Substituted morpholines or their pharmaceutically acceptable salts, method of production thereof, pharmaceutical composition and method of combating substance p or blocking receptors neirokinina-1

 

(57) Abstract:

The proposed substituted morpholines of the formula I or their pharmaceutically acceptable salts, where R2and R3each means hydrogen; R6, R7and R8selected from a hydrogen, fluorine or CF3; R11, R12and R13each independently mean hydrogen or halogen; A represents unsubstituted C1-6alkylene; B represents a heterocycle selected from 1,2,4-triazolyl, 5-oxo-1,2,4-triazolyl, 2-oxo-1,3-imidazolyl or imidazolyl, replaced by X, where X represents the residue of salt phosphoryla-PO(O-)22M+and M+is a pharmaceutically acceptable monovalent a counterion, Y is-O-; Z is a hydrogen atom or a C1-6alkyl; p = 0. The compounds of formula I are obtained by phosphorylation of corresponding derivatives of the research phosphorylethanolamine reagent. The technical result is to provide new compounds of antagonists of substance P and neirokinina-1, which are prodrugs and have an increased solubility in aqueous solutions compared to the parent drugs. The proposed pharmaceutical composition active blocking receptors neirokinina-1, with P at its receptor or receptor inhibitors neirokinina-1. 4 C. and 18 h. p. F.-ly.

Analgesia was historically achieved in the Central nervous system opiate and analogues, which are drugs and perifericheskie inhibitors of cyclooxygenase, which have gastric side effects. Antagonists of substance P can induce analgesia as Central and perifericheskie. In addition, antagonists of substance P are inhibitors of neurogenic inflammation.

Neuropeptide receptors substance P (neurokinin-1; NK-1) is widely distributed throughout the nervous system of mammals (especially ganglia of the brain and spinal ganglia), the cardiovascular system and peripheral tissues (especially the duodenum and jejunum) and participate in the regulation of various biological processes. It includes sensory perception of smell, sight, hearing and pain, motion control, motor function of the stomach, dilation of blood vessels, salivation, and urination (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141). Subtypes of receptors NK1 and NK2 participate in synaptic transmission [Laneuville et al., Life Sci., 42; 1295-1305 (1988)].

The receptor for substance P is a member of the superfamily of G-protein-linked receptorassociated functions. In addition to tachykinins receptors of this superfamily of receptors includes the opsins, adrenergic receptors, muscarinic receptors, dopamine receptors, serotonin receptors, the receptor for thyroid-stimulating hormone, the receptor for luteinizing hormone-human chorionic gonadotropin-releasing hormone, the product of the oncogene ras, receptors of the factor of mating yeast, receptor-camp(camp) Dictiostelium and receptors for other hormones and neurotransmitters (see A. D. Hershey et al., J. Biol. Chem. , 1991, 226, 4366-4373).

Substance P (called here also SP) is a natural undecapeptide belonging to theminimum family of peptides, the latter so named because of their rapid contractile action on extravascular tissue smooth muscle. These tachykinin differ stored carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH2. In addition to SP-known tachykinin mammals include neurokinin A and neurokinin B. Adopted in the present nomenclature denotes the SP receptors, neirokinina A and neirokinina In as NK-1, NK-2 and NK-3, respectively.

More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals and have characteristic amino acid poleci active neuropeptide, which is produced in mammals and acts as a vasodilator factor, depressant, stimulates salivation and causes increased capillary permeability. It can also cause the animals depending on the dose and pain sensitivity of the animal as analgesia and hyperalgesia [see R. C. A. Frederickson et al., Science, 199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980)] and plays a role in sensory transmission and pain perception [T. M. Jessell, Advan. Biochem. Psychopharmacol., 28, 189 (1981)] . For example, assume that substance P is involved in neuropterida pain [Otsuka et al., "Role of Subtance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance Pin the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Doses of Substance P act as a Pain Transmitter?" TIPS, 8, 506-510 (Dec. 1987)] , in particular in the transmission of pain in migraine [see C. E. C. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982); M. A. Moskowitz, Trends Pharmacol. Sci., 13, 307-311 (1992)] and arthritis [Levine, et al. , Science, 226, 547-549 (1984); M. Lotz. et al., Science, 235, 893-895 (1987)] . Tachykinin involved in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease [see Mantyh et al., Neuroscience, 25(3), 817-37 (1988) and D. Regoli in "Trends in Cluster Headache" Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, p. 85-95 (1987)] and vomiting [Trends in Pharmacol. Sci., 9, 334-341 (1988), F. D. Tatersall, et al., Eur. J. Pharmacol., 250, which may play the role of substance P [Kidd et al., "A Neurogenic Mechanism for Summetric Artritis" in The Lancet, November 11, 1989 and Gronblad et al. "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis", J. Rheumatol. 15(12) 1807-10 (1988)]. So, I think that substance P is involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis [O Byrne, et al., Arthritis and Rheumatism, 33, 1023-8 (1990)].

Evidence of the use of receptor antagonists of tachykinins in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of withdrawal syndrome of morphine, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases, such as rheumatoid arthritis, asthma, increased bronchial reactivity and other respiratory diseases including allergic rhinitis, inflammatory bowel disease, including ulcerative colitis and disease Chrohn's, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, syndrome, irritable bowel and disorders of the bladder, including cystitis and hyperreflexia of the sphincter of the bladder, considered "Tachikinin Receptors and Tachikin Receptor Antagonists", C. A. Maggi, R. Patacchini, P. Robero and A. Giachetti, J. Auton. Pharmacol. , 13, 23-93 (1933); see also R. M. Snider at al., Chem. Ind., 792-794 (1991). Tinina can also be useful for the prevention and treatment of inflammatory conditions in the lower part of the urinary tract especially cystitis [Giuliani et al., J. Of Urology, 150, 1014-1017 (1993)]. I think that other diseases, where the antagonists of tachykinins useful are allergic condition [Hamelet et al., Can. J. Pharmacol. Physiol. , 66, 1361-7 (1988)], immunoregulatory [Lotz et al., 241, 1218-21 (1988), Kimball, et al., J. Immunol., 141 (10), 3564-9 (1988); A. Perianin et al., Biochem. Biophys. Res. Commun. 161, 520 (1989)]; postoperative pain and nausea [C. Bountra, et al., Eur. J. Pharmacol., 249, R3-R4 (1993), F. D. Tattersall et al., Neuropharmacology, 33, 259-260 (1994)] , the dilation of blood vessels, bronchospasm, reflex or neuronal control of the activity of internal organs [Mantyh et al., PNAS, 85, 3235-9 (1988)] and, possibly, stopping or slowing-amyloid-mediasound neurodegenerative changes [Yankner et al., Science, 250, 279-82 (1990)] senile dementia of Alzheimer's type, Alzheimer's disease and down syndrome. Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod, et al., poster C. I. N. P. XVIII Congress, 28th June-2nd July, 1992] and in violation of the functions of the bladder, such as hyperreflexia of the sphincter of the bladder (Lancet, 16th May 1992, 1239]. Antagonists selective for receptor neirokinina-1 (NK-1) and/or neirokinina-2 (NK-2), can be useful in the treatment of asthma (Frossard et al., 49, 1941-1953 (1991); Advenier, will be also useful in the treatment of small cell lung cancers, in particular small cell lung cancer (SCLC) [Langdon et al., Cancer Research, 52, 4554-7 (1992)].

In addition, it was hypothesized that the receptor antagonists of tachykinins have application in the following disorders: depression, estimatesa disorders, chronic airway obstruction, allergic disorders, for example caused by poisonous plusem, vasospastic diseases such as angina and disease Reynauld''s fibrous and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder syndrome, disorders associated with addiction, such as alcoholism associated with stress somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus erythematosus (EPO Publication N 436334)eye diseases such as conjunctivitis, vernal conjunctivitis, and the like, and skin diseases such as dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis (EPO Publication N 0394989).

Antagonists of substance P may be useful when mediolani neurogenic mucus secretion in the respiratory tract of mammals and, therefore, the treatment and symptomatic nt'l Conterence, 16-19, 1993, published in Am. Rev. of Respiratory Dis. May, 1993].

Recently, some attempts were made to obtain peptidebinding substances, which are receptor antagonists of substance P and other tachykinins peptides to more effectively treat the above various disorders and diseases. For example, Lowe in Drugs of the Future, 17 (12), 1115-1121 (1992) and EPO publication N 0347802, 0401177 and 0412452 describe the different peptides as antagonists neirokinina A. patent publication PCT WO 93/14113 some peptides are described as antagonists of tachykinins. In addition, EPO publication N 0336230 describes heptapeptide, which are antagonists of substance P, are useful in the treatment of asthma. In U.S. patent N 4680283 (Megs) also describes peptide analogs of substance P. In U.S. patent N 4501733 describes some of the inhibitors of tachykinins, which remains in the sequence of substance P replaced by residues Thr. Another class of receptor antagonists of tachykinins, containing Monomeric or dimeric hexa - or heptapeptide link in linear or cyclic form, is described in UK patent A-2216529.

Peptideprophet nature of these substances makes them from a metabolic point of view is too unstable to serve as a researcher whom I on the other hand, do not have such a disadvantage as they are, as expected, more stable from a metabolic point of view, than the previously discussed tools.

Mastoideocentesis,cobalamin(-(aminoethyl)-4-chlorobenzophenone acid) effectively blocks in the Central nervous system stimulatory activity of substance P and, in addition, inhibits the response to excitation of other compounds, such as acetylcholine and glutamate. Patent applications Pfizer WIPO (PCT Publication N WO 90/05525, WO 90/05729, WO 91/18899, WO 92/12151 and WO 92/12152) and publications [Science, 251, 435-437 (1991); Science, 251, 437-439 (1991); J. Med. Chem., 35, 2591-2600 (1992)] describe derivatives of 2-arylmethyl-3-substituted of aminoquinuclidine as useful as antagonists of substance P in the treatment of gastrointestinal disorders, disorders of the Central nervous system, inflammatory diseases and pain or migraine. The application for the European patent Glaxo (EPO Publication N 0360390) describes the various spirolactone amino acids and peptides, which are antagonists or agonists of substance P. the Application for the patent Pfizer IPO (PCT Publication N WO 92/06079) describes condensed in the nucleus equivalents non-aromatic nitrogen-containing heterocycles as useful for the treatment of disease, m is[3.2.2] nonan-3-amine as antagonists of substance P. Patent Pfizer, WIPO (PCT Publication N WO 93/10073) describes Ethylenediamine derivatives as antagonists of substance P. Publication PCT N WO 93/01169 describes some aromatic compounds as receptor antagonists of tachykinins. Publication Sanofi [Life Sci., 50, PL101-PL106 (1992)] describes a derivative of 4-phenyl-piperidine as a receptor antagonist neirokinina A (NK2).

Howson and others (Biorg. and d. Chem. Lett., 2(6), 559-564 (1992) describe some of the compounds 3-amino - and 3-oksikhinolinom and their binding to receptors of substance P. Publication EPO 0499313 describes certain 3-hydroxy - 3-diazabicyclo compounds as antagonists of tachykinins. In U.S. patent N 3506673 describes some of the compounds 3-hydroxypyrrolidine as Central nervous system stimulants. Patent application EPO Pfizer (EPO Publication 0436334) describes some compounds 3 - aminopiperidine as antagonists of substance P. In U.S. patent N 5064838 as analgesics describes some 1,4 - disubstituted of piperidinylidene. In PCT publication N WO 92/12128 as analgesics describes some compounds of piperidine and pyrrolidine. Peyronel and others [Biorg. and Med. Chem. Lett., 2(!), 37-40 (1992)] describe condensed in the core of the connection pyrrolidine at kachestvenie substance P. U.S. patent N 4804661 describes some of the piperazine compounds as analgesics. In U.S. patent N 4943578 describes some of the piperazine compounds useful in the treatment of pain. Publication PCT N WO 92/01679 describes some 1,4-disubstituted piperazines useful in the treatment of mental disorders in which there is a dopaminergic deficit. Publication PCT N WO 94/00440 and EPO publication N 0577394 describe some morpholine and thiomorpholine antagonists of substance P, some of which are "parent" compounds are prodrugs of this specification.

Prodrugs essentially structurally belongs to the biologically active substance (the"parent drug"), which after the introduction frees the parent drug in the result of some metabolic processes, such as enzymatic or chemical hydrolysis of carboxylic, phosphate or sulfate ester, or recovery, or oxidation sensitive functional groups [see, for example, discussion (1) A. A. Sinkula and S. H. Yalkowsky, J. Parm. Sci., 64, 181(1975); (2) L. A. Svensson. Pharm. Weekbl. 122, 245-250 (1987); (3) L. P. Balant, E. Doelker and P. Buri Eur. J. Drug Metab, and Pharmacokinetics, 15, 143-153 (1990); (4) N. Bodor, Drugs of the Future, 6, 165-182 (1981); (5) Design of Biopharmaceutical Properties thro9)]. The advantage of prodrugs may be in its physical properties, such as high water solubility parenteral compared with the parent drug, or that it can promote the absorption from the digestive tract, or may increase the stability of drugs during long-term storage. Typically, the prodrug has a lower biological activity than the parent drug.

This invention relates to new compounds represented by structural formula I

< / BR>
where R2B3, R6, R7, R8, R11, R12, R13, A, B, p, Y, and Z have the values listed below.

This invention relates also to pharmaceutical finished preparative forms containing these new compounds as active ingredients, and the application of these new compounds and their ready preparative forms in the treatment of some disorders.

The compounds of this invention are antagonists of tachykinins receptors and useful in the treatment of inflammatory diseases, pain or migraine, asthma and vomiting.

The new compounds of the present invention to depict independently selected from the group consisting of:

1) hydrogen,

2) C1-6the alkyl, unsubstituted or substituted by one or more substituents selected from:

(a) hydroxy,

b) oxo,

C) C1-6alkoxy,

d) phenyl-C1-3alkoxy,

e) phenyl,

f) -CN,

g) halogen,

h) -NR9R10where R9and R10independently chosen from:

i) hydrogen,

ii) C1-6of alkyl,

iii) hydroxy-C1-6the alkyl and

iv) phenyl,

i) -NR9COR10where R9and R10have the above definition,

j) NR9CO2R10where R9and R10have the above definition,

k) -CONR9R10where R9and R10have the above definition,

j) -COR9where R9has the above definition,

m) -CO2R9where R9has the above definition;

3) C2-6alkenyl, unsubstituted or substituted by one or more substituents selected from:

(a) hydroxy,

b) oxo,

C) C1-6alkoxy,

d) phenyl-C1-3alkoxy,

e) phenyl,

f) -CN,

g) halogen,

h) -CONR9R10where R9and R10have the above definition,

i) COR9where R
4) C2-6the quinil;

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

(a) hydroxy,

b) C1-6alkoxy,

C) C1-6of alkyl,

d) C2-5alkenyl,

e) halogen,

f) -CN,

g) -NO2,

h) -CF3,

i) -(CH2)m-NR9R10where m, R9and R10have the above definition,

j) -NR9COR10where R9and R10have the above definition,

k) -NR9CO2R10where R9and R10have the above definition,

l) CON9R10where R9and R10have the above definition,

m) -CO2NR9R10where R9and R10have the above definition,

n) -COR9where R9has the above definition,

o-CO2R9where R9has the above definition; and alternative groups R2and R3joined together, forming a carbocyclic nucleus selected from the group consisting of:

a) cyclopentyl,

b) of cyclohexyl,

(C) phenyl,

and where the carbocyclic nucleus is unsubstituted or substituted by one or more substituents selected from:

i) C1-6
iv) halogen and

v) trifloromethyl;

and alternative groups R2and R3joined together, forming a heterocyclic nucleus 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 where the heterocyclic nucleus is unsubstituted or substituted by one or more substituents selected from:

i) C1-6of alkyl,

ii) oxo,

iii) C1-6alkoxy,

iv) -NR9R10where R9and R10have the above definition,

v) halogen and

vi) trifloromethyl;

R6, R7and R8independently selected from the group consisting of

1) hydrogen,

2) C1-6the alkyl, unsubstituted or substituted by one or more substituents selected from:

(a) hydroxy,

b) oxo,

C) C1-6alkoxy,

d) phenyl-C1-3alkoxy,

e) phenyl,

f) -CN

g) halogen,

h) -NR9R10where R9and R10have the above definition,

i) -NR9COR10where R9and R10have the above definition,

j) -NR9CO2R10>have the above definition,

l) -COR9where R9has the above definition,

m) -CO2R9where R9has the above definition;

3) C2-6alkenyl, unsubstituted or substituted by one or more substituents selected from:

(a) hydroxy,

b) oxo,

C) C1-6alkoxy,

d) phenyl-C1-3alkoxy,

e) phenyl,

f) -CN,

g) halogen,

h) -CONR9R10where R9and R10have the above definition,

i) COR9where R9has the above definition,

j) -CO2R9where R9has the above definition;

4) C2-6the quinil;

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

(a) hydroxy,

b) C1-6alkoxy,

C) C1-6of alkyl,

d) C2-5alkenyl,

e) halogen,

f) -CN,

g) -NO2,

h) -CF3,

i) -(CH2)m-NR9R10where R9and R10have the above definition,

j) -NR9COR10where R9and R10have the above definition,

k) -NR9CO2R10where R9and R10have the above ODA is SUB>NR9R10where R9and R10have the above definition,

n) -COR9where R9has the above definition,

o) -CO2R9where R9has the above definition;

6) halogen,

7) -CN,

8) -CF3,

9) -NO2,

10) -SR14where R14represents hydrogen or C1-5alkyl,

11) -SOR14where R14has the above definition;

12) -SO2R14where R14has the above definition;

13) NR9COR10where R9and R10have the above definition,

14) CONR9COR10where R9and R10have the above definition,

15) NR9R10where R9and R10have the above definition,

16) -NR9CO2R10where R9and R10have the above definition,

17) hydroxy,

18) C1-6alkoxy,

19) COR9where R9has the above definition,

20) CO2R9where R9has the above definition,

21) 2-pyridyl,

22) 3-pyridyl,

23) 4-pyridyl,

24) 5-tetrazolyl,

25) 2-oxazolyl and

26) 2-thiazolyl;

R11, R12and R13the independent 1) C1-6the alkyl, unsubstituted or substituted by one or more substituents selected from:

(a) hydroxy,

b) oxo,

C) C1-5alkoxy,

d) phenyl-C1-3alkoxy,

e) phenyl,

f) -CN,

(g) halogen where halogen is fluorine, chlorine, bromine or iodine,

h) -NR9R10where R9and R10have the above definition,

i) -NR9COR10where R9and R10have the above definition,

j) -NR9CO2R10where R9and R10have the above definition,

k) -CONR9R10where R9and R10have the above definition,

l) -COR9where R9has the above definition,

m) -CO2R9where R9has the above definition;

2) C2-6alkenyl, unsubstituted or substituted by one or more substituents selected from:

(a) hydroxy,

b) oxo,

C) C1-6alkoxy,

d) phenyl-C1-3alkoxy,

e) phenyl,

f) -CN,

g) halogen,

h) -CONR9R10where R9and R10have the above definition,

i) COR9where R9has the above definition,

j) -CO2R9where Rwhich is selected from the group consisting of:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
and where the heterocycle is substituted by in addition to X one or more substituents selected from:

i) hydrogen,

ii) C1-6the alkyl, unsubstituted or substituted with halogen, -CF3, -OCH3or phenyl,

iii) C1-6alkoxy,

iv) oxo,

v) hydroxy,

vi) thioxo,

vii) -SR9where R9has the above definition,

viii) halogen,

ix) cyano,

x) phenyl,

xi) trifloromethyl,

xii) -(CH2)m-NR9R10where m is 0, 1 or 2 and R9and R10have the above definitions.

xiii) -NR9COR10where R9and R10have the above definition,

xiv) -CONR9R10where R9and R10have the above definition,

xv) -CO2R9where R9has the above definition

and

xvi) -(CH2)m-OR9where m and R9have the above definitions;

p is 0 or 1;

X is chosen from:

a) -PO(OH)O-M+where M+is a pharmaceutically acceptable monovalent a counterion,

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

c) -PO(O-)<>
)-PO(OH)O-M+where R4represents hydrogen or C1-3alkyl,

(e) -CH(R4)-PO(O-)22M+,

f) -CH(R4)-PO(O-)2D2+,

g) -SO3-M+,

h) -CH(R4)-SO3-M+< / BR>
i) -CO-CH2CH2-CO2-M+,

j) -CH(CH3)-O-CO-R5where R5selected from the group consisting of:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
and

k) hydrogen, provided that when p is O and none of R11, R12and R13is not-OX, then X is not hydrogen;

Y is chosen from the group consisting of:

1) single (direct) connection,

2) -O-

3) -S-,

4) -CO-,

5) -CH2-,

6) -CHR15- and

7) -CR15R16- where R15and R16independently selected from the group consisting of:

a) C1-6the alkyl, unsubstituted or substituted by one or more substituents selected from:

(i) hydroxy,

ii) oxo,

iii) C1-6alkoxy,

iv) phenyl-C1-3alkoxy,

v) phenyl,

vi) -- CN;

vii) halogen,

viii) -NR9R10where R9and R10have the above definition,

ix) -NR9COR10where R9and R10the above definition,

xi) -CONR9R10where R9and R10have the above definition,

xii) -COR9- where R9has the above definition;

xiii) -CO2R9where R9has the above definition;

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

(i) hydroxy,

ii) C1-6alkoxy,

iii) C1-6of alkyl,

iv) C2-5alkenyl,

v) halogen,

vi) -- CN,

vii) -NO2,

viii) -CF3,

ix) -(CH2)m-NR9R10where m, R9and R10have the above definition,

x) -NR9COR10where R9and R10have the above definition,

xi) -NR9CO2R10where R9and R10have the above definition,

xii) -CONR9R10where R9and R10have the above definition,

xiii) -CO2NR9R10where R9and R10have the above definition,

xiv) -COR9where R9has the above definition,

xv) -CO2R9where R9has the above definition,

Z is chosen from:

1) hydrogen,

2) C1-6the alkyl and

3) hydroxy, provided that when Y is raised together, forming a double bond (together with the already existing relationship).

The compounds of this invention are prodrugs of their parent compounds. The main advantage of the compounds of the present invention is that they have a high solubility in aqueous solutions relative to their parent compounds. In addition, these prodrugs are usually of reduced activity as receptor antagonists of tachykinins than their parent compounds. Thus, activity, manifested in the introduction of prodrugs, mainly due to the presence of a parent compound that is the result of cleavage of the prodrug.

The term "prodrug" refers to compounds, which are precursors of drugs and that after the introduction and absorption of free drug in vivo by metabolic process.

Prodrugs in fact structurally related to biologically active substance (parent drug), which after the introduction of release the parent drug in vivo as a result of some metabolic process, such as fermentation susceptible functional groups [see, for example, the discussions held (1) A. A. Sinkula and S. H. Yalkowsky, J. Pharm. Sci., 64, 181 (1975); (2) L. A. Svensson. Pharm. Weekbl. 122, 245-250 (1987); (3) L. P. Balant, E. Doelker and P. Buri, Eur. J. Drug. Metab. and Pharmacokinetics, 15, 143-153 (1990); (4) N. Bodor, Drugs of the Future, 6, 165-182 (1981); (5) Design of Biopharmaceutical Properties through Prodrugs and Analogs, E. B. Roche, Ed. American Pharmaceutical Sciences, Washington, DC (1977); (6) H. Bundgaard, Advanced Drug Delivery Reviews, 3, 39-65 (1989)].

The advantage of prodrugs may be in its physical properties, such as high water solubility parenteral compared with the parent drug, or that it can promote the absorption from the digestive tract, or it can increase the stability of drugs during long-term storage. Typically, the prodrug has a lower biological activity than the parent drug. The prodrug may also improve the overall efficiency of the medicinal product, for example by reducing toxicity and unwanted effects of drugs by regulating its absorption, blood, metabolic distribution and enable the cell.

The term "parent connection" or "parent drug" refers to a biologically active form, codetables process or a chemical process. Parent connection may also be the source material for receiving the respective prodrugs.

Although all the usual routes of administration suitable for compounds

the present invention, the preferred routes of administration are oral and intravenous. After gastrointestinal absorption or intravenous administration of these compounds hydrolyzed, or broken down by other in vivo into the corresponding "parent" compounds of formula I, where X represents hydrogen or X is absent, or their salts. Because the parent compounds may be relatively insoluble in aqueous solutions, these prodrugs have a distinct advantage due to their relatively high water solubility.

The compounds of this invention have asymmetric centers, and this invention includes all their optical isomers and their mixtures.

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

When any variable part (for example, alkyl, aryl, R6, R7, R8, R9, R10, R11, R12, R13and so on) is found is each other.

The term "alkyl" as used here includes alkyl groups with a specific number of carbon atoms and normal, 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, cycloheptyl, norbornyl and similar alkali. "Alkoxy" represents an alkyl group with the specified number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy, pentox. "Alkenyl" is intended to include hydrocarbon chains having the specified number of carbon atoms and the normal or branched configuration and at least one unsaturated bond, which may be present in any position of the chain, for example, ethynyl, propenyl, butenyl, pentenyl, dimethylpentyl and similar alkenyl and, if possible, includes E - and Z-forms. "Halogen" as used here denotes fluorine, chlorine, bromine or iodine.

The compounds of this invention are capable of forming salts with various inorganic and organic acids and bases, and such salts are also within the scope of this invention. The use of the acetate, adipate, benzoate, bansilalpet, bisulfate, butyrate, comfort, camphorsulfonate, citrate, aconsultant, fumarate, polysulfate, 2 - hydroxyethylsulphonic, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, tosylate (p-toluensulfonate), undecanoate. Salts with bases (which are pharmaceutically acceptable monovalent cations, defined here as M+or K+or pharmaceutically acceptable divalent cations, defined here as D2+nif appropriate) include ammonium salts, alkali metal salts, for example sodium, lithium and potassium salts, alkaline earth metals, such as aluminum, calcium and magnesium salts, salts with inorganic bases, for example salts of c dicyclohexylamine, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine etc., If M+is a monovalent cation, it is recognized that if 2M+these M+may be the same or different. In addition, similarly, it is recognized that, if prisa group the main character can be quaternity such agents, as alkylhalogenide, for example methyl-, ethyl-, propyl - and butyl chloride, bromides and iodides; diallylsulfide similar to the dimethyl-, diethyl-, dibutil, tamilselvan; halides with long chain (high), for example decyl-, lauryl-, myristyl and sterilgarda, bromides and iodides; aralkylated like benzylbromide and others. The preferred non-toxic physiologically acceptable salts, although other salts are also useful, for example, for isolation and purification of the product.

Salt can be formed by conventional means, for example by reaction of the product in free base form with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent, for example water, which is removed in vacuum, or freeze-drying, or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.

In the compounds of formula I, preferably R2and R3independently selected from the group consisting of:

1) hydrogen,

2) C1-6of alkyl,

3) C2-6alkenyl and

4) phenyl;

R6, R7and R8independently selected from the group consisting of:

1) hydrogen,

2) C1-6of alkyl,

3) fluorine,

4) chlorophy, consisting of:

1) fluorine,

2) chlorine,

3) bromine and

4) iodine;

A represents unsubstituted C1-6alkyl;

B is selected from the group consisting of:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
p was O;

X is chosen from:

a) -PO(HE)-M+where M+is a pharmaceutically acceptable monovalent a counterion,

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

C) -PO(O-)2D2+where D2+is a pharmaceutically acceptable divalent counterion,

d) -CH(R4)-PO(OH)O-M+where R4represents hydrogen or methyl,

(e) -CH(R4)-PO(O-)22M+where R4represents hydrogen or methyl,

f) -CH(R4)-PO(O-)2D2+where R4represents hydrogen or methyl,

i) -CO-CH2CH2-CO2-M+,

j) -CH(CH3)-O-CO-R5where R5selected from the group consisting of:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Y was represented by hydrogen or-O-;

Z represents hydrogen or C1-4alkyl.

In the compounds of the present invention, the preferred embodiment includes those compounds in which Z represents the which Z represents-CH3. Connection with the Deputy at the alpha-carbon atom, exhibit advantageous pharmacological properties, in particular, increased duration of action models extravasation, probably because of the biological stability and resistance to enzymatic destruction.

In the compounds of the present invention, if p is 1, then it is preferable that X was a hydrogen or missing.

In the compounds of the present invention is particularly preferably the embodiment, in which A is-CH2- or-CH(CH3)-.

Especially preferred embodiment of the compounds of this invention include prodrugs of compounds of formula I, where A-B is (1,2,4-triazolo)methyl or (5-oxo-1,2, 4-triazolo)methyl group.

Another particularly preferred embodiment of the compounds of this invention include prodrugs of compounds of formula I, where A-B is (1,3-imidazo) methyl or (5-oxo-1,3-imidazo) methyl group.

Additional particularly preferred embodiment of the compounds of this invention includes those compounds of formula I in which A-B represents (1,2,4-triazolo)methyl or (5 - oxo-1,2,4-triazolo)methylcytisine embodiment of the compounds of this invention includes those compounds of formula I, have-A-A represents (1,3-imidazole)Metelkova or (1,3-imidazole)methyl group having a phosphoryl group attached to the heterocycle.

The preferred embodiment of the compounds of the present invention includes compounds of formula I in which X is chosen from:

a) -PO(O-)2M+where M+is a pharmaceutically acceptable monovalent a counterion,

b) -PO(O-)2D2+where D2+is a pharmaceutically acceptable divalent counterion,

C) -CH(CH3)-O-CO-CH2CH2-NH3+M-and

d) -CH(CH3)-O-CO-CH2CH2NH2+(CH2CH2-OH)M-.

In the compounds of this invention are particularly preferred embodiment, in which A-B is chosen from the following group of substituents:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Specific compounds within the scope of this invention include prodrugs of the following "parent" compounds:

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(trifluoromethyl)benzyloxy)-(3S)- phenyl-(6R)-methylmorpholine;
Thiel)benzyloxy)-3-phenyl-4 - methoxycarbonylmethylene;

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

7) 3-phenyl-2-(2-(3,5-bis(trifluoromethyl)phenyl)ethyl) 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-(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S) -methylmorpholine;

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

13) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6- (R)-methylmorpholine;

14) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R) -phenyl-6-(R)-methylmorpholine;

15) 2 - (S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6- (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-(R)- phenyl-6-(R)-methylmorpholine;

22) 2-(S)-(3,5-bis(cryptomate the oline;

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

25) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-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)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)-3-0) 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;

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

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

44) 4-(3-(1,2,4-triazolo)methyl)-2-(3,5-dimethylsiloxy) -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-(1,2,4-triazolo)methyl)-2-(3-(tert-butyl) -5-methylbenzylamino)-3-phenylmorpholine;

49) 4-(3-(5-oxo-1H,4H-1,2,4 - triazolo)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-dimethylsiloxy)-3 - phenylmorpholine-butyl)benzyloxy)-3-phenylmorpholine;
6-(R)- or 5-(R), 6-(3)-dimethyl]-3- (S)-phenylmorpholine;

73) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo - 1H,4H-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-1H,4H-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-(5)-(4-forfinal)-4-benzyl-2-morpholino;

78) 3-(5)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-forfinal) -4-benzylmorphine;

79) 3-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-forfinal) -the research;

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

81) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-((3-pyridyl) methylcarbamoyl)-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- (methylaminoethanol)-6-oxohexyl)-3-(R)-phenylmorpholine;

85) 2-(R)-(3,5-bis(triptime morpholine;

87) 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-phenylmorpholine;

88) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S) -phenylmorpholine;

89) 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S) -phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

90) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

91) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-forfinal) -4-benzylmorphine;

92) 2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)adenylate)-3- (S)-4-chloro)phenyl-4-benzylmorphine;

93) 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-chloro)-phenylmorpholine;

94) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy) -3-(S)-(4-chloro)-phenylmorpholine;

95) 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S) - (4-chloro)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

96) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-chloro)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo) methylmorpholine;

97) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl)ethoxy)-3- (S)-phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

98) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl)ethoxy)-3-(S) -phenyl-4-(4-(2-oxo-1,3-imidazole)methylmorpholine;

99) 2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)phenyl)ethoxy)-3- (S)-phenylmorpholine;

100) 2-(R)-(1-(1-(3-(fluoride)-5-(trifluoromethyl) phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo) m is R)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)of the research;

103) 2-(R)-(1-(R)-(3,5-dimethyl)phenyl)ethoxy)-3-(S)- phenylmorpholine;

104) 2-(R)-(1-(R)-(3,5(dimethyl)phenyl)ethoxy)-3-(5)-phenyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

105) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy) -3-(S)-phenylmorpholine;

106) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl) ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo) methylmorpholine;

107) 2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S) -phenylmorpholine;

108) 2-(R)-1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S) - phenyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

109) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)- 3-(S)-phenylmorpholine;

110) (2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3- (S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

111) 2-(R)-(1-(R)-3-(isopropoxy)phenyl)ethoxy)-3- (S)-phenylmorpholine;

112) 2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)- phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

113) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl) ethoxy)-3-(S)-phenylmorpholine;

114) 2-(R)-(1-(R)-(3-(isopropoxy)-5-trifluoromethyl)phenyl)ethoxy)- 3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

115) 2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S) -phenylmorpholine;

116) 2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S) - phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

117) 2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl what ash) methylmorpholine;

119) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl) ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

120) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl)ethoxy)- 3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

121) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(chloro)phenyl) ethoxy)-3-(S)-phenylmorpholine;

122) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(chloro)phenyl) ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl) research;

123) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(trifluoromethyl)phenyl) ethoxy)-3-(S)-phenylmorpholine;

124) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(trifluoromethyl))phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

125) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S) -phenylmorpholine;

126) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

127) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S) -phenylmorpholine;

128) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

129) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl) ethoxy)-3-(S)-phenylmorpholine;

130) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl) ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

131) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy) -3-(S)-phenylmorpholine;

132) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy) -3

134) 2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3- (5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

135)2- (R)-(1-(R)-(3,5-(debtor)phenyl)ethoxy)-3(S)- phenylmorpholine;

136) 2-(R)-(1-(R)-(3,5-(debtor)phenyl)ethoxy)-3-(S)-phenyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

137) 2-(R)-(1-(R)-(1-naphthyl)ethoxy)-3(S)-phenylmorpholine;

138) 2-(R)-(1-(R)-(1-naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo - 1H, 4H-1,2,4-triazolo)methyl)research;

139) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl)ethoxy)-3-(S)-phenylmorpholine

140) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl)ethoxy)-3-(S)-phenyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

141) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl)ethoxy)-3-(S)-phenylmorpholine

142) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl)ethoxy)-3-(5)-phenyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

143) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl)ethoxy)-3-(S)- phenylmorpholine;

144) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl)ethoxy)-3-(S)-phenyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

145) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl)ethoxy)-3-(S)- phenylmorpholine;

146) 2-(R)-(1-(S)-(1-(3-(methyl)naphthyl)ethoxy)-3-(S)-phenyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

147) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl) ethoxy)-3-(5)-phenylmorpholine;

148) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl)ethoxy)-3-(S)- phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

149) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-gidra)methyl)research;

151) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)- phenylmorpholine;

152) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro) phenylmorpholine;

153) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenyl)ethoxy)-3-(S) -phenylmorpholine;

154) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S) -(4-fluoro)phenylmorpholine;

155) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)- phenyl-(4-(3-(1,2,4-triazolo)methyl)research;

156) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro) phenyl-(4-(3-(1,2,4-triazolo)methyl)research;

157) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)- 3-(S)-phenyl-(4-(3-(1,2,4-triazolo)methyl)research;

158) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)- 3-(S)-(4-fluoro)phenyl-(4-(3-(1,2,4-triazolo)methyl)research;

159) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)- 3-(S)-phenyl-(4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

160) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)-(4 - fluoro)phenyl-(4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

161) 2-(R)(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S) -phenyl-(4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

162) 2-(R)(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S)- (4-fluoro)phenyl-(4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

163) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)-phenyl-4- (4-(2-oxo-1,3-imidazole)methylmorpholine;

164) 2-(S)-(2-fluoro-5-trifluoromethyl)b is hydroxy)-3-(S) -phenyl-(4-(4-(2-oxo-1,3-imidazole)methyl)research;

166) 2-(R)(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S)- (4-fluoro)phenyl-(4-(4-(2-oxo-1,3-imidazole)methyl)research;

167) 2- (S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)- phenyl-4-(2-imidazole)methylmorpholine;

168) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro) phenyl-4-(2-imidazole)methylmorpholine;

169) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S) -phenyl-4-(2-imidazole)methylmorpholine;

170) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)- 3-(5)-(4-fluoro)phenyl-4-(2-imidazole)methylmorpholine;

171) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S) - phenyl-4- (4-imidazole)methylmorpholine;

172) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro) phenyl-4-(4-imidazole)methylmorpholine;

173) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S) -phenyl-4-(4-imidazole)methylmorpholine;

174) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S) -(4-fluoro)phenyl-4-(4-imidazole)methylmorpholine;

175) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)-phenyl-4- (5-tetrazole)methylmorpholine;

176) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy)-3-(S)- (4-fluoro)phenyl-4-(5-tetrazole)methylmorpholine;

177) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3- (S)-phenyl-4-(5-tetrazole)methylmorpholine;

178) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S)- (4-fluoro)phenyl-4-(5-tetrazole)methylmorpholine;

179) 2-(S)-(2-l)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

181) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane) -3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

182) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S)- (4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;.

183) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)- phenylmorpholine;

184) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro) phenylmorpholine;

185) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S) -phenylmorpholine;

186) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S)- (4-fluoro)phenylmorpholine;

187) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

188) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methyl)research;

189) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S) -phenyl-4-(3-(1,2,4-triazolo)methyl)research;

190) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S)- (4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

191) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S)-phenyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

192) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3- (S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

193) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane) -3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl) research;

194) 2-(R)-(1-(R)-(2-chloro-5-triform is)benzyloxy-3-(S)-phenyl-4 -(4-(2-oxo-1,3-imidazole)methyl)research;

196) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

197) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S) - phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

198) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S) -(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

199) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S)-phenyl-4- (2-imidazole)methyl)research;

200) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S)- (4-fluoro)phenyl-4-(2-imidazole)methyl)research;

201) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S) -phenyl-4-(2-imidazole)methyl)research;

202) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S) -(4-fluoro)phenyl-4-(2-imidazole)methyl)research;

203) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S)-phenyl-4- (4-imidazole)methyl)research;

204) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S)- (4-fluoro)phenyl-4-(4-imidazole)methyl)research;

205) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3- (S)-phenyl-4-(4-imidazole)methyl)research;

206) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)- 3-(S)-(4-fluoro)phenyl-4-(4-imidazole)methyl)research;

207) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S) - phenyl-4-(5-tetrazole)methyl)research;

208) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S)- (4-fluoro)phenyl-4-(5-tetrazole)methyl)Mohali is 2-chloro-5-trifluoromethyl)phenylethane)-3-(S) -(4-fluoro)phenyl-4-(5-tetrazole)methyl)research;

211) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S) -phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl)research;

212) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy)-3-(S)- (4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl)research;

213) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S) -phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl)research;

214) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S) -(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl)research;

215) 2-(S)-(3-methyl)benzyloxy-3-(S)-phenylmorpholine;

216) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenylmorpholine;

217) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S)-phenylmorpholine;

218) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S)-(4 - fluoro)phenylmorpholine;

219) 2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4 - triazolo)methyl)research;

220) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2, 4-triazolo)methyl)research;

221) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

222) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methyl)research;

223) 2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1, 2,4-triazolo)methyl)research;

224) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (3-(5-oxo-1,2,4-triazolo)methyl)research;

225) 2-(R)-(1-(R)-3-methyl)phenylethane-3-(S)-phenyl-4-(3- (5-oxo-1,2,4-triazolo)methyl)research;

226) 2-(R)-(1-(R)-(3) - Rev. enyl-4-(4-(2-oxo-1, 3-imidazole)methyl)research;

228) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4- (2-oxo-1,3-imidazole)methyl)research;

229) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S)-phenyl-4 -(4-(2-oxo-1,3-imidazole)methyl)research;

230) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S)-(4-fluoro)phenyl - 4-(4-(2-oxo-1,3-imidazole)methyl)research;

231) 2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(2-imidazole) methyl)-the research;

232) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (2-imidazole)methyl)research;

233) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S)-phenyl-4- (2-imidazole)methyl)research;

234) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S)-(4-fluoro) phenyl-4-(2-imidazole)methyl)research;

235) 2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(4-imidazole) methyl)-the research;

236) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4 - imidazole)methyl)research;

237) 2-(R)-(1-(R)-(3-methyl)phenylethane)-3-(S)-phenyl-4- (4-imidazole)methylmorpholine;

238) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S)-(4-fluoro) phenyl-4-(4-imidazole)methylmorpholine;

239) 2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazole) methylmorpholine;

240) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (5-tetrazole)-methylmorpholine;

241) 2-(R)-(1-(R)-(3-methyl)phenylethane)-3-(S)-phenyl-4- (5-tetrazole)methylmorpholine;

242) 2-(R)-(1-(R)-(3-methyl)phenylethane)-3-(S)-(4-fluoro) phenyl-4-(5-tetrazole)methylsilane-3-(S)-(4-fluoro)phenyl-4-(2 - oxo-5H-pyrrol-4-yl)methylmorpholine;

245) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S)-phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

246) 2-(R)-(1-(R)-(3-methyl)phenylethane-3-(S) -(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

247) 2-(S)-(3-bromo)benzyloxy-3-(S)-phenylmorpholine;

248) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenylmorpholine;

249) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-phenylmorpholine;

250) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-(4-fluoro)phenylmorpholine;

251) 2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(3-(1,2, 4-triazolo)methylmorpholine;

252) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3- (1,2,4-triazolo)methylmorpholine;

253) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-phenyl-4-(3- (1,2,4-triazolo)methylmorpholine;

254) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

255) 2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(3- (5-oxo-1H, 4H-1,2,4-triazolo)methylmorpholine;

256) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

257) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-phenyl-4-(3- (5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

258) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

259) 2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3 - imidazole)methyl)research;

260) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4- (2-oxo-1,3-imidazole)IU)-(1-(R)-(3-bromo)phenylethane-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

263) 2-(S)-(3-bromo) benzyloxy-3-(S)-phenyl-4-(2-imidazole) methylmorpholine;

264) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(2-imidazole)-methylmorpholine;

265) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-phenyl-4- (2-imidazole)-methylmorpholine;

266) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-(4-fluoro) phenyl-4-(2-imidazole)methylmorpholine;

267) 2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4- (4-imidazole)methylmorpholine;

268) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (4-imidazole)-methylmorpholine;

269) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-phenyl-4- (4-imidazole)-methylmorpholine;

270) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-(4-fluoro) phenyl-4-(4-imidazole)methylmorpholine;

271) 2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(5 - tetrazole)methylmorpholine;

272) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (5-tetrazole)-methylmorpholine;

273) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-phenyl-4- (5-tetrazole)-methylmorpholine;

274) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-(4-fluoro)phenyl-4- (5-tetrazole)methylmorpholine;

275) 2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl) methylmorpholine;

276) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

277) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

278) 2-(R)-(1-(R)-(3-bromo)phenylethane-3-(S)-(4-fluoro)phenyl - 4-(2-ACS is-3-(S)-(4-fluoro)phenylmorpholine;

281) 2-(R)-(1- (R)-(3-chloro)phenylethane-3-(S) -phenylmorpholine;

282) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)- (4-fluoro)phenylmorpholine;

283) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4 - triazolo)methyl)research;

284) 2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl- -4-(3-(1,2,4-triazolo)methyl)research;

285) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-phenyl-4-(3- (1,2,4-triazolo)methyl)research;

286) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-(4 - fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

287) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)research;

288) 2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3- (5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

289) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-phenyl-4-(3- (5-oxo-1H,4H-1,2,4-tremolo)methyl)research;

290) 2-(R)-(1-(R) (3-chloro)phenylethane-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

291) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(4- (2-oxo-1,3-imidazole)methyl)research;

292) 2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

293) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-phenyl-4-(4- (2-oxo-1,3-imidazole)methyl)research;

294) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-(4-fluoro)phenyl - 4-(4-(2-oxo-1,3-imidazole)methyl)research;

295) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(2-imidazole) methyl)-the research;

296) 2-(S)-(3-CHL is imidazole)-methyl)research;

298) 2-(R)-(1-(R)-3-chloro)phenylethane-3-(S)-(4-fluoro) phenyl-4-(2-imidazole)methylmorpholine;

299) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(4-imidazole) methyl)-the research;

300) 2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-imidazole) -methyl)research;

301) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-phenyl-4- (4-imidazole)-methyl)research;

302) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-(4-fluoro) phenyl-4-(4-imidazole)methylmorpholine;

303) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4- (5-tetrazole)methylmorpholine;

304) 2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (5-tetrazole)-methylmorpholine;

305) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-phenyl-4- (5-tetrazole)-methylmorpholine;

306) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-(4-fluoro)phenyl-4- (5-tetrazole)methyl)research;

307) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

308) 2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

309) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-phenyl-4- (2-oxo-5H-pyrrol-4 - yl)methylmorpholine;

310) 2-(R)-(1-(R)-(3-chloro)phenylethane-3-(S)-(4 - fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

311) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S) -phenylmorpholine;

312) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro) phenylmorpholine;

313) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S)-phenylmorpholine;
316) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (3-1H,4H-1,2,4-triazolo)methylmorpholine;

317) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S) -phenyl-4-(3-1H,4H-1,2,4-triazolo)methylmorpholine;

318) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S)- (4-fluoro)phenyl-4-(3-1H,4H-1,2,4-triazolo)methylmorpholine;

319) 2-(R)-(1-(R)-3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4- (3-(5-oxo)-1H,4H-1,2,4-triazolo)methyl)research;

320) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo)-1H,4H-1,2,4-triazolo)methyl)research;

321) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3- (S)-phenyl-4-(3-(5-oxo)-1H,4H-1,2,4-triazolo)methyl)stock research

322) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo)-1H,4H-1,2,4-triazolo)methyl)research;

323) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4- (2-oxo-1,3-imidazole)methyl)research;

324) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

325) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S) -phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

326) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

327) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4- (2-imidazole)methylmorpholine;

328) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro) pinoline;

330) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S)-(4-fluoro) phenyl-4-(2-imidazole)methylmorpholine;

331) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4 - imidazole)methylmorpholine;

332) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(4-imidazole)methylmorpholine;

333) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3- (S)-phenyl-4-(4-imidazole)methylmorpholine;

334) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S)-(4-fluoro) phenyl-4-(4-imidazole)methylmorpholine;

335) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4- (5-tetrazole)-methylmorpholine;

336) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(5-tetrazole)methylmorpholine;

337) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S)-phenyl-4- (5-tetrazole)methylmorpholine;

338) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S)-(4-fluoro) phenyl-4-(5-tetrazole)methylmorpholine;

339) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

340) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

341) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S) -phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

342) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane-3-(S) -(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

343) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenylmorpholine;

344) 2-(S)-(3-tert-Buti is 2-(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)-(4-fluoro) phenylmorpholine;

347) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenyl-4-(3-(1, 2,4-triazolo)methylmorpholine;

348) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

349) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

350) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)-(4 - fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

351) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenyl-4-(3- (5-oxo-1H, 4H-1,2,4-triazolo)methylmorpholine;

352) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl - 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

353) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)- phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

354) 2-(R)-(1-(R-(3-tert-butyl)phenylethane-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

355) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenyl-4-(4- (2-oxo-1,3-imidazole)methylmorpholine;

356) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methylmorpholine;

357) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)-phenyl-4- (4-(2-oxo-1,3-imidazole)methylmorpholine;

358) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)- (4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methylmorpholine;

359) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenyl-4- (2-imidazole)methylmorpholine;

360) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(2-imidazo(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)- (4-fluoro)phenyl-4-(2-imidazole)methylmorpholine;

363) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenyl-4- (4-imidazole)methylmorpholine;

364) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (4-imidazole)methylmorpholine;

365) 2-(R)-(1-(R)-3-tert-butyl)phenylethane-3-(S)-phenyl-4- (4-imidazole)methylmorpholine;

366) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)- (4-fluoro)phenyl-4-(4-imidazole)methylmorpholine;

367) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenyl-4- (5-tetrazole)methylmorpholine;

368) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (5-tetrazole)methylmorpholine;

369) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)-phenyl-4- (5-tetrazole)methylmorpholine;

370) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)-(4-fluoro)phenyl - 4-(5-tetrazole)methylmorpholine;

371) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

372) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

373) 2-(R)-(1-(R)-(3-(tert-butyl)phenylethane-3-(S)-phenyl - 4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

374) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane-3-(S)-(4-fluoro)phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

375) 3-(4-(imidazole)methyl-2-(3-(tert-butyl)-5-(trifluoromethyl) benzyloxy)-3-phenylmorpholine;

376) 2-(R)-(2,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-forfinal)-4 - benzylmorphine;

377) 2-(R)-(1-(2,5-bis(trifluoromethyl)forfinal)of the research;

379) 2-(R)-(1-(R)-(2,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-forfinal)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

380) 2-(R)-(1-(R)-(2,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S) -(4-forfinal)-4-(3-(1,2,4-triazolo)methyl)research;

381) 2-(R)-(1-(R)-(2,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (4-forfinal)-4-(4-(2-oxo-1,3-imidazole)methyl)research;

382) 2-(R)-(1-(R)-(3-(thiomethyl)phenyl)ethoxy-3-(S)-phenylmorpholine;

383) 2-(R)-(1-(R)-(3-(dimethylphenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)research;

384) 2-(R)-(1-R)-(3-(dimethylphenyl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

385) 2-(R)-(1-(R)-(3-(dimethylphenyl)ethoxy)-3-(S)-phenyl)-4- (4-(2-oxo-1,3-imidazole)methyl)research;

386) 2-(R)-(1-(R)-(3-(thiomethyl)-5-(trifluoromethyl))phenyl)ethoxy) -3-(S)-phenylmorpholine;

387) 2-(R)-(1-(R)-(3-(thiomethyl)-5-(trifluoromethyl)phenyl)ethoxy)- 3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

388) 2-(R)-(1-(R)-(3-thiomethyl)-5-(trifluoromethyl)phenyl)ethoxy)- 3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl)research;

389) 2-(R-(1-(R)-(3-(thiomethyl)-5-(trifluoromethyl) phenyl)ethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole)methyl) research;

390) 2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)- 2, 3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenylmorpholine;

391) 2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3 - dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-4-(XY)-3-(S)-phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

393)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3 - dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-4-(2-oxo-1, 3-imidazole)methyl)research;

394) 2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)- phenylmorpholine;

395) 2-(R)-(1-(R)-(3,5-dimethoxy)phenyl)ethoxy)-3-(S)- phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

396) 2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-phenyl - 4-(3-(1,2,4-triazolo)methyl)research;

397) 2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-phenyl - 4-(4-(2-oxo-1,3-imidazole)methyl)research;

398) 2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-forfinal)of the research;

399) 2-(R)-(1-(R)-(3-(forfinal)-5-(trifluoromethyl)ethoxy)-3-(S)- (4-forfinal)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

400) 2-(R)-(1-(R)-(3-(forfinal)-5-(trifluoromethyl)ethoxy)-3- (S)-(4-forfinal)-4-(3-(1,2,4-triazolo)methyl)research;

401) 2-(R)-(1-(R)-(3-(forfinal)-5-(trifluoromethyl)ethoxy)- 3-(S)-(4-forfinal)-4-(4-(2-oxo-1,3-imidazole)methyl)research;

402) 2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl) phenyl)ethoxy)-3-(S)-(4-forfinal)of the research;

403) 2-(R)-(1-(R)-(3-(chlorophenyl)-5-(trifluoromethyl)ethoxy)- 3-(S)-(4-fluoro)phenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

404) 2-(R)-(1-(R)-(3-(chlorophenyl)-5-(trifluoromethyl)ethoxy)-3-(S)- (4-fluoro)phenyl)-4-(3-(1,2,4-triazolo)methyl)research;

405) 2-(R)-(1-(R)-(3-(chlorophenyl)-5-(trifluoromethyl)ethoxy)-3-(S)- (4-fluoro) is on;

407) 2-(R)-(1-(R)-(3,5-dimethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

408) 2-(R)-(1-(R)-(3,5-dimethyl)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methyl)research;

409) 2-(R)-(1-(R)-(3,5-dimethyl)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

410) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenylmorpholine;

411) 2-(R)-(1-(R)-(3-fluoro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

412) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

413) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

414) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenylmorpholine;

415) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)- 3-(S)-(4 - fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)IU - hilmarton;

416) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)morpholine;

417) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4 - fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

418) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-(4 - fluoro)phenylmorpholine;

419) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

m)-5-(methyl)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

422) 2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)- (4-fluoro)phenylmorpholine;

423) 2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy-3-(S)- (4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2, 4-triazolo)methyl)research;

424) 2-(R)-(1-(R)-(3-isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methyl)research;

425) 2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)- (4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

426) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy) -3-(S)-(4-fluoro)phenylmorpholine;

427) 2-(R)-(1-(R)-(3-isopropoxy)-5-(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo) methyl)research;

428) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

429) 2-(R)-(1-(R)-(3-isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-oxo-1,3-imidazole)methyl)research;

430) 2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-4 - fluoro)phenylmorpholine;

431) 2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S) -(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo) methyl)research;

432) 2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy) -3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

433) 2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy) -3-(S)-4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

434) 2-(R)-(1-(R)-(XI)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2, 4-triazolo)methyl)research;

436) 2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

437) 2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazo)methyl)stock research

438) 2-(R)-(1-(R)-(3-tert-butyl)-5-(chloro)phenyl)ethoxy)-3-(S) -(4-fluoro)phenylmorpholine;

439) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)stock research

440) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)- (4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

441) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

442) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(trifluoromethyl) phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

443) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(trifluoromethyl)phenyl)ethoxy) -3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl) research;

444) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(trifluoromethyl)phenyl)ethoxy) -3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

445) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

446) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)- (4-fluoro)phenylmorpholine;

447) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo the ina;

449) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

450) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S) -(4-fluoro)phenylmorpholine;

451) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

452) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl) ethoxy)-3- (S) (4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

453) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)- (4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl) research;

454) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy) -3-(S)-(4-fluoro)phenylmorpholine;

455) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

456) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

457) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy) -3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

458) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3- (S)-(4-fluoro)phenylmorpholine;

459) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

460) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)morpho is Polina

462) 2-(R)-(1-(R)-(3,5-(dichloro) phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

463) 2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

464) 2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methyl)research;

465) 2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

466) 2-(R)-(1-(R)-(3,5-(debtor)phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

467) 2-(R)-(1-(R)-(3,5-(debtor)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

468) 2-(R)-(1-(R)-(3,5-(debtor)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methyl)research;

469) 2-(R)-(1-(R)-(3,5-(debtor)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

470) 2-(R)-(1-(R)-naphthyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

471) 2-(R)-(1-(R)(1-naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H, 4H,1,2,4-triazolo)methyl)research;

472) 2-(R)-(1-(R)-(1-naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2, 4-triazolo)methyl)research;

473) 2-(R)-(1-(R)-(1-naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

474) 2-(R)-(1-(R)-(1-(4-fluoro)naphthyl)ethoxy-3-(S)-(4-fluoro) phenylmorpholine;

475) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl)ethoxy)-3-(S)- (4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl) research;

476) 2-(R)-(1-(R)-1(4-(fluoro)Nar) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

478) 2-(R)-(1-(R)-(1-(3-fluoro)naphthyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

479) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

480) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-(1,2,4-triazolo)methyl)research;

481) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

482) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

483) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

484) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl - 4-(3-(1,2,4-triazolo)methyl)research;

485) 2-(R)-(1-(R)-1-(3-chloro)naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

486) 2-(R)-(1-(R) -(1-(3-methyl)naphthyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

487) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl)ethoxy)-3-(S)-(4 - fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)stock research

488) 2-(R)-(1-(R)-(1-(3-methyl)naphthyl)ethoxy)-3-(S)(4-fluoro)phenyl-4- (3-(1,2,4-triazolo)methyl)research;

489) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

490) 2-(R)-(1-(R)-(1-(3-trifluoromethyl)naphthyl)ethoxy)-3-(S) -(4-fluoro)-phenylmorpholine;

491) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl)ethoxy)-3-(S)- (4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-Tria is orfelina;

493) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

494) 2-(R)-(1-(R)-(3-(thiomethyl)phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

495) 2-(R)-(1-(R)-(3-(thiomethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

496) 2-(R)-(1-(R)-(3-(thiomethyl)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methyl)research;

497) 2-(R)-(1-(R)-(3-(thiomethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

498) 2-(R)-(1-(R)-(3-(thiomethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluoro)phenylmorpholine;

499) 2-(R)-(1-(R)-(3-thiomethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

500) 2-(R)-(1-(R)-(3-(thiomethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

501) 2-(R)-(1-(R)-(3-(thiomethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)stock research

502) 2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl) ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

503) 2-(R)-(1-(R)-(2,2-dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

504) 2-(R)-(1-(R)-(2,2-dimethyl-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo-oxo-1,3-imidazole)methyl)-the research;

506) 2-(R)-(1-(R)-(3,5-dimethoxy)phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

507) 2-(R)-(1-(R)-(3,5-dimethoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

508) 2-(R)-(1-(R)-(3,5-dimethoxy)phenyl)ethoxy)-3-(S)-(4 - fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

509) 2-(R)-(1-(R)-(3,5-dimethoxy)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

510) 2-(R)-(1-(R)-(phenyl) ethoxy)-3-(S)-phenylmorpholine;

511) 2-(R)-(1-(R)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H, 4H-1,2,4 - triazolo)methyl)research;

512) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl) research;

513) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole) methyl)research;

514) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

515) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)research;

516) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo) methyl)research;

517) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3 - imidazole)methyl)research;

518) 2-(R)-(1-(R)-(3-fluoro)phenyl)ethoxy)-3-(S)-phenylmorpholine;

519) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3- (5-oxo-1H, 4H-1,2,4-triazolo)methyl)research;

520) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

521) 2-(R)-(1-(R)-(3-(fluoro)phenylmorpholine;

523) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

524) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-(1,2,4-triazolo)methyl)research;

525) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

526) 2-(R)-(1-(R)-(4-fluoro)phenyl)ethoxy)-3-(S)-phenylmorpholine;

527) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)research;

528) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

529) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(4- (2-oxo-1,3-imidazole)methyl)research;

530) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

531) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

532) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-(1,2,4-triazolo)methyl)research;

533) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

534) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(3-fluoro)phenylmorpholine;

535) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (3-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

536) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (3-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

539) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-debtor) phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

540) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-debtor) phenyl-4-(3-(1,2,4-triazolo)methyl)research;

541) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-debtor) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

542) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dichloro) phenylmorpholine;

543) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dichloro) phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

544) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(3,4-dichloro)phenyl-4-(3-(1,2,4-triazolo)methyl)research;

545) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dichloro) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

546) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dimethyl) phenylmorpholine;

547) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dimethyl) phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

548) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dimethyl) phenyl-4-(3-(1,2,4-triazolo)methyl)research;

549) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dimethyl) phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

550) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (3,4-methylenedioxyphenyl)methyl)research;

552) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4 - methylenedioxyphenyl-4-(3-(1,2,4-triazolo)methyl)research;

553) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (3,4-methylenedioxyphenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

554) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(2-naphthyl)of the research:

555) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(2-naphthyl) -4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)research;

556) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (2-naphthyl)-4-(3-(1,2,4-triazolo)methyl)research;

557) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S) -(2-naphthyl)-4-(4-(2-oxo-1,3-imidazole)methyl)research;

558) 2-(R)-(1-(R)-(3-(forfinal)-5-(trifluoromethyl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

559) 2-(R)-(1-(R)-(3-(forfinal)-5-(trifluoromethyl)ethoxy)-3-(S)-phenyl - 4-(4-(2-oxo-1,3-imidazole)methyl)research;

560) 2-(R)-(1-(R)-(3-(chlorophenyl)-5-(trifluoromethyl)-ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

561) 2-(R)-(1-(R)-(3-(chlorophenyl)-5-(trifluoromethyl)ethoxy)-3-(S)-phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

562) 2-(R)-(1-(R)-(3,5-dimethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4 - triazolo)methyl)research;

563) 2-(R)-(1-(R)-(3,5-dimethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(4-(2-oxo - 1,3-imidazole)methyl)research;

564) 2-(R)-(1-(R)-(3-fluoro)-5-(methyl)phenyl)ATOC-1,3-imidazole)methyl)research;

566) 2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4- (3-(1H,4H-1,2,4-triazolo)methyl)research;

567) 2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3 - imidazole)methyl)research;

568) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

569) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

570) 2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

571) of 2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(4- (2-oxo-1,3-imidazole)methyl)research;

572) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy)-3- (S)-phenyl-4-(3-(1H,4H-1,2,4-triazolo)methyl)research;

573) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

574) 2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4- (3-(1H,4H-1,2,4-triazolo)methyl)research;

575) 2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3- (S)-phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

576) 2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4- (3-(1H,4H-1,2,4-triazolo)methyl)research;

577) 2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

578) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(chloro)phenyl)ethoxy)-3-CSR-1,3-imidazole)methyl)research;

580) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(trifluoromethyl)phenyl)ethoxy-3-(S)- phenyl-4-(3-(1H,4H-1,2,4-triazolo)methyl)research;

581) 2-(R-(1-(R)-(3-(tert-butyl)-5-(trifluoromethyl)phenyl)ethoxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

582) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S) -phenyl-4-(3-(1,2,4-triazolo)methyl)research;

583) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl - 4-(4-(2-oxo-1,3-imidazole)methyl)research;

584) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4- (3-(1H,4H-1,2,4-triazolo)methyl)research;

585) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

586) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl) ethoxy)-3-(S)-phenyl-4-(3-(1H,4H-1,2,4-triazolo)methyl)research;

587) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl) ethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

588) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3-(S)- phenyl-4-(3-(1H,4H-1,2,4-triazolo)methyl)research;

589) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3- (S)-phenyl-4(4-(2-oxo-1,3-imidazole)methyl)research;

590) 2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3- (1H,4H-1,2,4-triazolo)methyl)research;

591) 2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-phenyl-4- (2-oxo-1,3-imidazole)methyl)research;

592) 2-(R)-(1-(R)-(3,5-(debtor)fexo-1,3-imidazole)methyl)research;

594) 2-(R)-(1-(R)-(1-naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4 - triazolo)methyl)research;

595) 2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-phenyl-4-(4- (2-oxo-1,3-imidazole)methyl)research;

596) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl)ethoxy-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

597) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl)ethoxy)-3-(S)- phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)research;

598) 2-(R)-1(R)-(1-(3-(fluoro)naphthyl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

599) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl)ethoxy)-3-(S) - phenyl-4-(4- (2-oxo-1,3-imidazole)methyl)research;

600) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methyl)research;

601) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl)ethoxy)-3-(S)-phenyl-4- (4-(2-oxo-1,3-imidazole)methyl)research;

and their pharmaceutically acceptable salts.

Representative examples of the items listed below:

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439) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;

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449) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methyl)morpholine;

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468) 2-(R)-(1-(R)-(3,5-(debtor)phenyl)ethoxy)-3-(S)-(4 - fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl)morpholine;

Specific compounds within the scope of the present invention include:

1) N-oxide 2(S)-ethyl)benzyloxy)-3-(S)-phenyl-4- (3-(4-(ethoxycarbonyl-1-ethyl)-5-oxo-1H-1,2,4-triazolo) methyl)morpholine;

3) 2(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro) -phenyl-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;

4) 2(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluoro)-phenyl-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl) morpholine;

5) 2(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)- phenyl-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;

6) 2(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxaphosphorin-1H-1,2,4-triazolo)methyl)morpholine;

7) 2(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl - 4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;

or their pharmaceutically acceptable salts.

Especially preferred compounds include those compounds in which the pharmaceutically acceptable salt is a salt of bis(N-methyl-D - glucamine).

Specific compounds within the scope of this invention also include

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where TO+is a pharmaceutically acceptable counterion.

Test for antagonism of the tachykinins

The compounds of this invention are useful as antagonists of tachykinins, especially substance and neirokinina And, when lichnyh diseases, pain or migraine and asthma in a mammal in need of such treatment. This activity can be demonstrated in the following test.

A. the expression of the receptor in COS-cells

For temporal expression of the receptor cloned human neirokinina-1 (NKIR) in COS-cells with cDNA for human NKIR cloned in the expression vector pCDM9, which was obtained from pCDM8 (INVITROGEN) by inserting resistant to ampicillin gene (nucleotide sequence 1973-2964 BLUESCRIPT SK+) in the website Sac II. Transfection of 20 ug of plasmid DNA into 10 million COS cells was achieved by electroporation in 800 μl of transfection buffer (135 mm NaCl, 1.2 mm CaCl2, 1.2 mm MgCl2, 2.4 mm K2HPO4, 0.6 mm KH2PO4, 10 mm glucose, 10 mm HEPES, pH 7.4) at 260 V and 950 μf using IBI GENEZAPPER (IBI, New Haven, CT). Cells were incubated in 10% fetal bovine serum, 2 mm glutamine, 100 u/ml penicillin-streptomycin, and 90% DMEM medium (modified by way of Dulbecco Wednesday Needle) (GIBCO, Grand Island, ny) in 5% CO2at 37oC for three days before analysis of binding.

Century Stable expression in CHO-cells

To establish stable cell lines expressing the cloned human NKIR, cDNA was subcloned into the vector pRcCMV (INVITROGEN). Transfection of 20 the sperm DNA of herring at 300 V and 950 μf using IBI GENEZAPPER (IBI). Transfection cells incubated in the medium for CHO-cells [10% fetal bovine serum, 100 u/ml penicillin-streptomycin, 2 mm glutamine, 1/500 gipoksantin-thymidine (ATSS), 90% IMDM medium (environment Dulbecco, modified by the method of Claims) (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml G418 (GIBCO)] in 5% CO2at 37oC up until colonies became visible. Each colony was separated and planted. The cell clone with the largest number of human NKIR were selected for subsequent use, for example for the selection of drugs.

C. Method of analysis using COS or CHO cells

Analysis of binding of human NKIR, expressed in COS cells or CHO, based on the use of125I-substance P (125I-SP, from DU PONT, Boston, MA) as of radiolabelled ligand which competes with unlabeled substance P or any other ligand in the binding of human NKIR. Monolayer cell cultures of COS or CHO dissociatively non-enzymatic solution (SPECIALITY MEDIA, Lavallette, NJ) and re-suspended in such volume buffer for binding (50 mm Tris, pH 7.5, 5 mm MgCl2, 150 mm NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mm of phosphoramidon) to 200 μl of cell suspension dawalia 200 μl of cells were added in a test tube, containing 20 μl of 1.5 to 2.5 nm125I-SP and 20 μl of unlabeled substance P or any other test compound. The tubes were incubated at 4oC or at room temperature for 1 h with gentle shaking. Related radioactive part was separated from the unbound radioactive part by means of filter GF/C (BRANDLER, Gaithersburg, MD), which is pre-moistened with 0.1% polyethylenimine. The filter three times washed with 3 ml of wash buffer (50 mm Tris, pH 7.5, 5 mm MnCl2, 150 mm NaCl, and its radioactivity was determined by gamma counter.

Activation of phospholipase C receptor NKIR can also be measured in CHO cells expressing human NKIR, by determining the accumulation of inosinmonofosfata, which is the product of the destruction IP3(Insectivora). The CHO cells are seeded in the plate with 12 holes, using 250,000 cells per well. After incubation in the medium of CHO within 4 days of cell load of 0.025 µci/ml3H-myoinositol at incubation over night. Extracellular radioactivity removed by washing containing phosphate buffer saline. Well add LiCl to a final concentration of 0.1 mm with the test compound or without him, and incubation continued at 37oC in accordance with Intego incubation at 37oC Wednesday, remove and add 0.1 n HCl. Each well is subjected to ultrasonic treatment (for cell disruption) at 4oC and extracted with a mixture of CHCl3/methanol (1: 1). The aqueous phase is injected into the ion exchange column with a 1 ml DOWEX AG HV. The column is washed with 0.1 n formic acid and then a solution of 0.025 M format ammonium-0.1 n formic acid. Emoticonist elute with a mixture of 0.2 M, the size of the ammonium of 0.1 n formic acid and quantify beta-counter.

Found that the compounds of formula I, are given as the following examples, replace the radioactive ligand to the receptor neirokinina-1 at concentrations ranging from 0.01 nm to 1.0 μm.

The activity of these compounds can also demonstrate using the analysis described Lri, et al., British J. Pharmacol., 105, 261-262 (1992).

The compounds of this invention useful for the prevention and treatment of a large number of clinical conditions which are characterized by the presence of an excess of activity tachykinin, in particular substance P.

These conditions may include disorders of the Central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders, for example associated with the disease, for example, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS; disease Lou Gehrig), and other neurotic diseases disorders such as peripheral neuropathy, for example, AIDS-related neuropathy, diabetic neuropathy induced by chemotherapy neuropathy and poligeneticheskie and other neuralgias; respiratory diseases such as chronic obstruction of the respiratory tract: bronchopneumonia, chronic bronchitis, bronchospasm and asthma; airway disease, modulation of neurogenic inflammation; disease characterized by neurogenic secretion of mucus, such as cystic fibrosis; diseases associated with increased glandular secretion, including lacrimation, such as Sjogren syndrome, hyperlipoproteinemias IV and V, hemochromatosis, sarcoidosis, or amyloidosis; inflammatory diseases such as inflammatory bowel disease, irritable bowel syndrome, psoriasis, fibrositis, ocular inflammation, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; hypersensitivity, for example caused by poisonous plusem; eye diseases such as conjunctivitis, vernal conjunctivitis, dry eye syndrome, and the like; cutaneous diseases such as Comte the config thermal damage; disorders associated with addiction, such as alcoholism; stress-related somatic disorders, reflex sympathetic dystrophy, such as the syndrome of the shoulder; estimatesa disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of the function of internal organs, such as ulcerative colitis, granulomatous disease and incontinence, nausea or emesis, including acute, delayed, post-operative, podnebesnuyu and premature vomiting, for example caused by chemotherapy, radiation, toxins, pregnancy, vestibular disorder, a sickness, post-operative illness, surgery, gastrointestinal obstruction, reduced motor function of the gastrointestinal tract, visceral pain, migraine, opioid analgesics and changes in intracranial pressure (except Quaternary salts); disorders of bladder function such as hyperreflexia of the sphincter of the bladder; EN dilation of blood vessels and angiospastic diseases, for example, angina, migraine and Reynaud disease; and pain or the perception of pain, such as chronic pain or pain, characteristic of or associated with any of the above conditions, especially the transmission of pain in migraine. Therefore, these compounds can easily be adapted for therapeutic use for the treatment of physiological disorders associated with excessive stimulation of the receptors of tachykinins, especially neirokinina-1, and as antagonists neirokinina-1 in the regulation and/or the treatment of any of the above clinical conditions in mammals, including humans.

The compounds of this invention are valuable in the treatment combinations of the above conditions, in particular in the treatment combination in postoperative pain and postoperative nausea and vomiting.

The compounds of this invention are particularly useful in the treatment of nausea or emesis, including acute, delayed, post-operative, podnebesnuyu and premature vomiting, such as vomiting or nausea caused by chemotherapy, radiation, surgery, migraine, toxins, such as metabolic or microbial toxins, viral or bacterial infections, pregnancy, vestibular naoi function of the gastrointestinal tract, visceral pain, psychological stress or disturbance, high altitude, weightlessness, opioid analgesics, intoxication, resulting, for example, alcohol consumption, and changes in intracranial pressure. Especially this compound suitable for the treatment of vomiting caused by antineoplastic (cytotoxic) means, including means that are commonly used in cancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, such as esters isothiocyanato acid, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action, such as nitrosocarbaryl, cisplatin and dacarbazine; antimetabolites, such as folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example vinylchloride and derivatives podofillotoksina; and cytotoxic antibiotics.

Specific examples of chemotherapeutic agents are described, for example, D. J. Stewart in "Nausea and Vomitting: Recent Research and Clinical Advances; Eds. J. Kucharczyk, et al., CRC Press Inc., Boca Exploration, Florida, USA (1991), p. 177-203, especially on R. 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (ether isothiocyanato procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al., Cancer Treatment Reports, 68 (1), 163-172 (1984)].

The compounds of this invention can be used in the treatment of vomiting caused by radiation, including radiation therapy, for example in the treatment of cancer or radiation sickness, and in the treatment of postoperative nausea and vomiting.

The compounds of this invention are also suitable for the prevention or treatment of disorders of the Central nervous system such as anxiety, psychosis and schizophrenia; neurodegenerative disorders such as senile dementia of Alzheimer's type, Alzheimer's disease and down syndrome; respiratory diseases, particularly diseases associated with excessive secretion of mucus, such as chronic airway obstruction, pneumonia, chronic bronchitis, cystic 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 (Gl) disorders and diseases of the Gl tract such as disorders associated with the neuronal control of blood flow disturbances, caused by dilation of blood vessels; and pain or sensitivity to pain, for example related to or associated with any of the above conditions or the transmission of pain in migraine (both prevention and treatment of acute pain).

As a means of blocking the calcium channels, some of the compounds of this invention useful for the prevention or treatment of clinical conditions which benefit from inhibition of the migration of calcium ions across cell membranes. They include diseases and disorders of the heart and vascular system, such as angina, myocardial infarction, cardiac arrhythmia, cardiac hypertrophy, cardiac vasospasm, hypertension, cerebrovascular spasm, and other coronary disease. In addition, these compounds may be able to reduce elevated intraocular pressure when introduced locally in hypertensive eyes in a solution of a suitable ophthalmic filler. These compounds can also be useful to reverse the development of resistance to many drugs in tumor cells by enhancing the effectiveness of chemotherapeutic agents. In addition, these compounds may have activity in blocking calcium the program of the present invention is particularly useful in the treatment of pain and/or sensitivity to pain, and/or inflammation and disorders associated with them, such as, for example, neuropathy, such as diabetic or peripheral neuropathy caused by chemotherapy neuropathy; poligeneticheskie and other neuralgias; asthma; osteoarthritis; rheumatoid arthritis and especially migraine. The compounds of this invention are also useful, in particular, in the treatment of diseases characterized by neurogenic secretion of mucus, in particular cystic fibrosis.

To treat some conditions it may be desirable to use the compounds of this invention in combination with another pharmacologically active agent. For example, the compound of this invention can be present together with other therapeutic agent as a combined preparation for simultaneous, separate or sequential application to ease the vomiting. Such a combination of drugs can be, for example, in the form of packaging, which consists of two parts. The preferred combination contains a compound of the present invention with chemotherapeutic agent such as an alkylating agent, an antimetabolite, a mitotic inhibitor or cytotoxic inhibitor described above. Typically for use in such combinations d="ptx2">

Similarly, for the treatment of respiratory diseases such as asthma, a compound of this invention may be useful in combination with bronchodilatory agent, for example an agonist2- adrenergic receptor or antagonist tachykinin, which acts as a receptor neirokinina-2. Suitable agonists2-adrenergic receptors include Bambuterol (US 4138581 issued to Draco on 12/6/83); Bitolterol mesilate (US 4138581 issued to Sterling 2/6/79); Postera (US 4276299 issued to Zambon 6/30/81 and US 4520200 issued to Zambon 5/28/85), Carbuterol (US 3763232 issued to Smith Kline 10/2/73); clenbuterol (US 3536712 issued to Boehringer Ingelheim 10/27/70); Cimaterol (US 4407819 issued to American Cyanamid 10/4/83); Doeblin (US 4228183 issued to Tanabe 10/14/80); Dopexamine (US 4645768 issued to Fisons 2/24/87); Formoterol (US 3994974 issued to Jamanouchi 11/30/76); Albuterol (US 4119710 issued to Boehringer Inhelheim 10/10/78); Pirbuterol hydrochloride (US 3700681 issued to Pfiser 10/24/72); Procaterol hydrochloride (US 4026897 issued to Oysuka 5/31/77); Ritodrin hydrochloride (US 3410944 issued to North American Philips 11/12/68) or Salmeterol (US 4992474 issued to Glaxo 2/21/91 and US 5091422 issued to Glaxo 2/25/92).

In addition, to treat conditions that require antagonism for neirokinina-1 and neirokinina-2, including violations related to bronchostenosis and/or radiolabeled plasma in the Airways, such as asthma, khronicheskoy neuropathy caused by chemotherapy neuropathy; osteoarthritis; rheumatoid arthritis and migraine, the compound of this invention can be used in combination with an antagonist tachykinin, which acts at receptors neirokinina-2, or antagonist of the receptor tachykinin, which acts as the receptor neirokinina-1 and neirokinina-2.

In this way the connection of the present invention can be applied with a leukotriene antagonist, such as an antagonist of leukotriene D4examples of these antagonists are described in patent publication EP 0480717, published April 15, 1992; patent publication EP 0604114; published in June 1994; U.S. patent N 5279324, issued December 14, 1993, and U.S. patent N 4859692, issued 22 August 1989. This combination, in particular, useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough.

The compound of this invention can also be used in combination with a corticosteroid, such as dexamethasone), kenalog, aristocort, nasalide, preferida, bencardino or other, such as described in U.S. patent N 2789118, 2990401, 3048581, 3126375, 3929768, 3996359, 3928326 and 3749712.

Similarly, for the prevention or treatment of vomiting compound of the present invention can be applied in whom triptamine), for example, ondansetron, granisetron, tropisternus, decadron and zatosetron, or agonists GABA8-a receptor (GABA stands for gamma-aminobutyric acid), such as baclofen. In the same way to prevent or treat migraine connection of the present invention can be used in combination with other anti-migraine, such as ergotamine or 5HT1agonists, specifically sumatriptan.

Similarly for the treatment of behavioral hyperalgesia compound of this invention can be used in combination with an antagonist of N-methyl-D-aspartate (NMDA), such as disciplinam. For the prevention or treatment of inflammatory conditions in the lower part of the urinary tract, especially cystitis, the compound of this invention can be used in combination with an anti-inflammatory agent, for example a receptor antagonist of bradykinin. The compound of this invention and another pharmacologically active agent can enter the patient simultaneously, sequentially or in combination.

In the treatment of the above clinical conditions, the compounds of this invention can be used in compositions such as tablets, capsules or elixirs for oral widenening introduction, etc.

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 compounds of the present invention as an active ingredient in a mixture with an organic or inorganic carrier or excipient suitable for external, internal or parenteral use. The active ingredient can be mixed, for example, conventional non-toxic pharmaceutically acceptable carriers to obtain pellets, pastilles, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The media that can be used are glucose, lactose, Arabian gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid or liquid form, and, in addition, you can apply auxiliary, stabilizing, thickening and coloring tools, and odorants. Active target compound include a pharmaceutical product in the quantity Doctorow, such as tablets, the principal active ingredient is mixed c pharmaceutically acceptable carrier, for example a conventional tabletiruemye ingredients such as starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a composition in the form of a solid pre-finished formulation containing a homogeneous mixture of the compounds of this invention or its non-toxic pharmaceutically acceptable salt. When these compositions are in the form of pre-prepared formulation are listed as a homogeneous, this means that the active ingredient is dispersed evenly throughout the composition so that the composition can easily be divided into equally effective, standardized dosage forms such as tablets, pellets and capsules. This composition is in the form of a solid pre-finished formulation is then divided into uniform dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Tablets or pellets of the new compositions can be covered with membrane or to handle any other way to get lekarstvennoyj dosage and an outer dosage component, the latter is in the form of a shell on the ground. Two components can be separated intersolubility layer, which serves as a barrier disintegration of the internal component in the stomach and permits the inner component to pass intact into the duodenum or to be released slowly. For such intersolubility layers or shells you can apply different materials, for example materials, including 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 you can enter the new compositions of this invention for oral or injection include aqueous solution suitable way OTDELENIE syrups, aqueous or oil suspensions, and OTDELENIE emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, elixirs and similar pharmaceutical excipients. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic and natural gums, for example tragakant, Arabian gum, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, Pelevin is nsii the addition of water, provide the active ingredient mixed with a dispersant or wetting agent, suspenders agent and one or more preservatives. Examples of suitable dispersing agents or wetting agents and suspendida agents mentioned above. May also contain additional excipients, for example sweetening substances, perfumes and colorants.

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 excipients mentioned above. The composition is preferably administered orally or nazalnam respiratory way to achieve local or systemic action. The composition preferably in a sterile pharmaceutically acceptable solvents can be sprayed by means of inert gases. Sprayed solutions can be inhaled directly from the spraying device or spray device can be attached to the face mask, tent or car for inhalation under intermittent positive pressure. Compositions in the form of solutions, suspensions Iliou preparative form properly.

To ensure the above clinical conditions and diseases of the compounds of this invention can be administered orally, topically, parenterally, by inhalation spray, or rectally in the form of uniform ready preparative forms containing conventional non-toxic pharmaceutically acceptable carriers, auxiliary ingredients and fillers. The term "parenteral" as used here includes the ways subcutaneous injections, intravenous, intramuscular, vnutrigrudne injections or infusions.

The compounds of this invention can be entered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The dose will vary from patient to patient depending on the nature and severity of the disease, weight of patient, special diets, which are then applied by the patient, while the ongoing drug therapy and other factors that will be recognized by experts in the field.

In the treatment of a condition associated with an excess of tachykinins, a suitable level doses generally will be from about 0.001 to about 50 mg per 1 kg of body weight of the patient per day, and this number can be entered in the form odnawialne from about 0.05 to about 10 mg per day. For example, in the treatment of conditions, including nanoperiodic pain perception suitable level of dose is from about 0.001 to 25 mg/kg / day, preferably from about 0.05 to about 10 mg/kg / day, and specifically from about 0.1 to about 5 mg/kg / day. The compound can be administered in scheme 1-4 times a day, preferably once or twice a day. In the treatment of vomiting with the use of injectable ready preparative form suitable level of dose is about 0.001 to 10 mg/kg / day, preferably about 0.005 to 5 mg/kg / day, and especially about 0.05 to 5 mg/kg / day. The compound can be administered in scheme 1-4 times a day, preferably once or twice a day.

In schemes 1-15 (in the end of the description and examples provides several ways to obtain the compounds of this invention where R2, R3, R6, R7, R8, R11, R12, R13, A, B, p, Y, and Z have the above values.

Abbreviations used in the schemes and examples

Reagents:

Et3- N triethylamine

Ph3P - triphenylphosphine

TFU - triperoxonane acid

NaOEt - ethoxide sodium

DCC - N,N'-dicyclohexylcarbodiimide

DCC - N,N'-dicyclohexylcarbodimide

DVS - 1,1'-carbonyldiimidazole

MJPBK - m-HLA-chloroethylphosphonic

DIA - N,N-diisopropylethylamine

N - N-hydroxysuccinimide

DEBUG - diisobutylaluminium

LCA - dimethylsulfate

The peso - hydrate of 1-hydroxybenzotriazole

ABOUT hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

Solvents:

DMF - dimethylformamide

THF - tetrahydrofuran

MeOH - methanol

EtOH - ethanol

AmOH - n-amyl alcohol

AcOH - acetic acid

MeCN is acetonitrile

DMSO - dimethyl sulfoxide

Other:

Ph - phenyl

Ar is aryl

Me - methyl

Et - ethyl

iPr is isopropyl

Am - n-amyl

Cbz - carbobenzoxy (benzyloxycarbonyl)

BOC - tert-butoxycarbonyl

IFC - interphase catalyst

cat. catalyst

FAB-MS - mass spectrometry with the bombardment of accelerated atoms

K. T. - room temperature

UG - leaving group (Cl, Br, I, OTs, OMs, OTf, and so on).

The compounds of this invention in which Y = O, can be obtained in a General way, is shown in scheme 1. For example, dimethylacetal respectively substituted-bromophenylacetonitrile (received by way Jacobs in Journal of Umerican Chemical Society, 1953, 75, 5500) may be transformed into dibenzalacetone II mixing I and excess benzyl alcohol in the presence of kiloohm II can be obtained N-alkylamino III; the use of chiral amerosport will lead to the formation of diastereomers, they can be divided into this (or later) stage using standard chromatographic methods. N-Alkylation or N-acylation can be obtained dialkyl - or acyl/alkylamino IV, in which the group a-b may serve as a protective group, or it can be used as a substituent in the target connection or can be turned into such Deputy. Cyclization to obtain substituted the research V can be accomplished by heating a solution of IV and acid catalyst. The diastereomers V, which may be formed, can be divided using standard chromatographic methods. If a-b is a protective group, it can be removed by known methods (Greene T. W., Wuts P. G. M. Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons, Inc., N. Y. 1991). If the I-V results in the formation of enantiomers can be separated by alkylation or acylation V (a-b= N) chiral auxiliary agent, separation of the resulting diastereomers known chromatographic methods, and removing the chiral auxiliary group to obtain the enantiomers V. Alternative diastereomers V can be divided by fractional is acid.

The compounds of this invention in which Y = CH2you can get a General way, is shown in scheme 2. so, for example, N-methoxy-N-methylamide protected phenylglycine VI (derived from carboxylic acids via the mixed anhydride in accordance with the methodology Rapoport in Journal of Organic Chemistry, 1985, 50, 2972) can be used for acylation of enolate lithium metaltitlepane to get califofnia VII. Sodium salt of VII can condense with appropriately substituted benzaldehyde to obtain the ,-unsaturated ketone VIII. The restoration of the ketone and the removal of the tert-BUTYLCARBAMATE protective group can get amerosport IX; the diastereomers, which may be formed, can be divided into this (or later) stage standard chromatographic methods. Turning IX in a simple broadcast on Williamson using substituted chloracetate and subsequent heating may lead to the formation of morpholine X. Restoration of the double bond and the carbonyl amide group can be a direct way to obtain the substituted morpholine XI. If the VI-XI leads to the formation of enantiomers can be separated by alkylation or acylation XI (A-B = N) chiral auxiliary agent, division tomatillos group to obtain the enantiomers XI. Alternative diastereomers XI can be divided by fractional crystallization from a suitable solvent of the diastereomeric salts formed from XI and chiral organic acid. If it is desirable that A-B was not H, the nitrogen atom of the research XI can be further functionalitywith standard methods of alkylation or acylation of secondary amines. If it is desirable that R2was not H, morpholine X can be turned into karunakaran (A-B = RO2C, R2= HE), semi-finished product, which can be alkilirovanii and which will allow changes in R2.

The compounds of this invention in which Y = O, can also be obtained in a General way, is shown in scheme 3. For example, dimethylacetal respectively substituted-bromoacetaldehyde (received by way Jacobs in Journal of American Chemical Soc., 1953, 75, 5500) may be transformed into another acetal mixing with a slight excess of the appropriate alcohol in the presence of an acid catalyst while removing formed methanol. Alkylation of substituted amerosport bromide can be obtained N-alkylamines; application of chiral amerosport will lead to the formation of diastereomers, which can be divided into this (or later) stage standard prospert, which group a-b may serve as a protective group, or it can be used as a substituent in the target connection or can be turned into such Deputy. Cyclization to obtain substituted the research can be done by heating the solution with an acid catalyst. The diastereomers, which may be formed, can be divided standard chromatographic methods. If A-B is a protective group, it can be removed by known methods (Greene T. W., Wuts P. G. M. Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc. , N. Y. 1991). If the receipt of such compounds leads to the formation of enantiomers can be separated by alkylation or acylation of the final product (A-B = H) chiral auxiliary agent, separation of the resulting diastereomers known chromatographic methods, and removing the chiral auxiliary group to retrieve the target enantiomers. Alternative diastereomers can be divided by fractional crystallization from a suitable solvent of the diastereomeric salts formed by this connection and chiral organic acid.

One method for the synthesis of enantiomerically pure substituted morpholino is shown in figure 4. Savodnik 1,2-dibromethane get morpholine. Restoring active hydride reagent, such as diisobutylaluminium, lithium aluminum hydride, three(sec-butyl)lithium borohydride (L-Selectride) or other reducing agents leads to the formation of predominantly derivatives of 2,3-TRANS-of the research. Alkylation of the alcohol, removing the protective group at the nitrogen atom (for example, with the use of palladium catalyst hydrogenation or 1-chloroethylphosphonic (Olofson in J. Org. Chem. , 1984, 2081 and 2795) and alkylation of the nitrogen atom (where A-B-CH2- or A-B-CHO are A-B, with the appropriate values) receive 2,3-Transmediale.

One way of obtaining enantiomerically pure 2,3-CIS-morpholino is shown in figure 5. In the first stage of education triftormetilfosfinov ester of the appropriate benzyl alcohol (specifically benzyl alcohols which are substituted by an electron-acceptor groups, for example-NO2, -F, -Cl, -Br, -COR, CF3and so on) is carried out in the presence of directionspanel base in an inert solvent. You can also apply other leaving group such as iodide, mesilate, tosylate, p-nitrophenylacetate and similar groups. Suitable bases include 2,6-di-tert-butylpyridinium, 2,6-di-tert-butyl-4-methylpyridin, toluol, hexane, benzene, carbon tetrachloride, dichloromethane, chloroform, dichloroethane, etc., and mixtures thereof. The filtered solution of the triflate is then added to a solution of the intermediate product formed in the contacting of morpholine with active hydride reagent, such as diisobutylaluminium, lithium aluminum hydride, or three(sec - butyl)lithium borohydride (L-Selectride) at a low temperature, preferably from -78 to -20oC. After a few hours of keeping the mixture at a low temperature, processing and purification receive the vast amount of 2,3-CIS-substituted products, which can be transformed to the final compounds as shown in scheme 5.

Enantiomerically pure phenylglycine substituted in the phenyl nucleus can be obtained by the method shown in scheme 6 (D. A. Evans, et al., J. Am. Chem. Soc., 1990, 112, 4011).

Methods of obtaining nitrogen alkylating agents A-B-CH2-LG (where LG denotes a suitable a suitable leaving group) used in scheme 4 and scheme 5 based on known literature methods [for A-B = 3-(1,2,4-triazolyl) or 5-(1,2,4-triazole-3-one)silt and LG=Cl, see Janagisawa I., Hirata, J. , Ishii J., Journal of Medical Chemistry, 27, 849 (1984); for A-B = 4-((2H)-imidazol-2-it)yl or 5-(4-etoxycarbonyl-(2H)-imidazol-2-yl) - Rev.,3-CIS-morpholino, which is substituted in position C2-benzyl simple ester, is shown in figure 7. So, for example, substituted 2-morpholino (obtained as described in scheme 4) is treated with active hydride reagent, such as Diisobutyl-aluminohydrides, lithium aluminum hydride, or three(sec-butyl)borohydride, lithium, and the resulting intermediate reaction product is quenched replaced by benzoylchloride, the anhydride of benzoic acid or other active transferring acyl reagent. After water processing gain 2-benzoyloxy-connection, is shown in scheme 7. This compound is converted into the corresponding

simple enol ether using "titanilla" derived from reagents, for example-chloro-methylene[bis(cyclopentadienyl) titanium] dimethylamine ("Tebbe Reagent Tebbe F. N., G. W. Parshall, Reddy, G. S., Journal of American Society, 100, 3611 (1978), dimethyltitanocene (Petasis, N. A., Bzowej E. I., Journal of American Chemical Society, 112, 6392 (1990) or reagent obtained by reduction of 1,1-dibromethane zinc-titanium tetrachloride in the presence of N, N, N', N'- tetramethylethylenediamine (K. Takai et al., Journal of Organic Chemistry 52, 4412 (1987)). Received a simple enol ether restore in a saturated analogue by hydrogenation in the presence of a rhodium catalyst on the basis of, for example rhodium on aluminum oxide or coal; the presence in the presence of catalyst palladium on coal. If this is the case, get the diastereomers, they can be separated by chromatographic methods or recrystallization of a mixture of diastereoisomers. The transformation thus obtained morpholino in the final product is carried out by methods similar to those described in schemes 4 and 5.

The ways in which the substituent at position C-3 of the phenyl nucleus of morpholinos of the present invention can be inserted or replaced with another Deputy, are shown in scheme 8. So, for example, substituted morpholine can be obtained as described in scheme 4, 5 or 7, of enantiomerically pure benzyloxypyridine of arigliano (obtained as described in the literature [e.g., L-n-benzyloxyaniline can be obtained according to the method of Kamiya et al. Tetrahedron, 35, 323 (1979) or using the methods described in scheme 6]. Selective cleavage of benzyl simple live via hydrogenolysis or non-selective hydrogenolysis and subsequent conduct of the synthetic sequence shown in scheme 8, you can get suitable protected phenolic intermediate product. The phenol can be converted into the corresponding alltravel (as shown or using N-phenyltrichlorosilane in the presence of a tertiary amine base in floristry Nickel ways, described in Ritter, Synthesis, 735 (1993) and references therein. The transformation in the target final product can be performed as described in scheme 4 or 5.

The "parent" compound, obtained above, turn in their proletarienne twins alkylation, atilirovanie, phosphorylation or sulfonylamine for the formation of a simple ester, complex ester, phosphate or sulfate derivatives (where the "parent" compounds are Deputy-X defined above) by usual means, indicated here by reference, or reasonable modifications of them.

In particular, as depicted in scheme 9, the processing, such as triazole or imidazolidinylideneamino antagonist tachykinin suitable base, for example n-butyllithium, sodium hydride, potassium hydride, hexamethyldisilazide lithium, hexamethyldisilazide sodium, hexamethyldisilazide potassium or diisopropylamide lithium in THF at low temperature and then adding a suitable fosfauriliruetsa reagent, such as tetraethylpyrophosphate, dibenzoylperoxide or dibenzylpiperazine receive the intermediate product with a protected hydrazide group. After purification, for example, gradient chromatography on silica gel and the spruce product by hydrogenolysis, for example by treatment with hydrogen gas in the presence of palladium on coal and in the presence of two equivalents of a suitable salt-forming agent, for example sodium bicarbonate (to obtain the disodium salt phosphoramidate product) or potassium bicarbonate (to get Pikalevo salt of the product). The product can be cleaned by crystallization or chromatography with normal or reversed phase.

As depicted in scheme 10, the processing, such as triazole or imidazolidinylideneamino antagonist tachykinin suitable base, such as diisopropylethylamine, 2.6-dimethylpyridine or triethylamine, and 1-chloritisation (where R may be ethyl, -CH2CO2CH2-phenyl or-CH2CH2NHP-BOC) in a compatible solvent, such as toluene or dichloroethane, followed by heating the mixture while boiling under reflux for 12-24 h are the corresponding N-alkylaromatic product, which can clean flash chromatography.

Similarly, the same substrate can be processed functionalized carbonate illustrated in figure 11, in similar conditions, for example by boiling under reflux in toluene in the presence of diisopropylate the receiving Boc-group, for example triperoxonane acid in methylene chloride or hydrogen chloride in ethyl acetate, to obtain the corresponding salt procarcinogen product.

Obtaining N-oxide prodrugs of the above Martinovich antagonists of tachykinins can be achieved as shown in scheme 12, the processing agent transfer oxygen (oxidant) such as nagkalat, such as 3 chloroperoxybenzoic acid or cryptometrics acid, or hydrogen peroxide or alkylhydroperoxide, such as tert-butylhydroperoxide, in the presence of a catalyst (transition metal) or acid Caro (H2SO5).

Compounds containing linking groups between the heterocycle and the phosphoryl group can be obtained, for example as shown in scheme 13 [see S. A. Varia, S. Schuller, K. B. Sloan and V. J. Stella, J. Pharm, Sci., 73, 1068-1073 (1984)]. Processing "parent" compounds aliphatic aldehyde, for example, aqueous formaldehyde, get the appropriate hydroxymethylpropane, which, after conversion into the chloride, phosphorus trichloride can be treated with dibenzylamino silver. Received protected phosphates can be divided in the usual ways, for example by chromatography on silica gel. Cleaned the reducing agent, for example gaseous hydrogen in the presence of palladium on coal.

The target compounds of formula I obtained in accordance with the reactions described above can be extracted and cleaned in the usual way, for example by extraction, precipitation, fractional crystallization, recrystallization, chromatography and so on

The compounds of this invention are capable of forming salts with various inorganic and organic acids and bases, such salts are also included in the scope of this invention. Examples of such salts with acids include 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. Salt with a base include ammonium salts, alkali metal salts, for example sodium, lithium and potassium salts, alkaline earth metals, for example calcium and magnesium salts, salts with organic bases, for example salts with dicyclohexylamine, N-methyl-D-glucamine, and salt aminea you can quaternionic such agents, as alkylhalogenide, for example methyl-, ethyl-, propyl - and butyl chloride, bromides and iodides; diallylsulfide similar to the dimethyl-, diethyl-, dibutil, tamilselvan; halides with long chain (high), for example decyl-, lauryl-, myristyl and sterilgarda, bromides and iodides; aralkylated like benzylbromide and others. The preferred non-toxic physiologically acceptable salts, although other salts are also useful, for example, for isolation and purification of the product.

Salt can be formed by conventional means, for example by reaction of the product in free base form with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent, for example water, which is removed in vacuum, or freeze-drying, or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.

Although the reaction schemes described herein are reasonably common, experts in the field of organic synthesis should be clear that one or more functional groups present in the compound of formula I, can give the molecule an incompatibility with a particular synthetic scheme. In this case, you can use an alternative path, such specific reaction conditions, including reagents, solvent, temperature and time so that they are consistent with the nature of functional groups present in the molecule.

Discover the expert in this field, examples 1-93 describe various "parent" compounds, whereas examples 94-96 detail the more specific prodrugs some "parent" compounds. In accordance with this methodology, available in the examples 94-96, easily adapted without undue experimentation to obtain the compounds of the present invention, including prodrugs of the parent compounds of examples 1-93.

The following examples are given to illustrate this invention and should not be construed as limitations of the scope and essence of the invention.

EXAMPLE 1

(+/-)- -Bromophenylacetonitrile, 3,5-bis(trifluoromethyl)benzylacetone

A solution of 2.50 g (10.2 mmol) of dimethylacetal-bromophenylacetonitrile, 8.00 g (32,8 mmol) 3,5-bis (trifluoromethyl)benzyl alcohol and 0.50 g (2.6 mmol) of the monohydrate of p-toluenesulfonic acid in 10 ml of toluene was stirred under vacuum (35 mm RT.CT.) in K. so in 3 days. The reaction mixture was distributed between 100 ml of ether and 50 ml of a saturated aqueous solution bicarbonates over magnesium sulfate and concentrated in vacuum. Flash chromatography on 200 g of silica gel using as eluent a mixture of hexane/methylene chloride (9:1, vol/about.) received 5,41 g (81%) of the title compound as a solid substance, so pl. 79-82oC.1H NMR spectrum: 4,47 and to 4.62 (AB, 2H, J=12,5), 4,78-is 4.93 (2H), 5,09 and to 5.21 (AB, 2H, J = 7,7), 7,31-7,44 (m, 7H), 7,70 (approx. s, 1H), 7,82 (approx. s, 1H), 7,84 (approx. s, 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.

EXAMPLE 2

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

A solution of 1.50 g (2.2 mmol) of (+/-)- -bromophenylacetonitrile in the form of 3,5-bis(trifluoromethyl)benzylacetone (example 1), 100 mg (0.67 mmol) of sodium iodide and 3 ml of ethanolamine in 6 ml of isopropanol was heated under reflux for 20 hours the Solution was cooled and concentrated in vacuo to about 25% of the initial volume. The concentrated solution was distributed between 50 ml of ether and 20 ml of 2 n aqueous sodium hydroxide solution, and the layers were separated. The organic layer was washed with 20 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuum. Flash chromatography on 50 g of silica gel using cm the Mr-range: 2,66 (Shir. s, 2H), 2,61 and $ 2.68 (dd AB, 2H, JAB= 12,4, J2,61= 6,8,6,2, J2,68= 6,2, 6,2), 3.57 and 3,66 (dd AB, 2H, JAB= 10,8, J3,57= 6,2, 6,2, J3,66=6,8, 6,2), was 4.02 (d, 1H, J = 7,0), 4,37, and with 4.64 (AB, 2 H, J = 12,5), 4,80, and to 4.87 (AB, 2H, J = 12,8), to 4.87 (d, 1H, J = 7,0), 7,31-7,40 (7H), 7,73 (approx. s, 1H), 7,81 (approx. s, 3H); IR-spectrum (net): 3342, 1456, 1373, 1278, 1278, 1173, 1128, 704, 682; FAB-MS: 650(M+1)+.

Analysis. Calculated for C28H23F12NO3: C 51,78; H 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 mol) of (+/-)-N-(2-hydroxyethyl)phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone (example 2), 1.0 g (7.2 mmol) of potassium carbonate, 3.0 ml (35,0 mmol) allylbromide and 15 ml of ethanol was stirred at 60oC for 20 h the Mixture was cooled and distributed between 100 ml of ether and 25 ml of water, and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 100 ml ether, the ether extract was dried and combined with the first organic layer. The combined organic layers were concentrated in vacuo. Flash chromatography on 50 g of silica gel using a mixture of hexane/ether (4: 1, vol/about as eluent received 1,36 g (88%) of the title compound in the form of butter.1H NMR spec,4), is 4.85 and 4.95 (AB, 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 to -7,40 (7H), 7,68 (s, 1H), 7,83 (c, 1H), 7,86 (c, 2H). IR-spectrum (net): 3457, 1362, 1278, 1174, 1132, 1056, 759, 705, 682; FAB-MS: 690(M+1)+.

Analysis. Calculated: 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) of (+/-)-N-(2-hydroxyethyl)- N-(prop-2-enyl)phenylglycinol in the form of 3,5-bis(trifluoromethyl)benzylacetone (example 3), 700 mg (3.7 mmol) of the monohydrate of p-toluenesulfonic acid in 15 ml of toluene was boiled under reflux for 1.5 hours, the Reaction mixture was cooled and distributed between 100 ml of ether and 25 ml of saturated aqueous sodium bicarbonate solution. The layers were separated, the organic layer washed with 25 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuum. Flash chromatography on 30 g of silica gel using as eluent a mixture of hexane/ether (50:1, about./about.) received 426 mg (78%) of N-allylnormorphine, which was used in the next stage without additional purification.

Stage: dvuhgolosy flask of 50 ml, equipped with a tube and a short device for distortin)radioid (Wilkinson catalyst) in 25 ml of a mixture acetonitrile/water (4: 1, about./vol.). The reaction mixture was heated to boiling, and the solvent drove from the reaction mixture. The volume of the reaction mixture was maintained between 10 and 20 ml by addition of a solvent through a closed tube inlet. After 1 h and 4 h, the reaction mixture was treated with additional portions 80 mg of Wilkinson catalyst. After 6 h the reaction mixture was cooled and distributed between 75 ml of ether and 50 ml of water. The layers were separated, and the organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 75 ml of ether, the extract was dried and combined with the first organic layer. The combined organic layers were concentrated in vacuo. Flash chromatography on 35 g of silica gel using as eluent a mixture of ether/hexane (1:1, about. /about. ) was allocated 200 mg of TRANS-isomer and 130 mg of a mixture of CIS - and TRANS-isomers (total yield 68%). Chromatography of the mixture on 8 g of silica gel using as eluent a mixture of hexane/ether (4:1, vol/about.) allocated 64 mg of the CIS isomer and 57 mg of a mixture of CIS - and TRANS-isomers of the title compound.

For the TRANS isomer:1H NMR spectrum: 2,03 (Shir. s, 1H), 2,94 (DDD, 1H, J= 11,0, 2,5, 2,5), 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, 3,2, 3,2), 4,43 (d, 1H, J = 7,0), 4,53 and 4,88 (AB, 2H, J = 13.3-inch), 7,26 was 7.45 (7H), 7,70 (c, 1H). IR-spectrum: 3333, 2859,/SUB>:

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.

For the CIS isomer:1H NMR spectrum: 2,10 (Shir. s, 1H), 3,13 (DD, 1H, J = 12,4, 3,0), 3,26 (dt, 1H, J= 12, 4, 3, 6), 3,65 (DD, 1H, J = 11,6, 3,6), 4,07 (dt, 1H, J = 11,6, 3,0), 4,14 (d, 1H, J = 2,4), to 4.52 (AB, 2H, J = 13,6), was 4.76 (d, 1H, J = 2,4), 7,30-7,42 (6H), of 7.70 (s, 1H); FAB-MS 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 was treated with 90 mg (0.50 mmol) of iodoacetamide, and the formed solution was stirred at K. T. for 16 hours the Solution was concentrated in vacuo and the residue was distributed between 20 ml ethyl acetate and 10 ml of 0.5 n aqueous solution of acid potassium sulfate. The layers were separated, the organic layer was washed with 10 ml 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 vacuum. Flash chromatography on 5 g of silica gel using as eluent a mixture of ethyl acetate/hexane (2:1, vol/about) were allocated 99 mg (82%) of TRANS-isomer of the title compound in the form of butter.+.

Analysis. Calculated for C21H20F6NO3:

C 54,54; H 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 performed with 40 mg (0,99 mmol) of the CIS isomer(+/-)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenylmorpholine (example 4), using the reaction of a 0.035 ml (0.2 mmol) of N,N-diisopropylethylamine and 37 mg (0.2 mmol) of iodoacetamide. After processing and flash chromatography of the product was obtained 30 mg (65%) of the CIS isomer of the title compound in the form of butter.1H NMR spectrum: 2,54 and 3.04 (AB, 2H, J = 16,8), 2,63 (dt, 1H, J = 3,6, 12,0), 3.04 from (d, 1H, 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 = 11,6, 2,4), of 4.44 and 4,89 (AB, 2H, J = 13,6), 4,71 (d, 1H, J = 2,8), 5,86 (Shir. s, 1H), 7,15 (Shir. s, 1H), 7.45 (7H), 7,73 (c, 1H); FAB-MS: 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) and 18 ml (1.00 mol) of N, N-diisopropylethylamine in 2 ml of acetonitrile was treated with 0,095 ml (1.00 mmol) of methylpropanoate, and the formed solution was stirred at K. T. in techstore acid potassium sulfate. The layers were separated, the organic layer was washed with 10 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuum. Flash chromatography on 10 g of silica gel using as eluent a mixture of hexane/ether (4:1, vol/about.) allocated 164 mg (93%) of TRANS-isomer of the title compound in the form of butter.1H NMR spectrum: 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 (dt, 1H, J = 2,8, 11,6), Android 4.04 (DDD, 1H, J = 11,6, 3,2, 1,6), 4,45, and 4,84 (AB, 2H, J = 13,2), to 4.46 (d, 1H, J = 7,2), 7,31-7,38 (m, 6H), 7,68 (s, 1H). IR-spectrum (net): 2861, 1744, 1455, 1375, 1346, 1278, 1170, 887, 759, 704, 682; FAB-MS: 478 (M+1)+.

Analysis. Calculated for C22H21F6NO4:

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

In a solution of 20.0 g (79,7 mmol) (N-tert-butoxycarbonyl)phenylglycine in 150 ml of ethyl acetate at -10oC were treated to 8.8 ml (79,7 mmol) 4-methylmorpholine. Within 10 min while maintaining a temperature of -10oC was added dropwise isobutylparaben (10.3 ml, 79,7 mmol), the resulting suspension was stirred in the cold for 15 minutes the Mixture was treated with 11.6 g (119.0 mmol) of the compound N,O-dimethylhydroxylamine HCl. Added a second portion of 4-metyou the mixture was distributed between 100 ml ethyl acetate and 100 ml of 10% aqueous citric acid solution, and the layers were 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 vacuum. Crystallization from hexane at -20oC for 72 h were isolated 8.0 g (34%) of the title compound as a solid substance.1H NMR spectrum of 1.40 (s, 9H), 3,20 (s, 3H), 3,40 (s, 3H), 5,80 (m, 2H), 7,40 (m, 5H).

EXAMPLE 8

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

The solution was 7.45 ml (51,0 mmol) diethylmalonate in tetrahydrofuran at -78oC were treated to 31.8 ml (51,0 mmol) of 1.6 M solution of n-utility in hexano, and the resulting mixture was stirred in the cold for 30 minutes was Added a solution of 4.0 g (14.0 mmol) of N-methoxy-N-methyl-(N-tert-butoxycarbonyl)phenylglycinate (example 7) in 20 ml of tetrahydrofuran, and the reaction mixture was stirred at -78oC for 15 min and at 25oC for 15 minutes the Reaction was suppressed 150 ml of a saturated aqueous solution of ammonium chloride, diluted with 300 ml of ethyl acetate, and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuum. Flash chromatography on silica gel using as eluent a mixture of ethyl acetate/hexane (7:3, vol/O3,20 (DD, 1H), 4,00-4,20 (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-phenyl)propylphosphonate (example 8) in 20 ml TF was added dropwise to a suspension of 1.05 g (26,3 mmol, 60% dispersion in mineral oil) of sodium hydride in 30 ml of tetrahydrofuran at 0oC. After 15 min was slowly added to 2.06 ml (12.5 mmol) of 3,5-bis(trifluoromethyl)benzaldehyde, and the mixture was stirred in the cold for 15 minutes the Reaction was suppressed to 50 ml of a saturated aqueous solution of ammonium chloride, diluted with 50 ml of ethyl acetate, and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuum. Flash chromatography on silica gel using as eluent a mixture of ethyl acetate/petroleum ether (19: 1, vol/about., then 9:1, vol/about.) allocated 3,30 g (56%) of the title compound as a solid substance.1H NMR spectrum 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

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

A solution of 1.00 g (2.1 mmol) of N-tert-butoxycarbonyl-1-phenyl-2-oxo - 4-(3,5-bis(trifluoromethyl)phenyl)but-3-enamine (example 8) in 30 ml 0 ml of water and concentrated in vacuo to remove methanol. The mixture was distributed between 100 ml ethyl acetate and 50 ml of water, and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuum. Crystallization from a mixture of ether/hexane received 680 mg (68%) of the title compounds as a mixture (5:1) of diastereomers (each protected as tert-BUTYLCARBAMATE). 1H NMR spectrum (*specifies the resonances of diastereoisomer present in smaller numbers): of 1.40 (s, 9H), 4,60 (DD, 1H), 4,90 (Shir. s, 1H), 5,20 (Shir. d, 1 H), 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).

A solution of BOC-zameshannogo the title compound in methanol (saturated with HCl) was left for 72 hours the Solution was concentrated in vacuum. By recrystallization formed solid product from a mixture of ether/hexane received 500 mg (80%) of the title compounds (as HCl) in the form of a solid substance.1H NMR spectrum: 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 title compound (as HCl) was dissolved in ethyl acetate and 1 n aqueous sodium hydroxide solution. The layers were separated, the organic layer was dried over magnesium sulfate and concentrated in vacuum, obtaining the title compound in free base form.

EXAMPLE 11

2-(2-(3,5-Bis(trifluoromethyl)phenyl)ethynyl)-3-phenyl-5-ox is of toluene was added to a suspension of 250 mg (6.2 mmol, 60% dispersion in mineral oil) of sodium hydride in 30 ml of toluene, and the formed mixture was stirred 15 min at K. T. was Slowly added a solution of 0.60 ml (1.15 mol) of ethylchloride in 5 ml of toluene and the formed mixture was boiled under reflux for 3 hours, the Reaction mixture was cooled and extinguished 50 ml of a saturated aqueous solution of ammonium chloride, diluted with 50 ml of ethyl acetate, and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuum. Flash chromatography using as eluent a mixture of ethyl acetate/hexane (4:1, vol/about., then 3:1, vol/about., then 1:1, vol/vol.), then ethyl acetate was received 300 mg of TRANS-isomer of the title compound and 800 mg of the CIS isomer of the title compound (total yield 55%) as solids. For the CIS isomer:1H NMR spectrum: 1,20-1,40 (m, 1H), 1,50-of 1.62 (m, 1H), 2,60 are 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

A solution of 95 mg (0.23 mmol) of 2-(2-(3,5-bis(trifluoromethyl)phenyl)ethynyl)-3-phenyl-5-oxaprotiline (example 11) in 10 ml of a mixture of ethanol/ethyl acetate (1:1, about. /about. ) was treated with 10 mg of palladium hydroxide, and the formed mixture was stirred for 2 hours in an atmosphere of wadali directly without further purification.

A solution of 65 mg of the crude morpholine in 10 ml of tetrahydrofuran was treated 0,84 ml of 1 M solution of the complex of borane-tetrahydrofuran in tetrahydrofuran, and formed a solution of 16 h was heated under reflux. The reaction was suppressed by adding 10 ml of methanol and 70 mg of potassium carbonate, and the reaction mixture is boiled for 3 hours under reflux. All volatile components were removed in vacuo, and the residue was distributed between 20 ml ethyl acetate and 10 ml of saturated solution of ammonium chloride. The organic layer was separated, dried over potassium carbonate and concentrated in vacuum. The residue was dissolved in methanol saturated with HCl, and concentrated in vacuum. The residue is triturated with ether, the formed solid product was filtered and dried, receiving 32 mg (46%) of the title compound in the form of a salt with HCl, so pl. 114-116oC. 1H NMR spectrum of 1.42 (m, 1H), 1,66-of 1.84 (m, 1H), 2,70-to 2.94 (m, 2H), 3,00 (m, 1H), 3,30-of 3.46 (m, 1H), 3,80-of 3.94 (m, 2H), 4,10 (m, 1H), 4,20 (d, 1H), 7,40 (m, 3H), of 7.64 (m, 5H); Cl-MS: 402 (M+1)+.

EXAMPLE 13

N-Benzyl-(S)-phenylglycine

A solution of 1.51 g (10.0 mmol) of (S)-phenylglycine in 5 ml of 2 n aqueous sodium hydroxide solution was treated with 1.0 ml (10.0 mmol) of benzaldehyde and stirred 20 min at room temperature. The solution was diluted with 5 ml of methanol, cooled tooC and ostacoli 1.5 h at room temperature. The reaction mixture was diluted with 20 ml water and was extracted with 2 x 25 ml methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid to pH 6 and the formed precipitate was separated by filtration, washed with 50 ml water, 50 ml of methanol/diethyl ether (1:1, vol/about.) and 50 ml of ether, and dried, obtaining of 1.83 g (76%) of product, so pl. 230-232oC.

Analysis. Calculated for C15H15NO2:

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

Found: C 74,17; H is 6.19; N 5,86

EXAMPLE 14

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

A mixture of 4.00 g (of 16.6 mmol) N-benzyl-(S)-phenylglycine (from example 13), of 5.00 g (36,0 mmol) of potassium carbonate, 10.0 ml of 1,2-dibromethane and 25 ml of N,N-dimethylformamide was stirred 20 h at 100oC. the Mixture was cooled and distributed between 200 ml of diethyl ether and 100 ml of water. The layers were separated, and the organic layer was washed with water h ml, dried over magnesium sulfate and concentrated in vacuum. The residue was purified flash chromatography on 125 g of silica gel, elwira a mixture hexane/ether (9: 1, about. /vol., 4:1, vol/vol.). Got to 2.41 g (54%) of product as a solid substance, so pl. 98-100oC. Mass spectrum (FAB): m/z 268 (M+H, 100%);1H NMR spectrum (CDCl3, 200 MHz, M. D.): 2,54 of 2.68 (m, 1H), 2,96 (dt, J = 12,8, 2,8, 1H), 3,14 (d, J = 13.3-inch, 1H, in), 3.75 (d, J = 13.3-inch, 1H), 4,23 (s, 1H), 4,29-4,37 (m, 1H), 4.53-in (dt, J= 3,2, 11,0), 7,20-7,56 (m, 10H).

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 1.00 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 dry carbon tetrachloride in the atmosphere of nitrogen was treated to 0.74 ml (of 4.38 mmol) of anhydride of triftoratsetata at room temperature. Soon after adding the anhydride formed a white precipitate. After 90 min the precipitate was filtered in a nitrogen atmosphere to filter Slanka, and the filtrate was concentrated in vacuum. The remainder, which was a two-phase oil was dissolved under nitrogen atmosphere in 10 ml of dry toluene. The obtained clear solution was immediately used in the following stage B.

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

In the solution 0,500 g (of 1.87 mmol) N-benzyl-3-(S)-phenylmorpholine-2-she (from example 14) in 10 ml dry THF after cooling to -75oC in an atmosphere of nitrogen was added dropwise to 2.06 ml (to 2.06 mmol) of 1M solution of three(sec-butyl)borohydride lithium (L-Selectrid) in THF. After stirring the solution at -75oC for 30 min through a cannula was added triftoratsetata e is bratvany the solution was stirred at -75oC for 1 h and then between -38 and -50oC for 2 h the Solution was then poured into a mixture of 25 ml of ethyl acetate and 20 ml of a saturated aqueous solution of sodium bicarbonate, and the layers were separated. The aqueous phase was extracted with ethyl acetate h ml), the combined organic layers were dried over sodium sulfate, the mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified flash chromatography on 130 g of silica, elwira 2 l of a mixture of hexane/ethyl acetate (100:5). Got to 0.68 g (73%) of an oil, which was shown1H NMR spectroscopy, was a mixture (20:1) of CIS - and TRANS-morpholino.1H-NMR spectrum (CDCl3, 400 MHz, M. D.): core (CIS)isomer: is 2.37 (TD, J = 12, 3,6, 1H), 2,86 (approx. t, J = 13,2 H) of 3.57 (d, J = 2,6, 1H), 3,63 (DK, 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), of 7.2 to 7.4 (m, 8H), 7,43 (c, 2H), 7,55 (Shir. d, 2H), 7,69 (s, 1H).

Stage C: 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 10% Pd/C in 36 ml of a mixture of ethanol/water (97:3) was stirred 15 h under nitrogen atmosphere. The mixture was filtered through celite, the filter cake was abundantly washed with ethanol, and the filtrate was concentrated in vacuum. The residue was purified flash HRO 0,443 g (80%) oil, which is as shown1H NMR spectroscopy, was pure CIS-morpholine.1H NMR spectrum (CDCl3, 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, 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, 13,3, 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 56,30; H 4,29; 3,34 N; F Of 27.94.

EXAMPLE 16

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

The title compound was obtained 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 was cooled to 0oC in nitrogen atmosphere and was treated with 0.1 g (1.8 mmol) of sodium methoxide. The mixture was left to warm to room temperature and stirred 30 min, then was added 0,106 ml (1.8 mmol) of acetic acid. In the resulting mixture then was added to 3.9 g (64,9 mmol) of formic acid hydrazide, and the mixture was stirred for 30 minutes, the Reaction mixture was concentrated in vacuum, obtaining a solid product, n is tormentil)benzyloxy)-3-(S)-phenylmorpholine

The solution 0,295 g (0.73 mmol) of 3-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine (from example 15) in 10 ml of dry DMF was treated 0,302 g (2,18 mmol) of anhydrous potassium carbonate and then has 0.168 g (1,24 mmol) of N-formyl-2-chloroacetamides (from example 17, step A), and the suspension was stirred at 60oC for 4 h the Mixture was then heated for 4.5 hours at a temperature of up to 120oC. After cooling, the reaction mixture was diluted with 80 ml of ethyl acetate, and the organic layer was washed 3h20 ml of water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified flash chromatography on 67 g of silicon dioxide, elwira 1.5 liters of a mixture of methylene chloride/methanol (100:2). Received 0,22 g of yellow solid product, which was recrystallize from a mixture of hexane/methylene chloride, getting 0,213 g (60%) of white crystalline solid product, so pl. 134-135oC. Mass spectrum (FAB): m/z 487 (M+H, 100%), 259 (35%), 243 (65%), 227 (40%), 174 (25%),1H NMR spectrum (CDCl3, 400 MHz, M. D.): to 2.67 (dt, J = 11,9, 3,4, 1H), 2,90 (Shir.d, J = 11,7, 1H), 3.43 points (d, J = 15,2, 1H), 3,66 (approx. DD, J = 13, 1,9, 2H), 3,88 (d, J = 15,1, 1H), 4,17 (TD, J = 11,7, 2,3, 1H), 4,42 (d, J = 13,5, 1H), 4,69 (d, J = 2,6, 1H), 4,77 (d, J = 13,5, 1H), 7,30-to 7.50 (m, 7H), of 7.70 (s, 1H), 7,94 (c, 1H).

EXAMPLE 18

4-(3-(5-Oxo-1H,4H-1,2,4-triazolo)methyl)-2-(S)-(3,5 - bis(trifluoromethyl)benzyloxy)-the Rila in 35 ml of dry methanol was cooled to 0oC and treated 0,105 g (1.9 mmol) of sodium methoxide. The ice bath was removed and the mixture was stirred at room temperature for 30 min. the reaction mixture was then added 0,110 ml (1.9 mmol) of acetic acid and then 5.8 g (64,9 mmol) of methylhydroperoxide. After stirring 30 min at room temperature, the suspension was concentrated in vacuo and left under high vacuum overnight, getting to 10.5 g (98%) of yellow product, which was used in the following stage C.1H NMR spectrum (CDCl3, 400 MHz, M. D.): 3,71 (s, 3H), 4,06 (s, 2H).

Stage B: 4-(2-(N-Methylcarbamate)-2-(S)-(3,5 - bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine

A solution of 2.30 g (5.7 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine (from example 15), 1.13 g (6.8 mmol) of N-methylcarbamic-2-chloroacetamides (stage A) and 1.50 ml (8.6 mmol) of N,N-diisopropylethylamine in 25 ml of acetonitrile was stirred at room temperature for 20 hours, the Product, which knocked out, was filtered off, washed with 5 ml ice acetonitrile and dried, getting to 1.83 g of a white solid. The filtrate was concentrated in vacuo, and the residue was distributed between 50 ml of methylene chloride and 20 ml of water. The layers were separated, and the organic layer was dried over Sul the organic layer, and the combined product was concentrated in vacuo. The residue was purified flash chromatography on 30 g of silica gel, elwira a mixture of methylene chloride/methanol/ammonium hydroxide (50:1: 0.1 and about. /about. /about. ). Thus, were additionally 1,09 g of product (total yield 96%). Mass spectrum (FAB): m/z 535 (M+H, 100%), 462 (16%), 291 (30%), 226 (35%), 173 (25%);1H NMR spectrum (CDCl3, 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), 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,7 = 13,2, 1H), 4,70 (d, J = 2,8, 1H), 4,79 (d, J = 13,2), 5,55 (Shir.s, 2H), 7,30-7,46 (m, 7H), 7,72 (s, 1H).

Stage C: 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-methylcarbamates)-2-(S)-(3,5 - bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine (from stage B) in 36 ml of xylenes was heated under reflux for 1.5 hours the Solution was cooled and concentrated in vacuum. The residue was transferred into a 50 ml mixture of hexane/ethyl acetate (3: 1, about. /vol.), which causes crystallization of the product. The product was filtered and washed, receiving 1.85 g solids. The recrystallization of his 30 ml of a mixture of hexane/ethyl acetate (4:1, vol/about.) received 1.19 g of pure product as a white solid, so pl. 156-157oC. All liquid is ecografia on 30 g of silica gel, elwira a mixture of methylene chloride/methanol/ammonium hydroxide (50:1: 0.1 and about. / about. /about.). Thus received additional 0.69 g of solid product. After three precrystallization of 20 ml of a mixture of hexane/ethyl acetate (4: 1, about. /about) were additionally 0.39 g of pure product as a white solid (58%). Mass spectrum (FAB): m/z 503 (M+H), 259 (55%), 226 (40%), 160 (30%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): 2.57 m (approx. t, J = 9,6, 1H), 2,87-of 2.97 (m, 2H), to 3.58-3,71 (m, 3H), 4,18 (approx. 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), to 7.64 (s, 1H), the 10.40 (Shir. s, 1H), of 10.73 (Shir. s, 1H).

EXAMPLE 19

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

A mixture of 1.00 g (1.5 mmol) of 3,5-bis(trifluoromethyl)benzylacetone (+/-)- -bromophenylacetonitrile (from example 12), 1.25 ml of (R)-1-amino-2-propanol, 225 mg (1.5 mmol) of sodium iodide and 3.75 ml of isopropanol was heated under reflux for 20 hours the Solution was cooled and concentrated to about 25% of the original volume under vacuum. The concentrated solution was distributed between 50 ml of ether and 20 ml of 2 n aqueous sodium hydroxide solution, and the layers were separated. The organic layer was washed with 20 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuum. Flash product in the form of a mixture (1:1) nonshared diastereomers. Mass spectrum (FAB): 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 experiment is identical to the previous example, received 940 mg (95%) of product as a mixture (1: 1) 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 mg (1,40 mmol) 3,5-bis(trifluoromethyl)benzylacetone N-(2-(R)-hydroxypropyl)phenylglycine (from example 19), 1 ml of allylbromide, 600 mg (4.3 mmol) of potassium carbonate and 5 ml of ethanol was stirred at 60 for 20 hours the Mixture was cooled and distributed between 100 ml of ether and 25 ml of water and the layers were separated. Flash chromatography on 50 g of silica gel, using as eluent a mixture of ether/hexane (20:1, vol/about), received 380 mg (R,R)-amerosport (Rf= 0,72, eluent a mixture of ether/hexane, 3:2, vol/vol.), 220 mg (R,S)-amerosport (Rf= 0,62, eluent a mixture of ether/hexane, 3:2, vol/about.) and 285 mg of a diastereomeric mixture of aminoalcohols.

For (RR)-amerosport: mass spectrum (FAB): m/z 704 (M+H). IR-spectrum (net): 3476, 2932, 1624, 1454, 1361, 1278, 1175, 1132, 760, 704, 682.1H YAM(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, 2H, J = 12,4), 4,86 and 4,92 (AB, 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 (RS)-amerosport: mass spectrum (FAB): m/z 704 (M+1). IR spectrum (neat connection): 3451, 2931, 1624, 1454, 1362, 1277, 704, 683.1H NMR spectrum (CDCl3, 400 MHz, M. D.): 1,09 (d, 3H, J = 6,0), 2.48 and 2,71 (giving K, JAB= 13,2, J2,28= 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, 2H, J = 12,8), 4,86 and 4,96 (AB, 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 C32H29F12NO3:

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

Found: C 54,80; H 4,16; N 1,90; F 32,36.

EXAMPLE 22

N-(2-(S)-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

Applying 880 mg (1,33 mmol) of N-(2-(S)-hydroxypropyl)phenylglycinol, 3,5-bis(trifluoromethyl)benzylacetone, (example 20) instead of N-(2-(R)-hydroxypropyl)phenylglycinol,

3,5-bis(trifl a mixture of ether/hexane, 3:2, vol. /vol.), 367 mg (S,R)-amerosport (Rf= 0,62, eluent a mixture of ether/hexane, 3: 2, vol/about.) 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, 3,3-bis(trifluoromethyl)benzylacetone (from example 21) and 285 mg (1.5 mmol) of the monohydrate of p-toluenesulfonic acid in 5 ml of toluene was boiled under reflux for 40 minutes the Solution was cooled and distributed between 40 ml of ether and 15 ml of saturated aqueous sodium bicarbonate solution. The layers were separated, the organic layer was washed with 10 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuum. Flash chromatography of the concentrate on 10 g of silica gel, elwira a mixture of hexane/ether (19:1, vol/vol.), received 122 mg of (2R,3R,6R)-product (Rf= 0,53, eluent hexane/ether, 4: 1, vol/about.) and 62 mg of (2S,3R,6R)-product (Rf= 0,23, eluent hexane/ether, 4:1, vol/vol.).

For (2S, 3R, 6R)-product: mass spectrum (FAB): m/z 460 (M+H, 65%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): to 1.37 (d, 3H, J = 6,8), 2,48-of 2.50 (m, 2H), 2,74, and 3,01 (DTV to, 2H, J = 6,4, J = 1,2, 12,4), of 3.84 (d, 1H, J = 3.6), and to 3.92-to 3.99 (m, 1H), 4,70, is 4.93 (AB, 2H, J = 13,6), to 4.87 (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(trifluoromethyl)benzyloxy)-3-(R)-phenyl-4-(2-propenyl)- 6-(R)-methylmorpholine (from example 22, step A) and 230 mg (0.25 mmol) of Tris(triphenylphosphine)radioid in 15 ml of a mixture acetonitrile/water (4:1, vol/about.) 30 min boiled under reflux. The reaction mixture was cooled and distributed between 50 ml of ethyl acetate and 15 ml of water. The layers were separated, and the organic layer was dried over magnesium sulfate. The aqueous layer was extracted with CH ml of ethyl acetate, the extracts were dried and combined with the original organic layer. The combined organic product was concentrated in vacuo. The residue was filtered through a layer of silica gel (20 g) using the solvent mixture of eluent a mixture of hexane/ether (17:3, about./about.) received 67 mg (64%) of 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy-3-(R)-phenyl-6-(R)-methylmorpholine in the form of oil. Mass spectrum (FAB): m/z 420 (M+H, 90%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): to 1.21 (d, 3H, J = 6,4), 2,02 (Shir. s, 1H), 2,67, 2,77 (d, AB, 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, 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 C: 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl - 6-(R)-methylmorpholin

A similar reaction was carried out 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) and 111 mg (0.12 mmol) of Tris(triphenylphosphine)radioid in 12 ml of a mixture acetonitrile/water (4:1, about. /about.). From product to flash chromatography on 4 g of silica gel, using as eluent a mixture of methylene chloride/acetonitrile (50:1, about./vol.), received 14 mg (28%) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methylmorpholine in the form of oil. Mass spectrum (FAB): m/z 420 (M+H, 90%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): of 1.39 (d, 3H, J = 6,8), 1,92 (Shir. s, 1H), 2,84 and 2.95 (giving to, 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, 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-(5)-(3,5-Bis(trifluoromethyl) Replacing N-(2-(R)-hydroxypropyl)-N-(2-propenyl)-(R)-phenylglycinol, as 3,5-bis(trifluoromethyl)benzylacetone, 350 mg of N-(2-(S)-hydroxypropyl)-N-(2-propenyl)-(S)-phenylglycinol as 3,5-bis(trifluoromethyl)benzylacetone (from example 22) in the experiment, similar to the previous example, received 50 mg of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)-methylmorpholine and 14 mg of 2-(R)-(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

The title compound was obtained in a manner analogous to the method of example 23, step A. the Cyclization of 300 mg (0.43 mmol) of N-(2-(R)-hydroxypropyl)-N-(prop-2-enyl)-(S)-phenylglycinol in the form of 3,5-bis(trifluoromethyl)benzylacetone (from example 23) was carried out using the 246 mg (1,29 mmol) of the monohydrate of p-toluenesulfonic acid and 5 ml of toluene. Flash chromatography on 8 g of silica gel, using as eluent a mixture of hexane/ether (20:1, vol/vol.), received 149 mg (75%) of product as a mixture of non-shared diastereomers. Mass spectrum (FAB): m/z 460 (M+H, 65%).

Stage B: 2-(R)-(3,5-Bis is morpholine

A solution of 150 mg (0.33 mol) 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) of Tris(triphenylphosphine)radioid in 20 ml of a mixture acetonitrile/water (4:1, about. /about. ) was boiled for 1 h under reflux. Flash chromatography on 5 g of silica gel, using as eluent a mixture of hexane/ether (9:1, vol/vol.), received 35 mg of product as a mixture and 26 mg of 2-(R)-(3,6-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine (Rf= 0,22, eluent a mixture of hexane-ether). Chromatography of the mixture of 5 g of silica gel, using as eluent a mixture (20:1) received 14 mg of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine (Rf= 0,14, eluent hexane/ether, 3:2, vol/about) and 17 mg of 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholin (total yield 41%).

For (2R, 3S, 6R)-product: (FAB): m/z 420 (M+H, 90%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): of 1.30 (d, 3H, J = 6,4), 1,74 (Shir. s, 1H), 2,73, and 2,98 (giving to, 2H, JAB= 11,8, 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, 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: (FAB): m/z 420 (M+H, 90%).1H NMR spectrum (CDCl= 2,8), 4.09 to to 4.15 (m, 1H), 4.53-in and 4,80 (AB, 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).

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 N-(2-(R)-hydroxypropyl)-N-(2-propenyl)-(R)-phenylglycinol as 3,5-bis(trifluoromethyl)benzylacetone, 250 mg of N-(2-(S)-hydroxypropyl)-N-(2-propenyl)-(S)-phenylglycinol as 3,5-bis(trifluoromethyl)benzylacetone (from example 22) in the experiment, similar to the previous example, received 42 mg of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-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

By carrying out the sequence of reactions described in example 19, replacing (R)-2-amino-1-propanol (R)-1-amino-2-propanol, received a mixture of 55 mg of the substance with a high value of Rfand 56 mg of the substance with a low value of Rf. A substance with a high Rfprocessed counterparts - 3-(S)-phenyl-5-(R)-methylmorpholin) and 7 mg of a substance with a low value of Rf(2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)- methylmorpholin). A substance with a low value of Rf(after combining with an additional 30 mg) was treated analogously to example 23, step A, receiving 24 mg of the substance with a high Rf(2-(R or S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)- methylmorpholin) and 18 mg of the substance with low Rf(2-(S or R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methylmorpholin).

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methylmorpholin. Mass spectrum (FAB): m/z 420 (M+H, 100%), 227 (50%), 192 (75%), 176 (65%), the NMR spectrum (CDCl3, 400 MHz, M. D.): 0,98 (d, 3H, J = 6.3 Hz), 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-(5)-phenyl-5-(R)-methylmorpholin. Mass spectrum (FAB): m/z 420 (M+H, 48%), 227 (35%), 192 (39%), 176 (100%). The NMR spectrum (CDCl3, 400 MHz, M. D.): 1,10 (d, 3H, J = 6.4 Hz), 3,23-3,26 (m, 1H), 3,56-3,61 (m, 2H), 4,17 (d, 1H, J = 2.3 Hz), 4,51 (DD, 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. Mass spectrum (FAB): m/z 281 (35%), 221 (55%), 207 (45%), 192 (40%), 147 (100%), the NMR spectrum (CDCl3, 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="ptx2">

2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)- methylmorpholin NMR spectrum (CDCl3, 400 MHz, M. D.): of 1.36 (d, 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, to 13.6 Hz), 7,26-7,35 (m, 3H), 7,26-the 7.43 (m, 7H), 7,68 (s, 1H).

EXAMPLE 28

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

By carrying out the sequence of reactions described in example 19, substituting (S)-2-amino-1-propanol (R)-1-amino-2-propanol, received a mixture of 78 mg of the substance with a high value of Rfand 70 mg of a substance with a low value of Rf. A substance with a high Rfprocessed analogously to example 23, step A, receiving less than 1 mg of the substance with a high value of Rf(2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(3)-methylmorpholin) and 9 mg of the substance with a low value of Rf(2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine). A substance with a low value of Rfprocessed analogously to example 23, step A, receiving 20 mg of the substance with a high Rf(2-(R or S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-metilo the

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

Mass spectrum (FAB): m/z 420 (M+H, 60%), 227 (68%), 192 (56%), 176 (100%), the NMR spectrum (CDCl3, 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 (d, 1H, 13,2 Hz), 7,28-7,35 (m, 3H), 7,47 (d, 2H, 7.0 Hz) to 7.64 (s, 1H), 7,74 (s, 1H).

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

Mass spectrum (FAB): m/z 420 (M+H, 50%), 227 (45%), 192 (40%), 176 (100%). The NMR spectrum (CDCl3, 400 MHz, M. D.): of 1.36 (d, 3H, J = 6.9 Hz), 3.27 to be 3.29 (m, 1H), 3,39 (DD, 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, of 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

The NMR spectrum (CDCl3, 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

By carrying out the sequence of reactions described in example 19, substituting (R)-2-amino-2-propanol a value of Rf. A substance with a high Rfprocessed analogously to example 23, step A, receiving 16 mg of the substance with a high value of Rf(2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine) and 4 mg of the substance with a low value of Rf(2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine). A substance with a low value of Rfprocessed analogously to example 23, step A, receiving 4 mg of 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

The NMR spectrum (CDCl3, 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

The NMR spectrum (CDCl3, 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

The NMR spectrum (CDCl3, 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) is 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

By carrying out the sequence of reactions described in example 19, substituting (R)-1-amino-2-propanol (S)-2-amino-2-phenylethanol, received a mixture of 75 mg of the substance with a high value of Rfand 64 mg of a substance with a low value of Rf. A substance with a high Rfprocessed analogously to example 23, step A, receiving 23 mg of the substance with a high value of Rf(2-(S)-(3,5-bis)trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine [L-740, 930]) and 7 mg of a substance with a low value of Rf(2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine). A substance with a low value of Rfprocessed analogously to example 23, step A, receiving 26 mg of the substance with a high Rf(2-(R or S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine) and 6 mg of the substance with low Rf((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

The NMR spectrum (CDCl3, 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

The NMR spectrum (CDCl3, 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 (dermorphin

The NMR spectrum (CDCl3, 400 MHz, M. D.): 3,93-3,95 (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)- methylmorpholin

The NMR spectrum (CDCl3, 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)methyl)morpholine

In accordance with the method given in example 17, step B, the reaction of 98 mg (0.24 mmol) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine (example 25), 38 mg (0.28 mmol) of N-formyl-2-chloroacetamides (from example 17, step A) and 97 mg (0.7 mmol) anhydrous potassium carbonate and subsequent flash chromatography of the product on the 28 g of silica gel with elution 1 l of a mixture of methylene chloride/methanol/aqueous ammonia (100:4:0.5) is received yellow solid, which was recrystallize from a mixture of hexane/methylene chloride. Received 77 mg (66%) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)- 6-(R)-methyl-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl)research in the form of a white powder. The NMR spectrum (CDCl3, 400 MHz, M. D.): 1,17 (d, J = 6,3, 3H), 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), 4,74 (d, J(5 - oxo-1H, 4H-1,2,4-triazolo)methyl)-3-(S)-phenyl)morpholine

A mixture of 96 mg (0.23 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine (example 25), 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 DMF was stirred at room temperature for 20 min, then at 60oC for 90 min and at 120oC for 2 h the Mixture was cooled to room temperature, transferred into 15 ml ethyl acetate and washed with 3x10 ml of water. The combined aqueous layers back was extracted with 10 ml ethyl acetate, the combined organic layers were washed with 10 ml brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified flash chromatography on 28 g of silica gel, elwira 1 l of a mixture of methylene chloride/methanol (100:4). Received 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)-phenyl)morpholine as a yellow powder.

The NMR spectrum (CDCl3, 400 MHz, M. D.): of 1.18 (d, J = 6,2, 3H), of 2.15 (t, J = 11,1, 1H), 2,89 (d, J = 14,2 (H) to 3.49 (d, J = 2,2, 1H), 3,61 (d, J = 14,4, 1H), 4,20-4,30 (m, 1H), 4,45 (d, 13,6, 1H), 4,67 (d, J = 2,5, 1H), 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)-3-(R)-phenylmorpholine

The article is obtained from (R)-phenylglycine, as described in example 14, 28 ml of CH2Cl2cooled in a bath with a temperature of -78oC in an atmosphere of nitrogen was added 14 ml of a 1.5 M solution DEBUG (21 mmol) in toluene. After stirring the solution for 0.5 h, it was left to warm to -50oC and kept at this temperature for 0.5 h, the Reaction mixture was suppressed by adding 10 ml of water tartrate of potassium and sodium. The mixture was diluted with CH2Cl2and the layers were separated. The aqueous layer was extracted 3 times with methylene chloride. Layers CH2Cl2washed with brine, dried over Na2SO4and filtered. Concentration of the filtrate was obtained of 3.32 g (88%) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine, suitable for use in the next stage.

The NMR spectrum (CDCl3, 400 MHz, M. D.): 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 = 13,1 H), 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

In the suspension 0,592 g (of 14.8 mmol) of NaH in 30 ml of dry THF at 0oC added of 3.32 g (12.3 mmol) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine obtained in stage A. After 15 min was added 0,915 g of tetrabutylammonium iodide (2,47 mmol) and 2.4 ml (13 mmol) of 3,5-Bitem was poured into a saturated solution of NaHCO3and were extracted with ethyl acetate (EtOAc). The organic layers were combined, washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated in vacuo, and the residue was chromatographically on high performance liquid chromatograph (HPLC) Waters Prep 500 using 50% EtoAc/hexane to highlight 3.6 g (59%) of 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine.

1H NMR spectrum (CDCl3): 2,3 (TD, J = 11 Hz and 3 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 Hz, 1H), 4,82 (d, J = 13 Hz, 1H), 7,19-7.5 (m, 12H), to 7.67 (s, 1H).

Stage C: 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 0,72 g 10% Pd/C, was first made in the apparatus Parra within 36 hours, the Catalyst was separated by filtration and thoroughly washed with EtOAc. The filtrate was concentrated, and the residue was distributed between water and EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified flash chromatography using a gradient of 10-60% EtOAc/hexane. Therefore allocated 2,05 g (70%) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-f 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

The target compound was obtained by the method of example 17, step B, using the product of example 33, step C as the starting compound.

1H NMR spectrum (CDCl3): 1,75 (Shir. s, 1H), 2,61 (TD, J = 12 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

The target compound was obtained by the method of example 18, parts B and C using the product of example 33, step C as the starting compound.

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 drops of glacial acetic acid in 3 ml of methanol was treated with 1.5 ml of 1 M solution of cyanoborohydride sodium in THF. After 16 h the reaction was suppressed with 5 ml saturated aqueous RA is over magnesium sulfate and concentrated in vacuum. Flash chromatography of the concentrate on 8 g of silica gel, using as eluent a mixture of methylene chloride/methanol/ammonium hydroxide (50: 1:0,1), received 54 mg (yield 44%) of the title compound as a white solid.

1H NMR spectrum (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 (approx. C, 26), 4,14 (dt, J = 2,2, 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 (approx. s, 2H), 7,25-of 7.48 (m, 6H), 7,72 (s, 1H). Mass spectrum (FA): m/z 486 (100%, M+H).

EXAMPLE 37

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

The title compound was obtained by the method of example 36, using the appropriate starting compound.

1H NMR spectrum (CDCl3): of 2.53 (dt, J = 11 Hz and 3 Hz, 1H) 2,74 (d, J = 12,4 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 Hz, 1H), 6,94 (s, 2H), 7,2 was 7.45 (m, 7H), to 7.67 (s, 1H).

EXAMPLE 38

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

The title compound was obtained by the method of example 36, using the appropriate starting compound.

1H NMR spectrum (CDCl3): 2,47 (dt, J = 12 Hz and 3 Hz, 1H), and 2.83 (d, J = 1, ,66 (s, 1H).

EXAMPLE 39

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

The title compound was obtained by the method of example 15 using the appropriate starting compound.

1H NMR spectrum (CDCl3): of 2.54 (dt, 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).

EXAMPLE 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

The title compounds were obtained by the methods of examples 15, 17 and 18, using correspondingly substituted starting compound and reagents.

EXAMPLE 44

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

Stage A: 3,5-Dichlorobenzoyl alcohol, triftoratsetata ether

The solution 6,09 g (34,4 mol) of 3,5-amyl-metacresol and 8,48 g (a 41.3 mmol) of 3,6-di-tert-butyl-4-methylpyridine in 280 ml of dry carbon tetrachloride in nitrogen atmosphere on the Alenia anhydride formed a white precipitate. After 90 min the suspension was filtered in a nitrogen atmosphere through a filter Slanka, and the filtrate was concentrated in vacuum. The remainder, which was a two-phase oil was dissolved in 60 ml of dry toluene under nitrogen atmosphere. The resulting solution was used immediately in the stage 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 was cooled to -75oC in nitrogen atmosphere and treated dropwise to 20.5 ml of 20.5 mmol) of 1 M solution three(sec-butyl)of lithium borohydride (L-Selectride) in THF. After stirring the solution at -75oC for 30 min was added via cannula a solution of triftormetilfosfinov ester 3,5-amyl-metacresol in toluene (from example 44, step A) so that the internal temperature was below -60oC. the Formed solution was stirred at a temperature between -38oC and 50oC for 9 h and then was treated with 14 ml of aqueous ammonia and kept at -20oC for 12 h the Solution was then poured into a mixture of 50 ml of ethyl acetate and 100 ml of water, and the layers were separated. The aqueous phase was extracted with 2x100 ml of ethyl acetate, each extract was washed with brine. United were organisasi flash chromatography on 235 g of silicon dioxide, using 1.5 l of a mixture of hexane/ethyl acetate (100:3) and then 1.9 l of a mixture of hexane/ethyl acetate (100:5). Received 4.4 g (54%) of oil.1H NMR spectroscopy showed that the oil is a mixture of CIS - and TRANS-morpholino. Mass spectrum (FAB): m/z 430, 428, 426 (M+H, 60%), 268 (M-ArCH2, 100%), 252 (M-ArCH2O, 75%), 222 (20%), 159 (45%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): core (CIS)isomer: 2,32 (TD, J = 12,3, 6, 1H), 2,84 (approx., t, J = 13,2 H), 3,52 (d, J = 2,6, 1H), 3,55 (DK, 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 C: 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)-phenylmorpholine (from example 44, step B) and 0.22 g (1.54 mmol) of 1-chloroethylphosphonic 4.5 ml of 1,2-dichloromethane was placed in a vial for the reaction under pressure, which was lowered into an oil bath heated to 110oC. After stirring for 60 h, the solution was cooled and concentrated in vacuum. The residue was dissolved in 7 ml of methanol, and the resulting solution was boiled under reflux for 30 minutes the Mixture was cooled and treated with a few drops of concentrated aqueous ammonia, and the solution was concentrated. The residue was partially purified flash x and flash HRO-matography 32 g of silicon dioxide, elwira a mixture of hexane/ethyl acetate (50:50) and then hexane/ethyl acetate/methanol (50:50:5). Received 0,051 g (20%) oil, which, as was shown 1H NMR spectroscopy, is pure CIS-morpholine. Mass spectrum (FAB): m/z 468, 466, 464 (max 8%), 338, 340 (M+H, 25%), 178 (20%), 162 (100%), 132 (20%).1H NMR spectrum (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, 1H), 7,14 (t, J = 1,8, 1H), 7,25-7,40 (m, 5H).

EXAMPLE 45

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

Stage A: N-Methylcarbamic-2-chloroacetamides

A solution of 5.0 g (66,2 mmol) chloroacetonitrile in 35 ml of dry methanol was cooled to 0oC and treated 0,105 g (1.9 mmol) of sodium methoxide. Bath ice was removed and the mixture was stirred 30 min at room temperature. In the reaction mixture is then added 0,110 ml (1.9 mmol) of acetic acid and then 5.8 g (64,9 mmol) of methylhydroperoxide. After stirring 30 min at room temperature, the suspension was concentrated under vacuum and placed in a high vacuum at night, getting to 10.5 g (98%) of yellow product, part of which was used in the following stage C.

Stage B: 4-(2-(N-Metalcarbon is hydroxy)-3-(S)-phenylmorpholine (from example 44, stage C), 0,034 g (0.21 mmol) of N-methylcarbamic-2-chloroacetamides (from 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 distributed between 20 ml of methylene chloride and 10 ml of water. The layers were separated, the organic layer was dried over sodium sulfate and then concentrated in vacuum. The residue was purified flash chromatography on 35 g of silica, elwira 1 l of a mixture of methylene chloride/methanol (50:1), then 500 ml of a mixture of methylene chloride/methanol/aqueous ammonia (25:1:0,05). Received 70 mg (100%) of product as a white solid. Mass spectrum (FAB): m/z 469 (M+H, 60%), 467 (M+H, 100%), 291 (40%), 160 (20%), 158 (25%).1H NMR spectrum (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, 3H), 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 C: 2-(S)-(3,5-Dichloraniline)-4-(3-(5-oxo-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 (stage B) in 6 ml of xylenes was heated under reflux for 2 hours the Solution was cooled and concentrated in Vacu the initial ammonia (50:1: 0,1), then 500 ml of a mixture of methylene chloride/methanol/aqueous ammonia (20:1:0,1). Received 56 mg (88%) of product as a white powder. Mass spectrum (FAB): m/z 437 (M+H, 65%), 435 (M+H, 100%), 259 (85%), 161 (55%), 1H NMR spectrum (CDCl3, 400 MHz, ppm,): 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)-phenylmorpholine

A solution of 300 mg (0,74 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine (from example 15, step C) and 0.35 ml (2.0 mmol) of DIEA in 5 ml of acetonitrile was treated to 0.19 ml (2.0 mmol) of methylpropanoate, and the mixture was stirred 16 h at room temperature. The solution is then concentrated in vacuo, and the residue was distributed between 30 ml of ether and 15 ml of 0.5 n aqueous solution of KHSO4. The layers were separated, and the organic phase was washed with 10 ml brine and dried over magnesium sulfate. After filtration the organic phase was concentrated in vacuo, and the residue was purified flash chromatography on 20 g of silica, elwira a mixture of hexane/ether (80:20). Received 351 mg (99%) of product []D= +147,3(c = 1,6, .): 3,02 (Shir.d, 2H), 3,13 (d, J = 16,9, 1H), 3,36 (n, 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

The solution 0,016 g (0,034 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy - 4-(methoxycarbonylmethyl)-3-(S)-phenylmorpholine (from example 46) in 2 ml of THF and 0.5 ml of water was treated 0,027 ml (0,067 mmol) of 2.5 n aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 5 hours the Mixture was treated with 2 drops of 2 n aqueous HCl and 3 ml of water, and the solution was extracted with 15 ml of a mixture of hexane/ethyl acetate (1:1). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified flash chromatography on 13 g of silicon dioxide, elwira 250 ml of a mixture of methylene chloride/methanol/acetic acid (100:3:0,1) and then 100 ml of a mixture of methylene chloride/methanol/acetic acid (50:2:0,1). Received of 0.014 g (90%) of oil. Mass spectrum (FAB): m/z 464 (M+H, 90%), 420 (M-CO2, 10%), 227 (ArCH2, 35%), 220 (M-OCH2AR, 100%), 161 (20%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): 2,9 (approx. d, 2H), 3,048

Hydrochloride of 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-(carboxymethyl)-3-(S)-phenylmorpholine (from example 46) and 0.15 ml of Ethylenediamine (2.3 mmol) in 1 ml of methanol was stirred 48 h at 55oC. the Mixture was concentrated, and the residue was purified flash chromatography on 16 g of silica, elwira 500 ml of a mixture of methylene chloride/methanol/aqueous ammonia (50:4:0,1). Received 57 ml (100%) oil. The oil was dissolved in ether, and the solution was treated with ether saturated with gaseous HCl. After concentration in vacuo was obtained 58 mg (95%) of persistent oil. Mass spectrum (FAB): m/z 506 (M+H, 100%), 418 (15%), 262 (35%), 227 (30%), 173 (40%),1H NMR spectrum (CDCl3, 400 MHz, M. D.): 2,56 (d, J = 15,5, 1H), 2,59 (TD, 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 (approx. dt, J = 11,4, about 2, 1H), 4,18 (TD, J = 11.8 in, 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 (Shir. t, 1H), 7,71 (s, 1H).

EXAMPLE 49

Hydrochloride of 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-(carboxymethyl)-3-(S)-phenylmorpholine (from example 46) and 0.21 ml of 1,3-profiles-chromatography on 16 g of silica, elwira 500 ml of a mixture of methylene chloride/methanol/aqueous ammonia (10:1: 0,05). Received 56 mg (88%) of oil. Oil restores in methylene chloride and was treated with methylene chloride, saturated with gaseous HCl. After concentration in vacuo got a white paste. Mass spectrum (FAB; free base): m/z 520 (M+H, 100%), 418 (10%), 276 (30%), 227 (20%), 174 (30%),1H NMR spectrum (CDCl3, 400 MHz, M. D.): 1,64 (pentec, J = 6,6, 2H), 2,53 (d, J = 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 (approx. dt, J = 11,4, about 2, 1H), 4,16 (TD, J = 11.8 in, 2,6, 1H), to 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. t, 1H), of 7.70 (s, 1H).

EXAMPLE 50

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

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 was added 6.9 ml (a 13.9 mmol) of trimethylaluminum (2.0 M in toluene). After incubation for 1 h at 0oC to the mixture was added dropwise of 0.625 ml (7.0 mmol) of (+/-)-TRANS-2,3-epoxybutane (dissolved in 2.0 ml of methylene chloride) and then it was stirred 16 h at 22oC. the Reaction mixture was then transferred to another flask containing 30 ml of a mixture of hexane/methylene chloride (1:1) and 30 ml of 1M solution of tartrate-catilina (g ml). The combined organic layers washed with 25 ml saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.

The crude alcohol was dissolved in 25 ml of toluene was treated with 93 mg (0.49 mmol) of p-toluenesulfonic acid and heated for 20 h at 50oC. the Reaction mixture was then cooled and concentrated in vacuum. The residue was distributed between 15 ml of diethyl ether and 10 ml saturated sodium bicarbonate solution. The layers were separated, and the organic layer was washed with water (3x10 ml). The combined organic layers were washed with 25 ml of saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography of the residue on a 145 g of silica gel using a mixture of ethyl acetate/hexane (1:4, vol/about.) as eluent received 567 mg of the lactone with high Rf(isomer A) and 388 mg of the lactone with low Rf(isomer B).1H NMR spectrum (CDCl3, 400 MHz, M. D.) isomer A: the 1.04 (d, 3H, J = 8.0 Hz), 1,24 (d, 3H, J = 8.0 Hz), 2,92 (Shir. KD, 1H), 3,41 (d, 1H, J = 16.0 Hz), 3,62 (d, 1H, J = 16.0 Hz), to 4.38 (s, 1H), 4,96 (Shir. KD, 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. KD, 1H), 3,53 (d, 1H, J = 16.0 Hz), 3,81 (d, 1H, J = 16.0 Hz), 4,33 (s, 1H), 4,67 (Shir. KD, 1H), 7.18 in is 7.50 (m, 10H). Master)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, from 251 mg (0.85 mmol) of isomer A of example 50 (4-benzyl-[5-(S),6-(R)- or 5-(R)-(6-(S)-dimethyl]-3-(S)-phenylmorpholine) received 238 mg (53%) of product in the form of butter.1H NMR spectrum (CDCl3, 400 MHz, M. D.): of 1.03 (d, 3H, J = 6,7 Hz) of 1.13 (d, 3H, J = 6.6 Hz), 2,61 (KD, 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 (KD, 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). Mass spectrum (FAB): 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, step C, 260 mg of the initial connection phase A [derived from isomer A in example 50 (4-benzyl-2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-[5-(S), 6-(R)- or 5-(R),6-(S)-dimethyl]-3-(S)-phenylmorpholine)] received 122 mg (57%) of product in the form of butter.1H NMR spectrum (CDCl3, 400 MHz, M. D.): 1,19 (d, 3H, J = 6.5 Hz), of 1.27 (d, 3H, J = 6,7 Hz), 2,97 (KD, 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). Mass spectrum (FAB): m/z 434 (M+H, 45%), 227 (35%), 206 (40%), 190 (100%).

/BR>Stage A: 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) or 5-(S)-6-(R)-dimethyl]-3-(S)-phenylmorpholine) received 400 mg (51%) of product in the form of butter.1H NMR spectrum (CDCl3, 400 MHz, M. D.): of 0.90 (d, 3H, J = 6.8 Hz), of 1.37 (d, 3H, J = 6.6 Hz), 2,86-2,89 (KD, 1H), 3,47 (d, 1H, J = 15,0 Hz), 3,82-of 3.85 (m, 2H), 3,99-was 4.02 (Shir. KD, 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, step C, from 400 mg initial connection phase A [derived from 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)] was obtained 230 mg (69%) of product in the form of butter.1H NMR spectrum (CDCl3, 400 MHz, M. D.): a 1.08 (d, 3H, J = 6,7 Hz) to 1.38 (d, 3H, J = 7.0 Hz), 3,41 is-3.45 (Shir. KD, 1H), 3,85-3,89 (Shir.KD, 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 (s, 1H). Mass spectrum (FAB): 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 (from example 51, stage B), 62 mg (0.45 mmol) of anhydrous potassium carbonate and 26 mg (0,19 mmol) of N-formyl-2-chloroacetamides (from example 17, step A) in 2.0 ml of N,N-dimethylformamide was heated for 2 hours at a temperature of 60oC and then 1.5 h to 118oC. the Mixture was then cooled to room temperature and put 5 ml of water and diluted with 15 ml of ethyl acetate. The layers were separated and the organic layer was washed with ethyl acetate (2 x 10 ml). The combined organic layers were washed with 10 ml brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography of the residue on 42 g of silica gel using as eluent a mixture of methylene chloride/methanol (95:5, vol. /about.) received 42 mg (57%) light oil.1H NMR spectrum (CDCl3, 400 MHz, M. D.): of 1.13 (d, 3H, J = 6.5 Hz), 1,19 (d, 3H, J = 6.5 Hz), 2,65 (KD, 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 (KD, 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). Mass spectrum (FAB): 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 mol) of 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-[5-(S), 6-(R)- or 5-(R) the carboxy-2-chloroacetamides (from example 18, stage A) in 4 ml of DMF was heated at 60oC for 1.5 h and at 120oC for 3.5 h the Mixture was cooled to room temperature and distributed between 15 ml of water and 25 ml of ethyl acetate. The aqueous layer was extracted with 3 x 10 ml of ethyl acetate, the combined organic layers were washed with 10 ml brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was partially purified flash chromatography on 42 g of silica gel using as eluent 2 l of a mixture of methylene chloride/methanol (98:2, vol/about.) and enriched fractions were purified under the same conditions, receiving 38 mg (33%) light oil. 1H NMR spectrum (CDCl3, 400 MHz, M. D.): 1,09 (d, 3H, J = 6.5 Hz), of 1.20 (d, 3H, J = 6.6 Hz), 2,64 (KD, 1H, J = 2.4 and 6.6 Hz) to 3.33 (s, 1H), 3,56 (d, 1H, J = 7,6 Hz), 4,11 (KD, 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). Mass spectrum (FAB): 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 of 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) was obtained after flash chromatog%) yellow oil.1H NMR spectrum (CDCl3, 400 MHz, M. D.): the 1.04 (d, 3H, J = 6.6 Hz), of 1.46 (d, 3H, J = 6,7 Hz), 3,05-is 3.08 (m, 1H), 3,74-3,81 (m, 2H), 3,91-3,95 (m, 2H), to 4.41 (d, 1H, J = 13,2 Hz), 4,69 (d, 1H, J = 3.2 Hz), 4,82 (d, 1H, J = 13.5 Hz), 7,43 was 7.45 (m, 2H), 7,68 (s, 1H), to $ 7.91 (s, 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 method of example 54 of 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) was obtained after flash chromatography on 73 g of silica gel using as eluent a mixture of methylene chloride/methanol (95: 5, vol. /about. ) 32 mg (30%) yellow oil.1H NMR spectrum (CDCl3, 400 MHz, M. D.): of 1.03 (d, 3H, J = 6,7 Hz) of 1.40 (d, 3H, J = 6.8 Hz), 3.00 and (KD, 1H, J = 3,8 and 6.8 Hz), 3,44 (d, 1H, J = 16.1 Hz), 3,63 (d, 1H, J = 16,9), 3,82 (d, 1H, J = 3.3 Hz), 3,95 (KD, 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 spectrum (FAB): 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 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine (50 mg, 0.12 mmol) and hydrochloride of 4-benzyl-1-(2-x is matney temperature. After 60 h, TLC (5% MeOH/2% Et2N/a 93% EtOAc) showed that the reaction was only partially. The reaction mixture was diluted with methylene chloride and washed with water, then with brine, dried over sodium sulfate and evaporated. Purification of the product of preparative TLC (5% MeOH/2% Et3N/a 93% EtOAc) received 36 mg (50%) of the title compound in the form of butter.1H NMR spectrum (CDCl3, 400 MHz, M. D.): 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 and 11 Hz, 1H), 4,15 (dt, J = 2 and 12 Hz, 1H), of 4.38 and of 4.75 (AB, 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

Through chiral synthesis

Stage A: 3-(4-Forfinal)acetyl-4-(S)-benzyl-2-oxazolidinone

Dried in a drying Cabinet 3-necked flask of 1 l equipped with a membrane, the insertion opening for nitrogen, a thermometer and a magnetic stirrer was filled with nitrogen and was loaded with a solution 5,09 g (33.0 mmol) of 4-florfenicol acid in 100 ml of anhydrous ether. The solution was cooled to -10oC and treated the ceiling of 5.60 ml (40.0 mmol) of triethylamine and then 4,30 ml (35,0 mmol) trimethylacetylchloride. Immediately formed a white precipitate. Formed mixture stirred the traditional flask 250 ml, equipped with a diaphragm and a magnetic stir bar, was filled with nitrogen and was loaded with a solution 5,31 g (30.0 mmol) of 4-(S)-benzyl-2-oxalidaceae in 40 ml of dry THF. The solution was stirred while cooling in a bath of dry ice and acetone for 10 min, then was slowly added 18.8 ml of 1.6 M solution of n-utility in hexane. After 10 min the solution literaturnogo oxazolidinone was added via cannula to a mixture of 3-necked flask. The cooling bath was removed and the temperature was raised to 0oC. the Reaction was suppressed 100 ml of a saturated aqueous solution of ammonium chloride, the mixture was transferred into a flask of 1 l of ether and THF were removed in vacuo. The concentrated mixture was distributed between 300 ml of methylene chloride and 50 ml of water, and the layers were separated. The organic layer was washed with 200 ml 2 n aqueous solution of hydrochloric acid, 300 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuum. Flash chromatography of the residue on 400 g of silica gel using as eluent a mixture of hexane/ether (3:2, vol/about.) received of 8.95 g of oil, which upon standing slowly tverdal. By recrystallization of the product from a mixture of hexane/ether (10:1) received 7,89 g (83%) of the title compound as a white solid, so pl. 64-66oC. Mass spectrum (FAB): m/z 314 (M, 4H), the 4.65-4,70 (m, 1H), 7,02-7,33 (m, 9H).

Analysis. Calculated for C18H16FNO:

C 69,00; H TO 5.57; N 4,47; F 6,06

Found: C 68,86; H 5,15; N 4,48; F Between 6.08.

Stage B: 3-((S)-Azido-(4-forfinal)acetyl-4-(S)-benzyl-2-oxazolidine

Dried in a drying Cabinet 3-necked flask of 1 l equipped with a membrane, the input for nitrogen, a thermometer and a magnetic stirrer was filled with nitrogen and was loaded with a solution 58,0 ml of 1 M solution of bis(trimethylsilyl) amide potassium in toluene and 85 ml TTF and was cooled to -78oC. Dried in a drying oven at a round bottom flask of 250 ml, equipped with a diaphragm and a magnetic stir bar, was filled with nitrogen and was loaded with a solution 7,20 (23,0 mmol) 3-(4-forfinal)acetyl-4-(S)-benzyl-2-oxazolidinone (from example 58, step A) in 40 ml THF. The solution allocatively was stirred while cooling in a bath of dry ice/acetone for 10 min, then transferred via cannula into a solution of bis(trimethylsilyl)amide potassium such a rate that the internal temperature of the mixture was maintained below -70oC. the Flask of allocatively was washed 15 ml of THF, and the THF was also added via cannula to the reaction mixture, and the resulting mixture was stirred at -78oC for 30 minutes, Dried in a drying oven at a round bottom flask of 250 ml, equipped with m laniazid in 40 ml of THF. The azide solution was stirred in the cooling bath of dry ice/acetone for 10 min, then transferred via cannula into the reaction mixture with such a rate that the internal temperature of the mixture was maintained below -70oC. After 2 min the reaction was suppressed to 6.0 ml of glacial acetic acid, the cooling bath was removed and the mixture was stirred at room temperature for 18 hours the Reaction mixture was distributed between 300 ml of ethyl acetate and 300 ml saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuum. Flash chromatography of the residue on 500 g of silica gel using as eluent a mixture of hexane/methylene chloride (2:1, vol/about., then 1:1, vol/about.) received of 5.45 g (67%) of the title compound as oil. IR-spectrum (pure, cm-1): 2104, 1781, 1702.1H NMR spectrum (CDCl3, 400 MHz, M. D.): 2,86 (DD, 1H, J = 13,2, 9,6), 3,40 (DD, 1H, 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 ARE 5.36

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

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

A solution of 5.40 g (15,2 mmol) 3-(S)-azido-(4-forfinal)acetyl-4-(S)-benzyl-2-oxazolidinone (from example 58, the hundred and the second portion was added 1.28 g (30.4 mmol) of the monohydrate of lithium hydroxide, and the resulting mixture was stirred in the cold for 30 minutes, the Reaction mixture was distributed between 100 ml of methylene chloride and 100 ml of 25% saturated aqueous solution of sodium bicarbonate, and the layers were separated. The aqueous layer was washed with 2 x 100 ml methylene chloride and acidified to pH 2 by addition of 2 n aqueous solution of hydrochloric acid. The resulting mixture was extracted with 2 x 100 ml of ethyl acetate; the extracts were combined, washed with 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuum, obtaining of 2.30 g (77%) of the title compound in the form of oil, which was used in the next stage without further purification. IR-spectrum (pure, cm-1): 2111, 1724.1H NMR spectrum (CDCl3, 400 MHz, M. D.): is 5.06 (s, 1H), 7,08 was 7.45 (m, 4H), 8,75 (Shir. s, 1H).

Stage D: (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 C), 250 mg of the catalyst, 10% palladium on coal, and 160 ml of a mixture of water/acetic acid (3:1, vol/about.) was stirred in an atmosphere of hydrogen for 18 hours, the Reaction mixture was filtered through celite and the flask and filter cake was well washed with about 1 l of a mixture of water/acetic acid (3: 1, about. /about.). The filtrate was concentrated in vacuum to a volume of about 50 ml was Added to the/ether (1:1, about./vol.), was filtered and dried, obtaining 1,99 g (100%) of the title compound.1H NMR spectrum (400 MHz, D2O + NaOD): 3,97 (s, 1H), 6,77 (approx. t, 2H, J = 8,8), 7,01 (approx. t, 2H, J = 5,6).

Through the separation of the isomers

Stage A: 4-Perforazione

A solution of 150 g (0,974 mol) 4-florfenicol acid and 1 ml of N,N-dimethylformamide in a 500 ml of toluene at 40oC was treated with 20 ml of chloride tiomila and was heated to 40oC. was added dropwise addition of 61.2 ml chloride tiomila for 1.5 hours After adding the solution was heated for 1 h at 50oC, the solvent was removed in vacuo, and the residual oil was distilled at reduced pressure (1.5 mm RT.cent.), receiving of 150.4 g (89,5%) of the title compound, so Kip. 68-70oC.

Stage B: Methyl 2-bromo-2-(4-fluoro)phenyl acetate

A mixture of 150.4 g (0,872 mol) of 4-perforazione (from example 58, step A) and of 174.5 g (of 1.09 mol) of bromine was covered with 40-50oC quartz lamp for 5 hours the Reaction mixture was added dropwise into 400 ml of methanol, and the solution was stirred 16 h the Solvent was removed in vacuo, and the residual oil was distilled at reduced pressure (1.5 mm RT.St), receiving is 198.5 g (92%) of the title compound, so Kip. 106-110oC.

Stage C: Methyl-()(4-forfinal)gli is antitrichomonal in 25 ml of methanol was treated with 6.8 g (0,105 mol), of sodium azide and the resulting mixture was stirred 20 h at room temperature. The reaction mixture was filtered, the filtrate was diluted with 50 ml of methanol and was first made in the presence of 0.5 g of 10% Pd/C at 3,515 antibodies for 1 h the Solution was filtered, and the solvent was removed in vacuum. The residue was distributed between 10% aqueous solution of sodium carbonate and ethyl acetate. The organic phase is washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuum, obtaining of 9.8 g of the title compound in the form of butter.

Stage D: Methyl-(S)-(4-forfinal)glycinate

The solution 58,4 g of methyl-()-4-torvenyhozasi (from example 58, step C) in 110 ml of a mixture of ethanol/water (7: 1, about./about.) was mixed with a solution of 28.6 g (0,0799 mol) of O,O'-(+)-Dibenzoyl tartaric acid ((+)-DBV)) (28.6 g, 0,0799 mol) in 110 ml of a mixture of ethanol/water (7:1, about./vol.), and the resulting solution was kept for the formation of crystals at room temperature. After crystallization was added ethyl acetate (220 ml) and the resulting mixture was cooled to -20oC and filtered, getting to 32.4 g of methyl(S)-(4-forfinal)glycinate in the form of a salt with (+)-DBV [ee (enantiomeric excess) = 93,2%]. The mother solution was concentrated in vacuo, and the free base was allocated raspredeleniya in 110 ml of a mixture of ethanol/water (7:1, about./about.) was mixed with a solution of 28.6 (0,0799 mol) of O,O'-(-)-dibenzoyltartaric acid ((-)-DBV)) (28.6 g, 0,0799 mol) in 110 ml of a mixture of ethanol/water (7:1, about./about.) and the resulting solution was kept for the formation of crystals at room temperature. After crystallization was added ethyl acetate (220 ml), and the formed mixture was cooled to -20oC and filtered, receiving and 47.0 g of methyl(R)-(4-forfinal)glycinate as salt with (-)-DBV (ee = 75.8 per cent). The recirculation of the mother solutions and adding (+)-DBV gave a second portion of 7.4 g (S)-(4-forfinal)glycinate as salt with (+)-DBV (ee = 96,4%). Two servings (S)-aminoether (39,8 g) were combined in 200 ml of a mixture of ethanol/water (7: 1, about. /about.) and was heated for 30 min and cooled to room temperature. By adding ethyl acetate, cooling and filtering of the received and 31.7 g (S)-(4-forfinal)glycinate as salt with (+)-DBV (ee > 98%). The enantiomeric excess was determined by chiral HPLC (Crownpak CR(+), 5% MeOH in water HClO4pH 2, 1.5 ml/min, 40oC, 200 nm).

A mixture of 17.5 g (S)-(4-forfinal)glycinate in the form of a salt with (+)-DBV and 32 ml of 5.5 n HCl (32 ml) was boiled under reflux for 1.5 hours the Reaction mixture was concentrated in vacuo, and the residue was dissolved in 40 ml of water. The aqueous solution was washed 3 x 30 ml of ethyl acetate, and the layers were separated; the pH of the aqueous layer established the CSOs connection (ee = 98,8%).

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 was treated with 165 mg (4.4 mmol) of sodium borohydride. The cooling bath was removed, and the resulting mixture was stirred 30 min at room temperature. In the reaction mixture was added to the second portion of benzaldehyde (1,12 ml, 11.1 mmol) and 165 mg (4.4 mmol) of sodium borohydride and stirring continued for 1.5 hours the Reaction mixture was distributed between 100 ml of ether and 50 ml of water, and the layers were separated. Separated water layer and was filtered to remove a small amount of insoluble material. The filtrate was acidified to pH 5 using 2 n aqueous solution of hydrochloric acid, and a solid portion, which precipitated was separated by filtration, washed thoroughly with water, then with ether, and dried, obtaining of 1.95 g of the title compound.1H NMR spectrum (400 MHz, D2O + NaOD): 3,33 (AB, 2H, J = 8,4), 3,85 (s, 1H), 6,79-7,16 (m, 4H).

Stage 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, 3,90 ml (to 22.5 mmol) of N,N-diisopropylethylamine, 6,50 ml (75,0 mmol) of 1,2-Deeb which when heated). The reaction mixture was cooled and concentrated in vacuum. The residue was distributed between 250 ml of ether and 100 ml of 0.5 n solution of acid potassium sulfate, and the layers were separated. The organic layer was washed with 100 ml saturated aqueous sodium bicarbonate solution, 3 x 150 ml of water, dried over magnesium sulfate and concentrated in vacuum. Flash chromatography of the residue on 125 g of silica gel using hexane/ether (3:1, about. /about.) as eluent, got 1,58 g (74%) of the title compound in the form of butter.1H NMR spectrum (400 MHz, CDCl3): to 2.65 (dt, 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

The title compound was obtained with the 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.1H NMR spectrum (200 MHz, CDCl3): is 2.37 (dt, J= 3,6, 11,8), 2,83-2,90 (m, 2H), 3,55-3,63 (m, 2H), 3,85 (d, 1H, J = 13,4), 4,14 (dt, 1H, J = 2,0, 11,8), of 4.44 (d, 1H, J = 13,6), of 4.66 (d, 1H, J = 2,8), 4,79 (d, 1H, J = 13,4), 7,00-7,70 (12H).

EXAMPLE 61

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

The title compound was obtained with the yield of 70% of 2-(S)-(3,5-bis(trifluoromethyl) is adiya C. Mass spectrum (FAB): m/z 424 (M+H, 40%).1H NMR spectrum (400 MHz, CDCl3): 1,80 (Shir. c, 1H), 3,11 (approx. DD, 1H, J = 2,2, 12,4) at 3.25 (dt, J = 3,6, 12,4), 3,65 (approx. 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),? 7.04 baby mortality (t, 2H, J = 7,2), 7,33-7,37 (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

The title compound was obtained with the yield of 69% of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy-3-(S)-(4-forfinal)research (from example 61) by applying the method similar to the method of example 18. Mass spectrum (FAB): m/z 521 (M+H, 100%).1H NMR spectrum (400 MHz, CDCl3): 1,80 (Shir. s, 1H), 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, 2H), 10,04 (Shir. s, 1H), 10,69 (Shir. s, 1H).

Analysis. Calculated for C22H19F7N4O3:

C 50,78; H 3,68; N 10,77; F 25,55

Found: C 50,89; H 3,76; N To 10.62; 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 CH2Cl2containing 0,079 ml (0,715 mmol) N-methylmorpholine, 53 mg (from 0.37 mmol), HOBt (butyl spilia (from example 33) in 1 ml of CH2Cl2. After stirring for 2 h, the solution was distributed between water and CH2Cl2. The organic layer was washed with water, with brine and was dried by filtration through Na2SO4. The filtrate was concentrated, and the residue was purified flash chromatography, elwira a mixture of 70% EtOAc/hexane. Received 152 mg (100%) of product. 1H NMR spectrum (400 MHz, CDCl3): 3,03-of 3.85 (m, 5H), 3,95, and 4.4 (Shir. s, 1H), 4,66 (d, J = 13 Hz), 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-(methoxycarbonylmethyl)- 3-(R)-phenylmorpholine

In the solution 0,259 g (0.64 mmol) of 3-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)-3-(R)-phenylmorpholine (from example 33) in 2 ml of DMF was added 0.16 g (0.77 mmol) of methyl-6-bromhexina, 0,155 g (1.12 mmol) of K2CO3and 2 crystal n-Bu4Ni. The resulting solution was heated in a bath at 60oC for 36 hours At this time, TLC showed that the reaction was incomplete. The bath temperature was raised to 100oC. After 3 h the reaction mixture was cooled and diluted with EtOAc. The EtOAc solution was washed with water (2 times), with brine and dried over Na2SO4. The filtrate was concentrated, and the residue was chromatographically using a mixture of 30% EtOAc/hexane, bedelean), 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, 7 Hz, 1H), 4,4 (d, J = 13 Hz, 1H), 4,79 (d, J = 13 Hz, 1H), of 7.2 to 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 3-(S)-(3,5-bis(trifluoromethyl)benzyloxy)- 4-(methoxycarbonylmethyl)-3-(R)-phenylmorpholine (example 64) in 3 ml of MeOH omilami processing 0.5 ml of 5 n NaOH solution at 65oC for 40 minutes the Solution was cooled, concentrated, and the residue was diluted with water. In aqueous solution was set to pH 6 by addition of 2 n HCl, and the solution was extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. Flash chromatography of the residue using a mixture of 50% EtOAc/hexane received 0,13 g (89%) of product.1H NMR spectrum (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-(methylaminoethanol)- 3-(R)-phenylmorpholine

A solution of 116 mg (0.22 mmol) of 3-(S)-(3,5-bis(trifluoromethyl)benzyloxy)- 4-(carboxypentyl)-3-(R)-phenylmorpholine (from example 65) in 1 ml of CH2Cl2was treated with 40 mg (and (40%), and the resulting mixture was stirred for 4 h, the Reaction mixture was diluted with water and was extracted with CH2Cl2. The combined layer of CH2Cl2washed with water, with brine and dried over Na2SO4and the filtrate was concentrated. Purification of the residue with flash chromatography using EtOAc was obtained 0.10 g of product. 1H NMR spectrum (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), 4,36 (d, J=7 Hz, 1H), 4,39 (d, J=13 Hz, 1H), 4,79 (d, J=13 Hz, 1H), 5,03 (Shir. s, 1H), 7,2-7,4 (m, 7H), the 7.65 (s, 1H).

EXAMPLE 67

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

A solution of 2.67 g (10.0 mmol) 3-(S)-phenyl-4-benzyl-2-morpholine (from example 14) in 40 ml of dry THF was cooled to -78oC. the Cooled solution was treated with 12.5 ml of 1.0 M solution of L-Selectridein THF, maintaining the internal temperature below -70oC. Alternative may require only 6% of the excess of (L-Selectride). The resulting solution was stirred in the cold for 45 min and added of 3.60 ml (20.0 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. Formed yellow mixture was stirred in the cold for 30 min, and the reaction was suppressed by adding 50 ml nasusunog the Le damping distributed between 300 ml of ether and 50 ml of water, and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300 ml of ether, the extract was dried and combined with the first organic layer. The combined layer was concentrated in vacuum. Flash chromatography of the residue on 150 g of silica gel using as eluent a mixture of hexane/ether (37: 3, vol/about.) received 4,06 g (80%) of the title compound as a solid substance. 1H NMR spectrum (CDCl3, 200 MHz, M. D.): 2,50 (dt, J=3,4, 12,0, 1H), 2,97 (approx. d, J=12,0, 1H), 2,99 (d, J=13,6, 1H), 3.72 points-with 3.79 (m, 1H), 3,82 (d, J= 2,6, 1H), 4.00 points (d, J=13,6, 1H), 4,20 (dt, J=2,4, 11,6), to 6.22 (d, J= 2,6, 1H), 7,22-7,37 (m, 7H), EUR 7.57 (approx. d, J=6,8, 2H), 8,07 (s, 1H), of 8.47 (s, 2H).

Analysis. Calculated for C26H21F6NO3:

C 61,29; H 4,16; N 2,75; F 22,38

Found: C 61,18; H 4,14; N 2,70; F 22,13.

EXAMPLE 68

2-(R)-(1-(3,5-Bis(trifluoromethyl)phenyl) adenylate)-3-(S)-phenyl-4-benzylmorphine

Stage a: Dimethyltitanocene

The solution 2,49 g (10.0 mmol) of titaniumdioxide in 50 ml of ether in the dark at 0oC was treated with 17.5 ml of 1.4 M solution metallice in the air, maintaining an internal temperature below 5oC. the yellow-orange mixture was stirred at room temperature for 30 min, and the reaction was suppressed by slow addition of 25 g of ice. The reaction mixture after Galeni Aravali in vacuum, getting 2,03 g (98%) of the title compound in the form of a photosensitive solid product. Alternative dimethylferrocene can be obtained from methylacrylamide. Dimethyltitanocene can be stored in the form of a solution in toluene at 0oC for at least 2 weeks with no apparent chemical destruction.1H NMR spectrum of CDCl3, 200 MHz, M. D.): 0,15 (s, 6H), the 6.06 (s, 10H).

Stage b: 2-(R)-(1- (3,5-Bis(trifluoromethyl)phenyl)adenylate)-3-(S)-phenyl-4 - benzylmorphine

A solution of 2.50 g (4.9 mmol) of 2-(R)-(3,5-bis(trifluoromethyl) benzoyloxy)-3-(S)-phenyl-4-benzylmorphine (example 67) and 2.50 g (12,0 mmol) dimethyltitanocene (from example 68, step A) in 35 ml of a mixture of THF/toluene (1:1, about. /about. ) was stirred under heating at an oil bath at 80oC for 16 hours the Reaction mixture was cooled and concentrated in vacuum. Flash chromatography of the residue on 150 g of silica gel using as eluent a mixture of hexane/methylene chloride (3:1, vol/vol.), getting 1,71 g (69%) of the title compound as a solid substance. Alternative product can be distinguished by crystallization from methanol, followed by precipitation of titanium residues. Mass spectrum (FAB): m/z 508 (M+H, 25%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): 2,42 (dt, J= 3,6, 12,0, 1H), 2,89 (approx. d, J =11,6), of 2.92 (d, J=13,6, 1H), 3,61-3,66 2H), 7,79 (s, 1H), to $ 7.91 (s, 2H).

Analysis. Calculated for C27H23F6NO2:

WITH 63,90; H OF 4.57; N WAS 2.76; F 22,46

Found: 63,71; H A 4.53; N 2,68; F Cushion 22.66.

EXAMPLE 69

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

A mixture of 1.50 g (2.9 mmol) of 2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl) adenylate)-3-(S)-phenyl-4 - benzylmorphine (example 68) and 750 mg of catalyst. 10% palladium on charcoal, in 25 ml of a mixture of isopropanol/ethyl acetate (3:2, vol/about.) was stirred in an atmosphere of hydrogen for 48 hours Alternative hydrogenation can be performed using 5% palladium on aluminium oxide. The catalyst was separated by filtration on a bed of celite, the flask for the reaction and filter the pillow was washed with 500 ml of ethyl acetate. The filtrate was concentrated in vacuum. Flash chromatography of the residue on 60 g of silica gel using as eluent a mixture of hexane/ether (2:1, vol/vol.), then a mixture of hexane/ether (2:1, vol/about.) received 106 mg of 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- phenylmorpholine and 899 mg of 2-(R) -(1-(R)-(3,5-bis(trifluoromethyl)- phenyl) ethoxy)-3-(S)-phenylmorpholine. Both are oil (total yield 84%).

2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S),92 (lat. s, 1H), 3,13 (DD, J= 3,0, 12,6, 1H), 3,24 (dt, J=3,6, 12,6 1H), 3,62 (DD, J=3,6, 11,2), Android 4.04 (d, J= 2,4, 1H), 4,14 (dt, J=3.0 a, 11,2, 1H), 4,48 (d, J=2,4 1H), 4,90 (K, J=6,8, 1H), 7,21-of 7.23 (m, 7H), to 7.64 (s, 1H).

Analysis. Calculated for C20H19F6NO2:

WITH 57,28; H OF 4.57; N 3,34; F 27.18 PER

Found: 57,41; H 4,13; N 3,29; F 27,23.

EXAMPLE 70

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)- 3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine

Stage A: 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S) - phenyl-4-(2-(N-methylcarbamates)morpholine

The solution 945 mg (2.3 mmol) of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3-(S)-phenylmorpholine (from example 69), 447 mg (2.7 mmol) of N-methylcarbamic-2-chloroacetamides (from example 45, step A) and 0.78 ml (4.5 mmol) of N, N-diisopropylethylamine in 17 ml of acetonitrile was stirred 20 h at room temperature. Alternative alkylation can be carried out in dimethyl sulfoxide, using potassium carbonate as the base. The reaction mixture was concentrated in vacuo, and the residue was distributed between 50 ml of methylene chloride and 25 ml of water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuum. Flash chromatography of the residue on 50 g of silica gel using as eluent a mixture of methylene chloride/methanol/hydroxide ammol)phenyl)ethoxy)- 3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine

A solution of 1.01 g (1.8 mmol) of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl) ethoxy)-3-(S)-phenyl-4-(2-(N - methylcarbamic-acetamidate)-research (from example 70, step A) in 15 ml of xylene for 2 hours boiled under reflux. There may be diisopropylethylamine. The reaction mixture was cooled and concentrated in vacuum. Flash chromatography of the residue on 50 g of silica gel using a mixture of methylene chloride/methanol/ammonium hydroxide (50:1: 0,1) as eluent received 781 mg (76%) of the title compound as a solid substance. The crude product can also select directly cooling the reaction mixture. The purified product can be obtained by crystallization from hot methanol (discoloration charcoal) and rubbing with water. Mass spectrum (FAB): m/z 517 (M+H, 18%), 178 (100%),1H NMR spectrum (CDCl3, 400 MHz, M. D.): 1,47 (d, J=6,8), 2,01-2,05 (m, 2H), by 2.55 (dt, J= 3,6, 12,0, 1H), only 2.91 (d, J=10,8, 1H), 2,95 (d, J=14,8, 1H), 3,49 (d, J=2,4 1H), the 3.65 (d, J= 14,8, 1H), 3,69 (d, J=10,8, 1H), 4,29 (dt, J=2,4, 10,0), to 4.38 (d, J= 2,8 1H), 4,88 (K, J=6,8, 1H), 7,14 (c, 2H), 7,33-7,40 (m, 5H), a 7.62 (s, 1H), to 9.91 (Shir. s, 1H), 10,16 (Shir. s, 1H).

Analysis. Calculated for C23H22F6N4O3.

WITH 53,49; H 4,06; N 10,85; F 22,07

Found: 53,64; H 4,33; N 10,81; F 22,27.

EXAMPLE 71

2-(R)-(1-(S)-(3,5-Bis (trifluoromethyl) phenyl) e- (R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenylmorpholine (from example 69), similar to the method of example 70. Mass spectrum (FAB): m/z 517 (M+H, 100%), 259 (50%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): 1,09 (d, J= 6,4, 3H), 2,27 of $ 2.53 (m, 1H), 2,83 (approx. d, J= 11,6, 1H), 2,95 (d, J=14,0, 1H), 3,51-the 3.65 (m, 3H), 4,01 (approx. t, J=11,6 1H), 4,60 (K, J=6,4, 1H), 4,84 (d, J= 2,4, 1H), 7,33-7,51 (m, 5H), 7,74 (s, 2H), 7,76 (s, 1H), 9,51 (Shir. s, 1H), 10,00 (Shir. s, 1H).

EXAMPLE 72

2-(R)-(3,5-Bis(trifluoromethyl)benzoyloxy)-3-(S)- (4-fluoro) phenyl-4-benzylmorphine

The title compound is obtained in yield of 83% of 3-(R)- (4-fluoro)phenyl-4-benzyl-2-morpholine (from example 59) in a manner analogous to example 67. Mass spectrum (FAB): m/z 528 (M+H, 25%), 270 (100%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): 2,50 (dt, J=3,2, 12,0, 1H), 2,96 (approx. d, J=12,0 1H), 2,98 (d, J= 13,6, 1H), 3,74-of 3.78 (m, 1H), 3,81 (d, J=2,8, 1H), 3,94 (d, J=13,6, 1H), 4,19 (dt, J= 2.0 a, 12,0), of 6.20 (d, J= 2,8, 1H), 6,99 (t, J=8,4, 2H), 7,27-7,38 (m, 5H), 7,52-7,56 (m, 2H), of 8.09 (s, 1H), 8,46 (s, 2H).

EXAMPLE 73

2-(R)-(1-(3,5-Bis(trifluoromethyl)phenyl) adenylate)-3-(S)-(4-fluoro)-phenyl-4-benzylmorphine

The title compound is obtained in yield of 60% from 3-(R)-(3,5-bis (trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro)phenyl-4 - benzylmorphine (example 72) in a manner analogous to the method of example 68. Mass spectrum (FAB): m/z 526 (M+H, 75%), 270 (100%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): 2,42 (dt, J=3,6, 12,0), 2,90 (approx. d, J=12,0, 1H), only 2.91 (d, J=13,6, 1H), 3,62-3,66 (m, 1H), and 3.72 (d, J=2,6), of 3.94 (d, J=13,6, 1H), 4.09 to (dt, J=2,4, 12.0, 1H), and 4.75 (d, J= 3,2, 1H), 5-Bis(trifluoromethyl)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenylmorpholine and 2-(S)-(1-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine

A mixture of 1.83 g (3.5 mmol) of 2-(R)-(1-(3,5-bis(triptorelin)phenyl)adenylate) - 3-(S)-(4-fluoro)phenyl-4-benzylmorphine (example 73) and 800 mg of catalyst, 5% rhodium on aluminum oxide in 40 ml of absolute ethanol was stirred in an atmosphere of hydrogen for 24 hours, the Catalyst was separated by filtration on a bed of celite, the reaction flask and filter cake were washed with 200 ml of ethyl acetate. The filtrate was concentrated in vacuo, and the residue was pumped out in high vacuum (1 mm RT.art., room temperature) dry.

The residue was re-dissolved in 40 ml of isopropanol, was added 800 mg of catalyst, 10% palladium on charcoal, and the resulting mixture was stirred in an atmosphere of hydrogen for 24 hours the Catalyst was filtered on a bed of celite, the reaction flask and filter cake were washed with 200 ml of ethyl acetate. The filtrate was concentrated in vacuum. Flash chromatography of the residue on 50 g of silica gel using as eluent a mixture of hexane/ether (2:1, vol/vol.), then hexane/ether (3: 2, vol. /about. ) received 283 mg of 2- (R)-(1-(S)-(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3-(S)-(4 - fluoro)phenylmorpholine and 763 mg of 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine, both in the form of oil (total yield 68%).

2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)FeNi.): of 1.47 (d, J=6,8, 3H), 1,87 (Shir. s, 1H), 3,03 (DD, J=2,8, 12,8), 3,17 (dt, J=4,0, 12,4, 1H), 3,43-3,47 (m, 1H), 3,80 (dt, J=3,2, 11,6), 4,10 (d,J =2,2, 1H), 4,70 (K, J=6,8, 1H), 4,87 (d, J=2,2, 1H), 6,99-7,03 (m, 2H), 7.23 percent-7,27 (m, 2H), 7,63 (s, 2H), 7,66 (s, 1H).

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluoro)phenylmorpholine: mass spectrum (FAB): m/z 438 (M+H, 76,5%), 180 (100%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): to 1.16 (d, J=6,8), 1,80 (Shir. s, 1H), 3,13 (DD, J= 3.2, and 12,4), 3,23 (dt, J=3,6, 12,4), 3,63 (DD, J =2,4, 11,2), to 4.01 (d, J=2,4, 1H), 4,13 (dt, J=3,2, 12,0), 4,42 (d, J=2,4, 1H), 4,19 (K, J=6,8, 1H),? 7.04 baby mortality-to 7.09 (m, 2H), 7,27-7,40 (m, 4H), 7,73 (c, 2H).

EXAMPLE 75

2-(R)-(1-(R)-(3,5 - Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5 - oxo-1,2,4-triazolo)methylmorpholine

The title compound was obtained with the yield 79% of 2-(R)-(1- (R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine (from example 74) by methods similar to the methods of example 70. Mass spectrum (FAB): m/z 535 (M+H, 100%), 277 (60%). 1H NMR spectrum (CDCl3+CD3OD, 400 MHz, M. D.): 1,48 (d, J=6,8, 3H), 2,52 (approx. t, J=10,4, 1H), 2,85-is 2.88 (m, 2H), 3,47 (d, J= 2,8, 1H), 3,63 (d, J=14,4, 1H), 3.70 (DD, J=2,0, 11,6, 1H), 4,24 (approx. t, J= 10,8, 1H), 4,35 (d, J =2,8, 1H), 4,91 (K, J=6,8, 1H), 7,07 (approx. t, J= 8,4, 2H), 7,15 (c, 2H), 7,37-7,40 (m, 2H), 7,65 (c, 1H).

EXAMPLE 76

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1, 2, 4-triazolo) methylmorpholine

The title compound was obtained with the yield of 60% from 2-(R)-(1- (S)-(3,5-b is. the ACC-spectrum (FAB): m/z 535 (M+H, 50%), 293 (100%), 1H NMR spectrum (CDCl3+CD3OD, 400 MHz, M. D.): a 1.11 (d, J= 6,8, 3H), 2.49 USD (dt, J =2,4, 11,2), 2,83 (approx. d, J =11,2, 1H), 2,95 (d, J= 14,4, 1H), 2,48-of 2.58 (m, 3H), 3,99 (approx. t, J=9,6, 1H), br4.61 (K, J =6,4, 1H), 4,81 (d, J= 2,4, 1H), to 7.09 (t, J =8,8, 2H), 7,50-7,53 (m, 2H), 7,75 (approx. s, 1H), the 10.40 (Shir. s, 1H), 11,00 (Shir. s, 1H).

EXAMPLE 77

2-(R)-(1-(R)-(3-(Trifluoromethyl) phenyl) ethoxy)-3- (S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine

Stage A: 2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)-3-(S) - phenylmorpholine

The title compound was obtained with the yield 25% of 3- (S)-phenyl-4-benzyl-2-morpholine (from example 14) by methods similar to the methods of examples 67-69.1H NMR spectrum (CDCl2, 400 MHz, M. D.): 1,39 (d, J =6,6, MN), 1,93 (Shir. s, 1H), 3,10 (DD, J =3,0, 12,7, 1H), 3,20 (dt, J =3,6, 12,4, 1H), to 3.58 (DDD, J =l,l, 3,8, and 11.2, 1H), 4.00 points (d, J =2,4, 1H), 4,12 (dt, J=3.0 a, 11,2, 1H), of 4.44 (d, J =2,4, 1H), 4,79 (K, J=6,6, 1H), 6,72 (d, J =7,7, 1H), 7,01 (c, 1H), to 7.09 (t, J=7,7, 1H), 7.18 in-7,25 (m, 2H), 7,25 of 7.3 (m, 3H), 7,34 (d, J =7,7, 1H).

Analysis. Calculated for C19H19F3N1O2:

C 65,14; H VS. 5.47; N 4,00; F 16,27

Found: 64,89; H 5,73; N 3,83; F 15,95.

Stage b: 2-(R)-(1-R)-(3-(Trifluoromethyl)phenyl)ethoxy)-3- (S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine

The title compound was obtained with the yield of 90% of 2-(R)-(1 - R)-(3-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenylmorpholine (from example 77, step 2, 1H), 2,86 (approx. d, J=12,2, 1H), 2,94 (d, J=14,3, 1H), 3,44 (Shir. s, 1H), 3,63 (Shir. d, J=14, 2H), 4,27 (approx. t, J=11,5, 1H), 4,34 (d, J =2,1, 1H), 4,76 (K, J=6,7, 1H), 6,63 (d, J=7,7, 1H), 6,93 (c, 1H), 7,06 (t, J=7,6, 1H), 7,25 was 7.45 (m, 6H), 9,63 (Shir. s, 1H), 9.74 (Shir. s, 1H).

Analysis. Calculated for C22H22F3N4O3:

C 59,06; H 4,96; N TO 12.52; F 12,74

Found: 58,84; H 5,17; N 12,37; F 12,50.

EXAMPLE 78

2-(R)-(1-(R)-(3-(Fluoro-5-(trifluoromethyl) phenyl) ethoxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine

Stage A: 2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl) phenyl)ethoxy)-3-(S)-phenylmorpholine

The title compound was obtained with the yield of 44% from 3-(S)-phenyl - 4-benzyl-2-morpholine (from example 14) by methods similar to the methods of examples 67-69. 1H NMR spectrum (CDCl3, 400 MHz, M. D.): to 1.38 (d, J=6,6, 3H), 1,90 (Shir. s, 1H), 3,17 (DD, J=3,0, 12,7, 1H), 3,18 (dt, J=3,6, 12,7, 1H), to 3.58 (DDD, J= 1,1, 3,8, and 11.2, 1H), was 4.02 (d, J=2,3, 1H), 4,11 (dt, J=3.0 a, 11,2, 1H), of 4.44 (d, J=2,3, 1H), 4,78 (K, J=6,6, 1H), 6,29 (d, J=9,2, 1H), 6,85 (c, 1H), 7,03 (t, J=8,4, 1H), 7.18 in-7,26 (m, 2H), 7,26-to 7.3 (m, 3H).

Analysis: Calculated for C19H18F4N1O2:

C OF 61.95; H IS 4.93; N OF 3.80; F 20,63

Found: C 61,78; H 5,14; N 3,71; F 20,35.

Stage b: 2-(R)-(1-(R)-(3-(Fluoro)-5- (trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1, 2, 4-triazolo)methylmorpholine

The title compound was obtained with the yield of 77% of 2-(R)-(1-(R)-(3-(fluoro)-5-(triform the NMR spectrum (CDCl3, 400 MHz, M. D.): 1,40 (d, J =6,3, 3H), 2,54 (Shir. t, J=11, 1H), 2,87 (approx. d, J = 12, 1H), 2,94 (d, J =14, 1H), 3,47 (Shir. s, 1H), 3,63 (Shir. d, J =14, 2H), 4,25 (approx. t, J=11, 1H), 4,35 (d, J=1,5, 1H), 4.75 V (K, J=6,3, 1H), 6,62 (d, J= 6,7, 1H), 6.78 (c, 1H), 7,01 (t, J =8,4, 1H), 7,24 (d, J=3,9, 1H), 7,35 (Shir. s, 4H), being 9.61 (Shir. s, 1H), 9,89 (Shir. s, 1H).

Analysis. Calculated for C22H22F4N4O3:

WITH 56,77; H 4,55; N 12,04; F 16,33

Found: 56,57; H 4,65; N 11,94; F 16,13.

EXAMPLE 79

2-(S)-(3-Fluoro-5-trifluoromethyl)benzoyloxy)-3-(S)- (4-fluoro)phenyl-4-benzylmorphine

The title compound was obtained with the yield 57% from 3-(S)-(4-fluoro)phenyl-4-benzyl-2-morpholine (from example 59) in a manner analogous to the method of example 67. Mass spectrum (CL): m/z 478 (M+H, 100%).1H NMR spectrum (CDCl3, 400 MHz, M. D. ): 2,50 (dt, J=3.3V, 12,0, 1H), 2,96 (d, J=12,0, 1H), 2,98 (d, J=13,6, 1H, in), 3.75 (DD, J= 1,7, 11,5, 1H), 3,80 (d, J=13,6, 1H, in), 3.75 (DD, J=1,7, 11,5, 1H), 3,80 (d, J=2,5, 1H), 3,92 (d, J=13,6, 1H), 4,19 (dt, J=2.1 a, 12,0, 1H), 6,20 (d, J=2,5, 1H), 6,99 (t, J=8,7, 2H), 7,2-7,37 (m, 5H), 7,51-of 7.55 (m, 3H), 7,89 (d, J=8,4, 1H), 8,09 (c, 1H).

EXAMPLE 80

2-(S)-(1-(3-Fluoro-5-trifluoromethyl) phenyl) adenylate)-3-((S)-(4-fluoro) -phenyl-4-benzylmorphine

The target compound was obtained with the yield of 85% from 2-(S)-(3-fluoro-5 - trifluoromethyl) benzoyloxy-3-(S)-(4-fluoro)phenyl-4-benzylmorphine (example 79) in a manner analogous to the method of example 68. Mass spectrum (S1): m/z 476 (M+H, 100%).1H NMR spectra is t, J=2,4, 12,0, 1H), 4,67 (d, J = 2,9, 1H), amounts to 4.76 (d, J=2,9, 1H), 5,28 (d, J =2,6, 12,0, 1H), 7,07 (t, J=8,7, 2H), 7,2-7,37 (m, 7H), 7,53 (s, 1H), EUR 7.57-to 7.61 (m, 2H).

EXAMPLE 81

2-(S)-(1-(S)-(3-Fluoro-5-trifluoromethyl) phenyl) ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine and 2-(S)-(1-(R)-(3-fluoro-5 - trifluoromethyl) phenyl) ethoxy)-3-(S)-(4-fluoro) phenylmorpholine

The title compound was obtained from 2-(S)-(1-(3-Fluoro-5 - trifluoromethyl) phenyl) adenylate)-3-(S)-(4-fluoro)phenyl-4 - benzylmorphine (from example 80) in a manner analogous to the method of example 74 but using as the catalyst 10% palladium on coal.

2-(S)-(1-(S)-(3-fluoro-5-trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine: Mass spectrum (S1): m/z 338 (M+H, 100%).1H NMR spectrum (CDCl3, 400 MHz, M. D.): 1,12 (d, J=6,5, 1H) and 1.83 (s, 1H), to 3.02 (d, J=10,1, 1H), and 3.16 (dt, J= 3,6, 12,5, 1H), 3,43 (DD, J=2,7, 11,4, 1H), 3,81 (dt, J=2,9, 11,7, 1H), 4.09 to (d, J=2,1, 1H), 4,62 (K, J=6,5, 1H), 4,84 (d, J=2,1, 1H), 7,05 (t, J=8,8, 2H), 7,2(d, J=8,8, 2H), 7,32 (c, 1H), 7,38 (DD, J=5,5, 8,5, 2H).

2-(S)-(1-(R)-(3- (fluoro-5-trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 - fluoro)phenylmorpholine: mass spectrum (CL): m/z 338 (M+H, 100%):1H NMR spectrum (CDCl3, 400 MHz, M. D.): to 1.42 (d, J=6,6, 3H), 1.91 a (s, 1H), 3,11 (DD, J= 3.2, and to 12.4, 1H), up 3.22 (dt, J=3,6, 12,4, 1H), to 3.58-3,62 (m, 1H), 4,01 (d, J= 2,3, 1H), 4,11 (dt, J =3,2, 12,0, 1H), to 4.41 (d, J=2,3, 1H), 4,80 (K, J=6,6, 1H), 6,41 (d, J =9,2, 1H), 6,86(s, 1H), 7,02 (t, J=8,7, 2H), was 7.08 (d, J=9,2, 2H), 7,21-7,26 (m, 2H).

EXAMPLE 82

2-(S)-(1-(R)-(3-Fluoro-5-trifluoromethyl) phenyl) this is riformati) phenyl) ethoxy)-3-(S)-(4-fluoro) phenylmorpholine (example 81), analogous to example 70, so pl. 209-211oC []D= +65,1o(C =1.0, methanol).1H NMR spectrum (CDCl3, 400 MHz, M. D.): 1,32 (d, J=6,4, 1H), of 2.38 (t, J=11,9, 1H), was 2.76 (d, J=13,9, 1H), 2,84 (d, J=11,5, 1H), 3,32 (c, 1H), 3,40 (d, J = 13,9, 1H), 3,49 (c, 1H), 3,61 (d, J =11,2, 1H), 4,11 (t, J=11,3, 1H), 4,8 (K, J=6,4, 1H), to 6.57 (d, J=9,4, 1H), 6,94 (c, 1H) and 7.1 (t, J=8,7, 2H), 7,39 (d, J=8,7, 2H), 7,51 (c, 2H), of 11.26 (c, 2H), 11,38 (c,1H).

EXAMPLE 83

2-(S)-(1-(R)-(3,5-Bis(trifluoromethyl) phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole) methylmorpholin

Stage A: N,N-Diacetyl-4-methyl bromide-2-imidazolin

The title compound was obtained in accordance with the method Dolan and Dushinsky (Journal of American Chem. Soc., 70, 657 (1948).

Stage b: 2-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methylmorpholin

A mixture of 1.00 g (2.28 mmol) of 2-(S)-(1-(R)-(3,5-bis (trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine (from example 74), and 0.62 g (2,40 mmol) of N, N-diacetyl-4-methyl bromide - 2-imidazolone (from example 83, step A) and 0.63 g (4,56 mmol) of potassium carbonate in 10 ml of N,N-dimethylformamide was stirred 15 min at room temperature. The reaction mixture was diluted with 100 ml ethyl acetate and washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The resulting oil was dissolved in 10 ml of ethanol, the solution abrames was concentrated in vacuum, getting a solid product. By recrystallization from a mixture of ethyl acetate/methanol was received to 0.63 g of the title compound, so pl. 192-194oC.1H NMR spectrum (d6-DMSO, 360 MHz, M. D.): 1,35 (d, J=6,5, 3H), of 2.25 (dt, J = 8,7, 1H), 2,60 (d, J =13,8, 1H), 2,89 (d, J=11,6, 1H), 3,28-to 3.36 (m, 2H), 3,62 (d, J=10,2, 1H), 4,1 (t, J=10,0, 1H), or 4.31 (d, J= 2,7, 1H), 4.92 in (K, J=6,5, 1H), 5,97 (s, 1H), 7,06 (t, J=8,8, 2H), was 7.36 (s, 2H), 7,65 is 7.85 (m, 2H), 7,84 (c, 1H), 9,58 (s, 1H), and 9.8 (s, 1H).

EXAMPLE 84

2-(S)-(1-(R)-(3-Fluoro-5-(trifluoromethyl)phenyl) ethoxy-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole) methylmorpholin

The title compound was obtained from 2-(S)-(1-(R)-(3 - fluoro-5-trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine from example 82) in a manner analogous to the method of example 83, so pl. 209-210oC []D= +92,8(C = 1.0, methanol).1H NMR spectrum (d6-DMSO, 360 MHz, M. D.): 1,31 (d, J=6,5, 3H), 2,24 (dt, J=3,0, 11,9, 1H), 2,6 (d, J=13,9, 1H), 3,61 (d, J=11,2, 1H), 4,1 (t, J= 11,0 1H), 4,29 (d, J =2,3, 1H), 4,8 (K, J=6,5, 1H), 6,00 (s, 1H), 6,55 (d, J=9,3, 1H), 6,94 (s, 1H), 7,11 (t, J=8,7, 2H), 7,39 (d, J=8,4, 1H), 7,51 (s, 2H), 9,59 (s, 1H), 9,84 (s, 1H).

EXAMPLE 85

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

The title compound was obtained from (R)-(4-fluoro)phenylglycine by methods similar to the methods of examples 59, 67, 67, 69 and 70, []D= -67,7(c = 0,7, MeOH, 20oC).

1) 2-(R)-(1-(R)-(3-(Chloro)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S) -phenylmorpholine;

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

3) 2-(R)-(1-(R)-(3-(fluoro)-5- (methyl)phenyl)ethoxy)-3-(S)-phenylmorpholine;

4) 2-(R)-(1- (R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenylmorpholine;

5) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-phenylmorpholine;

6) 2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-phenylmorpholine;

7) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl) ethoxy)-3-(S)-phenylmorpholine;

8) 2-(R)-(1-(R)-(3-(chloro)-5- (isopropoxy)phenyl)ethoxy)-3-(S)-phenylmorpholine;

9) 2-(R)-(1- (R)-(3-(fluoro)-5-(R> 11) 2-(R)-(1-(R)-(3-(tert-butyl)-5- (chloro) phenyl) ethoxy)-3-(S)-phenylmorpholine;

12) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(trifluoromethyl) phenyl)ethoxy)-3-(S)-phenylmorpholine;

13) 2-(R)-(1-(R)-(3,5- (dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenylmorpholine;

14) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)- phenylmorpholine;

15) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy-3- (S)-phenylmorpholine;

16) 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenylmorpholine;

17) 2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-phenylmorpholine;

18) 2-(R)-(1-(R)-(3,5-(debtor)phenyl)ethoxy)-3-(S)- phenylmorpholine;

19) 2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S) -phenylmorpholine;

20) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl)ethoxy)-3- (S)-phenylmorpholine;

21) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl) ethoxy)-3-(S)-phenylmorpholine;

22) 2-(R)-(1-(R)-(1-(3- (chloro)naphthyl)ethoxy)-3-(S)-phenylmorpholine;

23) 2-(R)-(1-(R)-(1-(3- (methyl)naphthyl)ethoxy)-3-(S)-phenylmorpholine;

24) 2-(R)-(1-(R)-(1- (3-(trifluoromethyl)naphthyl)ethoxy)-3-(S)-phenylmorpholine;

25) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)- phenylmorpholine;

26) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4 - fluoro)phenylmorpholine;

27) 2-(R)-(1-(R)-(2-fluoro-5 - trifluoromethyl)phenylethane)-3-(S)-phenylmorpholine;

28) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)- 3-(S)-(4-fluoro)phenylmorpholine;

29) 2-(S)-(2-chloro-5 - trifluoromethyl-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S)- phenylmorpholine;

32) 2-(R)-(1-(R)-(2-chloro-5 - trifluoromethyl)phenylethane)-3-(S)-(4-fluoro)phenylmorpholine;

33) 2-(S)-(3-methyl)benzyloxy)-3-(S)-phenylmorpholine;

34) 2-(S)-(2-methyl)benzyloxy)-3-(S)-(4-fluoro)phenylmorpholine;

35) 2-(R)-(1-(R)-(3-methyl)phenylethane)-3-(S) -phenylmorpholine;

36) 2-(R)-(1-(R)-(3-methyl)phenylethane)-3-(S)- (4-fluoro) phenylmorpholine;

37) 2-(S)-(3-bromo) benzyloxy)-3-(S)-phenylmorpholine;

38) 2-(S)-(3-bromo) benzyloxy)-3-(S)-(4-fluoro) phenylmorpholine;

39) 2-(R)-(1-(R)-(3-bromo)phenylethane)-3-(S)- phenylmorpholine;

40)-2-(R)-(1-(R)-(3-bromo)phenylethane)-3-(S)-(4-fluoro) phenylmorpholine;

41)-2-(S)-(3-chloro) benzyloxy-3-(S)-phenylmorpholine;

42) 2-(S)-(3-chloro)benzyloxy)-3-(S)-(4-fluoro)phenylmorpholine;

43) 2-(R)-(1-(R)-(3-chloro)phenylethane)-3-(S)-phenylmorpholine;

44) 2-(R)-(1-(R)-(3-chloro)phenylethane)-3-(S)-(4-fluoro) phenylmorpholine:

45) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)- phenylmorpholine;

46) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)- phenyl-(4-fluoro)phenylmorpholine;

47) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenylmorpholine;

48) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenyl-(4 - fluoro) phenylmorpholine;

49) 2-(R)-(1-(R)-(3-(thiomethyl)phenyl)ethoxy)-3-(S)-phenylmorpholine;

50) 2-(R)-(1-(R)-(3 - thiomethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenylmorpholine;

51) 2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3 - dihydrobenzofuran-7-yl)ethoxy)-3-(S)-penelo is hydroxy)-3-(S)-(4 - fluoro) phenylmorpholine;

54) 2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)phenyl)ethoxy) -3-(S)-(4-fluoro)phenylmorpholine;

55) 2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)phenyl)ethoxy) -3-(R)-(4-fluoro) phenylmorpholine;

56) 2-(R)-(1-(R)-(3,5-dimethyl)phenyl)ethoxy)-3-(S)-(4 - fluoro) phenylmorpholine;

57) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl) phenyl) ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

58) 2-(R)-(1-(R)- (3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

59) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl) ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

60) 2-(R)-(1-(R)-(3 - isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

61) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluoro)phenylmorpholine;

62)-2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy) -3-(S)-(4-fluoro)phenylmorpholine;

63) 2-(R)-(1-(R)-(3-(fluoro)-5- (isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

64) 2-(R)-(1-(R)-(3-(tert)butyl)phenyl)ethoxy)-3-(S)-(4 - fluoro) phenylmorpholine;

65) 2-(R)-(1-(R)-(3-(tert-butyl)-5- (chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine;

66) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluoro)phenylmorpholine;

67)-2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3- (S)-(4-fluoro)-phenylmorpholine;

68) 2-(R)-(1-(R)-(3,5-(dimethyl)- 4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine;

69) 2-(R)-(1-(R)- (3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

the toxi)-3-(S)-(4-fluoro)phenylmorpholine;

72) 2-(R)-(1-(R)-(3,5-(debtor)phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

73) 2-(R)-(1-(R)-(1-naphthyl) ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

74) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl)ethoxy)-3- (S)-(4-fluoro)phenylmorpholine;

75) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl)ethoxy)-3-(S)-(4 - fluoro)phenylmorpholine;

76) 2-(R)-(1-(R)-(1-(3- (chloro)naphthyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

77) 2-(R)- (1-(R)-(1-(3-(methyl)naphthyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

78) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl) ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine;

79) 2-(R)-(1-(R)- (3-(thiomethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

80) 2-(R)-(1-(R)-(3-thiomethyl)-5-(trifluoromethyl) phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

81) 2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3 - dihydrobenzofuran-7-yl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

82) 2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)- (4-fluoro) phenylmorpholine;

83) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenylmorpholine;

84) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

85) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-phenylmorpholine;

86) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine;

87) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-phenylmorpholine;

88) 2-(R)-(1-(R)-(4-fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro) phenylmorpholine;

89) 2-(R)-(1-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(3-fluoro)phenylmorpholine;

90) 2- (R)-(1-(R)-(3,5-bis(t is 4-dichloro)phenylmorpholine;

92) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3, 4-dimethyl)phenylmorpholine;

93) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(3,4-methylendioxy)phenylmorpholine;

94) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(2-naphthyl)morpholine;

EXAMPLE 87

The following compounds were obtained from the corresponding 2-(S)- (substituted benzyloxy)-3-(S)-kilmartin or 2-(R)-(1- (R)-(substituted aryl)ethoxy-3-(S)-kilmartin (example 86) by methods similar to the methods of examples 17, 18, 36, 38, 83 or, in the case of 4-(5-tetrazolyl)methylseleninic of morpholino, alkylation of the research (from example 86) chloroacetonitrile in the presence of tertiary amine (base) in acetonitrile, followed by the formation of the final product by reaction of the resulting nitrile with an azide or trimethylsilylmethyl sodium in a suitable solvent.

1) 2-(R)-(1-(R)-(3-(chloro)-5- (triptoreline)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4 - triazolo)methylmorpholine;

2) 2-(R)-(1- (R)-(3,5-dimethyl)phenyl)ethoxy) -3- (5)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

3) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl) ethoxy)-3-(S)-phenyl-4-(3- (5-oxo-1,2,4-triazolo)methylmorpholine;

4) 2-(R)-(1-(R)-(3- (chloro)-5-methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4 - triazolo)methylmorpholine;

5) 2-(R)-(1-(R)-(3-(bromo)-5-(methylpheni-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

7) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl) ethoxy) -3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

8) 2-(R)-(1-(R)-(3-(chloro)-5- (isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

9) 2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)- 3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

10) 2-(R)-(1-(R)-1-(3-(trifluoromethyl)naphthyl)ethoxy)-3-(S)- phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

11) 2-(R)- (1-(R)-(3-(tert-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4- (3-(5-oxo-1,2,4-triazolo)methylmorpholine;

12) 2-(R)-(1-(R)-(3- (tert-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3- (5-oxo-1,2,4-triazolo)methylmorpholine;

13) 2-(R)-(1-(R)-(3,5- (dimethyl)-4-(fluoro)phenyl)ethoxy)3-(S)-phenyl-4-(3-(5-oxo-1, 2,4-triazolo)methylmorpholine;

14) 2-(R)-(1-(R)-(3,5-(dimethyl)-4- (chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4 - triazolo)methylmorpholine;

15) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)- 4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2, 4 - triazolo)methylmorpholine;

16) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)- 4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4 - triazolo) methylmorpholine;

17) 2-(R)-(1-(R)-(3,5- (dichloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4 - triazolo) methylmorpholine;

18) 2-(R)-(1-(R)-(3,5- (debtor)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

19) 2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(iatola) methylmorpholin;

21) 2-(R)-(1-(R)-(1-(3-fluoro) naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

22) 2-(R)-(1-(R)-(1-(3-chloro)naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(5 - oxo-1,2,4-triazolo)methylmorpholine;

23) 2-(R)-(1-(R)-(1-(3 - methyl)naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

24) 2-(R)-(1-(R)-(1-(3-trifluoromethyl)naphthyl) ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

25) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3- (S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

26) 2-(S)-(2 - fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2, 4-triazolo)methylmorpholine;

27) 2-(R)-(1-(R)-(2-fluoro-5 - trifluoromethyl)phenylethane)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

28) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl) phenylethane)-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo) methylmorpholin;

29) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3- (S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

30) 2- (S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl - 4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

31) 2-(R)-(1- (R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S)-phenyl-4-(3-(5 - oxo-1,2,4-triazolo)methylmorpholine;

32) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S) -(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

33) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)- phenyl-4-(4-(2-oxo-1,3-imidazole)methylmorpholin;
(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S)-phenyl-4- (4-(2-oxo-1,3-imidazole)methylmorpholin;

36) 2-(R)-(1-(R)-(2 - fluoro-5-trifluoromethyl)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(4- (2-oxo-1,3-imidazole)methylmorpholin;

37) 2-(S)-(2-fluoro-5 - trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-imidazole) methylmorpholin;

38) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3- (S)-(4-fluoro)phenyl-4-(2-imidazole)methylmorpholin;

39) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S) -phenyl-4-(2-imidazole)methylmorpholin;

40) 2-(R)-(1-(R)-(2 - fluoro-5-trifluoromethyl)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(2 - imidazole)methylmorpholin;

41) 2-(S)-(2-fluoro-5 - trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4-imidazole) methylmorpholin;

42) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3- (S)-(4-fluoro)phenyl-4-(4-imidazole)methylmorpholin;

43) 2-(R)-(1- (R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S)-phenyl-4-(4 - imidazole)methylmorpholin;

44) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3- (S)-(4-fluoro)phenyl-4-(4-imidazole)methylmorpholin;

45) 2-(S)- (2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazole) methylmorpholin;

46) 2-(S)-(2-fluoro-5-trifluoromethyl) benzyloxy-3-(S)-(4 - fluoro)phenyl-4-(5-tetrazole)methylmorpholin;

47) 2-(R)-(1- (R)-(2-fluoro-5-trifluoromethyl)phenylethane)-3-(S)-phenyl-4-(5 - tetrazole)methylmorpholin;

48) 2-(R)-1-(R)-(2-fluoro-5 - trifluoromethyl) phenylethane)-3-(S)-(4-fluoro)phenyl-4- (5-tetrazole)methylmorpholin;

49) 2-(S)-(2-fluoro-5 - trifluoromethyl) is R) phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

51) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl) phenylethane)-3-(S)- phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

52) 2-(1R-(1- (R)-(2-fluoro-5-trifluoromethyl) phenylethane)-3-(S)-(4-fluoro) phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

53) 2-(S)-(2 - chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4 - triazolo) methylmorpholine;

54) 2-(S)-(2-chloro-5 - trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

55) 2-(R)-(1-(R)-(2-chloro-5 - trifluoromethyl)phenylethane)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

56) 2-(R)-(1-(R)-(2-chloro-5 - trifluoromethyl)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

57) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl - 4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

58) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4 - fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

59) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)- 3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

60) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3-(S)-(4 fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

61) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4- (2-oxo-1,3-imidazole)methylmorpholin;

62) 2-(S)-(2-chloro-5 - trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1, 3-imidazole)methylmorpholin;

63) 2-(R)-(1-(R)-(2-chloro-5 - trifluoromethyl)phenylethane)-3-(S)-phenyl-4-(4-(2-1,3-imidazole)methylmorpholin:

65) 2-(S)-(2-chloro-5-trifluoromethyl) benzyloxy-3-(S)-phenyl-4-(2-imidazole)methylmorpholin;

66) 2-(S) -(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2 - imidazole)methylmorpholin;

67) 2-(R)-(1-(R)-(2-chloro-5 - trifluoromethyl)phenylethane)-3-(S)- phenyl-4-(2-imidazole)methylmorpholin;

68) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl) phenylethane)-3-(S)-(4-fluoro)phenyl-4-(2-imidazole) methylmorpholin;

69) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4- (4-imidazole)methylmorpholin;

70) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4 - fluoro)phenyl-4-(4-imidazole)methylmorpholin;

71) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethane)-3- (S)-phenyl-4-(4-imidazole)methylmorpholin;

72) 2-(R)-(1-(R)- (2-chloro-5-trifluoromethyl)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(4 - imidazole)methylmorpholin;

73) 2-(S)-(2-chloro-5 - trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazole) methylmorpholin;

74) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3- (S)-(4-fluoro)phenyl-4-(5-tetrazole)methylmorpholin;

75) 2-(R) -(1-(R)-(2-chloro-5-trifluoromethyl) phenylethane)-3-(S)-phenyl-4- (5-tetrazole)methylmorpholin;

76) 2-(R)-1-(R)-(2-chloro-5 - trifluoromethyl)phenylethane)-3-(S)-(4-fluoro) phenyl-4-(5 - tetrazole) methylmorpholin;

77) 2-(R)-(2-chloro-5 - trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl) methylmorpholine;

78) 2-(S)-(2-chloro-5-trifluoromethyl) benzyloxy-3-(S)-(4-ftoo-5H-pyrrol-4-yl) methylmorpholine;

80) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl) phenylethane)-3-(S)-(4-fluoro) phenyl-4-(2-oxo-5H-pyrrol-4-yl) methylmorpholine;

81) 2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(3- (1,2,4-triazolo)methylmorpholine;

82) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

83) 2-(R)-(1-(R)-(3 - methyl) phenylethane)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

84) 2-(R)-(1-(R)-(3-methyl)phenylethane)-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

85) 2-(S)-(3-methyl) benzyloxy-3-(S)-phenyl-4-(3-(5 - oxo-1,2,4-triazolo)methylmorpholine;

86) 2-(S)-(3-methyl) benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

87) 2-(R)-(1-(R)-(3-methyl)phenylethane)-3- (S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

88) 2- (R)-(1-(R)-(3-methyl) phenylethane)-3-(S)-(4-fluoro)phenyl-4-(3- (5-oxo-1,2,4-triazolo)methylmorpholine;

89) 2-(S)-(3-methyl) benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole) methylmorpholin;

90) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4 - fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole) methylmorpholin;

91) 2-(R)- (1-R)-(3-methyl)phenylethane)-3-(S)-phenyl-4-(4-(2-oxo-1, 3 - imidazole)methylmorpholin;

92) 2-(R)-(1-(R)-(3-methyl)phenylethane) -3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole) methylmorpholin;

93) 2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(2 - imidazole)methylmorpholin;

94) 2-(S)-(3-methyl)benzyloxy-3-(S) -(4-fluoro)phenyl-4-(22-(R)-(1-(R)-(3-methyl)phenylethane)-3-(S)-(4-fluoro) phenyl-4-(2-imidazole)methylmorpholin;

97) 2-(S)-(3-methyl) benzyloxy-3-(S)-phenyl-4-(4-imidazole)methylmorpholin;

98) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl - 4-(4-imidazole)-methylmorpholin;

99) 2-(R)-(1-(R)-(3-methyl) phenylethane)-3-(S)-phenyl-4-(4-imidazole)methylmorpholin;

100) 2-(R)-(1-(R)-(3-methyl)phenylethane)-3-(S)-(4-fluoro) phenyl-4-(4-imidazole)methylmorpholin;

101) 2-(S)-(3-methyl) benzyloxy-3-(S)-phenyl-4-(5-tetrazole)methylmorpholin;

102) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl - 4-(5-tetrazole)methylmorpholin;

103) 2-(R)-(1-(R)-(3-methyl) phenylethane)-3-(S)-phenyl-4-(5-tetrazole)methylmorpholin;

104) 2-(R)-1-(R)-(3-methyl)phenylethane)-3-(S)-(4-fluoro)phenyl - 4-(5-tetrazole)methylmorpholin;

105) 2-(S)-(3-methyl) benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

106)2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

107) 2-(R)-(1-(R)-(3 methyl)phenylethane)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl) methylmorpholine;

108) 2-(R)-(1-(R)-(3-methyl)phenylethane)-3-(S)- (4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

109) 2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

110) 2-(S)-(3-bromo)benzyloxy-3- (S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

111) 2-(R)-(1-(R)-(3-bromo)phenylethane)-3-(S)-phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

112) 2-(R)-(1-(R)-(3-bromo) phenylethane)-3-(S)-(4-fluoro)FEIN;

114) 2-(S)-(3 - bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1, 2, 4 - triazolo)methylmorpholine;

115) 2-(R)-(1-(R)-(3-bromo)phenylethane) -3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

116) 2-(R-(1-(R)-(3-bromo)phenylethane)-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

117) 2-(S) -(3-bromo)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole) methylmorpholin;

118) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(4-(2-oxo-1,3-imidazole)methylmorpholin;

119) 2-(R)- (1-(R)-(3-bromo)phenylethane)-3-(S)-phenyl-4-(4-(2-oxo-1,3 - imidazole)methylmorpholin;

120) 2-(R)-(1-(R)-(3-bromo) phenylethane)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1, 3 - imidazole)methylmorpholin;

121) 2-(S)-(3-bromo)benzyloxy-3-(S)- phenyl-4-(2-imidazole)methylmorpholin;

122) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2 - imidazole)methylmorpholin;

123) 2-(R)-(1-(R)-(3 - bromo)phenylethane)-3-(S)-phenyl-4-(2-imidazole)methylmorpholin;

124) 2-(R)-(1-(R)-(3-bromo)phenylethane)-3-(S)-(4-fluoro)phenyl-4- (2-imidazole)methylmorpholin;

125) 2-(S)-(3-bromo)benzyloxy-3-(S)- phenyl-4-(4-imidazole)methylmorpholin;

126) 2-(S)-(3 - bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-imidazole)methylmorpholin;

127) 2-(R)-(1-(R)-(3-bromo)phenylethane)-3-(S)- phenyl-4-(4-imidazole)methylmorpholin;

128) 2-(R)-(1-(R)-(3 - bromo)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(4-imidazole) methylmorpholin;

129) 2-(S)-(3-bromo) methylmorpholin;

131) 2-(R)- (1-(R)-(3-bromo) phenylethane)-3-(S)-phenyl-4-(5-tetrazole)- methylmorpholin;

132) 2-(R)-1-(R)-(3-bromo) phenylethane)-3- (S)-(4-fluoro)phenyl-4-(5-tetrazole)methylmorpholin;

133) 2- (S)-(3-bromo) benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4 - yl)methylmorpholine;

134) 2-(S)-(3-bromo) benzyloxy-3-(S)-(4 - fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

135) 2-(R)-(1-(R)-(3-bromo)phenylethane)-3-(S)-phenyl-4- (2-oxo-5H-pyrrol-4-yl)methylmorpholine;

136) 2-(R)-(1- (R)-(3-bromo)phenylethane)-3-(S)-(4 - fluoro)phenyl-4-(2-oxo-5H - pyrrol-4-yl)methylmorpholine;

137) 2-(S)-(3-(chloro)benzyloxy-3- (S)-phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

138) 2-(S)-(3 - chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

139) 2-(R)-(1-(R)-(3-chloro)phenylethane)-3-(S)- phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

140) 2-(R)-(1-(R)-(3 - chloro)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

141) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(3- (5-oxo-1,2,4-triazolo)methylmorpholine;

142) 2-(S)-(3-chloro) benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

143) 2-(R)-(1-(R)-(3-chloro)phenylethane)-3- (S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

144) 2- (R)-(1-(3 chloro)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(3-(5 - oxo-1,2,4-triazolo)methylmorpholine;

145) 2-(S)- (3-chloro) benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole) methylmorpholin;

148) 2-(R)-(1-(R)-(3-chloro) phenylethane)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3 - imidazole)methylmorpholin;

149) 2-(S)-(3 - chloro) benzyloxy-3-(S)-phenyl-4-(2-imidazole)methylmorpholin;

150) 2-(S)-(3-chloro) benzyloxy-3-(S) - (4-fluoro)phenyl-4-(2-imidazole)methylmorpholin;

151) 2-(R)-(1- (R)-(3-chloro)phenylethane)-3-(5)-phenyl-4-(2-imidazole) methylmorpholin;

152) 2-(R)-(1-(R)-(3-chloro) phenylethane)-3-(S) - (4-fluoro)phenyl-4-(2-imidazole)methylmorpholin;

153) 2-(S)-(3 - chloro)benzyloxy-3-(S)-phenyl-4-(4-imidazole)methylmorpholin;

154) 2-(S)-(3-chloro)benzyloxy-3-(S)-4-fluoro) phenyl-4-(4 - imidazole)methylmorpholin;

155) 2-(R)-(1-(R)-(3-chloro) phenylethane)-3-(S)-phenyl-4-(4-imidazole)methylmorpholin;

156) 2- (R)-(1-(R)-(3-chloro)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(4 - imidazole)methylmorpholin;

157) 2-(S) -(3-chloro)benzyloxy-3-(S)- phenyl-4-(5-tetrazole)methylmorpholin;

158) 2-(S) -(3-chloro) benzyloxy-3-(S)-(4-fluoro)phenyl-4-(5-tetrazole)methylmorpholin;

159) 2-(R)-(1-(R)-(3-chloro)phenylethane)-3-(S)-phenyl - 4-(5-tetrazole)methylmorpholin;

160) 2-(R)-1-(R)-(3-chloro) phenylethane)-3-(S)-(4-fluoro)phenyl-4-(5-tetrazole)methylmorpholin;

161) 2-(S)-(3-chloro) benzyloxy-3-(S)-phenyl-4-(2-oxo-5H - pyrrol-4-yl)methylmorpholine;

162) 2-(S) -(3-chloro) benzyloxy-3-(S)-(4-fluoro)phenyl - 4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

163) 2-(R)-(1-(R)-(3-chloro)phenylethane)-3-(S)-phenyl - 4-(2-oxo-5H-Pierre is BR>
165) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

166) 2-(S)-(3-trifluoromethyl)benzyloxy - 3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

167) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane)-3-(S)-phenyl-4-(3-(1, 2,4-triazolo)methylmorpholine;

168) 2-(R)-(1-(R)-(3-trifluoromethyl) phenylethane)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

169) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)- phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

170) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

171) 2-(R)- (1-(R)-(3-trifluoromethyl)phenylethane)-3-(S)-phenyl-4-(3-(5-oxo-1, 2, 4-triazolo)methylmorpholine;

172) 2-(R)-(1-(R)-(3 - trifluoromethyl)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo - 1,2,4-triazolo)methylmorpholine;

173) 2-(S)-(3-trifluoromethyl) benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole)methylmorpholin;

174) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4- (4-(2-oxo-1,3-imidazole)methylmorpholin;

175) 2-(R)-(1-(R)-(3 - trifluoromethyl)phenylethane)-3-(S)-phenyl-4-(4-(2-oxo-1,3 - imidazole)methylmorpholin;

176) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane)-3-(S) -(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methylmorpholin;

177) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2 - imidazole)methylmorpholin;

178) 2-(S)-(3-trifluoromethyl) benzyloxy-3-(S)-(4-FPO is orfelin;

180) 2-(R)-(1-(R)-(3 - trifluoromethyl)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(2 - imidazole)methylmorpholin;

181) 2-(S)-(3-trifluoromethyl) benzyloxy-3-(S)-phenyl-4-(4-imidazole)methylmorpholin;

182) 2- (S)-(3-trifluoromethyl) benzyloxy-3-(S)-(4-fluoro) phenyl-4-(4 - imidazole)methylmorpholin;

183) 2-(R)-(1-(R)-(3-trifluoromethyl) phenylethane)-3-(S)-phenyl-4-(4-imidazole)methylmorpholin;

184) 2- (R)-(1-(R)-(3-trifluoromethyl)phenylethane)-3-(S)-(4-fluoro) phenyl-4-(4-imidazole)methylmorpholin;

185) 2-(S)-(3-trifluoromethyl) benzyloxy-3-(S)-phenyl-4-(5-tetrazole)methylmorpholin;

186) 2- (S)-(3-trifluoromethyl) benzyloxy-3-(S)-(4-fluoro) phenyl-4-(5 - tetrazole)methylmorpholin;

187) 2-(R)-(1-(R)-(3 - trifluoromethyl) phenylethane)-3-(S)-phenyl-4-(5-tetrazole) methylmorpholin;

188) 2-(R)-1-(R)-(3-trifluoromethyl) phenylethane)-3-(S)-(4-fluoro) phenyl-4-(5-tetrazole) methylmorpholin;

189) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)- phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

190) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro) phenyl - 4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

191) 2-(R)-(1-(R)-(3 - trifluoromethyl)phenylethane)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl) methylmorpholine;

192) 2-(R)-(1-(R)-(3-trifluoromethyl)phenylethane)- 3-(R)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

193) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

is ylethoxy)-3-(S)-phenyl-4-(3- (1,2,4-triazolo)methylmorpholine;

196) 2-(R)-(1-(R)-(3 - tert-butyl) phenylethane)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

197) 2-(S)-(3-tert-butyl)benzyloxy - 3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

198) 2-(S)-(3 - tert-butyl) benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1, 2, 4-triazolo)methylmorpholine;

199) 2-(R-(1-(R)-(3-tert - butyl)phenylethane)-3-(S)-phenyl-4-(3-(5-oxo-1, 2, 4-triazolo) methylmorpholine;

200) 2-(R-(1-(R)-(3-tert-butyl) phenylethane)-3- (S)-(4-fluoro) phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

201) 2-(S)-(3-tert-butyl) benzyloxy-3-(S)-phenyl-4- (4-(2-oxo-1, 3-imidazole)methylmorpholin;

202) 2-(S)-(3-tert - butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3 - imidazole)methylmorpholin;

203) 2-(R)-(1-(R)-(3-tert-butyl) phenylethane)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazole) methylmorpholin;

204) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane)-3-(S)-(4 - fluoro)phenyl-4-(4-(2-oxo-1,3-imidazole)methylmorpholin;

205) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-phenyl-4-(2-imidazole)- methylmorpholin;

206) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)- (4-fluoro)phenyl-4-imidazole)methylmorpholin;

207) 2-(R)-(1-(R)- (3-tert-butyl)phenylethane)-3-(S)-phenyl-4-(2-imidazole) methylmorpholin;

208) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane)- 3-(S)-(4-fluoro)phenyl-4-(2-imidazole)methylmorpholin;

209) 2-(S) -(3-tert-butyl)benzyloxy-3-(S)-phenyl-4-(4-imidazole)- methylmorpholin;
is teletaxi)-3-(S)-phenyl-4-(4-imidazole) methylmorpholin;

212) 2-(R)-(1-(R)-(3-tert-butyl)phenylethane)-3- (S)-(4-fluoro)phenyl-4-(4-imidazole)methylmorpholin;

213) 2-(S)- (3-tert-butyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazole) methylmorpholin;

214) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)- (4-fluoro)phenyl-4-(5-tetrazole)methylmorpholin;

215) 2-(R)- (1-(R)-(3-tert-butyl)phenylethane)-3-(S)-phenyl-4-(5 - tetrazole)methylmorpholin;

216) 2-(R)-1-(R)-(3-tert - butyl)phenylethane)-3-(S)-(4-fluoro)phenyl-4-(5-tetrazole) methylmorpholin;

217) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)- phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

218) 2-(S)-(3-tert-butyl)benzyloxy-3-(S)-(4-fluoro) phenyl-4-(2-oxo-5H-pyrrol-4-yl)methylmorpholine;

219) 2-(R)-(1-(R)- (3-tert-butyl)phenylethane)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl) methylmorpholine;

220) 2-(R)-(1-(R)-(3-tert-butyl) phenylethane)-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl) methylmorpholine;

221) 2-(R)-(1-(R)-(3-dimethylphenyl)ethoxy-3-(S)- phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

222) 2-(R)- (1-(R)-(3-thiomethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

223) 2-(R(-(1-(R)-(3-(dimethylphenyl) ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole) methylmorpholin;

224) 2-(R)-(1-(R)-(3-thiomethyl-5-(trifluoromethyl) phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

225) 2-(R)-(1-(R)-(3-thiomethyl-5-(trifluoromethyl) phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) IU Holin;

227) 2-(R)-(1-(R)-(2,2-dimethyl)-5-(thiomethyl)-2,3 dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-4-(3-to 5-oxo - 1,2,4-triazolo)methylmorpholine;

228) 2-(R)-(1-(R)-(2,2-(dimethyl)- 5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

229) 2-(R)-(1-(R)-(2,2- (dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl) ethoxy)-3-(S)-phenyl-4-(3-(-2-oxo-1,3-imidazole)methylmorpholin;

230) 2-(R)-(1-(R)-(3,5- (dimethoxy)phenyl)ethoxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4 - triazolo)methylmorpholine;

231) 2-(R)-(1-(R)-(3,5-(dimethoxy) phenyl)ethoxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine:

232) 2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy - 3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

233) 2- (R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy-3-(S)-(4-fluoro)- phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

234) 2-(R)- (1-(R )-(3-(fluoro)-5-(trifluoromethyl)ethoxy-3-(S)-(4-fluoro)-phenyl - 4-(3-(1,2,4-triazolo)methylmorpholine;

235) 2-(R)-(1-(R)-(3- (fluoro)-5-(trifluoromethyl)ethoxy-3-(S)-(4-fluoro)-phenyl-4-(3-(2 - oxo-1,3-imidazole)methylmorpholin;

236) 2-(R)-(1-(R)-(3-(chloro)- 5-(trifluoromethyl)ethoxy-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1, 2,4-triazolo)methylmorpholine;

237) 2-(R)-(1-(R)-(3-(chloro)-5- (trifluoromethyl)ethoxy-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

238) 2-(R)-(1-(R)-(3-(chloro)-5- (trifluoromethyl)ethoxy-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1, 3-imidazole)metalmorph is)-(1-(R)-(3,5 - dimethyl)phenyl)ethoxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

241) 2-(R)-(1-(R)-(3,5-dimethyl)phenyl)ethoxy-3-(S)-(4-fluoro) phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

242) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy - 3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

243) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy-3-(S)- (4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

244) 2- (R)-(1-(R)-(3-fluoro)-5-(methyl)phenyl)ethoxy-3-(S)-(4-fluoro) phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

245) 2-(R)-(1- (R)-(3-(chloro)-5-(methyl)phenyl)ethoxy-3-(S)-(4-fluoro)phenyl-4-(3- (5-oxo-1,2,4-triazolo)methylmorpholine;

246) 2-(R)-(1-(R)-(3- (chloro)-5-(methyl)phenyl)ethoxy-3-(S)-(4-fluoro)phenyl-4-(3-(1, 2,4-triazolo)methylmorpholine;

247) 2-(R)-(1-(R)-(3-(chloro)-5- (methyl)phenyl)ethoxy-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazole) methylmorpholin;

248) 2-(R)-(1-(R)-(3-bromo)-5-(methyl)phenyl)ethoxy-3-(S)- (4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

249) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl) phenyl)ethoxy-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

250) 2-(R)-(1-(R)- (3-(bromo)-5-(methyl)phenyl)ethoxy-3-(S)-(4-fluoro)phenyl-4-(3-(2 - oxo-1,3-imidazole)methylmorpholin;

251) 2-(R)-(1-(R)-(3- (isopropoxy)phenyl)ethoxy-3-(S)-(4-fluoro)phenyl-4-(3-(5 - oxo-1,2,4-triazolo)methylmorpholine;

252) 2-(R)-(1-(R)-(3- (isopropoxy)phenyl)ethoxy-3-(S)(4-fluoro)phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

253) 2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy-3-(S)-4 - fluoro)Fe is p)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

255) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl) phenyl)ethoxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

256) 2-(R)-(1-(R)-(3-(isopropoxy)-5- (trifluoromethyl)phenyl)ethoxy-3-(S)-(4-fluoro)phenyl-4-(3-(2 - oxo-1,3-imidazole)methylmorpholin;

257) 2-(R)-(1-(R)-(3-(chloro)- 5-(isopropoxy)phenyl)ethoxy)-3-(S)-4-fluoro)phenyl-4-(3-(5 - oxo-1,2,4-triazolo)methylmorpholine;

258) 2-(R)-(1-(R)-(3- (chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

259) 2-(R)-(1-(R)-(3- (chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-(2-oxo-1,3-imidazole)methylmorpholin;

260) 2-(R)-(1-(R)-(3- (fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-(5-oxo-1,2,4-triazolo)methylmorpholine;

261) 2-(R)-(1-(R)-(3- (fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

262) 2-(R)-(1-(R)-(3- (fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-(2-oxo-1,3-imidazole)methylmorpholin;

263) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(chloro)phenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

264) 2-(R)-(1-(R-(3-(tert-butyl)-5-(chloro)phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

265) 2-(R)-(1-(R)-(3-(tert-butyl)-5-(chloro)phenyl)ethoxy) -3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

266) 2-(R)-(1-(R)-(3-(tert-butyl)-5- (trifluoromethyl)phenyl)ethoxy)-C)-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

268) 2-(R)-(1-(R)- (3-(tert-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

269) 2-(R)-(1- (R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl - 4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

270) 2-(R)-(1-(R) -(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl - 4-(3-(1,2,4-triazolo)methylmorpholine;

271) 2-(R)-(1-(R)-(3,5- (dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3- (2-oxo-1,3-imidazole)methylmorpholin;

272) 2-(R)-(1-(R)- (3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-(5-oxo-1,2,4-triazolo)methylmorpholine;

273) 2-(R)-(1-(R)-(3,5-dimethyl)-4-(chloro) phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

274) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin

275) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4 - triazolo)methylmorpholine;

276) 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(1,2,4-triazolo)methylmorpholin;

277) 2-(R)-(1-(R)- (3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4 - fluoro)phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

278) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

279) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)etox is-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

281) 2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy-3-(S)-(4-fluoro)phenyl) -4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

282) 2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-(4 - fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

283) 2-(R)- (1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-14-fluoro)phenyl-4- (3-(2-oxo-1,3-imidazole)methylmorpholin;

284) 2-(R)-(1-(R)- (3,5-(debtor)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5 - oxo-1,2,4-triazolo)methylmorpholine;

285) 2-(R)-(1-(R)-(3,5- (debtor)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

286) 2-(R)-(1-(R)-(3,5-(debtor) phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3 - imidazole)methylmorpholin;

287) 2-(R)-(1-(R)-(1-(naphthyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

288) 2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-(4 - fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

289) 2-(R)- (1-(R)-(1-(naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2 - OXO-1,3-imidazole)methylmorpholin;

290) 2-(R)-(1-(R)-(1-(4- (fluoro)naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4 - triazolo)methylmorpholine;

291) 2-(R)-(1-(R)-(1-(4-fluoro)naphthyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

292) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

293) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

294) 2-(R)- (1-(R)-(1-(3-fluoro)naphthyl)e is-(3-(2-oxo-1,3-imidazole)methylmorpholin;

296) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl)ethoxy)-3-(S)- (4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

297) 2-(R)-(1-(R)-(1-(3-chloro)naphthyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

298) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4- (3-(2-oxo-1,3-imidazole)methylmorpholin;

299) 2-(R)-(1-(R)- (1-(3-(methyl)naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5 - oxo-1,2,4-triazolo)methylmorpholine;

300) 2-(R)-(1-(R)-(1-(3 - methyl)naphthyl)ethoxy)-3-(S)-((4-fluoro)phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

301) 2-(R)-(1-(R)-(1-(3- (methyl)naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3 - imidazole)methylmorpholin;

302) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl) naphthyl)ethoxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4 - triazolo)methylmorpholine;

303) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl) naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

304) 2-(R)-(1-(R)-(1-(3- (trifluoromethyl)naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2 - oxo-1,3-imidazole)methylmorpholin;

305) 2-(R)-(1-(R)-(1-(3- (dimethylphenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1, 2,4-triazolo)methylmorpholine;

306) 2-(R)-(1-(R)-(1-(3-(dimethylphenyl)ethoxy)-3- (S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

307) 2-(R)-(1-(R)-(1-(3-(dimethylphenyl)ethoxy)-3-(S)-(4 - fluoro)phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

308) 2-(R)-(1-(R)-(1-(3-(thiomethyl-5-(trifluoromethyl)phenyl)ethoxy) -3-(S)-(4-fluoro)fennel-4-(3-(1,2,4 - triazolo)methylmorpholine;

310) 2-(R)-(1-(R)-(1-(3-(thiomethyl-5- (trifluoromethyl)phenyl)ethoxy)-3-9S)-(4-fluoro)phenyl-4-(3-(2 - oxo-1,3-imidazole)methylmorpholin;

311) 2-(R)-(1-(R)-(2,2- (dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)- (4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine;

312) 2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3 - dihydrobenzofuran-7-yl)ethoxy-3-(S)-(4-fluoro)phenyl-4-(3-(1, 2,4-triazolo)methylmorpholine;

313) 2-(R)-(1-(R)-(2,2-(dimethyl)-5- (thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy-3-(S)-(4-fluoro) phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

314) 2-(R)- (1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3- (5-oxo-1,2,4-triazolo)methylmorpholine;

315) 2-(R)-(1-(R)-(3,5- (dimethoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4 - triazolo)methylmorpholine;

316) 2-(R)-(1-(R)-(3,5- (dimethoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3 - imidazole)methylmorpholin;

317) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5 - oxo-1,2,4-triazolo)methylmorpholine;

318) 2-(R)-(l-(R)-(phenyl) ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

319) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2 - oxo-1,3-imidazole)methylmorpholin;

320) 2-(R)-(1-(R)-(phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

321) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-1,2,4-triazolo)methylmorpholine;

322) 2-(R)-(1-(R)- (phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(morpholin;

324) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S) -phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

325) 2-(R)-(1-(R)- (3-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3 - imidazole)methylmorpholin;

326) 2-(R)-(1-(R)-(3- (fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4 - triazolo)methylmorpholine;

327) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)- 3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

328) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3- (2-oxo-1,3-imidazole)methylmorpholin;

329) 2-(R)-(1-(R)-(4- (fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-to 5-oxo-1,2,4 - triazolo)methylmorpholine;

330) 2-(R)-(1-(R)-(4-(fluoro) phenyl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

331) 2-(R)-(1-(R)-(4- (fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole) methylmorpholin;

332) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-(4 - fluoro) phenyl-4-(3-(5-oxo-I,2,4-triazolo)methylmorpholine;

333) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3- (1,2,4-triazolo)methylmorpholine;

334) 2-(R)-(1-(R)-(4-(fluoro) phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3 - imidazole)methylmorpholin;

335) 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3-fluoro)phenyl-4-(3- (5-oxo-1,2,4-triazolo)methylmorpholine;

336) 2-(R)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3-fluoro)phenyl-4-(3- (1,2,4-triazolo) methylmorpholine;

337) 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3-fluoro)Hairdryer is- (3-(5-oxo-1,2,4-triazolo)methylmorpholine;

339) 2-(R)-(1-(R)- (3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-debtor)phenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

340) 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-debtor)phenyl-4- (3-(2-oxo-1,3-imidazole)methylmorpholin;

341) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3-(S)-(3,4-dichloro)phenyl-4-(3-(5-oxo-1,2,4 - triazolo)methylmorpholine;

342) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (3,4-dichloro)phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

343) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(3,4-dichloro)phenyl-4-(3-(2-oxo-1,3 - imidazole)methylmorpholin;

344) 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dimethyl)phenyl-4-(3- (5-oxo-1,2,4-triazolo)methylmorpholine;

345) 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dimethyl)phenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

346) 2-(R)-(1-(R)-(3,5 bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(3,4-dimethyl)phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

347) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)3-(S)- (3,4-methylenedioxyphenyl-4-(3-(5-oxo-1,2,4-triazolo) methylmorpholine;

348)2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-methylenedioxyphenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

349) 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4 - methylenedioxyphenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

350) 2-(R)-(1-(R)-(3,5 - bis(trif is phenyl)ethoxy)-3-(S)-(2-naphthyl)-4-(3-(1,2,4- triazolo)methylmorpholine;

352) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3-(S)-(2-naphthyl)-4-(3-(2-oxo-1,3 - imidazole)methylmorpholin;

353) 2-(R)-(1-(R)-(3-(fluoro)-5- (trifluoromethyl)-ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3 - imidazole)methylmorpholin;

354) 2-(R)-(1-(R)-(3-(fluoro)-5- (trifluoromethyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4 - triazolo)methylmorpholine;

355) 2-(R)-(1-(R)-(3-(chloro)-5- (trifluoromethyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

356) 2-(R)-(1-(R)-(3-(chloro-5-(trifluoromethyl) ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole) methylmorpholin;

357) 2-(R)-(1-(R)-(3,5-dimethyl)phenyl)ethoxy)-3- (S)-phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

358) 2-(R)-(1-(R)-(3,5-dimethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3- (2-oxo-1,3-imidazole)methylmorpholin;

359) 2-(R)-1-(R)-(3-(fluoro)-5- (methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

360) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl) ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin

361) 2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)- phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

362) 2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3- (S)-phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

363) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)- 3-(S)-phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

364) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)- 3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

365) 2-(R)-(1-(R)-(3-(isopropoxy) is(3-(2-oxo-1,3 - imidazole)methylmorpholin;

367) 2-(R)-(1-(R)-(3-(isopropoxy)-5- (trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1, 2, 4- triazolo)methylmorpholine;

368) 2-(R)-(1-(R)-(3-(isopropoxy)-5- (trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1, 3 - imidazole)methylmorpholin;

369) 2-(R)-(1-(R)-(3-chloro)-5- (isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1, 2, 4- triazolo)methylmorpholine;

370) 2-(R)-(1-(R)-(3-chloro)-5- (isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1, 3 - imidazole)methylmorpholin;

371) 2-(R)-(1-(R)-(3-fluoro)-5- (isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

372) 2-(R)-(1-(R)-(3-fluoro)-5-(isopropoxy)phenyl) ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1, 3-imidazole) methylmorpholin;

373) 2-(R)-(1-(R)-(3-tert-butyl)-5-(chloro)phenyl) ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

374) 2-(R)-(1-(R)-(3-tert-butyl)-5-(chloro)phenyl)ethoxy)-3-(S) -phenyl-4-(3-(2-oxo-1, 3-imidazole)methylmorpholin;

375) 2-(R)-(1-(R)-(3-tert-butyl)-5-(trifluoromethyl)phenyl) ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

376) 2-(R)-(1-(R)-(3-tert-butyl)-5-(trifluoromethyl)phenyl) ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin

377) 2-(R)-(1-(R)-(3,5-(dimethyl)-4- (fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

378) 2-(R)-(1-(R)-(3,5-(dimethyl)-4- (fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole) methylmorpholin;

379) 2-(R)-(1-(R)-(3,5-(dimethyl)-4- (hornil-4-(3-(2-oxo-1,3-imidazole) methylmorpholin;

381) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4- (fluoro)phenyl) ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

382) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4- (fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3 - imidazole)methylmorpholin;

383) 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1, 2,4-triazolo)methylmorpholine;

384) 2-(R)-(1-(R)-(3,5-bis (trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2 - oxo-1,3-imidazole)methylmorpholin;

385) 2-(R)-(1-(R)-(3,5- (dichloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

386) 2-(R)-(1-(R)-(3,5-(dichloro)ethoxy)-3-(S)- phenyl-4-(3-(2-oxo-1,3-imidazole)methylmorpholin;

387) 2-(R)-(1-(R)-(3,5-(debtor)phenyl)ethoxy)-3-(S)-phenyl - 4-(3-(1,2,4-triazolo)methylmorpholine;

388) 2-(R)-(1-(R)-(3,5- (debtor)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole) methylmorpholin;

389) 2-(R)-(1-(R)-(1-naphthyl)ethoxy)-3-(S)-phenyl-4- (3-(1,2,4-triazolo)methylmorpholine;

390) 2-(R)-(1-(R)-(1 - naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole) methylmorpholin;

391) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl)ethoxy) -3-(S)-phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

392) 2-(R)-(1-(R)-(1-(4-fluoro(naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(2 - oxo-1,3-imidazole)methylmorpholin;

393) 2-(R)-(1-(R)-(1-(3- (fluoro)naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo) methylmorpholine;

394) 2-(R)-(1-(R)-(1-(3-fluoro)naphthyl)ethoxy)-3- (S)-phenyl-4-(3-(2-oxo-I, 3-imides what R)-(1-(R)-(1-(3 - chloro)naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazole) methylmorpholin;< / BR>
397) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl)ethoxy)-3- (S)-phenyl-4-(3-(1,2,4-triazolo)methylmorpholine;

398) 2-(R)-(1-(R)-(1-(3-methyl)naphthyl)ethoxy)-3-(S)-phenyl-4-(3- (2-oxo-1,3-imidazole)methylmorpholin.

EXAMPLE 88

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

The title compound was obtained from 3-(S)-(4-forfinal)- 4-benzyl-2-morpholine (from example 59) in a manner analogous to the method of example 67. Mass spectrum (S1): m/z 528 (M+H). 1H NMR spectrum (CDCl3, 360 MHz, M. D.); the 2.46 (dt, 1H), 2,90 (DD, 2H), was 2.76 (DD, J=11,6, 2,0, 1H), 3,88 (d, J=13,6, 1H), 4,18 (t, 1H), 6,20 (d, J=2,8, 1H),? 7.04 baby mortality (d, J =8,4, 2H), 7.24 to to 7.32 (m, 5H), to 7.50 (m, 2H), 7,60 (s, 1H), 7,88 (DD, 2H).

EXAMPLE 89

2-(R)-(1-(2,5-Bis(trifluoromethyl) phenyl) adenylate)-3-(S)-(4-forfinal)-4-benzylmorphine

The title compound was obtained from 2-(R)-(2,5-bis (trifluoromethyl)benzyloxy)-3-(S)-(4-forfinal)-4 - benzylmorphine (example 88) in a manner analogous to the method of example 68.1H NMR spectrum (CDCl3, 250 MHz, M. D.): 2,30 (dt, J=3,5, 11,9, 1H), 2,74 (approx. d, J=9,4, 1H), 2,82 (d, J= 13,5, 1H), 3,55-of 3.60 (m, 2H), and 3.72 (d, J=13,5, 1H), 4,10 (dt, J= 2,4, 11,7, 1H), 4,22 (d, J=2,7, 1H), 4,67 (d, J=2,8, 1H), 5,18 (d, J=2,8, 1H), 6.90 to (t, J=8,7, 2H), 7,08 (c, 1H), 7,13-of 7.23 (m, 5H), was 7.36 (DD, J=5,6, 8,7, 2H), 7.62mm (d, J=8,4, 1H), 7,72 (d, J =8,4, 1H).

EXAMPLE 90

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

Capital connect and the way similar to the method of example 74. Mass spectrum (C1): m/z 438 (M+H).1H NMR spectrum (salt with HCl, d6-DMSO, 360 MHz, M. D.): 1,47 (d, J=8,7, 3H), 3,88 (d, J = 11,8, 1H), 4,20 (dt, J=3,7, 11,8, 1H), 4,50 (c, 1H), 4,58 (c, 1H), 5,17 (m, 1H),? 7.04 baby mortality (c, 1H), 7.23 percent (t, J=8,8, 2H), 7,55 (m, 2H), to 7.77 (d, J= 8,1, 1H), 7,88 (d, J=8,3, 1H), 10,1 (Shir. s, 1H).

EXAMPLE 91

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

The title compound was obtained from 2-(R)-(1-(2,5-bis (trifluoromethyl) phenyl)ethoxy)-3-(S)-(4-forfinal)research (from example 90) in a manner analogous to the method of example 70. So pl. 162-168oC. 1H-NMR-spectrum (d6-DMSO, 360 MHz, M. D.): to 1.37 (d, J =6,4, 3H), 2.40 a (dt, J=3.3V, 11,9, 1H), 2,77 (d, J=14,0, 1H), 2,86 (d, J=11,5, 1H), 3,37 (d, J=14,4, 1H), 3,48 (d, J=2,7, 1H), 3,64 (d, J= 11,0, 1H), 4,11 (t, J=9,8, 1H), 4,18 (d, J=2,8, 1H), 5,16 (K, J=6,2, 1H), 6.90 to(s, 1H), was 7.08 (t, J=8,8, 2H), 7,50 (Shir. t, 1H), 7,74 (d, J=8,3, 1H), a 7.85 (d, J=8,3, 1H), 11,25 (s, 1H), 11,35 (s, 1H).

EXAMPLE 92

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

The title compound was obtained from 2-(R)-(1-(R)-(2,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal) research (from example 90) in a manner analogous to the method of example 17. So pl. 98-100oC. Mass spectrum (S1): m/z 519 (M+H).1H NMR spectrum of d6-DMSO, 360 MHz, M. D.): 1,36 (d,7=6,4, 3H), 2,46 (dt, J= 3,26, 11,9, 1H), 2,89 (d, J =11,0, 1H), and 3.16 (d, J=13,9, 1H), what), of 13.8 (s, 1H).

EXAMPLE 93

2-(R)-(1-(R)-(2,5-Bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-forfinal)-4-(4-(2-oxo-1,3-imidazole) methyl)morpholine

The title compound was obtained from 2-(R)-(1-(R)- (2,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal) research (from example 90) in a manner analogous to the method of example 83. The sample was recrystallize from aqueous ethanol. So pl. 203-205oC. 1H NMR spectrum (d6-DMSO, 360 MHz, M. D.): 1,35 (d, J=6,4, 3H), of 2.25 (dt, J =3,1, 11,8, 1H), 2,58 (d, J=13,9, is 2.88 (d, J= 11,6, 1H), 3,24 (d, J=14,0, 1H), 3,35 (d, J=2,7, 1H), 3,64 (DD, J=9,6, 1H), 4.09 to (t, J=9,8, 1H), of 4.16 (d, J=2,7, 1H), 5,14 (K, J=6,5, 1H), 5,97 (c, 1H), 6.89 in (s, 1H), 7,07 (t, J =8,7, 1H), 7,49 (m, 1H), 7,72 (d, J=8,l, 1H), 7,83 (d, J=8,3, 1H), to 9.57 (c, 1H), 9,80 (c, 1H).

EXAMPLE 94

N-Oxide 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4- (3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine

A solution of 125 mg (0.25 mmol)2-(S)-(3,5-bis(trifluoromethyl) benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H, 4H-1,2,4 - triazolo)methylmorpholine in 10 ml of methylene chloride was treated with 100 mg 80-85% 3-chloroperoxybenzoic acid, and the resulting mixture was stirred 1 h at room temperature. The reaction mixture was concentrated in vacuo, and the residue was distributed between 25 ml of ethyl acetate and 25 ml of saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with 15 ml of 0.1 n aqueous solution by chromatography residue on silica gel (column 15 ml) using a mixture of methylene chloride/methanol/water (95:5:0.5 to) as eluent received 83 mg (64%) of the title compound. Mass spectrum (NH3- Cl): m/z 519 (20% M+), 406(90%), 404(100%).1H NMR spectrum (500 MHz, CDCl3): 3,56-3,66(m, 1H), 3,80 (Shir.d, J=10,0, 1H), 3.95 to 4,20 (m, 3H), 4,43-4,47 (m, 1H), 4,50 (d, J=13,4, 1H), 4,86-4,94 (m, 3H), 7,32 (approx. s, 5H), 7,56 (s, 2H), 7,68 (s, 1H), 8,40 (Shir.s, 1H), 12,15 (Shir. s, 1H).

EXAMPLE 95

2-(S)-(3,5-Bis (trifluoromethyl)benzyloxy)-3- (S)-phenyl-4-(3-(4-(ethoxycarbonyl-1-ethyl)-5-oxo-1H, 4H - 1,2,4-triazolo)methyl)morpholine

A mixture of 250 mg (0.5 mmol) of 2-(S)- (3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo - 1H, 4H-1,2,4-triazolo) methylmorpholine, 70 mg (0.5 mmol) of N, N-diisopropylethylamine and 100 mg (1-chloroethyl)ethylcarbonate in 15 ml of dichloroethane was heated under reflux for 16 hours TLC showed that the reaction was incomplete. The dichloride was replaced with toluene. In the reaction mixture was added 70 mg of N,N - diisopropylethylamine and 100 mg (1-chloroethyl)-ethylcarbonate and a mixture of 24 h was heated under reflux. At this time have introduced an additional 70 mg of N,N-diisopropylethylamine and 100 mg (1 - chloroethyl)ethylcarbonate, and the resulting mixture is boiled for 24 hours under reflux. The reaction mixture was cooled to room temperature and distributed between 25 ml of ethyl acetate and 25 ml of a saturated aqueous solution of sodium bicarbonate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. Org what about the product in the form of foam. Flash chromatography of the residue on silica gel (column 25 ml) using as eluent a mixture of methylene chloride/isopropanol (100: 1, vol/about.) received 68 mg (22%) of the title compound). Mass spectrum (ESI): m/z 619 (15%, M+1), 575 (100%).1H NMR spectrum (CDCl3, 500 MHz, M. D.): to 1.38 (t, J =7,0, 3H), 2,61 (dt, J=3.0 a, 12,0, 1H), 2,90 (d, J= 11,5, 1H), 3,03 (d, J =15,5, 1H), 3,63 (d, J =2,0, 1H), 3,66-3,71 (m, 2H), 4,20 (dt, J=2.0 a, 11,5, 1H), to 4.41 is 4.45 (m, 2H), 4,48 (d, J = 13,5, 1H), 4,71 (d, J=2,0, 1H), 4,81 (d, J=13,5, 1H), 7,34-of 7.48 (m, 5H), 7,47 (s, 2H), 7,72 (s, 1H), 10,1 (Shir.s, 1H).13The NMR spectrum (CDCl3, 125 MHz, M. D.): 14,2, 25,2, 50,7, 52,6, 59,2, 64,1, 64,5, 67,7, 69,7, 97,9, 121,5, 123,1(K, J= 271), 127,2, 128,7, 129,1, 131,5 (K, J=32,9), 136,0, 140,0, 146,8, 148,4, 152,3, 163,1.

EXAMPLE 96

2-(R)-(1-(R)-(3,5 - Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-(4 - monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine, Duklja salt; or 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-monophosphoryl-5-oxo-1H - 1,2,4-triazolo)methyl)morpholine, Duklja salt; or 2-(R)-(1- (R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-4-fluoro) phenyl-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl) morpholine, Duklja salt; or 2-(R)-(1-(R)-(3,5 - bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro phenyl-4-(3-(5 - oxaphosphorin-1H-1,2,4-triazolo)methyl)-morpholine, Duklja salt

A solution of 450 mg (0.84 mmol) of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl)ataxia n-utility in hexane. The resulting solution was stirred 5 min in the cold and was treated with 630 mg (1.7 mmol) of tetraethylpyrophosphate (as one portion as a solid). The cooling bath was removed and the reaction mixture was stirred at room temperature for 45 minutes the Reaction was suppressed 25 ml saturated aqueous sodium bicarbonate solution and was extracted with 50 ml diethyl ether. The organic layer was separated, washed with 25 ml saturated aqueous solution of sodium bicarbonate, 25 ml of 0.5 n aqueous solution of acid potassium sulfate, 25 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuum. Untreated dimensiony ether was dissolved in 25 ml of methanol. In ether solution was added a solution of 168 mg (1,68 mmol) of potassium bicarbonate, and the resulting mixture was first made when 2,812 at in the presence of 45 mg of catalyst, 10% palladium on coal for 75 minutes, the Catalyst was separated by filtration on a bed of celite; the reaction flask and filter cake was washed thoroughly with methanol (200 ml), the filtrate was concentrated in vacuum and dried. The residue was partially dissolved in methanol and filtered, the filtrate was concentrated and dried. Dedicated hard part was to recrystallize from isopropanol, getting 280 mg neozidanije layers resulted in the formation of emulsions. The emulsion was broken by centrifugation at 2800 rpm for 15 minutes the Aqueous layer was separated and was liofilizovane getting 188 mg (33%) compounds experimentally identified as 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 - fluoro) phenyl-4- (3- (4-monophosphoryl-5-oxo-1H-1,2,4-triazolo) methyl) morpholine, disodium salt (a solid substance).1H NMR spectrum (CDCl3500 MHz, M. D. ): USD 1.43 (d, J=6,5, 3H), 2,45 (approx. t, J =8,5, 1H), 2,80 (d, J=14,0, 1H), 2,92 (d, J=11,5, 1H), 3,47-3,66 (m, 4H), 4,25 (approx. t, J=11,5, 1H), 4,36 (d, J = 1,5, 1H), 4,94 (K, J=6,6, 1H), 7,05 (t, J=8,5, 2H), 7,31 (c, 2H), 7,52 (Shir. s, 2H), 7,71 (s, 1H).13With the NMR-spectrum (CD3OD, 125 MHz, M. D.): 24,7, 52,3, 53,4, 60,5, 70,6, 73,7, 97,2, 116,1 (d, J=21,9), 122,3, 124,6 (K, J= 271,0), 127,7, 132,3, 132,6, 132,8, 134,3, 145,2 (d, J=11,0), 147,5, 159,0 (d, 7=10,1) 164,0 (d, J=244,4).

EXAMPLE 97

2-(S)-(1-(R)-(3,5-Bis(trifluoromethyl) phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2, 4-triazolo)methyl)morpholine,salt with bis(N-methyl-D-glucamine)

Tetraethylpyrophosphate received with 71% yield using the method similar to that described Khorana and Todd (J. Chem. Soc., 2257 (1953)). A solution of 2.00 g (3.7 mmol) of 2-(S)-(1-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1H, 4H-5-oxo-1,2,4-triazolo)methyl)research and 2,80 g (5.2 mmol) of tetraethylpyrophosphate in 50 ml of dry tetrahydrofuran was cooled to 0oC. the cooled reaction of smeeks/h, maintaining the internal temperature at 0oC. After addition of NaHMDS the reaction mixture was stirred at 0oC for 15 min and extinguished 100 ml saturated aqueous sodium bicarbonate solution. The mixture after quenching was extracted with 300 ml of diethyl ether, and the ether extract was washed with 100 ml of 0.5 n aqueous solution of potassium bisulfate, 100 ml saturated aqueous sodium bicarbonate solution, 100 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuum.

Mixed solution of the crude dimensional ester in 50 ml of methanol, a solution of 1.45 g (7.4 mmol) of N-methyl-D-glucamine in 10 ml of water and 200 mg of catalyst, 10% palladium on charcoal, and the mixture was first made at a pressure of 2,812 at over 2 hours, the Reaction mixture was filtered through a pad celite, the reaction flask and filter cake was well washed with methanol (400 ml). The filtrate was concentrated in vacuum. The crude product was re-dissolved in 25 ml of methanol, the solution was added 125 ml of isopropanol, and the resulting mixture was stirred at room temperature for 30 minutes the Precipitated solid product was separated by filtration, washed with 75 ml of isopropanol, 75 ml of diethyl ether, and air-dried. Solid product rasirenoj in centrifuge tubes 50 ml The separation of layers was achieved by centrifugation with a speed of 3000 rpm for 15 minutes. The organic layers were decanted and the aqueous layers were combined, filtered and the filtrate was liofilizovane getting 3,40 g of 2-(S)-(1-(R)-(3,5-bis (trifluoromethyl) phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1 - phosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)research, as salt with bis -(N-methyl-D-glucamine, in the form of amorphous salt. Was determined by HPLC, the purity of the salt is higher than 99%.1H NMR spectrum (CD3OD, 500 MHz, M. D.): USD 1.43 (d, J=6,6, 3H), 2,46 (approx. t, J=11,2, 1H), 2,72 (s, 6H), 2,84 (d, J=13,9, 1H), 2,94 (d, J=10,3, 1H), 3,12-3,30 (m, 4H), 3,42-a 3.83 (m, 14H), 4,19-of 4.25 (m, 3H), 4,35 (d, J=2,2, 1H),? 7.04 baby mortality (t, J=8,5, 2H), 7,30 (c, 2H), 7,52 (Shir. s, 2H) 7,70 (c, 1H).13With the NMR-spectrum (CD3OD, 125 MHz, M. D.): 24,7, 34,4 52,3, 53,1, 53,5, 60,6, 64,7, 69,9, 70,4, 72,0, 72,4, 72,6, 73,6, 97,1, 116,2 (d, J=21,9), 122,3, 124,5 (K, J=271,0), 127,7, 132,3, 132,7 (K, J=33,8), 134,2 145,9, 147,7, 158,9, 163,9 (d, J=245,3).

EXAMPLE 98

Typical pharmaceutical compositions containing the compound of the invention

A. Dry gelatin capsules containing 5 mg of active ingredient per capsule

The ingredient Quantity per capsule (mg)

Active ingredient - 5

Lactose - 194

Magnesium stearate - 1

Capsule (size No. 1) - 200

The active ingredient can be crushed into powder N 60, lactose and magnesium stearate to obtain since is a group of about 10 min to fill in dry gelatin capsule No. 1.

Century Tablets

A typical tablet would contain the active ingredient (25 mg), pre-klasterizovannykh starch USH (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).

C. Suppositories

Typical finished formulation in the form of suppositories contain the active ingredient (range: 0.08-1.0 mg), mixed and calcium disodium salt of ethylenediaminetetraacetic acid (0.25-0.5 mg), and polyethylene glycol (775-1600 mg). Other suppositories can be manufactured using bottled hydroxytoluene (0.04-0.08 mg) instead of the above salt and hydrogenated vegetable oil (675-1400 mg), for example Suppjcire L., Wecobee F. S. , Wecobee M, Witepspls and others, instead of polyethylene glycol.

D. Injectable form

A typical injectable ready preparative form contains the active ingredient, anhydrous secondary acidic sodium phosphate (11.4 mg) and water for injection (1.0 ml).

Although this invention has been described and illustrated with reference to some specific embodiments of the invention, the specialists usually understand what can be done in various adaptations, changes, modifications, substitutions, omissions or additions in the way and writing without derogating from sunstyle, may be suitable as a result of changes in the susceptibility of a mammal, which treat any indications of the compounds of the invention mentioned above. Similarly, the observed specific pharmacological reactions may vary according to or depending on the specific active compounds or whether pharmaceutical carriers, as well as the type of the finished formulation and method of an applied introduction, and such expected changes or differences in the results are discussed in accordance with the purpose and practical use of the present invention. Therefore, it is assumed that the invention should be determined by the scope of the claims which follows, and that the claims should be interpreted as broadly as is reasonable.

1. Substituted morpholines of the formula (I)

< / BR>
or their pharmaceutically acceptable salt,

where R2and R3each means hydrogen,

R6, R7and R8independently selected from the group consisting of hydrogen, fluorine or CF3;

R11, R12and R13each independently mean hydrogen or halogen;

A represents nesetril, 5-oxo-1,2,4-triazolyl, 2-oxo-1,3-imidazolyl or imidazolyl, replaced by X, where X represents the residue of salt phosphoryla-PO(O-)22M+and M+is a pharmaceutically acceptable monovalent a counterion;

Y represents-O-;

Z represents a hydrogen atom or a C1-6alkyl;

p=0.

2. Connection on p. 1, where R2and R3each means hydrogen, R6, R7and R8independently selected from the group consisting of: 1) hydrogen, 2) fluorine, or 3) -CF3;

R11, R12and R13independently selected from the group consisting of: 1) fluorine, 2) chlorine; A is an unsubstituted C1-6alkylene; B is chosen from the group consisting of 1,2,4-triazolyl, 5-oxo-1,2,4-triazolyl, 2-oxo-1,3-imidazolyl or imidazolyl, replaced by X, where X is-PO(O-)22M+and M+is a pharmaceutically acceptable monovalent a counterion; Y represents-O-; Z represents a hydrogen atom or a C1-4alkyl; p=0.

3. Connection on p. 1, where Z represents a C1-4alkyl.

4. Connection on p. 1, where Z represents-CH3.

5. Connection on p. 1, where A represents a-CH2-.

6. Connection on p. 1, where B is chosen is Toyama from:

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

< / BR>
or its pharmaceutically acceptable salt,

where R2, R3, R6, R7, R8, R11, R12, R13A , B and Z have the values listed in paragraph 1.

9. Connection on p. 1, structural formula III

< / BR>
or its pharmaceutically acceptable salt,

where R2, R3, R6, R7, R8, R11, R12, R13A , B and Z have the values listed in paragraph 1.

10. Connection on p. 1, which is selected from the group consisting of:

1) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)-methyl)research;

2) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)-methyl)research;

3) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)-methyl)research;

4) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxaphosphorin-5-oxo-1H-1,2,4-triazolo)-methyl)research;

5) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)-methyl)research;

or its pharmaceutically acceptable salt.

12. Connection on p. 10, where the pharmaceutically acceptable salt is a salt of bis(N-methyl-D-glucamine).

13. Connection on p. 10, which represents a 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)-methyl)morpholine, bis (N-methyl-D-glucamine).

14. Connection on p. 1, which is selected from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where K+is a pharmaceutically acceptable counterion.

15. Connection on p. 14, where K+represents N-methyl-D-glucamine.

16. Connection on p. 14 formula

< / BR>
where K+is a pharmaceutically acceptable counterion.

17. Connection on p. 16, where K+is N-methyl-D-glucamine.

18. The pharmaceutical composition active blocking receptors neirokinina-1 containing a pharmaceutically acceptable carrier and an effective amount of the compounds under item 1.

19. The pharmaceutical composition according to p. 18, where the pharmaceutically acceptable carrier is a water.

20. The pharmaceutical composition according to p. 18, where the pharmaceutically acceptable carrier is a physical is in or blocking receptors neirokinina-1 in a mammal, which provides an introduction to the mammal connection on p. 1 in a quantity which is effective for combating substance P at its receptor in a mammal.

22. The method of obtaining substituted morpholino formula I

< / BR>
or their pharmaceutically acceptable salts,

where Y, Z, R2, R3, R6, R7, R8, R11, R12, R13A , B and p have the meanings specified in paragraph 1, the reaction of the compound of the formula

< / BR>
where A, B, Y, Z, p, R1, R2, R3, R6, R7, R8, R11, R12and R13have the above values, except that within such mutable values, X is hydrogen, with phosphorylethanolamine reagent in the presence of a suitable base in a period of time sufficient for obtaining compounds of structural formula I.

 

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< / BR>
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< / BR>
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--carboline" target="_blank">

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