Substituted heterocyclic compounds or their pharmaceutically acceptable salt, pharmaceutical composition for blockade of receptors neirokinina-1 in a mammal, the method for blockade of receptors neirokinina-1 in mammals

 

(57) Abstract:

Describes the new substituted heterocycles of General formula I, where the values of R1-R5X specified in paragraph 1 of the claims, which are antagonists thickening receptor and is effective in the treatment of inflammatory diseases, pain or migraine, and asthma. In addition, some of these substances are agents, calcium channel blocking, and are useful in the treatment of cardiovascular disorders such as angina, hypertension and ischemia. Also described Pharmaceutical composition based on compounds of the formula I and a method for blockade of receptors neirokinina-1 in mammals. 3 S. and 6 C.p. f-crystals, 1 PL.

This application is a partial continuation of the jointly filed application, serial N 07/971448 registered 4 November 1992, which is a partial continuation of the jointly filed application, serial N 07/905976, filed June 29, 1992.

This invention relates to new substances represented by structural formula I:

< / BR>
in which R1, R2, R3, R4, R5and X is dened in the following.

This invention also relates to pharmaceutical formulations, the tour in the treatment of certain disorders.

Substances of this invention are antagonists thickening receptor and are effective in the treatment of inflammatory diseases, pain or migraine, and asthma.

In addition, some of these substances are agents, calcium channel blocking, and are useful in the treatment of cardiovascular disorders such as angina, hypertension and ischemia.

Background of the invention

Historically, pain in the Central nervous system was achieved using opiates and their analogues, which are drugs, and perifericheskie, with cyclo-oxygenase inhibitors, which have side effects on the stomach. Antagonists of substance P can cause pain both Central and peripheral nervous system. In addition, antagonists of substance P are inhibitors of neurogenic inflammation.

Neuropeptide receptors for substance P (neurokinin-1, NK-1) is widely distributed throughout the nervous system of mammals (especially in the brain and spinal nerve nodes), circulatory system and peripheral tissues (especially in the duodenum and jejunum) and is involved in the regulation of a number of diverse biological is a possibility, the vasodilation, salivation, and urination (B. Pernow, Pharmacol. Rev. 1983. so 35, S. 85 - 141). Subtypes of receptors NK1 and NK2 involved in synaptic transmission (Laneuville and other, Life Sci., so 42, S. 1295-1305, 1988).

The receptor for substance P is a member of versamento G protein-coupled receptors. This versamento is a very diverse group of receptors in terms of activating ligands and biological functions. In addition to tachykinin receptors, this receptor versamento includes opsins, adrenergicheskie receptors, muscarinic receptors, dopamine receptors, serotonin receptors, thyroid-stimulating hormone receptor, luteinizing hormone-choriogonadotropic hormone receptor, the product of the oncogene ras, receptors yeast factor hybridization, receptor Dictyostellium cAMP and receptors for other hormones and neurotransmitters (see A. D. Hershey etc., J. Biol.Chem., 1991, T. 226, S. 4366-4373).

Substance P (also referred to here as "SP") is undecapeptide of natural origin, belonging to theminimum family of peptides, the latter is called thus because of their fast diminishing effect on smooth muscle tissue outside the blood vessels. Thikin is In addition to SP, known tachykinin mammal include neurokinin A and neurokinin B. In modern nomenclature of receptors for SP, neirokinina A and neirokinina B are denoted as NK-1, NK-2 and NK-3, respectively.

More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence, which is shown below:

Arg - Pro - Lys - Pro - Gln - Gln - Phe - Phe - Gly - Leu - Met - NH2(Chang and others, Nature New Biol., so 232, S. 86, 1971; D. F. Weber and others, U.S. patent N 4680 283).

Neurokinin A has the following amino acid sequence:

His - Lys - Thr - Asp - Ser - Phe - Val - Gly - Leu - Met - NH2.

Neurokinin B has the following amino acid sequence: Asp - Met - His - Asp - Phe - Phe - Val - Gly - Leu - Met - NH2.

Substance P acts as a vasodilator agent, a depressant, stimulates salivation and producing increased capillary permeability. It is also able to produce both analgesia and verholesie in mammals, depending on the dose and pain susceptibility of the animal (see R. C. A. Frederickson and others, Science, I. 199, S. 1359, 1978, P. the OEM and others , Science, I. 208, S. 305, 1980) and plays a role in sensornogo P, along with other substances involved in the neurotransmission of pain sensations [report of Otsuki and others, "the Role of substance P as a sensory transmitter in spinal cord and sinteticheskih ganglia" in Symposium of the Foundation Ciba 91, 1982. Substance P in the Nervous System, S. 13-34 (published by the firm Pitman) and the article by Otsuki and Yanagisawa "whether substance P acts as a pain transmitter?" TIPS (December 1987), 8, S. 506-510]. In particular, it was shown that substance P is involved in the transmission of pain in migraine (see B. E. B. Sandberg and others, J. of Medicinal Chemistry, 25, c. 1009, 1982) and arthritis (Levin and other Science, 1984, 226 so, S. 547-549). These peptides were also involved in gastrointestinal disorders, and diseases of the gastrointestinal tract, such as inflammatory bowel disease, ulcerative colitis and Crohn's disease, and others (see Mantyh and others, Neuroscience, I. 25, N 3, S. 817 - 37, 1988 and Doctor of Regale in the book "Trends in cluster headache", Ed. F. Scuteri and others, Elsevier publishing house, scientific publishers, Amsterdam, 1987, S. 85-95).

In addition, it was assumed that there is a neurogenic mechanism for arthritis, in which the substance P may play a role (Kidd and others, "Neurogenic mechanism for symmetric arthritis," Lancet, November 11, 1989 and Gronblad and others, "IUM guess that substance P is involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (OA Byrne and others, in Arthritis & Rheumatism, 1990, T. 33, S. 1023-8). Other painful area in which tachykinins antagonists are useful are allergic condition (Hamlet and others , Can.J.Pharmacol. Physiol., 1988, T. 66, S. 1361 - 7), immunoregulation (Lotz and others, Science, 1988, 241 so, S. 1218 - 21, Kimball and others, J. Immunol., 1988, I. 141, No. 10, S. 3564-9 and A. Periann and others, Biochem. Biophys.Res.Commun. so 161, 520 S., 1989), vasodilation, bronchospasm, reflex or neuronal control of the viscera (Mantyh and others, PNAS, 1988, 85 so, S. 3235-9) and, possibly, stopping or slowing the neurodegenerative changes that are passed-amyloid (Yankner and others, Science, 1990, 250 so, S. 279-82), senile dementia of the type of Alzheimer, Alzheimer-type and down's syndrome. Substance P may also play a role in demyelinization diseases such as multiple sclerosis [j.Lover-People and others, poster presented at the 18th Congress of the C. I. N. P, 28 June - 2 July 1992, in press] . Antagonists selective for receptor neirokinina - 1 (NK-1) or neirokinina - 2 (NK-2), can be useful in the treatment of asthma (Frossard and other, Life Sci., so 49, S. 1941 - 1953, 1991; Adenier and others , Biochem. Biophys. Res.Sideline mucus in the respiratory tract of a mammal and for symptomatic relief of diseases characterized by mucus secretion, in particular, in listitem fibrosis [n Ramnarine and other title, abstract, presented at the International conference 1993 ALA/ATS, may 16-19, 1993, will be published in the journal of the Am.Rev. of Respiratory Dis., may 1993, in press].

In the recent past, some attempts were made to provide peptide-like compounds that are antagonists for substance P and other tachykinins peptides, in order to more effectively treat various disorders and diseases listed above. See, for example, applications for European patents (EPO publication NN 0347 802, 0401 0412 177 and 452), which disclosed various peptides as antagonists neirokinina A. Similarly, in the publication of Europatent N 0336230 described heptapeptide, which are antagonists of substance P, are useful in the treatment of asthma. In U.S. patent N 4680 283 firm Merck also disclosed are peptide analogs of substance P.

Certain inhibitors tachykinin have been described in U.S. patent N 4501 733 by substitution of residues in the sequence of substance P on tryptophan residues.

An additional class of antagonists thickening receptor, including Monomeric or dimeric link hexa - or heptapeptide and in such substances makes them too unstable from the point of view of metabolism, so they can serve as a practical therapeutic agents in the treatment of diseases.

Ones antagonists of the present invention, on the other hand, does not have this drawback, since it can be expected that they will be more stable from the point of view of metabolism than previously considered agents.

In this field of technology it is known that baclofen [ (aminoethyl)-4-chlorobenzophenone acid] in the Central nervous system effectively blocks the stimulating activity of substance P, but, as in many areas of excitatory responses to other substances, such as acetylcholine and glutamate, also inhibited, baclofen was not considered as a specific antagonist of substance p In patent applications of the company Pfizer WIPO (publication p-C-T WO 90/05525, WO 90/05729, WO 91/18899, WO 92/12151 and Wo 92/12152) and publications (Science, I. 251, C. 435-437, 1991; Science, I. 251, C. 437-439, 1991; J. Med, Chem., so 35, S. 2591-2600, 1992) discloses derivatives of 2-arylmethyl-3-substituted aminoquinuclidine, which are described as effective antagonists of substance P for the treatment of gastrointestinal disorders, Central nervous system disorders, inflammatory diseases and pain or migraine. In the application Europatent company Glaxo (EPO publication N 0360390) Rasmi substance P. In the patent application company Pfizer WIPO (publication p-C-T WO 92/06079) described kondensirovannoi-cyclic analogs of non-aromatic nitrogen-containing heterocycles as useful for the treatment of diseases that are transmitted by an excess of substance p In the patent application company Pfizer WIPO (publication p-C-T WO 92/15585) discloses derivatives of 1-azabicyclo[3,2,2]nonan-3-amine as antagonists of substance P. In the publication Sanofi (Life Sci., so 50, PL 101-6, 1992) described a derivative of 4-Phenoperidine as receptor antagonist neirokinina A (NK2).

Howson and others (Biorg. & Med. Chem. Lett, so 2, N 6, S. 559 - 64, 1992) have described certain 3-amino-3-oksikhinolinata compounds and their binding to receptors of substance P. In EPO publication 0499313 discloses certain 3-hydroxy - 3-thio-azabicyclic compounds as antagonists tachykinin. In U.S. patent N 3506673 describes certain 3-hydroxybenzylidene connection as Central nervous system stimulants. In the patent application company Pfizer (EPO publication 0436334) discloses certain 3-aminopiperidine compounds as antagonists of substance P. In U.S. patent N 5064838 disclosed certain 1,4-disubstituted piperidinyl compounds as analgesics. In publishing PI si TI N WO is. (Biorg & Med. Chem. Lett., so 2, N 1, S. 37-40, 1992) described pyrolidine connection with condensed rings as an antagonist of substance p In the publication EPO N 0360390 disclosed certain spirolactone derivatives as antagonists of substance P. In U.S. patent N 4804661 disclosed certain piperazinovogo compounds as analgesics. In U.S. patent N 4943578 disclosed certain piperazinovogo compounds effective in the treatment of pain. In publishing PI si Ti N WO 92/01679 disclosed certain 1,4-disubstituted piperazines useful in the treatment of brain disorders involving dopaminergic deficit.

Detailed description of the invention

New compounds of this invention represented by structural formula I:

< / BR>
or their pharmaceutically acceptable salts, in which:

R1selected from the group consisting of:

1) hydrogen atom,

2) C1-C6-alkyl, unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) oxo group,

c) C1-C6-alkoxy,

d) phenyl-C1-C3-alkoxy,

e) phenyl,

f) cyano,

g) halogen atom,

h) group - NR9R10in which R9and R10independently chosen from:

IUP>10in which R9and R10such as defined above,

(j) the group - NR9CO2R10in which R9and R10such as defined above,

k) group - CONR9R10in which R9and R10such as defined above,

l) group, - COR9in which R9such as defined above,

m) group - CO2R9in which R9such as defined above,

n) heterocycle, wherein the heterocycle is chosen from the group consisting of:

A) benzimidazolyl,

B) benzofuranyl,

C) benzothiophene,

D) benzooxazole,

E) furanyl,

F) imidazolyl,

G) indolyl,

H) isoxazolyl,

I) isothiazoline,

J) oxadiazolyl,

K) oxazolyl,

L) pyrazinyl,

M) pyrazolyl,

N) pyridyl,

O) pyrimidyl,

P) pyrrolyl,

Q) chinoline,

R) tetrazolyl,

S) thiadiazolyl,

T) thiazolyl,

U) tanila,

V) triazolyl,

W) azetidine,

X) 1,4-dioxane,

Y) hexahydroazepin,

Z) oxania,

AA) piperazinil,

AB) piperidinyl,

AC) pyrrolidinyl,

AD) tetrahydrofuranyl and

AE) tetrahydrothieno,

and in which the heterocycle is unsubstituted or is wow a halogen atom, by trifluoromethyl, methoxy group, or a phenyl,

II) C1-C6-alkoxy,

III) oxo group,

IV) hydroxy,

V) dioxo-,

(VI) the group - SR9in which R9such as defined above,

VII) halogen atom,

VIII) cyano-,

IX) phenyl,

X) trifloromethyl,

XI) the group - (CH2)m- NR9R10in which m represents 0, 1 or 2 and R9and R10such as defined above,

XII) the group - NR9COR10in which R9and R10such as defined above,

XIII) group - CONR9R10in which R9and R10such as defined above,

XIV) group - CO2R9in which R9such as defined above,

XV) group - (CH2)m- OR9in which m and R9such as defined above,

3) C2-C6-alkenyl, unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) oxo group,

c) C1-C6-alkoxy,

d) phenyl-C1-C3-alkoxy,

e) phenyl,

f) cyano,

g) halogen atom,

h) group, - CONR9R10in which R9and R10such as defined above,

i) group - COR9in which R9such as defined above,

j) group is the same as defined above,

4) C2-C6 - quinil,

5) phenyl, unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) C1-C6-alkoxy,

c) C1-C6-alkyl,

d) C2-C5-alkenyl,

e) halogen atom,

f) cyano,

(g) nitro,

(h) trifloromethyl,

i) group - (CH2)m- NR9R10in which m, R9and R10such as defined above,

(j) the group - NR9COR10in which R9and R10such as defined above,

k) the group - NR9CO2R10in which R9and R10such as defined above,

l) group, - CONR9R10in which R9and R10such as defined above,

m) group - CO2NR9R10in which R9and R10such as defined above,

n) group, - COR9in which R9such as defined above,

o) group - CO2R9in which R9such as defined above,

R2and R3chosen independently from the group consisting of:

1) hydrogen atom,

2) C1-C6-alkyl, unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) oxo group,

c) C1-C6-isR10in which R9and R10such as defined above,

i) group - NR9COR10in which m, R9and R10such as defined above,

(j) the group - NR9CO2R10in which R9and R10such as defined above,

k) group - CONR9R10in which R9and R10such as defined above,

l) group, - COR9in which R9such as defined above,

m) group - CO2R9in which R9such as defined above,

3) C2-C6 - alkenyl, unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) oxo group,

c) C1-C6-alkoxy,

d) phenyl-C1-C3-alkoxy,

e) phenyl,

f) cyano,

g) halogen atom,

h) group, - CONR9R10in which R9and R10such as defined above,

i) group - COR9in which R9such as defined above,

j) group - CO2R9in which R9such as defined above,

4) C2-C6 - quinil,

5) phenyl, unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) C1-C6-alkoxy,

c) C1-C6-alkyl,

d) C2-C5-UB> - NR9R10in which m, R9and R10such as defined above,

(j) the group - NR9COR10in which R9and R10such as defined above,

k) the group - NR9CO2R10in which R9and R10such as defined above,

l) group, - CONR9R10in which R9and R10such as defined above,

m) group - CO2NR9R10in which R9and R10such as defined above,

n) group, - COR9in which R9such as defined above,

o) group - CO2R9in which R9such as defined above,

group and R1and R2can be combined together to form a heterocyclic ring selected from the group consisting of:

a) pyrrolidinyl,

b) piperidinyl,

c) pyrrolyl,

(d) pyridinyl,

e) imidazolyl,

f) oxazolyl and

g) diazoline,

and in which the heterocyclic ring is unsubstituted or substituted by one or more substituents selected from:

I) C1-C6-alkyl,

II) C1-C6-alkoxy,

III) oxo group,

IV) group-NR9R10in which R9and R10such as defined above,

V) halogen atom iscoe ring, selected from the group consisting of:

a) cyclopentyl,

b) of cyclohexyl,

c) phenyl,

and in which carbocyclic ring is unsubstituted or substituted by one or more substituents selected from:

I) C1-C6-alkyl,

II) C1-C6-alkoxy,

III) group - NR9R10in which R9and R10such as defined above,

IV) a halogen atom, and

V) trifloromethyl,

group and R2and R3can be combined together to form a heterocyclic ring selected from the group consisting of:

a) pyrrolidinyl,

b) piperidinyl,

c) pyrrolyl,

(d) pyridinyl,

e) imidazolyl,

f) furanyl,

g) oxazolyl,

(h) tanila and

i) thiazolyl,

and in which the heterocyclic ring is unsubstituted or substituted by one or more substituents selected from:

I) C1-C6-alkyl,

II) C1-C6-alkoxy,

III) oxo group,

IV) group - NR9R10in which R9and R10such as defined above,

V) halogen atom, and

VI) trifloromethyl;

X is chosen from the group consisting of: -O-, -S-, -SO - and SO2;

R4selected from the group consisting of:

1)

,

2) -Y - C1-C8-alkyl, MOTOX group,

b) oxo group,

c) C1-C6-alkoxy,

d) phenyl-C1-C3-alkoxy,

e) phenyl,

f) cyano-

g) halogen atom,

h) group - NR9R10in which R9and R10such as defined above,

i) group - NR9COR10in which m, R9and R10such as defined above,

(j) the group - NR9CO2R10in which R9and R10such as defined above,

k) group - CONR9R10in which R9and R10such as defined above,

l) group, - COR9in which R9such as defined above,

m) group - CO2R9in which R9such as defined above,

3) -Y-C2-C6-alkenyl in which alkenyl is unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) oxo group,

c) C1-C6-alkoxy-

d) phenyl-C1-C3-alkoxy,

e) phenyl,

f) cyano,

g) halogen atom,

h) group, - CONR9R10in which R9and R10such as defined above,

i) group - COR9in which R9such as defined above,

j) group - CO2R9in which R9such as defined above,

4) -O(CO) - phenyl, where phenyl is one who indicate from the group consisting of:

1) phenyl, unsubstituted or substituted by one or more radicals R11, R12and R13,

2) C1-C8-alkyl, unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) oxo group,

c) C1-C6-alkoxy,

d) phenyl-C1-C3-alkoxy,

e) phenyl,

f) cyano,

g) halogen atom,

h) group - NR9R10in which R9and R10such as defined above,

i) group - NR9COR10in which m, R9and R10such as defined above,

(j) the group - NR9CO2R10in which R9and R10such as defined above,

k) group - CONR9R10in which R9and R10such as defined above,

l) group, - COR9in which R9such as defined above,

m) group - CO2R9in which R9such as defined above,

3) C2-C6-alkenyl, unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) oxo group,

c) C1-C6-alkoxy,

d) phenyl-C1-C3-alkoxy,

k) group - CONR9R10in which R9and R10such as defined above,

l) groupr> such as defined above,

3) C2-C6-alkenyl, unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) oxo group,

c) C1-C6-alkoxy,

d) phenyl-C1-C3-alkoxy,

e) phenyl,

f) cyano,

g) halogen atom,

h) group, - CONR9R10in which R9and R10such as defined above,

i) group - COR9in which R9such as defined above,

j) group - CO2R9in which R9such as defined above,

4) C2-C6-quinil,

5) phenyl, unsubstituted or substituted by one or more substituents selected from:

a) a hydroxy group,

b) C1-C6-alkoxy,

c) C1-C6-alkyl,

d) C2-C5-alkenyl,

f) phenyl,

f) cyano,

g) halogen atom,

h) group, - CONR9R10in which R9and R10such as defined above,

i) group - COR9in which R9such as defined above,

j) group - CO2R9in which R9such as defined above,

4) a heterocycle in which the heterocycle as defined above;

R6, R7, R8independently selected from the group consisting of:

1) hydrogen atom,

2) C1--group

b) oxo group,

c) C1-C6-alkoxy,

d) phenyl-C1-C3-alkoxy,

e) phenyl,

f) cyano,

g) halogen atom,

h) group - NR9R10in which R9and R10such as defined above,

i) group - NR9COR10in which m, R9and R10such as defined above,

(j) the group - NR9CO2R10in which R9and R10such as defined above,

e) halogen atom,

f) cyano,

(g) nitro,

(h) trifloromethyl,

i) group -(CH2)m- NR9R10in which m, R9and R10such as defined above,

(j) the group - NR9COR10in which R9and R10such as defined above,

k) the group - NR9CO2R10in which R9and R10such as defined above,

l) group, - CONR9R10in which R9and R10such as defined above,

m) group - CO2NR9R10in which R9and R10such as defined above,

n) group, - COR9in which R9such as defined above,

o) group - CO2R9in which R9such as defined above,

6) halogen atom,

7) cyano,

8) nitro,

9) trifloromethyl the R14such as defined above,

12) -SO2R14in which R14such as defined above,

13) -NR9COR10in which R9and R10such as defined above,

14) group,- CONR9COR10in which R9and R10such as defined above,

15) group-NR9R10in which R9and R10such as defined above,

16) group-NR9CO2R10in which R9and R10such as defined above,

17) hydroxy,

18) C1-C6-alkoxy,

19) - COR9in which R9such as defined above,

20) - CO2R9in which R9the same as defined above;

R11, R12and R13independently selected from the definitions of the radicals R6, R7and R8;

Y is chosen from the group consisting of: simple link, -O-, -S-, -CO-, -CH2-, -CHR15- and-CR15R16-, in which R15and R16independently selected from the group consisting of:

a) C1-C6-alkyl, unsubstituted or substituted by one or more substituents selected from:

I) a hydroxy group,

II) oxo group,

III) C1-C6-alkoxy,

IV) a phenyl-C1-C3-alkoxy,

V) phenyl,

VI) cyano,

VII) halogen atom,
9COR10in which R9and R10such as defined above,

X) group NR9CO2R10in which R9and R10such as defined above,

XI) group CONR9R10in which R9and R10such as defined above,

XII) - COR9in which R9such as defined above,

XIII) - CO2R9in which R9the same as defined above;

b) phenyl, unsubstituted or substituted by one or more substituents selected from:

I) a hydroxy group,

II) C1-C6-alkoxy,

III) C1-C6-alkyl,

IV) C2-C5-alkenyl,

V) halogen atom,

VI) cyano,

VII) nitro,

VIII) trifloromethyl,

IX) - (CH2)m- NR9R10in which m, R9and R10such as defined above,

X) - NR9COR10in which R9and R10such as defined above,

XI) - NR9CO2R10in which R9and R10such as defined above,

XII) group, - CONR9R10in which R9and R10such as defined above,

XIII) - CO2NR9R10in which R9and R10such as defined above,

XIV) - COR9in which R9such as defined above,
2) C1-C4-alkyl and

3) hydroxy group, provided that when Y is-O-, then Z is different from the hydroxy-group, or if Y is-CHR15-, then Z and R15can be joined together, forming a double bond.

Substances of the present invention have asymmetric centers, and this invention includes all optical isomers and their mixtures.

In addition, substances with carbon-carbon double bonds can exist in the Z - and E-forms, with all isomeric forms of these compounds included in the present invention.

When any variable (for example, alkyl, aryl, R6and R7, R8, R11, R12, R13and others) occurs more than one time in any variable or in formula I, its definition in each case is independent of its definition at every other case.

Used herein, the term "alkyl" includes those alkyl groups having the specified number of carbon atoms having either linear, branched or cyclic configuration. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, ISO-, sec - and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, calculating through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy, pentox. "Alkenyl" include hydrocarbon chains having the specified number of carbon atoms having either linear, branched or cyclic configuration and at least one unsaturation, which may be anywhere along the chain, such as ethynyl, propenyl, butenyl, pentenyl, dimethylpentane, etc. and includes E and Z forms where applicable. Used herein, the terms "halogen atom" or "galaida" means the fluorescent-, chloro-, bromo - and iodo.

The term "aryl" means phenyl or naphthyl, or unsubstituted or substituted one, two or three substituents selected from the group consisting of Galaico-, C1-C4-alkyl, C1-C4-alkoxy-, nitro-, trifloromethyl, C1-C4-alkylthio-, hydroxy-group, -NR6R6-, -CO2R6, C1-C4-perfluoroalkyl, C3-C6-perftoralkil and tetrazol-5-yl.

The term "heteroaryl" means unsubstituted, monosubstituted or disubstituted five - or six-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, and in which the substituents are members selected from the group consisting of-OH, -SH, C1-C4-alkyl, C1-C4-alkoxy, nitro, galayda, triptoreline in this field of technology pharmaceutically acceptable salts include, but are not limited to salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, para-toluensulfonate, 2-hydroacylation, pamoate, salicylate and stearate. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.

In the compounds of formula I is preferred that: R1was selected from the group consisting of:

1) C1-C6-alkyl, unsubstituted or substituted by one or more substituents selected from:

a) heterocycle, wherein the heterocycle is chosen from the group consisting of:

A) benzimidazolyl,

B) imidazolyl,

C) isoxazolyl,

D) isothiazole,

E) oxadiazolyl,

F) pyrazinyl,

G) pyrazolyl,

H) pyridyl,

I) pyrrolyl,

J) tetrazolyl,

K) thiadiazolyl,

L) triazolyl and

M) piperidinyl,

and in which the heterocycle is unsubstituted or substituted by one or more substituents selected from:

I) C II) C1-C6-alkoxy,

III) oxo group,

IV) dioxo-,

V) cyano,

Group VI-SCH3,

VII) phenyl,

VIII) hydroxy,

IX) trifloromethyl,

X) group -(CH2)m-NR9R10in which m represents 0, 1 or 2 and in which R9and R10independently selected from: hydrogen atom, C1-C6-alkyl, hydro-C1-C6-alkyl and phenyl,

XI) the group-NR9COR10in which R9and R10such as defined above,

XII) group,- CONR9R10in which R9and R10such as defined above,

R2and R3independently selected from the group consisting of:

1) hydrogen atom,

2) C1-C6-alkyl,

3) C2-C6-alkenyl and

4) phenyl;

X represents-O-;

R4is:

,

R5is phenyl, unsubstituted or substituted with halogen;

R6, R7and R8independently selected from the group consisting of:

1) hydrogen atom,

2) C1-C6-alkyl,

3) halogen atom, and

4) trifloromethyl;

Y represents-O-; and

Z represents a hydrogen atom or C1-C4-alkyl.

A variant embodiment of the novel compounds of this invention

is the substance in which X represents-O-, R4the ski acceptable salt, in which R1, R2, R3, R6, R7, R8, R11, R12and R13and Z are such as defined above.

Another alternative embodiment of the novel compounds of this invention is the substance in which X represents-S-, R4is a group-YCHZ-phenyl and R5is phenyl of structural formula:

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or its pharmaceutically acceptable salt, in which R1, R2, R3, R6, R7, R8, R11, R12and R13and Z are such as defined above.

Another alternative embodiment of the novel compounds of this invention is the substance in which X represents-SO-, R4is a group-YCHZ-phenyl and R5is phenyl of structural formula:

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or its pharmaceutically acceptable salt, in which R1, R2, R3, R6, R7, R8, R11, R12, R13and Z are such as defined above.

Another alternative embodiment of the novel compounds of this invention is the substance in which X represents-SO2-, R4is a group-YCHZ-phenyl and R5is phenyl of structural formula:

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or its pharmaceutically acceptable salt, in which R1

The substances of the present invention the preferred embodiment is the substance in which R1choose from the following group of substituents:

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2-

Specific substances within the scope of the present invention vklucheat:

1) (+/-)2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenylmorpholine;

2) (2R, S)-(3,5-bis(trifluoromethyl)benzyloxy)-(3R)-phenyl-(6R)- methylmorpholin;

3) (2R, S)-(3,5-bis(trifluoromethyl)benzyloxy)-(3S)-phenyl-(6R)- methylmorpholin;

4) (+/-)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl-4 - methylcarbamoylmethyl;

5) (+/-)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl-4 - methoxycarbonylaminophenyl;

6) 2-(2-(3,5-bis(trifluoromethyl)phenyl)ethynyl)-3-phenyl-5 - exomorphic;

7) 3-phenyl-2-(2-(3,5-bis(trifluoromethyl)phenyl)ethyl)-morpholine;

8) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)- methylmorpholin;

9) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)- methylmorpholine;

10) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)- methylmorpholine;

11) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)- methylmorpholine;

12) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)- methylmorpholin;

13) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)- methylmorpholin;

13-(S)-phenyl-5-(R)- methylmorpholin;

16) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)- phenylmorpholine;

17) 4-(3-(1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl) benzyloxy)-3-(S)-phenylmorpholine;

18) 4-(3-(5-oxo-1H,4H,-1,2,4-triazolo)methyl)-2-(S)- (3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine;

19) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)- methylmorpholin;

20) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)- methylmorpholin;

21) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)- methylmorpholin;

22) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)- methylmorpholin;

23) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)- methylmorpholine;

24) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)- methylmorpholine;

25) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)- methylmorpholine;

26) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)- phenylmorpholine;

27) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5- (R)-phenylmorpholine;

28) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5- (S)-phenylmorpholine;

29) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5- (S)-phenylmorpholine;

30) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-3- (S)-phenyl-4-(3-(1,2,4-triazolo)methyl)-morpholine;

31) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(S)- (3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine;

34) 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(S)- (3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine;

35) 4-(2-(imidazole)methyl)-2-(S)- (3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine;

36) 4-(4-(imidazole)methyl)-2-(S)-(3,5 - bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine;

37) 4-(aminocarbonyl)methyl)-2-(S)-(3,5 - bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine;

38) 4-(2-(imidazole)methyl)-2-(S)-(3,5 - bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine;

39) 4-(4-(imidazole)methyl)-2-(S)-(3,5 - bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine;

40) 4-(2-(imidazole)methyl)-2-(S)-(3,5 - bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholin;

41) 4-(4-(imidazole)methyl)-2-(S)-(3,5 - bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholin;

42) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- ((6-hydroxy)hexyl)-3-(R)-phenylmethylsulfonyl;

43) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (5-methylaminomethyl)pentyl)-3-(R)-phenylmethylsulfonyl;

44) 4-(3-(1,2,4-triazolo)methyl)-2-(3,5-dimethyl)benzyloxy)- 3-phenylmorpholine;

45) 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2- (3,5-dimethyl)benzyloxy)-3-phenylmorpholine;

46) 4-(3-(1,2,4-triazolo)methyl)-2- (3,5-di(tertbutyl)benzyloxy)-3-phenylmorpholine;

47) 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2- (3,5-di(tertbutyl)benzyloxy)-3-phenylmorpholine;

)methyl)-2- (3-(tert-butyl)-5-methylbenzylamino)-3-phenylmorpholine;

50) 4-(3-(1,2,4-triazolo)methyl)-2-(3-(trifluoromethyl)-5 - methylbenzylamino)-3-phenylmorpholine;

51) 4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)-2- (3-(trifluoromethyl)-5-methylbenzylamino)-3-phenylmorpholine;

52) 4-(3-(1,2,4-triazolo)methyl)-2- (3-(tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenylmorpholine;

53) 4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)-2- (3-tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenylmorpholine;

54) 4-(2-(imidazole)methyl)-2-(3,5-dimethyl)benzyloxy)- 3-phenylmorpholine;

55) 4-(4-(imidazole)methyl)-2-(3,5-dimethyl)benzyloxy)- 3-phenylmorpholine;

56) 4-(2-(imidazole)methyl)-2-(3,5-di-(tert-butyl)benzyloxy)- 3-phenylmorpholine;

57) 4-(4-(imidazole)methyl)-2-(S)-(3,5-decret - butyl)benzyloxy)-3-phenylmorpholine;

58) 4-(2-(imidazole)methyl)-2-(3-(tert-butyl)-5 - methylbenzylamino)-3-phenylmorpholine;

59) 4-(4-(imidazole)methyl)-2-(3-(tert-butyl)-5 - methylbenzylamino)-3-phenylmorpholine;

60) 4-(2-(imidazole)methyl)-2-(3-(trifluoromethyl)-5 - methylbenzylamino)-3-phenylmethylsulfonyl;

61) 4-(4-(imidazole)methyl)-2-(3-(trifluoromethyl)-5 - methylbenzylamino)-3-phenylmethylsulfonyl;

62) 4-(2-(imidazole)methyl)-2-(3-(tert-butyl)-5- (trifluoromethyl)benzyloxy)-3-phenylmorpholine;

A) 4-(4-(imidazole)methyl)-2-(3-(tert-butyl)-5- (trifluoromethyl)-5-methylbenzylamino)-3-phenylmethylsulfonyl;

63) 2-(S)-(3,5-dichlorobenzyl) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (methoxycarbonylmethyl)-3-(S)-phenylmorpholine;

66) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (carboxymethyl)-3-(S)-phenylmorpholine;

67) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- ((2-amino-ethyl)-aminocarbonylmethyl)-3-(S)-phenylmorpholine;

68) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- ((3-aminopropyl)aminocarbonylmethyl)-3-(S)-phenylmorpholine;

69) 4-benzyl-5-(S),6-(R)-(dimethyl)-3-(S)-phenylmorpholine and 4-benzyl-5-(R),6-(S)-(dimethyl)-3-(S)-phenylmorpholine;

70) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-[5-(S), 6-(R) or 5-(R),6-(S)-dimethyl]-3-(S)-phenylmorpholine;

71) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-[5-(R), 6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholine;

72) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (3-(1,2,4-triazolo)methyl)-[5-(S),6-(R) or 5-(R),6-(S)-dimethyl]-3-(S)-phenylmorpholine;

73) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (3-(5-oxo-1,2,4-triazolo)methyl)-[5-(S),6-(R) or 5-(R),6-(S)-dimethyl]-3-(S)-phenylmorpholine;

74) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (3-(1,2,4-triazolo)methyl)-[5-(R),6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholine;

75) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (3-(5-oxo-1,2,4-triazolo)methyl)-[5-(R),6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholine;

76) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (2-(1-(4-benzyl)piperidino)ethyl)-3-(S)-phenylmorpholine;

77) 3-(S)-(4-forfinal)-4-benzyl-2-phenylmorpholine;

78) 2-(S)-(3,5-bis(trifluoromethyl)Berlin;

80) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)- (4-forfinal)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

81) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- ((3-pyridyl)-methylcarbamyl)-3-(R)-phenylmorpholine;

82) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (methoxycarbonylmethyl)-3-(R)-phenylmorpholine;

83) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (carboxypentyl)-3-(R)-phenylmorpholine;

84) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (methylenedioxybenzyl)-6-oxo-hexyl)-3-(R)-phenylmorpholine

and their pharmaceutically acceptable salts.

Tests thickening antagonism

Substances of this invention are useful for antagonization of tachykinins, including substance P and neirokinina A, in the treatment of gastrointestinal disorders, Central nervous system disorders, inflammatory diseases, pain or migraine and asthma in a mammal in need of such treatment. This activity can be demonstrated by the following test.

A. Receptor expression in COS cells

In order temporarily to Express the cloned human receptor neirokinina-1 (NK1R) in COS cells, cdnc for human NKIR was cloned in the expression vector pCDM9 which was produced from the vector pCDM8 (Inviter is 20 µg of plasmid DNA into 10 million of COS cells was performed by electroporation in 800 µl transfection buffer (135 mmol/l sodium chloride, 1,2 mmol/l of calcium chloride, 1.2 mmol/l of magnesium chloride, 2,4 mmol/l monohydrogenphosphate potassium, 0.6 mmol/l potassium hydrogen phosphate, 10 mmol/l glucose, 10 mmol/l buffer HEPES with a pH of 7.4) at 260 V and 950 μf using Genesifter AI-Bi-AI, AI-Bi-AI, new haven, Connecticut). These cells were cultured in 10% serum, fetal calf, 2 mmol/l glutamine, 100 u/ml penicillin - streptomycin, and 90% DMEM medium (firm G IBCO, Grand island, NY) in 5% carbon dioxide at 37oC to binding analysis.

B. Stable expression in COS cells

In order to establish a stable cell line expressing the cloned human receptor neirokinina-1, cdnc was subcloned in the vector pR with CMV (Invitrogen). Transfection of 20 ug of the plasmid DNA into cells SNO was carried out by electroporation in 800 µl transfection buffer, supplemented with 0.625 mg/ml sperm DNA herring, at 260 V and 950 μf using Genesifter AI-Bi-AI, AI-Bi-AI). Transfection cells were cultured in the medium of CHO [10% serum, fetal calf, 2 mmol/ l glutamine, 100 u/ml penicillin-streptomycin, 1/500 gipoksantin-thymidine, (ATSS), 90% environment IMDM colonies become visible. Each colony was selected and reproduced. The cell clone with the highest number of human NK 1 R was selected for subsequent applications, such as screening of drugs.

B. Protocol testing using COS cells or CHO

Binding analysis of human NKIR, expressed either in COS cells or CHO cells, based on the use of substance P and isotope125iodine (125I-SP, from the DuPont company, Boston, Massachusetts) as a radioactive labeled ligand which competes with unlabeled substance P or any other ligand for binding to human NKI R. Monolayer cell cultures of COS or CHO was dissociative through non-enzymatic solution (Wednesday Specialty, Lavalette, new Jersey) and re-suspended in an appropriate volume of binding buffer [50 mmol/l Tris buffer with pH 7.5, 5 mmol/l of manganese dichloride, 150 mmol/l sodium chloride, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml protein bovine serum, 0.01 mmol/l of phosphoramidon] to 200 μl of the cell suspension could cause radioactivity of specific binding125I-Sp of about 10,000 pulses/min (from about 50,000 to 200,000 cells). In linking the analysis was added to 200 μl of cells in a test tube, with what has been created substances. The tubes were cultivated at 4oC or at room temperature for 1 h with gentle shaking. Bound radioactivity was separated from unbound radioactivity by using a filter CF/C (firm Brandel, Gaithersburg, Maryland), which was pre-wetted with 0.1% polyethylenimine. The filter was washed 3 times with 3 ml of wash buffer (50 mmol/l Tris buffer with pH 7.5, 5 mmol/l of manganese dichloride, 150 mmol/l sodium chloride), and determined its radioactivity gamma counter.

Activation of phospholipase C through NKIR could also be measured in CHO cells expressing human NKI R, by determining the accumulation of Inositol-monophosphate, which is a decay product IP3. The CHO cells were seeded in 12-hole plate in the amount of 250,000 cells per well. After culturing in the medium of CHO within 4 days, the cells were loaded 0,025 MK Curie/ml tritium - myoinositol by cultivation during the night. Extracellular radioactivity was removed by washing with salt solution, tebufelone phosphate. In the hole was added lithium chloride at a final concentration of 0.1 mmol/l with the test substance or without him, and the cultivation was continued at 37oC for 15 min STE 30 min of cultivation at 37oC the medium was removed and added to 0.1 N. hydrochloric acid. Each well was sounded at 4oC and were extracted with a mixture of chloroform/methanol 1: 1. The aqueous phase was applied at 1 ml ion exchange column Dowex Hey-Gee IX8. The column is washed with 0.1 G. of formic acid and then the mixture solution of 0.025 mol/l of ammonium formate and 0.1 G. of formic acid. Inositoltrifosfata was suirable mixture of solutions of 0.2 mol/l ammonium formate and 0.1 G. of formic acid and quantify the counter beta-particles.

Substances of the present invention have been useful for the prevention and treatment of a wide variety of clinical conditions which are characterized by the presence of excess tachykinins activity, in particular substance P.

These conditions may include disorders of the Central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as associated with AIDS dementia, senile dementia of the type of Alzheimer and down syndrome; demyelization diseases such as multiple sclerosis and amyotrophic lateral sclerosis (ALS; disease Lou Gehrig's disease (als) and other neuropathological disorders such as peripheral neuropathy, such as neuropathy, connected the other types of neuralgia; respiratory diseases such as chronic obstructive airway disease, bronchopneumonia, bronchospasm and asthma; a disease characterized by neurogenic mucus discharge, such as cility fibrosis; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; violations of hypersensitivity, such as sumac, which is developing; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, etc.; cutaneous diseases such as contact dermatitis, tropicheskii dermatitis, urticaria and other eczematoid dermatitis; drug disorders such as alcoholism; somatic disorders associated with stress; reflex simpaticheskaja dystrophy, such as hand/shoulder syndrome; desimovie violations, harmful immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematous; gastrointestinal disorders, and diseases of the gastrointestinal tract such as disorders associated with the neuronal control of viscera such as avimer, caused by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and changes in intracranial pressure, disorders of bladder function such as hyperreflexia discharging valve of the bladder; fibrous and collagen diseases, such as scleroderma and eosinophilous fascialis; disorders of blood flow caused by vasodilation and sosudospasticheskih diseases such as angina, migraine and Raynaud's disease; and pain or nociception, for example, which are attributed to or associated with any of the above conditions, especially the transmission of pain in migraine. Therefore, these substances can easily be adapted for therapeutic use in the treatment of physiological disorders associated with excessive stimulation tachykinin receptors, especially neirokinina-1, and as antagonists neirokinina-1, for monitoring and/or treatment of any of the above clinical conditions in mammals, including humans.

For example, substances of the present invention can be suitable used for the treatment of disorders of the Central nervous system such as anxiety, psychosis and schizophrenia; neurodegenerative disease, in particular those associated with excess mucus secretion, such as chronic obstructive airway disease, bronchopneumonia, chronic bronchitis, castity fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immunological reactions such as rejection of transplanted tissues; gastrointestinal disorders, and diseases of the gastrointestinal tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence, blood flow disorders caused by vasodilation and pain or nociception, for example, one that is attributed to or associated with any of the above conditions, or transmission of pain in migraine.

As agents, blocking the calcium channels, some of the substances of the present invention are useful for the prevention or treatment of clinical conditions which benefit from inhibition of the migration of calcium ions through the plasma membrane of cells. These conditions include diseases and disorders of the cardiovascular system, such as angina, heart attack miokar other ischemic diseases. Moreover, these substances may be able to reduce elevated intraocular pressure in their local appointment in hypertensive eyes in solution with a suitable ophthalmic carrier. In addition, these substances may be useful when returning policecourtneu resistance in tumor cells by enhancing the effectiveness of chemotherapeutic agents. In addition, these substances may possess activity by blocking calcium channels in brain membranes of insects, and therefore they can be useful as insecticide.

Substances of the present invention are particularly effective in the treatment of pain or nociception and/or inflammation and related disorders such as, for example: neuropathy, such as diabetic or peripheral neuropathy and neuropathy caused by chemotherapy, post herpetic neuralgia and others; asthma, osteoarthritis, rheumatoid arthritis, and especially migraine. Substances of the present invention, in particular, are also useful in the treatment of diseases characterized by neurogenic mucus discharge, especially when listitem fibrosis.

In the treatment of the above clinical conditions, substances of this invention can be used in the form of further destination sterile solutions or suspensions for parenteral or intramuscular destination, and the like.

The pharmaceutical compositions of this invention can be applied in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains one or more substances of the present invention, as an active ingredient, in a mixture with an organic or inorganic carrier or medium for medicines, suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers in tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. Possible to use carriers are water, glucose, lactose, resin acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in the manufacture of the preparations, in solid, semisolid, or liquid form and may be optionally used auxiliary, stabilizing, sagus will stifle the composition in an amount, which is sufficient to obtain the desired effect on the process or condition of diseases.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, for example, with traditional tabletiruemye ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, in order to shape prior prescription composition comprising a homogeneous mixture of substances of the present invention, or its non-toxic pharmaceutically acceptable salt. When these prior compositions are called homogeneous, this means that the active ingredient is uniformly dispersed throughout the composition so that the composition can easily be subdivided into equally effective form of unit dosages, such as tablets, pills and capsules. Then this solid pre-prepared composition is divided into the form of a single dosage of the above described type which contain from 0.1 to about 500 mg of the active component of the present invention. These tablets or pills new is providing the advantage of prolonged action. For example, the tablet or pill may include an inner dosage and an outer dosage component, the latter has the form of a coating over the internal dose. These two components can be separated gastric layer, which serves to limit the disintegration in the stomach and permits the inner component to pass intact into the duodenum or to slow its release. For such gastric layers or coatings can be used a variety of materials, such materials include a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the new compositions of the present invention can be introduced for oral or injectable purpose include aqueous solution, respectively OTDELENIE syrups, aqueous or oil suspensions, and OTDELENIE emulsions with edible oils such as oil of cotton seeds, hemp oil, coconut oil or oil of groundnuts, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic or natural resins such as resin tragic is Latin.

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 environment for drugs that are outlined above. Preferably the compositions are assigned to the oral or nasal respiratory method for local or systemic effect. The composition preferably in a sterile pharmaceutically acceptable solvents can be sprayed using an inert gas. Sprayed solutions can be inhaled directly from the spray device, or is it the spray device can be attached to the face mask, tent or breathing machine with a pulsed positive pressure. Solution, suspension, or powder compositions may be administered, preferably orally or through the nose of the device, which serves the recipe accordingly.

For the treatment of clinical conditions and the above diseases substance of this invention can be administered orally, topically, parenteral, by inhalation or spray rectal formulations dosing unit of sod is the term parenteral means of subcutaneous injection, intravenous, intramuscular, vnutrigrudne injection or infusion techniques.

For the treatment of certain conditions it may be desirable to use a substance of the present invention and combined with another pharmacologically active agent. For example, for the treatment of respiratory diseases such as asthma, substance of the present invention can be used in combination with bronchial dilator, such as agonist adrenergicheskoj receptor or thekennady antagonist, which acts as a receptor of NK-2. The substance of the present invention and a bronchial dilator may be administered to a patient simultaneously, sequentially or in combination.

Substances of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. This dosage can vary from patient to patient, depending on the nature and severity of the disease, the patient's weight, special diets, which will follow the patient, competing treatment and other factors that will be recognized experts in the field of medicine.

In the treatment of a condition associated with the La of the patient per day, moreover, this dosage may be administered in single or multiple doses. Preferably, the dose level will be from about 0.01 to 25 mg/kg per day; more preferably from about 0.05 to 10 mg/kg per day. For example, in the treatment of conditions, including neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005-5 mg/kg per day. These compounds can be administered in the mode from 1 to 4 times per day, preferably once or twice per day.

Several ways to obtain substances of this invention are illustrated in the following Schemes and Examples, in which the radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12and R13have the above values.

In table. 1 shows the abbreviations used in the schemes and examples.

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Substances of the present invention in which X = Y = 0, can be prepared according to the General route outlined in scheme 1. Thus, correspondingly substituted alpha-bromophenylacetate) can be transformed into dibenzalacetone II by mixing I and a small excess of benzyl alcohol in the presence of an acid catalyst with a concomitant removal of methanol. Alkylation of substituted amerosport methyl-benzyl II can give N-alkylamino III; the use of chiral amerosport can lead to the formation of diastereoisomers, and they can be separated at this stage /or later/ using standard chromatographic methods. Alkylation or acylation of matter III nitrogen atom can give dialkyl - or acyl/alkyl-amerosport IV in which the group R1can serve as a protecting group or be used as, or be entered in Deputy in the final target substance. Cyclization with the formation of substituted research V can be realized by heating the solution IV and acid catalyst. The diastereomers V, which may be formed can be isolated using standard chromatographic methods. If R1is a protecting group, it may be removed using known techniques /Green T. C. , Wuts P. G. M. "Protective groups in organic synthesis", 2nd edition, ed. John Willy & sons, Inc., New York, 1991/. If the preparation of compounds I-V results in the formation of enantiomers, these may be separated by alkylation or acylation V /R1=H/ auxiliary hee is raficheskih methods, and removal of the chiral auxiliary agent with obtaining enantiomers substances V. Alternative, diastereoisomer V can be separated by fractional crystallization of their suitable solvent diastereoisomeric salts derived from V and a chiral organic acid.

Substances of the present invention in which X=0 and Y = CH2can be prepared according to the General route outlined in scheme 2. Thus, N-methoxy-N-methylamide protected phenylglycine VI /prepared from the carboxylic acid via a mixed anhydride in accordance with the methodology Rapoport in the journal J. Org Chem., 1985, 50 so, S. 3972/ can be used for acylation of enolate lithium metaltitlepane to get ketotifen VII. Sodium salt of VII can be condensed with appropriately substituted benzaldehyde to obtain alpha, butanediamine ketone VIII. The restoration of this ketone and the removal of the tert-BUTYLCARBAMATE protecting group can give amerosport IX. The diastereomers, which may be formed, can be separated at this stage /or later/ using standard chromatographic techniques. Etherification IX by Williamson using substituted chloracetate and follow the Noah group can be carried out directly with obtaining substituted the research XI. If the preparation of compounds VI-XI leads to the formation of enantiomers, these may be separated by alkylation or acylation of XI (R1=H) chiral auxiliary agent, the allocation thus obtained diastereomers using known chromatographic methods, and removal of the chiral auxiliary agent, to obtain the enantiomers XI. Alternatively, the diastereomers XI can be separated by fractional crystallization from a suitable solvent of the diastereomeric salts formed by the substance XI and chiral organic acid. If it is desirable that R1different from a hydrogen atom, moholynagy the nitrogen atom in the compound XI can be further functionalized using standard methods of alkylation or acylation of secondary amines. If it is desirable that R2different from a hydrogen atom, morpholino X can be recycled in karunakaran (R1=RO2C, R2=OH) - intermediate substance, which may be alkylated and will be taken into account for changes in R2.

Substances of the present invention in which X=S-(O)n(n=0, 1, 2) and Y = 0, can be prepared according to the General route outlined in chestnykh techniques (R. P. The volant. Tetrahedron Zett, 1981, T. 22, S. 3119). Cleavage of the ester function to provide thiol XIII, can be made with a water base or reducing, depending on the constraints imposed by other functional groups present. Cyclization XIII thiomorpholine XIV can be carried out by heating a solution of XIII and acid catalyst. Oxidation XIV using metaperiodate sodium acetic acid can provide a sulfoxide or sulfon XV. The diastereomers XIV or XV, which may be formed, can be separated using standard chromatographic methods. If R1is a protecting group, it may be removed using known techniques (E.g Century Green, Wuts P. G. M. Protecting groups in organic synthesis, 2nd ed., J. Of Willy & sons, Inc., New York, 1991). If the preparation of compounds XII-XI leads to the formation of enantiomers, these may be separated by alkylation or acylation of compounds XIV or XV (R1=H) chiral auxiliary agent, separation of the diastereomers thus obtained, using known chromatographic methods, and removing the chiral auxiliary agent receipt is cristallization of a suitable solvent of the diastereomeric salts, formed by the connection of the XIV or XV and chiral organic acid.

Substances of the present invention in which X=Y=0, can also be obtained according to the General route outlined in scheme 4. Thus, correspondingly substituted dimethylacetal alpha bromoacetaldehyde (prepared using the method of Jacobs journal J. Am. Chem. Soc., 1953, 75 so, S. 5500) may be converted to the acetal by mixing with a slight excess of the appropriate alcohol in the presence of an acid catalyst with a concomitant removal of methanol. Alkylation of substituted amerosport bromide may be N-alkylamines. The use of chiral amerosport would lead to the formation of diastereomers which can be separated at this stage (or later), using standard chromatographic methods. Alkylation or acylation on the nitrogen atom can give dialkyl - or acyl/alkylamino, in which the group R1may serve as a protecting group, or may be used or processed in Deputy in the final target compound. Cyclization of obtaining substituted the research can be implemented by heating the solution with an acid catalyst. GeoStereo the Dov. If R1is a protecting group, it may be removed using known techniques (Green T. C. , P. G. M. Wuts, Protecting groups in organic synthesis, 2nd ed. , New York, 1991). If the preparation of such compounds leads to the formation of enantiomers, these may be separated by alkylation or acylation of the final product (R1=H) chiral auxiliary agent, separation of the diastereomers thus obtained, using known chromatographic methods, and removal of the chiral auxiliary agent to produce the desired enantiomers. Alternatively, these diastereomers can be separated by fractional crystallization from a suitable solvent of the diastereomeric salts formed by connection with a chiral organic acid.

One method for the synthesis of enantiomerically pure substituted morpholino illustrated in scheme 5. Protection of enantiomerically pure phenylglycine as //-benzyl-derivative followed by a double alkylation of 1,2-dibromethane derivative, leads to morpholine. Restoring active hydride reagent, such as diisobutylaluminium, sociallyengaged, lithium(tri-sec-butyl)borohydride/L-Selectively. Alkylation of the alcohol, removing the protecting group on the nitrogen atom (for example, hydrogenation with palladium catalyst or 1-chloritisation (Olofsson in the journal J. Org Chem, 1984, S. 2081 and 2795)) and alkylation on nitrogen produces 2,3-TRANS-compounds.

One way of obtaining enantiomerically pure 2,3-CIS-morpholino illustrated in scheme 6. In the first stage education triftormetilfosfinov ester of the appropriate benzyl alcohol (especially benzyl alcohols which are substituted electron-acceptor groups such as nitro, fluorescent-, chloro-, bromo-, -COR, trifluoromethyl and other) is carried out in the presence of directionspanel base, in an inert solvent. In addition, there may be used other otsepleniya group such as iodide, mesilate, toilet, para-nitrophenylacetate, etc. Suitable bases include 2,6-di-tert-butylpyridinium, 2,6-di-tert-butyl-4-methylpyridin, diisopropylethylamine, potassium carbonate, sodium carbonate, etc., Suitable solvents include toluene, hexane, benzene, carbon tetrachloride, dichloromethane, chloroform, dichloroethane, etc., and mixtures thereof. Then the filtered solution of the triflate are added to a solution of intermediate compounds formed when contacted lithium-three(verbatim)borohydride (L-Selectride) at low temperature, preferably from -78oC to -20oC. After a few hours at a low temperature, processing and cleaning provides mainly 2,3-CIS-substituted products, which can lead to end-connections, as shown in figure 6.

Enantiomerically pure phenylglycine, substituted at the phenyl ring, can be prepared according to the method shown in scheme 7 (D. A. Evans and others, J. Am. Chem. Soc., 1990, 112 so, S. 4011).

Methods of obtaining alkylating the nitrogen atom of agents R1CH2X, used in scheme 5 and scheme 6, based on known literature methods (for R1= 3-/1,2,4-triazolyl/ or 5/1,2,4-triazolyl-3-he-Il and X = chlorine, see Yanagisawa I.; I. Hirata. I. Ishin, J. Medicinal Chemistry, 1984, 27, S. 849; R1= 4((2H)-imidazol-2-one)-yl or 5-(4-etoxycarbonyl-(2H)-imidazol-2-one)-yl and X = bromo-, see R. Duschinsky, L. A. Dolan, J. Am. Chem. Soc, 1948, so 70, S. 657).

The target substances of the formula I obtained in accordance with the reactions that explained above can be isolated and purified in a traditional way, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, etc., of the Substance of the present invention are capable of forming salts with various inorganic and organizers additive salts include the acetate, adipate, benzoate, bansilalpet, bisulfate, butyrate, citrate, comfort, camphorsulfonate, aconsultant, fumarate, polysulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, methanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate, undecanoate. Basic salts include ammonium salts, alkali metal salts, such as salts of sodium, lithium and potassium, salts of alkaline earth metals such as calcium and magnesium, salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, etc., in Addition, the basic nitrogen-containing groups can be quaternity with such agents as lower halides of Akilov, as for example methyl-, ethyl-, propyl - and butyl chloride, bromides and iodides; diallylsulfide similar dimethyl-, diethyl, dibutil and dimycolate; long chain halides such as decyl-, lauryl-, myristyl and sterilgarda, bromides and iodides; aralkylamines like benzylbromide and others. Non-toxic physiologically acceptable salts are preferred, although other salts are also useful, as for example p is measures by interacting freely the basic form of the product 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 vacuum, or by drying, freezing or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.

Although described here the reaction schemes are reasonably generic, expert in this field of chemistry will understand that one or more functional groups present in the compound of formula I, can make this molecule is incompatible with a particular synthetic sequence.

In this case, we can use alternative routes, changed the order of the stages or strategy to protect and unprotect. In all cases, the specific reaction conditions, including reagents, solvent, temperature and reaction time should be selected so that they are consistent with the nature of functional groups present in the molecule.

The following examples are given to illustrate the present invention and they should not be construed as limiting the scope and intent of the present invention.

Example 1.

(+/-)-alpha-Bromophenylacetate, 3,5-bis(trifluoromethyl)benzylacetone

A solution of 2.50 g (10,2 mm is g (2.6 mmol) of monohydrate para-toluenesulfonic acid in 10 ml of toluene is stirred under vacuum (35 mm RT.CT.) at room temperature for 3 days. The reaction mixture was partitioned between 100 ml of ether and 50 ml of a saturated aqueous solution of sodium bicarbonate, and the layers separated. The organic layer was washed with 25 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. In the flash-chromatography on 200 g of silica gel using as eluent a mixture of 9:1 (by volume) hexane and methylene chloride receive 5,41 g (81%) indicated in the title compound in the form of a solid substance with a melting point (So square) 79-82oC.

Range PMR: 4,47 and to 4.62 (AB square, 2H, J = 12,5), 4,78-is 4.93 (2H), 5,09 and to 5.21 (AB square , 2H, J = 7,7), 7,31 - 7,44 (m, 7H), 7,70 (c, 1H), 7,82 (s, 1H), 7,84 (c, 2H).

IR spectrum (thin film) 1363, 1278, 1174, 1130, 704, 682.

Analysis calculated for C26H17BrF12O2:

C - 46,76; H - 2,23; Br - 11,64; F - 33,70;

found: C - 46,65; H - 2,56; Br - 11,94; F - to 34.06.

List of abbreviations used in the PMR spectra:

d - doublet,

square - Quartet

m - multiplet,

s - singlet,

t - triplet,

Shir. - wide.

Example 2.

(+/-)-N-(2-Hydroxyethyl)-phenylglycinol, 3,5-bis(trifluoromethyl) benzylacetone

A solution of 1.50 g (2.2 mmol) of (+/-)-bromophenylacetonitrile, 3,5-bis(trifluoromethyl)benzylacetone (example 1), 100 m is for 20 hours The solution is cooled and concentrated to 25% of the original volume under vacuum. The concentrated solution was dissolved in 1-molar potassium hydroxide (120 ml) and the solution partitioned between 50 ml of ether and 20 ml dohnalkova aqueous sodium hydroxide solution, and the layers separated. The organic layer is washed with 20 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. In the flash-chromatography on 50 g of silica gel using as eluent a mixture of 65: 35 by volume of ether and hexane obtain 1.18 g (83%) indicated in the title compound in the form of butter.

Range PMR: 2,66 (Shir. S., 2H), 2,61 and $ 2.68 (DD AB square, 2H, J (AB)=12,4, J (2,61)=6,8, 6,2, J(2,68)=6,2, 6,2), 3,57 and 3,66 (DD AB square, 2H, J (AB) = 10,8, J (3,57)=6,2, 6,2), J(3,66)=6,8, 6,2), 4,02 (d, 1H, J = 7,0), 4,37, and with 4.64 (AB square , 2H, J = 12,5), 4,80, and to 4.87 (AB square, 2H, J = 12,8), to 4.87 (d, 1H, J = 7,0), 7,31-7,40 (7H), 7,73 ( c, 1H), 7,81 (c, 3H).

IR-spectrum (in pure form) 3342, 1456, 1373, 1278, 1173, 1128, 704, 682.

MS-THE BELARUSIAN LIBRARY ASSOCIATION-650 (M+I)+< / BR>
Analysis calculated for C28H23F12NO3:

C - 51,78; H IS 3.57; N - 2,16; F - 35,11;

found: C - 51,80; H - to 3.67; N - 2,10, F - 35,41.

Example 3.

(+/-)-N-(2-Hydroxyethyl)-N-(prop-2-enyl)phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone

A mixture of 1.45 g (2.2 mmol) of (+/-)-N-(2-Hydroxyethyl) in order of avramidi and 15 ml of ethanol was stirred at 60oC for 20 hours the Mixture is cooled, partitioned between 100 ml of ether and 25 ml of water, and the layers separated. The organic layer is dried over magnesium sulfate. The aqueous layer was extracted with 100 ml of ether; the ether extract is dried and combined with the original organic layer. The combined organic layers concentrated in vacuo. In the flash-chromatography on 50 g of silica gel using as eluent a mixture of 4:1 (by volume) hexane and ether get 1,36 g (88%) indicated in the title compound in the form of butter.

Range PMR: 2,40 (dt, 1H, J = 13.2 and 2,8), 2,93 - is 3.08 (3H), 3,30 (DDT, 1H, J = 12,0, of 2.8 and 1.6), 3,54 (Shir. m, 2H), 3,65 (dt, 1H, J = 10,0, 2,8), to 4.23 (d, 1H, J = 8,4), to 4.52 and 4,58 (AB square:, 2H, J = 12,4), is 4.85 and 4.95 (AB square , 2H, J = 12,4 in), 5.25 (d, 1H, J = 9,6), 5,28 (d, 1H, J = 16,4), of 5.39 (d, 1H, J = 8,4), of 5.81 (m, 1H), 7,24 - 7,40 (7H), 7,68 (s, 1H), 7,86 (C. 2H).

IR-spectrum (in pure form) 3457, 1362, 1278, 1132, 1056, 759, 705, 682.

MS-THE BELARUSIAN LIBRARY ASSOCIATION-690 (M+I)+< / BR>
Analysis calculated for C31H27F12NO3:

C - 53,99, H - 3,95, N - 2,03, F - 33,07;

found: C - 54,11, H - 4,08, N - 1,78, F - 32,75.

Example 4.

(+/-)-2-(3,5-bis-(trifluoromethyl)benzyloxy)-3-phenylmorpholine

Stage A.

A solution of 850 mg (1.2 mmol( (+/-)-N-(2-Hydroxyethyl)-N-(prop-2-enyl) phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone (example 3) and 700 mg (3.7 mmol) predelay between 100 ml of ether and 25 ml of saturated aqueous sodium bicarbonate solution. The layers separated, the organic layer washed with 25 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. In the flash-chromatography on 30 g of silica gel using as eluent a mixture of 50:1 (by volume) hexane and ether get 426 mg (78%) of N-allylnormorphine that were used in the next stage without further purification.

Stage B.

In dvuhgolosy flask equipped with a stopper and a short device for distillation, download solution of N-allylnormorphine from the stage And example 4 (540 mg, 1.2 mmol) and 80 mg (0.09 mmol) chloride, Tris(triphenylphosphine)rhodium (Wilkinson catalyst) in 25 ml of a mixture of 4:1 (by volume) of acetonitrile and water. This reaction mixture is heated to boiling and allow the solvent to Athanasia from the reaction mixture. The volume of the reaction mixture support between 10-20 ml by adding solvent through a closed tube entrance. After 1 h the reaction mixture was treated with an additional portion 80 mg of catalyst Wilkinson. After 6 h the reaction mixture was cooled and partitioned between 75 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 75 ml of ether; the ether extract is dried and is the result of flash chromatography on 35 g of silica gel using as eluent a mixture of 1:1 (by volume) of ether and hexane receive 200 mg of transisomer and 130 mg of a mixture of CIS - and TRANS-isomers (total 68%). Chromatographic purification of the mixture on 8 g of silica gel using as eluent a mixture of 4:1 (by volume) hexane and ether to give 64 mg of CIS-V and 57 mg of a mixture of CIS - and TRANS-isomers specified in the connection header.

Range PMR for TRANS-V: 2,03 (Shir. s, 1H), 2,94 (DDD, 1H, J = 11,0, of 2.5 and 2.5), is 3.08 (dt, 1H, J = 11,0, 3,2), 3,71 (d, 1H, J = 7,0), 3,83 (dt, 1H, J = 11,2, 2,8), of 4.05 (DDD, 1H, J = 11,2, the 3.2 and 3.2), 4,43 (d, 1H, J = 7,0), 4,53 and 4,88 (AB square, 2H, J = 13.3-inch), 7,26 was 7.45 (7H), of 7.70 (s, 1H).

IR-spectrum (in pure form) 3333, 2859, 1456, 1374, 1278, 1131, 1082, 757, 702, 682.

MS-THE BELARUSIAN LIBRARY ASSOCIATION-406 (M+I)+< / BR>
Analysis calculated for C19H17F6NO4:

C - 56,30, H - TO 4.23; N - OF 3.46; F - 28,12;

found: C - 56,39; H - 4,28; N - 3,36; F - weighing 28.32.

Range PMR for CIS-V: 2,10 (Shir. s, 1H), 3,13 (DD, 1H, J = 12,4, 3,0), 3,26 (dt, 1H, J = 12,4, 3,6), the 3.65 (DD, 1H, J = 11.6 and 3,6), 4,07 (dt, 1H, J = 11,6, 3,0), 4,14 (d, 1H, J = 2,40, to 4.52 and 4,82 (AB square, 2H, J = 13,6), was 4.76 (d, 1H, J = 2,4), 7,30-7,42 (6H), of 7.70 (s , 1H).

MS-THE BELARUSIAN LIBRARY ASSOCIATION-406 (M+1)+.

Example 5.

(+/-)-2-(3,5-bis-(trifluoromethyl)benzyloxy)-3-phenyl-4 - methylcarbamoylmethyl

A solution of 105 mg (0.26 mmol) of TRANS-isomer(+/-)-2-(3,5-bis-(trifluoromethyl)benzyloxy)-3-phenylmorpholine (example 4) and 0.09 ml (0.50 mmol) of N, N-diisopropylethylamine in 3 ml of acetonitrile is treated with 90 mg (0.5 mmol) of iodoacetamide, and the resulting solution stirred at to the ATA and 10 ml of a 0.5 normal aqueous solution of potassium hydrosulfate. The layers separated, the organic layer washed with 10 ml of 5% aqueous sodium thiosulfate solution, 10 ml of saturated aqueous sodium bicarbonate solution, 10 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. In the flash-chromatography on 5 mg of silica gel using as eluent a mixture of 2:1 (by volume) of ethyl acetate and hexane to get 99 mg (82%) of TRANS-isomer is specified in the header connection in the form of oil.

Range PMR: 2,56 (dt, 1H, J=3.2 and 11,6), 2,67, and to 3.16 (AB square, 2H, J= 16,4), 2,96 (dt, 1H, J=12,0, 1,6), 3,30 (d, 1H, J=7,0), 3,86 (dt, 1H, J=3,2, 12,0), 4,08 (DDT, 1H, J=11,6, of 3.2 and 1.6), 4,48, and 4,84 (AB square, 2H, J=13,2), of 4.49 (d, 1H, J= 7,0), 5,98 (Shir.s, 1H), 6,83 (Shir.S., 1H), 7,33 (s, 7H), of 7.70 (s, 1H).

IR-spectrum (in pure form) 3445, 2838, 1682, 1278, 1132, 760, 704, 682.

MS-THE BELARUSIAN LIBRARY ASSOCIATION - 463 (M+1)+.

Analysis calculated for C12H20F6NO3:

C - 54,54; H IS 4.36; N - 6,06; F - 24,65;

found: C - 54,54; H - to 4.52; N - 5,61; F - 24,45.

A similar experiment was conducted with 40 mg (0,99 mmol) of the CIS isomer(+/-)-2-(3,5-bis-(trifluoromethyl)benzyloxy)-3 - phenylmorpholine (example 4) using a 0.035 ml (0.2 mmol) of N,N-diisopropylethylamine and 37 mg (0.2 mmol) of iodoacetamide in this reaction. Processing and flash chromatography of the mixture of 30 mg (65%) of the CIS isomer Okasan, J=11,6), the 3.65 (d, 1H, J=2,8), 3,71 (DDT, 1H, J=11,6, 3,2, 1,2), 4,21 (dt, 1H, J=1,6, 2,4), of 4.44 and 4,89 (AB square, 2H, J=13,6), 4,71 d, 1H, J= 2,8), 5,86 (Shir.S., 1H), 7,15 (Shir.s, 1H), 7,27 was 7.45 (7H), 7,73 (s, 1H).

MS-THE BELARUSIAN LIBRARY ASSOCIATION - 463 (M+1)+.

Example 6.

(+/-)-2-(3,5-bis-(trifluoromethyl)benzyloxy)-3-phenyl-4- (methoxycarbonylmethyl)morpholine

A solution of 150 mg (from 0.37 mmol), TRANS-isomer(+/-)-2-(3,5-bis-(trifluoromethyl)benzyloxy)-3-phenylmorpholine (example 4, R1=H) and 0.18 ml (1.0 mmol) of N, N-diisopropylethylamine in 2 ml of acetonitrile is treated with 0,095 ml (1.0 mmol) of methylpropanoate, and the resulting solution was stirred at room

temperature for 20 h the Solution was concentrated in vacuo, and the residue partitioned between 20 ml of ethyl acetate and 5 ml of a 0.5 normal aqueous solution of potassium hydrosulfate. The layers separated, the organic layer washed with 10 ml of 5% aqueous sodium thiosulfate solution, 10 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. In the flash-chromatography on 10 g of silica gel using as eluent a mixture of 4: 1 (by volume) of hexanol and ether obtain 164 mg (93%) of TRANS-isomer is specified in the header connection in the form of oil.

Range TMR: and 2.79 (dt, 1H, J=3.2 and 11,2), with 2.93 (dt, 1H, J=11,2, 1,6), 3,52 (d, 1H, J=7,2), 3,63 (s, 3H), 3,92 (LW net) 2861, 1744, 1455, 1375, 1346, 1278, 1170, 887, 759, 704, 682.

MS-THE BELARUSIAN LIBRARY ASSOCIATION - 478 (M+1)+.

Analysis calculated for C221H21F6NO4:

C - 55,35, H - 4,43, N - 2,93, F - 23,88;

found: C is 55.74, H - 4,50, N - 2,79, F - 24,01.

Example 7.

N-Methoxy-N-methyl-(N-tert-butoxycarbonyl)-phenylglycinate

A solution of 20.0 g (79,7 mmol) (N-tert-butoxycarbonyl)-phenylglycine in 150 ml of ethyl acetate at -10oC handle of 8.8 ml (79,7 mmol) 4-methylmorpholine. Added dropwise over 10 min 10.3 ml isobutylphthalate (79,7 mmol), maintaining the temperature at -10oC. the Resulting suspension is stirred in the cold for 15 minutes. The reaction mixture was treated with 11.6 g (119.0 mmol) hydrochloric N, O-dimethylhydroxylamine. Add the second portion of 4-methylmorpholine (13 ml, 119 mmol) and the mixture stirred at -10oC 15 minutes at 25oC for 2 h, the Reaction mixture was partitioned between 100 ml ethyl acetate and 100 ml of 10% aqueous citric acid solution and the layers separated. The organic layer was washed with 100 ml saturated aqueous sodium bicarbonate solution, 100 ml of a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate and concentrated in vacuo. Crystallization from hexanol at -20oC for 72 h gives 8.0 g (34%) of the criminal code is, 2H), 7,40 (m, 5H).

Example 8.

Diethyl (2-oxo-3-tert-butoxycarbonyl-3-phenyl)-propylphosphonic

The solution was 7.45 ml (51,0 mmol) diethylmalonate in tetrahydrofuran at -78oC handle of 31.8 ml (51,0 mmol) of a 1.6 molar solution of n-utility in hexane, and the resulting mixture is stirred in the cold for 30 minutes. Add a solution of N-methoxy-N-methyl-(N-tert-butoxycarbonyl)-phenylglycinate (4.0 g, 14.0 mmol) from example 7 in 20 ml of tetrahydrofuran, and the reaction mixture stirred at -78oC 15 min and at 25oC 15 minutes the Reaction is interrupted by adding 150 ml of a saturated aqueous solution of ammonium chloride, diluted with 300 ml of ethyl acetate and the layers separated. The organic layer is dried over magnesium sulfate and concentrated in vacuo. In the flash-chromatography on silica gel using as eluent a mixture of 7:3 and then 4:1 (by volume) of ethyl acetate and hexane obtain 4.8 g (92%) of TRANS-isomer is specified in the header connection in the form of oil.

Range PMR: 1,2-1,42 (15H), 2,84 (DD, 1H), 3,20 (DD, 1H), 4,0-4,20 (m, 4H), of 5.50 (d, 1H), 5,94 (Shir.S., 1H), 7,32 (m, 5H).

Example 9.

N-tert-Butoxycarbonyl-1-phenyl-2-oxo-4-(3,5-bis(trifluoromethyl) phenyl)but-3-enamine

The solution 4,80 g (12.5 mmol) of diethyl (2-oxo-3-tert-butoxycarbonyl-3 dispersion in mineral oil) of sodium hydride in 30 ml of tetrahydrofuran at 0oC. After 30 minutes, slowly add to 2.06 ml (12.5 mmol) of 3,5-bis(trifluoromethyl)benzaldehyde, and the resulting mixture is stirred in the cold for 15 minutes the Reaction is interrupted by adding 50 ml of a saturated aqueous solution of ammonium chloride, diluted with 50 ml of ethyl acetate, and the layers separated. The organic layer is dried over magnesium sulfate and concentrated in vacuo. In the flash-chromatography on silica gel using as eluent a mixture of 19:1 then 9:1 (by volume) of ethyl acetate and petroleum ether 3,3 get g (56%) indicated in the title compound in the form of a solid substance.

Range PMR: of 1.40 (s, 9H), 5,38 (d, 1H), 5,90 (d, 1H), 6,80 (d, 1H), 7,39 (m, 5H), of 7.70 (s, 1H), to 7.84 (s, 3H).

Example 10.

Hydrochloric 1-phenyl-2-hydroxy-4-(3,5-bis(trifluoromethyl) phenyl)but-3-enamine

A solution of 1.0 g (2.1 mmol) of N-tert-butoxycarbonyl-1-phenyl - 2-oxo-4-(3,5-bis(trifluoromethyl)phenyl)but-3-enamine (example 9) in 30 ml of methanol at 0oC handle 241 mg (6.3 mmol) of sodium borohydride. After 30 minutes, the reaction is interrupted by adding 50 ml of water, and concentrated in vacuo, removing the methanol. The mixture is partitioned between 100 ml ethyl acetate and 50 ml of water, and the layers separated. The organic layer is dried over magnesium sulfate and concentrated in vacuo. In resultatredigerare (each protected by tert-butoxycarbonyl).

Range PMR (*specifies the resonances smaller diastereoisomer):

of 1.40 (s, 9H), 4,60 (DD, 1H), 4,90 (Shir.S., 1H), 5,20 (Shir.D., 1H), 6.30-in (DD, 1H), 6,40 (DD, 1H*), 6,70 (DD, 1H), 6,80 (DD, 1H*), 7,40 (m, 5H), 7,80 (m, 3H).

The solution specified in the title compound, protected by tert-butoxycarbonyl in methanol (saturated with hydrogen chloride), incubated for 72 hours the Solution was concentrated in vacuo. As a result of recrystallization of the resulting solid from a mixture of ether and hexanol receive 500 mg (80%) of the hydrochloride is indicated in the title compound in the form of a solid substance.

Range PMR: 4,20 (Shir. s, 1H), and 4.40 (d, 1H), of 6.20 (DD, 1H), 6,60 (DD, 1H), 7,30 (m, 5H), 7,80 (m, 3H).

The hydrochloride of the compounds dissolved in ethyl acetate and 1 N. aqueous sodium hydroxide solution. The layers are separated. The organic layer is dried over magnesium sulfate and concentrated in vacuo, obtaining mentioned in the title compound as free base.

Example 11.

2-(2-(3,5-bis(trifluoromethyl)phenyl)ethynyl)-3-phenyl-5-exomorphic

A solution of 1.95 g (5.2 mmol) of 1-phenyl-2-hydroxy-4-(3,5-bis(trifluoromethyl)phenyl)but-3-enamine (example 10) in 20 ml of toluene is added to a suspension of 250 mg (6.2 mmol, 60% dispersion in mineral oil) gist solution of 0.6 ml (1.15 mm) of ethylchloride in 5 ml of toluene and the resulting mixture is heated at boiling point for 3 hours The reaction mixture is cooled, terminate the reaction by adding 50 ml of a saturated aqueous solution of ammonium chloride, diluted with 50 ml of ethyl acetate, and the layers separated. The organic layer is dried over magnesium sulfate and concentrated in vacuo. As a result, the flash chromatography using as eluent a mixture of 4: 1, then 3:1 and 1:1 (by volume) of ethyl acetate and hexane, and then elwira pure ethyl acetate, receive 300 mg of TRANS-isomer and 800 mg of the CIS isomer of the compound indicated in the heading and (a total of 55%), both isomers in solid form.

Range of TMR for the CIS isomer: 1,20-1,40 (m, 1H), 1,5-of 1.62 (m, 1H), 2,6 - 2,98 (m, 2H), 3,86 (dt, 1H), 4,24 (d, 1H), 4,34 (DD, 1H), 4,45 (d, 1H), 6,40 (Shir. s, 1H), 7,24 (m, 2H), 7,40 (m, 3H), 7,50 (s, 2H), of 7.70 (s, 1H).

Example 12.

3-phenyl-2-(2-(3,5-bis(trifluoromethyl)phenyl)ethyl)-morpholine

The solution 0,095 g (0.23 mmol) of 2-(2-(3,5-bis-(trifluoromethyl)- phenyl)ethynyl)-3-phenyl-5-oxaprotiline (example 11) in 10 ml of a mixture 1 : 1 (by volume) of ethanol and ethyl acetate was treated with 10 mg of palladium hydroxide, and the resulting mixture is stirred in hydrogen atmosphere for 2 hours the Catalyst is filtered off and the filtrate was concentrated in vacuo. The crude product is used directly without further purification.

A solution of 65 mg of this crude of morpholine in which hydrofuran, and the resulting solution is boiled for 16 hours the Reaction is interrupted by adding 10 ml of methanol and 70 mg of potassium carbonate, and the resulting mixture is heated at boiling for 3 hours, All volatiles are removed in vacuo, and the residue partitioned between 20 ml of ethyl acetate and 10 ml of a saturated aqueous solution of ammonium chloride. The organic layer is separated, dried over sodium carbonate and concentrated in vacuo. The residue is dissolved in methanol saturated with hydrogen chloride, and concentrated in vacuo. The residue is dissolved with ether; the resulting solid is filtered off and dried, receiving 32 mg (46%) of the hydrochloride specified in the connection header with so pl. 114 - 116oC.

Range PMR: to 1.42 (m, 1H), 1,66 - of 1.84 (m, 1H), 2,7 - to 2.94 (m, 2H), 3,00 (m, 1H), 3,3 - of 3.46 (m, 1H), 3,8 - of 3.94 (m, 2H), 4,10 (m, 1H), 4,20 (d, 1H), 7,40 (m, 3H), of 7.64 (m, 3H), of 7.64 (m, 5H).

MC-Cl 402 (M + 1)+< / BR>
Example 13.

N-benzyl-(S)-phenylglycine

A solution of 1.51 g (10 mmol) of S-phenylglycine in 5 ml of 2-normal aqueous solution of sodium hydroxide is treated with 1.0 ml (10 mmol) of benzaldehyde and stirred 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. Remove the cooling bath, and reaktsionnuyu 25 ml methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid to pH 6, and the precipitated solid precipitate is filtered off, washed with 50 ml water, 50 ml of a mixture 1 : 1 (by volume) of methanol and ethyl ether and 50 ml of ether and dried, obtaining of 1.83 g (76%) of the product so melting 230 - 232oC.

Analysis calculated for C15H15NO2:

C - 74,66, H - 6,27, N - 5,81;

found C - 74,17, H - to 6.19, N - 5,86.

Example 14.

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

A mixture of 4.0 g (of 16.6 mmol) N-benzyl-S-phenylglycine (from example 13), of 5.00 g (36 mmol) of potassium carbonate, 10 ml of dibromoethane and 25 ml of dimethylformamide was stirred at 100oC for 20 hours the Mixture is cooled and partitioned between 200 ml of ethyl ether and 100 ml of water. The layers separated, and the organic layer is washed with 3 times 50 ml of water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by the method of flash chromatography on 125 g of silica gel, elute with a mixture of 9 : 1, then 4 : 1 (by volume) hexane and ether, and get to 2.41 g (54%) of product as a solid with so pl. 98 - 100oC.

MC-the Belarusian library Association: m/z 268 (M + H, 100%).

Range PMR (in deuterium chloroform), 200 MHz, M. D.): 2,54 of 2.68 (m, 1H), 2,96 (dt, J = 12.8 and 2,8, 1H), 3,14 (dt, J = 13.3-inch, 1H, in), 3.75 (d, J = 13.3-inch, 1H), 4,23 (s, 1H), 4,29 - to 4.38 (m, 1H), 4.53-in (dt, J = 3.2 and 11,0), 7,2 - 7,56 (m, 10H).

Anal is>Example 15.

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

Stage A.

3,5-bis(trifluoromethyl)benzyl alcohol, triftoratsetata ether

A solution of 1.0 g (4.1 mmol) of 3,5-bis(trifluoromethyl)benzyl alcohol and 1.05 g (5,12 mmol) of 2,6-di-tert-butyl-4-methylpyridine in 45 ml of dried carbon tetrachloride in nitrogen atmosphere process of 0.74 ml (of 4.38 mmol) of anhydride of triftoratsetata at room temperature. Soon after adding the anhydride of a white precipitate is formed. After 90 min, the suspension is filtered in a nitrogen atmosphere to filter Slanka, and the filtrate was concentrated in vacuo. The remainder, which represents a two-phase oil, dissolved in 10 ml dry toluene in a nitrogen atmosphere. The obtained transparent solution was used immediately at the stage B below.

Stage B.

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

A solution of 0.50 g (of 1.87 mmol) N-benzyl-3-(S)-phenylmorpholine-2 - she (from example 14) in 10 ml of dry THF cooled to -75oC in nitrogen atmosphere and treated dropwise to 2.06 ml (to 2.06 mmol) of 1-molar solution of three(sec-butyl)borohydride lithium (L-Selectride) in tetrahydrofuran. After stirring the solution at -75oC in t is analnogo ether in toluene, so that the internal temperature was maintained below -60oC. the Resulting solution was stirred at -75oC 1 h and then at a temperature of between -38oC and -50oC for 2 h Then the solution was poured into a mixture of 25 ml of ethyl acetate and 20 ml of a saturated aqueous solution of sodium bicarbonate, and the layers separated. The aqueous phase is extracted with 2 times 30 ml of ethyl acetate, the combined organic layers dried over sodium sulfate, the mixture is filtered, and the filtrate was concentrated in vacuo. The residue is purified by the method of flash chromatography on 130 g of silica gel, elute with 2 liters of a mixture of 100 : 5 hexane and ethyl acetate, receiving of 0.68 g (73%) of oil which according to the PMR spectrum is a mixture of 20 : 1 CIS-: TRANS-morpholino.

Range PMR (in deuterium chloroform, 400 MHz, M. D.): core (CIS-isomer): 2,37 (so , J = 12, 3,6, 1H), 2,86 ( t, J = 13, 2H), 3,57 (d, J = 2,6, 1H), 3,63 (doctor kV, J = 11,3, 1,6, 1H), 3,89 (d, J = 13.3-inch, 1H), 4,12 (TD, J = 11,6, 2,4, 1H), and 4.40 (d, J = 13,6, 1H), 4,69 (d, J = 2,9, 1H), 4,77 (d, J = 13,6, 1H), 7,2 - 7,4 (m, 8H), 7,43 (s, 2H), 7,55 (Shir. D., 2H), 7,69 (s, 1H).

Stage Century.

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

A mixture of 0.68 g (1.37 mmol) of 4-benzyl-2-(S)-3,5-bis (trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine and 280 mg of the catalyst 10% palladium on coal in 36 ml of a mixture of 97 : 3 ethanol and water premesis washed with ethanol, and the filtrate concentrated in vacuo. The residue is purified by the method of flash chromatography on 68 g of silica gel, elute with 1 liter of a mixture of 25 : 75 hexane and diethyl ether, receiving 0,443 g (30%) of oil which according to the PMR spectrum is pure CIS-morpholine.

Range PMR (in deuterium chloroform, 400 MHz, M. D.): 1,8 (Shir. s, 1H), 3,10 (DD, J = 12,5, 2,9, 1H), 3,24 (TD, J = 12,2, 3,6, 1H), 3,62 (DD, J = 11,3, 2,5, 1H), Android 4.04 (dt, J = 11,7, 7,3, 1H), 4,11 (d, J = 2,4, 1H), 4,49 (d, J = 13,5, 1H), 4,74 (d, J = 2,5, 1H), 4,80 (d, J = 13.3-inch, 1H), 7,25 - 7,40 (m, 5H), 7,40 (s, 2H), 7,68 (s, 1H).

Analysis calculated for C19H17F6NO2:

C - 56,30; H - TO 4.23; N - OF 3.46; F - 28,12;

found: C - 56,20; H - 4,29; N - 3,34; F - of 27.94.

Example 16.

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

Specified in the title substance was prepared from (R)-phenylglycine using the methods of examples 13, 14 and 15.

Example 17.

4-(3-(1,2,4-Triazolo)methyl)-2-(S)-(3,5-bis-(trifluoromethyl)- benzyloxy)-3-(S)-phenylmorpholine

Stage A.

N-formyl-2-chloroacetamides

A solution of 5 g (66,2 mmol) chloroacetonitrile in 30 ml of dry methanol is cooled to 0oC in nitrogen atmosphere and treated with 0.1 g (1.8 mmol) of sodium methoxide. Mixture is allowed to warm to room temperature and stirred for 30 min and doba is linoy acid, this material is stirred for 30 minutes, the Reaction mixture was concentrated in vacuo to a solid substance, which is used as such in stage B below.

Stage B.

4-(3-(1,2,4-Triazolo)methyl)-2-(S)-(3,5-bis-(trifluoromethyl)- benzyloxy)-3-(S)-phenylmorpholine

The solution 0,295 g (0.73 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine (from example 15) in 10 ml of dry dimethylformamide is treated, 0,302 g (2,18 mmol) of anhydrous potassium carbonate and then add has 0.168 g (1,24 mmol) of N-formyl-2-chloroacetamides (from example 17, step A), and the suspension is stirred at 60oC for 4 h and Then the mixture is heated to 120oC for 4.5 hours After cooling, the reaction mixture is diluted with 80 ml of ethyl acetate, and the organic layer washed 3 times with 20 ml of water. The organic layer is dried under magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by the method of flash chromatography on 67 g of silica gel, elute with 1.5 liters of a mixture of 100 : 2 methylene chloride and methanol, getting 0,22 g of a yellow substance, which was recrystallized from a mixture of hexane/methylene chloride, getting 0,213 g (60%) of white crystalline substance with so pl. 134 - 135oC.

Range MS-Belarusian library Association: m/z 487 (M + H, 100%), 259 (35%), 243 (65%), 227 (50%), 174 (25%).

Example 18.

4-(3-(5-Oxo-1H,4H-1,2,4-triazolo)methyl)-2-(S)- (3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine

Stage A.

N-Methylcarbamic-2-chloroacetamides

A solution of 5 g (66,2 mmol) chloroacetonitrile in 35 ml of dry methanol is cooled to 0oC and treated 0,105 g (1.9 mmol) of sodium methoxide. Remove the bath with ice, and the mixture is allowed to mix at room temperature for 30 minutes Then to the reaction mixture add 0,110 ml (1.9 mmol) of acetic acid and then added 5.8 g (64,9 mmol) of methylhydroperoxide. After stirring 30 min at room temperature, the suspension was concentrated in vacuo and placed overnight in a high vacuum line, receiving of 10.5 g (98%) of yellow powder, which is used in stage B below.

Range PMR (watermethanol, 400 MHz, M. D.): 3,71 (s, 3H), 4,06 (s, 2H).

Stage B.

4-(2-(N-Methylcarbamic-acetamidino-2-(S)-(3,5-bis(trifluoromethyl) benzyloxy)-3-(S)-phenylmorpholine

A solution of 2.30 g (5.7 mmol) (2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine (from example 15), 1.13 g (6.8 mmol) of N-methylcarbamic-2-chloroacetophenone for 20 hours Precipitated precipitated product is filtered off, washed with 5 ml ice acetonitrile and dried, obtaining of 1.83 g of a white solid. The filtrate was concentrated in vacuo, and the residue partitioned between 50 ml of methylene chloride and 20 ml of water. The layers separated, and the organic layer extracted with 50 ml methylene chloride. The extract is dried, combined with the original organic layer, and the combined organic layers concentrated in vacuo. The residue is purified by the method of flash chromatography on 30 g silica gel, elute with a mixture of 50:1:0,1 (by volume) methylene chloride/methanol/ammonium hydroxide, receiving additional 1,09 g of product (total of 96%).

Range MS-Belarusian library Association: m/z 535 (M+H, 100%), 462 (16%), 291 (30%), 226 (35%), 173 (25%).

Range PMR (in deuterium chloroform, 400 MHz, M. D.): 2,53 (dt. J = 3,5, 12,2, 1H), 2,59 (d, J = 14,6, 1H), 2,94 (d, J = 11,8, 1H), 3,37 (d, J = 14,6, 1H), to 3.58 (d, J = 2,8, 1H), 3,62 - and 3.72 (m, 1H, in), 3.75 (s, 3H), 4.16 the (dt, J = 2,2, 11,8, 1H), of 4.44 (d, J = 13,2, 1H), 4,70 (d, J = 2,8, 1H), 4,79 (d, J = 13,2), 5,55 (W, s, 2H), 7,30 - 7,46 (m, 7H), 7,72 (s, 1H).

Stage B.

2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)-3-(S)-phenylmorpholine

The solution 2,89 g (5.4 mmol) of 4-(2-(N-Methylcarbamic-acetamidino-2-(S)-(3,5-bis(trifluoromethyl) benzyloxy)-3-(S)-phenylmorpholine (stage B) in 36 ml of xylenes mixture 3:1 (by volume) of hexanol and ethyl acetate, what causes crystallization of the product. The product is filtered and dried, obtaining 1.85 g solids. Recrystallization of this solid from 30 ml of a mixture of 4:1 (by volume) hexane/ethyl acetate to give 1.19 g of pure product as a white crystalline substance with so pl. 156-157oC. All uterine stage of crystallization solutions were combined and concentrated in vacuum. The residue is purified by the method of flash chromatography on 30 g silica gel, elute with a mixture of 50:1:0,1 (by volume) methylene chloride/methanol/ammonium hydroxide, receiving additional 0.69 g of solid substance. Three recrystallization from 20 ml of a mixture of 4:1 hexane and ethyl acetate additionally give 0.39 g of the pure product as a white solid (for a total of 58%).

Range MS-Belarusian library Association: m/z 503 (M+H), 259 (55%), 226 (40%), 160 (30%).

Range PMR (in deuterium chloroform, 400 MHz, M. D.): -- to 2.57 ( t, J = 9,6, 1H), 2,87 - of 2.97 (m, 2H), to 3.58 - 3,71 (m, 3H), 4,18 ( t, J = 10,4, 1H), 4,46 (d, J = 13,6), and 4.68 (d, J = 2,8, 1H), around 4.85 (d, J = 13,6, 1H), 7,30 was 7.45 (m, 7H), the 7.65 (s, 1H), the 10.40 (W, s, 1H), of 10.73 (W, s, 1H).

Example 19.

N-(2-(R)-Hydroxypropyl)-phenylglycinol, 3,5-bis(trifluoromethyl) benzylacetone

A solution of 1.0 g (1.5 mmol) of (+/-)bromophenylacetonitrile, 3,5-bis(trifluoromethyl)benzylacetone (example 1), 1.25 ml of (R)-1-amino-2-propanol, 225 mg thief is cooled and concentrated to 25% of the original volume under vacuum. The concentrated solution was partitioned between 50 ml of ether and 20 ml dohnalkova aqueous sodium hydroxide solution, and the layers separated. The organic layer is washed with 20 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. In the flash-chromatography on 50 g of silica gel using as eluent a mixture of 65:35 by volume of ether and hexane receive 948 mg (95%) of product as a mixture 1:1 inseparable diastereomers.

Range MS-Belarusian library Association: m/z 664 (M+H, 25%), 420 (20%), 226 (100%).

Example 20.

N-(2-(S)-Hydroxypropyl)-phenylglycinol, 3,5-bis(trifluoromethyl) benzylacetone

Replacing (R)-1-amino-2-propanol (S)-1-amino-2-propanol in the experience, similar to the previous example, receive 940 mg of the product as a 1:1-mixture of diastereomers.

Example 21.

N-(2-(R)-Hydroxypropyl)-N-(prop-2-enyl)-(R)-phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone and N-(2-(R)-Hydroxypropyl)-N-(prop-2-enyl)-(S)-phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone

The mixture 933 g (1,40 mmol) of N-(2-(R)-Hydroxypropyl)-phenylglycinol, 3,5-bis(trifluoromethyl) benzylacetone (from example 19), 1 ml of allyl bromide, 600 mg (4.3 mmol) of potassium carbonate and 5 ml of ethanol was stirred at 60oC use the W-chromatography on 50 g of silica gel using as eluent a mixture of 20:1 (by volume) ether and hexanol obtain 380 mg of (R,R)-amerosport (Rf= 0,72 with eluent a mixture of 3: 2 (by volume) ether and hexanol), 220 mg (R,S)-amerosport (Rf= 0,62 with eluent a mixture of 3:2 (by volume) ether and hexanol) and 285 mg of a diastereomeric mixture of aminoalcohols.

For (R,R)-amerosport:

MS-the Belarusian library Association (FAB): m/z 704 (M+H)

IR (net) 3476, 2932, 1624, 1454, 1361, 1278, 1175, 1132, 760, 704, 682

Range PMR (CDCl3, 400 MHz, M. D.): of 1.12 (d, 3H, J = 6,4), 2,19 and 2,62 (giving square, 2H, JAB= 13,0, J2,19= 2,3, J2,62= 10,4), of 2.97 (DD, 1H, J= 14,0, 8,8 ), 3,25 - 3,30 (m, 1H), 3,76 (s, 1H), of 3.77 - of 3.85 (m, 1H), 4,21 (d, 1H, J = 8,8), 4,49 and 4,55 (AB sq 2H, J = 12,4), 4,86 and 4,92 (AB kV, 2H, J = 12,4), 5,27 - 5,33 (m, 2H), 5,39 (d, 1H, J = 8,8), 5,79 - of 5.89 (m, 1H), 7,21 - 7,26 (m, 4H), 7,35 - 7,40 (m, 3H), to 7.67 (s, 1H), 7,81 (s, 1H), 7,85 (s, 2H).

Analysis:

Calculated for C32H29F12NO3:

C 54,63, H 4,15, N 1,99, F 32,41.

Found: C 54,72, H 3,94, N 1,95, F 32,17.

For (R,S)-amerosport:

MS-the Belarusian library Association (FAB): m/z 704 (M+I)

IR (net) 3451, 2931, 1624, 1454, 1362, 1277, 704, 683.

Range PMR (in deuterium chloroform, 400 MHz, M. D.) of 1.09 (d, 3H, J = 6,0), 2.48 and 2,71 (giving square 2H, JAB= 13,2, J2,48= 9,6, J2,62= 3,6), was 3.05 (DD, 1H, J= 14,4, 6,8), 3,34 - 3,39 (m, 1H), 3,35 (s, 1H), 3,76-3,81 (m, 1H), 4,21 (d, 1H, J = 8,4), 4,50, and of 4.54 (AB kV, 2H, J = 12,8), 4,86 and 4,96 (AB kV, 2H, J = 12,4), 5,10 - 5,17 (m, 2H), 5,39 (d, 1H, J= 8,4), 5,68 - 5,78 (m, 1H), 7.23 percent - to 7.32 (m, 4H), 7,34 - 7,39 (m, 3H), of 7.69 (s, 1H), 7,83 (s, 1H), 7,86 (s, 2H).

Analysis:

Calculated for C22.

N-(2-(R)-Hydroxypropyl)-N-(prop-2-enyl)-(S)-phenylglycinol, 3,5-bis(trifluoromethyl)-benzylacetone and N-(2-(S)-Hydroxypropyl)-N- (prop-2-enyl)-(R)-phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone

Replacing 880 mg (1,33 mmol) of N-(2-(S)-hydroxypropyl)-phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone (example 20) N-(2-(R)-hydroxypropyl)phenylglycinol, 3,5-bis-(tri-permitil)benzylacetone in the methods of the previous example, obtain 281 mg of (S,S)-amerosport (Rf= 0,72 with eluent a mixture of 3:2 (by volume) ether and hexanol), 367 mg

(S,R)-amerosport (Rf= 0,62 with eluent a mixture of 3:2 (by volume) ether and hexanol) and 197 mg of a diastereomeric mixture of aminoalcohols.

Example 23.

2-(R)-3,5-Bis(trifluoromethyl)-benzyloxy)-3-(R)-phenyl-6-(R)- methylmorpholin and (2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)- 3-(R)-phenyl-6-(R)-methylmorpholin

Stage A.

2(R)-(3,5-Bis-(trifluoromethyl)-benzyloxy)-3-(R)-phenyl-4- (2-propenyl)-6-(R)-methylmorpholin and 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)- 3-(R)-phenyl-4-(2-propenyl)-6- (R)-methylmorpholin

A solution of 355 mg (0.50 mmol) of N-(2-(R)-hydroxypropyl) - N-(2-propenyl)-(R)-phenylglycinol, 3,5-bis(trifluoromethyl)-benzylacetone (from example 21), and 285 mg (1.5 mmol) of monohydrate para-toluenesulfonic acid in 5 ml of toluene is heated at boiling for the sodium carbonate. The layers are separated; the organic layer is washed with 10 ml saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. In the flash chromatography on 10 g of silica gel using as eluent a mixture of 19: 1 (by volume) of hexanol and ether to obtain 122 mg of (2R, 3R, 6R)-product (Rf= 0,53 with eluent a mixture of 4:1 (by volume) of hexanol and ether) and 62 mg of (2S, 3R, 6R)-product (Rf= 0,23 with eluent a mixture of 4:1 (by volume) of hexanol and ether).

For (2R, 3R, 6R) product:

Range MS-Belarusian library Association: m/z 460 (M+H, 65%)

Range PMR (in deuterium chloroform, 400 MHz, M. D.) to 1.35 (d, 3H, J = 6,4), 2,53 and 2,63 (giving square 2H, JAB= 12,0, J2,53= 3,2, J2,63= 6,8), 2,83 - 2,96 (m, 2H), 3,60 (d, 1H, J = 4,0), 4,27 - 4,32 (m, 1H), 4,57 and 4,84 (AB sq 2H, J = 13,2), to 4.87 (d, 1H, J = 4,0), 5,08 - 5,13 (m, 2H), 5,76 and 5.86 (m, 1H), 7,31 - 7,37 (m, 3H), 7,50 - 7,52 (m, 2H), 7,58 (C. 2H), 7,71 (s, 1H).

for (2S, 3R, 6R) product:

MS-the Belarusian library Association (FAB): m/z 460 (M + H, 65%)

Range PMR (in deuterium chloroform, 400 MHz, M. D.) to 1.37 (d, 3H, J = 6,8), 2,48 - of 2.50 (m, 2H), 2,74, and a 3.01 (dt, kV, 2H, J= 6,4, 1,2, 12,4), 3,84 (d, 1H, J = 3.6), and to 3.92 - to 3.99 (m, 1H), 4,70 and 4.93 (AB kV, 2H, J = 13,6), equal to 4.97 (d, 1H, J = 3.6), and 5,08 - 5,14 (m, 2H), 5,74 of 5.84 (m, 1H), 7,28 and 7.36 (m, 3H), 7,43 - 7,46 (m, 2H), to 7.64 (s, 2H), of 7.75 (s, 1H).

Stage B.

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)- methylmorpholin

A solution of 115 mg (0.25 mmol) 2-(R)-(3,5-Bis-(triptorelin(triphenylphosphine)rhodium in 15 ml of a mixture of 4:1 (by volume) of acetonitrile and water is heated to boiling for 30 minutes The reaction mixture is cooled and partitioned between 50 ml of ethyl acetate and 15 ml of water, and the layers separated. The organic layer is dried over magnesium sulfate. The aqueous layer was extracted with 2 times 25 ml of ethyl acetate; the extracts are dried and combined with the original organic layer. The combined organic layers concentrated in vacuo. The residue is filtered through a layer of silica gel ( 20 g) using as solvent a mixture of 2:1 ether and hexanol. The filtrate is concentrated. In the flash-chromatography on 5 g of silica gel using as eluent a mixture of 17:3 (by volume) of hexanol and ether get 676 mg (64%) of 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)- methylmorpholine in the form of butter.

MC-the Belarusian library Association: m/z 420 (M+H, 90%)

Range PMR (in deuterium chloroform, 400 MHz, M. D.) to 1.21 (d, 3H, J = 6,4), 2,02 (width, s, 1H), 2,67 and 2.77 (giving, kV, 2H, JAB= 13,2, J2,67= 8,8, J2,77= 3,2), with 3.89 (d, 1H, J = 2,4,), 4,07-to 4.15 (m, 1H), 4,68 and the 4.90 (AB square, 2H, J = 12,8), to 5.03 (d, 1H, J = 2,4), 7,28-7,38 (m, 3H), 7,51-7,53 (m, 2H), to 7.77 (s, 2H), 7,79 (s, 1H).

Stage Century.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)- methylmorpholin

Similar reaction was conducted using 55 mg (0.12 mmol) of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-4-(2-propenyl)- 6-(R)-methylmorpholine (from example 23, step A) ATA flash chromatography on 4 g of silica gel using as eluent a mixture of 50:1 (by volume) methylene chloride and acetonitrile obtain 14 mg (28%) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)- methylmorpholine in the form of butter.

MC-the Belarusian library Association: m/z 420 (M+H, 90%)

Range PMR (in deuterium chloroform, 400 MHz, M. D.) of 1.39 (d, 3H, J = 6,8), 1,92 (Shir.s, 1H), 2,84 and 2.95 (giving, kV, 2H, JAB= 12,8, J2,84= 6,4, J2,95= 3,6), 3,93-4,00 (m, 1H), 4,07 (d, 1H, J = 2,8), 4,68 and 4.95 (AB square, 2H, J = 13,2), is 4.93 (d, 1H, J = 2,8), 7,28-7,37 (m, 3H), of 7.48-7,52 (m, 2H), 7,55 (s, 2H), 7,72 (s, 1H).

Example 24.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)- methylmorpholine and 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)- methylmorpholin

Replacing 350 mg of N-(2-(S) - hydroxypropyl)-N-(2-propenyl)-(S)- phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone (from example 22) N-(2-(R)-hydroxypropyl)-N-(2-propenyl)-(R)- phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone in the experiment, similar to the previous example, receive 50 mg of 2-(S)-3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)- methylmorpholine and 14 mg of 2-(S)-3,5-Bis(trifluoromethyl/benzyloxy)-3-(S)-phenyl-6-(S)- methylmorpholine.

Example 25.

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)- methylmorpholin and 2-(S)-3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)- methylmorpholin

Stage A.

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(2 - propenyl)-6-(R)-methylmorpholin and 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(2 - propenyl)-6-(R)-methylmorpholin

Specified in the header link)-hydroxypropyl)-N-(2-propenyl)-(S)-phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone (from example 23) was carried out using 246 mg (1,29 mmol) monohydrate para-toluenesulfonic acid in 5 ml of toluene. In the flash-chromatography on 8 g of silica gel using as eluent a mixture of 20: 1 (by volume) of hexanol and ether to obtain 149 mg of products in the form of inseparable diastereomers.

Range MC-the Belarusian library Association: m/Z 460 (M+H, 65%).

Stage B.

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)- methylmorpholin and 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)- methylmorpholin

A solution of 150 mg (0.33 mmol) of 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(2-propenyl)- 6-(R)-methylmorpholine and 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(2-propenyl)- 6-(R)-methylmorpholine (from example 25, step A) and 318 mg (0.32 mmol) chloride, Tris(triphenylphosphine)rhodium in 20 ml of a mixture of 4:1 (by volume) of acetonitrile and water is heated to boiling for 1 hour. In the flash-chromatography on 5 g of silica gel using as eluent a mixture of 90:1 (by volume) of hexanol and ether to obtain 35 mg of product as a mixture and 26 mg of 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)- methylmorpholine (Rf= 0,22 with eluent a mixture of 3: 2 (by volume) of hexanol and ether). Chromatographic clear the S)-phenyl-6-(R)-methylmorpholine (Rf= 0,53 with eluent a mixture of 4 : 1 (by volume) of hexanol and ether) and 17 mg of 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)- methylmorpholine (total yield 41%).

For (2R, 3S, 6R) product:

Range PMR (in deuterium chloroform, 400 MHz, M. D.) of 1.30 (d, 3H, J = 6,4), 1,74 (Shir.s, 1H), 2,73, and 2,98 (giving, kV, 2H, JAB= 11,6, J2,73= 10,0, J2,98= 2,4), the 3.65 (d, 1H, J = 7,2), 3,89-of 3.94 (m, 1H), 4,45 (d, 1H, J = 7,2), 4,53 and the 4.90 (AB kV, 2H, J = 13,2), 7,28-7,38 (m, 3H), 7,41-the 7.43 (m, 2H), 7,45 (s, 2H), of 7.70 (s, 1H).

For (2S, 3S, 6R) product:

Range MS - Belarusian library Association: m/Z 420 (M + H, 90%).

Range PMR (in deuterium chloroform, 400 MHz, M. D.) of 1.20 (d, 3H, J = 6,4), 2,04 (Shir.s, 1H), 2,84 and 3.15 (giving, kV, 2H, JAB= 12,8, J2,84= 10,8, J3,15= 2,8), 4,08 (d, 1H, J = 2,8), 4,08-to 4.15 (m, 1H), 4.53-in and 4,80 (AB kV, 2H, J = 13,2), 4,79 (d, 1H, J = 2,8), 7,28-7,38 (m, 5H), 7,43 (s, 2H), of 7.70 (s, 1H)

(TD, J = 11 Hz and 3 Hz, 1H), 3,68 (d, J = 7 Hz, 1H), 3,81 (TD, J = 11 Hz and 3 Hz, 1H), 4,01 (m, 1H), of 4.44 (d, J = 7 Hz), and 4.5 (d, J = 13 Hz, 1H), around 4.85 (d, J = 13 Hz, 1H), 7,28-7,42 (m, 7H), to 7.67 (s, 1H).

Example 26.

2-(S)-(3,5-Bis)-(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)- methylmorpholine and 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)- phenyl-6-(S)-methylmorpholin

Replacing 250 mg of N-(2-(S)-hydroxypropyl)-N-(2-propyl)-(S)- phenylglycinol, 3,5-bis(trifluoromethyl)-benzylacetone (from example 22) N-(2-(R)-hydroxypropyl)-N-(2-propyl)-(R)-phenylglycinol, 3,5-bis(trifluoromethyl)-benzilic enyl-6-(S)- methylmorpholine and 17 mg of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)- methylmorpholine.

Example 27.

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)- methylmorpholine, 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)- phenyl-5-(R)-methylmorpholine, 2-(R or S)-3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)- methylmorpholine and 2-(S or R)-3,5-Bis(trifluoromethyl/benzyloxy)-3-(R)-phenyl-5-(R)- methylmorpholin

Carrying out the sequence described in example 19 with the substitution of (R)-1-amino-2-propanol (R)-2-amino-1-propanol provides a mixture of 55 mg of material with a high value of Rfand 56 mg of material with a low value of Rf. Material with a high value of Rfhandle in accordance with the method of example 23, step A (above), to obtain 10 mg of material with a high value of Rf(2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5- (R)-methylmorpholin) and 7 mg of material with a low value of Rf(2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5- (R)-methylmorpholin). Material with a low value of Rf(after combining with an additional 30 mg of material processed in accordance with the method of example 23, step A (above) to obtain 24 mg of material with a high value of Rf(2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5- (R)-methylmorpholin) and 18 mg of material with a low value of Rf(2-(S or R)-(3,5-Bis-(tri- (R)-methylmorpholin)

MC-the Belarusian library Association (FAB): m/z 420 (M+H, 100%), 227 (50%), 192 (75%), 176 (65%).

Range PMR (in deuterium chloroform, 400 MHz, M. D.): 0,98 (d, 3H, J = 6,3), 3,16-3,20 (m, 1H), 3,43-3,47 (m, 1H), 3,79 (d, 1H, J = 7.5 Hz), 3,91 (DD, 1H, J = 3,2 and 11.5 Hz), 4,51 (d, 2H, J = 13,4 Hz), is 4.85 (d, 1H, J = 13,2 Hz), 7.29 trend was 7.45 (m, 7H), to 7.67 (s, 1H).

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)- methylmorpholin

MC-the Belarusian library Association (FAB): m/z 420 (M+H, 48%), 227 (35%), 192 (39%), 176 (100%).

Range PMR (in deuterium chloroform, 400 MHz, M. D.): 1,10 (d, 3H, J = 6,4), 3,23-3,26 (m, 1H), 3,56-3,61 (m, 2H), 4,17 (d, 1H, J = 2.3 Hz), 4,51 (d, 1H, J = 13,7 Hz), 4,71 (d, 1H, J = 2.4 Hz), 4,78 (d, 1H, J = 13.5 Hz), 7,28-7,39 (m, 7H), 7,68 (s, 1H).

2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)- methylmorpholin

MC-the Belarusian library Association (FAB): m/z 281 (35%), 221 (55%), 207 (45%), 192 (40%), 147 (100%).

Range PMR (in deuterium chloroform, 400 MHz, M. D.): of 1.13 (d, 3H, J = 6.6 Hz), 3,10-3,14 (m, 1H), 3,66 (DD, 1H, J = 6,6 and 11.4 Hz), 3,76 (DD, 1H, J = 3.5 and 11.2 Hz), Android 4.04 (d, 1H, J = 4.0 Hz), br4.61 (d, 1H, J = 13,2 Hz), 4,74 (d, 1H, J = 3,9 Hz), 4,89 (s, 1H, 13,2 Hz), 7,26-7,35 (m, 3H), 7,47-7,49 (m, 2H), to 7.64 (s, 1H), 7,74 (s, 1H).

2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)- methylmorpholin

Range PMR (in deuterium chloroform, 400 MHz, M. D.): 1,36 (doctor 3H, J = 6,7 Hz), 3.27 to and 3.31 (m, 1H), 3,39 (DD, 1H, J = 2.2 and 11.3 Hz), 4,16 (DD, 1H, J = 3,2 and 11.0 Hz), 4,37 (d, 1H, J = 2.3 Hz), a 4.53 (d, 1H, J = 13.5 Hz), and 4.75 (d, 1H, J = 2.5 Hz), to 4.81 (d, 1H, of 13.6 Hz), 7,26-7,35 (m, 3H), 7,26-the 7.43 (m, 7H), 7,68 (s, 1H).

Example 28.

2-(R and enyl-5-(S)-methylmorpholine and 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy-3-(R)-5-(S)-methylmorpholin

Carrying out the sequence described in example 19 with the substitution of (R)-1-amino-2-propanol (S)-2-amino-1-propanol is a mixture of 78 mg of material with a high value of Rfand 70 mg of material with a low value of Rf. Material with a high value of Rfhandle in accordance with the method of example 23, step A (above) to get less than 1 mg of material with a high value of Rf(2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine) and 9 mg of material with a low value of Rf(2-(S)-(3,5-Bio-(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine). Material with a low value of Rfhandle in accordance with the method of example 23, step A to obtain 20 mg of material with a high value of Rf(2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine) and 14 mg of material with a low value of Rf(2-(S or R)-(3,5-Bis(trifluoromethyl)benzyloxy-3-(S)-phenyl-5-(S)-methylmorpholine).

2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholin

MS-the Belarusian library Association (FAB): m/z 420 (M+H, 60%), 227 (68%), 192 (56%), 176 (100%)

Range PMR (in deuterium chloroform, 400 MHz, M. D.) of 1.12 (d, 3H, J = 6.6 Hz), 3,09 - 3,14 (m, 1H), 3,65 (DD, 1H, J = 6,6 and 11.0 Hz in), 3.75 (DD, 1H, J = 3,6 and 11.1 Hz), Android 4.04 (d, 1H, J = 3,9 Hz), br4.61 (d, 1H, J = 13,2 Hz), to 4.73 (d, 1H, J = 3,9 Hz), 4,89 (the Nile-5-(S)-methylmorpholin

MS-the Belarusian library Association (FAB): m/z 420 (M+H, 50%), 227 (45%), 192 (40%), 176 (100%).

Range PMR (in deuterium chloroform, 400 MHz, M. D.): of 1.36 (d, 3H, J = 6.9 Hz), 3.27 to be 3.29 (m, 1H), 3,39 (d, 1H, J = 2,2 and 11.1 Hz), 4,15 (DD, 1H, J = 3.3V and 11.1 Hz), 4,37 (d, 1H, J = 2.5 Hz), to 4.52 (d, 1H, J = 13.3 Hz), and 4.75 (d, 1H, J = 2.4 Hz), to 4.81 (d, 1H, 13.5 Hz), 7,28-the 7.43 (m, 7H), 7,68 (s, 1H).

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-methylmorpholin

Range PMR (in deuterium chloroform, 400 MHz, M. D.): 1,10 (d, 3H, J = 6.4 Hz), 3,22-of 3.25 (m, 1H), 3,55-of 3.60 (m, 2H), 4,17 (d, 1H, J = 2.3 Hz), 4,51 (d, 1H, J = 13.5 Hz), 4,71 (d, 1H, J = 2.4 Hz), of 4.77 (d, 1H, J = 13,6 Hz), 7,28-7,38 (m, 7H), to 7.67 (s, 1H).

Example 29.

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine, 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine and 2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-phenylmorpholine

Carrying out the sequence described in example 149, replacing (R)-1-amino-2-propanol (R)-2-amino-2-phenylethanol is a mixture of 62 mg of material with a high value of Rfand 52 mg of material with a low value of Rf. Material with a high value of Rfhandle in accordance with the method of application 23, A stage (above) to obtain 16 mg of material with a high value of Rf(2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine) and 4 mg of material with Nachinaem Rfhandle in accordance with the method of example 23, step A to obtain 4 mg of product (2-(R or S)-(3,5-Bis-(trifluoromethyl)-benzyloxy)-3-(R)-phenyl-5-(R)-phenylmorpholine).

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

Range PMR (in deuterium chloroform, 400 MHz, M. D.) 3,62 (t, 1H, J = 10.7 and a 21.5 Hz), 3,93 (d, 1H, J = 7,4 Hz) to 3.99 (DD, 1H, J = 3.1 and 11.2 Hz), 4,18 (DD, 1H, J = 3.0 and a 10.2 Hz), 4,46 (d, 1H, J = 7.4 Hz), a 4.53 (d, 1H, J = 13.5 Hz), 4,89 (d, 1H, J = 13.3 Hz), 7,28-of 7.55 (m, 12H), of 7.69 (s, 1H). 2-(S)-(3,5)-Bis-(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine

Range PMR (in deuterium chloroform, 400 MHz, M. D.): to 3.67 (DD, 1H, J = 3,5, and 11.0 Hz), with 3.89 (d, 1H, J = 10,8 and 21.6 Hz), 4,25 (DD, 1H, J = 3.3V and 11.0 Hz), 4,34 (d, 1H, J = 2.2 Hz), to 4.52 (d, 1H, J = 13,8 Hz), 4,78-to 4.87 (m, 2H), 7,28-7,51 (m, 12H), of 7.69 (s, 1H)

2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-phenylmorpholine

Range PMR (in deuterium chloroform, 400 MHz, M. D.): 4,10-of 4.25 (m, 2H), 4,30-to 4.38 (m, 1H), 4,48-of 4.54 (m, 1H), 4,59-of 4.66 (m, 1H), 4,86-5,00 (m, 2H), 7,25-7,74 (m, 13H).

Example 30

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine, 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine, 2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine and 2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine

Conduct sequences described the high value of Rfand 64 mg of material with a low value of Rf. Material with a high value of Rfhandle in accordance with the method of example 23, step A (above), to obtain 23 mg of material with a high value of Rf(2-(S)-(3,5-(Bis-(trifluoromethyl)-

benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine [L-740, 390]) and 7 mg of material with a low value of Rf2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)- phenylmorpholine). Material with a low value of Rfhandle in accordance with the method of example 23, step A to obtain 26 mg of product with a higher Rf(2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy-3-(S) - phenyl-5-(S)-phenylmorpholine) and 6 mg of the product of lower Rf-value (2-(R or S)-(3,5-Bis-(trifluoromethyl)-benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine).

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

Range PMR (deuterium chloroform, 400 MHz, M. D.): 3,60-3,74 (m, 1H), 3,94 (d, 1H, J = 7,6 Hz), 4,00 (DD, 1H, J = 3.2 and 11.3 Hz), 4,18-is 4.21 (m, 1H), 4,50-4,55 (m, 2H), 4,89 (m, 1H), 7,26-of 7.55 (m, 12H), of 7.69 (s, 1H).

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

Range PMR (in deuterium chloroform, 400 MHz, M. D.): 3,68 (DD, 1H, J = 3,0 and 11.0 Hz), 3,88-of 3.94 (m, 1H), 4.26 deaths-4,30 (m, 1H), 4,36 (s, 1H), to 4.52 (d, 1H, J = 13.5 Hz), 4,77-a 4.86 (m, 2H), 7,27-7,51 (m, 12H), of 7.69 (s, 1H).

2-(R or S)-(3,5-Bis(m, 1H), 4,06-is 4.21 (m, 2H), of 4.38 was 4.42 (m, 1H), 4,59-and 4.68 (m, 2H), a 4.83-4,94 (m, 2H), 7,25-7,81 (m, 13H).

2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine

Range PMR (in deuterium chloroform, 400 MHz, M. D.): 3,43-3,59 (m, 2H), 3,82 (d, 1H, J = 7,2 Hz), 4,25 (d, 1H, J = 12,5 Hz), to 4.52-4.63 to (m, 3H), 4.80 to 4,90 (Shir. s, 1H), 7,11-7,81 (m, 13H).

Example 31.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-3-(S)-phenyl - 4-(3-(1,2,4-triazolo)methylmorpholin

In accordance with the methodology described in example 17, step B, 98 mg (0.24 mmol) 2-(S)-(3,5-Bis-(trifluoromethyl)-benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine (from example 25 above), 38 mg (0.28 mmol) of N-formyl-2-chloroacetamides (from example 17, step a) and 97 mg (0.7 mmol) of anhydrous potassium carbonate to give after flash chromatography on 28 mg of silica gel, aliremove 1 liter of the mixture 100:4 level:0.5 methylene chloride/methanol/aqueous ammonia, light yellow solid, which after recrystallization from a mixture of hexane/methylene chloride, provides 77 mg (66%) of 2-(S)-3,5-Bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-3-(S)-phenyl-4-(3- (1,2,4-triazolo)-methylmorpholine in the form of white crystalline powder.

Range PMR (in deuterium chloroform, 400 MHz, M. D.): 1,17 (d, 3H, J = 6,3), to 2.29 (t, J = 11,1, 1H), 2,92 (d, J = 11,1, 1H), 3,42 (d, J = 15,3, 1H), to 3.58 (s, 1H), 3,88 (d, J = 15,4, 1H), 4,20-to 4.33 (m, 1H), 4,43 (d, 13,5, 1H), 4,71 (d, J = 2,4, 1H), 4,6-(R)-methyl-4-(3-(5-oxo - 1H, 4H-(1,2,4-triazolo)methyl-3-(S)-phenylmorpholine

A mixture of 96 mg (0.23 mmol) of 2-(S)-3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)- methylmorpholine (from example 25 above), 46 mg (0.28 mmol) of N-methylcarbamic-2-chloracetamide and 95 mg (0.69 mmol) of anhydrous potassium carbonate in 3 ml of dry dimethylformamide was stirred at 60oC for 90 min and then at 120oC for 2 hours the Mixture is cooled to room temperature, dissolved in 15 ml ethyl acetate and washed with 3 times 10 ml of water. The combined aqueous layers are re-extracted with 10 ml ethyl acetate. The combined organic layers are washed with 10 ml brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by the method of flash chromatography on 28 mg of silica gel, elute with 1 liter of a mixture of 100:4 methylene chloride and methanol, receiving 65 mg (55%) of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-4-(3-(5-oxo - 1H, 4H-(1,2,4-triazolo)methyl-3-(S)-phenylmorpholine in the form of a light yellow solid powder.

Range PMR (in deuterium chloroform, 400 MHz, M. D.): of 1.18 (d, 3H, J = 6,2), of 2.15 (t, J = 11,1, 1H), 2,89 (d, J = 14, 2H), 3,49 (d, J = 2,2, 1H), 3,61 (d, J = 14,4, 1H), 4,20-4,30 (m, 1H), 4,45 (d, J = 13,6, 1H), 4,67 (d, J = 2,5, 1H), rate 4.79 (d, J = 13,5, 1H), 7,25 is 7.50 (m, 7H), a 7.62 (s, 1H), 10,07 (s, 1H), 10,35 (s, 1H).

Example 33.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy g (a 13.9 mmol) of 4-benzyl-3-(R)-phenyl-2-morpholino, prepared from 3-(R)-phenylglycine as described in example 14, in 28 ml of methylene chloride is cooled in a bath at -78oC in nitrogen atmosphere and add 14 ml of 1.5 molar solution of diisobutylaluminium (21 mmol) in toluene. After stirring the resulting solution for 0.5 h, and it is allowed to warm to -50oC and kept at this temperature for 0.5 hours the Reaction is interrupted by adding 10 ml of aqueous solution of potassium sodium tartrate. The mixture is diluted with methylene chloride and separated layers. The aqueous layer was extracted 3 times with methylene chloride. The organic layers washed with brine, dried over sodium sulfate and filtered. Concentration of the filtrate gives of 3.32 g (88%) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine suitable for use in the next stage.

Range PMR (CDCl3)

of 2.28 (m, 1H), 2,71 (m, 1H), only 2.91 (d, J = 13 Hz, 1H), 3,09 (d, J = 6 Hz, 1H), 3,69 (d, J = 13 Hz, 1H), 3,82 (TD, J = 10 Hz and 2 Hz, 1H), 3,91 (d, J = 10 Hz, 1H), 4,73 (t, J = 6 Hz, 1H), 7,2-7,52 (m, 10H).

Stage B.

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

To a suspension 0,592 g (of 14.8 mmol) of sodium hydride in 30 ml of dry tetrahydrofuran at 0oC type of 3.32 g (12.3 mmol) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine prepared on stevioside. The resulting mixture is stirred at the temperature of the ice bath for 1 h, then poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. Organic salts combine, washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue is purified chromatographically on GHUR system Waters Prep" using a mixture of 50% ethyl acetate/hexane to highlight 3.6 g (59%) of 4-Benzyl-2-(S)-(3,5-bis (trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine.

Range PMR (in deuterium chloroform):

2,3 (TD, J = 11 Hz, 1H), 2,71 (d, J = 11 Hz, 1H), 2,90 (d, J = 13 Hz, 1H), up 3.22 (d, J = 7,3 Hz, 1H, in), 3.75 (m, 2H), 3,93 (m, 1H), 4,43 (d, J = 13 Hz, 1H), 4,45 (d, J = 7,3, 1H), 4,82 (d, J = 13 Hz, 1H), 7,19-7.5 (m, 12H), to 7.67 (s, 1H).

Stage Century.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine

A solution of 3.6 g (7,27 mmol) of 4-benzyl-2-(S)-(3,5-bis (trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine in 100 ml of ethanol and 5 ml of water containing 720 mg of the catalyst 10% palladium on coal, hydronaut in the Parr autoclave within 36 hours the Catalyst is filtered off and thoroughly washed with ethyl acetate. The filtrate is concentrated, and the residue distributed between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and conc the shape of 2.05 g (70%) of 2-(S)-(3,5-bis (trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine.

Range PMR (CDCl3): 1,92 (Shir. s, 1H), 2.91 in (m, 1H), 3,05 (TD, J = 11 Hz and 3 Hz, 1H), 3,68 (d, J = 7 Hz, 1H), 3,81 (TD, J = 11 Hz and 3 Hz, 1H), 4,01 (m, 1H), of 4.44 (d, J = 7 Hz), and 4.5 (d, J = 13 Hz, 1H), around 4.85 (d, J = 13 Hz, 1H), 7,28 - 7,42 (m, 7H), to 7.67 (s, 1H).

Example 34.

4-(3-(1,2,4-Triazolo)methyl)-2-(S)-(3,5-bis-(trifluoromethyl)- benzyloxy)-3-(R)-phenylmorpholine

Specified in the title substance was obtained by the method of example 17, step B, using the product of example 33, step In as the starting material.

Range PMR (deuterochloroform):

1,75 (Shir. s, 1H), 2,61 (TD, J = 12 Hz and 2 Hz, 1H), and 2.83 (d, J = 12 Hz, 1H), 3,33 (d, J = 7 Hz, 1H), 3,48 (d, J = 15 Hz, 1H), 3,78 (d, J = 15 Hz, 1H), 3,85 (m, 1H), 3,99 (m, 1H), of 4.44 (d, J = 13 Hz, 1H), 4,49 (d, J = 7 Hz, 1H), 4,81 (d, J = 13 Hz, 1H), 7.23 percent was 7.45 (m, 7H), to 7.67 s, 1H), of 7.96 (s, 1H).

Example 35.

4-(3-(5-Oxo-1H,4H-1,2,4-triazolo)methyl)-2-(S)-(3,5-bis (trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine

Specified in the title substance was obtained by the method of example 18, stages B and C using the product of example 33, step In as the starting material.

Example 36.

4-(2-(Imidazole)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)- 3-(S)-phenylmorpholine

A solution of 101 mg (0.25 mmol) 2-(S)-(3,5-bis-(trifluoromethyl)- benzyloxy)-3-(S)-phenylmorpholine (example 15), 98 mg (1.0 mmol) imidazole-2-carboxaldehyde and 5 Kaia in tetrahydrofuran. After 16 h the reaction is interrupted by adding 5 ml of saturated aqueous sodium bicarbonate solution, and the mixture is partitioned between 40 ml of ethyl acetate and 20 ml of water. Separate the organic layer, dried over magnesium sulfate and concentrated in vacuo. In the flash-chromatography on 8 g of silica gel, aliremove mixture 50: 1: 0.1 to methylene chloride/methanol/ammonium hydroxide, to obtain 54 mg (yield 44%) indicated in the title compound as a white crystalline substance.

Range PMR (CDCl3)

2,60 (dt, J = 3.2 Hz and 12.4 Hz, 1H), 2,85 (d, J = 12,4 Hz, 1H), 3,28 (d, J = 14.4 Hz, 1H) and 3.59 (d, J = 2,8 Hz, 1H), 3,66 (DD, J = 2.0 a, and 11.6 Hz, 1H), 3,84 (d, J = 14.4 Hz, 1H), 3,94 ( s, 2H), 4,14 (dt, J = 2,0, 12.0 Hz, 1H), 4,43 (d, J = 13,6 Hz, 1H), 4,71 (d, J = 2,8 Hz, 1H), 4,78 (d, J = 13,6 Hz, 1H), 6,99 ( s, 2H), 7,25-of 7.48 (m, 6H), 7,72 (s, 1H),

Range MS-Belarusian library Association (FAB): m/z 486 (100%, M+H)

Example 37.

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

Specified in the title substance was obtained by the method of example 36, using the appropriate starting materials.

Range PMR (CDCl3)

of 2.53 (dt, J = 11 Hz and 3 Hz, 1H), 2,74 (d, J = 12 Hz, 1H), 3,23 (d, J = 7 Hz, 1H), 3,32 (d, J = 15 Hz, 1H), 3,66 (d, J = 15 Hz, 1H), of 3.77 (dt, J = 11 Hz and 2 Hz, 1H), 3,99 (m, 1H), of 4.44 (m, 2H), 4.8V (d, J = 13,0 Hz, 1H), 6,94 (s, 2H), 7,2 was 7.45 (m, 7H ), to 7.67 (s, 1H).

Example 38

4-(5-(Imla obtained by the method of example 36, using suitable starting materials.

Range PMR (CDCl3)

2,47 (TD, J = 12 Hz and 3 Hz, 1H), and 2.83 (d, J = 12 Hz, 1H), 3,2 (m, 2H), 3,61 (d, J = 14 Hz, 1H), 3,79 (TD, J = 12 Hz and 2 Hz, 1H), 3.96 points (m, 1H), of 4.44 (m, 2H), 4,80 (d, J = 13 Hz, 1H), for 6.81 (s, 1H), 7,28 was 7.45 (m, 7H), 7,60 (s, 1H), 7,66 (s, 1H).

Example 39.

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

Specified in the title substance was obtained by the method of example 15, using the appropriate starting materials.

Range PMR (CDCl3)

of 2.54 (TD, J = 11 Hz and 2 Hz, 1H), 2,64 (d, J = 17 Hz, 1H), 2,93 (d, J = 12 Hz, 1H), 3,14 (d, J = 17 Hz, 1H), 3.27 to (d, J = 7 Hz, 1H), 3,83 (TD, J = 11 Hz and 2 Hz, 1H), of 4.05 (m, 1H), 4,46 (m, 2H), 4,81 (d, J = 13 Hz, 1H), 5,62 (Shir. s, 1H), 6,80 (Shir. s, 1H), 7,28-to 7.32 (m, 7H), to 7.67 (s, 1H).

Examples 40-43.

4-(3-(1,2,4-Triazolo)methyl-2-(3-(tert-butyl)-5 - methylbenzylamino)-3-phenylmorpholine, 4-(3-(5-Oxo-1H,4H-1,2,4-triazolo)- methyl)-2-(3-(tert-butyl)-5-methylbenzylamino)-3-phenylmorpholine, 4-(2-(Imidazole)methyl)-2-(3-(tert-butyl)-5-methylbenzoate)- 3-phenylmorpholine, 4-(4-(Imidazole)methyl)-2-(3-tert-butyl)-5-methylbenzylamino)-3-phenylmorpholine

Specified in the title substance was obtained (each) according to the methods of examples 15, 17 and 18, using correspondingly substituted starting materials and reagents.

Example 44.

Sulfonate ether

The solution 6,09 g (to 34.4 mmol) of 3,5-amyl-metacresol and 8,48 g (a 41.3 mmol) of 2,6-di-tert-butyl-4-methylpyridine in 280 ml of dried carbon tetrachloride in nitrogen atmosphere is treated 5,95 ml (35,4 mmol) of anhydride of triftoratsetata at room temperature. Soon after adding the anhydride of a white precipitate is formed. After 90 min, the suspension is filtered in a nitrogen atmosphere to filter Slanka, and the filtrate was concentrated in vacuo. The remainder, which represents a two-phase oil, dissolved in 60 ml of dry toluene under nitrogen atmosphere. The obtained transparent solution was used immediately at the stage B below.

Stage B.

4-Benzyl-2-(S)-(3,5-dichloraniline)-3-(S)-phenylmorpholine

A solution of 5.11 g (19,1 mmol) N-benzyl-3-(S)-phenylmorpholine-2-she (from example 14) in 100 ml dry THF is cooled to -75oC in nitrogen atmosphere and treated dropwise to 20.5 ml of 20.5 mmol) of 1-molar solution three (sec-butyl)borohydride lithium (L-Selectride) in tetrahydrofuran. After stirring the solution at -75oC for 30 min, through a hollow tube add a solution of 3,5-dichlorobenzoyl alcohol-triftormetilfosfinov ether in toluene (from example 44, step A), so that the internal temperature was maintained> and -50oC for 9 hours and Then the solution is treated with 14 ml of aqueous ammonia and stored at -20oC 12 h Then the solution was poured into a mixture of 50 ml of ethyl acetate and 100 ml of water, and the layers separated. The aqueous phase is extracted with 2 times 100 ml of ethyl acetate, each extract is washed with brine, the combined organic layers dried over sodium sulfate, the mixture is filtered and the filtrate concentrated in vacuo. The residue is purified by the method of flash chromatography on 235 g of silica gel, elute with 1.5 liters of a mixture of 100:2 hexane and ethyl acetate, then with 1.5 liters of a mixture of 100:3 hexane and ethyl acetate, and then to 1.9 liters of a mixture of 100: 5 hexane and ethyl acetate, to obtain 4.4 g (54%) of oil which according to the PMR spectrum is a mixture of 8:1 CIS-: TRANS-morpholino.

Range MC of the Belarusian library Association: m/z 430, 428, 426 (M+H, 60%), 268 (M-ArCH2, 100%), 252 (M-ArCH2O, 75%), 222 (20%), 159 (45%).

Range PMR (in deuterium chloroform, 400 MHz, M. D.): core (CIS-isomer):

2,32 (so, J = 12, 3,6 1H), 2,84 ( t, J = 13, 2H), 3,52 (d, J = 2,6, 1H), 3,55 (doctor kV, J = 11,3, 1,6, 1H), 3,91 (d, J = 13.3-inch, 1H), 4,12 (TD, J = 11,6, 2,4, 1H), 4,29 (d, J = 13,6, 1H), 4,59 (d, J = 2,9, 1H), 4,60 (d, J = 13,6), 6,70 (s, 2H), 7,13 (t, J = 1,9, 1H), 7,2-7,6 (m, 8H), 7,53 (Shir.D., 2H).

Stage Century.

2=(S)-(3,5-Dichloraniline)-3-(S)-phenylmorpholine

A solution of 0.33 g (0.77 mmol) of 4-benzyl-2-(S)-(3,5-dichloraniline)-3-(S)-Fenimore pressure. The ampoule is immersed in an oil bath that is heated to 110oC. After stirring for 60 h, the solution is cooled and concentrated in vacuo. The residue is dissolved in 7 ml of methanol and the resulting solution is heated at boiling for 30 minutes the Mixture is cooled and treated with few drops of concentrated aqueous ammonia, and the solution concentrated. The residue partially purified by the method of flash chromatography on 67 g of silica gel, elute with 1.5 liters of a mixture of 100:1 methylene chloride and methanol, and rich fraction purified by the method of flash chromatography on 32 g of silica gel, aliremove a mixture of 50: 50 hexane and ethyl acetate and then a mixture of 50:50:5 hexane:ethyl acetate and methanol, to obtain 0,051 g (20%) of oil which according to the PMR spectrum is pure CIS-morpholine.

Range MC-the Belarusian library Association: m/z 468, 466, 464 (max 8%), 338, 340 (M+H, 25%), 178 (20%), 162 (100%), 132 (20%).

Range PMR (CDCl3, 400 MHz, M. D.): 1,89 (Shir.s, 1H), is 3.08 (DD, J = 12,5, 2,9, 1H), 3,23 (TD, J = 12,2, 3,6, 1H) and 3.59 (DD, J = 11,3, 2,5, 1H), a 4.03 (dt, J = 11,7, 3, 1H), 4.09 to (d, J = 2,4, 1H), 4,37 (d, J = 13,5, 1H), to 4.62 (d, J = 13.3-inch, 1H), 4,67 (d, J = 2,5, 1H), 6,72 (d, J = 1,8, 2H), 7,14 (d, J = 1,8, 1H), 7,25-7,40 (m, 5H).

Example 45.

2-(S)-(3,5-Dichloraniline)-4-(3-(5-Oxo-1H, 4H-1,2,4-triazolo) methyl)-3-(S)-phenylmorpholine

Stage A.

N-Methylcarbamic-2-vrbata 0,105 g (1.9 mmol) of sodium methoxide. Remove the bath with ice, and the mixture is allowed to mix at room temperature for 30 minutes Then to the reaction mixture add 0,110 ml (1.9 mmol) of acetic acid and then added 5.8 g (64,9 mmol) of methylhydroperoxide. After stirring 30 min at room temperature, the suspension was concentrated in vacuo and placed overnight in a high vacuum line, receiving of 10.5 g (98%) of yellow powder, which is used both at the stage In below.

Stage B.

4-(2-(N-Methylcarbamic-acetamidino-2-(S)-(3,5 - chloraniline)-3-(S)-phenylmorpholine

A solution of 0.05 g (0.15 mmol) 2-(S)-3,5-dichloraniline)- -3-(S)-phenylmorpholine (from example 44, step C) 0,034 g (0.21 mol) of N-methylcarbamic-2-chloroacetamides (stage A) and 0.044 ml (0.25 mmol) of N,N-diisopropylethylamine in 1 ml of acetonitrile was stirred at room temperature for 3 hours the Mixture was partitioned between 20 ml of methylene chloride and 10 ml of water. The layers separated, the organic layer dried over sodium sulfate and then concentrated in vacuo. The residue is purified by the method of flash chromatography on 35 g silica gel, elute 1 l of a mixture of 50:1 methylene chloride and methanol, and then 500 ml of a mixture of 25:1:0.05 to methylene chloride/methanol/ammonium hydroxide, receiving 70 mg of product ( 100%) in the form of bis (CDCl3, 400 MHz, M. D.): 2,48 (TD, J = 3,5, 12,2, 1H), 2,53 (d, J = 14,6, 1H), 2,90 (d, J = 11,8, 1H), 3,37 (d, J = 14,6, 1H), 3,52 (d, J = 2,8, 1H), 3,62 (DM, J = 11,4, 1H, in), 3.75 (s, 1H), 4,14 (TD, J = 2,2, 11,8, 1H), 4,28 (d, J = 13,5, 1H), 4,58 (d, J = 13,6), 4,60 (d, J = 2,8, 1H), 5,45 (Shir.s, 2H), 6,74 (d, J = 1,9, 2H), 7,15 (t, J = 1,9, 1H), 7,30-7,46 (m, 6H).

Stage Century.

2-(S)-(3,5-Dichloraniline)-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo) methyl)-3-(S)-phenylmorpholine

The solution 0,069 g (0.15 mmol) of 4-(2-(N-methylcarbamates)-2-(S)-(3,5-dichloraniline)-3- (S)-phenylmorpholine (from step B) in 6 ml of xylene is heated at boiling for 2 hours the Solution is cooled and concentrated in vacuo. The residue is purified by the method of flash chromatography on 35 g silica gel, elute with 500 ml of a mixture of 50:1:0.1 to methylene chloride/methanol/aqueous ammonia, and then 500 ml of a mixture of 20:1:0.1 to methylene chloride/methanol/aqueous ammonia, receiving 56 mg (88%) of product as a white powder.

Range MC-the Belarusian library Association: m/z 437 (M+H, 65%), 435 (M+H, 100%), 259 (85%), 161 (55%)

Range PMR (CDCl3, 400 MHz, M. D.): 2,53 (t, J = 11,7, 3,6, 1H), 2,88 (d, J = 11,6, 1H), 2,96 (d, J = 14,3, 1H), 3,54 (d, J = 2,6, 1H), 3,63 (DD, J = 11,6, 1,9, 1H), 3,68 (d, J = 14,6, 1H), 4,16 (t, J = 11,7, 2,2, 1H), 4,30 (d, J = 13,6), 4,58 (d, J = 2,7, 1H), 4,67 (d, J = 13,6, 1H), 6,65 (d, J = 1,8, 2H), 7,07 (t, J = 1,9, 1H), 7,29-7,44 (m, 5H), of 10.25 (Shir.s, 1H), 10,75 (Shir.s, 1H).

Example 46.

2-(S)-(3,5-Bis-trifluoromethyl)benzyloxy)-4-methoxycarbonylmethyl)- 3-(S)-5, stage b) and 0.35 ml (2.0 mmol) of N,N-diisopropylethylamine in 5 ml of dry acetonitrile is treated at 0.19 ml (2.0 mmol) of methylpropanoate, and the mixture is stirred at room temperature for 16 hours Then the solution was concentrated in vacuo, and the residue partitioned between 30 ml of ether and 15 ml of 0.5 N. aqueous solution of potassium bisulfate. The layers separated, and the organic layer washed with 10 ml of brine and dried over magnesium sulfate. After filtration the organic phase was concentrated in vacuo. The residue is purified by the method of flash chromatography on 20 g silica gel, elute with a mixture of 80:20 hexanol and ether, receiving 351 mg of product (99%).

[]D= +147,3o(C = 1,6, in chloroform).

Range MC-the Belarusian library Association: m/z 478 (M+H, 40%), 477 (65%), 418 (50%), 250 (95%), 234 (90%), 227 (100%).

Range PMR (CDCl3, 400 MHz, M. D.): 3,02 (Shir.D., 2H), 3,13 (d, J = 16,9, 1H), 3,36 (d, J = 16,8), 3,62 (s, 3H), of 3.69 (dt, J = 11,7, 2,2, 1H), 4,03 (Shir. s, 1H), 4,23-4,32 (m, 1H), of 4.44 (d, J = 13.3-inch, 1H), and 4.68 (d, J = 2,6, 1H), 4,81 (d, J = 13,5, 1H), 7,30-7,38 (m, 3H), of 7.4-7.5 (m, 3H), of 7.70 (s, 1H).

Analysis

calculated for C22H21F6NO4: C 55,35, H 4,43, N 2,93, F 23,88;

found: C 55,09, H 4,43, N 2,83, F 24,05.

Example 47.

2-(S)-(3,5-Bis-trifluoromethyl)benzyloxy)-4-(carboxymethyl)- 3-(S)-phenylmorpholine

A solution of 16 mg (0,034 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)organisms or 0.027 ml (0,067 mmol) of 2.5 N. an aqueous solution of sodium hydroxide, and the mixture is stirred at room temperature for 5 hours the Mixture is treated with 2 drops of 2 N. hydrochloric acid and 3 ml of water, and the solution is extracted with 15 ml of a mixture 1:1 of hexanol and ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by the method of flash chromatography on 13 g of silica gel, elute with 250 ml of a mixture of 100:3:0,1 methylene chloride-methanol:acetic acid, then 100 ml of a mixture of 50:2:0,1 methylene chloride:methanol:acetic acid, receiving 14 mg of an oil (90%).

Range MC-the Belarusian library Association: m/z 464 (M+H, 90%), 420 (M-CO2, 10%), 227 (ArCH2, 35%), 220 (M-OCH2Ar, 100%), 161 20%).

Range PMR (CDCl3, 400 MHz, M. D.): 2,9 ( d, 2H), 3,03 (d, 1H), 3.33 and (d, 1H), and 3.72 (d, 1H), 3,90 (d, 1H), 4,25 (t, 1H), of 4.44 (d, 1H), 4,71 (d, 1H), 4,79 (d, 1H), 7.3 to 7.4 (m, 5H), 7,44 (s, 2H), 7,71 (s, 1H).

Example 48.

2-(S)-(3,5-Bis-trifluoromethyl)benzyloxy)-4-((2-amino-ethyl) aminocarbonylmethyl)-3-(S)-phenylmorpholine

A solution of 54 mg (0.11 mmol) 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylmethyl)- 3-(S)-phenylmorpholine (from example 46) and 0.15 ml of Ethylenediamine (2.3 mmol) in 1 ml of methanol was stirred at 55oC for 48 hours the Mixture is concentrated, and the residue purified by the method of flash chromatography on 16 g of silica gel, which elwer the Ira and treated with ether, saturated with gaseous hydrogen chloride. After concentration in vacuo obtain 58 mg (95%) stable oils.

Range MC-Belarusian library Association (free base): m/z 506 (M+H, 100%), 418 (15%), 262 (35%), 227 (30%), 173 (40%).

Range PMR (CDCl3, 400 MHz, M. D.): 2,56 (d, J = 15,5, 1H), 2,59 (so, J = 12,0, 3,6, 1H), 2,82 (t, J = 6,5, 2H), 2,96 (d, J = 11,8, 1H), 3,21 (d, J = 15,8, 1H), 3.25 to 3.40 in (m, 2H), 3,65 (d, J = 2,6, 1H), 3,67 ( DG, J = 11,4, 2, 1H), 4,18 (so, J = 11,8, 2,6, 1H), 4,33 (d, J = 13,5, 1H), 4,69 (d, J = 2,7, 1H), 4,79 (d, J = 13,5, 1H), 7,25-7,40 (m, 5H), 7,46 (s, 2H), to 7.59 (sh.T., 1H), 7,71 (s, 1H).

Example 49.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-((3-aminopropyl) aminocarbonylmethyl)-3-(S)-phenylmorpholine

A solution of 59 mg (0.12 mmol) of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylmethyl)- 3-(S)-phenylmorpholine (from example 46) and 0.21 ml of 1,3-Propylenediamine (2.5 mmol) in 1 ml of methanol was stirred at 55oC for 72 h the Mixture was concentrated, and the residue purified by the method of flash chromatography on 16 g of silica gel, elute with 500 ml of a mixture of 10:1:0.05 to methylene chloride:methanol:aqueous ammonia, receiving 56 mg oil (88%). This oil is dissolved in methylene chloride and treated with methylene chloride, saturated with gaseous hydrogen chloride. After concentration in vacuo get a white paste.

Range MC-Belarusian library Association (free base= 15,5, 1H), 2,58 (TD, J = 12,0, 3,6, 1H), 2,73 (t, J = 6,5, 2H), 2,92 (d, J = 11,8, 1H), 3,19 (d, J = 15,8, 1H), 3.25 to 3.40 in (m, 2H), 3,62 (d, J = 2,6, 1H), 3,65 ( dt, J = 11,4, 2, 1H), 4,16 (TD, J = 11.8 in, 2,6, 1H), 4.41(d, J = 13,5, 1H), and 4.68 (d, J= 2,7, 1H), 4,79 (d, J= 13,5 1H), 7,25-7,40 (m, 5H), was 7.45 (s, 2H), EUR 7.57 (Shir. so, 1H), 7,70 (C. 1H).

Example 50.

4-benzyl-5-(S), 6-(R)-(dimethyl)-3-(S)-phenylmorpholine-2

4-benzyl-5-(R), 6-(S)-(dimethyl)-3-(S)-phenylmorpholine-2

To a suspension of 1.7 g (7.0 mmol) of N-benzyl-(S)- phenylglycine (example 13) in 15 ml of methylene chloride at 0oC added 6.9 ml (a 13.9 mmol) 2-mearnog solution of trimethylaluminum in toluene. After 1 h at 0oC added dropwise of 0.625 ml (7.0 mmol) of (+/-)-TRANS-2,3-epoccipitals (dissolved in 2 ml of methylene chloride), and then left to mix with the 22oC, 16 hours and Then the reaction mixture was transferred into another flask containing 30 ml of 1:1-mixture of hexane and methylene chloride and 30 ml of 1-molar solution of potassium sodium tartrate and stirred at 22oC 2 h Layers separated, and the aqueous layer was extracted with methylene chloride 3 times 100 ml the combined organic layers are washed with 25 ml saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered concentrated in vacuo.

The crude alcohol was dissolved in 25 ml of toluene, treated with 93 mg (0.49 mmol) of p-toluols partitioned between 15 ml of diethyl ether and 10 ml saturated aqueous sodium bicarbonate solution. The layers separated, and the organic layer is washed with 3 times 10 ml of water. The combined organic layers are washed with 25 ml saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Cleaning method flash chromatography on a 145 g of silica gel using a mixture of 1:4 (by volume) of ethyl acetate and hexane as eluent gives 567 mg of the lactone with a high value of Rf(isomer a) and 388 mg of the lactone with a low value of Rf(isomer B).

Range PMR (CDCl3, 400 MHz) isomer A: the 1.04 (d, 3H, J= 8.0 Hz), 1,24 (d, 3H, J= 8.0 Hz), 2,92 (width, square d), 1H) 3,41 (d, 1H, J = 16.0 Hz), 3,62 (d, 1H, J= 16.0 Hz), to 4.38 (s, 1H), 4,96 (width, square D. 1H), 7,20 - 7,42 (m, 8H), 7,58-to 7.64 (m, 2H), isomer B: was 1.04 (d, 3H, J = 10.0 Hz), of 1.39 (d, 3H, J= 10.0 Hz), 3,06 (Shir. square d, 1H), 3,53 (d, 1H, J = 16.0 Hz), 3,81 (d, 1H, J = 16.0 Hz), 4,33 (C. 1H), 4,67 (width, square D. 1H), 7.18 in -7,50 (m, 10H).

Range MS-Belarusian library Association: m/z 478 (M+H, 40%), 477 (65%), 418 (50%), 250 (95%), 234 (90%), 227 (100%).

Example 51.

2(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-[5-(S), 6-(R) or 5-(R), 6(S)-dimethyl]-3-(S)-phenylmorpholine

Stage A.

4-benzyl-2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-[5-(S), 6-(R) or 5-(R), 6(S)-dimethyl]-3-(S)-phenylmorpholine.

In accordance with the method of example 15, step B 251 mg (0.85 mmol) of isomer from example 50 (4-benzyl-[5-(S), 6(R) or 5-(R), 6(S)-dimethyl)-3-(S)-FGC), of 1.13 (d, 3H, J= 6.6 Hz), 2,61 (kV, d, 1H, J = 2.2 and 6.6 Hz), 3,26 (d, 1H, J= a 13.9 Hz), 3,55 (d, 1H, J = a 13.9 Hz), 3,63 (d, 1H, J= 7,6 Hz), 4,01 (square D. 1H, J = 2,3 and 6.6 Hz), of 4.44 (D. 1H, J = 13.1 Hz), a 4.53 (d, 1H, J = 7,7 Hz), 4,71 (s, 1H), around 4.85 (d, 1H, J= 13,2 Hz), 7,20-7,35 (m, 9H), 7,46-of 7.48 (m, 2H), to 7.67 (s, 1H), 7,81 (s, 1H).

Range MS-Belarusian library Association: m/z 523 (M+H, 100%), 296 (95%), 280 (40%), 227 (50%)

Stage B

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-[5-(S), 6-(R) or 5-(R), 6(S)-dimethyl]-3-(S)-phenylmorpholine.

In accordance with the method of example 15, stage 260 mg source material from the stage And [made from isomer in example 50 (4-benzyl-2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-[5-(S), 6-(R) or 5(R),6(S)-dimethyl]-8-(S)-phenylmorpholine)] obtain 122 mg (57%) of product in the form of butter.

Range PMR (400 MHz, CDCl3) to 1.19 (d, 3H, J = 6.5 Hz), of 1.27 (d, 3H, J = 6,7 Hz), 2,97 (square D. 1H, J = 2.9 and 6.9 Hz), 3.96 points (d, 1H, J= 7,7 Hz), 4,08 - 4,11 (m, 2H), 4,39 (d, 1H, J = 7,7 Hz), 4,50 (d, 1H, J= 13.3 Hz), 4,88 (d, 1H, J = 13,2 Hz), 7,27-7,33 (m, 3H), 7,40-7,42 (m, 4H), to 7.67 (s, 1H).

MS-the Belarusian library Association: m/z 433 (M+H, 45%), 227 (35%), 206 (40%), 190 (100%).

Example 52.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-[5-(R), 6-(S) or 5-(S), 6(R)-dimethyl]-3-(S)-phenylmorpholine

Stage AND

4-benzyl-2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-[5-(R), 6-(S) or 5-(S),6(R)-dimethyl]-3-(S)-phenylmorpholine

In accordance with the method of example 15, step B 449 mg (of 1.52 mmol) of isomer B from example 50 (4-benzyl-[5-(R), 6-(S) Il/SUB>, 400 MHz) : of 0.90 (d, 3H, J= 6.8 Hz), of 1.37 (d, 3H, J = 6.6 Hz), 2,86-2,89 (Shir. square d, 1H), 3,47 (d, 1H, J = 15,0 Hz), 3,82-of 3.85 (m, 2H), 3,99-was 4.02 (Shir. square d, 1H), 4,45 (d, 1H, J= 13,6 Hz), to 4.81 (d, 1H, J= 2.0 Hz), to 4.87 (d, 1H, J= 13.5 Hz), 7,17-7,83 (m, 13H)

Stage B

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-[5-(S), 6(R) or 5-(R), 6(S)-dimethyl]-3-(S)-phenylmorpholine

In accordance with the method of example 15, stage 400 mg source material from the stage And [made of isomer B from example 50 (4-benzyl-2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-[5-(R), 6-(S) or 5-(S), 6(R) -dimethyl]-3-(S)-phenylmorpholine)] obtain 230 mg (69%) of product in the form of butter.

Range PMR (CDCl3, 400 MHz) : 1,08 (d, 3H, J = 6,7 Hz) to 1.38 (d, 3H, J = 7.0 Hz), 3,41 is - 3.45 (Shir. square d, 1H), 3,85-3,89 (Shir. square D., 1H), 4.16 the (d, 1H, J = 2,9 Hz), 4,49 (d, 1H, J= 13,6 Hz), 4,71 (d, 1H, J = 2,9 Hz), 4,82 (d, 1H, J = 13,6 Hz), 7,25 was 7.36 (m, 7H), 7,66 (C. 1H)

Range MS-Belarusian library Association: m/z 434 (M+H, 35%), 227 (40%), 206 (40%), 190 (100%)

Example 53.

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(3-(1,2,4-triazolo) -methyl)-[5-(S), 6(R) or 5-(R),6(S)-dimethyl]-3-(S)-phenylmorpholine

A mixture of 62 mg (0.14 mmol) of 2-(R)-(3,5-bis)trifluoromethyl)-benzyloxy)-[5-(S), 6-(R) or 5-(R), 6(S)-dimethyl]-3-(S)-phenylmorpholine (from example 51, step B), 62 mg (0.45 mmol) of anhydrous potassium carbonate and 26 mg (0,19 mmol)

N-formyl-2-chloroacetamides (from example 17, step A) in 2 ml of dimethylformamide is heated at 60oC for 2 Thu, adding 5 ml of water and diluted with 15 ml of ethyl acetate. The layers separated and the organic washed with 2 times 10 ml ethyl acetate. The combined organic layers are washed with 10 ml brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Cleaning method flash chromatography on 42 g of silica gel, using as eluent a mixture of 95:5 methylene chloride and methanol, to give 42 mg of a clear oil.

Range PMR (CDCl3, 400 Hz, M. D.) of 1.13 (d, 3H, J = 6.5 Hz), 1,19 (d, 3H, J= 6.5 Hz), 2,65 (kV, d, 1H, J = 1.9 and 6.5 Hz), to 3.58 (d, 1H, J = 15,5 Hz), the 3.65 (d, 1H, J = 7,7 Hz in), 3.75 (d, 1H, J= 15,4 Hz) 4,06 (kV, d, 1H, J = 2.2 and 6.6 Hz), of 4.45 (d, 1H, J = 13,2 Hz), of 4.54 (d, 1H, J = 7,7 Hz), 4,84 (d, 1H, J = 13,2 Hz), 7,28 - 7,37 (m, 7H), to 7.67 (s, 1H), 7,89 (s, 1H).

Range MS-Belarusian library Association: m/Z 516 (M+H, 52%), 287 (28%), 271 (100%), 227 (40%), 202 (38%).

Example 54

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1,2,4 - triazolo)methyl)-[5-(S), 6-(R) or 5-(R), 6-(S)-dimethyl]-3-(S)-phenylmorpholine

A solution of 96 mg (0.22 mmol) 2-(R)-(3,5-bis(trifluoromethyl)-benzyloxy)-[5-(S), 6(R) or 5-(R), 6(S)-dimethyl]-3-(S)-phenylmorpholine (from example 51, step B), 92 mg (0.66 mmol) of potassium carbonate and 48 mg (0.28 mmol) of N-methyl-carboxy-2-chloroacetamides (stage a of example 18) in 4 ml of dimethylformamide is heated at 60oC 1.5 h and at 120oC for 3.5 hours the Mixture is cooled to komnatnaya, the combined organic layers are washed with 10 ml brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue partially purified by the method of flash chromatography on 42 g of silica gel, elute with 2 l of a mixture of 98:2 (by volume) methylene chloride and methanol; rich fraction purified in the same conditions with 38 mg of a clear oil (33%).

Range PMR (CDCl3, 400 MHz) : 1,09 (d, 3H, J = 6.5 Hz), of 1.20 (d, 3H, J = 6.6 Hz), 2,64 (kV, d, 1H, J= 2.4 and 6.6 Hz), to 3.33 (s, 1H), 3,56 (d, 1H, J = 7,6 Hz), 4,11 (kV, d, 1H, J = 2.4 and 6.6 Hz), to 4.41 (d, 1H, J = 13,2 Hz), of 4.57 (d, 1H, J = 7,7 Hz), 4,82 (d, 1H, J = 13,2 Hz), 7,25-7,30 (m, 5H), 7,40 (d, 2H, J= 5.7 Hz), the 7.65 (s, 1H), 9,46 (s, 1H), 10,51 (s, 1H).

Range MS-Belarusian library Association: M/Z 531 (M+H, 98%), 287 (100%), 227 (80%), 189 (65%)

Example 55.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(3"-(1,2,4- triazolo)methyl)-[5-(R), 6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholine

In accordance with the method of example 53, 75 mg (0,17 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-[5-(R), 6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholine (from example 52, step B) provided, after flash chromatographic purification on 73 g of silica gel using as eluent a mixture of 38 : 2 (by volume) chloride and methylene methanol, 46 mg of a yellow oil (52%).

Range PMR (CDCl3, 400 MHz) : was 1.04 (d, 3H, J = 6.6 Hz), of 1.46 (d, 3H, J = 6,7 Hz), 3,05 - is 3.08 (m, 1H (, 1H).

Mass spectrum (EI): m/z 432 (36%), 287 (60%), 270 (65%), 227 (30%), 187 (48%), 83 (100%).

Example 56.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo - 1,2,4-triazolo)methyl)-[5-(R),6-(S) or 5-(S), 6-(R)-dimethyl]-3-(S)-phenylmorpholine

In accordance with the procedure of example 54, 86 mg (0.2 mmol) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-[5-(R), 6-(S) or 5-(S), 6-(R)-dimethyl]-3-(S)-phenylmorpholine (from example 47, step B) provided, after flash chromatographic purification on 73 g of silica gel using as eluent a mixture of 95:5 (by volume) chloride and methylene methanol, 32 mg of a yellow oil (30%).

Range PMR (CDCl3, 400 MHz) : of 1.03 (d, 3H, J = 6,7 Hz) of 1.40 (d, 3H, J = 6.8 Hz), 3,00 (square d, 3H, J = 3,8 and 6.8 Hz), 3,44 (d, 1H, J = 16.1 Hz), 3,63 (d, 1H, J = 16.0 Hz), 3,82 (d, 1H, J = 3.3 Hz), 3,95 (square d, 1H, J = 3.7 and a 6.7 Hz), 4,43 (d, 1H, J = 13.5 Hz), to 4.73 (d, 1H, J = 3.3 Hz), 4,84 (d, 1H, J = 13,6 Hz), 7,28 - 7,47 (m, 7H), 7,68 (s, 1H), 9,52 (d, 2H).

Mass MS of the Belarusian library Association: m/z 531 (M + H, 100%), 287 (55%), 227 (25%), 147 (50%).

Example 57.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(2-(1-4- benzyl)piperidino)ethyl)-3-(S)-phenylmorpholine

To a solution of 50 mg (0.12 mmol) of 2-(S)-(3,5-bis (trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine and 50 mg (0.18 mmol) of 4-benzyl-1-(2-chloroethyl)piperidine in 0.5 ml of acetonitrile at room temperature add 65 μl (0.36 mmol) diisopropylethylamine methylene chloride, washed with water, then brine, dried over sodium sulfate and evaporated. By the method of preparative TLC obtain 36 mg (50%) specified in the header of the substance in the form of butter.

Range PMR (CDCl3, 400 MHz) : 1.1 to 1.4 (m, 2H), 1,4 - 1,65 (2m, 4H), 1,65 - 2,05 (m, 3H), 2.05 is a 2.3 (m, 1H), 2,35 - 2,5 (m, D., J = 7 Hz, 3H), 2,55 (Shir. t, J = 11 Hz, 1H), 2,65 - 2,8 (m, 2H), 3,09 (d, J = 11 Hz, 1H), 3,50 (d, J = 2.5 Hz, 1H), 3,66 (DD, J = 2 or 11 Hz, 1H), 4,15 (dt, J = 2 and 12 Hz, 1H), of 4.38 and of 4.75 (AB, q, J = 13 Hz, 2H), br4.61 (d, J = 2.5 Hz, 1H), 7,06 (d, J = 7 Hz, 2H), 7,15 (t, J = 7 Hz, 1H), 7,2 - to 7.35 (m, 5H), was 7.36 (m, 4H), of 7.75 (s, 1H).

Example 58.

(S)-(4-Forfinal)glycine

Stage A.

3-(4-Forfinal)acetyl-4-(S)-benzyl-2-oxazolidinone

Kiln dried three-neck flask with a capacity of 1 l, equipped with a septum, the input of nitrogen, a thermometer and a magnetic stirrer, rinsed with nitrogen and download it solution 5,09 g (33 mmol) of 4-florfenicol acid in 100 ml of anhydrous ether. The solution is cooled to -10oC and treated with 5.6 ml (40 mmol) of triethylamine and then 4.3 ml (35 mmol) of trimethylacetylchloride. Immediately a white precipitate is formed. The resulting mixture was stirred at -10oC for 40 min, then cooled to -78oC.

Kiln dried round bottom flask with a capacity of 0.25 l, equipped with a septum and a magnetic stirrer, about the and. The solution is stirred in a bath of dry ice in acetone for 10 minutes, then slowly add to 18.8 ml of a 1.6 molar solution of n-utility in hexane. After 10 minutes, add a solution literaturnogo oxazolidinone through a hollow tube to the mixture in a three-neck flask. Remove the cooling bath and allowed to warm the mixture to 0oC. the Reaction is interrupted by addition of 100 ml saturated aqueous solution of ammonium chloride, the mixture is transferred into a flask with a capacity of 1 l and ether and tetrahydrofuran 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 2 normal hydrochloric acid (200 ml), saturated aqueous sodium bicarbonate (300 ml), dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 400 g of silica gel using as eluent a mixture of 3 : 2 (by volume) of hexanol and ether gives of 8.95 g of oil which slowly hardens when standing. Upon recrystallization from a mixture of 10 : 1 hexanol and ether get 7,89 g (83%) indicated in the title compounds as white solids with so pl. 64 - 66oC.

Range MS-Belarusian library Association: m/z 314 (M + H, 100%), 177 (M-ArCH2CO + H, 85%).

Range PMR (400 MHz, CDCl3) : was 2.76 (SUB>18
H16FNO3: C 69,00, H 5,15, 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)-4-benzyl-2-oxazolidinone

Kiln dried three-neck flask with a capacity of 1 l, equipped with a septum, the input of nitrogen, a thermometer and a magnetic stirrer, rinsed with nitrogen and download it 58 ml of 1-molar solution of bis(trimethylsilyl)amide in toluene and 85 ml of tetrahydrofuran. This solution is cooled to -78oC. kiln Dried round bottom flask with a capacity of 0.25 l, equipped with a septum and a magnetic stirrer, rinsed with nitrogen and boot into it a solution of 7.20 g (23 mmol) of 3-(4-forfinal)acetyl-4-(S)-benzyl-2-oxazolidinone (from example 58, stage A) in 40 ml of tetrahydrofuran. Allocatively the solution is stirred in a bath of dry ice in acetone for 10 minutes, then transferred through a tube in a solution of bis(trimethylsilyl)amidon such a rate that the internal temperature of the mixture was maintained below -70oC. Allocatedmemory flask was washed with 15 ml of tetrahydrofuran, and this wash liquid is added through a tube into the reaction mixture, and the resulting mixture was stirred at -78oC for 30 minutes

Kiln dried round bottom flask with a capacity of 2,4,6-triisopropylphenylsulfonyl in 40 ml of tetrahydrofuran. Azide solution is stirred in a bath of dry ice in acetone for 10 minutes, then transferred through a tube into the reaction mixture with such speed, that the inside temperature of the mixture was maintained below -70oC. After 2 minutes the reaction is interrupted by the addition of 6.0 ml of glacial acetic acid, remove the cooling bath and the mixture is stirred at room temperature for 18 hours Quenched reaction mixture was partitioned between 300 ml of ethyl acetate and 300 ml of 50% aqueous sodium bicarbonate solution. Separate the organic layer, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 500 g of silica gel using as eluent a mixture of 2 : 1 and then 1 : 1 (by volume) of hexanol and methylene chloride gives the 5.45 g (67%) indicated in the title compound in the form of butter.

IR-spectrum (in pure form), cm-1: 2104, 1781, 1702.

Range PMR (400 MHz, CDCl3): of 2.86 (DD, 1H, J = 13,2, 9.6 Hz), 3,40 (DD, J= 13,2, 3,2), 4,09 - 4,19 (m, 2H), 4,62 - and 4.68 (m, 1H), 6,14 (s, 1H), 7,07 - 7,47 (m, 9H).

Analysis:

Calculated for C18H15FN4O3: C 61,01, H 4,27, N 15,81, F 4,36.

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

Stage Century.

(S)-Azido-(4-forfinal)acetic acid

A solution of 5.4 g (15,2 mmol) 3-((S)-Azido-(4-forfinal)acetyl - 4-(S in the bath with ice for 10 minutes. In one type of 1.28 g (30.4 mmol) of the monohydrate of lithium hydroxide, and the resulting mixture is stirred in the cold for 30 minutes. The reaction mixture was partitioned between 100 ml of methylene chloride and 100 ml of 25% aqueous sodium bicarbonate, and the layers separated. The aqueous layer was washed with 2 times 100 ml of methylene chloride and acidified to pH 2 dwuhmomentnam solution of hydrochloric acid. The resulting mixture is extracted with 2 times 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, obtaining of 2.30 g of oil (77%), which is used in the next stage without additional purification.

IR-spectrum (in pure form), cm-1: 2111, 1724.

Range PMR (CDCl3, 400 MHz) : is 5.06 (s, 1H), 7,08 was 7.45 (m, 4H), 8,75 (Shir.S., 1H).

Stage,

(S)-(4-Forfinal)glycine

A mixture of 2.30 g (to 11.8 mmol) of (S)-azido-(4-forfinal)acetic acid (from example 58, step B), 250 mg of the catalyst is palladium-on-coal and 160 mg of a mixture of 3:1 (by volume) of water and acetic acid is stirred under atmospheric pressure of hydrogen for 18 hours, the Reaction mixture was filtered through Celite, and the flask and cake on the filter, well washed with 1 liter of a mixture of 3:1 (by volume) of water and acetic kit, getting solid. This substance is suspended in a mixture of 1:1 (by volume) of methanol and ether, filtered and dried, obtaining 1,99 g (100%) specified in the connection header.

Range PMR (400 MHz, D2O+NaOD): 3,97 (s, 1H), 6,77 (t, 2H, J=8,8), 7,01 (t, 2H, J=5,6).

Example 59.

3-(S)-(4-Forfinal)-4-benzyl-2-morpholino

Stage A.

N-Benzyl (S)-(4-forfinal)glycine

A solution of 1.87 g (11,05 mmol) of (S)-(4-forfinal)glycine (from example 58) and 1.12 ml (11.1 mmol) of benzaldehyde 11.1 ml of 1 N. aqueous sodium hydroxide solution and 11 ml of methanol at 0oC handle 165 mg (4.4 mmol) of sodium borohydride. Remove the cooling bath, and the resulting mixture is stirred for 30 minutes at room temperature. The reaction mixture was added

the second portion (1,12 ml (11.1 mmol) of benzaldehyde and (165 mg (4.4 mmol) of sodium borohydride and stirring is continued for 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 small amount of insoluble material. The filtrate is acidified to pH 5 dwuhmomentnam solution of hydrochloric acid, and precipitated precipitated solid is filtered, well washed with water, then ether and dried, obtaining 1,95 g specified in reception the Oia B.

3-(S)-(4-Forfinal)-4-benzyl-2-morpholino

A mixture of 1.95 g (7.5 mmol) of N-benzyl (S)-(4-forfinal)glycine, 3,9 ml (to 22.5 mmol) of N, N-diisopropylethylamine, 6,5 ml (75 mmol) of 1,2-dibromethane and 40 ml of dimethylformamide was stirred at 100oC 20 hours (all solids dissolved 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 bisulfate, and the layers separated. The organic layer was washed with 100 ml saturated aqueous sodium bicarbonate solution, water (3 x 150 ml), dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 125 mg of silica gel using as eluent a mixture of 3:1 (by volume) of hexanol and ether gives 1,58 g (74%) indicated in the title compound in the form of butter.

Range PMR (400 MHz, CDCl3): to 2.65 (dt, 1H, J=3,2, 12,8), of 3.00 (dt, 1H, J=12,8, 2,8), and 3.16 (d, 1H, J=13,6), 3,76 (d, 1H, J=13,6), 4,24 (s, 1H), 4,37 (dt, 1H, J=13,2, 3,2), of 4.54 (dt, 1H, J=2,8, 13,2), 7,07-7,56 (m, 9H).

Example 60.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-4-(forfinal)- 4-benzylmorphine

Specified in the title compound was obtained with a yield of 72% from 3-(S)-(4-forfinal)-4-benzyl-2-morpholine (from example 59), using methods similar to the methods of example 15, stage a and B.

Example 61.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-4-(forfinal)- 4-morpholine

Specified in the title compound was obtained with a yield of 70% of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-4-(forfinal)-4-benzylmorphine (from example 60), using a technique similar to the method of example 15, step C.

Range MS-Belarusian library Association: m/z 424 (M+H, 40%)

Range PMR (400 MHz, CDCl3): 1,80 (Shir.S., 1H), 3,11 (DD, 1H, J=2,2, 12,4) at 3.25 (dt, 1H, J=3,6, 12,4), the 3.65 (DD, 1H, J=3,6, 11,4), of 4.05 (dt, 1H, J=2,2, 11,8), 4,11 (d, 1H, J=2,2), a 4.53 (d, 1H, J=13,6), 4,71 (d, 1H, J= 2,2), a 4.83 (d, 1H, J=13,6), ? 7.04 baby mortality (t, 2H, J=7,2), 7,3-7,37 (m, 2H), 7,42 (s, 2H), 7,72 (s, 1H).

Example 62.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-4-(forfinal)- 4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methylmorpholine

Specified in the title compound was obtained with a yield of 69% of 2-(S)-(3,5-bis-(triterpenes)benzyloxy)-3-(S)-4-(forfinal)- 4-research (from example 61), using a technique similar to the method of example 18.

Range MS-Belarusian library Association: m/z 521 (M+H, 100%)

Range PMR (400 MHz, CDCl3): to 2.55 (dt, 1H, J=3,6, 12,0), only 2.91 (d, 1H, J= 11,6), with 2.93 (d, 1H, J=14,4), 3,57 (d, 1H, J=2,8) and 3.59 (d, 1H, J=14,4), 3,67-3,70 (m, 1H), 4,18 (dt, 1H, J=2,4, 11,6), 4,48 (d, 1H, J=13,6) and 4.65 (d, 1H, J= 2,8), 4,84 (d, 1H, J=13,6), 7,07 (t, 2H, J=8,4), 7,40 (s, 2H), 7,45-of 7.48 (m, 2H), 7,68 (s, 1H), 10,04 (Shir.s, 1H), 10,69 (Shir.S., 1H).

Anal, H 3,76, TO 10.62 N, F 25,56.

Example 63.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-((3-pyridyl) methylcarbamoyl)-3-(R)-phenylmorpholine

A solution of 55 mg (0,315 mmol) 4-pyridyloxy acid in 1 ml of methylene chloride containing 79 μl (0,175 mmol) N-methylmorpholine, 53 mg (from 0.37 mmol) of hydrate of 1-hydroxybenzotriazole and 73 mg (from 0.37 mmol) of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, stirred for 10 minutes. Add a solution of 2-(S)-(3,5-Bis-(triterpenes)benzyloxy)-3-(R)-phenylmorpholine (from example 33) in 1 ml of methylene chloride. After stirring the mixture for 2 hours, it is distributed between water and methylene chloride. The organic layer is washed with water, brine and dried by filtration through sodium sulfate. The filtrate is concentrated, and the residue purified by flash chromatography using a mixture of 70% ethyl acetate/hexane, to obtain 152 mg of product (yield 100%).

Range PMR (400 MHz, CDCl3): 3,0-of 3.85 (m, 5H), 3,95, and 4.4 (Shir.s, 1H), 4,66 (d, J=13 Hz, 1H), 4,82 (d, J=13 Hz, 1H), 5.0 and 5,9 (Shir.S., 1H), 5,23 (s, 1H), 7,1-the 7.65 (m, 7H), and 7.8 (m, 3H), 8,43 (Shir.S., 2H).

Example 64.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(metacarbonate)-3- (R)-phenylmorpholine

To a solution of 259 mg (0.64 mmol) of 2-(S)-3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine (I1,12 mmol) of potassium carbonate and 2 crystal iodine Tetra-n-butylamine. The resulting solution is heated for 36 hours in a bath at 60oC, in this period, according to TLC, the reaction was not completed. The bath temperature was raised to 100oC. After 3 h the reaction mixture is cooled and diluted with ethyl acetate. An ethyl acetate solution is washed 2 times with water, brine and dried over sodium sulfate. The filtrate is concentrated, and the residue purified by flash chromatography using a mixture of 30% ethyl acetate/hexane to highlight 220 mg of product (yield 65%).

Range PMR (400 MHz, CDCl3): 1,0-1,4 (m, 4H), 1,47 (m, J=8 Hz, 2H), 1,95 (m, 1H), 2,2 (t, J=8 Hz, 2H), 2,35 (m, 2H), 2,9 (d, J=13 Hz, 1H), of 3.07 (d, J=7 Hz, 1H), 3,62 (s, 3H), 3,81 (TD, J=8 Hz and 2 Hz, 1H), Android 4.04 (DD, J=10 Hz and 2 Hz, 1H), 4,36 (d, J=7 Hz, 1H), 4,4 (d, J= 13 Hz, 1H), 4,79 (d, J=13,0 Hz, 1H), 7,2-7,4 (m, 7H), 7,66 (s, 1H).

Example 65.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(carboxypentyl)-3(R)- phenylmorpholine

A solution of 0.15 g (0.28 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)-4-(methoxycarbonylmethyl)- 3-(R)-phenylmorpholine (example 64) in 3 ml of methanol omelet by treatment with 0.5 ml of 5 normal sodium hydroxide solution for 40 minutes at 65oC. the Solution is cooled, concentrated and the residue diluted with water. The aqueous solution is brought to pH 6 by addition of 2-normal hydrochloric acid and extracted with ethyl acetate. About the th 50% mixture of ethyl acetate/hexane, provides 0,13 g (89%) of product.

Range PMR (400 MHz, CDCl3): 1.0 to 1.5 (m, 4H), 1,5 (m, 2H), 2,2 (m, 2H), 2,35 (m, 2H), 2,9 (d, J=13 Hz, 1H), is 3.08 (d, J=7 Hz, 1H), 3,82 (t, J=8 Hz, 1H), 4.09 to (d, J=7 Hz, 1H), to 4.38 (s, 1H), 4,4 (d, J=13 Hz, 1H), rate 4.79 (d, J=13 Hz, 1H), 7,2-7,4 (m, 7H), 7,66 (s, 1H).

Example 66.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methylamino-carbonylmethyl)- 6-oxo-hexyl)-3-(R)-phenylmorpholine

A solution of 116 mg (0.22 mmol) 2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)-4-(carboxypentyl)-3-(R)- phenylmorpholine (from example 65) in 1 ml of methylene chloride is treated with 40 mg (0.29 mmol) of hydrate of 1-hydroxybenzotriazole, 57 mg (0.29 mmol) of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.037 ml N-methylmorpholine. After 10 minutes add 0,027 ml (0.3 mmol) of aqueous 40% methylamine, and the resulting mixture is stirred for 4 hours. The reaction mixture was diluted with water and extracted with methylene chloride. United chlorotoluene layers washed with water, brine and dried over sodium sulfate, and the filtrate concentrated. Purification of the residue by flash-chromatography column with ethyl acetate to provide 0.10 g of product.

Range PMR (400 MHz, CDCl3): 1,0-1,4 (m, 4H), of 1.47 (m, 2H), 1,95 (m, 1H), 2,04 (t, J=8 Hz, 2H), 2,35 (m, 2H), 2,74 (d, J=5 Hz, 3H), 2,89 (d, J=12 Hz, 1H), is 3.08 (d, J=7 Hz, 1H), 3,81 (t, J=7 Hz, 1H), was 4.02 (d, J=11 Hz, 1H), 4,3 cnie pharmaceutical composition, containing the substance of the invention

A. the Capsules dry filling, containing 50 mg of active ingredient per capsule

Component - Quantity per capsule, mg

Active ingredient - 50

Lactose - 149

Magnesium stearate - 1

Capsule (size No. 1) - 200

The active component can be crushed to powder N 60, with lactose and magnesium stearate can be passed through a blotting fabric N 60 powder. Then the combined components can be mixed for approximately 10 minutes and filled into dry gelatin capsule No. 1.

B. Tablets

A typical tablet can contain the active ingredient (25 mg), pre-gelatinising starch (82 mg, USP), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).

Century Candles

A typical candle formulations for rectal destination contain the active ingredient (range: 0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg). Other candle recipes can be made by substituting, for example, disodium-calcium edetate on bottled hydroxytoluene (0.04-0.08 mg) and polyethylene glycol on gidrirovannoe vegetable oil (675-1400 mg), such as Suppocire e, Jacobie EF-es, Jacobie Em, Watersipora active component (11.4 mg), benzyl alcohol (0.01 ml) and water for injection (1.0 ml).

Although the preceding description discloses the principles of the present invention, with examples provided for purposes of illustration, it can be understood that practice of the invention covers all accidental variations, adaptations, modifications, exceptions, or additions of procedures and protocols described herein, as they are included in the scope of the following claims and their equivalents.

1. Substituted heterocycles of General structural formula

< / BR>
or their pharmaceutically acceptable salt, in which R1selected from the group consisting of: 1) hydrogen atom, 2)1- C6-alkyl, unsubstituted or substituted by one or more substituents selected from (a) phenyl, (b) group-NR9R10C) group-CO2R9d) group-CONR9R10, e) heterocycle, which is chosen from the group consisting of: (a) triazolyl,) imidazolyl,) piperidinyl, D) pyridyl, and in which the heterocycle is unsubstituted or substituted by an oxo group or1- C6-alkyl substituted by phenyl; 3)2- C6-alkenyl;

R2and R3chosen independently from a hydrogen atom or a C1- C6-Alki the>5
Z is a hydrogen atom, or if Y is-CHR15then Z and R15combined together, form a double bond;

R5represents phenyl, possibly substituted by halogen atoms;

R6, R7and R8independently selected from the group consisting of hydrogen, C1- C6-alkyl, halogen atom or trifloromethyl;

R9and R10independently selected from hydrogen or C1- C6-alkyl.

2. Connection on p. 1, in which R1selected from the group consisting of: 1) hydrogen atom, 2)1- C6-alkyl, unsubstituted or substituted by one or more substituents selected from: a) heterocycle, wherein the heterocycle is selected from the group consisting of: imidazolyl, pyridyl, triazolyl and piperidinyl, and in which the heterocycle is unsubstituted or substituted by an oxo group or1- C6-alkyl substituted by phenyl; R2and R3independently selected from hydrogen or C1- C6-alkyl, X represents-O-, R4represents a group:

< / BR>
R5is phenyl, unsubstituted or substituted with halogen; R6, R7and R8independently selected from the group consisting of a hydrogen atom.

3. Connection on p. 1, in which R1selected from the group consisting of

< / BR>
4. Connection on p. 1, having structural formula II

< / BR>
or its pharmaceutically acceptable salt, where R1, R2, R3, R6, R7, R8and Z have the values listed in paragraph 1, R11, R12and R13- independently of each other a hydrogen atom or a halogen.

5. Connection on p. 1, having structural formula III

< / BR>
or its pharmaceutically acceptable salt, where R1, R2, R3, R6, R7, R8and Z have the values listed in paragraph 1, R11, R12and R13- independently of each other a hydrogen atom or a halogen.

6. Connection on p. 1, in which X is an oxygen atom, having the structural formula

< / BR>
or its pharmaceutically acceptable salt, where R1, R2, R3, R6, R7, R8, Y and Z have the values listed in paragraph 1, R11, R12and R13- independently of each other a hydrogen atom or a halogen.

7. Connection on p. 1, which is selected from the group consisting of: 1) 2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenylmorpholine; 2) (2R, S)-(3,5-bis(trifluoromethyl)benzyloxy)-(3R)-phenyl-(6R)-methylmorpholine; 3) (2R, S)-(3,5-bis(trifter ethylmorpholine; 7) 3-phenyl-2-(2-(3,5-bis(trifluoromethyl)phenyl)ethyl)-the research; 8) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)-methylmorpholine; 9) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)-methylmorpholine; 10) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)-methylmorpholine; 11) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)-methylmorpholine; 12) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methylmorpholine; 13) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methylmorpholine; 14) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methylmorpholine; 15) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methylmorpholine; 16) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine;

17) 4-(3-(1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine; 18) 4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine; 19) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methylmorpholine; 20) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methylmorpholine; 21) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine; 22) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine; 23) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine; 24) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5 the l)benzyloxy)-6-(R)-methyl-3-(S)-phenyl-4-(3(1,2,4-triazolo)methyl)-the research; 31) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)-3-(S)-phenylmorpholine; 32) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine;

33) 4-(3-(1,2,4-triazolo)methyl)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine; 34) 4(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine; 35) 4-(2-(imidazole)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine; 36) 4-(4-imidazole)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine; 37) 4-(aminocarbonylmethyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine; 38) 4-(2-(imidazole)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine; 39) 4-(4-imidazole)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine; 40) 4-(2-(imidazole)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine; 41) 4-(4-(imidazole)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine; 44) 4-(3-(1,2,4-triazolo)methyl)-2-(3,5-dimethyl)benzyloxy)-3-phenylmorpholine; 45) 4(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)2-(3,5-dimethyl)benzyloxy)-3-phenylmorpholine; 46) 4-(3-(1,2,4-triazolo)methyl)-2-(3,5-di(tert-butyl)benzyloxy)-3-phenylmorpholine; 47) 4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)-2-(3,5-di(tert-butyl)benzyloxy)-3-phenylmorpholine; 48)

4-(3-the pet-butyl)-5-methylbenzylamino)-3-phenylmorpholine; 50) 4-(3-(1,2,4-triazolo)methyl)-2-(3-(trifluoromethyl)-5-methylbenzylamino)-3-phenylmorpholine; 51) 4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)-2-(3-(trifluoromethyl)-5-methylbenzylamino)-3-phenylmorpholine; 52) 4-(3-(1,2,4-triazolo)methyl)-2-(3-(tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenylmorpholine; 53) 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(3-(tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenylmorpholine; 54) 4-(2-(imidazole)methyl)-2-(3,5-dimethyl)benzyloxy)-3-phenylmorpholine; 55) 4-(4-(imidazole)methyl)-2-(3,5-dimethyl)benzyloxy)-3-phenylmorpholine; 56) 4-(2-(imidazole)methyl)-2-(3,5-di(tert-butyl)benzyloxy)-3-phenylmorpholine; 57) 4-(4-(imidazole)methyl)-2-(S)-(3,5-di(tert-butyl)-benzyloxy)-3-phenylmorpholine; 58) 4-(2-(imidazole)methyl)-2-(3-(tert-butyl)-5-methylbenzylamino)-3-phenylmorpholine; 59) 4-(4-(imidazole)methyl)-2-(3-(tert-butyl)-5-methylbenzylamino)-3-phenylmorpholine; 62)

4-(2-(imidazole)methyl)-2-(3-(tert-butyl)-5-(trifluoromethyl)benzyloxy-3-phenylmorpholine; a) 4-(4-(imidazole)methyl)-2-(3-(tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenylmorpholine; 63) 2-(S)-(3,5-dichloraniline)-3-(S)-phenylmorpholine; 64) 2-(S)-(3,5-dichloraniline)-4-(3-(5-oxo-1,2,4-triazolo)methyl)-3-(S)-phenylmorpholine; 65) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylmethyl)-3-(S)-phenylmorpholine; 66) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(carboxymethyl)-3-(S)-fenimor rmutil)benzyloxy)-[5-(R), 6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholine; 72) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(1,2,4-triazolo)methyl)-[5-(S), 6-(R) or 5-(R),6-(S)-dimethyl]-3-(S)-phenylmorpholine; 73) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)methyl)-[5-(S), 6-(R) or 5-(R),6-(S)-dimethyl]-3-(S)-phenylmorpholine; 74) 2-(S)-(3.5-bis(trifluoromethyl)benzyloxy)-4-(3-(1,2,4-triazolo)methyl)-[5-(R), 6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholine;

75) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)methyl)-[5-(R), 6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholine; 76) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(2-(1-(4-benzyl)piperidino)ethyl)-3-(S)-phenylmorpholine; 78) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-forfinal)-4-benzylmorphine; 79) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-forfinal)of the research; 80) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-forfinal)-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)research; 82) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylmethyl)-3-(R)-phenylmorpholine; 83) 2-(S)-(3,5 bis(trifluoromethyl)benzyloxy)-4-(carboxypentyl)-3-(R)-phenylmorpholine; or its pharmaceutically acceptable salt.

8. Pharmaceutical composition for blockade of receptors neirokinina-1 in a mammal, comprising a pharmaceutically acceptable carrier and an effective amount of the compounds under item 1.

Priority signs:

29.06.92 on the grounds of p. 1, except for R1- heterocycle, p. 7 for compounds 1 - 15 and signs of PCP.8 and 9;

04.11.92 on the grounds of p. 1 applies to each of the heterocycle in R1, signs of PCP.2 - 6 p. 7 for compounds 16 - 62;

19.05.93 on the basis of p. 7 for connection 63 - 84.

 

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< / BR>
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