Derivatives of piperidine, methods for their preparing, pharmaceutical composition based on thereof, their using and treatment method

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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

18 cl, 138 tbl, 527 ex

 

The scope of the invention

The present invention relates to new piperidine compound, which has an excellent antagonistic activity against receptor tachykinin.

Background of the invention

Tachykinin is a General name for a group of neuropeptides, and were previously known to occur in mammalian substance P (hereinafter referred to as SP), neurokinin and neurokinin-Century, it is Known that these peptides demonstrate various types of biological activities by binding their respective receptors, which exist in vivo (neurokinin-1, neurokinin-2, neurokinin-3). Among them, the SP is one of those peptides that were known before the rest of neuropeptides and were studied in detail. Its existence was confirmed in the extract obtained from the intestinal tract of the horse in 1931, and he was a peptide consisting of 11 amino acids, the structure of which was determined in 1971.

SP is present throughout the peripheral nervous system and has physiological activities such as vasodilator capacity, promotion of vascular permeability, smooth muscle contraction, stimulation of neurons), activity against salivation, diuretic activity, immunological activity, etc. and can also perform neurotransmi the characteristic function of primary sensory neurons. More specifically, it is known that SP released from the end of the posterior horns of the spinal cord after the pain impulse, transmits information about pain secondary neurons, and that SP released from peripheral endings, induces an inflammatory response of the receptors. On the basis of these facts, believe that SP is involved in different types of diseases (for example, pain, inflammation, allergies, pollakiuria, incontinence, respiratory diseases, mental disorders, depression, anxiety, vomiting etc), and also believe that SP is associated with dementia type Alzheimer's disease [Review: Physiological Reviews, vol.73, pp.229-308 (1993), Journal of Autonomic Pharmacology, vol.13, pp.23-93 (1993)].

To date, as a therapeutic agent for the above diseases (especially vomiting, depression, disorders of the urinary system and so on) found no connection that would have excellent antagonistic activity against receptors tachykinin (especially antagonistic activity against SP receptor), and at the same time would have a satisfactory stability (metabolism, dynamics in vivo and absorption), etc. were Therefore undertaken the search for compounds that would have excellent antagonistic activity against receptors tachykinin and would have been enough to meet writelines clinical effect in as a therapeutic agent.

Accordingly, the purpose of the present invention is to obtain compounds with excellent antagonistic activity against receptors tachykinin and with satisfactory clinical effect from the point of view of security, stability (metabolism, dynamics in vivo and absorption), etc.

The invention

The present invention relates to a piperidine compound represented by the formula [I]:

where ring A is optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, R1represents optionally substituted alkyl group, optionally substituted hydroxyl group, substituted Tilney group, substituted carbonyl group, a substituted sulfinyl group, substituted sulfonyloxy group or a group represented by the formula:

where R11and R12the same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyloxy group optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as a heteroatom, where the heterocyclic group is optionally Zam is schena, and the nitrogen atom in the heterocyclic group is optionally oxidized; or R11and R12taken together with the adjacent nitrogen atom, form a heterocyclic group selected from piperidino, azacycloheptane group, pyrrolidinone, imidazolidinyl group, hexahydropyridine group, thiazolidine group, morpholinopropan, triazolines group, tetrazolyl group and parinello group, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized,

R2represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by-N(R3)-, where R3represents a hydrogen atom or optionally substituted alkyl group, R4represents a hydrogen atom or optionally substituted alkyl group, or its pharmaceutically acceptable salt.

In the present invention, the ring A represents an optionally substituted benzene ring, and examples of the substituents of the benzene ring can serve as an alkyl group, halogen atom, cyano, optionally protected hydroxyl or alkoxygroup. The A ring which may contain 1 to 3 of these substituents, which may be the same or different.

In the present invention, ring B represents an optionally substituted benzene ring, and examples of the substituents of the benzene ring are trigalogenmetany group, halogen atom, cyano, phenyl group, heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as a heteroatom, an alkyl group, optionally substituted hydroxyl or alkoxygroup. The ring B can contain from 1 to 3 of these substituents, which may be the same or different.

Preferred examples of ring A and ring B in the compound of the present invention are compounds in which ring A represents A benzene ring of the formula:

and ring B represents a benzene ring of the formula:

where A1, A2and A3the same or different, and each represents a hydrogen atom, halogen atom, alkyl group, optionally protected hydroxyl or alkoxygroup,

B1B2and B3the same or different, and each represents a hydrogen atom, trigalogenmetany group, halogen atom, cyano, phenyl group, heterocyclic group containing 1-4 atoms selected from a nitrogen atom,oxygen atom and sulfur atom as a heteroatom, alkyl group, optionally protected hydroxyl or alkoxygroup. Examples trihalogenmethanes groups are triptorelin group or trichlorethylene group, etc. Examples of the heterocyclic group is tetrataenia group, etc.

In the present invention, examples of the protective group optionally protected hydroxyl group are conventional protective group such as optionally substituted arylalkyl group, optionally substituted silyl group, and acyl group. Of the above preferred arylalkyl groups such as benzyl group and penicilina group, substituted silyl groups such as tert-butyldimethylsilyl group and tert-butyldiphenylsilyl group, and acyl groups such as formyl group, acetyl group, propylaniline group, melonella group, calolina group and benzoline group.

In the present invention, R1represents optionally substituted alkyl group, optionally substituted hydroxyl group, substituted Tilney group, substituted carbonyl group, a substituted sulfinyl group, substituted sulfonyloxy group or a group represented by the formula:

where R11and R12the same or different, and each performance is to place a hydrogen atom, substituted carbonyl group, a substituted sulfonyloxy group optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as heteroatoms, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized; or R11and R12taken together with the adjacent nitrogen atom, form a heterocyclic group selected from piperidino, azacycloheptane group, pyrrolidinone, imidazolidinyl group, hexahydropyridine group, thiazolidine group, morpholinopropan, triazolines group, tetrazolyl group and parinello group, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized.

Of the above R1preferably represents optionally substituted alkyl group, optionally substituted hydroxyl group, substituted Tilney group, substituted carbonyl group, a substituted sulfinyl group, substituted sulfonyloxy group or a group represented by the formula:

where R11and R12the same or different, and each represents a hydrogen atom, a substituted carbonyl group, for sennou sulfonyloxy group, optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as heteroatoms, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized,

further preferred optionally substituted alkyl group, optionally substituted hydroxyl group, substituted Tolna group, substituted carbonyl group, a substituted sulfonylurea group, substituted sulfonylurea group, or a group represented by the formula:

where R11represents a substituted carbonyl group, a substituted sulfonyloxy group or heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as heteroatoms, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized, and R12represents a hydrogen atom, optionally substituted alkyl group, substituted carbonyl group, a substituted sulfonyloxy group or heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as heteroatoms, where the heterocyclic group is optionally substituted and the nitrogen atom in GE is eroticlinks group optionally oxidized.

In the present invention, examples of the substituents in the optionally substituted alkyl group, R1are alkoxycarbonyl group, morpholinosydnonimine group, predicamentkayley group, morpholinomethyl group, piperidinecarboxylate group, substituted alkoxyphenyl group, dialkylaminoalkyl group, hydroxyl group, hydroxyethylaminomethyl or alkylpiperidines group.

In the present invention, examples of the substituents optionally substituted hydroxyl group, R1are

(1) substituted carbonyl group,

(2) substituted sulfonylurea group,

(3) substituted sulfonylurea group or

(4) optionally substituted alkyl group.

Examples of substituents of the substituted carbonyl group in the above p.(1) are optionally substituted alkyl group, optionally substituted alkoxygroup, substituted amino group, a monocyclic heterocyclic group containing 1-2 atoms selected from nitrogen atom and oxygen atom as heteroatoms (monocyclic heterocyclic group optionally substituted). Example of the substituent optionally substituted alkyl group is a hydroxyl group. Examples of the substituents optionally substituted alkoxygroup Vlada alkoxygroup, hydroxyl group or halogen atom. Examples of substituents of the substituted amino group is an alkyl group substituted by a group selected from a halogen atom, dialkylamino, piperidinyl group, morpholinopropan, carboxyl group, morpholinomethyl group, dialkylaminoalkyl group, alkylaminocarbonyl group, alkanolamines, allylthiourea, alkoxygroup, alkylsulfonyl group, alkanoyloxy and hydroxyl group; piperidinyl group, substituted hydroxyalkanoates group or alkoxyalkanols group; or dialkylaminoalkyl group. Examples of the monocyclic heterocyclic groups are morpholinopropan, piperazinilnom group, imidazolidinyl group, thiomorpholine, piperidinium, furilla group, tetrahydroisoquinoline group or pyrrolidinyl group. Examples of the substituents monocyclic heterocyclic group include an alkyl group which may be substituted by a hydroxyl group, alkoxycarbonyl group, a carboxyl group, hydroxyethylaminophenol group, alkoxycarbonyl group, alkyldiethanolamine group, alkylanthraquinones group, alkylanthraquinones group or morpholinopropan, oxo the group or hydroxyl group.

Examples of substituents of substituted sulfanilic group p. in the above(2) is an alkyl group or thienyl group.

Examples of substituents of substituted sulfonyloxy group p. in the above(3) is an alkyl group or thienyl group.

Examples of the optional substituents of substituted alkyl groups in the above p.(4) are optionally substituted hydroxyl group, dialkylamino or monocyclic heterocyclic group containing 1-4 atoms selected from a sulfur atom, nitrogen atom and oxygen atom as heteroatoms (monocyclic heterocyclic group optionally substituted). Examples of the optional substituents of the substituted hydroxyl group are an alkyl group, alkylsulfonyl group or tetrahydropyranyl group. Examples of the monocyclic heterocyclic groups are Peregrina group, piperidinyl group, morpholinopropan, isoxazolidine group, thiazolidine group, tetrataenia group or pyrrolidinyl group. Examples of the substituents monocyclic heterocyclic group are an alkyl group or phenyl group.

In the present invention, examples of substituents of substituted Tilney group in R1are substituted phenyl group, substituted carbonyl group is or optionally substituted alkyl group. Examples of the substituent of the substituted phenyl group is a hydroxyl group. Examples of the substituent of the substituted carbonyl group is an alkyl group. Examples of the optional substituents of substituted alkyl groups are alkylaminocarbonyl group, dialkylaminoalkyl group, alkoxycarbonylmethyl, hydroxylcontaining, morpholinosydnonimine, hydroxyethylaminophenol, alkanoyloxy or hydroxyl group.

In the present invention, examples of the substituents of the substituted carbonyl group, R1are hydroxyl group, alkoxygroup, optionally substituted amino group or a monocyclic heterocyclic group containing 1-4 atoms selected from a sulfur atom, nitrogen atom and oxygen atom as heteroatoms (monocyclic heterocyclic group optionally substituted). Examples of the optional substituents of the substituted amino groups are (a) the group(s) selected from peredelnoj group, optionally substituted hydroxyl group(or groups), pyrimidines group, alkylpyridine, personalni groups and alkyl groups, optionally substituted hydroxyl group or cyano. Examples of the monocyclic heterocyclic groups are piperidinium, p is personalgripe, morpholinopropan, thiomorpholine or pyrrolidinone.

Examples of the substituents monocyclic heterocyclic group include an alkyl group, a hydroxyl group, oxoprop, piramidalnaya group, piratininga group, alkylsulfonyl group, alcoolica group or hydroxyalkyl group.

In the present invention, examples of substituents of substituted sulfanilic group in R1are hydroxyl group or an optionally substituted alkyl group. Examples of the substituent optionally substituted alkyl group is a hydroxyl group.

In the present invention, examples of the substituent substituted sulfonyloxy group in R1is an optionally substituted alkyl group. Examples of the optional substituents of the substituted alkyl group are hydroxyl group or alkanoyloxy.

In the present invention, if R1represents a group of the formula:

(1) examples of the substituents of the substituted carbonyl in R11and R12are optionally substituted alkyl group, optionally substituted alkoxygroup, optionally substituted aryl group, substituted amino group or heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and the atom is sulfur as heteroatoms, where heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized. Examples of the optional substituents of substituted alkyl groups are alkylaminocarbonyl group, dialkylaminoalkyl group in which the alkyl fragment optionally substituted hydroxyl group, aminocarbonyl group, alkoxycarbonylmethyl, alkanolamines, amino group, substituted alkoxycarbonyl group and alkyl group, amino group, substituted alkanoyloxy group and alkyl group, alkoxygroup, halogen atom, tetrataenia group, Peregrina group, furilla group, hydroxyl group, allylthiourea, 2-oxopyrrolidin, 2-aminothiazolyl group, 2-thiol-4-alkylethanolamine group, 2,2-dialkyl-1,3-DIOXOLANYL group, cycloalkyl group, alkylsulfonyl group, alkylsulfonyl group, thienyl group, 5-methyl-2,4(1H,3H)-pyrimidinedione, amino group or dialkylamino. Examples of the optional substituents of the substituted aryl group are the nitro-group or amino group, and examples of the aryl group are phenyl group, naftalina group, phenanthroline group or antarctilyne group. Examples of substituents of the substituted amino group are an alkyl group, optional for asenna group, selected from a halogen atom, alkoxygroup and hydroxyl group, and amino group is monosubstituted or disubstituted. Examples of the heterocyclic group is a saturated or unsaturated monocyclic or bicyclic aromatic group such as thienyl group, furilla group, tetrahydrofuryl group, Pernilla group, pyrrolidine group, imidazolidinyl group, pyrazolidine group, isothiazolinone group, isoxazolyl group, Peregrina group, piratininga group, pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolidinone group, imidazolidinyl group, imidazolidine group, pyrazolidinone group, piratininga group, piperideine group, piperazinilnom group, morpholinyl group, thiomorpholine group, benzothiazoline group, benzoperylene group, isobenzofuranyl group, chromadorina group, indayla group, isoindoline group, indazolinone group, polylina group, hyalinella group, naphthyridinone group, khinoksalinona group, indolenine group, kinolinna group, izochinolina group, benzothiazolyl group, benzisothiazolinone group, chinadaily group, phthalazinone group, benzoxazolyl group, benzimidazolyl group, pteridinyl the Naya group, pyridopyrimidines group, thrombilia group, chromadorina group, indolinyl group, isoindolyl group, tetrahydropyridine group, tetrahydroisoquinoline group, tetrahydroisoquinoline group, dihydroartemisinin group, etc. Of these heterocyclic groups are preferable pyridyloxy group, pyrrolidinyl group, piperazinilnom group, pinolillo group, piperidinyl group, pyramidalnou group, thiazolidine group, personilnya group, morpholinopropan, thiomorpholine, indolenine group, indolinyl group, follow group, tetrahydrofuryl group, thienyl group, etc. Examples of the substituents of the heterocyclic group are dialkylamino, alkoxycarbonyl group, morpholinoethyl group, hydroxyalkyl group, an alkyl group, benzyloxy, alkoxycarbonyl group, alcoolica group, hydroxyl group, oxoprop or formyl group.

(2) Examples of the substituents of the substituted sulfonyloxy group in R11and R12are optionally substituted alkyl group, cyanoptila group, dialkylamino or Alchemilla group. Examples of the optional substituents of the substituted alkyl group include halogen atom, hydroxyl group, dialkylamino, obazatelno substituted hydroxyl group, morpholinopropan, piperidino or 4-methylpiperazine.

(3) Examples of the optional substituents of the substituted alkyl group in R11and R12are dialkylaminoalkyl group, alkoxygroup, dialkylamino, cyano, morpholinopropan, Peregrina group or halogen atom.

(4) Heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as heteroatoms, R11and R12are saturated or unsaturated monocyclic or bicyclic aromatic heterocyclic groups such as thienyl group, furilla group, Pernilla group, pyrrolidine group, imidazolidinyl group, pyrazolidine group, isothiazolinone group, isoxazolyl group, Peregrina group, piratininga group, pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolidinone group, imidazolidinyl group, imidazolidine group, pyrazolidinone group, piratininga group, piperideine group, piperazinilnom group, morpholinyl group, benzothiazoline group, benzoperylene group, isobenzofuranyl group, chromadorina group, indayla group, isoindolyl group, indazolinone group, polylina group, hyalinella group, naphthyridinone GRU is PA, khinoksalinona group, indolenine group, kinolinna group, izochinolina group, benzothiazolyl group, benzisothiazolinone group, chinadaily group, phthalazinone group, benzoxazolyl group, benzimidazolyl group, pteridinyl group, pyridopyrimidines group, thrombilia group, chromadorina group, indolinyl group, isoindolyl group, tetrahydropyridine group, tetrahydroisoquinoline group, tetrahydroisoquinoline group, dihydroartemisinin group. Of these heterocyclic groups are preferable pyridyloxy group, pyrrolidino group, piperazinilnom group, pinolillo group, piperidinyl group, pyramidalnou group, thiazolidine group, personilnya group, morpholinopropan, indolenine group, indolinyl group, follow group, thienyl group, etc. Examples of the substituents of the heterocyclic group are dialkylamino, alkoxycarbonyl group, an alkyl group, alkoxygroup, hydroxyl group, halogen atom, etc.

Further, if R11and R12form a link between their ends, to form with the adjacent nitrogen atom a heterocyclic group selected from piperidino, azacycloheptane group, pyrrolidinone, imidazolidinyl group, Huck is hydropyridine group, thiazolidine group, morpholinopropan, triazolines group, tetrazolyl group and parinello group, then examples of the substituents of the heterocyclic group include an alkyl group, substituted alkoxygroup or a hydroxyl group, piperidinyl group, alkoxyphenyl group, alcoolica group, hydroxyl group, oxoprop and amino group.

If the nitrogen atom of the heterocyclic group is oxidized, the oxidized state of the nitrogen atom means a condition in which the nitrogen atom cationization, examples of which are N-ecomorphology or N-alkalifying.

In the present invention R2represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom.

In the present invention Deputy optionally substituted hydroxyl group, R2is an alkyl group.

In the present invention Deputy optionally substituted amino group, R2is an alkyl group.

In the present invention Deputy optionally substituted alkyl groups in R2is alkoxygroup.

In the present invention, examples of the substituents of the substituted carbonyl group, R2are the I a hydroxyl group, alkoxygroup or alkylamino.

In the present invention, examples of Z is an oxygen atom or the group-N(R3)-.

In the present invention examples R3are a hydrogen atom or optionally substituted alkyl group. Examples of the optional substituents of the substituted alkyl group in R3are hydroxyl group, alcoolica group, halogen atom, alkoxygroup or alkylamino.

In the present invention examples R4are a hydrogen atom or optionally substituted alkyl group. Examples of the optional substituents of the substituted alkyl group in R4are halogen atom, alkoxygroup or alkylamino.

Preferred compounds of the present invention are compounds in which R1represents optionally substituted alkyl group.

Preferred optional substituents of substituted alkyl groups are dialkylaminoalkyl group, morpholinosydnonimine group, hydroxyl group, alkoxycarbonyl group or hydroxyethylaminomethyl.

The preferred compounds of the present invention it is possible to specify a connection in which R1is optionally substituted hydroxyl group. Of these compounds are preferable from the unity, in which R1is optionally substituted by alkoxygroup. In addition, preferred compounds in which R1is optionally substituted by carbonyloxy.

Preferred substituents optionally substituted alkoxygroup are hydroxyl group, alkylsulfonates, tetrahydropyranyloxy, thiazolidine group, tetrataenia group, optionally substituted alkyl group or alkoxygroup, and more preferably a hydroxyl group or tetrahydropyranyloxy. Preferred substituents optionally substituted carbonyloxy are morpholinopropan, imidazolidine group, alkylamino, in which the alkyl fragment optionally substituted hydroxyl group, morpholinomethyl group, dialkylaminoalkyl group, alkylaminocarbonyl group, alkanolamines, alkylthiol, alkoxygroup, alkylsulfonyl group, alkanoyloxy or a carboxyl group; piperidino, substituted hydroxyl group, alkoxycarbonyl group, a carboxyl group, hydroxyethylaminophenol group, alkoxycarbonyl group, alkyldiethanolamine group, alkylanthraquinones group, alkylsulfonyl alkylaminocarbonyl group or hydroxyalkyl group; piperidylamine, substituted hydroxyalkanoates group or alkoxyalkanols group; thiomorpholine, in which the sulfur atom optionally substituted by oxopropoxy; oxopyrrolidin group; oxitetraciclina group; or dialkylaminoalkyl, and more preferably morpholinopropan; alkylamino, in which the alkyl fragment optionally substituted hydroxyl group; or thiomorpholine, in which the sulfur atom substituted by exography.

The preferred compounds of the present invention it is possible to specify a connection in which R1is substituted Tilney group.

Preferred substituents optionally substituted Tilney groups are alcoolica group or alkyl group, optionally substituted hydroxyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, alkoxycarbonylmethyl, hydroxylcontaining, morpholinosydnonimine, hydroxyethylaminophenol or alkanoyloxy. The preferred compounds of the present invention it is possible to specify a connection in which R1represents a substituted carbonyl group.

Preferred optional substituents of the substituted carbonyl group include ALCO is a sigroup; amino group, optionally substituted pyrimidines group or alkylpyridine; alkylamino, in which the alkyl fragment optionally substituted hydroxyl group, or cyano; di(hydroxyalkyl)amino group; pyridylamino in which it peredelnyj fragment optionally substituted hydroxyl group; piperidino, substituted hydroxy-group or oxopropoxy; piperazinone, replaced by exography, alkyl group, alkylsulfonyl group or alkanoyloxy group; morpholinopropan; thiomorpholine; or pyrrolidinones, substituted hydroxyalkyl group or a hydroxyl group, and more preferably pyrimidinamine or hydroxypiperidine.

The preferred compounds of the present invention it is possible to specify a connection in which R1is substituted sulfonyloxy group.

Preferred substituents optionally substituted sulfanilic group are an alkyl group, optionally substituted hydroxyl group or hydroxyl group, and more preferably an alkyl group, optionally substituted hydroxyl group.

As a preferred compound of the present invention it is possible to specify a connection in which R1is replaced by sulfo the ilen group.

Preferred substituents optionally substituted sulfonyloxy group are an alkyl group, optionally substituted hydroxyl group or alkanoyloxy, and more preferably an alkyl group, optionally substituted hydroxyl group.

Preferred compounds of the present invention are compounds in which R1represents a group of the formula:

where R11and R12the same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyloxy group optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as heteroatoms, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized; or R11and R12taken together with the adjacent nitrogen atom, form a heterocyclic group selected from piperidino, azacycloheptane group, pyrrolidinone, imidazolidinyl group, hexahydropyridine group, thiazolidine group, morpholinopropan, triazolines group, tetrazolyl group and parinello group, where the heterocyclic group is optionally substituted, and the atom azo is in heterocyclic group optionally oxidized.

Of these compounds, preferably a compound in which R11represents a substituted carbonyl group, and R12represents a hydrogen atom or alkyl group. Further, preferably, each of the compounds in which R11represents respectively optionally substituted alkanoyloxy group, optionally substituted aminocarbonyl group, morpholinomethyl group and piperidinylcarbonyl group, substituted alkanoyloxy group. Another preferred example is a compound in which R11is substituted sulfonyloxy group, and R12represents a hydrogen atom or alkyl group.

Preferred substituents optionally substituted alkanoyloxy groups are alcoolica group, alkylaminocarbonyl group, dialkylaminoalkyl group, aminocarbonyl group, alkoxycarbonylmethyl, alkanolamines, amino group, substituted alkoxycarbonyl group and alkyl group, amino group, substituted alkanoyloxy group and alkyl group, alkoxygroup, optionally substituted phenyl group, shriley group, tetrazolyl group, a hydroxyl group, alkylthiol, alkylsulfonyl group, alkylsulfonyl group, 2-aminothiazolyl group, 2-oxopyrrolidin is, 2-thiol-4-alkylresorcinols group or cycloalkyl group, and more preferably alkoxygroup, hydroxyl group or cycloalkyl group. Preferred substituents optionally substituted aminocarbonyl groups are a halogen atom, hydroxyl group or alkyl group, optionally substituted by alkoxygroup, and more preferably an alkyl group. Preferred substituents optionally substituted sulfonyloxy group are an alkyl group, optionally substituted hydroxyl group or halogen, Alchemilla group or dialkylamino, and more preferably an alkyl group.

Compounds of the present invention compound represented by formula [I]in which the ring A represents A benzene ring of the formula:

and ring B represents a benzene ring of the formula

where A1represents an alkyl group, a hydrogen atom, halogen atom or alkoxygroup, A2represents a hydrogen atom or a halogen atom, A3represents a hydrogen atom, B1is trigalogenmetany group, halogen atom or alkyl group, B2is trigalogenmetany group, halogen atom or alkyl group, B3represents the atom bodoro is and,

R1represents a hydroxyl group; alkyl group substituted dialkylaminoalkyl group, morpholinomethyl group, a hydroxyl group, alkoxycarbonyl group, morpholinomethyl group, hydroxyethylaminophenol or alkylpiperidines group; dihydroxyphenylethanol; alcoholcheap; allylthiourea, optionally substituted hydroxyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, alkoxycarbonylmethyl, hydroxylcontaining, morpholinosydnonimine, hydroxyethylaminophenol or alkanoyloxy; dialkyltins group; alkoxygroup, optionally substituted hydroxyl group, alkylsulfonates, tetrahydropyranyloxy, dialkylamino, peredelnoj group, triazolines group, tetrazolyl group optionally substituted alkyl group, piperidino, morpholinopropan, pyrrolidinone or alkoxygroup; thienylboronic; morpholinoethoxy; alkylpiperidines; imidazolecarboxamide; piperidinecarboxylate; morpholinylcarbonyl; alkylaminocarbonyl, in which the alkyl fragment it is certainly substituted hydroxyl group, morpholinosydnonimine group, dialkylaminoalkyl group, alkylaminocarbonyl group, alkanolamines, alkylthiol, alkoxygroup, alkylsulfonyl group, alkanoyloxy or a carboxyl group; dialkylaminomethylcarbonyl; piperidinecarboxylate, substituted hydroxyl group, alkoxycarbonyl group, a carboxyl group, hydroxyethylaminophenol group, alkoxycarbonyl group, alkyldiethanolamine group, alkylanthraquinones group, alkylanthraquinones group or hydroxyalkyl group; dialkylaminoalkyl, optionally substituted hydroxyl group; piperidinecarboxylate, substituted hydroxyalkanoates group or alkoxyalkanols group; timorgaleevich, in which the sulfur atom optionally substituted by oxopropoxy; oxopentanenitrile; oxotetrahydrothalifendine; dialkyldimethylammonium; carboxyl group; alkoxycarbonyl group; aminocarbonyl group, optionally substituted pyrimidinyl group or personalni group; alkylaminocarbonyl group in which the alkyl fragment is not necessary for the of Eden hydroxyl group or cyano; di(hydroxyalkyl)aminocarbonyl group; piperidinylcarbonyl group, in which the fragment peredelnoj group optionally substituted by a hydroxyl group; aminocarbonyl group, substituted alkylpyridine; piperidinylcarbonyl group, a substituted hydroxyl group or oxopropoxy; piperazinylcarbonyl group, substituted exography, alkyl group, pyrimidinyl group, personalni group, alkylsulfonyl group or alkanoyloxy group; morpholinosydnonimine group; tomorrooooooooow group; pyrrolidinecarbonyl group, a substituted hydroxyalkyl group or a hydroxyl group; alkylsulfonyl group, optionally substituted hydroxyl group; hydroxymethylene group; alkylsulfonyl group, optionally substituted hydroxyl group or alkanoyloxy; or a group of the formula:

where R11represents a hydrogen atom; pyridyloxy group; alkanoyloxy group optionally substituted by a group selected from alkanoyloxy group, alkylaminocarbonyl group, dialkylaminoalkyl group, aminocarbonyl group, amino group, alkoxycarbonylmethyl, alkanolamines, amino, substituted alkoxycarbonyl group and alkyl group, and is kinogruppy, substituted alkanoyloxy group and alkyl group, halogen atom, dialkylamino, alkoxygroup, optionally substituted phenyl group, shriley group, tetrazolyl group, a hydroxyl group, alkylthiol, alkylsulfonyl group, alkylsulfonyl group, 2-aminothiazolyl group, 2-oxopyrrolidin, 2,2-dialkyl-1,3-DIOXOLANYL group, 2-thiol-4-alkylresorcinols group, cycloalkyl group and 5-alkyl-2,4(1H,3H)-pyrimidinedione group; phenylcarbonylamino group, optionally substituted amino group or a nitro-group; pyridylcarbonyl group optionally substituted alkyl group or a hydroxyl group; fuelleborni group, optionally substituted formyl group; morpholinoethyl group or hydroxyalkyl group; taylorsville group; hinolincarbonova group; indolocarbazole group, substituted alkyl group; pyrazinecarboxamide group optionally substituted alkyl group or alkanoyloxy group; morpholinosydnonimine group; pyrrolidinylcarbonyl group, optionally substituted by benzyloxycarbonyl, alkoxycarbonyl group, alkanoyloxy group, a hydroxyl group or oxopropoxy; tetrahydrofuranyl group; piperidinylcarbonyl group, Zam is on alkoxycarbonyl group or alkanoyloxy group; tomorrooooooooow group in which a sulfur atom optionally substituted by oxopropoxy;

3-alkyl-2,4(1H,3H)-pyrimidinecarbonitrile group; alkylaminocarbonyl group in which the alkyl fragment is optionally substituted by a halogen atom, a hydroxyl group or alkoxygroup; dialkylaminoalkyl group; alkoxycarbonyl group, optionally substituted by alkoxygroup, a hydroxyl group or a halogen atom; alkylsulfonyl group optionally substituted by a group selected from a hydroxyl group, morpholinopropan, alkylpiperazine, dialkylamino, optionally substituted hydroxyl group and a halogen atom; alkanesulfonyl group; dialkylaminoalkyl group; or alkyl group, optionally substituted by morpholinopropan, a halogen atom, alkoxygroup, cyano, peredelnoj group, dialkylaminoalkyl group or dialkylamino, and R12represents a hydrogen atom; pyridyloxy group; personilnya group; or an alkyl group, or-N(R11)(R12) is triazolyl group, tetrazolyl group, aminopenicillin group, morpholinopropan, morpholinopropan, in which the nitrogen atom is substituted by an alkyl group, N-ecomorphology, piperidino, optionally substituted piperidino who sing, pyrrolidino, optionally substituted hydroxyl group or alkoxyalkyl group, imidazolidinyl group, a substituted hydroxyalkyl group and exography, hexahydropyridine group, a substituted hydroxyalkyl group and exography, dioxopyrimidine, thiazolidine group or azacycloheptane group,

R2represents a hydrogen atom,

Z represents an oxygen atom or a group represented by-N(R3)-,

R3represents an alkyl group, optionally substituted hydroxyl group or alkanoyloxy group,

R4represents a hydrogen atom or alkyl group, optionally substituted hydroxyl group.

Of these compounds, the preferred compounds in which R1substituted hydroxyl group; alkyl group substituted dialkylaminoalkyl group, morpholinomethyl group, morpholinomethyl group or alkylpiperidines group; dihydroxyphenylethanol; alkanoyloxy; alkylthiol, optionally substituted hydroxyl group; alkoxygroup, optionally substituted hydroxyl group, alkylsulfonates, tetrahydropyranyloxy, dialkylamino, peredelnoj group, triazolines group, tetrazolyl groups is th optionally substituted alkyl group, piperidinol, morpholinopropan, pyrrolidinone or alkoxygroup; morpholinoethoxy; alkylpiperidines; imidazoledicarboxylic; piperidinecarboxylate; morpholinylcarbonyl; alkylaminocarbonyl, in which the alkyl fragment optionally substituted hydroxyl group, morpholinosydnonimine group or a carboxyl group; dialkylaminomethylcarbonyl; piperidinecarboxylate, optionally substituted hydroxyl group or hydroxyalkyl group; dialkylaminoalkyl, optionally substituted hydroxyl group; dimorpholinyldiethyl, in which the sulfur atom optionally substituted by oxopropoxy; oxopentanenitrile; oxotetrahydrothalifendine; dialkyldimethylammonium; alkoxycarbonyl group; aminocarbonyl group, optionally substituted by hydroxyalkyl; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group, optionally substituted hydroxyl group; or a group of the formula:

where R11represents a hydrogen atom; alkanoyloxy group, but not necessarily the replacement of the seal group selected from amino group, halogen atom, dialkylamino, alkoxygroup, shriley group, tetrazolyl group, hydroxyl group, allylthiourea, alkylsulfonyl group, alkylsulfonyl group, 2-aminothiazoline groups, 2,2-dialkyl-1,3-dioxolan, 2-thiol-4-alkylresorcinols group, cycloalkyl group and 5-alkyl-2,4(1H,3H)-pyrimidinedione group; phenylcarbonylamino group, optionally substituted amino group or a nitro-group; pyridylcarbonyl group; fuelleborni group, optionally substituted formyl group, morpholinoethyl group or hydroxyalkyl group; taylorsville group; hinolincarbonova group; pyrazinecarboxamide group optionally substituted alkyl group; morpholinosydnonimine group; pyrrolidinecarbonyl group; tetrahydrofuranyl group; piperidinylcarbonyl group, substituted alkoxycarbonyl group; alkylaminocarbonyl group optionally substituted by a halogen atom, a hydroxyl group or alkoxygroup; dialkylaminoalkyl group; alkoxycarbonyl group, optionally substituted by alkoxygroup, a hydroxyl group or a halogen atom; alkylsulfonyl group optionally substituted by a group selected from a hydroxyl group, morpholinopropan is s, alkylpiperazine, dialkylamino, optionally substituted hydroxyl group and a halogen atom; alkanesulfonyl group; dialkylaminoalkyl group; or alkyl group, optionally substituted by morpholinopropan, a halogen atom, alkoxygroup, cyano, peredelnoj group, dialkylaminoalkyl group or dialkylamino, and

R12represents a hydrogen atom; pyridyloxy group; or an alkyl group.

Further preferred compounds in which R1represents a hydroxyl group; alkyl group substituted dialkylaminoalkyl group, morpholinomethyl group, morpholinomethyl group or alkylpiperidines group; dihydroxyphenylethanol; alcoholcheap; allylthiourea, optionally substituted hydroxyl group; alkoxygroup, optionally substituted hydroxyl group, alkylsulfonates, tetrahydropyranyloxy, peredelnoj group, triazolines group, tetrazolyl group optionally substituted alkyl group or alkoxygroup; morpholinoethoxy; imidazolecarboxamide; piperidinecarboxylate; morpholinylcarbonyl; alkylaminocarbonyl, optionally substituted guide is auxillou group; morpholinosydnonimine group or a carboxyl group; dialkylaminomethylcarbonyl; piperidinecarboxylate, optionally substituted hydroxyl group or hydroxyalkyl group; dialkylaminoalkyl, optionally substituted hydroxyl group; timorgaleevich, in which the sulfur atom optionally substituted by oxopropoxy; oxopentanenitrile; oxotetrahydrothalifendine; dialkyldimethylammonium; alkoxycarbonyl group; aminocarbonyl group, optionally substituted hydroxyalkyl group; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group, optionally substituted hydroxyl group; or a group of the formula:

where R11is alkanoyloxy group optionally substituted by a group selected from amino group, halogen atom, alkoxygroup, shriley group, tetrazolyl group, hydroxyl group, allylthiourea, alkylsulfonyl group, alkylsulfonyl group, 2-aminothiazolyl group, 2,2-dialkyl-1,3-DIOXOLANYL group, 2-thiol-4-alkylresorcinols group, cycloalkyl group and 5-alkyl-2,4(1H,3H)-pyrimidinedione group; phenylcarbinol g is the SCP, optionally substituted amino group or a nitro-group; pyridylcarbonyl group; fuelleborni group, optionally substituted formyl group or hydroxyalkyl group; hinolincarbonova group; morpholinosydnonimine group; pyrrolidinecarbonyl group; tetrahydrofuranyl group; piperidinylcarbonyl group, substituted alkoxycarbonyl group; alkylaminocarbonyl group optionally substituted by a halogen atom, a hydroxyl group or alkoxygroup; dialkylaminoalkyl group; alkoxycarbonyl group, optionally substituted by alkoxygroup, a hydroxyl group or a halogen atom; alkylsulfonyl group, optionally substituted hydroxyl group or a halogen atom; alkanesulfonyl group; or thienylmethyl group, and

R12represents a hydrogen atom; pyridyloxy group; or an alkyl group.

Of the compounds of the present invention, the preferred compounds can be specified compounds in which ring A represents A benzene ring of the formula:

and ring B represents a benzene ring of the formula:

where a1represents an alkyl group, a hydrogen atom, halogen atom or alkoxygroup, A2 represents a hydrogen atom or halogen atom, A3represents a hydrogen atom, B1is trigalogenmetany group, a hydrogen atom or alkyl group, B2is trigalogenmetany group, a hydrogen atom or alkyl group, B3represents a hydrogen atom,

R1represents a hydroxyl group; alkyl group substituted dialkylaminoalkyl group, morpholinomethyl group, a hydroxyl group, alkoxycarbonyl group or hydroxyethylaminophenol; dihydroxyphenylethylamine group; alcoholcheap; allylthiourea, optionally substituted hydroxyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, alkoxycarbonylmethyl, hydroxylcontaining, morpholinosydnonimine, hydroxyethylaminophenol or alkanoyloxy; dialkyltins group; alkoxygroup, optionally substituted hydroxyl group, alkylsulfonates, tetrahydropyranyloxy, triazolines group, tetrazolyl group optionally substituted alkyl group or alkoxygroup; thienylboronic; morpholinoethoxy; imidazolecarboxamide; alkylaminocarbonyl, in which the alkyl fragment is optionally substituted by hydroxyl groups is th, morpholinosydnonimine group, dialkylaminoalkyl group, alkylaminocarbonyl group, alkanolamines, alkylthiol, alkoxygroup, alkylsulfonyl group, alkanoyloxy or a carboxyl group; piperidinecarboxylate, substituted hydroxyl group, alkoxycarbonyl group, a carboxyl group, hydroxyethylaminophenol group, alkoxycarbonyl group, alkyldiethanolamine group, alkylanthraquinones group, alkylanthraquinones group or hydroxyalkyl group; dialkylaminoalkyl, optionally substituted hydroxyl group; piperidinecarboxylate, substituted hydroxyalkanoates group or alkoxyalkanols group; timorgaleevich, in which the sulfur atom optionally substituted by oxopropoxy; oxopentanenitrile; oxotetrahydrothalifendine; dialkyldimethylammonium; carboxyl group; alkoxycarbonyl group; aminocarbonyl group, optionally substituted pyrimidinyl group; alkylaminocarbonyl the group in which the alkyl fragment optionally substituted hydroxyl group, or cyano; di(hydroxyalkyl)amino ronilo group; pyridylmethyl group, in which the fragment peredelnoj group optionally substituted by a hydroxyl group; aminocarbonyl group, substituted alkylpyridine; piperidinylcarbonyl group, a substituted hydroxyl group or oxopropoxy; piperazinylcarbonyl group, substituted exography, alkyl group, alkylsulfonyl group or alkanoyloxy group; morpholinosydnonimine group; tomorrooooooooow group; pyrrolidinecarbonyl group, a substituted hydroxyalkyl group or a hydroxyl group; alkylsulfonyl group, optionally substituted hydroxyl group; hydroxymethylene group; alkylsulfonyl group, optionally substituted hydroxyl group or alkanoyloxy; or a group of the formula:

where R11is alkanoyloxy group, optionally substituted by (a) group(s)selected from alkanoyloxy group, alkylaminocarbonyl group, dialkylaminoalkyl group, aminocarbonyl group, alkoxycarbonylmethyl, alkanolamines, amino, substituted alkoxycarbonyl group and alkyl group, amino group, substituted alkanoyloxy group and alkyl group, alkoxygroup, optionally substituted phenyl group, Furi is Inoi group, tetrazolyl group, a hydroxyl group, alkylthiol, alkylsulfonyl group, alkylsulfonyl group, 2-aminothiazolyl group, 2-oxopyrrolidin, 2,2-dialkyl-1,3-DIOXOLANYL group, 2-thiol-4-alkylresorcinols group and cycloalkyl group; phenylcarbonylamino group, optionally substituted amino group or a nitro-group; pyridylcarbonyl group, optionally substituted hydroxyl group; fuelleborni group, optionally substituted formyl group or hydroxyalkyl group; taylorsville group; indolocarbazole group, substituted alkyl group; morpholinosydnonimine group; pyrrolidinylcarbonyl group, optionally substituted by benzyloxycarbonyl, alkoxycarbonyl group, alkanoyloxy group, a hydroxyl group or oxopropoxy; tetrahydrofuranyl group; piperidinylcarbonyl group, substituted alkoxycarbonyl group or alkanoyloxy group; tomorrooooooooow group in which a sulfur atom optionally substituted by oxopropoxy; 3-alkyl-2,4(1H,3H)-pyrimidinecarbonitrile group; alkylaminocarbonyl group in which the alkyl fragment is optionally substituted by a halogen atom, a hydroxyl group or alkoxygroup; dialkylaminoalkyl group; aldoxycarb the ilen group, optionally substituted by alkoxygroup, a hydroxyl group or a halogen atom; alkylsulfonyl group optionally substituted by a group selected from a hydroxyl group and halogen atom; alkanesulfonyl group; or dialkylaminoalkyl group; and

R12represents a hydrogen atom; personilnya group; or an alkyl group, or

-N(R11)(R12) is triazolyl group, tetrazolyl group, aminopenicillin group, morpholinopropan, in which the nitrogen atom is substituted by an alkyl group, N-ecomorphology, imidazolidinyl group, a substituted hydroxyalkyl group and exography, hexahydropyridine group, a substituted hydroxyalkyl group and exography, or dioxopyrimidine,

R2represents a hydrogen atom,

Z represents an oxygen atom or a group represented by-N(R3)-,

R3represents an alkyl group, optionally substituted hydroxyl group,

R4represents a hydrogen atom or alkyl group, optionally substituted hydroxyl group.

Of these compounds, the preferred compounds in which ring A represents A benzene ring of the formula:

and ring B represents a benzene ring of the formula:

where A1represents an alkyl group, A2represents a halogen atom, A3represents a hydrogen atom, B1is trigalogenmetany group, B2is trigalogenmetany group, B3represents a hydrogen atom,

R1is alkoxygroup, substituted hydroxyl group or tetrahydropyranyloxy; alkylaminocarbonyl, in which the alkyl fragment optionally substituted hydroxyl group; timorgaleevich, in which the sulfur atom substituted by oxopropoxy; alkylthio group; alkanoyloxy group, a substituted hydroxyl group; aminocarbonyl group substituted by a group(or groups)selected from alkyl groups, personalni group and pyrimidinyl group; piperazinylcarbonyl group, substituted alkanoyloxy group; piperidinylcarbonyl group, a substituted hydroxyl group; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group, optionally substituted hydroxyl group; or a group of the formula:

where R11is alkanoyloxy group, optionally substituted by (a) the group(or groups)selected from alkoxygroup, hydroxyl group and cycloalkyl group; alkoxycarbonyl is inuu group; pyridylcarbonyl group, a substituted hydroxyl group; morpholinosydnonimine group; alkylaminocarbonyl group; or alkylsulfonyl group; personilnya group, and

R12represents a hydrogen atom or alkyl group

-N(R11)(R12) is triazolyl group, tetrazolyl group or N-ecomorphology,

R2represents a hydrogen atom,

Z represents a group represented by-N(R3)-,

R3represents an alkyl group,

R4represents a hydrogen atom or alkyl group.

Even more preferred compounds in which R1is alkylaminocarbonyl, in which the alkyl fragment is substituted by a hydroxyl group; timorgaleevich, in which the sulfur atom substituted by oxopropoxy; alkanoyloxy group, a substituted hydroxyl group; piperazinylcarbonyl group, substituted alkanoyloxy group; piperidinylcarbonyl group, a substituted hydroxyl group; alkylsulfonyl group, a substituted hydroxyl group; alkylsulfonyl group, optionally substituted hydroxyl group; or a group of the formula:

where R11is alkanoyloxy group substituted with hydroxyl group, and

R12is and what Ohm hydrogen.

In the present invention, particularly preferred compounds selected from the following compounds (A) to (BK), or their pharmaceutically acceptable salts.

(A) (2R,4S)-1-[N-(1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-methylpropionamide)piperidine,

(B) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-morpholinobutyrophenone,

(C) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethoxy)piperidine,

(D) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-{2-(2-tetrahydropyranyloxy)ethoxy}piperidine,

(E) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-methoxyacetanilide,

(F) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-methoxycarbonylaminophenyl,

(G) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-ethoxycarbonyl-2-(4-fluoro-2-were)piperidine,

(H) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-methanesulfonylaminoethyl,

(I) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethoxy)piperidine,

(J) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-ethyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxyethylaminophenol,

(K) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(3-hydroxypropoxy)piperidine,

(L) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-(2-cyclopropyl-2-hydroxyacetylamino)-2-(4-fluoro-2-were)piperidine,

(M) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxy-2-methylpropionamide)piperidine,

(N) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-3-hydroxyethylamino)piperidine,

(O) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine,

(P) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-methanesulfonanilide,

(Q) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-methanesulfonanilide,

(R) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-ethylenedicarboxylic-2-(4-fluoro-2-were)piperidine,

(S) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-methoxypropylamine)piperidine,

(T) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(N-methanesulfonyl-N-methylamino)piperidine,

(U) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine,

(V) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(3-hydroxy-3-methylbutylamine)piperidine,

(W) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethanesulfonic)piperidine,

(X) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxyethylaminophenol,

(Y) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-2-hydroxypropylamino)piperidine,

(Z) (2R,4S)-1-{N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-((R)-3-hydroxyethylamino)piperidine,

(AA) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxy-2-methylpropanesulfonic)piperidine,

(AB) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethanesulfonic)piperidine,

(AC) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-{(S)-((S)-2-hydroxypropan)sulfinil)piperidine,

(AD) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-{(R)-((S)-2-hydroxypropan)sulfinil}piperidine

(AE) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxy-2-methylpropanesulfonic)piperidine,

(AF) (2R,4S)-1-[N-{1(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-2-hydroxypropanesulfonic)piperidine,

(AG) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1-methylaminoethanol)piperidine,

(AH) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxy-2-methylpropanesulfonic)piperidine,

(AI) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{(S)-((S)-2-hydroxypropan)sulfinil}piperidine,

(AJ) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{(R)-((S)-2-hydroxypropan)sulfinil)piperidine,

(AK) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{(R)-((R)-2-hydroxypropan)sulfinil}piperidine,

(AL) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{(S)-((R)-2-hydroxypropan)sulfinil}piperidine,

(AM) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-2-hydroxypropanesulfonic)piperidine,

(AN) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-3-hydroxyethylamino)piperidine,

(AO) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((R)-3-hydroxyethylamino)piperidine,

(AP) (2R,4S)-4-(4-acetylpiperidine)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine,

(AQ) (2R,4S)-1-{N-(3,5-bistrutturate the ZIL)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-methylethenyl)piperidine,

(AR) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-associationvoice)piperidine,

(AS) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethanesulfonic)piperidine,

(AT) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-methylaminoethanol)piperidine,

(AU) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(4-hydroxypiperidine)piperidine,

(AV) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-methanesulfonanilide,

(AW) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((R)-2-hydroxypropyl)piperidine,

(AX) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(N-methyl-N-pyrazin-2-enaminocarbonyl)piperidine,

(AY) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(pyrazin-2-ylamino)piperidine,

(AZ) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(N-methyl-N-pyrazin-2-ylamino)piperidine,

(BA) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1-mutilations)piperidine,

(BB) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1-t is isorel)piperidine,

(BC) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1-tetrazolyl)piperidine,

(BD) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(N-oxaprotiline)piperidine,

(BE) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-15 fluoro-2-were)-4-(N-oxaprotiline)piperidine,

(BF) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(N-oxaprotiline)piperidine,

(BG) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxypyridine-5-ylcarbonyl)piperidine,

(BH) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(N-pyrimidine-4-enaminocarbonyl)piperidine,

(BI) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(N-methyl-N-pyrimidine-4-enaminocarbonyl)piperidine,

(BJ) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyacetylamino)piperidine or

(BK) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1-metalicity)piperidine.

In the present invention, more preferred compounds selected from the following (a) to (s) or their pharmaceutically acceptable salts.

(a) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-m is Teal]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxy-2-methylpropionamide)piperidine,

(b) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-3-hydroxyethylamino)piperidine,

(c) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine,

(d) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(3-hydroxy-3-methylbutylamine)piperidine,

(e) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-((R)-3-hydroxyethylamino)piperidine,

(f) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxy-2-methylpropanesulfonic)piperidine,

(g) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxy-2-methylpropanesulfonic)piperidine,

(h) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-2-hydroxypropanesulfonic)piperidine,

(i) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-3-hydroxyethylamino)piperidine,

(j) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((R)-3-hydroxyethylamino)piperidine,

(k) (2R,4S)-4-(4-acetylpiperidine)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine,

(1) (2R,4S)-1-{N-(3,5-bistrutturate the ZIL)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-associationvoice)piperidine,

(m) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethanesulfonic)piperidine,

(n) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-methylaminoethanol)piperidine,

(o) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(4-hydroxypiperidine)piperidine,

(p) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-methanesulfonanilide,

(q) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((R)-2-hydroxypropyl)piperidine,

(r) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyacetylamino)piperidine or

(s) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1-metalicity)piperidine.

Among the compounds of the present invention, the preferred compounds can be specified compounds in which ring A represents A benzene ring of the formula:

and ring B represents a benzene ring of the formula:

where A1represents an alkyl group, A2represents a halogen atom, A3represents a hydrogen atom, B1is trigalogenmetany g is the SCP or halogen atom, B2is trigalogenmetany group or a halogen atom, B3represents a hydrogen atom,

R1represents a hydroxyl group; alkyl group substituted dialkylaminoalkyl group or morpholinosydnonimine group, alkoxygroup, optionally substituted hydroxyl group, alkylsulfonates, triazolines group or tetrazolyl group optionally substituted alkyl group; morpholinoethoxy; hydroxyethylaminomethyl; imidazolecarboxamide; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group; alkylaminocarbonyl group, a substituted hydroxyl group; piperidinylcarbonyl group, a substituted hydroxyl group; or a group of the formula:

where R11is alkanoyloxy group, optionally substituted hydroxyl group or a group of 5-alkyl-2,4(1H,3H)-pyrimidinedione; pyridylcarbonyl group; fuelleborni group; taylorsville group; morpholinosydnonimine group; alkoxycarbonyl group or alkylsulfonyl group;

R12represents a hydrogen atom; or an alkyl group, or-N(R11)(R12) is triazolyl group, morpholinopropan, the cat is Roy nitrogen atom substituted alkyl group, or N-ecomorphology,

R2represents a hydrogen atom,

Z represents a group represented by-N(R3)-,

R3represents an alkyl group,

R4represents a hydrogen atom or alkyl group.

Among these compounds, preferred compounds in which R1represents a hydroxyl group; alkyl group substituted dialkylaminoalkyl group or morpholinosydnonimine group; alkoxygroup, optionally substituted hydroxyl group, alkylsulfonates, triazolines group or tetrazolyl group optionally substituted alkyl group; morpholinoethoxy; hydroxyethylaminomethyl; imidazolecarboxamide; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group; alkylaminocarbonyl group, a substituted hydroxyl group; piperidinylcarbonyl group, a substituted hydroxyl group; or a group of the formula:

where R11is alkanoyloxy group, optionally substituted hydroxyl group or a 5-alkyl-2,4(1H,3H)-pyrimidinedione group; pyridylcarbonyl group; fuelleborni group; taylorsville group; morpholinosydnonimine group; alkoxycarbonyl is the Rupp; alkylsulfonyl group;

R12represents a hydrogen atom; or an alkyl group.

Among the compounds of the present invention, more preferred compounds in which R1represents a hydroxyl group; alkoxygroup, substituted hydroxyl group or triazolines group; hydroxyethylaminomethyl; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group; alkylaminocarbonyl group, a substituted hydroxyl group; piperidinylcarbonyl group, a substituted hydroxyl group; or a group of the formula:

where R11is alkanoyloxy group, optionally substituted hydroxyl group; and

R12represents a hydrogen atom; or an alkyl group, or-N(R11)(R12) represents morpholinopropan, in which the nitrogen atom is substituted by an alkyl group, piperazinone, substituted N-ecomorphology, alkyl group or alkanoyloxy group,

R2represents a hydrogen atom,

Z represents a group represented by-N(R3)-,

R3represents an alkyl group,

R4represents a hydrogen atom or alkyl group.

More preferred compounds in which R1represents a hydroxyl group; al is oxygraph, substituted hydroxyl group, or triazolines group; hydroxyethylaminomethyl; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group; alkylaminocarbonyl group, a substituted hydroxyl group; piperidinylcarbonyl group, a substituted hydroxyl group; or a group of the formula:

where R11is alkanoyloxy group, optionally substituted hydroxyl group;

R12represents a hydrogen atom; or an alkyl group.

Among the compounds of the present invention, other preferred compounds are compounds in which R1represents a hydroxyl group; alkoxygroup, optionally substituted hydroxyl group, alkylsulfonates or tetrazolyl group; hydroxyethylaminomethyl; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group; alkylaminocarbonyl group, a substituted hydroxyl group; piperidinylcarbonyl group, a substituted hydroxyl group; or a group of the formula:

where R11is alkanoyloxy group, optionally substituted hydroxyl group; fuelleborni groups is; morpholinosydnonimine group; alkoxycarbonyl group; or alkylsulfonyl group; and

R2represents a hydrogen atom; or an alkyl group, or-N(R11)(R12) is triazolyl group, or tetrazolyl group,

R2represents a hydrogen atom,

Z represents a group represented by-N(R3)-,

R3represents an alkyl group,

R4represents a hydrogen atom or alkyl group.

Examples of other preferred compounds are compounds in which ring A represents A benzene ring of the formula

and ring B represents a benzene ring of the formula:

where A1represents an alkyl group, A2represents a halogen atom, A3represents a hydrogen atom, B1is trigalogenmetany group, B2is trigalogenmetany group, B3represents a hydrogen atom,

R1is hydroxyethylaminomethyl; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group; alkylaminocarbonyl group, a substituted hydroxyl group; piperidinylcarbonyl group, a substituted hydroxyl group; or a group of the formula:

where R11is alkanoyloxy group, optionally substituted hydroxyl group; or alkoxycarbonyl group; and

R12represents a hydrogen atom; or an alkyl group,

R2represents a hydrogen atom,

Z represents a group represented by-N(R3)-,

R3represents an alkyl group,

R4represents a hydrogen atom or alkyl group.

Other preferred compounds are preferred compounds in which ring A represents A benzene ring of the formula:

and ring B represents a benzene ring of the formula

where A1represents an alkyl group, A2represents a halogen atom, A3represents a hydrogen atom, B1is trigalogenmetany group, B2is trigalogenmetany group, B3represents a hydrogen atom,

R1is hydroxyethylaminomethyl; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group; alkylaminocarbonyl group, a substituted hydroxyl group; piperidinylcarbonyl group, a substituted hydroxyl group; or a group of the formula:

where R11 is alkanoyloxy group, optionally substituted hydroxyl group, and

R12represents a hydrogen atom; or an alkyl group, or-N(R11)(R12) represents morpholinopropan, in which the nitrogen atom is substituted by an alkyl group, or N-ecomorphology,

R2represents a hydrogen atom,

Z represents a group represented by-N(R3)-,

R3represents an alkyl group,

R4represents a hydrogen atom or alkyl group.

More preferred compounds in which R1is hydroxyethylaminomethyl; alkylsulfonyl group, optionally substituted hydroxyl group; alkylsulfonyl group; alkylaminocarbonyl group, a substituted hydroxyl group; piperidinylcarbonyl group, a substituted hydroxyl group; or a group of the formula:

where R11is alkanoyloxy group, optionally substituted hydroxyl group, and R12represents a hydrogen atom; or an alkyl group.

The compound [I] of the present invention can be used for pharmaceutical purposes or in free form or in the form of pharmaceutically acceptable salts.

As pharmaceutically acceptable salts of the compounds [I] of the present invention can MC is to say, for example, inorganic salts such as hydrochloride, sulfate, phosphate and Hydrobromic; and organic acid salts, etc. such as acetate, fumarate, oxalate, citrate, methanesulfonate, bansilalpet, tosylate, maleate, succinate and tartrate.

In addition, the compounds [I] of the present invention or their pharmaceutically acceptable salts include any of their salts, solvate and hydrate, etc.

In the compounds [I] of the present invention due to the presence of asymmetric carbon atoms may be present optical isomers, and the present invention includes any of these optical isomers and their mixtures. In the present invention, among these optical isomers, the preferred compounds, with R configuration at position 2 piperidino rings (the position of the joining ring A), and particularly preferred compounds with R configuration at position 2 piperidino rings (the position of the joining ring A) and S configuration at position 4 (the position of the join R1).

The compounds [I] or pharmaceutically acceptable salts of the present invention have excellent antagonistic activity against receptor tachykinin, particularly antagonistic activity against SP receptor, so that they can be useful as a safe drug profile is ctice and treatment of inflammatory or allergic diseases (for example, atopic dermatitis, dermatitis, herpes, psoriasis, asthma, bronchitis, expectoration, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, OFTAL, cystitis etc), pain, migraine, neuralgia, pruritus, cough and, in addition, diseases of the Central nervous system (e.g., schizophrenia, Parkinson's disease, depression, anxiety, psychosomatic disorders, morphine dependence, dementia (such as Alzheimer's and so on), and so on), digestive diseases (e.g., state of hypersensitivity of the bowel, ulcerative colitis, Crohn's disease, disorders (e.g., gastritis, gastric ulcers and so on)associated with urease positive Spirillum (for example, helicobacter pylori, etc. and so on), nausea, vomiting, disorders of urinary system (e.g., pollakiuria, incontinence, etc.), circulatory disorders (e.g., angina, hypertension, congestive heart failure, thrombosis etc) and immune system disorders, etc. in mammals (e.g. mice, Mongolian gerbils, ferrets, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, people, etc).

In particular, since the compounds [I] or their pharmaceutically acceptable salts which are active ingredients of the present invention, are easily transported into the brain, and at the same VRU is due to their low toxicity almost not demonstrate adverse effects, they can be used as therapeutic or prophylactic agents for diseases of the Central nervous system, such as vomiting, depression, etc., or disorders of the urinary system, such as pollakiuria etc.

Measurements relating to the compounds of the present invention or their pharmaceutically acceptable salts can be carried out in accordance with the method disclosed in European Journal of Pharmacology, vol. 254, pages 221-227 (1994) in relation to the binding of the receptor neirokinina-1, and in accordance with the method disclosed in European Journal of Pharmacology), vol. 265, pages 179-183 (1994) in relation to their actions against the induction of receptors neirokinina-1, and in accordance with the method disclosed in British Journal of Pharmacology, vol. 119, pages 931-936 (1996) in relation to their effectiveness against vomiting; in addition, in accordance with the method disclosed in the Journal of Urology, vol. 155, No. 1, pages 355 to 360 above (1996) in relation to inhibition pollakiuria.

The compounds of formula [I] or pharmaceutically acceptable salts of the present invention can be administered orally or parenteral, and they can be prepared in the form of their drugs using commonly used pharmaceutical carriers for oral or parenteral administration. As such pharmaceutical carriers can be specified, for example, binder (syrup, gum Arabic, gelatin, sorbitol, tragakant, polivinilpirrolidon etc), excipients (lactose, sugar, corn starch, potassium phosphate, sorbitol, glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silicon dioxide, etc.), disintegrant (potato starch, etc.) and wetting agents (anhydrous sodium dodecyl sulfate, etc.), etc.

In addition, if these pharmaceutical preparations are administered orally, they can be prepared in the form of solid preparations such as tablets, granules, capsules, powders, or liquid preparations such as solutions, suspensions and emulsions. On the other hand, if they are administered parenteral, for example, you can enter them in the form of injection solutions or infusion solutions, using distilled water for injection, saline solutions, aqueous solutions of glucose, etc. or you can enter them in the form of suppositories, etc.

The dose of a compound [I] or its pharmaceutically acceptable salt of the present invention may vary depending on the method of administration, age, weight or condition of the patient, etc. and, for example, in the case of oral administration, the compound is usually administered in a dose of from 0.1 to 20 mg/kg / day, particularly preferably from 0.1 to 10 mg/kg / day, and in the case of parenteral introduction usually in a dose of from 0.01 to 10 mg/kg / day, particularly preferably from 0.01 to 1 mg/kg / day.

[Method A]

The target compound [I] of the present invention MoE is but to get for example, through the interaction of the compounds of formula [II]:

where ring A is optionally substituted benzene ring, R1represents optionally substituted alkyl group, optionally substituted hydroxyl group, substituted Tilney group, substituted carbonyl group, a substituted sulfinyl group, substituted sulfonyloxy group, or a group of the formula:

where R11and R12the same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyloxy group optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as heteroatoms, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized, or

R11and R12taken together with the adjacent nitrogen atom, form a heterocyclic group selected from piperidino, azacycloheptane group, pyrrolidinone, thiazolidine group, morpholinopropan, triazolines group, tetrazolyl group and parinello group, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is battelino oxidized,

R2represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom,

with the compound of the formula [III]:

where ring B is optionally substituted benzene ring, R3represents a hydrogen atom or optionally substituted alkyl group, and R4represents a hydrogen atom or optionally substituted alkyl group,

in the presence of urea.

[Method B]

Among the target compounds [I] of the present invention,

the compounds of formula [I-a]:

where ring A, ring B, R2, Z, R3and R4have the above values,

can be obtained, for example, restoring the connection formula [IV]:

where ring A, ring B, R2, Z, R3and R4have the above values,

[Method C]

Among the compounds of the present invention, the compound of the formula [I-b]:

where ring A, ring B, R11, R12, R2, Z, R3and R4have the above values,

can be obtained through the interaction of the compounds of formula [IV]

where the ring A, ring B, R2, Z, R3and R4have the above values,

with the compound of the formula [V]:

where X1represents a hydrogen atom, a hydroxyl group, a silicon atom, a lithium atom or an atom of magnesium, and R11and R12have the above values.

[Method D]

Among the compounds of the present invention, the compound of the formula [I-c]:

where ring A, ring B, R2, Z, R3and R4have the above significance, and R13is optionally substituted carboxyl group,

can be obtained through the interaction of the compounds of formula [IV]

where ring A, ring B, R2, Z, R3and R4have the above values,

with the compound of the formula [VI]:

where X2represents a leaving group, and R13has the above values

and recovering the resulting compound of the formula [VII]:

where ring A, ring B, R13, Z, R3and R4have the above values.

[Method E]

Among the compounds of the present invention, the compound of the formula [I"]:

where ring A, ring B, R1, R2and R4have the above values,

m who should get through the interaction of the compounds of formula [II]:

where ring A, R1and R2have the above values,

with the compound of the formula [III']:

where ring B and R4have the above values,

in the presence of the agent, forming a urea bond.

These methods [Method A-Way E] can be performed as disclosed below.

[Method A]

The reaction of the compound [II] with the compound [III] can be carried out in a suitable solvent in the presence of the agent, forming a urea bond. Examples of forming a urea bond agents are compounds of the formula:

where W1and W2the same or different, and each represents a leaving group, etc.

W1and W2may be the same or different, and each represents imidazolidinyl group, halogen atom, fenoxaprop, etc. are Particularly preferred 1,1'-carbonyldiimidazole, phosgene, etc. and carbonylchloride, such as 1,1'-carbonyldiimidazole, triphosgene or phosgene, and so on, you can use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, can be used appropriately acetonitrile, dichloromethane, tetrahydrofuran, etc. This reaction can occur, is for example, at a temperature of from 0°C to 80°C, preferably from 0°C to 50°C.

Further, in this reaction, the compound [I] can also be obtained through the interaction of the compound [II]

with forming a urea bond agent of the formula:

where W1and W2the same or different, and each represents a leaving group,

getting in the compound of the formula [VIII-a]:

where ring A, R1, R2and W2have the above values,

turning then the compound [VIII-a] in its reactive derivative, and through its interaction with the compound [III],

or, alternatively, the compound [I] can be obtained by interaction of the compound [III] and forming a urea bond agent is of the formula:

where W1and W2have the above values,

getting in the compound of the formula [VIII-b]:

where ring B, R3,R4and W2have the above values,

turning then the compound [VIII-b] in its reactive derivative, and through its interaction with the compound [II].

As reactive derivatives can be specified compounds in which W2provides reception GRU is dust, represented by the formula:

in the compound [VIII-a] or the compound [VIII-b], etc.

The reaction of the compound [II] or compound [III] with forming a urea bond agent may be, for example, at a temperature of from 0°C to 80°C, preferably from 0°C to 50°C. Further, it is possible to use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, you can use it appropriately acetonitrile, dichloromethane, tetrahydrofuran, etc.

The reaction, which will lead to the transformation of the compound [VIII-a] or the compound [VIII-b] in its reactive derivative can be carried out using the agent providing derivative, such as methyl iodide, at a temperature of from 0°C to 80°C, preferably from 0°C to 50°C. Further, it is possible to use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, can be used appropriately acetonitrile, dichloromethane, tetrahydrofuran etc.

The response of each of the reactive derivative with the compound [III] or compound [II] can be performed in the presence of a base, for example, at a temperature of from 0°C to 80°C, preferably from 0°C to 50°C. Further, as the base can be used triethylamine, and so the., and you can use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, accordingly you can use acetonitrile, dichloromethane, tetrahydrofuran, etc.

[Method B]

The reduction of compound [IV] can be carried out in a suitable solvent in the presence of a reducing agent. As the reducing agent, it is possible it is preferable to use sodium borohydride and the like, for example, sodium borohydride, aluminum hydride, such as diisobutylaluminium and so on, you can use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, accordingly it is possible to use ethanol, tetrahydrofuran, dichloromethane, etc. This reaction can be performed, for example, at a temperature of from -70°C to the boiling temperature under reflux, preferably at a temperature of from -70°C to 20°C.

[Method C]

The reaction of the compound [IV] with a compound [V] can be carried out in a suitable solvent, subjecting compounds reactions of reductive amination. This reaction reductive amination can be accomplished by hydrogenation in acidic conditions in the presence of a reducing agent such as sodium borohydride, mixing createtextarea, cyanoborohydride three the or such a catalyst recovery as palladium. As a group [X1] connection [V] you can specify, for example, a hydrogen atom, a hydroxyl group, a silicon atom, a lithium atom or an atom of magnesium, and the preferred hydrogen atom and hydroxyl group. You can use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, accordingly you can use dichloromethane, acetic acid, ethanol, methanol, etc. as the salt of compound [V]can be used appropriately hydrochloride, acetate, etc. this reaction may proceed, for example, at a temperature of from -10°C to 80°C, preferably at temperatures from 0°With 30°C.

[Method D]

The reaction of the compound [IV] with a compound [VI] can be carried out in a suitable solvent optionally in the presence of a base. As tseplyaesh groups [X2] compound [VI], you can specify diethylphosphonate, triphenylphosphonio group, etc. as the reason you can specify, for example, tert-piperonyl potassium, triethylamine, sodium hydroxide, etc. and preferred tert-piperonyl potassium, triethylamine, etc. furthermore, you can use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, can be used appropriately tetrahydrofuran, dichloromethane, etc. are considered to be ivema the reaction may proceed, for example, at a temperature of from -30°C to 80°C, preferably at temperatures between -20°With 30°C.

Further, the reduction of compound [VII] can be done in the usual way, by hydrogenation in the presence of catalysts recovery, such as palladium, etc. as a solvent can be used suitably methanol, ethanol, etc. this reaction may proceed, for example, at a temperature of from 0°C to 50°C.

[Method E]

The reaction of the compound [II] with the compound [III'] can be performed in the presence of forming a urea bond agent in a suitable solvent. As forming a urea bond agents, you can specify those represented by the formula:

where W1and W2the same or different, and each represents a leaving group.

As W1and W2regardless, they are the same or different, you can specify imidazolidinyl group, halogen atom or fenoxaprop etc. Especially preferably 1,1'-carbonyldiimidazole, phosgene and, for example, carbonylchloride, such as 1,1'-carbonyldiimidazole, triphosgene, phosgene and so on, you can use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, you can use sootvetstvuyuschaya acetonitrile, dichloromethane, tetrahydrofuran, etc. this reaction may proceed, for example, at a temperature of from 0°C to 80°C, preferably from 0°C to 50°C.

Further, the compound [I] can be obtained by interaction of the compound [II] with forming a urea bond agent of the formula:

where W1and W2the same or different, and each represents a leaving group receiving compound of the formula [VIII-a]:

where ring A, R1R2and W2have the above values,

turning then the compound [VIII-a] in its reactive derivative and through its interaction with the compound [III'], or, alternatively, the compound [I] can be obtained by interaction of the compound [III'] forming a urea bond agent of the formula:

where W1and W2have the above values, obtaining the compound of formula [VIII']:

where ring B, R4and W2have the above values,

turning then the compound [VIII'] in its reactive derivative and through its interaction with the compound [II].

Examples of the reactive derivatives are, for example, compounds in which W2provides recip is in the group, represented by the formula:

in the compound [VIII-a] or compound [VIII'].

The reaction of the compound [II] or compound [III'] forming a urea bond agent may be, for example, at a temperature of from 0°C to 80°C, preferably from 0°C to 50°C. Further, it is possible to use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, can be used appropriately acetonitrile, dichloromethane, tetrahydrofuran, etc.

The reaction conversion of the compound [VIII-a] or the compound [VIII'] in their reactive derivatives can be carried out using the agent providing such a derivative, such as methyl iodide, for example, at a temperature of from 0°C to 80°C, preferably from 0°C to 50°C. Further, it is possible to use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, can be used appropriately acetonitrile, dichloromethane, tetrahydrofuran, etc.

The response of each of the reactive derivative with the compound [III] or compound [II] can be performed in the presence of a base, for example, at a temperature of from 0°C to 80°C, preferably from 0°C to 50°C. Further, as the base can be used triethylamine, etc. and it is possible and the use of any solvent, if only he did not have a deleterious effect on the course of the reaction, for example, can be used appropriately acetonitrile, dichloromethane, tetrahydrofuran, etc.

The compound [I] of the present invention can also be obtained by transforming the group R1and the group R3the compound obtained above way, in the right substitute. A way of turning substituents you can choose accordingly depending on the types of desired substituents; moreover, you can use the following methods (methods a-q).

(method a)

The compound [I]in which R1represents a group containing a substituted hydroxyl group (for example, optionally substituted by alkoxygroup, replaced carbonyloxy or alkylsulfonates etc) in the formula [I]can be obtained by alkylating, acylurea or sulfonylurea in the usual way, the corresponding compound containing a hydroxyl group as R1. For example, the alkylation can take place at temperatures from -10°C to 80°With, the acylation can take place at temperatures between 5°C to 80°and sulfonylamine can proceed at temperatures from 5°C to 80°C.

(method b)

The compound [I]in which R1represents a group containing a substituted an amino group in the formula [I]can be obtained by replacing the usual pic is BOM of the corresponding compounds containing the amino group as R1Deputy(deputies) amino group (for example, alkoxycarbonyl group, such as tert-butoxycarbonyl, allamoxicillinpills group, such as benzyloxycarbonyl group, etc., alkanoyloxy group such as formyl group, acetyl group, propylaniline group, etc., alkyl group such as methyl group, ethyl group, through the group, etc., alkylsulfonyl group, such as methanesulfonyl group, acanaloniidae group, etc., alkanesulfonyl group, such as vinylsulphonyl group, etc., heterocyclic group, such as Peregrina group and so on, and so on). Alternatively, this compound can be obtained by using the reagent for synthesis of carbamate, such as N,N'-succinimidylester etc., interacting, for example, with alkoxyalkyl alcohol, etc. Substitution is convenient to carry out the normal way, depending on the types of substituents, by alkylation, acylation, sulfonylamine, arilirovaniya and so on, replacing a hydrogen atom on the amino group, it is possible to obtain the disubstituted compound. This reaction may proceed at temperatures from -20°C to 50°C.

Further, if the compound [I]in which R1represents a group containing samewe the ing the amino group, contains urea bond, can be obtained through the interaction of the compounds amine to form a urea bond agent, in a manner analogous to the method [method A], or the method disclosed in Japanese Provisional Patent Publication No.10-195037.

Further, the compound [I]in which R1represents a group containing a substituted an amino group in the formula [I]can be obtained by adding the compound containing the amino group, the corresponding compound containing a carbon-carbon double bond in R1. Consider the reaction can be carried out at the boiling temperature of the solvent, or in the absence of a catalyst.

(method c)

The compound [I]in which R1represents a group containing an amino group in the formula [I]can be obtained by removing the protective group from the corresponding compounds containing substituted by an amino group in R1. The removal of the protective group can be performed in the usual way (for example, by treatment with an acid, by treatment with a base, catalyst recovery, and so on). Among these reactions, the reaction is carried out by treatment with acid, may be at a temperature of from 5°to 120°C, the reaction is carried out by treatment with base, can take place at temperatures between 5°C to 40°and the reaction catalytic reduction can proteotype temperature of 10° With up to 40°C.

Further, the compound [I]in which R1represents a group containing an amino group in the formula [I]can be obtained by restoring the corresponding compound containing the nitro-group in R1. Recovery can be accomplished in the presence of acid, interacting with chloride of tin, zinc, etc. for Example, consider the reaction can be carried out at the boiling temperature of the solvent.

Further, the compound [I]in which R1represents a group containing an amino group in the formula [I]can be obtained by subjecting the corresponding compound containing a carboxyl group in R1, rearrangement of kurzius, etc. the Rearrangement of kurzius can be done, for example, by the way, opened in Advanced Organic Chemistry, vol.4, page 1054. That is, it can be done, converting the carboxyl group into an acid chloride using thionyl chloride, etc. and then asidero it with the help of sodium azide, etc. with subsequent hydrolysis.

(method d)

The compound [I]in which R1represents a group containing a hydroxyl group in the formula [I]can be obtained by removing the usual way the protective group of the corresponding compounds containing substituted hydroxyl group at R1. The removal of the protective group can be carried out using a treatment with an acid, the processing base, Catalytica is Kim restoration etc. depending on the type of the protective group. This reaction may proceed, for example, at a temperature of from 0°C to 80°S, especially preferably from 5°C to 50°C.

Further, the compound [I]in which R1represents a group containing a hydroxyl group in the formula [I]can be obtained by restoring the corresponding compound containing a formyl group at R1. Recovery can be accomplished by reaction of the compound in the presence of a reducing agent such as sodium borohydride, etc. this reaction may proceed, for example, at temperatures from -80°C to 80°S, especially preferably from -70°to 20°C.

Further, the compound [I]in which R1represents a group containing a hydroxyl group in the formula [I]can be obtained by restoring the appropriate compound containing ester or carboxyl group in R1. Recovery can be accomplished by subjecting the reaction of the compound in the presence of a reducing agent, such as sociallyengaged etc. this reaction may proceed, for example, at a temperature of from -50°to 200°S, especially preferably from -20°C to 60°C.

(method e)

In that case, if R1in the formula [I] represents a hydroxyl group and contains an asymmetric center at asiausa part, the connection configuration can be changed to the opposite configuration, for example, by the method Mitsunobu, etc. as disclosed in Synthesis, pages 1 to 28, 1981. More specifically, the transformation can be accomplished by conducting the reaction of the compound in the presence of triphenylphosphine, benzoic acid and diethylazodicarboxylate in a suitable solvent. This reaction may proceed, for example, at a temperature of from 0°C to 60°S, especially preferably from 5°C to 40°C.

(method f)

The compound [I]in which R1represents a group containing an optionally substituted Tilney group in the formula [I]can be obtained by interaction of the corresponding compounds containing a hydroxyl group in R1with the appropriate compound containing Tilney group, for example, by the method Mitsunobu, etc. as disclosed in Synthesis, pages 1 to 28, 1981. More specifically, the reaction can be performed by reaction of the compound in the presence of triphenylphosphine and diethylazodicarboxylate in a suitable solvent. This reaction may proceed, for example, at the boiling temperature of the solvent when heated.

The compound [I]in which R1represents a group containing an optionally substituted Tilney group in the formula [I]can be obtained through the interaction of the compounds [I, containing a halogen atom in R1with the appropriate compound containing Tilney group. This reaction may proceed, for example, at a temperature of from -50°to 150°S, especially preferably from 10°to 100°C.

In addition, compound [I]in which R1represents a group containing allylthiourea, can be obtained by alkylating a corresponding compound [I]containing Tilney group in R1or the corresponding compound containing a protected Tilney group (for example, acetylated Tilney group). This reaction may proceed in the presence of a base, for example, at a temperature of from -10°C to 80°S, especially preferably from 5°C to 50°C.

(method g)

The compound [I]in which R1in the formula [I] represents a group containing a substituted an amino group, can be obtained by subjecting a corresponding compound [I]which contains a hydroxyl group in R1the amination reaction, for example, by the method Mitsunobu, etc. as disclosed in Synthesis, pages 1 to 28 1981.

(method h)

The compound [I]in which R1in the formula [I] represents a group containing a free carboxyl group, can be obtained by subjecting a corresponding compound [I]containing esterified carboxyl group at R1the reactions of deesterification in the usual way, for example, by hydrolysis with base, such as sodium hydroxide, etc., acid treatment hydrogen chloride, hydrogen bromide, etc., recovery in the atmosphere of hydrogen using palladium (palladium black), palladium-on-coal, etc. depending on the type of ester residue). When the reactions deesterification, for example, hydrolysis using a base can take place at temperatures between 5°C to 70°processing acid be carried out at a temperature of from 5°C to 80°, recovery may occur at a temperature of from 10°C to 40°C.

(method i)

The compound [I]in which R1in the formula [I] represents a group containing an amide bond, can be obtained through the interaction of the compounds [I], containing a free carboxyl group at R1with the appropriate amine, or by the interaction of the compound [I]which contains a free amino group at R1with the corresponding carboxylic acid, in the presence or absence of a condensing agent. As the condensing agent used is 1,1'-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, isobutylparaben or N-methylmorpholin etc. which are usually used in the reaction for the formation of amide linkages, using Urbanova acid and amine. This reaction may proceed, for example, at a temperature of from -20°C to 50°C.

(method j)

The compound [I]in which R1in the formula [I] represents a group containing a heterocyclic group, the nitrogen atom of which is substituted by oxopropoxy (the nitrogen atom oxidized) (for example, N-ecomorphology and so on) can be obtained by treating a corresponding compound [I]containing heterocyclic group in R1oxidizing agent (for example, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, axonom etc). This reaction may proceed, for example, at a temperature of from 5°C to 50°C.

(method k)

The compound [I]in which R1in the formula [I] represents a group containing a heterocyclic group, the nitrogen atom of which is oxidized, different from the above compounds (method j) (for example, N-alkyl-4-morpholinopropan etc), can be obtained through the interaction of the compounds [I]containing heterocyclic group in R1with alkylhalogenide. This reaction may proceed, for example, at a temperature of from 20°C to 80°C.

(method l)

The compound [I]in which R1in the formula [I] represents alkyl group, can be obtained by alkylating the usual way a corresponding compound [I]in which R3is Alamogordo. The alkyl group may be substituted. This reaction may proceed, for example, at a temperature of from 20°C to 80°C.

(method m)

The compound [I]in which R1in the formula [I] represents a group containing group, a sulfur atom which monogamist oxopropoxy (for example, sulfonyloxy group, and so on), can be obtained by treating a corresponding compound [I], contains tigroup in R1oxidizing agent (for example, 3-chloroperbenzoic acid, peracetic acid, periodate sodium, axonom etc). This reaction may proceed, for example, at temperatures from -80°C to 150°S, especially preferably from 0°C to 40°C.

(method n)

The compound [I]in which R1in the formula [I] represents a group containing group, a sulfur atom which Disaese oxopropyl (for example, sulfonyloxy group, and so on) can be obtained by treating a corresponding compound [I], contains tigroup in R1oxidizing agent (for example, 3-chloroperbenzoic acid, peracetic acid, periodate sodium, axonom etc). This reaction may proceed, for example, at temperatures from -80°C to 150°S, especially preferably from 0°C to 40°C.

(method o)

The compound [I]in which R1in the formula [I] represents a group containing an amino group, can be obtained by p is derga a corresponding compound [I], containing carbonyl group in R1the reaction of reductive amination. Consider the reaction can be performed as indicated above [Method C].

(method p)

The compound [I]in which R1in the formula [I] represents a group containing sulinowo acid, can be obtained through the interaction of the compounds [I], containing alkylsulfonyl group in R1for example, by the way, opened the way Synlett, April, pages 375 to 377, 1997.

(method q)

The compound [I]in which R1in the formula [I] represents a group containing imidazolidinyl group or hexahydropyridine group, can be obtained by carrying out the cyclization reaction of a corresponding compound [I], contains aminoalkylindole in R1for example, in the presence of a condensing agent such as 1,1'-carbonyldiimidazole etc. this reaction may proceed, for example, at a temperature of from -20°C to 50°C.

As solvents that can be used in the above reactions (method a) to (method q), it is possible to use any solvent, if only he does not have a deleterious effect on the course of the reaction, for example, you can use solvents selected appropriately from dioxane, dimethyl ether of ethylene glycol, dimethylacetamide, demetillo mamita, hexamethylphosphoramide, benzene, tetrahydrofuran, toluene, ethyl acetate, ethanol, dichloromethane, carbon tetrachloride, 1,3-dimethyl-2-imidazolidine, acetic acid, diethyl ether, methoxyethane, dimethyl sulfoxide, acetonitrile, water and mixtures thereof.

Incidentally, the compound [IV]is used in the present invention as the starting material, is a new compound and can be obtained, for example, as shown in the following scheme:

where R51represents an alkyl group, R61represents a protective group for the amino group, R52represents an alkyl group, which may form the connection on your end, X3represents a leaving group, X4represents a leaving group, and ring A, ring B, R3and R4have the above values.

So, carry out the condensation reaction of pyridine compounds [IX] and the Grignard reagent [X], and further protect the amino group receiving the compound [XI]. Then, the compound obtained restore, receiving the compound [XII]. Further, the carbonyl group of the compound [XII] protect Cetelem, receiving the compound [XIII], the protective group of the amino group is removed, obtaining the compound [XIV]. Then carry out the condensation reaction of the compound [XIV] and the compound [XV], obtaining the compound [XVI], thus making it mutual the action with the compound [XVII], or carry out the condensation reaction of the compound [XIV] and the compound [III], obtaining the compound [XVIII], and by removing the protective group to obtain the compound [IV].

The compound [IV] contains an asymmetric carbon atom, and due to this asymmetric carbon, there are optical isomers. Using optical isomer of the above compound [XIV], it is possible to obtain the desired optical isomer of the compound [IV].

Optical isomer of the compound [XIV] can be obtained by subjecting the racemic mixture of the compound [XIV] the separation of the optical isomers in the usual way. The separation of the optical isomers can be accomplished, for example, by interaction of the compound [XIV] with N-acyl-optically active amino acid, or N-sulfonyl-optically active amino acid, receiving two types diastereoisomeric salts, and separating and collecting one of diastereoisomeric salts, using the difference in their solubilities.

Examples of acyl groups, N-acyl-optically active amino acids are acetyl group, propylaniline group, Casilina group or benzyloxycarbonyl group, and examples of optically active amino acids are of L-phenylalanine, L-leucine, L-glutamine, L-methionine, L-valine, L-threonine, D-phenylalanine or D-phenylglycine.

Further, the compound [II]used in the present invention as an initial matter, one is by new connection and it can be obtained, for example, as shown in the diagram below:

where the ring A, the ring R11, R12, R61and X1have the above values.

Thus, the compound [XII] and the compound [V] is subjected to the reaction of reductive amination, receiving the compound [XIX], and removing the protective group for the amino group, get the compound [II-a]. The reaction of reductive amination can be performed similarly to the method [Method C].

Upon receipt of the above compound [IV]each of the intermediate compounds are not limited to those which are represented in the reaction scheme, and can be successfully used their salts or their reactive derivatives, unless they have no harmful effects on the course of the reaction.

Further, among the starting compounds [II] of the present invention, the compound [II-b] can be obtained, for example, as shown in the following scheme:

where R53represents an alkyl group, X3represents a halogen atom, and ring A has the above values.

That is, condense connection pyridine [XX] and the compound [XXI], and the obtained compound [XXII] restore, receiving the compound [II-b].

Further, among the starting compounds of the present invention, the compound of the formula[II-c]:

where the symbols have the above meanings, can be obtained below way.

where the symbols have the above values.

That is, the compound [XII] restore, receiving the compound [XXIII], and carry out the removal of the protective group from the amino group of the obtained compound [XXIII], obtaining the compound [II-c].

Although there are optical isomers of compound [II-c], in a manner analogous to the above method of separation of optical isomers for the compound [XIV], it can be obtained by separation of the racemic mixture of optical isomers.

Further, when the connection or starting substances of the present invention, if the source of the substance or intermediate compounds contain functional groups, for each of the functional groups you can enter a suitable protective group in the usual way, in addition to the above method, and, if their presence is optional, these protective groups can be deleted.

In the present description, the term alkyl group means, for example, branched or unbranched alkyl group containing 1-6 carbon atoms, such as methyl group, ethyl group, through the group, bucilina group, isobutylene group, tert-bucilina group, isopentyl group, etc., preferably a group containing 1-4 and the Ohm carbon. The term Alchemilla group means, for example, branched or unbranched alkenylphenol group containing 2 to 7 carbon atoms, such as vinyl group, aryl group, protanilla group, isopropylene group, etc., preferably a group containing 1-4 carbon atoms. The term alkoxygroup means a branched or unbranched alkoxygroup containing 1-6 carbon atoms, such as methoxy group, ethoxypropan, propoxylate, isopropoxide, butoxypropan etc., preferably a group containing 1-4 carbon atoms. The term alcoolica group means a branched or unbranched alkanoyloxy group containing from 1 to 6 carbon atoms, such as formyl group, acetyl group, propylaniline group, Butyrina group, valerina group, tert-butylcellosolve group, etc., preferably a group containing 1-4 carbon atoms. The term lower cyclic alkyl group means cycloalkyl group containing 3-8 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, etc., preferably those groups which contain 3-6 carbon atoms. Further, the halogen atoms represented by a chlorine atom, a bromine atom, fluorine atom and iodine atom.

<> EXAMPLES

Hereinafter the present invention will be disclosed in more detail with reference to examples and comparative examples, but these examples of the present invention is not limited.

Example 1

(1) In 30 ml of methanol is dissolved 1,43 g of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine and added 114 mg sodium borohydride. The mixture is stirred at room temperature for 3 hours. To the reaction mixture an aqueous solution of ammonium chloride and ethyl acetate, and after stirring the mixture, the layers separated. The organic layer is washed with water and brine, dried and then the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:acetone=4:1), receiving 0,99 g of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, as shown in table 1 below.

(2) 200 mg of the above compound (1) and then purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1)to give 18 mg (a) TRANS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine and 125 mg (b) CIS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, as shown in table 1 below.

the example 2

In 10 ml of tetrahydrofuran was dissolved 200 mg (2R)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine add 60 mg of sodium borohydride and the mixture is refluxed. Continuously maintaining boiling the mixture under reflux, to the mixture are added dropwise a mixed solvent consisting of 1 ml of methanol and 5 ml of tetrahydrofuran. After 5 hours the reaction mixture was poured into water and the layers separated. The aqueous layer was extracted with ethyl acetate, the combined organic layers washed with water and saturated saline solution, dried and then the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=1:1 to 1:2)to give 33 mg (a) (2R,4R)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine and 160 mg (b) (2R,4S)-1-[N-(1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, as presented below in table 2.

Example 3

Using (2R)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidin and treated according to the method of example 2, obtaining (a) (2R,4R)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine and (b) (2R,4S)-1-{N-(3,5-bistri formatives)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, as presented below in table 2.

Example 4

In 5 ml of dimethylformamide was dissolved 150 mg of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine and add 40 mg of sodium hydride (60%) at 0°C. To the solution was added 0.2 ml of methyl iodide at 0°and the mixture is stirred at room temperature for 16 hours. Then to the solution was added water and ethyl acetate, the mixture is stirred and the layers separated. The organic layer was washed with water, dried over magnesium sulfate and concentrate under reduced pressure. The concentrated residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=2:1)to give 72 mg (a) CIS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-methoxypiperidine and 36 mg (b) TRANS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-methoxypiperidine, as presented below in table 3.

Example 5

Using 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine hydrochloride and 2-picolylamine and treated according to the method of example 4 above, receiving 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-pyridyloxy)piperidine as shown below in table 4.

Example 6

In 2 ml of toluene solution containing 8 mg of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, add 57.6 mg of hydrochloride of dimethylaminoethoxide, 12.5 mg of tetrabutylammonium and 1 ml of 10M aqueous sodium hydroxide solution at room temperature. After stirring the mixture at room temperature for 2 hours, stirring is carried out further at 60°C for 16 hours. After completion of the reaction, to the reaction mixture are added ethyl acetate and aqueous sodium bicarbonate solution and the layers separated. The organic layer is then washed with water, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1). The obtained oily substance is treated with a 4M solution of hydrochloric acid in ethyl acetate. The resulting precipitates are collected by filtration and dried, obtaining 53 mg of the hydrochloride of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-(1-dimethylaminoethoxy)-2-(4-fluoro-2-were)piperidine as shown below in table 4.

Example 7

Hydrochloride of 1-(2-chloroethyl)piperidine and 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine treated according to the method of example 6, receiving hydrochloride 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-piperidylidene)piperidine as shown below in table 4.

Example 8

the 3 ml of dichloromethane was dissolved 100 mg of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine, add 0,03 ml of piperidine and 0,018 ml of acetic acid and the mixture is stirred. Add 129,7 mg triacetoxyborohydride sodium and the mixture is stirred at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, the layers separated and the aqueous layer was extracted with dichloromethane. The combined organic layers washed with water and brine, dried and the solvent is removed using distillation under reduced pressure. Then the residue purified using a chromatographic column with NH-silica gel (hexane:ethyl acetate=4:1)to give TRANS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-piperidineacetic and CIS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-piperidineacetic. Each of the obtained compounds are dissolved in 1 ml of chloroform, respectively, and add 0.2 ml of 4M hydrochloric acid in ethyl acetate. After brief mixing, the mixture is concentrated under reduced pressure, receiving 58 mg (a) hydrochloride of TRANS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-piperidinylidene and 16 mg hydrochloride (b) CIS-1-{N-(3,5-bis-trifloromethyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-piperidinylidene, as presented below in table 5.

Examples 9 through 44

Use appropriate source materials, which are processed according to the method of example 8, when receiving the connection presented below in tables 6 through 18.

Example 45

In 20 ml of acetic acid are dissolved at 2.45 g of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine and 3.85 g of ammonium acetate and add 5 g of sodium sulfate. The mixture is stirred at room temperature for one hour. Then added 1.18 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 24 hours. After completion of the reaction add 2M aqueous sodium bicarbonate solution, the chloroform and water. The mixture is stirred for 0.5 hour and the layers separated. The aqueous layer was again extracted with chloroform, the combined organic layer is dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=10:1). The obtained oily substance is treated with a solution of 4M hydrochloric acid in ethyl acetate and concentrated under reduced pressure. Then the concentrate is triturated with isopropyl ether, receiving of 1.16 g of the hydrochloride of 4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 19.

Example 46

sportsouth (2R)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidin, which is treated according to the method of example 45, receiving hydrochloride (2R)-4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 19.

Example 47

In 20 ml of dichloromethane solution containing 1.06 g of 4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)of piperidine type of 0.42 ml of triethylamine and 660 mg of dibutyldithiocarbamate and the mixture is stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1)to give 130 mg (a) TRANS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene and 120 mg (b) CIS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene, as presented below in table 20.

Example 48

100 mg of TRANS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene treated with a 4M solution of hydrochloric acid in ethyl acetate. Add ether and hexane, the resulting precipitates are collected by filtration, washed with hexane and dried in vacuum, obtaining 56 mg of the hydrochloride of TRANS-4-amino-1-{N-(3,5-bistrutturate the ZIL)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine, as presented below in table 21.

Example 49

Use of CIS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylamino, which is treated by the method of example 48, receiving hydrochloride CIS-4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 21.

Example 50

In 1.2 ml of dichloromethane was dissolved 60 mg of 4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine add 0,02 ml of triethylamine and of 0.013 ml Propionaldehyde under ice cooling and the mixture is stirred under ice cooling for 20 minutes, the Reaction mixture was poured into saturated brine and the layers separated. The aqueous layer was extracted with dichloromethane, the combined organic layers washed with brine, dried and the solvent is removed using distillation. The residue is purified using thin-layer chromatography on silica gel (chloroform:methanol=9:1)to give 40 mg (a) TRANS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-propionylcarnitine and 27 mg (b) CIS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-propionylcarnitine as presented below in table 22.

Examples c 51 69

Use appropriate recognize the substances, which is treated according to the method of example 50, receiving the connection represented below in tables c 23 to 33.

Example 70

In 4 ml of dichloromethane solution containing 98 mg of 4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)of piperidine added sequentially 0,056 ml of triethylamine and 0,028 ml acetylchloride at 0°and the mixture was stirred at 5°for 0.5 hour. After completion of the reaction add aqueous sodium bicarbonate solution and chloroform, the mixture is stirred and the layers separated. The aqueous layer was again extracted with chloroform, the combined organic layers are dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:ethyl acetate=4:1)and dried in vacuum, obtaining 86 mg of 4-acetylamino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)of piperidine in the form of powder, as presented below in table 34.

Example 71

Using 4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine hydrochloride and nicotinamide, which is treated by the method of example 70, receiving 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(3-pyridylcarbonyl)piperidine as shown below in table 34.

Example 72

To 3 ml of dimetilformamide solution, containing 124 mg of 4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)of piperidine added 44 mg of N-tert-butoxycarbonylamino, 58 mg of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 13.5 mg of 1-hydroxy-1H-benzotriazole and the mixture is stirred at room temperature for 16 hours. After completion of the reaction add aqueous sodium bicarbonate solution and chloroform, the mixture is stirred and the layers separated. The aqueous layer was again extracted with chloroform, the combined organic layers are dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)and treated with 4M solution of hydrochloric acid in ethyl acetate. The mixture is concentrated under reduced pressure. The formed precipitation was washed with isopropyl ether, collected by filtration and dried in vacuum, obtaining 83 mg of the hydrochloride of 4-aminoethylamino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 35.

Example 73

Using 4-Amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine and N,N-dimethylglycine, which is treated by the method of example 72, receiving hydrochloride 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-d is methylaminoacetaldehyde-2-(4-fluoro-2-were)piperidine, as presented below in table 35.

Example 74

To 25 ml of an ethanol solution containing 320 mg of CIS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(4-nitrobenzoyl)aminopiperidine add 480 mg diloreto tin and the mixture is refluxed for 4 hours. After completion of the reaction, the ethanol is removed using distillation under reduced pressure. Add diethyl ether and 2M aqueous sodium hydroxide solution and the layers separated. The organic layer is again washed with 2M aqueous sodium hydroxide solution and then washed with water. This organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1), and the resulting oily substance is treated with a 4M solution of hydrochloric acid in ethyl acetate. The reaction mixture was concentrated under reduced pressure and triturated with isopropyl ether, getting 152 mg of the hydrochloride CIS-4-(4-aminobenzoyl)amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 36.

Example 75

To 60 ml of tertrahydrofuran ring solution containing 3,91 g of N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methylamine, type of 2.34 g of 1,1'-carbonyldiimidazole and the mixture is peremeshivayte at 40° C during the night. After the solvent is removed using distillation, add ethyl acetate. All organic layers washed with water and saturated salt solution and dried. White crystals, obtained by removal of the solvent by distillation under reduced pressure, collecting, using diisopropyl ether. The obtained white crystals are dissolved in 60 ml of acetonitrile and add 3.5 ml of methyl iodide. After the reaction proceeds at 60°C for 2 hours, the solvent is removed using distillation under reduced pressure. 224 mg of residue is dissolved in 2 ml of dichloromethane, added with ice cooling to 100 mg of CIS-2-(4-fluoro-2-were)-4-(propanolamine)of piperidine and 0.11 ml of triethylamine and the mixture is stirred at room temperature overnight. The reaction mixture was poured into water and the layers separated. The aqueous layer was extracted with dichloromethane, the combined organic layers washed with water and saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=1:3), getting to 83.5 mg (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-propenylbenzene, as presented below in table 37.

Examples from 76 to 84

Ispolzuyuschihsya initial matter, which is treated according to the method of example 75, receiving connections, are presented below in tables 37 to 39.

Example 85

To 1 ml of an ethyl acetate solution containing 212 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene, add 2 ml of 4M hydrochloric acid in ethyl acetate under ice cooling and the mixture is stirred under ice cooling for 30 minutes After the solvent is removed using distillation under reduced pressure, to the residue is added chloroform and 2M aqueous the sodium hydroxide solution. The layers separated, the aqueous layer was extracted with chloroform, the combined organic layers are dried and the solvent is removed using distillation under reduced pressure, getting 177 mg (2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 40.

Example 86

Using (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylamino, which is treated by the method of example 85, receiving (2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 40.

Example 87

To a 2 ml dichloromethane solution, terasawa 253 mg of (2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)of piperidine and 0,139 ml of triethylamine, add 0,071 ml methanesulfonanilide under ice cooling and the mixture is stirred for one hour. The reaction mixture was poured into water and the layers separated. The aqueous layer was extracted with chloroform, the combined organic layers are washed, dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=1:1)to give 243 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-methanesulfonamido-2-(4-fluoro-2-were)piperidine as shown below in table 41.

Example 88

Using (2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine and acanaloniidae, which is treated by the method of example 87, receiving (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-ethanolamine-2-(4-fluoro-2-were)piperidine as shown below in table 41.

Example 89

To 1 ml dimethylformamide solution containing 58,4 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-methanesulfonamido-2-(4-fluoro-2-were)piperidine add to 4.6 mg of sodium hydride under ice cooling. The mixture is stirred for 30 min, add 0,010 ml of methyl iodide and the mixture is stirred for one hour. The reaction mixture is then poured the water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers washed with water and saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. Then the residue purified using a chromatographic column with silica gel (hexane:ethyl acetate=2:1)getting to 36.7 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-(N-methanesulfonyl-N-methyl)amino-2-(4-fluoro-2-were)piperidine as shown below in table 41.

Example 90

Using (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-ethanolgasoline, which is treated by the method of example 89, receiving (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(N-methyl-N-econsultancy)aminopiperidin, as presented below in table 41.

Example 91

To 20 ml of toluene solution containing 985 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine and 129 mg tetrabutylammonium and 10 ml of 10M aqueous sodium hydroxide solution, added at room temperature to 1.21 ml of 2-(2-bromoethoxy)tetrahydropyran, the temperature of the mixture was raised to 60°S-70°and the mixture is stirred over night. Then add to 2.42 ml of 2-(2-bromoethoxy)tetrahydropyran and the mixture is stirred over night. The reaction mixture is poured is in a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=3:2)to give 1.12 g (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{2-(tetrahydropyran-2-yloxy)ethoxy}piperidine as shown below in table 42.

Example 92

To 30 ml of a methanol solution containing 1.04 g of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{2-(tetrahydropyran-2-yloxy)ethoxy}piperidine add 64 mg of the monohydrate of p-toluensulfonate acid and the mixture is stirred for 20 minutes, the Reaction mixture was concentrated under reduced pressure, then the residue purified using a chromatographic column with silica gel (chloroform:ethyl acetate=1:1)getting 703 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethoxy)piperidine as shown below in table 42.

Example 93

To 2 ml of tertrahydrofuran ring solution containing 53,6 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethoxy)piperidine, 13,8 mg 4H-[1,2,4]triazole and 24.4 mg of triphenylphosphine, add 0,092 ml of 40% solution of diethylazodicarboxylate in toluene under ice cooling is m The temperature of the mixture was raised to room temperature and the mixture is stirred over night. Then the temperature was raised to 50°C, add to 24.4 mg of triphenylphosphine and the mixture is stirred for 30 minutes, the Reaction mixture was poured into water and extracted with ethyl acetate, the organic layer was washed with saturated saline solution, dried and the solvent is removed using distillation. The residue is purified using a chromatographic column with silica gel (chloroform:ethyl acetate=1:1 and chloroform:methanol=19:1)getting to 43.2 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{2-(1,2,4)triazolinone}piperidine as shown below in table 42.

Examples 94 and 95

Relevant source materials treated by the method of example 93, obtaining the compounds shown below in table 42.

Example 96

To 2 ml of dichloromethane solution containing 215 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethoxy)of piperidine and 0,084 ml of triethylamine, add 0.037 ml methanesulfonanilide under ice cooling and the mixture is stirred for 30 minutes, the Reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with brine, dried and the solvent is removed using distillation under reduced pressure. The residue is cleaned, use the Zuya chromatographic column with silica gel (chloroform:ethyl acetate=2:1), getting 189 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-methanesulfonylaminoethyl)piperidine as shown below in table 42.

Example 97

(1) To 1 ml of dichloromethane solution containing 61,5 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-methanesulfonylaminoethyl)of piperidine and 0,028 ml of triethylamine, add 0,013 ml of the research under ice cooling and the mixture is refluxed under heating overnight. Next, add 1 ml of the research and the mixture is stirred for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried and the solvent is removed using distillation. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1) and chromatographic column with NH-silica gel (hexane:ethyl acetate=2:1), receiving of 36.3 mg (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-morpholinoethoxy)piperidine.

(2) In 1.0 ml of chloroform is dissolved in a 30.7 mg of the above compound (1) and add 0,02 ml of 4M hydrochloric acid in ethyl acetate. The mixture is stirred for some time and concentrate under reduced pressure, getting to 35.3 mg hydrochloride (2R,4S)-1-{N-(3,5-vitriform tenbensel)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-morpholinoethoxy)piperidine, as presented below in table 42.

Example 98

Using (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-methanesulfonylaminoethyl)piperidine and diethylamin, which is treated by the method of example 97(1)to give (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-(2-diethylaminoethoxy)-2-(4-fluoro-2-were)piperidine as shown in table 42.

Example 99

In 2 ml of dichloromethane was dissolved 200 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, then add 0.1 ml utilizationof and 0.1 ml of triethylamine and the mixture is stirred under heating at 60°C for 3 days. The reaction mixture is cooled to room temperature, add water and chloroform and the layers separated. The aqueous layer was again extracted with chloroform and the combined organic layers dried over sodium sulfate. The solvent is removed using distillation under reduced pressure, and the residue purified using a chromatographic column with silica gel (hexane:ethyl acetate=1:1)to give 78 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-ethylenedicarboxylic-2-(4-fluoro-2-were)piperidine as shown below in table 42.

Example 100

In 2 ml of dichloromethane was dissolved 200 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-4-fluoro-2-were)-4-hydroxypiperidine, then add 0.1 ml of the chloride morpholine-4-carboxylic acid and 0.1 ml of triethylamine and the mixture is stirred under heating at 60°C for 3 days. Then the reaction mixture is cooled to room temperature, add water and chloroform and the layers separated. The aqueous layer was again extracted with chloroform and the combined organic layers dried over sodium sulfate. Then the solvent is removed using distillation under reduced pressure, the residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=1:1)to give 68 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-morpholinobutyrophenone, as presented below in table 42.

Example 101

In 5 ml of tetrahydrofuran is dissolved 248 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, then add 81 mg of 1,1'-carbonyldiimidazole and the mixture is stirred under heating at 60°C for 16 hours. The reaction mixture is cooled to room temperature, add water and chloroform and the layers separated. The aqueous layer was again extracted with chloroform, and then the combined organic layers washed with water. The organic layer is dried over sodium sulfate and the solvent is removed using distillation under reduced pressure. Received concentri is consistent residue is purified using the chromatographic column with NH-silica gel (hexane:ethyl acetate=1:1)to give 135 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-imidazolyl)carbonylcontaining, as presented below in table 42.

Example 102

(1) In 3 ml of acetonitrile is dissolved 298 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-imidazolyl)carbonylcontaining, then add to 0.06 ml of methyl iodide and the mixture is stirred under heating for one hour. The solution is cooled to room temperature and the solvent is removed using distillation under reduced pressure. To the residue add 2.5 ml of methylene chloride, of 0.11 ml of 4-methylpiperazine and 0.14 ml of triethylamine and the mixture is stirred at room temperature for 16 hours. To the reaction mixture an aqueous solution of sodium bicarbonate and chloroform and the mixture is stirred for 30 minutes, the Layers separated, the organic layer was washed further with water and dried over magnesium sulfate. The solvent is removed using distillation under reduced pressure and the resulting residue purified using a chromatographic column with NH-silica gel (hexane:ethyl acetate=2:1)to give (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(4-methylpiperazine)carbonitesetuplite.

(2) Specified to enter the compound (1) is treated with 4M solution of hydrochloric acid in ethyl acetate, getting 78 mg hydrochloride (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-(4-methylpiperazine)carbonyloxy-2-(4-fluoro-2-were)piperidine as shown below in table 43.

Examples 103 105

Use appropriate source materials, which are processed according to the method of examples 102 (1) and (2), obtaining the compounds shown below in table 43.

Example 106

(1) In 100 ml of tetrahydrofuran was dissolved 5 g of CIS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, and 10.5 g of triphenylphosphine and 4,88 g of benzoic acid, then add to 18.3 ml of a 40% toluene solution of diethylazodicarboxylate under ice cooling and the mixture is stirred at room temperature for 3 hours. To the reaction mixture are added water and ethyl acetate and the mixture is stirred for 30 minutes a Solution of layers, the organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1), receiving 4,36 g of TRANS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-benzoyloxy-2-(4-fluoro-2-were)piperidine.

(2) In 10 ml of methanol was dissolved 1.4 g obtained above compounds (1), then add 325 mg of potassium carbonate and the mixture is stirred at room Tempe is the atur for 16 hours. After the solution is concentrated under reduced pressure to remove solvent, adding water and ethyl acetate and the layers separated. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1)to give 0.68 g of TRANS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, as presented below in table 44.

Example 107

To 10 ml of tetrahydrofuran added 98 mg of TRANS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, 70 mg [1,2,4]triazole and 262 mg of triphenylphosphine, then add to 0.48 ml of a 40% toluene solution of diethylazodicarboxylate and the mixture is stirred at the boil under reflux for 16 hours. After completion of the reaction, add an aqueous solution of sodium bicarbonate and ethyl acetate and the mixture is stirred for 30 minutes, the Reaction is divided into layers, the organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=9:1)to give 46 mg of CIS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1,2,4-triazolyl)piperidine as shown below in table 44.

Example 108

Use of CIS-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine and 4,6-dihydroxy-2-mercaptopyrimidine, which is treated by the method of example 107, when receiving the connection as shown below in table 45.

Example 109

Using (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, which is treated by the method of example 106 (1) and (2)to give (2R,4R)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, as presented below in table 46.

Examples from 110 to 112

Use appropriate source materials, which are processed according to the method of example 107, when receiving the connection below in table 46.

Example 113

(1) 30 ml of tertrahydrofuran ring of a solution containing 1.2 ml of triethylphosphate, cooled with ice and slowly add sodium hydride. Maintaining the same temperature, the mixture is stirred for 30 min and added dropwise 30 ml of tertrahydrofuran ring solution containing 3,02 g (2R)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine. The mixture is stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. Obyedinenny the organic layers washed with water and saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1)to give (2R)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-ethoxycarbonylmethylene-2-(4-fluoro-2-were)piperidine as a colourless liquid.

(2) the above compound (1) dissolved in 50 ml of methanol, add 500 mg of palladium-on-coal and the mixture is stirred in hydrogen atmosphere at room temperature overnight. The catalyst was removed and the methanol removed using distillation under reduced pressure; the residue purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1), receiving 3,23 g 2R)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-ethoxycarbonylmethyl-2-(4-fluoro-2-were)piperidine as shown below in table 46.

Example 114

(1) In 20 ml of methanol is dissolved 3,23 g (2R)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-ethoxycarbonylmethyl-2-(4-fluoro-2-were)of piperidine and add 5,73 ml of 2M aqueous solution of sodium hydroxide. The mixture is stirred at room temperature overnight. After neutralization of the mixture of 2M hydrochloric acid and the methanol removed by distillation under reduced pressure and the aqueous layer was extracted with ethyl acetate. The organic layer industry is with water and saturated saline solution, dried and the solvent is removed using distillation under reduced pressure, obtaining of 2.97 g (2R)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-carboxymethyl-2-(4-fluoro-2-were)of piperidine in the form of a yellow powder.

(2) 200 mg of the above compound (1) dissolved in 2 ml of dimethylformamide, added 84 mg of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 65 mg of 1-hydroxy-1H-benzotriazole and 0.037 ml of the research and the mixture is stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous citric acid, saturated aqueous sodium bicarbonate and saturated saline solution. The organic layer is dried, the solvent is removed using distillation to obtain a residue, which was purified using a chromatographic column with NH-silica gel (hexane:ethyl acetate=2:1)to give 138 mg of (2R)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-morpholinobutyrophenone, as presented below in table 46.

Examples 115 to 117

Use appropriate source materials, which are processed according to the method of example 114 (2), obtaining the compounds shown below in table 46.

Example 118

(1) In 10 ml of ethanol is dissolved 1,49 g (2R)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]amino ronil-2-(4-fluoro-2-were)-4-oxopiperidine and add 226 mg of hydroxylamine hydrochloride and 267 mg of sodium acetate. The mixture is stirred over night. The ethanol is removed using distillation under reduced pressure, to the residue water is added and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried. The solvent is removed using distillation under reduced pressure, obtaining the compound in the form of resin.

(2) the above compound (1) dissolved in 50 ml of methanol and add 844 mg of Nickel chloride. The mixture is cooled in ice and slowly add 224 mg sodium borohydride. After stirring the mixture during the night it concentrated under reduced pressure, add water and ethyl acetate and the layers separated. The organic layer was washed with saturated saline solution and dried. The solvent is removed using distillation under reduced pressure, getting 1.44 g (2R)-4-amino-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 47.

Example 119

Using (2R)-1-{N-(3,5-bistrifluormethylbenzene)methyl-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidin, which is treated by the method of example 119 (1) and (2)to give (2R)-4-amino-1-{N-(3,5-bistrifluormethylbenzene)methyl-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 47.

Example 120

Using (2R)-4-amino-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]AMI is carbonyl-2-(4-fluoro-2-were)piperidine, which is treated according to the method of example 50, receiving (a) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-pyrazinecarboxamide)piperidine and (b) (2R,4R)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-pyrazinecarboxamide)piperidine as shown below in table 47.

Example 121

In 2 ml of the combined acetonitrile solution containing 80 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-morpholinopropan add 0,034 ml of methyl iodide and the mixture is stirred at 60°With during the night. The solvent is removed using distillation, and loose precipitated yellow powder is dried, receiving 98 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(N-methyl-4-morpholino)piperidinedione, as presented below in table 48.

Example 122

Using (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-morpholinopropan, which is treated by the method of example 121, receiving (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(N-methyl-4-morpholino)piperidinium, as presented below in table 48.

Example 123

In 2 ml of dichloromethane solution containing 80 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistritei enyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-morpholinopropan, added 34 mg of 3-chloroperbenzoic acid and the mixture is stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and the aqueous layer was extracted with dichloromethane. The combined organic layers washed with water and saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. Precipitated precipitated white powder is dried, receiving 79 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(N-oxaprotiline)piperidine as shown below in table 48.

Example 124

Using (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-morpholinopropan, which is treated by the method of example 123, receiving (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(N-oxaprotiline)piperidine as shown below in table 48.

Examples from 125 127

Use appropriate source materials, which are processed according to the method of example 8, when receiving the connection below in table 49.

Examples from 128 to 136

Use appropriate source materials, which are processed according to the method of example 50, receiving the connection represented below in tables 49-51.

Example 137

In 2 ml dig armeana dissolve 263 mg (2R)-4-amino-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine, at room temperature add 52 ál 2-chlorotriazine and 167 μl of triethylamine and the mixture is stirred for 2 hours. To the solution was added saturated sodium bicarbonate solution, the dichloromethane layer is isolated and the aqueous layer was further extracted with chloroform. The combined organic layers washed with saturated saline solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=9:1)to give 109 mg of (2R)-4-(2-chloroethyl)ureido-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown in table 51.

Example 138

In 20 ml of dimethylformamide is dissolved 2.65 g of hydrochloride (2R)-4-amino-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)of piperidine and 1 g of 5-formylfuran-2-carboxylic acid and added 1.92 g of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 0.6 g of 1-hydroxy-1H-benzotriazole and 1.4 ml of triethylamine. The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, add an aqueous solution of citric acid and ethyl acetate and the layers separated. The organic layer is further washed with saturated brine, and the combined organic layers are dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using chromatog aricescu column with NH-silica gel (hexane:ethyl acetate=2:1), getting 289 mg (a) (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-4-(5-formylfuran-2-yl)carbarnoyl-2-(4-fluoro-2-were)of piperidine and 185 mg (b) (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-4-(5-formylfuran-2-yl)carbarnoyl-2-(4-fluoro-2-were)piperidine as shown below in table 52.

Examples from 140 168

Use appropriate source materials, which are processed according to the method of example 138, getting a connection, as shown in tables 53-57 below.

Example 169

In 1 ml of tetrahydrofuran was dissolved 80 mg of (2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine, while cooling with ice add to 25.7 mg of 1,1-carbonyldiimidazole and the mixture is stirred under ice cooling for 30 minutes To a solution of 19 ál 2-aminoethanol while cooling with ice add 44 μl of triethylamine and the mixture is stirred at room temperature for 22 hours. The solvent is removed using distillation, to the residue add water and dichloromethane and the layers separated. The organic layer was washed with saturated saline solution, dried and concentrated. To the residue is added isopropyl ether, and the precipitated precipitated crystals white is collected by filtration, receiving 74 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethyl)in which endopeptidase, as presented below in table 57.

Examples from 170 to 173

Use appropriate source materials, which are processed according to the method of example 169, receiving connection represented as shown below in table 57.

Examples from 174 177

Use appropriate source materials, which are processed according to the method of example 87, receiving connection represented as shown below in table 58.

Example 178

In 10 ml of dichloromethane is dissolved 1.01 g (2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)of piperidine and 0,558 ml of triethylamine while cooling with ice add 0,314 ml of 2-chloroethanesulfonate and the mixture is stirred for 4 hours. The solution was poured into water, the layers separated and the aqueous layer was further extracted with dichloromethane. The combined organic layers washed with saturated saline solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=2:1)to give 725 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-ethylenesulphonic-2-(4-fluoro-2-were)piperidine as shown below in table 58.

Example 179

Using (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-methylaminopropane that treatment is indicate by the method of example 178, receiving (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-(1-atranslator-1-methylamino)-2-(4-fluoro-2-were)piperidine as shown in table 58.

Examples 180-181

Use appropriate source materials, which are processed according to the method of example 87, receiving connections, are presented below in table 59.

Examples 183-184

Use appropriate source materials, which are processed according to the method of example 89, receiving connections, are presented below in table 59.

Example 185

Using (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine and 2-methoxyethanol, which is treated by the method of example 91, receiving (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-methoxyethoxy)piperidine as shown below in table 59.

Examples from 186 189

Use appropriate source materials, which are processed according to the method of examples 91 and 92, receiving connections, are presented below in tables 59 and 60.

Example 190

Using (2R,4S)-1-{N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethoxy)piperidine and methansulfonate, which is treated by the method of example 96, receiving (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)e is Il}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-methanesulfonylaminoethyl)piperidine, as presented below in table 60.

Examples from 191 through 196

Use appropriate source materials, which are processed according to the method of example 97, receiving connections, are presented below in tables 60 and 61.

Examples 197-198

Use appropriate source materials, which are processed according to the method of example 101, receiving the compounds shown below in table 62.

Examples from 199 at 205

Use appropriate source materials, which are processed according to the method of examples 102 (1) or 102 (1) and (2), obtaining the compounds shown below in table 63.

Example 206

Using (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-piperidinophenyl, which is treated by the method of example 123, receiving (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(N-oxopiperidine)piperidine as shown below in table 65.

Example 207

In 4 ml of ethanol is dissolved 124 mg of (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-4-(5-formylfuran-2-yl)carbarnoyl-2-(4-fluoro-2-were)piperidine add 3.8 mg sodium borohydride and the mixture is stirred at room temperature for 2 hours. To the solution was added an aqueous solution of sodium bicarbonate, the mixture is stirred for 10 min and concentrated, and then the ethanol is removed, used in the distillation. To the residue is added ethyl acetate and water and the layers separated. The organic layer is dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)to give 68 mg of (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(5-hydroxymethylene-2-yl)carbamoylbiphenyl, as presented below in table 65.

Example 208

In 4 ml of dichloroethane was dissolved 124 mg of (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-4-(5-formylfuran-2-yl)carbarnoyl-2-(4-fluoro-2-were)piperidine, 44 μl of the research and 2.9 μl of acetic acid, add 106 mg triacetoxyborohydride sodium and the mixture is stirred at room temperature for 3 hours. To the solution was added an aqueous sodium carbonate solution and chloroform, the mixture was stirred for 10 min and the layers separated. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified using a chromatographic column with NH-silica gel (n-hexane:ethyl acetate=1:1). The obtained oily substance is treated with a 4M solution of hydrochloric acid in ethyl acetate, receiving 78 mg hydrochloride (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(5-morpholinomethyl-2-yl)carbamoylbiphenyl, as presented below in table 65.

Example 209

In a mixture of 3.3 ml toluole 0.4 ml of dichloromethane is dissolved 197 mg (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine and added 78 mg of 1,1'-carbonyldiimidazole. The mixture was stirred at 60°C for 4 hours. Add distilled water, the mixture is extracted with chloroform, dried over magnesium sulfate and concentrate under reduced pressure. The residue is dissolved in 3.7 ml of acetonitrile, add 100 μl of methyl iodide and the mixture is stirred at 50°C for 3 hours. The solution is concentrated under reduced pressure, to the residue add 3.6 ml of toluene and 156 μl thiomorpholine and the mixture was stirred at 70°C for 16 hours. Add distilled water, the mixture is extracted with chloroform, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=2:1 to 1:2)to give 197 mg (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-tamahomeeeeeeeeeeeeeeee, as presented below in table 65.

Examples from 210 through 212

Use appropriate source materials, which are processed according to the method of example 209, receiving connections, are presented below in table 65.

Example 213

1.9 ml of dichloromethane is dissolved 62 mg of (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-tamahomeeeeeeeeeeeeeeee, while cooling with ice add 22 mg of 3-chloroperbenzoic acid and the mixture is stirred at 0°during the 30 minutes The solution is extracted by adding 0,1M aqueous sodium hydroxide solution and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified using thin-layer chromatography on silica gel (chloroform:acetone=4:1)to give 63 mg of (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1-oxathiolane)carbonitesetuplite, as presented below in table 65.

Example 214

2.4 ml of dichloromethane is dissolved 79 mg of (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-tamahomeeeeeeeeeeeeeeee, added 68 mg of 3-chloroperbenzoic acid and the mixture is stirred at room temperature for 4 hours. The solution is extracted by adding 0,1M aqueous sodium hydroxide solution and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified using thin-layer chromatography on silica gel (chloroform:acetone=4:1)to give 76 mg of (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-4-(1,1-dioxothiazolidine)carbonyloxy-2-(4-fluoro-2-were)piperidine as shown in table 65 below.

Example 215

In 1 ml of tetrahydrofuran is dissolved 78 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2,2,5-trimethyl[1,3]dioxolane-5-yl)carbamoylbiphenyl and cooling Edom add 0.5 ml of 2M aqueous solution of hydrochloric acid. After 15 min the temperature was raised to room temperature and the mixture is further stirred for 30 minutes the Mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:ethyl acetate=2:1)to give 64 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1,1-di(hydroxymethyl)ethyl}carbamoylbiphenyl, as shown in table 66 below.

Example 216

In 1 ml of dichloromethane is dissolved 50.5 mg (2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)of piperidine and while cooling with ice add to 25.2 mg of methyl isocyanate. After the temperature of the mixture was raised to room temperature, the mixture is stirred for 30 minutes the Solution is poured into water, the dichloromethane layer is isolated and the aqueous layer was further extracted with chloroform. The combined organic layers washed with saturated saline solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1), receiving of 47.9 mg (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-methylenedianiline, as presented in tab is itzá 66 below.

Example 217

Using (2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine and tert-utilitzant that process by way of example 216, receiving (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-tert-butylurea-2-(4-fluoro-2-were)piperidine as shown in table 66.

Example 218

In 1 ml of dichloromethane is dissolved 50.5 mg (2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)of piperidine and while cooling with ice add 42 μl of triethylamine and 18 μl of dimethylcarbamodithioato. After the temperature of the mixture was raised to room temperature, the mixture is stirred over night. The solvent was poured into water, the dichloromethane layer is isolated and the aqueous layer was further extracted with chloroform. The combined organic layers washed with saturated saline solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=39:1), receiving of 41.8 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-(3,3-dimethylurea)-2-(4-fluoro-2-were)piperidine as shown in table 66 below.

Examples 219 to 224

Use appropriate source materials, which are processed according to the method of example 216, receiving the connection made is Lenna below in table 67.

Example 225

(1) Used 80 mg of (2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine, which is treated by the method of example 216, receiving (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(4-methylpiperidino)piperidine.

(2) the above compound (1) dissolved in 1 ml ethyl acetate while cooling with ice, add 0.5 ml of 4M hydrochloric acid in ethyl acetate and the mixture is stirred for 30 minutes under ice cooling. The solvent is removed using distillation under reduced pressure, and add diethyl ether. Precipitated precipitated crystals white is collected by filtration, receiving 80 mg of hydrochloride (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(4-methylpiperidino)piperidine as shown below in table 67.

Example 226

In 2 ml of dichloromethane was dissolved 100 mg of (2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine, while cooling with ice add 33 μl of triethylamine and 19 μl of methylchloroform and the mixture is stirred under ice cooling for 30 minutes the Solution was poured into water and the dichloromethane layer is isolated and the aqueous layer was further extracted with dichloromethane. United organizes the f layers are washed with saturated salt solution, dry and concentrate. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)to give 80 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-ethoxycarbonylpyrimidine, as presented below in table 66.

Examples 227 229

Use appropriate source materials, which are processed according to the method of example 226, receiving connections, are presented below in table 68.

Example 230

1.2 ml of acetonitrile dissolving 22 mg of 2-ethoxyethanol, and to this add 94 mg N,N'-disuccinimidyl and 0.1 ml of triethylamine and the mixture is stirred at room temperature for 1.5 hours. The solvent is removed using distillation, to the residue is added saturated aqueous sodium bicarbonate solution and ethyl acetate and extracted. The organic layer was washed with saturated saline solution, dried and concentrated. The residue is dissolved in 0.8 ml dichloromethane, add 80 mg of (2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)of piperidine and 33 μl of triethylamine and the mixture is stirred at room temperature for 30 minutes To the solution was added saturated aqueous sodium bicarbonate solution and dichloromethane and extracted. The combined organic layers washed with saturated saline solution, dried, and to the center. The residue is purified using thin-layer chromatography on silica gel (chloroform:methanol=19:1)to give 85 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-(2-ethoxyethoxy)carbarnoyl-2-(4-fluoro-2-were)piperidine as shown in table 68 below.

Example 231

Use the 3-hydroxy-3-methylbutanol and (2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine, which is treated by the method of example 230, receiving (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(3-hydroxy-3-methylbutoxy)carbamoylbiphenyl, as shown in table 68 below.

Example 232

(1) In 1 ml of tetrahydrofuran is dissolved 119 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-vinylsulfonylacetamido. Added 26 μl of the research at room temperature and the mixture is refluxed under heating. After 5 hours added 26 μl of the research and the mixture is further refluxed under heating for 2.5 hours. The solution is concentrated and the residue purified using a chromatographic column with silica gel (chloroform:methanol=19:1)to give 129 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-morpholinoethyl)sulfonylamine the A.

(2) In 1 ml of chloroform is dissolved to 34.1 mg of the above compound (1) and add 25 ál of 4M solution of hydrochloric acid in ethyl acetate. The mixture is concentrated and receiving 33,1 mg hydrochloride (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-morpholinoethyl)sulfonylacetanilide, as presented below in table 69.

Examples 233 238

Use appropriate source materials, which are processed according to the method of example 232 (1) and (2), obtaining the compounds shown below in table 69.

Example 239

In a mixture of 1.6 ml of dimethylformamide and 0.2 ml of dichloromethane is dissolved 101 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine add 39 mg of (S)-(-)-2-pyrrolidone-5-carboxylic acid, 58 mg of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 12 mg of 4-(dimethylamino)pyridine and the mixture is stirred at room temperature for 6 hours, then continue stirring at 60°C for 4 days. To the solution was added 5% aqueous citric acid solution and the mixture extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, dried over magnesium sulfate and concentrated. The residue is purified using a chromatographic column with Seeley what ielem (chloroform:acetone=4:1 to 2:1), getting 64 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-((2S)-5-oxopyrrolidin-2-yl}carbonyloxy-2-(4-fluoro-2-were)piperidine as shown below in table 70.

Example 240

(1) In a mixture of 3.2 ml of toluene and 0.4 ml of dichloromethane is dissolved 179 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine add 69 mg of 1,1'-carbonyldiimidazole and the mixture was stirred at 60°C for 3 hours. Add distilled water and the mixture extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is dissolved in 3.2 ml of acetonitrile, add 88 μl of methyl iodide and the mixture is stirred at 50°C for 3 hours. After the solution will concentrate add 3.2 ml of toluene and 114 μl of thiazolidine and the mixture was stirred at 70°C for 16 hours. Add distilled water and the mixture extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=1:1 to 1:2)to give 141 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1,3-tetrahydrothieno-3-yl)carbonylcontaining.

(2) In 2 ml of dichloroethane was dissolved mg the above compounds (1), while cooling with ice add 22 mg of 3-chloroperbenzoic acid and the mixture is stirred at 0°within hours. To the mixture is added saturated aqueous sodium bicarbonate solution and extracted. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using thin-layer chromatography on silica gel (chloroform:acetone=4:1)to give 42 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1-oxo-1,3-tetrahydrothieno-3-yl)carbonylcontaining, as presented below in table 70.

Example 241

(1) In 1.9 ml of toluene is dissolved 101 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine add 46 ál complex ethyl ester isocyanate acetic acidand one drop of acetic acid and the mixture was stirred at 70°C for 16 hours. The solution is concentrated and the residue purified using a chromatographic column with silica gel (hexane:ethyl acetate=2:1 to 1:1)to give 124 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-ethoxycarbonylmethoxy-2-(4-fluoro-2-were)piperidine.

(2) In a mixture of 1.35 ml of tetrahydrofuran and 0.15 ml of methanol is dissolved 106 mg of the above compound (1), add 92 μl of 2M aqueous sodium hydroxide solution and the mixture is PE is amerivault at room temperature for 1 hour. After the solution will concentrate, add 10% aqueous citric acid solution, precipitates are collected by filtration and washed with water, receiving 92 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-carboxymethylaminomethyl-2-(4-fluoro-2 - were)piperidine as shown below in table 70.

Example 242

In 0.9 ml of dimethylformamide is dissolved 61 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-carboxymethylaminomethyl-2-(4-fluoro-2-were)piperidine add 9 ál of the research, 15 mg of the monohydrate of 1-hydroxybenzotriazole and 19 mg of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the mixture is stirred at room temperature during the day. To the solution was added distilled water, the mixture is extracted with chloroform, the organic layer is dried over magnesium sulfate and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)to give 50 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-morpholinopropanecarboxylic, as presented below in table 70.

Example 243

1.9 ml of toluene is dissolved 101 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine add 37 μl of chlorosulfonyl the cyanate and the mixture is stirred at room temperature for 10 minutes Add 207 μl of diethylamine and the mixture is stirred at room temperature for one hour. To the solution was added distilled water and the mixture extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)to give 116 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-diethylaminoethylmethacrylate-2-(4-fluoro-2-were)piperidine as shown below in table 70.

Example 244

Using (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine and (S)-(-)-2-pyrrolidone-5-carboxylic acid, which is treated by the method of example 239, receiving (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-4-{(2S)-5-oxopyrrolidin-2-yl}carbonyloxy-2-(4-fluoro-2-were)piperidine as shown below in table 70.

Example 245

In 2 ml of toluene is dissolved 264 mg hydrochloride (2R)-4-amino-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine, 80 mg of 2-bromopyridine, 12 mg of palladium acetate, 32 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 48 mg of tert-butoxide sodium and the mixture is stirred at 80°C for 16 hours. The solution is cooled to room temperature, add ethyl acetate and an aqueous solution of bicarbona the sodium and the mixture is extracted. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified using a chromatographic column with NH-silica gel (hexane:ethyl acetate=2:1)to give 68 mg (a) (2R,4S)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-prodiamine)of piperidine and 56 mg (b) (2R,4R)-1-[N-(3,5-bistrifluormethylbenzene)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-prodiamine)piperidine as shown below in table 71.

Examples 246-247

Use appropriate source materials, which are processed according to the method of example 245, receiving connections, are presented below in tables 71 and 72.

Examples 248-249

Use appropriate source materials, which are processed according to the method of example 75, obtaining the compounds shown below in table 72.

Example 250

(1) In 5 ml of tetrahydrofuran was dissolved 800 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-ethyl]aminocarbonyl-4-etoxycarbonyl-2-(4-fluoro-2-were)piperidine, add 5 ml of 2M aqueous sodium hydroxide solution and the mixture is stirred at room temperature for 3 days. To the reaction mixture an aqueous solution of citric acid to acidify, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried. The solution is concentrated and receiving 700 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistriflate fenil)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-were)piperidine.

(2) In dimethylformamide was dissolved 110 mg of the above compound (1), added 96 mg of the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, 30 mg of 1-hydroxybenzotriazole, 0.1 ml of 40% aqueous solution of ammonia and the mixture is stirred at room temperature for 3 hours. To the solution was added an aqueous citric acid solution and ethyl acetate and the layers separated. The organic layer was washed with saturated saline solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=9:1)to give 87 mg of (2R,4S)-4-aminocarbonyl-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 73.

Examples 251 253

Use appropriate source materials, which are processed according to the method of examples 250 (1) and (2) or 250 (2), obtaining the compounds shown below in table 73.

Example 254

(1) In 40 ml of tetrahydrofuran was dissolved 2 g of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine add 1,59 g chetyrehpostovye carbon and 1.26 g of triphenylphosphine and the mixture was stirred at room temperature for 2 hours. To the solution was added 80 ml of diethyl ether and after stirring the mixture precipitated precipitated insoluble substances UDA is EUT by filtration. The organic layer is concentrated and the residue purified using a chromatographic column with silica gel (n-hexane:ethyl acetate=10:1)to give 1.26 g of (2R,4R)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-bromo-2-(4-fluoro-2-were)piperidine.

(2) In 20 ml of dimethylformamide is dissolved to 1.14 g of the above compound (1)add to 1.14 g thioacetate potassium and the mixture was stirred at 80°C for 2 hours. Then the solution is cooled to room temperature, add aqueous citric acid solution and ethyl acetate and the layers separated. The organic layer was washed with saturated saline solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (n-hexane:ethyl acetate=6:1)to give 920 mg of (2R,4S)-4-acetylthio-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 74.

Examples 255-256

Use appropriate source materials, which are processed according to the method of example 254 (1) and (2), obtaining the compounds shown below in table 74.

Example 257

In 10 ml of methanol is dissolved 880 mg of (2R,4S)-4-acetylthio-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine, add methyl iodide and 5 ml of 1M aqueous sodium hydroxide solution and the mixture is stirred at room temperature is PE within 2 hours. To the solution was added an aqueous solution of citric acid to neutralize him and the methanol removed using distillation. To the residue is added ethyl acetate and a saturated saline solution and the layers separated. The organic layer is dried and concentrated. The residue is purified using a chromatographic column with silica gel (n-hexane:ethyl acetate=6:1)to give 560 mg of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-methylthiopyrimidine, as presented below in table 74.

Examples 258 on 263

Use appropriate source materials, which are processed according to the method of example 257, receiving connections, are presented below in tables 74 and 75.

Examples from 264 to 270

Use appropriate source materials, which are processed according to the method of example 213, receiving connections, are presented below in tables 76-77.

Examples 271 278

Use appropriate source materials, which are processed according to the method of example 214, receiving connections, are presented below in tables 78-79.

Examples 279 312

Use appropriate source materials, which are processed according to the method of example 138, receiving connections, are presented below in tables 80-87.

Example 313

To 4.2 ml of 4M hydrochloric acid in ethyl acetate add 361 mg of (2R,4S)-1-{N-(3,5-bistri formatives)-N-methyl}aminocarbonyl-4-[{(2S,4R)-4-benzyloxy-1-tert-butyloxycarbonyl-2-ylcarbonyl}amino]-2-(4-fluoro-2-were)of piperidine and the mixture is stirred for 1 hour at room temperature. After evaporation in vacuo the residue is triturated with hexane and the solvent is removed by decantation. The residue is dissolved in 4 ml of methylene chloride and to the mixture under cooling with ice add 158 ml of triethylamine and 36 ml of acetylchloride. After stirring for 1 hour while cooling with ice to the mixture, water is added and the mixture extracted with chloroform. The organic layer is dried over magnesium sulfate and evaporated in vacuum. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=49:1 to 19:1)to give 304 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-{[(2S,4R)-4-benzyloxy-1-acetylpyrrolidine-2-ylcarbonyl]amino}-2-(4-fluoro-2-were)piperidine as shown in table 86.

Examples 314 through 316

Use appropriate source materials, which are processed according to the method of example 313, receiving connections, are presented below in tables 86 and 87.

Examples 317-318

Use appropriate source materials, which are processed according to the method of example 113(2), obtaining the compounds shown below in table 87.

Example 319

1.8 ml of toluene is dissolved 98 mg of (2R,4S)-4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)of piperidine added 24 mg of succinic anhydride and 0,033 ml of triethylamine and the mixture is refluxed for casul. The mixture is cooled to room temperature and then add water. The mixture is extracted with ethyl acetate, the organic layer is dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)to give 79 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-(2,5-dioxaborolan)-2-(4-fluoro-2-were)piperidine as shown below in table 87.

Examples from 320 to 330

Use appropriate source materials, which are processed according to the method of example 209, receiving connections, are presented below in tables 88-90.

Example 331

Use appropriate source materials, which are processed according to the method of example 113, receiving (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(ethoxycarbonylmethyl)piperidine as shown in table 91 below.

Example 332

In 20 ml of tetrahydrofuran is dissolved 2,03 g (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-ethoxycarbonylpyrimidine add 450 mg sociallyengaged under ice cooling and the mixture is stirred for one hour. Slowly add 2 ml of water and after stirring the mixture for 10 min, add 5 ml of 1M aqueous sodium hydroxide solution and the mixture is further stirred for 10 minutes the Resulting precipitate white UDA is Aut, to the filtrate add diethyl ether and water and the layers separated. The organic layer is then washed with water, dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1 to 3:2)to give 830 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethyl)piperidine, as presented below in table 91.

Example 333

Use appropriate source materials, which are processed according to the method of example 245, receiving (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(N-pyrazin-2-ylamino)piperidine as shown below in table 91.

Example 334

In 2 ml of N,N-dimethylformamide was dissolved 114 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(N-pyrazin-2-ylamino)of piperidine added under ice cooling to 10 mg of sodium hydride (40% mixture in oil), after stirring the mixture for 5 min add 0,013 ml of methyl iodide and the mixture is stirred at room temperature for 2 hours. To the solution was added water and ethyl acetate, after stirring the mixture for 10 min, the layers separated. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with NH-silicagel the m (hexane:ethyl acetate=85:15 to 1:1), getting 98 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(N-pyrazin-2-yl-N-methylamino)piperidine as shown below in table 91.

Example 335

In 40 ml of dichloromethane was dissolved 8.0 g of (2R)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine add 10 ml ethanolic solution of methylamine (35%, about 8M), 2 ml of acetic acid and 4,24 g triacetoxyborohydride sodium and the mixture is stirred at room temperature for 16 hours. To the solution was added 2M aqueous sodium carbonate solution and chloroform, and after stirring the mixture for 30 min, the layers separated. The aqueous layer was further extracted with chloroform, the combined organic layers dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with NH-silica gel (hexane:ethyl acetate=2:1)to give a mixture of (a) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-methylaminopropane and (b) (2R,4R)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-methylaminopropane.

(2) the above compound (1) dissolved in 40 ml of dichloromethane, added 4.4 g of dicret-BUTYLCARBAMATE and the mixture is stirred at room temperature for 16 hours. The solution is concentrated under reduced pressure and the residue purified using XP is matographique a column of silica gel (hexane:ethyl acetate=10:1), receiving of 4.2 g of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(tert-butoxycarbonyl-N-methylamino)piperidine.

(3) the above compound (2) is treated with 4M solution of hydrochloric acid in ethyl acetate and concentrated under reduced pressure. The residue is recrystallized from a mixed solution of hexane and ethyl acetate, getting 3.6 g of hydrochloride (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-methylaminopropane, as presented below in table 91.

Example 336

(1) Use a 2.12 g of (2R,4S)-4-etoxycarbonyl-2-(4-fluoro-2-were)-4-piperidine, which is treated by the method of example 248, obtaining 3.8 g (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-etoxycarbonyl-2-(4-fluoro-2-were)piperidine.

(2) the above compound (1) is treated according to the method of example 250(1)to give 2.3 g (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}amino-4-carboxy-2-(4-fluoro-2-were)piperidine as shown below in table 91.

Examples from 337 to 340

Use appropriate source materials, which are processed according to the method of example 250(2), obtaining the compounds shown below in table 91.

Example 341

Use (1) 4-etoxycarbonyl-2-(4-fluoro-2-were)piperidine and related source materials, which process with the lady of example 248, and purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1)to give (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-ethoxycarbonylpyrimidine.

(2) Use the above compound (1),which is treated by the method of example 250(1)to give (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-were)piperidine as shown below in table 92.

Examples from 342 to 349

Using (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-were)piperidine and related source materials, which are processed according to the method of example 250 (2), obtaining the compounds shown below in table 92.

Example 350

In 12 ml of tetrahydrofuran is dissolved of 1.62 g of (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-were)of piperidine are added dropwise 2 ml dimethylsulfide complex of borane (about 10 M) and the resulting mixture was stirred at room temperature for 16 hours. To the reaction mixture are added 10 ml of methanol and the mixture is stirred for 0.5 hour. After completion of the reaction the mixture was concentrated under reduced pressure and the residue purified using a chromatographic column with silica gel (chloroform:methanol=9:1), receiving of 1.32 g of (2R,4S)-1-N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxyethylpiperazine, as presented below in table 93.

Examples from 351 to 352

Using (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxyethylpiperazine and relevant source materials, which are processed according to the method of example 209, receiving connections, are presented below in table 93.

Example 353

Use 4-etoxycarbonyl-2-(4-fluoro-2-were)piperidine and related source materials, which are processed according to the method of example 341, receiving (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-were)piperidine as shown below in table 94.

Examples 354 365

Using (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-were)piperidine and related source materials, which are processed according to the method of example 250 (2), obtaining the compounds presented below in tables 94 and 95.

Example 366

In 2 ml of dichloromethane is dissolved 132 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-were)piperidine add 0,027 ml of oxalic acid dichloride and one drop of N,N-dimethylformamide and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue DOB is given in 2.5 ml of tetrahydrofuran and 0.12 ml of 2-aminopyrazine and the mixture is stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue purified using a chromatographic column with NH-silica gel (hexane:ethyl acetate=1:1)to give 63 mg of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-parilamentary)piperidine as shown below in table 96.

Example 367

Using (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-were)piperidine, which is treated by the method of example 350, receiving (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxyethylpiperazine, as presented below in table 96.

Example 368

In a mixture of 20 ml of toluene and 20 ml of acetic anhydride dissolved 1.07 g of the compound of example 268, add 165 mg of sodium acetate and the mixture is stirred, continuing to boil under reflux for 16 hours. After the reaction mixture was cooled to room temperature, is added slowly an aqueous solution of sodium bicarbonate until then, until it stops foaming. To the mixture are added water and ethyl acetate and the layers separated. The aqueous layer was further extracted with ethyl acetate, the combined organic layers dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (Gex is n:ethyl acetate=1:1), getting 980 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-acetoxypiperidine as presented below in table 97.

Example 369

Using (2R,4S)-4-acetoxymethyl-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine, which is treated by the method of example 214, receiving (2R,4S)-4-acetoxymethyl-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 97.

Example 370

In 10 ml of tetrahydrofuran and 5 ml of 2M aqueous solution of sodium hydroxide dissolved 200 mg of (2R,4S)-4-acetoxymethyl-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)of piperidine and the mixture is stirred at room temperature for 3 hours. The reaction mixture is neutralized 2M hydrochloric acid and the mixture extracted twice with ethyl acetate. The combined organic layers dried and concentrated under reduced pressure, receiving 80 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxymethylbenzene, as presented below in table 97.

Example 371

In 2.5 ml of acetonitrile was dissolved 130 mg of the compound of example 261, and to this add 0.5 ml of methyl iodide and the mixture is stirred at 50°C for 2 hours. The reaction mixture is concentrated and the residue was washed with diethyl ether, getting 117 mg of (2R,4S)-[1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine-4-yl]dimethylsulfonium, as presented below in table 97.

Example 372

In 100 ml of tetrahydrofuran is dissolved 10.7 g (2R)-1-{N-(3,5-bistrifluormethylbenzene)-N-hydroxypropyl}aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine, add 20 ml of pyridine and 20 ml of acetic anhydride and the mixture is stirred at room temperature for 5 hours. To the reaction mixture an aqueous solution of sodium bicarbonate and diethyl ether and the mixture is stirred for one hour. The layers are separated, then the organic layer washed twice with water, dried and concentrated under reduced pressure. The residue is dissolved in 100 ml of ethanol, add 1.5 g of sodium borohydride under ice cooling and the mixture is stirred for 0.5 hour. To the reaction mixture an aqueous solution of ammonium chloride and, after stirring the mixture for 30 min, the solvent is removed using distillation under reduced pressure. To the residue water is added and the solution extracted twice with chloroform. The combined organic layers dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=9:1)to give 9.6 g (2R,4S)-1-{N-(3-acetoxyphenyl)-N-(3,5-bistrifluormethylbenzene)}aminocarbonyl-2-(4-fluoro-2-IU is ylphenyl)-4-hydroxypiperidine, as presented below in table 98.

Examples 373 through 376

Using (2R,4S)-1-{N-(3-acetoxyphenyl)-N-(3,5-bistrifluormethylbenzene)}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine and relevant source materials, which are processed according to the method of example 209, getting a connection, as shown below in table 98.

Example 377

In 5 ml of methanol was dissolved 600 mg of (2R,4S)-1-{N-(3-acetoxyphenyl)-N-(3,5-bistrifluormethylbenzene)}aminocarbonyl-4-ethylenedicarboxylic-2-(4-fluoro-2-were)piperidine, add 5 ml of 2M aqueous sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. To the reaction mixture are added 2M aqueous solution of hydrochloric acid for neutralization, and the mixture was twice extracted with chloroform. The combined organic layers are dried, concentrated under reduced pressure and purified using a chromatographic column with silica gel (chloroform:methanol=9:1) getting 550 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-(3-hydroxypropyl)}aminocarbonyl-4-ethylenedicarboxylic-2-(4-fluoro-2-were)piperidine as shown in table 99 below.

Examples from 378 in 381

Use appropriate source materials, which are processed according to the method of example 377, receiving connections, are presented below in table 99.

Example 382

Using (2R,4S)-1-{N-(3,5-b is triftormyetil)-N-(3-hydroxypropyl)}aminocarbonyl-4-timorgaleevich-2-(4-fluoro-2-were)piperidine, which is treated according to the method of example 213, receiving (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-(3-hydroxypropyl)}aminocarbonyl-4-(1-oxathiolane)carbonyloxy-2-(4-fluoro-2-were)piperidine as shown below in table 99.

Example 383

(1) Using (2R,4S)-1-{N-acetoxymethyl-N-(3,5-bistrifluormethylbenzene)}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, which is treated by the method of example 254 (1) and (2)to give (2R,4S)-1-{N-acetoxymethyl-N-(3,5-bistrifluormethylbenzene)}aminocarbonyl-2-(4-fluoro-2-were)-4-acetylthiophene.

(2) Use the above compound (1), which is treated by the method of example 257, receiving (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-hydroxypropyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-propylthio)piperidine.

(3) Use the above compound (2), which is treated by the method of example 213, receiving (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-hydroxypropyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(propane-2-sulfinil)piperidine as shown below in table 99.

Example 384

Using (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-hydroxypropyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-propylthio)piperidine, which is treated by the method of example 214, receiving (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-hydroxypropyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(propane-2-sulfonyl)piperidine as is redstavlena below in table 99.

Example 385

Use 148 mg of (2R,4S)-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)of piperidine and a corresponding starting material, which is treated by the method of comparative example 6, receiving 36 mg of (2R,4S)-1-{N-(3,5-dimethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine as shown in the following table 100.

Example 386

Use appropriate source materials, which are processed according to the method of example 385, receiving (2R,4S)-1-{N-(3,5-dichlorobenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine as shown in the following table 100.

Example 387

In 10 ml of tetrahydrofuran is dissolved 676 mg hydrochloride (2R,4S)-2-(4-fluoro-2-were)-4-(2-atsetoksimetilnitraminov)piperidine, add, and 0.28 ml of triethylamine and the mixture is stirred for 30 minutes To the reaction mixture are added 330 mg of 1,1'-carbonyldiimidazole and the mixture was stirred at 65°C for 2 hours. The solvent is removed using distillation under reduced pressure, and the residue is dissolved in 5 ml of dichloromethane. The mixture is washed with water and saturated salt solution and dried. The mixture is evaporated in vacuum and the residue is dissolved in 5 ml of acetonitrile. To the solution was added 1 ml of methyl iodide and the mixture is stirred at 60°C for 2 hours. The solvent in Aleut, using distilled under reduced pressure. The residue is dissolved in 20 ml of tetrahydrofuran, add 600 mg of N-{1-(3,5-bistrifluormethylbenzene)-2-hydroxyethyl}-N-methylamine and 0.5 ml of triethylamine and the mixture was stirred at 70°C for 3 hours. To the reaction mixture are added ethyl acetate and water and the layers separated. The organic layer is dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)to give 780 mg of the mixture of compounds (a) (2R,4S)-4-(2-atsetoksimetilnitraminov)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)-2-hydroxyethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine derivatives and compounds (b) (2R,4S)-4-(2-atsetoksimetilnitraminov)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)-2-hydroxyethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 101.

Example 388

In 2 ml of methanol is dissolved 122 mg of the compound of example 387, add 1 ml of 2M aqueous sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is neutralized 6M aqueous solution of hydrochloric acid and the solvent is removed using distillation under reduced pressure. To the residue is added chloroform and water and the layers separated. The aqueous layer was further extracted with chloroform, the combined organic layers are dried and the con is intronaut under reduced pressure. The residue is dried in vacuum, obtaining 88 mg of a mixture of compounds (a) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)-2-hydroxyethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine and (b) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)-2-hydroxyethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine as shown below in table 101.

Example 389

(1) In 50 ml of dichloromethane is dissolved to 4.92 g of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine to the solution at room temperature add 2,43 g carbodiimide and the mixture is stirred for 1.5 hours. To the reaction mixture, water is added and the layers separated dichloromethane. The organic layer was washed with saturated saline solution, dried and the solvent is removed using distillation under reduced pressure, obtaining of 5.99 g of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-imidazoledicarbonitrile)piperidine.

(2) In toluene solution (12 ml) and N,N-dimethylformamide (5 ml) dissolved 1,17 g of the above compound (1)add 0,925 ml telnperature at room temperature and the mixture is stirred over night. To the reaction mixture are added ethyl acetate, the mixture is washed with water and saturated salt solution and dried. The solvent is removed, use the Zuya distillation under reduced pressure, and the residue purified using a chromatographic column with silica gel (chloroform:methanol=39:1)to give 1.24 g (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-(4-ethoxycarbonylpyrimidine)-2-(4-fluoro-2-were)piperidine as shown in table 102.

Example 390

In 15 ml of ethanol is dissolved 1.08 g of the compound of example 389, add 4.8 ml of 1M solution of potassium hydroxide in ethanol at room temperature. After the temperature of the mixture was raised to 50°C, the mixture is stirred for 3 hours. To the reaction mixture are added 2M aqueous solution of hydrochloric acid and the ethanol is removed using distillation under reduced pressure. Add water and chloroform and the layers separated chloroform. The organic layer was washed with saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=9:1), receiving of 1.05 g of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-(4-carboxybenzeneboronic)-2-(4-fluoro-2-were)piperidine as shown in table 102 below.

Example 391

In 1 ml of dichloromethane is dissolved to 64.8 mg of the compound of example 390 and 18.6 mg ethanolamine, add at room temperature to 48.6 mg carbodiimide and the mixture is stirred at room t is mperature during the night. Add saturated aqueous solution of ammonium chloride and the mixture extracted with dichloromethane. The organic layer is dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)getting to 17.8 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{4-(2-hydroxyethylaminomethyl)piperidinecarboxylate}piperidine as shown in table 102.

Examples 392 on 398

Use the compound of example 390 and related source materials, which are processed according to the method of example 391, receiving connections, are presented below in tables 102-103.

Example 399

(1) In 12 ml of toluene was dissolved 1,17 g (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-imidazoledicarbonitrile)of piperidine added at room temperature to 1.14 g of 4-amino-1-benzylpiperidine and the mixture is stirred for 3 days. To the reaction mixture are added ethyl acetate, the mixture is washed with water and saturated salt solution and dried. The solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)getting to 0.89 g of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-(1-benzylpiperidine-4-yl)aminaka is bonelace-2-(4-fluoro-2-were)piperidine.

(2) In 10 ml of methanol is dissolved 890 mg of the above compound (1)add 400 mg of palladium-on-coal and one drop of concentrated hydrochloric acid and the mixture is stirred in hydrogen atmosphere for 4.5 hours. Then the reaction mixture is filtered and the filtrate is evaporated in vacuo, the residue is crystallized (ethyl acetate-hexane)to give 802 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(4-piperidinyl)aminocarbonylmethyl.

(3) In 2 ml of dichloromethane is dissolved 14,2 mg of 3-hydroxy-3-methylbutanoic acid, add at room temperature of 21.1 mg carbodiimide and the mixture is stirred at room temperature overnight. To the reaction mixture of 61.9 mg of the above compound (2) and the mixture is further stirred overnight. To the reaction mixture, water is added and the mixture extracted with chloroform. The organic layer is dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1), receiving of 57.5 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{1-(3-hydroxy-3-methylbutyryl)piperidine-4-yl}aminocarbonylmethyl, as shown in table 104 below.

Examples with 400 402

The compound of example 399 (2) and the corresponding recognize the substances treated by the method of example 399 (3), receiving connection, as shown below in table 104.

Example 403

(2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-ethyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine obtained by processing the compound of comparative example 11 (2) by way of example 215, the process according to the method of example 209, receiving the connection below in table 105.

Example 404

The corresponding starting material is treated according to the method of example 209, receiving the connection below in table 105.

Example 405

Connection example 404 process by way of example 213, receiving the connection below in table 105.

Example 406

Connection example 404 process by way of example 214, receiving the connection below in table 105.

Examples of 407 on 413

Relevant source materials treated by the method of example 257, receiving the connection presented below in tables 106-107.

Example 414

In 50 ml of methanol is dissolved 1,17 g (2R,4S)-4-acetylthio-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)of piperidine and add at room temperature 1,17 g of tert-butyl 2-bromethylamine. Then added dropwise 25 ml of 1M aqueous sodium hydroxide solution. The reaction mixture was stirred for 5 min, the solvent is removed using p is Regency under reduced pressure, the mixture is extracted with dichloromethane, washed with saturated salt solution and dried. The solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=2:1)to give 710 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-4-(2-tert-butoxycarbonylamino)-2-(4-fluoro-2-were)piperidine as shown below in table 107.

Example 415

(1) To 681 mg of the compound of example 414 add 2 ml of 4M hydrochloric acid in ethyl acetate under ice cooling and the mixture is stirred at room temperature for one hour. The solvent is removed using distillation, add saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried and the solvent is removed using distillation under reduced pressure, getting 612 mg hydrochloride (2R,4S)-4-(2-aminoacetic)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 107.

(2) In 1 ml N,N-dimethylformamide is dissolved to 55.2 mg of the above compound (1) and 9.1 mg of glycolic acid, add 24,9 mg of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 19.9 ml of the monohydrate of N-hydroxybenzotriazole and the mixture is stirred at room temperature overnight. Doba is by ethyl acetate, the mixture is washed with water and saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1), receiving of 28.8 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-(1-hydroxyacetylamino)ethylthio}piperidine as shown below in table 107.

Examples 416 through 419

The compound of example 415 (1) and the appropriate source materials treated by the method of example 415 (2), receiving the connection below in table 108.

Example 420

In 1 ml of N,N-dimethylformamide is dissolved to 55.2 mg of the compound of example 415 (1)add to 9.1 mg carbodiimide and the mixture is stirred at room temperature for 3 hours. To the reaction mixture are added ethyl acetate, the mixture is washed with water and brine and dried. The solvent is removed using distillation, the residue is dissolved in 1 ml of acetonitrile and added to 0.025 ml of methyl iodide. The mixture was stirred at 50°With during the night. Then add 0,025 ml of methyl iodide and the mixture is stirred at the same temperature throughout the night. After removal of the N,N-dimethylformamide and methyl iodide using distillation under reduced pressure, add 1 ml of toluene and 0,040 ml of the research and the mixture is stirred at room temperature is in 5 days. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer is dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1), receiving 38,0 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl)}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-morpholinosydnonimine)piperidine as shown in table 108.

Example 421

The compound of example 415 (1) and the corresponding starting material is treated according to the method of example 420, receiving (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-(2-hydroxyethylamino)carboalumination)piperidine as shown in table 108.

Example 422

Use appropriate source materials, which are processed according to the method of example 213, receiving (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{4-(2-methylsulfonylbenzoyl)piperidinecarboxylate}piperidine as shown below in table 108.

Example 423

Use appropriate source materials, which are processed according to the method of example 214, receiving (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{4-(3-methylsulfonylbenzoyl)piperidinecarboxylate}piperidine is, as presented below in table 108.

Examples 424-425

Use appropriate source materials, which are processed according to the method of example 209, receiving connections, are presented below in table 109.

Example 426

1.5 ml of dichloromethane is dissolved 82,0 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-methylthiosemicarbazone)piperidine, add at room temperature of 99.5 mg of metallocarboranes acid and the mixture is stirred for one hour. To the reaction mixture is added saturated aqueous sodium bicarbonate solution and the layers separated with ethyl acetate. The organic layer was washed with saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)getting to 48.6 mg (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-methylsulfonylmethane)piperidine as shown below in table 109.

Example 427

(2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(3-methylthiosemicarbazone)piperidine treated according to the method of example 426, receiving (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(3-metilsulfonilmetane is bonelace)piperidine, as presented below in table 109.

Examples from 428 in 431

Relevant source materials treated by the method of example 169, receiving connections, presented in table 110 below.

Examples 432-433

Relevant source materials treated by the method of example 213, receiving connections, are presented below in table 111.

Examples 434-435

Relevant source materials treated by the method of example 25 214, receiving connections, are presented below in table 111.

Example 436

2.8 ml of acetonitrile was dissolved 130 mg of N-(3,5-bistrifluormethylbenzene)-N-(2-methoxyethyl)amide imidazol-1-carboxylic acid, add 411 μl of methyl iodide and the mixture is stirred at 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue is suspended in 2.7 ml of dichloromethane, added 89 mg of (2R,4S)-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)of piperidine and 50 μl of triethylamine and the mixture is stirred at room temperature for 20 hours. To the reaction mixture are added 5% aqueous citric acid solution and the mixture extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using thin-layer chromatography on silica gel (chloroform:methanol=19:1)to give 63 mg of (2R,4S)-1-{N-(3,5-bistritei nil)-N-(2-methoxyethyl)}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine, as presented below in table 112.

Example 437

2.7 ml of dichloromethane is dissolved 94 mg of 2-(4-fluoro-2-methoxyphenyl)-4-(2-hydroxyethylaminomethyl)of piperidine added 163 mg of 3-[(3,5-bistrifluormethylbenzene)methylcarbamoyl]-1-methyl-3H-imidazol-1-iodide and 50 μl of triethylamine and the mixture is stirred at room temperature for 18 hours. To the reaction mixture add distilled water and the mixture extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using thin-layer chromatography on silica gel (chloroform:methanol=19:1)to give 84 mg of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methoxyphenyl)-4-(2-hydroxyethylaminomethyl)piperidine as shown in the following table 112.

Example 438

5.2 ml of acetonitrile is dissolved 201 mg of N-[(1S)-1-(3,5-bistrifluormethylbenzene)ethyl]-N-methylamide imidazol-1-carboxylic acid, add 137 μl of methyl iodide. After the mixture was stirred at 50°C for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue is dissolved in 4.5 ml of dichloromethane, added 132 mg of 4-(2-hydroxyethylcellulose)-2-phenylpiperidine and 84 μl of triethylamine and the mixture is stirred at room temperature for 18 hours. To the reaction mixture are added 5% aqueous solution l is money acid, the mixture is extracted with chloroform, the organic layer is dried and concentrated under reduced pressure. The residue is purified using thin-layer chromatography on silica gel (chloroform:acetone=4:1)to give 75 mg of (2R,4R)-1-[N-{(S)-1-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-(2-hydroxyethylaminomethyl)-2-phenylpiperidine, as presented below in table 112.

Example 439

(1) In 3 ml of acetonitrile is dissolved 127 mg of 1-(3,5-bistrifluormethylbenzene)ethyl imidazole-1-carboxylate add 448 μl of methyl iodide. The mixture was stirred at 50°C for 3 hours and the reaction mixture is concentrated. The residue is suspended in 2.7 ml of dichloromethane, added 102 mg of 2-[(2R,4S)-2-(4-fluoro-2-were)piperidine-4-eloxierarbeiten]ethyl acetate and 50 μl of triethylamine and the mixture is stirred at room temperature for 18 hours. To the reaction mixture add distilled water and the mixture extracted with chloroform. The organic layer is dried and concentrated. The residue is purified using thin-layer chromatography on silica gel (hexane:ethyl acetate=1:1)to give 43 mg of (2R,4S)-4-(2-atsetoksimetilnitraminov)-1-{(S)-1-(3,5-bistrifluormethylbenzene)ethyl}oxycarbonyl-2-(4-fluoro-2-were)piperidine.

MS(m/z):623 [M++1]

(2) In a mixture of 0.9 ml of tetrahydrofuran and 0.1 ml of methanol is dissolved 43 mg of the above compound (1)add 103 MK is 1M aqueous sodium hydroxide solution and the mixture is stirred at room temperature for one hour. To the reaction mixture add distilled water and the mixture extracted with ethyl acetate. The organic layer is dried and concentrated. The residue is purified using thin-layer chromatography on silica gel (chloroform:methanol=19:1)to give 37 mg of (2R,4S)-1-{(S)-1-(3,5-bistrifluormethylbenzene)ethyl}oxycarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine as shown in the following table 112.

Example 440

2.4 ml of N,N-dimethylformamide was dissolved 50 mg of (2R,4S)-2-(4-fluoro-2-methyl)phenyl-4-hydroxypiperidine add in a nitrogen atmosphere at room temperature 0,044 ml of triethylamine and 99.3 mg N-(3,5-bistrifluormethylbenzene)-N-methylenechloride. The reaction mixture was stirred at room temperature for 21 hours. The reaction mixture was poured into water and the mixture extracted twice with ethyl acetate. The organic layers are combined and washed with saturated saline solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=2:1 to 1:2)to give 128 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine, as presented below in table 113.

Example 441

In 2.0 ml of dichloromethane is dissolved 560 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine add in Atmos is ore of nitrogen under ice cooling, 1.5 ml dichloromethane solution, containing 0,22 ml of pyridine and 0,314 ml phenylcarbamate. The reaction mixture is stirred at a temperature of from 0°to 5°C for 3.5 hours and then stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted twice by adding dichloromethane. The organic layers are combined and washed twice 1M aqueous solution of hydrochloric acid and then washed with saturated saline solution. The organic layer is dried and concentrated. The residue is dissolved in 11 ml of N,N-dimethylformamide, is added in nitrogen atmosphere and at room temperature 0,274 ml ethanolamine and the mixture was stirred at 60°C for 26 hours. The reaction mixture was poured into water and extracted twice by adding ethyl acetate. The organic layers are combined, washed with saturated salt solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=39:1)to give 493 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine as shown below in table 113.

Example 442

In 8 ml of dichloromethane was dissolved 1.0 g of (2R)-4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine add at 0.31 ml of triethylamine and 466 mg of di-tert-butyloxycarbonyl and the mixture is displaced is more at room temperature for 16 hours. To the reaction mixture, water is added and the mixture is twice extracted with dichloromethane. The organic layers are combined, washed with saturated salt solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1)to give 481 mg (a) (2R,4R)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene and 516 mg (b) (2R,4S)- 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl 2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene, as presented below in table 113.

Example 443

In 3.5 ml of ethyl acetate was dissolved 700 mg (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene add under ice cooling 3.5 ml of 4M solution of hydrochloric acid in ethyl acetate and the mixture is stirred under ice cooling for 30 minutes the Solvent is removed using distillation, to the residue is added ethyl acetate and filtered. To the collected substances added chloroform and 2M aqueous sodium hydroxide solution and the layers separated. The aqueous layer was extracted with chloroform. The combined organic layers are dried and concentrated, getting 489 mg (2R,4S)-4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)piperidine as shown below in table 113.

the reamers with 444 through 449

Use appropriate source materials, which are processed according to the method of example 138, receiving connections, are presented below in table 114.

Examples 450-451

Use appropriate source materials, which are processed according to the method of example 102 (1), obtaining the compounds shown below in table 114.

Examples 452 on 469

Use appropriate source materials, which are processed according to the method of example 250, receiving connections, are presented below in tables 115-117.

Example 470

In 1 ml of dichloromethane is dissolved 52,8 mg hydrochloride (2R,4S)-4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)of piperidine added at room temperature of 0.017 ml of triethylamine and 24.3 mg of 1,1-carbodiimide and the mixture is stirred for 30 minutes To the reaction mixture, water is added and the mixture extracted with dichloromethane. The organic layers washed with saturated saline solution, dried and concentrated. In 1 ml of acetonitrile was dissolved residue, add 0,025 ml of methyl iodide and the mixture is stirred at 60°With during the night. The reaction mixture was concentrated and the residue is dissolved in 1 ml of toluene in acetonitrile (7:3)add to 24.4 mg of ethanolamine and the mixture is stirred at room temperature for 30 minutes To the reaction mixture, water is added and the mixture extragere is by ethyl acetate. The organic layer is dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=9:1)getting to 53.1 mg (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylamino)piperidine as shown below in table 118.

Examples 471 480

Use appropriate source materials, which are processed according to the method of example 470, receiving connections, are presented below in tables 118-119.

Example 481

In 10 ml of dichloromethane is dissolved 490 mg of (2R)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine and 312 mg of 2-(2-aminoethylamino)ethanol, add at room temperature 0,086 ml of acetic acid and 669 mg triacetoxyborohydride sodium and the mixture is stirred over night. To the reaction mixture are added water and extracted with chloroform. The organic layer was washed with saturated saline solution, dried and concentrated, getting 581 mg (2R,4RS)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{2-(2-hydroxyethylamino)ethylamino}piperidine [(2R,4S):(2R,4R)=74:26]. In 2 ml of dichloromethane is dissolved 116 mg of (2R,4RS)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-{2-(2-hydroxyethylamino)ethylamino}piperidine, add at room temperature 39 mg of 1,1-carbodiimide and CME is ü stirred for 40 minutes To the reaction mixture, water is added and the mixture extracted with chloroform. The organic layers washed with saturated saline solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=9:1), receiving (a) and 75.5 mg (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-[3-(2-hydroxyethyl)-2-Oxymetazoline-1-yl]piperidine and (b) to 22.6 mg (2R,4R)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-[3-(2-hydroxyethyl)-2-Oxymetazoline-1-yl]piperidine as shown in the table below 120.

Examples from 482 to 486

Use appropriate source materials, which are processed according to the method of example 481, receiving connections, are presented below in tables 120 and 122.

Example 487

In 1 ml of dichloromethane is dissolved and 12.4 ml of ethylene glycol and added dropwise at room temperature 32.4 mg 1,1-carbodiimide. The mixture is stirred at room temperature for 7.5 hours and added to the mixture of 52.8 mg hydrochloride (2R,4S)-4-amino-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)of piperidine and 0,021 ml of triethylamine. The mixture is stirred for 4 days and the reaction mixture is concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=9:1)getting to 16.4 mg of (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene the)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylnitrosamine)piperidine, as presented below in table 123.

Example 488

(1) In 3 ml of dichloromethane is dissolved 58 mg triphosgene and to this are added dropwise at a temperature of -60°With 2 ml of dichloromethane solution containing 138 mg of N-{2-methoxy-5-(5-cryptomaterial-1-yl)benzyl}-N-methylamine and 0,201 ml of triethylamine and the mixture is then heated to 0°C. the Mixture is concentrated and the residue is dissolved in 2 ml of dichloromethane. To the mixture are added dropwise 2 ml of dichloromethane solution containing 135 mg of (2R,4S)-4-(2-acetylenedicarboxylate)-2-(4-fluoro-2-were)of piperidine and 0,084 ml of triethylamine and the mixture is stirred at room temperature for one day. To the reaction mixture, water is added and the mixture extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified using thin-layer chromatography on silica gel (chloroform:acetone=10:1)to give 44 mg of (2R,4S)-4-(2-acetylenedicarboxylate)-1-[N-{2-methoxy-5-(5-cryptomaterial-1-yl)benzyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine.

MS(m/z): 652 [M++1]

(2) In 0.9 ml of mixed solution (tetrahydrofuran: methanol=8:1) dissolve 44 mg of (2R,4S)-4-(2-acetylenedicarboxylate)-1-[N-{2-methoxy-5-(5-cryptomaterial-1-yl)benzyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine add 0,101 ml of 1M aqueous solution of hydroxide into three and the mixture is stirred at room temperature for 6 hours. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layers are dried over magnesium sulfate and concentrated. The residue is purified using thin-layer chromatography on silica gel (chloroform:methanol=19:1)to give 36 mg of (2R,4S)-1-[N-{2-methoxy-5-(5-cryptomaterial-1-yl)benzyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine as shown in the following table 124

Comparative example 1

To the Grignard reagent derived from 14.2 g of magnesium, br93.1 g of 2-bromo-5-Tortolla and 500 ml of tetrahydrofuran, are added dropwise 50 ml of 4-methoxypyridine at -20°C in nitrogen atmosphere. After completion of adding dropwise, the mixture is stirred at the same temperature for 20 minutes and Then the reaction mixture is cooled to -50°and added dropwise 85 ml benzylmalonate, while maintaining the temperature at -40°With or below. After completion of adding dropwise, the temperature of the reaction mixture is slowly increased, add 200 g of ice at -15°and the mixture is stirred for 30 minutes Then add 200 ml of 5M aqueous solution of citric acid and the mixture is stirred at room temperature for one hour. From the reaction mixture to remove the tetrahydrofuran, using distillation under reduced pressure. To the residue is added 200 ml of ethyl acetate and the mixture is extracted twice. The organic layers are combined and washed with aqueous sodium bicarbonate solution and saturated saline solution, dried over magnesium sulfate and the solvent is removed using distillation under reduced pressure. The residue is collected by filtration and washed with isopropyl ether, receiving 146,5 g 1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-oxo-3,4-dihydro-2H-pyridine, as presented below in table 125.

Comparative example 2

4600 ml of acetic acid are dissolved in 190 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-oxo-3,4-dihydro-2H-pyridine, added 91 g of powdered zinc, and the mixture is stirred at room temperature for 24 hours. From the reaction mixture by filtration to remove insoluble substances and the solvent is removed using distillation under reduced pressure. To the residue add 400 ml of ethyl acetate, the mixture was washed with aqueous sodium bicarbonate solution and saturated saline and dried over magnesium sulfate. The solvent is removed using distillation under reduced pressure, and the residue purified using a chromatographic column with silica gel (ethyl acetate:hexane=2:1)to give 166 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine, as presented below in table 125.

Comparative example 3

To 132 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine add 650 ml of m is of canola, 84 ml trimethoxymethane and 2 g of a strongly acidic resin IR-120 (production of Japan Organo Co., Ltd.) and the mixture is stirred at room temperature for 3 days. From the reaction mixture by filtration to remove insoluble substances and the solvent is removed using distillation under reduced pressure, getting 146 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4,4-dimethoxypyridine, as presented below in table 125.

Comparative example 4

To 300 ml of ethanol is added 30 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4,4-dimethoxypyridine and 3.0 g of 10% palladium-on-coal and the mixture is stirred in hydrogen atmosphere at room temperature for 3 hours. From the reaction mixture by filtration to remove insoluble substances and the solvent is removed using distillation under reduced pressure. To the residue add 300 ml of ethyl acetate. Under ice cooling slowly added dropwise 20 ml of 4M hydrochloric acid in ethyl acetate. The crystals are collected by filtration and washed with ethyl acetate. After drying the crystals add to the mixture dichloromethane-aqueous solution of sodium carbonate and the mixture is stirred. After distinguish the organic layer, the aqueous layer was further extracted with dichloromethane. The organic layers are combined and dried over sodium sulfate, the solvent is removed using distillation under reduced pressure, olucha 16.7 g of 2-(4-fluoro-2-were)-4,4-dimethoxypyridine, as presented below in table 125.

Comparative example 5

To 130 ml of suspension in ethyl acetate to 10.1 g of 2-(4-fluoro-2-were)-4,4-dimethoxypyridine and 3,18 g L-N-acetylamino add 35 ml of methanol, the mixture is heated until dissolution and then cooled to room temperature. After 3.5 hours, the precipitated precipitated crystals are collected by filtration and washed with 20 ml of ethyl acetate. The obtained crystals are dried under reduced pressure. Then add 50 ml of chloroform, the mixture is washed with 30 ml of a 2M aqueous solution of sodium hydroxide and 30 ml of saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. To the obtained residue is added ether and precipitated precipitated crystals then concentrated under reduced pressure, getting 2,94 g (2R)-2-(4-fluoro-2-were)-4,4-dimethoxypyridine (degree of optical purity:97,0% ee) as shown in table 125 below.

Comparative example 6

To 36 ml of tertrahydrofuran ring solution of 5.0 g of N-(3,5-bistrifluormethylbenzene)-N-methylamine add 3,47 g of 1,1'-carbonyldiimidazole and the mixture was stirred at 65°C for 20 minutes the Solvent is removed using distillation under reduced pressure, and add dichloromethane. The whole organic layer was washed with saturated saline solution, dried and the solvent is removed using distillation. The residue is dissolved in 26 ml acetonic the sludge and add and 4,84 ml of methyl iodide. The mixture was stirred at 60°C for 2 hours. The solvent is removed using distillation under reduced pressure, and the residue is dissolved in 80 ml of dichloromethane. While cooling with ice add to 5.17 g of 2-(4-fluoro-2-were)-4,4-dimethoxypyridine and 3 ml of triethylamine and the mixture is stirred at room temperature for 2 hours. The reaction mixture was poured into water and the layers separated. The aqueous layer was extracted with dichloromethane. The combined organic layers washed with saturated saline solution, dried and the solvent is removed using distillation. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:3)to give 9.7 g of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4,4-dimethoxypyridine, as presented below in table 126.

Comparative example 7

In 180 ml of tetrahydrofuran is dissolved 9.7 g of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4,4-dimethoxypyridine, while cooling with ice, add 70 ml of 1M aqueous solution of sulfuric acid and the mixture is stirred at room temperature for one hour. After adjusting pH of the mixture up to 8-9 using 1M aqueous sodium hydroxide solution, the tetrahydrofuran is removed using distillation. To the residue is added water and ethyl acetate and the layers separated. The aqueous layer was extracted with ethyl acetate. Together the major organic layers washed with saturated saline solution and dried. The solvent is removed using distillation. To the obtained residue is added diisopropyl ether and the white crystals are collected by filtration, getting 7,86 g of 1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine, as presented below in table 126.

Comparative example 8

To 60 ml of tertrahydrofuran ring solution 3,91 g of N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methylamine type of 2.34 g of 1,1'-carbonyldiimidazole and the mixture was stirred at 40°With during the night. From the reaction mixture to remove the solvent, using distillation, add ethyl acetate, the entire organic layer is washed with water and saturated salt solution and dried. The solvent is removed using distillation, and the resulting white crystals are collected by filtration, using diisopropyl ether. The obtained white crystals are dissolved in 60 ml of acetonitrile, add 3.4 ml of methyl iodide and the mixture is stirred at 60°C for 2 hours. The solvent is removed using distillation under reduced pressure, and the residue is dissolved in 40 ml of dichloromethane. While cooling with ice add 3,47 g of 2-(4-fluoro-2-were)-4,4-dimethoxypyridine and 3,82 ml of triethylamine and the mixture is stirred at room temperature overnight. The reaction mixture was poured into water and the layers separated. The aqueous layer was extracted with dichloromethane. Obyedinenny the organic layers washed with water and saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. The residue is dissolved in 90 ml of tetrahydrofuran, while cooling with ice to this add 30 ml of 1M aqueous solution of sulfuric acid and the mixture is stirred at room temperature for 5 hours. After adjusting pH of the mixture up to 8-9 using 1M aqueous sodium hydroxide solution, the tetrahydrofuran is removed using distillation. To the residue is added water and ethyl acetate and the layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers washed with water and saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=2:1), receiving a 2.12 g of (2R)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine, as presented below in table 126.

Comparative examples 9 through 11

Use appropriate source materials, which are processed according to the method of comparative example 8, when receiving the connection represented below in tables 126-127.

Comparative example 12

In 140 ml of ethanol is dissolved 16.7 g 1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine add 3,74 g of hydroxylamine hydrochloride and to 4.41 g of sodium acetate and the mixture is stirred at room the Oh temperature for 2 hours. The ethanol is removed under reduced pressure. To the residue is added water and ethyl acetate and the layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers washed with saturated saline solution, dried and the solvent is removed under reduced pressure. The residue is dissolved in 500 ml of methanol, add to 23.2 g of uranyl chloride Nickel after stirring the mixture slowly add 3.7 g of sodium borohydride under ice cooling and the mixture is stirred under ice cooling for 4 hours. The methanol is removed using distillation under reduced pressure, to the residue add aqueous ammonia solution and dichloromethane and the mixture is stirred at room temperature for one hour. The reaction mixture was separated into layers and the aqueous layer was extracted with dichloromethane. The combined organic layers washed with saturated saline solution, dried and the solvent is removed using distillation. The residue is dissolved in 480 ml of dichloromethane while cooling with ice add to 8.2 ml of triethylamine and 5.1 ml of propionitrile and the resulting mixture is stirred under ice cooling for one hour. The reaction mixture was poured into saturated brine and the layers separated. The aqueous layer was extracted with dichloromethane. The combined organic layers washed with saturated saline solution, dried and the solvent is removed using distillation when eigendom pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=1:1)getting to 6.43 g (a) TRANS-1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-propenylbenzene and the 5.65 g (b) CIS-1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-propenylbenzene, as presented below in table 127.

Comparative example 13

Use 1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-oxopiperidin and isobutyrophenone, which is treated by the method of comparative example 12, receiving (a) TRANS-1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-isobutyronitrile and (b) CIS-1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-isobutyronitrile, as shown in the table below 128.

Comparative example 14

In 17 ml of ethanol is dissolved 1.73 g of TRANS-1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-propenylbenzene add 280 mg of palladium-on-coal (moisture content of 50.9%) and the mixture is stirred in hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through celite and the ethanol is removed using distillation. The residue is purified using a chromatographic column with NH-silica gel (chloroform:hexane:ethyl acetate=5:5:2)to give 772 mg of TRANS-2-(4-fluoro-2-were)-4-propenylbenzene, as presented below in table 129.

Comparative examples 15 to 17

ISOE is isout relevant source materials, which is treated by the method of comparative example 14, when receiving the connection represented below in tables 129-130.

Comparative example 18

In 900 ml of ethanol was dissolved 110 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine add 24.8 g of hydroxylamine hydrochloride and of 29.3 g of sodium acetate and the mixture is stirred at room temperature for 5 hours. The ethanol is removed using distillation, and to the residue is added water and ethyl acetate. The layers are separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers washed with saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. The residue is dissolved in 2.4 liters of methanol and type of 92.5 g of uranyl chloride Nickel. After stirring to the mixture is added slowly with ice cooling to 18.4 g of sodium borohydride and the mixture is stirred under ice cooling for 4 hours. The methanol is removed using distillation, to the residue add aqueous ammonia solution and dichloromethane and the mixture is stirred at room temperature for one hour. The reaction mixture was separated into layers and the aqueous layer was extracted with dichloromethane. The combined organic layers washed with saturated saline solution, dried and the solvent is removed using distillation. The residue is dissolved in 1.2 l of dichloromethane under ice cooling is m add to 45.2 ml of triethylamine, to 74.5 ml of di-tert-BUTYLCARBAMATE and the mixture is stirred at room temperature for one hour. The reaction mixture was poured into saturated salt solution and the aqueous layer was extracted with dichloromethane. The combined organic layers washed with saturated saline solution, dried and the solvent is removed using distillation under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1)getting to 36.7 g (a) TRANS-1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene and 37.9 g (b) CIS-1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene, as presented below in table 131.

Comparative example 19

In 350 ml of ethanol is dissolved 37,0 g of CIS-1-benzyloxycarbonyl-2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene add 5.5 g of palladium-on-coal (moisture content of 50.9%) and the mixture is stirred in hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through celite and the ethanol is removed using distillation, receiving, and 25.8 g of CIS-2-(4-fluoro-2-were)-4-tert-butoxycarbonylmethylene, as presented below in table 132.

Comparative example 20

To of 1.34 g of 3-hydroxyl-2-hydroxymethyl-2-methylpropionic acid and 13 ml of acetonylacetone add 95 mg of the monohydrate drugs is loulslana acid at room temperature and the mixture is stirred for 6 hours. Next, add 95 mg of the monohydrate paratoluenesulfonyl acid and the mixture is stirred over night. The resulting solution was concentrated, poured into water and extracted. The aqueous layer was extracted with chloroform. The combined organic layers washed with saturated saline solution, dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=19:1)to give 333 mg 2,2,5-trimethyl[1,3]dioxolane-5-carboxylic acid, as shown below in table 132.

Comparative example 21

In 400 ml of tetrahydrofuran is dissolved to 31.5 g of 2-chloroethylamino acid and type of 32.5 g of 1,1'-carbonyldiimidazole. The mixture is stirred under ice cooling for one hour. To the solution add 50 ml of ethanol and the mixture is stirred at room temperature for 2 hours. The solution is concentrated and extracted by adding ethyl acetate and water. The organic layer is dried over magnesium sulfate and the residue is dried in vacuum, obtaining of 35.6 g of ethyl 2-chlorisondamine, as presented below in table 132.

Comparative example 22

In a mixed solvent consisting of 250 ml of toluene and 50 ml of ethanol, dissolve 20 g of ethyl 2-chlorisondamine and 20 g of 2-methyl-4-ftorhinolonovy acid, and 5.8 g of palladium tetranitroaniline and 250 ml of 2M aqueous sodium carbonate solution and the mixture was stirred at 50-70°SV 2 hours. The solution is cooled to room temperature and extracted by adding ethyl acetate and water. The organic layer is then washed with water, dried over magnesium sulfate and concentrated. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=6:1)to give 24.8 g of 4-etoxycarbonyl-2-(4-fluoro-2-were)pyridine, as presented below in table 132.

Comparative example 23

In 200 ml of ethanol is dissolved and 5.2 g of 4-etoxycarbonyl-2-(4-fluoro-2-were)of pyridine and 1.5 g of platinum oxide and to the solution add 15 ml of concentrated hydrochloric acid. The mixture is stirred in hydrogen atmosphere at room temperature for 5 hours. Add 200 ml of water, the mixture is stirred for 30 min and then the insoluble matter is removed by filtration through celite. The insoluble matter is washed with ethanol, the filtrate and the liquid used in the washing are combined and concentrated. To the residue is added ethyl acetate and saturated aqueous sodium bicarbonate solution. After confirming that the aqueous solution is quite basic, carry out the extraction. The aqueous layer was extracted with ethyl acetate three times, the combined organic layers dried over sodium sulfate and concentrated, gaining 3.6 g of 2,4-CIS-4-etoxycarbonyl-2-(4-fluoro-2-were)piperidine as shown below in tables is 132.

Comparative example 24

(1) In a mixture of 50 ml of ethyl acetate and 50 ml of diethyl ether was dissolved by heating to 7.4 g of 2,4-CIS-4-etoxycarbonyl-2-(4-fluoro-2-were)of piperidine and 4.0 g N-p-toluensulfonyl-D-phenylalanine. The solvent is concentrated by heating, add 30 ml of diisopropyl ether and the mixture is stirred. Precipitated precipitated crystals are removed, the mother liquor is washed with a concentrated aqueous solution of ammonia, dried and concentrated under reduced pressure. To the residue add 4.0 g of N-p-toluensulfonyl-1-phenylalanine, add 50 ml of ethyl acetate and 30 ml of diisopropyl ether and dissolved by heating, the mixture is stirred at room temperature for 16 hours. Precipitated precipitated crystals are collected by filtration, washed with diisopropyl ether and dried, obtaining 4.0 g of N-p-toluensulfonyl-1-phenylalanine salt of (2R,4S)-4-etoxycarbonyl-2-(4-fluoro-2-were)-4-piperidine.

(2) the above compound (1) dissolved in an aqueous solution of ammonia, and after confirming that the solution is fairly basic, it twice extracted with chloroform. The combined organic layers dried and concentrated under reduced pressure, obtaining 2.6 g of (2R,4S)-4-etoxycarbonyl-2-(4-fluoro-2-were)-4-piperidine (optical purity: 96% ee)as shown below in table 133.

Comparative example 5

(1) In 50 ml of N,N-dimethylformamide was dissolved 7.5 g of 3-aminopropanol and 16 g of tert-butyldimethylsilyloxy add 6.8 g of imidazole and the mixture is stirred at room temperature for 16 hours. To the reaction mixture is added 11 g of citric acid and after stirring the mixture at room temperature for one hour the mixture was concentrated under reduced pressure. To the residue add 2M aqueous sodium hydroxide solution and diethyl ether and the layers separated. The organic layer is dried and concentrated under reduced pressure. Balance and 12.1 g of 3,5-bistrifluormethylbenzene dissolved in 300 ml of dichloromethane, added to 21.2 g triacetoxyborohydride sodium and 2.9 ml of acetic acid and the mixture is stirred at room temperature for 3 hours. To the reaction mixture are added 2M aqueous solution of sodium carbonate. The mixture is stirred for 30 min and extracted twice with chloroform. The combined organic layers are dried, concentrated under reduced pressure and purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1)to give 20 g of 3-tert-butyldimethylsiloxy-3,5-bistrifluormethylbenzene.

(2) Used 12.5 g obtained above compounds (1) and the compound of comparative example 5, which is treated by the method of comparative example 6, receiving 19 g of (2R)-1-{N-(3,5-bistrifluormethylbenzene)-N-(3-tre is-butyldimethylsiloxy)}aminocarbonyl-2-(4-fluoro-2-were)-4,4-dimethoxypyridine.

(3) Use 19,0 g of the above compound (2), which is treated by the method of comparative example 7, receiving 19 g of (2R)-1-{N-(3,5-bistrifluormethylbenzene)-N-(3-hydroxypropyl)}aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine, as presented below in table 133.

Comparative example 26

In 40 ml of dichloromethane is dissolved 4.8 g of the compound of comparative example 5, add 4.4 g of di-tert-BUTYLCARBAMATE and the mixture is stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue is dissolved in 100 ml of acetone, add 200 mg of the acid resin (IR-120) and the mixture is stirred at room temperature for 3 days. After removal from the reaction mixture of the resin mixture is concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1)to give 3.9 g (R)-1-tert-butoxycarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine.

(2) In 20 ml of ethanol is dissolved 3.9 g of the above compound (1)add 400 mg of sodium borohydride at a temperature of -20°and the mixture is stirred for one hour. To the reaction mixture an aqueous solution of ammonium chloride and ethanol is removed using distillation. To the residue is added ethyl acetate and water, the layers separated and further washed with water. The organic layer is dried and concentrated PR is the reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1)to give 3.1 g (2R,4S)-1-tert-butoxycarbonyl-2-(4-fluoro-2-were)-4-hydroxypiperidine.

(3) Using 3.1 g of the above compound (2) and the corresponding starting material, which is treated by the method of comparative example 209, obtaining 2.3 g of (2R,4S)-1-tert-butoxycarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine.

(4) In 20 ml of 4M hydrochloric acid in ethyl acetate was dissolved 2.3 g of the above compound (3) and the solution stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. The residue is dried, obtaining 1.5 g of hydrochloride (2R,4S)-2-(4-fluoro-2-were)-4-(2-atsetoksimetilnitraminov)piperidine.

(5) In 25 ml of 1M aqueous solution of sodium hydroxide dissolved 1.5 g of the above compound (4) and the solution extracted twice with chloroform. The combined organic layers dried and concentrated under reduced pressure. The residue is dried, obtaining 1.5 g of (2R,4S)-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine as shown below in table 133.

Comparative example 27

In 250 ml of acetonitrile was dissolved 4.8 g of 3,5-bistrifluormethylbenzene add 6.6 g of trimethylsulfonium, 3.2 g of crushed hydroxide CA the Oia and 0.5 ml of water and the mixture is stirred at a temperature of 65° S-70°C for 16 hours in the presence of balls of aluminum oxide. After completion of the reaction, insoluble materials are removed to the filtrate add ethyl acetate and water and the layers separated. The organic layer is washed, dried, and concentrated under reduced pressure. To the residue are added 50 ml of 40% solution of methylamine in methanol and the mixture is stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue is purified using a chromatographic column with NH-silica gel (hexane:ethyl acetate=1:2)to give 1.23 g of 1-(3,5-bistrifluormethylbenzene)-2-hydroxyethylamino as presented below in table 133.

Comparative example 28

(1) In 43 ml of dichloromethane is dissolved of 2.45 g of 3,5-bistrifluormethylbenzene, 835 mg of 2-methoxyethylamine and 687 μl of acetic acid, add 3.12 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for one hour in nitrogen atmosphere. The reaction mixture was washed with 0.5m aqueous sodium hydroxide solution, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with NH-silica gel (hexane:ethyl acetate=19:1 to 9:1)to give 2.76 g of 3,5-bistrifluormethylbenzene-2-methoxyethylamine.

MS(m/z):302 [M++1]+

(2) In a mixed solution of 37 ml of toluene and 4 ml of methylene chloride is dissolved is 2.76 g of 3,5-bistrifluormethylbenzene-2-methoxyethylamine, added 1.78 g of 1,1'-carbonyldiimidazole and the mixture was stirred at 60°C for 3 hours. To the reaction mixture add distilled water and extracted with chloroform. The organic layer is dried over magnesium sulfate, dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:acetone=9:1 to 2:1), receiving of 3.45 g of 3,5-bistrifluormethylbenzene-2-methoxyethylamine imidazol-1-carboxylic acid, as shown below in table 133.

Comparative example 29

(1) In 15 ml of N,N-dimethylformamide is dissolved 3.94 g of 2-bromo-5-terfenol and of 1.62 ml of methyl iodide and slowly add to 5.08 g of potassium carbonate under ice cooling. The mixture is stirred at room temperature for 3 hours. Then the insoluble matter is removed by filtration, to the filtrate add distilled water, the mixture extracted with diethyl ether and washed with saturated saline solution. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=19:1 to 9:1), receiving of 4.10 g of 1-bromo-4-fluoro-2-methoxybenzene.

MS(m/z): 204/206 (M++1).

(2) To 7 ml of tetrahydrofuran, add 486 mg of magnesium and trace amounts of iodine, is added dropwise a solution of 4.10 g of the above compound (1 in 16 ml of tetrahydrofuran, getting the Grignard reagent. To the solution is added dropwise a solution to 1.96 g of 4-methoxypyridine in 7 ml of tetrahydrofuran at a temperature of -60°With or below. Then added dropwise a solution of 3.75 g of benzylchloride in 18 ml of tetrahydrofuran and the mixture is stirred for 3 hours. The temperature of the mixture was raised to room temperature and to the mixture is added 40 ml of 5% aqueous citric acid solution. The mixture is extracted with ethyl acetate and washed with saturated saline solution. The organic layer is dried and concentrated. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=2:1 to 1:2)to give 3.15 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methoxyphenyl)-4-oxo-3,4-dihydro-2H-pyridine.

MS(m/z): 356 [M++1]

(3) In a mixed solution of 79 ml of ethanol and 6 ml of tetrahydrofuran is dissolved 3,15 g of the above compound (2)add 706 mg of sodium borohydride and the mixture is stirred at room temperature for 6 hours. The reaction mixture was concentrated and to the residue add distilled water. The mixture is extracted with chloroform, the organic layer is dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:acetone=19:1 to 9:1), receiving of 1.62 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methoxyphenyl)-4-hydroxypiperidine.

MS(m/z): 360 [M++1]

(4) In 20 ml of toluene is astonaut of 1.62 g of the above compound (3), add 876 mg of 1,1'-carbonyldiimidazole and the mixture was stirred at 60°within hours. Add 1,09 ml ethanolamine and the mixture was stirred at 60°C for 6 hours. To the reaction mixture add distilled water and the mixture extracted with chloroform. The organic layer is dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:acetone=4:1 to 1:1), receiving of 1.81 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methoxyphenyl)-4-(2-hydroxyethylaminomethyl)piperidine.

MS(m/z): 447 [M++1]

(5) In 20 ml of methanol is dissolved is 1.81 g of the above compound (4)add 90 mg of 10% palladium-on-coal and the mixture is stirred at room temperature for one hour in hydrogen atmosphere. After insoluble materials are removed by filtration, the filtrate is concentrated. To the residue is added diethyl ether and the amount of precipitation collected by filtration, receiving of 1.30 g of 2-(4-fluoro-2-methoxyphenyl)-4-(2-hydroxyethylaminomethyl)piperidine as shown below in table 134.

Comparative example 30

(1) In 40 ml of tetrahydrofuran is dissolved 5,46 g of 4-methoxypyridine and to this are added dropwise 55 ml of 1M solution phenylmagnesium-tetrahydrofuran in a nitrogen atmosphere at -60°With or below. Then added dropwise a solution 10,24 g benzylchloride in 50 ml of tetrahydrofuran and the mixture p is remediat for 3 hours. The temperature of the mixture was raised to room temperature and add 120 ml of 5% aqueous citric acid solution. The mixture is extracted with ethyl acetate and washed with saturated saline solution. The organic layer is dried and concentrated. To the residue is added diisopropyl ether and the precipitates are collected by filtration, getting 8,51 g 1-benzyloxycarbonyl-4-oxo-2-phenyl-3,4-dihydro-2H-pyridine.

MS(m/z): 308 [M++1]

(2) In 260 ml of acetic acid are dissolved 8,48 g of the above compound (1)add 3,61 g of powdered zinc, and the mixture is stirred at room temperature for 18 hours. Then add 1.8 g of powdered zinc, after stirring the mixture at room temperature for 6 hours add further 1.8 g of powdered zinc, and the mixture was stirred at 50°C for 3 days. After using the filter, remove the insoluble matter, the filtrate is concentrated under reduced pressure. The residue is extracted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated saline solution. The organic layer is dried and concentrated, obtaining 8,54 g 1-benzyloxycarbonyl-4-oxo-2-phenylpiperidine.

MS(m/z): 310 [M++1]

(3) In 15 ml of tetrahydrofuran is dissolved 619 mg of the above compound (2) and added dropwise to 4 ml of 1M solution of diisobutylaluminium in toluene in a nitrogen atmosphere at -60°or the who. The mixture is stirred for 10 minutes To the reaction mixture 667 μl of 6M aqueous hydrochloric acid and the mixture concentrated. To the residue add distilled water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane: ethyl acetate=2:1 to 1:1)to give 553 mg 1-benzyloxycarbonyl-4-hydroxy-2-phenylpiperidine.

MS(m/z): 312 [M++1]

(4) To a mixed solution of 14 ml of toluene and 1.6 ml of dichloromethane added 511 mg of the above compound (3)add 319 mg of 1,1'-carbonyldiimidazole and the mixture was stirred at 60°C for 2 hours. To this mixture 396 μl of ethanolamine and the mixture was stirred at 60°C for 3 hours. To the reaction mixture add distilled water and the mixture extracted with chloroform. The organic layer is dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:acetone=9:1 to 2:1)to give 462 mg 1-benzyloxycarbonyl-4-(2-hydroxyethylaminomethyl)-2-phenylpiperidine.

MS(m/z): 399 [M++1]

(5) In 10 ml of methanol is dissolved 430 mg of the above compound (4)add 30 mg of 10% palladium-on-coal and the mixture is stirred at room temperature for 5 days is hydrogen atmosphere. Insoluble substances are removed by filtration and the filtrate is concentrated and getting 348 mg of 4-(2-hydroxyethylaminomethyl)-2-phenylpiperidine, as presented below in table 134.

Comparative example 31

(1) In 47 ml of ethanol is dissolved 2,61 g of 3,5-bistrifluormethylbenzene add 478 mg sodium borohydride and the mixture is stirred at room temperature for 30 minutes To the reaction mixture is added saturated aqueous solution of ammonium chloride and the mixture concentrated. The residue is extracted with ethyl acetate and washed with saturated saline solution. The organic layer is dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=9:1 to 4:1), receiving of 2.51 g of 1-(3,5-bistrifluormethylbenzene)ethanol.

MS(m/z): 258 [M++1]

(2) In a mixed solution of 40 ml of toluene and 4 ml of acetonitrile is dissolved 2,49 g of the above compound (1)add 1,72 g of 1,1'-carbonyldiimidazole and the mixture is stirred at room temperature for 3 hours. To the reaction mixture, water is added, the mixture extracted with ethyl acetate and washed with saturated saline solution. The organic layer is dried, concentrated under reduced pressure, getting 3,40 g of 1-(3,5-bistrifluormethylbenzene)ethyl imidazole-1-carboxylate, as presented below in table 134.

Comparative example 32

K1,74 g of magnesium and 40 ml of tetrahydrofuran, add trace amounts of iodine in the atmosphere of nitrogen at room temperature is added dropwise 10.4 g of 2-bromo-5-Tortolla for 40 minutes The reaction mixture was refluxed under heating for one hour, obtaining a solution of the Grignard reagent. To the obtained solution of the Grignard reagent is added dropwise 5,46 g of 4-methoxypyridine for 20 min in nitrogen atmosphere at a temperature of -40°C. After completion of adding dropwise, the mixture is stirred at temperatures from -40°C to -30°C for 30 minutes and Then the reaction mixture was cooled to -40°while maintaining the temperature at -40°or lower added dropwise a solution of 12 g of di-tert-BUTYLCARBAMATE in 20 ml of tetrahydrofuran. After completion of adding dropwise, the temperature of the reaction mixture is slowly increased. At a temperature of -15°add ice to the mixture and the mixture is stirred for 20 minutes Then add an aqueous solution of citric acid and the mixture is stirred at room temperature for 40 minutes, the Tetrahydrofuran is removed using distillation, to the residue is added ethyl acetate and extracted twice. The combined organic layers washed with saturated saline solution, dried and concentrated under reduced pressure. To the residue is added diisopropyl ether and the resulting crystals are collected by filtration, using diisopropyl ether and receiving 11.9 g of 1-tert-butoxycarbonyl-2-(4-fluoro-2-were)-4-oxo-3,4-dihydro-2H-pyridine, as shown below in Alice 134.

Comparative example 33

6,0 ml ethanol add 916 mg of 1-tert-butoxycarbonyl-2-(4-fluoro-2-were)-4-oxo-3,4-dihydro-2H-pyridine and 110 mg of 10% palladium-on-coal (moisture content of 50.5%) and the mixture is stirred at room temperature for 12 hours in an atmosphere of hydrogen. After insoluble materials are removed by filtration, the solvent is removed using distillation. The residue is dissolved in 15 ml of toluene and the solution is cooled to -78°C. To the resulting solution was slowly added dropwise in a nitrogen atmosphere add 1.8 ml of butylethylenediamine (65 wt.% solution in toluene). After completion of adding dropwise, the mixture is stirred at a temperature of from -78°C to -60°within hours. To the reaction mixture are added 1M aqueous sodium hydroxide solution and the mixture is stirred for 10 minutes the Resulting precipitates are filtered through celite and extracted twice with ethyl acetate. The organic layers are combined and washed with saturated aqueous ammonia and saturated salt solution. The organic layer is dried and concentrated under reduced pressure. After adding to the residue 7.5 ml of ethyl acetate is slowly added dropwise 7.5 ml of 4M hydrochloric acid in ethyl acetate under cooling with ice. The crystals are collected by filtration and washed with ethyl acetate. After drying the crystals add xmasy ethyl acetate-1M aqueous sodium hydroxide solution and stirred. The organic layer is isolated and the aqueous layer was extracted three times with ethyl acetate. The organic layers are combined and dried over sodium sulfate. The solvent is removed using distillation under reduced pressure, getting 471 mg of 2-(4-fluoro-2-methyl)phenyl-4-hydroxypiperidine, as presented below in table 134.

Comparative example 34

In 3.0 ml of dichloromethane was dissolved 831 ml triphosgene and added dropwise a solution of 1.08 g of N-(3,5-bistrifluormethylbenzene)-N-methylamine and 1.76 ml of triethylamine in 5.0 ml of dichloromethane for 10 min, in nitrogen atmosphere under ice cooling. The reaction mixture is stirred at a temperature of from 0°to 5°C for 30 minutes the Solvent is removed using distillation, and the residue is dried. To the residue add water and dichloromethane and the mixture is twice extracted with dichloromethane. The organic layers are combined, washed with saturated salt solution and dried. Then the solvent is removed using distillation. The residue is purified using a chromatographic column with silica gel (hexane to a mixture of hexane:ethyl acetate=10:1)to give 760 mg of N-(3,5-bistrifluormethylbenzene)-N-methylenechloride, as presented below in table 134.

Comparative example 35

In 20 ml of methanol is dissolved 24.5 g of 3,5-bistrifluormethylbenzene and while cooling with ice, add 60 ml of ethylamine (2M solution in tetrahydrofuran). ZAT is m is added slowly to 4.38 g of sodium borohydride and the mixture is stirred at room temperature for 3 hours. To the reaction mixture add distilled water and concentrated under reduced pressure. The residue is extracted with dichloromethane, the organic layer is dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (hexane:ethyl acetate=4:1 to chloroform:methanol=9:1), receiving 6,35 g of N-(3,5-bistrifluormethylbenzene)-N-ethylamine, as presented below in table 135.

Comparative example 36

(1) To 20 ml of tetrahydrofuran type of 1.34 g of magnesium and trace amounts of iodine and added dropwise a solution of 9.50 g of 2-bromthymol in 45 ml of tetrahydrofuran, receiving the Grignard reagent. To the resulting Grignard reagent is added dropwise a solution 5,46 g of 4-methoxypyridine in 20 ml of tetrahydrofuran in a nitrogen atmosphere at a temperature of -60°With or below. Then added dropwise a solution 10,24 g Chlorobenzilate in 50 ml of tetrahydrofuran at -40°and the mixture is stirred for 3 hours. The temperature of the mixture was raised to room temperature and add 120 ml of 5% aqueous citric acid solution. The mixture is extracted with ethyl acetate and washed with saturated saline solution. The organic layer is dried and concentrated under reduced pressure. The residue is crystallized using diisopropyl ether, and the crystals are collected by filtration, receiving of 11.15 g of 1-benzyloxycarbonyl-2-(2-were)--oxo-3,4-dihydro-2H-pyridine.

MS(m/z): 322[M++1]

(2) In a mixed solution of 125 ml of ethanol and 35 ml of tetrahydrofuran is dissolved of 11.15 g of 1-benzyloxycarbonyl-2-(2-were)-4-oxo-3,4-dihydro-2H-pyridine, added 2.76 g of sodium borohydride and the mixture is stirred at room temperature during the day. Next add to 1.38 g of sodium borohydride and the mixture is stirred at room temperature during the day. The reaction mixture was concentrated under reduced pressure and to the residue add distilled water. The mixture is extracted with chloroform, the organic layer is dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:acetone=49:1 to 9:1), receiving 6,18 g 1-benzyloxycarbonyl-4-hydroxy-2-(2-were)piperidine.

MS(m/z): 326 [M++1]

(3) In 21 ml of toluene is dissolved 1.63 g of 1-benzyloxycarbonyl-4-hydroxy-2-(2-were)piperidine add 973 mg of 1,1'-carbonyldiimidazole and the mixture was stirred at 60°within hours. To the solution was added to 1.21 ml ethanolamine and the mixture is stirred at a temperature of 60°C for 6 hours. To the reaction mixture add distilled water and extracted with chloroform. The organic layer is dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:acetone=9:1 to chloroform:methanol=19:1)to give 1.4 g of 1-benzyloxycarbonyl-4-(2-hydroxyethylaminomethyl)-2-(2-were)piperidine.

MS(m/z): 413 [M++1]

(4) In 30 ml of methanol is dissolved 1,33 g 1-benzyloxycarbonyl-4-(2-hydroxyethylaminomethyl)-2-(2-were)of piperidine added 70 mg of 10% palladium-on-coal and the mixture is stirred at room temperature for 14 hours in an atmosphere of hydrogen. After insoluble materials are removed by filtration, the filtrate is concentrated and receiving 880 mg of 4-(2-hydroxyethylaminomethyl)-2-(2-were)piperidine as shown below in table 135.

Comparative example 37

(1) Use 25 g of 4-fluoro-1-bromine benzol, which is treated by the method of comparative example 1, the receiving of 22.3 g of 1-benzyloxycarbonyl-2-(4-forfinal)-4-oxo-3,4-dihydro-2H-pyridine.

(2) In 400 ml of ethanol was dissolved 20 g of the above compound (1), added 7.6 g sodium borohydride and the mixture is stirred at -20°C for 2 hours. After completion of the reaction, to the mixture is added slowly an aqueous solution of citric acid until then, until it stops foaming. The solvent is removed using distillation under reduced pressure and the layers separated by adding water and chloroform. The aqueous layer was then extracted with chloroform, the combined organic layers dried and concentrated under reduced pressure. The residue is purified using a chromatographic column with silica gel (chloroform:ethyl acetate=10:1)to give 6.3 g is MESI (a) (2R,4S)-1-benzyloxycarbonyl-2-(4-forfinal)-4-hydroxypiperidine and (b) (2S,4R)-1-benzyloxycarbonyl-2-(4-forfinal)-4-hydroxypiperidine.

(3) Using 6.2 g of the above compound (2), which is treated by the method of comparative example 209, getting to 7.3 g of a mixture of (a) (2R,4S)-1-benzyloxycarbonyl-2-(4-forfinal)-4-(2-hydroxyethylaminomethyl)piperidine and (b) (2S,4R)-1-benzyloxycarbonyl-2-(4-forfinal)-4-(2-hydroxyethylaminomethyl)piperidine.

(4) Using 6.3 g of the above compound (3), which is treated by the method of comparative example 4, obtaining 2.6 g of a mixture of (a) (2R,4S)-2-(4-forfinal)-4-(2-hydroxyethylaminomethyl)piperidine and (b) (2S,4R)-2-(4-forfinal)-4-(2-hydroxyethylaminomethyl)piperidine as shown below in table 135.

Comparative example 38

In 5 ml of methanol is dissolved 0,639 g N-tosyl-D-phenylalanine and the solution is heated to 59°and then added dropwise 1.3 ml of methanol solution containing 0,418 g of 2-(4-fluoro-2-methyl)phenyl-4-hydroxypiperidine. After the crystals are formed within 20 minutes after the onset of crystal formation, to the mixture are added dropwise other a methanol solution of 2-(4-fluoro-2-methyl)phenyl-4-hydroxypiperidine within 5 minutes the Mixture is cooled to 59°With 30°within hours and then the crystals are formed within 1.5 hour. The resulting crystals are removed by filtration and washed with cold methanol, dried by air at a temperature of 60°during the night, getting 0,325 g of salt (2R,4S)-2-(4-fluoro-2-IU who yl)phenyl-4-hydroxypiperidine N-tosyl-D-phenylalanine. To add the salts of 0.62 ml of a 2M aqueous solution of hydrogen chloride, the mixture is extracted with ethyl acetate. To the aqueous layer add 0.3 ml of 5M aqueous sodium hydroxide solution and then extracted four times with ethyl acetate. The organic layer is dried, concentrated under reduced pressure, getting 0,129 g (2R,4S)-2-(4-fluoro-2-methyl)phenyl-4-hydroxypiperidine, as presented below in table 136.

Comparative example 39

In 40 ml of dichloromethane is dissolved 2,72 g 2-methoxy-5-(5-cryptomaterial-1-yl)benzaldehyde add 2,5 ml of a 8M solution of methylamine in ethanol, 0,572 ml of acetic acid and 3.12 g of triacetoxyborohydride sodium, the mixture is stirred at room temperature for 6 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate, the organic layers dried and concentrated. The residue is purified using a chromatographic column with silica gel (chloroform:methanol=49:1 to 4:1)to give 2.2 g of N-{2-methoxy-5-(5-cryptomaterial-1-yl)benzyl)-N-methylamine, as presented below in table 136.

Industrial applicability of the invention

The compound of the present invention or its salt have excellent antagonistic activity against receptor tachykinin. In addition, the compound of the present invention or its salt is excellent from the viewpoint of security, the absorption capacity of the transfer in the brain, metabolic stability, concentration in the blood and stability, so it has excellent pharmaceutical properties.

Table 136
Comparative example No.The structural formulaMS
38210 (M++1)
39288 (M++1)

Pharmacological exp is imenti

In accordance with the method described in European Journal of Pharmacology, vol.254, pp.221-221 (1994), the cells IM-9 (4×106cells/tube) were subjected to interaction with 0.3 nm [3N] (Sar9, Met11(O2)) substance P (Kd: to 0.17 nm) and test compound, brought to 10 nm in 50 mm Tris-HCl (pH 7,4, 25° (C)containing 150 mm NaCl, 3 mm MnCl2, 40 μg/ml bacitracin, 4 μg/ml leupeptin, 4 μg/ml of hemostatis, 4 μg/ml of phosphoramidon and 0.02% bovine serum albumin at room temperature for 60 minutes. The mixture was subjected to vacuum filtration on GF/C glass filter, pre-treated with 0.3% polyethylenimine, and washed twice in 3 ml ice reaction buffer not containing either bovine serum albumin or any of the inhibitors proteinase, and the radioisotope (imp./min) on the filter was measured using a liquid scintillation counter. Specific binding was calculated by subtracting nonspecific binding (L-703606 (2 μm)having an antagonistic activity against NK1 receptor) from the total binding, and calculated the level of inhibition against specific binding of labeled ligand based on 10 nm of the test compound.

The results are presented in the following Tables A1 and A2.

Table A1
Example No..The level of inhibition (%)Example No..The level of inhibition (%)
58(a)7327669
896127767
928927858
1346128475
1438328583
1526828684
1538128790
1546128893
1565928990
1577329095
1607829194
1616929292
1635830390
1806630590
1867230690
1897530891

70
20131492
2106331592
2137031690
2159231894
2658933792
2669434990
2699135790
2708835882
2727135991
2746836493
Table A2
Example No.The level of inhibition (%)Example No.The level of inhibition (%)
37198 46392
4077646790
4289447094
4459247390
4528947591
4539247791
4556248091
46192

Industrial applicability of the invention

The compound of the present invention or its salt have excellent antagonistic activity against receptor tachykinin. In addition, the compound of the present invention or its salt is excellent from the viewpoint of security, the absorption capacity of the transfer in the brain, metabolic stability, concentration in the blood and stability, so it has excellent pharmaceutical properties.

1. The connection of piperidine to provide the by the formula [I]:

where ring a is optionally substituted benzene ring, ring b is optionally substituted benzene ring, R1represents optionally substituted alkyl group, optionally substituted hydroxyl group, substituted Tilney group, substituted carbonyl group, a substituted sulfinyl group, substituted sulfonyloxy group or a group represented by the formula:

where R11and R12the same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyloxy group optionally substituted alkyl group, heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as a heteroatom, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized; or R11and R12taken together with the adjacent nitrogen atom, form a heterocyclic group selected from piperidino, azacycloheptane group, pyrrolidinone, imidazolidinyl group, hexahydropyridine group, thiazolidine group, morpholinopropan, triazolines group, tetrazolyl group and parinello GRU is dust, where heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized,

R2represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by-N(R3)-, where R3represents a hydrogen atom or optionally substituted alkyl group, R4represents a hydrogen atom or optionally substituted alkyl group, provided that excluded N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidine, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1represents optionally substituted alkyl group.

3. The compound according to claim 1, where R1is optionally substituted hydroxyl group.

4. The compound according to claim 1, where R1is substituted Tilney group.

5. The compound according to claim 1, where R1represents a substituted carbonyl group.

6. The compound according to claim 1, where R1is substituted sulfonyloxy group.

7. The compound according to claim 1, where R1is substituted sulfonyloxy group.

8. The compound according to claim 1, where R1represents a group represented by FD is moloi:

where R11and R12the same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyloxy group optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as heteroatoms, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized; or R11and R12taken together with the adjacent nitrogen atom, form a heterocyclic group selected from piperidino, azacycloheptane group, pyrrolidinone, imidazolidinyl group, hexahydropyridine group, thiazolidine group, morpholinopropan, triazolines group, tetrazolyl group and parinello group, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized.

9. A compound selected from the following (a) through (s):

(a) (2R,4S)-1-[N-(1-(8)-(3,5-bistrifluormethylbenzene)ethyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxy-2-methylpropionamide)piperidine,

(b) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-3-hydroxyethylamino)piperidine,

(c) (2,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyethylaminomethyl)piperidine,

(d) (2R,4S)-1-[N-{1-(8)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(3-hydroxy-3-methylbutylamine)piperidine,

(e) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-((R)-3-hydroxyethylamino)piperidine,

(f) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxy-2-methylpropanesulfonic)piperidine,

(g) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxy-2-methylpropanesulfonic)piperidine,

(h) (2R,4S)-1-{N - (3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-2-hydroxypropanesulfonic)piperidine,

(i) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((S)-3-hydroxyethylamino)piperidine,

(j) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((R)-3-hydroxyethylamino)piperidine,

(k) (2R,4S)-4-(4-acetylpiperidine)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)piperidine,

(l) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-associationvoice)piperidine,

(m) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hidroxi insulter)piperidine,

(n) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-(1-methylaminoethanol)piperidine,

(o) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(4-hydroxypiperidine)piperidine,

(R) (2R,4S)-1-{N - (3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-methanesulfonanilide,

(q) (2R,4S)-1-{N-(3,5-bistrifluormethylbenzene)-N-methyl}aminocarbonyl-2-(4-fluoro-2-were)-4-((R)-2-hydroxypropyl)piperidine,

(r) (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(2-hydroxyacetylamino)of piperidine and

(s) (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-(1-metalicity)piperidine,

or their pharmaceutically acceptable salts.

10. The method of obtaining compounds of piperidine derivatives of the formula [I']:

where ring a is optionally substituted benzene ring, ring b is optionally substituted benzene ring, R1represents optionally substituted alkyl group, optionally substituted hydroxyl group, substituted Tilney group, substituted carbonyl group, a substituted sulfinyl group, substituted sulfonyloxy group Il the group, represented by the formula:

where R11and R12the same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyloxy group optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as a heteroatom, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized; or R11and R12taken together with the adjacent nitrogen atom, form a heterocyclic group selected from piperidino, azacycloheptane group, pyrrolidinone, imidazolidinyl group, hexahydropyridine group, thiazolidine group, morpholinopropan, triazolines group, tetrazolyl group and parinello group, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized,

R2represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom, where R3represents a hydrogen atom or optionally substituted alkyl group, 4represents a hydrogen atom or optionally substituted alkyl group,

or its pharmaceutically acceptable salts, including the implementation of the interaction of the compounds of formula [II]:

where ring A, R1and R2have the above meanings, with a compound of the formula [III]:

where ring B, R3and R4have the above meanings, in the presence of forming a urea bond agent, and if desired, the transformation into its pharmaceutically acceptable salt.

11. The method of obtaining compounds of piperidine derivatives of the formula [I-a]:

where ring a is optionally substituted benzene ring, ring b is optionally substituted benzene ring, R2represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by-N(R3)-, where R3represents a hydrogen atom or optionally substituted alkyl group, and R4represents a hydrogen atom or optionally substituted alkyl group,

or farm citiesi acceptable salt, including the restoration of the compounds of formula [IV]:

where ring A, ring B, R2, Z and R4have the above values, and optionally, the transformation into its pharmaceutically acceptable salt.

12. The method of obtaining compounds of piperidine derivatives of the formula [I-b]:

where ring a is optionally substituted benzene ring, ring b is optionally substituted benzene ring, R2represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by-N(R3)-, where R3represents a hydrogen atom or optionally substituted alkyl group, R4represents a hydrogen atom or optionally substituted alkyl group,

R11and R12the same or different and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyloxy group optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as heteroatoms, where geterotsiklicheskikh is a group optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized, or R11and R12taken together with the adjacent nitrogen atom, form a heterocyclic group selected from piperidino, azacycloheptane group, pyrrolidinone, imidazolidinyl group, hexahydropyridine group, thiazolidine group, morpholinopropan, triazolines group, tetrazolyl group and parinello group, where the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized,

or its pharmaceutically acceptable salts, including the implementation of the interaction of the compounds of formula [IV]:

where ring A, ring B, R2, Z, R3and R4have the above meanings, with a compound of the formula [V]:

where R11and R12have the above values, X1represents a hydrogen atom, a hydroxyl group, a silicon atom, a lithium atom or an atom of magnesium,

and if desired transformation into its pharmaceutically acceptable salt.

13. The method of obtaining compounds of piperidine derivatives of the formula [I-c]:

where ring a is optionally substituted benzene ring, ring b is neobyazatel is substituted benzene ring, R13is optionally substituted carboxyl group, R2represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by-N(R3)-, where R3represents a hydrogen atom or optionally substituted alkyl group, R4represents a hydrogen atom or optionally substituted alkyl group,

or its pharmaceutically acceptable salts, including the implementation of the interaction of the compounds of formula [IV]:

where ring A, ring B, R2, Z, R3and R4have the above meanings, with a compound of the formula [VI]:

where X2is tsepliaeva group, and R13has the above values, recovering the obtained compound of the formula [VII]:

where ring A, ring B, R13, R2, Z, R3and R4have the above values,

and if desired, the transformation into its pharmaceutically acceptable salt.

14. The method of obtaining compounds of piperidine derivatives of the formula [I"]:

where ring a is optionally substituted benzene ring, ring b is optionally substituted benzene ring, R1represents optionally substituted alkyl group, optionally substituted hydroxyl group, substituted Tilney group, substituted carbonyl group, a substituted sulfinyl group, substituted sulfonyloxy group or a group represented by the formula:

where R11and R12the same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyloxy group optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom as heteroatoms, where the heterocyclic group optionally substituted, a nitrogen atom in the heterocyclic group is optionally oxidized, or R11and R12taken together with the adjacent nitrogen atom, form a heterocyclic group selected from piperidino, azacycloheptane group, pyrrolidinone, imidazolidinyl group, hexahydropyridine group, thiazolidine group, morpholinopropan, triazolines group, tetrazolyl group and parinello group, where the heterocyclic group is optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized,

R2represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom, and R4represents a hydrogen atom or optionally substituted alkyl group,

or its pharmaceutically acceptable salts, including the implementation of the interaction of the compounds of formula [II]:

where ring A, R1and R2have the above meanings, with a compound of the formula [III']:

where ring b and R4have the above meanings, in the presence of forming a urea bond agent, and if desired, transforming it into a pharmaceutically acceptable salt.

15. Pharmaceutical composition having antagonistic activity against NK1 receptor tachykinin containing an effective amount of a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

16. The use of compounds according to any one of claims 1 to 9 to obtain drugs for treatment or prevention of a disease selected from inflammatory, allergic diseases, pain, migraine, neuralgia, pruritus, cough, C the illnesses of the Central nervous system, diseases of the digestive system, nausea, vomiting, disorders of urinary system, diseases of the circulatory system and immune system disorders.

17. Method for the treatment and prevention of diseases selected from inflammatory, allergic diseases, pain, migraine, neuralgia, pruritus, cough, Central nervous system diseases, diseases of the digestive system, nausea, vomiting, disorders of urinary system, diseases of the circulatory system and immune system disorders, comprising the administration to a mammal a clinically effective dose of a compound according to any one of claims 1 to 9.

18. The method according to 17, where disease is a disorder of the urinary system.

Priority from 29.05.2002 according to the application JP 2002-155744 installed according to claims 1 and 9-18 adjusted claims; priority from 12.07.2002 according to claim US 60/395,343 installed on all items specified claims; priority from 28.08.2002 according to the application JP 2002-248755 installed on all items specified claims; priority from 11.09.2002 according to claim US 60/409,595 installed on all items specified in the claims.



 

Same patents:

The invention relates to the derivatives of purine, which has antiviral activity against human cytomegalovirus and human immunodeficiency virus type 1, of General formula:

where n = 0 to 4; m = 0 to 3; R1= N, HE or NH2; R2= HE, NH2, acetylamino or benzoylamine; R3= H or lower alkyl (C1-C4; R4= H, lower alkyl (C1-C4or phenyl; X = CH2, O, S, NH or C(O)O; and Y = CH2, CH=CH, C(O), or ordinary communication; Ar = phenyl, pyridyl, naphthyl or substituted phenyl of the formula

where independently R5-R9= alkyl1-C8cycloalkyl C5-C6, 1-substituted, allyl, phenyl, benzyl, F, Cl, Br, J, trifluoromethyl, alkoxy, C1-C5phenoxy, benzyloxy, benzoyloxy, cyano, carboxy, acetyl, or nitro, antiviral effect of the most active compounds against human cytomegalovirus in vitro manifests itself in concentrations of 0.01-0,0005M and is characterized by selectivity 1-400 thousand

The invention relates to new compounds of General formulas I, II, III

< / BR>
or their pharmaceutically acceptable salts, in which the dotted lines indicate optional double bonds; A is-CR7or N; - - NR1R2, -CR1R2R11, -C(= CR2R12R1, -NHCHR1R2, -ОСHR1R2, -SCHR1R2, -CHR2OR12,

-CHR2SR12, -C(S)R2or-C(O)R2N-ethyl-2,2,2-triptorelin; G is oxygen, sulfur, NH, NH3hydrogen, methoxy, ethoxy, triptoreline, methyl, ethyl, dimethoxy, NH2, NHCH3N(CH3)2or trifluoromethyl; Y Is N; Z is NH, O, S, -N(C1-C2alkyl) or-C(R13R14), where R13and R14independently of one another represent hydrogen, trifluoromethyl or methyl, or one of the elements of R13and R14is cyano and the other is hydrogen or stands; R1- C1-C6alkyl which may be optionally substituted by one or two substituents R8independently from each other selected from the group comprising hydroxy, fluorine, chlorine, bromine, iodine, CF3C1-C4alkoxy, -O-CO-(C1-C4alkyl), where (C1-C2- C1-C12alkyl, aryl or -(C1-C4alkylene)aryl, where aryl is phenyl, naphthyl; R3is methyl, ethyl, fluorine, chlorine, bromine, iodine, cyano, methoxy, OCF3, methylthio, methylsulphonyl, CH2HE or CH2OCH3; R4is hydrogen, C1-C4alkyl, fluorine, chlorine, bromine, iodine, C1-C4alkoxy, triptoreline, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2, -NHCOCH3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, COOH, cyano, or-COO(C1-C4alkyl), where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -NHCOCH3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano, nitro; R5is phenyl, naphthyl, pyridyl, pyrimidyl, where each of the above groups R5substituted with one to three substituents that are independently from each other selected from fluorine, chlorine, C1-C6the alkyl or C1-C6alkoxyl, or one Deputy chosen from the group comprising hydroxy, iodine, bromine, formyl, cyano, nitro, trifluoromethyl, amino, -(C1-C6these groups of R5may be optionally substituted with one hydroxy-group; R6is hydrogen or C1-C6alkyl; R7is hydrogen, methyl; R11is hydrogen, hydroxy, fluorine or methoxy; R12is hydrogen or C1-C4alkyl, and R16and R17independently of one another represent hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy, except that both R16and R17cannot both be methoxy or ethoxy; or R16and R17together form oxo (=O) group; provided that if G is an atom of oxygen, sulfur, NH or NCH3he is joined by a double bond to a five-membered ring of the formula III, and further provided that R6is absent when the nitrogen atom to which it is linked, is attached by a double bond to an adjacent carbon atom in the ring

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

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

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted indoles or its pharmaceutically acceptable salts of the formula (I): , wherein R1 means hydrogen (H) atom, halogen atom, -CN, nitro-group, -SO2R4, -OH, -OR4, -SO2NR5R6, -CONR5R6, -COOH, -COOCH3, -NR5R6, phenyl, naphthyl or (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atom, -OR8 and -NR5R6 wherein x = 2; R2 means (C1-C7)-alkyl; R3 means phenyl, naphthyl or heteroaryl and each of them is possibly substituted with one or more substitutes chosen independently from H, halogen atom, -CN, -OH, -SO2R4, -OR4, -SO2NR5R6, -CONR5R6, phenyl, naphthyl, (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atoms, -OR8 and -NR5R6, -S(O)xR7 wherein x = 2; R4 means (C1-C6)-alkyl; R5 and R6 mean independently H, (C1-C6)-alkyl, or R5 and R6 in common with nitrogen atom to which they are bound can form 6-membered saturated heterocyclic ring comprising one atom chosen from -NR16; R7 means (C1-C6)-alkyl; R8 means H, (C1-C6)-alkyl; R16 means H, -COY-(C1-C4)-alkyl wherein Y means oxygen atom (O) and wherein alkyl group in the substitute group can be direct, branched or cyclic, and wherein heteroaryl means 5-6-membered heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or means 6,6-condensed bicyclic aromatic ring system comprising one nitrogen atom. Compounds of the formula (I) can be used in production of a medicinal agent used in treatment of asthma and chronic obstructive disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl, 59 ex

FIELD: organic chemistry, herbicides.

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

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new polymorphous crystalline forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate of formula and stereomers thereof.

EFFECT: polymorphous crystalline forms of high stability.

12 cl, 1 tbl, 13 dwg, 5 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

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

SUBSTANCE: invention relates to a method for preparing an antidiabetic agent pioglitazone of the formula (I): . Method involves condensation of 4-substituted phenol or phenolate of the general formula (II): wherein R represents organic radical comprising amino-group and chosen from group comprising group of the general formula: -NHRa (IIa) wherein Ra means hydrogen atom or protective group that is removed before the following treatment, and group of the general formula: wherein Rb represents carboxyl group as free acid or as salt or ester; M represents hydrogen atom or alkaline metal with pyridine base of the general formula (III): wherein Z means a removing group distinguishing from halogen atom and wherein the following steps are carried out: (a) diazotization reaction of amino-group as a moiety of organic radical R; (b) conversion of diazotized radical R to derivative of 2-halogenpropionate or 2-halogenpropionitrile of the formula: wherein Rb is determined above; X represents halogen atom; (c) cyclization of derivative of 2-halogenpropionate or 2-halogenpropionitrile with thiourea, and (d) hydrolysis of imine prepared. In case when R represents group of the formula (IIa) method involves firstly carrying out the condensation reaction followed by carrying out steps (a)-(d) to obtain agent of the formula (I); or in case when R represents group of the formula (IIb) then method involves firstly carrying out steps (a)-(d) followed by condensation with pyridine base of the general formula (III) to obtain agent of the formula (I). Also, invention describes compounds of the formula (V): wherein Ra represents a protective group chosen from group comprising acyl, n-alkoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-cyanoethoxycarbonyl as an intermediate substance in synthesis of compound of the formula (I).

EFFECT: improved preparing method of agent.

12 cl, 5 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

Benzothiazoles // 2293736

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-4H-pyran-3-yl, 5,6-dihydro-4H-pyran-2-yl, tetrahydropyran-2,3- or 4-yl, cyclohex-1-enyl, cyclohexyl, or it represents 1,2,3,6-tetrahydropyridin-4-yl or piperidin-4-yl that are optionally substituted with -C(O)CH3 or -C(O)OCH3 in position 1 at nitrogen atom (N); R2 represents lower alkyl, piperidin-1-yl substituted with hydroxy-group optionally, or it represents phenyl optionally substituted with -(CH2)n-N(R')-C(O)-(CH2)n-NR'2, -(CH2)n-halogen, lower alkyl or -(CH2)n-N(R')-(CH2)n-O-lower alkyl, or it represents morpholinyl or pyridinyl that is substituted optionally with halogen atom, -N(R')-(CH2)n-O-lower alkyl, lower alkyl, lower alkoxy-group, morpholinyl or -(CH)n-pyrrolidinyl; n = 0, 1 or 2; R' represents hydrogen atom or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicament possessing affinity to adenosine A2A-receptors and containing one or some compounds of the general formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds.

17 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

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

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 2-cycloalkylimino-5-(4-nitrophenyl)-1,3,4-thiadiazines of the general formula (I): wherein the group represents: piperidino-, pyrrolidino-, methylpiperazino-, hexamethyleneimino-group that possess the biological activity against smallpox virus. Invention provides preparing novel biological active compounds possessing an antiviral effect, in particular, against smallpox virus.

EFFECT: valuable biological and medicinal properties of compounds.

1 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

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