Derivatives (azetidin-1-illlil)lactam, pharmaceutical composition and method of treatment of a human, which disease is treated by producing antagonistic action on tachykinin, working in human pc1- pc2and pc3the receptor or in combination

 

(57) Abstract:

The invention relates to a derivative (azetidin-1-illlil)lactams of the formula (I) and their pharmaceutically acceptable salts, where R - (C1-C6)-alkyl, optionally substituted by-COOH, -COO((C1-C4)-alkyl), (C3-C7-cycloalkyl, aryl or het1and (C3-C7-cycloalkyl, optionally substituted with 1-2 substituents selected from (C1-C4)-alkyl and fluorine; R1is phenyl, optionally substituted by 1-2 halosubstituted; R2- -CONR3R4, -CONR5((C3-C7-cycloalkyl), -NR3R4that gets3or a group of formula (a), (b), (C); X - (C1-C4-alkylene; X1- directional communication, X2- directional communication or CO; m = 1; used in the treatment of diseases by producing antagonistic action on tachykinin, working in human NK1-, NK2- and NK3the receptor or in their combinations. Proposed intermediate compounds used during their preparation, pharmaceutical composition and method of treatment. 4 C. and 11 C.p. f-crystals, 29 PL.

The invention relates to lactam. More specifically, the present invention relates to azetidine the receiving of such derivative, the compositions containing these derivatives, and their use.

Asotidokukysanan derivatives of the present invention are antagonists of tachykinins, including, NKA, NKB and substance P, acting on the human receptor neirokinina-1 (NK1), neirokinina-2 (NK2or neirokinina-3 (NK3), or a combination thereof. Therefore, the mentioned derivatives are suitable for the prevention or treatment of inflammatory diseases such as arthritis, psoriasis, asthma or inflammatory bowel disease, disorders of the Central nervous system (CNS), such as fear, depression, dementia or psychosis, gastrointestinal (GI) disorder such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflux, fecal incontinence, colitis or Crohn's disease, disorders in the urogenital tract, such as incontinence, hyperreflexia or cystitis, a pulmonary disorder such as chronic obstruction of the respiratory tract, allergies, such as eczema, contact dermatitis or rhinitis, allergic diseases, such as caused by poison ivy, southpasadena diseases such as angina and Raynaud's disease, fibrous or collagen diseases, such as Sclerotinia, such as alcoholism, stress related somatic disorders, peripheral neuropathies, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, neuralgia when shingles or after shingles, neurotic diseases disorders such as Alzheimer's disease or multiple sclerosis, diseases associated with increased or immune suppression such as systemic lupus erythematosus, rheumatic diseases, such as fibrosis, or vomiting, cough, acute or chronic pain or migraine.

Derivative of the present invention are especially potent and selective antagonists of tachykinins, including NKA, NKB and substance P, acting on the human NK2the receptor. They are particularly suitable for treating or preventing inflammatory diseases such as arthritis, psoriasis, asthma or inflammatory bowel disease, disorders of the Central nervous system (CNS), such as fear, depression, dementia or psychosis, gastrointestinal disorders such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflux, fecal incontinence, colitis or Crohn's disease, disorders of the genitourinary putari, such as eczema, contact dermatitis or rhinitis, allergic diseases, such as caused by poison ivy, peripheral neuropathies, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, neuralgia when shingles or after shingles, cough, or chronic pain.

The present invention relates to compounds of General formula (I):

< / BR>
and their pharmaceutically acceptable salts, while in the above formula

R is a (C3-C7-cycloalkyl, aryl or (C1-C6)-alkyl, and referred (C1-C6)-alkyl is optionally substituted by fluorine, -COOH, -COO((C1-C4)-alkyl), (C3-C7-cycloalkyl, adamantium, aryl or het1(het1), and the above-mentioned (C3-C7-cycloalkyl optionally substituted by 1 or 2 substituents, each of which is selected independently among (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C4-alkoxygroup, hydroxyl group, fluorine, fluorine(C1-C4)-alkyl and fluorine(C1-C4-alkoxygroup;

R1represents phenyl, thienyl, benzothiazyl or indolyl, each of which is, neamatalla, (C1-C4-alkoxygroup, halogen and trifloromethyl;

R2represents-CO2H, -CONR3R4, -CONR5((C3-C7-cycloalkyl), -NR5((C2-C5-alkanoyl), -NR3R4, -NR5CONR5R6, ((C3-C7-cycloalkyl- (C1-C4)-alkyl)R5N-, ((C3-C7-cycloalkyl- (C1-C4)-alkyl)2N-, -NR5COCF3,

-NR5SO2CF3, -NR5(SO2(C1-C4)- alkyl), -NR5SO2NR5R6, -NR5(SO2aryl), -N(aryl)(SO2(C1-C4)- alkyl), -OR5, -O((C3-C7-cycloalkyl), -SO2NR5R6that gets3(het3or a group represented by one of the formulas:

< / BR>
R3and R4each and independently selected among H and (C1-C4)-alkyl, optionally substituted hydroxyl group, (C1-C4-alkoxygroup, -S(O)p((C1-C4)-alkyl), amino, -NH((C1-C4)-alkyl), -N((C1-C4)-alkyl)2or gets2(het2);

R5and R6each and independently selected among H, (C1-C4)-alkyl and (C3-C7-cycloalkyl- (C1-C4)-alkyl, with battelino, fluorine;

R7represents H, (C1-C4)-alkyl, hydroxyl group, fluorine (C1-C4)-alkyl or phenyl, and mentioned phenyl optionally substituted by 1 or 2 substituents, each of which, independently, is selected among (C1-C4)-alkyl, fluorine(C1-C4)-alkyl, halogen, (C1-C4-alkoxygroup and fluorine (C1-C4-alkoxygroup;

R8represents H, fluorine, a hydroxyl group, (C1-C4)-alkoxygroup, (C2-C5-alkanoyl or (C2-C5)-alkanoyloxy; R9represents-NR5R6, -NR5COR, -NR5SO2CF3, -NR5(SO2(C1-C4)-alkyl),

-NR5SO2NR5R6, NR5COO((C1-C4)-alkyl), -NR5CONR5R6, -NR5-(SO2-morpholinopropan), -NR5(SO2aryl), -N(aryl)(SO2((C1-C4)-alkyl) or a group of the formula:

< / BR>
X is a (C1-C4-alkylen;

X1represents a directed link or (C1-C6-alkylen;

X2represents a directed link, CO, SO2or NR5CO;

W represents a methylene, CO, CH(OH) C(OH)2, CHR>CF2CH(azetidin-1-yl), CH(pyrrolidin-1-yl), CH-(morpholinopropan), CH(benzoxazol-2-yl), CHR9, O, S(O)p, NR5N((C3-C7-cycloalkyl, NSO2((C1-C4)-alkyl), NSO2((C1-C4)-alkyl), NSO2NR5R6, NSO2CF3, NSO2(morpholinopropan), NSO2-aryl, CH(piperidine-1-yl),

< / BR>
NCONR5R6, NCOR5, NCO(aryl) or NCO2((C1-C4)-alkyl);

W1represents a methylene, CO, CH(OH) C(OH)2CH((C1-C4)-alkoxygroup), CHCO2H, CHCO2((C1-C4)-alkyl), CHCONR5R6, CHF,

CF2CH(azetidin-1-yl), CH(pyrrolidin-1-yl), CH(piperidine-1-yl), CH(morpholinopropan) or CHR9;

W2is a W1, -CH2W1-, -CH2WCH2- or - CH2CH2WCH2-;

m = 0, 1, or 2;

n = 1 or 2 when W is other than methylene, and n = 0, 1, or 2 when W is methylene;

p = 0, 1, or 2;

q = 1 or 2;

r = 1, 2, 3 or 4;

the term "aryl" used in the definition of R, R2, R9and W denotes a naphthyl or phenyl, each of which is optionally substituted C1-C4)-alkyl, halogen, -OR5fluorine(C1-C4)-alkyl, (C2-C5-alkanoyl, -CONR1-C4)-alkyl, (C1-C4-alkoxygroup, halogen, fluorine(C1-C4)-alkyl and fluoro-(C1-C4-alkoxygroup;

the term "het2"used to determine the R3and R4means 4-7-membered ring non-aromatic heterocyclic group containing 1 or 2 heteroatoms, each of which, independently, is selected among the atoms of nitrogen, oxygen, and S(O)pand said group optionally is C-substituted by 1 or 2 substituents, each of which, independently, is selected among (C1-C4)-alkyl, (C1-C4-alkoxygroup and fluorine(C1-C4)-alkyl, and referred to the ring nitrogen heteroatom optionally bears, as Deputy, H, (C1-C4)-alkyl, (C2-C5-alkanoyl, -CON-R5R6or SO2NR5R6; and the term "het3"used to determine the R2means optional sonde 1 to 4 nitrogen heteroatoms, optionally substituted, including in the benzene part, 1 or 2 substituents, each of which, independently, is selected among (C1-C4)-alkyl, fluorine and fluorine (C1-C4)-alkyl.

In the above definitions, the term "halogen" means fluorine, chlorine, bromine or iodine, alkyl, alkylene and CNS group containing three or more carbon atoms, and alcoholnye groups containing four or more carbon atoms may be linear or branched.

Preferably, R is a (C1-C6)-alkyl, optionally substituted by-COOH, -COO((C1-C4)-alkyl), (C3-C7-cycloalkyl, aryl or het1and mentioned cycloalkyl optionally substituted by 1 or 2 substituents, each of which, independently, is selected among (C1-C4)-alkyl and fluorine.

Preferably, R is a (C1-C6)-alkyl, optionally substituted by-COOH, -COO((C1-C4)-alkyl), (C3-C7-cycloalkyl, optionally substituted by 1 or 2 substituents, each of which, independently, is selected among (C1-C4)-alkyl and fluorine, phenyl, optionally substituted 1 or 2 zamestitelyami, fluorine(C1-C4)-alkyl, (C2-C5)-alkanoyl, SO2N((C1-C4)-alkyl)2and phenyl, or a 5 - or 6-membered cyclic heteroaryl group containing 1 or 2 nitrogen heteroatom.

More preferably, R is a (C1-C6)-alkyl, optionally substituted by-COOH, -COO((C1-C4)-alkyl), (C3-C7-cycloalkyl, optionally substituted by 1 or 2 substituents, each of which, independently, is selected among methyl and fluorine, phenyl, optionally substituted by 1 or 2 substituents, each of which, independently, is selected among methyl, fluorine, chlorine, metoxygroup, trifloromethyl, acetyl, -SO2N((CH3)2and phenyl, or pyridinyl.

And more preferably, R represents a 5-carboxypentyl, 5-tert-butyloxycarbonyl, cyclopropylmethyl, dicyclopropyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methylcyclohexyl, 4,4-diverticulectomy, 2-cyclopropylethyl, 2,2-dicyclopropyl, 1-cyclohexylethyl, 2-cyclohexylethyl, cycloheptylmethyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-tormentil, 2,4-dichlorobenzyl, 3-methoxybenzyl, 2-trifloromethyl, 3,5-di(trifluoromethyl)benzyl, 3 4-pyridinylmethyl.

Most preferably, R represents cyclopropylmethyl, dicyclopropyl, 2-cyclopropylethyl, 2,2-dicyclopropyl, cyclohexylmethyl, 4,4-diverticulectomy, cycloheptylmethyl or benzyl.

Preferably, R1represents phenyl, optionally substituted by 1 or 2 halogen substituents.

Preferably, R1represents phenyl, optionally substituted by 1 or 2 substituents, each of which, independently, is selected among fluorine and chlorine.

More preferably, R1represents phenyl, 3,4-differenl, 3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl.

Most preferably, R1represents a 3,4-differenl, 4-chlorophenyl or 3,4-dichlorophenyl.

Preferably, R2is a-CONR3R4, -CONR5(C3-C7-cycloalkyl), -NR3R4that gets3or a group of the formula:

< / BR>
where R3and R4each and independently are chosen from among (C1-C4)-alkyl and (C1-C4)-alkyl, substituted hydroxyl group, or (C1-C4-alkoxygroup, and R5and R6each and independently selected among H, (C1-C4)-artistalley a H, hydroxyl group, or phenyl, R8represents a hydroxyl group or a (C2-C5)-alkanolamine, W represents a methylene, CH(OH), CH((C1-C4)-alkoxygroup), CHCO2H, CHCO2((C1-C4)-alkyl), CH(benzoxazol-2-yl), CHNR5R6, CHNR5COR5, CHNR5(SO2(C1-C4)-alkyl), CHNR5COO((C1-C4)-alkyl), O, S(O)p, NR5, NSO2((C1-C4)-alkyl), NSO2NR5R6, NSO2(morpholinopropan), NCONR5R6, NCOR5, NCO(aryl) or NCO2((C1-C4)-alkyl), n = 1 or 2 when W is other than methylene, and n = 0 or 1 when W is methylene, and p = 0, 1, or 2.

Preferably, R2is a-CONR3R4, -CONR5((C3-C7-cycloalkyl), -NR3R4N-attached 5-membered cyclic heteroaryl group containing 1 or 2 heteroatoms of nitrogen, a group of the formula:

< / BR>
where R3and R4each and independently are selected among methyl and (C1-C4)-alkyl, substituted hydroxyl group or a methoxy group, R5and R6each and independently selected among H, methyl, trifloromethyl and cyclopropylmethyl, R7is the PU, W represents a methylene, CH(OH), CHOCH3, CHOCH2CH3CHO(CH2)2CH3, CHOC(CH3)3, CHCO2H, CHCO2CH3, CHCO2CH2CH3CH(benzoxazol-2-yl), CHNH2, NCOCH3, CHNHCH2(cyclopropyl), CHNHCOCH3, CHNHSO2CH3, CHNHCO2C(CH3)3, O, S(O)p, NH, NCH3, NCH2(cyclopropyl), NSO2CH3, NSO2NH2, NSO2NHCH3, NSO2N(CH3)2, NSO2-(morpholinopropan), NCONH2, NCONHCH3, NCOCF3, NCO(phenyl) or NCO2C(CH3)3n = 1 or 2 when W is other than methylene, n = 0 or 1 when W is methylene, and p = 0, 1, or 2.

More preferably, when R2represents N-(2-methoxyethyl)-N-methylcarbamoyl, N-cyclohexylcarbonyl, N-(2-hydroxyethyl)-N-methylaminopropyl, N-(2-hydroxy-2-methylpropyl)-N-methylaminopropyl, N-(2-methoxyethyl)-N-methylaminopropyl, imidazol-1-yl, 3-hydroxypyrrolidine-1-yl, piperidine-1-yl, 2,6-dimethylpiperidin-1-yl, 3-hydroxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-methoxypiperidine-1-yl, 4-ethoxypyridine-1-yl, 4-(n-propoxy)-piperidine-1-yl, 4-(tert-butoxy)-piperidine-1-yl, 4-carboxypeptidase-1-yl, 4-ethoxycarbonylpyrimidine-1-yl, 4-ethoxycarbonylpyrimidine-1-yl, 4-(benzoxazolphenylethinyl-1-yl, 4-(tert-butoxycarbonylamino)piperidine-1-yl, morpholinopropan, 2-phenylmorpholine, homomorpholine, thiomorpholine, 1-associationtype, 1,1-dioxothiazolidine, piperazine-1-yl, 4-methylpiperazin-1-yl, 4-cyclopropylamines-1-yl, 4-methanesulfonylaminoethyl-1-yl, 4-aminosulphonylphenyl-1-yl, 4-methylaminoacetaldehyde-1-yl, 4-dimethylaminocarbonylmethyl-1-yl, 4-morpholinobutyrophenone-1-yl, 4-carbamoylbiphenyl-1-yl, 4-N-methylcarbamoylmethyl-1-yl, 4-acetylpiperidine-1-yl, 4-triftoratsetilatsetonom-1-yl, 4-benzylpiperazine-1-yl, 4-(tert. butoxycarbonyl)piperazine-1-yl, pyrrolidin-1-ylcarbonyl, piperidine-1-ylcarbonyl, 3-ecomorphology, 3-hydroxy-8-azabicyclo-[3,2,1]Oct-8-yl or 3-atomic charges-8-azabicyclo[3,2,1]Oct-8-yl.

Most preferably, when R2is a 4-aminopiperidin-1-yl, 4-carboxypeptidase-1-yl, 4-hydroxypiperidine-1-yl, morpholinopropan, 1-associationtype, 4-aminosulphonylphenyl-1-yl, 4-methanesulfonylaminoethyl-1-yl, 4-methylaminoacetaldehyde-1-yl or 4-morpholinobutyrophenone-1-yl.

Other preferred examples of R2include 4-foreperiod-1-yl, 4,4-deformability-1-yl, 4-oxopiperidin-1-yl, 4-(pen is ecstasy an ethylene or propylene.

Most preferably, when X represents ethylene.

X1preferably represents a directed link.

X2preferably represents a directed link or CO.

Most preferably, when X2represents a directed link.

Preferably, when m = 1.

Pharmaceutically acceptable salts of compounds of formula (I) include their salts accession of acids and bases.

Suitable salts of joining acids are formed from acids which form non-toxic salts and examples of such salts are hydrochloride, hydrobromide, hydroiodide, sulphates, hydrosulfate, nitrates, phosphates, hydrogen phosphates, acetates, maleate, fumarate, lactates, tartratami, citrate, gluconate, succinate, benzoate, methanesulfonate, benzosulfimide and p-toluensulfonate.

Suitable salts of the bases are formed from bases which form non-toxic salts and examples of such salts are aluminum, calcium, lithium, magnesium, potassium, sodium, zinc salts, and salts of diethanolamine.

An overview of suitable salts see Berge et al. J. Pharm. Sci., 66, 1-19 (1977).

The compound of formula (I) Mogi more stereoisomeric forms. The present invention includes the individual stereoisomers of compounds of formula (I) and mixtures thereof.

Division of diastereoisomers can be carried out by conventional means, for example, by fractional crystallization, chromatography or HPLC of a mixture of stereoisomers of the compounds of formula (I) or a suitable salt or its derivative. Single enantiomer of compounds of formula (I) can also be obtained from a corresponding optically pure intermediate or by cleavage, such as by HPLC, of the corresponding racemate using a suitable optically active acid or base.

Preferred compounds of formula (I) and their salts in which X represents-CH2CH2- have (S)-stereochemistry at the position of joining of the groups X and R1to lactam ring.

Preferred examples of compounds of formula (I) are compounds in which

(I) R is cyclopropylmethyl, R1represents 3,4-dichlorophenyl, R2is morpholinopropan, X represents-CH2CH2-, X1represents a directed link, and m = 1;

(II) R represents a 4,4-diverticulosis a-CH2CH2-, X1represents a directed link, and m = 1;

(III) R represents a 4,4-diverticulectomy, R1represents 3,4-dichlorophenyl, R2is a 4-aminopiperidin-1-yl, X represents-CH2CH2-, X1represents a directed link, and m = 1;

(IV) R is cyclopropylmethyl, R1represents 3,4-dichlorophenyl, R2is a 4-aminosulphonylphenyl-1-yl, X represents-CH2CH2-, X1represents a directed link, and m = 1;

(V) R is a 4,4-diverticulectomy, R1represents 3,4-dichlorophenyl, R2is a 4-hydroxypiperidine-1-yl, X represents-CH2CH2-, X1represents a directed link, and m = 1;

(VI) R is a 2-cyclopropylethyl, R1represents 3,4-dichlorophenyl, R2is morpholinopropan, X represents-CH2CH2-, X1represents a directed link, and m = 1;

(VII) R is a 2-cyclopropylethyl, R1represents 3,4-dichlorophenyl, R2is a 4-methanesulfonylaminoethyl-1-yl, X predstavimoe cyclopropylmethyl, R1represents 3,4-dichlorophenyl, R2is a 4-foreperiod-1-yl, X represents-CH2CH2-, X1represents a directed link, and m = 1;

(IX) R is a 4,4-diverticulectomy, R1represents 3,4-dichlorophenyl, R2is a 4-oxopiperidin-1-yl, X represents-CH2CH2-, X1represents a directed link, and m = 1;

(X) R is cyclopropylmethyl, R1represents 3,4-dichlorophenyl, R2is a 4-carboxypeptidase-1-yl, X represents-CH2CH2-, X1represents a directed link, and m = 1; or

(XI) R is cyclohexylmethyl, R1represents 3,4-dichlorophenyl, R2is a 4-carboxypeptidase-1-yl, X represents-CH2CH2-, X1represents a directed link, and m = 1;

or any such connection (S)-stereochemistry at the position of joining of the groups X and R1to lactam ring, or any pharmaceutically acceptable salt.

The compounds of formula (I) according to the present invention can be obtained by the methods listed below.

1)and which is connected to the nitrogen atom of azetidine, and R, R1, R2X1and m have the values set previously for compounds of formula (I) can be obtained by hydroamination when using as starting compounds, the compounds of formula (II):

< / BR>
where R, R1and m have the values set previously for compounds of formula (I), and compounds of formula:

< / BR>
or its salt accession acid, in which R2and X1have the values set previously for compounds of formula (I). The reaction is carried out preferably in the presence of a suitable acid, for example acetic acid.

The reaction proceeds through the formation, first, the intermediate salt imine formula (IIIA):

< / BR>
which can be sustainable and which can be distinguished. The reaction is carried out, preferably without isolation of the intermediate compounds of formula (IIIA), and in this case the connection is restored in situ and gives compound of formula (I).

In a typical procedure, the aldehyde of formula (II) is first injected into interaction with azetidinol formula (III) in a suitable solvent, e.g. tetrahydrofuran, and the mixture is then treated with a suitable reducing agent, for example, triacetoxyborohydride sodium or cyanoborohydride este initial substance use salt accession acid of azetidine formula (III), before adding the reducing agent can be added a suitable acid acceptor, e.g. triethylamine.

The reaction is carried out usually at room temperature.

Source aldehydes of the formula (II) can be obtained by the method shown in scheme I.

< / BR>
< / BR>
Here in the formulas, R, R1and m have the values set previously for compounds of formula (I), and Z, Z1and Z2each and independently represent a suitable useplease group, for example, chlorine-, bromine-, I-, methanesulfonate-, p-toluensulfonate or triftormetilfullerenov.

In a typical procedure, allmechanical formula (IV) first deprotonated, using a suitable base, such as sodium hydride, and then alkylate in situ alkylating agent of the formula (V) in which Z represents bromine. The reaction is carried out, as a rule, in a suitable solvent, e.g. tetrahydrofuran, at a temperature of about 0oC for deprotonation, and at room temperature for alkylation. The reaction can also be carried out in conditions of phase transfer, using a suitable base, such as sodium hydroxide, a suitable catalyst phase transfer, e.g. the

The combined acetonitrile derivative of formula (VI), which is obtained, which is then deprotonated, using a suitable base, for example, diisopropylamide lithium, and then alkylate in situ a compound of formula (VII), where Z1represents, preferably bromine. The reaction is carried out, as a rule, in a suitable solvent, e.g. tetrahydrofuran (THF) at -70oC, heating the reaction mixture to room temperature to complete the reaction. After adding the compounds of formula (VII) to the reaction mixture can be added to increase the reaction rate, iodide, Tetra-n-butyl-ammonium.

The compound obtained of the formula (VIII) then restore and under suitable conditions cyclist in the lactam of formula (IX), using, for example, Raney Nickel, in an atmosphere of hydrogen at atmospheric pressure and room temperature, using as solvent ammonia ethanol.

Then lactam of the formula (IX) first deprotonated, using a suitable base, such as sodium hydride, and then alkylate in situ with the compound of the formula RZ2where Z2represents, preferably, bromine, methanesulfonamido or p-toluensulfonate. The reaction is carried out, as a rule, in approaching the rmula (X) is then treated with a saturated solution of hydrogen chloride in a suitable (C1-C4)-alcohol, for example methanol, at room temperature, to remove tetrahydropyranol protective group. Cleavage of the protective group can also be carried out using a suitable ion-exchange resin, for example, Amberlyst 15 (trademark), and in a suitable solvent, e.g. methanol.

The resulting alcohol of the formula (XI) under suitable conditions to oxidize the aldehyde of formula (II), for example, under the conditions of Swern oxidation (oxalicacid, dimethylsulfoxide, triethylamine, and use as a solvent dichloromethane).

The original azetidine formula (III) can be obtained in the usual way.

2) the compounds of formula (I) in which X, X1, R, R1, R2and m have the values set previously for compounds of formula (I), except for those compounds in which R represents a trifluoromethyl, -CF2((C1-C5)-alkyl, optionally substituted by fluorine or aryl, can be obtained by alkylation of N-deprotonated compounds of the formula (XII):

< / BR>
in which X, X1, R1, R2and m have the values set previously for compounds of formula (I), the compound of the formula RZ2where R has the values set earlier in opisaniehellboj-, p-toluensulfonate or triftormetilfullerenov.

In a typical procedure, the compound of formula (XII) first deprotonized a suitable base, e.g. sodium hydride, and then alkylate in situ with the compound of the formula: RZ2where Z2represents, preferably, chlorine, bromine or methansulfonate. The reaction is carried out, as a rule, in a suitable solvent, for example dimethylformamide, at temperatures from room temperature up to 50oC.

Alternatively, the reaction may be accomplished by interaction of the starting substances of the formulae (XII) and RZ2together, in the presence of a suitable base, e.g. potassium hydroxide, in a suitable solvent, for example dimethylsulfoxide at room temperature. If you use the connection formula; RZ2in which Z2represents chlorine, to increase the rate of reaction can also add potassium iodide.

Educt of the formula (XII) can be obtained by conventional means, using, for example, preparative method described in method (1) and the diagram I (i.e., omitting the stage of N-alkylation to form compounds of formula (X)).

Starting compound of the formula: RZ2could2and m have the values set previously for compounds of formula (I) can be obtained by reacting the compounds of formula (XIII):

< / BR>
in which X, R, R1and m have the values set previously for compounds of formula (I), and Z3constitutes a suitable useplease group, for example, chlorine-, bromine-, iodine-, methanesulfonate, tripterocalyx - or p-toluensulfonate, with the compound of the formula:

< / BR>
where R2has the values set previously for compounds of formula (I).

In a typical procedure, the compound of formula (XIII), in which Z3represents, preferably, methysulfonylmethane, enter into interaction with the compound of the formula (III) in the presence of a suitable acid acceptor, e.g. triethylamine or potassium carbonate, or combinations thereof, in a suitable solvent, e.g. acetonitrile, at a temperature near its boiling point under reflux.

The compound of formula (III) can be obtained in situ from its salts accession acid when using a molar excess of acid acceptor.

Educt of the formula (XIII) can be obtained by conventional means, such as cord methysulfonylmethane, by reacting the alcohol of formula (XI) with methanesulfonamide in the presence of a suitable acid acceptor, such as triethylamine.

4) the compounds of formula (I) in which R1represents phenyl, and X, X1, R, R2and m have the values set previously for compounds of formula (I) can be obtained by the hydrogenolysis of compounds of formula (I) in which R1represents phenyl substituted by chlorine, bromine or iodine, and X, X1, R, R2and m have the values set previously for compounds of formula (I).

In a typical procedure, the hydrogenolysis is carried out in an ammonia ethanol, using a suitable catalyst, such as Raney Nickel or, preferably, palladium-on-charcoal, at the 50oC and in an atmosphere of hydrogen at a pressure of 345 kPa (50 f/d2).

5) the compounds of formula (I) in which R2represents a group of formula: -other4, ((C3-C7-cycloalkyl- (C1-C4)-alkyl)NH-,

< / BR>
R9is an-other5W represents NH or CHNHR5, W1represents CHNHR5, W2is a W1, -CH2W1-, -CH2WCH2- or-CH2CH2WCH2-, and X, X1X2
< / BR>
R10predstavlyaemogoakterom:-NZ4R4,((C3-C7-cycloalkyl-(C1-C4)-alkyl)Z4N-,

< / BR>
accordingly, R9Arepresents-NZ4R5, WArepresents NZ4or CHNZ4R5, W1Arepresents CHNZ4R5, W2Ais a W1A, -CH2W1A-, -CH2WACH2- or-CH2CH2WACH2-, X, X1X2, R, R1, R4, R5, R6, R7, m and n have the values set previously for compounds of formula (I), and Z4represents a suitable protective group, for example, tert-butoxycarbonyl (for example, the compounds of formula (I) in which W represents an NCO2C-(CH3)3or R9represents-NR5CO2C(CH3)3), or benzyloxycarbonyl.

Suitable protective groups that can be used in this way as a means of removal of protective groups are well known to specialists in this field of technology, see, for example, Greene et al., "Protective Groups in Organic Synthesis", Second Edition, 1991, Wiley-Interscience.

In a typical procedure, when Z4represents tributoxy-Carbo who eat solvent, for example, in dichloromethane, at room temperature.

Educt of the formula (XIV) can be obtained by conventional means, such as described here, the methods for obtaining compounds of formula (I), with appropriate adaptation.

6) the compounds of formula (I) in which R2represents a group of the formula:

< / BR>
where p = 1 or 2, W2represents-CH2S(O)pCH2- or-CH2CH2S(O)pCH2-, and X, X1X2, R, R1, R5, R6, R7, m and n have the values set for the compounds of formula (I) can be obtained by oxidation of the corresponding compounds of formula (I) in which R2represents a group of the formula:

< / BR>
in which W2represents-CH2(S or SO)CH2- or-CH2CH2(S or SO)CH2-, and X, X1X2, R, R1, R5, R6, R7, m and n have the values set previously for compounds of formula (I). The oxidation is carried out by at least one molar equivalent of a suitable oxidant, when sulfoxide turn in sulfon, at least two molar equivalents of a suitable oxidant, when the sulfide is transformed into sulfon, and, in fact, one of the mo is La this purpose oxidizers and oxidizing conditions are an aqueous solution of hydrogen peroxide in alkaline medium (for example, acetonitrile, in the presence of potassium carbonate, and the use as solvent of methanol) or m-chloroperbenzoic acid in a suitable solvent, e.g. dichloromethane.

7) the compounds of formula (I) in which R2represents a group of the formula:

< / BR>
and X, X1, R, R1and m have the values set previously for compounds of formula (I) can be obtained by removal of the protective group from compounds of formula (XV):

< / BR>
where Z5represents a suitable protective group, for example, acetyl (i.e., the compound of formula (I) in which R8is acetyloxy) or tetrahydropyran-2-yl, and X, X1, R, R1and m have the values set previously for compounds of formula (I).

Suitable protective groups that can be used for this method, as well as ways of removal of protective groups are well known to specialists in this field of technology, see, for example, Greene et al., "Protective Groups in Organic Synthesis", Second Edition, 1991, Wiley-Interscience.

In a typical procedure, when Z5represents acetyl, cleavage of the protective group can be carried out using a hydroalcoholic solution of a suitable strong base, voltage is="ptx2">

Educt of the formula (XV) can be obtained by conventional means, such as described here, the methods for obtaining compounds of formula (I), with appropriate adaptation.

8) Compounds of formula (I) in which X, X1, R, R1, R2and m have the values set previously for compounds of formula (I), except for compounds in which R2represents-CO2H, R is a (C1-C6)-alkyl, substituted by-COOH, W is a CHCO2H, or W1represents CHCO2H, can be obtained by intramolecular dehydration of compounds of formula (XVI):

< / BR>
where X, X1, R, R1, R2and m have the meanings previously established for this method.

In a typical procedure, the dehydration is carried out at conditions under Dean-stark, in a suitable solvent, for example toluene, and in the presence of a suitable acid, for example, p-toluensulfonate acid. Alternatively, the dehydration can be accomplished by mixing the solution of the compounds of formula (XIV) in a suitable solvent, e.g. dichloromethane, in the presence of silica gel.

Educt of the formula (XVI) can be obtained in the usual way.

9) organisations of the formula (I), with the exception of compounds in which R2represents-CO2H, R is a (C1-C6)-alkyl, substituted by-COOH, W is a CHCO2H, or W1represents CHCO2H, can be obtained by cyclization of compounds of formula (XVII):

< / BR>
where X, X1, R, R1, R2and m have the meanings previously established for this method, and Z6constitutes a suitable useplease group, for example, (C1-C4)-alkoxygroup, benzyloxy, imidazol-1-yl or benzotriazol-1-lexigraphy.

In a typical procedure,

(I) when Z6is a (C1-C4)-alkoxygroup or benzyloxy, a solution of the compounds of formula (XVII) in a suitable solvent, for example methanol or ethanol, is heated to the boiling point of the solvent under reflux;

(II) when Z6represents imidazol-1-yl, the compound of formula (XVII) are obtained by reacting compounds of the formula (XVI) with 1,1-carbonyl diimidazol in a suitable solvent, e.g. dichloromethane, and cyclization in situ intermediate imidazole gives the desired product; and

(III) when Z6is benzotriazol-1 iloxi what azole in the presence of a suitable dehydrating agent, for example, 1,3-dicyclohexylcarbodiimide, and in a suitable solvent, e.g. dichloromethane, and cyclization in situ gives the desired product.

Educt of the formula (XVII) can be obtained by conventional means, for example, from compounds of formula (XVI), methods, examples of which are described above.

10) Compounds of formula (I) in which X1represents a direct bond, and R2represents-NR3R4, ((C3-C7-cycloalkyl- (C1-C4)-alkyl)R5N-, ((C3-C7-cycloalkyl- (C1-C4)-alkyl)2N - or a group of the formula:

< / BR>
and X, W, W1, R, R1, R3, R4, R5, R6, R7, R8, R9, m and n have the values set previously for compounds of formula (I) can be obtained by reacting the compounds of formula (XVIII):

< / BR>
in which X, R, R1and m have the values set previously for compounds of formula (I), and Z7constitutes a suitable useplease group, for example, methanesulfonamido or p-toluensulfonate, with the compound of the formula:

-NR3R4, ((C3-C7-cycloalkyl- (C1-C4)-alkyl)R5NH-, ((C3-C7-the cycle is SUP>6
, R7, R8, R9and n have the values set previously for compounds of formula (I).

In a typical procedure, the reaction is carried out using an excess of amine, in a suitable solvent, e.g. acetonitrile or dichloromethane, and at the boiling temperature of the solvent under reflux. On the other hand, to the reaction mixture may be added additional acid acceptor, such as potassium carbonate.

Source amines can be obtained in the usual way.

Educt of the formula (XVIII) can be obtained by conventional means, such as hydroamination, using as starting compounds for the compounds of formula (II) and ammonia to obtain the corresponding primary amine, the interaction of the amine with epichlorohydrin or 1,3-dichloropropan-2-I to obtain the corresponding azetidin-3-Aulnay derived, followed by the mutual conversion of the hydroxyl functional group with the formation of the compounds of formula (XVIII).

11) Compounds of formula (I) in which X, X1, R, R1, R2and m have the values previously established for the method (10), can be obtained by gidroaminirovaniya using as the frost for the compounds of formula (I), and a suitable compound of the formula:

-NR3R4, ((C3-C7-cycloalkyl- (C1-C4)-alkyl)R5NH-, ((C3-C7-cycloalkyl- (C1-C4)-alkyl)2NH,

< / BR>
or its salt accession acid, where W, W1, R3, R4, R5, R6, R7, R8, R9and n have the values set previously for compounds of formula (I). The reaction is carried out preferably in the presence of a suitable acid, e.g. acetic acid.

A typical procedure may be such that what is described in method (1).

If you are using a primary amine, the reaction proceeds through the formation of an intermediate amine. If you use a secondary amine, the reaction proceeds through the formation of an intermediate salt imine (EUR. the compound of formula (IIIA). As Imin and salt imine can be sustainable and allow their separation. The reaction is preferably carried out without isolating the intermediate imine or salt imine, and in this case, the intermediate connection is restored in situ with the formation of the compounds of formula (I).

Educt of the formula (XIX) can be obtained by oxidation of corresponding azetidin-3-Aulnay derivatives (palautouriam as oxidant chloramine pyridinium or perruthenate of tetrapropylammonium.

12) the compounds of formula (I) in which R2is morpholinopropan, and X, X1, R, R1and m have the values set previously for compounds of formula (I) can be obtained by reacting the compounds of formula (I) in which R2represents-NH2and X, X1, R, R1and m have the values set previously for compounds of formula (I) with bis(2-chloration) ether.

In a typical procedure, the compound of formula (I) in which R2represents-NH2enter into interaction with bis(2-chloration) ether in the presence of a suitable acid acceptor, e.g. triethylamine, in a suitable solvent, e.g. dichloromethane.

Some of the original amino derivatives, for example, derivatives of 3-aminoacridine can be obtained by the coupling of compounds of formula (XVIII) in which Z7constitutes a suitable useplease group, for example, methanesulfonamido, with a suitable azide, e.g. sodium azide or trimethylsilylmethyl, with the formation of the corresponding 3-azidothymidine derivative, and subsequent restoration derived, for example, using sodium borohydride, that's X, X1, R, R1, R2and m have the values set previously for compounds of formula (I), except for compounds in which R2represents-CO2H, R is a (C1-C6)-alkyl, substituted by-COOH, W is a CHCO2H, or W1represents CHCO2H, can be obtained by reductive cyclization of the compounds of formula (XX):

< / BR>
where X, X1, R, R1, R2and m have the meanings previously established for this method, and R11constitutes a suitable afrobrazil group, for example, (C1-C4)-alkyl, preferably methyl or ethyl, or benzyl.

In a typical procedure, the compound of formula (XX) are first obtained in situ by reacting the compounds of formula (XXI):

< / BR>
where X, X1, R1, R2, R11and m have the values set previously for compounds of formula (XX) with a compound of the formula: RNH2in which R has the values set previously for this method, and subsequent reductive cyclization easier, thanks to the presence of a suitable reducing agent, for example, Raney Nickel. The reaction is carried out in a suitable solvent, for example methanol or ethanol, and the atmosphere is that of compounds of formula (I) can be obtained by a derivation of some amines of the formula (I). For example, the compound of formula (I) in which R2is:

< / BR>
when W represents NH or CHNHR5, W1represents CHNHR5, W2is a W1, -CH2W1-, -CH2WCH2- or-CH2CH2WCH2-, or R9is an-other5and X, X1X2, R, R1, R5, R6, R7, m and n have the values set previously for compounds of formula (I) may be converted into the following compounds.

a) a compound of formula (I) in which W represents NR5or CHNR5R6, W1represents CHNR5R6or R9is an-other5or its salt accession acid, as required, with R5and R6have the values set previously for compounds of formula (I), provided that R5does not represent H, and has a methylene group linked to the nitrogen atom by gidroaminirovaniya with the aldehyde of the formula: ((C1-C3)-alkyl)CHO or ((C3-C7-cycloalkyl-(C1-C3)-alkyl)CHO, and referred (C1-C3)-alkyl and (C3-C7-cycloalkyl-(C1-C4)-alkyl substituted optionally fluorine.

6or CHNR5CONHR6, W1represents CHNR5CONHR6or R9represents-NR5CONHR6as required, while R5and R6have the values set previously for compounds of formula (I), provided that R6is not H, by reacting with the isocyanate of formula R6NCO, in which R6matter previously established for this method.

The reaction is carried out, as a rule, using a suitable solvent, for example dichloromethane or tetrahydrofuran.

c) In the compound of formula (I) in which W represents NSO2CF3or CHNR5SO2CF3, W1represents CHNR5SO2CF3or R9represents-NR5SO2CF3as required, while R5has the values set previously for compounds of formula (I), by interacting with triftormetilfullerenov or anhydride triftormetilfullerenov acid, in the presence, optionally, of a suitable acid acceptor, e.g. triethylamine, pyridine or potassium carbonate. The reaction is carried out, as a rule, in the appropriate organic which W represents NSO2((C1-C4)-alkyl), NSO2NR5R6, NSO2(morpholinopropan), NSO2(aryl), CHNR5(SO2(C1-C4)-alkyl) or CHNR5SO2NR5R6, W1represents CHNR5(SO2(C1-C4)-alkyl) or CHNR5SO2NR5R6or R9represents-NR5(SO2(C1-C4)-alkyl or NR5SO2NR5R6as required, while R5and R6have the values set previously for compounds of formula (I), by reacting with (C1-C4-alkanesulfonyl or bromide, anhydride (C1-C4)-alkanesulphonic acid or a compound of the formula; R5R6NSO2(Cl or Br), (morpholino)SO2(Cl or Br) or (aryl)SO2(Cl or Br), as required, in the presence, optionally, of a suitable acid acceptor, e.g. triethylamine.

The reaction is carried out, as a rule, in a suitable organic solvent, e.g. dichloromethane, at a temperature of from 0oC to room.

e) In a compound of formula (I) in which W represents NCOR6or CHNR5COR6, W1represents CHNR5COR6or R9presented is for the compounds of formula (I), provided that R6is not H, by reacting with the compound of the formula: R6CO(Cl or Br) or (R6CO)2O, R6matter previously established for this method, in the presence, optionally, of a suitable acid acceptor, e.g. triethylamine.

The reaction is carried out, as a rule, in a suitable organic solvent, e.g. dichloromethane, at a temperature of from 0oC to room.

f) the compound of formula (I) in which W, W1or R9have the meanings previously established method 14(e), as required, by condensation with the compound of the formula: R6CO2H, R6matter previously established for this method. The reaction can be carried out under normal conditions, for example, using 1,1-carbonyldiimidazole or 1-hydroxybenzotriazole/1,3-dicyclohexylcarbodiimide (see , for example, the method (9)) to obtain activated intermediates.

g) the compound of formula (I) in which W represents NSO2NR5R6or CHNR5SO2NR5R6, W1represents CHNR5SO2NR5R6or R9represents-NR5SO2NR the I of the formula (I), by interacting with the compound of the formula: R5R6NSO2NH2.

The reaction is carried out usually at an elevated temperature in a suitable organic solvent, for example 1,4-dioxane.

15) Compounds of formula (I) in which R2is:

< / BR>
thus W and W1are CHCO2H and W2is a W1, -CH2W1-, -CH2WCH2- or-CH2CH2WCH2-, and X, X1X2, R, R1, R5, R6, R7, m and n have the values set previously for compounds of formula (I) can be obtained by hydrolysis of compounds of formula (I) in which W and W1are CHCO2((C1-C4)-alkyl), W2is a W1, -CH2W1-, -CH2WCH2- or-CH2CH2WCH2-, and X, X1X2, R, R1, R5, R6, R7, m and n have the values set previously for compounds of formula (I). Preferably, W and W1are CHCO2CH3or CH2CO2CH2CH3.

The hydrolysis is carried out typically using an aqueous solution of a suitable acid or base, for example, reorganize the potassium, in the presence, optionally, of a suitable organic co-solvent, such as methanol or ethanol.

16) Compounds of formula (I) in which R2is:

< / BR>
thus W and W1are CHNR5R6, W2is a W1, -CH2W1-, -CH2WCH2- or-CH2CH2WCH2-, R9represents-NR5R6and X, X1X2, R, R1, R5, R6, R7, m and n have the values set previously for compounds of formula (I) can be obtained by reacting the compounds of formula (XXII):

< / BR>
where R12is:

< / BR>
thus WBand W1Bare CHZ8and W2Bis a W1B, -CH2W1B-, -CH2W1BCH2- or-CH2CH2WBCH2-, Z8constitutes a suitable useplease group, for example, halogen (preferably chlorine or bromine), methysulfonylmethane, triftormetilfullerenov or p-toluensulfonate, and X, X1X2R, R1, R5, R6, R7, m and n have the values set previously for compounds of formula (I), with the connection formal), in the presence, optionally, of a suitable acid acceptor, e.g. triethylamine or potassium carbonate.

The reaction is carried out, as a rule, in a suitable solvent, such as acetonitrile.

17) the compounds of formula (I) in which R2is:

< / BR>
thus W and W1are CHNR5R6and X, X1X2, R, R1, R5, R6, R7, m and n have the values set previously for compounds of formula (I) can be obtained by gidroaminirovaniya using as starting compounds for the compounds of formula (I) in which R2is:

< / BR>
and X, X1X2, R, R1, R5, R6, R7, m and n have the values set previously for compounds of formula (I), and compounds of the formula: HNR5R6while R5and R6have the values set previously for compounds of formula (I).

Using conventional conditions, such as described in method (1). And again, the resulting intermediate Imin or salt imine can be sustainable and allow their separation. The reaction is preferably carried out without the isolation of intermediate compounds, which, in this case, postanal the circular cyclization of the compounds of formula (XXIII):

< / BR>
in which X, X1, R, R1, R2and m have the values set previously for compounds of formula (I), and Z9constitutes a suitable useplease group, for example, halogen (preferably chlorine or bromine), methanesulfonamido or p-toluensulfonate, in the presence, optionally, of a suitable acid acceptor, e.g. triethylamine.

The reaction is carried out, as a rule, in a suitable solvent, e.g. dichloromethane.

19) All the compounds of formula (I), with the exception of compounds in which m = 0, can be obtained by catalyzed with the addition of carbonyl cyclization of compounds of formula (XXIV);

< / BR>
when t = 0 or 1, and X, X1, R, R1and R2have the values set previously for compounds of formula (I).

The reaction is carried out usually in an atmosphere of carbon monoxide using a suitable catalyst, for example, tetranitropentaerithrite (0), a suitable base, such as triethylamine and in a suitable organic solvent, e.g. tetrahydrofuran, at room temperature.

All of the above reactions and methods of obtaining new starting compounds used in the above is received, as methods highlight the desired products will be well known to experts in this field of technology when referring to the literature and here the preparative examples and examples.

Pharmaceutically acceptable salt accession acid or base compounds of formula (I) can be easily obtained by mixing solutions of the compounds of formula (I) and the desired acid or base, depending on requirements. Salt can be precipitated out of solution and collect by filtration, or it can be extracted through solvent evaporation.

The affinity of the compounds of formula (I) and their salts for human NK1the receptor can be tested in vitro by testing their ability to inhibit the binding of [3H] -substance P with membranes obtained from the line of man IM9 cells expressing human NK1-the receptor, using a modified method described in McLean, S., et al., J. Pharm. Exp. Ther., 267, 472-9 (1993), which use the whole cell.

The affinity of the compounds of formula (I) and their salts for human NK1the receptor can be tested in vitro by testing their ability to compete with the binding of [3H]-substance P, [125I]NKA (neurokinin NK2the receptor. In this way the washed cell membranes of Chinese hamster ovary receive as described in the previous case, when used IM9 cells. Membranes incubated (90 min, 25oC) with [125I]NKA and check the connection in the range of concentration. The nonspecific binding determined in the presence of 10 μm NKA.

Antagonistic NK2receptor activity of the compounds of formula (I) can be tested, in vitro, by checking out the ability to counteract the contractile action of selective NK2-receptor agonist [Ala8] NKA(4-10)in the rabbit pulmonary artery, using the method Patacchini and Maqqi, Eur. J. Pharmacol, 236, 31-37 (1993).

The compounds of formula (I) and their salts can be checked on the antagonistic NK2receptor activity in vivo by examining their ability to inhibit bronchostenosis induced [ Ala8]NKA(4-10)we are anesthetized Guinea pigs, using the method described in Murai et al., J. Pharm. Exp. Ther., 262, 403-408 (1992), or Metcalfe et al., Br. J. Pharmacol., 112, 563P (1994).

The compounds of formula (I) and their salts can be checked on the antagonistic NK3receptor activity, in vitro, by checking their ability protivetsa Guinea pigs, using the method Maqqi et al., Br. J. Pharmacol., 996-1000 (1990).

When applied to humans, the compounds of formula (I) and their salts can be administered alone, but generally, they will be introduced in a mixture with a pharmaceutically acceptable diluent or carrier selected with regard to the intended route of administration and generally accepted pharmaceutical practice. For example, they can be administered orally, including under the tongue, in the form of tablets containing such excipients as starch or lactose, or in capsules or wafers, alone or in a mixture with excipients, or in the form of elixirs, solutions or suspensions containing the corrigentov or dyes. They can be administered parenterally by injection, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration they are best used in the form of sterile aqueous solutions which may contain other substances, for example, salts or glucose in an amount sufficient to make the solution isotonic with blood.

For oral and parenteral administration to humans, the daily dose of the compounds of formula (I) and their salts will be from 0.001 to 20 mg/kg, preferably from 0.01 to 20 mg/kg, preferably from 0.5 to 5 mg/kg and most predpochitayut from 0.1 to 500 mg, preferably from 50 to 200 mg, of active connections for simultaneous reception of one, two or more of their number as required. In any case, the actual dosage which will be most appropriate for the individual patient, will determine the attending physician, and it will vary depending on age, weight and response of the individual patient. The above doses are examples of average case; and it is possible that in some cases, deserve the attention of a wider or shorter dosage intervals, and they are included in the scope of the present invention.

On the other hand, the compounds of formula (I) can be administered by inhalation or in the form of suppositories or vaginal suppositories, or they may be applied topically in the form of lotions, solutions, creams, ointments or powders. An alternative method of transdermal injection is the use of a skin patch. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or paraffin oil; or you can enter them, at a concentration of from 1 to 10%, into an ointment consisting of a white wax or colourless soft paraffin as the basis, with such stabilizers which may be required.

It should be noted, "ptx2">

Thus, the present invention relates

I), to pharmaceutical compositions containing the compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier;

II) to the compound of formula (I) or its pharmaceutically acceptable salts or compositions, for use as a drug;

III) to the use of compounds of formula (I) or its pharmaceutically acceptable salt, or composition for the manufacture of a medicinal product for the treatment of disease by antagonistic action on tachykinin, working in human NK1-, NK2- or NK3the receptor or in combination;

IV) for use in (III), when the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a disorder of the Central nervous system (CNS), such as fear, depression, dementia or psychosis, gastrointestinal (GI) disorder such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflux, fecal incontinence, colitis or Crohn's disease, a disease of the urinary tract, such as incontinence, gikuyu as eczema, contact dermatitis or rhinitis, allergic disorder such as caused by poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, neuralgia when paasivaara versicolor or after shingles, cough or acute or chronic pain;

V) the method of treatment of a human in which the disease can be cured due to the antagonistic action on tachykinin, working in human NK1-, NK2- or NK3the receptor or in combination, which comprises treating said human an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, or their compositions;

VI) to method (V), when the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a disorder of the Central nervous system (CNS), such as fear, depression, dementia or psychosis, gastrointestinal (GI) disorder such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflux, fecal incontinence, colitis or Crohn's disease, a disease of the urinary tract, such as incontinence, hyperreflexia or cystitis, Legon the atita or rhinitis, allergic disorder such as caused by poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, neuralgia when shingles or after shingles, cough or acute or chronic pain;

VII) to the compound of formula (II), (IIIA), (XII), (XIV), (XV), (XVI) (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII) or (XXIV).

The following are examples of preparing compounds of formula (I).

(Reference) example 1

5-(3,4-Dichlorophenyl)-5-(2-[-morpholinomethyl-1-yl]ethyl)-2(1H)- piperidin

< / BR>
To a solution of aldehyde (see preparative example 6) (150 mg, 0.52 mmol) and hydrochloride 3-morpholinoethyl (see preparative example 56) (103 mg, 1,1 mol. EQ. ) in tetrahydrofuran (7.5 ml) under nitrogen atmosphere add triethylamine (0,08 ml to 1.1 mol. EQ.). After 1 hour, add triacetoxyborohydride sodium (171 mg, 1,5 mol. equiv.) then immediately add glacial acetic acid (0,03 ml), and the mixture is stirred for 2 hours. Then add water (1 ml), and then add saturated aqueous sodium bicarbonate solution (10 ml). The mixture is extracted with dichloromethane (3 x 20 ml) and the combined organic layers are dried over magnesium sulfate. The solution is filtered, the solvent is removed and the of astorias methanol with ethyl acetate (1 : 9 to 1 : 4, by volume) to remove impurities, and then re-chromatographic using silica gel, elwira mixture of methanol with dichloromethane (1 : 9, by volume), and get named in the title compound (78 mg).

HSC Rf= 0,27 (silica, methanol : dichloromethane, 1 : 9, by volume). ICSD (LRMS - mass spectrometry low resolution) m/z = 411 (m+1)+. Elem. analysis: found: C - 57,57; H - 6,76; N - 9,78. For C20H27Cl2N3O2= 1,60-1,70 (m, 1H), 1,80-1,85 (m, 1H), 2.00 in to 2.40 (m, 10H), 2,65 is 2.75 (m, 2H), 2,85-2,90 (m, 1H), 3,35 is 3.40 (m, 3H), 3,65 of 3.75 (m, 5H), of 6.20 (s, W, 1H), 7,15-to 7.50 (m, 3H) ppm.

Examples 2 through 59

Compounds of General formula:

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the examples listed below in table. 1, receives a manner similar to the method of example 1, using as starting substances, the corresponding aldehyde (see preparative examples 39-43, 137-140 and 187-191), azetidin (see preparative examples 56, 61, 65, 66, 67, 70, 77-80, 82, 84, 85, 87, 89, 107-118, 121, 134, 154, 180 and 181).

Footnotes

1. Use at least 2 mol. EQ. of triethylamine.

2. Another way to get see example 103.

3. When the reaction as a co-solvent used dichloroethane.

4. The dihydrochloride of 3-(1H-imidazol-1-yl) azetidine used as the source Loretana on the way, described in the publication of international patent N WIPO 93/19059.

5. Receive (S)-enantiomer.

6. To bring the reaction to the end, and later add an additional amount of source of azetidine (approx. 1 mol. EQ. ), triethylamine (approx. 2 mol. EQ.) and tetrahydrofuran, and then add triacetoxyborohydride sodium (approx. to 1.5 mol. EQ.) and glacial acetic acid.

As eluent for column using methanol with dichloromethane.

7. Carry out elution with a gradient, using as eluent dichloromethane and then dichloromethane with methanol.

8. Elution with a gradient of exercise, using the first as eluent ethyl acetate and then ethyl acetate with methanol, and in the last stages of this mixture is replaced with a mixture of dichloromethane with methanol.

9. As the initial substance use bestrefiratecom 3-(4-aminosulphonylphenyl-1-yl)azetidine (see preparative example 154).

10. The crude reaction product is purified in the form of a salt triperoxonane acid by chromatography on silica gel, elwira a mixture of dichloromethane with methanol and 0,880 aqueous solution of ammonia (89:10:1, by volume). Refined salt is treated with 10% Wonkie layers dried (Na2SO4) and concentrated under reduced pressure, and get the right product.

11. Purify by chromatography with reversed phase, using MCI gel (trade mark) (highly porous polystyrene CHP 20P [75-150 μm]), using as eluent methanol and then the methanol with water.

12. Receive (R)-enantiomer.

13. As the initial substance use DATEFORMAT of azetidine.

14. The example for comparison purposes only.

15. As the initial substance use dihydrochloride of azetidine.

16. Elution with a gradient carried out, using as eluent dichloromethane and then dichloromethane with methanol and concentrated aqueous solution of ammonia.

17. []2D5+48,9o(c = 0,0009 in methanol).

Example 60

5-(3,4-Dichlorophenyl)-1-(3-methoxybenzyl)-5-(2-[3-morpholinomethyl - 1-yl] ethyl)-2-piperidin

< / BR>
To a solution of piperidine (see example 1) (350 mg, 0.85 mmol) in dry N,N-dimethylformamide (5 ml) under nitrogen atmosphere add 60% (W/V) dispersion of sodium hydride in oil (37 mg, of 1.05 mol. equiv.) and the mixture is stirred at room temperature for 30 minutes. Then add 3-methoxybenzylamine (0,13 ml of 1.05 mol. equiv.) and a mixture of AC is onata sodium (20 ml) and saturated aqueous solution of ammonium chloride (20 ml). The mixture is extracted with ethyl acetate (2 x 20 ml) and the combined organic layers washed with saturated aqueous ammonium chloride (2 x 20 ml) and then dried over magnesium sulfate. After filtration and removal of the filter of the solvent under reduced pressure to obtain resin, which chromatographic on silica gel, elwira with a gradient solvent of methanol with dichloromethane (1: 19 to 1:9, by volume). Get named in the title compound (140 mg).

HSC Rf= 0,45 (silica, methanol : dichloromethane, 1:9, by volume). ICSD m/z = 532 (m)+. Elem. analysis: found: C - 62,07; H - 6,74; N - 7,19. For C28H35Cl2N3O3= 1,50-2,90 (m, 16H), 3,25-of 3.80 (m, 7H), of 3.80 (s, 3H), 4,30 (d, 1H), 6,80-of 6.90 (m, 4H), 7,05 (d, 1H), 7,25-7,30 (m, 2H) ppm.

Examples 61 through 75

Compounds of General formula:

< / BR>
the examples listed below in table. 2, receives a manner similar to the method of example 60 (with heating of the reaction mixture, if necessary), using as starting compounds corresponding piperidone (see example 1) and chlorine-, bromine - or methanesulfonanilide derivatives.

Footnotes

1. Two pairs of enantiomers in the product obtained after treatment, divided by chromatography on silica gel, e is Erna pair And, and then the more polar enantiomeric pair b

2. As the initial substance use chloroalkane derived.

3. As the initial substance use bromaline derived.

4. As the initial substance use methanesulfonanilide derived.

Example 76

1-Cycloheptylmethyl-5-(3,4-dichlorophenyl)-5-(2-[3-morpholinomethyl - 1-yl] ethyl)-2-piperidin

< / BR>
To a solution of piperidine (see example 1) (200 mg, 0.49 mol) in dry N,N-dimethylformamide (3.5 ml), at 0oC and in an atmosphere of nitrogen was added 60% (W/V) dispersion of sodium hydride in oil (21 mg, 1,1 mol. equiv.) and the mixture was allowed to warm to room temperature over 1 hour. Then add a solution of methysulfonylmethane (see preparative example 13) (120 mg, 1,2 mol. EQ. ) in dry N,N-dimethylformamide (0.5 ml) and the mixture heated to 50oC. To implement the full interaction of initial piperidone the mixture is cooled, then add a further portion of sodium hydride (0,5 mol. EQ.) original nelfinavir 0,5 mol. equiv.) and the reaction mixture is warm at 50oC for 2 hours. The reaction mixture was cooled to 0oC, add water (1 ml) and remove the dimethylformamide at pomagne. After filtration and removal of the filtrate solvent under reduced pressure get the foam, which chromatographic using silica gel, elwira with a gradient solvent of dichloromethane with methanol (from 100:0 to 85:15, by volume), and get named in the title compound (120 mg).

HSC Rf= 0,45 (silica, methanol:dichloromethane, 1:9, by volume). ICSD m/z = 522 (m+1)+. Elem. analysis: found: C - 62,11; H - 7,63; N - 7,55. For C28H41Cl2N3O2= of 1.1-1.3 (m, 2H), of 1.35 to 1.8 (m, 11H), 1,8-of 1.95 (m, 2H), 1,95-2,1 (m, 1H), 2,1 to 2.35 (m, 7H), 2,35-2,5 (m, 1H), 2,75-2,95 (m, 2H), 2.95 points to 3.0 (m, 2H), 3,05-3,2 (m, 2H), of 3.25 to 3.45 (m, 2H), 3.45 points and 3.6 (m, 2H), 3,6-of 3.75 (m, 4H), 7,05 to 7.1 (m, 1H), and 7.3-7,35 (m, 1H), 7,4 was 7.45 (m, 1H) ppm.

Example 77

5-(3,4-Dichlorophenyl)-5-(2-[3-morpholinomethyl-1-yl] ethyl)-1-(4 - phenylbenzyl)-2-piperidin

< / BR>
To a solution of nelfinavir (see preparative example 35) (290 mg, 0.55 mmol) in dry acetonitrile (10 ml) add the dihydrochloride of 3-morpholinoethyl (see preparative example 56) (200 mg, 2,0 mol. equiv.) then add triethylamine (0.15 ml, 2 mol. EQ.) and potassium carbonate (150 mg, 2 mol. EQ.). The mixture is refluxed for 4 hours. After that the reaction mixture is cooled, add water (1 ml), the mixture is evaporated to dryness under reduced pressure, and the residue treated over magnesium sulfate, filtered and from the filtrate under reduced pressure to remove the solvent. Get the resin, which chromatographic on silica gel, elwira with a gradient solvent of methanol with dichloromethane (1: 19 to 1:9, by volume, and get named in the title compound (85 mg).

HSC Rf= 0,47 (silica, methanol:dichloromethane, 1:9, by volume), so pl. 72-82oC. ICSD m/z = 578 (m+1)+. Elements. analysis: found: C - 67,56; H - 6,27; N - 7,24. For C33H37Cl2N3O2= 1,5-1,8 (m, 3H), 1,95-2,3 (m, 8H), from 2.4 to 2.55 (m, 1H), 2,6-of 2.75 (m, 2H), 2,8-2,9 (m, 1H), 3,3-to 3.35 (m, 3H), 3,55-3,7 (m, 5H), 4,4 (d, 1H), 4,9 (d, 1H), 6,85-6,9 (m, 1H), and 7.1 (s, 1H), 7,25 to 7.7 (m, 10H) ppm.

Examples 78 96

Compounds of General formula:

< / BR>
the examples listed below in table. 3, receives a manner similar to the method of example 77, using as starting compounds corresponding mesilate (see preparative examples 33, 34, 36, 37 and 38) and the corresponding azetidin (see preparative examples 56, 68, 77, 81, 82, 83, 86, 87, 88, 119, 134, 154, 179 and 181).

Footnotes

1. In the reaction using 3 mol. EQ. derived azetidine as the original substance, and 3 mol. EQ. of triethylamine.

2. As the initial substance use DATEFORMAT of azetidine.

3. Instead of triethylene acceptor acid is used to 2.5 mol. EQ. potassium carbonate.

5. As the initial substance use dihydrochloride of azetidine.

Example 97

1-Benzyl-5-(2-[3-morpholinomethyl-1-yl]ethyl)-5-phenyl-2-piperidin

< / BR>
Piperidone (see example 18) (95 mg, 0.2 mmol) dissolved in ethanol saturated with ammonia (20 ml), and added Raney Nickel (10 mg). The mixture is then stirred at 50oC in an atmosphere of hydrogen at a pressure of 345 kPa (50 f/d2within 10 hours. The catalyst was then removed by filtration and added 5% palladium-on-coal (10 mg). The mixture was then stirred for 16 hours at 50oC and a pressure of 345 kPa in an atmosphere of hydrogen. Then the catalyst is removed by filtration, the filtrate is concentrated under reduced pressure, and the residue chromatographic using silica gel, elwira with a gradient solvent of methanol with dichloromethane (0:100 to about 9:91, by volume), and get named in the title compound (19 mg).

HSC Rf= 0,3 (silica, methanol:dichloromethane, 1:9, by volume). ICSD m/z = 434 (m)+. Elem. analysis: found: C - 66,22; H compared to 8.26; N is at 8.60. For C27H35N3O23H2O calculated: C - 66,50; H - of 8.47; N - 8,62%.

1H NMR (CDCl3: = 0,8-1,0 (d, 2H), 1.1 to 1.4 (m, 1H), 1,9-2,6 (m, 12H), 2,6-2,8 (m, 1H), 3,2-3,4 (m, 2H), 3.5 to 3.8 (m, 5H), 4,5 (e) - Rev.-1-yl] ethyl - 2-piperidone

< / BR>
To a solution of piperazine (see example 7) (101 mg, 0.16 mmol) in dry dichloromethane (3.5 ml), in an atmosphere of hydrogen at room temperature quickly add triperoxonane acid (3.5 ml, 45 mmol). The reaction mixture was stirred for 20 minutes and then under reduced pressure to evaporate the solvent. To remove excess triperoxonane acid from the reaction mixture, the reaction mixture was twice subjected to the azeotropic distillation using dichloromethane (50 ml). The reaction mixture is alkalinized (pH 9) using a saturated aqueous solution of sodium carbonate (30 ml) and the aqueous phase extracted with ethyl acetate (4 x 50 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting foam was dissolved in dichloromethane (0.25 ml), filter the solution and remove the solvent from the filtrate under reduced pressure. Get named in the title compound (88 mg).

HSC Rf= 0,16 (silica, methanol : dichloromethane : COC. aq. the ammonia solution, 9:90:1, by volume). ICSD m/z = 467 (m)+. Elem. analysis: found: C - 55,15; H - 5,74; N - 6,84. For C27H34N4Cl2O = 1.2 to 1.3 (m, 1H), is 1.4-1.6 (m, 2H), 1,9-2,3 (m, 6H), of 2.3-2.5 (m, 4H), 2,7-2,8 (m, 2H), 2,9-of 3.25 (m, 2H), 3,25 (d, 1H), 3,3-chlorphenyl)-5-(2-[3-morpholinomethyl - 1-yl]ethyl)-2-piperidin

< / BR>
To a solution of powdered potassium hydroxide (110 mg, 4 mol. EQ. ) in dry dimethylsulfoxide (4 ml), under stirring, add a solution of piperidine (see example 1) (200 mg, 0.49 mmol) in dry dimethylsulfoxide (4 ml) and then add 2,4-DICHLOROSILANE (0,068 ml, 1 mol. EQ.) and potassium iodide (8 mg, 0,1 mol. EQ.). The mixture is then stirred at room temperature for 16 hours. Then add ethyl acetate (50 ml), the mixture washed with water (3 x 50 ml) and the organic phase is dried over anhydrous magnesium sulfate. Then the solution is filtered, the solvent removed from the filtrate under reduced pressure, the residue chromatographic using silica gel, elwira with a gradient solvent of ethyl acetate with methanol and diethylamine (from 100:0:0 to 100:5:1, by volume).

Get named in the title compound (49 mg).

ICSD m/z = 572 (m+1)+.

1H NMR (CDCl3): = of 1.55 to 1.8 (m, 2H), 1,95-2,3 (m, 10H), 2,4-2,5 (m, 1H), 2,65 is 2.7 (m, 1H), 2,85 is 2.9 (m, 1H), 3,3-3,4 (m, 3H), up 3.6-3.7 (m, 5H), 4,6 (d, 1H), around 4.85 (d, 1H), 6,9-to 6.95 (m, 1H), 7,05 (m, 1H), of 7.2 to 7.4 (m, 4H) ppm.

Example 100

5-(3,4-Dichlorophenyl)-1-(4-terbisil)-5-(2-[3-morpholinomethyl - 1-yl]ethyl)-2-piperidin

< / BR>
To dry dimethylsulfoxide (3 ml) at room temperature add powdered hydrox is the target of piperidone (see example 1) (240 mg, 0.46 mmol) in dimethyl sulfoxide (5 ml), and then add 4-florantyrone (0,058 ml, 1 mol. equiv.) and the mixture is stirred at room temperature for 50 minutes. Then the reaction mixture was poured into ethyl acetate (40 ml), washed with water (3 x 40 ml) and the organic phase is dried over anhydrous magnesium sulfate. Then the solution was filtered and from the filtrate under reduced pressure to remove the solvent, and the residue chromatographic on silica gel, elwira with a gradient solvent of ethyl acetate with methanol and diethylamine (from 100:0:0 to 10:1:2 and 20:3:1, by volume). Get named in the title compound (100 mg).

ICSD m/z = 521 (m+1)+. TXC Rf= 0,4 (silica, ethyl acetate:methanol: diethylamine 20: 30:1, by volume). Elem. analysis: found: C - 61,46; H - 6,27; N - 7,55. For C27H32Cl2N3O2F calculated: C - 62,31; H - 6,20; N - 8,07%.

1H NMR (CDCl3): a = 1,5-of 1.85 (m, 4H), 1,95-2,2 (m, 8H), 2,6-of 2.75 (m, 2H), 2,8-2,9 (m, 1H), 3,15-to 3.35 (m, 4H), 3,65 of 3.75 (m, 4H), 4,3 (d, 1H), and 4.8 (d, 1H), 6,8-of 7.3 (m, 7H) ppm.

Examples 101 and 102

Connect two are summarized in the following table. 4 examples having the General formula:

< / BR>
get a manner similar to the method of example 100 using as starting compounds the same piperidone and 3,5-di-(triform"ptx2">

Example 103

1-Benzyl-5-(3,4-dichlorophenyl)-5-(2-[3-(1-oxathiolane)- azetidin-1-yl]ethyl)-2-piperidin

< / BR>
It chilled with ice to a solution of methanol (7 ml), thiomorpholine (see example 2) (0,76 ml, 1.0 mol. equiv.) acetonitrile (0.09 g, 1,5 mol. EQ.) and potassium carbonate (0,147 g to 0.72 mol. EQ.) add, within 30 minutes, 30% (V/o) hydrogen peroxide solution in water (0,175 g of 1.05 mol. EQ.) in methanol (5 ml). The reaction mixture was stirred at 0oC for 2 hours and then allow to warm to room temperature and stirred for 16 hours. Then remove most of the solvent under reduced pressure at room temperature. Add saturated aqueous sodium bicarbonate solution (20 ml) and the mixture extracted with ethyl acetate (CH ml). The combined organic layers are dried over magnesium sulfate and evaporated under reduced pressure. The resulting oil is purified column flash chromatography on silica gel, elwira methanol with dichloromethane (1:9, by volume), and get named in the title compound (121 mg).

HSC Rf= 0,10 (silica, methanol: dichloromethane, 1 : 9, by volume). ICSD m/z = 534 (m+1)+. Elem. analysis: found: C - 57,91; N Is 5.77; N - 7,58. For C27H33N3Cl2O2S 0,37 CH2Cl

Example 104

1-Benzyl-5-(3,4-dichlorophenyl)-5-(2-[3-(endo-3-hydroxy-8 - azabicyclo[3,2,1] Oct-8-yl)-azetidin-1-yl]ethyl)-2-piperidin

< / BR>
A mixture of piperidine (see example 24) (78 mg), 6N aqueous sodium hydroxide solution (0.5 ml) and methanol (1.5 ml) was stirred at room temperature for 16 hours. The solution is concentrated under reduced pressure, and then water is added (5 ml) and dichloromethane (10 ml). The layers separated, and the aqueous phase is then extracted with dichloromethane (2x10 ml). The combined organic layers dried over anhydrous sodium sulfate and then filtered. Remove the solvent from the filtrate under reduced pressure, and get named in the title compound as a white foam (67 mg).

ICSD m/z = 543 (m+1)+. Elem. analysis: found: C - 62,15; N - 6,11; N - 7,43. For C30H39Cl2N3O 0,56 CH2Cl2calculated: C - 62,40; H - 6,87; N - 7.16 percent.

1H NMR (CDCl3): a = 1,5 - 2,2 (m, N), 2,4 - 2,5 (m, 1H), 2,6 - 2,7 (m, 2H), 2.95 and (W, s, 2H), 3,1 - 3,2 (m, 1H), of 3.25 to 3.35 (m, 3H), 3,5 - 3,6 (m, 1H), 3.95 to of 4.05 (m, 1H), 4.2V (d, 1H), and 4.8 (d, 1H), 6.75 in-6,8 (m, 1H), and 7.1 (d, 1H), 7,2 - 7,4 (m, 6N) ppm.

Example 105

5(S)-1-Cyclopropylmethyl-5-(3,4-dichlorophenyl)-5-(2-[3-(piperazin is) add 10% (V/V) aqueous solution of sodium hydroxide (5,44 ml). The mixture is refluxed for 48 hours. Then remove the methanol by evaporation under reduced pressure, and the residue is acidified to pH 7 using 2N aqueous solution of hydrochloric acid. The mixture is extracted with dichloromethane (2x40 ml). The combined organic extracts evaporated to dryness under reduced pressure, and get named in the title compound as a white foam (0.5 g).

HSC Rf= 0,1 (silicon dioxide, conc. aq. ammonia solution : methanol : dichloromethane, 20 : 80 : 320, by volume). ICSD m/z = 465 (m)+.

1H NMR (CDCl3): = 0,2 - 0,4 (m, 2H), of 0.5 - 0.7 (m, 2H), 1,0 - 1,1 (m, 1H), 1,6 - 2,6 (m, 17H), 2,7 - 2,8 (m, 2H), 2,9 - 3,05 (m, 2H), 3,1 - 3,2 (m, 1H), 3,4 - 3,6 (m, 3H), 3,7 - of 3.85 (m, 1H), 7,1 - 7,2 (m, 1H), and 7.3 - 7.5 (m, 2H) ppm.

Example 106

5(S)-1-(2 - Cyclopropylethyl)-5-(2-[3-(4-cyclopropylmethyl - aminopiperidin-1-yl)azetidin-1-yl]ethyl)-5-(3,4-dichlorophenyl)-2 - piperidin

< / BR>
To a solution of compound of example 115 (0.1 g, 0.11 mmol) in tetrahydrofuran (3 ml) under nitrogen atmosphere add cyclopropanecarboxaldehyde (8 mg) and triethylamine (0,017 ml). After stirring for 5 minutes add triacetoxyborohydride sodium (32 mg) and glacial acetic acid (0,007 ml) and the reaction mixture stirred at room temperature for 16 hours. The reactions/V) aqueous solution of sodium carbonate (4 ml). The layers separated, and the aqueous phase extracted with dichloromethane (2x10 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filter and remove the solvent from the filtrate by evaporation under reduced pressure. The remainder chromatographic on silica gel, elwira dichloromethane with methanol and concentrated aqueous ammonia (89 : 10 : 1, by volume). Get named in the title compound (37 mg).

HSC Rf= 0,18 (silica, dichloromethane : methanol : conc. the ammonia solution, 89 : 10 : 1, by volume). ICSD m/z = 547 (m+1)+.

1H NMR (CDCl3): a = 0.1 to 0.15 (m, 4H), and 0.4 - 0.5 (m, 4H), of 0.6 - 0.7 (m, 1H), 0.9 to 1.0 (m, 1H), 1,25 - 1,4 (m, 2H), 1,45 to 1.7 (m, 4H), about 1.75 to 1.9 (m, 5H), 1,95 - 2,2 (m, 5H), 2,3 at 2.45 (m, 4H), 2,6 - 2,7 (m, 4H), 2,8 - 2,9 (m, 1H), 3,3 - 3,4 (m, 4H), of 3.5 - 3.7 (m, 2H), 7,0 - 7,4 (m, 3H) ppm.

Examples 107 and 108

Connect two of the following, given in the table. 5 examples having the General formula:

< / BR>
get a manner similar to the method of example 106, using as starting compounds corresponding amine (see examples 105 and 113) and cyclopropanecarboxaldehyde.

Example 109

DATEFORMAT 5(S)-5-(2-[3-(4-aminosulphonylphenyl-1 - yl)azetidin-1-yl]ethyl)-1-(5-carboxypentyl)-5-(3,4-dichlorophenyl)-2 - piperidone

< / BR>
To a solution of xunwu acid (0.05 ml). The mixture is stirred for 2 hours at room temperature. The solvent dichloromethane is removed under reduced pressure, and get the pitch, which crystallizes after processing diethyl ether and after filtration get named in the title compound as a white solid (20 mg).

HSC Rf= 0,48 (silica, methanol : dichloromethane, 1 : 9, by volume). ICSD m/z = 604 (m+1)+. Elem.analysis: found: C - 42,47; N - 4,73; N - of 7.90. For C26H39Cl2N5O5S 2CF3CO2H H2O calculated: C - of 42.46; H - 4,88; N is 8.25%.

Example 110

5-(2-[3-(4-Carboxypeptidase-1-yl)-azetidin-1-yl] ethyl)-1 - cyclohexylmethyl-5-(3,4-dichlorophenyl)-2-piperidin

< / BR>
To a solution of compound of example 95 in ethanol (1 ml) is added 1N aqueous sodium hydroxide solution (to 0.24 ml), and the mixture is stirred at room temperature for 16 hours. The ethanol is removed under reduced pressure and to the residue is added water (1 ml). Bring the pH to 5 using 2N aqueous hydrochloric acid solution, and get the oil, which crystallized upon scratching. The resulting solid is filtered off, treated with water (2x3 ml) and then diethyl ether (3x3 ml), then dried with UP>+
. Elem. analysis: found: C - 55,80; N - 7,14; N - 6,44. For C29H41N3Cl2O30,75 H2O NaCl calculated: C - 55,95; N - 6,88; N to 6.75%.

Example 111

5-(S)-(2-[3-(4-Carboxypeptidase-1-yl)-azetidin-1-yl] ethyl)-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidin

This compound is obtained by the method similar to the method of example 110 using as the starting material the corresponding methyl ester (see example 59) and 3.8 mol. EQ. an aqueous solution of sodium hydroxide. ICSD m/z = 508 (m)+.

Example 112

Tretreetterreter 5(S)-5-(2-[3-(4-aminopiperidin-1-yl)-azetidin-1 - yl]ethyl)-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidone

< / BR>
To a solution of compound of example 48 (1.4 g, 24,1 mmol) in dichloromethane (20 ml), at +4oC and under nitrogen atmosphere, add triperoxonane acid (6.6 ml) and the reaction mixture stirred at room temperature for 1 hour. The solvent and excess triperoxonane acid is removed under reduced pressure, and get named in the title compound (907 mg). ICSD m/z = 479 (m+1)+.

Examples from 113 to 115 of the

The link given below, are summarized in table. 6 examples having the General formula:

< / BR>
get a manner similar to the method of example 112, using the S="ptx2">

Example 116

Tretreetterreter 5-(2-[3-(4-aminopiperidin-1-yl)-azetidin-1-yl] ethyl)-1-cyclohexylmethyl-5-(3,4-dichlorophenyl)-2 piperidone

< / BR>
To a solution of compound of example 96 (0,53 g, 0.85 mmol) in dichloromethane (5 ml), at 0oC and under nitrogen atmosphere, gradually add triperoxonane acid, and the solution was stirred at room temperature for 1 hour. Excess triperoxonane acid and dichloromethane is removed under reduced pressure, the residue is treated with dichloromethane (5 ml) and remove the solvent under reduced pressure. The residue is treated with diethyl ether, filtered, and the obtained solid is quickly washed with diethyl ether, then dried under reduced pressure at 70oC and get named in the title compound (580 mg). ICSD m/z = 522 (m+1)+.

H1NMR (CDCl3)/ d6-DMSO: = 0,75 - 0,9 (m, 2H), 0,95 - 1,1 (m, 3H), 1,35 - 4,0 (m, N), 6,95 approximately-7.0 (m, 1H), 7,15 - 7,20 (m, 1H), 7,30 - 7,35 (m, 1H), 8,35 (W, s, 2H) ppm.

Example 117

1-Cyclohexylmethyl-5-(3,4-dichlorophenyl)-5-(2-[3- (4-methanesulfonamido-1-yl)azetidin-1-yl]ethyl)-2-piperidin

< / BR>
To a solution of compound of example 116 (0,29 g, 0.34 mmol) and triethylamine (0,23 ml) in dichloromethane (6 ml), at 0oC and under nitrogen atmosphere, add methansulfonate pressure, the residue is dissolved in ethyl acetate (30 ml) and washed with 1% (V/V) aqueous solution of sodium bicarbonate (5 ml). The organic phase is dried using anhydrous magnesium sulfate, filtered, and removed solvent from the filtrate under reduced pressure, and get the oil. This oil chromatographic on silica gel, elwira methanol with dichloromethane (1 : 9, by volume), and get named in the title compound (85 mg).

HSC Rf= 0,25 (silica, methanol : dichloromethane, 1 : 9, by volume).

1H NMR (CDCl3): = 0,9 - 1,1 (m, 2H), 1,15 - 1,30 (m, 3H), 1,45 was 2.25 (m, 19H), 2,30 - to 2.40 (m, 1H), 2,55 is 2.7 (m, 4H), 3,8 - 3,9 (m, 1H), 2.95 and (s, 3H), 3,1 - 3,2 (m, 1H), 3,3 - 3,4 (m, 5H), 3,5-3,6 (m, 1H), 4,1-to 4.15 (m, 1H), a 7.1 to 7.15 (m, 1H), 7,3 was 7.45 (m, 2H) ppm.

Example 118

5(S)-1-Cyclopropylmethyl-5-(3,4-dichlorophenyl)-5-(2-[3-( 4-methanesulfonamido-1-yl)azetidin-1-yl]ethyl)-2-piperidin

Named the title compound is obtained by the method similar to the method of example 117, using as the starting material the appropriate aminopiperidin (see example 112).

ICSD m/z = 557 (m+1)+.

1H NMR (CDCl3): = 0,25 - 0,35 (m, 2H), 0,5 - 0,65 (m, 2H), 0,8 - 1,1 (m, 3H), 1.2 to about 1.35 (m, 3H), of 1.5 - 1.7 (m, 3H), 1.8 - 2.4m (m, N), 2,6 - 2,8 (m, 3H), 2,85 - 3,0 (m, 3H), 3,1 - 3,2 (m, 1H), 3.25 to 3.5mm (m, 4H), of 3.7 - 3.8 (m, 1H), 4,15 - 4,2 (m, 1H), and 7.1 to 7.4 (m, 3H) ppm.


< / BR>
To a solution of compound of example 105 (100 mg, 0.2 mmol) in dichloromethane (3 ml) at room temperature and under nitrogen atmosphere, add trimethylsilyltriflate (to 0.032 ml), and the mixture is stirred at room temperature for 16 hours. The solvent is removed under reduced pressure and the product purified column chromatography using silica gel, elwira dichloromethane with methanol and concentrated aqueous ammonia (89 : 10 : 1, by volume). Get named in the title compound (69 mg).

HSC Rf= 0,25 (silica, dichloromethane : methanol : conc. the ammonia solution, 89 : 10 : 1, by volume). ICSD m/z = 508 (m+1)+.

1H NMR (CDCl3): = 0,25 - 0,4 (m, 2H), 0,55 - 0,7 (m, 2H), 0,95 - 1,1 (m, 1H), 1,6-1,9 (m, 2H), 1,95 - 2,4 (m, 10H), 2,7 - of 2.75 (m, 2H), 2,9 - 2,95 (m, 1H), 3,1 - 3,2 (m, 1H), 3,35 - 3,5 (m, 8H), of 3.7 - 3.8 (m, 1H), 4,4 (W, s, 2H), and 7.1 to 7.4 (m, 3H) ppm.

Example 120

5(S)-5-(2-[3-(4-Acetamidophenyl-1-yl)azetidin-1-yl]ethyl)-1 - cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidin

< / BR>
To a solution of compound of example 112

(300 mg, 3.65 mmol) and triethylamine (255 μl) in dichloromethane (40 ml) at room temperature and under nitrogen atmosphere, add acetic anhydride (4 ml) and the reaction mixture stirred for 18 hours. Then add an additional one (I ml), and then brine (30 ml). The combined organic layers are dried using anhydrous magnesium sulfate, and then evaporated under reduced pressure, and receives a yellow oil. This oil is dissolved in ethyl acetate (40 ml) and extracted with 2N hydrochloric acid (g ml). The combined acidic aqueous extracts alkalinized saturated aqueous sodium bicarbonate, and the aqueous layer was extracted using ethyl acetate (CH ml). The combined organic layers are dried using anhydrous sodium sulfate. The solvent is removed under reduced pressure, and get named in the title compound (53 mg).

HSC Rf= 0,1 (silica, methanol : dichloromethane, 1 : 9, by volume). ICSD m/z = 629 (m)+.

1H NMR (CDCl3): = 0,2 - 0,4 (m, 2H), of 0.5 - 0.7 (m, 2H), 0,95 - 1,05 (m, 1H), 1,3 - 1,4 (m, 2H), 1.5 and 1.7 (m, 1 H), 1,75 -2,2 (m, 13H), 2.3 to 2.4 (m, 1H), 2.5 and 2.7 (m, 4H), 2.95 and (t, 1H), 3,05 - 3,1 (m, 1H), 3,4 - 3,6 (m, 4H), of 3.8 (d, 2H), and 5.2 (s, 1H), and 7.1 (d, 1H), 7,35 to 7.4 (m, 2H) ppm.

Examples 121 and 122

Connect two are summarized in the following table. 7 examples having the General formula: -

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get a manner similar to the method of example 120, using as the starting material the appropriate piperazine (see example 105) and the corresponding allerease agent.

2. As Alliluyeva agent use acetylchloride.

3. As Alliluyeva agent use the anhydride triperoxonane acid.

Example 123

5(S)-5-(2-[3-(4-Aminosulphonylphenyl-1-yl)azetidin-1-yl] ethyl)-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidin

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(a) 4(S)-4-Cyano-4-(3,4-dichlorophenyl)-5-(1,3-dioxolane-2-yl) pentane-1-OIC acid

To a 1.0 M solution hexamethyldisilazide lithium in tetrahydrofuran (4,69 l), 5oC and under nitrogen atmosphere, is added dropwise within 45 minutes, a solution of 3,4-dichlorobenzonitrile (750 g, 4,28 mol) in tetrahydrofuran (750 ml). The reaction mixture is stirred for 2 hours. The reaction mixture is again cooled to 5oC and added dropwise over 50 minutes, add a solution of 2-methyl bromide-1,3-dioxolane (782 g) in tetrahydrofuran (780 ml). Add portions, iodide, Tetra-n-butylamine (75 g), and the mixture allow to warm to room temperature and stirred for 14 hours. Then the reaction mixture is cooled to 5oC and added dropwise 1.0 M solution hexamethyldisilazide lithium in tetrahydrofuran (4,69 l). The mixture is stirred for 5 hours at room temperature. The solution is cooled to 5oC and ka is stirred for 14 hours. The reaction mixture is cooled to 5oC and add 1.5 M aqueous solution of sodium hydroxide (containing 255 g of sodium hydroxide, and the mixture is stirred for 14 hours. Add water (5 l), and the mixture is extracted with ethyl acetate (2x3 l). The combined organic extracts washed with water (2x5 l). The aqueous phases are combined and acidified to pH 1 with 5N hydrochloric acid, and then extracted with ethyl acetate (2 x 3 l). The combined organic extracts are concentrated under reduced pressure to a concentration of approximately 3 ml/g (theoretical yield).

The above experimental procedure is then repeated in an identical scale.

To the combined organic solutions from both reactions add (S)-(-)-alpha-methylbenzylamine (1.13 kg), and the mixture is stirred for 14 hours. The thick slurry is then stirred while cooling in an ice bath for 2 hours, filtered, the solid washed with ethyl acetate (2x1 l) and then dried under reduced pressure at 35oC, and get 1,85 kg of substance.

Part of this substance (1.34 kg) dissolved in a mixture of butanone (2 l) and water (503 ml) by boiling under reflux. Add an extra amount of butanone (4,7 l), and rest filtered off (the filtrate used in preparative example 192), washed with butanone (2x1 l) and dried under reduced pressure at 35oC for 10 hours. Receive 563 g of substance (purity level (E. E.) 93,8%). Additional recrystallization from butanone and water yields named in the title compound in the form of salt (S)-(-)-alpha-methylbenzylamine with E. E. 99,8%. To a solution of this salt in ethyl acetate and water, with stirring, add 5N hydrochloric acid to achieve a pH of 1. The mixture is stirred for 30 minutes, the layers separated, and the aqueous phase extracted with ethyl acetate. The combined organic layers washed with water, and removing the solvent by evaporation under reduced pressure. Get named in the header of the connection.

1H NMR (CDCl3): = of 2.05 to 2.35 (m, 4H), from 2.4 to 2.65 (m, 2H), 3,7 - 4,0 (m, 4H), 4.75 V - is 4.85 (m, 1H), 7,25 - of 7.55 (m, 3H), 9,9 (s, W, 1H, acid) ppm.

(b) 5(S)-5-(3,4-Dichlorophenyl-5-(1,3-dioxolane-2-ylmethyl)-2(1H)- piperidin

To a solution of compound of example 123(a) (13.5 g, to 39.22 mmol) in glacial acetic acid (130 ml) is added platinum oxide (1,21 g), and the mixture is stirred in hydrogen atmosphere at 414 kPa (60 f/d2) and at room temperature for 17 hours. The catalyst was removed by filtration, and add additional portion of platinum oxide (1,21 g). The reaction mixture is then stirred in atmostaties, and concentrate the solution under reduced pressure. The residue is dissolved in ethyl acetate (80 ml) and washed with saturated aqueous sodium bicarbonate (2 x 75) ml Then the organic phase is separated, and remove the solvent under reduced pressure. The resulting solid is stirred in hexane solution (20 ml) and ethyl acetate (20 ml) for 2 hours at 0oC, then filtered off, and get named in the title compound (8,15 g).

1H NMR (CDCl3): = 1,85 - of 1.95 (m, 1H), a 2.0 to 2.25 (m, 4H), 2,35 - 2,4 (m, 1H), 3,45 - 3,55 (m, 1 H), 3,65 of 3.75 (m, 2H), 3,8 - 3,9 (m, 3H), 4,35 - 4,4 (m, 1H), x 6.15 (s, W, 1H), 7,2 was 7.45 (m, 3H) ppm.

(C) 5(S)-1-Cyclopropylmethyl-5-(3,4-dichlorophenyl-5-(1,3-dioxolane - 2-ylmethyl)-2-piperidin

To a solution of compound of example 123 (b) (38,6 g, 117 mmol) in dimethyl sulfoxide (190 ml) is added potassium hydroxide (19.7 g) and the mixture was stirred at room temperature for 20 minutes. Then within 20 minutes add bromelicola (17,37 g), and the reaction mixture was stirred for 140 minutes. The reaction mixture was poured into a mixture of ice (100 g) with water (900 ml) and the mixture extracted with dichloromethane (I ml). The combined organic layers washed with water (400 ml), and remove the solvent under reduced pressure. Get the), 1,9 - of 1.95 (m, 1H), a 2.0 to 2.25 (m, 4H), 2,35 at 2.45 (m, 1H), 3,15 - 3,2 (m, 1H), 3,5 - 3,55 (m, 2H), 3,65 of 3.75 (m, 2H), 3,9 - 4,0 (m, 3H), 4,35 - 4,4 (m, 1H), 7,2 - 7,5 (m, 3H) ppm.

(d) 5(S)-1-Cyclopropylmethyl-5-(3,4-dichlorophenyl)-5-formylmethyl - 2-piperidin

To a solution of compound of example 123 (C) (73,16 g, 190 mmol) in tetrahydrofuran (730 ml) in 5oC for 20 minutes, add 5N hydrochloric acid (730 ml). The reaction mixture was stirred at room temperature for 17 hours. The tetrahydrofuran is removed under reduced pressure, the residue diluted with water (200 ml) and extracted with ethyl acetate (2x500 stretch-forming press ml). The combined organic layers are then washed with water (500 ml), and remove the solvent under reduced pressure. Get named in the title compound (62,1 g).

1H NMR (CDCl3): = 0,25 - 0,35 (m, 2H), 0,55 - 0,65 (m, 2H), 1,05 - 1,1 (m, 1H), 2,15 was 2.25 (m, 3H), 2,35 - 2,5 (m, 1H), 2,65 is 2.75 (m, 1H), 2.95 and was 3.05 (m, 1H), 3,15 - 3,2 (m, 1H), 3.45 points and 3.6 (m, 2H), 3.95 to 4.0 a (m, 1H), 7,2 was 7.45 (m, 3H), and 9.5 (s, 1H) ppm.

(e) 1-Aminosulfonyl-4-benzylpiperazine

A solution of 1-benzylpiperazine (5 g, 28.4 mmol) and sulphonamide (2, 77 g) in 1,4-dioxane (25 ml) is refluxed for 24 hours. The solution is cooled and poured into water (100 ml). The solid is filtered off, washed with toluene (100 ml) and dried under reduced pressure. Get title (s, 2H), 7,25 - to 7.35 (m, 5H) ppm.

(f) 1-Aminosulphonylphenyl

A mixture of compound of example 123 (e) (20 g, to 78.3 mmol) and 10% (V/V) of palladium-on-coal (4 g) in ethanol (140 ml) is stirred in hydrogen atmosphere at 345 kPa (50 f/d2and if 50oC for 23 hours. The catalyst was removed by filtration and washed with ethanol (100 ml). The filtrate is concentrated under reduced pressure to a volume of approximately 40 ml, and the suspension is maintained at 0-5oC for 12 hours. The solid is filtered off and receive the first portion of the compound (2 g). Previously separated catalyst is refluxed in ethanol (150 ml). The mixture is filtered while hot, and the pad washed with ethanol (50 ml). The solvent is removed under reduced pressure. The solid is stirred with acetone (100 ml) and filtered receive the second portion named the title compound (8 g).

1H NMR (d6-DMSO): = 2,3 - 2,9 (m, N), of 6.65 (s, W, 1H) ppm.

(g) 1-Aminosulfonyl-4-(1-diphenylethylamine-3-yl)-piperazine

A solution of 1-diphenylmethyl-3-methanesulfonanilide (see preparative example 54) (4.8 g, 15.1 mmol) and 1-aminomethylpyridine (see example 123 (f) (5 g) in acetonitrile (50 ml) is refluxed for rat concentrated under reduced pressure, and the residue is washed with hot toluene (50 ml), cooled, the solid is filtered off and washed with toluene (50 ml), then the product is optionally purified, mixing with hot ethyl acetate (3 ml), cooling and filtering, and get named in the title compound (0.47 in).

1H NMR (d6-DMSO): 2,25 - 2,3 (m, 4H), 2,7 - of 2.75 (m, 2H), 2,85 - 2,95 (m, 3H), 3,05 - 3,1 (m, 2H), 3,2 - of 3.25 (m, 2H), 4,4 (m, 1H), 6,7 (m, 2H), 7,15 to 7.4 (m, 10H) ppm.

(h) Dihydrochloride 1-aminosulfonyl-4-(azetidin-3-yl)-piperazine

To a solution of compound of example 123 (g) (15 g) in methanol (50 ml) is added 10% aqueous hydrochloric acid (9.4 ml) and Pearlman catalyst ((20% (V/Pd(OH)2-on-coal) (0.6 g). The mixture is shaken in hydrogen atmosphere using a rocking Parra, within 14 hours. Then the catalyst is removed by filtration, the filtrate is returned to the rocking chair Parra, and add an additional 0.6 g of Pearlman catalyst. The reaction mixture was shaken in a hydrogen atmosphere for 14 hours. The catalyst was removed by filtration and washed with water (100 ml). The filtrate is concentrated under reduced pressure. The residue is stirred with acetonitrile (50 ml) for 1 hour, and the mixture is left to stand for 14 hours. The solid is filtered off and dried under reduced pressure. P IS N), of 3.25 to 3.35 (m, 1H), 3.75 to a 3.9 (m, 4H), 6,8 (s, W, 2H) ppm.

i) 5(S)-5-(2-[3 (4-Aminosulphonylphenyl-1-yl) azetidin-1-yl]ethyl)-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidin

To a solution of compound of example 123 (h) (18,97 g) in tetrahydrofuran (140 ml) at room temperature is added triethylamine (18 ml) and the mixture stirred for 30 minutes. Then add a solution of the compound of example 123 (d) (20 g) in tetrahydrofuran (60 ml). After 2 hours the solution is cooled to 2oC, and add portions triacetoxyborohydride sodium (17,44 g), then add acetic acid (3,37 ml) and the reaction mixture was allow to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into water (50 ml) and add 10% (V/V) aqueous sodium bicarbonate solution to achieve a pH of 9. Add ethyl acetate (200 ml) and the layers separated. The aqueous phase is extracted with ethyl acetate (50 ml), the combined organic extracts are washed with 10% (V/V) aqueous solution of sodium bicarbonate (100 ml), and remove the solvent under reduced pressure. Get named in the header of the connection (of 28.27 g).

1H NMR for the compound of example 32.

Pharmacological results

Selected representatives of the compounds to prikurivatel with [125I] NKA when binding to membranes derived from cells of the Chinese hamster ovary expressing cloned human NK2-receptor (method a), and by their ability to counteract the contractile action [ Ala8] NKA(4-10)in the pulmonary artery of the rabbit (method), in accordance with the methods described in SS. 46 and 48 of the description.

The results are shown in table. 8.

The following preparative examples illustrate some of the original substances used in the synthesis of compounds of the preceding examples.

Preparative example 1

2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)Botanical

To a mixture of 60% (V/V) dispersion of sodium hydride in oil (19,24 g of 1.05 mol. EQ.) in dry tetrahydrofuran (450 ml), at 0oC and under nitrogen atmosphere, is added dropwise within 40 minutes, a solution of 3,4-dichlorobenzonitrile (89,5 g, 1 mol. EQ.) in dry tetrahydrofuran (450 ml). Even after 30 minutes, add a solution of 2-prematureejaculation (100 g, 1 mol. EQ.) in tetrahydrofuran (100 ml) and the mixture was allowed to warm to room temperature and stirred for 14 hours. Add 30% aqueous solution of ammonium chloride (500 ml) and the mixture extracted with diethyl estuarial under reduced pressure. The residue is then chromatographic using silica gel, elwira with a gradient solvent of diethyl ether and hexane (1 : 9 to 1 : 1, by volume), and get named in the title compound (51 g).

HSC Rf= 0,55 (silicon dioxide, methyl tertiary butyl ether : hexane, 1 : 1, by volume). ICSD m/z = 333 (m+NH4)+.

1H NMR (CDCl3): = of 1.5 - 1.9 (m, 6N), 2,05 - 2,3 (m, 2H), from 2.4 to 2.65 (m, 2H), 2.8 to 2.95 and (m, 2H), 4,0 - 4,1 (m, 1H), 4,5 - 4,6 (m, 1H), 7,2 - 7,25 (m, 1H), of 7.25 - 7.5 (m, 2H) ppm.

Preparative example 2

Ethyl-4-cyano-4-(3,4-dichlorophenyl)-6-(tetrahydropyran-2-yl-oxy) hexanoate

To a solution of Diisopropylamine (15 ml, of 0.77 mol. EQ.) in tetrahydrofuran (80 ml) at -78oC and under nitrogen atmosphere, add n-utility (77,3 ml of 2.5 M solution in hexane, 1,4 mol. equiv.) and then allow the solution to warm to room temperature for 2 hours. The solution is cooled to -78oC and slowly add a solution of the compound of preparative example 1 (43,9 g, 138 mmol) in tetrahydrofuran (180 ml). The resulting solution enable gradually over 2 hours to warm to room temperature. Then the solution is cooled to -78oC, and add dropwise a solution of ethyl-3-bromopropionate (22,36 ml of 1.3 mol. EQ.) in terriost to warm to room temperature and stirred for 14 hours. Then add water (10 ml) and the solution concentrated under reduced pressure. Add water (400 ml) and brine (400 ml) and the mixture extracted with ethyl acetate (2x500 stretch-forming press ml). The combined organic layers washed with water (I ml), dried over magnesium sulfate and remove the solvent under reduced pressure. Chromatography using silica gel and elution with diethyl ether-hexane (1 : 1, by volume) gives named the title compound (35 g).

HSC Rf= 0,30 (silica, diethyl ether : hexane, 1 : 1, by volume).

1H NMR (CDCl3): = a 1.25 (t, 3H), of 1.35 to 1.8 (m, 6N), 2,05 - to 2.55 (m, 6N), 3,3 - of 3.45 (m, 2H), 3,65 to 3.8 (m, 2H), 4,0 - 4,1 (m, 2H), 4.4 to 4.5 (m, 1H), 7,2 - of 7.55 (m, 3H), ppm.

Preparative example 3

5-(3,4-Dichlorophenyl)-5-(2-[tetrahydropyran-2-yl-oxy] ethyl)-2(1H)- piperidin

The compound of preparative example 2 (18.7 g, 45,2 mol) is dissolved in a saturated ethanolic ammonia solution (500 ml) containing Raney Nickel (3.5 g). The mixture is stirred in hydrogen atmosphere at atmospheric pressure for 7 hours. Then the catalyst is removed by filtration, the ethanol is removed under reduced pressure, and the residue chromatographic using silica gel, elwira first diethyl ether and then methanol with dichlor Rennie, methanol : dichloromethane, 1 : 9, by volume). ICSD m/z = 372 (m+1)+.

1H NMR (CDCl3): = 1,4 - 1,8 (m, 6H), 1,9 - 2,1 (m, 5H), 2,3 at 2.45 (m, 1H), 3,0 - 3,2 (m, 1H), 3,0 - 3,2 (m, 1H), 3,35 - of 3.85 (m, 4H), 4,35 - 4,4 (m, 1H), equal to 6.05 (s, W, 1H), 7,15 was 7.45 (m, 3H) ppm.

Preparative example 4

5-(3,4-Dichlorophenyl)-5-(2-peroxyacyl)-2(1H)-piperidin

To a saturated solution of hydrogen chloride in methanol (350 ml) at room temperature add the compound of preparative example 3 (10.4 g, 28 mmol), and then through the solution with stirring miss gaseous hydrogen chloride for 40 minutes and then the reaction mixture is left to stand at room temperature for 14 hours. The solvent is removed under reduced pressure. Add saturated aqueous sodium bicarbonate solution (300 ml) and the aqueous phase extracted with ethyl acetate (4x300 ml). The combined organic layers are dried over magnesium sulfate, filtered, and removed solvent under reduced pressure. Get white solid. This substance is crystallized from ethyl acetate, and get named in the title compound (5.5 g).

HSC Rf= 0,23 (silica, methanol : dichloromethane, 1 : 9, by volume). So pl. 167-168oC. ICSD m/z = 288 (m+1)+. Elem. analysis: found: C - 54,02; N - To 5.03; N - to 4.52.a 1.7 - 2,2 (m, 6N), 3,1 is 3.15 (m, 2H), 3.25 to 3,3 (m, 1H), up 3.6 - 3.7 (m, 1 H), 4,3 - of 4.35 (m, 1H), 7,35 - the 7.65 (m, 4H) ppm.

Preparative example 5

5-(3,4-Dichlorophenyl)-5-(2-methanesulfonylaminoethyl)-2(1H)-piperidin

To a saturated solution of the compound of preparative example 4 (5,44 g of 18.9 mmol) in dry dichloromethane (100 ml), add triethylamine (3,95 ml of 1.5 mol. equiv.) and the solution is cooled to 0oC. Then add methanesulfonanilide (1.9 ml, 1,3 mol. equiv.) and the reaction mixture was allow to warm to room temperature and stirred for 2.5 hours. The reaction mixture was washed with water (I ml), dried over magnesium sulfate, filtered, and removed solvent under reduced pressure. Get named in the title compound (7,1 g).

HSC Rf= 0,24 (silica, methanol : dichloromethane, 1 : 19, by volume).

1H NMR (CDCl3): = 2.0 to 2.5 (m, 6N), 2,9 (s, 3H), 3.45 points of 4.1 (m, 4H), 6,7 (s, W, 1H), 7,2 - 7,5 (m, 3H) ppm.

Preparative example 6

5-(3,4-Dichlorophenyl)-5-formylmethyl-2(1H)-piperidin

To a solution of oxalicacid (1.6 ml, 1,1 mol. EQ.) in dry dichloromethane (200 ml) at -78oC is added dropwise dry dimethylsulfoxide (3.0 ml, 2,4 mol. equiv.) and the solution is stirred for 1 hour. Then added dropwise within 15 minutes, p and the mixture was stirred at -78oC for 1 hour. Then add triethylamine (12 ml, 5 mol. equiv.) and mixtures allow to warm to room temperature for 4 hours. Add water (25 ml) and the mixture extracted with dichloromethane (I ml). The combined organic layers are dried over magnesium sulfate, filtered, and removed solvent under reduced pressure. Get the resin, which chromatographic using silica gel, elwira with a gradient solvent of methanol with dichloromethane (1 : 49 to 1 : 5, by volume), and get a named connection (1,09 g).

1H NMR (CDCl3): = 2,05 - 2,2 (m, 2H), 2,35 - 2,5 (m, 1H), 2,7 - of 2.75 (m, 1H), 2.95 points to 3.0 (m, 1H), 3.45 points and 3.6 (m, 2H), 3,85 to - 3.9 (m, 1H), 6,0 (s, W, 1H), 7,2 was 7.45 (m, 3H), and 9.5 (m, 1H) ppm.

Preparative example 7

5-(3,4-Dichlorophenyl)-1-(4-phenylbenzyl)-5-(2-[tetrahydropyran-2 - hydroxy] ethyl)-2-piperidin

To a solution of the compound of preparative example 3 (500 mg, of 1.34 mmol) in dry dimethylformamide (10 ml) at room temperature and under nitrogen atmosphere, add 60% (W/V) dispersion of sodium hydride in oil (54 mg, of 1.05 mol. equiv.) and the mixture is stirred at room temperature for 1 hour. Then add dropwise a solution of 4-phenylendiamine (365 mg, 1,1 mol. EQ. ) in dimethylformamide (1 ml) and the mixture was stirred at room temp the ATA sodium (10 ml) and a saturated solution of ammonium chloride (10 ml), the mixture is then extracted with ethyl acetate (CH ml) and the combined organic layers washed with saturated aqueous ammonium chloride (CH ml). The organic phase is dried over magnesium sulfate, filter and remove the solvent under reduced pressure. Get white foam. This crude product is then chromatographic using silica gel, elwira with ethyl acetate, and get named in the title compound (456 mg).

HSC Rf= 0,47 (silica, ethyl acetate).

1H NMR (CDCl3): or = 1.5 to 1.8 (m, 6N), 1,8 - 2,05 (m, 2H), 2.05 is - 2,2 (m, 3H), 2,4 - by 2.55 (m, 1H), 2,85 - 3,1 (m, 1H), 3,3 - of 3.75 (m, 4H), 3.75 to of 3.85 (m, 1H), 4,2 - 4,4 (m, 2H), a 5.0 to 5.1 (d, 1H), 6.8 or 6.9 (t, 1H), 7,05 and 7.1 (d, 1H), 7,2 - 7,3 (m, 1H), and 7.3 - 7.5 (m, 5H), 7,55 - the 7.65 (m, 4H) ppm.

Preparative example 8

5-(4-Chlorophenyl)-1-(cyclohexylmethyl)-5-(2-hydroxyethyl)-2-piperidin

To a methanol solution (20 ml) of the compound of preparative example 51 (1 g, 1 mol. EQ.) add ion-exchange resin Amberlyst H-15 (trade mark) (0.33 g, of 0.33 mol. EQ. in/in), and the reaction mixture is stirred for 20 hours at room temperature. The resin is removed by filtration, and the methanol removed from the filtrate under reduced pressure. The residue is dissolved in ethyl acetate (20 ml) and the mixture washed with water (5 ml) and brine (5 ml). Organization is the pressure. Get named in the title compound as a white solid (0,81 g), which is used without further purification.

HSC Rf= 0,7 (silica, methanol : dichloromethane, 1 : 9, by volume). ICSD m/z = 350 (m+1)+.

Preparative example 9

Ethyl-4,4-diverticulopexia

To a solution TRIFLUORIDE diethylaminosulfur (7,76 ml, 2 mol. EQ.) in carbon tetrachloride (75 ml) at 0oC is added dropwise ethyl-4-oxocyclohexanecarboxylate (5 g, 29.4 mmol) and the mixture was stirred at room temperature for 14 hours. Then carefully add water (50 ml). The organic phase is washed with water (I ml), dried over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Get named in the title compound as a yellow oil (1,96 g) which is purified by distillation.

1H NMR (CDCl3): = 1,2 - 1,3 (t, 3H), of 1.65 to 1.9 (m, 4H), 1,95 - 2,2 (m, 3H), 2,2 - of 2.45 (m, 2H), 4,05 - 4,2 (K, 2H) ppm.

Preparative example 10

4,4-Diverticulectomy

To a suspension of lithium aluminum hydride (350 mg) in dry diethyl ether (30 ml), at 0oC and under nitrogen atmosphere, with stirring, add dropwise a solution of the compound of preparative example 9 (1,96 is E. it was added 2N aqueous sodium hydroxide solution (0.5 ml) and then water (0.5 ml). Inorganic solids are removed by filtration, and the filtrate concentrated under reduced pressure. Get named in the title compound as a colourless oil (1,59 g).

1H NMR (CDCl3): = 1,15 - 1,4 (m, 2H), 1,4 - 1,5 (m, 2H), 1.5 and 1.7 (m, 1 H), 1,7 - 2,0 (m, 3H), 2,0-2,3 (m, 2H), 3.45 points and 3.6 (m, 2H) ppm.

Preparative example 11

4,4-Debtor-1-(4-methylphenylsulfonyl)cyclohexane

To a solution of the compound of preparative example 10 (500 mg, of 3.33 mmol) in dichloromethane (10 ml) at room temperature is added triethylamine (of 0.62 ml of 1.5 mol. equiv.) then add p-toluensulfonate (570 mg, 1 mol. EQ. ), and the reaction mixture is stirred for 14 hours. Then add water (25 ml), the layers separated, the organic phase is washed with water (I ml) and the organic layer is dried over anhydrous magnesium sulfate. The solution is filtered, and removed solvent under reduced pressure. Then the crude product is passed through a small layer of silica gel, elwira diethyl ether and hexane (1 : 4, by volume). The solvent is removed from elyuirovaniya fractions under reduced pressure, and the product is crystallized by powdering with hexane. Get named in the title compound as a white solid (100 2H), 7.3 to 7.4 (d, 2H), 7,75 to 8.0 (d, 2H) ppm.

Preparative example 12

5-(3,4-Dichlorophenyl)-1-(4,4-diverticulectomy)-5-(2- [tetrahydropyran-2-hydroxy]ethyl)-2-piperidin

To a solution of the compound of preparative example 3 (121 mg, 0.33 mmol) in dry dimethylformamide (3 ml) under nitrogen atmosphere add 60% (W/V) dispersion of sodium hydride in oil (14 mg), and the mixture is allowed the opportunity to mix at room temperature for 45 minutes. To this mixture is added the compound of preparative example 10 (99 mg, 1 mol.equiv.) and the mixture is heated at 50oC for 5 hours. For a more complete reaction add an additional portion of 60% (V/V) dispersion of sodium hydride in oil (7 mg, 0.5 mol. equiv.) and the reaction mixture is warm at 50oC for another 3 hours. Then add water (1 ml) and the mixture is evaporated to dryness under reduced pressure. Then the residue is dissolved in ethyl acetate (20 ml) and the organic phase washed with water (2x20 ml). Then the organic phase is dried over anhydrous magnesium sulfate, filtered, and removed solvent under reduced pressure. Receive the resin. This clear resin column chromatography, using silica gel, elwira with a gradient solvent of dichloromethane with methanol (from 100 : 1 to 9 : 1, by volume). Get the= 1,15 - of 1.6 (m, 8H), 1,6 - 1,9 (m, 5H), of 1.9 - 2.3 (m, 7H), 2,4 - 2,5 (m, 1H), 3,03 - 3,3 (m, 2H), 3,3 - 3,6 (m, 4H), 3,6 - 3,8 (m, 2H), from 4.3 to 4.4 (m, 1H), 7,05 - to 7.15 (d, 1H), 7.3 to 7.4 (s, 1H), 7,4 was 7.45 (d, 1H) ppm.

Preparative example 13

Methanesulfonylaminoethyl

To a solution of cycloheptylamine (1.0 g, 7,81 mmol) in dichloromethane (20 ml), at 0oC and under nitrogen atmosphere, add triethylamine (1,63 ml of 1.5 mol. EQ. ). Add dropwise methanesulfonanilide (0,73 ml of 1.2 mol. equiv.) and the reaction mixture allow to mix for 2 hours at room temperature. Add water (50 ml) and dichloromethane (50 ml). The organic phase is separated, washed with water (I ml) and then dried over anhydrous magnesium sulfate. Then the solution is filtered, and removed solvent under reduced pressure. Get named in the title compound as oil (1, 66 g).

1H NMR (CDCl3): = 1,15 - 1,3 (m, 2H), is 1.4 - 1.6 (m, 6H), of 1.6 - 1.8 (m, 4H), 1.85 to 2.0 (m, 1H), 2.95 points to 3.0 (s, 3H), 3.95 to of 4.05 (d, 2H) ppm.

Preparative examples 14 to 16

Connections the following, given in the table. 9 preparative examples, having the General formula:

< / BR>
get a manner similar to the method of preparative example 1, using as starting compounds corresponding to the combined acetonitrile derivatives.

Preparative examples 20 through 22

Connections the following, given in the table. 11 preparative examples, having the General formula;

< / BR>
get a manner similar to the method of preparative example 3, using as starting compounds corresponding butanoate derivatives (see preparative examples 17-19).

Subscript comments

1. The reaction is carried out at a pressure of 414 kPa (60 f/d2and 50oC.

2. The reaction is carried out at 50oC.

Preparative examples 23 to 32

Connections the following, given in the table. 12 preparative examples, having the General formula:

< / BR>
get a manner similar to the method of preparative example 4, using as starting compounds corresponding tetrahydropyrane derivatives (see preparative examples 7, 12, 44 to 50 and 52).

Preparative examples 33 to 38

Connections the following, given in the table. 13 preparative examples, having the General formula;

< / BR>
get a manner similar to the method of preparative examples 8, 27-30 and 32).

Preparative examples 39 43

Connections the following, given in the table. 14 preparative examples, having the General formula;

< / BR>
get a manner similar to the method of preparative example 6, using as starting compounds corresponding ethanol derivatives (see preparative examples 23-26 and 31).

Preparative examples 44 through 52

Connections the following, given in the table. 15 preparative examples, having the General formula;

< / BR>
get a manner similar to the method of preparative example 7, using as starting compounds corresponding derivatives of 2(1H)-piperidone (see preparative examples 3, 20, 21 and 22) and were synthesized.

Subscript note

1. To the reaction mixture of potassium iodide, and the mixture is then heated at 50oC for 4 hours.

Preparative example 53

1-Diphenylethylamine-3-ol

The solution benzhydrylamine (200 ml of 1.16 mol) and epichlorohydrin (186 ml, 1 mol. EQ. ) in methanol (600 ml) was stirred at room temperature for 5 days and then heated at 40oC for 2 days. Then remove the solvent under reduced pressure, the residue is dissolved in isopropyl alcohol (500 ml), and rasstropyvajut the precipitation. The solid is treated with dichloromethane (400 ml) and saturated aqueous sodium bicarbonate (500 ml). The aqueous phase is extracted with dichloromethane (I ml) and the combined organic phases are dried over magnesium sulfate. Then the solution is filtered and from the filtrate under reduced pressure to remove the solvent. Get named in the title compound (86 g) in the form of a solid crystalline substance.

1H NMR (CDCl3): = 1.8 to 2.3 (s, W, 1H), 2,85 is 2.9 (m, 2H), 3,5 - 3,55 (m, 2H), 4,35 (s, 1H), 4.4 to 4.5 (m, 1H), 7,15 to 7.4 (m, 10H) ppm.

Preparative example 54

1-Diphenylmethyl-3-methanesulfonanilide

To a solution of 1-diphenylethylamine-3-ol (see preparative example 53) (65.9 g, 275,7 mmol) in dry dichloromethane (700 ml), at 0oC and under nitrogen atmosphere, add triethylamine (57 ml of 1.5 mol. EQ.). After 5 minutes add methanesulfonanilide (25.6 ml of 1.2 mol. equiv.) and the mixture is stirred for 1 hour. Then add water (300 ml) and the mixture extracted with dichloromethane (I ml). The combined organic layers are dried over magnesium sulfate. Then the solution is filtered and from the filtrate under reduced pressure to remove the solvent. The remainder chromatographic using silica gel, elwira methanol with dichloromethane (1 : 49, objem): = 2,95 (s, 3H), 3.15 and is 3.25 (m, 2H), 3,6 - the 3.65 (m, 2H), 4,4 (s, 1H), of 5.05 - of 5.15 (m, 1H), 7,15 to 7.4 (m, 10H) ppm.

Preparative example 55

1-Diphenylmethyl-3-morpholinomethyl

A solution of 1-diphenylmethyl-3-methanesulfonanilide (see preparative example 54) (24,46 g, 7,72 mmol), potassium carbonate (32 g, 3 mol. EQ.) and research (7,34 ml of 1.09 mol. EQ.) in acetonitrile (200 ml) is refluxed for 4 hours. Then the solution is cooled to room temperature, add water (50 ml) and the mixture is concentrated under reduced pressure. The residue is distributed between ethyl acetate (400 ml) and water (400 ml) and the organic phase is separated and washed with water (I ml). The organic phase is dried over magnesium sulfate, filtered and from the filtrate under reduced pressure to remove the solvent. The residue is then chromatographic using silica gel, elwira hexane diethyl ether (1 : 1, by volume), and get named in the title compound (16.5 g).

1H NMR (CDCl3): = 2,25 - 2,3 (m, 4H), 2,85 was 3.05 (m, 3H), 3,35 - 3,4 (m, 2H), 3,7 - of 3.75 (m, 4H), of 4.45 (s, 1H), 7,15 was 7.45 (d, 10H) ppm.

Preparative example 56

The dihydrochloride of 3-morpholinoethyl

A mixture of 1-diphenylmethyl-3-morpholinoethyl (see preparative example 55) (18.6 g, 60,4 mmol), palladium hydroxide (2 is for 3 days. Then the catalyst is removed by filtration, and the filtrate evaporated to dryness. Add dichloromethane (100 ml) to the residue and poroshkovaya give a solid, which is recrystallized from methanol, and get named in the title compound (10.2 g) in the form of a solid crystalline substance. ICSD m/z = 179 (m+1)+. (Note. Monohydrochloride used in some reactions instead dihydrochloride, can be obtained in a similar way, using the reaction of one molar equivalent of hydrogen chloride.)

Preparative example 57

3-Cyano-1-(diphenylmethyl)azetidin

To a solution of the compound of preparative example 54 (10 g, to 31.5 mmol) in dimethylformamide (100 ml) in five portions over 2 minutes, add a solution of sodium cyanide (4,63 g, 3 mol. EQ.) in water (50 ml). The mixture was then heated at 70oC for 16 hours. The reaction mixture is cooled to room temperature and then poured into a mixture of ice water (300 ml).

The resulting brown solid substance is removed by filtration, dissolved in dichloromethane and the solution is dried over anhydrous magnesium sulfate. The solution is filtered, and under reduced pressure removed from the filtrate the solvent. The residue is then chromatographic using silica">

1H NMR (CDCl3): = 3,2 - to 3.35 (m, 3H), 3.45 points to 3.5 (m, 2H), 4,4 (s, 1H), 7,15 was 7.45 (m, 10H) ppm.

Preparative example 58

1-(Diphenylmethyl)azetidin-3-carboxylic acid

To a suspension of the compound of preparative example 57 (5.9 g, to 23.8 mmol) in n-butanol (60 ml) dropwise over 3 minutes, add a solution of potassium hydroxide (4.8 g) in water (9 ml). The mixture was then heated at 90 - 100oC for 20 hours. The reaction mixture is cooled to room temperature and remove the solvent under reduced pressure. The residue was poured into ethyl acetate (100 ml) and water (100 ml). The aqueous layer was separated and filtered, then acidified to pH 4 using 2N hydrochloric acid. Precipitated precipitated white solid is filtered off, washed with ethyl acetate (15 ml) and dried under reduced pressure. Get named in the title compound (3.5 g). ICSD m/z = 268 (m+1)+.

1H NMR (d6-DMSO): = 3,1 - 3,3 (m, 5H), 4,4 (W, s, 1H), 7,15 to 7.4 (m, 10H), 12,3 (W, s, 1H) ppm.

Preparative example 59

1-Diphenylmethyl-3-(N-[2-hydroxyethyl]-N-methylcarbamoyl)-azetidin

A mixture of 1-diphenylethylamine-3-carboxylic acid (see preparative example 58) (1.8 g, of 6.73 mmol), 2-methylaminoethanol (0,76 g to 1.5 mol. equiv.) hydrochloride of 1-[3-dimethylaminopropyl] -3-tilcara is.) in dry dichloromethane (50 ml) was stirred at room temperature for 16 hours. The solvent is removed under reduced pressure, and the residue distributed between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The layers are separated and the aqueous layer was additionally extracted with ethyl acetate (30 ml). The combined organic layers dried over anhydrous sodium sulfate. The solution is filtered under reduced pressure from the filtrate to remove the solvent, and the residue chromatographic using silica gel, elwira methanol with dichloromethane (7 : 93, by volume). Get named in the title compound (1,76 g).

TLC Rf= 0,3 (silica, methanol : dichloromethane 7 : 93, by volume). ICSD m/z = 325 (m+1)+. Elem. analysis: found: C - 71,99; N - 7,60; N - of 8.47. For C20H24N2O20,13 CH2Cl2calculated: C - 72,14; N - 7,30; N - at 8.36%.

1H NMR (CDCl3): = 2,85 - 2,95 (m, 5H), 3,2 - to 3.35 (m, 2H), 3,45 - 3,55 (m, 4H), 3,65 to 3.8 (m, 2H), 4,4 (s, 1H), 7,15 was 7.45 (m, 10H) ppm.

Preparative example 60

1-Diphenylmethyl-3-(N-[2-methoxyethyl]-N-methylcarbamoyl)-azetidin

To a solution of the compound of preparative example 59 (0,93 g, 2,87 mmol) in tetrahydrofuran (12 ml), at 0oC and under nitrogen atmosphere, add in two installments, 60% (V/V) dispersion of sodium hydride in oil (0.126 g, 1,1 mol. EQ.). After the 30-minute peroral removed under reduced pressure, and the residue is treated with ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic layer is dried over anhydrous sodium sulfate, filtered, and removed solvent under reduced pressure. Get the oil. This crude reaction product is purified column chromatography using silica gel, elwira methanol (1 : 19 by volume), and get named in the title compound (0.95 g).

TLC Rf= 0,45 (silica, methanol : dichloromethane 1 : 19, by volume). ICSD m/z = 339 (m+1)+. Elem. analysis: found: C - 72,42; N - 7,60; N - 7,89. For C21H26N2O213CH2Cl2calculated: C - 72,69; N - 7,58; N - 8,03%.

1H NMR (CDCl3): = 2,9 - 2,95 (m, 3H), 3,2 - to 3.35 (m, 6N), 3,4 - 3,55 (m, 6N), 4,4 (s, 1H), 7,15 was 7.45 (m, 10H) ppm.

Preparative example 61

The dihydrochloride of N-(2-methoxyethyl)-N-methylcarbamoylmethyl

To a solution of the compound of preparative example 60 (473 mg, 1.4 mmol) in dichloromethane (5 ml), at 0oC and under nitrogen atmosphere, is added dropwise alpha chloroethylphosphonic (0,22 ml to 1.1 mol. EQ.). After 20 minutes, add another portion of alpha-chloroethylphosphonic (0.1 ml, 0,5 mol. equiv.) and the reaction mixture was allow to warm to room temperature for 20 minutes. After tons of potassium (620 mg, 3 mol. EQ. ). The mixture is then refluxed for 1 hour. The reaction mixture is cooled to room temperature, filtered, and the filtrate is acidified to pH 3 using ethereal HCl solution. The solid is removed by filtration. The solvent of the filtrate is removed under reduced pressure, and get the resin, which was washed several times with diethyl ether and dried under reduced pressure. Get named in the title compound as a crude product (0.35 g), which is used directly.

Preparative examples 62 to 64

Connections the following, given in the table. 16 preparative examples, having the General formula;

< / BR>
get a manner similar to the method of preparative example 59, using as starting compounds 1-diphenylethylamine-3-carboxylic acid and the appropriate amine.

Preparative examples 65 to 68

Connections the following, given in the table. 17 preparative examples, having the General formula:

< / BR>
get a manner similar to the method of preparative example 61, using as starting compounds corresponding azetidine (see preparative examples 62-64 and 105).

Footnotes

1. The crude product use the ATA, in the processing of potassium carbonate is added.

Preparative example 69

1-(tert-Butoxycarbonyl)-3-(3-hydroxypiperidine)azetidin

A mixture of 1-(tert-butoxycarbonyl)-3-methanesulfonanilide (see publication of the application for international patent WOES/19059) (1.5 g, 4,78 mmol) and 3-hydroxypiperidine (1.9 g, 4 mol. EQ.) warm at 110oC for 16 hours. The mixture is cooled to room temperature and distributed between ethyl acetate (100 ml) and 5% aqueous sodium bicarbonate solution (100 ml). The layers separated, and the aqueous phase is extracted with another portion of ethyl acetate (100 ml). The combined organic layers dried over anhydrous magnesium sulfate. The solution is filtered, the solvent removed from the filtrate under reduced pressure, and the crude product is purified column chromatography using silica gel, elwira methanol with dichloromethane (1 : 9, by volume). Get named in the title compound (1.4 g).

TLC Rf= 0,3 (silica, methanol : dichloromethane 1 : 9, by volume).

1H NMR (CDCl3): = 1,45 (s, N), 1,5 - of 1.85 (m, 6N), of 2.15 - 2.45 (m, 4H), 3,05 is 3.15 (m, 1H), 3.25 to 3,95 (m, 4H) ppm.

Preparative example 70

Bestrefiratecom 3-(3-hydroxypiperidine)azetidine

To a solution of the compound of preparative who usnow acid (5 ml). Then the mixture allow to warm to room temperature and stirred for 1 hour. The mixture is concentrated under reduced pressure, the resulting resin was washed with diethyl ether, and get named in the title compound as a white solid (1.2 g).

Elem. analysis: found: C - 37,32; N - 4,73; N - 7,03. For C8H16N2O 2CF3CO2H calculated: C - 37,51; N - 4,72; N - 7,29%.

Preparative examples 71 through 76

Connections the following, given in the table. 18 preparative examples, having the General formula;

< / BR>
receive, using a method similar to the preparative method of example 69, using as starting compounds 1-(tert-bout-oxycarbonyl)-3-methanesulfonanilide and the corresponding amines.

A footnote.

1. When processing the reaction mixture is cooled and removed the excess piperazine under reduced pressure. The crude product is used directly.

Preparative examples from 77 to 89

Connections the following, given in the table. 19 preparative examples, having the General formula;

< / BR>
receive, using a method similar to the method of preparative example 70, using as source>Footnotes

1. Get trifenatate.

2. Get bestreferat.ru.

3. At the stage of processing using finite poroshkovaya with ethyl acetate.

Preparative example 90

1-(tert-Butoxycarbonyl)-3-(2-oxaprotiline)azetidin

To a suspension of sodium hydride (60% (V/V) dispersion in mineral oil, 0.29 grams, 1 mol. EQ.) in toluene (20 ml) at room temperature and under nitrogen atmosphere, with stirring, in parts, the compound of preparative example 75 (1,57 g, 1 mol. EQ.). The reaction mixture is stirred for 30 minutes and then cooled to 0oC. Then, within 15 minutes, add ethylchloride (0,78 ml, 1 mol. equiv.) the reaction mixture is stirred for 1 hour at room temperature and then refluxed for 90 minutes. The solution is cooled, diluted with diethyl ether (20 ml) and washed with saturated aqueous sodium bicarbonate (30 ml). The organic layer is dried over anhydrous sodium sulfate. Remove the organic solvent under reduced pressure and the residue purified column flash chromatography on silica gel, elwira methanol with dichloromethane (4 : 96 by volume). Get named zagalo the x2">

1H NMR (CDCl3): = 1,4 (, N), 3,5 - 3,6 (m, 2H), 3,9 - 4,0 (m, 4H), 4,1 - 4,2 (m,4H), 5,2 - 5,4 (m, 1H) ppm.

Preparative example 91

1-Diphenylmethyl-3-(2,6-dimethylpiperidino)azetidin

Heat together 1-diphenylmethyl-3-methanesulfonanilide (see preparative example 54) (2 g, 1 mol. EQ.) and 2,6-dimethylpiperidin (6,79 ml, 3 mol. EQ.) if 110oC, in an atmosphere of nitrogen for 6 hours. Add saturated aqueous sodium bicarbonate solution (60 ml) and the mixture extracted with ethyl acetate (CH ml). The combined organic extracts are dried over magnesium sulfate. The organic solvent is removed under reduced pressure, and the residue is purified column flash chromatography on silica gel, elwira methanol with dichloromethane (1: 9, by volume), and get named in the title compound (0,48 g).

TLC Rf= 0,39 (silica, methanol : dichloromethane 1 : 93, by volume). ICSD m/z = 335 (m+1)+. Elem. analysis: found: C - 80,29; 9,00; N - 8,14. For C23H30N2O 0,125 CH2Cl2calculated: C - 80,48; N - 8,84; N - 8,12%.

1H NMR (CDCl3): = 1,0 (C, 6N), 1,4 - 1,8 (m, 6N), 2,7 - 2,9 (m, 4H), 3,35 - 3,4 (m, 2H), 3,7 (s, 1H), 4,4 (s, 1H), and 7.1 to 7.4 (m, 10H) ppm.

Preparative examples 92 and 93

Connect two of the following, given in the table. 20 prerational example 91, using as starting compounds 1-diphenylmethyl-3-methanesulfonanilide and the corresponding amines.

Preparative example 94

1-Diphenylmethyl-3-(piperidine-1-yl) azetidin

A mixture of 1-diphenylmethyl-3-methanesulfonanilide (see preparative example 54) (1.5 g, 1 mol. equiv.) piperidine (0.6 g, 1,5 mol. EQ.) and potassium carbonate (1.31 g, 2 mol. EQ.) in acetonitrile (20 ml) is refluxed under nitrogen atmosphere for 4 hours. Add saturated aqueous sodium bicarbonate solution and saline solution, and the mixture is extracted with ethyl acetate (2x40 ml). The organic extracts are combined and dried using magnesium sulfate. The organic solvent is removed under reduced pressure, and the residue is purified column flash chromatography on silica gel, elwira methanol with dichloromethane (1 : 9, by volume), and get named in the title compound (0.65 g).

TLC Rfequal to 0.5 (silica, methanol : dichloromethane 1 : 9, by volume). ICSD m/z = 307 (m+1)+. Elem. analysis: found: C - 81,50; N - 8,51; N - 9,02. For C21H26N20,06 CH2Cl2calculated: C - 81,14; N - 8,45; N - 8,99%.

1H NMR (CDCl3): = 1,4 - 1,5 (m, 2H), a 1.5 - 1.6 (m, 5H), to 2.1 - 2.3 (m, 4H), of 2.9 - 3.0 (m, 2H), 3,4 - 3,5 (m, 2H), 4,4 (s, 1H), 7,1 - 7,3 (m, 6N), of 7.35 - 7.5 (data examples having the General formula:

< / BR>
(where Ph = phenyl) are obtained in a manner similar to preparative method of example 94, using as starting compounds 1-diphenylmethyl-3-methanesulfonanilide and the corresponding amines.

Footnotes

1. As a starting amine hydrochloride use homomorpholine (see preparative example 127).

2. Before boiling under reflux bring the pH of the reaction mixture to 9, using N-methylmorpholine.

Preparative example 107

The dihydrochloride of 3-(piperidine-1-yl)azetidine

To a solution of the compound of preparative example 94 (0.64 g) in dry dichloromethane (7 ml), at 0oC and under nitrogen atmosphere, add (-chloro-ethylchloride (0.3 ml, 1 mol. equiv.) and the reaction mixture is stirred for 30 minutes. The solvent is removed under reduced pressure, and the residue is again dissolved in methanol (10 ml) and refluxed for 45 minutes. Then remove the solvent under reduced pressure, and the obtained resin proscout with diethyl ether (5 ml). Get named in the title compound as a beige powder (0.14 g).

ICSD m/z = 141 (m+1)+.

1H NMR (d6-DMSO): = to 1.3 - 1.4 (m, 1H), 1.7 to 1.9 (m, 5H)reamers with 108 119

Connections the following, given in the table. 22 preparative examples, having the General formula:

< / BR>
receive, using a method similar to the preparative method of example 107 using as starting compounds corresponding azetidinone derivatives (see preparative examples 91, 92, 95, 96, 98 - 103, 104 and 120).

Footnotes

1. Receive in the form of the dihydrochloride.

2. Get as hydrochloride.

Preparative example 120

1-Diphenylmethyl-3(N-[2-methoxyethyl]-N-methylamino)azetidin

To a solution of the compound of preparative example 93 (0.85 grams, 1 mol. EQ.) in tetrahydrofuran (12 ml), at 0oC and under nitrogen atmosphere, add 60% (W/V) dispersion of sodium hydride in oil (0.126 g, 1,1 mol. equiv.) and the reaction mixture was stirred at room temperature for 1 hour. Then add methyliodide (0,448 g, 1,1 mol. equiv.) and the reaction mixture is stirred for another 2 hours. Part of the solvent (10 ml) was removed under reduced pressure, add saturated aqueous sodium bicarbonate solution (25 ml) and the mixture extracted with ethyl acetate (CH ml). The combined organic extracts are dried over magnesium sulfate. The organic solvent is removed under reduced pressure, and the residue ocist named the title compound (0.64 g).

TLC Rf= 0,3 (silica, methanol : dichloromethane 4 : 96 by volume). ICSD m/z = 311 (m+1)+< / BR>
1H NMR (CDCl3): = 2,1 (s, 3H), 2,4 (t, 2H), 2,85 - 2,95 (m, 2H), 3,0 - 3,1 (m, 1H), 3,3 (s, 3H), 3,4 - of 3.45 (m, 4H), 4,4 (s, 1H), 7,15 - to 7.3 (m, 6N), 7,4 was 7.45 (m, 4H) ppm.

Preparative example 121

Hydrochloride 3-(4-tert-butoxycarbonylmethyl)azetidine

The compound of preparative example 97 (1,471 g, 1 mol. EQ.) dissolved in a mixture of 1M hydrochloric acid (4 ml) and ethanol (16.6 ml) and add 10% palladium-on-coal (14,7 mg). The mixture is stirred in hydrogen atmosphere at a pressure of 345 kPa (50 f/d2) for 16 hours. Then the catalyst is filtered off and the solvent is removed under reduced pressure and the last traces of water are removed by azeotropic distillation with ethanol. Get named in the title compound in the form of a cream solid color (0,83 g), which is used without further purification.

TLC Rr= 0,84 (silica, ethyl acetate : hexane, 1 : 2, by volume). ICSD m/z = 242 (m+1)+. Elem. analysis: found: C - 50,30; N - 8,33; N - 14,39. For C12H23N3O2HCl calculated: C - 50,25; H - 8,79; N - 14,65%.

1H NMR (d6-DMSO): = 1,4 (, N), of 2.3 - 2.5 (m, 4H), 3,4 - 3,5 (m, 6N), 3,9 - 4,2 (m, 4H), and 9.7 (s, W, 1H) ppm.

Preparative example the L. EQ.) in dichloromethane (140 ml), at 0oC and under nitrogen atmosphere, add triethylamine (6,29 ml of 1.2 mol. EQ.). The reaction mixture is vigorously stirred, and added dropwise to acetylchloride (3,21 ml of 1.2 mol. EQ.). The mixture is stirred for 24 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (30 ml) and the organic layer is dried using magnesium sulfate. The organic solvent is removed under reduced pressure, and the residue is purified column flash chromatography on silica gel, elwira methanol with ethyl acetate (1 : 19 by volume). Get named in the title compound (8,19 g).

TLC Rr= 0,33 (silica, methanol : ethyl acetate 1 : 19, by volume). ICSD m/z = 229 (m+1)+. Elem. analysis: found: C - 57,83; N - 8,83; N - 12,27. For C11H20N2O3calculated: C - 57,87; N - Of 8.92; N - 12,14%.

1H NMR (CDCl3): = 1,4 (, N), 2,1 (s, 3H), 3,3 - 3,4 (m, 6N), 3,5 - 3,6 (m, 2H) ppm.

Preparative example 123

Triptorelin N-acetylpiperidine

To a solution of the compound of preparative example 122 (8,2 g, 1 mol. EQ.) in dichloromethane (78 ml), at 0oC and under nitrogen atmosphere, add triperoxonane acid (39 ml). The mixture is then warmed to room temperature and stirred for further in thecut azeotropic distillation with dichloromethane (30 ml), and you get named in the title compound in the form of resin (11,7 g).

MSRR m/z = 129 (m+1)+.

1H NMR (CDCl3): = 2,0 (s, 3H), 3,0 - 3,2 (m, 4H), of 3.5 - 3.7 (m, 4H), 8,8 - 9,0 (s, W, 2H) ppm.

Preparative example 124

The oxime Piran-4-it

To a solution (240 ml) of hydroxylamine hydrochloride (60,53 g, 4 mol. EQ.) in water (240 ml) cautiously add 3.6 M aqueous solution of sodium hydroxide (240 ml). Within 5 minutes add Piran-4-one (20 g, 1 mol. EQ.). The mixture is refluxed for 1.5 hours, cooled, and then stirred for 18 hours at room temperature. The reaction mixture was extracted with dichloromethane (4x50 ml) and the combined extracts dried over magnesium sulfate. Removal of the solvent under reduced pressure gives named the title compound as a white solid (18,86 g).

1H NMR (CDCl3): = 2,4 (t, 2H), and 2.7 (t, 2H), of 3.7 - 3.9 (m, 4H), 7,35 (s, 1H) ppm.

Preparative example 125

Homomorpholine-5-he

To methanesulfonic acid (228,8 ml, 27 mol. EQ.) in nitrogen atmosphere add, parts, within 5 minutes, phosphorus pentoxide (37,72 g, 2 mol. EQ. ). The solution was stirred at room temperature for 2 hours, and then added in portions within 10 minutes, mesilat for 1 hour at this temperature. The reaction mixture was then stirred for 18 hours at room temperature. The mixture is slowly added to water (500 ml) and add parts of sodium bicarbonate until then, until the mixture becomes alkaline (pH 9). The mixture is filtered, and the pad washed several times with dichloromethane (I ml). The filtrate is extracted with dichloromethane (I ml). The combined extracts are dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The resulting solid proscout with diethyl ether and get named in the title compound as a white foam (2.1 g).

ICSD m/z = 116 (m+1)+.

1H NMR (CDCl3): = 2,6 - 2,8 (m, 2H), 3,3 - 3,4 (m, 2H), of 3.7 - 3.9 (m, 4H), 6,2 (s, W, 1H) ppm.

Preparative example 126

4-(tert-Butoxycarbonyl) homomorpholine

To a suspension of lithium aluminum hydride (777 mg, 2 mol. EQ.) in tetrahydrofuran (87 ml) in nitrogen atmosphere at the temperature of boiling, while stirring, gradually over 30 minutes, add a solution homomorpholine-5-it (see preparative example 125) (1.1 g, 1 mol. EQ.) in tetrahydrofuran (37 ml). The mixture is refluxed for 210 minutes, cooled to room temperature and gradually over 10 minutes, add dissolve the ü cooled to 0oC for 15 minutes, add a solution of distritbution (2,46 g, 1,1 mol. EQ.) in dichloromethane (25 ml). The reaction mixture then allow to warm to room temperature and stirred for 16 hours. To the mixture with vigorous stirring, the sodium sulfate (25 g). The resulting pellets white solid is filtered off and washed several times with dry dichloromethane. The combined filtrate and wash liquid is then evaporated under reduced pressure, and the residue is dissolved in dichloromethane (50 ml). The solution is dried over magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure, and get the oil. This oil is purified using flash column chromatography on silica gel, elwira with ethyl acetate hexane (1 : 1, by volume), and get named in the title compound (1.7 g).

TLC Rfequal to 0.5 (silica, ethyl acetate : hexane 1 : 1, by volume).

1H NMR (CDCl3): or = 1.5 (s, N), 1,8-2,0 (m, 2H), 3.45 points and 3.6 (m, 4H), of 3.7 - 3.8 (m, 4H) ppm.

Preparative example 127

Hydrochloride homomorpholine

The compound of preparative example 126 (1.7 g) is dissolved in ethyl acetate (51 ml) and the solution cooled to 0oC. Then through the mixture for 30 min the ATEM through the solution for 16 hours miss nitrogen. During this time in the sediment falls a white solid, which is filtered off and then washed with cold ethyl acetate (5 ml). Then the white solid is dried under reduced pressure for 4 hours, and get named in the title compound (0,92 g).

1H NMR (CDCl3): = 2,25 - 2,4 (m, 2H), of 3.25 to 3.45 (m, 4H), at 3.9 (t, 2H), 3.95 to 4.0 a (m, 2H), 9,75 (s, W, 2H) ppm.

Preparative example 128

4-Benzyloxycarbonylamino

To a solution of thiomorpholine (5 g, 1 mol. EQ.) triethylamine (5.4 g, 1,1 mol. EQ.) in dichloromethane (200 ml), at 0oC and under nitrogen atmosphere, gradually, within 15 minutes, add benzylchloride (8,68 g of 1.05 mol. equiv.) then the reaction mixture was allowed to warm to room temperature and stirred for another 16 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate. The organic layer is dried using magnesium sulfate, filtered, and removed solvent under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira dichloromethane, and get named in the title compound (10 g).

TLC Rf= 0,3 (silica, dichloromethane). Elem. analysis: found: C - 59,24; N - Of 6.49; N - 5,78. For C12H15NO< to 7.4 (m, 5H) ppm.

Preparative example 129

4-Benzyloxycarbonylamino-1,1-dioxide

To a solution of 4-benzyloxycarbonylamino (see preparative example 128) (4.11 g, 1 mol. EQ.) in dichloromethane (240 ml) under nitrogen atmosphere add meta-chlorbenzoyl acid (11,96 g, 2,2 mol. equiv.) and the reaction mixture is stirred for 16 hours at room temperature. The resulting solid is filtered off and the filtrate washed with saturated aqueous sodium carbonate. The organic layer is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The resulting solid is then purified column flash chromatography on silica gel, elwira with dichloromethane-methanol (95 : 5, by volume), and get named in the title compound (0,83 g).

TLC Rf= 0,75 (silica, methanol : dichloromethane, 1 : 19, by volume). Elem. analysis: found: C - 53,21; N - Of 5.68; N - 5,14. For C12H15NO4S calculated: C - 53,51; N - 5,61; N - 5,20%.

1H NMR (CDCl3): = 2,9 - 3,1 (m, 4H), 3,9 - of 4.05 (m, 4H), of 5.15 (s, 2H), of 7.35 - 7.5 (m, 5H) ppm.

Preparative example 130

Thiomorpholine-1,1-dioxide

The compound of preparative example 129 (3.5 g, 1 mol. EQ.) dissolved IU the nom pressure for 4.5 hours. The catalyst is filtered off and the solvent is removed under reduced pressure, and the residual traces of methanol are removed by azeotropic distillation with dichloromethane. Get named in the title compound in the form of oil, which is used without further purification (1.6 g).

TLC Rf= 0,3 (silicon dioxide, ammonium hydroxide : methanol : dichloromethane, 1 : 10 : 90 by volume). ICSD m/z = 136 (m+1)+.

1H NMR (CDCl3): = 2,95 was 3.05 (m, 4H), 3,35 is - 3.45 (m, 5H) ppm.

Preparative example 131

1-(tert-Butoxycarbonyl)-4-methanesulfonylaminoethyl

To a solution of 1-(tert-butoxycarbonyl)piperazine (7 g 1 mol. EQ.) in dichloromethane, at 0oC and under nitrogen atmosphere, add triethylamine (6,29 ml of 1.2 mol. EQ. ). The mixture is vigorously stirred, adding dropwise methanesulfonanilide (3,49 ml of 1.2 mol. EQ.). The mixture is then stirred for 24 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (30 ml) and the organic layer is dried using magnesium sulfate. The organic solvent is removed under reduced pressure, and the residue is purified column flash chromatography on silica gel, elwira with ethyl acetate hexane (1 : 2, by volume), and get named in the title compound UP>+. Elem. analysis: found: C - 45,25; N - Of 7.68; N - 10,49. For C10H20N2SO4calculated: C - 45,43; N - 7,63; N - 10.60% of.

1H NMR (CDCl3): = 1,4 (, N), and 2.8 (s, 3H), 3,15 - 3,2 (m, 4H), 3,5 - 3,6 (m, 4H) ppm.

Preparative example 132

Triptorelin 1-methanesulfonylaminoethyl

To a solution of the compound of preparative example 131 (6.9 g, 1 mol. EQ.) in dichloromethane (78 ml), at 0oC and under nitrogen atmosphere, add triperoxonane acid (28 ml). The mixture was then warmed to room temperature and stirred for another 30 minutes. The solvent is removed under reduced pressure and the resulting oil azeotropic distillation with dichloromethane (30 ml). The obtained resin was treated with diethyl ether (10 ml), and get named in the title compound as a white solid (7 g).

ICSD m/z = 164 (m)+Elem. analysis: found: C - 30,10; N - 4,80; N - 10,00. For C5H12N2SO2CF2CO2H calculated: C - 30,21; N - 4,71; N - 10,07%.

1H NMR (d6-DMSO): = 2,9 (c, 3H), 3,1 - 3,3 (m, 4H), 3,3 - 3,4 (m, 4H), from 9.0 to 9.2 (s, W, 2H) ppm.

Preparative example 133

1-Diphenylmethyl-3-(4-methanesulfonylaminoethyl-1-yl)azetidin

A solution of the compound of preparative example 54 (1.5 g, 1 mol. EQ.), the L. EQ.) in acetonitrile (20 ml) under nitrogen atmosphere is stirred and refluxed for 18 hours. Add a saturated solution of sodium bicarbonate (45 ml) and the mixture extracted with ethyl acetate (CH ml). The organic solvent is removed under reduced pressure, and the residue is purified column flash chromatography on silica gel, elwira first diethyl ether and then methanol with ethyl acetate (1 : 9, by volume). Get named in the title compound (0,38 g).

TLC Rfor = 0.51 (silica, methanol : ethyl acetate, 1 : 9, by volume). ICSD m/z = 350 (m+1)+.

1H NMR (CDCl3): = 2.3 to 2.4 (m, 4H), and 2.7 (s, 3H), of 2.9 - 3.0 (m, 2H), 3,0 - 3,2 (m, 1H), 3,2 - 3,3 (m, 4H), 3,4 - 3,5 (m, 2H), 4,4 (s, 1H), 7,2 - 7,4 (m, 6N), of 7.4 - 7.5 (m, 4H) ppm.

Preparative example 134

The dihydrochloride of 3-(4-methanesulfonylaminoethyl-1-yl)azetidine

To a solution of the compound of preparative example 133 (0,350 g, 1 mol. EQ.) in dichloromethane (5 ml), at 0oC add-chloroethylphosphonic (0.15 ml, 1,5 mol. equiv.) and the reaction mixture is stirred for 24 hours. The solvent is removed under reduced pressure, the residue is dissolved in methanol (10 ml) and refluxed for 1 hour. Then pH of the mixture was adjusted to 3 using intense races and the resulting resin is treated with diethyl ether (5 ml). Get named in the title compound as a white solid (0.12 g). ICSD m/z = 219 (m)+.

Preparative example 135

Endo-3-acetoxy-8-methyl-8-azabicyclo [3,2,1] octane

A mixture of tropine (20 g), acetic anhydride (20 ml) and pyridine (1 ml) was stirred at room temperature for 24 hours under nitrogen atmosphere. The mixture is then poured on ice, add 4 drops of concentrated hydrochloric acid and allowing the solution to stand for 30 minutes. Part of the solvent is removed under reduced pressure, and the mixture is treated with saturated aqueous sodium bicarbonate (20 ml) and ethyl acetate (50 ml). The layers separated, and the aqueous layer was additionally extracted with ethyl acetate (CH ml). The organic extracts are combined and dried (MgSO4). The solvent is removed under reduced pressure, and get named in the title compound (4 g).

TLC Rf= 0,2 (silicon dioxide, ammonium hydroxide : methanol : dichloromethane, 1 : 9 : 90 by volume).

1H NMR (CDCl3): 1.6 to 1.7 (m, 2H), 1,9 - 2,2 (m, 7H), 2.05 is - of 2.15 (m, 2H, in), 2.25 (m, 2H), 3,1-3,2 (m, 2H), 5,1 (t, 1H) ppm.

Preparative example 136

Hydrochloride endo-3-acetoxy-8-azabicyclo [3,2,1] octane

To a solution of the compound of preparative example 135 (3.8 g, 1 mol. acqu.), and the reaction mixture is stirred for 30 minutes. Then remove the solvent under reduced pressure, and the residue is dissolved in methanol (50 ml) and refluxed for 1 hour. Then remove the solvent under reduced pressure, and the resulting resin is treated with diethyl ether (10 ml) and ethyl acetate (5 ml), and get named in the title compound as a yellow powder (3.7 g).

1H NMR (d6- DMSO): = 1,8-2,4 (m, 11H), 3,8-4,0 (m, 2H), 4,9-5,0 (m, 1H), 8,9-9,4 (m, 2H) ppm.

Preparative example 137

5(S)-1-Cyclopropylmethyl-5-(3,4-dichlorophenyl)-5 - formylmethyl-2-piperidin

Into a solution of the compound of preparative example 141 (0,763 g, 1 mol. EQ.) in methanol (24 ml) in nitrogen atmosphere at -78oC, for 30 minutes to let the ozone at 50 ml/min (using the charge of 1.5 And for generating ozone from oxygen). Then reduce the current to zero, and through the reaction mixture for 2 minutes, allow oxygen at a speed of 5 ml/min. Then stop flowing oxygen through the reaction mixture for 20 minutes miss nitrogen. Then, gently, drop by drop, add a solution of dimethyl sulfide (1.7 ml, 10 mol. EQ.) in methanol (3.5 ml) and the reaction mixture is left to warm d is treated with ethyl acetate (20 ml) and water (15 ml). The organic layer is separated, and the aqueous layer was additionally extracted with ethyl acetate (2x20 ml). The organic layers are then combined, dried using sodium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure. Get named in the title compound (0,69 g), which is used without further purification.

TLC Rf= 0,31 (silica, ethyl acetate). ICSD m/z = 340 (m)+.

1H NMR (CDCl3): = 0,2 - 0,4 (m, 2H), of 0.5 - 0.7 (m, 2H), from 1.0 to 1.15 (m, 1H), a 2.0 to 2.25 (m, 2H), 2,3 at 2.45 (m, 1H), 2,6 - 2,8 (m, 1H), 2,9 - 3,05 (m, 1H), 3,1 - 3,2 (m, 1H), 3,4 - 3,6 (m, 2H), 3,9 - 4,0 (m, 1H), 4,05 - to 4.15 (m, 1H), 7,15 to 7.2 (m, 1H), and 7.3 - 7.5 (m, 2H), and 9.5 (s, 1H) ppm.

Preparative examples from 138 140

Connections the following, given in the table. 23 preparative examples, having the General formula:

< / BR>
get a manner similar to preparative method of example 137, using the appropriate starting arylpiperazine (see preparative examples 142-144).

Footnote

1. Clear column flash chromatography, elwira with a gradient solvent of ethyl acetate with hexane (60 : 40 to 100 : 0, by volume).

Preparative example 141

5(S)-5-Allyl-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidin

Potassium hydroxide (0,78 g, 1 mol. EQ.based temperatures. To this solution add a solution of the compound of preparative example 145 (0,982 g, 1 mol. EQ.) and cyclopropanemethylamine (0,37 ml to 1.1 mol. EQ.) in dimethyl sulfoxide (20 ml). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture is treated with ethyl acetate (50 ml) and water (20 ml), and remove the aqueous layer. The organic layer is then washed with water (3h20 ml), dried using sodium sulfate, filtered and evaporated to dryness under reduced pressure. The resulting clear resin column flash chromatography on silica gel, elwira methanol with dichloromethane (1 : 19 by volume), and get named in the title compound (0,763 g).

TLC Rf= 0,33 (silica, methanol : dichloromethane, 1 : 19, by volume).

ICSD m/z = 338 (m)+.

1H NMR (CDCl3): = 0,2 - 0,4 (m, 2H), of 0.5 - 0.7 (m, 2H), from 1.0 to 1.15 (m, 1H), a 2.0 to 2.25 (m, 3H), of 2.3 to 2.6 (m, 3H), 3,1 - of 3.25 (m, 1H), 3,4 - 3,6 (m, 2H), 3,65 to 3.8 (m, 1H), 5,0 - of 5.05 (m, 2H), 5,2 - 5,5 (m, 1H), 7,15 to 7.2 (m, 1H), and 7.4 - 7.5 (m, 2H) ppm.

Preparative examples 142 144

Connections the following, given in the table. 24 preparative examples, having the General formula;

< / BR>
get a manner similar to the method of preparative example 141 using as the source of vases tronie notes

1. As the initial substance use bromaline derived.

2. As the initial substance use p-toluensulfonate derived.

Preparative example 145

5(S)-5-Allyl-5-(3,4-dichlorophenyl)-2(1H)-piperidin

A solution of the compound of preparative example 146 (120 mg) in ethanol (5 ml) is refluxed with concentrated sulfuric acid (0.4 ml) for 24 hours. The reaction mixture was diluted with water (5 ml) and alkalinized using sodium carbonate. The solution is extracted with ethyl acetate (2x10 ml). The combined organic layers are dried using anhydrous magnesium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure. The remainder chromatographic on silica gel, elwira with a gradient solvent of dichloromethane with methanol (from 100 : 0 to 97 : 3 to 95 : 5, by volume). Get named in the title compound (10 mg).

ICSD m/z = 284 (m+1)+. TLC Rf= 0,4 (silica, CH2Cl2: CH3OH, 95 : 5 by volume).

[]25589= 31,2o(c = 0,00125).

1H NMR (CDCl3): = 2,0 - 2,2 (m, 3H), of 2.3 - 2.5 (m, 2H), 2,5 - 2,6 (m, 1H), 3,4 (d, 1H), 3,6 (d, 1H), 4,9 - of 5.05 (m, 2H), 5.25 - in to 5.4 (m, 1H), 6,0 (s, W, 1H), 7,15 to 7.2 (m, 1H), and 7.4 - 7.5 (m, 2H) ppm.


A solution of the compound of preparative example 147 (1 g, 1 mol. EQ.) in diethyl ether (200 ml), at 0oC and under nitrogen atmosphere, is added with stirring, dropwise, over 1 hour to a suspension of lithium aluminum hydride (3.7 g, 1 mol. EQ. ) in diethyl ether (200 ml). The reaction mixture is stirred for 1 hour at 0oC. Add water (3,7 ml), and then add 15% (V/V) aqueous solution of sodium hydroxide (3,7 ml) and water (11,1 ml). The mixture is stirred for 15 minutes, filtered, and the filtrate is evaporated to dryness under reduced pressure. Get the oil, which after standing for 18 hours gives gelatinousness resin. The resin is treated with ethyl acetate (200 ml) and 2N hydrochloric acid (100 ml). The organic portion is separated, dried using anhydrous magnesium sulfate, filtered, and under reduced pressure removed from the filtrate the solvent. The obtained solid substance chromatographic on silica gel, elwira with a gradient solvent of dichloromethane with methanol (from 100 : 1 to 95 : 5 and 90 : 10, by volume), and get named in the title compound (21,4 g).

ICSD m/z = 369 (m)+.

1H NMR (CDCl3): = of 0.7-0.8 (m, 3H), 0.9 to 1.0 (m, 3H), of 1.6 - 1.8 (m, 1H), 1,95 - 2,2 (m, 3H), 2,2 - 2,4 (m, 1H), 2,4 - by 2.55 (m, 1H), 2.8 to 3.0 (m, 1H), 3,3 - 3,5 (m, 2H), 3.6 and 4.0 (m, 3H), 4,9 - 5,1
2-(3 (S)-3-Cyano-3-(3,4-dichlorophenyl) Gex-5-EN-1-yl)-4 (S)-4-isopropylimidazole

A solution of the compound of preparative example 148 (3 g, 1 mol. EQ.) and S-valinol (1.04 g, 1 mol. EQ.) in toluene (30 ml) is refluxed under conditions in Dean-stark for 18 hours. Then add toluene and the reaction mixture is refluxed for 48 hours. Then the toluene is removed by evaporation under reduced pressure, and the residue chromatographic on silica gel, elwira with a gradient solvent of hexane diethyl ether (100 : 0 to 80 : 20 and 60 : 40, by volume), and get named in the title compound (1 g).

ICSD m/z = 365 (m)+.

1H NMR (CDCl3): = 0,8 (d, 3H), of 0.95 (m, 3H), of 1.6 - 1.8 (m, 1H), 2,05 - 2,3 (m, 2H), 2,4 - by 2.55 (m, 2H), 2,6 - 2,8 (m, 2H), 3,8 - 4,0 (m, 2H), 4,15 - 4,2 (m, 1H), 5,1 - 5,2 (m, 2H), 5.5 to 5.7 (m, 1H), 7,2 - 7,25 (m, 1H), 7,5 - of 7.55 (m, 2H) ppm.

Preparative example 148

4(S)-4-Cyano-4-(3,4-dichlorophenyl)hept-6-ANOVA acid

To a solution of the compound of preparative example 149 (5.5 g) in dichloromethane (100 ml) with stirring, add 1N hydrochloric acid (100 ml). Then remove the aqueous layer and the organic portion was washed with 1N hydrochloric acid (70 ml). The organic layer is dried using anhydrous magnesium sulfate, filtered, and filtr m/z = 316 (m+NH4)+.

1H NMR (CDCl3): = 2,15 - 2,8 (m, 6N), 5,1 - a 5.25 (m, 2H), 5,55 - 5,7 (m, 1H), 7,2 - 7,25 (m, 1H), 7.5 to at 7.55 (m, 2H) ppm.

Preparative example 149

(R)-(+)-1-(1-Naphthyl) atramonova salt 4(S)-4-cyano-4-(3,4-dichlorophenyl)hept-6-ene acid

To a solution of the compound of preparative example 150 (16 g) in ethyl acetate (50 ml) add R-(+)-1-(1-naphthyl) ethylamine (4.8 g). The solution is stirred for 30 minutes at room temperature, and then at reduced pressure to remove the solvent and obtain a resin. The resin is partially dissolved in hexane with diethyl ether (4 : 1, by volume, 150 ml) and scratching on the walls, to cause crystallization. Thus obtained white solid is filtered off and three times crystallized from ethyl acetate. Get named in the title compound (4.9 g), so pl. 153-154oC.

[]25589= -7,1oC (=0,0012).

1H NMR (CDCl3): = 1,6 (d, 3H), of 2.0 - 2.2 (m, 2H), 2,25 - 2,5 (m, 2H), 2.5 and 2.7 (m, 2H), 3,8 - 4,1 (s, W, 3H), 5,0 - 5,2 (m, 3H), 5.5 to 5.7 (m, 1H), 7,15 - 7,25 (m, 1H), 4,7 - 4,6 (m, 6N), of 7.75 (d, 1H), 7,9 (d, 1H) ppm.

Preparative example 150

4-Cyano-4-(3,4-dichlorophenyl) hept-6-ANOVA acid

To a suspension of 60% (V/V) dispersion of sodium hydride (231 g) dimitrakopoulou (17 l), -10oC ) (806,5 g) in tetrahydrofuran (6 l). The reaction mixture was allowed to warm to room temperature for 22 hours. Then the reaction mixture is cooled to -10oC. at the same time, in an atmosphere of nitrogen and at -10oC, with stirring, dropwise, over 2 hours, a solution of the compound of preparative example 151 (1633,5 g) in tetrahydrofuran (2.5 l) is added to tetrahydropyranol suspension (2.5 l) 60% (V/V) dispersion of sodium hydride in oil (221 g) in 2.5 l of tetrahydrofuran. When adding end, this second reaction mixture was allowed to warm to room temperature for 18 hours. Then this reaction mixture is cooled to - 10oC, and for 3 hours kanyoro in the above-mentioned mixture of the sodium salt of 3-bromopropane acid. The reaction mixture for 5 hours warm at 50oC. Then the reaction mixture is cooled, poured into water (8 l) and alkalinized to pH of 9.3, using an aqueous solution of sodium bicarbonate. This mixture was washed with dichloromethane (5 x 2 l) and the aqueous portion is acidified to a pH of 1.0 using concentrated hydrochloric acid. The aqueous solution is extracted with dichloromethane (4x2,5 l) and the organic layers combined, dried using anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. Get jeltova substances cream color (1155,3 g), used without any additional purification.

TLC Rf= 0,42 (silica, methanol : dichloromethane, 1 : 9, by volume). ICSD m/z = 316 (m+NH4)+.

1H NMR (CDCl3): = 2,15 - 2,8 (m, 6N), 5,1 - a 5.25 (m, 2H), 5,55 - 5,7 (m, 1H), 7,2 - 7,25 (m, 1H), 7.5 to at 7.55 (m, 2H) ppm.

Preparative example 151

2-(3,4-Dichlorophenyl)Penta-4-enitel

To a solution of 3,4-dichlorobenzonitrile (800 g, 4,3 mol. EQ.) in cyclohexane (16 l) at room temperature, with stirring, carefully add aqueous sodium hydroxide solution (1600 g of sodium hydroxide in 8 l of water). The addition causes an increase in the temperature of the reaction mixture to 50oC. Then add allylbromide (572 g, 1,1 mol. EQ.) and the hydrate of Tetra-n-butylammonium (40 g 0,03 mol. equiv.) and the reaction mixture is stirred for 1 hour at 50oC. the Aqueous phase is removed, the organic layer washed with water (10 l). The organic phase is filtered through silica gel (1 kg) under reduced pressure, and receive the filtrate solution is yellow. From the filtrate under reduced pressure to remove the solvent, and get named in the title compound as oil (960 g) 70% purity, which is used without any additional purification.

TLC Rf=UB>3): = 2,6 - of 2.75 (m, 2H), 3,85 (t, 1H), 5,1 - a 5.25 (m, 2H), 5,7 - 5,9 (m, 1H), 7,2 - 7,25 (m, 2H), 7.5 to at 7.55 (m, 2H) ppm.

Preparative example 152

Methanesulfonate 1-(tert-butoxycarbonyl)-3- (piperazine-1-yl)-azetidine

Melt piperazine (149,2 g, 8 mol. EQ.) and then add 1-(tert-butoxycarbonyl)-3-methanesulfonanilide (see publication of the application for international patent WOES/19059) (54,5 g, 217 mmol). The mixture is then heated at 115oC for 24 hours. The reaction mixture is cooled, and the excess piperazine removed under reduced pressure. The residue is purified column flash chromatography on silica gel, using as eluent methanol with dichloromethane (5 : 95, by volume), and get named in the title compound (51 g).

ICSD m/z = 242 (m+1)+.

1H NMR (CDCl3): = 1,4 (m, N), 2,5 - 2,6 (m, 4H), 3,1 - of 3.25 (m, 5H), of 3.7 - 3.8 (m, 2H), 3,9 - 3,95 (m, 2H), 4,6 (W, s, 1H) ppm.

Preparative example 153

3-(4-Aminosulphonylphenyl-1-yl)-1-(tert-butoxycarbonyl)- azetidin

A solution of the compound of preparative example 152 (50 g, to 132.6 mmol) and sulphonamide (88 g of 6.9 mol. EQ.) in 1,4-dioxane (1300 ml) is refluxed for 55 hours. The solution is cooled, and removed the solvent under reduced pressure. The residue is purified colonoscopy because it allows the and get named in the title compound (50 g).

1H NMR (CDCl3): = 1,45 (s, N), 2,4 - 2,5 (m, 4H), 3,1 - 3,2 (m, 1H), 3.25 to 3,3 (m, 4H), of 3.75 to 3.8 (m, 2H), 3,85 to - 3.9 (m, 2H), 4,3 (W, s, 2H) ppm.

Preparative example 154

Bestrefiratecom 3-(4-aminosulphonylphenyl-1-yl) azetidine

To a solution of the compound of preparative example 153 (364 mg, to 1.14 mmol) in dichloromethane (6 ml), under nitrogen atmosphere and at 0oC, gradually add triperoxonane acid (3 ml, 35 mol. EQ.) and the reaction mixture was allowed to warm to room temperature for 2 hours. Then under reduced pressure to remove the solvent, and the residue is subjected to azeotropic distillation with dichloromethane (3x10 ml). The resulting oil is treated with diethyl ether, and get named in the title compound (379 mg), used without further purification.

1H NMR (CDCl3): = 2,4 - 2,6 (m, 4H), 2.95 and is 3.15 (m, 4H), 3,35 - 3,5 (m, 1H), of 3.8 - 4.1 (m, 4H), 6,6 - 6,8 (m, 2H), 8,6 cent to 8.85 (m, 3H) ppm.

Preparative example 155

1,1-Dicyclopropyl

To a suspension of methyltriphenylphosphonium (133,5 mg, 3 mol. EQ.) in dimethyl sulfoxide (200 ml), under nitrogen atmosphere, is added dropwise within 15 minutes with stirring a solution of tertbutoxide potassium (42 g, 3 mol. EQ.) in dimethyl sulfoxide (200 ml). Add diznee 16 hours at room temperature. The reaction mixture was poured into 20% (V/V) aqueous solution of sodium chloride (900 ml), and add ice (200 g). The mixture is extracted with diethyl ether (2 l) and the organic extract washed with water (2x1,5 l), dried using anhydrous magnesium sulfate, and filtered. Then from the filtrate under reduced pressure to remove the solvent, and the residue shaken with a mixture of diethyl ether (50 ml) and hexane (50 ml).

The mixture is filtered, removed from the filtrate solvent under reduced pressure, and the residue shaken with a mixture of hexane and diethyl ether (50 ml, 9: 1, by volume). The mixture is filtered, removed from the filtrate solvent under reduced pressure, and get named in the title compound (4.5 g).

1H NMR (CDCl3): = 0,55 - 0,7 (m, 8H), from 1.3 to 1.45 (m, 2H), 4,6 (s, 2H) ppm.

Preparative example 156

2.2-Dicyclopropyl

To a solution of the compound of preparative example 155 (1 g, 9,24 mmol) in tetrahydrofuran (15 ml), under nitrogen atmosphere, add 9-borabicyclo[3.3.1] nonan (18,5 ml of 0.5 M solution in tetrahydrofuran, 1 mol. equiv.) and the solution is stirred for 18 hours. Add sodium hydroxide (is 3.08 ml of 3M aqueous solution, 1 mol. EQ.) and then ethanol (5 ml). The reaction mixture is cooled to 5oC, and add the peroxide volochine 1 hour. The reaction mixture is treated with ethyl acetate (50 ml) and water (50 ml), the organic phase is separated and dried using anhydrous magnesium sulfate. The solution is filtered, and the solvent removed from the filtrate under reduced pressure. Get the oil that chromatographic on silica gel, elwira diethyl ether with hexane (2 : 1, by volume), and get named in the title compound (160 mg).

1H NMR (CDCl3): = 0,1 - 0,35 (m, 4H), 0,4 - 0,55 (m, 4H), 0.6 to 0.8 (m, 2H), 1,65 (t, 1H), and 3.7 (t, 2H) ppm.

Preparative example 157

2-Methanesulfonylaminoethyl

Named the title compound is obtained by the method similar to the method of preparative example 13, except that they use to 1.2 mol. EQ. of triethylamine and 1.3 mol. EQ. methanesulfonanilide. ICSD m/z = 182 (m+NH4)+.

1H NMR (CDCl3): a = 0.1 to 0.15 (m, 2H), 0,5 - 0,55 (m, 2H), of 0.7 - 0.8 (m, 1H), 1.6 to 1.7 (m, 2H), 3.00 and (s, 3H), 4,25 - 4,3 (m, 2H) ppm.

Preparative example 158

2.2-Dicyclopropyl-1-methanesulfonamide

To a solution of the compound of preparative example 156 (1 g, 7.9 mmol) in dichloromethane (20 ml), 5oC and under nitrogen atmosphere, add triethylamine (1,32 ml of 1.2 mol. equiv.) then add methanesulfonanilide (of 0.67 ml, 1,1 mol. equiv.) and R is abayat with ethyl acetate (100 ml) and water (100 ml). The organic layer is separated, dried using anhydrous magnesium sulfate, filtered and from the filtrate to remove the solvent under reduced pressure. The remainder chromatographic on silica gel, elwira diethyl ether with hexane (2 : 1, by volume), and get named in the title compound (1.5 g).

1H NMR (CDCl3): a = 0.1 to 0.15 (m, 4H), of 0.2 - 0.3 (m, 5H), 0,35 - 0,4 (m, 2H), 3.00 and (s, 3H), 4,15 (d, 2H) ppm.

Preparative example 159

N-Methylsulfinylpropyl

To a solution of chloride of Sulfuryl (35,7 ml, 3 mol. EQ.) in acetonitrile (30 ml) under nitrogen atmosphere added methylamine hydrochloride (10 g, 148 mmol), and then acetonitrile (30 ml). The reaction mixture is refluxed for 20 hours. The reaction mixture is cooled to room temperature, and the mixture is concentrated under reduced pressure. Get named in the title compound (20,51 g), which is used without further purification.

1H NMR (CDCl3): = 3.0 (d, 3H), 5,7 (s, W, 1H) ppm.

Preparative examples 160 and 161

Connect two of the following, given in the table. 25 examples get a manner similar to the method of preparative example 159 using chloride Sulfuryl and the corresponding amines.

Preparative example at -78oC add fuming sulfuric acid (0.5 ml). To this solution is added dropwise liquid isobutylene (50 ml). The reaction mixture then allow to warm to room temperature and stirred for 18 hours. The mixture is then poured into ice saturated aqueous solution of sodium carbonate. The mixture is extracted with dichloromethane (2x40 ml) and the combined extracts washed with brine (40 ml). The organic layer is dried using magnesium sulfate. The mixture is filtered, and the solvent removed from the filtrate under reduced pressure. Get named in the title compound as a yellow oil which is used without further purification.

TLC Rf= 0,25 (silica, methanol : dichloromethane, 1 : 9, by volume). ICSD m/z = of 267.8 (m+18)+.

1H NMR (CDCl3): = a 1.3 to 1.45 (m, 11N), of 1.45 to 1.6 (m, 2H), 1,7 - of 1.85 (t, 2H), 3,35 (t, 2H) ppm.

Preparative example 163

4-(2-Benzoxazolyl) piperidine

A mixture of 2-aminophenol (20 g, 183 mmol), isonipecotic acid (23.7 g, 1 mol. EQ.) and polyphosphoric acid (50 ml) is heated under stirring for 2 hours, the reaction mixture is cooled, poured onto ice (400 g), and add solid sodium hydroxide (85 g) to achieve pH 8. Solid hoteltravel portion named the title compound was prepared by the above-mentioned extraction of the filtrate with dichloromethane (I ml). The combined organic extracts are dried using anhydrous magnesium sulfate, filtered, and removed from the filtrate solvent under reduced pressure. Get named in the title compound (9 g).

1H NMR (CDCl3): = 1,9 - 2,1 (m, 3H), 2,15 - 2,3 (m, 2H), 2,8 - 2,9 (m, 2H), 3,1 - 3,3 (m, 3H), 7.3 to 7,35 (m, 2H), 7.5 to at 7.55 (m, 1H), 7,7 - of 7.75 (m, 1H) ppm.

Preparative example 164

1-Benzyl-4-(tert-butoxycarbonylamino) piperidine

To a solution of 4-amino-1-benzylpiperidine (10 g, 53 mmol) in dichloromethane (200 ml) at 0oC add di-tert-BUTYLCARBAMATE (12,6 g, 1,1 mol. equiv.) and the mixture is stirred at room temperature for 16 hours.

The crude reaction mixture is washed with 2% (W/V) aqueous solution of sodium bicarbonate (300 ml), dried using anhydrous magnesium sulfate, and the solution is filtered. Remove from the filtrate solvent under reduced pressure gives a solid beige color, which is purified column chromatography on silica gel, elwira with dichloromethane-methanol (95 : 5, by volume). Get named in the title compound (13.1 g).

TLC Rf= 0,3 (dichloromethane : methanol, 95 : 5, by volume).

1H NMR (CDCl3): = 1,35 - 1,5 (m, 11N), 1,85 - of 1.95 (m, 2H), 2.05 is - of 2.15 (m, 2H), 2,75 - 2,8 (m, 2H), 3,4 - 3,5 (m, 3H), 4>To a solution of the compound of preparative example 164 (13,1 g, 45,1 mmol) in ethanol (135 ml) is added 10% (V/V) palladium-on-coal (0.6 g), and the mixture is stirred in hydrogen atmosphere at 414 kPa (60 f/d2) for 16 hours. After that add another 0.6 g of the catalyst, and the mixture is stirred in hydrogen atmosphere at 414 kPa (60 f/d2) within 72 hours. Then the reaction mixture is filtered through a filter on a cellulose basis, and the filtrate concentrated under reduced pressure, and get a solid substance. This solid proscout with diethyl ether (50 ml), filtered, and the obtained solid is dried under reduced pressure. Get named in the title compound (8.1 g).

1H NMR (CDCl3): = 1,15 - 1,3 (m, 2H), 1,35 - 1,5 (m, 10H), 1,9 - of 1.95 (m, 2H), 2,6 - 2,7 (m, 2H), 3,0 - 3,1 (m, 2H), 3,5 (s, W, 1H), 4,4 (s, W, 1H) ppm.

Preparative example 166

1-Benzyloxycarbonyl-4-hydroxypiperidine

To a solution of 4-hydroxypiperidine (4,2 g, 41 mmol) in dichloromethane (50 ml), at 0oC and under nitrogen atmosphere, gradually add benzylchloride (7.7 ml to 1.3 mol. equiv.) then add triethylamine (6,94 ml of 1.2 mol. EQ.). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture is washed nasyshennye, and the filtrate evaporated under reduced pressure to dryness. The crude product was purified flash chromatography on silica gel, elwira methanol with dichloromethane (1 : 20, by volume), and get named in the title compound (9,24 g).

TLC Rf= 0,68 (silica, methanol : dichloromethane, 1 : 10, by volume). ICSD m/z = 236 (m+1)+.

1H NMR (CDCl3): = 1,35 - of 1.55 (m, 2H), of 1.75 (m, 1H), 1,8 - 2,0 (m, 2H), 3,1 - 3,2 (m, 2H), 3,8 - 4,0 (m, 3H), of 5.15 (s, 2H), 7,35 (s, 5H) ppm.

Preparative example 167

1-Benzyloxycarbonyl-(4-tert-Butylochka) piperidine

To a solution of the compound of preparative example 166 (9,24 g) in cyclohexane with dichloromethane (120 ml, 3 : 1, by volume), at 0oC and under nitrogen atmosphere, add tert-butyltrichlorosilane (14.1 ml, 2 mol. EQ. and athirat of boron TRIFLUORIDE (0.8 ml, 0,16 mol. EQ.). The reaction mixture was allowed to warm to room temperature and stirred for 48 hours.

The solvent is removed from the reaction mixture by evaporation under reduced pressure. The reaction mixture was dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution (30 ml). The aqueous layer was extracted with ethyl acetate (CH ml). The organic layers are combined, dried using anhydrous magnesium sulfate, filtered, the and silica gel, elwira methanol with dichloromethane (3: 97 by volume), and then the second time column chromatography on silica gel, elwira methanol with dichloromethane (1 : 5, by volume). Get named in the title compound (9 g).

TLC Rf= 0,56 (silica, methanol : dichloromethane, 1 : 20, by volume). ICSD m/z = 292 (m+1)+.

1H NMR (CDCl3): = 1,2 (C, N), 1,4 - of 1.55 (m, 2H), 1,65 - 1,8 (m, 2H), 3,1 - of 3.25 (m, 2H), up 3.6 - 3.7 (m, 1H), 3,8 - 4,0 (m, 2H), further 5.15 (s, 2H), and 7.4 (s, 5H) ppm.

Preparative example 168

4-(tert-Butylochka) piperidine

The compound of preparative example 167 (to 8.41 g, 28.8 mmol) dissolved in ethanol (100 ml) and add 10% (V/V) palladium-on-coal (0.34 g). The mixture is stirred in hydrogen atmosphere at a pressure of 414 kPa (60 f/d2) within 24 hours. The catalyst is filtered off and the solvent removed from the filtrate under reduced pressure. The resulting oil is purified column chromatography on silica gel, elwira mixture of concentrated aqueous ammonia with methanol and dichloromethane (1 : 10 : 89, by volume). Get named in the title compound (2.48 in).

TLC Rf= 0,23 (silicon dioxide, conc. aq. aq ammonia : methanol : dichloromethane, 1 : 10 : 89, by volume). ICSD m/z = 158 (m+1)+.

(23,69 g, 8 mol. equiv.) and add 1-(tert-butoxycarbonyl)-3-methanesulfonanilide (see publication of the application for international patent WOES/19059) (8,64 g, to 34.4 mmol). The mixture is heated at 120oC for 15 hours under nitrogen atmosphere. The reaction mixture is cooled to room temperature, and the excess piperazine removed under reduced pressure. The residue is then chromatographic on silica gel using gradient elution (methanol : dichloromethane, change from 1 : 19 to 1 : 4, by volume), and get named in the title compound (6,32 g).

ICSD m/z = 242 (m+1)+.

1H NMR (CDCl3): = 1,35 (s, N), 2,4 - 2,5 (m, 4H), 3,0 - 3,1 (m, 5H), 3,2 - 4,2 (m, W, 5H) ppm.

Preparative example 170

4-(tert-Butoxycarbonyl)-3-(4-methylsulfonylmethane - 1-yl)-azetidin

To a solution of the compound of preparative example 169 (8.06 g, is 21.3 mmol) in dichloromethane (160 ml), add triethylamine (13.4 ml). The solution is kept in a nitrogen atmosphere and cooled to 0oC. is Added dropwise, within 30 minutes, methansulfonate (the 5.25 ml, to 7.77 g, 3 mol. EQ.). The reaction mixture was allowed to warm to room temperature for 2.5 hours and then stirred for 18 hours. The reaction mixture was washed with water (I ml), and then salt astvatsatryan from the filtrate under reduced pressure. The remainder chromatographic on silica gel, elwira mixture of concentrated aqueous ammonia with methanol and dichloromethane (1 : 10 : 89, by volume). The product after this phase chromatography again subjected to column chromatography on silica gel, elwira methanol with ethyl acetate (1 : 10, by volume). Get named in the title compound (0.9 g).

TLC Rfor = 0.6 (silica, conc. aq. aq ammonia : methanol : dichloromethane, 1 : 10 : 89, by volume). ICSD m/z = 320 (m+1)+.

1H NMR (CDCl3): = 1,4 (, N), a 2.45 (t, N), and 3.8 (s, 3H), 3,1 - 3,2 (m, 1H), 3,2 - 3,3 (m, 4H), of 3.75 to 3.8 (m, 2H), 3,9 - 4,0 (m, 2H) ppm.

Preparative example 171

3-(4-Benzylpiperazine-1-yl)-1-(tert-butoxycarbonyl)-azetidin

To a solution of the compound of preparative example 169 (3,3 g) in dichloromethane (70 ml) at room temperature and under nitrogen atmosphere, add triethylamine (4,06 ml) and benzoyl chloride (2.30 ml). The mixture is stirred at room temperature for 16 hours. The reaction mixture was washed with water (I ml) and brine (CH ml), dried using anhydrous magnesium sulfate, filtered, and removed solvent from the filtrate under reduced pressure. The residue is subjected to column chromatography on silica gel, elwira ethylacetate arbonyl)-3-(4-methylcarbamoylmethyl-1-yl)-azetidin

To a solution of the compound of preparative example 169 (3,3 g) in dichloromethane (70 ml) was added methyl isocyanate, and the mixture is stirred at room temperature for 72 hours. Then remove dichloromethane, passing through a solution of nitrogen. The residue is dissolved in dichloromethane (100 ml) and washed with 10% (V/V) aqueous solution of sodium bicarbonate (100 ml) and then brine (100 ml). The organic layer is dried using anhydrous magnesium sulfate, filtered, and removed solvent from the filtrate under reduced pressure. The remainder chromatographic on silica gel, elwira with dichloromethane-methanol (95 : 5, by volume), and get named in the title compound (1.8 g).

ICSD m/z = 299 (m+1)+.

1H NMR (CDCl3): = 1,40 (c, 9H), of 2.25 to 2.35 (m, 4H), 2,8 - to 2.85 (m, 3H), 3,0 - 3,1 (m, 1H), 3,35 - 3,4 (m, 4H), 3.75 to of 3.85 (m, 2H), 3,9 - 3,95 (m, 2H), 4,4 (s, W, 1H) ppm.

Preparative example 173

1-(tert-Butoxycarbonyl)-3-(4-methylaminoacetaldehyde - 1-yl)-azetidin

To a solution of the compound of preparative example 169 (500 mg, 2,07 mmol) in acetonitrile (5 ml) in an atmosphere of nitrogen was added triethylamine (0,43 ml of 1.5 mol. EQ.). Add dropwise a solution of preparative example 159 (295 mg, 1,1 mol. EQ.) in acetonitrile (3 ml) and the reaction mixture heated at 90

The residue is treated with ethyl acetate (50 ml) and water (50 ml). The organic layer is separated and washed with brine (50 ml), dried using anhydrous magnesium sulfate, filtered, and removed solvent from the filtrate under reduced pressure. The remainder chromatographic on silica gel, elwira methanol with dichloromethane (1 : 19 by volume), get named in the title compound (374 mg).

TLC Rf= 0,73 (silica, methanol : dichloromethane, 1 : 9, by volume). ICSD m/z = 335 (m+1)+.

1H NMR (CDCl3): = 1,4 (, N), 2,4 - of 2.45 (m, 4H), 2,7 - of 2.75 (m, 3H), 3.1 to 3.15 in (m, 1H), 3.25 to 3,3 (m, 4H), 3.75 to a 3.9 (m, 4H), 4,15 - 4,2 (m, 1H) ppm.

Preparative examples 174 and 175

Connections the following, given in the table. 26 examples, having the General formula:

< / BR>
get a manner similar to preparative method of example 173, using as starting substances, the same piperazine and related sulfhemoglobin (see preparative examples 160 and 161).

Preparative example 176

1-(tert-Butoxycarbonyl)-3-(4-methoxypiperidine-1-yl)azetidin

To a solution of the compound of preparative example 71 (1 g, 4,12 mmol) in tetrahydrofuran (12 ml), at 0oC and under nitrogen atmosphere, add in two installments, 60% (V/V) dispersion of the hydride is square), and the mixture is stirred for 16 hours.

Remove the solvent under reduced pressure, and the residue is treated with ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic layer is separated and dried using anhydrous sodium sulfate. The mixture is filtered and from the filtrate under reduced pressure to remove the solvent, and get the oil. This crude product is purified column chromatography on silica gel, elwira methanol with dichloromethane (3 : 97 by volume), and get named in the title compound as a colorless oil (0.84 g).

TLC Rf= 0,2 (silica, methanol : dichloromethane, 3 : 97 by volume).

1H NMR (CDCl3): = 1,4 (m, N), of 1.55 to 1.7 (m, 2H), 1,8 - 2,0 (m, 2H), a 2.0 to 2.15 (m, 2H), 2,55 - to 2.65 (m, 2H), 3,0 - 3,1 (m, 1H), 3,2 - 3,3 (m, 1H), 3,35 (s, 3H), of 3.75 to 3.8 (m, 2H), 3,9-4,0 (m, 2H) ppm.

Preparative examples 177 and 178

Connections the following, given in the table. 27 examples, having the General formula:

< / BR>
receive, using a method similar to the preparative method of example 176, by using as starting substances, the same piperidinol and, as alkiliruyuscikh agents, respectively, ethyliodide or n-propyliodide.

Preparative example 179

Bestreferat.ru (18 ml), at 0oC and under nitrogen atmosphere, is added dropwise triperoxonane acid (9 ml), and the mixture is stirred at room temperature for 1 hour. The solvent is carefully removed by evaporation under reduced pressure, and the residue is subjected to azeotropic distillation with dichloromethane (3h20 ml). The resulting oil was washed with diethyl ether (3h20 ml). Then add ethyl acetate (50 ml), and precipitated precipitate is collected by filtration and dried. Get named in the title compound (132 mg). The second portion is named the title compound (186 mg) obtained by concentration of the filtrate under reduced pressure, when you get the oil. This oil is treated with diethyl ether and ethyl acetate, and the resulting solid is collected by filtration and dried. Get named in the title compound (0.32 g).

1H NMR (d6-DMSO): = 2,3 at 2.45 (m, 4H), 3,3 - 3,7 (m, 5H), 3,8 - of 4.05 (m, 5H), 7.3 to 7.4 (m, 5H), 8,65 (s, W, 1H) ppm.

Preparative example 180

The dihydrochloride of 3-(4-ethoxycarbonylpyrimidine-1-yl) azetidine

To a solution of the compound of preparative example 105 (7.5 g, 19,81 mmol) in dichloromethane (100 ml), at 0oC and under nitrogen atmosphere, add-chloroethylphosphonic (2,6 ml of 1.2 mol. equiv.) and the reaction mixture load.), and the reaction mixture is refluxed for 3 hours. The reaction mixture is cooled to room temperature, filtered, and the filtrate is acidified to pH 3 with a solution of hydrogen chloride in methanol. The mixture is filtered, and removed solvent by evaporation under reduced pressure. The residue was washed with diethyl ether (CH ml) and then proscout with diethyl ether.

Get a solid substance is filtered off and dried, and get named in the title compound (5.1 g).

ICSD m/z = 199 (m+1)+.

Preparative example 181

Bestrefiratecom 3-(4-tert-butoxycarbonylamino-1-yl) -azetidine

To a solution of the compound of preparative example 106 (6.8 g, 16,1 mmol) in dichloromethane (70 ml), at 0oC and under nitrogen atmosphere, add alpha chloroethylphosphonic (1,91 ml to 1.1 mol. equiv.) and the mixture is stirred at room temperature for 1 hour. After that, the solvent is removed by evaporation under reduced pressure, the residue is dissolved in methanol (80 ml) and add potassium carbonate (4.9 g, 2,2 mol. equiv.) the mixture is then refluxed for 1 hour. The reaction mixture is cooled to room temperature, filtered, and the filtrate is acidified to pH 5 by adding euroscut with diethyl ether, and get a solid substance. This solid is collected by filtration and dried under reduced pressure, and get named in the title compound as crude product, which is used directly.

Preparative example 182

5(S)-5-(3,4-Dichlorophenyl)-1-(4,4-diverticulectomy)-5- (1,3-dioxolane-2-ylmethyl)-2-piperidin

To a mixture of dimethyl sulfoxide (50 ml) and potassium hydroxide (2.1 g), with stirring at 0oC and under nitrogen atmosphere, add a solution of the compound of example 123 (C) (3 g, 9.1 mmol) in dimethyl sulfoxide (50 ml), and then add the compound of preparative example 11 (3.1 g), and the mixture is stirred at room temperature for 16 hours. Add water (300 ml) and brine (300 ml) and the mixture extracted with ethyl acetate (CH ml). The combined organic extracts washed with brine (300 ml), dried using anhydrous magnesium sulfate, filtered, and removed from the filtrate solvent under reduced pressure. The remainder chromatographic on silica gel, elwira with a gradient solvent of ethyl acetate with hexane (change from 1 : 1 to 7 : 3 to 4 : 1 to pure ethyl acetate), and get named in the title compound (3.3 g).

ICSD m/z = 462 (m+1)+.

1

Preparative examples from 183 186

Connections the following, given in the table. 28 preparative examples, having the General formula:

< / BR>
(* - asymmetric center)

get a manner similar to preparative method of example 182, using the appropriate piperidine (see example 123 (b) and preparative example 193) and the corresponding source mesylates for preparative examples 183 and 184, and the corresponding source of bromide for preparative examples 185 and 186.

Footnotes

1. Receive (S)-enantiomer.

2. Receive (R)-enantiomer.

Preparative example 187

5(S)-5-(3,4-Dichlorophenyl)-5-formylmethyl-2(1H)-piperidin

A solution of the compound of example 123 (b) (280 mg, 0.85 mmol) in tetrahydrofuran (3 ml) and 5N hydrochloric acid (3 ml) was stirred at room temperature under nitrogen atmosphere for 4 hours. The reaction mixture was poured into a mixture of ethyl acetate (20 ml) and saturated aqueous sodium bicarbonate solution (20 ml). The organic phase is separated, dried using anhydrous magnesium sulfate, filter and remove the solvent by evaporation under reduced pressure. Get named in the title compound (283 mg), used without extra the tx2">

Preparative examples from 188 through 191

Connections the following, given in the table. 29 examples, having the General formula:

< / BR>
(* - asymmetric center)

get a manner similar to preparative method of example 187, by using as starting compounds corresponding dioxolane (see preparative examples 183-186).

The footnotes.

1. The product contains as an impurity approx. 35% of the original dioxolane, according to1H NMR spectroscopy.

2. The product contains as an impurity approx. 6% source dioxolane, according to1H NMR spectroscopy.

3. Receive (R)-enantiomer.

4. Receive (S)-enantiomer.

Preparative example 192

4(R)-4-Cyano-4-(3,4-dichlorophenyl)-5-(1,3-dioxolane-2-yl)-pentane-1-OIC acid

The filtrate, obtained by fractional crystallization of salts of (S)-(-)-alpha-methylbenzylamine 4(R)- and 4(S)-4-cyano (3,4-dichlorophenyl)-5-(1,3-dioxolane-2-yl)pentane-1-OIC acid (see example 123 (a)), evaporated to dryness under reduced pressure, and get a solid substance (800 g). This solid is dissolved in methylethylketone (3 l) and water (300 ml) by boiling under reflux. Add a further quantity (1 l) meta happens therefore, the volume of solution is reduced to half by evaporation under reduced pressure. The mixture is left to stand for 72 hours, forming a solid, which is filtered and washed with methyl ethyl ketone (CH ml). This white solid is dried at 35oC under reduced pressure for 3 hours, and then dissolved in methyl ethyl ketone (1.5 l) and water (165 ml). The solution is refluxed for 1 hour. Add ethyl ketone (700 ml) and the mixture again enter the seed crystal of the desired connection, and leave the mixture to stand for 56 hours. The resulting solid is filtered off and washed with methyl ethyl ketone (CH ml), then dried under reduced pressure at 35oC for 4 hours, and get (S)-(-)-alpha-methylbenzylamine salt named the title compound (133 g). HPLC (column Ultron ES-OVM, the mobile phase = buffer 0.01 M KH2PO4pH of 6.6 : acetonitrile, 92 : 8, by volume, flow rate = 1 ml/min) shows that the said salt is present in the amount of 98.4 per cent.

This salt is in turn named the title compound in a manner similar to the method described in example 123 (a) for its enantiomer.

1H NMR (CDCl3the first example 193

5(R)-5-(3,4-Dichlorophenyl)-5-(1,3-dioxolane-2-ylmethyl)-2-(1H)- piperidin

Named the title compound is obtained by the method similar to the method of example 123 (b), except that as a starting substance is used as a compound of preparative example 192.

1H NMR (CDCl3): = 1,85 - of 1.95 (m, 1H), a 2.0 to 2.25 (m, 4H), 2,35 - 2,4 (m, 1H), 3,45 - 3,55 (m, 1H), 3,65 of 3.75 (m, 2H), 3,8 - 3,9 (m, 3H), 4,35 - 4,4 (m, 1H), x 6.15 (s, W, 1H), 7,5 was 7.45 (m, 3H) ppm.

1. Derivatives (azetidin-1-yl-alkyl)lactams of General formula (I)

< / BR>
or their pharmaceutically acceptable salt,

where R is - (C1- C6)-alkyl, optionally substituted by COOH, -COO((C1- C4)-alkyl), (C3- C7-cycloalkyl, aryl or Het1and (C3- C7-cycloalkyl, optionally substituted by 1 or 2 substituents, each independently selected from (C1- C4)-alkyl and fluorine;

R1is phenyl, optionally substituted 1 or 2 halosubstituted;

R2- -CONR3R4, -CONR5(C3- C7-cycloalkyl), -NR3R4That gets3or a group of the formula

< / BR>
or

< / BR>
R3and R4each and independently selected among H and (C1- C4)-alkyl, (C1- C4)-alkyl, substituted ubiraetsa among H, (C1- C4)-alkyl, optionally substituted by fluorine, and (C3- C7-cycloalkyl-(C1- C4)-alkyl;

R7Is H, a hydroxyl group, or phenyl;

R8is a hydroxyl group, or (C2- C5-alkanoyloxy;

X - (C1- C4-alkylen;

X1- directional communication;

X2- directional communication or CO;

W is methylene, CH((C1- C4-alkoxygroup), CHCO2H, CHCO2((C1- C4)-alkyl), CH(benzoxazol-2-yl), CHNR5R6, CHNR5COR5, CHNR5(SO2C1- C4alkyl), CHNR5COO(C1- C4alkyl), O, S(O)p, NR5, NSO2(C1- C4alkyl), NSO2NR5R6, NSO2(morpholino)group, CH(OH), NCONR5R6, NCOR5, NCO(aryl) or NCO2((C1- C4)-alkyl);

m = 1;

n = 1 or 2 when W is other than methylene, and n = 0 or 1 when W is methylene;

p = 0, 1, or 2;

the term "aryl" used to determine R, W denotes phenyl, optionally substituted by 1 or 2 substituents, independently selected from (C1- C4)-alkyl, halogen, -OR5, fluorine (C1- C4)-alkyl, (C2- C5)-alkanoyl, -SO2NR5R6or FeNi is the function group, containing either 1 or 2 nitrogen heteroatom;

the term "Het3"used to determine the R2means N-linked 5-membered cyclic heteroaryl group containing 1 or 2 nitrogen heteroatoms.

2. Connection on p. 1, where R - (C1- C6)-alkyl, optionally substituted by-COOH, -COO((C1- C4)-alkyl), (C3- C7-cycloalkyl, aryl or Het1and mentioned cycloalkyl optionally substituted by 1 or 2 substituents, each of which is independently chosen among (C1- C4)-alkyl and fluorine; R1is phenyl, optionally substituted by 1 or 2 halogen substituents; R2- -CONR3R4, -CONR5((C3- C7-cycloalkyl), -NR3R4That gets3or a group of the formula

< / BR>
where R3and R4each and independently choose among (C1- C4)-alkyl and (C1- C4)-alkyl, substituted hydroxyl group, or (C1- C4-alkoxygroup; R5and R6each and independently chosen among H, (C1- C4)-alkyl, optionally substituted by fluorine, and (C3- C7-cycloalkyl-(C1- C4)-alkyl; R7Is H, a hydroxyl group, or phenyl; R8- hydroxyl groups, CHCO2((C1- C4)alkyl), CH(benzoxazol-2-yl), CHNR5R6, CHNR5COR5, CHNR5(SO2(C1- C4)-alkyl), CHNR5COO (C1- C4)-alkyl), O, S(O)p, NR5, NSO2(C1- C4)-alkyl), NSO2NR5R6, NSO2(morpholinopropan), NCONR5R6, NCOR5, NCO(aryl) or NCO2((C1- C4)-alkyl); n = 1 or 2 when W is other than methylene, and n = 0 or 1 when W represents a methylene, and p = 0, 1, or 2; and X, X1X2, m, aryl, Het1and Gets3matter under item 1.

3. Connection on p. 2, where R - (C1- C6)-alkyl, optionally substituted by-COOH, -COO((C1- C4)-alkyl), (C3- C7-cycloalkyl, optionally substituted by 1 or 2 substituents, each of which is independently selected among (C1- C4)-alkyl and fluorine, phenyl, optionally substituted by 1 or 2 substituents, each of which is independently selected among (C1- C4)-alkyl, halogen, (C1- C4-alkoxygroup, fluorine(C1- C4)-alkyl, (C2- C5)-alkanoyl, -SO2N((C1- C4)-alkyl)2and phenyl, or a 5 - or 6-membered heteroaryl group containing 1 or 2 heteroatom and is among fluorine and chlorine; R2- -CONR3R4, -CONR5((C3- C7-cycloalkyl, -NR3R4N-attached 5-membered cyclic heteroaryl group containing 1 or 2 nitrogen heteroatom, or a group of the formula

< / BR>
where R3and R4each and independently selected among methyl and (C1- C4)-alkyl, substituted hydroxyl group or a methoxy group; R5and R6each independently selected among H, methyl, trifloromethyl and cyclopropylmethyl; R7Is H, a hydroxyl group, or phenyl, R8is a hydroxyl group or acetyloxy; W is methylene, CH(OH), CHOCH3, CHOCH2CH3CHO(CH2)2CH3, CHOC(CH3)3, CHCO2H, CHCO2CH3, CHCO2CH2CH3CH(benzoxazol-2-yl), CHNH2, CHNHCH2(cyclopropyl), CHNHCOCH3, CHNHSO2CH3, CHNHCO2C(CH3)3, O, S(O)p, NH, NCH3, NCH2(cyclopropyl), NSO2CH3, NSO2NH2, NSO2NHCH3, NSO2N(CH3)2,

NSO2(morpholinopropan), NCONH2, NCONHCH3, NCOCH3, NCOCF3, NCO(phenyl) or NCO2C(CH3)3; n = 1 or 2 when W is other than methylene, and n = 0 or 1 when W is methylene, and p = 0, 1, or 2; and X, X1X1- C4)-alkyl), (C3- C7-cycloalkyl, optionally substituted by 1 or 2 substituents, each independently is selected among methyl and fluorine, phenyl, optionally substituted by 1 or 2 substituents, each independently is selected among methyl, fluorine, chlorine, metoxygroup, trifloromethyl, acetyl SO2N(CH3)2and phenyl, or pyridinyl; and R1, R2X, X1X2and m have values under item 3.

5. Connection on p. 4, R - 5-carboxypentyl, 5-tert-butyl-oxycarbonyl, cyclopropylmethyl, dicyclopropyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methylcyclohexyl, 4,4-diverticulectomy, 2-cyclopropylethyl, 2,2-dicyclopropyl, 1-cyclohexylethyl, 2-cyclohexylethyl, cycloheptylmethyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-tormentil, 2,4-dichlorobenzyl, 3-methoxybenzyl, 2-trifloromethyl, 3,5-di(trifluoromethyl)benzyl, 3-acetylphenyl, 3-(N,N-dimethylsulphamoyl) benzyl, 4-phenylbenzyl, 1-phenylethyl, 2-pyridinylmethyl, 3-pyridinylmethyl or 4-pyridinylmethyl; R1- phenyl, 3,4-differenl, 3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl; R2- N-(2-methoxyethyl)-N-methylcarbamoyl, N-cyclohexylcarbonyl, N-(roppa, imidazol-1-yl, 3-hydroxypyrrolidine-1-yl, piperidine-1-yl, 2,6-dimethylpiperidin-1-yl, 3-hydroxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-methoxypiperidine-1-yl, 4-ethoxypyridine-1-yl, 4-(H-propoxy)piperidine-1-yl, 4-(tert-butoxy)-piperidine-1-yl, 4-carboxypeptidase-1-yl, 4-ethoxycarbonylpyrimidine-1-yl, 4-ethoxycarbonylpyrimidine-1-yl, 4-(benzoxazol-2-yl)-piperidine-1-yl, 4-aminopiperidin-1-yl, 4-cyclopropanemethylamine-1-yl, 4-acetamidophenyl-1-yl, 4-methanesulfonamido-1-yl, 4-(tert-butoxycarbonylamino)-piperidine-1-yl, morpholinopropan, 2-phenylmorpholine, homomorpholine, thiomorpholine, 1-associationtype, 1,1-dioxothiazolidine, piperazine-1-yl, 4-methylpiperazin-1-yl, 4-cyclopropylamines-1-yl, 4-methanesulfonylaminoethyl-1-yl, 4-amino-sulfonylureas-1-yl, 4-methylaminoacetaldehyde-1-yl, 4-dimethylaminocarbonylmethyl-1-yl, 4-morpholinobutyrophenone-1-yl, 4-carbamoylbiphenyl-1-yl, 4-N-methylcarbamoylmethyl-1-yl, 4-acetylpiperidine-1-yl, 4-triftoratsetilatsetonom-1-yl, 4-benzylpiperazine-1-yl, 4-(tert-butoxycarbonyl) piperazine-1-yl, pyrrolidin-1-yl-carbonyl, piperidine-1-ylcarbonyl, 3-ecomorphology, 3-hydroxy-8-azabicyclo[3,2.1]Oct-8-yl or 3-atomic charges-8-adabiat values under item 4.

6. Connection on p. 5, where R is cyclopropylmethyl, 2-cyclopropylethyl, cyclohexylmethyl, 4,4-diverticulectomy, cycloheptylmethyl or benzyl; R13,4 - differenl, 4-chlorophenyl or 3,4-dichlorophenyl; R2- 4-aminopiperidin-1-yl, 4-carboxypeptidase-1-yl, 4-hydroxypiperidine-1-yl, morpholinopropan and 1-associationtype; X is ethylene; X2- directional communication; m = 1; X1- directional communication.

7. The compound according to any one of paragraphs.1 - 6, where X is-CH2CH2-, and the above-mentioned compound has the (S)-stereochemistry at the position of joining of the groups X and R1to lactam ring.

8. Connection on p. 1, where

(I) R - cyclopropylmethyl, R13,4 - dichlorophenyl, R2- morpholinopropan, X-CH2CH2-, X1- directional communication, m = 1;

(II) R - 4,4-diverticulectomy; R13,4-dichlorophenyl; R2- morpholinopropan; X-CH2CH2-; X1- directional communication and m = 1;

(III) R - 4,4-diverticulectomy, R13,4 - dichlorophenyl; R2- 4-aminopiperidin-1-yl; X is-CH2CH2-, X1- directional communication and m = 1;

(IV) R - 4,4-diverticulectomy; R13,4 - dichlorophenyl; R2- 4-hydroxypiperidine-1-yl; X is-CH2CH2-; X1- directional communication and m>
- directional communication and m = 1;

(VI) R - cyclopropylmethyl; R13,4 - dichlorophenyl; R2- 4-carboxypeptidase-1-yl; X is-CH2CH2-; X1- directional communication and m = 1, or

(VII) R - cyclohexylmethyl; R13,4 - dichlorophenyl; R2- 4-carboxypeptidase-1-yl; X is-CH2CH2-; X1- directional communication and m = 1;

or any such connection (S)-stereochemistry at the position of joining of the groups X and R1to lactam ring, or any pharmaceutically acceptable salt.

9. Connection on p. 1 of formula (I)

< / BR>
or its pharmaceutically acceptable salt,

where R is - (C1- C6)-alkyl, optionally substituted (C3- C7-cycloalkyl, aryl or Het1and mentioned cycloalkyl optionally substituted by 1 or 2 substituents, each independently selected among (C1- C4)-alkyl and fluorine;

R1is phenyl, optionally substituted 1 or 2 halosubstituted;

R2- -CONR3R4, -CONH((C3- C7-cycloalkyl), -CON((C1- C4)-alkyl)-((C3- C7-cycloalkyl), -NR3R4That gets3or a group of the formula

< / BR>
R3and R4each and independently selected among H, (C1- C
R5and R6each and independently selected among H and (C1- C4)-alkyl substituted by fluorine;

R7- H, hydroxy-group or phenyl;

R8is a hydroxyl group, or (C2- C5-alkanoyloxy;

X - (C1- C4-alkylen;

W is methylene, CH(OH), CH((C1- C4)-alkoxygroup), CHNH((C1- C4)-alkyl), CHN(C1- C4)-alkyl)2, CHNHSO2((C1- C4)-alkyl), CHN((C1- C4)-alkyl) (SO2((C1- C4)-alkyl), O, S(O)p, NH, N((C1- C4-alkyl), NSO2((C1- C4)-alkyl), NSO2NH2, NSO2NH((C1- C4)-alkyl), NSO2N((C1- C4)-alkyl)2, NCONH2, NCONH((C1- C4)-alkyl), NCON((C1- C4)-alkyl)2or NCO2((C1- C4)-alkyl);

m = 1;

n = 1 or 2 when W is other than methylene, and n = 0 or 1 when W is methylene;

p = 0, 1, or 2;

the term "aryl" used to determine R, W denotes phenyl, optionally substituted by 1 or 2 substituents, each independently selected among (C1- C4)-alkyl, halogen, (C1- C4-alkoxygroup, fluorine(C1- C4)-alkyl, fluorine(C1- C4)-SUB>1
- C4)-alkyl)2and phenyl;

the term "Het1"used to determine R, means a 5 - or 6-membered cyclic heteroaryl group containing either 1 or 2 nitrogen heteroatom;

the term "Het3"used to determine the R2means N-attached 5-membered cyclic heteroaryl group containing 1 or 2 nitrogen heteroatom.

10. Pharmaceutical composition for the treatment of diseases by producing antagonistic action on tachykinin, working in human NK1-, NK2- or NK3-the receptor, or combinations thereof, characterized in that it contains an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 9 as the active ingredient together with a pharmaceutically acceptable diluent or carrier.

11. The composition according to p. 10, where the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a disorder of the Central nervous system (CNS), such as fear, depression, dementia or psychosis, gastrointestinal (GI) disorder such as functional bowel disease, sindona in the urogenital tract, such as incontinence, hyperreflexia or cystitis, pulmonary violation, such as chronic obstruction of the respiratory tract, allergies such as eczema, contact dermatitis or rhinitis, allergic disease, such as caused by poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, neuralgia when shingles or after shingles, cough or acute or chronic pain.

12. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of paragraphs.1 to 9 or a composition according to p. 10, used in the treatment of diseases by producing antagonistic action on tachykinin, working in human NK1-, NK2- or NK3the receptor or both.

13. The method of treatment of a human, which disease is treated by producing antagonistic action on tachykinin, working in human NK1-, NK2- or NK3the receptor or in combination, which comprises treating said human an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, or a composition according to any one of paragraphs.1 - 9 or 10, respectively.

14.mA or inflammatory bowel disease, disorder of the Central nervous system (CNS), such as fear, depression, dementia or psychosis, gastrointestinal (GI) disorder such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflux, fecal incontinence, colitis or Crohn's disease, a disorder in the urogenital tract, such as incontinence, hyperreflexia or cystitis, pulmonary violation, such as chronic obstruction of the respiratory tract, allergies such as eczema, contact dermatitis or rhinitis, allergic disease, such as caused by poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, neuralgia when shingles or after shingles, cough or acute or chronic pain.

15. Derivatives of lactams of the formula

(a)

< / BR>
in which R, R1and m have values under item 1;

(b)

< / BR>
in which X1, R, R1, R2and m have values under item 1;

(C)

< / BR>
in which X, X1, R1, R2and m have values under item 1;

(d)

< / BR>
where R10group of the formula-NZ4R4,

< / BR>
where WA- NZ4or CHNZ4R5;

X, X1X2de Z5- protective group;

X, X1, R, R1and m have values under item 1.

Priority signs and items:

09.08.94 on PP.1 - 15 (in addition to the compounds where R is cyclopropylmethyl, R13,4 - dichlorophenyl, X is-CH2CH2-; -X1-R2- 4-aminosulphonylphenyl-1-yl; m = 1).

06.09.94 on PP.1 - 15 (where R is cyclopropylmethyl, R13,4 - dichlorophenyl, X is-CH2CH2-; -X1-R2- 4-aminosulphonylphenyl-1-yl; m = 1).

 

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