3,7-diazabicyclo[3.3.0]octanes and their using in treatment of cardiac arrhythmia

FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to novel 3,7-diazabicyclo[3.3.0]octanes of the formula (I): wherein wavy lines mean the possible relative cis- or trans-stereochemistry; R means (C1-C12)-alkyl (possibly substituted and/or terminating by one or more groups chosen from aryl, Het1, -C(O)R5a, -OR5b, -N(R6)R5c, -C(O)XR7, -C(O)N(R8)R5d and -S(O)2R9), Het2, -C(O)R5a, -C(O)XR7 or -S(O)2R9 wherein R5a - R5d in each case mean independently hydrogen atom (H), (C1-C6)-alkyl (possibly substituted and/or terminating by one or more substitute chosen from -OH, (C1-C6)-alkoxy-group, cyano-group, aryl, Het3 and -NHC(O)R10), aryl or Het4; R10means H, (C1-C4)-alkyl; R6 means H, aryl; X means oxygen atom (O); R7 means in each case (C1-C12)-alkyl (wherein alkyl group can be substituted and/or terminating by one substitute chosen from -OH, cyano-group, (C1-C6)-alkoxy-group, -SO2R13a, -C(O)R13b and Het5) wherein R13a and R13b mean independently (C1-C6)-alkyl; R8 means in each case H, (C1-C12)-alkyl, (C1-C6)-alkoxy-group (wherein two latter groups are substituted possibly and/or terminating by one substitute chosen from -OH, (C1-C4)-alkyl and (C1-C4)-alkoxy-group), -D-aryl, -D-Het6, -D-S(O)2R15a wherein R15a means independently aryl; D means a direct bond or (C1-C6)-alkylene; R9 means in each case (C1-C6)-alkyl (possibly substituted and/or terminating by one substitute chosen from aryl) or aryl; R2 means H, -E-OR16, -E-N(R17)R18 or in common with R3 represent =O; R3 means H or in common with R2 represent =O; R16 means H, (C1-C6)-alkyl or -E-aryl; R17 means H; R18 means H; E means in each case a direct bond or (C1-C4)-alkylene; A means -G-; B means -Z-, -Z-N(R22)-Z-, -Z-S(O)n-. -Z-O- (wherein in two latter groups Z is bound to carbon atom carrying R2 and R3); G means a direct bond or (C1-C6)-alkylene; Z means a direct bond or (C1-C4)-alkylene; R22 means independently H; R4 means aryl or het13 wherein both these groups are substituted possibly with one or more substitute chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; Het13 means 5-6-membered heterocyclic group comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur; Het1 - Het6 in each case mean independently 5-6-membered heterocyclic groups comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur wherein these heterocyclic groups are substituted possibly with one or more substitutes comprising (C1-C6)-alkyl or -C(O)R24c wherein R23c means in each case independently (C1-C6)-alkyl; R24c means in each case H or (C1-C6)-alkyl; n means 0, 1 or 2 in each case; Ra - R1 mean independently H or (C1-C4)-alkyl wherein each aryl or aryloxy-group (if not indicated otherwise) is substituted possibly with one or more substitutes chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; or it pharmaceutically acceptable derivative under condition that: (a) when R2 means -E-OR16 or -E-N(R17)R18 wherein E means a direct bond then: (1) A can't mean a direct bond; and (2) B doesn't mean -N(R22)-, -S(O)n-. -O- or -N(R22)-Z- (wherein in the latter group -N(R22) is bound to carbon atom carrying R2 and R3; (b) this compound is not 3,7-bis-(1-phenylethyl)-3,7-diazabicyclo[3.3.0]octane, 3-methyl-7-benzyl-3,7-diazabicyclo[3.3.0], 3-cyclohexyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(thiazol-2-yl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(2-pyrimidyl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(5,5-dimethoxy)pentyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane; (c) when R in common with R3 represent =O, and B means -Z-N(R22)- or -N(R22)-Z- then G is not a direct bond. Compounds of the formula (I) can be used as components of a pharmaceutical composition in treatment or prophylaxis of arrhythmia. Also, invention describes methods for its synthesis and intermediate compounds used in these methods.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

38 cl, 6 ex

 

The scope of the invention

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

Prior art

Cardiac arrhythmias can be defined as deviations from the norm in the rate, regularity, or site of origin of cardiac impulse or as abnormalities in conduction that causes abnormal sequence of excitation. From the point of view of the clinic arrhythmia can be classified according to the alleged place of occurrence (i.e., either supraventricular arrhythmias, including atrial and atrio-ventricular and ventricular arrhythmia) and/or frequency of contractions (i.e. bradyarrhythmia (slow) and tachyarrhythmias (fast)).

Negative results of some clinical trials (see, for example, the test result for the suppression of cardiac arrhythmia (Cardiac Arrhythmia Suppression Trial (CAST))set forth in the New England Journal of Medicine 321, 406 (1989)) in the treatment of cardiac arrhythmias "traditional" antiarrhythmic drugs acting mainly by reducing the speed of conduction (antiarrhythmic drugs class I)caused to guide the development of drug compounds that selectively inhibit cardiac repolarization, thereby extending the QT-interval. Anti-arrhythmic drugs class III mouthbut defined as drugs, lengthening the duration of the transmembrane action potential (which may be caused by blocking aimed outward currents K+or increase inward ionic currents) and refractoriness without affecting cardiac conduction.

It is known that one of the key disadvantages of the known prior to the present time, drugs that act by slowing repolarization (class III or others) is the fact that they all lead to a unique form of proaramme known as pointes de pointes (Torsade de pointes), which can sometimes be fatal. From a security standpoint to minimize this phenomenon (which has also been shown that it occurs as a result of the introduction of neserbeznyh drugs, such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key that requires solving the problem by offering an effective anti-arrhythmic drugs.

Antiarrhythmic drugs based on Besedina (3,7-diazabicyclo[3.3.1]nonanes) is known inter alia from the international patent applications WO 91/07405 and WO 99/31100, European patent applications 306871, 308843 and 665228 and U.S. patent 3962449, 4556662, 4550112, 4459301 and 5468858, and journal articles, including, among others, J. Med. Chem. 39, 2559 (1996); Pharmacol. Res. 24, 149 (1991); Circulation 90, 2032 (1994), and Anal. Sci. 9, 429 (1993). Neither of the nome of these documents are not disclosed and are not supposed to join on the basis of 3,7-diazabicyclo[3.3.0]octane.

It is known that compounds based on 3,7-diazabicyclo[3.3.0]octane are used in several medical applications, including, without limitation, anti-migraine (as described in WO 98/06725 and WO 97/11945); antibiotics (as described in WO 97/10223 and WO 96/35691); antipsychotics (as described in WO 95/15327 and WO 95/13279); inhibitors of serotonin reuptake (as described in WO 96/07656); thrombin inhibitors (as described in Helvetica. Chim. Acta 83, 855 (2000); Chem. & Biol. 4, 287 (1997) and Angew. Chem. Int. Ed. Eng. 34, 1739 (1995)), and anxiolytic agents (as described in J. Med. Chem. 32, 1024 (1989)). In addition, compounds 3,7-diazabicyclo[3.3.0]octane were used in the treatment of, inter alia, gastrointestinal disorders (as described in DE 3930266 A1) and diseases caused by dysfunction glutaminergic system (as described in WO 01/04107).

Other 3,7-diazabicyclo[3.3.0]octane compounds known as rare chemical compounds, among others, due to J. Heterocyclic. Chem. 20, 321 (1983), Chem. Ber. 101, ZOE (1968), J. Chem. Soc., Perkin Trans. I 1475 (1983), Tetrahedron, Suppl. 8 Part I, 279 (1966) and J. Org. Chem. 61, 8897 (1996). Furthermore, it is known that 3,7-bis(1-phenylethyl)was 3.7-diazabicyclo[3.3.0]octane useful for controlling the enantioselectivity of the reactions between Grignard reagents and aldehydes (as described in Tetrahedron 5, 569 (1994)).

None of the documents of the prior art mentioned above and related to 3,7-diazabicyclo[3.3.0]octanal, not disclosed, or not provided is by no assumption, as described there, the compounds may be useful in the treatment of cardiac arrhythmias.

The authors of the present invention unexpectedly found that a new group of compounds based on 3,7-diazabicyclo[3.3.0]octane shows electrophysiological activity, preferably electrophysiological activity of class III, and as a consequence that they can be useful in the treatment of cardiac arrhythmias.

Description of the invention

According to the proposed invention the compounds of formula I

where the wavy lines indicate possible relative CIS - or TRANS-stereochemistry;

R1represents a C1-12alkyl (possibly substituted and/or terminated with one or more than one group selected from halogeno, cyano, nitro, aryl, Het1, -C(O)R5a, -OR5b, -N(R6R5c, -C(O)XR7, -C(O)N(R8R5dand-S(O)2R9), Get2, -COR5a, -C(O)XR7, -C(O)N(R8R5dor-S(O)2R9;

R5a- R5dg whenever used here, independently represent H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, C1-6alkoxy, halogeno, cyano, nitro, aryl, Het3and-NHC(O)R10), aryl or Het4or R5dtogether the R 8represent3-6alkylen (and Allenova the group could be interrupted by an atom and/or possibly substituted by one or more than one C1-3alkyl group);

R10represents H, C1-4alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, cyano, aryl, and-NHC(O)R11or aryl;

R11represents H, C1-4alkyl or aryl;

R6represents H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl), aryl, -C(O)R12a, -C(O)OR12bor-C(O)N(H)R12c;

R12a, R12band R12represents a C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl) or aryl, or R12aand R12brepresent N;

X represents O or S;

R7in each case, when used here, represents aryl or1-12alkyl (which alkyl group possibly substituted and/or ends with one or more than one Deputy, selected from HE, halogeno, cyano, nitro, aryl, C1-6alkoxy, -SO2R13a, -C(O)R13bGets the5);

R13aand R13bindependently depict ablaut a C 1-6alkyl or aryl;

R8in each case, when used here, represents H, C1-12alkyl, C1-6alkoxy (which latter two groups possibly substituted and/or over one or more than one Deputy, selected from HE, halogeno, cyano, nitro, C1-4the alkyl and C1-4alkoxy), -D-aryl, -D-aryloxy, -D-Het6, -D-N(H)C(O)R14a, -D,-S(O)2R15a, -D-C(O)R14b, -D-C(O)R15b, -D-C(O)N(R14cR14dor R8together with R5drepresent3-6alkylen (and Allenova the group could be interrupted by an atom and/or possibly substituted by one or more than one C1-3alkyl group);

R14a-R14dindependently represent H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl), aryl or R14cand R14dtogether represent a3-6alkylen;

R15aand R15bindependently represent a1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl) or aryl;

D represents a direct bond or C1-6alkylen;

R9in each case, when used here, represents a C1-6alkyl (possibly substituted and/is whether terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl), aryl or Het7;

R2represents H, halogeno,1-6alkyl, -E-OR16, -E,-N(R17R18or together with R3represents =O;

R3represents H, C1-6alkyl or together with R2represents =O;

R16represents H, C1-6alkyl, -E-aryl, -O-Het8, -C(O)R19a, -C(O)OR19bor-C(O)N(R20aR20b;

R17represents H, C1-6alkyl, -E-aryl, -O-Het8, -C(O)R19a, -C(O)OR19b, -S(O)2R19c, -[(CO)]pN(R20aR20bor-C(NH)NH2;

R18represents H, C1-6alkyl, -E-aryl or-C(O)R19d;

R19a-R19din each case, when used here, independently represent a1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, aryl and Het9), aryl, Het10or R19aand R19dindependently represent H;

R20aand R20din each case, when used here, independently represent N or C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, aryl and Het11), aryl, Het12or together represent a3-6alkylen, who is interrupted by one atom On;

E, in each case, when used here, represents a direct link or1-4alkylen;

p represents 1 or 2;

But a-G-, -J-N(R21)- or-J-O- (the latter two groups N(R21)- or - attached to the carbon atom bearing R2and R3);

In represents-Z-, -Z-N(R22)-, -N(R22)-Z-, -Z-S(O)n-, -Z-O- (the latter two groups, Z is attached to the carbon atom bearing R2and R3);

G represents a direct bond or C1-6alkylen;

J represents a C2-6alkylen;

Z represents a direct bond or C1-4alkylen;

R21and R22independently represent N or C1-6alkyl;

R4represents aryl or Het13and both of these groups possibly substituted by one or more than one Deputy, selected from HE, cyano, halogeno, nitro, C1-6the alkyl (possibly ending in-N(H)C(O)R23a), C1-6alkoxy, Het1, aryl, -N(R24aR24b, -C(O)R24c-C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23d, -S(O)2N(R24nR24pand only if it Gets13) oxo;

Gets the13is a four-dvenadtsatiletnyuyu GE is eroticlick group, containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur;

Gets the1-Het12in each case, when used here, independently represent four-dvenadcatiletnie heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, and heterocyclic group possibly substituted by one or more than one Deputy, includes =O, -HE, cyano, halogeno, nitro, C1-6alkyl (possibly ending in-N(H)C(O)OR23a)1-6alkoxy, Het1, aryl, -N(R24aR24b, -C(O)R24c, -C(O)R24d, -C(O)N(R24eR24f-N(R24g)C(O)R24h-N(R24j)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23dand-S(O)2N(R24nR24p;

R23a-R23din each case, when used here, is independently represents a C1-6alkyl;

R24A-R24pin each case, when used here, independently represent N or C1-6alkyl;

n in each case represents 0, 1 or 2 and

Ra-Rfindependently represent N or C1-4alkyl;

where each aryl and alloctype, unless otherwise specified, possibly substituted;

or their pharmaceutically acceptable derivatives;

in terms of the AI, that

(a) when R3represents N or C1-4alkyl and a represents-J-N(R21)- or-J-O-,

then does not represent-N(R22)-, -S(O)n-, -O - or-N(R22)Z- (and in the latter group-N(R22) attached to the carbon atom bearing R2and R3);

(b) when R2represents-E-OR16or-E-N(R17R18where E represents a direct bond, then

(1) And is not a direct link, -J-N(R21)- or-J-O-

and

(2) does not represent-N(R22)-, -S(O)n-, -O - or-N(R22)Z- (and in the latter group-N(R22) attached to the carbon atom bearing R2and R3);

() Gets the1and Gets13does not represent a 9-membered heterocycles, which contain condensed benzene ring or pyridine ring, and

(d) this compound is not:

3,7-bis(1-phenylethyl)was 3.7-diazabicyclo[3.3.0]octane;

2-{4-(7-benzyl-3,7-diazabicyclo[3.3.0]Octan-3-yl)butyl}-1,2-benzisothiazol-3-one-1,1-dioxide;

3-methyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane;

3-cyclohexyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane;

3-(thiazol-2-yl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane;

3-(2-pyrimidyl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane or

3-(5,5-dimethoxy)pentyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane,

such compounds are referred to herein as "connection is obreteniyu".

Unless otherwise specified, alkyl groups and alkoxygroup as defined herein may be straight-chain or, when there is a sufficient number of carbon atoms (i.e. at least three), can be branched-chain and/or cyclic. In addition, when there is a sufficient number of carbon atoms (i.e. a minimum of four), these alkyl and alkoxygroup may also be partially cyclic/acyclic. Such alkyl and alkoxygroup may also be saturated or, when there is a sufficient number of carbon atoms (i.e. at least two)may be unsaturated and/or can be interrupted by 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 halogen atom, in particular fluorine.

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

The term "aryl", when it is used here, includes With6-10aryl groups such as phenyl, naphthyl and the like. The term "aryloxy", when it is used here, includes With6-10alloctype, such as phenoxy, naphthoxy and the like. For the avoidance of doubt, alloctype, shown here attached to the remainder of the molecule through an atom Of actigraphy. Unless otherwise specified, aryl and alloctype can be substituted by one or more than one Deputy, including HE, cyano, halogeno, nitro, C1-6alkyl (possibly ending in-N(H)C(O)OR23a), C1-6alkoxy, Het1, aryl (which aryl group may not be substituted for any additional aryl groups), -N(R24aR24b, -C(O)R24c, -C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23dand-S(O)2N(R24nR24p(where Het1, R23a- R23d, R24a- R24pand n are such as defined above). Aryl and alloctype when they are substituted, preferably substituted by substituents in the amount of from one to three.

The term "halogeno", when it is used here, includes fluorescent, chloro, bromo and iodo.

Gets group (Het1-Het13that can be the ü 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. The character Gets group (Het1-Het13can be fully saturated, wholly aromatic, partly aromatic and/or bicyclic. Heterocyclic groups that may be mentioned include benzodioxane, benzodioxepine, benzodioxolyl, benzofuranyl, benzofurazanyl, benzimidazolyl, bensbargains, benzothiophene, bromanil, cinnoline, dioxane, furanyl, hydantoinyl, imidazolyl, imidazo[1,2-a]pyridinyl, indolyl, ethenolysis, isoxazolyl, maleimido, morpholinyl, oxazolyl, phthalazine, piperazinil, piperidinyl, purinol, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolyl, pyrrolyl, hintline, chinoline, 3-sulfolene, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thienyl, thiochroman, triazolyl and the like. Value Gets1that may be mentioned include piperazinil and thiazolyl. Value Gets2that may be mentioned include thiazolyl. Value Gets4that may be mentioned include isoxazolyl and tetrahydropyranyl. Value Gets5that can be mentioned in luchot morpholinyl, piperazinil and pyridinyl. Value Gets6that may be mentioned include isoxazolyl and tetrahydropyranyl.

If Het is group (Het1- Het13) is substituted by one or more than one aryl and/or Gets1group, the aryl and/or Gets1the Deputy himself cannot be replaced by any aryl and/or Gets1-group. The substituents on Het-groups (Het1-Het13) can be located on any atom, where appropriate, in the ring system including a heteroatom. The point of attachment of Het-groups (Het1- Het13may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any condensed carbocyclic ring, which may be presented as part of a ring system. In addition, Het (Het1-Het13) can be N - or S-oxidised form.

Pharmaceutically acceptable derivatives include salts and solvate. Salts that may be mentioned include salts of joining acids. In addition, pharmaceutically acceptable derivatives include, 3,8-diazabicyclo[3.2.1]octane or (when Het is group (Het1-Het13) contain a Quaternary nitrogen atom) with Quaternary heterocyclic nitrogen atoms, With1-4alkyl Quaternary ammonium salt and N-oxides, with the proviso that when presented N-oxide,

(a) no Het (Het1-Het13) do not contain unoxidized atom S and/or

(b) n is not 0 when is a-Z-S(O)n-.

The compounds of formula I can be tautomerism. All tautomeric forms and mixtures thereof are included in the scope of this invention.

In addition, the compounds of formula I can contain one or more than one asymmetric carbon atom and can therefore exhibit optical and/or diastereoisomerism. Diastereoisomer can be separated using conventional techniques such as chromatography or fractional crystallization. Various stereoisomers may be isolated by separation of racemic or other mixture of the compounds using conventional techniques such as fractional crystallization or HPLC. Alternatively, the desired optical isomers may be obtained by interaction of the corresponding optically active starting materials under conditions which will not cause racemization or epimerization, or by derivatization, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional methods (e.g., HPLC, chromatography on silica). All stereoisomers are included in the scope of this invention.

Abbreviations are listed at the end of this description.

The compounds of formula I that may be mentioned include compounds where

R1represents a C1-12alkyl (possibly substituted and/or terminated with one or more than one group selected from halogeno, cyano, nitro, aryl, Het1, -C(O)R5a, -OR5b, -N(R6R5c, -C(O)XR7, -C(O)N(R8R5dand-S(O)2R9), -C(O)XR7, -C(O)N(R8R5dor-S(O)2R9;

R5a- R5din each case, when used here, independently represent H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, C1-6alkoxy, halogeno, cyano, nitro, aryl and Het3), aryl or Het4or R5dtogether with R8represent3-6alkylen (and Allenova the group could be interrupted by an atom and/or possibly substituted by one or more than one C1-3alkyl group);

R7in each case, when used here, represents a C1-12alkyl (which alkyl group possibly substituted and/or ends with one or more than one Deputy, selected from HE, halogeno, cyano, nitro, aryl, C1-6alkoxy, -SO2R13a, -C(O)R13band Gets5);

R9in each case, when used here, represents a C1-6/sub> alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl) or aryl;

R2represents H, halogen, C1-6alkyl, -OR16, -E,-N(R17R18or together with R3represent =O;

R4represents an aryl or pyridyl, and these groups possibly substituted by one or more than one Deputy, selected from HE, cyano, halogeno, nitro, C1-6the alkyl (possibly ending in-M(H)C(O)OR23a), C1-6alkoxy, -N(R24aR24d, -C(O)R24c-C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23cand-OS(O)2R23d.

The following compounds that may be mentioned include compounds where

Gets the1and Gets13independently represent a 4-8-membered heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, and these groups possibly substituted, as defined above.

Another connection that may be mentioned include compounds where

R1represents a C1-12alkyl (possibly substituted and/or terminated with one or more than one group selected from halogeno, C is ANO, nitro, aryl, Het1, -OR5b, -N(R6R5c, -C(O)XR7, -C(O)N(R8R5dand-S(O)2R9), Get2, -C(O)R5a, -C(O)XR7, -C(O)N(R8R5d, -S(O)2R9, -CH2-C(O)-(unsubstituted C1-6alkyl), or-CH2-C(O)-(aryl) (aryl part of the latter group possibly substituted by one or more than one Deputy, selected from HE, cyano, halogeno, nitro, C1-6the alkyl (possibly ending in-N(H)C(O)R23a), C1-6alkoxy, Het1, aryl (which aryl group may not be substituted for any additional aryl groups), -N(C1-6alkyl)R24b, -C(O)R24c-C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23dand-S(O)2(R24nR24p);

R2and R3together represent =O;

G is not a direct link and/or

Gets the3and Gets4independently represent a 4-8-membered heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, and these groups possibly substituted, as defined above.

Preferred compounds according to the invention include compounds where

wavy lines indicate the relative CIS-CTE is eufemio;

R1represents a C1-8alkyl (possibly substituted and/or terminated with one or more than one group selected from halogeno, possibly substituted phenyl, Het1, -C(O)R5a, -OR5b, -C(O)OR7, -C(O)N(H)R8and-S(O)2-C1-6the alkyl), Het2, -C(O)OR7, -C(O)N(H)R8or-S(O)2R9;

R5Aand R5bin each case, when used here, independently represent H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, C1-4alkoxy, halogeno), possibly substituted phenyl or Het4;

R7in each case, when used here, represents a C1-8alkyl (and this group possibly substituted and/or ends with one or more than one Deputy, selected from HE, halogeno, cyano, possibly substituted phenyl, With1-4alkoxy, -SO2R13a, -C(O)R13bGets the5);

R13Aand R13bindependently represents a C1-6alkyl;

R8in each case, when used here, represents a C1-8alkyl (and this group possibly substituted and/or ends with one or more than one Deputy, selected from HE, halogeno, cyano, and C1-4alkoxy), -D-(possibly substituted phenyl), -D-Het6, -D,-S(O)2Rsup> 15a, -D-C(O)-C1-6alkyl or D-C(O)OR15b;

R15aand R15bindependently represents a C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, cyano and possibly substituted phenyl) or possibly substituted phenyl;

D represents a direct bond or C1-3alkylen;

R9in each case, when used here, represents a C1-5alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, cyano and possibly substituted phenyl) or possibly substituted phenyl;

R2represents H, C1-2alkyl, -OR16, -N(H)R17or together with R3represent =O;

R3represents H, C1-2alkyl, or together with R2represent =O;

R16represents H, C1-4alkyl, -S-(possibly substituted phenyl), -C(O)R19aor-C(O)N(H)R20a;

R17represents H, C1-4alkyl, -S-(possibly substituted phenyl), -C(O)R19aor-C(O)R19b;

R19aand R19bin each case, when used here, is independently represents a C1-6alkyl, possibly substituted phenyl or Het10;

R20arepresents N or C1-4alkyl;

E, in each case, when using the I am here represents a direct bond or C1-2alkylen;

But a-G-;

In represents-Z-, -Z-N(H)-, -Z-S(O)n-, -Z-O- (the latter three groups, Z is attached to the carbon atom bearing R2and R3);

G represents a direct link or1-5alkylen;

Z represents a direct bond or C1-3alkylen;

R4represents phenyl or Het13and both of these groups possibly substituted by one or more than one Deputy, selected from cyano, halogeno, nitro, C1-4the alkyl (possibly ending in-N(H)C(O)R23a)1-4alkoxy, possibly substituted phenyl, -C(O)N(H)R24e, -N(H)C(O)R24h, -N(H)C(O)N(H)R24j, -N(H)S(O)2R23b, -S(O)2R23cand-S(O)2N(R24nR24p;

Gets the13is a five-decatizing heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur;

Gets the1-Het12in each case, when used here, independently represent a five-desyatiletnie heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, and data heterocyclic group possibly substituted by one or more than one Deputy, includes =O, -HE, cyano, halogeno, nitro, C14 alkyl, C1-4alkoxy, possibly substituted phenyl, -NH2, -C(O)R24c, -C(O)OR24d, -C(O)N(H)R24e, -N(H)C(O)R24hand-S(O)nR23c;

Ra-Rfindependently represent N or C1-4alkyl;

possible substituents on the phenyl groups are one or more than one group selected from HE, cyano, halogeno, nitro, C1-4the alkyl (possibly ending in-N(H)C(O)OR23a)1-4alkoxy, -NH2, -C(O)R24c-C(O)OR24d, -C(O)N(H)24e, -N(H)C(O)R24h, -N(H)C(O)N(H)R24j, -N(H)S(O)2R23b, -S(O)nR23cand-S(O)2N(R24nR24p;

R23a-R23 ° C, R24C, R24d, R24th, R24h, R24j, R24nand R24pin each case, when used here, independently represent a1-4alkyl;

n represents 0 or 2;

alkyl groups and alkoxygroup may be, unless otherwise specified:

(1) straight or branched chain or cyclic or part cyclic/acyclic;

(2) saturated or unsaturated;

(3) interrupted by one or more than one oxygen atom and/or

(4) substituted by one or more than one atom of fluorine or chlorine. More preferred compounds according to the invention include compounds where

R1represents a C1-6alkyl (possibly substituted and/and and ending with one or more than one group, selected from halogeno, phenyl (possibly substituted by one or more than one group selected from halogeno, cyano and C1-2alkoxy), Get1, -C(O)R5a, -OR5b, -C(O)N(H)-C1-4the alkyl and-S(O)2-C1-4the alkyl), Het2, -C(O)OR7, -C(O)N(H)R8or-S(O)2-C1-5alkyl;

Gets the2represents a 5-membered heterocyclic group containing one to four heteroatoms selected from oxygen, nitrogen and/or sulfur, and this heterocyclic group possibly substituted by one or more than one Deputy, selected from cyano, halogeno, nitro, C1-4the alkyl and C1-4alkoxy;

R5Aand R5bin each case, when used here, independently represent H, C1-5alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from C1-2alkoxy, halogen) or phenyl (possibly substituted by one or more than one halogen, cyano, and C1-2alkoxy);

R7represents a C1-6alkyl (and this group possibly substituted and/or ends with one or more than one Deputy, selected from HE, halogeno, cyano, C1-2alkoxy, -SO2-C1-4of alkyl, -C(O)-C1-5the alkyl and Het5);

Gets the1and Gets5independently represent a 5-7-membered heterocyclic is the group moreover, these groups contain from one to four heteroatoms selected from oxygen, nitrogen and/or sulfur, and data heterocyclic group possibly substituted by one or more than one Deputy, selected from cyano, halogeno, nitro, C1-4of alkyl, C1-4alkoxy and-C(O)-C1-4of alkyl;

R8in each case, when used here, represents a C1-6alkyl (and this group possibly substituted and/or ends with one or more than one Deputy, selected from halogeno and C1-3alkoxy), phenyl (and this group possibly substituted by one or more than one of IT, cyano, halogeno, nitro, C1-4of alkyl, C1-4alkoxy and-S-(C1-4the alkyl)), Get6or-S(O)2R15a;

Gets the6is a 5-7-membered heterocyclic group, and this group contains from one to four heteroatoms selected from oxygen, nitrogen and/or sulfur, and this heterocyclic group possibly substituted by one or more than one Deputy, selected from cyano, halogeno, nitro, C1-4the alkyl and C1-4alkoxy;

R15arepresents a C1-4alkyl or phenyl (and this group possibly substituted by one or more than one of IT, cyano, halogeno, nitro, C1-4the alkyl and C1-4alkoxy);

R2represents H, -OR16or N(H)R 17;

R3represents H or methyl;

R16represents H, C1-2alkyl or phenyl (and this group possibly substituted by one or more than one of IT, cyano, halogeno, nitro, C1-4the alkyl and C1-4alkoxy);

R17represents H, C1-2alkyl, -(CH2)0-1-phenyl (and this group possibly substituted by one or more than one of IT, cyano, halogeno, nitro, C1-4the alkyl and C1-4alkoxy), or-C(O)O-(C1-4alkyl);

But a1-4alkylen;

In represents-Z-, -Z-N(H)-, -Z-S(O)2-, -Z-O- (the latter three groups, Z is attached to the carbon atom bearing R2and R3);

Z represents a direct bond or C1-2alkylen;

R4represents phenyl, and this group possibly substituted by one or more than one Deputy, selected from cyano, halogeno, nitro, C1-4the alkyl and C1-4alkoxy;

Ra-Rfall represent H;

alkyl groups and alkoxygroup may be, unless otherwise specified:

(1) straight or branched chain or cyclic or part cyclic/acyclic;

(2) saturated or unsaturated;

(3) is interrupted by an oxygen atom and/or

(4) substituted by one or more than one fluorine atom.

In particular, the preferred connection is possible according to the invention include compounds where

R1represents a C1-5alkyl (and this alkyl group is perhaps in part cyclic/acyclic, interrupted by an oxygen atom and/or substituted or ends with one phenyl (possibly substituted by one or more than one fluorescent and methoxy), Get1-C(O)R5a, -OR5b-C(O)N(H)-C1-3the alkyl and-S(O)2-C1-3by alkyl), Het2, -C(O)OR7, -C(O)N(H)R8or-S(O)2-C1-5alkyl;

Gets the2represents a 5-membered heterocyclic group containing one or two heteroatoms selected from oxygen, nitrogen and/or sulfur, and this heterocyclic group possibly substituted by one or more than one Deputy, selected from halogeno,1-2the alkyl and C1-2alkoxy;

R5Aand R5band in each case, when used here, independently represent H, C1-4alkyl (possibly substituted or terminated with methoxy or phenyl (possibly substituted by one or more than one fluorescent and methoxy);

R7represents a C1-5alkyl (and this group is probably unsaturated and/or substituted or ends with one of the-HE, cyano, methoxy, -SO2-C1-2of alkyl, -C(O)-C1-4the alkyl and Het5);

Gets the1and Gets5independently represent a 5-7-membered heterocyclic groups which, moreover, these groups contain from one to three heteroatoms selected from oxygen, nitrogen and/or sulfur, and data heterocyclic group possibly substituted by one or more than one Deputy, selected from C1-2of alkyl, C1-2alkoxy and-C(O)-C1-2of alkyl;

R8in each case, when used here, represents a C1-5alkyl (and this group is probably unsaturated, partially cyclic/acyclic, interrupted by an oxygen atom and/or substituted or ends methoxy), phenyl (and this group possibly substituted by one or more than one fluorescent, With1-2the alkyl, C1-2alkoxy and-S-(C1-2by alkyl) (alkyl part of the latter group possibly substituted by one or more than one fluorine atom)), Get6or-S(O)2R15a;

Gets the6is a 5-7-membered heterocyclic group, and this group contains from one to three heteroatoms selected from oxygen, nitrogen and/or sulfur, and this heterocyclic group possibly substituted by one or more than one Deputy, selected from C1-2the alkyl and C1-2alkoxy;

R15arepresents phenyl (and this group possibly substituted by one or more1-2the alkyl and C1-2alkoxy);

R2represents H, -OR16or-NH ;

R3represents N;

R16represents H or phenyl (and this group possibly substituted by one or more than one cyano or1-2alkoxygroup);

Rather it represents a C1-3alkylen;

In represents-Z-, -Z-N(H)-, -Z-S(O)2-, -Z-O- (the latter three groups, Z is attached to the carbon atom bearing R2and R3);

Z represents a direct bond or CH2;

R4represents phenyl, and this group possibly substituted by at least one cyano and this group possibly substituted by one or two additional substituents selected from cyano, halogen and nitro;

alkyl groups and alkoxygroup may be, unless otherwise stated, a straight or branched chain.

Particularly preferred compounds according to the invention include compounds where

R16represents H or phenyl (and this group possibly substituted by a methoxy group in an amount of from one to three);

Rather it represents a C1-3alkylen;

In represents-Z-, -Z-N(H)-, -Z-S(O)2-, -Z-O- (the latter three groups, Z is attached to the carbon atom bearing R2and R3);

Z represents a direct bond, or, when R2is a HE or NH2Z represents CH2;

R4 represents phenyl, substituted at position 4 (relative to the group) cyano, and possibly substituted at position 2 (the group) more cyano.

According to another aspect of the present invention proposed the compounds of formula I, which are compounds of formula Ia

where the wavy lines indicate possible relative CIS - or TRANS-stereochemistry;

R1represents a C1-12alkyl (possibly substituted and/or terminated with one or more than one group selected from halogeno, cyano, nitro, aryl, Het1a, -C(O)R5a1, -OR5b, -N(R6R5c, -C(O)XR7, -C(O)N(R8R5dand-S(O)2R9), Get2, -C(O)R5a2, -C(O)XR7, -C(O)N(R8R5d, -S(O)2R9or-CH2C(O)-(unsubstituted C1-6alkyl);

R5a1represents aryl (which latter group possibly substituted by one or more than one Deputy, selected from HE, cyano, halogeno, nitro, C1-6the alkyl (possibly ending in-N(H)C(O)OR23a), C1-6alkoxy, Het1, aryl (this aryl group may not be substituted for any additional aryl groups), -N(C1-6acrylic)R24b, -C(O)R24c, -C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i/sup> )C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23dand-S(O)2N(R24nR24por Gets4a;

R5a2represents H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, C1-6alkoxy, halogeno, cyano, nitro, aryl, Het3aand-N(H)C(O)R10), aryl or Het4a;

R5b-R5din each case, when used here, independently represent H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, C1-6alkoxy, halogeno, cyano, nitro, aryl, Het3and-NHC(O)R10), aryl or Het4or R5dtogether with R8represent3-6alkylen (and Allenova the group could be interrupted by an atom and/or possibly substituted by one or more than one C1-3alkyl group);

R10represents H, C1-4alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, cyano, aryl, and-NHC(O)R11or aryl;

R11represents H, C1-4alkyl or aryl;

R6represents H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from-O is, halogeno, cyano, nitro and aryl), aryl, -C(O)R12a, -C(O)R12bor-C(O)N(H)R12c;

R12a, R12band R12to represent a1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl) or aryl, or R12aand R12crepresent N;

X represents O or S;

R7in each case, when used here, represents aryl or1-12alkyl (which alkyl group possibly substituted and/or ends with one or more than one Deputy, selected from HE, halogeno, cyano, nitro, aryl, C1-6alkoxy, -SO2R13a, -C(O)R13band Gets5);

R13Aand R13bindependently represent a1-6alkyl or aryl;

R8in each case, when used here, represents H, C1-12alkyl, C1-6alkoxy (which latter two groups possibly substituted and/or over one or more than one Deputy, selected from HE, halogeno, cyano, nitro, C1-4the alkyl and C1-4alkoxy), -D-aryl, -D-aryloxy, -D-Het6, -D-N(H)C(O)R14a, -D,-S(O)2R15a, -D-C(O)R14b, -D-C(O)OR15b, -D-C(O)N(R14cR14dor R8together with R5drepresent3-6alkylen (and Allenova the group could be interrupted at the PTO and/or possibly substituted by one or more than one C 1-3alkyl group);

R14a- R14dindependently represent H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl), aryl, or R14cand R14dtogether represent a3-6alkylen;

R15aand R15bindependently represents a C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl) or aryl;

D represents a direct bond or C1-6alkylen;

R9in each case, when used here, represents a C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl), aryl or Het7;

R2represents H, halogeno,1-6alkyl, -E-OR16or-E-N(R17R18;

R3represents N or C1-6Walker;

R16represents H, C1-6alkyl, -E-aryl, -O-Het8, -C(O)R19a, -C(O)OR19bor-C(O)N(R20aR20b;

R17represents H, C1-6alkyl, -E-aryl, -O-Het8, -C(O)R19a, -C(O)OR19b, -S(O)2R19c, -[C(O)]pN(R20aR20bor-C(NH)NH2;

R18represents H, C16 alkyl, -E-aryl or-C(O)R19d;

R19a-R19dg whenever used here, independently represent a1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, aryl and Het9), aryl, Het10or R19aand R19dindependently represent H;

R20aand R20bin each case, when used here, independently represent N or C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, aryl and Het11), aryl, Het12or together represent a3-6alkylen, possibly interrupted by an atom Of;

E, in each case, when used here, represents a direct link or1-4alkylen;

p represents 1 or 2;

But a-G-, -J-N(R21)- or-J-O- (the latter two groups N(R21)- or - attached to the carbon atom bearing R2and R3);

In represents-Z-, -Z-N(R22)-, -N(R22)-Z-, -Z-S(O)n-, -Z-O- (the latter two groups, Z is attached to the carbon atom bearing R2and R3);

G represents a C1-6alkylen;

J represents a C2-6alkylen;

Z represents a direct bond or C1-4alkylen;

R21 and R22independently represent N or C1-6alkyl;

R4represents aryl or Het13and both of these groups possibly substituted by one or more than one Deputy, selected from HE, cyano, halogeno, nitro, C1-6the alkyl (possibly ending in-N(H)C(O)OR23a), C1-6alkoxy, Het1, aryl, -N(R24aR24b, -C(O)R24c-C(O)OR24d, -C(O)N(R24eR24f-N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23d, -S(O)2N(R24nR24pand only if it Gets13)oxo;

Gets the13represents a four to eight-membered heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur;

Gets the1-Het12in each case, when used here, independently represent four-dvenadcatiletnie heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, and data heterocyclic group possibly substituted by one or more than one Deputy, includes =O, -HE, cyano, halogeno, nitro, C1-6alkyl (possibly ending in-N(H)C(O)OR23a), C1-6alkoxy, Het1, aryl, -N(R24aR24b, -C(O)R24c-C(O)OR24d24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23dand-S(O)2N(R24nR24p;

Gets the1aThat gets3aand Gets4ain each case, when used here, independently represent four-to eight-membered heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, and data heterocyclic group possibly substituted by one or more than one Deputy, includes =O, -HE, cyano, halogeno, nitro, C1-6alkyl (possibly ending in-N(H)C(O)OR23a), C1-6alkoxy, Het1, aryl, -N(R24aR24b, -C(O)R24c-C(O)OR24d-C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23dand-S(O)2N(R24nR24p;

R23a-R23din each case, when used here, independently represent a1-6alkyl;

R24A-R24pin each case, when used here, independently represent N or C1-6alkyl;

n in each case represents 0,1 or 2, and

Ra-Rfindependently represent N or C1-4alkyl;

where each aryl and al is oxygraph, if not indicated otherwise, is a possibly substituted;

or their pharmaceutically acceptable derivatives;

provided that

(a) when R3represents N or C1-4alkyl and a represents-J-N(R21)- or-J-O-;

then does not represent-N(R22)-, -S(O)n-, -O - or-N(R22)-Z- (and in the latter group-N(R22) attached to the carbon atom bearing R2and R3), and

(b) when R2represents-E-OR16or-E-N(R17R18where E is a direct bond; then

(1) represents-J-N(R21)- or-J-O - and

(2) does not represent-N(R22)-, -S(O)n-, -O - or-N(R22)-Z- (and in the latter group-N(R22) attached to the carbon atom bearing R2and R3);

moreover, such compounds are also referred to herein as "compounds of the invention".

Preferred compounds of formula la include (where appropriate) preferred compounds of formula I, defined above.

Preferred compounds of formula la include compounds where

R1represents a C1-2alkyl (substituted or terminated by the group Gets1aor-C(O)R5a1), -C(O)R5a2or-CH2C(O)-(unsubstituted C1-4alkyl);

R5a1represents phenyl (which latter group is possibly substituted by one or two substituents, selected from halogeno and C1-2alkoxy);

R5a2represents H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from C1-3alkoxy, halogeno) or Gets4a;

G represents a C1-4alkylen;

Gets the13represents a five - or six-membered heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur;

Gets the1aThat gets3aand Gets4ain each case, when used here, independently represent a five - or six-membered heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, and data heterocyclic group possibly substituted by substituents in the amount of from one to three, selected from =O, cyano, halogeno, nitro, C1-4of alkyl, C1-4alkoxy, aryl, -N(H)R24a, -C(O)R24c-C(O)OR24d, -C(O)N(H)R24e, -N(R24g)C(O)R24hand-S(O)nR23c.

Preferred compounds according to the invention include compounds of the examples disclosed below in this description.

Getting

According to this invention is also a method for obtaining compounds of the formula I, in which

(a) carry out the interaction of the compounds of formula II

where R1and Ra-Rfsuch as defined above, with a compound of formula III

where L1represents a leaving group (for example, mesilate, toilet or halogeno), and R2, R3, R4And In such, as defined above, for example, at a temperature of from -10°to the temperature of reflux distilled in the presence of a suitable base (e.g. triethylamine or2CO3) and the appropriate organic solvent (e.g. dichloromethane, acetonitrile or DMSO);

(b) for compounds of formula I in which a represents a C2alkylene and R2and R3together are =O, interact corresponding compounds of formula II, as defined above, with a compound of formula IV

where R4and In such, as defined above, for example, at room temperature in the presence of a suitable organic solvent (e.g. ethanol);

(C) for compounds of formula I in which a represents a CH2and R2represents-IT or-N(H)R17and communicates the corresponding compounds of formula II, as defined above, with a compound of formula V

where Y represents O or N(R17and R3/sup> , R4, R17and In such, as defined above, for example, at elevated temperature (for example, from 60°to the temperature of reflux distilled in the presence of a suitable solvent (for example, lower Olkiluoto alcohol (e.g. isopropyl alcohol), acetonitrile, or a mixture of lower Olkiluoto alcohol and water);

(g) for compounds of formula I in which a represents a C1-6alkylen, is a1-4alkylene and R2and R3both represent H, carry out reduction of the corresponding compounds of formula I, where R2and R3together are =O, in the presence of a suitable reducing agent in a suitable reaction conditions, for example by activating the relevant group C=O using an appropriate agent (such as tailgatin) in the presence of a suitable reducing agent (e.g. sodium borohydride or lamborginid sodium) and an appropriate organic solvent (e.g. a lower (for example, C1-6) Olkiluoto alcohol);

(d) for compounds of formula I in which R2and R3both represent H, and (1) And represents a simple bond or-J-N(R21)and is a1-4alkylene, or (2) A represents a C1-6alkylen, and is represented by N(R22or-N(R22)-Z- (and in the latter group-N( 22) attached to the carbon atom bearing R2and R3), carry out reduction of the corresponding compounds of formula I, where R2and R3together are =O, in the presence of a suitable reducing agent (for example, LiAIH4) and a suitable solvent (such as THF);

(e) for compounds of formula I in which a represents a C1-6alkylen, represents a direct link,1-4alkylene, -Z,-N(R22)-, -Z-S(O)n- or-Z-O- (the latter three groups, Z represents a C1-4alkylen), R2HE is a and R3represents H, carry out reduction of the corresponding compounds of formula I, where R2and R3together are =O, in the presence of a suitable reducing agent (for example, NaBH4) and a suitable organic solvent (such as THF);

(g) for compounds of formula I, which represents-Z-O-, interact the compounds of formula VI

where R1, R2, R3, Ra-RfAnd Z are such as defined above, with a compound of formula VII

where R4such as defined above, for example, in terms of types of conditions, Mitsunobu (Mitsunobu), for example at a temperature from the temperature surrounding the it environment (for example, 25° (C) to the temperature of reflux distilled in the presence of a tertiary phosphine (for example, tributylphosphine or triphenylphosphine), azodicarboxylate derived (for example, diethylazodicarboxylate or 1,1'-(azodicarbon)dipiperidino) and a suitable organic solvent (e.g. dichloromethane or toluene);

(C) for compounds of formula I, which represents-Z-O-, interact the compounds of formula VI, as defined above, with a compound of formula VIII

where L2represents a leaving group, such as halogen, alkanesulfonyl, performancereport or arenesulfonic, and R4such as defined above, for example under conditions known to experts in the art (for example, when R4represents a 2 - or 4-pyridyl, interaction at a temperature of from 10°to the temperature of reflux distilled in the presence of a suitable base (e.g. sodium hydride) and an appropriate solvent (such as N,N-dimethylformamide));

(I) for compounds of formula I in which a represents a C1-6alkylen and represents-N(R22)-Z- (where the group-N(R22)is attached to the carbon atom bearing R2and R3), interact the compounds of formula IX

where aapredstavljaet a C 1-6alkylene and R1, R2, R3, R22and Ra- Rfsuch as defined above, with a compound of formula X

where L2, R4and Z are such as defined above, for example, at 40°in the presence of a suitable organic solvent (e.g. acetonitrile);

(K) for compounds of formula I in which R2represents-O-NH2carry out the recovery of the corresponding compounds of formula XI

where R1, R3, R4, Ra-Rf, A, b and E such as defined above, for example, by hydrogenation under suitable pressure in the presence of a suitable catalyst (e.g. palladium on carbon) and a suitable solvent (e.g. water-ethanol mixture);

(l) for compounds of formula I in which R2represents-E-N(R18)C(O)N(H)R20aand communicates the corresponding compounds of formula I, where R2represents-E-N(R18)H, with a compound of formula XII

where R20asuch as defined above, for example, at ambient temperature (e.g. 25° (C) in the presence of a suitable solvent (e.g. benzene);

(m) for compounds of formula I in which R2represents-E-N(H)[C(O)]sub> 2NH2and communicates the corresponding compounds of formula I, where R2represents-E-NH2with diamido oxalic acid, for example, at a temperature of from -10 to 25°in the presence of a suitable agent combinations (for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), a suitable activating agent (for example, 1-hydroxybenzotriazole), a suitable base (e.g. triethylamine) and a reaction-inert organic solvent (such as DMF);

(h) for compounds of formula I in which R2represents-E-N(R17R18where R17and R18such as defined above, provided that R17does not represent H, interact corresponding compounds of formula I, where R2is a-D-N(H)R18with a compound of formula XIII

where R17ais an R17as defined above, except that it does not represent H, and L3is a leaving group, such as halogen (for example, chloro or bromo), p-nitrophenolate,1-4the alkoxide, C1-4alkylthiol, -OC(O)R19a, -OC(O)OR19bor-OS(O)2R19cwhere R19a-R19csuch as defined above, for example, in conditions that are well known to experts in the field of equipment;

(o) for compounds of formula I in which R2represents-E-OR16where R16represents a C1-6alkyl, -E-aryl or-E-Het8and communicates the corresponding compounds of formula I, where R2represents-O-HE, with the compound of the formula XIV

where R16arepresents a C1-6alkyl, -E-aryl or-E-Het8where Get8such as defined above, for example, at a temperature of from ambient temperature (e.g. 25° (C) to the temperature of reflux distilled under conditions types of conditions, Mitsunobu (Mitsunobu) (i.e. in the presence of, for example, triphenylphosphine, azodicarboxylate derived (for example, 1,1'-(azodicarbon)dipiperidino) and a suitable organic solvent (e.g. dichloromethane));

(p) for compounds of formula I in which R2represents-E-OR16(where R16represents a C1-6balkin, -E-aryl or-E-Het8), interact corresponding compounds of formula XV

where L2, R1, R3, R4, Ra-Rf, A, b and E such as defined above, with a compound of formula XIV as defined above, for example, at a temperature of from ambient temperature (e.g. 25° (C) to the temperature of reflux distilled in terms of the s-type conditions Williamson (i.e. in the presence of a suitable base (for example, KOH or NaH) and a suitable organic solvent (such as DMSO or DMF));

(p) for compounds of formula I in which R2represents-E-OR16where R16such as defined above, provided that it does not represent H, interact corresponding compounds of formula I in which R2represents-O-HE, with the compound of the formula XVI

where R16bis an R16as defined above, except that it does not represent H, and L4represents a leaving group, such as HE, halogeno, alkanesulfonyl, arenesulfonyl or-OC(O)R19awhere R19asuch as defined above, for example, at a temperature of from room temperature to the temperature of reflux distilled, possibly in the presence of a reaction-inert organic solvent (such as THF or CH2CI2), a suitable base (e.g. triethylamine or2CO3and/or a suitable agent combinations (for example, 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, possibly combined with a suitable catalyst, such as 4-dimethylaminopyridine) (for example, when R16brepresents-C(O)R19aand L4is a HE, this interaction can be done is to leave at ambient temperature (for example, 25° (C) in the presence of the agent combinations, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, a suitable catalyst, such as 4-(dimethylamino)pyridine and a solvent such as THF);

(C) for compounds of formula I in which R2represents halogeno, carry out the substitution of the corresponding compounds of formula I in which R2is a HE, using a suitable halogenation agent (for example, compounds in which R2is a fluorescent, interact with TRIFLUORIDE (diethylamino)sulfur);

(t) interact corresponding compounds of formula XVII

where R2, R3, R4, Ra-RfAnd In such, as defined above, with a compound of formula XVIII

where L5represents a leaving group, such as halogen, HE alkanesulfonyl, performancereport, arenesulfonyl, imidazole, R25O- (where R25represents, for example, With1-10alkyl or aryl, and these groups possibly substituted by one or more than one halogen - or nitro-group), -OC(O)R5a, -OC(O)OR7or-OS(O)2R9and R1, R5a, R7and R9such as defined above, for example, at a temperature of from -10°before the temperature of the reflux distilled possible in the presence of a suitable solvent (for example, CHCl3CH3CN, 2-propanol, diethyl ether, CH2Cl2, DMSO, DMF, THF, toluene or mixtures thereof) and/or a suitable base (For example, a2CO3, pyridine or triethylamine);

(u) for compounds of formula I in which R1represents-C(O)XR7or-C(O)N(R8R5dcarry out the interaction of the compounds of formula XIX

where R2, R3, R4, Ra-RfAnd, and L5such as defined above, with a compound of formula XX

where R26represents-XR7or-N(R8R5dand R5d, R7, R8and X are such as defined above, for example, in the conditions described above (stage (t) method of obtaining);

(f) for compounds of formula I in which R1represents-C(O)N(H)R8and communicates the corresponding compounds of formula XVII, as defined above, with a compound of formula XXI

where R8such as defined above, for example, at a temperature of from 0°to the temperature of reflux distilled in the presence of an appropriate organic solvent (e.g. dichloromethane)or by solid-phase synthesis under conditions known to specialists in this field of technology;

(x) for compounds f is rmula I, in which R1represents a C1-12alkyl, and an alkyl group substituted on C-2-C (relative to nitrogen ispidina) HE or N(H)R6or maybe substituted for otherwise one or more than one additional Deputy, as defined above for R1and communicates the corresponding compounds of formula XVII, as defined above, with a compound of formula XXII

where Yarepresents O or N(R6), R13represents a C1-10alkyl, possibly substituted by one or more than one Deputy, as defined above for R1and R6such as defined above, for example, as described above for preparing compounds of formula I (stage (C) of the method of receipt);

(C) for compounds of formula I in which R1represents-C(O)OR7and Randand/or Rbrepresent1-4alkyl, interact corresponding compounds of formula I in which R1represents-C(O)OR7and Raand Rbare N, with one or more than one equivalent of the compound of formula XXIII

where R27represents a C1-4alkyl and L2such as defined above, in the presence of a suitable strong base (e.g. base, capable of deprotonation 3,7-diazabicyclo[3.3.0]octane ring position α relative to the nitrogen bearing the group-C(O)OR7(for example, utility)), for example, at temperatures from -80°C to room temperature in the presence of a suitable solvent (for example, N,N,N',N'-tetramethylethylenediamine, THF or mixtures thereof);

(h) for compounds of formula I, which are the N-oxide derivatives nitrogen-3,7-diazabicyclo[3.3.0]octane, carry out the oxidation of the corresponding nitrogen 3,7-diazabicyclo[3.3.0]octane of the corresponding compounds of formula I in the presence of a suitable oxidizing agent (e.g. m-SRV), for example, at 0°in the presence of a suitable organic solvent (for example, DHM);

(W) for compounds of formula I which are derived from C1-4alkyl Quaternary ammonium salts in which the alkyl group attached to the nitrogen 3,7-diazabicyclo[3.3.0]octane, interact on this nitrogen 3,7-diazabicyclo[3.3.0]octane, the corresponding compounds of formula I with a compound of formula XXIII as defined above, for example, at room temperature in the presence of an appropriate organic solvent (such as DMF), followed by purification (using, for example, HPLC) in the presence of a suitable source of counterion (e.g., NH4OAc);

(g) undertake Aut conversion of one substituent on R 4in another using techniques well known to specialists in this field of technology, or

(e) carry out the conversion of one group R1to another using techniques well known to specialists in this field of technology.

The compounds of formula II can be obtained by interaction of the corresponding compounds of formula XXIV

where Ra-Rfsuch as defined above, with a compound of formula XVIII, as defined above, for example, as described above for the synthesis of compounds of formula I (stage (t) method get).

The compounds of formula III can be obtained using standard techniques. For example, the compounds of formula III, in which

(1) represents-Z-O-, can be obtained by combining the compounds of formula VII, as defined above, with a compound of formula XXV

where R2, R3, A, Z and L1such as defined above, and two groups of L1may be the same or different, or

(2) represents-N(R22)-Z- (where N(R22) attached to the carbon atom bearing R2and R3), and R2and R3together are =O, can be obtained by combining the compounds of formula XXVI

where R4, R2 and Z are such as defined above, with a compound of formula XXVII

where L6represents a suitable leaving group (for example, HE or halogeno), and a and L1such as defined above;

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

The compounds of formula III in which a is a C2alkylene and R2represents-OR16where R16represents a C1-6alkyl, -E-aryl or-E-Het8alternative can be obtained by interaction of the compounds of formula XIV as defined above, with a compound of formula XXVIII

where R3, R4, R27and In such, as defined above, 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 transformation of essential functional groups in the group-CH2-L1(where L1such as defined above) under conditions that are well known to specialists in this field of technology.

The compounds of formula III in which a is a C2-6alkylen, can be perceived by the s by restoring the corresponding compounds of formula XXIX

where abrepresents a direct bond or C1-4alkylene and R2, R3, R4and In such, as defined above, with a suitable boranova complex or a complex of borane-Lewis base (for example, borane-dimethyl sulfide) in the presence of a suitable solvent (e.g. diethyl ether, THF or mixtures thereof) with subsequent oxidation of the resulting boranova adduct suitable oxidizing agent (for example, perborate sodium) and then converting the resulting Oh-group of the group L1in conditions known to specialists in this field of technology.

The compounds of formula III in which a is a C1-6alkylen and represents-Z-N(R22)- (and in the latter case, Z is attached to the carbon atom bearing R2and R3), can be obtained by combining the compounds of formula VIII as defined above, with a compound of formula XXX

where Aa, Z, R2, R3and R22such as defined above, for example, at a temperature of from room temperature to the temperature of reflux distilled, possibly in the presence of a suitable solvent and/or a suitable base, followed by conversion of the Oh-group of the group L1in conditions known to specialists in this field of technology.

With the unification of the formula III, which is a-Z-S(O)- or-Z-S(O)2-can be obtained by oxidation of the corresponding compounds of formula III, in which a represents-Z-S-, where Z is as defined above, in the presence of an appropriate quantity of a suitable oxidizing agent (e.g. m-SRV) and a suitable organic solvent.

The compounds of formula V can be obtained in accordance with methods which are well known to specialists in this field of technology. For example, the compounds of formula V, in which

(1) represents-CH2O - and Y is Oh, can be obtained by interaction of the compounds of formula VII, as defined above, with a compound of formula XXXI

where R3and L2such as defined above, for example, at elevated temperature (for example, 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) R3represents H, b represents a direct bond, C1-4alkylene, -Z,-N(R22)-, -Z-S(O)n- or-Z-O- (and in each case, the group Z represents a C1-4alkylene attached to the atom is carbon, bearing R3), and Y is Oh, can be obtained by recovering the compounds of formula XXXIIA or XXXIIB

whereais a-Za-N(R22), Za-S(O)nor Za-O- (and in each case, the group Zarepresents a direct bond or C1-3alkylene attached to the carbon atom bearing R3),brepresents a direct bond or C1-4alkylene, and R4, R22and n are such as defined above, for example, at a temperature of 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(R22)-, -Z-S(O)2- or-Z-O- (and in each case, the group Z represents a C1-4alkylene attached to the carbon atom bearing R3), and Y is Oh, can be obtained by oxidation of compounds of formula XXXIIIA and the and XXXIIIB

where R3, R4andbsuch as defined above, and3such as defined above, except that n is equal to 2, in the presence of a suitable oxidizing agent (e.g. m-SRV), for example, by boiling under reflux in the presence of a suitable organic solvent (e.g. dichloromethane), or

(4) represents-Z-O-, and the group Z represents a C1-4alkylene attached to the carbon atom bearing R3and Y represents-N(R17), where R17represents-C(O)OR19bor-S(O)2R19ccan be obtained by cyclization of compounds of formula XXXIV

where R17brepresents-C(O)OR19bor-S(O)2R19c, Zbrepresents a C1-4alkylene and R3, R4, R19b, R19cand L2such as defined above, for example, at a temperature of 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).

Compounds of formula VI, IX, XI and XV can be obtained in the same way, to the and to the compounds of formula I (see, for example, stage (a) - (C) of the method of receipt).

The compounds of formula XI alternative can be obtained by interaction of the corresponding compounds of the formula I, in which R2represents-O-HE, with the compound of formula XXXV

where R28represents a C1-4alkyl or aryl (these two groups possibly substituted by one or more than one Deputy, selected from C1-4of alkyl, halogen and nitro), for example, at a temperature of from -10 to 25°in the presence of a suitable solvent (e.g. dichloromethane) followed by interaction with a suitable source of azide ion (e.g. sodium azide), for example, at a temperature from ambient temperature to the temperature of reflux distilled in the presence of an appropriate solvent (e.g. N,N-dimethylformamide) and a suitable base (e.g. sodium bicarbonate).

The compounds of formula XI can also be obtained by interaction of the compounds of formula II, as defined above, with a compound of formula XXXVI

where R3, R4And, b, E and L2such as defined above, for example, under conditions similar to those described above for the synthesis of compounds of formula I (stage (a) of the method of receipt).

The compounds of formula XV alternative is actively can be obtained by substitution of the group-HE corresponding compounds of formula I, in which R2represents-O-HE, on the group of L2in conditions that are well known to specialists in this field of technology.

The compounds of formula XVII can be obtained by interaction of the corresponding compounds of formula XXIV as defined above, with a compound of formula III, as defined above, for example, under conditions similar to those described above for the synthesis of compounds of formula I (stage (a) of the method of receipt).

The compounds of formula XVII, in which a represents a C2alkylene, and R2and R3together are =O, can be obtained by interaction of the corresponding compounds of formula XXIV as defined above, with a compound of formula IV, as defined above, for example, as described above for the synthesis of compounds of formula I (stage (b) of the method of receipt).

The compounds of formula XVII, in which a represents CH2and R2represents-IT or-N(H)R17can be obtained by interaction of the corresponding compounds of formula XXIV as defined above, with a compound of formula V as defined above, for example, as described above for the synthesis of compounds of formula I (stage (C) of the method of receipt).

The compounds of formula XIX can be obtained through the implementation of suitable interaction is of the compounds of formula II, as defined above, with a compound of formula XXXVII

where L5such as defined above, and where both groups L5may be the same or different, for example, at a temperature of from 0°to the temperature of reflux distilled in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. toluene or dichloromethane).

The compounds of formula XXIV in which Raand Rbboth represent H may be obtained by recovering the corresponding compounds of formula XXXVIII

or N-protected derivative, where Rc- Rfsuch as defined above, for example, at a temperature of from room temperature to the temperature of reflux distilled in the presence of a suitable reducing agent (for example, LiAl4) and a suitable organic solvent (such as THF).

The compounds of formula XXIV in which Raand Rbboth represent H, an alternative can be obtained by interaction of the corresponding compounds of formula XXXIX

or N-protected derivative, where Rc-Rfand L2such as defined above, with ammonia or a protected derivative (e.g. benzylamine), for example, in conditions that are described in published international application WO 96/07656 included in this description by reference, 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 or DMF)).

The compounds of formula XXIV in which Rcand Rdboth represent methyl, a Ra, Rb, Reand Rfall represent H, an alternative can be obtained according to the method described in J. Org. Chem. 61, 8897 (1996), included in this description by reference.

The compounds of formula XXIX, which represents a C1-4alkylen, can be obtained by combining the compounds of formula XL

wherecrepresents a C1-4alkylen, Hal represents a chloro, bromo or iodo andb, R2and R3such as defined above, with a compound of formula VIII as defined above, for example, at temperatures from -25°C to room temperature in the presence of a suitable salt of zinc(II) (for example, anhydrous ZnBr2), a suitable catalyst (such as Pd(PPh3)4or Ni(PPh3)4and reaction-inert organic solvent (such as THF, toluene or diethyl ether).

The compounds of formula XXXVI mo the ut can be obtained in the same way, as for compounds of formula XI (i.e. from the corresponding alcohol).

The compounds of formula XXXVIII in which Rcand Rdboth represent H may be obtained by recovering the corresponding compounds of formula XLI

or N-protected or N,N'-dvuzameshchennogo derived, for example, as described in J. Heterocyclic Chem. 20, 321 (1983), included in this description by reference, for example, by hydrogenation at high pressure (for example, from 25 to 35 kPa) in the presence of a suitable catalyst (e.g. palladium on carbon) and a suitable solvent (for example, glacial acetic acid).

The compounds of formula XXXVIII alternative can be obtained by combining the compounds of formula XLIIA or XLIIB

or N-protected derivative, where L7represents a leaving group (such as halogen or HE) and Rc-Rfsuch as defined above, with ammonia or a protected derivative (for example, benzylamino), for example, in conditions that are well known to experts in the art (for example, when the reactant is a compound of formula XLIIB, the interaction may be carried out at a temperature of from room temperature to the temperature de is legally in the presence of a suitable solvent (such as THF) followed by cyclization of the resulting amide intermediate compound under conditions which are well known to experts in the art (e.g., through interaction with dehydrating agent such as SOCl2)).

The compounds of formula XXXVIII can also be obtained by interaction of the compounds of formula XLIII

or N-protected (e.g. N-benzyl) derivative, where L8represents a suitable leaving group (such as lower alkoxy (e.g. methoxy) or cyano), R29a-R29cindependently represents a C1-6alkyl or phenyl, Rxis an Reor Rf, Ryis an Rfor Re(as appropriate), and Reand Rfsuch as defined above, with a compound of formula XLIV

or N-protected (e.g. N-benzyl) derivative, where Rcand Rdsuch as defined above, for example, in terms identical or similar to those described in published international application WO 97/11945 and Tetrahedron 41(17), 3529 (1985), included in this description by reference, for example, at a temperature of from room temperature to the temperature of reflux distilled in the presence of a suitable solvent (e.g. dichloromethane) and a suitable catalyst (for example, acids, such as triperoxonane acid, or the source of the ICA fluoride ion, such as tetrabutylammonium or silver fluoride)).

The compounds of formula XXXIX can be obtained by interaction of diapir maleic acid, such as compound of formula XLV

where R27, Rcand Rdsuch as defined above, with a compound of formula XLVI

where Rxsuch as defined above, in the presence of the compounds of formula XLVII

where Rysuch as defined above, for example, in terms identical or similar to those described in the publications of international applications WO 96/07656 and WO 95/15327 included in this description by reference, with the subsequent transformation of two groups-C(O)OR27in the resulting intermediate compound in group-CH2-L2in conditions that are well known to specialists in this field of technology.

The compounds of formula XLI can be obtained by combining the compounds of formula XLVIIIA or XLVIIIB

or N-protected (e.g. N-benzyl) derivative, where Re, Rfand L7such as defined above, with ammonia or a protected derivative (for example, benzylamino), for example, under the conditions described in this application with respect to receipt of the compounds of formula XXXVIII, with subsequent cyclization of the resulting amide intermediate compound under conditions known to specialists in this field of technology.

The compounds of formula XLIIA can be obtained by interaction of the corresponding compounds of formula XLV or

(1) with the compound of the formula XLIII, as defined above, or N-protected (e.g. N-benzyl) derivative, for example, in the conditions described above for preparing compounds of formula XXXVIII, with subsequent transformation of two groups-C(O)OR27in the resulting intermediate compound in the group-C(O)L7in conditions that are well known to experts in the art (for example, for compounds of formula XLIIA, in which L7is a HE, by hydrolysis in the presence of alkali metal base (such as KOH) and a suitable solvent (e.g. ethanol, water or mixtures thereof), or

(2) with a compound of formula XLVI, as defined above, in the presence of the compounds of formula XLVII, as defined above, for example, in the conditions described above for preparing compounds of formula XXXIX, with subsequent transformation of two groups-C(O)OR27in the resulting intermediate compound in the group-C(O)L7under conditions well known to specialists in this field of technology.

The compounds of formula XLIIB can be the ü is obtained by interaction of the corresponding compounds of formula XLIX

where Rcand Rdsuch as defined above, or

(1) with the compound of the formula XLIII, as defined above, or N-protected (e.g. N-benzyl) derivative, for example, in the conditions described above for preparing compounds of formula XXXVIII, or

(2) with a compound of formula XLVI, as defined above, in the presence of the compounds of formula XLVII, as defined above, for example, in the conditions described above for preparing compounds of formula XXXIX.

The compounds of formula XLIIB alternative can be obtained by cyclization of the corresponding compounds of formula XLIIA, where L7is a HE, for example, under conditions well known to experts in the art (e.g., through interaction with dehydrating agent (such as N,N'-dicyclohexylcarbodiimide) in the presence of a suitable solvent (such as THF)).

The compounds of formula XLIII can be obtained by interaction of the corresponding compounds of formula L

or N-protected (e.g. N-benzyl) derivative, where Rxand R29A- R29csuch as defined above, with a compound of formula XLVII, as defined above, in the presence of either low Olkiluoto alcohol, that the CSOs as methanol (obtaining the compounds of formula XLIII, in which L8represents lower alkoxy; for example, in terms identical or similar to those described in published international application WO 97/11945 (for example, at a temperature of from 0°C to room temperature in the presence of water), or the source of cyanide ion, such as potassium cyanide (obtaining the compounds of formula XLIII in which L8represents cyano, for example, in terms identical or similar to those described in Tetrahedron 41(17), 3529 (1985)).

Compounds of formula XLVIIIA and XLVIIIB can be obtained using known methods, for example according to the procedures described in J. Chem Heterocyctic. 20, 321 (1983).

The compounds of formula L can be obtained using known methods, for example according to the procedures described in published international application WO 97/11945.

Compounds of formulae IV, VII, VIII, X, XII, XIII, XIV, XVI, XVIII, XX, XXI, XXII, XXIII, XXV, XXVI, XXVII, XXVIII, XXX, XXXI, XXXIIA, XXXIIB, XXXIIIA, XXXIIIB, XXXIV, XXXV, XXXVII, XL, XLIV, XLV, XLVI, XLVII, XLIX and their derivatives are either commercially available, known from the literature data, or can be obtained or similar methods described here, or by using conventional methods of synthesis in accordance with the standard methods of easily accessible starting materials using appropriate reagents and reaction conditions. For example, transformation, gives the compounds of formula I (for example, stage (d), (d), (e), (K), (l), (m), (n), (o, (p), (b), (C), (d), (g) and (e) ways to obtain), it is possible to carry out, where appropriate, at the intermediate compounds described in this application (for example, the compounds of formulae II, VI, IX, XI, XV, XVII and XIX), with the production of other intermediates which are useful in the synthesis of compounds of formula I.

The substituents on aryl (e.g. phenyl) and (if applicable) heterocyclic group(s) in the compounds defined in the present description, can be converted to any other claims deputies using techniques well known to specialists in this field of technology. For example, the hydroxy may be converted to alkoxy, phenyl may be galogenidov with getting halogenfree, nitro can be recovered by obtaining amino, halogeno may be replaced by cyano and so on.

The specialist is also evident that the interconversion and transformation of various standard substituents or functional groups within certain compounds of formula I will provide other compounds of formula I. for Example, the carbonyl can be restored to a hydroxy or alkylene, and hydroxy can be converted into halogen.

Compounds according to the invention can be isolated from their reaction mixtures using conventional techniques.

Specialists in the art it is obvious that in the ways of sannich above, functional groups of intermediate compounds may be protected or may need to be protected with protective groups.

Functional group, which is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protective groups for hydroxy include trialkylsilyl and diarylethylene group (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and acylcarnitine group (e.g. methyl - and ethylcarbodiimide group). Suitable protective groups for amino include benzyl, sulfonamide (for example, benzosulfimide), tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protective groups for amidino and guanidino include benzyloxycarbonyl. Suitable protective groups for carboxylic acids include C1-6alkalemia or benzyl esters.

Protect and unprotect functional groups can take place before or after any one of the reaction stages described above.

The protective group may be removed in accordance with techniques which are well known to experts in the art and which are described below.

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

Specialists in the art it is obvious that in order to obtain compounds according to the invention an alternate and in some cases more convenient way mentioned in the description of the individual stages of the method of obtaining may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. can be added substituents other intermediate compounds and/or chemical transformation performed on other intermediate compounds compared to those that were here associated with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the strategy (if it exists) protective groups. Obviously, the type of chemical reaction will influence the choice of reagent used in these stages of the synthesis, the need and the type of protective groups and the sequence of synthesis.

In addition, specialists in the art it is obvious that despite the fact that certain protected derivatives of compounds of formula I which can be obtained before the final stage of removing protection, mogote to 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 the invention which are pharmacologically active. Therefore, such derivatives can be described as "prodrugs". Moreover, certain 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.

Specialists in this field of technology is also clear that certain compounds of formula I are useful as intermediates in the synthesis of other compounds of formula I.

Some intermediate compounds mentioned above, are new. Thus, according to another aspect of the present invention proposed (a) compound of formula II, as defined above (provided that when Ra-Rfall represent H, then R1is not a (1) C1-12alkyl, possibly substituted by aryl or Het1, (2) -C(O)-(possibly substituted aryl), or (3) tert-butyloxycarbonyl), or a protected derivative; (b) a compound of formula VI, as defined above, or a protected derivative; (C) the compound of formula IX, as defined above, or a protected derivative; (d) compound of formula XI, as defined in the above, or a protected derivative; (d) the compound of formula XV as defined above, or a protected derivative; (e) compound of formula XVII, as defined above (provided that when is a Z, then R2represents-O-O-(possibly substituted aryl)), or a protected derivative and (g) the compound of formula XIX as defined above, or a protected derivative.

The compounds of formula II which may be mentioned include such compounds, in which

(a) when R1represents-C(O)XR7then

R7does not represent unsubstituted With1-12alkyl;

R7represents aryl;

X represents S;

(b) when Ra-Rfall represent H, then R1is not a

(1) -C(O)XR7;

(2) unsubstituted With1-4alkyl straight or branched chain;

(3) unsubstituted With1-5alkyl straight or branched chain;

(4)1-4alkyl straight or branched chain, substituted by phenyl (which latter group is mono - or disubstituted by one fluorescent, chloro, bromo, stands or methoxy);

(5)1-4alkyl straight or branched chain, substituted by one fluorescent, chloro, bromo, stands or phenyl (which latter group is mono - or disubstituted by one or two methoxy pami);

(6)1-4alkyl straight or branched chain, substituted by one fluorescent, chloro, bromo, stands, methoxy or phenyl;

(7)1-4alkyl straight or branched chain, substituted, halogen, stands, methoxy or aryl;

(C) R1represents a

(1) Gets2, -C(O)R5a, -C(O)XR7, -C(O)N(R8R5d, -S(O)2R9, unsubstituted cyclic or part cyclic/acyclic With4-12alkyl or C1-4alkyl, substituted or terminated, or C5-12alkyl, possibly substituted and/or terminated with one or more than one group selected from the

halogeno,

cyano,

nitro,

phenyl (which latter group possibly substituted-HE, cyano, nitro, C2-6the alkyl (possibly ending in-N(H)C(O)OR23a)2-6alkoxy, Het1, aryl (which aryl group may not be substituted for any additional aryl groups), -N(R24aR24b, -C(O)R24c-C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24g, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23dand-S(O)2N(R24nR24p),

naphthyl (which latter group possibly substituted by one or more than one group selected from HE, cyano, halogeno, nitro, C1-6the alkyl (possibly ending in-N(H)CO)OR 23a)1-6alkoxy, Het1, aryl (which aryl group may not be substituted for any additional aryl groups), -N(R24aR24b, -C(O)R24c, -C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23dand-S(O)2N(R24nR24p),

Gets the1,

-C(O)R5a,

-OR5b,

-N(R6R5c,

-C(O)XR7,

-C(O)N(R8R5dand

-S(O)2R9;

(2) Gets2, -C(O)R5a, -C(O)XR7, -C(O)N(R8R5d, -S(O)2R9, unsubstituted cyclic or part cyclic/acyclic With4-12alkyl or C1-5alkyl, substituted or terminated, or C6-12alkyl, possibly substituted and/or terminated with one or more than one group selected from the

cyano,

nitro,

phenyl (which latter group possibly substituted-HE halogeno, cyano, nitro, C1-6the alkyl (possibly ending in-N(H)C(O)OR23a)2-6alkoxy, Het1, aryl (which aryl group may not be substituted for any additional aryl groups), -N(R24aR24b, -C(O)R24c-C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)n R23c, -OS(O)2R23dand-S(O)2N(R24nR24p),

naphthyl (which latter group possibly substituted by one or more than one group selected from HE, cyano, halogeno, nitro, C1-6the alkyl (possibly ocenivajuscim-N(H)C(O)OR23a), C1-6Alcoi, Gets1, aryl (which aryl group may not be substituted for any additional aryl groups), -N(R24aR24b-C(O)R24c-C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23dand-S(O)2N(R24nR24p),

Gets the1,

-C(O)R5a,

-OR5b,

-N(R6R5c,

-C(O)XR7,

-C(O)N(R8R5dand

-S(O)2R9;

(3) Gets2, -C(O)R5a, -C(O)XR7, -C(O)N(R8R5d, -S(O)2R9, unsubstituted cyclic or part cyclic/acyclic With4-12alkyl or C1-4alkyl, substituted or terminated, or C5-12alkyl, possibly substituted and/or terminated with one or more than one group selected from halogeno, cyano, nitro, Het1-C(O)R5a, -OR5b, -N(R6R5c, -C(O)XR7, -C(O)N(R8R5dand-S(O)2R9;

(4) Gets2, -C(O)R5a, -C(O)XR7, -C(O)N(R8R5d, -S(O)2R9 , unsubstituted cyclic or part cyclic/acyclic With4-12alkyl or C1-5alkyl, substituted or terminated, or C6-12alkyl, possibly substituted and/or terminated with one or more than one group selected from cyano, nitro, Het1, -C(O)R5a, -N(R6R5c, -C(O)XR7, -C(O)N(R8R5d, -S(O)2R9and-OR5b(where R5brepresents H, C2-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, C1-6alkoxy, halogeno, cyano, nitro, aryl, Het3and-NHC(O)R10), aryl or Het4).

The compounds of formula XVII, which can be mentioned include compounds where

(a) when Ra-Rfall represent N and group A-C(R2)(R3)-B - represents a C1-4alkylen, then R4does not represent a phenyl group which is mono - or disubstituted by one fluorescent, chloro, bromo, stands or methoxy;

(b) when Ra-Rfall represent N and group A-C(R2)(R3)-B - represents a C1-5alkylen or1-4alkylen, replaced halogeno, then R4does not represent a phenyl group which is mono - or disubstituted by methoxy;

(C) R4represents naphthyl or Het13when the eat both of these groups possibly substituted by one or more than one Deputy, selected from HE, cyano, halogeno, nitro, C1-6the alkyl (possibly ending in-N(H)C(O)OR23a)1-6alkoxy, Het1, aryl, -N(R24aR24b, -C(O)R24c-C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23d, -S(O)2N(R24nR24pand only if it Gets13) oxo, or R4represents phenyl substituted by one or more than one Deputy, selected from HE, cyano, nitro, C2-6the alkyl (possibly ending in-N(H)C(O)OR23a)2-6Alcoi, Gets1, aryl, -N(R24aR2b, -C(O)R24c-C(O)OR24d, -C(O)N(R24eR24f, -N(R24g)C(O)R24h, -N(R24i)C(O)N(R24jR24k, -N(R24m)S(O)2R23b, -S(O)nR23c, -OS(O)2R23dand-S(O)2N(R24nR24p.

Medical and pharmaceutical application

Compounds according to the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.

Thus, according to another aspect of the present invention proposed compounds according to the invention for use as pharmaceuticals.

In particular, the compounds according to the invention exhibit myocardial elec is revisionaries activity for example, as demonstrated in the tests described below.

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

Thus, the compounds according to the invention is shown in the treatment or prevention of heart disease or testimony related to heart disease, in which, as I believe, adults play a major role, including coronary heart disease, sudden heart attack, myocardial infarction, heart failure, heart surgery and thromboembolic events.

In the treatment of arrhythmias was found that the compounds according to the invention selectively inhibit cardiac repolarization, thereby increasing the QT-interval, and, in particular, active class III. Although it has been shown that the compounds according to the invention show activity of class III, in particular, in the treatment of arrhythmias, view(s) of their activity is not necessarily limited(s) of this class.

According to another aspect of the present invention, a method for treating arrhythmia in which the subject suffering from such conditions or subject to such condition, introducing a therapeutically effective amount of the compounds according to the invention.

Pharmaceutical

Connection given the WMD invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermal, intranasal, by inhalation, or by any other parenteral route of administration, in the form of pharmaceutical preparations containing the active ingredient either as a free base, or a non-toxic salt accession of organic or inorganic acid, in a pharmaceutically acceptable dosage form. Depending on the disease and the patient being treated, and the method of administration, the composition can be injected at various doses.

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

Thus, according to another aspect of the present invention proposed a pharmaceutical preparation comprising the compound according to the invention in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Suitable daily doses of the compounds according to the invention in therapeutic treatment of humans are about 0.005 to 25.0 mg/kg body weight by oral administration and approximately 0.005 to 10.0 mg/kg body weight at parenteral administration. The preferred spacing of doses of the compounds according to the invention in therapeutic treatment of humans are priblizitel is but 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.

Compounds according to the invention have the advantage that they are effective against cardiac arrhythmias.

Compounds according to the invention also have the advantage that they can be more effective, less toxic, have a greater range of activity (including the manifestation of any combination of the activity of class I, class II, class III and/or class IV (in particular the activity of class II and/or class IV in addition to the activity of class III), to be more potent, have a longer activity, to cause fewer side effects (including lower percentage of proirity, such as pointes de pointes), easier to absorb, or that they can to have other useful pharmacological properties, in addition to the compounds known from the prior art.

Biological tests

Test And

Primary electrophysiological effects shot on Guinea pigs

Used Guinea pigs weighing from 660 to 1100 Animals were kept for at least one week before the experiment with free access during this period to food and tap water.

Anesthesia was carried out by intraperitoneal injection of pentobarbital (40 to 50 mg/kg), and catheters were introduced into one carotid artery (to check blood pressure and blood collection) and one jugular vein (in the of use drugs). Needle electrodes were placed on the limbs for recording ECG (lead II). thermistor was placed in the rectum and the animal was placed on a heating pad, setting the rectal temperature of from 37.5 to 38.5°C.

Performed the tracheotomy and the animal was subjected to artificial ventilation with room air using a small fan for animals, mounted so as to maintain blood gases within normal limits for these species. In order to reduce the impact on the autonomic nervous system, 15 minutes before the start of the experiment cut both wandering nerve in the neck and was intravenously injected 0.5 mg/kg of propranolol.

The epicardium of the left ventricle was exposed through a left thoracotomy and the free wall of the left ventricle put custom suction electrode for the Desk phase of the action potential (cap). The electrode was kept in this position until, until it was registered an acceptable signal, otherwise, it was moved to a new position. Bipolar electrode for elektrocardiostimulyatsii attached to the left atrium. Elektrocardiostimulyatsia (duration 2 MS, twice diastolic threshold) was performed using a custom stimulator DC. The heart is stimulated with a frequency slightly above the norm is inogo sinus rhythm within 1 minute every five minutes throughout the study.

Blood pressure, PDX-signal and lead II ECG were recorded on a jet recorder Mingograph (Siemens-Elema, Sweden). All signals were collected (collection frequency 1000 Hz) to the PC in the last 10 seconds of each sequence of stimulation and the last 10 seconds, the next minute sinus rhythm. The signals were processed using custom software developed for the collection and analysis of physiological signals measured on laboratory animals (see Axenborg and Hirsch, Comput. Methods Programs Biomed. 41, 55 (1993)).

The test procedure consisted of removing two basic audit records with interval of 5 minutes in the sequel as pacing and sinus rhythm. After the second audit records conducted infusion of the first dose of a test substance for 30 seconds in a volume of 0.2 ml in the catheter in the jugular vein. Three minutes later started elektrocardiostimulyatsia and made a new account. Five minutes after the previous dose was administered following the dose of the test substance. In continuation of each experiment were given from six to ten consecutive doses.

Data analysis

Of the many variables measured in this type of analysis selected three as the most important for comparison and selection of the active compounds. These three selected variables were the duration of the cap at 75%repose the purpose in the continuation of pacing, time atrioventricular (AV) conduction (defined as the interval between the atrial stimulating pulse and the beginning of ventricular PDX) continued pacing and heart rate (defined as RR-interval in the continuation of sinus rhythm). Systolic and diastolic blood pressure were measured in order to assess the hemodynamic status of the animal shot. Next I checked the ECG for arrhythmias and/or morphological changes.

Average of the two control recordings were taken for the zero value and the effects registered after sequential doses of the test substance, expressed as deviations from this value, in percent. The construction of curves dose-response was done by drawing on a graph of these values in percentage against the total injected dose before each entry. Thus, each experiment had three curves dose-response, one for the duration of the cap, one for the time AV-conduction, and one for the frequency of sinus rhythm (RR-interval). To calculate the average curve for all experiments conducted with the test substance, and the average curve obtained values of efficiency. All curves dose-response in these experiments built by linear connection of experimental points. The total dose increases the duration of the cap by 10% compared with the baseline, used as an index for electrophysiological assessment of the effectiveness of class III investigational agent (D10).

Test B

Fibroblasts of mice treated with glucocorticoids, as a model for the detection of blockers To+channels slow straightening

IC50for blockade of K+channels were determined using the method of screening in microtiter tablets based on the change in membrane potential of fibroblasts of mice treated with glucocorticoids. The membrane potential of fibroblasts of mice treated with glucocorticoids, was measured using the fluorescence dye bisoxazole (bisoxonol) DiBac4(3)that can with certainty be detected when using the tablet reader with laser forming images of fluorescence (fluorescence laser imaging plate rider, FLIPR). The expression of the slow potassium channel straightening in fibroblasts of mice induced, subjecting them to the influence of glucocorticoid dexamethasone (5 μm) for 24 hours. Blockade of these potassium channels were depositfile fibroblasts, resulting in increased fluorescence DiBac4(3).

1tk the mice fibroblasts (L-cells) obtained 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 teachanywhere (5% vol./vol.), penicillin (500 U/ml), streptomycin (500 μg/ml) and L-alanyl-L-glutamine (0,862 mg/ml). Cells were perseval every 3-4 days using trypsin (0.5 mg/ml in phosphate buffer solution, free from calcium ions, Gibco BRL). Three days before the start of the experiments, the cell suspension was pietravalle in 96-well tablets of black plastic with clear bottom (Costar) at 25,000 cells per well.

The sensor DiBac fluorescence4(3) (DiBac Molecular probes) was used to measure membrane potential. DiBac4(3)maximally absorbs at a wavelength of 488 nm and emits at 513 nm. DiBac4(3)is bisexual and therefore negatively charged at pH 7. Due to its negative charge distribution DiBac4(3)through the membrane depends on the transmembrane potential: if the cell is depolarized (i.e. within the cell becomes less negatively charged than the 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 the lipids and proteins that cause an increase in fluorescent emission. Thus, the depolarization will be reflected in the increase in fluorescence DiBac4(3). The change in fluorescence DiBac4(3)recorded using FLIPR.

Before each experiment, cells were washed 4 times sabaf is completely eliminated phosphate saline (PBS) to remove culture medium. The cells were then treated with 5 μm DiBac4(3)(180 ál PBS) at 35°C. as soon As was achieved by the constant fluorescence (usually 10 minutes), was added 20 μl of a test substance using internal 96-well pipetting system FLIPR. Then measurements of fluorescence every 20 seconds in the next 10 minutes. All experiments were carried out at 35°due to its high sensitivity to temperature as conductance potassium channels slow straightening and DiBac fluorescence4(3). The test substance was prepared in the second 96-well tablet in PBS containing 5 μm DiBac4(3). The concentration of the prepared medium was 10 times higher than the concentration required for the experiment, as there was additional dilution 1:10 while adding substance in the course of the experiment. As a positive control used dofetilide (10 μm), that is, determine the maximum increase in fluorescence.

Curve fitting the points used to define the values for IC50, were conducted according to the Graphpad Prism program (Graphpad Software Inc., San Diego, CA).

Test

Metabolic stability of test compounds

To determine the metabolic stability of compounds of the formula I conducted the screening in vitro.

Used liver fraction S-9 dog, the man is a, rabbit and rats with NADPH as 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 addition of the test compounds and finished in 0, 1, 5, 15 and 30 minutes by increasing the pH in the sample above 10 (NaOH; 1 mm). After extraction the solvent concentration of the test compounds was measured against an internal standard using LC (detection of fluorescence/UV).

Expected percentage remaining after 30 minutes of test compounds (and, hence, t1/2) and used it as the unit of measurement of metabolic stability.

The invention is illustrated by the following examples.

Examples

General experimental procedures

Mass spectra were recorded on one of the following instruments: spectrometer Perkin-Elmer SciX API 150ex; strainnom quadrupole mass spectrometer VG Quattro II single quadrupole mass spectrometer VG Platform II or single quadrupole mass spectrometer Micromass Platform LCZ (the last three are equipped with pneumatically controlled electrospray interface (LC-MS).1H NMR and13With the NMR measurements were performed on a spectrometer BRUKER ACP 300 and Varian 300, 400 and 500 running on1H-frequencies of 300, 400 and 500 MHz, respectively, and13With the frequency of 75.5, 100,6 and 125,7 MHz with the NGOs. Alternative,13With the NMR measurements were performed on a spectrometer BRUKER ACE at a frequency of 200 to 50.3 MHz.

Rotamer may vary or may not vary in the spectrum, depending on the ease of interpretation of the spectrum. Unless otherwise stated, the chemical shifts are given in ppm with the solvent as internal standard.

Synthesis of intermediate compounds

The following intermediate compounds were absent in the sale, and therefore, they were received of the methods described below.

Obtaining And

tert-Butylacrylamide[3,4-C]pyrrol-2(1H)-carboxylate

(a) 3,7-Dibenzyl-CIS-3,7-diazabicyclo[3.3.0]octane-2,4-dione

Triperoxonane acid (1-3 ml) was added dropwise to a solution of N-(methoxymethyl)-N-trimethylsilylmethyl)benzylamine (137,0 g, 580 mmol) and imide N-benzylmaleimide acid (95,0 g, 500 mmol) in CH2Cl2(1 l) to achieve an exothermic reaction. After the exothermic reaction (approximately 10 min) the mixture was heated at the temperature of reflux distilled for 3 hours the Reaction mixture was cooled and then extinguished 1 N. NaOH (200 ml). The organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to obtain 170,0 g of the crude product. Crystallization from isopropyl ether gave 109,0 g (67%) indicated in the subtitle is connected to the I.

1H NMR (300 MHz, CDCl3) δ 7.4-7.0 (m, 10H), 4.65 (s, 2H), 3.55 (s, 2H), 3.30 (d, 2H, J=12 Hz), 3.15 (d, 2H, J=6 Hz), 2.35 (m, 2H).

(b) 3-Benzyl-CIS-3,7-diazabicyclo[3.3.0]octane-2,4-dione hydrochloride

Concentrated hydrochloric acid (28,4 ml, 341 mmol) was added to a suspension of 3.7-dibenzyl-3,7-diazabicyclo[3.3.0]octane-2,4-dione (109,0 g, 341 mmol; from step (a)described above) in CH3OH in the atmosphere N2. To the resulting solution was added 10%Pd/C (wt.%; 5 g). The atmosphere of the N2replaced with H2(pressure of 98 kPa (1 ATM)and the reaction mixture was stirred for 12 h the Reaction mixture was diluted with H2O (160 ml), filtered through a gasket cellulose to remove catalyst and the filtrate was concentrated under vacuum to obtain a solid substance. Rubbing with absolute EtOH was allowed to get 74,6 g (82%) indicated in the subtitle compound as a whitish solid after drying in a vacuum Cabinet at 50°From/To 66.5 PA (0.5 mm Hg).

1H NMR (300 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 4.6 (s, 2H), 3.5 (d, 2H, J=12.5 Hz), 3.25 (d, 2H, J=7.5 Hz), 3.0 (dd, 2H, J=7.5, 12.5).

(in) 3-Benzyl-CIS-3,7-diazabicyclo[3.3.0]octane

3-Benzyl-3,7-diazabicyclo[3.3.0]octane-2,4-dione hydrochloride (73,8 g, 275 mmol; from step (b)described above) was added in portions to a suspension of LiAlH4(83,5 g; and 2.26 mol) in THF at 0°Creaction the mixture was slowly heated up to the temperature of reflux distilled. After boiling OBR is Tim refrigerator for 16 h, the reaction mixture was cooled to 0° C. To the cooled reaction mixture dropwise sequentially added H2O (84 ml), 3 M NaOH (84 ml) and H2O (250 ml). Then the reaction mixture was stirred for additional 15 minutes and filtered through a gasket celite (Celite®) to remove inorganic salts. The filtrate was concentrated under vacuum to obtain the crude product. Distillation on Kugeler (Kugelrohr) (95-115°From/To 66.5 PA (0.5 mm Hg)) was given to 46.8 g (84%) indicated in the subtitle compound as a colourless oil.

1H NMR (300 MHz, CDCl3) δ 7.3-7.2 (m, 5H), 3.51 (s, 2H), 2.9 (dd, 2H, J=6.6, 12 Hz), 2.75 (d, 12 Hz), 2.7-2.5 (m, 4H), 2.3 (d, 2H, J=7.5 Hz), 2.0 (bs, 2H).

(g) 3-Benzyl-7-(tert-butoxycarbonyl)-CIS-3,7-diazabicyclo[3.3.0]octane hydrochloride

A solution of di-tert-BUTYLCARBAMATE (65,3 g, 299 mmol) in THF (100 ml) was added dropwise to a stirred solution of 3-benzyl-3,7-diazabicyclo[3.3.0]octane (55 g, 272 mmol; from step (C)above) in THF (650 ml) at 0°C. Upon completion of addition the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was diluted with EtOAc (300 ml) and with brine (300 ml). The organic layer was separated and retained, the aqueous layer was extracted with EtOAc (5×200 ml).

The combined organic extracts were dried with Na2SO4, filtered and concentrated under vacuum to obtain a colorless oil. This oil dissolve the Yali in EtOAc (750 ml) was cooled to 0°and was slowly added 1 M HCl in Et2O (275 ml). The precipitated HCl salt was collected and dried in a vacuum Cabinet with getting to 91.1 g (99%) indicated in the subtitle compound as a whitish solid.

1H NMR (300 MHz, CD3OD) δ 7.6-7.4 (m, 5H), 4.4 (s, 2H), 3.8-3.6 (bs, 2H), 3.5-3.3 (bs, 4H), 3.3-3.0 (bs, 2H), 1.45 (s, N).

(d) tert-Butylacrylamide[3,4-C]pyrrol-2(1H)-carboxylate hydrochloride

To a solution of 3-benzyl-7-(tert-butoxycarbonyl)was 3.7-diazabicyclo[3.3.0]octane hydrochloride (for 91.1 g, 269 mmol; from step (g)above) in methanol (250 ml) in an atmosphere of N2was added 10%Pd/C (wt.%; of 9.8 g). The atmosphere of the N2replaced with H2(pressure of 98 kPa (1 ATM)and the reaction mixture was stirred for 18 hours the Reaction mixture was filtered through a gasket cellulose to remove the catalyst. The filtrate was concentrated under vacuum to obtain a whitish solid. This solid is suspended in EtOAc and collected. After drying in a vacuum Cabinet for 18 h at 60°From/To 66.5 PA (0.5 mm Hg) received 58,0 g (87%) indicated in the title compound in the form of a whitish solid.

TPL 175-178°C.

Rf=0,45 (50:40:9:1, CH2Cl2/CHCl3/Meon/conc. NH4OH).

MS(CI): m/z=213(M+H).

1H NMR (300 MHz, CD3OD) δ 3.6 (m, 4H), 3.35 (dd, 2H), 3.14 (m, 4H), 1.48 (s, N).

13With NMR (75 MHz, CD3D) δ 156, 81.5, 50.5, 51.2, 43.0, 28.5.

The corresponding free base was obtained by the following procedure. The hydrochloride salt was dissolved in CH3CN. Added four equivalent To2CO3together with a small amount of water. The mixture was stirred for 2 h and then filtered and evaporated to obtain the base with a quantitative yield.

Getting B

tert-Butyl(1S)-2-(4-cianfrocca)-1-(hexahydropyrazino[3.4-C]pyrrol-2(1H)-ylmethyl)ethylcarbamate

(a) 4-(2-Oxiranylmethyl)benzonitrile

Specified in the subtitle compound was obtained with 75%yield according to the procedure described in published international application WO 99/31100 (i.e. through the implementation of the interaction p-cyanophora and epichlorohydrin).

(b) 4-[(3-Amino-2-hydroxypropyl)oxy]benzonitrile

4-(2-Oxiranylmethyl)benzonitrile (100 g; or 0.57 mol; see stage (a), described above) was added to a mixture of concentrated aqueous ammonium hydroxide (500 ml) and isopropanol (300 ml). The obtained suspension was stirred at room temperature for 3 days. The reaction mixture was filtered to remove insoluble by-product, and the filtrate was concentrated under vacuum to obtain the crude product, which was led from acetonitrile to obtain 50 g (46%) indicated in the subtitle of the connection.

(C) tert-Butyl 3-(4-cianfrocca)-2-hydrox propellernet

Chilled (0° (C) a solution of 4-[(3-amino-2-hydroxypropyl)oxy]benzonitrile (from step (b)described above; 44,6 g; 0.23 mol) in a mixture of THF/N2About 1.5 litres (1:1)) was treated with di-tert-BUTYLCARBAMATE (53 g; 0.24 mol). The mixture was stirred at room temperature overnight, then added NaCl and the organic layer was separated. The aqueous layer was extracted with ether and the combined organic extracts were dried and concentrated under vacuum. The obtained oil (70 g) was filtered through a gasket silicon dioxide and then was led from a mixture of diethyl ether/diisopropyl ether to obtain 50 g specified in the subtitle of the connection.

(g) 2-[(tert-Butoxycarbonyl)amino]-1-[(4-cianfrocca)methyl]ethylmethanesulfonate

Methanesulfonanilide (22,3 g; of € 0.195 mol) was added over 1.5 hours to a cooled (0° (C) to a solution of tert-butyl 3-(4-cianfrocca)-2-hydroxypropionate (from stage (C)above; 51,2 g; 0,177 mol) and 4-(dimethylamino)pyridine (1.3 g; 10.6 mmol) in pyridine (250 ml) in an atmosphere of inert gas. The reaction mixture was stirred for 2 h at room temperature before adding water and DHM. The organic layer was separated, washed with water, dried (MgSO4) and concentrated under vacuum to obtain to 68.1 g (100%) specified in the subtitle of the connection.

(d) tert-Butyl-2-[(4-cianfrocca)met the l]-1-aziridination

Chilled (0° (C) a solution of 2-[(tert-butoxycarbonyl)amino]-1-[(4-cianfrocca)methyl]ethylmethanesulfonate (from step (g)above; 30,6 g; to 82.6 mmol) and tetrabutylammonium hydrosulfate (3 g; 8,8 mmol) in DHM (100 ml) was treated with 50 wt.% aqueous NaOH (60 ml) in an atmosphere of inert gas. The resulting mixture was stirred and left, giving her the temperature to slowly rise to room for more than 4 h, and then extraorally ether. The organic layer was washed with water and concentrated under vacuum to obtain a residue, which was purified column chromatography (eluent dichloromethane). Crystallization from a mixture of diethyl ether/diisopropyl ether gave specified in the subtitle compound with a quantitative yield.

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

Specified in the subtitle compound was obtained according to the procedures described above for stages (a) - (d) for the synthesis of tert-butyl 2-[(4-cianfrocca)methyl]-1-aziridination, but using in stage (a) (S)-(+)-epichlorohydrin instead of epichlorohydrin.

(g) Benzyl-tert-butyltetrahydrofuran[3,4-C]pyrrole-2,5(1H,3H)-in primary forms

tert-Butylacrylamide[3,4-C]pyrrol-2(1H)-carboxylate hydrochloride (10.0 g; 0.04 mol; see Obtaining As described above) and triethylamine (14 ml, 0.1 mol) was mixed in CHCl3(100 ml). Was added N-benzyloxycarbonyloxy cinemed (11 g; 0,044 mol)dissolved in CHCl3(100 ml)at 0-5°C. the Mixture was left to slowly reach room temperature and was stirred at room temperature for 5 hours the Reaction mixture was washed with water, dried (Na2SO4) and was evaporated to obtain specified in subheading connection with a quantitative yield.

13With NMR (CDCl3) δ 155.01, 155.64, 136.99, 128.71, 128.22, 128.13, 79.80, 67,12, 50.30, 49.88, 41.76, 28.71.

(C) Benzyloxypropionic[3,4-C]pyrrol-2(1H)-carboxylate

Benzyl-tert-butyltetrahydrofuran[3,4-C]pyrrole-2,5(1H,3H)-in primary forms (40 mmol; from step (g)above) was dissolved in ethyl acetate. Was added at 0°With ethyl acetate saturated with HCl (g) (500 ml), and stirred until the temperature reached room temperature. The solvent is evaporated and the product was dissolved in CH3CN. Added To2CO3(4 equiv.) and water (2 ml). The mixture was stirred for 2 h before filtered and was evaporated, obtaining 8 g (82%) indicated in the subtitle compound that was used without further purification in the next stage.

(and) Benzyl-5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-cianfrocca)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate

tert-Butyl(2S)-2-[(4-cianfrocca)methyl]aziridine-1-carboxylate (2.5 g; 9.1 mmol; from step (e)above) and benzyloxypropionic[3,4-C]pyrrol-2(1H)-carboxy is at (2.24 g; 9.1 mmol; from step (C)above) was dissolved in isopropanol (30 ml) and stirred at 56°C for 24 h and Then the solvent evaporated. The product was purified by chromatography on silica (eluent ethyl acetate, 0-5% Meon) to obtain 3.8 g (80%) indicated in the subtitle of the connection.

MS (ES): m/z=521 (M+N)+.

(C) tert-Butyl(1S)-2-(4-cianfrocca)-1-(hexahydrofuro[3,4-C]pyrrol-2(1H)-ylmethyl)ethylcarbamate

Benzyl-5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-cianfrocca)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (3.6 g; 6,9 mmol; from step (I)above) was dissolved in ethanol (300 ml 95%) and was first made over a 5%Pd/C (wt./wt.). The reaction was stopped when it was spent theoretical amount of N2(173 ml). The mixture was filtered through Celite®) and then evaporated. Purification by chromatography on silica (eluent DHM, 5% Meon) gave 1.7 g (63.6 per cent) specified in the connection header.

13With NMR (CDCl3) δ 161.86, 155.48, 154.42, 136.81, 133.91, 128.36, 127.84, 127.73, 118.99, 115.21, 104.22, 79.69, 68.14, at 66.64, 60.28, at 55.20, 51.72, 48.72, 42.04,41.06,28.41.

MS (ES): m/z=387 (M+N)+.

Getting Into

4-[1-(3,4-Dimethoxyphenoxy)-4-hexahydrofuro[3,4-[pyrrol-2(1H)-libutil]benzonitrile

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

Chilled (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 whole (500 ml) was treated with tributylphosphine (32,14 ml 97,%purity; 25,6 g; 126,4 mmol) followed by addition of 1,1'-(azodicarbon)dipiperidino (31.8 g; 126,4 mmol). Upon completion of addition the reaction mixture was condensed and the temperature rose to 15°C. was Added an additional amount of toluene (500 ml) and the mixture was stirred at room temperature overnight. The precipitate of oxide tributylphosphine then removed by filtration and the filtrate was concentrated under vacuum to obtain 65.8 g of the crude product. This product 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.

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

The complex of borane-metilsulfate (2 M in 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 (from step (a)described above; and 17.6 g; of 56.8 mmol) in anhydrous THF (15 ml) over a period of time of 15 minutes (during this time the reaction temperature rises to 0°). The resulting mixture was stirred at a temperature of from 0 to 10°C for 1.5 h before you leave to come to room temperature. Stirring was continued for an additional 3.5 h at this temperature before adding water (22 ml) and sodium perborate tetrahydrate (11 g, 66 mmol). Biphasic mixture was stirred tip is of 2 h at room temperature before how to separate the aqueous layer and extracted with ether. The combined organic layers were washed with brine, dried and concentrated under vacuum. The obtained 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.

(b) 4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butylmalonate

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 (from stage (b)above; 11 g; 34 mmol) and triethylamine (7 ml; 5,2 g; and 50.6 mmol) in DHM (50 ml), while adding temperature does not rise above 2°C. the Stirring was continued at a temperature of from 0 to 5°C for additional 2 h before adding the water. The obtained organic layer was separated and washed with water, again separated and then dried to obtain specified in the subtitle compound with 100%output.

(d) tert-Butyl-5-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate

4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butylmalonate (1.12 g; 2.8 mmol; see stage (C)above), tert-butylacrylamide[3,4-C]pyrrol-2(1H)-carboxylate (0,59 g; 2.8 mmol; see Obtaining As described above) and Cs 2CO3mixed in CH3CN (30 ml) and stirred at room temperature for 3 days. Then the mixture was filtered and evaporated. Purification on silica (eluent ethyl acetate/Meon (9:1)) gave 0.9 g (60%) indicated in the subtitle of the connection.

MS (ES): m/z=522 (M+N)+.

(d) 4-[1-(3,4-Dimethoxyphenoxy)-4-hexahydrofuro[3,4-C]pyrrol-2(1H)-libutil]benzonitrile

tert-Butyl-5-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (0.9 g; 1.7 mmol; from step (g)above) was dissolved in ethyl acetate (25 ml). The solution was cooled to 0°C. was Added ethyl acetate (25 ml), saturated with gaseous HCl and the mixture was stirred at room temperature for 4 h the mixture was evaporated and then dissolved in CH3CN. Added To2CO3(1 g) and water (0.05 ml) and the mixture was stirred for 2 hours Salt was filtered and the solvent evaporated to obtain 0.71 g (100%) specified in the connection header.

MS (ES): m/z=421 (M+N)+.

Getting G

4-[{(2S)-3-Hexahydrofuro[3,4-C]pyrrol-2(1H)-yl-2-hydroxypropyl]oxy}benzonitrile

(a) tert-Butyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate

4-[(2S)-Oxiranylmethyl]benzonitrile (4,36 g; 0,025 mol; obtained as described in published international application WO 99/31100) and tert-butylacrylamide[3,4-C]p is rrol-2(1H)-carboxylate (6.2 g; 0,025 mol; see Obtaining As described above) were mixed in isopropanol and stirred at 60°With during the night. The solvent is evaporated and the product was purified flash chromatography on silica, elwira-ethyl acetate, 10%Meon. There was obtained 1.2 g (88%) indicated in the subtitle of the connection.

(b) 4-{[(2S)-3-Hexahydrofuro[3,4-C]pyrrol-2(1H)-yl-2-hydroxypropyl]oxy}benzonitrile

Specified in the title compound was obtained with 90%yield according to the procedure described above in stage (d) Receiving, using tert-butyl 5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (0.9 g; 2.3 mmol; see stage (a)above) instead of tert-butyl-5-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate.

Getting D

4-[(3-Hexahydrofuro[3,4-C]pyrrol-2(1H)-ylpropyl)amino]benzonitrile

(a) 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°C in an atmosphere of inert gas for 3 hours before adding water (150 ml). The mixture was left to cool to room temperature and then was extracted with diethyl ether. The organic layer was separated, dried (Na2SO4), filtered and concentrated under vacuum to obtain 17 g (97%) indicated in the title compound in the form of oil, which crystallizes upon standing.

(b) 3-(4-Cyanoaniline)propyl-4-methylbenzenesulfonate

Chilled (0° (C) a solution of 4-[(3-hydroxypropyl)amino]benzonitrile (from step (a)described above; 17 g; of 96.5 mmol) in anhydrous MeCN (195 ml) was treated with triethylamine (9.8 g; of 96.5 mmol) and then p-toluensulfonate (20,2 g, 106 mmol). The mixture was stirred at 0°C for 90 minutes before concentrating under vacuum. To the residue was added water (200 ml) and the aqueous solution was extracted with DHM. The organic phase was dried (Na2SO4), filtered and concentrated under vacuum. The obtained residue was purified by crystallization from isopropanol to obtain 24.6 g (77%) indicated in the subtitle of the connection.

(C) tert-Butyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate

3-(4-Cyanoaniline)propyl-4-methylbenzenesulfonate (1.98 g; 6 mmol; see stage (b), above), and tert-butyl hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (1,49 g; 6 mmol; see Obtaining As described above) was mixed with K2CO3(1,93 g; 14 mmol) and CH3CN (100 ml) and then stirred at 50°With during the night. The solvent is evaporated and the product was purified by chromatography on silica (DHM/Meon (20:1)) to obtain 1,83 g (82%) indicated in the subtitle of the connection.

(g) 4-[(3-Hexahydrofuro[3,4-C]pyrrol-2(1H)-ylpropyl)is mine-benzonitrile

Specified in the title compound was obtained with a quantitative yield according to the procedure described above in stage (d) Receiving, using tert-butyl 5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (see stage (C)above) instead of tert-butyl-5-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate.

Receive E

4-(2-Hexahydrofuro[3,4-C]pyrrol-2(1H)-ylethoxy)benzonitrile

(a) 4-(2-Bromoethoxy)benzonitrile

A mixture of 4-cyanophora (35,7 g; 0.3 mol), K2CO3(41,4 g; 0.3 mol) and 1,2-dibromethane (561 g, 3.0 mol) in MeCN (450 ml) was stirred at the temperature of reflux distilled during the night. The mixture was filtered and evaporated to obtain 30,2 g (45%) indicated in the subtitle compound that was used without further purification.

(b) tert-Butyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate

Specified in the subtitle compound was obtained with 91%yield according to the procedure described above in stage (C) Receive D, using 4-(2-bromoethoxy)benzonitrile (see stage (a)above) instead of 3-(4-cyanoaniline)propyl-4-methylbenzenesulfonate.

(b) 4-(2-Hexahydrofuro[3,4-C]pyrrol-2(1H)-ylethoxy)benzonitrile

Specified in the title compound was obtained with a 100%yield according to the procedure described above in stage (d) Receiving the Oia, using tert-butyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (see stage (b)above) instead of tert-butyl-5-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate.

Obtain W

4-[(3-Hexahydrofuro[3,4-C]pyrrol-2(1H)-ylpropyl)sulfonyl]benzonitrile

(a) 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 of solvent gave a brown oil, which crystallized in the processing of EtOH. The crystals were separated by filtration to obtain specified in the subtitle compound (24.5 g; 62%).

(b) 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 (from step (a)described above; and 23.4 g, 91 mmol) in DHM (250 ml). Then the mixture was stirred at room temperature overnight and the resulting precipitate was filtered. The filtrate was concentrated under vacuum to obtain a residue, which is shown (by NMR analysis)that it contains 25% sulfoxide in addition to the desired product. The remainder of pererestorani in DHM (250 ml), we use the additional amount of 3-chloroperoxybenzoic acid (5.6 g 70%; 23 mmol) and the mixture was stirred for 30 minutes To neutralize the excess m-SRV was added dimethylsulfoxide (20 mmol) before DHM-solution rinse water NaHCO3, separated, dried and concentrated under vacuum. Got mentioned in the subtitle compound with 76%yield.

(C) tert-Butyl-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate

Specified in the subtitle compound was obtained with 75%yield according to the procedure described above in stage (C) Receive D, using 4-[(3-bromopropyl)sulfonyl]benzonitrile (see stage (b)above) instead of 3-(4-cyanoaniline)propyl-4-methylbenzenesulfonate.

(g) 4-[(3-Hexahydrofuro[3,4-C]pyrrol-2(1H)-ylpropyl)sulfonyl]benzonitrile

Specified in the title compound was obtained with a 100%yield according to the procedure described above in stage (d) Receiving, using tert-butyl 5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (see stage (C)above) instead of tert-butyl-5-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]hexahydrofuro[3,4-C]pyrrole-2(1H)-carboxylate.

Getting 3

4-(2-Hexahydrofuro[3,4-C]pyrrol-2(1H)-ylethoxy)isophthalonitrile

(a) 4-(2-Bromoethoxy)isophthalonitrile

Specified in the subtitle compound was obtained with a 64%yield according to the procedure described you the e stage (a) Obtain E, using 4-hydroxyisophthalate instead of 4-cyanophora.

(b) tert-Butyl-5-[2-(2,4-dicyanobenzene)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate

Specified in the subtitle compound was obtained with 75%yield according to the procedure described above in stage (C) Receive D, using 4-(2-bromoethoxy)isophthalonitrile (see stage (a)above) instead of 3-(4-cyanoaniline)propyl-4-methylbenzenesulfonate.

(b) 4-(2-Hexahydrofuro[3,4-C]pyrrol-2(1H)-ylethoxy)isophthalonitrile

Specified in the title compound was obtained with 80%yield according to the procedure described above in stage (d) Receiving, using tert-butyl-5-[2-(2,4-dicyanobenzene)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (see stage (b)above) instead of tert-butyl-5-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate.

Obtaining And

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 room temperature. Then the mixture was transferred to a closed vessel and heated to 100°With during the night. The mixture was concentrated under vacuum before adding ether and water. The organic phase was separated, dried and concentrated under vacuum. The obtained residue behaviour is whether chromatography on silica gel, elwira a mixture of THF/heptane (1:1), obtaining specified in the connection header with 20%output.

Getting To

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 room temperature overnight. Added water and the organic layer was separated, dried (Na2SO4) and concentrated under vacuum. The obtained residue was purified by chromatography on silica gel, elwira with ethyl acetate, to obtain 2.7 g (50%) specified in the connection header.

Obtaining L

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 room temperature. Added 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 was evaporated to obtain 6.0 g (70%) specified in the connection header.

Obtaining M

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

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

Obtaining N

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

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

Getting About

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

(1) 1-[4-(2-Hydroxyethyl)-1-piperazinyl-1 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)was added dropwise. During the addition the temperature of the reaction mixture rose from 22 to 60°C. This reaction mixture was evaporated several times with toluene to obtain 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 room temperature overnight before adding the water. The layers were separated, the organic layer was washed with water, dried and concentrated under vacuum to obtain 7.4 g (96%) specified in the connection header.

Obtaining Paragraph

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 mol) was stirred at room temperature for 4 h the Mixture was washed with water, 4×100 ml), 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 were extracted with 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 under vacuum to obtain 4.1 g (32%) specified in the connection header.

Obtaining P

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)was added dropwise. The mixture was stirred for 2 h at room temperature before concentrating under vacuum. NMR analysis showed that the obtained residue consists of 40% of the desired product and 60% of the corresponding O-acetate. This acetate is hydrolyzed by dissolving the reaction mixture in 200 ml of methanol and add 3 g of NaOH (dissolved in a little water). This mixture was stirred over night at room temperature, then concentrated under vacuum. The crude product was dissolved in DHM and insoluble material 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 with adiu (1), described above; a 13.4 g; 88 mmol) and p-toluensulfonate (16,8 g; 88 mmol in DHM (150 ml) was treated with the tea (13,4 g, 132 mmol)was added dropwise. The resulting mixture was stirred at room temperature for 3 h before washed with an aqueous solution of ammonium chloride. Then the organic layer was separated, dried and concentrated under vacuum. The product was led from ether containing a small amount DHM, to obtain 17.9 g (66%) specified in the connection header.

The synthesis of compounds of formula I

Example 1

The following is a General description of obtaining compounds of example 2.

One of the products above to Receive from B to C (0.25 mmol) was dissolved in CHCl3(0.5 ml). Added a suitable electrophile (0.25 mmol)dissolved in CH3CN (2 ml), followed by adding To the2CO3or triethylamine (0,375 mmol) of (such reasons are not necessary, if the electrophile is isocyanate).

The reaction mixture was stirred at a temperature of from room temperature to 50°within 2 to 5 days. The reaction was monitored using LC-MS. Upon completion of the reaction, the reaction mixture was filtered, the solvent evaporated and then the residues were dissolved in MeCN or CH2Cl2(2 ml). The resulting solutions were added in gaskets for ion-exchange solid-phase extraction (2 g IAS). Gaskets then e is Aravali mixture DHM/MeCN (4:1, fraction 1), followed by elution with a mixture DHM/Meon/tea(8:1:1, 4×2 ml). Fractions were evaporated. Further analysis using HPLC and MS allowed us to identify the fraction(s), where(s) is the product.

Example 2

The following compounds were obtained from the corresponding intermediate compounds (such as described above) according to or by analogy with the described in this application means (for example, using the procedure described above) and/or by using standard techniques of liquid-phase chemistry (mass spectra of compounds when they were registered, given in parentheses):

tert-butyl-5-[3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=388);

tert-butyl-5-[2-(4-cyanophenyl)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=342);

tert-butyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=388);

tert-butyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=371);

tert-butyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=358);

5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-N-ethylhexanediol[3,4-C]pyrrol-2(1H)-carboxamide (m/z=359);

4-({(2R)-3-[5-[2-(3,4-acid)ethyl]hexahydrofuro[3,4-C]-pyrrol-2(1H)-yl]-2-hydroxypropyl}oxy)benzonitrile (m/z=452);

4-({3-[5-(butylsulfonyl)hexahydrofuro what about[3,4-C]pyrrol-2(1H)-yl]propyl}amino)benzonitrile (m/z=391);

4-({3-[5-(3,3-dimethyl-2-oxobutyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}amino)benzonitrile (m/z=369);

4-({3-[5-[2-(3,4-acid)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}amino)benzonitrile (m/z=435);

5-[2-(4-cianfrocca)ethyl]-N-ethylhexanediol[3,4-C]pyrrol-2(1H)-carboxamide (m/z=329);

5-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-N-ethylhexanediol[3,4-C]pyrrol-2(1H)-carboxamide (m/z=493);

4-{2-[5-(butylsulfonyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}benzonitrile (m/z=378);

4-[4-[5-(butylsulfonyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile (m/z=542);

4-{2-[5-(3,3-dimethyl-2-oxobutyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}benzonitrile (m/z=356);

4-{1-(3,4-dimethoxyphenoxy)-4-[5-(3,3-dimethyl-2-oxobutyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]butyl}benzonitrile (m/z=520);

4-{2-[5-[2-(3,4-acid)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}benzonitrile (m/z=422);

4-{1-(3,4-dimethoxyphenoxy)-4-[5-[2-(3,4-acid)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]butyl}benzonitrile (m/z=586);

4-({(2S)-3-[5-(butylsulfonyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-2-hydroxypropyl}oxy)benzonitrile;

4-({(2S)-3-[5-(3,3-dimethyl-2-oxobutyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-2-hydroxypropyl}oxy)benzonitrile (m/z=386);

5-{3-[(4-cyanophenyl)amino]propyl}-N-ethylhexanediol[3,4-C]pyrrol-2(1H)-carboxamide (m/z=32);

tert-butyl-5-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=522);

tert-butyl-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=420);

5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-N-(3,5-dimethylisoxazol-4-yl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

N-{[5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]carbonyl}-4-methylbenzenesulfonamide;

5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-N-(4-methoxyphenyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-N-{4-[(trifluoromethyl)thio]phenyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=507);

5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-N-tetrahydro-2H-Piran-2-electorale[3,4-C]pyrrol-2(1H)-carboxamide;

5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-N-(cyclopropylmethyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=385);

5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-N-isopropylideneglycerol[3,4-C]pyrrol-2(1H)-carboxamide;

5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-N-(3,4-differenl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=443);

N-butyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydro-pyrrolo[3,4-C]pyrrol-2(1H)-carboxamide (m/z=387);

5-{3-[(4-cyanophenyl)amino]propyl}-N-(3,5-dimethylisoxazol-4-yl)hexahydrofuro[3,4-C]pyrrol-2(1H)carboxamide;

5-{3-[(4-cyanophenyl)amino]propyl}-N-(4-methoxyphenyl)hexahydrofuro[3,4-C]pyrrol-2(1 H)-carboxamide;

5-{3-[(4-cyanophenyl)amino]propyl}-N-{4-[(trifluoromethyl)thio]phenyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=490);

5-{3-[(4-cyanophenyl)amino]propyl}-N-tetrahydro-2H-Piran-2-electorale[3,4-C]pyrrol-2(1H)-carboxamide;

5-{3-[(4-cyanophenyl)amino]propyl}-N-(cyclopropylmethyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=490);

5-{3-[(4-cyanophenyl)amino]propyl}-N-isopropylideneglycerol[3,4-C]pyrrol-2(1H)-carboxamide (m/z=356);

5-{3-[(4-cyanophenyl)amino]propyl}-N-(3,4-differenl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=426);

N-butyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

5-[2-(4-cianfrocca)ethyl]-N-(3,5-dimethylisoxazol-4-yl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

N-{[5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]carbonyl}-4-methylbenzenesulfonamide;

5-[2-(4-cianfrocca)ethyl]-N-(4-methoxyphenyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=407);

5-[2-(4-cianfrocca)ethyl]-N-{4-[(trifluoromethyl)thio]phenyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=477);

5-[2-(4-cianfrocca)ethyl]-N-tetrahydro-2H-Piran-2-electorale[3,4-C]pyrrol-2(1H)-carboxamide;

5-[2-(4-cianfrocca)ethyl]-N-(cyclopropylmethyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z355);

5-[2-(4-cianfrocca)ethyl]-N-isopropylideneglycerol[3,4-C]pyrrol-2(1H)-carboxamide (m/z=343);

5-[2-(4-cianfrocca)ethyl]-N-(3,4-differenl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=413);

N-butyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=357);

5-{3-[(4-cyanophenyl)sulfonyl]propyl}-N-ethylhexanediol[3,4-C]pyrrol-2(1H)-carboxamide;

5-{3-[(4-cyanophenyl)sulfonyl]propyl}-N-(3,5-dimethylisoxazol-4-yl)-hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

N-{[5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]-pyrrol-2(1H)-yl]carbonyl}-4-methylbenzenesulfonamide;

5-{3-[(4-cyanophenyl)sulfonyl]propyl}-N-(4-methoxyphenyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

5-{3-[(4-cyanophenyl)sulfonyl]propyl}-N-{4-[(trifluoromethyl)thio]phenyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=539);

5-[3-[(4-cyanophenyl)sulfonyl]propyl}-N-tetrahydro-2H-Piran-2-electorale[3,4-C]pyrrol-2(1H)-carboxamide;

5-{3-[(4-cyanophenyl)sulfonyl]propyl}-N-(temporoparietal)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=417);

5-{3-[(4-cyanophenyl)sulfonyl]propyl}-N-isopropylideneglycerol[3,4-C]pyrrol-2(1H)-carboxamide;

5-{3-[(4-cyanophenyl)sulfonyl]propyl}-N-(3,4-differenl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=475);

N-butyl-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H-carboxamid (m/z=419);

5-[(2S)-2-amino-3-(4-cianfrocca)propyl]-N-ethylhexanediol[3,4-C]pyrrol-2(1H)-carboxamide (m/z=358);

5-[(2S)-2-amino-3-(4-cianfrocca)propyl]-N-(3,5-dimethylisoxazol-4-yl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

N-{[5-[(2S)-2-amino-3-(4-cianfrocca)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]carbonyl}-4-methylbenzenesulfonamide;

5-[(2S)-2-amino-3-(4-cianfrocca)propyl]-N-(4-methoxyphenyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=436);

5-[(2S)-2-amino-3-(4-cianfrocca)propyl]-N-{4-[(trifluoromethyl)thio]phenyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=506);

5-[(2S)-2-amino-3-(4-cianfrocca)propyl]-N-(temporoparietal)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=384);

5-[(2S)-2-amino-3-(4-cianfrocca)propyl]-N-isopropylideneglycerol[3,4-C]pyrrol-2(1H)-carboxamide (m/z=372);

5-[(2S)-2-amino-3-(4-cianfrocca)propyl]-N-(3,4-differenl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=442);

5-[(2S)-2-amino-3-(4-cianfrocca)propyl]-N-butylacrylamide[3,4-C]pyrrol-2(1H)-carboxamide (m/z=386);

5-[2-(2,4-dicyanobenzene)ethyl]-N-ethylhexanediol[3,4-C]pyrrol-2(1H)-carboxamide;

5-[2-(2,4-dicyanobenzene)ethyl]-N-(3,5-dimethylisoxazol-4-yl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

N-{[5-[2-(2,4-dicyanobenzene)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]carbonyl}-4-methylbenzenesulfonamide;

5-[2-(2,4-dicyanobenzene)ethyl]-N-(4-methoxyphenylacetonitrile[3,4-C]pyrrol-2(1H)-carboxamide (m/z=432);

5-[2-(2,4-dicyanobenzene)ethyl]-N-{4-[(trifluoromethyl)thio]phenyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=502);

5-[2-(2,4-dicyanobenzene)ethyl]-N-tetrahydro-2H-Piran-2-electorale[3,4-C]pyrrol-2(1H)-carboxamide (m/z=410);

N-(cyclopropylmethyl)-5-[2-(2,4-dicyanobenzene)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=380);

5-[2-(2,4-dicyanobenzene)ethyl]-N-isopropylideneglycerol[3,4-C]pyrrol-2(1H)-carboxamide (m/z=368);

5-[2-(2,4-dicyanobenzene)ethyl]-N-(3,4-differenl)hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

N-butyl-5-[2-(2,4-dicyanobenzene)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=382);

ethyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=360);

2-hydroxy-1,1-dimethylethyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=404);

1-cyano-1-methylethyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate;

but-2-inyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=384);

2-methoxyethyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate;

3-(methylsulphonyl)propyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate;

2-morpholine-4-ileti-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]g is kageromaru[3,4-C]pyrrol-2(1H)-carboxylate;

2-pyridine-4-ileti-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=437);

2-(4-acetylpiperidine-1-yl)ethyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate;

5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-N-[2-(2-methoxyethoxy)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

ethyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=343);

2-hydroxy-1,1-dimethylethyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=387);

1-cyano-1-methylethyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=382);

but-2-inyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=367);

2-methoxyethyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydropyrazino-[3,4-C]pyrrol-2(1H)-carboxylate (m/z=373);

3-(methylsulphonyl)propyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate;

2-morpholine-4-ileti-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate;

2-pyridine-4-ileti-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=420);

2-(4-acetylpiperidine-1-yl)ethyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate;

5-{3-[(4-cyanophenyl)amino]propyl}-N-[2-(2-metakit the XI)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide;

ethyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=330);

2-hydroxy-1,1-dimethylethyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=374);

1-cyano-1-methylethyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=369);

but-2-inyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=354);

2-methoxyethyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=359);

3-(methylsulphonyl)propyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate {m/z=422);

2-morpholine-4-ileti-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=415);

2-pyridine-4-ileti-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=407);

2-(4-acetylpiperidine-1-yl)ethyl-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=456);

5-[2-(4-cianfrocca)ethyl]-N-[2-(2-methoxyethoxy)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=403);

ethyl-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=392);

2-hydroxy-1,1-dimethylethyl-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=436);

1-cyano-1-methylethyl-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=431);

but-2-ine the l-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=416);

2-methoxyethyl-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=422);

3-(methylsulphonyl)propyl-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=484);

2-morpholine-4-ileti-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=477);

2-pyridine-4-ileti-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=469);

2-(4-acetylpiperidine-1-yl)ethyl-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate (m/z=518);

5-{3-[(4-cyanophenyl)sulfonyl]propyl}-N-[2-(2-methoxyethoxy)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide (m/z=465);

4-({(2S-3-[5-(cyclopropylmethyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-2-hydroxypropyl}oxy)benzonitrile (m/z=342);

4-({(2S)-3-[5-[3-(4-acetylpiperidine-1-yl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-2-hydroxypropyl}oxy)benzonitrile (m/z=456);

2-[5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-N-isopropylacetate (m/z=387);

4-({(2S)-3-[5-[3-(ethylsulfonyl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-2-hydroxypropyl}oxy)benzonitrile (m/z=422);

4-({(2S)-2-hydroxy-3-[5-[2-(2-methoxyethoxy)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}oxy)benzonitrile (m/z=390);

4-({3-[5-(cyclopropylmethyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}amino)benzo is nitrile (m/z=325);

4-({3-[5-[3-(4-acetylpiperidine-1-yl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}amino)benzonitrile (m/z=439);

2-[5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-N-isopropylacetate (m/z=370);

4-({3-[5-[3-(ethylsulfonyl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}amino)benzonitrile (m/z=404 (M-1));

4-({3-[5-[2-(2-methoxyethoxy)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}amino)benzonitrile (m/z=373);

4-{2-[5-[3-(4-acetylpiperidine-1-yl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}benzonitrile (m/z=426);

2-[5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-N-isopropylacetate (m/z=357);

4-{2-[5-[3-(ethylsulfonyl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}benzonitrile (m/z=392);

4-{2-[5-[2-(2-methoxyethoxy)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}benzonitrile (m/z=360);

4-{2-[5-(4-terbisil)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}benzonitrile (m/z=366);

4-({3-[5-(3,3-dimethyl-2-oxobutyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}sulfonyl)benzonitrile (m/z=418);

4-({3-[5-(cyclopropylmethyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}sulfonyl)benzonitrile (m/z=375);

4-({3-[5-[3-(4-acetylpiperidine-1-yl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}sulfonyl)benzonitrile (m/z=488);

2-[5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-N-isopropylacetate (m/z=419);

4-({3-[5-[3-(this is sulfonyl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}sulfonyl)benzonitrile (m/z=454);

4-({3-[5-[2-(2-methoxyethoxy)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}sulfonyl)benzonitrile (m/z=422);

4-({3-[5-[2-(4-methoxyphenyl)-2-oxoethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}sulfonyl)benzonitrile (m/z=468);

4-({(2S)-2-amino-3-[5-(3,3-dimethyl-2-oxobutyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}oxy)benzonitrile (m/z=385);

4-({(2S)-2-amino-3-[5-(cyclopropylmethyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}oxy)benzonitrile (m/z=341);

4-({(2S)-3-[5-[3-(4-acetylpiperidine-1-yl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-2-aminopropyl}oxy)benzonitrile (m/z=455);

2-[5-[(2S)-2-amino-3-(4-cianfrocca)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-N-isopropylacetate (m/z=386);

4-({(2S)-2-amino-3-[5-[3-(ethylsulfonyl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}oxy)benzonitrile (m/z=421);

4-({(2S)-2-amino-3-[5-[2-(2-methoxyethoxy)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}oxy)benzonitrile (m/z=389);

4-({(2S)-2-amino-3-[5-(4-terbisil)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]propyl}oxy)benzonitrile (m/z=395);

4-{2-[5-(3,3-dimethyl-2-oxobutyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}isophthalonitrile (m/z=381);

4-{2-[5-(cyclopropylmethyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}isophthalonitrile (m/z=337);

4-{2-[5-[3-(4-acetylpiperidine-1-yl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}isophthalonitrile (m/z=451);

2-[5-[2-(2,4-dicyanobenzene)ethyl]hexahydrofuro is[3,4-C]pyrrol-2(1H)-yl]-N-isopropylacetate (m/z=382);

4-{2-[5-[3-(ethylsulfonyl)propyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}isophthalonitrile (m/z=417);

4-{2-[5-[2-(2-methoxyethoxy)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}isophthalonitrile (m/z=385);

4-{2-[5-(4-terbisil)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}isophthalonitrile (m/z=391);

4-{2-[5-[2-(4-methoxyphenyl)-2-oxoethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]ethoxy}isophthalonitrile (m/z=431);

tert-butyl-5-[2-(2,4-dicyanobenzene)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate;

3,3-dimethyl-2-oxobutyl-5-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate;

5-{3-[(4-cyanophenyl)amino]propyl}-N-methylhexahydrophthalic[3,4-C]pyrrol-2(1H)-carboxamide;

5-{3-[(4-cyanophenyl)amino]propyl}-N-propylhexedrine[3,4-C]pyrrol-2(1H)-carboxamide;

N-allyl-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide and

N-(tert-butyl)-5-{3-[(4-cyanophenyl)amino]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxamide.

Example 3

Compounds of the above Examples were tested in the Test As described above, and found that they show the value of D10at least 5,5.

Example 4

Compounds of the above Examples were tested in the Test B described above, and found that they show the magnitude pIC50at least 4,5.

PR is measures 5

Getting 2-morpholine-4-ileti-5-[2-(4-cianfrocca)ethyl]hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate

0.25 mmol of 4-(2-hexahydrofuro[3,4-C]pyrrol-2(1H)-ylethoxy)benzo-nitrile (see E) was dissolved in CHCl3(0.5 ml). Added 0.25 mmol of 2-(4-morpholinyl)ethyl-1H-imidazolecarboxamide (see Obtaining L)dissolved CH3CN (2 ml), followed by adding To the2CO3or triethylamine (0,375 mmol).

The reaction mixture was stirred at a temperature of 50°within 2 to 5 days. The reaction was monitored using LC-MS. Upon completion of the reaction, the reaction mixture was filtered, the solvent evaporated and then the residue was dissolved in CH2Cl2(2 ml). The resulting solution was added to the stuffing for ion-exchange solid-phase extraction (2 g IAS). Gaskets then suirable mixture DHM/MeCN (4:1, fraction 1), followed by elution with a mixture DHM/Meon/tea(8:1:1, 4×2 ml). Fractions were evaporated. Further analysis using HPLC and MS allowed us to identify the fraction containing the product specified in the header (m/z=415).

Example 6

Getting 2-pyridine-4-ileti-5-{3-[(4-cyanophenyl)sulfonyl]propyl}hexahydrofuro[3,4-C]pyrrol-2(1H)-carboxylate

0.25 mmol of 4-[(3-hexahydrofuro[3,4-C]pyrrol-2(1H)-ylpropyl)sulfonyl]benzonitrile (see Obtaining G) was dissolved in CHCl3(0.5 ml). Added 0.25 mmol of 2-(4-shall original)ethyl-1H-imidazole-1-carboxylate (see Obtaining M), dissolved CH3CN (2 ml), followed by adding To the2CO3or triethylamine (0,375 mmol).

The reaction mixture was stirred at a temperature of 50°within 2 to 5 days. The reaction was monitored using LC-MS. Upon completion of the reaction, the reaction mixture was filtered, the solvent evaporated and then the residue was dissolved in CH2Cl2(2 ml). The resulting solution was added to the stuffing for ion-exchange solid-phase extraction (2 g IAS). Gaskets then suirable mixture DHM/MeCN (4:1, fraction 1), followed by elution with a mixture DHM/Meon/tea(8:1:1, 4×2 ml). Fractions were evaporated. Further analysis using HPLC and MS allowed us to identify the fraction containing the product specified in the header (m/z=469).

Reduction
AU=acetyl
API=ionization at atmospheric pressure (in relation to MS)
aq.=water
br=advanced (in relation to NMR)
Bt=benzotriazol
tert-BuOH=tert-butanol
Cl=chemical ionisation (in relation to MS)
m-SRV=meta-chloroperoxybenzoic acid
d=doublet (in relation to NMR)
DBU=diazabicyclo[5.4.0]undec-7-EN
DHM=dichloromethane
dd=the doublet of doublets (in relation to NMR)
DMAP=4-dimethylaminopyridine
DMF=N,N-dimethylformamide
DMSO=the sulfoxide
EDC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
Et=ethyl
EtOAc=the ethyl acetate
EQ.=equivalents
ES=electrospray (in relation to MS)
FAB=the 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 the
IMS=industrial methylated spirit
IPS=isopropyl 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
OAc=acetate
Pd/C=palladium on carbon
q=Quartet (in relation to NMR)
CT=room temperature
s=the singlet (in relation to NMR)
t=the triplet (in relation to NMR)
The tea=the triethylamine
THF=tetrahydrofuran
TLC=thin-layer chromatog afia
The prefixes n-, sec-, ISO - and tert - have the usual meanings: normal, secondary, ISO-and tertiary.

1. 3,7-diazabicyclo[3.3.0]octane of formula I,

where the wavy lines indicate possible relative CIS - or TRANS-stereochemistry;

R1represents a C1-12alkyl (possibly substituted and/or terminated with one or more than one group selected from aryl, Het1, -C(O)R5a, -OR5b, -N(R6R5c, -C(O)XR7, -C(O)N(R8R5dand-S(O)2R9), Get2, -C(O)R5a, -C(O)XR7or-S(O)2R9;

R5a-R5din each case, when used here, independently represent H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, C1-6alkoxy, cyano, aryl, Het3and-NHC(O)R10), aryl or Het4;

R10represents H, C1-4alkyl;

R6represents H, aryl,

X represents O;

R7in each case, when used here, is a1-12alkyl (which alkyl group possibly substituted and/or ends with one Deputy, selected from HE, cyano, C1-6alkoxy, -SO2R13a, -The(O)R 13band Gets5);

R13Aand R13bindependently represents a C1-6alkyl;

R8in each case, when used here, represents H, C1-12alkyl, C1-6alkoxy (which latter two groups possibly substituted and/or end with one Deputy, selected from HE, C1-4the alkyl and C1-4alkoxy), -D-aryl, -D-Het6, -D,-S(O)2R15a;

R15aindependently represents an aryl;

D represents a direct bond or C1-6alkylen;

R9in each case, when used here, represents a C1-6alkyl (possibly substituted and/or terminated by one Deputy selected from aryl) or aryl;

R2represents H, -E-OR16, -E,-N(R17R18or together with R3represent =O;

R3represents H or, together with R2represent =O;

R16represents H, C1-6alkyl or-S-aryl;

R17represents N;

R18represents N;

E. in each case, when used here, represents a direct link or1-4alkylen;

But a-G-;

In represents-Z-, -Z-N(R22)-, -N(R22)-Z-, -Z-S(O)n-, -Z-O- (in the last two GRU the groin Z is attached to the carbon atom, bearing R2and R3);

G represents a direct bond or C1-6alkylen;

Z represents a direct bond or C1-4alkylen;

R22independently represents H;

R4represents aryl or Het13and both of these groups possibly substituted by one or more than one Deputy, selected from HE, cyano, halogeno, C1-6of alkyl, C1-6alkoxy, -C(O)R24cor-S(O)nR23c;

Gets the13represents a five or six-membered heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur;

Gets the1-Het6in each case, when used here, independently represent a five or six-membered heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, and data heterocyclic group possibly substituted by one or more than one Deputy, including C1-6alkyl or-C(O)R24c;

R23cin each case, when used here, is independently represents a C1-6alkyl;

R24cin each case, when used here, is independently represents N or C1-6alkyl;

n in each case represents 0, 1 or 2 and

where each aryl and alloctype, unless otherwise specified, possibly substituted by one or more than one Deputy, selected from HE, cyano, halogeno,1-6of alkyl, C1-6alkoxy, -C(O)R24cor-S(O)nR23c,

or its pharmaceutically acceptable derivative, provided that:

(a) when R2represents-E-OR16or-E-N(R17R18where E represents a direct link, then:

(1) And is not a direct link and

(2) does not represent-N(R22)-, -S(O)n-, -O - or-N(R22)-Z- (and in the latter group-N(R22) attached to the carbon atom bearing R2and R3);

(b) this connection is not

3,7-bis(1-phenylethyl)was 3.7-diazabicyclo[3.3.0]octane;

3-methyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane;

3-cyclohexyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane;

3-(thiazol-2-yl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane;

3-(2-pyrimidyl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane or

3-(5,5-dimethoxy)pentyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane;

(C) when R2together with R3represent =O and represents-Z-N(R22)- or-N(R22)-Z-, then G is not a direct link.

2. Soedinenie to claim 1, where the wavy lines indicate the relative CIS-stereochemistry.

3. The compound according to any one of claims 1 and 2, where R1represents a C1-8alkyl (possibly substituted and/or terminated with one or more than one group selected from a possibly substituted phenyl, Het1, -C(O)R5a, -OR5b, -C(O)OR7-C(O)N(H)R8and-S(O)2-C1-6alkyl), Het2-C(O)OR7or-S(O)2R9.

4. The compound according to any one of claims 1 to 3, where R5aand R5bin each case, independently represent H, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, and1-4alkoxy), possibly substituted phenyl or Het4.

5. The compound according to any one of claims 1 to 4, where R7in each case represents a C1-8alkyl (and this group possibly substituted and/or ends with one Deputy, selected from HE, cyano, C1-4alkoxy, -SO2R13a, -C(O)R13band Gets5).

6. The compound according to claim 5, where R13aand R13bindependently represents a C1-6alkyl.

7. The compound according to any one of claims 1 to 6, where R8in each case represents a C1-8alkyl (and this group possibly substituted and/or ends with one Deputy, selected from HE, and1-4alkoxy), -D- (possibly substituted phenyl), -D-Het6 and-D-S(O)2R15a.

8. The connection according to claim 7, where R15aindependently represents a possibly substituted phenyl.

9. The compound according to any one of claims 1 to 8, where D represents a direct bond or C1-3alkylen.

10. The compound according to any one of claims 1 to 9, where R9in each case represents a C1-5alkyl (possibly substituted and/or terminated by one Deputy, selected from a possibly substituted phenyl) or possibly substituted phenyl.

11. The compound according to any one of claims 1 to 10, where R2represents H, -OR16, -N(H)R17or together with R3are =O.

12. The compound according to any one of claims 1 to 11, where R3represents H or, together with R2are =O.

13. The compound according to any one of claims 1 to 12, where R16represents H, C1-4alkyl or-O-(possibly substituted phenyl).

14. The compound according to any one of claims 1 to 12, where R17represents N.

15. The compound according to any one of claims 1 to 14, where in each case represents a direct bond or C1-2alkylen.

16. The compound according to any one of claims 1 to 15, where In represents-Z-, -Z-N(H)-, -Z-S(O)n-, -Z-O- (the latter three groups, Z is attached to the carbon atom bearing R2and R3).

17. The compound according to any one of claims 1 to 15, where G represents a direct bond or C1-5alkylen.

18. Connection Ljubo is in one of claims 1 to 17, where Z represents a direct bond or C1-3alkylen.

19. The compound according to any one of claims 1 to 18, where R4represents phenyl or Het13and both of these groups possibly substituted by one or more than one Deputy, selected from cyano, halogeno,1-4of alkyl, C1-4alkoxy or-S(O)2R23c.

20. The compound according to any one of claims 1 to 19, which Gets1- Het6in each case, when used here, independently represent a five or six-membered heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, and heterocyclic group possibly substituted by one or more than one Deputy With1-4alkyl or-C(O)R24c.

21. The compound according to any one of claims 1 to 20, where Ra- Rfindependently represent N or C1-2alkyl.

22. The compound according to any one of claims 1 to 21, where the possible substituents on the phenyl groups are one or more than one group selected from HE, cyano, halogeno,1-4of alkyl, C1-4alkoxy, -C(O)R24cor-S(O)nR23c.

23. Connection p.22, where R23cand R24cindependently represent a1-4alkyl.

24. The compound according to any one of claims 1 to 23, where n represents 0 or 2.

25. The compound according to any one of claims 1 to 24, where the alkyl groups of alkoxygroup can be unless otherwise specified:

(1) straight or branched chain or cyclic or part cyclic/acyclic;

(2) saturated or unsaturated;

(3) interrupted by one or more than one oxygen atom and/or

(4) substituted by one or more than one atom of fluorine or chlorine.

26. Pharmaceutical drug, selectively inhibiting cardiac repolarization, thereby increasing the QT-interval, comprising the compound according to any one of claims 1 to 25 in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

27. Pharmaceutical formulation for use in the prevention or treatment of arrhythmia containing compound according to any one of claims 1 to 25.

28. The compound according to any one of claims 1 to 25 for use as pharmaceutical agents, selectively inhibiting cardiac repolarization, thereby increasing the QT-interval.

29. The compound according to any one of claims 1 to 25, but without the condition (b), for use in the prevention or treatment of arrhythmia.

30. The use of compounds according to any one of claims 1 to 25, but without the condition (b), as the active ingredient for the production of medicines for use in the prevention or treatment of arrhythmia.

31. The application of article 30, where the arrhythmia is an atrial or ventricular fibrillation.

32. The method of prevention or treatment of arrhythmia in which subje the one suffering from this condition or subject to such condition, introducing a therapeutically effective amount of a compound according to any one of claims 1 to 25, but without the condition (b).

33. The method of obtaining the compounds of formula I according to claim 1, in which

interact the compounds of formula II

where R1and Ra-Rfsuch as defined in claim 1,

with the compound of the formula III,

where L1represents a leaving group, and R2, R3, R4And In such, as defined in claim 1.

34. The method of obtaining the compounds of formula I according to claim 1, in which a represents a CH2and R2represents-IT or-N(H)R17at which carry out the interaction of the corresponding compounds of formula II

where R1and Ra-Rfsuch as defined in claim 1,

with the compound of the formula V

where Y represents O or N(R17and R3, R4, R17and such as defined in claim 1.

35. The method of obtaining the compounds of formula I according to claim 1, in which

interact corresponding compounds of formula XVII

where R2, R3, R4, Ra- RfAnd In such, as defined in claim 1,

with the compound of the formula XVIII

where L5represents a leaving group, and R1such as defined in claim 1.

36. The method of obtaining the compounds of formula I according to claim 1, in which R1represents a C1-12alkyl, and an alkyl group substituted on C-2-C (relative to nitrogen ispidina) HE or N(H)R6or maybe substituted for otherwise one or more than one additional Deputy, as defined in claim 1 for R1,

at which carry out the interaction of the corresponding compounds of formula XVII

where R2, R3, R4, Ra- RfAnd In such, as defined in claim 1,

with the compound of the formula XXII

where Yarepresents O or N(R6), R1arepresents a C1-10alkyl, possibly substituted by one or more than one Deputy, as defined in claim 1 for R1; and R6such as defined in claim 1.

37. The compound of formula II

where R1and Ra- Rfare as defined in claim 1, provided that when Ra- R fall represent H, then R1does not represent:

(1) C1-12alkyl, possibly substituted by aryl or Het1;

(2) -C(O)-(possibly substituted aryl), or

(3) tert-butyloxycarbonyl.

38. The compound of formula XVII

where R2, R3, R4, Ra- Rf, A and b are as defined in claim 1, provided that when is a Z, then R2represents-O-O- (possibly substituted aryl).



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel compound 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]-1,3,5-triazine of the formula (I):

, its steroisomeric forms or pharmaceutically acceptable salts, pharmaceutical composition comprising thereof and its using for preparing pharmaceutical composition used in treatment of anxiety in mammals.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

7 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and its pharmaceutically acceptable salts possessing properties of tumor necrosis factor (TNF-α) and to pharmaceutical composition based on thereof wherein R1 means substituted or unsubstituted phenyl wherein substitutes are chosen from halogen atoms or halide-(C1-C6)-alkyl; R4b is substituted or unsubstituted with 1-3 aryl substituted chosen from phenyl, naphthyl wherein substitutes are chosen from halogen atoms, (C1-C6)-alkyl, halide-(C1-C6)-alkyl, (C1-C6)-alkoxyl, cyano-, amino-, (C1-C6)-acylamino-group, (C1-C6)-alkanesulfonyl, or two adjacent substitutes in benzene ring form dioxol group, or unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with 1-3 nitrogen atoms in ring wherein substitutes are chosen from halogen atoms.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 9 sch, 10 tbl, 15 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel pyrimidotriazines of the general formula (I):

wherein each R1 and R2 is chosen from the group comprising hydrogen atom, or R1 and R2 form in common chemical bond, -CH2-Ar and Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono- or disubstituted with (lower)-alkoxy-group and naphthyl mono- or disubstituted with (lower)-alkyl, or their pharmaceutically acceptable salts. Also, invention relates to a method for synthesis of these compounds, pharmaceutical composition based on thereof and to using novel pyrimidotriazines for prophylaxis and/or treatment of diabetes mellitus as these compounds possess the strong expressed inhibitory effect on activity of protein tyrosine phosphatase PTP1B.

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

15 cl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: chemical industry; method of production of the fluorine-containing compounds.

SUBSTANCE: the invention is pertaining to the chemical industry, in particular, to the improved method of production of fluorine-containing compounds from the halogen-containing, compounds, preferably, from chlorine-containing compounds due to an exchange of halogen for fluorine at presence of the HF-additional compound of the mono- or bicyclic amine with at least two atoms of nitrogen. At that at least one atom of nitrogen is built in the cyclic system as the fluorating agent; or at presence of anhydrous hydrogen fluoride - as the fluorating agent and the indicated HF-additional compound of the mono- or bicyclic amine as the catalyst. At usage of the applicable solvents the reaction mixtures can be divided into two phases and thus to simplify the reprocessing of the products. The invention also is pertaining to the HF-additional compounds of 1.5-diazabicyclo[4.3.0]non-5-en and N,N-dialkylaminopiridin, where alkyl represents C1-C4alkyl and where the molar ratio of HF to amine makes 1:1, and to HF- additional compounds 1.8- diazabicyclo[5.4.0]undecyl-7-ene, where the molar ratio of HF to amine compounds more than 1:1.

EFFECT: the invention ensures at usage of the applicable solvents to divide the reaction mixture into two phases and thus to simplify reprocessing of the products.

17 cl, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel derivative of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole, namely its hydrobromide, eliciting properties of antagonist of serotonin 5-HT3-receptors that can be used in therapy of cytotoxic nausea and vomiting. New salt is low toxic and exceeds bemesetron by anti-serotonin activity that is a selective 5-HT3- antagonist.

EFFECT: improved and valuable medicinal properties of derivative.

2 cl, 2 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

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

15 cl, 5 tbl, 6 ex

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to an anti-arrhythmic medicament in combination with amiodarone that comprises thiotriazoline in the ratio to amiodarone = 1:2 by dry matter. Proposed medicament possesses the more expressed anti-arrhythmic effect as compared with prototype (preparation amiodarone).

EFFECT: enhanced and valuable medicinal property of agent.

2 cl, 4 tbl, 4 dwg, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to derivatives of benzopyrane of the formula (1)

or the formula (2) ,

wherein each R1 and R2 means independently of one another hydrogen atom; R3 means hydroxyl group; R4 means hydrogen atom; R5 means (C1-C6)-alkyl group substituted with (C6-C14)-aryl group wherein indicated (C1-C6)-group can be substituted optionally with hydroxyl, methyl group and indicated (C6-C14)-aryl group can be substitute optionally with 1-3 radicals R7 (wherein R7 represents halogen atom or amino-group) or linear (C5-C8)-alkyl group; R6 means (C1-C6)-alkyl group (wherein indicated alkyl group can be substituted optionally with hydroxyl or amino-group), halogen atom, nitro-group or -C(O)NH2 but excluding compound of the formula (1) wherein R means -NO2 at position 6; R5 means -CH2CH2Ph, and R1 and R2 mean methyl group, and compound of the formula (1) wherein R6 means bromine atom at position 6; R5 means benzyl and R1 and R2 mean methyl group, or their pharmaceutically acceptable salts, and a pharmaceutical preparation based on thereof. Proposed compounds are useful as anti-arrhythmic agents.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 7 tbl, 26 ex

FIELD: medicine.

SUBSTANCE: invention relates to application of Acizol, namely bis(1-vinylimidazole) zinc diacetate as coronary active anti-ischemia and anti-arrhythmia agent. Acizol makes it possible to limit development of necrosis zone in acute myocardium ischemia, to reduce frequency of complications and fatal cases, to normalize antrioventricular and intraventricular electrical conductivity , to prevent ciliary arrythmia.

EFFECT: improved anti-ischemia and anti-arrhythmia agent.

15 tbl, 7 dwg, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel solid formulation of anti-arrhythmic medicinal agents. Invention describes crystalline formulation of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benznitrile, tert.-butyl-2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-dizabicyclo[3.3.1]non-3-yl}ethylcarbamate, tert.-butyl-2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or tert.-butyl-2-{7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate and their pharmaceutically acceptable salts. Also, invention describes methods for their synthesis, a pharmaceutical preparation based on thereof, a method for prophylaxis or treatment of arrhythmia and their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: pharmaceuticals, organic chemistry.

SUBSTANCE: invention relates to anthranilic acid amides of general formula I , wherein R1 represents or

R2 represents hydrogen or alkyl; R3 represents dialkoxyphenyl; R4, R5, R6, R7 represent hydrogen, halogen alkyl. Pharmaceutical composition based on compounds of formula I and uses thereof in pharmaceutical agent production. Abovementioned compounds are useful as antiarrhythmic biologically active agents in particular for prevention and prophylaxis of arrhythmias.

EFFECT: new agents for prevention and prophylaxis of arrhythmias.

13 cl, 152 ex

FIELD: medicine, cardiology.

SUBSTANCE: invention relates to prophylaxis of disorders of the cardiac activity rhythm. Method involves simultaneous administration of para-aminobenzoic acid β-diethylaminoethylamide and 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, 30-40 min before the suggested development of disorders of cardiac activity rhythm. Such performance of method allows carrying out the effective prophylactic of disorders of cardiac rhythm caused by arhythmogenic factor of different etiology.

EFFECT: improved method of prophylaxis.

2 cl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bis-aryl compounds of the formula (I): wherein one among A1-A4 means nitrogen atom and others mean -CH or -CR5; A5-A8 mean -CH or -CR5; R5 means halogen atom or (C1-C)-alkyl; R(1) means -C(O)OR(9), -COR(11); R(9) and R(11) mean CxH2x-R(14); x means 0, 1,2, 3 or 4 and x can't mean 0 if R(14) means -OR(15); R(14) means (C1-C6)-alkyl or phenyl; R(15) means (C1-C5)-alkyl; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y means 0, 1, 2, 3 or 4 and y can't mean 0 if R(16) means -OR(17); R(16) means (C1-C6)-alkyl, phenyl or pyridyl; R(17) means hydrogen atom, (C1-C5)-alkyl, phenyl or pyridyl, or R(3) means -CHR(18)R(19); R(18) means hydrogen atom or CzH2z-R(16) wherein R(16) means abovementioned values; z means 0, 1, 2 or 3; R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and to their pharmaceutically acceptable salts also. Compounds of the formula (I) possess anti-arrhythmic activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

11 cl, 30 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to arylated amides of furan and thiophene carboxylic acids of the formulae (Ia) and (Ib) wherein W means oxygen or sulfur atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x means 0, 1, 2 or 3; R(14) means phenyl, and to their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition and using proposed compounds a medicinal agents. Compounds can be used as anti-arrhythmic biologically active substances and especially in treatment and prophylaxis of atrium arrhythmia.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 29 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

FIELD: medicine, pharmacology.

SUBSTANCE: the suggested preparation contains ethacyzine, interpolymeric complex of polymetacrylic or polyacrylic acid and polyethylene glycol, lactose and/or microcrystalline cellulose and a slipper, and, also, method to obtain the mentioned preparation has been suggested due to mixing the components followed by dry granulation. The preparation provides prolonged maintenance of concentration of active substance at therapeutically efficient level.

EFFECT: higher efficiency of application.

7 cl, 5 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of sulfonamide of the general formula (I): wherein A means a substitute chosen from 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) optionally substituted with 1 or 2 halogen atoms, (C1-C4)-alkyl or phenyl radical, or 5- or 6-membered heteroaryl radical comprising 1 or 2 atoms of O, N or S; bicyclic heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from O, N or S and optionally substituted with 1 or 2 halogen atoms or (C1-C4)-alkyl; R1 means hydrogen atom (H), (C1-C4)-alkyl, benzyl; n means 0, 1, 2, 3 or 4; R2 means -NRR5 or the group of the formula: wherein a dotted line means optional chemical bond; R, R4 and R5 mean independently H or (C1-C4)-alkyl; or one of its physiologically acceptable salts. Compounds of the formula (1) possess antagonistic activity with respect to serotonin HT6-receptors that allows their using in pharmaceutical composition and for preparing a medicament.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

10 cl, 2 tbl, 7 ex

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