethyl - 5-oxo-1-azabicyclo[2.2.2]Octan-3-carboxamide L-DWT salt 92% optical purity. Repeat the same process permissions based on 220 g of (3R*4S*)-N,N-diethyl-5-oxo-1-azabicyclo[2.2.2] octane-3-carboxamide. From this experience L-DWT salt (+) enantiomer (180 g, 31%) are obtained with 95% optical purity and l-DWT salt of the (-) enantiomer (91 g, 16%( get with 97% optical purity and L-DWT salt of the (-) enantiomer of the above two experiments are combined and suspended in 1.5 l of ethanol. The resulting suspension is boiled with reverse Holodny amine by treatment with a base (aqueous bicarbonate) followed by extraction with methylene chloride, receiving (-)(3S, 4S)-N,N - diethyl - 5-oxo-2-azabicyclo[2.2.2]Octan-3-carboxamide (73 g, 18%), with more than 99% optical purity. Similarly, 83 g (+) enantiomer (21%) receive more than 99% optical purity. The above-mentioned optical impurities determined using gel penetrating liquid chromatography. The absolute configuration was determined by x-ray crystallography salt Dibenzoyl-L-tartaric acid, (- ) enantiomer.

(3S, 4S)-N, N-diethyl-5-oxo-1-azabicyclo[2.2.2]-3-carboxamide (69), Dibenzoyl-L-tartaric acid salt.

So pl. 120-135oC (decomposes, so there is no clean coal-seam).

Analysis calculated: C 60,27% H 6.48% N 4.39% Found: C, 60.10% H 6.43% N 4.45%

(+)-(3S, 4S)-N, N-diethyl - 5-oxo-1-azabicyclo[2.2.2]Octan-3-carboxamide (69).

So pl. 108.6-112.1oC (ethyl acetate).

Analysis calculated: C 64,26% H 8.99% N 12.49% Found: C, 63.96% H 9.243% N 12.38%

[]D= 59oC (C=1.00 ethanol).

(3S, 4S)-N,N-diethyl-5-oxo-1-azabicyclo[2.2.2]Octan-3-carboxamide (70), Dibenzoyl-L-tartaric acid salt.

So pl. 120-135oC (decomposes, so there is no clean coal-seam).

Analysis calculated: C 60,27% H 6.48% N 4.39% Found: C, 60.10% H 6.43% N 4.45%

(+)-(3R, 4R)-N, N-diethyl-5-oxo-1-azabicyclo[2.2.2] Octan-3-carboxamide (69).

So pl. 108-112,1oC (3S, 4S(-N, N-diethyl-5-oxo-1-azabicyclo[2.2.2]Octan-3-carboxamide (70( salt dibenzoyltartaric acid.

So pl. 158.7-159.3oC (Razlog.).

Analysis calculated: C, 61.85% H 5.88% N 4.81% Found: C 61.54% H 5.91% N 4.81%

(-)-(3S, 4S)-N, N-diethyl-5-oxo-1-azabicyclo[2.2.2] Octan-3-carboxamide (70(

So pl. 108.6-11.5oC (Razlog.).

Analysis calculated: C at 64.26% H 8.99% N 12.49% Found: C, 63.90% H 9.24% N 12.33%

-58.8oC (c=1.00, ethanol).

Specified in the title compound is an optical isomer mentioned in the title compound of example 31, and it is obtained from 70 in a manner analogous to that described in examples 5, 9, 19 and 20.

So pl. 215-219oC.

IR(KBr): 3320, 3200, 1685, 1505 cm-1.

1H-NMR (270 MHz, CDCL3, M. D.): 7.35-7.00(m, 11N), 6.67(d, J=8.4 Hz, 1H), 6.57(d, J= 2.8 Hz, 1H), 5.36 (m, 2H), 4.48 (d, J=11.1 H), 3.70-3.62(m, 2H), 3.55(s, 3H), 3.26-2.90(m, 5H), 2.80-2.26(m, 2H), 2.51-2.40 (m, 2H), 1.92-1.80(m, 1H), 1.70-1.66(m, 1H), 1.21(d, J=7.0 Hz, 3H), 1.18 (d, J=7.0 Hz, 3H).

+15.5oC(c=1.00, DMSO).

Example 50. (3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxybenzylamine)-6-diphenylmethyl-1 - azabicyclo[2.2.2]octane-3-carboxylic acid dihydrochloride.

Specified in the title compound is an optical isomer mentioned in the title compound of example 32, and it is derived from specified is; 30oC.

IR(KBr): 3400, 3200, 1735, 1500 cm-1.

1H-NMR (270 MHz, CDCl3, M. D. free base): 7.40-6.98(m, 11N), 6.63(d, J= 8.8 Hz, 1H), 6.57(s, 1H), 4.45(d, J=12.4 Hz, 1H), 3.50 (s, 3H), 3.97-3.80(m, 1H), 3,64(d, J= 12.4 Hz, 1H),3.50(s, 3H), 3.97-3.80(m, 1H), 3.64(d, J= 12.4 Hz, 1H), 3.50-3.00(m, 6N), 2.90-2.50(m, 4H), 1.97-1.82(m, 1H), 1.70-1.52(m, 1H), 1.19(d, J=7.0 Hz, 3H(, 1.17(d, J=7.0 Hz, 3H).

[]2D5+9.90oC(c=1.00, E OH).

Example 51. (3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylthiophenethylamine)-6-diphenylmethyl-1 - azabicyclo[2.2.2]Octan-3-carboxamid the dihydrochloride.

Specified in the title compound is an optical isomer mentioned in the title compound of example 33, and it is obtained from 70 in a manner analogous to the method described in examples 9, 19 and 20.

So pl. 218-225oC.

IR(KBr): 3300, 3200, 1690, 1496 cm-1.

1H-NMR (270 MHz, C Cl3, M. D.): 7.33-7.10(11N, m), 6.72(1H, d, J=2.6 Hz), 6.67(d, J= 8.4 Hz, 1H), 5.76 (s, 1H), 5.42 (Shir.s, 1H), 4,46(d, J=12.1 Hz, 1H(, 3.85-3.74(m, 1H), 3.61-3.56(m, 1H), 3.55 (s, 1H), 3.28-2.98(m, 5H), 2.80-2.43(m, 3H), 1.92-1.65 (m, 2H).

+20.8oC(c=0.50, DMSO).

Example 52. (3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylthiophenethylamine)-6-diphenylmethyl-1 - azabicyclo[2.2.2]octane-3-carboxylic acid dihydrochloride.

Indicated in the name of the connection is optical isome the way, similar to that described in example 21.

So pl. 212-215oC.

IR(KBr): 3400, 3200, 1720, 1495 cm-1.

1H-NMR (270 MHz, CDCL3, M. D. free base): 7.45-7.10(m, 11N), 6.72(C. 1H), 6.65(d, J=8.8 Hz, 1H), 7.47(d, J=11.0 Hz, 1H), 3.53 (s, 3H), 3.62-2.62(m, 11N), 2.41(s, 3H), 2.04-1.90(m, 1H), 1.82-1.62(m, 1H).

+12.0oC(c=1.00, DMSO).

Example 53. (3R, 4S, 5S, 6S)-5-(2.5-dimethoxyphenethylamine)-6-diphenylmethyl-1 - azabicyclo[2.2.2]Octan-3-carboxamid the dihydrochloride.

Specified in the title compound is an optical isomer mentioned in the title of example 20, and it is obtained in a manner similar to that described in examples 5, 9, 19 and 20.

So pl. 191-196oC.

IR(KBr): 3300, 3200, 1685, 1505 cm-1.

1H-NMR (270 MHz, CDCL3, M. D.): 7.33-7.08(m, 10H), 6.71-6.62(m, 2H), 6.35(d, J= 2.9 Hz, 1H), 5.44(Shir.s, 2H), 4.46(d, J=12.1 Hz, 1H), 3.73 (s, 3H), 3.53 (s, 3H), 3.70-3.45(m, 2H), 3.30-2.93(m, 5H), 2.75-2.60(m, 1H), 2.54-of 2.38(m, 2H), 1.93-1.77(m, 1H), 1.70-1.55(m, 1H).

+18.6oC(c=0.50, DMSO).

Example 54. (3R, 4S, 5S, 6S)-5-(2.5-dimethoxyphenethylamine(-6-diphenylmethyl-1 - azabicyclo[2.2.2]octane-3-carboxylic acid dihydrochloride.

Specified in the title compound is an optical isomer of the compound indicated in the title of example 21, and is produced from compound ukazannoj IR(KBr): 3500, 1720, 1505, 1440 cm-1.

1H-NMR (270 MHz, CDCl3, M. D. free base): 7.32-7.02(m, 10H), 6.71-6.56(m, 2H), 6.41(Shir. s, 1H), 4.38(d, J=11.0 Hz, 1H), 3.68(3H), 3.90-3.45 (m, 2H), 3.44(s, 3H), 3.25-2.95(m, 4H), 2.74-2.20(m, 5H), 1.90-1.55 (m, 2H),

+12.7oC(c=1.00, DMSO).

Example 56. (3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxybenzylamine(-6-diphenylmethyl-1 - azabicyclo[2.2.2]Octan-3-carboxamid the dihydrochloride.

Specified in the title compound is an optical isomer of the compound indicated in the title compound of example 31, and receive it from 69 in a manner analogous to the method described in examples 5, 9, 19 and 20.

So pl. 246-249oC.

Analysis calculated: C, 63.35% H 7.48% N 6.93% Found: C 63,16% H rate of 7.54% N 6.93%

-15.0oC(c=1.00, DMSO).

Example 56. (3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxybenzylamine)-6-diphenylmethyl-1 - azabicyclo[2.2.2]octane-3-carboxylic acid dihydrochloride.

Specified in the title compound is an optical isomer of the compound indicated in the title of example 32, and receive it from the connection specified in the title of example 55, in a manner analogous to the method described in example 21.

So pl. 210-213oC.

Analysis calculations: C, 64.21% H 7.24% N 4.68% Found: C, 64.32% H 7.33% N 4.89%

-9.80o(c 1.00, EtOH).

Specified in the title compound is obtained by the method similar to the method described in examples 15 and 21.

So pl. 138 141oC.

IR(KBr): 3420, 2970, 1740, 1510 cm-1.

1H-NMR(270 MHz, CDCl3M. D. free base): 7.41 - 7.14( m, 10H(, 7.08(DD, J=2.6, 8.4 Hz, 1H), 6.66(d, J=8.4 Hz, 1H), 6.60(d, J=2.60 Hz, 1H), 4.69(d, J=12.1 Hz, 1H), 4.32(DD, J=8.8 and 12.1 Hz, 1H), 3.90 - 3.78 (m, 1H), 3.42-3.33 (m, 2H), 3.30-3.22 (m, 2H), 2.90 2.72 (m, 1H), 2.65-2.55(m, 1H), 2.46-2.35(m, 1H), 2.23-2.14(m, 1H), 2.09-1.92(m, 1H), 1.73-1.56(m, 1H), 1.21(d, J=7.0, 3H), 1.20 (d, J=7.0 Hz, 3H), 1.20 (d 7.0 Hz, 3H).

Example 58. (3R, 4S, 5S, 6S)-5-(2-Methoxybenzylamine)-6-diphenylmethyl-1 - azabicyclo[2.2.2]Octan-3-carboxamide.

Specified in the title compound was obtained from (3R, 4S)-6-diphenylmethyl-5-oxo-1-azabicyclo[2.2.2]octane-3-carboxamide (compound 71), according to the procedure of examples 5, 9, 19 and 20.

IR (net): 3470, 3400, 3350, 3200, 1670 cm-1.

1H-NMR (CDCl3): 3.34-7.05 (m, 11H), 6.79-6.70 (m, 2H), 6.58 (DD, J=7.3, 1.5 Hz, 1H), 5.62 (Shir.with. 1H), 5.38 (Shir.with. 1H), 4.46 (d, J=12.1 Hz, 1H), 3.66-3.57 (m, 1H), 3.57 (s, 3H), 3.31 (d, J=13.2 Hz, 1H), 3.25-2.90 (m, 4H(, 2.70-2.60 (m, 1H), 2.50-2.35 (m, 2H), 1.90-1.80 (m, 1H), 1.69 (Shir.with. 1H), 1.69-1.55 (m, 1H).

Example 59. The dihydrochloride (3R, 4S, 5S, 6S)-5-(2-isopropoxy-5-isopropylbenzylamine)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide.

The target compound from example PI room temperature for 17 h

The catalyst was removed by filtering through Celite with suction, and the filtrate was concentrated, giving 10.02 g of a pale yellow amorphous solid, which was dissolved in water (30 ml).

This aqueous solution was washed with ethyl acetate (50 ml), then was podslushivaet saturated aqueous sodium bicarbonate and was extracted with a mixture of methanol/dichlormethane mixed solvent (1:5, 100 ml). The extracts were combined and dried (sodium sulfate) and concentrated, giving 6.16 g of a pale-yellow amorphous solid.

This solid substance was precrystallization from a mixture of dichloromethane/ether, giving (3R, 4S, 5S, 6S)-5-amino-6-diphenylmethyl-1 - azabicyclo[2.2.2] Octan-3-carboxamide (compound 72) (5.17 g) as pale yellow powder.

So pl. 229-290oC.

IR (Nujol): 3440, 3300, 3250, 3150, 1670 cm-1.

1H-NMR (CDCl3): 7.42-7.08 (m, 10H), 5.45 (Shir.with. 2H), 4.51 (d, J=12.1 Hz, 1H), 3.62 (DD, J= 12.1, 8.1 Hz, 1H), 3.34 (DD, J=7.7, 4.4 Hz, 1H), 3.25-3.10 (m, 2H), 3.10-2.95 (m, 1H), 2.75-2.63 (m, 1H), 2.60-2.50 (m, 1H), 2.15-2.10 (m, 1H), 1.90-1.73 (m, 1H), 1.70-1.55 (m, 1H), 1.45 (Shir.with. 1H).

A mixture of compound 72 (503 mg, 1.5 mmole), 2-isopropoxy-5-isopropylbenzaldehyde (330 mg, 1.6 mmole), triacetoxyborohydride sodium (636 mg, 3 mmole) and acetic Ki is giving 10.02 g of a pale yellow amorphous solid, which was dissolved in water (30 ml).

This aqueous solution was washed with ethyl acetate (50 ml), then was podslushivaet saturated aqueous sodium bicarbonate and was extracted with a mixture of methanol/dichlormethane mixed solvent (1:5, 100 ml). The extracts were combined and dried (sodium sulfate) and concentrated, giving 6.16 g of a pale-yellow amorphous solid.

This solid substance was precrystallization from a mixture of dichloromethane/ether, giving (3R, 4S, 5S, 6S)-5-amino-6-diphenylmethyl-1 - azabicyclo[2.2.2] Octan-3-carboxamide (compound 72) (5.17 g) as pale yellow powder.

So pl. 229-290oC.

IR (Nujol): 3440, 3300, 3250, 3150, 1670 cm-1.

1H-NMR (CDCl3): 7.42-7.08 (m, 10H), 5.45 (Shir.with. 2H), 4.51 (d, J=12.1 Hz, 1H), 3.62 (DD, J= 12.1, 8.1 Hz, 1H), 3.34 (DD, J=7.7, 4.4 Hz, 1H), 3.25-3.10 (m, 2H), 3.10-2.95 (m, 1H), 2.75-2.63 (m, 1H), 2.60-2.50 (m, 1H), 2.15-2.10 (m, 1H), 1.90-1.73 (m, 1H), 1.70-1.55 (m, 1H), 1.45 (Shir.with. 1H).

A mixture of compound 72 (503 mg, 1.5 mmole), 2-isopropoxy-5 - isopropylbenzaldehyde (330 mg, 1.6 mmole), triacetoxyborohydride sodium (636 mg, 3 mmole) and acetic acid (1 drop) in dichloromethane (15 mm) were mixed at room temperature for 3 hours, the Reaction mixture was extinguished saturated aqueous bicarbonate is asenne purple amorphous solid.

To a stirred solution of this solid (0.84 g) in ethyl acetate (10 ml) was added saturated HCl methanol solution (5 ml) at 0oC. After 1 hour stirring at 0oC appearing precipitates were collected by filtration, yielding 229 mg of a pale pink powder.

The filtrate was concentrated in vacuo, and the resulting pale grey solid was rinsed with ether, giving 591 mg of pale gray powder. The total yield was 820 mg (91.3%).

51 g of the first collection was podslushivaet saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo, giving the target compound (47 mg), a colorless viscous oil in the form of a free amine.

So pl. (dihydrochloride): 173-174oC.

IR (pure free amine): 3470, 3350, 3200, 3150, 1670 cm1.

1H-NMR (CDCl3free amine) 7.37-7.04 (m, 10H), 6.98 (DD, J=2.2, 8.4 Hz, 1H), 6.72 (d, J=8.4 Hz, IH), 6.41 (D. J 1.8 Hz, IH), 5.44 (Shir.with. 2H), 4.47 (D. J 12.1 Hz, IH), 4.39 (hept. J 6.2 Hz, IH), 3.67 (DD. J 8.1, 12 Hz, IH), 3.57 (D. J 12.8 Hz, IH), 3.21-3.02 (m, IH), 3.09 (D. J 12.5 Hz, IH), 3.01-2.94 (m, IH), 2.74 (hept. J 7.0 Hz, IH), 2.70-2.60 (m, IH), 2.48 (Shir. so J 9.2 Hz, IH), 2.41-2.35 (m, IH), 1.95-1.80 (m, IH), 1.80-1.50 (m, 2H), 1.24 (doctor J=5.9 Hz, 3H), 1.23 (doctor J=5.9 Hz, 3H), 1. the but)-6-diphenylmethyl-1 - azabicyclo(2.2.2) Octan-3-carboxylic acid.

This compound was obtained in accordance with the procedure of example 21 of the target compound of example 59.

So pl. (free amine): 225-230oC.

IR (nujol free amine): 3350, 3100, 2580, 2350, 1710 cm1.

IH-NMR (CDCI3free amine) d 7.62 (Shir.D. J=7.3 Hz, 2H), 7.51 (Shir. D. J=7.0 Hz, 2H), 7.40-7.12 (m, 6H), 7.02 (DD. J=8.4, 1.8 Hz, IH), 6.73 (doctor J= 8.4 Hz, IH), 6.44 (Shir. S. IH), 5.18 (Shir.with. IH), 4.60-4.40 (m, 2H), 3.95-3.30 (m, 9H), 3.12 (Shir.with. IH), 2.83 (Shir.with. IH), 2.74 (hept. J=7.0 Hz, IH), 2.30-2.15 (m, IH), 1.90-1.70 (m, IH), 1.27 (doctor J=6.2 Hz, 3H), 1.24 (doctor J=6.2 Hz, 3H), 1.18 (doctor J=7.0 Hz, 3H), 1.18 (doctor J=7.0 Hz, 3H).

Example 61. The dihydrochloride (3R, 4S, 5S, 6S)-6-diphenylmethyl-5-(2-methoxy-5-methylsulfinyl)benzylamino-1 - azabicyclo(2.2.2) Octan-3-carboxamide.

This compound was obtained in accordance with the procedure of example 59 from compound 72 and 5-methylsulfinyl-o-anisaldehyde.

So pl. 211-214oC (decomp.).

IR (KBr): 3040, 1690, 1495, 1260, 1095, 980, 820, 760, 720 cmI.

IH-NMR (CDCI3free amine) d 7.50-7.06 (m, 12H), 6.84, 6.77 (two days J=8.4, 8.8 Hz, IH), 6.37 (Shir.with. IH), 6.04 (Shir.with. IH), 5.52, 5.47 (two Shire. S. IH), 4.47, 4.56 (two days J=12.1 Hz, IH), 3.86-3.64 (m, 2H), 3.61, 3.50 (two C. 3H), 3.38-2.72 (m, 3H), 2.70, 2.68 (two C. 3H), 2.57-2.32 (m, 3H), 2.30-1.40 (m, 3H). (Due diastereomeric mixture was observed pair of peaks. )

Example 62. Dihydrochloride the CLASS="ptx2">

This compound was obtained in accordance with the procedure of example 21 of the connection 61.

So pl. 208-213oC (Razlog.).

IR (KBr): 3045, 3015, 1720, 1605, 1495, 1405, 1255, 1200, 1085, 1020, 820, 755, 715 cmI.

IH-NMR (CDCI3free amine, partial) d 7.52 (DD. J=2.9, 8.4 Hz, IH), 7.41-7.09 (m, IOH), 6.82 (doctor J=8.4 Hz, IH), 4.49 (doctor J=12.1 Hz, IH), 3.57 (C. 3H), 2.67 (C. 3H), 1.92 (Shir.with. 2H), 1.62 (Shir.with. 2H).

Example 63. Trihydrochloride (3R, 4S, 5S, 6S)-5-(5-N,N-dimethylamino-2-methoxybenzylamine)-6-diphenylmethyl-1 - azabicyclo(2.2.2)-octane-3-carboxamide.

The target compound was obtained according to the method similar to the synthesis of example 59 from compound 72 and 5-dimethylamino-o-anisaldehyde.

So pl. 172.0-174.0oC (Razlog.).

IR (KBr): 3430, 3180, 1678, 1619, 1508, 1458, 1272, 1020, 760, 715 cmI.

IH-NMR (CDCI3free amine, partial) d 7.35-7.05 (m, IOH), 6.65 (doctor J= 8.8 Hz, IH), 6.59 (DD. J=2.9, 8.8 Hz, IH), 6.35 (doctor J=2.9 Hz, IH), 5.81 (Shir. S. IH), 5.41 (Shir.with. IH), 4.48 (doctor J=12.1 Hz, IH), 3.65-3.55 (m, 2H), 3.48 (C. 3H), 3.19 (doctor J=12.8 Hz, IH), 3.15-2.90 (m, 4H), 2.82 (C. 6H), 2.63 (m, IH), 2.42 (m, 2H), 1.84 (m, IH), 1.60 (m, IH).

Example 64. (3R, 4S, 5S, 6S)-5-(5-N,N-dimethylamino-2-methoxybenzylamine)-6-diphenylmethyl-1 - azabicyclo(2.2.2)Octan-3-carboxylic acid.

The target compound was obtained according to the method similar to the synthesis of example 2I.

IH-NMR (CDCI3free amine) d 7.35-7.05 (m, IOH), 6.63 (doctor J=8.8 Hz, IH)6.59 (DD. J=2.6, 8.8 Hz, IH), 6.36 (doctor J=2.6 Hz, IH), 4.53 (doctor J=11.7 Hz, IH), 3.95 (m, IH), 3.63 (doctor J=12.5 Hz, IH), 3.45 (C. 3H), 3.42-2.91 (m, 5H), 2.80 (C. 6H), 2.75-2.43 (m, 3H), 1.94 (m, IH), 1.62 (m, IH).

In table. 1 shows the indicators JC50that testify to the activity of the compounds obtained in respect of the binding receptor for substance P in the table. 2 examples of pharmaceutical forms containing the active compound, corresponding to the present invention.

1. Substituted 3-aminoquinuclidine General formula I

< / BR>
where R1hydrogen, halogen, C1C6-alkyl, optionally substituted by 1 to 3 halogen atoms, WITH1- C6-alkoxy, optionally substituted by 1 to 3 halogen atoms, WITH1C6-alkylthio,1C6-alkylamino, di-C1- C6-alkylamino or C1C6-alkylsulfanyl;

W X(CH2)nor Y, where X is a phenyl, hydroxyl, COOH, CO2-C1C6-alkyl, NR2R3or COR4where R2and R3independently hydrogen, C1C6-alkyl or C1-C6-alkoxy, R4-

< / BR>
where n is 0 to 6;

Y1C6-alkyl or C2C6alkenyl,

or its pharmaceutical is where W y

4. Connection on p. 1, where R1methoxy.

5. Connection on p. 1, where X is phenyl.

6. Connection on p. 1, where X dialkylaminoalkyl.

7. Connection on p. 1, where X aminocarbonyl.

8. Connection on p. 1, where X is a carboxyl group.

9. Connection on p. 1, where X alkoxycarbonyl.

10. Connection on p. 3, where Y alkenyl containing from 2 to 6 carbon atoms.

11. Connection on p. 1, selected from the group consisting of (3R, 4S, 5S, 6S)-N, N-diethyl-5-(5-isopropyl-2-methoxybenzylamine)-6-diphenylmethyl-1-azabicyclo [2,2,2]Octan-3-carboxamid, (3R, 4S, 5S, 6S)-N,N-diethyl-5-(2,5-dimethoxyaniline)-6-diphenylmethyl-1 - azabicyclo[2,2,2] Octan-3-carboxamid, (3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxybenzylamine)-6-diphenylmethyl-1 - azabicyclo[2,2,2] octane-3-carboxylic acid, (3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylthiophenethylamine)-6-diphenylmethyl-1 - azabicyclo[2,2,2]octane-3-carboxylic acid, (3R, 4S, 5S,6S)-5-(2,5-dimethoxyaniline)-6-diphenylmethyl-1-azabicyclo[2,2,2] octane-3-carboxylic acid, (3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo [2,2,2]octane-3-carboxylic acid, (3R, 4S, 5S, 6S)-5-(5-ethyl-2-methoxybenzylamine)-6-diphenylmethyl-1-azabicyclo [2,2,2] octane-3-carboxylic acid, (3R, 4S, 5S, 6S)-5-(2-methoxy-5-n-propylaniline)ylmethyl-1 - azabicyclo[2,2,2]octane-3-carboxylic acid, (3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylsulfonylbenzoyl)- 6-ciphermail-1-azabicyclo[2,2,2]octane-3-carboxylic acid, (3R, 4S, 5S, 6S)-5-(2-methoxy-5-triphtalocyaninine)- 6-ciphermail-1-azabicyclo[2,2,2]octane-3-carboxylic acid, (3R, 4S, 5S, 6S)-5-(5-dimethylamino-2-methoxybenzylamine)- 6-diphenylmethyl-1-azabicyclo[2,2,2] octane-3-carboxylic acid, (2S, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxybenzylamine)-6-diphenylmethyl-1 - azabicyclo[2,2,2] octane-2-carboxylic acid, (2S, 4S, 5S, 6S)-5-(2-methoxy-5-methylthiophenethylamine)-6-diphenylmethyl-1 - azabicyclo[2,2,2] Octan-2-carbonous acid, (2S, 4S, 5S, 6S)-5-(2,5-dimethoxyaniline)-6-diphenylmethyl-1-azabicyclo[2,2,2] octane-2 - carboxylic acid, (2S, 4S, 5S, 6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2,2,2] octane - 2-carboxylic acid, (2S, 4S, 5S, 6S)-5-(5-ethyl-2-methoxybenzylamine)-6-diphenylmethyl-1-azabicyclo[2,2,2]octane - 2-carboxylic acid, (2S, 4S, 5S, 6S)-5-(2-methoxy-5-n-propylaniline)-6 - diphenylmethyl-1-azabicyclo[2,2,2] octane-2-carboxylic acid, (2S, 4S, 5S, 6S)-5-(5-sec-butyl-2-methoxybenzylamine)-6 - diphenylmethyl-1-azabicyclo[2,2,2]octane-2-carboxylic acid, (2S, 4S, 5S, 6S)-5-(2 methoxy-5-methylsulfonylbenzoyl)-6 - diphenylmethyl-1-azabicyclo[2,2,2]octane-2-carboxylic acid, (2S, 4S, 5S, 6S)-5-(2-methoxy-5-triphtalocyaninine)- 6-diphenylmethyl-1-Aza is yclo[2,2,2]octane-2-carboxylic acid.

12. Connection on p. 2 having the formula

< / BR>
where R1halogen, C1C6-alkyl, optionally substituted by 1 to 3 halogen atoms, WITH1C6- alkoxy, optionally substituted by 1 to 3 halogen atoms, WITH1- C6-alkylthio or1C6-alkylsulfanyl;

X is phenyl, CO2-C1-C6-alkyl, CONR2R3or COR4where R2and R3independently, each WITH1- C6-alkyl or C1C6-alkoxy, R4morpholino or thiomorpholine;

n 0 6.

13. Connection on p. 2 having the formula

< / BR>
where R1hydrogen, chlorine, methyl, ethyl, n-propyl, isopropyl, sec-butyl, tert-butyl, methoxy, methylthio, methylsulfinyl, triptoreline, dimethylamino;

X is phenyl, diethylcarbamyl, carboxamide, monoethylamine, N-methoxy-N-methylcarbamyl, hydroxyl, carboxyl, methoxycarbonyl or COR4where R4selected from the group of formulas

< / BR>
n 0, 1, 2.

14. Connection on p. 13, the absolute configuration of (3R, 4S, 5S, 6S), X carboxyl group and n is 0.

15. Connection on p. 13, the absolute configuration of (3R, 4S, 5S, 6S), X carboxamidine group and n is 0.

16. Connection on p. 13, the absolute configuration to the (3R, 4S, 5S, 6S), X is a hydroxy-group and n is 1.

18. Connection on p. 1 having the formula

where R1halogen, C1C6-alkyl, optionally substituted by 1 to 3 halogen atoms, WITH1C6-alkoxy, optionally substituted by 1 to 3 halogen atoms, WITH1C6- alkylthio or1C6-alkylsulfanyl;

X is phenyl, CO2-C1-C6-alkyl, CONR2R3or COR4where R2and R3independently hydrogen, C1- C6-alkyl or C1C6-alkoxy, R4morpholino or thiomorpholine;

n 0 6.

19. Connection on p. 18, where R1hydrogen, chlorine, methyl, ethyl, n-propyl, ISO-propyl, sec-butyl, tert-butyl, methoxy, methylthio, methylsulfinyl, triptoreline, dimethylamino, phenyl, diethylcarbamyl, carboxamide, monoethylamine, N-methoxy-N-methylcarbamyl, carboxyl, methoxycarbonyl or COR4where R4selected from the group of formulas

< / BR>
n 0, 1, 2.

20. Connection on p. 19, the absolute configuration of (2S, 4S, 5S, 6S), X carboxyl group and n is 0.

21. Connection on p. 14, where R1the isopropyl group.

22. Connection on p. 14, where R1the methoxy group.

23. Connection on p. 14, where R1matitiahu the a and n 0.

25. Connection on p. 3, where Y1C6is an alkyl group.

 

Same patents:

The invention relates to new derivatives of 1-phenyl-3-azabicycloalkanes-2-ones, to a method for producing them, to pharmaceutical compositions containing them and to their use as therapeutic agents

The invention relates to new compounds with pharmacological activity, in particular bicyclic 1-Aza-cycloalkanes General formula

(I) where R is lower alkyl, unsubstituted or substituted furan, thiophene or imidazole; alkenyl with 3-6 carbon atoms; quinil with 3-6 carbon atoms; phenyl, unsubstituted or substituted lower alkyl, alkoxygroup or by halogen; benzyl, unsubstituted or substituted by halogen; pyridyl; pyrimidinyl;

A, b and C independently of one another denote-CH2or a simple bond;

n is 0 or 1, mixtures of isomers, or individual isomers and their pharmacologically tolerable acid additive salts exhibiting holinoliticheskoy properties

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .

EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinuclidine of the general formula (I):

wherein © represents phenyl ring, (C4-C9)-heteroaromatic group comprising one or some heteroatoms, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R1, R2 and R3 represent hydrogen halogen atom, phenyl and others; n represents a whole number from 0 to 4; A represents group -CH=CR6-, -CR6=CH-, -CR6R7 and others; R6 and R7 represent hydrogen atom, alkyl and others; m represents a whole number from 0 to 8; p represents a whole number from 1 to 2; and a substitute in azoniabicyclic ring can be at position 2, 3 or 4 including all possible configurations of asymmetric carbon atoms; B represents the group of the formula i) or ii) wherein R10 represents hydrogen atom, hydroxyl group or methyl; each R8 and R9 represents: wherein R11 represents hydrogen, halogen atom, alkyl; Q represents a single bond, -CH2- and others; X represents pharmaceutically acceptable anion of mono- or polyvalent acid. Compounds of the formula (I) possess antagonistic activity with respect to muscarinic M3-receptors and can be used in medicine for treatment of diseases wherein muscarinic M3-receptors are implicated.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

36 cl, 164 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry.

SUBSTANCE: invention relates to quinuclidine compounds of the formula (I) , its salts or their hydrates wherein R1 represents hydroxyl group; W represents: (1) -CH2-CH2-; 2) -CH=CH-, or 3) -C≡C-; HAr represents 5-10-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom that in addition to the group -X-Ar can be substituted with 1-3 groups taken among: (1) halogen atom; (2) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group substituted optionally with: (a) hydroxy-group; (b) (C1-C6)-alkoxycarbonyl; (c) (C1-C6)-alkanoyl optionally substituted with (C1-C6)-alkoxy-group; (d) hydroxylated (C3-C8)-cycloalkyl; (e) (C1-C6)-alkoxy-group; (f) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom, or (g) cyano-group; (3) (C1-C6)-alkoxy-group optionally substituted with: (a) hydroxy-group; (b) (C1-C6)-alkoxy-group optionally substituted with (C1-C6)-alkoxy-group; (c) halogen atom; (d) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (e) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (4) (C1-C6)-alkylthio-group optionally substituted with (C1-C6)-alkoxy-group or hydroxy-group; (5) 5-6-membered heterocyclyloxy-group comprising 1-2 oxygen atoms in heterocycle; (6) amino-group represented by the formula: -N(R3)R4 wherein R3 and R4 are similar or different and each represents hydrogen atom or group taken among: (a) (C1-C6)-alkyl group; (b) (C1-C6)-alkoxy-(C1-C6)-alkyl group; (c) carbonyl substituted with (C6-C14)-aryl; (d) (C6-C14)-arylsulfonyl or (e) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (7) (C3-C8)-cycloalkyl or cycloalkenyl hydrocarbon group optionally substituted with: (a) oxo-group or (b) hydroxy-group; (8) (C6-C14)-aromatic hydrocarbon ring optionally substituted with: (a) (C1-C4)-alkylene dioxy-group or (b) hydroxy-group; (9) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with: (a) cyano-group or (b) (C1-C6)-alkoxy-group; (10) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with one or some groups taken among: (a) hydroxy-group; (b) halogen atom; (c) cyano-group; (d) (C1-C6)-alkoxycarbonyl; (e) (C1-C6)-alkyl; (f) (C1-C6)-alkoxy-group that is optionally substituted with halogen atom or (C1-C6)-alkoxy-group; (g) (C1-C6)-alkanoyl; (h) (C1-C6)-alkoxy-(C1-C6)-alkyl; (i) oxo-group; (j) (C1-C4)-alkylenedioxy-group; (k) (C3-C8)-cycloalkylalkoxy-group or (C3-C8)-cycloalkenylalkoxy-group; (11) carbamoyl of the formula: -CO-N(R5)R6 wherein R5 and R6 can be similar or different and represent hydrogen atom, (C6-C14)-aryl wherein indicated aryl is optionally substituted with halogen atom, or (C3-C8)-cycloalkyl; or R5 and R6 form in common 3-6-membered ring; (12) carbonyl optionally substituted with (C1-C6)-alkoxy-group; X represents: (1) a simple bond; (2) (C1-C6)-alkylene chain; (3) (C1-C6)-alkenylene chain; (4) (C1-C6)-alkynylene chain; or (5) formula: -Q- wherein Q represents oxygen atom or sulfur atom; Ar represents: (1) (C6-C14)-aromatic hydrocarbon ring optionally substituted with one or some groups taken among: (a) halogen atom; (b) (C1-C4)-alkoxy-group or (c) (C1-C6)-alkylthio-group; or (2) 5-6-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom. Compounds of the formula (I) show inhibitory activity with respect to a squalene-synthesizing enzyme. Also, the invention relates to an inhibitor of squalene-synthesizing enzyme and the corresponding medicinal composition based on compound of the invention, a method for prophylaxis and treatment of disease wherein inhibition of squalene-synthesizing enzyme is effective. Also, invention proposes some methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable of medicinal and biochemical properties of com[pounds and composition.

25 cl, 10 tbl, 214 ex

FIELD: organic chemistry, pharmacology, pharmacy.

SUBSTANCE: invention relates to derivatives of quinuclidine of the general formula (I): wherein B means phenyl, pyrrolyl and other group; each among R1, R2 and R3 represents hydrogen, halogen atom, phenyl group and others; n means a whole number from 0 to 4; A represents the group chosen from -CH2-, -CH=CR9, -CR9R10 and others wherein R9 and R10 represent hydrogen atom or (C1-C8)-alkyl; m means a whole number from 0 to 8 under condition that if m = 0 then A doesn't mean -CH2-; p means a whole number from 1 to 2; R4 represents phenyl or 5-membered heteroaromatic cycle comprising oxygen or sulfur atom; R5 represents (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl and others; R6 represents hydrogen atom, hydroxy-group and others; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid. Compounds of the formula (I) possess the inhibitory activity with respect to M3-muscarinic receptors and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

34 cl, 2 tbl, 104 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to an agent eliciting immunomodulating, antitumor, bacteriostatic and anti-aggregation properties and representing 1-hexadecyl-R-(-)-3-oxy-1-azoniabicyclo[2.2.2]octane bromide and a method for its synthesis. Method involves quartenization of R-(-)-azabicyclo[2.2.2]octane-3-ol with hexadecyl bromide at heating in organic solvent medium. Agent shows low toxicity, high effectiveness, it doesn't cause allergic effect and doesn't possess cumulative effect.

EFFECT: valuable medicinal properties of agent.

3 cl, 9 dwg, 6 tbl, 2 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carbamate of the formula (I): or to their pharmaceutically acceptable salts wherein R1 represents compounds of formulas: , , , ,

, , , or ; R3 means hydrogen, halogen atom or alkyl; R2 means benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophene-2-ylmethyl, thiophene-3-ylmethyl or alkyl; p = 1 or 2, and substitution in azabicyclic ring can be at position 2, 3 or 4. Compounds of the formula (I) and their salts possess inhibitory activity with respect to muscarinic M3 receptors and can be used in medicine.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

25 cl, 1 tbl, 165 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds selected from 3(R)-(2-hedroxy-2,2-dithiene-2yl acetoxy)-1-(3-phenoxypropyl)-1-azoaniabicyclo[2,2,2]octane,X-, and 1-phenerhyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoaniabicyclo[2,2,2]octane,X-, wherein X- represents pharmaceutically acceptable anion of mono- or polyvalen acid having inhibiting activity in relates to muscarinic M3 receptors. Also disclosed are pharmaceutical compositions containing such compounds and method for treatment of respiratory diseases.

EFFECT: new quinuclidine analogs useful in treatment of respiratory diseases.

20 cl, 1 tbl, 184 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 1-(2S,3S)-2-benzhyryl-N-(5-tert.-butyl-2-methoxybenzyl)quinuclidin-3-amine (further named in the claim as "compound of the formula (I)" ) and its pharmaceutically acceptable salts. Invention relates to an improved method of synthesis of citrate monohydrate salt of compound of the formula (Ia):

EFFECT: improved method of synthesis.

10 cl, 2 sch,

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds that represent quaternary ammonium salt of the formula (II): wherein R1 means group chosen from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl; R2 means group chosen from (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, saturated or unsaturated (C3-C7)-cycloalkyl, saturated or unsaturated (C3-C7)-cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl and pyridylmethyl; cyclic groups in R1 and R2 are optionally substituted with one, two or three substitutes chosen from halogen atom, linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy group is unsubstituted or substituted with one or more halogen atoms or hydroxy groups; p means 1 or 2, and carbamate group is joined at positions 2, 3 or 4 of azoniabobicyclic ring system; m means a whole number from 1 to 6; n means 0 or 1; A represents -CH2-, -CH=CH-, -C(O)-, -O-, -S- and -NMe-group; B represents hydrogen atom or group chosen from linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy, cyano, nitro, -CH=CR'R'', -C(O)OR', -OC(O)R', (C3-C7)-cycloalkyl, phenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1.3]dioxolyl, 5-10-membered heteroaryl or heterocyclyl group wherein each R' and R'' represents independently hydrogen atom or linear or branched (C1-C8)-alkyl group, and wherein cyclic groups represented as B are substituted optionally with one, two or three substitutes chosen from halogen atom, hydroxy, linear or branched (C1-C8)-alkyl, -OR', -CONR'R'', -CN, and -COOR'; R' and R'' are given above and wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid, and involving all individual stereoisomers of compound of the formula (II) and their mixtures. Also, invention relates to a method for inhibition, pharmaceutical composition, combined product and their using in therapeutic treatment as antagonists of M3 muscarinic receptors. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 187 ex

FIELD: organic chemistry, medicine, chemical technology.

SUBSTANCE: invention describes a method for synthesis of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represented by the formula: . Method involves interaction of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane with hydrobromic acid or its inorganic salt (for example, sodium bromide or potassium bromide) in water in the ionic exchange reaction. 1-Hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represents an immunotropic agent that shows versatile effect on human immune status and elicits antitumor, bacteriostatic and anti-aggregate effects. Invention proposes a method for synthesis of a novel synthetic low-molecular preparation possessing the expressed stimulating effect on the antitumor immunity system that is equal or exceeding by effectiveness effect of the modern domestic and foreign preparation - immunomodulators that represent natural high-molecular biologically active substances prepared by methods of genetic engineering.

EFFECT: improved method of synthesis, valuable medicinal and biological properties of substance.

1 cl, 6 tbl, 21 dwg, 4 ex

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