Substituted derivatives of the research, the method of production thereof, pharmaceutical composition based on them, the way to reduce the number of tachykinins in the treatment or prevention of physiological conditions associated with an excess of tachykinins

 

(57) Abstract:

Substituted derivatives of the research formula 1, where R1, R2is hydrogen, halogen, alkyl, alkoxy or CF3; R3is hydrogen, halogen or CF3; R4is hydrogen; R5is hydrogen or 4-fluoro; R6- 5 - or 6-membered heterocyclic ring containing 2 or 3 nitrogen atom, possibly substituted by =0, =S, alkyl or ZNR7R8, Z - C1-4-alkylen, R7is hydrogen, alkyl, C3-7-cycloalkyl, or C3-7-cycloalkyl-C1-4-alkyl or C2-4alkyl, substituted alkoxy or hydroxyl (values of other radicals, see p. 1 f-ly), or its pharmaceutically acceptable salts, pharmaceutical composition based on them, has the properties of antagonists of tachykinins. 4 c.p. and 24 C.p. f-crystals, 3 PL.

The invention relates to the class of aromatic compounds, which are used as antagonists of tachykinins. More specifically, the compounds of the present invention contain aminosilane azaheterocyclic group.

Tachykinin are a group common to the nature of the peptides, which are more common, as found in mammalian tissues, as in the Central nervous system and is considered carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH2.

Currently, there are three tachykinin mammals, referred to as substance P, narocin A (NKA, substance K, neuromedin L) and neurokin B (NKB, neuromedin K) (see review by J. E. Meggio, Peptides (1985) 6 (Suppl. 3), 237-242). The generally accepted nomenclature defines three tachykinin receptor, mediating the biological activity of substance P, NKA and NKB as NK1-, NK2- and NK3receptors, respectively.

The evidence for the usefulness antagonists tachykinin receptors for pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, withdrawal syndrome of morphine, cardiovascular changes, oedema, such as oedema caused by thermal burn, chronic inflammatory diseases, such as rheumatoid arthritis, asthma increased bronchial reactivity and other respiratory diseases including allergic rhinitis, inflammatory bowel disease, including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, rheumatoid irritation of the colon and disorders of the bladder, including cystitis and hyperreflexia of the bladder muscles, are considered "Tachyki, that substance P, among others, involved in the neurotransmission of pain sensations (Otsuka et al, "Role of Substance Pas c Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" b 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman), u Otsuka and Yanagisawa, "Does Substance P Actas a Pain (1987), 8, 506-510), especially in Ttansmitter?" TIPS the transmission of pain in migraine (B. E. B. Sandberg et al. , J. Med. Chem, (1982), 25, 1009) arthritis (Levine et al., Science (1984) 226, 547-549). Tachykinin also involved in gastrointestinal (G1) disorders and diseases G1-tract, such as inflammatory bowel disease [(Mantyh et al. , Neuroscience(1988) 25(3), 817-37, u D. Regoli, "Trends in Cluster Headache" Ed. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam (1987) page 85)] and vomiting [E. D. Tattersall et al., Eur. J. Pharmacol. , (1993), 250, R5-R6). It is also assumed that there is a neurogenic mechanism for arthritis, where a certain can the role of substance P (Kidd et al., "Neurogenic Mechanism for Symmetrical Arthiritis" in The Lancet, November 11, 1989, u Gronblad et al., "Neuropeptides in Synovium of Patients with Pheu matoid Arthritis and Osteoartritis in Rhtumatol, (1988), 15 (12), 1807-10). So, I think that substance P is included in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis, fibrositis (O Byrne et al., Arthritis and Rheumatism (1990), 33, 1023-8). Other related disease areas, which are believed to be useful antagonists tachykinin are allergic States (Hamelet et al, Can. J. Pharmacol Physiol reflex and neural regulation of internal organs (Mantyh et al, PNAS (1988), 85, 3235-9), and possibly through the reduction or attenuation-amyloidogenic neurodegenerative changes (Yankner et al, Science (1990) 250, 279-82), senile dementia of the Alzheimer's type, Alzheimer's disease and down syndrome.

Antagonists of tachykinins may also be useful in the treatment of small cell lung cancer, in particular small cell lung cancer (SCLC) (Landgon et al, Cancer Research (1992) 52, 4554-7).

Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis (J. Luber-Narod et al, poster C. I. N. P. XVIIIth Congress, 28th June-2nd July 1992), and disorders of bladder function such as hyperreflexia of the bladder muscles (Lancet, 16th May 1992, 1239).

In addition, it is assumed that tachykinin are of secondary importance when the following disorders: depression, estimatesa disorders, chronic airway obstruction, allergic disorders, such as under the action of sumac, wetpanties diseases such as angina and disease of the Rhine (Reynauld), fibrous and collagen diseases such as scleroderma and eosinophilic fasciitis (fascioliasis), reflex sympathetic dystrophy such as shoulder syndrome, disease, Viy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus erythematosus (description of the European patent N 0436334), ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, etc., and cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematous dermatitis (European patent N 0394989).

In the European patent N 0577394 (published 5 January 1994) described morpholine and thiomorpholine antagonists tachykinin receptors General formula

< / BR>
where R1arepresents various substituents;

R2aand R3aamong other things, represent hydrogen;

R4aamong other things, is a

< / BR>
R5arepresents, inter alia, optionally substituted phenyl;

R6a, R7aand R8arepresents various substituents;

Xarepresents O, S, SO or SO2;

Yarepresents, among other things, O; and

Zarepresents hydrogen or C1-4-alkyl.

In the European patent N 0528495 (published February 24, 1993) described the acyclic derivatives useful as antagonists of tachykinins, koorifestival an optionally substituted phenyl,

R2brepresents aryl, heteroaryl, benzhydryl or benzyl;

R4band R5brepresents, independently, H, halogen, CH2OR9bC1-6- alkyl, oxoprop, CO2R10bor CONR10bR11b;

R8brepresents H, COR9b, CO2R10bor optionally substituted C1-6- alkyl,

R9brepresents H, C1-6-alkyl or phenyl, and

R10band R11bindependently, represents H or C1-6-alkyl.

Applicants have discovered another class ones connections that are strong antagonists of tachykinins, especially substance P.

Preferably, the compounds can be administered orally and by injection. In the present invention are disclosed compounds, which act as strong ones antagonists of tachykinins, and which, because of their preferential solubility in water, especially easy to include in a composition for administration as an oral or by injection, for example, in the aquatic environment.

In addition, the compounds of the present invention have a particularly advantageous profile of activity, with a strong activity of the antagonist to NK1

The present invention relates to compounds of formula (1)

< / BR>
where R1represents hydrogen, halogen, C1-6-alkyl, C1-6-alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRbC2-6alkenyl,2-6-quinil or C1-4-alkyl, substituted C1-4-alkoxy, where Raand Rbeach, independently, represents hydrogen or C1-4alkyl,

R2represents hydrogen, halogen, C1-6-alkyl, C1-6-alkoxy, substituted C1-4-alkoxy, or CF3,

R3represents hydrogen, halogen or CF3,

R4represents hydrogen, halogen, C1-6-alkyl, C1-6-alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRbC2-6alkenyl, C2-6-quinil or C1-4-alkyl, substituted C1-4-alkoxy-group, where Raand Rbeach independently represents hydrogen or C1-4-alkyl,

R5represents hydrogen, halogen, C1-6alkyl, C1-6-ALCO is ical ring, containing 2 or 3 nitrogen atom, optionally substituted by =O, =S or C1-4is an alkyl group, and optionally substituted group of the formula ZNR7R8where

Z represents a C1-6-alkylene or C3-6- cycloalkyl,

R7represents hydrogen, C1-4-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-4alkyl or C2-4-alkyl, substituted C1-4-alkoxy group or a hydroxyl,

R8represents hydrogen, C1-4-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-4-alkyl or C2-4-alkyl, substituted by one or two substituents selected among C1-4-alkoxygroup, hydroxyl or 4-, 5-, or 6-membered heteroaromatics ring containing one or two heteroatoms selected among N, O and s

or R7, R8and the nitrogen atom to which they are attached, form heteroaromatics ring of 4-7 atoms, optionally substituted by one or two groups selected among hydroxyl or C1-4-alkyl, optionally substituted C1-4-alkoxygroup or hydroxyl group, and optionally containing a double bond, and this ring may optionally contain a ring atom of the acid is
where Rcrepresents a C1-4-alkyl, optionally substituted hydroxyl group or a C1-4-alkoxygroup;

or R7, R8and the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system with 6 to 12 ring atoms;

or Z, R7and the nitrogen atom to which they are attached, form heteroaromatics ring of 4-7 atoms in the ring, which optionally may contain a ring oxygen atom;

R9aand R9beach and independently represents hydrogen or C1-4-alkyl, or R9aand R9bare joined, together with the carbon atoms to which they are attached, so that the formed ring C5-7,

X represents alkylenes chain of 1-4 carbon atoms, optionally substituted by exography, and

Y represents a C1-4is an alkyl group, optionally substituted hydroxyl group,

provided that when Y represents a C1-4-alkyl, R6is substituted at least by a group of the formula ZNR7R8, the definition of which is given above;

and their pharmaceutical acceptable salts and prodrugs.

Some especially podhodyashi-4-alkyl, C1-4-alkoxy, halogen or CF3.

Most suitably, when R2represents hydrogen, C1-4-alkyl, C1-4-alkoxy, halogen or CF3.

Most suitably, when R3represents hydrogen, fluorine, chlorine or CF3.

Positive when R1represents a fluorine, chlorine or CF3.

Positive when R2represents hydrogen, fluorine, chlorine or CF3.

Positive when R3represents hydrogen, fluorine, chlorine or CF3.

Preferably, when R1and R2are in positions 3 and 5 of the phenyl ring.

More preferably, when R1represents 3-fluoro or 3-CF3.

More preferably, when R2represents 5-fluoro or 5-CF3.

More preferably, when R3represents hydrogen.

More preferably when R1is a 3-F or 3-CF3, R2represents a 5-CF3and R3represents hydrogen.

Most suitably, when R4represents hydrogen.

Most suitably, when R5previ hydrogen, and R5represented a hydrogen or 4-fluoro.

Most suitably, when R9aand R9beach, independently, represents hydrogen or methyl.

R9apreferably represents hydrogen, R9bpreferably represents hydrogen. Most preferably, when R9aand R9bboth are hydrogens.

From the foregoing it is clear that it is particularly suitable sub-group of compounds of the present invention are the compounds of formula (Ia) and their pharmaceutically acceptable salts and prodrugs.

< / BR>
where A1represents fluorine or CF3;

A2represents fluorine or CF3;

A3represents a fluorine or hydrogen;

X, Y, and R6have the values set in the definition of formula (I).

In accordance with another aspect of the present invention, a preferred class of compounds of formula (I) or (Ia) are compounds in which Y represents C1-4is an alkyl group substituted with hydroxyl group; or pharmaceutically acceptable salts or prodrugs.

In accordance with another or alternative aspect of the present installaed a C1-4is an alkyl group, provided that R6is substituted at least by a group of the formula ZNR7R8, as defined above, or pharmaceutically acceptable salts or prodrugs.

In accordance with another aspect of the present invention, another preferred class of compounds of formula (I) or (Ia) are compounds in which

Y represents a C1-4is an alkyl group, and

R6represents 5 - or 6-membered heterocyclic ring containing 2 or 3 nitrogen atom, optionally substituted by =O or =S, and substituted by a group of the formula ZNR7R8in which

Z represents a C1-6-alkylene or C3-6-cycloalkyl,

R7represents hydrogen, C1-4-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-4-alkyl or C2-4-alkyl, substituted C1-4-alkoxygroup or hydroxyl,

R8represents hydrogen, C1-4-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-4-alkyl or C2-4-alkyl, substituted by one or two substituents selected among C1-4-alkoxygroup, hydroxyl or 4-, 5 - or 6-membered heteroaromatics ring containing prisoedinneny, form heteroaromatics ring of 4-7 atoms, optionally substituted hydroxyl group, and containing, optionally, the double bond, and the ring may contain, optionally, the ring oxygen atom or a sulfur atom, a group S(O) or S(O)2or a second nitrogen atom which will be part of a group NH or NRcor Rcrepresents a C1-4-alkyl, optionally substituted hydroxyl group or a C1-4-alkoxygroup,

or Z, R7and the nitrogen atom to which they are attached, form heteroaromatics ring of 4-7 atoms, which optionally may contain a ring oxygen atom;

or their pharmaceutically acceptable salts or prodrugs.

In accordance with another aspect of the present invention, another preferred class of compounds of formula (I) or (Ia) are compounds in which

Y represents a C1-4is an alkyl group; and

R6represents 5 - or 6-membered heterocyclic ring containing 2 or 3 nitrogen atom, optionally substituted by =O or =S, and substituted by a group of the formula ZNR7R8where

Z represents a C1-6-alkylene or C3-6-cycloalkyl,

R7paraxylene group, R8represents hydrogen or C1-4-alkyl or C2-4-alkyl, substituted C1-4-alkoxygroup, hydroxyl or a 5 - or 6-membered heteroaromatics ring containing one or two heteroatoms selected among N, O and S,

or R7, R8and the nitrogen atom to which they are attached, form heteroaromatics ring of 4-7 atoms, optionally substituted hydroxyl group, and the ring may contain, optionally, the ring oxygen atom or a sulfur atom, a group S(O) or S(O)2or a second nitrogen atom which will be part of a group NH or NRCwhere RCrepresents a C1-4-alkyl, optionally substituted hydroxyl group or a C1-4-alkoxygroup,

or Z, R7and the nitrogen atom to which they are attached, form heteroaromatics ring of 4-7 atoms, which optionally may contain a ring oxygen atom,

or their pharmaceutically acceptable salts or prodrugs.

In accordance with another aspect of the present invention, another preferred class of compounds of formula (I) or (Ia) are compounds in which

Y represents a C1-4is an alkyl group, and

R6hand =O or =S, and optionally substituted group of the formula ZNR7R8where

Z represents a C1-6-alkylene or C3-6-cycloalkyl,

R7represents hydrogen or C1-4-alkyl or C2-4-alkyl, substituted C1-4-alkoxygroup or a hydroxyl group, R8represents hydrogen or C1-4-alkyl or C2-4-alkyl, substituted C1-4-alkoxygroup or hydroxyl,

or R7, R8and the nitrogen atom to which they are attached, form heteroaromatics ring of 4-7 atoms, which may contain, optionally, the ring oxygen atom or a second nitrogen atom which will be part of a group NH or NRcwhere Rcrepresents a C1-4-alkyl, optionally substituted hydroxyl group or a C1-4-alkoxygroup,

or Z, R7and the nitrogen atom to which they are attached, form heteroaromatics ring of 4-7 atoms, which optionally may contain a ring oxygen atom,

or their pharmaceutically acceptable salts or prodrugs.

In accordance with another aspect of the present invention, another preferred class of compounds of formula (I) or (Ia) are compounds the PTA, optionally substituted by =O or =S, and optionally substituted group of the formula ZNR7R8where

Z represents a C1-6-alkylene or C3-6-cycloalkyl,

R7represents hydrogen or C1-4-alkyl or C2-4-alkyl, substituted C1-4-alkoxygroup or a hydroxyl group, R8represents hydrogen or C1-4-alkyl or C2-4-alkoxygroup or hydroxyl,

or R7, R8and the nitrogen atom to which they are attached, form heteroaromatics ring of 4-7 atoms, which may contain, optionally, the ring oxygen atom or a second nitrogen atom which will be part of a group NH or NRcwhere Rcrepresents a C1-4-alkyl, optionally substituted hydroxyl group or a C1-4-alkoxygroup,

or Z, R7and the nitrogen atom to which they are attached, form heteroaromatics ring of 4-7 atoms, which optionally may contain a ring oxygen atom,

or their pharmaceutically acceptable salts or prodrugs.

A preferred group Y for the compounds of formula (I) or (Ia) is a group CH2OH.

Another preferred connected to the s of formulas (I) or (Ia) include groups CH2CH(CH3and CH2CH2, of which preferred is the group CH2.

Positive when R6represents a 5-membered ring.

In particular, R6can be a, having in mind the condition exhibited in the definition of formula (I), heterocyclic ring, selected among

< / BR>
< / BR>
< / BR>
Particularly preferred heterocyclic rings, which is R6can be chosen among

< / BR>
< / BR>
R6may be a heterocyclic ring selected mainly among

< / BR>
Particularly preferred heterocyclic ring, which is represented by R6is

< / BR>
One of the preferred groups of compounds of the present invention are the compounds of formula (Ib) and their pharmaceutically acceptable salts and prodrugs.

< / BR>
where A1, A2and A3have the meanings specified in the definition of formula (Ia),

Z, R7and R8have the meanings specified for formula (I).

Another preferred group of compounds of the present invention are the compounds of formula (Ic) and their pharmaceutically acceptable salts and prodrugs.

Another preferred group of compounds of the present invention are the compounds of formula (1d) and their pharmaceutically acceptable salts and prodrugs.

< / BR>
where A1, A2and A3have the values set for the formula (1a), Q2represents CH or N, and Z, R7and R8have the values set for the formula (1).

With regard to compounds of formula (1), (1a), (1b), (1c) and (1d) and Z can represent a linear, branched or cyclic group. Preferably, Z contains 1 to 4 carbon atoms, and most preferably 1 or 2 carbon atoms. Especially preferred group Z is a group CH2.

With regard to compounds of formula (1), (1a), (1b), (1c) and (1d), R7may, appropriately, be a C1-4is an alkyl group or a C2-4is an alkyl group substituted by hydroxyl or C1-2-alkoxygroup, R8can be a C1-4is an alkyl group or a C1-4is an alkyl group substituted by hydroxyl or C1-2-alkoxygroup, or R7and R8can be linked in Abregu group, piperidino group, morpholinopropan, thiomorpholine, piperazinone or piperazinone, substituted at the nitrogen atom of C1-4is an alkyl group substituted by a hydroxyl group or a C1-2-alkoxygroup.

When the group NR7R8represents heteroaromatics ring of 4-7 atoms in the ring and said ring contains a double bond, particularly preferred group is a 3-prolinnova group.

When the group NR7R8represents a non-aromatic azabicyclic ring system, such a system may contain from 6 to 12 atoms, preferably from 7 to 10 atoms. Such a suitable ring systems include

5-azabicyclo[2.1.1] hexyl, 5-azabicyclo[2.2.1] heptyl, 6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[2.3.1] nonyl, 6-azabicyclo[3.2.2]decyl, 7-azabicyclo[4.3.1]decyl, 7-azabicyclo[4.4.1] undecyl and 8-azabicyclo[5.4.1]dodecyl, especially, 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.

When R8represents a C2-4is an alkyl group, a substituted 5 - or 6-membered heteroaromatics ring containing one or two heteroatoms selected among N, O and S, suitable colinagrosu. Especially preferred are nitrogen-containing heteroaromatics rings, especially rings pyrrolidinone and morpholinopropan.

Particularly suitable groups ZNR7R8include groups in which Z represents CH2or CH2CH2and NR6R8represents an amino group, methylaminopropyl, dimethylaminopropyl, diethylaminopropyl, azetidinol group, pyrrolidinone and morpholinopropan.

Other preferred groups represented ZNR7R8are groups in which Z represents CH2or CH2CH2, R7represents hydrogen, C1-4-alkyl or C3-6-cycloalkyl, and R8represents a C2-4-alkyl, substituted by one or two substituents selected among hydroxyl group, a C1-2-alkoxygroup, azetidine, pyrrolidinone, piperidine, morpholinopropan or thiomorpholine.

In particular, Z is preferably CH2or NR7R8represents, preferably, dimethylaminopropyl, azetidine or pyrrolidinone, especially dimethylaminopropyl.

When considering joint is Ino, is a CF3and A3preferably represents fluorine.

Used herein, the terms "alkyl" or "alkoxy" in relation to a group or part of a group means that this group is a linear or branched. Examples of suitable alkyl groups are methyl, ethyl, n-propyl, ISO-propyl, n-butyl, sec-butyl and tert-butyl. Examples of suitable alkoxygroup are a methoxy group, ethoxypropan, n-propoxylate, out-propoxylate, n-butoxypropyl, second-butoxypropan and tert-butoxypropan.

Cycloalkyl groups mentioned herein may constitute, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Suitable cycloalkylation group can represent, for example, cyclopropylmethyl.

Used herein, the terms "alkenyl" or "quinil" to refer to a group or part of a group means that this group is a linear or branched. Examples of suitable alkenyl groups are the vinyl group and allyl group. Suitable alkenylphenol group is propargyl.

When I use the term "halogen" means fluorine, chlorine, bromine and iodine. The most suitable halogenases in the scope of the present invention, are

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2,3 - dihydro-5-(N, N-dimethylamino)methyl-2-oxo-1,3-imidazol-4-yl)methyl - 3-(S)-(4-forfinal)morpholine,

4-(2,3-dihydro-5-(N, N-dimethylamino)methyl-2-oxo-1,3 - imidazol-4-yl)methyl-3-(S)-(4-forfinal)-2-(R)-(1-(R)- (3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)morpholine,

3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)- phenyl)ethoxy)-4-(2,3-dihydro-2-oxo-5-pyrrolidinyl-1,3-imidazol - 4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)(phenyl)ethoxy)-3-(S)- (4-forfinal)-4-(2,3-dihydro-2-oxo-5-pyrrolidinyl-1,3-imidazol - 4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)(phenyl)ethoxy)-3-(S)- (4-forfinal)-4-(2,3-dihydro-5-(4-hydroxypiperidine)methyl-2-oxo - 1,3-imidazol-4-yl)methylmorpholine,

3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)- phenyl)ethoxy)-4-(2,3-dihydro-5-morpholinomethyl-2-oxo-1,3-imidazol - 4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)(phenyl)ethoxy)-3-(S)- (4-forfinal)-4-(2,3-dihydro-5-morpholinomethyl-2-oxo-1,3-imidazol - 4-yl)methylmorpholine,

4-(5-azetidine-2,3-dihydro-2-oxo-1,3-imidazol-4-yl)- methyl-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)(phenyl)ethoxy)-3- (4-forfinal)methylmorpholin,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)(phenyl)ethoxy)-3-(S)- (4-forfinal)-4-(2,3-dihydro-5-(N-methylpiperazine)methyl-2-oxo-1,3 - is morpholinoethyl)aminomethyl)-2 - oxo-1,3-imidazol-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3(S)-(4-forfinal)-4-(2,3 - dihydro-2-oxo-5 - (N-(2-pyrrolidinyl)aminomethyl)-1,3-imidazol-4-yl)- methylmorpholin,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-dimethylamino)-methyl - 1,2,3-triazole-4-yl)methyl-3-(S)-(4-forfinal)-morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy-3-(S)-(4-forfinal)-4-(N- (N'-methylaminomethyl)-1,2,4-triazole-3-yl)methylmorpholine,

and their pharmaceutically acceptable salts or prodrugs.

Other preferred compounds included in the scope of the present invention, are

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4- (5-(N-methylaminomethyl)-1,2,3-triazole-4-yl)methylmorpholine,

4-(4-aminomethyl)-1,2,3-triazole-4-yl)methyl-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3-(S)-(4-forfinal)morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4- (5-pyrrolidinyl)-1,2,3-triazole-4-yl)methylmorpholine,

4-(5-(azetidine)-1,2,3-triazole-4-yl)methyl-3-(S)-(4-forfinal)-2- (R)-(1-(R)-(4-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-morpholine,

3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)-phenyl) ethoxy)-4-(5-(pyrrolidinyl)-1,2,3-triazole-4-yl)methylmorpholine,

3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)- phenyl)ethoxy)-4-(5-(morpholinomethyl) is iformity)phenyl)ethoxy)morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4- (5-(N'-methylpiperazine)-1,2,3-triazole-4-yl)-methylmorpholin,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- (1-(2-pyrrolidinyl)-1,2,3-triazole-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4- (2-(2-pyrrolidinyl)-1,2,3-triazole-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S) (4-forfinal)-4-(5-(morpholinomethyl)-1,2,3-triazole-4-yl)methylmorpholine,

4-(5-azetidinol)-1,2,3-triazole-4-yl)-methyl - 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-4-forfinal) morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S) (4-forfinal)-4-(5-(prolinamide)-1,2,3-triazole-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5- (bis(methoxyethyl)aminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)- 4-forfinal)morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2 - chloro-5-morpholinomethyl-1,3-imidazol-4-yl)methyl-3-(S)-(4-forfinal)- morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5 - N,N-dimethylaminomethyl)-1,3-imidazol-4-yl)methyl-3-(S)-(4-forfinal)- morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5 - N,N-dimethylaminomethyl)-1,2,4-triazole-3-yl)methyl-3-(S)-(4-forfinal)- morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)autoformer)phenyl)ethoxy)-4-(5- (2-methoxyethyl)aminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)-phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5- (N-(2-methoxyethyl)-N-methyl)aminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)- phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5- (N-isopropyl-N-(2-methoxyethyl)aminomethyl)-1,2,3-triazole-4-yl)methyl-3- (S)-phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5- (N-cyclopropyl-N-(2-Metacity)aminomethyl)-1,2,3-triazole-4-yl)-methyl-3- (S)-phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5 - N, N-dibutylaminoethanol-1,2,3-triazole-4-yl)methyl-3-(S)-phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5 - N, N-diisopropylaminomethyl-1,2,3-triazole-4-yl)methyl-3-(S)-phenylmorpholine,

and their pharmaceutically acceptable salts or prodrugs.

Other preferred compounds included in the scope of the present invention are the following compounds:

2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-forfinal)-4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)- methylmorpholin,

2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-4-(forfinal)-4-(1,2,4-triazole-3-yl)methylmorpholine,

4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-3-(S)-(4-forfinal)- 2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)- morpholine,

4-(2,3-dihydro-2-oxo-1,3-imidazol-4-yl) shall irreligiosity-1,3-imidazol-4-yl)methyl - 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-forfinal)morpholine,

4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)-3-(S)-phenyl - 2-(R)-(1-(S)-(3-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine,

4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)- 2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)- phenylmorpholine,

2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy-4- (2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)-3-(S)-phenylmethyl-morpholine,

3-(S)-phenyl-4-(1,2,4-triazole-3-yl)- 2-(R)-(1-(S)-(3-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine,

and their pharmaceutically acceptable salts or prodrugs.

Other preferred compounds included in the scope of the present invention are described in the examples.

In accordance with another aspect of the present invention, will be offered to obtain the compounds of formula (1) in the form of pharmaceutically acceptable salts, in particular in the form of salts accession acids.

Salts of compounds of formula (1) for use in medicine will be a non-toxic pharmaceutically acceptable salt. However, other salts may be suitable for obtaining the compounds of the present invention or their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention VK is I of the present invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, fumaric acid, p-toluensulfonate acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid. Salts of amino groups can also include Quaternary ammonium salts in which the nitrogen atom of the amino group carries a suitable organic group such as alkyl, Alchemilla, Alchemilla or kalkilya group. In addition, the compounds of the present invention are acid group, suitable pharmaceutically acceptable salts which may include metal salts, such as alkali metal salts, e.g. sodium or potassium salts; and salts of alkaline earth metals, e.g. calcium or magnesium salts.

The present invention includes scope prodrugs of the compounds of formula (1) above. In General, such prodrugs will be functional derivatives of the compounds of formula (1), which are easily transformed into the desired compounds of formula (1) in vivo. The usual procedure for selecting and receiving proletarienne derivatives are described, for example, in "design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The prodrug may present with the substance," or "parent molecules"), which requires a transformation in the body, in order to highlight the active drug, and that has improved delivery properties relative to the parent molecule drug substances. Transformation in viv may be, for example, the result of some metabolic process, such as chemical or enzymatic hydrolysis of the ether carboxylic, phosphoric or sulfuric acid, or the recovery or oxidation amenable to this process functional group.

For example, some offer prodrugs may not be antagonists tachykinin, in particular, substance P, and not to be active enough (or does not possess activity). However, such compounds are useful in the treatment of various described here States, especially when the preferred formulation, which can be entered by injection.

The advantages of prodrugs may be in its physical properties, such as increased water solubility compared to the parent drug, which can be useful for parenteral, or it can increase the absorption from the gastrointestinal tract, or may increase the stability of the drug prepa medicinal substance, for example, by reducing toxicity and side effects of drugs by regulating their absorption, blood, metabolism, distribution and assimilation of the cell.

Especially preferred class of prodrugs of the compounds of the present invention are those prodrugs in which a hydroxyl group in the group Y in the formula (1) (when Y represents a C1-4-alkyl substituted by hydroxyl), modified.

Be aware that another class of prodrugs of the compounds of the present invention are compounds in which the converted heterocyclic group represented by R6in the formula (1), or, on the other hand, when converted as a hydroxyl group in the group Y (when Y represents a C1-4-alkyl substituted by hydroxyl), and the heterocyclic group denoted by R6in the formula (1).

Suitable proletarienne derivatives include groups

(a) -(CHR10)n-PO(OH)O-M+,

(b) -(CHR10)n-PO(O-)22M+,

(c) -(CHR10)n-PO(O-)2D2+,

(d) -(CHR10)n-SO3-) M+,

(e) -COCH2CH3CO2- M+
M+is a pharmaceutically acceptable monovalent counter-ion,

D2+is a pharmaceutically acceptable divalent counter ion,

R10represents hydrogen or C1-3-alkyl, and

R11represents a group chosen among O(CH2)2NH3-M-, -O(CH2)2NH2(R12)+M-, -OCH2CO2- M+, -OCH(CO2- M+) CH2CO2- M+, -OCH2CH(NH3-)CO2-, -OC(CO2- M+) (CH2CO2- M+)2and

< / BR>
where M-is a pharmaceutically acceptable monovalent counter-ion, and R12represents hydrogen, C1-4-alkyl or C1-4-alkyl substituted by hydroxyl or C1-4-alkoxygroup.

Especially preferred proletarienne derivatives are derivatives containing groups

(a) -(CHR10)n-PO(OH)O-M+,

(b) -(CHR10)n-PO(O-)22M+,

(c) -(CHR10)n-PO(O-)2D2+,

in particular, when n is equal to zero.

The terms "parent molecule", "parent connection" or "creation is ntatives actions metabolic or catabolic process, or during the chemical process, following the introduction of the prodrug. Parent connection may also be the starting substance to obtain their respective prodrugs.

Although all the usual routes of administration suitable for the aforementioned prodrugs, preferred routes of administration are oral way and intravenously. After absorption in the gastrointestinal tract or intravenous prodrug hydrolyzed, or broken down in vivo to the corresponding parent compounds of formula (1) or their pharmaceutically acceptable salts. Because the parent compounds may have a solubility less than optimal, the aforementioned prodrugs have an advantage due to its relatively high solubility in water.

Examples of negative monovalent counter-ions, defined here as "M-include acetate, adipate, benzoate, bansilalpet, bisulfate, butyrate, comfort, camphorsulfonate, citrate, aconsultant, fumarate, hemisulfate, 2-acetylacetonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, ASS="ptx2">

Basic salts (which contain pharmaceutically acceptable monovalent cations, denoted here as M+", or pharmaceutically acceptable divalent cations, denoted here as "D2+"if appropriate) include ammonium salts, alkali metal salts, such as sodium, lithium and potassium, salts of alkaline earth metals, such as aluminium, calcium and magnesium, salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, etc., If M+represents a monovalent cation, it is believed that if it is determined that there are 2M+each of M+may be the same or different. In addition, it is also considered that if there are 2M+instead, they may be divalent cation D2+. Also, the basic nitrogen-containing groups can be quaternity such agents as lower haloalkyl, such as methyl, ethyl, propyl and butylchloride, -bromides and iodides; diallylsulfide similar to the dimethyl-, diethyl - and dibutylated; long chain halides such as decyl-, lauryl-, mesityl and stearyl-chlorides, bromides and iodides; aralkylated like benzylbromide, and other Agay is suitable camping, for example, when selecting or clearing the product.

Salts can be formed by conventional means, such as the interaction of the product in free base form with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in a vacuum or freeze-drying or by exchanging the anions present in salts, other suitable anions of ion exchange resins.

Especially preferred sub-group of prodrugs of the compounds of the present invention are prodrugs that is defined by the formula (1e), and their pharmaceutically acceptable salts.

< / BR>
where R1, R2, R3, R4, R5, R6, R9a, R9band X have the meanings specified in the definition of formula (1), and P in the circle represents PO(OH) (O-M+'PO(O-)22M+or PO(O-)2D2+.

Another preferred sub-group of prodrugs of the compounds of the present invention are prodrugs that is defined by the formula (1f), and their pharmaceutically acceptable salts.

< / BR>
where A1, A2and A3matter, to ascertain the PO(OH)O2M+, PO(O-)22M+or PO(O-)2D2+.

Especially preferred sub-group of prodrugs of the compounds of the present invention are prodrugs that are defined by formula (1g), and their pharmaceutically acceptable salts.

< / BR>
where A1, A2and A3have the meanings specified for formula (1a), Q1has the values set for the formula (1c), and P in the circle represents PO(OH)O-M+, PO(O-)22M+or PO(O-)2D2+.

Another preferred sub-group of prodrugs of the compounds of the present invention are prodrugs that are defined by formula (1h), and their pharmaceutically acceptable salts.

< / BR>
where A1, A2and A3have the meanings specified for formula (1a), Q1and Q2have the meanings specified for formula (1c) and (1d), respectively, and P in the circle represents PO(OH)OM+, PO(O-)22M+or PO(O-)2D2+. Specific proletarienne derivatives included in the scope of the present invention, are

2-(R)-1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphorylations)-3-(S) -(4-forfinal)-4-(2,3-dihydro-3-oxo-1,2,4-triazole--3-yl)methylmorpholine,

4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-2-(R)-(1-(S)-3-fluoro-5 -(trifluoromethyl)phenyl)-2-phosphorylations)-3-(S)-phenylmorpholine,

2-(R)-1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphorylations)-4- (2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-3-(S)-phenylmorpholine,

and their pharmaceutically acceptable salts.

With regard to compounds of formula (1f) and (1g) and (1h), they A1preferably represents fluorine or CF3, A2preferably represents CF3and A3preferably represents fluorine.

The present invention includes in its scope a solvate of the compounds of formula (1) and their salts, for example, hydrates.

Compounds corresponding to the present invention, have at least three asymmetric centre, and may accordingly exist both as enantiomers and as diastereoisomers. You must understand that all such isomers and mixtures thereof are within the scope of the present invention.

Preferred compounds of formula (1), (1a), (1b), (1c), (1d), (1e, (1f) and (1h) will have the CIS-configuration of the substituents is 2 or 3, and the preferred stereochemistry at position 2 is stereochemistry, which has a connection example 1 (i.e. 2-(R)-), and predpochtitaemye carbon atoms, attached to the group Y is either (R), when Y represents a C1-4-alkyl (e.g. methyl), or (S), when Y represents a C1-4-alkyl, substituted hydroxyl group (for example, CH2OH). It looks, for example, as shown in the formula (1i).

< / BR>
The present invention also relates to pharmaceutical compositions containing one or more compounds of formula (1) in combination with a pharmaceutically acceptable carrier.

Preferably, the compositions of the present invention is a unit dosage form as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or for administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, for example, with the usual ingredients for the preparation of tablets, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form twerkin pharmaceutically acceptable salt. When such prepreparation compositions are referred to as homogeneous, this means that the active ingredient is uniformly dispersed in the composition so that the composition can easily be divided into equally effective unit dosage forms such as tablets, pills or capsules. Such solid prepreparation composition is then divided into unit dosage forms of the type described above containing from 0.1 to 500 mg of the active ingredient of the present invention. The tablets or pills of the new composition can then be coated, or they can be made in any other way, in order to obtain a dosage form, which has the advantage of prolonged action. For example, tablets or pills may contain an internal and external component of the dosage form, the latter is a form of shell for the first. Both components can be separated intersolubility layer which serves to resist destruction in the stomach, and allow the inner component to pass intact into the duodenum or to be delayed in the allocation. A number of materials can be used for such intersolubility layers or coatings, and t is the lacquer, cetyl alcohol and cellulose acetate.

Liquid forms, which include the compositions of the present invention for introducing them orally or by injection include aqueous solutions, syrups, with a corresponding auxiliary medicine, aqueous or oil suspensions, and emulsions with auxiliary medicine with edible oils such as cottonseed oil, sesamee oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable for the aqueous suspensions or dispersing suspendresume agents include synthetic and natural resins, such as tragakant, Arabian gum, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Preferred compositions for administration by injection include compositions containing a compound of formula (1) as an active ingredient in combination with a surface-active agent (or smeshivateley or surface-active additive), or in the form of an emulsion (such as emulsion water in oil or oil in water").

Suitable surfactants include anionic materials, such as bis(2-ethylhexyl)sulfoxy the ID cetyltrimethylammonium (centrimide), and especially non-ionic substances, such as polyoxyethylenesorbitan (for example, twinTM20, 40, 60, 80 or 85) and other sorbitan (for example, spanTM20, 40, 60, 80 or 85). Composition with a surface-active agent will typically contain from 0.05 to 5% surfactant, preferably from 0.1% to 2.5%. You should take into account that, if necessary, may be added other ingredients such as mannitol, or other pharmaceutically acceptable carriers.

Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LyposynTM, InfonutrolTM, LipofundinTMand LipiphysanTM. The active ingredient may be either dissolved in a pre-mixed emulsion composition, or, on the other hand, it can be dissolved in oil (e.g. soybean oil, sunflower oil, cottonseed oil, sesamum oil, corn oil or almond oil), and the emulsion is formed when mixed with phospholipids (for example, phospholipids eggs, soybean phospholipid or soybean lecithin) and water. You should take into consideration that may be added other ingredients, for example, glycerol or glucose, to install and the second emulsion will contain, preferably, the oil droplets ranging in size from 0.1 to 1.0 μm, especially from 0.1 to 0.5 μm, and have a pH in the range from 5.5 to 8.0.

Particularly preferred emulsion compositions are compositions obtained by mixing the compounds of formula (1) with IntralipidTMor its components (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or their mixtures, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable additives mentioned above. Preferably, the composition is administered by respiratory through the mouth or nose for local or systemic action. Composition in a sterile, preferably, pharmaceutically acceptable solvents can be sprayed using an inert gas. Sprayable solutions can be inhaled directly from the spraying device or spray device can be attached to the face mask, tent or respiratory device with periodic positive pressure. Compositions in the form of solutions, suspensions or powders may be introduced, preferably through the mouth is s also relates to a method for producing a pharmaceutical composition, containing the compound of formula (1), and the above-mentioned method comprises a combination of compounds of formula (1) with a pharmaceutically acceptable carrier or additive.

The compounds of formula (1) are valuable in the treatment of a wide range of clinical conditions which are characterized by excessive activity of tachykinin, in particular substance P. These conditions may include disorders of the Central nervous system such as anxiety, depression, psychosis and schizophrenia; epilepsy; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease and down's syndrome; demyelinating diseases such as multiple sclerosis (MS) and lateral amiotroficheskii sclerosis (ALS), and other neurotic diseases disorders such as peripheral neuropathy, for example, diabetic and caused chemotherapy neuropathy and post herpetic and other neuralgias; small cell lung cancer such as small cell lung cancer; respiratory diseases, particularly diseases associated with excessive mucous secretions, such as chronic airway obstruction, pneumonia, chronic bronchitis, mukoviszidose and asthma, and bronchospasm; ospitalieri, prurigo and solar erythema; allergies such as eczema and rhinitis; allergic disorders, such as caused by poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, etc.; eye diseases associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematous dermatitis, diseases due to harmful habits, such as alcoholism; related stress somatic disorders; reflex sympathetic dystrophy such as shoulder syndrome; estimatesa disorders; adverse immunological reactions, such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal disorders and diseases of the gastrointestinal tract, such as diseases associated with neural regulation of internal organs, ulcerative colitis, Crohn's disease, symptoms of irritation of the colon and emesis, including acute, late or ahead of vomiting, such as caused by chemotherapy, radiation, toxins, viral or bacterial infections, buramago pressure, in particular, for example, caused by drugs or irradiation vomiting, or post-operative nausea and vomiting; disorders of the bladder such as cystitis, hyperreflexia of the bladder muscles and incontinence; fibrous and collagen diseases such as scleroderma and eosinophilic fasciitis; disorders of blood flow caused vasodilatation and vasospastic diseases such as angina, migraine and Raynaud's disease; and pain or nociception, for example, inherent in or associated with any of the foregoing conditions especially the transmission of pain in migraine.

The compounds of formula (1) also have value in the treatment combinations of the above-mentioned conditions, in particular, in the treatment combination in postoperative pain and postoperative nausea and vomiting.

The compounds of formula (1) is particularly suitable for the treatment of emesis, including acute, delayed and quicker emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, disorders of movement, during operations, migraine, and variations in intracranial pressure. The compounds of formula (1) to the greatest extent applicable in the treatment of vomiting caused by antineoplastic (cytotoxic) is Biotherapeutics funds include alkylating agents, for example, nitrogen mustards, connection etilenimina, alkyl sulphonates and other compounds with an alkylating action, such as nitrocefin, cisplatin and dacarbazine; antimetabolites, such as folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinylchloride and derivatives podofillotoksina; and cytotoxic antibiotics.

Specific examples of chemotherapeutic agents are described, for example, D. J. Stewart, Nausea and Vomiting: Recent Recearch and Clinical Advnces, Eds. J. Kucharczyk et al, CRC Press.Inc., Boca Raton. Florida, USA (1991), pages 177-203, in particular, on S. 188. Commonly used chemotherapeutics are cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustin (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil (P. J. Gralla et al, Cancer Treatment Reports(1984) 68 (1), 163-172).

The compounds of formula (1) are also useful in the treatment of vomiting caused by radiation, including radiation therapy, such as cancer or radiation sickness; and in the treatment of postoperative nausea and vomiting.

Should presovannogo preparation for simultaneous, separate or sequential use for soothing vomiting. Such combination therapies may exist, for example, in the form of double packaging.

Another aspect of the present invention includes compounds of formula (1) in combination with 5-HT3-antagonist, such as ondansetron, granisetron or tropisetron, or with other antiemetic drugs, for example, a dopamine antagonist such as metoclopramide. In addition, the compound of formula (1) may be administered in combination with anti-inflammatory corticosteroid, such as dexamethasone. In addition, the compound of formula (1) may be administered in combination with a chemotherapeutic agent such as an alkylating agent, an antimetabolite, a mitotic inhibitor or cytotoxic antibiotic, as described above. In General, for use in such combinations will be appropriate currently available dosage forms known therapeutic drugs.

When testing for korikovoy model caused by cisplatin vomiting, described by F. D. Tattersall et al, Eur. J. Pharmacol., (1993) 250, R5-R6, it is found that the compound of the present invention mitigate the urge to vomit and vomiting caused by cisplatinum.

The connection form of the measures, with neuropathy, such as diabetic and caused chemotherapy neuropathy, post herpetic and other neuralgia, asthma, osteoarthritis, rheumatoid arthritis, and especially migraine.

The present invention also relates to the compound of formula (1) for use in therapy.

In accordance with another aspect, the present invention relates to the compound of formula (1) for use in the manufacture of medicinal products for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.

The present invention also relates to a method of treatment or prevention of physiological disorders associated with an excess of Tashkinov, especially substance P, and the above-mentioned method comprises administration to a patient in need of such treatment, reducing tachykinin amount of the compounds of formula (1) or a composition containing the compound of formula (1).

In the treatment of some conditions it may be desirable to use the compound of the present invention in combination with another pharmacologically active agent. For example, in the treatment of respiratory diseases such as asthma, a compound of formula (1) can be used in acetyicholine, which affects NK-2 receptors. The compound of formula (1) and bronchodilatory can be administered to a patient simultaneously, sequentially or in combination.

The present invention relates, accordingly, to a method of treatment of respiratory diseases such as asthma, and the above-mentioned method comprises administration to a patient in need of such treatment, an effective amount of the compounds of formula (1) and an effective amount of a bronchodilator.

The present invention also relates to compositions containing a compound of formula (1), bronchodilatory and a pharmaceutically acceptable carrier.

Excellent pharmacological profile of the compounds of the present invention provides an opportunity for their use in treatment in low doses, thereby reducing the risk of unwanted side effects.

In the treatment of conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg / day, in particular from 0.01 to 25 mg/kg, such as from 0.05 to 10 mg/kg per day.

For example, in the treatment of conditions, including neurotransmission of pain sensations, a suitable dose level SOS Compositions can be entered in mode 1-4 times a day, preferably once or twice per day.

In the treatment of vomiting with the use of formulations suitable for injection dose level is from about 0.001 to 10 mg/kg per day, preferably 0.005 to 5 mg/kg per day, and especially preferably from 0.01 to 2 mg/kg per day. Connections can be entered in mode 1-4 times per day, preferably once or twice per day.

You should take into account that the amount of the compounds of formula (I) required for use in any treatment will vary not only with changes in the selected connection-specific or selected song, but also depending on the method of administration, the nature of the condition being treated and the age and condition of the patient and will be determined, ultimately, by the treating physician.

In accordance with the General method (A), compounds of the present invention can be obtained from compounds of formula (II)

< / BR>
where R1, R2, R3, R4, R5and Y have the meanings indicated for formula (I), by reacting with the compound of the formula (III)

X1-X-R6a< / BR>
where X has the meanings indicated for formula (I); R6arepresents a group of formula R6athat determination to the PPU, such as bromine or chlorine, and, if R6arepresents a group-predecessor, making it the group R6(in the process, in which any reactive group may be protected, and then, if desired, the protective group can be removed).

This interaction can be carried out in the usual way, for example, in an organic solvent, such as dimethylformamide, in the presence of an acid acceptor such as potassium carbonate.

In accordance with another method (B), compounds of formula (I), where R6represents a 1,2,3-triazole-4-yl, substituted CH2NR7R8and X represents-CH2- can be obtained by the reaction of compounds of formula (IV)

< / BR>
with azide, e.g. sodium azide, in a suitable solvent, such as dimethylsulfoxide, at a temperature of from 40oC to 100oC, followed by reduction of the carbonyl group adjacent to the-R7R8when using a suitable reducing agent, such as alumalite lithium, at a temperature of from -10oC to room temperature, typically at room temperature.

On the other hand, in accordance with the method (c), compounds of formula (I), where R6shackles can be obtained by reacting the compounds of formula (V)

< / BR>
with an amine of the formula with other7R8in a suitable solvent, such as a simple ether, for example, dioxin, at elevated temperature, for example, from 50oC to 100oC in a sealed tube or similar. This reaction is based on the interaction described in Chemische Berichte (1989) 122, p. 1963.

In accordance with another method (D), compounds of formula (I), where R6represents a substituted or unsubstituted 1,3,5-triazine, can be obtained by reacting the intermediate compounds of formula (VI)

< / BR>
with a substituted or unsubstituted 1,3,5-triazine.

The reaction can conveniently be in a suitable organic solvent, such as acetonitrile, at an elevated temperature, such as 80-90oC, preferably at 82oC.

In accordance with another method (E), compounds of formula (I), where R6represents a substituted or unsubstituted 1,2,4-triazine can be obtained by reacting the intermediate compounds of formula (VII) with a dicarbonyl compound of the formula (VIII)

< / BR>
where R35represents H or a suitable substitute, such as ZNR7R8.

The reaction can conveniently be in the right organic CLASS="ptx2">

In accordance with another method (F), compounds of formula (I), where R6represents a substituted 1,2,4-triazole group, can be obtained by reacting the intermediate compounds of formula (I) with the compound of the formula (IX)

< / BR>
where X has the values set for the formula (I), Hal represents a halogen atom, e.g. bromine, chlorine or iodine, and R18represents H, CONH2or OCH3(which turns into oxazolidine under the reaction conditions),

in the presence of a base, followed, if required, converting the compounds of formula (I), for example, by restoring the CONH group2until CH2NH2.

Suitable bases for use in this reaction include carbonates of alkali metals, such as, for example, potassium carbonate. The reaction can conveniently be in an anhydrous organic solvent, such as, for example, anhydrous dimethylformamide, preferably at elevated temperature, such as 140oC.

A suitable reducing agent for a group CONH2is alumoweld lithium, which is used at temperatures from - 10oC to room temperature.

In accordance with another method (G compounds of the formula (X)

< / BR>
by interacting with the compound of the formula HNCS in the presence of a base.

Suitable bases for use in this reaction are organic bases, such as, for example, 1,8-diazabicyclo[5.4.1]undec-7-ene (DBU). The reaction can conveniently be in a suitable organic solvent, such as alcohol, for example butanol.

Other details of the relevant procedures can be found in the accompanying examples.

The compounds of formula (I) can also be obtained from other compounds of formula (I), using the appropriate methods of interconversion. For example, the compounds of formula (I) in which X represents a C1-4-alkyl, can be obtained from compounds of formula (I) in which X represents a C1-4-alkyl, substituted oxopropoxy through recovery, for example, when using borane or lithium aluminum hydride. Suitable interconversion procedures will be obvious to a person skilled in this technical field.

Intermediate compounds of formula (IV) can be obtained from intermediates of formula (II) by interacting with acetimophen compound of the formula HC= C-CH2-Hal in the presence of a base such as potassium carbonate, in a suitable races is ashegoda in the acetylene intermediate connection amidol formula Hal-CO-NR7R8in the presence of suitable catalysts, including bis(triphenylphosphine)palladium(II)chloride, copper iodide (I) and triphenylphosphine, in a suitable solvent, such as triethylamine, preferably at the boiling under reflux.

Intermediate compounds of formula (V) can be obtained from compounds of formula (XI)

< / BR>
where Hal represents a halogen atom, e.g. chlorine, bromine or iodine, especially chlorine, by interacting with azide, e.g. sodium azide, in a suitable solvent such as dimethylsulfoxide at room temperature or at a temperature lower than room temperature,

The compounds of formula (XI) can be obtained by adding dropwise the intermediate compounds of formula (II) to dehalogenation formula Hal-CH2-C C-CH2-Hal, where each Hal is independently chlorine, bromine or iodine, especially chlorine. The reaction can conveniently be in a suitable solvent, such as dimethylformamide, in the presence of a base such as potassium carbonate.

Intermediate compounds of formula (VI) can be obtained from intermediates of formula (II) by reaction with a compound of formula Hal-X-C(NH)NH2where Hal and X have the previously established is of the formula (II) by reacting with the compound of the formula Hal-X-C(NH)NHNH-Boc, where Hal and X have the previously set value, and Boc represents tert-butoxy-carbonyl, followed by removal of the group in the acidic conditions of the environment.

The compounds of formula (VIII) are commercially available or can be obtained by known methods from commercially available compounds.

The compounds of formula (IX) can be obtained as described in J. Med. Chem. (1984), 27, 849.

Intermediate compounds of formula (X) can be obtained from the corresponding complex ester by treatment with hydrazine. The reaction can conveniently be in a suitable organic solvent such as an alcohol, e.g. ethanol, at elevated temperature.

In the case of compounds where R6represents a heterocycle substituted by a group ZNR7R8where represents CH2some preferred compounds of formula (I) can be obtained from corresponding compounds with a hydrogen atom in place of a group ZNR7R8. For example, the compound of formula (I), where R6represents imidazolinone group, carrier group CH2NR7R8can be obtained from the corresponding compounds not containing the group CH2NR7R8by interaction of the heat. Optionally, you can use the pre-formed reagent, such as R7R8N+= CH21-and the tertiary amine such as triethylamine as acid acceptor.

On the other hand, the compound of formula (I), where R6represents imidazolinone group, devoid of CH2NR7R8may be entered into interaction with paraformaldehyde and an amine, for example, with a secondary amine, such as pyrrolidin that gives compound in which imidazolinone ring substituted by the group CH2NR7R8where R7, R8and the nitrogen atom to which they are attached, form heteroaromatics ring of 4-7 atoms, which may contain, optionally, the ring oxygen atom or a second nitrogen atom which will be part of a group NH or NRcwhere Rchas the values set previously.

This reaction can be performed in the usual way, for example, in a suitable solvent such as an alcohol, e.g. methanol, at elevated temperatures up to the boiling point of the solvent.

Another alternative way of getting some compounds of formula (I) includes the interaction promezhutochnoe LG, which may be the same or different, represent useplease groups, such as alkyl - or arylsulfonate (for example, mesilate or tosylate), or, in particular, a halogen atom (for example, an atom of bromine, chlorine or iodine), and X and Z have the values set for the formula (I), followed by the interaction of the resulting compound with an amine other7R8to complete the formation of the group ZR7R8.

This reaction can conveniently be in an organic solvent, such as dimethylformamide, in the presence of an acid acceptor such as potassium carbonate.

You should take into account that, if necessary, reactive groups can be protected, for example, the NH-group of imidazolinone formula (XIIa) can be secured any suitable protective for the amino group, such as acetyl group.

Preferred phosphate prodrugs of the compounds of the present invention can be obtained stepwise manner from the compounds of formula (I) in which Y represents, for example, -CH2OH.

So, oxycoedone first treated with dibenzylethylenediamine in a suitable solvent, such as tetrahydrofurane (Y=CH2OP-(OCH2Ph)2) is then oxidised using, for example, 4-methylmorpholin-N-oxide, and get the phosphate protective dibenzyline group. Cleavage of the protective group by catalytic hydrogenation or transfer hydrogenation with (the catalyst is palladium-on-coal and ammonium formate) in a suitable solvent, such as methanol, boiling under reflux gives the desired phosphate prodrug which can be converted into any desired salt in the usual way.

In another two-step method oxycoedone formula (I) can be entered into cooperation with a suitable base such as sodium hydride in tetrahydrofuran, and added tetraethylpyrophosphate that leads to the formation of protected dibenzyl phosphate, from which you can split a protective group, as described above.

The compounds of formula (II) can be obtained as shown in the diagram, which Ar1is an R1, R2, R3substituted phenyl group, Ar2is an R4, R5substituted phenyl group, and Ph means phenyl.

L-Selectride represents a three-second-butylbromide.

In the following links op is that given in the present description.

(i) D. A. Evans et al., J. Am. Chem. Soc., (1990), 112, 4011

(ii) I. Yanagisawa et al., J. Med. Chem., (1984) 27, 849

(iii) R. Duschinsky et al., J. Am. Chem. Soc., (1948), 70, 657

(iv) F. N. Tebbe et al., J. Am. Chem. Soc., (1978) 100, 3611

(v) N. A. Petasis et al., J. Am. Chem. Soc., (1990) 112, 6532

(vi) K. Takai et al., J. Org. Chem., (1987) 52, 4412.

These examples reveal, mainly getting the preferred isomers. Isomers that are not preferred, is also obtained as a minor component. If desirable, they can be distinguished by conventional means, for example, by chromatography using the corresponding column, and used for various stereoisomers. However, the expert should take into account that although the examples optimized to obtain the preferred isomers, change of solvent, reagents, chromatography method, etc., can be used to obtain at the output of the other isomers.

You should take into account that compounds of the formula (I) In which R6contains Deputy =O or =S, can exist in tautomeric forms. All such tautomeric forms and mixtures thereof are included within the present invention. The most appropriate Deputy from among =O or =S, R6is Deputy =O.

When visable, described in the accompanying examples, or by other means that will be apparent to a person skilled in this technical field.

When performing any of the aforementioned, the sequence of reactions for the synthesis may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules related to this process. This can be achieved using a conventional protective groups such as those described in Protective Groups in Organic Chemistry, ed, J. E. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protective groups can be removed at an appropriate stage of the sequence using methods known in the art.

Given as examples of the compounds of the present invention have methods set out on pages 36-39 description international patent WIPO 93/01165. Found that the compounds or, in the case of prodrugs, the parent compounds are active with the value of the IC50when NK1-the receptor of less than 10 nm when tested according to these methods.

Example description 1

(S) -4-(forfinal)glycine

By chiral synthesis

Stage A. 3-(4-forfinal)acetyl-4-(S)-benzyl-2-oxazolidinone

Dried in p is up nitrogen and download it solution 5,09 g (33.0 mmol) of 4-florfenicol acid in 100 ml of anhydrous ether. The solution is cooled to -10oC and process the ceiling of 5.60 ml (40.0 mmol) of triethylamine, and then 4,30 ml (35,0 mmol) trimethylacetylchloride. Immediately a white precipitate is formed. The resulting mixture was stirred at -10oC for 40 minutes and then cooled to -78oC.

Kiln dried 250-ml round bottom flask, equipped with a diaphragm and a magnetic stirrer, rinsed with nitrogen and download it solution 5,31 g (30.0 mmol) of 4-(S)-benzyl-2-oxazolidinone in 40 ml of dry THF. The solution is stirred for 10 minutes in a bath of dry ice with acetone, and then gradually add 18.8 ml of 1.6 M solution of n-utility in hexane. 10 minutes to the above mixture in 3-throat flask through the tube add a solution litoraneo oxazolidinone. The cooling bath is removed from the resulting mixture and allow the temperature to rise to 0oC. the Reaction is quenched with 100 ml saturated aqueous solution of ammonium chloride, transfer mixture to a 1-liter flask, and the ether and THF removed in vacuo. The concentrated mixture is partitioned between 300 ml of methylene chloride and 50 ml of water and the layers separated. The organic layer was washed with 100 ml of 2n. aqueous hydrochloric acid, 300 ml of a saturated aqueous solution of bicarbonate into three the m as eluent a mixture of hexane and ether (3:2 by volume) gives of 8.95 g of oil, which slowly solidifies upon standing. Recrystallization from a mixture of hexane and ether (10:1) gives 7,89 g (83%) indicated in the title compounds as white solids. So pl. 64-66oC. M.-C. (FAB): m/z 314 (M++ H, 100%), 177 (M-ArCH2CO+H, 85%).3H NMR (400 MHz, CDCl3was 2.76 (1H, D. D., J = 13,2, 9,2), 3,26 (DD., J= 13,2, 3,2), 4,16 - 4,34 (4H, m) and 4.65 (1H, m), 7,02 - 7,33 (9H, m). Elem. analysis:

calculated for C18H16FNO3: C 69,00, H 4,15, N 4,47, F 6,06,

found: C 68,86, H 5,14, N 4,48, F between 6.08.

Stage B. 3-((S)-Azido-(4-forfinal))acetyl-4-(S)-benzyl-2-oxazolidinone

Kiln dried 1-liter 3-necked flask equipped with a membrane, the input for nitrogen, a thermometer and a magnetic stirrer, rinsed with nitrogen and download it solution 58,0 Il 1M solution of bis(trimethylsilyl)amide potassium in toluene and 85 ml of THF and cooled to -78oC. kiln Dried 250-ml round bottom flask, equipped with a diaphragm and a magnetic stirrer, rinsed with nitrogen and boot into it a solution of 7.20 g (23,0 mmol) 3-(4-forfinal)acetyl-4-(S)-benzyl-2-oxazolidinone (from step A) in 40 ml THF. The solution allocatively stirred in a bath with a mixture of dry ice with acetone for 10 minutes, then transferred, through a tube, into a solution of bis(trimethylsilyl)amide potassium with such speed, that temperamental liquid type, through a tube, to the reaction mixture, and the resulting mixture was stirred at -78oC for 30 minutes. Kiln dried 250-ml round bottom flask, equipped with a diaphragm and a magnetic rods for stirring, rinsed with nitrogen and download it solution 10,89 g (35,0 mmol) of 2,4,6-triisopropylphenylsulfonyl in 40 ml of THF. The azide solution is stirred in a bath with a mixture of dry ice with acetone for 10 minutes, then transferred through the tube into the reaction mixture with such speed, that the inside temperature of the mixture remained below -70oC. After 2 minutes the reaction is quenched with 6.0 ml of glacial acetic acid, the cooling bath removed and the mixture is stirred at room temperature for 18 hours. Quenched the reaction mixture was partitioned between 300 ml of ethyl acetate and 300 ml of 50% aqueous saturated solution of sodium bicarbonate. The organic layer is separated, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 500 g of silica gel using as eluent a mixture of hexane with methylene chloride, first, 2: 1, by volume, then 1:1, by volume, gives the 5.45 g (67%) indicated in the title compound in the form of oil. IR-spectrum (pure, cm-1): 2104, 1781, 1702.3H NMR (400 MHz, CDCl3) of 2.86 (1H, D. D., J = 13,3 B>FN4O3: C 61,01, H 4,27, N 15,81, F ARE 5.36,

found: C 60,99, H 4,19, N 15,80, F 5,34.

Stage C. (S)-Azido-(4-forfinal)acetic acid

A solution of 5.40 g (15,2 mmol) 3-((S)-azido-(4-forfinal))-acetyl-4-(S)-benzyl-2-oxazolidinone (stage B) in 200 ml of a mixture of THF with water (3:1 by volume) stirred in an ice bath for 10 minutes. Add one dose of 1.28 g (30.4 mmol) of the monohydrate of lithium hydroxide and the resulting mixture is stirred under cooling for 30 minutes. The reaction mixture was partitioned between 100 ml of methylene chloride and 100 ml of 25% saturated aqueous sodium bicarbonate solution and the layers separated. The aqueous layer was washed with 2 x 100 ml of methylene chloride and acidified to pH 2 2H. solution of hydrochloric acid. The resulting mixture is extracted with 2 x 100 ml of ethyl acetate; the extracts are combined, washed with 50 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo, to obtain 2.30 g (77%) indicated in the title compound in the form of oils, which are used in the next stage without additional purification. IR-spectrum (net, C-1): 2111, 1724. 1H NMR (400 MHz, CDCl3) of 5.06 (1H, s), 7,08 was 7.45 (4H, m), is 8.75 (1H, sh.S.).

Stage (D). (S)-(4-forfinal)glycine

A mixture of 2.30 g (to 11.8 mmol) of (S)-azido-(4-forfei (3:1 by volume) was stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through celite, and the flask and the filter residue is well rinsed ~ 1 l of a mixture of water with acetic acid (3:1 by volume). Filter, concentrate in vacuo to a volume of about 50 ml Add 300 ml of toluene, and the mixture is concentrated to obtain a solid substance. The solid is suspended in a mixture of methanol and ether (1:1 by volume), filtered and dried, get 1,99 g (100%) named in the connection header.3H NMR (400 MHz, D2O + NaOD) of 3.97 (1H, s), 6,77 (2H, approx.T., J = 8,8), 7,01 (2H, approx.T. J = 5,6).

Through cleavage

Stage A'. (4-forfinal)acetylchloride

A solution of 150 g (0,974 mmol) 4-(forfinal)acetic acid and 1 ml of N,N-dimethylformamide in a 500 ml of toluene at 40oC treated with 20 ml of thionyl chloride and heated to 40oC. Add to 61.2 ml of thionyl chloride dropwise over 1.5 hours. Once added, the solution is heated at 50oC for 1 hour, the solvent is removed under vacuum and the remaining oil is distilled under reduced pressure (1.5 mm RT.cent.), and receive of 150.4 g (89.5 per cent) specified in the connection header, so Kip. 68-70oC.

Stage B'. Methyl 2-bromo-3-(4-forfinal)acetate

A mixture of 150.4 g (0,872 mol) 4-(forfinal)acetylchloride (from step A') and of 174.5 g (of 1.09 mol) of bromine is irradiated with 40-50ooC.

Stage C'. Methyl ()-(4-forfinal)glycine

A solution of 24.7 g (0.1 mol) of methyl 2-bromo-2-(4-forfinal)-acetate (from step B') and 2.28 g (0.01 mol) of the chloride of benzyltriethylammonium in 25 ml of methanol is treated with 6.8 g (0,105 mol) of sodium azide, and the resulting mixture is stirred for 20 hours at room temperature. The reaction mixture is filtered, the filtrate is diluted with 50 ml of methanol and hydronaut in the presence of 0.5 g of 10% Pd/C at 345 kPa (50 f/d2within 1 hour. The solution is filtered and the solvent is removed in vacuum. The residue is partitioned between 10% aqueous sodium carbonate solution and ethyl acetate. The organic phase is washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo, get 9,8 g specified in the connection header in the form of butter.

Stage (D'). Methyl-(S)-(4-forfinal)glycinate

The solution 58,4 g of methyl-()-4(forfinal)glycinate (stage C') in 110 ml of ethanol-water (7:1 by volume) mixed with a solution of 28.6 g (0,0799 mol) of O,O'-(+)-dibenzyline acid ((+)-DBT) (28.6 g), (0,799 mmole temperature. After completion of the crystallization add ethyl acetate (220 ml) and the resulting mixture is cooled to -20oC and filtered receive 32,4 g of salt (+)-DBT (S)-(4-forfinal)glycinate. The mother liquor was concentrated in vacuo and allocate basis through distribution between ethyl acetate and aqueous solution of sodium carbonate. The solution thus obtained free base in 110 ml of ethanol-water (7:1 by volume) mixed with a solution of 28.6 g (0,0799 mol) of O,O'-(-)-dibenzoyltartaric acid ((-)-DBT) (28.6 g, 0,0799 mol) in 110 ml of ethanol-water (7:1 by volume) and the resulting solution allowed to stand at room temperature. After completion of the crystallization add ethyl acetate (220 ml) and the resulting mixture is cooled to -20oC and filtered, receive and 47.0 g of salt (-)-DBT methyl-(R)-(4-forfinal)glycinate (ee= 75.8 per cent). Repeat the cycle with uterine fluid and adding (+)-DBT give a second collection of the 7.4 g of salt (+)-DBT (S)-(4-forfinal)glycinate (ee = 96,4%). Both collection (S)-aminoether (39,8 g) are combined in 200 ml of ethanol-water (7:1 by volume), heated for 30 minutes and cooled to room temperature. The addition of ethyl acetate, cooled and filtered to give 31.7 g of salt (+)-DBT (S)-(4-forfinal)glycinate (ee &P>C, 200 nm).

A mixture of 17.5 g of salt (+)-DBT (S)-(4-forfinal)glycinate and 32 ml of 5.5 N. HCl is refluxed for 1.5 hours. The reaction mixture is concentrated under vacuum and the residue is dissolved in 40 ml of water. The aqueous solution was washed with (3 x 30 ml ethyl acetate) and separate the layers. Bring the pH of the aqueous layer to 7 using ammonium hydroxide, and precipitated precipitated solid is filtered off, and get 7,4 g specified in the connection header (ee = 98,8%).

Example-description 2

4-Benzyl-3-(S)-(4-forfinal)-2-morpholino

Stage A. N-Benzyl-(S)-(4-forfinal)glycine

A solution of 1.87 g (11,05 mmol) of (S)-(4-forfinal)glycine (example-describe 1) and 1.12 ml (11.1 mmol) of benzaldehyde 11.1 ml of 1N. aqueous sodium hydroxide solution and 11 ml of methanol at 0oC handle 165 mg (4.4 mmol) of sodium borohydride. The cooling bath is removed and the resulting mixture was stirred at room temperature for 30 minutes. Add to the reaction mixture of the second portion of benzaldehyde (1,12 ml, 11.1 mmol) and sodium borohydride (165 mg, 4.4 mmol) and stirring is continued for another 1.5 hours. The reaction mixture was partitioned between 100 ml of ether and 50 ml of water and the layers separated. The aqueous layer was separated and filtered to remove a little to Edisto, which precipitate, is filtered off, thoroughly washed with water, then ether, and dried, get 1,95 g specified in the connection header.1H NMR (400 MHz, D2O+NaOD) to 3.33 (2H, AB, K., J = 8,4) of 3.85 (1H, c), 6,79 - 7,16 (4H, m).

Stage B. 4-Benzyl-3-(S)-(4-forfinal)-2-morpholino

A mixture of 1.95 g (7.5 mmol) of N-benzyl-(S)-(4-forfinal)glycine, 3,90 ml (to 22.5 mmol) of N,N-diisopropylethylamine, 6,50 ml (75,0 mmol) of 1,2-dibromethane and 40 ml of N, N-dimethylformamide was stirred at 100oC for 20 hours (the dissolution of all solids occurs when heated). The reaction mixture is cooled and concentrated in vacuo. The residue is partitioned between 250 ml of ether and 100 ml of 0.5 n solution of potassium hydrosulfate and the layers separated. The organic layer was washed with 100 ml saturated aqueous sodium bicarbonate solution, h ml of water, dried over magnesium sulfate and concentrate under vacuum. Flash chromatography on 125 g of silica gel with a mixture of hexane and ether (3:1 by volume) as eluent gives 1,58 g (74%) indicated in the title compound in the form of butter.1H NMR (400 MHz, CDCl3) to 2.65 (1H, dt, J = 3,2, 12,8), of 3.00 (1H, dt, J = 12,8, 2,8), and 3.16 (1H, dt, J = 13,6), 3,76 (1H, d, J = 13,6), 4,24 (1H, s), 4,37 (1H, d, J = 13,2, 3,2), of 4.54 (1H, dt, J= 2,8, 13,2), 7,07 - 7,56 (9H, m).

Example-description 3

4-Benzyl-2-(R)-(3,5-bis(triptime is on (example-description 2) in 40 ml of dry THF cooled to -78oC. the Cold solution was treated with 12.5 ml of 1.0 M L-selectridein THF, maintaining the temperature of the mixture below 70oC. the Resulting solution is stirred in the cold for 45 minutes and the reaction mixture was added of 3.60 ml (20.0 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellow mixture is stirred cold for 30 minutes and the reaction quenched with 50 ml saturated aqueous sodium bicarbonate solution. The quenched mixture was partitioned between 300 ml of ether and 50 ml of water and the layers separated. The organic layer is dried over magnesium sulfate. The aqueous layer was extracted with 300 ml of ether, the extract is dried and combined with the original organic layer. The combined organic solution was concentrated in vacuo. Flash chromatography on 150 g of silica gel using a mixture of hexane and ether (37:3 by volume) as eluent gives 4,06 g (8)%) specified in the connection header in the form of a solid substance.1H NMR (200 MHz, CDCl3) of 2.50 (1H, dt, J = 3,4, 12,0), of 2.97 (1H, approx. d, J = 12,0), 2,99 (1H, d, J = 13,6), and 3.72 - with 3.79 (1H, m), 3,82 (1H, d, J = 2,6), 4,00 (1H, d, J = 13,6), 4,20 (dt, J = 2,4, 11,6), to 6.22 (1H, d, J = 2,6), 7,22 - 7,37 (7H, m), EUR 7.57 (2H, approx. d, J = 6,8), 8,07 (1H, c), of 8.47 (2H, c), M.-c. (FAB) m/z 528 (M+H), 25%), 270 (100%). Elem. analysis: calculated for C26H20F7
Stage A. Dimethyltitanocene.

The solution 2,49 g (10.0 mmol) of dichloride of titanocene in 50 ml of ether in the dark at 0oC handle of 17.5 ml of 1.4 M solution metallice in ether, maintaining the temperature within the mixture below 5oC. the Resulting yellow or orange mixture was stirred at room temperature for 30 minutes and the reaction quenched by adding gradually to 25 g of ice. Quenched reaction mixture is diluted with 50 ml of ether and 25 ml of water and separated layers. The organic layer is dried over magnesium sulfate and concentrated in vacuo, get 2,03 g (98%) named in the title compounds as a light-sensitive solids. Dimethyltitanocene can be stored in the form of a solution in toluene at 0oC at least 2 weeks without any noticeable signs of chemical decomposition.1H NMR (200 MHz, CDCl3) to 0.15 (6H, c), the 6.06 (10H, c).

Stage B. 4-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)-phenyl) adenylate)-3-(S)-(4-forfinal)morpholine

A solution of compound of example descriptions 3 (2.50 g, 4.9 mmol) and 2.50 g (12,0 mmol) dimethyltitanocene (from step A) in 35 ml of a mixture of THF to toluene (1:1 by volume) was stirred on an oil bath at 80oC for 16 hours. The reaction mixture is cooled and concentrated in vacuo. Flash h gives 1,71 g (69%) indicated in the title compounds as solids. The sample for analysis is obtained by recrystallization from isopropanol.1H NMR (400 MHz, CDCl3) to 2.42 (1H, dt, J = 3,6, 12,0), 2,90 (1H, approx. D., J = 12,0), only 2.91 (1H, d, J = 13,6), 3,62 - 3,66 (1H, m), and 3.72 (1H, d, J = 2,6), of 3.94 (1H, d, J = 13,6), 4.09 to (1H, dt, J = 2,4, 12,0), and 4.75 (1H, d, J = 3,2), 4,82 (1H, d, J = 3,2), 5,32 (1H, d, J = 2,6), to 7.09 (2H, t, J = 8,8), 7,24 - 7,33 (5H, m), 7,58 to 7.62 (2H, m), 7,80 (1H, c), m c-c. (FAB) 526 (M+H, 75%), 270 (100%). Elem. analysis: calculated for C27H22F7NO2: C 61,72, H 4,22, N TO 2.67, F 25,31. Found: C 61,79, H 4,10, N To 2.65, F 25,27%.

Example-5

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal) morpholine

Connection example-description 4 (4.0 g) dissolved in ethyl acetate (50 ml) and isopropanol (16 ml). To this solution was added palladium-on-coal (1.5 g) and the mixture hydronaut at a pressure of 275 kPa (40 f/d2within 36 hours. The catalyst was removed by filtration through the zeolite and the solvents removed in vacuo. The residue is purified flash chromatography on silica gel using 100% ethyl acetate, and then 1-10% methanol in ethyl acetate. This procedure provides 500 mg of isomer A (15%) and 2.6 g of isomer B (80%) as a transparent oil - isomer B crystallizes upon standing. Specified in the connection header1H NMR (400 MHz, CDCl3) to 1.16 (3H, d, J = 6,8 MHz) of 1.80 (1H, user.C) of 3.13 (1H, together, J = 3,2, and 12.4 Hz), 3,23 (1H, dt, J = 3,6, and 12.4 Hz), 3,63 (1H, DD, J = 2M.c-c. (FAB) 438 (M + H, 75%), 180 (100%).

Getting the HCl salt. To a solution of free base (0,77 g) in diethyl ether (10 ml) was added 1 M HCl in methanol (1.75 ml). The solution is evaporated to dryness, and adding ether crystals are formed. The solution is filtered, and the residue was washed with diethyl ether, and receive hydrochloride specified in the connection header, so pl. 248-250oC. Found: C 50,46, H of 3.85, N 3,01, Cl 7,31, C20H18F7NO2HCl, calculated C 50,70, H of 4.04, N 2,96, Cl of 7.48%.

Example-description 6

4-Benzyl-3-(S)-(4-forfinal)-2-(R)-(3-fluoro-5-(trifluoromethyl)benzoyloxy) Morfin

Specified in the title compound were obtained when the interaction of the compounds of the example-base 2 with 3-fluoro-5-(trifluoromethyl)benzoyl chloride according to the procedure set forth in example 3. 1H NMR (360 MHz, CDCl3) of 2.50 (1H, dt, J = 3.3V, 12,0), 2,96 (1H, d, J = 12,0), 2,98 (1H, d, J = 13,6 in), 3.75 (1H, DD, J = 1,7, 11,5), 3,80 (1H, d, J = 2,5), to 3.92 (1H, d, J = 13,6), 4,19 (1H, dt, J = 2.1 a, 12,0), of 6.20 (1H, d, J = 2,5), of 6.99 (2H, t, J = 8,7), 7,2 - 7,37 (5H, m), 7,51 - of 7.55 (3H, m), 7,89 (1H, d, J = 8,4), of 8.09 (1H, c), M.-c. (Cl+) m/z 478 (M++ 1, 100%). Elem. analysis: calculated for C25H20F5NO3: C 62,88, H TO 4.23, N 2,93. Found: C 62,59, H Is 4.03, N Of 3.07%.

Example-description 7

4-Benzyl-3-(S)-(4-forfinal)-2-(R)-(1-3-fluoro-5-(trifluoromethyl)phenyl) adenylate)Mustvee with the procedure example-description 4.1H NMR (360 MHz, CDCl3) to 2.42 (1H, dt, J=3,6, 12,0), 2,90 (1H, d, J= 12,0), only 2.91 (1H, d, J=13,6), 3,60-3,62 (1H, m), and 3.72 (1H, d, J=2,6), to 3.92 (1H, d, J=13,6), 4.09 to (1H, dt, J=2,4, 12,0), of 4.67 (1H, l, J=2,9), 5,28 (1H, d, J= 2,6), 7,07 (2H, t, J=8,7), 7,2-7,37 (7H, m), 7,53 (1H, c), EUR 7.57-to 7.61 (2H, m). M.-S. (Cl+) 476 (M+1, 100%).

Example-description 8

3-(S)-4-(forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) ethoxy)formalin

Hydronaut connection example-describe 7 in accordance with the method described in example 5. Get a mixture of 2 epimeric products - isomer A and isomer B (main product) in the form of a transparent oil. For the connection specified in the header: 1H NMR (360 MHz, CDCl3) to 1.42 (3H, d, J=6.6 Hz), at 1.91 (1H, c), the 3.11 (1H, DD, J=3.2, and to 12.4 Hz), up 3.22 (1H, dt, J=3,6, and 12.4 Hz), to 3.58-3,62 (1H, m) to 4.01 (1H, d, J=2.3 Hz), 4,11 (1H, dt, J=3.2, and 12.0 Hz), to 4.41 (1H, d, J=2.3 Hz), 4,80 (1H, kV, J=6.6 Hz), 6,41 (1H, d, J= 9,2 Hz), 6,86 (1H, c), 7,02 (2H, t, J=8.7 Hz), was 7.08 (2H, d, J=9,2 Hz), 7,21-7,26 (2H, m). M.-S. (Cl+) m/z 387 (M+1, 100%). Elem. analysis: calculated for C19H18F5NO2: C 58,91, H 4,69, N 3,62. Found: C 58,88, H To 4.81, N 3,76%.

Example-description 9

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl(phenyl)ethoxy)-3-(S)-(4 - forfinal)-4-(2,3-dihydro-2-oxo-1,3-imidazol-4-yl)methylmorpholine

A mixture of compound of example descriptions 5 (1 g), N,N-diacetyl-4-bromoethyl-2-imidazolinone (0,62 g) (obtained in soybean room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water and saline solution. An ethyl acetate layer is dried (MgSO4) and evaporated in vacuo. The resulting oil is dissolved in ethanol (10 ml), add 33% ethanolic solution of methylamine (1 ml) and the mixture is stirred at room temperature for 10 minutes. The mixture was concentrated in vacuo and get a solid substance. Recrystallization from ethyl acetate/methanol gives specified in the header connection (0,63 g). So pl. 192-194oC.1H NMR (360 MHz, DMSO-d6) to 1.35 (3H, d, J=6,5 Hz in), 2.25 (1H, dt, J=8.6 Hz), 2,60 (1H, d, J=13,8 Hz), 2,89 (1H, d, J= 11,6 Hz), 3,28-to 3.36 (2H, m), 3,62 (1H, d, J=10,2 Hz), 4,1 (1H, d, J=10.0 Hz), or 4.31 (1H, d, J=2.7 Hz), to 4.92 (1H, q, J=6.5 Hz), 5,97 (1H, c), 7,06 (2H, t, J=8,8 Hz), was 7.36 (2H, c), 7,65 is 7.85 (2H, m), to 7.84 (1H, c), 9,58 (1H, c), and 9.8 (1H, c).

Example-description 10

3-(S)-(4-Forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) ethoxy)-4-(2,3-dihydro-2-oxo-1,3-imidazol-4-yl)methylmorpholine

Specified in the title compound is obtained from the compound of example descriptions 8 using a procedure similar to the procedure of example descriptions 9. So pl. 209-210oC. ( )D= +92,8 (c=1.0, methanol).1H NMR (360 MHz, DMSO-d6) is 1.31 (3H, d, J= 6.5 Hz), 2,24 (1H, dt, J=3,0, to 11.9 Hz), 2,6 (1H, d, J=a 13.9 Hz), 3,61 (1H, d, J=11.2 Hz), 4,1 (1H, t, J=11,0 Hz), the 4.29 (1H, d, J=2.3 Hz), 4,8 (1H, q, J=6.5 Hz), 6,00 (1HR>
2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 - forfinal)-4-(1,2,4-triazole-3-yl)-methylmorpholin

A solution of compound of example descriptions 5 (3.77 g) and potassium carbonate (3,59 g) in dry dimethylformamide (7 ml) was stirred at room temperature for 10 minutes. Add N-formyl-2-chloroacetamides (obtained by I. Yanagisawa, J. Med. Chem. (1984) 27, 849) and the reaction mixture is heated at 60oC for 1 hour. The temperature was then raised to 140oC for 2 hours. The mixture is cooled and distributed between ethyl acetate and water and the organic phase is washed with water, with brine, dried (MgSO4) and evaporated, get a brown oil. The residue is purified by chromatography on silica gel using 1-5% methanol in dichloromethane.1H NMR (360 MHz, DMSO) of 8.25 (1H, c), a 7.85 (1H, c), to 7.50 (2H, t), 7,11 (2H, t, J=9.0 Hz), is 4.93 (1H, q, J=6.6 Hz), 4,32 (1H, d, J=2,8 Hz), 4.09 to (1H, dt, J=11.5 Hz), 3,63 (1H, d, J=14.1 Hz) and 3.59 (1H, d, J=3.0 Hz), 3,17 (1H, d, J=14,0 Hz), 2.49 USD (1H, dt, J=15.7 Hz), of 1.36 (3H, J= 6.6 Hz). M.-S. (Cl+) m/z 519. Elem. analysis: calculated for C23H19F7NO2: C 53,29, H 4,08, N 10,81. Found: C 52,92, H 3,94, N 10,33.

Example-description 12

4-Benzyl-3-(S)-(4-forfinal)-2-(R)-(3-trifluoromethyl)benzoyloxy)morpholine

Specified in the title compound were obtained when the interaction of the compound with the1H NMR (360 MHz, CDCl3) 2,48 (1H, dt, J= 12,0, 3,5), to 2.94 (1H, d, J=13,6), to 3.73 (1H, approx.d, J=11,4), of 3.78 (1H, d, J=2,7), 3,91 (1H, d, J=13,6), is 4.21 (1H, dt, J=11,7, 2,4), of 6.20 (1H, d, J= 2,8), 6,97 (2H, t, J=8,7), 7,25-7,37 (5H, m), 7,53 (2H, m), to 7.61 (1H, t, J= 7,8), to 7.84 (1H, d, J=8,0), 8:21 (1H, d, J=7,8), 8,30 (1H, c). M.-S. (Cl+) m/z 460 (M+1, 100%).

Example-description 13

4-Benzyl-3-(S)-(4-forfinal)-2-(R)-(1-(3-(trifluoromethyl)phenyl) adenylate)morpholine

Specified in the title compound is obtained from the compound of example descriptions 12 in accordance with the procedure described in example-description 4.1H NMR (360 MHz, CDCl3) to 2.40 (1H, dt, J=11,9, 3.6 Hz), 2,87 (1H, approx.d, J=11.8 Hz), 2,89 (1H, d, J=13.5 Hz), 3,62 (1H, approx.d, J=11.5 Hz), 3,70 (1H, d, J=2.7 Hz), 3,91 (1H, d, J=13.5 Hz), 4,12 (1H, dt, J=11,7, 2.4 Hz), to 4.62 (1H, d, J= 2.7 Hz), 4,74 (1H, d, J=2.7 Hz), and 5.30 (1H, d, J=2.7 Hz), 7,07 (2H, t, J=8.7 Hz), 7,21-to 7.32 (5H, m), 7,40 (1H, t, J=7.8 Hz), 7,53-7,63 (4H, m), 7,74 (1H, c). M.-S. (Cl+) m/z 458 (M+1, 100%).

Example-description 14

3-(S)-(4-Forfinal)-2-(R)-(1-(R)-(3-(triterpenes)phenyl)ethoxy)morpholine

Connection example-description 13 hydronaut according to the method described in example 5. Get a mixture of 2 epimeric products - isomer A and isomer B, approximately equal numbers, in the form of a yellow oil. Specified in the title compound (isomer B): 1H NMR (360 MHz, CDCl3) was 1.43 (3H, d, J= 6,6), 3,11 (1H, DD, J=12,6, 2,9), up 3.22 (1H, dt, J=12,4, 3,7), 3,60 (1H, d is), M.-c. (Cl+) m-z 370 (M+1, 100%). Elem. analysis: calculated for C19H19F4NO2: C 61,77, H 5,20, N 3,79. Found: C 61,60, H 5,16, N 3,95%.

Example-description 15

4-Benzyl-3-(S)-phenyl-2-morpholino

Cnflbz A. N-Benzi-(S)-phenylglycine

A solution of 1.51 g (10.0 mmol) of (S)-phenylglycine in 5 ml of 2n. an aqueous solution of sodium hydroxide is treated with 1.0 ml (10.0 mmol) of benzaldehyde and stirred the mixture at room temperature for 20 minutes. The solution was diluted with 5 ml of methanol, cooled to 0oC and carefully treated with 200 mg (5.3 mmol) of sodium borohydride. Cooling Tanya removed and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with 20 ml of water and extracted with CH ml of methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid to pH 6 and the solids which precipitate, is filtered off, washed with 50 ml water, 50 ml of a mixture of methanol with ethyl ether (1:1 by volume) and dried. Receive 1.83 g (76%) of product, so pl. 230-232oC. Elem.analysis: calculated for C15H15NO2: C 74,66, H 6,72, N 5,81. Found: C 74,17, H Is 6.19, N 5,86.

Stage B. 4-Benzyl-3-(S)-phenyl-2-morpholino

A mixture of 4.00 g (of 16.6 mmol) N-benzyl-(S)-phenylglycine (from step A), 5.0 g (36,0 mmol) carbonate cdout and partitioned between 200 ml of ethyl ether and 100 ml of water. The layers are separated and the organic layer washed h ml of water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified flash chromatography on 125 g of silica gel, elwira first with a mixture of hexane with ethyl ether 9:1 (by volume), and then 4: 1, and get 2,41 (54%) of product as a solid substance, so pl. 98-100oC.1H NMR (250 MHz, CDCl3) 2,54 of 2.68 (1H, m), 2,96 (1H, dt, J=12,8, 2,8), 3,14 (1H, d, J=a 13.3 in), 3.75 (1H, d, J=13.3-inch), to 4.23 (1H, s), 4,29-4,37 (1H, m), 4.53-in (dt, J=3,2, 11,0), 7,20-7,56 (10 nm), M.-C. (FAB): m/z 268 (M+H, 100%). Elem.analysis: calculated for C17H17NO2: C 76,38, H 6,41, N 5,24. Found: C 76,06, H 6,40, N 5,78.

Example-description 16

4-Benzyl-2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)- phenylmorpholine

A solution of 2.67 g (10.0 mmol) of the compound of example descriptions 15 in 40 ml of dry THF cooled to -78oC. the Cold solution was treated with 12.5 ml of 1, Ω L-selectridein THF, while maintaining the inside temperature of the mixture below -70oC. the Resulting solution is stirred for 45 minutes in a cold state and in the reaction mixture loads of 3.60 ml (20.0 mmol) of 3,5-bis(trifluoromethyl)benzanilide. The resulting yellow mixture is stirred cold for 30 minutes and quenched the reaction with 50 ml of saturated aqueous bicarbonate NAT is magnesium sulfate. The aqueous layer was extracted with 300 ml of ether, the extract is dried and combined with the original organic layer. The combined organic solution was concentrated in vacuo. Flash chromatography on 150 g of silica gel using a mixture 4,06 g (80%) indicated in the title compounds as solids. 1H NMR (200 MHz, ppm, CDCl3) of 2.50 (1H, dt, J=3,4, 12,0), of 2.97 (1H, approx. D., J=12,0), 2,99 (1H, d, J=13,6), and 3.72-with 3.79 (1H, m), 3,82 (1H, d, J=2,6), 4,00 (1H, d, J=13,6), 4,20 (DT, J=2,4, 11,6), to 6.22 (1H, d, J=2,6), 7,22-7,37 (2H, approx.D., J=6,8), 8,07 (1H, s), 8,78 (2H, s). Elem. analysis: calculated for C26H21F6NO3: C 61,29, H 4,16, N 2,75, F 22,38. Found: C 61,18, H 4,14, 2,70 N, F 22,13.

Example-description 17

4-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)-adenylate)- 3-(S)-phenylmorpholine

A solution of 2.50 g (4.9 mmol) of the compound of example descriptions 16 and 2.50 g (12,0 mmol) of dimethyltitanocene (example-description 4a) in 35 ml of a mixture of THF to toluene (1: 1 by volume) was stirred on an oil bath at 80oC for 16 hours. The reaction mixture is cooled and concentrated in vacuo. Flash chromatography on 150 g of silica gel using as eluent a mixture of hexane with methylene chloride (3:1 by volume) receive 1,71 g (69%) indicated in the title compound in the form of a solid substance.1H NMR (400 MHz, CDCl3) to 2.42 (1H, dt, J= 3,6, 12,0), (H, d, J=2,4), 7,34-7,41 (7H, m), 7,63 (1H, approx.d, J=7,2), 7,79 (1H, s), to $ 7.91 (2H, s). M.-C. (FAB) m/z 508 (M+1, 25%). Elem.analysis: calculated for C27H23F6NO2: C 63,90, H OF 4.57, N WAS 2.76, F 22,46. Found: C 63,71, H 4,53, N 2,68, F Cushion 22.66.

Example-description 18

2(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)- -3-(S)-phenylmorpholine

A mixture of compound of example descriptions 17 (1.5 g) and 10% palladium-on-coal (750 mg) in a mixture of isopropanol with ethyl acetate (25 ml, 3:2 by volume) was stirred in hydrogen atmosphere for 48 hours. The catalyst was removed by filtration through celite and the reaction flask and the gasket of the filter is washed with ethyl acetate (500 ml). The filtrate is concentrated under vacuum. Flash chromatography gives the epimer A (106 g) and epimer B (899 mg) as clear oils. Named in the header connection - epimer B - has the following characteristics.

1H NMR (CDCl3, 400 MHz) of 1.46 (3H, d, J=6.8 Hz), with 1.92 (1H, user.C) of 3.13 (1H, DD, J=3,0, of 12.6 Hz), 3,24 (1H, dt, J=3,6, and 12.6 Hz), 3,62 (1H, DD, J= 3,6, 11.2 Hz), Android 4.04 (1H, d, J=2.4 Hz), 4,14 (1H, dt, J=3,0, 11.2 Hz), 4,48 (1H, d, J=2.4 Hz), the 4.90 (1H, q, J=6.8 Hz), 7,21-to 7.32 (7H, m) to 7.64 (1H, s). M.-S. (Cl+) m/z 420 (M++1, 20%), 178 (100%). Elem.analysis: calculated for C20H19F6NO2: C 57,28, H OF 4.57, N 3,84, F 27.18 PER. Found: C 57,41, H Br4.61, N 3,29, F 27,23.

Example-description 19

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy) the compliance with the procedure described in example 11. M-. (Cl+) m/z 501 (M++1, 100%).

Example-description 20

4-Benzyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2 - hydroxyethoxy)-3-(S)-(4-forfinal)morpholine

Connection example-description 4 (12.8 g) was dissolved in tetrahydrofuran (50 ml) and the mixture is cooled on ice. Added dropwise borane (49 ml of 1.0 M solution in tetrahydrofuran) and the reaction mixture was stirred at room temperature for 3 hours. The solution is cooled in an ice bath and added dropwise, slowly, a solution of sodium hydroxide (120 ml, 1M) and hydrogen peroxide (36 ml, 30 wt.%). The resulting mixture is stirred for 1 hour, then diluted with water (200 ml) and extracted with ethyl acetate (CH ml). The organic extracts are washed with a solution of sodium sulfite and then with brine. The organic phase is dried (MgSO4) and evaporated, get a clear oil. TLC (ethyl acetate/hexane, 50:50) shows two major products that share flash chromatography on silica gel using gradient elution is 1-30% ethyl acetate in hexane. First elute by-product (2.3 g), and then eluted main product (8 g). The main product isolated in the form of a white foam.1H NMR (360 MHz, DMSO-d6) 2,23-2,29 (), to 4.92 (1H, t, J = 5.5 Hz), 7,14 (2H, t, J = 9.0 Hz), 7.23 percent - 7,33 (5H, m), 7,35 (2H, t, ArH), a 7.85 (1H, s, ArH). M.-S. (Cl+) m/z 544 (M++ 1, 100%).

Example-description 21

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3- (S)-(4-forfinal)morpholine

Connection example-description 20 (8 g) dissolved in ethyl acetate (100 ml) in isopropanol (50 ml) and added to a solution of palladium-on-coal (1.5 g). The mixture hydronaut at 275 kPa (40 f/d2) during the night. The catalyst was removed by filtration and the solvents removed in vacuo. The residue is purified flash chromatography, using as eluent 1 to 10% methanol in dichloromethane. The target product is obtained in the form of a white powder (5.7 g, 90%).

1H NMR (360 MHz, CDCl3) 2,68 - by 2.73 (1H, m), 3,03 is 3.15 (1H, m), 3.43 points - of 3.65 (3H, m), 3,95 (1H, d, J = 3.0 Hz), 4,12 - 4,22 (1H, m), and 4.40 (1H, d, J = 3.0 Hz), 4,89 (1H, t, J = 7.0 Hz), 6,99 (t, J = 9.0 Hz, ArH), to 7.15 (2H, s), 7,26 - 7,31 (1H, m, ArH), a 7.62 (1H, s, ArH). M.-S. (Cl+) m/z 454 (M++ 1, 100%).

Example-description 22

3-(S)-(4-Forfinal)-2-(R)-(1-(S)-(3-fluoro-5- (triterpenes)phenyl)-2-hydroxyethoxy)morpholine

Stage A. 4-Benzyl-3-(S)-(4-forfinal)-2-(R)-(1-(S)- (3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

Connection example-describe 7 (0.8 g) dissolved in tetrahydrofuran (5 ml) at room temperature and added dropwise borane (5 ml, 1.0 M lastweek original products. To a cooled (0oC) the solution, which is much boils, add dropwise hydrogen peroxide (5 ml, 29%, aq.) and sodium hydroxide (10 ml, 4n). The resulting mixture is extracted with ethyl acetate, the organic phase is washed with a solution of sodium bisulfite and saturated solution of salt, dried (MgSO4) and evaporated receive a colorless oil (1 g). This substance is further purified and subjected to interaction, as described in the next stage.

Stage B. 3-(S)-(4-Forfinal)-2-(R)-(1-(S)-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxy)morpholine

Connection with the above stage (A) (1 g) dissolved in a mixture of ethyl acetate with 2-propanol (20 ml, 3:1) and treated with a solution of Pd-on-coal (100 mg). The mixture hydronaut at 414 kPa (60 f/d2within 12 hours. The catalyst was removed by filtration and the solvent is removed in vacuum. The residue is purified by medium pressure chromatography on silica (Lobar), using as eluent 5% methanol in dichloromethane. The product is recrystallized from ether.1H NMR (360 MHz, DMSO-d6) 2,77 totaling 3.04 (3H, m), 3,36 - 3,51 (2H, m), 3,93 (1H, user.C) 4,05 is 4.13 (1H, m), 4,36 (1H, d, J = 2.0 Hz), 4.72 in (1H, t, J = 5.0 Hz), to 4.98 (t, J = 7.0 Hz), of 6.66 (1H, d, J = 9,2 Hz), 6.89 in (1H, s), 7,10 (2H, t, J = 9.0 Hz), 7,33 - 7,37 (2H, m), 7,41 (1H, d, J = 9.0 Hz). M. - S. (Cl+) m/z 404 (M+1, 100%). the target of chloroacetonitrile (54,1 g) in anhydrous methanol (100 ml) at 0oC add sodium methoxide (20 ml, 1M). The mixture is stirred at room temperature for 30 minutes and then neutralized with acetic acid (1.2 ml). Methylhydroperoxide (64,5 g, previously distilled under vacuum) was dissolved in warm dimethylformamide (35 ml) and methanol (300 ml) and added dropwise to the reaction mixture at 0oC. the Mixture is stirred for 30 minutes, the crystalline solid is formed, is removed by filtration, washed it with ethyl acetate and get listed in the title compound, so square 138 - 140oC.

Example-description 24

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-2- (S)-phenylmorpholine

Stage A. 4-Benzyl-2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)- 2-hydroxyethoxy)-3-(S)-phenylmorpholine

Connection example-description 17 enter into interaction with borane and then with alkaline hydrogen peroxide in accordance with the method shown in the example of description 20. This intermediate compound is not clear, and enter it raw in the interaction at the next stage.

Stage B. 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)- 2-hydroxyethoxy)-3-(S)-phenylmorpholine

Connection with the above stage (A) is subjected to removal of the protective group by hydrolysis, as 1
H NMR (360 MHz, CDCl3) to 2.85 (1H, approx. d, J = 11.0 in Hz) and 3.15 (1H, dt, J = 12,0,, 3.5 Hz), to 3.58 (1H, DD, J = to 11.0, 3.0 Hz), 3,63 - 3,71 (2H, m), was 4.02 (1H, d, J = 3.0 Hz), 4,25 (dt, J = 12,0, 3.0 Hz), a 4.53 (1H, d, J = 3.0 Hz), is 4.93 (1H, t, J = 5.0 Hz), 7,22 (2H, s), to 7.35 (5H, user. C) to 7.67 (1H, s). M.-S. (Cl+) m/z 436 (M + 1, 100%).

Example-25

4-Benzyl-2-(R)-(3-fluoro-5-(trifluoromethyl)benzyloxy)-3-(S)- phenylmorpholine

Connection example-description 15 enter into interaction with L-selectride, and then with 3-fluoro-5-(trifluoromethyl)benzoyl chloride, in accordance with the method shown in example 3, and get mentioned in the title compound as a clear oil.1H NMR (250 MHz, CDCl3) 2,47 (1H, dt, J = 8,5, 2,5 Hz), 2,93 - of 2.97 (2H, m), 3.72 points is 3.76 (1H, m), with 3.79 (2H, d, J = 3.0 Hz), of 3.97 (1H, d, J = 9.5 Hz), 4,17 (1H, dt, J = 8,5, 2,5 Hz), to 6.22 (1H, d, J = 3.0 Hz), 7,19 - to 7.35 (8H, m), 7,45 - 7,56 (3H, m), 7,88 (1H, user. d), of 8.09 (1H, s). M.-S. (Cl+) m/z 460 (M + 1, 100%).

Example-description 26

4-Benzyl-2-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) adenylate)-3-(S)-phenylmorpholine

Connection example-description 25 enter into interaction with dimethyltitanocene in accordance with the procedure described in example-description 4. Get listed in the title compound as a clear oil (66%).1H NMR (250 MHz, CDCl3) 2,29 - 2,39 (1H, m), 2,79 - of 2.86 (2H, m), 3,53 - of 3.64 (2H, m), 3,92 (1H, d, J = 13.5 Hz), 4,00 - 4, 100%).

Example-description 27

2-(R)-(1-(S)-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-phenylmorpholine

Stage A. 4-Benzyl-2-(R)-(1-(S)-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-phenylmorpholine

Connection example-description 26 enter into interaction with borane followed by treatment with sodium peroxide in accordance with the procedure shown in example-description 20, and get a clear oil. M.-S. (Cl+) m/z 476 (M + 1, 100%).

Stage B. 2-(R)-(1-(S)-(3-Fluoro-5-(trifluoromethyl)phenyl)-2 - hydroxyethoxy)-3-(S)-phenylmorpholine

Remove the protective group in connection with the above stage (A), following the method described in example-description 21. Get listed in the title compound as a white solid. Elem. analysis: calculated for C19H19F4NO3: C 59,22, H EQUAL TO 4.97, N 3,63. Found: C 59,18, H 5,12, N 3,62. M.-S. (Cl+) m/z 386 (M + 1, 100%).

Example-description 28

4-Benzyl-3-(S)-phenyl-2-(R)-(3-(trifluoromethyl)benzyloxy)morpholine

Produced from compound of example descriptions 15 in accordance with the method described in example 3.1H NMR (250 MHz, CDCl3) 2,47 (1H, dt), 2,89 - to 2.99 (2H, m), 3,69 - 3,82 (2H, m), 3,98 (1H, d), to 4.23 (1H, dt), from 6.22 (1H, d), 7,22 - 7,40 (8H, m), 7,54 - 7,66 (3H, m), 7,83 (1H, d), by 8.22 (1H, d), 8,31 (1H, s).

connection example-description 28 in accordance with the method, set forth in example-description 4.

1H NMR (250 MHz, CDCl3) to 2.41 (1H, dt), 2,84 - 2,96 (2H, m), to 3.58 - 3,66 (1H, d), and 3.72 (1H, d), 3,99 (1H, d), 4,13 (1H, d), 4,63 (1H, d), 4.72 in (1H, d), of 5.34 (1H, d), 7,21 - the 7.43 (9H, m), 7,50 - to 7.68 (4H, m), of 7.75 (1H, s).

Example-description 30

3-(S)-Phenyl-2-(R)-(1-(S)-(3-(trifluoromethyl)phenyl)-2 - hydroxyethoxy)morpholine

Stage A. 4-Benzyl-3-(S)-phenyl-2-(R)-(1-(S)-(3- (trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

Produced from compound of example descriptions 29 in accordance with the method described in the example of description 20.

Stage B. 3-(S)-Phenyl-2-(R)-(1(S)-(3-(trifluoromethyl)phenyl)-2 - hydroxyethoxy)morpholine

Substance from step (A) without treatment until the date stated in the title compound by the method shown in example - description 21.1H NMR (250 MHz, CDCl3) 2,81 - 2,90 (1H, user.D.), and 3.16 (1H, dt), 3,54 - 3,68 (3H, m), was 4.02 (1H, dt), 4,28 (1H, dt), a 4.53 (1H, d), 4,85 to 4.92 (1H, m), 6,85 (1H, d), of 6.99 (1H, c), 7,15 - 7,24 (1H, m), 7,34 was 7.45 (6H, m).

Example 1

2-(R)-1-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(2,3 - dihydro-5-(N, N-dimethylaminomethyl)-2-oxo-1,3-imidazol-4-yl)meteo-2-(S)- (4-forfinal)morpholine.

Connection example-description 9 (0.35 g) is treated with N,N - dimethylmethyleneammonium (0,48 g) and triethylamine (111 μl) in tetrahydrofuran 910 ml) and the mixture is refluxed during the e eluent 1 - 10% methanol in dichloromethane, and get mentioned in the title compound (0.2 g).1H NMR (250 MHz, CDCl3) 9,72 (1H, s) 9,68 (1H, s), 7,86 (1H, s), 7,50 - of 7.60 (2H, m), of 7.36 (2H, s), 7,07 (2H, t, J=8,8 Hz), 4,96 - 4,89 (1H, sq J=6.5 Hz), or 4.31 (1H, d, J=2.7 Hz), 4,08 (1H, t, J= 10.1 Hz), 3,62 (1H, d, J=10.1 Hz), to 3.34 (2H, s), 3,24 (1H, d, J=13,6 Hz) of 3.00 (1H, d, J=13,4 Hz), 2,85 (1H, d, J=11,1 Hz), 2,62 (1H, d, J=13,6 Hz), 2,2 (1H, t, J=11 Hz), a 2.01 (6H, s) and 1.35 (3H, d, J=6.5 Hz), M-(Cl+) m/z 591 (M+1).

4-(2,3-Dihydro-5-(N, N-dimethylaminomethyl)-2-oxo-1,3-imidazol-4-yl)methyl-3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-( trifluoromethyl)phenyl)ethoxy)morpholine.

Produced from compound of example descriptions 10 according to the method similar to the method of example 1.1H NMR (250 MHz, CDCl3) to 1.38 (3H, d, J=6.2 Hz), 2,22 (6H, s), 2,78 (1H, d, J=14 Hz), 2,92 (1H, d, J=11.2 Hz), 3,14 (2H, approx.kV. J=14 Hz), 3,34 (1H, d, J=2,8 Hz), of 3.46 (1H, d, J=11.2 Hz), 3,60 (1H, d, J=10 Hz), 4,22 (2H, m), 4.26 deaths (1H, d, J=2,8 Hz), 4,74 (1H, q, J=6.2 Hz), 6,32 (1H, d, J=8,4 Hz), 6,72 (1H, s), 7,06 (3H, t, J=8,4 Hz), was 7.36 (2H, user, C) to 8.70 (1H,user.C) 9,20 (1H, user. C).

Example 3

3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) toxi)-4-(2,3-dihydro-2-oxo-5-pyrrolidinyl)1,3-imidazol-4-yl) methylmorpholin

The mixture of compounds from example-description 10 (0.1 g), paraformaldehyde (0,012 g) and pyrrolidine (0.04 ml) in methanol (2 ml) is heated at 90oC for 1 hour. To this mixture add oritel removed in vacuum. The residue is purified by chromatography on silica gel using, using 0.5% aqueous ammonia and 5% methanol in dichloromethane. Get the product in the form of foam. Next, the product is distilled in the form of hydrochloride. So pl. 157 - 150oC.1H NMR (250 MHz, (free base), CDCl3) of 1.40 (3H, t, J=6.2 Hz), 1,72 (4H, user.C) to 2.41 (4H, user.C) was 2.76 (1H, d, J=12.9 Hz), 2,92 (1H, d, J=11.2 Hz), 3,14 - 3,50 (5H, m), 3,62 (1H, d, J=11.2 Hz), 4,16 (1H, d, J= 12.9 Hz), 4.26 deaths (1H, d, J=2,8 Hz), 4,71 (1H, q, J=6.2 Hz), 6,30 (1H, d, J= 8,4 Hz), to 6.75 (1H, C) to 7.0 (3H, t, J=8,4 Hz), 7,34 (2H, user.C) 8,86 (1H, user.C) 9,14 (1H, user.C). M-m (Cl+) m/z 567 )M++H).

Example 4

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)toxi)-3-(S)- (4-forfinal)-4-(2,3-dihydro-2-oxo-5-pyrrolidinyl-1,3 - imidazol-4-yl)methylmorpholine

A solution of compound of example descriptions 5 (1.5 g) in anhydrous dimethylformamide (15 ml) under cooling with ice and with stirring is added dropwise during 5 minutes to a solution of 4,5-bis-(methyl bromide)-1,3-diacetyl-2-imidazolinone (1.8 g) (obtained according to the method of Dolan and Duchinsky JACS (1984) 70, 657) in dimethylformamide (10 ml) containing potassium carbonate (1.4 g). The reaction mixture is stirred for 10 minutes and add in one reception pyrrolidine (1.1 g), and stirring is continued for another 20 minutes. The reaction mixture was diluted with water (250 ml) and extracted with utilize dried (K2CO3) and concentrate under vacuum. The residue is purified by chromatography on silica gel, using a gradient elution from 100% dichloromethane to a mixture of dichloromethane/methanol/aqueous ammonia (85:15: 0.5), and get the specified title compound in the form of foam.1H NMR (360 MHz, DMSO-d6) 9,63 (2H, user.C) to 7.84 (1H, s), 7,53 (2H, user.C) of 7.36 (2H, s), 7,06 (2H, t, J=8.7 Hz), 4,94 - of 4.90 (1H, q, J=6.5 Hz), or 4.31 (1H, d, J=2,68 Hz), 4,07 (1H, t, J=11,4 Hz), 3,61 (1H, d, J=11,20 Hz) to 3.34 (1H, J=2.7 Hz), with 3.27 (1H, d, J=13,7 Hz), 3,17 (16, d, J=13,4 Hz) of 3.00 (1H, d, J= 13,4 Hz), 2,86 (1H, d, J=11,6 Hz), 2,62 (1H, d, J=13,6 Hz), 2,40 - of 2.20 (5H, m), 1,64 is 1.58 (2H, m) of 1.35 (3H, d, J=6.5 Hz), M.-S. (Cl+) m/z 615 (M+1H).

Connection examples 5 through 11 in table 1 are the same way described in example 4 from the relevant research, 4,5-bis(methyl bromide)-1,3-diacetyl-2-imidazolinone and the appropriate amine.

Example 12

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl(phenyl)ethoxy)-4-(5 - dimethylaminomethyl)01,2,3-triazole-4-yl)methyl-3-(S)-(4-forfinal)morpholine

How A

a) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy-3-(S)- (4-forfinal)-4-propargylation

To a mixture of compound of example descriptions 5 (5 g) and potassium carbonate (4,76 g) in dry dimethylformamide at 23oC under stirring add propylbromide (1.9 ml). After 15 minutes the reaction mixture by resetform (g ml), then dried (K2CO3and concentrate, is oil. This oil is purified by chromatography on silica gel, using as eluent ethyl acetate with hexane (first 1:9 then 1:4), and get mentioned in the title compound in the form of butter.1H NMR (250 MHz, CDCl3) a 1.50 (3H, d, J= 6.6 Hz), of 2.21 (1H, s) 2,84 (1H, d, J=11,1 Hz), 2,97 (1H, TD, J=3.2, and an 11.7 Hz), 3,26 (2H, d, J=1,8 Hz), 3,62 (1H, d, J=2.2 Hz), 3,71 (1H, DD, J=2,3, 11,1 Hz) to 4.33 (2H, m), 4,89 (1H, q, J=6.6 Hz), 7,03 (2H, t, J=8.6 Hz), 7,18 (2H, s), 7,38 (2H, sh.C), 7,63 (1H, s). M.-c (Cl+) m/z 476 (MH, 100).

b) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4- (4-dimethylamino-4-oxo-but-2-inyl)-3-(S)-(4-forfinal)morpholine

A mixture of N, N-dimethylammoniumchloride (of € 0.195 ml), copper iodide (1) (2 g), bis(triphenylphosphine(palladium(11)chloride (2 mg), triphenylphosphine (3 mg) and the compound described above in stage (a) (1 g) in triethylamine (4 ml) is heated at 90oC for 5 hours in an inert atmosphere. The mixture is cooled to 23oC, add methanol (1 ml), removed the solvent in vacuo. The residue is distributed between water and ethyl acetate and the layers separated. The aqueous phase is extracted with ethyl acetate (2x20 ml). The combined organic phases are washed with water, brine, dried (MgSO4and concentrate, is oil. The residue is purified by chromatography on silica compound is ke connection in the form of butter.1H NMR (250 MHz, CDCl3) 1,49 (3H, d, J=6.6 Hz), 2,84 - of 3.06 (2H, m) of 3.00 (3H, s), 3,17 (3H, s), 3,44 (2H, s) to 3.64 (1H, user. C) to 3.73 (1H, d, J=2,0 and 11.1 Hz), 4,33 (2H, m), 4,88 (1H, q, J= 6.6 Hz), 7,03 (2H, t, J=8.7 Hz), 7,17 (2H, s), 7,38 (2H, user.C), 7,63 (1H, s), m-c. (Cl+) m/z 547 (NH, 100%).

c) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N, N - dimethylcarbamyl-1,2,3-triazole-4-yl)methyl-3-(S)-(4-forfinal)morpholine

The mixture of the compounds described above in stage (b) (1.1 g) and sodium azide (0.65 g) in dimethyl sulfoxide (7.5 ml) is heated at 70oC for 17 hours. The mixture is cooled to 23oC and excess dimethyl sulfoxide is removed under vacuum. The residue is partitioned between salt solution and ethyl acetate. The layers separated, and the organic layer washed with brine (2x20 ml), then dried (MgSO4and concentrate, get the oil. This oil is purified by chromatography on silica gel, using as eluent first ethyl acetate in hexane (1:2, then 1:1) and then ethyl acetate, and get named in the title compound as a pale yellow foam.1H NMR (360 MHz, CDCl3) to 1.47 (3H, d, J= 6,6 Hz) of 2.64 (1H, m), 2,90 (1H, d, J=11,6 Hz) to 3.09 (3H, c) to 3.34 (3H, c), the 3.65 (3H, m), 3,92 (1H, d, J=15,5 Hz), 4,27 (1H, TD, J=2,1, 9.5 Hz), 4,35 (1H, d, J= 2.6 Hz), 4,89 (1H, q, J=6.6 Hz), 7,01 (T, J=8.7 Hz), 7,16 (2H, user.c) to 7.64 (1H, c). m/z 590 (MH, 100%).

d) 2-(R)-(1-(R)-(3,5-Bis(triptime is to be placed, described above in stage (c), (0.11 g) in dry tetrahydrofuran (1 ml) at 23oC in an inert atmosphere is added dropwise to alumoweld lithium (of 0.47 ml, 1M solution in tetrahydrofuran). After 30 minutes, add sodium hydroxide (10 drops, 1M), and then water (5 drops). Then add ethyl acetate (50 ml) and the resulting mixture is filtered through Hyflo filter. The filtrate is concentrated under vacuum, and the residue purified by chromatography on silica gel, using as eluent ethyl acetate in methanol (9: 1, then 4:1), and get named in the title compound in the form of foam.1H NMR (360 MHz, CDCl3) of 1.44 (3H, d, J=6,6 Hz in), 2.25 (6H, c), to 2.57 (1H, TD, J=3,4, 8,55 Hz), 2,90 (1H, d, J=11.7 Hz) at 3.25 (1H, d, J=14,0 Hz), 3,43 (1H, d, J=13,6 Hz), of 3.45 (1H, d, J=2.2 Hz), 3,53 (1H, d, J=13,6 Hz), 3,61 (1H, d, J=11.2 Hz), of 3.78 (1H, d, J=14,0 Hz), 4,22 (1H, t, J=9,3 Hz), 4,32 (1H, d, J=2.2 Hz), a 4.86 (1H, q, J=6.6 Hz), 7,06 (2H, t, J=8.7 Hz), 7,16 (2H, c), of 7.48 (2H, user.c), 7,63 (1H, c). m/z 576 (MH).

Method B

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 - forfinal)-4-(4-harbut-2-inyl)formalin

a) a solution of the product from example descriptions 5 (free base, 5 g) in N, N-dimethylformamide (20 ml) is gradually added to a heated (50oC) a solution of 1,4-dichlorobut-2-in (2.2 ml) and potassium carbonate (4.8 g) in N,N-dimethylformamide (20 ml). The solution is heated for reginout with ethyl acetate (CH ml). The combined organic phases are washed with water, saturated salt solution and dried (MgSO4). The solvent is removed under vacuum, and the residue chromatographic on silica gel (elution with 10% ethyl acetate in petroleum ether, so Kip. 60-80oC), and receive specified in the header of the connection.1H NMR (250 MHz, CDCl3) of 1.41 (3H, d, J=6.6 Hz), 2,80 (1H, approx.t, J=10,8 Hz), 2,87 (1H, TD, J=3,5, 11.7 Hz), up 3.22 (2H, t, J= 1.9 Hz), 3,52 (1H, d, J=2,8 Hz), 3,68 (1H, d, J=1.4 Hz and 11.1 Hz), of 4.00 (2H, t, J=1.9 Hz), 4,22-4,32 (2H, m), to 4.81 (1H,, J=6.6 Hz), of 6.96 (2H, t, J= 8.7 Hz), 7,10 (2H, c), 7,31 (2H, sh.c), 7,56 (1H, c). m/z (Cl+) 524 (M+H, 100%).

b) N-(4-Useabout-2-inyl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3-(S)-(4-forfinal)morpholine

To a solution of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)- 3-(S)-(4-forfinal)-4-(4-harbut-2-inyl)research (4 g) in dimethyl sulfoxide (17 ml) is added sodium azide (0,562 g). The solution is stirred for 20 hours and add ammonium chloride and ethyl acetate. The organic phase is washed with water (2 times) and saturated salt solution and dried (MgSO4). The solvent is removed in vacuo, and the residue chromatographic on silica gel (elution with 20% ethyl acetate in petroleum ether, so Kip. 60-80oC), and receive specified in the header connection. 1H NMR (360 MHz, CDCl3) to 1.48 (3H, s, J=6.6 Hz), 2,87 (1H, m), 4,89 (1H, q, J=6.6 Hz), 7,03 (2H, t, J=8.7 Hz), 7,17 (2H, c), 7,27 (2H, user.c), 7,63 (1H, c).

c) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(5 - dimethylaminoethyl)-1,2,3-triazole-4-yl)methyl-3-(S)-(4-forfinal)morpholine

Dimethylamine (approximately 10 ml) condense at 80oC in the tube for high pressure and add to it a solution of N-(4-useabout-2-inyl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)- 3-(S)-(4-forfinal)of the research (3.2 g) in dioxane (15 ml). The tube is sealed and the solution is heated at 90oC for 16 hours. The solution is evaporated to dryness, and the residue chromatographic on silica gel (elution with 5% methanol in dichloromethane containing 0.25% ammonia (tank weight 0,88), and the fractions containing the desired product, evaporated in vacuum, and receive specified in the header connection. To a solution of the residue in diethyl ether added 1M HCl in methanol. The solution is evaporated to dryness and again dissolved in diethyl ether, get crystals of the dihydrochloride specified in the connection header, so pl. 194-198oC ()2D2+ 65,0o(c=0.5, H2O). Discovered that crystals of at least a few days in the 40oC, at a relative humidity of 40oC/75%, 80oC, and at 2000 Lux.

Example 13

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)PHE-Bis(trifluoromethyl)phenyl)ethoxy)-4-(N - carboxylatomethyl-1,2,4-triazole-3-yl)methyl-3-(S)-(4-forfinal)morpholine

Connection example-description 11 (2,94 g), potassium carbonate (2,03 g) and methylbromide (0,74 ml) is heated in dimethylformamide for 45 minutes. The reaction mixture is treated with water and ethyl acetate, the organic phase is washed (brine), dried (MgSO4) and purified on silica using a mixture of gasoline with ethyl acetate. Get two products - isomer A and isomer B as a white foam.

Isomer A.1H NMR (360 MHz, DMSO) 7,89 (1H, c), to 7.84 (1H, c), of 7.48 (3H, c), 7,33-7,30 (3H, m, J=10.1 Hz), of 5.26 (1H, d, J=17,8 Hz), 5,07 (1H, d, J= 17,8 Hz), 4,96 (1H, q, J=6.5 Hz), 4,39 (1H, d, J=2,8 Hz), Android 4.04 (1H, user.t, J= 10.1 Hz), and 3.72 (3H, c) to 3.58 (2H, d, J=14,0), 3,51 (1H, d, J=2,8), 3,20 (1H, d, J= 14,0), to 2.55 (1H, d, J=11,5), is 2.37 (1H, user.t, J=3.5 Hz), of 1.40 (3H, d, J=6,6).

Isomer B.1H NMR (360 MHz, DMSO) 8,43 (1H, c), of 7.82 (1H, c), 7,44 (2H, d, J=1.4 Hz), 7,37 (2H, c), 7,31-of 7.25 (3H, m, J=3.2 Hz), 5,16 (2H, c), 4,91 (1H, q, J= 6.5 Hz), 4,35 (1H, d, J=2,8 Hz), 4,08 (1H, user.s, J=10.1 Hz), of 3.69 (3H, c), of 3.60 (1H, d, J=8,8 Hz), 3,55 (1H, d, J=2.7 Hz), 3,30 (1H, d, J= 8.7 Hz), is 3.08 (1H, d, J= 13,7 Hz), 2,95 (1H, d, J=11.5 Hz), 2,47 (1H, user.s, J=3,4 Hz) of 1.35 (3H, d, J=6.5 Hz). M-.. (Cl+) m/z 573 (M+1).

b) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 - forfinal)-4-(N-(N'-methylcarbamate)methyl-1,2,4-triazole-3-yl)methylmorpholine

Gaseous monomethylamine bubbled through a solution of the compound of the above stage (b) (375 mg, isomer B) in methanol (25 ml is acetate and concentrated in vacuo, get white solid (374 mg).1H NMR (250 MHz, CDCl3) of 8.09 (1H, c), to 7.61 (1H, c), was 7.45 (2H, user.c), 7,33 (2H, c), 7,31 (1H, user.c), 7,13 (2H, user.c) is 4.85 (1H, q, J=6.5 Hz), was 4.76 (2H, user.c) 4,37 (1H, user.c) 4,36 (1H, user.c), 3,85 (1H, d, 3,66 (1H, user.c), 3,63 (1H, user.c) to 3.49 (1H, d), 3,03 (1H, user.c) 2,82 (3H, d), 2,80 (1H, user.c) a 1.46 (3H, d). M.-S. (Cl+) 573 (M++1).

c) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (4-forfinal)-4-(N-(2-methylaminomethyl)-1,2,4-triazole-3-yl) methylmorpholine

The cooled solution of the above compound (b) (302 mg) in tetrahydrofuran (5 ml) and the complex of borane-tetrahydrofuran (1,59 ml, 1M) and stirred for 60 minutes, then heated (60oC) for 60 minutes. The reaction mixture is evaporated, and the residue is again dissolved in CH3OH c K2CO3and then refluxed for 30 minutes. The reaction mixture was poured into ethyl acetate, washed with water (×2, brine) and dried (MgSO4). After purification on silica gel using mixtures of CH3OH with dichloromethane get mentioned in the title compound as a colourless oil (54 mg).1H NMR (250 MHz, CDCl3) of 7.97 (1H, s), 7,53 (1H<C), 7,39 (2H, user. C), 7,29 - of 7.23 (3H, m, J = 2,61), 7,06 (2H, s), of 4.77 (1H, sq J = 6,6), the 4.29 (1H, d, J = 2,9), 4,25 (1H, user. t, J = 2,6), of 4.13 (2H, t, J = 5,7), 3,76 (1H, d, J = 14,2), of 3.57 (1H, t, J = 3,5), 3,53 (1H, d, J = 2,8), 3,38 (M++ 1).

Compounds of examples 14-21 in table 2 receives a manner similar to the method described in example 12, method B, through the appropriate N-(4-useabout-2-inyl)morpholines and the corresponding amines.

Example 22

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4- (1-(2-pyrrolidinyl)-1,2,4-triazole-3-yl)methylmorpholine

a) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(1-(2-oxo-2 - pyrrolidinyl)-1,2,4-triazole-3-yl)methyl-3-(S)-phenylmorpholine

A solution of compound of example descriptions 19 (2.86 g), potassium carbonate (2.37 g) and 1-bromotetradecane (1,21 g) is heated in dimethylformamide (15 ml) at 60oC. the Mixture is cooled and partitioned between water and ethyl acetate. The organic phase is washed with water, brine and dried (MgSO4). The solvent is removed in vacuo and the residue purified on silica using 1.5% methanol in dichloromethane as eluent. Get 2 product - isomer A and isomer B.

Isomer A (alkylation in position 2 in 1,2,4-triazole).1H NMR (250 MHz, CDCl3) 7,83 (1H, s), to 7.61 (1H, s), 7,39 - 7,30 (5H, m), 7,16 (2H, c), 5,00 (2H, d, J = 16.4 Hz), 4,88 (1H, square, J = 6.6 Hz), of 4.67 (1H, d, J = 16.4 Hz), 4,35 (1H, d, J = 2,8 Hz), 4,20 (1H, user. t, J = 11,6 Hz), of 3.77 (1H, d, J = 14.4 Hz), 3,62 (1H, DD, J = 11.3 Hz), 3,51 - 3,44 (4H, m), 3,39 (1H, s) to 3.33 (1H, d, J = 14.4 Hz), 2,90 (1H, d, J = 11.4 in the Institute of 1,1,2,4-triazole). 1H NMR (250 MHz, CDCl3) 8,19 (1H, s), 7,60 (1H, s), 7,47 (2H, user, C) of 7.36 - 7,27 (3H, m), 7,14 (2H, s), 4,89 (1H, q, J = 6.6 Hz), 4,36 (1H, d, J = 2,8 Hz), or 4.31 (1H,user. t, J = 11,4 Hz), 3,86 (1H, d, J = 14,0 Hz), 3,60 (1H, DD, J = 11.3 Hz) and 3.59 (1H, d, J = 2.7 Hz), 3,53 - of 3.48 (4H, m), 3,35 (1H, d, J = 14.1 Hz), 3,03 (1H, d, J = 11.8 Hz), 2.60 (1H, user. t, J = 11,9 Hz), 2,08 is 2.00 (2H, m), 1,94 -1,84 (2H, m) of 1.44 (3H, d, J = 6,6 Hz).

b) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- phenyl-4-(1-(2-pyrrolidinyl)-1,2,4-triazole-3-yl)methylmorpholine

To a solution of the compound described above in paragraph (a) (isomer B), in tetrahydrofuran (5 ml) at 0oC add alumoweld lithium (a 1.0 M solution in tetrahydrofuran). The mixture is heated to room temperature and stirred for 1 hour. The reaction is quenched (sodium hydroxide and water) and the reaction mixture is filtered through a zeolite for removal of inorganic substances. The filtrate is evaporated and the residue purified on silica using as eluent 10% methanol in dichloromethane. Get the product as yellow oil. 1H NMR (250 MHz, CDCl3) 8,08 (1H, s), 7,60 (1H, s), 7,49 (2H, user.C), 7,37 - 7,31 (3H, m), 7,13 (2H, s), is 4.85 (1H, q, J = 6.6 Hz), 4,36 (1H, d, J = 2,8 Hz), 4,33 - 4,24 (1H, m), 4,22 (2H, t, J = 6.5 Hz), 3,86 (1H, DD, J = 14.1 Hz), 3,63 (1H, d, J = 9,2 Hz), 3,60 (1H, d, J = 2,9 Hz), to 3.38 (1H, DD, J = 14,0 Hz) of 3.00 (1H, d, J = 11.7 Hz), 2,89 (2H, t, J = 6.6 Hz), 2,59 (1H, user. t, J = 11,9 Hz), 2,59 - 2,49 (4H, m) to 1.79 (4H, m)oethyl)-1,2,4-triazole-3-yl) methylmorpholine

The compound described in example 22a (isomer A), enter into interaction in accordance with the procedure described in example 22b, and get mentioned in the title compound as a yellow oil.1H NMR (250 MHz, CDCl3) 7,80 (1H, s, CH), to 7.61 (1H, s, ArH), 7,53 - of 7.48 (2H, m, PhH), 7,38 - 7,34 (3H, m), 7,17 (2H, s), 4,88 (1H, q, J = 6.5 Hz), 4,36 (1H, d, J = 2,9 Hz), 4,34 - 4,20 (1H, m), 4,23 - 4,07 (3H, m), 3,83 (1H, d, J = 14,0 Hz), 3,66 (1H, m), 3,42 (1H, d, J = 2,8 Hz), with 3.27 (1H, d, J = 14.1 Hz), 2,88 - by 2.73 (1H, m), 2,88 - by 2.73 (2H, m), 2,88 - by 2.73 (1H, m) of 2.50 (3H, user.C) of 1.73 (4H, user.(C) a 1.4 (4H, d, J = 6,6 Hz).

Example 24

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-vermeil)- 4-(5-morpholinomethyl)-1,2,3-triazole-4-yl)methylmorpholine

This connection is produced by a method described in example 12 (method A), and purified by chromatography on silica, using ethyl acetate, petroleum ether (60-80oC) and methanol (3:10:0, then 1:0:0, and then 9:0:1) as eluent, and get mentioned in the title compound as a white foam.1H NMR (360 MHz, CDCl3) of 1.44 (3H, d, J = 6.6 Hz), 2,43 (4H, m), 2.57 m (1H, d, J = 11,9, and 3.4 Hz), 2,90 (1H, d, J = 11,6 Hz), with 3.27 (1H, d, J = 14.1 Hz), 3,4 - to 3.67 (8H, m), 3,82 (1H, d, J = 14.1 Hz), to 4.23 (1H, m), 4,32 (1H, d, J = 2,8 Hz), to 4.87 (1H, m), 7,06 (2H, t, J = 8.7 Hz), 7,16 (2H, s), of 7.48 (2H, user.C) to 7.64 (1H, s), m-c. (ES+) m/z 618 (MH1, 54%).

Compounds of examples 25-27 in table 2, we can get way, dtweedie amines.

Example 28

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy-4- (2-chloro-5-morpholinomethyl-1,3-imidazol-4-yl)-(S)-(4-forfinal) morpholine

The product of example 7 (0.2 g) and phosphorus oxychloride is refluxed for 20 hours. The mixture is cooled and treated her dichloromethane and an aqueous solution of potassium carbonate. The organic layer is washed (H2O), dried (MgSO4) and evaporated under vacuum. The product was then purified by chromatography on silica using initially 100% ethyl acetate, then 5% methanol and 95% of ethyl acetate, and get mentioned in the title compound in the form of oil. M. c-c. (ES+) m/z 651 (MH+, 100%).

Example 29

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N, N-dimethylaminomethyl) imidazol-4-yl)methyl-3-(S)-(4-forfinal)morpholine

Hydrochloride 4,5-bis(chloromethyl)imidazole (description of the United Kingdom patent GB-2068362-(A) enter into interaction with the compound of example descriptions 5 in accordance with the method described in example 4, and get mentioned in the title compound as a white solid. 1H NMR (250 MHz, CDCl3) of 1.44 (3H, d, J = 6 Hz), 2,19 (3H, c), 2,46-2,62 (2H, m), 2,92 - of 3.07 (2H, m), 3.25 to 3,44 (3H, m), 3,56 - 3,70 (2H, m), 4,16 - to 4.33 (2H, m), is 4.85 (1H, q, J = 6 Hz), 7,01 - 7,17 (4H, m), 7,38 - to 7.67 (4H, m), m-c. (ES) m/z 575 (M + 1+, 100%).


3,5-Bis(chloromethyl)triazole (J. Het. Chem. (1986) 23, 361-368) enter into interaction with the compound of example descriptions 5 in accordance with the method illustrated in example 4, and get named in the title compound in the form of solids.1H NMR (250 MHz, CDCl3) of 1.27 (3H, d, J = 6.6 Hz), of 2.15 (6H, c, CH3), 2,43 (1H, d, J = 11.7 Hz), 2,79 - and 2.83 (1H, m), and 3.16 (1H, d, J = 15,4 Hz) to 3.38 (1H, d, J = 2,8 Hz), 3.43 points-of 3.48 (1H, m), of 3.48 (2H, s, CH2), 3,63 (1H, d, J = 14,5 Hz), 4,12 (1H, dt, J = 11,7, a 3.2 Hz), 4,15 (1H, d, J = 2,8 Hz), 4,69 (1H, sq J = 6.6 Hz), 6,85 (2H, t, J = 8,75 Hz), 6,97 (2H, c), 7,27 (2H, user. t), was 7.45 (1H, c). M.-c. (ES) m/z 576 (M+1, 100%).

Connection examples 31-37 in table 2, we can get by the method similar to the method described in example 12, method B, through the appropriate N-(4-useabout-2-inyl)morpholines and the corresponding amines.

Compounds of examples 38-41 in table 1 are according to the method similar to the method described in example 4 from the respective morpholino, 4,5-bis(methyl bromide)-1,3-diacetyl-2-imidazolinone and the corresponding amines.

Example 42

5-Oxide-2-(R)-(1-(R)-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)- 4-(2,4-dihydro-2-oxo-5-timeframestr-1,3-imidazol-4-yl)methylmorpholine

The compound of example 38 (67 mg, 1 EQ.) dissolve in CF3CO2H (0.3 ml) in an atmosphere of N2then races stirring at 0oC for 1 hour the solvent is removed in vacuo, and the residue is dissolved in EtOAc and washed with saturated aqueous NaHCO3, dried (K2CO3and concentrate, get a remainder of a yellow foam. This foam is purified column chromatography, using as eluent MeOH/CH2Cl2/NH3(3:97:0,25), and get mentioned in the title compound as a white solid.1H NMR (250 MHz, CDCl3) 9,48 (1H, c), 8,66 (1H, c), to 7.64 (1H, c), 7,40 (2H, m), 7,14 (2H, c), 7,06 (2H, t, J = 8.6 Hz), to 4.87 (1H, q, J = 6.5 Hz), 4,30 (1H, d, J = 2.7 Hz), to 4.23 (1H, t, J = 10.0 Hz), the 3.65 (1H, d, J = 9.6 Hz), of 3.45 (1H, m in), 3.75 (1H, m) to 3.36 (1H, d, J = 2.7 Hz), 3,30 (1H, d, J = 14 Hz), 3,20 (1H, d, J = 14 Hz), 3,05 - 2,60 (9H, m), a 2.36 (1H, m) of 1.46 (3H, d, J = 6.5 Hz).

Connection examples 43-62 in table 2, we can get by the method similar to the method described in example 12, method B, through the appropriate N-(4-useabout-2-inyl)morpholines and the corresponding amines.

Example 63

2-(R)-(2-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(1-(2-(N, N - diisopropylamino)ethyl)-1,2,4-triazole-3-yl)methyl-3-(S)-phenylmorpholine.

a) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(1-(2-hydroxyethyl)- 1,2,4-triazole-3-yl)methyl-3-(S)-phenylmorpholine

Connection example-description 19 (3,90 g, 7.8 mm) heat (60oC) in dimethylformamide (20 ml) containing 2-poprobyvat water and salt solution, dried (MgSO4) and evaporated. Two isomers purified and separated by silica, elwira mixtures of methanol with dichloromethane (of 3.06 g), M.-c. (ES)+m/z 545.

b) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(1-(2 - Casinocity)-1,2,4-triazole-3-yl)methylmorpholine

Alcohol with the above stage (a) (1,81 g, 3,22 mm) dissolved in dichloromethane (20 ml), add taillored (1.84 g, to 9.66 mm) and triethylamine (of 1.34 ml, to 9.66 mm) and the reaction mixture was stirred at room temperature for 18 hours. The solvent is removed, the residue is again dissolved in ethyl acetate and the solution washed with water and brine, dried (MgSO4) and evaporated. The product was then purified on silica, elwira mixtures of methanol with dichloromethane (1.87 g).

c) 2-(R)-(2-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(1-(2-(N, N-diisopropylamino) ethyl)-1,2,4-triazole-3-yl)methyl-3-(S)-phenylmorpholine

Toilet with the above stage (b) (0.29 grams, 0,41 mm) dissolved in dimethylformamide (5 ml), add dipropylamine (of 0.18 ml, 1,24 mm) and triethylamine (of 0.18 ml, 1,24 mm) and the reaction mixture is heated in a sealed tube for 18 hours. The residue is dissolved in ethyl acetate, washed with a solution of water and salt solution, dried (MgSO4) and evaporated. After purification on silica with (360 MHz, DMSO-d6) 8,31 (1H, c), of 7.82 (1H, c), 7,46 - 7,42 (2H, m), of 7.36 (2H, s), 7,32 - 7,22 (3H, m), 4,89 to 4.92 (1H, sq J = 6.5 Hz), 4,34 (1H, d, J = 2,8 Hz), 4,18 - Android 4.04 (3H, m), 3,60 of 3.56 (3H, m) to 3.09 (1H, d, J = 13,6 Hz), of 3.94 (1H, d, J = 11.5 Hz), a 2.71 (2H, t, J = 5.8 Hz), 2,44 - to 2.40 (1H, m), 2,30 (4H, t, J = 7,0 Hz) of 1.34 (3H, d, J = 6.5 Hz), 1.32 to - 1,20 (4H, m) and 0.73 (6H, t, J = 7.4 Hz). M/S + 628.

Connection examples 64-74 table 3 receive according to the method similar to the method described in example 63, from the corresponding 1,2,4-triazole-3-ylmethylamino and the corresponding amines.

Example 75

2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N, N - dimethylaminomethyl)-1,2,4-triazole-3-yl)methyl-3-(S)-(4-forfinal)morpholine

a) 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 - forfinal)-4-(1-(tetrahydro-2-pyranyl)-5-(N, N-dimethylamino-methyl)- 1H-1,2,4-triazole-3-yl)methylmorpholine

Connection example-description 5 (1 g, 2,28 mm) dissolved in isopropanol (20 ml), add 3,5-bis(chloromethyl)-1-(tetrahydro-2-pyranyl)-1H-1,2,4-triazole (1,14 g, 4,58 mm) obtained by the method Bradshaw, H. Het.Chem. (1986), 23, 361) and potassium carbonate (0.95 g, 6,84 mm), and the reaction mixture is heated at 60oC for 18 hours. Then add dimethylamine (3 equiv.) and reagents are transferred into a tube, which is sealed, and heated for 18 hours. Then remove the solvents and the residue purified on silica, Elya is 1-(R)-3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N,N - dimethylaminomethyl)-1,2,4-triazole-3-yl)methyl-3-(S)-(4-forfinal)morpholine

Connection with the above stage (a) with a protected amino group (0,62 g 0,94 mm) dissolved in methanol (15 ml) and treated with HCl in methanol (1N, 25 ml) and stirred the reaction mixture for 1 hour at room temperature. Then the solvent is removed, and the residue purified on silica, elwira mixtures of methanol with dichloromethane and ammonia, and get named in the title compound (0,48 g).1H NMR (250 MHz, CDCl3) was 7.45 (1H, c), 7,30-7,22 (2H, m), 6,97 (2H, c), 6,85 (2H, t, J=8.7 Hz), 4,72-of 4.66 (1H, q, J= 6.5 Hz), 4,15 (1H, d, J=2,8 Hz), 4,15-4,07 (1H, m), 3,63 (1H, d, J=14.4 Hz), 3,48 (4H, c), 3,44-to 3.41 (1H, m), to 3.38 (1H, d, J=2,8 Hz), and 3.16 (1H, d, J=14,5 Hz), of 2.81 (1H, d, J=11,1 Hz), 2,50-2,39 (1H, m), of 2.15 (6H, c), and of 1.27 (3H, d, J=6.6 Hz). M/S ES+576.

Example 76

4-(5-N,N-Dimethylaminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)-(4 - forfinal)-2-(R)-(1-(R)-(3-methylthio-5-(trifluoromethyl)phenyl)ethoxy)morpholine

The compound of example 57 (270 mg, 0.51 mmol) is heated at 120oC thiamethoxam sodium (178 mg, 2.55 mmol) in anhydrous DMF (10 ml) for 2-5 hours. After cooling, the solution was diluted with water (150 ml), extracted with ethyl acetate (4x40 ml), the extracts dried (MgSO4) and evaporated under vacuum. Receive crude oil (372 mg), which was purified flash chromatography on silica gel, 5-10% methanol in dichloromethane, and receive specified in the B>3) is 1.31 (3H, d, J=6.6 Hz), 2,17 (6H, c), of 2.28 (3H, c), 2,47 (1H, d, J=12,1, 3,4 Hz), 2,82 (1H, d, J=11,6 Hz), 3,14 (1H, d, J=a 13.9 Hz), the 3.35 (2H, m), of 3.46 (1H, d, J=13.5 Hz), 3,52 (1H, DD, J=11,2, 1.9 Hz), 3,70 (1H, d, J=a 13.9 Hz), 4,14 (1H, dt, J=11,6 Hz), 4.26 deaths (1H, d, J=2.7 Hz), of 4.66 (1H, q, J=6.5 Hz), only 6.64 (2H, c), H, c), of 6.99 (2H, t, J=8.6 Hz), 7,11 (1H, c), 7,41 (2H, user.c) of 10.0 and 10.8 (1H, very broad (c). M.-C. (ES+) m/z 554 M+1, 100%).

Example 77

3-(S)-(4-Forfinal)-2-(R)-(1-(R)-(3-methylthio-5-(trifluoromethyl) phenyl)ethoxy)-4-(5-pyrrolidinyl-1,2,3-triazole-4-yl)methylmorpholine

Named the title compound is obtained from the compound of example 18 according to the method described in example 76, in the form of foam (620 mg, 81%).1H NMR (360 MHz, CDCl3) of 1.40 (3H, d, J=6.6 Hz), to 1.79 (4H, user.c) a 2.36 (3H, c), 2,5-2,6 (5H, m), 2,87 (1H, d, J=11.7 Hz), 3,23 (1H, d, J=a 13.9 Hz), 3,43 (1H, d, J= a 13.9 Hz), 3,57-of 3.64 (2H, m), 3,71 (1H, d, J=13,7 Hz), of 3.78 (1H, d, J= 14,0 Hz), is 4.21 (1H, m) to 4.33 (1H, d, J=2,8 Hz), 4,74 (1H, q, J=6.5 Hz), of 6.71 (2H, c), 7,06 (2H, t, J=8.7 Hz), 7,19 (1H, c), 7,47 (2H, user.c). M.-C. (ES+) m/z 580 (M+1, 100%).

Example 78

3-(S)-(4-Forfinal)-2-(R)-(1-(R)-(3-methylthio-5-(trifluoromethyl) phenyl)ethoxy)-4-(5-morpholinomethyl)-1,2,3-triazole-4-yl)methylmorpholine

Specified in the title compound obtained as foam from the compound of example 19 according to the method described in example 76 (126 mg, 66%). 1H NMR (360 MHz, CDCl3) of 1.40 (3H, s, J=6.6 Hz), is 2.37 (3H, c), 2,32-2,49 (4H, m), of 2.54 (1H, dt, J=11,9, and 3.4 Hz), 2,90 (1H, d, J=11.7 Hz) at 3.25 (1H, d, J=1 7,19 (1H, c), 7,49 (2H, user.c). M.-C. (ES+) m/z 596 (M+1, 55%), 203 (100%).

Example 79

4-(5-(N, N-Dimethylaminomethyl)-1,2,3-triazole-4-yl)-methyl - 2-(R)-(1-(R)-(3-methylthio-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenylmorpholine

Specified in the title compound obtained as foam from a triazole of example 102 according to the method described in example 76 (116 mg, 36%). 1H NMR (250 MHz, CDCl3) of 1.39 (3H, d, J=6.5 Hz), 2,24 (6H, c), 2,32 (3H, c), 2,59 (1H, dt, J=11.8 in, 3,3 Hz) at 3.25 (1H, d, J=13,8 Hz), 3,38-3,44 (2H, m), 3,52 (1H, d, J= 13,6 Hz), 3,62 (1H, DD, J=11,2, 1.8 Hz), 3,81 (1H, d, J=a 13.9 Hz), to 4.23 (1H, m), 4,39 (1H, d, J=2,6 Hz), and 4.75 (1H, q, J=6.5 Hz), of 6.71 (2H, c), 7,17 (1H, c), 7,34-7,41 (3H, m), 7,49 (2H, user.c). M.-C. (ES+) m/z 536 (M+1, 100%).

Example 80

4-(5-(N, N-Dimethylaminomethyl)-1,2,3-triazole-4-yl)-methyl-3-(S)- (4-forfinal)-2-(R)-(1-(R)-(3-tert-butylthio-5-(trifluoromethyl)phenyl) ethoxy)morpholine

Specified in the title compound is obtained from the compound of example 57 in the form of foam, according to the method described in example 76 (117 mg, 68%).1H NMR (360 MHz, CDCl3) to 1.19 (9H, c) of 1.42 (3H, d, J=6.6 Hz), of 2.23 (6H, c), to 2.57 (1H, dt, J= 12,0,, 3.5 Hz), 2,92 (1H, d, J=11,6 Hz), 3,24 (1H, d, J=a 13.9 Hz), 3,39-3,44 (2H, m), 3,51 (1H, d, J=14,8 Hz), 3,62 (1H, m), 3,80 (1H, d, J= a 13.9 Hz), to 4.23 (1H, m) to 4.41 (1H, d, J=2.7 Hz), of 4.77 (1H, q, J=6.5 Hz), 6.89 in (1H, c), 7,14 (1H, c), 7,31-to 7.35 (3H, m), 7,46 (2H, user.c) 7,51 (1H, s). M-.(ES+) m/z 578 (M+1, 100%).

Example 81

4-(5-(N, N-Dimethylaminomethyl)-1,2,3-triazole-4-yl)- methyl-g, 0.28 mmol) is dissolved in triperoxonane acid (800 ml), cooled to 0oC and treated with a 2.0 M solution cryptanalyses acid in triperoxonane acid (153 μl, 0,308 mmol) and stirred for 30 minutes. The reaction mixture was poured into 0.5 M sodium bicarbonate solution (50 ml), extracted with a mixture of dichloromethane (I ml), dried extract (MgSO4) and concentrated in vacuo. The resulting crude solid is purified flash chromatography on silica gel in methanol (8%) with dichloromethane and get listed in the title compound in the form of undigested stereoisomers in the form of a white foam (81 mg, 51%).1H NMR (360 MHz, CDCl3) of 1.44 and a 1.46 (3H, just 2 x d, J=6.6 Hz), 2,24 (6H, s), of 2.56 (1H, m), 2,59 and 2,62 (3H, just 2 x C), is 2.88 (1H, d, J=11,9 Hz), of 3.23 and 3.26 (1H, only 2 x d, J=a 13.9 Hz), 3,42-3,55 (3H, m), 3,62 (1H, user.d, J= 11.3 Hz), 3.75 to and with 3.79 (1H, only 2 x d, J=14.4 Hz), 4,22 (1H, m), 4,32 and 4.35 (1H, only 2 x d, J=2.7 Hz), 4,89 (1H, m), 6,85 (1/2H, s),? 7.04 baby mortality-7,13 (3H, m), 7,24 (1/2H, s) to 7.50 (2H, user.C) 7,73 and 7.75 (1H, only 2 x). M.-C. (ES+) m/z 570 (M+1, 100%).

Example 82

3-(S)-(4-Forfinal)-2-(R)-(1-(R)-(3-methylsulfinyl - 5-(trifluoromethyl)phenyl)ethoxy)-4-(5-pyrrolidinyl - 1,2,3-triazole-4-yl)methylmorpholine

Specified in the title compound in the form of undigested stereoisomers or in the form of foam produced from soedin (3H, just 2 x d, J=6,6), to 1.86 (4H, user.C) 2,50-2,60 (1H, m), 2,59 and 2,62 (3H, just 2 x C), 2,70-2,90 (5H, m), 3,24 and 3.26 (1H, 2 x d, J=14,0), of 3.46 (1H, d, J<2), 3,62 (1H, user.d, J=11,2), 3,71-3,86 (3H, m), 4,20 (1H, m), 4,32 and 4.35 (1H, only 2 x d, J=2,7), 4,89 (1H, m), 6.89 in (1/2, s), 7.03 is-7,13 (3H, m), 7,25 (1/2H, s), 7,49 (2H, user.with(, 7,73 and 7.75 (1H, 2 x s). M.-C. (ES+) m/z 596 (M+1, 100%).

Example 83

3-(S)-(4-Forfinal)-2-(R)-(1-(R)-(3-methylsulfinyl - 5-(trifluoromethyl)phenyl)ethoxy)-4-(5-morpholinomethyl - 1,2,3-triazole-4-yl)methylmorpholine

Specified in the header connection receive in the form of undigested mixture of stereoisomers or in the form of foam, from the compound of example 78 according to the method described in example 81 (113 mg, 92%).1H NMR (360 MHz, CDCl3) of 1.3 and 1.41 (3H, just 2 x d, J= 6,6), of 2.54 and 2.57 (3H, 2 x s), 2,54-to 2.65 (1H, m), 2,82-2,89 (1H, m), 3,05-of 3.25 (4H, very wide C.), at 3.35 (1H, m), 3,50 (1H, m), 3,61 (1H, m), and 3.72 and 3.74 (1H, 2 d, J=14,5), 3,85-4,22 (6H, m), 4,29, and to 4.33 (1H, 2 x d, J=2,5), to 4.81 (1H, m), 6,99 - 7,09 (3 1/2, m), 7,30 (1/2H, s), 7,42 (2H, user.C) to 7.64 and 7,66 (1H, 2 x s). M.-C. (ES+) m/z 612 (M+1, 100%).

Example 84

3-(S)-(4-Forfinal)-2-(R)-(1-(R)-(3-methylsulphonyl - 5-(triterpenes)phenyl)ethoxy)-4-(5-morpholinomethyl - 1,2,3-triazole-4-yl)methylmorpholine

Sulfoxide of example 83 (78 mg, 0,128 mmol) dissolved in triperoxonane acid (500 μl), the solution is cooled to 0oC and treated with a 2.0 M solution triperoxonane acid in trifter referencesee acid (70 μl, 0,140 mmol) and after 3 hours the product was then purified according to the method described in example 81, receiving specified in the title compound as a foam (27 mg, 34%).1H NMR (360 MHz, CDCl3) to 1.47 (3H, d, J=6.6 Hz), 2,38 at 2.45 (4H, m), 2.57 m (1H, dt, J=11,9, 3,5), 2,90 (1H, d, J=11.7 Hz), 2,96 (3H, s), 3,26 (1H, d, J=14, 0 Hz), 3.46 in-3,51 (2H, m), 3,56-3,68 (6H, m), with 3.79 (1H, d, J=14.1 Hz), 4,22 (1H, m), 4,35 (1H, d, J=2,8 Hz), the 4.90 (1H, q, J=6.8 Hz), 7,07 (2H, t, J=8.6 Hz), 7,17 (1H, s) to 7.50 (2H, user.d), to 7.67 (1H, s), of 7.97 (1H, s). M-(ES+) m/z 628 (M+1, 100%).

Example 85

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)- -(S)-(4-forfinal)-4-(2-(5-((S)-(+)-2-ethoxymethylenemalononitrile) -1,2,3-triazole-4-yl)ethyl)-morpholine

Stage A. 2-(R)-1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy - 4-(but-3-inyl)-3-(S)-(4-forfinal)morpholine

A solution of compound of example descriptions 5 (1.24 g, 1 EQ.), 3-butyl-1-ol-tosilata (1,43 g, 2.5 EQ.) K2CO3(1,32 g, 3.7 EQ.) and Nal (cat.) in dry DMF (7 ml) is heated at 100oC for 12 hours. After cooling to room temperature the reaction mixture is treated with H2O and EtOAc. The layers are separated and the aqueous phase is extracted with EtOAc (2x). The combined organic phases are dried (Mg SO4) and evaporated, and the residue purified by chromatography (hexane/EtOAc 9: 1 ---> 4:1), and get mentioned in the title compound as a clear colorless oil. M-with m/z 490 (MH+).

Acetylene compound from step A (1.2 g, 1.0 EQ.) dissolved in dry THF, then the solution is cooled to -78oC and add n-BuLi (2.5 M in hexane, 1 ml of 1.05 EQ.). The reaction mixture was stirred at -78oC for 1 hour, then passed through a solution of gaseous HCHO before saturation. The reaction mixture is heated to room temperature, stirred for 1 hour. Processing (NH4Cl/EtOAc) followed by purification on silica gel (hexane-EtOAc) 9:1 ---> 4:1) get mentioned in the title compound in the form of a clear viscous oil. M.-C. m/z 520 (MH+).

Stage C. 2-((R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)- ethoxy)-4-(4-harbut-3-inyl)-3-(S)-(4-forfinal)morpholine

The alcohol from step B (0,42 g, 1 EQ.) dissolved in dry THF (5 ml) in an atmosphere of N2and add triphosgene (84 mg, of 0.35 equiv.) and then pyridine (128 μl, 2.0 EQ.). The reaction mixture was stirred at room temperature for 0.5 hours, then diluted with EtOAc and washed with H2O and brine, dried (MgSO4) and concentrate remains yellow oil. This oil is purified by chromatography (hexane/EtOAc 9:1 ---> 4:1) and get named in the title compound in the form of a clear viscous oil. M.-C. m/z 538, 540 (MH6+)

Stage D. N-(4-Useabout-3-inyl)-2-(R)-(1-(R)-(3,5-bis(three-the MCO (0.8 ml) was stirred at room temperature for 14 hours. Processing (NH4Cl/EtOAc) gives specified in the title compound in the form of oil, which is used without further purification.

Stage E. 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy-3- (S)-(4-forfinal)-4-(2-(5-((S)-(+)-2-methoxymethyl-pyrrolidinyl)- 1,2,3-triazole-4-yl)ethyl)formalin

A solution of the azide from step D (0,205 g, 1 EQ.) and (S)-(+)-2-methoxypiperidine (114 μl, 3 EQ. ) is heated at 80oC in an atmosphere of N2remove the solvent under vacuum, and the residue purified by chromatography, using as eluent CH2Cl2/MeOH/NH3(98: 2: 0.1, then 97:3:0,1), and get mentioned in the title compound as a white foam.1H NMR (250 MHz, CDCl3) a 7.62 (1H, s), 7,24 (2H, m), 7,14 (2H, s), to 6.95 (2H, t, J = 8.7 Hz), to 4.87 (1H, q, J = 6.5 Hz), 4,30 (2H, m), 3,95 (1H, d, J = 14 Hz), 3,70 (1H, DD, J = 2, 11.3 Hz), 3,53 - 3,34 (7H, m), 3,19 (1H, d, J = 11,6 Hz), 2,86 - of 2.56 (6H, m) to 2.29 (1H, m), is 2.09 (1H, m), a 1.88 (1H, m) to 1.70 (3H, m) of 1.45 (3H, d, J = 6.5 Hz), M.-C. m/z = 660.

Example 86

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxy-ethoxy) -4-(5-(N, N-dimethylaminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)-(4 - forfinal)morpholine

Stage A. 2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-tert - butyldimethylsilyloxy)-3-(S)-(4-forfinal)morpholine

The product of example descriptions 21 (2 g) dissolved in anhydrous dichloromethane (16 ml) in atmosphear (1.0 ml) and the mixture is stirred for 15 minutes. The reaction mixture was washed (H2O, brine), dried (MgSO4) and evaporated under vacuum. Purification by gravity column of silica using as eluent 20 to 50% ethyl acetate in petroleum ether gives named the title compound as a colourless oil.1H NMR (250 MHz, CDCl3) to 0.04 (3H, s) 0,00 (3H, s) of 0.87 (9H, s), 3,15 - to 3.36 (2H, m), 3,64 - 3,70 (2H, m), 3,90 - of 3.96 (1H, m), 4,10 (1H, d, J = 2.2 Hz), 4,22 - a 4.53 (1H, m), a 4.53 (1H, d, J = 2.2 Hz), 4,91 (1H, t, J = 5,9 Hz),? 7.04 baby mortality - 7,14 (2H, m), 7.29 trend was 7.36 (4H, m), 7,74 (1H, user. C). M.-C. (ES+) m/z = 567.

Stage B. 2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-tert - butylmethacrylate)-3-(S)-(4-forfinal)-4-(4-harbut-2-inyl)morpholine

Get a manner analogous to the method of stage (a) of example 12, method B, using the product of the above stage A. Get mentioned in the title compound as a colourless oil.1H NMR (360 MHz, CDCl3) 0,00 (3H, s), and 0.04 (3H, s) of 0.91 (9H, s), 2,95 - to 3.09 (2H, m), 3,40 (2H, user.C), and 3.72 - a 3.83 (3H, m) to 4.01 (1H, DD, J = 10,2, 5,5 Hz), 4,25 (2H, m), 4,50 (2H, m), 4,9 (1H, t, J = 5,9 Hz), to 7.15 (2H, t, J = 8.7 Hz), 7,29 (2H, s), 7,52 (2H, user.C) 7,76 (1H, s).

Stage C. 2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-tert - butyldimethylsilyloxy)-4-(5-(N, N-dimethylaminomethyl)-1,2,3 - triazole-4-yl)methyl-3-(S)-(4-forfinal)morpholine

By analogy with the stages (b) and (1H NMR (250 MHz, CDCl3) 0,02 (3H, s) 0,00 (3H, s) to 0.88 (9H, s), is 2.30 (6H, s), 2,60 - 2,70 (1H, m), 2.93 which are 2.98 (1H, user. d, J = 11,6 Hz), 3,30 (1H, d, J = 13,8 Hz), 3,48 - 3,63 (3H, m), 3,68 - 3,74 (2H, m), 3,84 - of 3.97 (2H, m), 4,33 - to 4.41 (1H, m), 4,46 (1H, d, J = 2,8 Hz), the 4.90 (1H, t, J = 5.6 Hz), 7,16 (2H, t, J = 8.7 Hz), 7,25 (2H, user. C) to 7.59 (2H, very broad m), 7,74 (1H, user. C).

Stage D. 2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2 - hydroxyethoxy)-4-(5-(N, N-dimethylaminomethyl)-1,2,3-triazole-4-yl) methyl-3-(S)-(4-forfinal)morpholine

The product from above and C (0.2 g) in anhydrous tetrahydrofuran (2 ml) is stirred with tetrabutylammonium (1.0 M in tetrahydrofuran at 0.42 ml) for 30 minutes. The mixture is treated with a solution of ammonium chloride and ethyl acetate, and the organic layer washed (H2O, brine), dried (MgSO4) and evaporated under vacuum. Purification using gravity column dioxolan silica with elution 4 - 10% MeOH/0.1% of NH4OH/dichloromethane gives the named header connection.1H NMR (250 MHz, CDCl3) and 2.26 (6H, s), of 2.51 (1H, m) to 3.09 (2H, m) to 3.35 (2H, m), 3,51 - 3,63 (4H, m), of 3.78 (2H, d, J = 13,8 Hz), 4,30 is 4.36 (2H, m), 4,88 (1H, m), 7,01 - 7,10 (4H, m) to 7.50 (2H, very broad (C), to 7.59 (1H, user. C).

Example 87

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy-4-(5-N-ethyl-N - isopropylaminomethyl)-1 (or 2, or 3) -methyl-1,2,3-triazole-4-yl)methyl-3-(S)-phenylmorpholine2O 2, brine), dried (MgSO4) and evaporated under vacuum. Purification by gravity chromatography on silica with elution with 100% ethyl acetate and then a mixture of 10% methanol, 0.1% of NH4OH and dichloromethane gives specified in the header of the connection.1H NMR (250 MHz, CDCl3) 0,85 - of 1.02 (9H, m) of 1.44 (3H, d, J = 6.6 Hz), 2,25 - to 2.40 (2H, m), 2.57 m) of 2.68 (1H, m), of 2,75 2,85 (1H, m), 2,96 (1H, user. d, J = 13.5 Hz) and 3.15 (1H, d, J = 13.5 Hz), 3,38 (1H, d, J = 2.7 Hz), 3,44 (2H, s), 3,60 - to 3.73 (2H, m), 4,07 (3H, s), 4,18 (1H, m), 4,35 (1H, d, J = 2,8 Hz), a 4.83 (1H, m), to 7.15 (2H, user. C), 7,33 (3H, m), of 7.48 (2H, very broad s), to 7.61 (1H, user.C). M.-C. (ES+) m/z = 613 (MH+, 100%).

Example 88

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl-2-hydroxyethoxy)-3-(S)-(4 - forfinal)-4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methylmorpholine

Connection example-description 6 (0.5 g), N-carbomethoxy-2-chloracetamide (example-description 23) (182 mg) and potassium carbonate (0.3 g) is suspended in dimethylformamide (3.6 ml) and the mixture is heated at 60oC for 2 hours. Then the mixture is warm at 140oC for 2 hours. The mixture is cooled and then filtered through celite to remove neorganic what cografya on the silicon dioxide, using 1-10% methanol in dichloromethane. Get listed in the title compound as a white powder (300 mg).1H-NMR (360 MHz, DMSO-d6) 2,38 - to 2.41 (1H, m), 2,78 (1H, d, J = 14,0 Hz), 2,81 - 2,84 (1H, m) to 3.36 (1H, d, J = 14,0 Hz), 3.45 points - of 3.48 (1H, m), 3,52 (1H, d, J = 3.0 Hz), to 3.58 - 3,61 (2H, m), to 4.81 (1H, t, J = 6.0 Hz), 4,88 (1H, user. so), to 7.09 (2H, t, J = 9.0 Hz), 7,33 (2H, s) to 7.50 (2H, user.t), the 7.85 (1H, c), of 11.26 (1H, s), 11,30 (1H, S. M.-S. (Cl+) m/z 551 (M+1, 10%), 454 (M+-CH2-triazole, 20).

Example 89

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl-2-hydroxyethoxy)-3-(S)-(4 - forfinal)-4-(1,2,4-triazole-3-yl)morpholine

Connection example-description 6 (270 g), anhydrous potassium carbonate (250 mg) and N-formyl-2-chloroacetanilides (92 mg) (obtained by I. Yanagisawa, J. Med. Chem. (1984), 27, 849) is heated at 60oC in anhydrous dimethylformamide for 1 hour and then at 140oC for 2 hours. The reaction mixture is cooled and diluted with water (100 ml). The product is extracted with ethyl acetate (3 x 50 ml) and the organic layer washed with brine, dried (MgSO4), and evaporated in vacuum. The residue is purified by chromatography on silica using as eluent 7% methanol in dichloromethane. Get listed in the title compound (200 mg, 60%) as a white solid.1H NMR (360 MHz, DMSO-d6) 2,47 (1H,,0 Hz), to 4.81 (1H, t, J = 5.0 Hz), 7,11 (2H, t, J = 9.0 Hz), 7,34 (2H, c), 7,52 (2H, m), a 7.85 (1H, s), 8,19 (1H, user.C.), M.-S. (Cl) m/z 535 (M+1, 10%).

Example 90

4-(2,3-Dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-3-(S)-(4-forfinal)-2-(R)-(1-(S) -(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

Connection example-description 22 (350 mg), N-carbomethoxy-2-chloroacetamides (150 mg) (example-description 23) and potassium carbonate (150 mg) in dimethylformamide by warming at 60oC until until used all the original substance. Then the mixture is heated at 140oC for 3 hours. The mixture is cooled and filtered through celite to remove inorganic substances. The residue is evaporated using xylene for azeotropic removal of residual dimethylformamide. The residue is purified by chromatography on silica, using 1-10% methanol and dichloromethane as eluent. Get listed in the title compound in the form of foam, which is recrystallized from ether.1H NMR (360 MHz, DMSO-d6) 2,34 is 2.46 (1H, m), 2,74 - 2,84 (2H, m), 3,34 - of 3.43 (3H, m), 3,50 - 3,60 (2H, m), 4,21 - or 4.31 (2H, m), and 4.68 (1H, t, J = 5.0 Hz), the 4.90 (1H, t, J = 7.0 Hz), is 6.54 (1H, d, J = 9.0 Hz), to 6.88 (1H, s), 7,14 (t, J = 9.0 Hz), 7,42 (1H, t, J = 9.0 Hz), 7,44 (2H, m).

Example 91

4-(2,3-Dihydro-2-oxo-1,3-imidazol-4-yl)methyl-2-(R)-(1-(S)-(3,5-bis (trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluoro who built the way Dolan and Dushinsky, JASC (1948) 70, 657) and potassium carbonate (1.2 g) in dimethylformamide (14 ml) was stirred at room temperature for 30 minutes, until reacts entire source morpholine. The mixture was diluted with water (150 ml) and extracted with ethyl acetate (3 x 50 ml). The combined extracts washed with brine and the organic solvent is removed in vacuum. The remaining oil is dissolved in ethanol (20 ml) and added dropwise methylamine (2 ml 8M R-RA in ethanol). This solution is stirred for 1 hour, then the solvent is removed in vacuum. The remaining oil purified on silica using 1-10% methanol in dichloromethane as eluent. Receive the product (2 g, 83%) as a white foam. Then it is treated with hydrogen chloride in methanol, and get a more solid1H NMR (360 MHz, DMSO-d6) 2,22-of 2.34 (1H, m), 2,62 (1H, d, J = 14,0 Hz), 2,89 (1H, approx. d, J = 11,0 Hz), 3,26 (1H, d, J = 14,0 Hz) to 3.38 (1H, d, J = 3.0 Hz), 3.43 points - of 3.50 (1H, m), 3,57 - 3,62 (2H, m), 4,19 - to 4.28 (1H, m), 4,32 (1H, d, J = 3.0 Hz), to 4.81 (1H, t, = 5,5 Hz), is 4.93 (1H, t, = 6.0 Hz), 6,00 (1H, s), to 7.09 (1H, t, = 9.0 Hz), 7,33 (2H, c), 7,54 (2H, user. so ), 7,86 (1H, s), 9,63 (1H, s). M.-S. (Cl) m/z 550 (M+1, 20%), 454 (80) 116 (100).

Example 92

4-(2,3-Dihydro-2-oxo-5-pyrrolidinyl-1,3-imidazol-4-yl)methyl-2-(R)-1-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-forfinal)-morpholine

The mixture JACS (1948) 70, 657) (2.2 g) and potassium carbonate in dimethylformamide (13 ml) was stirred at room temperature for 10 minutes, until you react all of the original substance. To the resulting brown mixture is added dropwise pyrrolidin (1.65 ml, excess), resulting in an exothermic reaction. The solvent is removed in vacuum, the residue is extracted with ethyl acetate (3 x 50 ml) and the extracts washed with saline. The organic phase is dried (MgSO4) and remove the solvent in vacuo. The brown residue is purified by chromatography with a medium pressure silica gel, reversed phase, using as eluent 30% acetonitrile in 0.1% aqueous triperoxonane acid. Get listed in title product as a dark yellow solid (1 g).1H NMR (360 MHz, DMSO-d6) to 1.61 (4H, user.C), and 2.26 - of 2.30 (5H, m), 2,66 (1H, d, J = 14,0 Hz), 2,83 - 2,87 (1H, user.d) to 3.02 (1H, d, J = 13.5 Hz) and 3.15 (1H, d, J = 13.5 Hz), 3,23 (1H, d, J = 14,0 Hz), 3,37 (1H, d, J = 3.0 Hz), 3,42 - 3,47 (1H, m), 3,57 - of 3.60 (2H, m), 4,17 - 4,24 (1H, m), 4,32 (1H, d, J = 3.0 Hz), 4,79 (1H, t, J = 5.5 Hz), 4,89 (1H, t, J = 5.5 Hz), was 7.08 (2H, t, J = 9.0 Hz), 7,32 (2H, s), 7,56 (2H, m C.), the 7.85 (1H, s), being 9.61 (1H, s), 9,65 (1H, s). M.-S. (Cl+) m/z 633 (M++ 1), 454 (50%).

Example 93

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl-2-phosphorylations)- 3-(S)-(4-forfinal)-4-(2,3-dihydro-3-oxo-1,2,4-triaxialities (200 mg) and tetrazole (100 mg). The reaction mixture is stirred for 2 hours, and then process it further 100 mg of dibenzylethylenediamine, and 1 hour later - tetrazole (100 mg). The reaction mixture is stirred for 1 hour before adding 4-methylmorpholin-N-oxide (1.0 g), after which it is stirred for 16 hours. The reaction mixture was poured into a solution of potassium carbonate and extracted with ethyl acetate. The organic layer is dried (MgSO4), filtered, evaporated and purified by chromatography on silica gel, using as eluent a mixture of methanol with dichloromethane (4 : 96), and get the oil. This oil is dissolved in methanol (2 ml) and add ammonium formate (100 mg) and palladium hydroxide (20% on coal). The reaction mixture is refluxed for one hour and then filtered, evaporated and dried by freezing of acetonitrile with water, get ammonium salt named the title compound (93 mg).1H NMR (360 MHz, D6-DMSO) of 11.29 (1H, s), a 7.85 (1H, s), 7,53 (2H, s), of 7.36 (2H, m), 7,06 (2H, t, J = 7.2 Hz), 4,96 (1H, t, J = 5.4 Hz), 4,34 (1H, d, J = 3.6 Hz), the 4.29 (1H, t, J = 11.2 Hz), 3,92 - of 3.85 (1H, m), 3,68 - 3,63 (1H, m), 3,62 - 3,55 (1H, m), 3,49 (1H, d, J = 3.6 Hz), 3,38 (1H, d, J = 14.4 Hz), 2,82 - and 2.79 (1H, m), 2,77 (1H, d, J = 14.4 Hz), 2,41 to 2.35 (1H, m). M.-C. (ES+) 631 (M + H).

Example 94

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)Peninsula in the title compound from the compound of example 89 by the way, described in example 93.1H NMR (250 MHz, D6-DMSO + 0.1% of TFA) to € 8.74 (1H, s), 7,95 (1H, s), 7,68 (2H, user. C), 7,54 (2H, s), 7,30 (2H, t, J = 8.7 Hz), 5,16 (1H, DD, J = 7 Hz and 5 Hz), 4.72 in (1H, d, J = 1 Hz), of 4.66 (1H, d, J = 1 Hz), 4,42 (1H, t, J = 11 Hz), 3.95 to 4,27 (3H, m), and 3.72 (1H, d, J = 11 Hz) and 3,41 - 3,55 (1H, m).

Example 95

4-(2,3-Dihydro-3-oxo-1,2,4-triazole-5-yl)-3-(S)-phenyl-2- (R)-(1-(S)-(3-trifloromethyl)-2-hydroxyethoxy)morpholine

Produced from compound of example descriptions 30, following the method described in example 88. M.-C. (C++) m/z 465 (M + 1)+, 71%).

Example 96

4-(2,3-Dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-2-(R)- (1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3- (S)-phenylmorpholine

Connection example-description 27 (600 mg), N-carbomethoxy-2-chloromethylation (271 mg) and potassium carbonate (258 mg) was injected into the interaction in dimethylformamide according to the procedure described in example 88. Get the product as a white solid, which is recrystallized from ether-hexane (220 mg, 30%).1H NMR (360 MHz, DMSO-d6) of 2.38 (1H, m), 2,78 (1H, d, J = 14,0 Hz), 2,84 (1H, s), 3,38 - 3,39 (2H, m), of 3.45 (1H, d, J = 14,0 Hz), 3,50 (1H, d, J = 3.0 Hz), of 3.56 (1H, d, J = 11,0 Hz), 4.26 deaths (1H, t, J = 11,0 Hz), 4,34 (1H, d, J = 3.0 Hz), and 4.68 (1H, t, J = 6.0 Hz), is 4.85 (1H, t, J = 6.0 Hz), 6,40 (1H, d, J = 9.0 Hz), of 6.96 (1H, s), 7,33 (3H, m), of 7.36 (1H, d, J = 9.0 Hz), 7,49 (2H, m). M.-S. (Cl+) m/z 483 (M + 1, 20%).
From the compound of example 96 receive ammonium salt mentioned in the title compound using the method of example 93.1H NMR (360 MHz, DMSO-d6) of 11.29 (1H, s), 7,49 - 7,29 (5H, m), 7,38 (1H, d, J = 10,8 Hz), of 6.96 (1H, s), of 6.45 (1H, d, J = 10,8 Hz), 4,84 (1H, d, J = 7,2 Hz), 4,34 (1H, d, J = 3.6 Hz), 4,28 (1H, t, J = 10,8 Hz), 3,80 is 3.76 (1H, m), 3,57 (1H, d, J = 3.6 Hz), 3,57 - to 3.49 (2H, m), 3,47 (1H, d, J = 14.4 Hz), 2,83 was 2.76 (1H, m), 2,78 (1H, d, J = 14.4 Hz), 2,46 - of 2.36 (1H, m).

Example 98

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-3-(S)-phenylmorpholine

Connection example-description 17 enter into interaction with N-carboxymethoxy-2-chloroacetamides (example-description 23) and potassium carbonate according to the method described in example 88. Get the product as a white solid. 1H NMR (360 MHz, DMSO-d6) to 2.42 (1H, dt, J = 12,0,, 3.5 Hz), was 2.76 (1H, d, J = 14,0 Hz), and 2.83 (1H, d, J = 12.0 Hz), 3,39 (1H, d, J = 14,0 Hz), 3,44 - 3,47 (1H, m), 3,50 (1H, d, J = 3.0 Hz), 3,60 (2H, m), 4,22 - to 4.28 (1H, m), and 4.40 (1H, d, J = 3.0 Hz), 4,77 of 4.83 (2H, m), 7,25 - 7,34 (3H, m), 7,41 (2H, s), of 7.48 - to 7.50 (2H, m), 7,82 (1H, s), 11,20 (1H, s), 11,25 (1H, s). M.-S. (Cl) m/z 533 (M+ 1, 30%) 434 (20), 117 (100).

Example 99

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-phosphorylations)- 4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-3-(S)-phenylmorpholine

Get ammonium salt specified in the connection header from the, is), of 4.95 (1H, t, J = 5.4 Hz), 4,39 (1H, d, J = 3.6 Hz), the 4.29 (1H, t, J = 11.2 Hz), 3,92 - to 3.89 (1H, m), 3,60 - of 3.64 (1H, m), 3,5 - 3,59 (1H, m), 3,48 (1H, d, J = 3.6 Hz), 3,42 (1H, d, J = 14.4 Hz), 2,84 - and 2.79 (1H, m), 2,78 (1H, d, J = 14.4 Hz), 2,42 (1H, m). GHUR on a column with Bond Z-Ph (250 x 4.6 mm, EXT.D. 5 μm), elution with 40% acetonitrile in 25 mm KH2PO4with 0.2% triethylamine (pH 3), flow rate 1 ml/min, UV detector 210 nm. Retention time and 4.68 min

Example 100

3-(S)-Phenyl-4-(1,2,4-triazole-3-yl)-2-(R)-(1-(S)-3-(trifluoromethyl)phenyl)- 2-hydroxy-ethoxy)morpholine

Get the salt - hydrochloride - from the compound of example descriptions 30, following the method described in example 89. M.-c. (ES+) m/z 449 (M+1)+100%)

Compounds of examples 101 and 201 in table 2, we can get by the method similar to the method described in example 12, method B, on the basis of the corresponding N-(4-useabout-2-inyl)morpholines and the corresponding amines.

In the following tables 1-3 (see the end of the description and examples, the following notation is used:

MS - m-S. - mass spectrometry

Aral (analysis) elem.analysis elemental analysis Calcd.For - computed for

Found - found

Hz - Hz - Hertz

MHz - MHz - megahertz

DMSO - DMSO - dimethylsulfoxide

NMR NMR - nuclear magnetic resonance

S - s - singlet, d - d - doublet, t - t - triplet, q - kV - the Shire. so broadened triplet, br qn - user. Queen. broadened quintet, br m - user. m - broadened multiplet, vbr s - PTS. W.with. is a very broad singlet, dd - DD double doublet, dt - dt - double triplet, td - TD - triple doublet, br dt - user. dt. - extended double triplet, HRMS - m-senior - high-resolution.

The following examples illustrate the composition of the present invention.

Example 103A.

Tablets containing 1-25 mg connection - Number, mg

The compound of the formula(1) - 1,0; 2,0; 25,0

Microcrystalline cellulose - 20,0; 20,0; 25,0

Modified food corn starch - 20,0; 20,0; 20,0

Lactose - 58,5; 57,5; 34,5

Magnesium stearate - 0,5; 0,5; 0,5

Example 103B.

Tablets containing 26-10 mg connection - Number, mg

The compound of the formula(1) - 26,0; 50,0; 100,0

Microcrystalline cellulose - 80,0; 80,0; 80,0

Modified food corn starch - 80,0; 80,0; 80,0

Lactose - 213,5; 189,5; 139,5

Magnesium stearate - 0,5; 0,5; 0,5

The compound of formula (1), cellulose, lactose and a portion of the corn starch are mixed and granularit with 10% paste of cornstarch. The resulting granules are screened, dried, and mixed with the remainder of the corn starch and the NT is g, 2.0 mg, 25.0 mg, 26,0 mg, 50.0 mg and 100 mg of active compound per tablet.

Example 104.

Parenteral injection - Quantity

The compound of formula (1) is 1-100 mg

Citric acid, monohydrate - 0.75 mg

Sodium phosphate 4.5 mg

Sodium chloride 9 mg

Water for injection up to 10 ml

Sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in parts of water. Dissolved or suspended in this solution the compound of formula (1) and adjusted to the desired volume.

Example 105.

Outer composition - Number

The compound of formula (1) is 1-10 g

The wax and emulsifier 30 grams

Liquid paraffin 20 g

Colorless soft paraffin to 100 g

Colorless soft paraffin is heated to melting. Enter into it with petroleum jelly and wax emulsifier and stirred until dissolution. Add the compound of formula (1) and continue stirring until the formation of a dispersion. The mixture is then cooled to a solid state.

Example 106A.

The composition for injection (surfactant)

The compound of formula (1) up to 10 mg/kg

Tween 80TMup to 2.5%

(in 5% aqueous mannitol (isotonic R-R))

The compound of formula (1) is dissolved directly in a solution of technical R-R).

Example 106B

The composition for injection (emulsion)

The compound of formula (1) 30 mg/ml

IntralipidTM- 10 - 20%

The compound of formula (1) is dissolved directly in commercially available IntralipidTM(10 or 20%) with the formation of the emulsion.

Example 106C

An alternative composition, which can be introduced by injection (emulsion) - Number

The compound of formula (1) is 0.1 - 10 mg

Soybean oil 100 mg

Egg phospholipid - 6 mg

Glycerin - 22 mg

Water for injection to 1 ml

All materials are sterilized and cleaned from pyrogens. The compound of formula (1) dissolved in soybean oil. Then get the emulsion, mixing this solution with egg phospholipids, glycerol and water. Then the emulsion is placed in a sterile ampoules which are sealed.

Biological data

Obtained in the examples of the compounds of the present invention were tested in the manner described below, to determine the affinity to human NK1the receptor. It was found that the compounds or, in the case proletarienne drugs prior to the original compounds show activity against NK1the receptor of the man with the value of the IC50less than 10 nm. The following characteristic data are given for R> 12 - 0.1

16 - 0.2

17 - 0.2

18 - 0.2

21 - 0.2

22 - 0.3

23 - 0.1

32 - 0.5

33 - 0.35

64 - 0.14

65 - 0.45

67 - 0.3

72 - 0.1

78 - 0.3

83 - 0.9

84 - 0.3

88 - 0.05

90 - 0.35

91 - 0.06

92 - 0.06

Analysis of the antagonism of substance P,

A. receptor Expression in the cell line of monkey kidney (COS)

To temporarily Express the cloned human neurokinin-1 receptor (NK1R) in COS, cDNA for the human NK1R cloned in the expression vector pCDM9 derived from pCDM8 (INVITRO-GEN), by introduction of a gene resistant to ampicillin (nucleotides from 1973 until 2964 from BLUESCRIPT SK+ (trade mark, STRATAGENE, La Jolla, CA, USA), site Sac II. Transfection of 20 ug of plasmid DNA into 10 million COS cells was performed by electroporation in 800 µl transfection buffer (135 mm NaCl, 1.2 mm CaCl2, 1.2 mm MgCl2, 2.4 mm, K2HPO4, 0.6 mm KH2PO4, 10 mm glucose, 10 mm N-2-hydroxyethyl-piperazine-N'-2-econsultancy acid (HEPES) pH 7.4) at 260 B and 950 μf using IBI GENEZAPPER (brand IBI, New Haven, CT, USA). Cells were incubated in 10% fetal calf serum, 2 mm glutamine, 100 Units/ml penicillin-streptomycin, and 90% DMEM medium (modified by way of Dulbecco Wednesday Needle, GIBCO, Grand island by boat to watch, NY, USA) in 5% CO
For the Foundation of a stable cell line expressing the cloned human NK1R, cDNA was subcloned into the vector pRcCMV (INVITRO-GEN). Transfection of 20 ug of plasmid DNA into the cells of the Chinese hamster ovary (CHO) was carried out by electroporation in 800 µl transfection buffer, supplemented with 0.625 mg/ml sperm DNA of herring at 300 B and 950 μf using IBI GENEZAPPER (IBI). Transfection cells were incubated in CHO medium (10% fetal calf serum, 100 units /ml penicillin-streptomycin, 2 mm glutamine, 1/500 gipoksantin-thymidine (ATSS), 90% IMDM medium (environment Dulbecco, modified according to the method Claims, JRH BIOSCIENCES, Lenexa, KS, USA), 0.7 mg/ml G418 (GIBCO)] in 5% CO2at 37oC as long as the colony did not become visible. Each colony was separated and cultured. Cell clones with the highest value of human NK1R were selected for further use, such as drug screening.

C. Protocol analysis using COS or CHO

Analysis of binding of human NK1R, expressed or COS or CHO cells, based on the use of labeled 125I-substance P (125I-SP from DU PONT, Boston, MA) as a radioactively labeled ligand which competes with unlabeled substance P or any other is Ali in non-enzymatic solution (SPECIALTY MEDIA, Lavellette, NJ) and resuspendable in an appropriate volume of the binding buffer (50 mm Tris pH 7.5, 5 mm MnCl2, 150 mm NaCl, 0.04 mg/ml bacitracin, 0.04 mg/ml leupeptin, 0.2 mg/ml bovine serum albumin, 0.01 mm of phosphoramidon) so that 200 ál of cell suspension resulted in approximately 10,000 pulses per minute specific125I-SP binding (approximately 50,000 to 200,000 cells). In linking the analysis, 200 ul of cells added to a test tube containing 20 ul of 1.5 to 2.5 nm125I-SP and 20 μl of unlabeled substance P or any other test compound. The tubes were incubated at 4oC or at room temperature for 1 hour with gentle shaking. Bound radioactivity was separated from unbound radioactivity by using GF/C filters (BRANDEL, Gaithersburg, MD), which was previously soaked in 0.1% polyethylenimine. The filter three times washed with 3 ml of wash buffer (50 mm Tris pH 7.5, 5 mm MnCl2, 150 mm NaCl) and its radioactivity was determined by count of gamma radiation.

Activation of phospholipase C via NK1R can also be measured in CHO cells expressing the human NK1R, by determining the accumulation of monophosphate Inositol, which is a product of decomposition IP3. Cells CHO vysivky have introduced 5 mccoury3H-myoinositol in 1 ml of medium per well by incubation over night. Intracellular radioactivity was removed by washing with saline phosphate buffer. To the wells was added LiCl to a final concentration of 10 mm with or without test compounds and continued incubation at 37oC for 15 minutes. Substance P was added to the wells at a final concentration of 0.3 nm to activate the human NK1R. After 30 minutes incubation at 37oC the medium was removed and added 0.1 G. of HCl. Each well was destroyed by ultrasound at 4oC and was extracted with CHCl3/methanol (1:1). The aqueous phase was applied to a 1 ml ion-exchange resin Dowex AG 1X8 column. The column was washed with 0.1 n formic acid, and then of 0.025 M ammonium formate - 0.1 G. of formic acid.

Inositol monophosphate was suirable of 0.2 M ammonium formate 0.1 G. of formic acid and evaluated quantitatively using counter beta radiation.

1. Substituted derivatives of the research of the formula I

< / BR>
where R1represents hydrogen, halogen, C1-4-alkyl, C1-4-alkoxy or CF3;

R2represents hydrogen, halogen, C1-4-alkyl, C1-4-alkoxy or CF3;

R3is dorod or 4-fluoro;

R6represents 5 - or 6-membered heterocyclic ring containing 2 or 3 nitrogen atom, optionally substituted by =O, =S or C1-4is an alkyl group, and optionally substituted group of the formula ZNR7R8,

where Z represents a C1-4-alkylen;

R7represents hydrogen, C1-4-alkyl, C3-7-cycloalkyl, or C3-7-cycloalkyl-C1-4-alkyl or C2-4-alkyl, substituted C1-4-alkoxy or hydroxyl;

R8represents hydrogen, C1-4-alkyl, C3-7-cycloalkyl, or C3-7-cycloalkyl-C1-4-alkyl or C2-4-alkyl, substituted by one or two substituents selected from C1-4-alkoxy, hydroxyl or 4-, 5 - or 6-membered heteroaromatics ring containing one or two heteroatoms selected from N, O and S;

or R7, R8and the nitrogen atom to which they are attached, form heteroaromatics ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy, or C1-4-alkyl, optionally substituted C1-4-alkoxy or hydroxyl group, and containing, optionally, the double bond, and the ring may contain, optionally, if uppy NH or NRcwhere Rcrepresents a C1-4-alkyl, optionally substituted by hydroxy or C1-4-alkoxy;

or R7, R8and the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;

or Z, R7and the nitrogen atom to which they are attached, form heteroaromatics ring of 4 to 7 ring atoms, which optionally may contain a ring oxygen atom;

R9aand R9beach, independently, represents hydrogen;

X represents alkylenes chain of 1 to 2 carbon atoms;

Y represents a C1-4is an alkyl group, optionally substituted hydroxyl group

provided that when Y represents a C1-4-alkyl, R6is substituted at least by a group of the formula ZNR7R8above, or its pharmaceutically acceptable salt or functional derivative, where Y denotes when is PO(OH)O-.M+, PO(O-)2.2M+or PO(O-)2. D2+where M+denotes a pharmaceutically acceptable monovalent counterion, and D2+refers to pharmaceutically acceptable divalently>;

A2represents fluorine or CF3;

A3represents a fluorine or hydrogen;

X, Y, and R6have the values listed in paragraph 1,

or its pharmaceutically bielema salt or functional derivative, specified in paragraph 1.

3. Connection under item 1 or 2, where Y represents a C1-4is an alkyl group substituted with hydroxyl group, or its pharmaceutically acceptable salt or functional derivative, specified in paragraph 1.

4. Connection under item 1 or 2, where Y represents a C1-4is an alkyl group, provided that R6substituted at least by a group of the formula ZNR7R8specified in paragraph 1, or its pharmaceutically acceptable salt or functional derivative, specified in paragraph 1.

5. The compound according to any one of paragraphs.1 to 4, where R6represents a heterocyclic ring selected from

< / BR>
< / BR>
< / BR>
< / BR>
or its pharmaceutically acceptable salt or functional derivative, specified in paragraph 1.

6. Connection under item 1 or 2 of formula 1b

< / BR>
where A1, A2and A3have the values listed in paragraph 2;

Z, R7and R8have the values listed in paragraph 1,

or its pharmaceutically acceptable where A1, A2and A3have the values listed in paragraph 2;

Q1represents CH, N or C-ZNR7R8where Z, R7and R8have the values listed in paragraph 1,

or its pharmaceutically acceptable salt or functional derivative, specified in paragraph 1.

8. Connection under item 1 or 2 of formula 1d

< / BR>
where A1, A2and A3have the values listed in paragraph 2;

Q2represents CH or N;

Z, R7and R8have the values listed in paragraph 1,

or its pharmaceutically acceptable salt or functional derivative, specified in paragraph 1.

9. Connection on p. 1, selected from the group including:

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2,3-dihydro-5 - (N, N-dimethylamino)methyl-2-oxo-1,3-imidazol-4-yl)methyl-3-(S)-(4-forfinal)morpholine,

4-(2,3-dihydro-5 - (N, N-dimethylamino)methyl-2-oxo-1,3-imidazol-4-yl)methyl-3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)morpholine,

3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-trifluoromethyl)phenyl)ethoxy)-4-(2,3-dihydro-2-oxo-5-pyrrolidinyl-1,3-imidazol-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(2,3-dihydro-2-oxo-5-pyrrolidinyl-1,3-imidazol-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(torfaen,

3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(2,3-dihydro-5-morpholinomethyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(2,3-dihydro-5-morpholinomethyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine,

4-(5-azetidine-2,3-dihydro-2-oxo-1,3-imidazol-4-yl)methyl-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-forfinal)morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(2,3-dihydro-5-(N-methylpiperazine)methyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(2,3-dihydro-5-(N-(2-morpholinoethyl)aminomethyl)-2-oxo-1,3-imidazol-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(2,3-dihydro-2-oxo-5-(N-(2-pyrrolidinyl)aminomethyl)-1,3-imidazol-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-dimethylamino)methyl-1,2,3-triazole-4-yl)methyl-3-(S)-(4-forfinal)morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(N-(N'-methylaminomethyl)-1,2,4-triazole-3-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(5-(N-methylaminomethyl)-1,2.3-triazole-4-yl)methylmorpholine,

4-(5-aminomethyl)-1,2,3-triazole-4-yl)methyl-2-(R)-(1-S)-(4-forfinal)-4-(5-pyrrolidinyl)-1,2,3-triazole-4-yl)methylmorpholine,

4-(5-(azetidine-1,2,3-triazole-4-yl)methyl-3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)morpholine),

3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-(pyrrolidinyl)-1,2,3-triazole-4-yl)methylmorpholine,

3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-morpholinomethyl)-1,2,3-triazole-4-yl)methylmorpholine,

4-(5-(N, N-dimethylaminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)-(4-forfinal)-2-(R)-(1-(R)-(3-trifluoromethyl)phenyl)-ethoxy)morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(5-(N'-methylpiperazine)-1,2,3-triazole-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-(1-(2-pyrrolidinyl)-1,2-3-triazole-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(2-(2-pyrrolidinyl)-1,2,3-triazole-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(5-(morpholinomethyl)-1,2,3-triazole-4-yl)methylmorpholine,

4-(5-azetidinol)-1,2.3-triazole-4-yl)methyl-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-4-forfinal)morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(5-(prolinamide)-1,2,3-triazole-4-yl)methylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(bis(methoxyethyl)am is-5-morpholinomethyl-1,3-imidazol-4-yl)methyl-3-(S)-(4-forfinal)morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N, N-dimethylaminomethyl)-1,3-imidazol-4-yl)methyl-3-(S)-(4-forfinal)morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N, N-dimethylaminomethyl)-1,2,4-triazole-3-yl)methyl-3-(S)-(4-forfinal)morpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N-(2,2-dimethoxymethyl)-N-methylaminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)-phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(2-methoxyethyl)aminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)-phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-(2-methoxyethyl)-N-methyl)aminomethyl)-1,2,3-triazole-4-yl)-methyl-3-(S)-phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-isopropyl-N-(2-methoxyethyl)aminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)-phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-cyclopropyl-N-(2-methoxyethyl)aminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)-phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N, N-dibutylaminoethanol-1,2,3-triazole-4-yl)methyl-3-(S)-phenylmorpholine,

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N, N-diisopropylaminomethyl-1,2,3-triazole-4-yl)methyl-3-(S)-phenylmorpholine,

2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-forfinal)-4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)IU orfelin,

4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-3-(S)-(4-forfinal)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine,

4-(2,3-dihydro-2-oxo-1,3-imidazol-4-yl)methyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-forfinal)morpholine,

4-(2,3-dihydro-2-oxo-5-pyrrolidinyl-1,3-imidazol-4-yl)methyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-forfinal)morpholine,

4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)-3-(S)-phenyl-2-(R)-(1-(S)-(3-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine,

4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-phenylmorpholine,

2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)-3-(S)-phenylmethylsulfonyl,

3-(S)-phenyl-4-(1,2,4-triazole-3-yl)-2-(R)-(1-(S)-3-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine, or its pharmaceutically acceptable salt or functional derivative, specified in paragraph 1.

10. Connection on p. 1 of formula 1E

< / BR>
where R1, R2, R3, R4, R5, R6, R9a, R9band X have the meanings specified in paragraph 1, and P in the circle represents PO(OH)O-.M+, PO(O-)2.2M+or PO(O-)2. D2+,

where M+PR is rmaceuticals acceptable divalently the counterion.

11. Connection under item 1 or 2 of formula 1f

< / BR>
where A1, A2and A3have the values listed in paragraph 2;

X and R6have the values listed in paragraph 1;

P in the circle represents PO(OH)O-.M+, PO(O-)2.2M+or PO(O-)2. D2+,

where M+is a pharmaceutically acceptable monovalent counterion,

D2+is a pharmaceutically acceptable divalently the counterion.

12. Connection under item 1 or 2 of formula 1g

< / BR>
where A1, A2and A3have the values listed in paragraph 2;

Q1represents CH, N or C-ZNR7R8where Z, R7and R8have the values listed in paragraph 1,

P in the circle represents PO(OH)O-.M+, PO(O-)2.2M+or PO(O-)2. D2+,

where M+is a pharmaceutically acceptable monovalent counterion,

D2+is a pharmaceutically acceptable divalently the counterion.

13. Connection under item 1 or 2 of formula 1h and its pharmaceutically acceptable salts

< / BR>
where A1, A2and A3have the values listed in paragraph 2;

Q1represents CH, N Il the th CH or N;

P in the circle represents PO(OH)O-.M+, PO(O-)2.2M+or PO(O-)2. D2+,

where M+is a pharmaceutically acceptable monovalent counterion,

D2+is a pharmaceutically acceptable divalently the counterion.

14. Connection on p. 10, selected from

2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphorylations)-3-(S)-(4-forfinal)-4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methylmorpholine,

2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphorylations)-3-(S)-(4-forfinal)-4-(1,2,4-triazole-3-yl)methylmorpholine,

4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-2-(R)-(1-(S)-3-fluoro-5-(trifluoromethyl)phenyl)-2-phosphorylations)-3-(S)-phenylmorpholine,

2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphorylations)-4-(2,3-dihydro-3-oxo-1,2,4-triazole-5-yl)methyl-3-(S)-phenylmorpholine, or its pharmaceutically acceptable salt.

15. Connection on p. 1 of formula 1i

< / BR>
where R1, R2, R3, R4, R5, R6, R9a, R9bX and Y have the values listed in paragraph 1,

or its pharmaceutically acceptable salt or functional derivative, specified in paragraph 1.

16. Connection under item 1, with the properties of the antagonist tahini or prevention of physiological conditions associated with an excess of tachykinins, containing an effective amount of the compounds under item 1 in combination with a pharmaceutically acceptable carrier or excipient.

18. The way to reduce the number of tachykinins in the treatment or prevention of physiological conditions associated with an excess of tachykinins, which consists in the introduction to a patient in need of such treatment, which reduces tachykinin number of connections on p. 1 or its pharmaceutically acceptable salt or its functional derivative, specified in paragraph 1.

19. The method according to p. 18 for the treatment or prevention of pain or inflammation.

20. The method according to p. 18 for the treatment or prevention of migraine.

21. The method according to p. 18 for the treatment or prophylaxis of vomiting.

22. The compound of formula I on p. 1 used in the preparation of a medicinal product having the properties of antagonists of tachykinins in the treatment of psychological diseases associated with an excess of tachykinins.

23. The compound of formula I on p. 1 used in the preparation of a medicinal product having the properties of antagonists of tachykinins in the treatment of pain or inflammation.

24. The compound of formula I on p. 1 used when the floor is ptx2">

25. The compound of formula I on p. 1 used when getting lekarstvennogo drug, possessing properties of antagonists of tachykinins in the treatment of vomiting.

26. The method of obtaining the compounds of formula (1) under item 1, where R6represents a 1,2,3-triazole-4-yl, substituted CH2NR7R8and X represents-CH2- consisting in the interaction of compounds of formula IV

< / BR>
with azide, followed by reduction of the carbonyl group adjacent to the-NR7R8; followed, if necessary, removing any protective groups that are present, and when the compound of the formula I obtained as a mixture of enantiomers or diastereoisomers, optional separation of the mixture to give the desired enantiomer, and/or, if desired, converting the compounds of formula 1 or its salts in its pharmaceutically acceptable salt or functional derivative, specified in paragraph 1.

27. Connection on p. 1 representing 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N, N-dimethylaminomethyl)-1,2,3-triazole-4-yl)methyl-3-(S)-(4-forfinal)morpholine or its pharmaceutically acceptable salt.

28. Connection on p. 1 representing 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2S="ptx2">

Priority signs:

29.12.93 - p. 2 subclass (Ia); p. 3 Y - hydraxis1-4alkyl; p. 4 Y - C1-4-alkyl; p. 6 subclass (Ib); p. 7 subclass (Ic);

22.04.94 - p. 9 species; p. 10 subclass (Ie); p. 11 subclass (If); p. 12 subclass (Ig); p. 13 subclass (Ih); p. 14 species (prodrugs); p. 26 (B); p. 28 example 89 - 12.04.94; p. 8 subclass (Id); p. 27 example 12;

15.08.94 - p. 9 varieties;

23.12.94 - p. 1, p. 5 R6preferences; p. 15 subclass (Ij); PP.16 - 25.

 

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