Azabicyclooctane derivative, pharmaceutical preparations, method for prophylaxis or treatment, methods for preparing compounds, compounds

FIELD: organic chemistry, cardiology, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I)

wherein R1, R2, R3 and Ra-Rh have values given in the description. Proposed compounds are useful in prophylaxis and treatment of arrhythmia, in particular, atrial and ventricular arrhythmia, Also, the invention relates to methods for preparing compounds of the formula (I) and intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

41 cl, 1 tbl, 8 ex

 

The scope of the invention

This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias.

Prior art

Cardiac arrhythmias can be defined as violations of frequency, regularity or place of origin of wave excitation of the heart muscle or conduction disorders that cause abnormal sequence of stimulation. Arrhythmia can be classified clinically by the proposed place of origin (i.e. as supraventricular, including atrial and atrio-ventricular, arrhythmia and ventricular arrhythmia) and/or by frequency (i.e. bradyarrhythmia (slow) or tachyarrhythmias (fast)).

In the treatment of cardiac arrhythmias negative consequence in clinical trials (see, for example, the effect of testing on the suppression of cardiac arrhythmias (IASA), which was reported in the New England Journal of Medicine, 321, 406 (1989)), "the usual" anti-arrhythmic drugs, which act mainly by slowing down the speed of conduction (antiarrhythmic drugs class I), has directed the development of drugs in the direction of the compounds that selectively delay cardiac repolarization, therefore lengthening the QT interval. Anti-arrhythmic drugs class III can be Oh bacteriology as medications, further extending the duration of the transmembrane action potential (which may be caused by blocking aimed outward flows To+or increase the inward flow of ions) and refractoriness without changes in cardiac conduction.

One of the key disadvantages of the known prior to the present time, drugs that act by delaying repolarization (class III or other), is that they all, as you know, are a unique form of proaramme, known as polymorphic ventricular tachyarrhythmia (pointes de pointes, turning of points), which may, under certain circumstances, be fatal. From a security standpoint to minimize this phenomenon (which, as has also been shown that manifests as a result of the introduction of neserbeznyh drugs, such as phenothiazines, tricyclic antidepressants, antihistamine agents and antibiotics) is a key issue that must be resolved when receiving effective anti-arrhythmic drugs.

Antiarrhythmic drugs based on Besedina (3,7-diazabicyclo[3.3.1]nonanes), well-known, in particular from international patent applications WO 91/07405 and WO 99/31100, applications for European patents 306871, 308843 and 665228 and U.S. patent 3962449, 4556662, 4550112, 4459301 and 5468858 and magazine articles, including, in particular, J. Med. Chem. 9, 2559, (1996), Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal. Sci. 9, 429, (1993). 3-Azabicyclo[3.2.1]octane compounds are not disclosed and are not proposed in any of these documents.

It is known that compounds based on 3-azabicyclo[3.2.1]octanol can be used in many other medical applications, including antagonism of serotonin (as described in EP 212802 and EP 645391), the antagonism of receptors neirokinina-1 (as described in WO 98/18788), inhibition of synthase nitric oxide (as described in WO 97/36871) and analgesia (as described in Rico, et al., J. Heterocycl. Chem. 31(2), 313-318 (1994)). None of these documents describes and does not offer the use of compounds based on 3-azabicyclo[3.2.1]octane as antiarrhythmic agents.

The inventors have unexpectedly found that a new group of compounds based on 3-azabicyclo[3.2.1]octane shows electrophysiological activity, preferably electrophysiological activity of class III, and it is therefore expected that it is useful in the treatment of cardiac arrhythmias.

Description of the invention

According to this invention proposed derivatives azabicycloalkanes General formula I

where the wavy line represents a possible endo - or eksoterikon;

one of R1and R2is an R1aand the other represents fragmentarily Ia,

R1arepresents a C1-12alkyl (possibly substituted and/or terminated with one or more than one group selected from phenyl, Het1, -C(O)R7a, -OR7b, -N(R8R7c, -C(O)XR9, -C(O)N(R10R7dand-S(O)2R11), Het2, -C(O)R7a, -C(O)XR9, -C(O)N(R10R7dor-S(O)2R11;

R7a-R7dindependently represent H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from C1-6alkoxy, halogeno, phenyl, Het3and-NHC(O)R12), phenyl or Het4;

R12represents a C1-4alkyl (substituted or possibly ending with-NHC(O)R13);

R13represents a C1-4alkyl;

R8represents H or phenyl;

X represents O;

R9represents a C1-12alkyl (possibly substituted and/or terminated with-OH, cyano, C1-6alkoxy, -SO2R15or Het5);

R15represents a C1-6alkyl;

R10represents H, C1-12alkyl, C1-6alkoxy (which latter two groups possibly substituted and/or end With1-4alkoxy), -D-phenyl, -D-Het6or-D-S(O)2R17a;

R17arepresents phenyl;

D submitted is a direct link or 1-6alkylen;

R11represents a C1-6alkyl, phenyl or Het7;

R4represents H, -OR18, -E,-N(R19R20or together with R5represents =O;

R5represents H or, together with R4represents =O;

R18represents H, -O-phenyl or-C(O)OR21;

R19represents H or-C(O)OR21b;

R20represents N;

R21brepresents a C1-6alkyl (possibly substituted and/or terminated phenyl);

E represents a direct bond or C1-4alkylen;

Het1-Het7independently represent isoxazolyl, tetrahydropyranyl, pyrazolyl, piperazinil, morpholinyl, pyridinyl, benzoxadiazole, imidazolyl, imidazolidinyl, pyrrolyl, thiazolyl or benzodioxolyl, and these groups possibly substituted by one or more than one Deputy, selected from oxo, halogeno,1-6of alkyl, -C(O)R23cand-N(R23g)C(O)R23h;

R23c, R23gand R23hindependently represent N or C1-6alkyl;

And represents a direct bond or-J-;

In represents-Z-, -Z-N(R25)-, -N(R25)-Z-, -Z-S(O)n-, -Z-O- (the latter two groups, Z is attached to the carbon atom bearing R4and R5);

J represents a C1-6alkylen, in what can be substituted by the Deputy, selected from-OH and amino;

Z represents a direct bond or C1-4alkylen;

R25represents N;

G represents CH;

R6represents one or more than one possible substitute selected from cyano, halogeno,1-6the alkyl and C1-6alkoxy;

n represents 2; and

Ra-Rhindependently represent H;

R3represents N or C1-4alkyl;

where each phenyl and fenoxaprop possibly substituted;

or their pharmaceutically acceptable derivatives;

provided that

if a represents a direct bond, R4and R5together represent =o

These compounds are hereinafter referred to as "compounds of the invention".

Unless otherwise specified, alkyl groups and alkoxygroup, as defined here, can be unbranched or, if there is a sufficient number (i.e. a minimum of three) of carbon atoms, branched and/or cyclic. In addition, if there is a sufficient number (i.e. a minimum of four) carbon atoms, such alkyl and alkoxygroup may also be partially cyclic/acyclic. Such alkyl and alkoxygroup may also be saturated or, when there is a sufficient number (i.e. at least two) of carbon atoms, unsaturated and/or pre is a private one, or more than one oxygen atom and/or sulfur. Unless otherwise specified, alkyl and alkoxygroup may also be substituted by one or more than one atom halogeno, and in particular fluorescent.

Unless otherwise specified, alkylene group, as defined here, can be unbranched or, if there is a sufficient number (i.e. at least two) of carbon atoms, branched. Such alkylene circuit may also be saturated or, when there is a sufficient number (i.e. at least two) of carbon atoms, unsaturated and/or interrupted by one or more than one oxygen atom and/or sulfur. Unless otherwise specified, alkylene groups may also be substituted by one or more than one atom halogeno.

In order to avoid ambiguities, fenoxaprop, which are here referred to, is attached to the remainder of the molecule through the O atom of actigraphy. Unless otherwise specified, phenyl and fenoxaprop can be substituted by one or more than one Deputy, comprising-OH, halogeno, Het1, cyano, nitro, C1-6alkyl, C1-6alkoxy, -N(R27g)C(O)R27hand/or-S(O)nR-26 C(where Het1, R-26 C, R27g, R27hand n are as defined above). Phenyl and fenoxaprop being substituted, preferably substituted by one to three substituents.

Used herein, the term "halogen" includes the impact of fluorescent, chloro, bromo and iodide.

Group Het (Het1, Het2, Het3, Het4, Het5, Het6and Het7)that may be mentioned include groups containing from 1 to 4 heteroatoms (selected from the group of oxygen, nitrogen and/or sulfur) and in which the total number of atoms in the ring system is five to twelve. Group Het (Het1, Het2, Het3, Het4, Het5, Het6and Het7can be fully saturated, wholly aromatic, partly aromatic and/or bicyclic nature. Heterocyclic groups include isoxazolyl, tetrahydropyranyl, pyrazolyl, piperazinil, morpholinyl, pyridinyl, benzoxadiazole, imidazolyl, imidazolidinyl, pyrrolyl, thiazolyl or benzodioxolyl and the like. The substituents of the groups Het (Het1, Het2, Het3, Het4, Het5, Het6and Het7may, where appropriate, be located on any atom in the ring system including a heteroatom. The place of attachment of groups Het (Het1, Het2, Het3, Het4, Het5, Het6and Het7can be conducted via any atom in the ring system including (where appropriate) a heteroatom, or an atom of any condensed carbocyclic ring, which may be present as part of a ring system. Group Het (Het1, Het2, Het3, Het4, Het5, Het and Het7can also be in the form of N - or S-oxide.

Pharmaceutically acceptable derivatives include salts and solvate. Salts that may be mentioned include the salts of accession acid. Pharmaceutically acceptable derivatives include derivatives of nitrogen 3-azabicyclo[3.2.1]octane, With1-4-alkyl Quaternary ammonium salts and N-oxides, provided that if there are N-oxide:

(a) none of the groups Het (Het1, Het2, Het3, Het4, Het5, Het6and Het7) does not contain non-oxidized S-atom; and/or

(b) n is not O, if is a-Z-S(O)n-.

Compounds according to the invention can also be tautomerism. All tautomeric forms and mixtures thereof are included in the scope of the present invention.

Compounds according to the invention may also contain one or more than one asymmetric carbon atom and can therefore exhibit optical and/or diastereoisomerism. Diastereoisomer can be separated using conventional methods, for example by chromatography or fractional crystallization. Various stereoisomers may be isolated by separation of racemic or other mixture of the compounds using conventional methods such as fractional crystallization or high performance liquid chromatography (HPLC). As lternative, the desired optical isomers may be obtained by reacting the appropriate optically active starting materials in conditions that do not cause racemization or epimerization, or by derivatization, for example using a homochiral acid followed by separation of the diastereomeric esters by usual methods (for example, by HPLC, chromatography on silica). All stereoisomers are included in the scope of this invention.

Abbreviations listed at the end of the description.

Preferred compounds according to the invention include compounds where:

R1arepresents a C1-8alkyl (possibly substituted and/or terminated with one or more than one group selected from a possibly substituted phenyl, Het1, -C(O)R7a, -OR7b, -N(R8R7c, -C(O)XR9, -C(O)N(R10R7band-S(O)2R11), Het2-C(O)R7a, -C(O)XR9, -C(O)N(R10R7dor-S(O)2R11;

R7a-R7dindependently represent H, C1-5alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from C1-4alkoxy, halogeno, possibly substituted phenyl, Het3and-NHC(O)R12), possibly substituted phenyl or Het4;

R12represents a C1-3alkyl (possibly someseni and/or ending with-NHC(O)R 13);

R13represents a C1-3alkyl;

R8represents H or phenyl;

R9represents a C1-8alkyl (possibly substituted and/or terminated with-OH, cyano, C1-4alkoxy, -SO2R15and Het5);

R15represents a C1-4alkyl;

R10represents H, C1-8alkyl, C1-4alkoxy (which latter two groups possibly substituted and/or end With1-4alkoxy), -D-(possibly substituted phenyl), -D-Het6or-D-S(O)2R17a;

R17arepresents phenyl;

D represents a direct bond;

R11represents a C1-5alkyl, possibly substituted phenyl or Het7;

R4represents H, -OR18or-E-N(R19R20;

R5represents N;

R18represents H or-O-(possibly substituted phenyl);

R19represents H or-C(O)OR21b;

R20represents N;

R21bindependently represent a1-4alkyl (possibly replaced or terminated phenyl);

E represents a direct bond;

Het1-Het7possibly substituted by one or more than one Deputy, selected from oxo, halogeno,1-5the alkyl and-N(R23g)C(O)R23h;

R23c, R23gand R23hindependent pre whom represent N or C 1-3alkyl;

And represents a direct bond or-J-;

In represents-Z-, -Z-N(R25)-, -Z-S(O)n- or-Z-O- (in the last three groups, Z is attached to the carbon atom bearing R4and R5);

J represents a C1-5alkylen, possibly substituted by a Deputy selected from-OH and amino;

Z represents a direct bond or C1-3alkylen;

n represents 2;

R25represents N;

G represents CH;

R6represents one or more than one possible substitute selected from cyano, halogeno,1-3the alkyl and C1-4alkoxy;

R3represents N or C1-2alkyl;

Ra-Rhall represent N.

More preferred compounds according to the invention include compounds where:

R1arepresents a linear, branched or part cyclic/acyclic With1-6alkyl (which alkyl group (1) possibly interrupted by one or more than one oxygen atom; and/or (2) possibly substituted and/or ends of one or more than one group selected from a phenyl (possibly substituted by one or more than one Deputy, selected from halogeno and methoxy), Het1(possibly substituted-C(O)R23c), -C(O)R7a, -OR7b, -C(O)N(H)R10and-S(O)2R11), Het2, -C(O)R7a/sup> , -C(O)OR9, -C(O)N(H)R10or-S(O)2R11;

R7aand R7bindependently represent H, linear or branched C1-5alkyl (which alkyl group (1) may be unsaturated; and/or (2) possibly substituted and/or ends with one or more than one Deputy, selected from C1-2alkoxy, Het3and-NHC(O)R12), phenyl (possibly substituted, halogen or methoxy) or Het4(possibly replaced With1-4by alkyl);

R12represents a C1-2alkyl (possibly substituted and/or terminated-NHC(O)R13);

R13represents a C1-2alkyl;

R9represents a linear, branched or part cyclic/acyclic With1-6alkyl (which alkyl group (1) may be unsaturated; (2) possibly interrupted by one or more than one oxygen atom; and/or (3) possibly substituted and/or ends-OH, cyano, C1-2alkoxy, -SO2R15or Het5(possibly substituted-C(O)R23c));

R15represents a C1-2alkyl;

R10represents in each case H, a linear, branched or part cyclic/acyclic With1-7alkyl (which alkyl group (1) possibly interrupted by one or more than one oxygen atom; and/or (2) possibly substituted and/or ends with the 1-2alkoxy), phenyl (possibly substituted by one or more than one Deputy, selected from halogeno and methoxy), Het6(possibly substituted by one or more than one1-2alkyl group) or-S(O)2R17a;

R-26 Crepresents a C1-2alkyl;

R17arepresents phenyl;

R11represents in each case, a linear, branched or part cyclic/acyclic With1-5alkyl, phenyl (possibly substituted by one or more than one Deputy, selected from nitro, methoxy and N(H)C(O)R27hor Het7(possibly substituted by one or more than one Deputy, selected from halogeno,1-2the alkyl and N(H)C(O)R23h);

R4represents H, -OR18or-N(H)R19;

R5represents N;

R18represents H or phenyl (possibly substituted by one or more than one Deputy, is selected from OH and methoxy);

R19represents H or-C(O)OR21b;

R21brepresents a C1-2alkyl;

R23crepresents a C1-2alkyl;

And represents a direct bond or-J-;

In represents-Z-, -Z-N(H)-, -Z-SO2- or-Z-O- (in the last three groups, Z is attached to the carbon atom bearing R4and R5);

J represents a C1-3alkylen, who is one substituted by-OH or amino;

Z represents a direct bond or C1-2alkylen;

R6represents one or two ceanography;

R3represents H or methyl.

Particularly preferred compounds according to the invention include compounds where:

R1arepresents-C(O)R7a, -C(O)N(H)R10or-S(O)2R11;

R10represents a linear, branched or part cyclic/acyclic With1-5alkyl (which alkyl group possibly interrupted by one or more than one oxygen atom);

R4represents H, -OH or-NH2;

And represents a direct bond or-J-;

In represents-Z-N(H)-or-Z-O- (in these groups, Z is attached to the carbon atom bearing R4and R5);

J represents a C1-3alkylen;

R6represents the cyano in the para-position, which is joined In;

R3represents methyl.

Preferred compounds according to the invention include compounds of the examples described below.

Getting

According to this invention also suggested:

(a) Method of producing compounds of the formula I, characterized in that

the compound of the formula IIA or IIB,

where R1, R2, R3and Ra-Rhare such as identifying what about the above, subjected to interaction with the compound of the formula III,

R28-L1III

where R28represents (as appropriate) or R1or R2L1represents a leaving group, and R1and R2are as defined above;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I.

(b) the Method of producing compounds of the formula I, where R1or R2(as appropriate) represents-C(O)N(H)R10, characterized in that

the compound of the formula IIA or IIB (as appropriate),

as defined above (except that R1or R2(as appropriate) does not represent R1a), is subjected to the interaction with the compound of the formula VI,

R10-N=C=O VI

where R10is as defined above;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I.

(C) the Method of obtaining the compounds of formula I, where R1or R2(as appropriate) represents a fragment of formula Ia, where a is a CH2and R4represents-OH or-N(H)R19, characterized in that

the compound of the formula IIA or IIB

as defined above (except that R1or R2(as appropriate) does not represent a fragment of formula Ia), is subjected to the interaction with the compound of the formula VII

where Y represents O or N(R19), and R5, R6, R19, And G are as defined above;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I.

(g) the Method of obtaining the compounds of formula I, where R4represents-OR18where R18represents-O-phenyl, characterized in that

the corresponding compound of formula I, where R4represents OH, is subjected to the interaction with the compound of the formula XI,

R18aOH XI

where R18arepresents-O-phenyl, and E is as defined above;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I.

(d) the Method of obtaining the compounds of formula I, where R4represents-E-NH2, characterized in that

restore the connection formula XIIIA or XIIIB,

where R1or R2(as appropriate) represents R1a1a, R3, R5, R6, Ra-RhAnd, b, E and G are as defined above;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I.

(e) the Method of obtaining the compounds of formula I, where R4represents-E-N(R19R20where R19represents-C(O)OR21b, characterized in that

the corresponding compound of formula I, where R4represents-E-N(H)R20, is subjected to the interaction with the compound of the formula XIV

R19a-L1XIV

where R19arepresents-C(O)OR21band R21b, R20and E are as defined above, and L1is as defined above;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I.

(g) the Method of obtaining the compounds of formula I, where R3represents N, and R2represents unsubstituted With1-4alkyl, characterized in that

the compound of formula XXI

where R4, R5, R6, Ra-RhA, b and G are as defined above, is subjected to the interaction with the compound of the formula XXII

R31-NH2

where R31represents a C1-4alkyl, in the presence of a reducing agent;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I according to claim 1.

The compounds of formula IIA and IIB can be obtained by reacting the compounds of formula XXIV

or N-protected derivative, where R3, Ra-Rhare as defined above, with a compound of formula III, as defined above, for example as described above for the synthesis of compounds of formula I (method (a)), or in the case of compounds of formula IIA or IIB, where R1or R2(as appropriate) represents a fragment of formula Ia, where a is a CH2and R4represents-OH or N(H)R19where R19is the same as defined above, with a compound of formula VII, as defined above, for example as described above for the synthesis of compounds of formula I (method ()).

The compounds of formula III can be obtained using conventional methods. For example, the compounds of formula III, where R28represents a fragment of formula Ia, where:

In represents-Z-O-, can be obtained by combining the compounds of formula IX

where R6and G are such that ka is defined above, with a compound of formula XXV,

L2-Z-C(R4)(R5)-A-L2XXV

where R4, R5And Z are as defined above, and L2represents a leaving group, such as halogen, alkanesulfonyl, performancereport or arenesulfonic, and two groups of L2may be the same or different;

in conditions that are well known to specialists in this field of technology.

The compounds of formula III, where R28represents a fragment of formula Ia, where a is a C2alkylene, and R4represents-OR18where R18represents a C1-6alkyl, -S-phenyl, or-E-Het8may, alternatively, be obtained by reacting the compounds of formula XI, as defined above, with a compound of formula XXVIII,

where R5, R6, And G are as defined above, and R32represents a C1-4-alkyl, for example at a temperature of from ambient temperature (e.g. 25° (C) to the temperature of reflux distilled in the presence of a suitable base (e.g. potassium carbonate) and an appropriate organic solvent (e.g. acetonitrile), followed by conversion of the ester functional group L2(where L2is the same as defined above), in terms of the s, well-known specialists in this field of technology.

The compounds of formula VII can be obtained in accordance with methods known to experts in this field of technology. For example, the compounds of formula VII where:

(1) represents-CH2O-, and Y is O, can be obtained by reacting the compounds of formula IX, as defined above, with a compound of formula XXX,

where R5and L2are as defined above, for example at elevated temperature (for example, at a temperature of from 60°to the temperature of reflux distilled in the presence of a suitable base (e.g. potassium carbonate or NaOH) and an appropriate organic solvent (e.g. acetonitrile or a mixture of toluene/water) or as otherwise described in the prior art;

(2) R5represents H, b represents a direct bond, C1-4alkylene, -Z,-N(R25)-, -Z-S(O)n- or-Z-O- (and in each case, the group Z represents a C1-4alkylene attached to the carbon atom bearing R5), and Y represents O may be obtained by recovering the compounds of formula XXXIA or XXXIB,

whereais a-Za-N(R25), Za-S(O)nor Za-O- (and in each the m case, the group Z arepresents a direct bond or C1-3alkylene attached to the carbon atom bearing R5),brepresents a direct bond or C1-4alkylene, and R6, R25, G, and n are as defined above, for example at temperatures from -15°C to room temperature in the presence of a suitable reducing agent (for example, NaBH4) and a suitable organic solvent (such as THF) followed by implementation of the response of the internal substitution in the resulting intermediate compound, for example at room temperature in the presence of a suitable base (e.g. potassium carbonate) and an appropriate organic solvent (e.g. acetonitrile);

(3) represents a direct link,1-4alkylene, -Z,-N(R25)-, -Z-S(O)2- or-Z-O-(and in each case, the group Z represents a C1-4alkylene attached to the carbon atom bearing R5), and Y represents O may be obtained by oxidation of compounds of formula XXXIIA or XXXIIB,

where R5, R6InaInband G are as defined above, in the presence of a suitable oxidizing agent (e.g. m-HPBC), for example by boiling under reflux in the presence of a suitable organic solvent (for example dichloromethane); what does

(4) represents-Z-O-, where Z represents a C1-4alkylene attached to the carbon atom bearing R5and Y represents-N(R19), where R19represents-C(O)OR21bor-S(O)2R21ccan be obtained by cyclization of compounds of formula XXXIII,

where R19brepresents-C(O)OR21bor-S(O)2R21c, Zbrepresents a C1-4alkylene, and R5, R6, R21b, R21c, G, and L2are as defined above, for example at temperatures from 0°to the temperature of reflux distilled in the presence of a suitable base (e.g. sodium hydroxide), a suitable solvent (e.g. dichloromethane, water or mixtures thereof) and, if necessary, interphase catalyst (such as tetrabutylammonium hydrosulfate).

The compounds of formula XIIIA and XIIIB, where E represents a direct bond, can be obtained by reacting corresponding compounds of formula I, where R4represents-OH, with a compound of formula XXXIV

R33S(O)2Cl XXXIV

where R33represents a C1-4alkyl or phenyl (these two groups possibly substituted by one or more than one Deputy, selected from C1-4of alkyl, halogen and nitro), for example at temperatures from -10 to 25°C, the presence of a suitable solvent (for example, dichloromethane), followed by interaction with a suitable source of azide ion (e.g. sodium azide), for example at a temperature of from ambient temperature to the temperature of reflux distilled in the presence of a suitable solvent (such as N,N-dimethylformamide) and a suitable base (e.g. sodium bicarbonate).

The compounds of formula XIIIA and XIIIB may, alternatively, be obtained by reacting the compounds of formula IIA or IIB as defined above (except that R1or R2(as appropriate) does not represent a fragment of formula Ia), with a compound of formula XXXV,

where R5, R6And, b, E, G and L2are as defined above, for example under conditions similar to the conditions described above for the synthesis of compounds of formula I (method ()).

The compounds of formula XXI can be obtained by reacting the compounds of formula III, where R28represents a fragment of formula Ia with a compound of formula XXXVI,

where Ra-Rhare as defined above, for example under the conditions described above (method ()).

The compounds of formula XXI, where Raand Rbrepresent H, in the alternative, can be obtained by reacting the compounds of formula XXXVII,

where Rc-Rhare as defined above, with a compound of formula XXXVI,

where R4, R5, R6, A, b and G are as defined above, in the presence of formaldehyde (i.e. suitable source of formaldehyde, such as a solution of paraformaldehyde or formalin), for example at a temperature of from room temperature to the temperature of reflux distilled in the presence of a suitable solvent (for example, lower Olkiluoto alcohol, such as methanol), and possibly in the presence of a suitable acid (e.g. acetic acid).

The compounds of formula XXIV can be obtained by reacting the compounds of formula XXXVI, as defined above, or N-protected derivative with a compound of formula XXXIX,

R3-NH2XXXIX

or (in the case when R3represents H) its protected derivative (for example, N-benzyl) for example under the conditions described above for the synthesis of compounds of formula I (method (g)).

The compounds of formula XXXV can be obtained similarly to the formation of compounds of formulae XIIIA and XIIIB (i.e. from the corresponding alcohol).

The compounds of formula XXXVI, where Raand Rbrepresent H, can be obtained by reacting the compounds of formula XXXVII with ammonia or its N-f the th derivative (for example, benzylamino) in the presence of formaldehyde, for example under conditions described above for the synthesis of compounds of formula XXI.

Compounds of formula VI, IX, XI, XIV, XXII, XXV, XXX, XXXIA, XXXIB, XXXIIA, XXXIIB, XXXIII, XXXVII, XXXVIII and XXXIX and their derivatives are commercially available or known from the literature or can be obtained either by analogy with the ways described here, or conventional synthesis methods, in accordance with standard methods from readily available starting compounds using suitable reagents and reaction conditions.

The substituents on aryl (e.g. phenyl) and (if applicable) heterocyclic group(s) in the compounds described in this invention can be converted into any other claims deputies using methods well-known to specialists in this field of technology. For example, the hydroxy may be converted into alkoxy, phenyl may be subjected to galogenirovannyie with getting halogenfree, nitro can be recovered by obtaining amino, amino may be subjected to acetylation with getting acetylamino and so on.

Specialist in the art will understand that various standard interconversion and conversion of substituents or functional groups in some compounds of formula I will provide other compounds of formula I. for Example, the carbonyl can be restore is to hydroxy or alkylene, and hydroxy can be converted into halogen.

Compounds according to this invention can be isolated from reaction mixtures using conventional methods.

Specialist in the art will understand that the method described above, the functional groups of intermediate compounds may be protected by a protective group, or may require that they be protected by a protective group.

Functional group, which is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protective groups for hydroxy include trialkylsilyl and diarylalkylarsines group (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarboxylic group (e.g. methyl - and acylcarnitine group). Suitable protective groups for amino include benzyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protective groups for amidino and guanidino include benzyloxycarbonyl. Suitable protective groups for carboxylic acids include1-6alkyl or benzyl esters.

The introduction and removal of protective groups with functional groups can be performed before or after any one of the reaction stages described above.

The protective groups may be the ü removed in accordance with the methods, which are well known to experts in the art, and as described above.

The use of protective groups is fully described in "Protective Groups in Organic Chemistry", edited by J. W. F. McOmie, Plenum s (1973), and "Protective Groups in Organic Synthesis", 3rdedition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

Specialist in the art it is clear that in order to obtain compounds according to this invention an alternative and, in some cases, more convenient way, the individual stages of the method, referred to herein may be performed in a different order, and/or the individual reactions may be performed at a different stage all the way (i.e. different intermediate compounds can be added substituents, and/or over them can be carried out chemical transformations in the intermediate compounds, associated above with a particular reaction). It depends, among other things, on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the selected strategy, the protective groups (if applicable). It is clear that the type of chemistry will influence the choice of reagent that is used in these stages of the synthesis, the needs and the type of protective groups and the sequence of synthesis implementation.

Specialist in the art lakepalace, although some protected derivatives of compounds of formula I which can be obtained before the final stage of removal of the protective groups may not possess pharmacological activity as such, they can be injected parenterally or orally and thereafter to be metabolized in the body to form compounds according to this invention which are pharmacologically active. Such derivatives can, therefore, be described as "prodrugs". Moreover, some compounds of formula I may act as prodrugs of other compounds of formula I.

All prodrugs of the compounds of formula I included in the scope of this invention.

Some intermediate compounds referred to above, are new. Therefore, in accordance with another aspect of this invention offered:

(a) Compound of formula IIA or IIB as defined above, or a protected derivative, provided that it does not represent:

(±)-(8α,β)-3-ethyl-3-azabicyclo[3.2.1]Octan-8-amine;

8-amino-3-methyl-3-azabicyclo[3.2.1]octane;

8-amino-3-isopropyl-3-azabicyclo[3.2.1]octane;

8-amino-3-benzyl-3-azabicyclo[3.2.1]octane;

3-{2-[4-(6-aminopyridine-2-yl)phenyl]ethyl}-3-azabicyclo[3.2.1]Oct-8-ylamine; or

3-azabicyclo[3.2.1]Oct-8-ylamine tert-BUTYLCARBAMATE;

(b) a Compound of formula XIIIA or XIIIB, as is defined above, or a protected derivative; and

(C) a Compound of formula XXI as defined above (provided that if Ra-Rhall represent H, G represents CH, and R6no, the group-A-C(R4)(R5)-B - does not represent unsubstituted ethyl), or a protected derivative.

Medical and pharmaceutical application

The compounds of this invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.

Thus, in accordance with another aspect of the present invention, the compounds according to this invention, intended for use as pharmaceuticals.

In particular, the compounds of this invention exhibit myocardial electrophysiological activity, such as blocking the potassium current of the detained straightening activity, as demonstrated in the test described below.

Thus, it is expected that the compounds according to this invention will be useful in the prevention and treatment of arrhythmias, in particular atrial fibrillation and ventricular fibrillation.

Thus, the compounds according to this invention is shown in the treatment or prevention of heart disease, or when indications related to diseases of the heart, when the cat is older adults, believed to play a major role, including coronary heart disease, sudden heart attack, myocardial infarction, heart failure, heart surgery and thromboembolism.

It was found that in the treatment of arrhythmias compounds according to this invention selectively inhibit cardiac repolarization, therefore lengthening the QT interval and, in particular, demonstrate the activity of class III. Although it was found that the compounds according to this invention demonstrate activity of class III, in particular in the treatment of arrhythmias, their type(s) of activity is not necessarily limited to this class.

In accordance with another aspect of the present invention, a method for prevention or treatment of arrhythmia, wherein the subject suffering from such condition or affected by it, introducing a therapeutically effective amount of the compounds according to this invention.

Pharmaceutical

The compounds of this invention are typically administered orally, subcutaneously, intravenously, intraarterially, transdermal, intranasal, by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient in the form of a free base, pharmaceutically acceptable ion-exchange or non-toxic organic or inorganic salt to recognize the value acid, in pharmaceutically acceptable dosage form. Depending on the disorder and the patient to be treated and the route of administration, the compositions can be injected at various doses.

Compounds according to this invention can also be combined with any other drugs useful in the treatment of arrhythmias and/or other cardiovascular disorders.

In accordance with another aspect of the present invention, thus, a pharmaceutical preparation with a blocking potassium current of the detained straightening activity comprising the compound according to this invention in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

A pharmaceutical preparation with a blocking potassium current of the detained straightening activity designed for use in the prevention or treatment of arrhythmia, comprising the compound according to this invention.

Suitable daily doses of the compounds according to this invention in therapeutic treatment of humans are about 0.005 to 10.0 mg/kg body weight by oral administration and approximately 0.005 to 5.0 mg/kg body weight at parenteral administration.

The compounds of this invention have the advantage that they are effective against heart and is itmi.

Compounds according to this invention may also have the advantage that they can be more effective, less toxic, to have a wider range of activities (including the manifestation of any combination of the activity of class I, class II, class III and/or IV class (in particular the activity of class I and/or class IV in addition to the activity class III)), to be stronger, to have a longer effect, to give less side effects (including lower frequency proirity, such as polymorphic ventricular tachyarrhythmia), to be more easily absorbed or have other useful pharmacological properties compared to the compounds known from the prior art.

Biological tests

Test And

Treated with glucocorticoids mouse fibroblasts as a model for the detection of blockers potassium current of the detained straightening

IR50to block channels To the defined screening method using titration microplate based on the change in membrane potential of mouse fibroblasts treated with glucocorticoids. The membrane potential of mouse fibroblasts treated with glucocorticoids, was measured using fluorescence bisoxazolines dye DiBac4(3)that can be reliably detected by luorescence apparatus for reading tablets with laser image (FLIPR). The expression of the potassium channels of the detained straightening induced in murine fibroblasts, exposing glucocorticoid dexamethasone (5 μm) for 24 hours. Blocking these potassium channels were depositvalue fibroblasts, leading to increased fluorescence DiBac4(3).

Murine Itk fibroblasts (L-cells) was purchased from the American type culture collection (ATS, Manassa, VA)and were cultured on modified according to the method of Dulbecco environment the Needle with the addition of fetal calf serum (5%), penicillin (500 units/ml), streptomycin (500 μg/ml) and L-alanyl-L-glutamine (0,862 mg/ml). The cells were passively every 3-4 days using trypsin (0.5 mg/ml free from calcium phosphate buffered saline solution, Gibco BRL). Three days before the experiments, the cell suspension was excavated in 96-well black plastic tablets with a clear bottom (Costar) at 25,000 cells/well.

To measure membrane potential used fluorescent probe DiBac4(3)(DiBac Molecular probes). The maximum absorption DiBac4(3)corresponds to 488 nm, and emission - 513 nm. DiBac4(3)is bisexual and, thus, negatively charged at pH 7. Due to its negative charge distribution DiBac4(3)from edge to edge of the membrane depends on the transmembrane potential: if cell d is polarized (i.e. inside the cell less negative charge, than outside), the concentration of DiBac4(3)inside the cell increases due to electrostatic forces. Once inside the cell, the molecules of DiBac4(3)can contact lipids and proteins, causing an increase in fluorescence emission. Thus, the depolarization will be reflected in increasing DiBac fluorescence4(3). The change in fluorescence DiBac4(3)found using FLIPR.

Before each experiment the cells 4 times washed with phosphate buffered saline (PBS) to remove all culture medium. The cells were then treated with 5 μm DiBac4(3)(180 ál PBS) at 35°C. After reaching steady fluorescence (usually 10 min) was added 20 μl of a test substance using internal 96-well digging out the FLIPR system. Measurement of fluorescence was performed every 20 seconds for an additional 10 minutes All the experiments were carried out at 35°due to the high temperature sensitivity as the conductivity of the potassium channels of the detained straightening, and DiBac fluorescence4(3). The test substance was prepared in the second 96-well tablet in PBS containing 5 m DiBac4(3). The concentration of the prepared medium was 10 times more desired in the experiment the concentration, because at the time of adding substances during a pilot phase of the enta implement the additional dilution of 1:10. As a positive control to determine the maximum gain of fluorescence, used dofetilide (10 μm).

The construction of the curve used to estimate IR50, was performed using Graphpad Prism program (Graphpad Software Inc., San Diego, CA).

Test B

Metabolic stability of test compounds

To determine the metabolic stability of the compounds of this invention were screened in vitro.

Used the fraction of S-9 liver dog, human, rabbit and rat together with the use of adenine dinucleotide phosphate (NADPH) as a cofactor. Analysis conditions were as follows: S-9 (3 mg/ml), NADPH (0,83 mm), buffer Tris-HCl (50 mm) at pH 7.4 and 10 μm test compound.

The reaction was started by adding the test compound and finished in 0, 1, 5, 15 and 30 minutes by increasing the pH of the sample to approximately 10 (NaOH; 1 mm). After extraction the solvent concentration of the test compounds was measured against an internal standard by using liquid chromatography (LC) (detection of fluorescence/UV).

Expected percentage of tested compounds remaining after 30 minutes (and, thus, t1/2), and used it as an indicator of metabolic stability.

The invention is illustrated by the trace of the sponding examples.

Examples

General experimental procedures

Mass spectra were recorded on one of the following tools:

the spectrometer Perkin-Elmer SciX API 150ex; mass spectrometer triple quadrupole VG Quattro II single quadrupole VG Platform II or with a single quadrupole Micromass Platform LCZ (the latter three instruments were equipped with pneumatically controlled electrospray interface (liquid chromatography-mass spectroscopy (LC-MS))). Measurement1H NMR and13With NMR (nuclear magnetic resonance) was performed on a spectrometer BRUKER ACP 300 and Varian 300, 400 and 500, operating at a frequency of1H 300, 400 and 500 MHz, respectively, and at frequencies13With 75,5, 100,6 and 125,7 MHz, respectively. Alternatively, the measurements13With NMR was performed on a spectrometer BRUKER ACE 200 at a frequency to 50.3 MHz.

Rotamer can be marked or not marked in the spectra depending on the ease of interpretation of the spectra. Unless otherwise specified, the chemical shifts are given in million-1with the solvent as internal standard.

Synthesis of intermediate compounds

The following intermediate compounds were not commercially available and therefore were obtained using the methods described below.

Obtaining And

3-Benzyl-3-azabicyclo[3.2.1]octane-8-he

The solution benzylamine (127,4 g, 1,19 mol) in methanol (125 ml) was added dropwise during the course the e 3 h to heated under reflux to a solution of Cyclopentanone (100 g, 1,19 mol), paraformaldehyde (107 g of 3.57 mol) and glacial acetic acid (71,4 g, 1,19 mol) in methanol (600 ml) under nitrogen atmosphere. After heating under reflux for 1 h brown mixture was stirred overnight at 25°and concentrated in vacuum. The resulting oil was diluted with water (200 ml) and podslushivaet 6 n NaOH (200 ml). The aqueous solution was extracted with dichloromethane (3×400 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuum. The residue was subjected to chromatography elwira a mixture of ethyl acetate:dichloromethane (1:35) to obtain the 47,6 g (19%) indicated in the subtitle compound as a yellow oil.

1H NMR (300 MHz, CDCl3): δ 7,40-7,10 (m, 5H), of 3.60 (s, 2H), 3,01 of 2.92 (m, 2H), 2.57 m-2,50 (m, 2H), 2,18 to 2.0 (m, 4H), 1,90-of 1.81 (m, 2H).

Getting B

3-Benzyl-N-methyl-3-azabicyclo[3.2.1]Octan-8-amine

A mixture of cyanoborohydride sodium (35,0 g, 0,557 mol) and zinc chloride (37,9 g, 0,278 mol) in methanol (500 ml) was added dropwise to a mechanically stirred mixture of 3-benzyl-3-azabicyclo[3.2.1]octane-8-it (Getting A; 120g; 0,557 mol) and methylamine hydrochloride (151 g of 2.23 mol) in methanol (1.0 l) at 25°C in nitrogen atmosphere. After 2.5 h stirring dropwise added 6 n NaOH (90 ml). The mixture was filtered through a layer of Celite®by washing with methanol (500 ml). The filtrate was concentrated in vacuum. Was added water (500 ml) and water mixture which was xtraceroute with ethyl acetate (3× 500 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuum. The residue was subjected to chromatography elwira a mixture of methanol:dichloromethane (1:10) to obtain the 63,0 g (49%) indicated in the subtitle compound as a solid substance.

1H NMR (300 MHz, CDCl3): δ 7,40-7,10 (m, 5H), 3,88 (s, 2H), 3,60 (s, 2H), 3.45 points (s, 1H), 2,85 is 2.80 (m, 1H), 2,60 at 2.45 (m, 2H), 2,50 (s, 3H), of 2.15 (s, 2H), 2.40 a-2,30 (m, 2H), 1.70 to of 1.62 (m, 2H).

Getting Into

tert-Butyl 3-benzyl-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate

A mixture of 3-benzyl-N-methyl-3-azabicyclo[3.2.1]Octan-8-amine (Receive B; 168,1 g, at 0.730 mol) and di-tert-BUTYLCARBAMATE (159 g, at 0.730 mol) in dichloromethane (2.5 l) was stirred overnight at 25°C in nitrogen atmosphere. The mixture was concentrated in vacuum to obtain 240 g (100%) specified in the subtitle compound as a white solid, which was used without purification.

1H NMR (300 MHz, CDCl3): δ 7,40-7,30 (m, 5H), 4,0 (s, 2H), 3,60 (s, 2H), 3.45 points (s, 1H), 3,02-of 2.50 (m, 5H), 2,80 (s, 3H), 2,0 is 1.70 (m, 4H), of 1.50 (s, 9H).

Getting G

tert-Butyl-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate

A solution of 1 M HCl in diethyl ether (730 ml, 730 mmol) was added dropwise to a solution of tert-butyl 3-benzyl-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (Getting In; 241 g; at 0.730 mol) in diethyl ether (1.5 l). The resulting precipitate was collected by filtering through sintezirovannoi glass funnel and ZAT is dried in vacuum. The solid was dissolved in methanol (4.0 l) was added 10% palladium on carbon (24 g). The mixture was stirred in hydrogen atmosphere at a pressure of 101325,3 PA at 40°With during the night. The catalyst was filtered through a layer of Celite®by washing with methanol (1.0 l). The filtrate was concentrated in vacuo and subjected to chromatography, elwira a mixture of dichloromethane:methanol:concentrated ammonium hydroxide (88:10:2) to give 70 g (40%) oil. The solution of this oil (70 g, 296 mmol) in diethyl ether (1.0 l) was treated dropwise added 1 M HCl in diethyl ether (300 ml). The resulting precipitate was removed by filtration through sintezirovannoi glass funnel. Salt suspended in acetonitrile and the solid was collected to obtain 80 g of HCl-salt specified in the connection header.

So pl. (melting point): 170-177°

1H NMR (300 MHz, CD3OD): δ 3,35-3,10 (m, 6H), 2,90 (s, 3H), 3,02 is 2.80 (m, 2H), 2,02 is 1.70 (m, 4H), 1,45 (s, 9H).

13With NMR (75 MHz, CD3OD): δ 159,2, 81,8, 61,6, 45,6, 36,6, 36,0, 28,5, 24,8.

HEE-MS (chemical ionization - mass spectroscopy): (M+1)=241 m/z

The free base was obtained by treating the HCl-salt By2CO3in MeCN.

Getting D

4-{3-[3-Azabicyclo[3.2.1]Oct-8-yl(methyl)amino]-2-hydroxypropoxy}-benzonitrile

(1) 4-(2-Oxiranylmethyl)benzonitrile

The epichlorohydrin (800 ml) and K2CO3(414 g) was added to the plumage is esibaevna solution of para-cyanophora (238 g) in 2.0 l of MeCN and the reaction mixture is boiled under reflux in an inert atmosphere for 2 hours The hot solution was filtered and the filtrate was concentrated to obtain a clear oil. It crystallized from di-isopropyl ether to obtain specified in the subtitle compound with 75% yield.

(2) 4-{3-[(3-Benzyl-3-azabicyclo[3.2.1]Oct-8-yl)(methyl)amino]-2-hydroxypropoxy}benzonitrile

To a solution of 3-benzyl-N-methyl-3-azabicyclo[3.2.1]Octan-8-amine (Receive B; and 3.72 g of 16.1 mmol) in dichloromethane (80 ml) at 25°C in an atmosphere of nitrogen was added trimethylaluminum (8,05 ml of 2.0 M in hexane, at 16.1 mmol). After stirring at 25°C for 30 min to one portion was added 4-(2-oxiranylmethyl)benzonitrile (see stage (1) above; 2.83 g, 16,1 mmol) and the mixture was stirred over night. The mixture is extinguished 6 n NaOH (13.5 ml) and stirred 1 h was Added water (100 ml) and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum to obtain oil. The residue was subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol (98:2), with 4,30 g (66%) indicated in the subtitle compound as a colourless oil.

1H NMR (300 MHz, CDCl3): δ 7,58 (d, J=8,2 Hz, 2H), 7,32-7,20 (m, 5H), 6,97 (d, J=8,2 Hz, 2H), 4,22-to 4.14 (m, 1H), 4,08 to 4.0 (m, 2H), 3,50 (s, 2H), 2,82-2,70 (m, 1H), 2,64-2,52 (m, 2H), 2,48-of 2.30 (m, 5H), is 2.30 (s, 3H), 1,94-to 1.82 (m, 2H), 1,72 of 1.50 (m, 4H).

13With NMR (75 MHz, CDCl3): 5 162,4, 139,4, 134,0, 128,2, 128,0, 126,8,119,5, 115,6, 104,4, 70,6, 68,0, 66,0, 62,4, 57,7, 52,4, 52,0, 40,4, 36,8, 36,2, 27,8.

HEE-MS:(M+1)=406 m/z

(3) 4-{3-[3-Azabicyclo[3.2.1]Oct-8-yl(methyl)amino]-2-hydroxypropoxy}-benzonitrile

A solution of HCl in diethyl ether (4.3 ml 1.0 M, 4.3 mmol) was added dropwise to a solution of 4-{3-[(3-benzyl-3-azabicyclo[3.2.1]Oct-8-yl)(methyl)amino]-2-hydroxypropoxy}benzonitrile (see stage (2) above; 1,75 g, 4,32 mmol) in diethyl ether (50 ml) at 0°C. Concentration in vacuo allowed to obtain the HCl-salt. HCl-salt and 10% palladium on carbon (175 mg) suspended in methanol (25 ml), then stirred in an atmosphere of hydrogen for 5 h at 40°C. the Catalyst was removed by filtration through a small layer of Celite®by washing with methanol (50 ml). The filtrate was concentrated in vacuo and subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol:concentrated ammonium hydroxide (88:10:2) to give 980 mg (72%) indicated in the title compound as a white foam.

1H NMR (300 MHz, CDCl3): δ 7,58 (d, J=8,2 Hz, 2H), 6,97 (d, J=8,2 Hz, 2H), 4,30-4,16 (m, 1H), 4,12 to 4.0 (m, 2H), 3.33 and-3,10 (m, 4H), 2,82-2,70 (m, 1H), 2,52-of 2.30 (m, 4H), of 2.30 (s, 3H), 2,20-2,05 (m, 2H), 1,91 is 1.70 (m, 4H).

13C NMR (75 MHz, CDCl3): δ 162,4, 134,0, 119,5, 115,6, 104,4, 70,6, 68,0, 66,0, 57,7, 52,0, 40,4, 36,8, 36,2, 27,8.

HEE-MS:(M+1)=316 m/z.

Receive E

4-{2-Hydroxy-3-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]propoxy}benzonitrile

(1) tert-Butyl-3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[art-8-yl(methyl)carbamate

To a solution of tert-butyl 3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (Receiving G; 1.68 g, 7.0 mmol) in dichloromethane (35 ml) at 25°C in an atmosphere of nitrogen was added trimethylaluminum (3,75 ml of 2.0 M in hexano, 7.0 mmol). After stirring at 25°C for 30 min to one portion was added 4-(2-oxiranylmethyl)benzonitrile (obtain D (1); 1.22 g, 7.0 mmol) and the mixture was stirred over night. The mixture is extinguished 3 n NaOH (11.5 ml) and was stirred for 1 h was Added water (30 ml) and the aqueous layer was extracted with dichloromethane (3×30 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum to obtain oil. The residue was subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol (98:2), to obtain 2.35 g (81%) indicated in the subtitle compound as a white solid.

So pl.: 109-112°

1H NMR (300 MHz, CDCl3): δ 7,58 (d, J=8,2 Hz, 2H), 6,97 (d, J=8,2 Hz, 2H), 4,10-3,70 (m, 3H), 3,22-and 3.16 (m, 1H), 2,90 (s, 3H), 2,70 was 2.25 (m, 8H), 1,50-to 1.82 (m, 5H), 1,45 (s, 9H).

13C NMR (75 MHz, CDCl3): δ 162,2, 157,6, 134,0, 132,7, 119,2, 115,6, 104,1, 79,8, 70,6, 65,2, 60,8, 59,8, 58,0, 55,2, 52,0, 37,8, 37,2, 35,4, 28,4, 26,1, 26,0.

HEE-MS:(M+1)=416 m/z.

(2) 4-{2-hydroxy-3-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]-propoxy}benzonitrile

A suspension of tert-butyl 3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (see stage (1) above; 3,15 g, 7,58 mmol) in atilas the Tata, saturated HCl (40 ml)was stirred for 5 h at 25°C in nitrogen atmosphere. The mixture was distributed between water (100 ml) and ethyl acetate (50 ml). The aqueous layer was separated and washed with ethyl acetate. The aqueous layer was separated, podslushivaet saturated sodium bicarbonate (30 ml) and then was extracted with dichloromethane (3×50 ml). The organic extracts were dried (Na2SO4), filtered, concentrated in vacuo and then subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol:concentrated ammonium hydroxide (88:10:2), to obtain 2.30 g (96%) indicated in the title compounds as colorless oils.

1H NMR (300 MHz, CDCl3): δ 7,58 (d, J=8,2 Hz, 2H), 6,97 (d, J=8,2 Hz, 2H), 4,10-3,90 (m, 4H), 3,90 (d, J=8,2 Hz, 1H), 2,70-to 2.67 (m, 1H), 2,60-of 2.30 (m, 5H), 2.40 a (s, 3H), 2,08-2,0 (m, 2H), 1,82-of 1.64 (m, 5H).

13With NMR (75 MHz, CDCl3): δ 162,2, 134,0, 132,7, 119,2, 115,6, 104,1, 70,6, 65,2, 60,8, 59,8, 54,2, 50,4, 37,8, 37,2, 35,4, 27,4, 27,2.

HEE-MS:(M+1)=316 m/z.

Obtain W

4-({3-[8-(Methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]propyl}amino)-benzonitrile

(1) 4-[(3-Hydroxypropyl)amino]benzonitrile

A mixture of 4-perbenzoate (12.0 g, of 99.1 mmol) and 3-amino-1-propanol (59,6 g, 793 mmol) was stirred at 80°in an inert atmosphere for 3 hours before adding water (150 ml). The mixture was left to cool to K.T. (room temperature) and then was extracted with diethyl ether. The organic layer was separated, dried (Na SO4), filtered and concentrated in vacuum to obtain 17 g (97%) indicated in the title compound in the form of oil, which crystallized upon standing.

(2) 3-(4-Cyanoimino)propyl-4-methylbenzenesulfonate

Chilled (0° (C) a solution of 4-[(3-hydroxypropyl)amino]benzonitrile (see stage (1) above; 17 grams of 96.5 mmol) in dry MeCN (195 ml) was treated with triethylamine (9.8 g, of 96.5 mmol) and then pair-toluensulfonate (20.2 g, 106 mmol). The mixture was stirred at 0°C for 90 minutes before concentration in vacuo. To the residue was added water (200 ml) and the aqueous solution was extracted with dichloromethane (DHM). The organic phase was dried (Na2SO4), filtered and concentrated in vacuum. The resulting residue was purified by crystallization from ISO-propanol to obtain 24.6 g (77%) indicated in the subtitle of the connection.

(3) tert-Butyl-3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl-(methyl)carbamate

A mixture of tert-butyl 3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (receiving G; 2,90 g, 12.1 mmol), 3-(4-cyanoimino)propyl-4-methylbenzenesulfonate (see stage (2) above; 3,98 g, 12.1 mmol) and potassium carbonate (1,67 g, 12.1 mmol) in N,N-dimethylformamide (DMF) (50 ml) was heated at 90°C in nitrogen atmosphere for 4 hours the Mixture was distributed between water (50 ml) and diethyl ether (50 ml). The aqueous layer was separated and then extracted diatrofi the ether (2× 50 ml). The combined organic extracts were washed with saturated brine (2×30 ml), dried (Na2SO4), filtered and then concentrated in vacuum. The residue was subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol (98:2), with 2.85 g (59%) indicated in the subtitle of the connection.

1H NMR (300 MHz, CDCl3): δ 7,40 (d, J=8,2 Hz, 2H), of 6.52 (d, J=8,2 Hz, 2H), 3.25 to 3,18 (m, 4H), 2,80 (s, 3H), 2,72-2,60 (m, 4H), 2,50-to 2.42 (m, 2H), 2,28-of 2.20 (m, 2H), 1.85 to to 1.70 (m, 6H), 1,45 (s, 9H).

13With NMR (75 MHz, CDCl3): δ 157,4, 152,0, 133,8, 133,2, 120,4, 111,8, 97,7, 79,8, 61,4, 57,8, 53,9, 44,2, 37,8, 35,0, 28,0, 26,0, 24,2.

HEE-MS: (M+1)=399 m/z.

(4) 4-({3-[8-(Methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]propyl}amino)-benzonitrile

A suspension of tert-butyl 3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl-(methyl)carbamate (see stage (3) above; 2.66 g, to 6.67 mmol) in ethyl acetate saturated with HCl (40 ml)was stirred overnight at 25°C in nitrogen atmosphere. The mixture was distributed between water (100 ml) and ethyl acetate (50 ml). The aqueous layer was podslushivaet saturated sodium bicarbonate (50 ml) and then was extracted with dichloromethane (3×50 ml). The organic extracts were dried (Na2SO4), filtered, concentrated in vacuo and then subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol:concentrated ammonium hydroxide (92:7:1), to obtain 1.07 g (54%) indicated in the title compound in the form of logo solids.

1H NMR (300 MHz, CD3OD): δ 7,40 (d, J=8,2 Hz, 2H), of 6.52 (d, J=8,2 Hz, 2H), 3,40-3,10 (m, 6H), 2,72-to 2.40 (m, 6H), 2.40 a (s, 3H), 2,22-2,0 (m, 2H), 1,80-of 1.62 (m, 5H).

13With NMR (75 MHz, CD3OD): δ 154,0, 134,2, 113,4, 97,7, 64,4, 57,8, 53,9, 42,5, 37,8, 34,0, 28,0, 26,0.

HEE-MS:(M+1)=299 m/z.

Getting 3

4-({3-[3-Azabicyclo[3.2.1]Oct-8-yl(methyl)amino]propyl}amino)-benzonitrile

(1) 4-({3-[(3-Benzyl-3-azabicyclo[3.2.1]Oct-8-yl)(methyl)amino]propyl}amino)benzonitrile

A mixture of 3-benzyl-N-methyl-3-azabicyclo[3.2.1]Octan-8-amine (receive B; 4.0 g, to 17.4 mmol), 3-(4-cyanoimino)propyl-4-methylbenzenesulfonate (obtain W (2); 5,74 g of 17.4 mmol) and potassium carbonate (2,40 g of 17.4 mmol) in DMF (85 ml) was heated at 90°C in nitrogen atmosphere overnight. The mixture was distributed between water (200 ml) and diethyl ether (150 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (2×30 ml), dried (Na2SO4), filtered and then concentrated in vacuum. The residue was subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol (98:2), with 3,40 g (50%) specified in the subtitle compound as a white solid.

TPL: 91-93°

1H NMR (300 MHz, CDCl3): δ of 7.48 (d, J=8,2 Hz, 2H), 7,32-7,20 (m, 5H), 6,60 (d, J=8,2 Hz, 2H), 5,78-5,70 (m, 1H), 3,50 (s, 2H), 3,30-3,20 (m, 2H), 2,62-2,52 (m, 4H), 2,40 of-2.32 (m, 2H, in), 2.25 (s, 3H), 2,25-2,10 (m, 3H), 1,92-of 1.80 (m, 4H), 1,72 is 1.60 (m, 2H).

13C NMR (75 MHz, CDCl3): ´ 152,2, 140,0, 133,8, 128,4, 128,2, 136,4, 121,2, 112,2, 98,4, 68,8, 62,4, 54,5, 52,8, 43,0, 39,9, 36,4, 28,8, 25,8.

HEE-MS:(M+1)=389 m/z.

(2) 4-({3-[3-Azabicyclo[3.2.1]Oct-8-yl(methyl)amino]propyl}amino)-benzonitrile

A solution of HCl in diethyl ether (3.4 ml of a 1.0 M, 3.4 mmol) was added dropwise to a solution of 4-({3-[(3-benzyl-3-azabicyclo[3.2.1]Oct-8-yl)(methyl)amino]propyl}amino)benzonitrile (see stage (1) above; 1,32 g, 3,39 mmol) in diethyl ether (50 ml) at 0°C. Concentration in vacuo allowed to obtain the HCl-salt. HCl-salt and 10% palladium on carbon (132 mg) suspended in methanol (20 ml) and stirred in an atmosphere of hydrogen for 2 h at 40°C. the Catalyst was removed by filtration through a small layer of Celite®by washing with methanol (50 ml). The filtrate was concentrated in vacuo and subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol:concentrated ammonium hydroxide (88:10:2), to obtain 590 mg (59%) indicated in the title compound as a white foam.

So pl.: 59-63°

1H NMR (300 MHz, CD3OD): δ of 7.48 (d, J=8,2 Hz, 2H), 6,66 (d, J=8,2 Hz, 2H), 4,80 m (s, 1H), 3,35-3,10 (m, 4H), 2,62-to 2.40 (m, 4H), 2,30 is 2.10 (m, 4H), of 2.25 (s, 3H), 1,91 is 1.70 (m,6H).

13With NMR (75 MHz, CD3OD): δ 154,0, 133,8, 122,2, 113,2, 97,8, 68,8, 54,5, 45,8, 42,0, 40,4, 37,0, 26,8, 26,6.

HEE-MS:(M+1)=299 m/z.

Obtaining And

4-{1-(3,4-Dimethoxyphenoxy)-4-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]butyl}benzonitrile

(1) 4-[1-(3,4-Dimethoxyphenoxy)-3-butenyl]benzonitrile

The cooling gap is n (0° (C) a mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (14.6 g, of 84.3 mmol) and 3,4-dimethoxyphenol (19.5 g, and 125.4 mmol) in toluene (500 ml) was treated with tributylphosphine (32,14 ml of 97% purity, of 25.6 g, 126,4 mmol) and then 1,1'-(azodicarbon)dipiperidino (31.8 g, 126,4 mmol). After complete addition, the reaction mixture has thickened and the temperature increased to 15°C. was Added an additional amount of toluene (500 ml) and the mixture was stirred at K.T. during the night. The precipitate of oxide tributylphosphine then removed by filtration and the filtrate was concentrated in vacuum to obtain 65.8 g of the crude product. It was purified by chromatography on silica gel, elwira a mixture of toluene: methanol (98:2), to obtain 17.9 g specified in the subtitle of the connection.

(2) 4-[1-(3,4-Dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile

Borane-methylsulfinyl complex (2 M in diethyl ether, 11 ml, 22 mmol) was added dropwise to a cooled (-5° (C) to a solution of 4-[1-(3,4-dimethoxyphenoxy)-3-butenyl]benzonitrile (see stage (1) above; and 17.6 g of 56.8 mmol) in dry THF (15 ml) for 15 minutes (during this time the reaction temperature rose to 0°). The resulting mixture was stirred at a temperature of from 0 to 10°C for 1.5 h before it was allowed to warm to K.T. Stirring was continued for an additional 3.5 h at this temperature, pridobivanje water (22 ml) and tetrahydrate sodium perborate (11 g, 66 mmol). A two-phase mixture was stirred for 2 h at K.T. before separating the aqueous layer and extraction of its diethyl ether. The combined organic layers were washed with brine, dried and concentrated in vacuum. The resulting residue was purified by chromatography on silica gel, elwira with a mixture of isopropyl alcohol: ethyl acetate:heptane (5:25:70), with 14.5 g (77%) indicated in the subtitle of the connection.

(3) 4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate

The solution methanesulfonanilide (3.4 ml, 5.0 g, 44 mmol) in DHM (15 ml) was slowly added to a cooled (-5° (C) a mixture of 4-[1-(3,4-dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile (see stage (2) above; (11 g, 34 mmol) and triethylamine (7 ml, 5.2 g, and 50.6 mmol) in DHM (50 ml), and during this addition the temperature did not rise above 2°C. Stirring is continued at a temperature of from 0 to 5°C for additional 2 h before addition of water. The resulting organic layer was separated and washed with water, again separated and then dried to obtain specified in the subtitle compound with 100% yield.

(4) tert-Butyl-3-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate

A mixture of tert-butyl 3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (receiving G; 2,60 g, 10.9 mmol), 4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl-metasolv the ATA (see stage (3) above; and 4.40 g, 10.9 mmol) and potassium carbonate (1.50 g, 10.9 mmol) in DMF (50 ml) was heated at 90°C in nitrogen atmosphere for 4 hours the Mixture was distributed between water (50 ml) and diethyl ether (50 ml). The aqueous layer was extracted with diethyl ether (2×50 ml). The combined organic extracts were washed with brine (2×30 ml), dried (Na2SO4), filtered and then concentrated in vacuum. The residue was subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol (98:2), with the receipt of 3.60 g (60%) indicated in the subtitle compound as an amorphous solid.

1H NMR (300 MHz, CDCl3): δ a 7.62 (d, J=8,2 Hz, 2H), 7,46 (d, J=8,2 Hz, 2H), 6,62 (d, J=8,2 Hz, 2H), 6,50 (s, 1H), 6,18 (d, J=4.0 Hz, 2H), 5,10 (m, 1H), 3,80 (s, 3H), 3,76 (s, 3H), 3,20-and 3.16 (m, 1H), 2,90 (s, 3H), 2,62-of 2.56 (m, 2H), 2,50-2,12 (m, 6N), a 2.0 to 1.60 (m, 7H), USD 1.43 (s, 9H).

13With NMR (75 MHz, CDCl3): δ 157,8, 152,0, 149,8, 148,2, 143,6, 132,4, 130,0, 118,4, 112,0, 111,7, 105,6, 102,2, 79,6, 79,4, 61,8, 57,6, 56,4, 55,8, 53,8, 53,4, 37,6, 35,8, 35,4, 28,2, 26,4, 22,4.

HEE-MS:(M+1)=550 m/z.

(5) 4-{1-(3,4-Dimethoxyphenoxy)-4-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]butyl}benzonitrile

A suspension of tert-butyl 3-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (see stage (4) above; 2.67 g, a 4.86 mmol) in ethyl acetate saturated with HCl (60 ml)was stirred overnight at 25°C in nitrogen atmosphere. The mixture was distributed between water (100 ml) and ethyl acetate (50 ml). The aqueous layer PR is mawali with ethyl acetate (50 ml) before the separation, the alkalization saturated sodium bicarbonate (50 ml) and subsequent extraction with dichloromethane (3×50 ml). The organic extracts were dried (Na2SO4), filtered, concentrated in vacuo and then subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol:concentrated ammonium hydroxide (92:7:1), obtaining of 1.32 g (61%) indicated in the title compound as a yellow oil.

1H NMR (300 MHz, CDCl3): δ a 7.62 (d, J=8,2 Hz, 2H), 7,46 (d, J=8,2 Hz, 2H), 6,62 (d, J=8,2 Hz, 2H), 6,50 (s, 1H), 6,18 (d, J=4.0 Hz, 2H), to 5.21-5,10 (m, 1H), 3,80 (s, 3H), 3,76 (s, 3H), 3,50-of 3.48 (m, 1H), 2,70-2,62 (m, 1H), is 2.40 (s, 3H), 2,48-of 2.30 (m, 4H), 2,10-of 1.40 (m, 10H).

13With NMR (75 MHz, CDCl3): δ 152,0, 149,8, 148,2, 143,6, 132,4, 126,5, 118,4, 112,0, 111,7, 105,6, 102,2, 79,6, 79,4, 62,5, 57,6, 56,4, 55,8, 53,8, 53,4, 37,6, 35,8, 35,4, 28,2, 26,4.

HEE-MS: (M+1)=450 m/z.

Getting To

4-[4-[3-Azabicyclo[3.2.1]Oct-8-yl(methyl)amino]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile

(1) 4-[4-[(3-Benzyl-3-azabicyclo[3.2.1]Oct-8-yl)(methyl)amino]-1-(3.4-dimethoxyphenoxy)butyl]benzonitrile

A mixture of 3-benzyl-N-methyl-3-azabicyclo[3.2.1]Octan-8-amine (receive B; 1.3 g, 5,95 mmol), 4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butylmalonate (receipt, And (3); to 2.41 g, 5,95 mmol) and potassium carbonate (822 mg, 5,95 mmol) in DMF (25 ml) was heated at 90°C in nitrogen atmosphere overnight. The mixture was distributed between water (50 ml) and diethyl ether (40 ml). The aqueous layer was extracted with diethyl EPE is ω (2× 40 ml). The combined organic extracts were washed with brine (2×30 ml), dried (Na2SO4), filtered and then concentrated in vacuum. The residue was subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol (98:2), to obtain 860 mg (27%) indicated in the subtitle of the connection.

1H NMR (300 MHz, CDCl3): δ a 7.62 (d, J=8,2 Hz, 2H), 7,46 (d, J=8,2 Hz, 2H), 7,38-7,20 (m, 5H), 6,62 (d, J=8,2 Hz, 2H), 6,50 (s, 1H), 6,18 (d, J=4.0 Hz, 2H), 5,22-5,10 (m, 1H), 3,80 (s, 3H), 3,76 (s, 3H), 3,50 (s, 2H), 2,68-2,52 (m, 2H), 2,50-of 2.28 (m, 4H), of 2.15 (s, 3H), 2.0 to about 1.75 (m, 4H), 1,68 of 1.50 (m, 5H).

13With NMR (75 MHz, CDCl3): δ 152,0, 149,8, 148,2, 143,6, 140,0, 132,4, 128,0, 127,8, 126,0, 118,4, 112,0, 111,7, 105,6, 102,2, 79,6, 68,4, 61,8, 59,2, 57,6, 56,4, 55,8, 53,8, 53,4, 39,8, 35,8, 35,4, 28,2, 22,4.

HEE-MS:(M+1)=540 m/z.

(2) 4-[4-[3-Azabicyclo[3.2.1]Oct-8-yl(methyl)amino]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile

A solution of HCl in diethyl ether (4,1 ml of 1.0 M, 4.1 mmol) was added dropwise to a solution of 4-[4-[(3-benzyl-3-azabicyclo[3.2.1]Oct-8-yl)(methyl)amino]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile (see stage (1) above; (2.20 g, 4,08 mmol) in diethyl ether (50 ml) at 0°C. Concentration in vacuo allowed to obtain the HCl-salt. HCl-salt and 10% palladium on carbon (220 mg) suspended in methanol (20 ml) and stirred in a hydrogen atmosphere at a pressure of 101325,3 PA over night at 40°C. the Catalyst was removed by filtration through a small layer of Celite®by washing with methanol (50 ml). The filtrate is concentrated is Ali in vacuo and subjected to chromatography on silica gel, elwira a mixture of dichloromethane:methanol:concentrated ammonium hydroxide (88:10:2), to obtain 502 mg (28%) indicated in the title compound in the form of foam, white with a yellowish tinge.

So pl.: 47-53°

1H NMR (300 MHz, CD3OD): δ a 7.62 (d, J=8,2 Hz, 2H), 7,46 (d, J=8,2 Hz, 2H), 6,62 (d, J=8,2 Hz, 2H), 6,50 (s, 1H), 6,18 (d, J=4.0 Hz, 2H), 5,22-5,10 (m, 1H), 3,80 (s, 3H), 3,76 (s, 3H), 3.33 and-3,20 (m, 2H), 2,50-of 2.30 (m, 6N), of 2.15 (s, 3H), 2,20-2,0 (m, 3H), 1,92 of 1.50 (m, 5H).

13With NMR (75 MHz, CD3OD): δ 152,0, 149,8, 148,2, 143,6, 132,4, 128,0, 118,4, 112,0, 111,7, 105,6, 102,2, 79,6, 68,4, 57,6, 56,4, 55,8, 50,5, 44,6, 39,8, 35,8, 35,4, 26,2, 22,4.

HEE-MS:(M+1)=450 m/z.

Obtaining L

4-{2-[8-(Methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]ethoxy}benzonitrile

(1) 4-(2-Bromoethoxy)benzonitrile

A mixture of 4-cyanophora (35,7 g, 0.3 mol), K2CO3(up 41.4 g, 0.3 mol) and 1,2-dibromethane (561 g, 3.0 mol) in MeCN (450 ml) was stirred while boiling under reflux overnight. The mixture was filtered and evaporated to obtain 30,2 g (45%) indicated in the subtitle compound that was used without further purification.

(2) tert-Butyl-3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate

A mixture of 4-(2-bromoethoxy)benzonitrile (see stage (1) above; 0,94 g, 4.2 mmol), tert-butyl-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (Receiving G; 0,91 g, 3.8 mmol) and K2CO3(0,79 g, 5.7 mmol) in 15 ml of dry DMF was stirred at 90°With over night before adding additional is th number K 2CO3(1 g). The mixture was diluted with 300 ml DHM and the mixture was washed with water. The organic layer was separated, dried using Na2SO4and then evaporated. The crude product was purified by flash chromatography on silica gel, elwira mixture DHM:MeOH (10:1)containing 0.1% triethylamine (tea), with 1.1 g (76%) indicated in the subtitle of the connection.

(3) 4-{2-[8-(Methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]ethoxy}-benzonitrile

Ethyl acetate (30 ml), saturated with gaseous HCl at 0° (C) was added to a solution of tert-butyl 3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (see stage (2) above; 1.1 g, 2.8 mmol) in ethyl acetate. The resulting mixture was stirred for 4 h at K.T.

The solvent was removed in vacuum before adding MeCN (29 ml), water (1.5 ml) and K2CO3(2.4 g). The resulting mixture was stirred overnight before filtration, washed with CHCl3and then was concentrated in vacuum to obtain 0,79 g (99%) specified in the connection header.

Obtaining M

4-({3-[8-Methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]propyl}sulfonyl)benzonitrile

(1) 4-[(3-Bromopropyl)sulfanyl]benzonitrile

A mixture of 4-cyanothiophene (20,8 g, 154 mmol), 1,3-dibromopropane (155 g, 0.77 mol) and K2CO3(21,3 g, 154 mmol) in MeCN (300 ml) was boiled under reflux overnight. Filtration and evaporation process is itele allowed to obtain brown oil, which crystallized in the processing of EtOH. The crystals were isolated by filtration to obtain specified in the subtitle compound (24.5 g, 62%).

(2) 4-[(3-Bromopropyl)sulfonyl]benzonitrile

3-Chloroperoxybenzoic acid (44,9 g 70%, 182 mmol) was slowly added to a cooled (0° (C) to a solution of 4-[(3-bromopropyl)sulfanyl]-benzonitrile (see stage (1) above; and 23.4 g, 91 mmol) in DHM (250 ml). The mixture was then stirred at K.T. overnight and the resulting precipitate was filtered. The filtrate was concentrated in vacuo to obtain a residue, which, as was shown by NMR analysis), contains 25% sulfoxide in addition to the desired product. The residue was re-dissolved in DHM (250 ml), was added an additional amount of 3-chloroperoxybenzoic acid (5.6 g 70%, 23 mmol) and the mixture was stirred for 30 minutes was Added dimethylsulfoxide (20 mmol) to neutralize the excess m-HPBK before washing solution DHM aqueous NaHCO3, separation, drying and concentrating in vacuo. It is possible to obtain specified in the subtitle compound with 76% yield.

(3) tert-Butyl 3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate

Specified in the subtitle compound was obtained in 70% yield (1.1 g) in accordance with the method described in Obtaining L (2) above, using 4-[(3-bromopropyl)sulfonyl]bentonite is (see stage (2) above) instead of 4-(2-bromoethoxy)benzonitrile.

(4) 4-({3-[8-(Methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]propyl}sulfonyl)-benzonitrile

Specified in the title compound was obtained with 100% yield according to the method described in Obtaining L (3) above, using tert-butyl 3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (see stage (3) above) instead of tert-butyl 3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate.

Obtaining N

4-{2-[8-(Methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]ethoxy}isophthalonitrile

(1) 4-(2-Bromoethoxy)isophthalonitrile

Specified in the subtitle compound was obtained with a 64% yield according to the method described in Obtaining L (1) above, using 4-hydroxyisophthalate instead of 4-cyanophora.

(2) tert-Butyl-3-[2-(2.4-dicyanobenzene)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate

Specified in the subtitle compound was obtained with 85% yield according to the method described in Obtaining L (2) above, using 4-(2-bromoethoxy)isophthalonitrile (see stage (1) above) instead of 4-(2-bromoethoxy)benzonitrile.

(3) 4-{2-[8-(Methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]ethoxy}isophthalonitrile

Specified in the title compound was obtained with 20% yield according to the method described in Obtaining L (3) above, using tert-butyl 3-[2-(2,4-dicyanobenzene)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)shall arbamate instead of tert-butyl 3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate.

Getting O

4-{1-(4-Hydroxyphenoxy)-4-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]butyl}benzonitrile

(1) 4-{1-[4-(Tetrahydro-2H-Piran-2-yloxy)phenoxy]-3-butenyl}benzonitrile

Chilled (0° (C) a mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (4,93 g, 28.5 mmol) and 4-(tetrahydro-2H-Piran-2-yloxy)phenol (8,3 g, and 42.7 mmol) in dry THF (200 ml) was treated with tributylphosphine (cent to 8.85 ml, and 42.7 mmol)and then 1,1'-(azodicarbon)dipiperidino (10,77 g, and 42.7 mmol). After complete addition, the reaction mixture was stirred at 0°C for 10 min before mixing with K.T. during the night. The precipitate of oxide tributylphosphine was removed by filtration and the filtrate was concentrated in vacuum to obtain 24.6 g of the crude product. It was purified by chromatography on silica gel, elwira with a mixture of isopropyl alcohol:EtOAc:heptane (5:5:90), to obtain 4.6 g (47%) indicated in the subtitle of the connection.

(2) 4-{4-Hydroxy-1-[4-(tetrahydro-2H-Piran-2-yloxy)phenoxy]butyl}benzonitrile

Borane-dimethylsulfide complex (3.5 ml 2 M in diethyl ether, 7 mmol) was added dropwise to a chilled (5° (C) to a solution of 4-{1-[4-(tetrahydro-2H-Piran-2-yloxy)phenoxy]-3-butenyl}benzonitrile (see stage (1) above; 4.6 g, 13 mmol) in dry THF for 15 min the Resulting mixture was stirred at a temperature of from 0 to 5°for 1.5 hours Stirring then continued for an additional 4 h p and K.T. Was added water (14 ml) and NaBO3(5 g) and the mixture was stirred over night. Added diethyl ether and the resulting organic layer was separated, washed with water and brine, dried and then evaporated. The resulting residue was purified by chromatography on silica gel, elwira with a mixture of isopropyl alcohol:Eyes:heptane (5:20:70), with the receipt of 2.44 g (58%) indicated in the subtitle of the connection.

(3) 4-(4-Cyanophenyl)-4-[4-(tetrahydro-2H-Piran-2-yloxy)phenoxy]butyl methanesulfonate

A solution of 4-{4-hydroxy-1-[4-(tetrahydro-2H-Piran-2-yloxy)phenoxy]butyl}benzonitrile (see stage (2) above; 2,37 g of 6.45 mmol) and triethylamine (tea) (1.35 ml, 9,68 mmol) in DHM (10 ml) was cooled to -5°C. was Slowly added methanesulfonamide (0,65 ml, scored 8.38 mmol) in DHM (5 ml). After complete addition the temperature was maintained below 5°C for 1 h before adding DHM and water. The organic layer was washed with water, dried (Na2SO4) and then evaporated to obtain 2,87 g (100%) specified in the subtitle compound. It was used in the next stage without additional purification.

(4) tert-Butyl 3-{4-(4-cyanophenyl)-4-[4-(tetrahydro-2H-Piran-2-yloxy)-phenoxy]butyl}-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate

Specified in the subtitle compound was obtained from 93.4% yield according to the method described in Obtaining L (2) above, using 4-(4-cyanophenyl)-4-[4-(those who rehydro-2H-Piran-2-yloxy)phenoxy]butyl methanesulfonate (see stage (3) above) and MeCN instead of 4-(2-bromoethoxy)benzonitrile and DMF, respectively.

(5) 4-{1-(4-Hydroxyphenoxy)-4-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]butyl}benzonitrile

Specified in the title compound was obtained with 83.4% of the output in accordance with the method described in Obtaining L (3) above, using tert-butyl 3-{4-(4-cyanophenyl)-4-[4-(tetrahydro-2H-Piran-2-yloxy)-phenoxy]butyl}-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (see stage (4) above) instead of tert-butyl 3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate.

Obtaining Paragraph

Methyl-(1S)-2-(4-cianfrocca)-1-{[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]methyl}ethylcarbamate

(1) 4-[(2R)-Oxiranylmethyl]benzonitrile

Specified in the title compound was obtained in accordance with the method described in Obtaining D (1) above using S-epichlorohydrin instead of epichlorohydrin.

(2) 4-{[(2R)-3-Amino-2-hydroxypropyl]oxy}benzonitrile

4-[(2R)-Oxiranylmethyl]benzonitrile (see stage (1) above; 14,65 g, with 83.6 mmol) was mixed with NH4OH (conc., 64 ml) and 87 ml of isopropanol. The mixture was stirred at K.T. within 18 hours, the Reaction mixture was then filtered and evaporated to obtain 14.6 g (91%) indicated in the subtitle compound as a white solid.

(3) Benzyl-(2R)-3-(4-cianfrocca)-2-hydroxypropionate

A mixture of 4-{[(2R)-3-amino-2-hydroxypropyl]oxy}benzonitrile (see stage (2) above; 3,4 is, to 17.7 mmol), tea (2,69 g of 26.6 mmol) and CHCl3(20 ml) was cooled to 0°before the slow addition of N-(benzyloxycarbonyloxy)succinimide (a 4.86 g of 19.5 mol) in CHCl3(15 ml). The mixture was allowed to reach K.T. and it was stirred at this temperature overnight. The solvent is evaporated to obtain a residue, which was dissolved in DHM. This solution was washed with water and brine and then dried (Na2SO4). Evaporation of the solvent was allowed to get 5,79 g (100%) specified in the subtitle of the connection.

(4) (1R)-2-{[(Benzyloxy)carbonyl]amino}-1-[(4-cyanogenetic)methyl]-ethyl-methanesulfonate

To a solution of benzyl-(2R)-3-(4-cianfrocca)-2-hydroxypropionate (see stage (3) above; 5,79 g of 17.7 mmol) in pyridine (15 ml) was added 4-(dimethylamino)pyridine (0,22 g, 1.77 mmol). The mixture was cooled to 0°and slowly at 0°With added methanesulfonamide (2,23 g of 19.5 mmol). The mixture was allowed to reach K.T., in which it then was stirred for 4 hours the Solvent is evaporated. Added DHM (100 ml), washed with water, 1 n H2SO4and brine, dried (Na2SO4) and evaporated to obtain 6.0 g (84%) of a yellow oil.

(5) Benzyl-(2S)-2-[(4-cianfrocca)methyl]-1-aziridination

The NaOH solution in water (11 ml of 50 wt.%) was added with vigorous stirring to a solution of (1R)-2-{[(benzyloxy)carbonyl]amino}-1-[(4-cianfrocca)-methyl]this is methansulfonate (see stage (4) above; 5.7 g, 14.1 mmol) and tetrabutylammonium hydrosulfate (0.6 g, 1.7 mmol) in DHM (34 ml). The mixture was stirred for 1 h before addition of water (200 ml) and diethyl ether (200 ml). The organic phase is washed with water and then dried. The solvents are evaporated and the resulting residue was purified using chromatography (DHM as eluent) to give 3.0 g (69%) indicated in the subtitle of the connection.

(6) Benzyl(1S)-2-{8-[(tert-butoxycarbonyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-1-[(4-cianfrocca)methyl]ethylcarbamate

Benzyl(2S)-2-[(4-cianfrocca)methyl]-1-aziridination (see stage (5) above; 1.3 g, 4.2 mmol) and tert-butyl-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (Receiving G; 1.1 g, 4.6 mmol) was mixed with isopropyl alcohol (15 ml) and stirred at 60°With during the night. The solvent is then evaporated to obtain a residue, which was purified by chromatography on silica gel, elwira mixture DHM:MeOH (100:3), with 1.9 grams (82%) indicated in the subtitle of the connection.

(7) tert-Butyl 3-[(2S)-2-amino-3-(4-cianfrocca)propyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate

Benzyl(1S)-2-{8-[tert-butoxycarbonyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-1-[(4-cianfrocca)methyl]ethylcarbamate (see stage (6) above; 1.8 g, 3.3 mmol) was dissolved in ethanol (50 ml 95%). The solution was first made over 5% Pd/C for 1 h, after which the mixture was filtered through Celite®. Shown that the antibody was concentrated in vacuum to obtain 1.3 g (95%) indicated in the subtitle of the connection.

(8) Methyl-(1S)-2-{8-[(tert-butoxycarbonyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-1-[(4-cianfrocca)methyl]ethylcarbamate

Methylchloroform (0,24 ml of 3.32 mmol) was added at 0°to a mixture of tert-butyl 3-[(2S)-2-amino-3-(4-cianfrocca)propyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (see stage (7) above; 1.2 g, 2.9 mmol) and tea (1.2 ml, 9 mmol) in DHM (30 ml). The mixture was allowed to reach K.T. for 3 h, after which was added a saturated solution of Na2CO3. The organic phase was separated, dried and evaporated to obtain the crude product, which was purified by chromatography on silica gel. It is possible to obtain 0.6 g (45%) indicated in the subtitle of the connection.

(9) Methyl-(1S)-2-(4-cianfrocca)-1-{[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]methyl}ethylcarbamate

Specified in the title compound was obtained from 87% yield according to the method described in Obtaining L (3) above, using methyl-(1S)-2-{8-[(tert-butoxycarbonyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-1-[(4-cianfrocca)methyl]ethylcarbamate (see stage (8) above) instead of tert-butyl 3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate.

Obtaining P

tert-Butyl(1S)-2-(4-cianfrocca)-1-{[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]methyl}ethylcarbamate

(1) tert-Butyl(2R)-3-(4-cianfrocca)-2-hydroxypropionate

4-{[(2R)-3-Amino-2-hydroxypropyl]oxy}benzonitrile (Obtaining P(2); 6.8 g, 3.5 mmol) was dissolved in a mixture of THF/water (8:1). The solution was cooled in an ice bath and was added di-tert-BUTYLCARBAMATE (7.7 g, 3.5 mmol). The mixture was stirred at K.T. during the night before the evaporation of solvents and adding DHM. The resulting solution was washed with water, dried (Na2SO4) and evaporated to obtain 9.2 grams specified in the subtitle of the connection.

(2) (1R)-2-[(tert-Butoxycarbonyl)amino]-1-[(4-cianfrocca)methyl]ethyl-methanesulfonate

Specified in the subtitle compound was obtained with 100% yield according to the method described in Obtaining Paragraph (4) above, using tert-butyl(2R)-3-(4-cianfrocca)-2-hydroxypropionate (see stage (1) above) instead of benzyl-(2R)-3-(4-cianfrocca)-2-hydroxypropionate.

(3) tert-Butyl(2S)-2-[(4-cianfrocca)methyl]-1-aziridination

Specified in the subtitle compound was obtained in accordance with the method described in Obtaining Paragraph (5) above, using (1R)-2-[(tert-butoxycarbonyl)amino]-1-[(4-cianfrocca)methyl]ethyl-methanesulfonate (see stage (2) above) instead of (1R)-2-{[(benzyloxy)carbonyl]amino}-1-[(4-cianfrocca)methyl]ethyl-methanesulfonate.

(4) tert-Butyl methyl[3-(2,2,2-TRIFLUOROACETYL)-3-azabicyclo[3.2.1]Oct-8-yl]carbamate

Triperoxonane anhydride (10.5 g, 50 mmol) was added dropwise to a cooled (0° (C) a mixture of tert-butyl 3-azabicyclo[3.2.1]Oct-8-yl(METI is)carbamate (Receiving G; 11.1 g, 46 mmol), tea (5.6 g, 55 mmol) and toluene (120 ml). The mixture was stirred for 3 h and then evaporated. The resulting residue was dissolved in DHM and the resulting solution washed with 1 M HCl (cold). The organic layer was separated, dried and evaporated to obtain 14.8 g (96%) indicated in the subtitle of the connection.

(5) 2,2,2-Cryptor-1-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]-1-alanon

Ethyl acetate (100 ml)saturated with HCl (gas.), was added at 0°to a solution of tert-butyl methyl[3-(2,2,2-TRIFLUOROACETYL)-3-azabicyclo[3.2.1]Oct-8-yl]carbamate (see stage (4) above; 5 g, 15 mmol) in ethyl acetate (50 ml). The mixture was allowed to reach K.T. for 3 h, after which the solvent is evaporated. It is possible to obtain 4 g (100%) of the hydrochloride salt specified in the subtitle of the connection.

(6) 1-{8-[Benzyl(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-2,2,2-Cryptor-1 alanon

A mixture of 2,2,2-Cryptor-1-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]-1-ethanone (see stage (5) above; 4.5 g, 16 mmol), benzylchloride (3.0 g, 16 mmol) and tea (6.6 ml) in MeCN (50 ml) was stirred at 60°With during the night. The mixture is evaporated and then added DHM and water. The organic phase is washed with a solution of NaHCO3, dried (Na2SO4) and then evaporated. The resulting crude product was purified by chromatography on silica gel (DHM as eluent) to give 2.2 g (42%) indicated the CSOs in the subtitle of the connection.

(7) N-Benzyl-N-methyl-3-azabicyclo[3.2.1]Octan-8-amine

A mixture of 1-{8-[benzyl(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-2,2,2-Cryptor-1 ethanone (see stage (6) above; 2.1 g, 6.4 mmol) and K2CO3(3 g, and 21.7 mmol) in a mixture of MeOH/water (110 ml of a mixture of 10:1) was stirred at K.T. over night and then evaporated. Added DHM and water and the layers were separated. The aqueous layer was extracted with DHM (3 x). The combined organic layers were dried and evaporated to obtain 1.2 g (81%) indicated in the subtitle of the connection.

(8) tert-Butyl(1S)-2-{8-[benzyl(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-1-[(4-cianfrocca)methyl]ethylcarbamate

A mixture of tert-butyl(2S)-2-[(4-cianfrocca)methyl]-1-aziridination (see stage (3) above; 1.26 g, 4.6 mmol) and N-benzyl-N-methyl-3-azabicyclo[3.2.1]Octan-8-amine (see stage (7) above; 1,05 g, 4.6 mmol) in isopropyl alcohol (15 ml) was stirred at 60°With during the night. The solvent is evaporated and the residue was purified by chromatography on silica gel, elwira mixture DHM:MeOH (20:1). It is possible to obtain 1.8 g (78%) indicated in the subtitle of the connection.

(9) tert-Butyl(1S)-2-(4-cianfrocca)-1-{[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]methyl}ethylcarbamate

A mixture of tert-butyl(1S)-2-{8-[benzyl(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-1-[(4-cianfrocca)methyl]ethylcarbamate (0.8 g, 1.6 mmol), 1 M HCl (0.8 ml) and MeOH (30 ml) was first made over 5% Pd/C. the Reaction was stopped when the consumed amount of N2, rasschitanna is to complete the reaction. The mixture was filtered through silica and the filtrate evaporated. The resulting crude product was purified on silica gel, elwira mixture DHM:ammonia-methanol (9:1), to obtain 0.4 g (61%) specified in the connection header.

Getting

2-(atomic charges)-1,1-dimethylethyl-1H-imidazole-1-carboxylate

A mixture of 2-hydroxy-2-methylpropylamine (3,35 g, to 25.3 mmol) and 1,1'-carbonyldiimidazole (4.11 g, to 25.3 mmol) in DHM was stirred for 8 h at K.T. Mixture then was transferred into a closed vessel and heated to 100°With during the night. The mixture was then concentrated in vacuum before adding diethyl ether and water. The organic phase was separated, dried and concentrated in vacuum. The resulting residue was purified by chromatography on silica gel, elwira a mixture of THF:heptane (1:1), obtaining specified in the connection header with 20% yield.

Getting T

1-Cyano-1-methylethyl-1H-imidazole-1-carboxylate

A mixture of 1,1'-carbonyldiimidazole (5 g, 31 mmol) and 2-hydroxy-2-methylpropionitrile (2.6 g, 31 mmol) in DHM was stirred at K.T. during the night. Added water and the organic layer was separated, dried (Na2SO4) and concentrated in vacuum. The resulting residue was purified by chromatography on silica gel, elwira with ethyl acetate, to obtain 2.7 g (50%) specified in the connection header.

Receiving At

2-(4-Morpholinyl)ethyl-1H-imidazole-1-carboxylate

A mixture of 1,1'-carbonyldiimidazole (6.5 g, 40 mmol) and 2-(4-morpholinyl)-1-ethanol (5.0 g, 38,1 mmol) in DHM (200 ml) was stirred for 22 h at K.T. was Added diethyl ether (400 ml) and the mixture was washed with water. The aqueous layer was then extracted DHM. The combined organic layers were dried over Na2SO4and evaporated to obtain 6.0 g (70%) specified in the connection header.

Getting f

2-(4-Pyridinyl)ethyl-1H-imidazole-1-carboxylate

Specified in the title compound was obtained with 100% yield according to the method described in Obtaining The above using 2-(4-pyridinyl)-1-ethanol instead of 2-(4-morpholinyl)-1-ethanol.

Getting X

N-[2-(2-Methoxyethoxy)ethyl]-1H-imidazol-1-carboxamid

Specified in the title compound was obtained with 40% yield according to the method described in Obtaining The above using 2-(2-methoxyethoxy)ethylamine instead of 2-(4-morpholinyl)-1-ethanol.

Getting C

2-(4-Acetyl-1-piperazinil)ethyl-1H-imidazole-1-carboxylate

(1) 1-[4-(2-Hydroxyethyl)-1-piperazinil]-alanon

A solution of 2-(1-piperazinil)-1-ethanol (6.5 g, 0.05 mol) in DHM (5 ml) was treated with acetic anhydride (5.1 g, 0.05 mol)is added dropwise. During the addition the temperature of the reaction mixture increased from 22 to 60°C. the Reaction mixture is evaporated several times using toluene with p is the receiving of 5.6 g (65%) indicated in the subtitle of the connection.

(2) 2-(4-Acetyl-1-piperazinil)ethyl-1H-imidazole-1-carboxylate

A solution of 1,1'-carbonyldiimidazole (5 g, 31 mmol) in DHM (200 ml) was treated with a solution of 1-[4-(2-hydroxyethyl)-1-piperazinil]-1-ethanone (see stage (1) above; 5 g, 29 mmol) in DHM (50 ml). The reaction mixture was stirred at K.T. over night before adding water. The layers were separated and the organic layer was washed with water, dried and concentrated in vacuum to obtain 7.4 g (96%) specified in the connection header.

Getting H

1-[4-(3-Bromopropyl)-1-piperazinil]-1-alanon

A mixture of 1-(1-piperazinil)-1-ethanone (6.7 g, 0,052 mol), dibromopropane (330 ml, excess) and K2CO3(10.2 g, 0.079 in mol) was stirred at K.T. within 4 hours the Mixture was washed 4×100 ml of water and the organic phase (diluted DHM) was acidified aqueous Hydrobromic acid (7 ml 62% HBr dissolved in 150 ml of water). The organic layer was separated and washed with water (2×50 ml). The combined aqueous layers was extracted with diethyl ether, neutralized (to pH 7) 13 ml of 10 M NaOH and then was extracted with DHM. The combined organic layers were dried and concentrated in vacuum to obtain 4.1 g (32%) specified in the connection header.

Getting sh

3-(Ethylsulfonyl)propyl-4-methylbenzenesulfonate

(1) 3-(Ethylsulfonyl)-1-propanol

A solution of 3-(ethylthio)-1-propanol (13 g, 0.11 mol) in acetic acid (40 ml) was treated with N2O2 (30% in water, 12.2 g, 0.11 mol)is added dropwise. The mixture was stirred for 2 h at K.T. before concentrating in vacuo. Analysis using NMR showed that the resulting residue consists of 40% of the desired product and 60% of the corresponding O-acetate. The acetate is hydrolyzed by dissolving the reaction mixture in 200 ml of methanol and add 3 g of NaOH (dissolved in a little water). The mixture was stirred over night at K.T., then concentrated in vacuo. The resulting crude product was dissolved in DHM and the insoluble substance was filtered. DHM was removed by evaporation to obtain a 13.4 g (88%) indicated in the subtitle of the connection.

(2) 3-(Ethylsulfonyl)propyl-4-methylbenzenesulfonate

A mixture of 3-(ethylsulfonyl)-1-propanol (see stage (1) above; and 13.4 g, 88 mmol) and para-toluensulfonate (16,8 g, 88 mmol) in DHM (150 ml) was treated with the tea (13,4 g, 132 mmol)added dropwise. The resulting mixture was stirred at K.T. for 3 h before washing with an aqueous solution of ammonium chloride. The organic layer was then separated, dried and concentrated in vacuum. The product was crystallized from diethyl ether containing a small amount DHM, to obtain 17.9 g (66%) specified in the connection header.

The following intermediate compounds or were selling the same or received in accordance with published methods:

3,4-dimethoxyphenethyl-methanesulfonate;

exisitant;

utilitzant;

butanolate;

1-butanesulfonate;

1-chlorination;

4-isocyanato-3,5-dimethylisoxazol;

pair-toluensulfonate;

4-methoxyphenylalanine;

2 isocyanatoacetate-2H-Piran;

isopropyltoluene;

3,4-differentiational;

utilitzant;

1-(isocyanatomethyl)cyclopropane;

2-(acetylamino)-4-methyl-1,3-triazole-5-sulphonylchloride;

4-nitrobenzenesulfonamide;

N-acetylsulfapyridine;

isopropylacetanilide;

3,4-dimethoxybenzenesulfonamide;

5-chloro-1,3-dimethylpyrazol-4-sulphonylchloride;

1,1-dioxo-2,5-dihydro-1-thiophene-3-sulphonylchloride;

acanaloniidae;

ethylchloride;

2-buten-1-chloroformiate;

2-methoxyethylamine;

the as-5-acetic acid;

2-{[2-(acetylamino)acetyl]amino}acetic acid;

metacercaria acid;

DL-glyceric acid;

pyrrole-2-carboxylic acid;

2-methylpropionate acid;

benzofurazan-5-carboxylic acid;

2-hydroxy-3-budinova acid;

3-(tert-butyl)-1-methyl-1H-pyrazole-5-carboxylic acid;

(chloromethyl)cyclopropane;

2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-Etalon;

N-isopropylacrylamide;

1-bromo-2-(2-methoxyethoxy)ethane;

4-florantyrone;

2-bromo-4'-methoxyacetophenone;

4-(triptoreline)phenylisocyanate;

3-(methylsulphonyl)propyl-1-chloroformiate and

3-matlakala acid.

The synthesis of compounds of formula I

Example 1

tert-Butyl 8-{[3-(4-cyanoimino)propyl](methyl)amino}-3-azabicyclo[3.2.1]octane-3-carboxylate

A mixture of 4-({3-[3-azabicyclo[3.2.1]Oct-8-yl(methyl)amino]propyl}amino)-benzonitrile (Getting 3; 170 mg, 0,569 mmol) and di-tert-BUTYLCARBAMATE (124 mg, 0,569 mmol) in dichloromethane (3.0 ml) was stirred for 2 h at 25°C in nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was subjected to chromatography on silica gel, elwira mixture ethylacetoacetate (1:2), to obtain 90 mg (40%) indicated in the title compounds as colorless oils.

1H NMR (300 MHz, CDCl3): δ 7,40 (d, J=8,2 Hz, 2H), 6,50 (d, J=8,2 Hz, 2H), of 5.45 (s, 1H), 3,68-of 3.60 (m, 1H), 3,52 is 3.40 (m, 1H), 3,32-3,10 (m, 4H), 2,60 (s, 2H), 2,30 (s, 3H), 2,22-of 2.15 (m, 3H), 1,92 is 1.60 (m, 6H), 1,45 (s, 9H).

13With NMR (75 MHz, CDCl3): δ 156,4, 151,6, 133,6, 120,6, 112,0, 108,1, 79,4, 67,8, 54,2, 45,0, 44,0, 42,7, 39,8, 35,6, 28,4, 26,0, 25,4.

HEE-MS:(M+1)=399 m/z.

Example 2

tert-Butyl 8-[[3-(4-cianfrocca)-2-hydroxypropyl](methyl)amino]-3-azabicyclo[3.2.1]octane-3-carboxylate

A mixture of 4-{3-[3-azabicyclo[3.2.1]Oct-8-yl(methyl)amino]-2-hydroxypropoxy}benzonitrile (Getting D; 229 mg, 0,726 mmol) and di-tert-BUTYLCARBAMATE (158 mg, 0,726 mmol) in dichloro ethane (3.0 ml) was stirred for 2 h at 25° C in nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was subjected to chromatography on silica gel, elwira a mixture of ethyl acetate:dichloromethane (1:2), to obtain 70 mg (25%) indicated in the title compounds as colorless oils.

1H NMR (300 MHz, CDCl3): δ 7,58 (d, J=8,2 Hz, 2H), 6,97 (d, J=8,2 Hz, 2H), 4,30-4,16 (m, 1H), 4,12 to 4.0 (m, 2H), 3,70-3,10 (m, 5H), 2,82-2,70 (m, 1H), 2,52 is 2.10 (m, 4H), of 2.30 (s, 3H), 1,80-of 1.52 (m, 4H), 1,45 (s, 9H).

13With NMR (75 MHz, CDCl3): δ 162, 4, 156,5, 134,0, 119,5, 115,6, 104,4, 79,5, 70,6, 68,0, 66,0, 57,7, 45,0, 43,8, 40,4, 36,8, 36,2, 28,5, 27,8.

HEE-MS:(M+1)=416 m/z.

Example 3

N-{3-[2-(4-Cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-ethyl-N-metalmachine

The solution utilizationof (0.8 ml, to 9.66 mmol) in DHM (3 ml) dropwise at 0° (C) was added to a mixture of 4-{2-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]ethoxy}benzonitrile (Receiving L; 2.5 g, 8,76 mmol) and MeCN (50 ml). The mixture was stirred at K.T. for 3 h, was added To the2CO3(2 g, 14.4 mmol) and the mixture was stirred for additional 2 h Filtration and evaporation was allowed to get 2,96 g of the crude product. It was twice purified by chromatography on silica gel, first time elwira gradient EtOAc:MeOH:ammonia-methanol (10:1:0 to 10:0:1) and the second time elwira mixture DHM:MeOH:tea (190:10:1). It is possible to obtain 2.3 g (71,4%) specified in the connection header.

13With NMR (CD3OD): δ 15,84, 26,98, 36,35, 36,54, 38,70, 55,02, 57,88, 61,99, 67,68, 104,67, 116,66, 120,11, 135,16, 163,68,163,94.

MS(elektrorazpredelenie (ER)): (M+1)=357,0 m/z.

Example 4

N-{3-[3-(4-Cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-1-butanesulfonate

A solution of 1-butanesulfinamide (39,1 mg, 0.25 mmol) in MeCN (2 ml) was added to a solution of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]propyl}amino)benzonitrile (Getting W; 74,6 mg, 0.25 mmol) in CHCl3(0.5 ml). Added To2CO3and the mixture was stirred at K.T. within 24 hours the Mixture was filtered through a plug of silica (500 mg), which was then implemented the elution mixture MeCH:CHCl3(80:20; 3×2.5 ml), and then a mixture of CHCl3:MeOH (95:5), obtaining specified in the connection header with 35% yield.

MC(ER):(M+1)=419,2 m/z.

Example 5

Ethyl-3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate

A mixture of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]propyl}amino)-benzonitrile (Getting W; 74,6 mg, 0.25 mmol) and ethylchloride (29,8 mg, 0.27 mmol) in DMF (2.5 ml) was stirred at K.T. within 24 hours of Mass spectroscopic analysis showed that the starting amine compound has trashdolls not completely, and so it was added an additional amount of ethylchloride (50 μl). The mixture was stirred overnight, after which it was concentrated in vacuum. The resulting residue was dissolved in a mixture DHM (0.5 ml) and MeCN (2 ml). Added To2CO3(100 mg, 0.7 mmol) and the MCA is ü was stirred for 4 h Filtration of the mixture and evaporation of the filtrate allowed to obtain a residue, which was dissolved in CHCl3(1 ml). The solution was filtered through a plug for ion-exchange solid-phase extraction (IAS, 2 g). The original flask was rinsed with additional CHCl3(0.75 ml), which was then added to the extraction tube and suirable as fraction 1. The tube was then subjected to elution with a mixture of CHCl3:MeOH:tea(8:1:1, 4×2 ml) with additional fractions, which were found not to contain any product. Fraction 1 was then added to the tube of silicon dioxide, which was then subjected to elution with a mixture of CHCl3:MeCN (4:1, 3×2.5 ml).

Evaporation of the collected fractions was allowed to get to 79.6 mg (85,9%) specified in the connection header.

MC(ER):(M+1)=371,5 m/z.

Example 6

N-{3-[3-(4-Cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,3-Dimethylbutane

1,3-Dicyclohexylcarbodiimide N metropolitical (0,67 g 2,39 mmol/g of 1.74 mmol) was added to a solution of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]propyl}amino)benzonitrile (Getting W; 74,6 mg, 0.25 mmol) in DMF (3.0 ml). Solution was added 3-methylmalonic acid (105,0 mg of 1.02 mmol) in DHM (1.0 ml) and the mixture was stirred over night at K.T., and then further 72 h at 50°C. was Added politicalization (150 mg) and DHM (1.5 ml) and the mixture was stirred for 1.5 hours was Added to the 2CO3(75 mg) and the mixture was stirred for additional 5 hours, the Solvent evaporated and the resulting residue was added DHM (3 ml). This mixture was added to the tube for ion-exchange solid-phase extraction (IAS). The tube was washed with a mixture DHM:MeCN (4:1; 10 ml). The product was then suirable mixture DHM:MeOH:tea (90:5:5; 7.5 ml) to give 75 mg (70.9 per cent) specified in the connection header.

MS(ER): 383,3 m/z.

Example 7

The following compounds were obtained from the appropriate intermediates (such as intermediate compounds described above) according to or by analogy with the methods described above and/or using standard methods of solid-phase or liquid-phase combinatorial chemistry (mass spectra of compounds, if their definitions are listed in parentheses: unless otherwise noted, values apply to ions (M+1)defined by electrocapillary):

4-{3-[(3-butyryl-3-azabicyclo[3.2.1]Oct-8-yl)(methyl)amino]-2-hydroxypropoxy}benzonitrile (m/z=386,2);

4-{3-[[3-(butylsulfonyl)-3-azabicyclo[3.2.1]Oct-8-yl](methyl)amino]-2-hydroxypropoxy}benzonitrile (m/z=436,2);

4-{3-[[3-(3,3-dimethyl-2-oxobutyl)-3-azabicyclo[3.2.1]Oct-8-yl](methyl)amino]-2-hydroxypropoxy}benzonitrile (m/z=414,3);

4-{3-[[3-(3,4-dimethoxyphenethyl)-3-azabicyclo[3.2.1]Oct-8-yl](methyl)amino]-2-hydroxypropoxy}benzonitrile (m/z=480,3);

8-[[3-(4-cyanoimino)propyl](methyl)am is but]-N-hexyl-3-azabicyclo[3.2.1]Octan-3-carboxamid (m/z=426,3);

8-[[3-(4-cyanoimino)propyl](methyl)amino]-N-ethyl-3-azabicyclo[3.2.1]Octan-3-carboxamid (m/z=370,3);

4-({3-[(3-butyryl-3-azabicyclo[3.2.1]Oct-8-yl)(methyl)amino]propyl}-amino)benzonitrile (m/z=369,3);

4-({3-[[3-(butylsulfonyl)-3-azabicyclo[3.2.1]Oct-8-yl](methyl)amino]-propyl}amino)benzonitrile (m/z=419,2);

4-({3-[[3-(3,3-dimethyl-2-oxobutyl)-3-azabicyclo[3.2.1]Oct-8-yl](methyl)-amino]propyl}amino)benzonitrile (m/z=397,3);

4-({3-[[3-(3,4-dimethoxyphenethyl)-3-azabicyclo[3.2.1]Oct-8-yl](methyl)-amino]propyl}amino)benzonitrile (m/z=463,3);

8-[[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl](methyl)amino]-N-hexyl-3-azabicyclo[3.2.1]Octan-3-carboxamid (m/z=577,4);

8-[[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl](methyl)amino]-N-ethyl-3-azabicyclo[3.2.1]Octan-3-carboxamid (m/z=521,3);

4-[4-[(3-butyryl-3-azabicyclo[3.2.1]Oct-8-yl)(methyl)amino]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile (m/z=520,3);

4-[4-[[3-(butylsulfonyl)-3-azabicyclo[3.2.1]Oct-8-yl](methyl)amino]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile (m/z=570,3);

4-{1-(3,4-dimethoxyphenoxy)-4-[[3-(3,3-dimethyl-2-oxobutyl)-3-azabicyclo[3.2.1]Oct-8-yl](methyl)amino]butyl}benzonitrile (m/z=548,3);

4-[4-[[3-(3,4-dimethoxyphenethyl)-3-azabicyclo[3.2.1]Oct-8-yl](methyl)amino]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile (m/z=614,4);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-hexyl-N-metalmachine (m/z=443,3);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-e is Il-N-metalmachine (m/z=387,2);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methylbutane (m/z=386,2);

4-(3-{8-[(3,3-dimethyl-2-oxobutyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-2-hydroxypropoxy)benzonitrile (m/z=414,3);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-hexyl-N-metalmachine (m/z=426,3);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-ethyl-N-metalmachine (m/z=370,3);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-butanamide (m/z=369,3);

4-[(3-{8-[(3,3-dimethyl-2-oxobutyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)amino]benzonitrile (m/z=397,3);

4-[(3-{8-[(3,4-dimethoxyphenethyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)amino]benzonitrile (m/z=463,3);

N-{3-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-hexyl-N-metalmachine (m/z=577,4);

N-{3-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-ethyl-N-metalmachine (m/z=521,3);

N-{3-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methylbutane (m/z=520,3);

N-{3-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-1-butanesulfonate (m/z=570,3);

4-(1-(3,4-dimethoxyphenoxy)-4-{8-[(3,3-dimethyl-2-oxobutyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}butyl)benzonitrile (m/z=548,3);

4-[4-{8-[(3,4-dimethoxyphenethyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile (m/z=614,4);

N-{3-[3-(4-qi is noproxy)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-N'-tetrahydro-2H-Piran-2-rocephine (m/z=443);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(cyclopropylmethyl)-N-metalmachine (m/z=413);

3-[3-(4-cyanoimino)propyl]-8-[methyl({[(4-were)sulfonyl]-amino}carbonyl)amino]-3-azabicyclo[3.2.1]octane (ER (M-1): m/z=494);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(cyclopropylmethyl)-N-metalmachine (m/z=397);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-isopropyl-N-metalmachine (m/z=384);

N'-butyl-N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-metalmachine (ER (M-1): m/z=396);

4-(3-{8-[(3,4-dimethoxyphenethyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-2-hydroxypropoxy)benzonitrile (m/z=480,3);

3-[3-(4-cianfrocca)-2-hydroxypropyl]-8-[methyl({[(4-were-sulfonyl]amino}carbonyl)amino]-3-azabicyclo[3.2.1]octane (ER (M-1): m/z=511);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(3,4-differenl)-N-metalmachine (m/z=471);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(4-methoxyphenyl)-N-metalmachine (m/z=448);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(3,4-differenl)-N-metalmachine (m/z=454);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(3,5-dimethyl-4-isoxazolyl)-N-metalmachine (m/z=424);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(4-methoxyphenyl)-N-metalmachine (m/z=435);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-N'-tetrahydro-2H-Piran-elmhaven (m/z=413);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(cyclopropylmethyl)-N-metalmachine (m/z=383);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-isopropyl-N-metalmachine (m/z=371);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(3,4-differenl)-N-metalmachine (m/z=441);

N-(3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl)-N'-(3,5-dimethyl-4-isoxazolyl)-N-metalmachine (m/z=486);

3-{3-[(4-cyanophenyl)sulfonyl]propyl}-8-[methyl({[(4-were-sulfonyl]amino}carbonyl)amino]-3-azabicyclo[3.2.1]octane (ER (M-1): m/z=543);

N-(3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl)-N'-(4-methoxyphenyl)-N-metalmachine (m/z=497);

N-(3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl)-N'-(cyclopropylmethyl)-N-metalmachine (m/z=445);

N-(3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl)-N'-(3,4-differenl)-N-metalmachine (m/z=503);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-1-butanesulfonate (m/z=436,2);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-3,4-dimethoxy-N-methylbenzenesulfonamide (m/z=516,2);

5-chloro-N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,1,3-trimethyl-1H-pyrazole-4-sulfonamide : m/z=508,2);

N-(5-{[{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}(methyl)-amino]sulfonyl}-4-methyl-1,3-thiazol-2-yl)ndimethylacetamide (m/z=from 517.2);

N-{3-[3-(4-cyanoaniline)propyl]-3-AZ is bicyclo[3.2.1]Oct-8-yl}-N-methyl-4-nitrobenzenesulfonamide (m/z=484,2);

N-(4-{[{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}(methyl)-amino]sulfonyl}phenyl)ndimethylacetamide (m/z=496,2);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-3,4-dimethoxy-N-methylbenzenesulfonamide (m/z=499,2);

5-chloro-N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,1,3-trimethyl-1H-pyrazole-4-sulfonamide : m/z=491,2);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-1-econsultant (m/z=391,2);

N-(3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl)-N-methyl-4-nitrobenzenesulfonamide (m/z=533,1);

N-(3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl)-3,4-dimethoxy-N-methylbenzenesulfonamide (m/z=548,2);

N-(5-{[{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-(methyl)amino]sulfonyl}-4-methyl-1,3-thiazol-2-yl)ndimethylacetamide (m/z=504,2);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-4-nitrobenzenesulfonamide (m/z=471,2);

N-(4-{[{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-(methyl)amino]sulfonyl}phenyl)ndimethylacetamide (m/z=483,2);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-2-propanesulfinamide;

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-3,4-dimethoxy-N-methylbenzenesulfonamide (m/z=486,2);

5-chloro-N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,1,3-trimethyl-1H-pyrazole-4-sulfonamide : m/z=478,2);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,1-dimethyl-1H-imidazole-4-sulfonamide : m/z=430,2);

2-butenyl-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=412,5);

2-methoxyethyl-3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=418,5);

3-(methylsulphonyl)propyl-3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate(m/z=480,5);

2-(4-acetyl-1-piperazinil)ethyl-3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate;

2-hydroxy-1,1-dimethylethyl-3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate;

1-cyano-1-methylethyl-3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=410,5);

2-butynyl-3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl-(methyl)carbamate (m/z=395,5);

2-methoxyethyl-3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl-(methyl)carbamate (m/z=401,6);

3-(methylsulphonyl)propyl-3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=463,5);

2-(4-pyridinyl)ethyl-3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=448,6);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-[2-(2-methoxyethoxy)ethyl]-N-metalmachine (m/z=444,6);

ethyl-3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=420,5);

2-hydroxy-1,1-dimethylethyl-3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate;

2-(4-morpholinyl)ethyl-3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=505,5);

N-(3-{3-[(4-cyanophenyl)sulfonyl]propyl}3-azabicyclo[3.2.1]Oct-8-yl)-N'-[2-(2-methoxyethoxy)ethyl]-N-metalmachine (m/z=493,5);

ethyl-3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=358,5);

2-hydroxy-1,1-dimethylethyl-3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate;

1-cyano-1-methylethyl-3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=397,5);

2-butynyl-3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl-(methyl)carbamate (m/z=382,5);

2-methoxyethyl-3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl-(methyl)carbamate (m/z=388,5);

3-(methylsulphonyl)propyl-3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=450,5);

2-(4-pyridinyl)ethyl-3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=435,5);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-2-methoxy-N-methylacetamide (m/z=388,2);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,2-dimethylpropanamide (m/z=386,3);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,3-Dimethylbutane (m/z=400,3);

N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-2,1,3-benzoxadiazole-5-carboxamide (m/z=461,5);

3-(tert-butyl)-N-{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (m/z=480,3);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-2-(2,5-dioxo-4-imidazolidinyl)-N-methylacetamide (m/z=RUR 439,3);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-m is l-1H-pyrrol-2-carboxamid (m/z=392,3);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,2-dimethylpropanamide (m/z=369,3);

N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-2,1,3-benzoxadiazole-5-carboxamide (m/z=445,2);

3-(tert-butyl)-N-{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (m/z=463,3);

N-(3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl)-2-(2,5-dioxo-4-imidazolidinyl)-N-methylacetamide (m/z=488,2);

2-(acetylamino)-N-{2-[(3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl)(methyl)amino]-2-oxoethyl}ndimethylacetamide (m/z=504,2);

N-(3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl)-N-methyl-2,1,3-benzoxadiazole-5-carboxamide (m/z=494,1);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-2-(2,5-dioxo-4-imidazolidinyl)-N-methylacetamide (m/z=to 426.2);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,2-dimethylpropanamide (m/z=356,2);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,3-Dimethylbutane (m/z=370,3);

N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-2,1,3-benzoxadiazole-5-carboxamide (m/z=432,2);

3-(tert-butyl)-N-{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (m/z=450,3);

4-(3-{8-[(cyclopropylmethyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-2-hydroxypropoxy)benzonitrile (m/z=370,5);

4-(3-{8-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl](methyl)-amino]-3-azabicyclo[3.2.1]Oct-3-yl-2-hydroxypropoxy)benzonitrile (m/z=492,5);

4-(3-{8-[[3-(4-acetyl-1-piperazinil)propyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-2-hydroxypropoxy)benzonitrile (m/z=484,5);

2-[{3-[3-(4-cianfrocca)-2-hydroxypropyl]-3-azabicyclo[3.2.1]Oct-8-yl}(methyl)amino]-N-isopropylacetate (m/z=415,5);

4-(3-{8-[[3-(ethylsulfonyl)propyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-2-hydroxypropoxy)benzonitrile (m/z=450,5);

4-(3-{8-[(4-terbisil)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-2-hydroxypropoxy)benzonitrile (m/z=424,5);

4-(2-hydroxy-3-{8-[[2-(4-methoxyphenyl)-2-oxoethyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propoxy)benzonitrile (m/z=464,5);

4-[(3-{8-[(cyclopropylmethyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)amino]benzonitrile (m/z=353,5);

4-[(3-{8-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl](methyl)-amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)amino]benzonitrile (m/z=475,5);

4-[(3-{8-[[3-(4-acetyl-1-piperazinil)propyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)amino]benzonitrile (m/z=467,6);

2-[{3-[3-(4-cyanoimino)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}(methyl)-amino]-N-isopropylacetate (m/z=398,5);

4-[(3-{8-[[3-(ethylsulfonyl)propyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)amino]benzonitrile (m/z=433,5);

4-[(3-{8-[(4-terbisil)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-propyl)amino]benzonitrile (m/z=of 407.5);

4-[(3-{8-[[2-(4-methoxyphenyl)-2-oxoethyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)amino]benzonitrile (m/z=447,5);

4-[(3-{8-[(3,3-dimethyl-2-oxobutyl)(METI is)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)sulfonyl]benzonitrile (m/z=446,5);

4-[(3-{8-[(cyclopropylmethyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-propyl)sulfonyl]benzonitrile (m/z=402,5);

4-[(3-{8-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl](methyl)-amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)sulfonyl]benzonitrile (m/z=524,4);

2-[(3-{3-[(4-cyanophenyl)sulfonyl]propyl}-3-azabicyclo[3.2.1]Oct-8-yl}-(methyl)amino]-N-isopropylacetate (m/z=447,5);

4-[(3-{8-[[3-(ethylsulfonyl)propyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)sulfonyl]benzonitrile (m/z=482,4);

4-[(3-{8-[[2-(2-methoxyethoxy)ethyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)sulfonyl]benzonitrile (m/z=450,5);

4-[(3-{8-[(4-terbisil)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-propyl)sulfonyl]benzonitrile (m/z=456,5);

4-[(3-{8-[[2-(4-methoxyphenyl)-2-oxoethyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}propyl)sulfonyl]benzonitrile (m/z=496,4);

4-(2-{8-[(3,3-dimethyl-2-oxobutyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}ethoxy)benzonitrile (m/z=384,5);

4-(2-{8-[(cyclopropylmethyl)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-ethoxy)benzonitrile (m/z=340,5);

4-(2-{8-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}ethoxy)benzonitrile (m/z=462,5);

2-[{3-[2-(4-cianfrocca)ethyl]-3-azabicyclo[3.2.1]Oct-8-yl}(methyl)amino]-N-isopropylacetate (m/z=385,5);

4-(2-{8-[[2-(2-methoxyethoxy)ethyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}ethoxy)benzonitrile (m/z=388,5);

4-(2-{8-[(4-terbisil)(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-the toxi)benzonitrile (m/z=394,5);

methyl-(1S)-2-(4-cianfrocca)-1-({8-[methyl({[(4-were-sulfonyl]amino}carbonyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}methyl)-ethylcarbamate (m/z=570,4);

methyl-(1S)-2-(4-cianfrocca)-1-({8-[methyl({4-[(trifluoromethyl)-sulfonyl]aniline}carbonyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}methyl)-ethylcarbamate (m/z=592,3);

methyl-(1S)-2-(4-cianfrocca)-1-[(8-{methyl[(tetrahydro-2H-Piran-2-ylamino)carbonyl]amino}-3-azabicyclo[3.2.1]Oct-3-yl)methyl]-ethylcarbamate (m/z=500,5);

methyl-(1S)-2-(4-cianfrocca)-1-({8-[{[(cyclopropylmethyl)amino]-carbonyl}(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}methyl)-ethylcarbamate(m/z=equal to USD 470.5);

methyl-(1S)-2-(4-cianfrocca)-1-({8-[[(isopropylamino)carbonyl]-(methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}methyl)ethylcarbamate (m/z=458,5);

methyl-(1S)-2-(4-cianfrocca)-1-({8-[[(3,4-diptiranjan)carbonyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}methyl)ethylcarbamate (m/z=528,5);

methyl-(1S)-2-{8-[[(butylamino)carbonyl](methyl)amino]-3-azabicyclo[3.2.1]Oct-3-yl}-1-[(4-cianfrocca)methyl]ethylcarbamate (m/z=472,5);

N-{3-[(2S)-2-amino-3-(4-cianfrocca)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(4-methoxyphenyl)-N-metalmachine (m/z=464,5);

N-{3-[(2S)-2-amino-3-(4-cianfrocca)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(cyclopropylmethyl)-N-metalmachine (m/z=412,5);

N-{3-[(2S)-2-amino-3-(4-cianfrocca)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(3,4-differenl)-N-metalmachine (m/z=equal to USD 470.5);

N-{3-[(2S)-2-amino-3-(4-cianfrocca)propyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-butyl-N (m/z=414,6);

N-{3-[4-(4-cyanophenyl)-4-(4-hydroxyphenoxy)butyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(3,5-dimethyl-4-isoxazolyl)-N-metalmachine (m/z=544,5);

N-{3-[4-(4-cyanophenyl)-4-(4-hydroxyphenoxy)butyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N'-(4-methoxyphenyl)-N-metalmachine (m/z=555,5);

N-{3-[4-(4-cyanophenyl)-4-(4-hydroxyphenoxy)butyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-methyl-N'-{4-[(trifluoromethyl)sulfanyl]phenyl}urea (m/z=625,3);

N'-butyl-N-{3-[4-(4-cyanophenyl)-4-(4-hydroxyphenoxy)butyl]-3-azabicyclo[3.2.1]Oct-8-yl}-N-metalmachine (m/z=505,6) and tert-butyl 3-[(2S)-2-amino-3-(4-cianfrocca)propyl]-3-azabicyclo[3.2.1]Oct-8-yl(methyl)carbamate (m/z=415,5).

Example 8

Compounds of the above examples were tested in the above Test and how it was discovered, demonstrate value pIC50more than 5.5. Results of testing specific compounds according to the invention are given below in table 1.

Reduction

Ac = acetyl

IBP = ionization at atmospheric pressure (in relation to MS)

aq. = water

br = broad (in relation to NMR)

Bt = benzotriazol

t-BuOH = tert-butanol

HEE = chem is ical ionization (in relation to MS)

mjpbk = meta-chloroperoxybenzoic acid

d = doublet (in relation to NMR)

DBU = diazabicyclo[5.4.0]undec-7-ene

DHM = dichloromethane

dd = double doublet (in relation to NMR)

DMAP = 4-dimethylaminopyridine

DMF = N,N-dimethylformamide

DMSO = dimethyl sulfoxide

DMAPI = 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide

Et = ethyl

EtOAc = ethyl acetate

EQ. = equivalents

ER = elektrorazpredelenie (in relation to MS)

The Belarusian library Association = fast atom bombardment (in relation to MS)

h = hour(s)

HCl = hydrochloric acid

HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

HPLC = high performance liquid chromatography

IPS = ISO-propyl alcohol (propan-2-ol)

m = multiplet (in relation to NMR)

Me = methyl

MeCN = acetonitrile

MeOH = methanol

min = minute(s)

TPL = melting point

MS = mass spectroscopy

NADPH = nicotinamide adenine dinucleotide phosphate, reduced form

SLA = acetate

Pd/C = palladium on carbon

q = Quartet (in relation to NMR)

K.T. = room temperature

s = singlet (in relation to NMR)

t = triplet (in relation to NMR)

The tea = triethylamine

THF = tetrahydrofuran

TLC = thin layer chromatography

The prefixes n-, s-, i-, t -, and t have their usual meanings: normal, secondary, ISO - and tertiary.

1. Derived azabicycloalkanes General the th formula I

where the wavy line represents a possible endo - or eksoterikon;

one of R1and R2is an R1aand the other represents a fragment of formula 1A

R1arepresents a C1-12alkyl (possibly substituted and/or terminated with one or more than one group selected from phenyl, Het1, -C(O)R7a, -OR7b, -N(R8R7c, -C(O)XR9, -C(O)N(R10R7band-S(O)2R11), Het2, -C(O)R7a, -C(O)XR9, -C(O)XR9, -C(O)N(R)10R7dor-S(O)2R11;

R7a-R7dindependently represent H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from C1-6alkoxy, halogeno, phenyl, Het3and - NHC(O)R12), phenyl or Het4;

R12represents a C1-4alkyl (substituted or possibly ending with-NHC(O)R13);

R13represents a C1-4alkyl;

R8represents H or phenyl;

X represents O;

R9represents a C1-12alkyl (possibly substituted and/or terminated with-OH, cyano, C1-6alkoxy, -SO2R15or Het5);

R 15represents a C1-6alkyl;

R10represents H, C1-12alkyl, C1-6alkoxy (which latter two groups possibly substituted and/or end With1-4alkoxy), -D-phenyl, -D-Het6or-D-S(O)2R17A;

R17arepresents phenyl;

D represents a direct bond or C1-6alkylen;

R11represents a C1-6alkyl, phenyl or Het7;

R4represents H, -OR18, -E,-N(R19R20or together with R5represents =O;

R5represents H or, together with R4represents =O;

R18represents H, -O-phenyl or-C(O)OR21;

R19represents H or-C(O)OR21b;

R20represents N;

R21brepresents a C1-6alkyl (possibly substituted and/or terminated phenyl);

E represents a direct bond or C1-4alkylen;

Het1-Het7independently represent isoxazolyl, tetrahydropyranyl, pyrazolyl, piperazinil, morpholinyl, pyridinyl, benzoxadiazole, imidazolyl, imidazolidinyl, pyrrolyl, thiazolyl or benzodioxolyl, and these groups possibly substituted by one or more than one Deputy, selected from oxo, halogeno, C1-6 of alkyl, -C(O)R23cand-N(R23g)C(O)R23h;

R23c, R23gand R23hindependently represent N or C1-6alkyl;

And represents a direct bond or-J-;

In represents-Z-, -Z-N(R25)-, -N(R25)-Z-, -Z-S(O)n-, -Z-O- (the latter two groups, Z is attached to the carbon atom bearing R4and R5);

J represents a C1-6alkylen, possibly substituted by a Deputy selected from-OH and amino;

Z represents a direct bond or C1-4alkylen;

R25represents N;

G represents CH;

R6represents one or more than one possible substitute selected from cyano, halogeno, C1-6the alkyl and C1-6alkoxy;

n represents 2, and

Ra-Rhindependently represent H;

R3represents N or C1-4alkyl;

where each phenyl and fenoxaprop possibly substituted;

or its pharmaceutically acceptable derivative,

provided that if a represents a direct bond, R4and R5together represent=o

2. The compound according to claim 1, where the possible substituents on the phenyl and phenoxypropan represent one or more than one group selected from-O, halogeno, cyano, nitro, C1-6of alkyl, C1-6alkoxy, -N(R27g)C(O)R27hand-S(O)nR-26 Cwhere R-26 Crepresents a C1-6alkyl, R27gand R27hindependently represent N or C1-6alkyl, and n is as defined in claim 1.

3. The compound according to any one of claims 1 and 2, where R1arepresents a C1-8alkyl (possibly substituted and/or terminated with one or more than one group selected from a possibly substituted phenyl, Het1, -C(O)R7a, -OR7b, -N(R8R7c, -C(O)XR9, -C(O)N(R10R7dand-S(O)2R11), Het2, -C(O)R7a, -C(O)XR9, -C(O)N(R10R7dor-S(O)2R11.

4. The compound according to claim 3, where R7a- R7dindependently represent H, C1-5alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from C1-4alkoxy, halogeno, possibly substituted phenyl, Het3and-NHC(O)R12), possibly substituted phenyl or Het4.

5. The compound according to claim 4, where R12represents a C1-3alkyl (substituted or possibly ending with-NHC(O)R13).

6. The compound according to claim 5, where R13represents a C1-3alkyl.

7. The compound according to any one of claims 1 to 6, where R9represents a C1-8alkyl (possibly substituted and/or terminated with-OH, qi is but With1-4alkoxy, -SO2R15or Het5).

8. The connection according to claim 7, where R15represents a C1-4alkyl.

9. The compound according to any one of claims 1 to 8, wherein R10represents H, C1-8alkyl, C1-4alkoxy (which latter two groups possibly substituted and/or end With1-4alkoxy), -D-(possibly substituted phenyl), -D-Het6or-D-S(O)2R17a.

10. The compound according to any one of claims 1 to 9, where D is a direct link.

11. The compound according to any one of claims 1 to 10, where R11represents a C1-5alkyl, possibly substituted phenyl or Het7.

12. The compound according to any one of claims 1 to 11, where R4represents H, -OR18or-E-N(R19R20.

13. The compound according to any one of claims 1 to 12, where R5represents N.

14. The compound according to any one of claims 1 to 13, where R18represents H or-O-(possibly substituted phenyl).

15. The compound according to any one of claims 1 to 14, where R21brepresents a C1-4alkyl (possibly replaced or terminated phenyl).

16. The compound according to any one of claims 1 to 15, where E is a direct link.

17. The compound according to any one of claims 1 to 16, where Het1- Het7possibly substituted by one or more than one Deputy, selected from oxo, halogeno,1-5of alkyl, -C(O)R23cand-N(R23g)C(O)R23h.

18. The connection 17, where R 23c, R23gand R23hindependently represent N or C1-3alkyl.

19. The compound according to any one of claims 1 to 18, where In represents-Z-, -Z-N(R25)-, -Z-S(O)n- or-Z-O- (in the last three groups, Z is attached to the carbon atom bearing R4and R5).

20. The compound according to any one of claims 1 to 19, where J represents a C1-5alkylen, possibly substituted by the Deputy, selected IT and amino.

21. The compound according to any one of claims 1 to 20, where Z represents a direct bond or C1-3alkylen.

22. The compound according to any one of claims 1 to 21, where R6represents one or more than one possible substitute selected from cyano, halogeno, C1-3the alkyl and C1-4alkoxy.

23. Connection p.22, where R6represents one or two ceanography.

24. The compound according to any one of claims 1 to 23, where R3represents N or C1-2alkyl.

25. Pharmaceutical drug with blocking potassium current of the detained straightening activity comprising the compound according to any one of claims 1 to 24 in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

26. Pharmaceutical drug with blocking potassium current of the detained straightening activity designed for use in the prevention or treatment of arrhythmias, including connection on l is the Boma one of claims 1 to 24.

27. The compound according to any one of claims 1 to 24, intended for use as a pharmaceutical product.

28. The compound according to any one of claims 1 to 24, intended for use in the prevention or treatment of arrhythmia.

29. The compound according to any one of claims 1 to 24 as the active ingredient for the manufacture of drugs for use in the prevention or treatment of arrhythmia.

30. The connection clause 29, where the arrhythmia is an atrial or ventricular fibrillation.

31. The method of prevention or treatment of arrhythmia, wherein the subject suffering from such condition or affected by it, introducing a therapeutically effective amount of a compound according to any one of claims 1 to 24.

32. The method of obtaining the compounds of formula I according to claim 1, characterized in that the compound of the formula IIA or IIB

where R1, R2, R3and Ra-Rhare as defined in claim 1,

subjected to interaction with the compound of the formula III,

R28-L1III

where R28represents (as appropriate) or R1or R2L1represents a leaving group, and R1and R2are as defined in claim 1;

if necessary, make one substituent R6in the other; if necessary, remove protection from protected proizvodi the th compounds of formula I according to claim 1.

33. The method of obtaining the compounds of formula I according to claim 1, where R1or R2(as appropriate) represents-C(O)N(H)R10, characterized in that the compound of the formula IIA or IIB (as appropriate)

as defined above (except that R1or R2(as appropriate) does not represent R1a),

subjected to interaction with the compound of the formula VI,

R10-N=C=O, VI

where R10is such as defined in claim 1;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I according to claim 1.

34. The method of obtaining the compounds of formula I according to claim 1, where R1or R2(as appropriate) represents a fragment of formula Ia, where a is a CH2and R4represents-OH or-N(H)R19, characterized in that the compound of the formula IIA or IIB

as defined above (except that R1or R2(as appropriate) does not represent a fragment of formula Ia),

subjected to interaction with the compound of the formula VII

where Y represents O or N(R19and R5, R6, R19, And G are what I like, as defined in claim 1;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I according to claim 1.

35. The method of obtaining the compounds of formula I according to claim 1, where R4represents-OR18where R18represents-O-phenyl, wherein the corresponding compound of formula I, where R4represents OH, is subjected to the interaction with the compound of the formula XI

R18OH, XI

where R18arepresents-O-phenyl, and E is as defined in claim 1;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I according to claim 1.

36. The method of obtaining the compounds of formula I according to claim 1, where R4represents-E-NH2, characterized in that the restoring compound of formula XIIIA or XIIIB

where R1or R2(as appropriate) represents R1aand R1a, R3, R5, R6, Ra-RhAnd, b, E and G are as defined in claim 1;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative of the compound forms of the crystals of I according to claim 1.

37. The method of obtaining the compounds of formula I according to claim 1, where R4represents-E-N(R19R20where R19represents-C(O)OR21b, characterized in that the compound of formula I, where R4represents-E-N(H)R20, is subjected to the interaction with the compound of the formula XIV

R19a-L1XIV

where R19arepresents-C(O)OR21b, R21b, R20and E are as defined in claim 1, and L1is as defined above;

if necessary, make one substituent R6in the other;

if necessary, remove protection from protected derivative compounds of formula I according to claim 1.

38. The method of obtaining the compounds of formula I according to claim 1, where R3represents N, and R2represents unsubstituted With1-4alkyl, wherein the compound of formula XXI

where R4, R5, R6, Ra-RhA, b and G are as defined in claim 1,

subjected to interaction with the compound of the formula XXII

R31-NH2, XXII

where R31represents a C1-4alkyl in the presence of a reducing agent;

if necessary, make one substituent R6in the other;

if necessary, remove the protection of the protected derivative of the compound of formula I according to claim 1.

39. The compound of the formula IIA or IIB

where R1, R2, R3and Ra-Rhare as defined in claim 1,

or a protected derivative, provided that the compound is not:

(±)-(8α,β)-3-ethyl-3-azabicyclo[3.2.1]Octan-8-amine;

8-amino-3-methyl-3-azabicyclo[3.2.1]octane;

8-amino-3-isopropyl-3-azabicyclo[3.2.1]octane;

8-amino-3-benzyl-3-azabicyclo[3.2.1]octane;

3-{2-[4-(6-aminopyridine-2-yl)phenyl]ethyl}-3-azabicyclo[3.2.1]Oct-8-ylamine; or

3-azabicyclo[3.2.1]Oct-8-ylamine tert-BUTYLCARBAMATE.

40. The compound of formula XIIIA or XIIIB

where R1or R2(as appropriate) represents R1aand R1a, R3, R5, R6, Ra-RhAnd, b, E and G are as defined in claim 1,

or a protected derivative.

41. The compound of formula XXI

where R4, R5, R6, Ra-RhA, b and G are as defined in claim 1 (provided that if Ra-Rhall represent H, G represents CH and R6no, the group-A-C(R4)(R5)-B - does not represent unsubstituted ethyl),

or a protected derivative is.



 

Same patents:

FIELD: medicine, neurology.

SUBSTANCE: the present innovation deals with treating cerebral vascular diseases accompanied with psychic disorders. For this purpose one should introduce homeopathic preparations named Cerebrum compositum and Hepar compositum per 2.2 ml every other day for 20 d intramuscularly, and beginning since the 11th d one should additionally prescribe Vertigohel preparation per 10 drops thrice daily for 10 d. The innovation suggested provides decreased different psychotic and unpsychotic depressive syndromes that considerably improves quality of life in this category of patients.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to 2-aminomethylthieno[2,3-d]pyrimidines of the general formula (I): wherein R1 and R2 in common with C-atoms with which they are bound form 5-7-membered monounsubstituted cycloalkenyl ring; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl, (C1-C8)-alkoxy-group, amine, mono-(C1-C8-alkyl)-amine or di-(C1-C8-alkyl)-amine groups, or in common with nitrogen atom to which they are bound form a heterocyclic ring that comprises optionally one or more additional nitrogen atoms and substituted with one or more hydroxyl, (C1-C8)-alkoxy- or (C1-C8)-alkylol groups. Compounds elicit the inhibitory effect with respect to activity of phosphodiesterase V and can be used in treatment of cardiovascular system states and in disturbance in the potency injury. Also, invention describes a medicinal preparation based on compounds said, a method for its preparing and a method for preparing compounds.

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

6 cl, 1 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment or prophylaxis of hypertension, heart diseases, vascular disorders and kidney diseases. The composition comprises compound of the formula (1) as antagonist of angiotensin II receptors and one or some diuretics. The composition shows enhanced effectiveness.

EFFECT: valuable medicinal properties of composition.

23 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: method involves passing physiologically permissible gas mixture dispersed in blood and aqueous sclerosing liquid through one or several canals having at least one cross-section size from 0.1 to 30 mcm. Gas-to-liquid proportion is varied in a way that foamed material containing gas micro-bubbles is produced. The material has density of 0.07 g/ml to 0.19 g/ml and half-transformation period not less than 2 min. the device has casing enclosing a chamber allowing pressure to be increased and containing aqueous sclerosing liquid, canal-shaped passage having one or several outlet openings allowing liquid to be released from the chamber allowing liquid pressure to be increased or passage canal to be closed from the chamber to outer space. Fluid medium enclosed in the chamber is forced out along the passage canal through single or several outlet openings when container pressure is high and the passage canal is open. The foamed material containing gas micro-bubbles and has density of 0.07 g/ml to 0.19 g/ml and is able to flows through a needle of size 21 so that 50% and more bubbles having diameter equal to or less than 150 mcm and at least 95% of those bubbles retain diameter equal to or less than 280 mcm.

EFFECT: enhanced effectiveness of blood vessel sclerotherapy by introducing the foamed material into blood vessel.

59 cl, 11 dwg

FIELD: organic chemistry, peptides, medicine, pharmacy.

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

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, vitamins, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: medicine, cardiology, pharmacy.

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EFFECT: valuable medicinal properties of composition.

3 cl, 1 tbl, 1 ex

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

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

5 cl, 1 tbl, 4 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

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

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

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

21 cl, 70 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: medicine, phthisiology.

SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.

EFFECT: higher efficiency of differential diagnostics.

3 ex

The invention relates to heterocyclic compounds with substituted phenyl group of formula Ior its pharmaceutically acceptable salt, in which R1represents a C1-C6alkyl; R2represents a C1-C6alkyl; R3represents H or halogen andrepresents a substituted heterocycle, as defined in paragraph 1 of the claims; and X represents NH or O

The invention relates to the derivatives of imidazopyridine formula

or its pharmaceutically acceptable salts, where R1- H, CH3or CH2OH; R2- CH3CH2CH3; R3- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl, halogen; R4- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or halogen; R5- H or halogen; R6, R7are the same or different and mean H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or C1-C6alkoxy-substituted C1-C6alkyl; X represents NH or O, which inhibit exogenously or endogenously stimulated secretion of gastric acid and therefore can be used for the prevention and treatment of gastrointestinal inflammatory diseases

The invention relates to pharmaceutical industry and relates to inhibitors lks-channel simultaneous action as inhibitors KQT1 channel to obtain drugs for the treatment of diseases caused by helminths and ectoparasites, while inhibitors KQT1 channel have high selectivity and are non-toxic to warm-blooded animals and humans

The invention relates to organic chemistry and can find application in medicine

FIELD: medicine, phthisiology.

SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.

EFFECT: higher efficiency of differential diagnostics.

3 ex

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