Morpholine derivatives as sip modulators

FIELD: medicine, pharmaceutics.

SUBSTANCE: in the general formula (I), R1 is specified in cyano, (2-4C)alkynyl, (1-4C)alkyl, (3-6C)cycloalkyl, (4-6C)cycloalkenyl, (6-8C)bicycloalkyl, (8-10C)bicyclic group, each of which can be substituted by (1-4C)alkyl, phenyl, biphenyl, naphthyl each of which can be substituted by three substitutes independently specified in halogen, (1-4C)alkyl substituted as may be necessary by one or more atoms of fluorine, (2-4C)alkynyl, (1-4C)alkoxy substituted as may be necessary by one or more atoms of fluorine, amino, di(1-4C)alkylamino and (3-6C)cycloalkyl, phenyl substituted by phenoxy, benzyl, benzyloxy, phenylethyl or a monocyclic heterocycle, each of which can be substituted by (1-4C)alkyl, 5-6-merous monocyclic heterocycle containing 1-3 heteroatoms specified in N, O and S substituted as may be necessary by a halogen, (1-4C)alkyl or phenyl substituted as may be necessary by (1-4C)alkyl, and 9-10-merous bicyclic heterocycle containing 1-2 heteroatoms specified in N and O substituted as may be necessary by (1-4C)alkyl; A is specified in -CO-O-, -NH-CO-, -CO-NH, -C=C-, -CCH3-O- and a binding group -Y-(CH2)n-X-, wherein Y is attached to R1 and specified in a bond, -O-, -SO2-, -CH2-O-, -CO-, -CO-O-, -CO-NH-, -NH-CO-, -C=C- and -C≡C-; n means an integer from 1 to 7; and X is attached to a phenylene group and specified in a bond, -O-, -S-, and -NH; the ring structure B represents phenylene; R2 means H, (1-4C)alkyl substituted as may be necessary by one or more atoms of fluorine, (1-4C)alkoxy or halogen; and R3 means (1-4C)alkylene-R5, wherein the alkylene group can be substituted by one or more atoms of a halogen, or R3 means (3-6C)cycloalkylene-R5 or -CO-CH2-R5, wherein R5 means -OH, -PO3H2, -OPO3H2, -COOH or tetrazol-5-yl; R4 means H or (1-4C)alkyl; R6 means one or more substitutes independently specified in H, (1-4C)alkyl or oxo; W means -O- or -S-.

EFFECT: invention refers to (thio)morpholine derivatives of formula (I) possessing the property of a sphingosine-1-phosphate (S1P) modulator, a based pharmaceutical composition and using them.

18 cl, 1 dwg, 237 ex

 

Field of the invention

This invention relates to a new derivative of (thio)morpholine having an affinity to S1P receptors, to pharmaceutical compositions containing these compounds and to the use of these compounds for obtaining a medicinal product for the treatment, relief or prophylaxis of diseases and conditions involving any S1P receptor or in which modulation of the endogenous system transduction of signals via any S1P receptor S1P.

Art

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid, which mediates a wide range of cellular responses such as proliferation, cytoskeleton organization and migration, adhesive and rigid Assembly and morphogenesis. S1P can contact members of the gene family differentiation of endothelial cells (receptors ED D) localized in the plasma membrane, associated with G-protein receptors. To date, five members of this family have been identified as S1P receptors in different types of cells, S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8). S1P can lead to rearrangements of the cytoskeleton in many cell types by regulating the traffic of immune cells, vascular homeostasis and communication of cells in the Central nervous system (CNS) and in peripheral organ systems.

Knows h�of S1P is secreted by vascular endothelium, and is present in blood at concentrations 200-900 nanomol, and binds to albumin and other plasma proteins. This provides a stable reservoir in the extracellular fluids, and effective delivery of receptors on the cell surface with high affinity. S1P is associated with low mu affinity with these five receptors S1P1-5. In addition, platelets also contain S1P can be released locally, causing, for example, vasoconstriction. Subtypes of receptors S1P1, S1P2 and S1P3 are widely expressed and are the dominant receptors in the cardiovascular system. Furthermore, S1P1 is also a receptor on lymphocytes. S1P4 receptors are found almost exclusively in hematopoietic and lymphoid systems. S1P5 primarily (although not exclusively) expressed in the Central nervous system. The expression of S1P5 in mice, apparently, limited to oligodendrocytes, milenisium brain cells, while in rats and humans was discovered expression at the level of astrocytes and endothelial cells but not oligodendrocytes.

Modulators of S1P receptor are compounds which signal as (ant)agonists at one or more S1P receptors. The present invention relates to modulators of the S1P5 receptor, in particular agonists, and is preferable to agonists with selectivity for receptor� S1P1 and/or S1P3 due to unwanted cardiovascular and/or immunomodulatory effects. Currently found that S1P5 agonists can be used in the treatment of cognitive disorders, in particular age-related loss of cognitive function.

Although research continues with the aim of developing therapies that can be used for the treatment of age-related decline in cognitive function and dementia, they have not led to many successful results. There is therefore a need for a new therapy with desired properties.

Description of the invention

Now been discovered that derivatives of (thio)morpholine of formula (I)

in which

R1 is selected from

cyano,

(2-4C)alkenyl,

(1-4C)alkyl,

(3-6C)cycloalkyl,

(4-6C)cycloalkenyl,

(6-8C)bicycloalkyl, (8-10C)bicyclic group, each of which may be substituted (1-4C)alkyl,

phenyl, biphenyl, naftel, each of which may be substituted by one or more substituents independently chosen from halogen, (1-4C)alkyl, if necessary substituted by one or more fluorine atoms, (2-4C)alkynyl, (1-4C)alkoxy, if necessary substituted by one or more fluorine atoms, amino, di(1-4C)alkylamino, -SO2-(1-4C)alkyl, -CO-(1-4C)alkyl, -CO-O-(1-4C)alkyl, -NH-CO-(1-4C)alkyl and (3-6C)cycloalkyl,

phenyl, substituted phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle, each�th of which may be substituted (1-4C)alkyl,

monocyclic heterocycle, if necessary substituted by halogen, (1-4C)alkyl or phenyl, if necessary substituted (1-4C)alkyl,

and

bicyclic heterocycle, if necessary substituted (1-4C)alkyl;

A is selected from-CO-O-, -O-CO-, -NH-CO-, -CO-NH, -C=C-, -CCH3-O - linking group-Y-(CH2)n-X-, in which

Y is attached to R1 and selected from-O-, -S-, -SO-, -SO2-, -CH2-O-, -CO-, -O-CO-, -CO-O-, -CO-NH-, -NH-CO-, -C=C - and-C≡C-;

n means an integer from 1 to 10; and

X is attached to the phenylene/peredelnoj group selected from-O-, -S-, -SO-, -SO2-, -NH, -CO-, -C=C - and-C≡C-;

the ring structure B may contain one nitrogen atom;

R2 denotes H, (1-4C)alkyl, if necessary substituted by one or more fluorine atoms, (1-4C)alkoxy, if necessary substituted by one or more fluorine atoms, or halogen; and

R3 represents (1-4C)alkylene-R5, in which Allenova group may be substituted (CH2)2forming a cyclopropyl group, or one or two halogen atoms, or R3 denotes a (3-6C)cycloalkyl-R5 or-CO-CH2-R5, in which R5 represents-OH, -PO3H2, -OPO3H2, -COOH, -COO(1-4C)alkyl or tetrazol-5-yl;

R4 denotes H or (1-4C)alkyl;

R6 represents one or more substituents independently selected from H, (1-4C)alkyl or oxo;

W denotes-O-, -S-, -SO - or-SO2 -;

or their pharmaceutically acceptable salt, solvate or hydrate; provided that a derivative of formula (I) is not 2-(4-ethylphenyl)-4-morpholinoethyl or 4-[4-(2-hydroxyethyl)-2-morpholinyl]benzoylacetonitrile,

demonstrate the affinity to S1P receptors.

In particular, the compounds according to the invention exhibit a selective affinity for the receptor S1P5 compared with the receptor(s) S1P1 and/or S1P3.

Use of a compound 2-(4-ethylphenyl)-4-morpholinoethyl as reagent in obtaining 2-(2-kilmartin)ethyl esters of naproxen is described in Database CA [Online] Chemical Abstracts Service, Columbus, OHIO, US; 2008, Hu, Ai-Xi et al., XP002558960, retrieved from STN database access Number 2008:1527686; Huaxue Xuebao, 66 (22), 2553-2557 Coden: HHHPA4; ISSN: 0567-7351, 2008. There have been no reports of any pharmacological activity of this compound.

Similarly, Farmatsiya (Sofia), Vol.45, No. 1, 1998, pp. 3-11, XP009126794 Yordanova, K. et al. describe the use of 4-[4-(2-hydroxyethyl)-2-morpholinyl]-benzoylacetonitrile as reagent in receiving antidepressant derivatives phenylmorpholine. There have been no reports of any pharmacological activity of this compound.

In addition, only the synthesis and characterisation of 3-methyl-2-[4-(phenylmethoxy)phenyl]-4-morpholinoethyl hydrochloride is indicated in Database CA [Online] Chemical Abstracts Service, Columbus, OHIO, US; 2005, Hu, Ai-Xi et al.: “Synthesis and characterization of 2-arylmorpholine hydrochloride” Hunan Daxue Xuebao, Ziran Kexueban, vol.32, No. 4, 2005, with�R. 72-76. There have been no reports of any pharmacological activity of this compound.

Compounds of the invention are modulators of S1P receptor, in particular of the S1P5 receptor. More specifically, the compounds of the invention are agonists of the receptor S1P5. Compounds according to the invention can be used for the treatment, relief and prevention of diseases and conditions that involve (any) receptor(s) S1P - especially S1P5 - or in which modulation of the endogenous system of signal transmission via any S1P receptor S1P. In particular, the compounds according to the present invention can be used for the treatment, relief or prevention of disorders of the CNS (Central nervous system), such as neurodegenerative disorders, in particular - but not limited to cognitive disorders (in particular, age-related decline in cognitive function) and related conditions, Alzheimer's disease, (vascular) dementia, Niemann-pick and cognitive deficits in schizophrenia, obsessive-compulsive behavior, major depression, autism, multiple sclerosis, pain, etc., Preferably, compounds according to the present invention can be used to treat, relief or prevention of cognitive disorders (in particular, age-related loss of cognitive function) and related �of ostani.

In embodiments, the ring structureBrepresents a phenylene.

In an embodiment, compounds have the structure (II)

In another embodiment the compounds have the formula (I) in which R3 is selected from -(CH2)2-OH, -CH2-COOH, -(CH2)2-COOH, -(CH2)3-COOH, -CH2-CHCH3-COOH, -CH2-C(CH3)2-COOH, -CHCH3-CH2-COOH,-CH2-CF2-COOH, -CO-CH2-COOH, 1,3-cyclobutyl-COOH, -(CH2)2-PO3H2, -(CH2)3-PO3H2, -(CH2)2-OPO3H2, -(CH2)3-OPO3H2, -CH2-tetrazol-5-yl, -(CH2)2-tetrazol-5-yl and -(CH2)3-tetrazol-5-yl. Preferred groups R3 are selected from-CH2-COOH, -(CH2)2-COOH, -(CH2)3-COOH, -CH2-CHCH3-COOH, -CH2-C(CH3)2-COOH, -CHCH3-CH2-COOH, -(CH2)2-PO3H2, -(CH2)3-PO3H2and -(CH2)2-OPO3H2and, in particular, -(CH2)2-COOH and -(CH2)2-PO3H2. Most preferred is -(CH2)2-COOH.

In another embodiment, the implementation of W denotes-O - or-S-. In preferred embodiments, W represents O-.

In another embodiment, R4 denotes H or methyl and, in particular, R4 denotes N.

In another embodiment, the compounds have the formula (I) in which R2 denotes H, methyl, methoxy, trifluoromethyl, deformity, triptoreline, deformedarse, Cl or F. In other preferred embodiments, R2 denotes H or trifluoromethyl.

Further, in an embodiment, A is selected from-CO-O-, -NH-CO-, -CO-NH, -C=C-, -CCH3-O - linking group-Y-(CH2)n-X-, in which

Y is attached to R1 and selected from-O-, -SO2-, -CH2-O-, -CO-, -CO-O-, -NH-CO-, -C=C - and-C≡C-; n is an integer from 1 to 7; and X is attached to the phenylene/peredelnoj group selected from-O-, -S - and-NH. Preferably A is selected from CO-NH, -C=C-, -CCH3-O - linking group -(CH2)n-X - and-O-(CH2)n-X-. In preferred embodiments, A denotesCH2-O-.

In other embodiments, R1 is selected from cyano, ethinyl, (1-4C)alkyl, cyclopentyl, cyclohexyl, cyclohexenyl, 6,6-dimethyl-bicyclo[3.1.1]hept-2-yl, indanyl, if necessary substituted bromide, biphenyl, naftel, phenyl, if necessary substituted one, two or three substituents, independently selected from chlorine, fluorine, bromine, (1-4C)alkyl, (2-4C)alkynyl, (1-4C)alkoxy, dimethylamino, trifloromethyl, �reformatory and (3-6C)cycloalkyl, and R1 is further selected from phenyl, monosubstituted phenoxy, benzyl, benzyloxy, phenylethyl, pyrazolyl or triazolyl, and R1 is further selected from pyrazolyl, thiazolyl, oxadiazolyl, teinila, tetrahydrofuranyl, pyridinyl, tetrahydropyranyl, each of which can be substituted by chlorine, (1-4C)alkyl or phenyl, substituted (1-4C)alkyl, and R1 is further selected from indolyl, imidazopyridine, dihydrobenzofuranyl and benzodioxane, each of which may be substituted (1-4C)alkyl. In preferred embodiments, R1 is selected from ethinyl, (1-4C)alkyl, cyclopentyl, cyclohexyl, cyclohexenyl, biphenyl, naftel, phenyl, if necessary substituted one, two or three substituents, independently selected from chlorine, fluorine, bromine, (1-4C)alkyl, (1-4C)alkoxy, dimethylamino, trifloromethyl and triptoreline, and further selected from phenyl, monosubstituted phenoxy, benzyl, benzyloxy, phenylethyl, pyrazolyl or triazolyl, and further selected from thiazolyl, teinila, tetrahydrofuranyl, pyridinyl, tetrahydropyranyl, each of which may be substituted with chlorine or (1-4C)alkyl, and benzodioxane. In particular, R1 is selected from (1-4C)alkyl, cyclopentyl, cyclohexyl, pyridinyl and phenyl, the latter two groups may be substituted by one or two substituents, independently selected from chlorine, fluorine, bromine, (1-4C)alkyl, (1-4C)and�cocci and trifloromethyl. In preferred embodiments, R1 represents (1-4C)alkyl or dichlorophenyl.

In an extremely preferred embodiment of the invention R1 represents 2,6-dichlorophenyl; A denotes a connecting group,- Y-(CH2)n-X-where Y is attached to R1 and denotes a bond, n=1, and X is attached to the phenylene group and a represents-O-; R2 represents H; R3 represents -(CH2)2-COOH; and R4 denotes N.

In other preferred embodiments, R1 represents (1-4C)alkyl; A denotes a connecting group,- Y-(CH2)n-X-where Y is attached to R1 and denotes a bond, n is an integer selected from the integers from 1 to 6, and X is attached to the phenylene/peredelnoj group and represents-O - or a bond; R2 denotes H; R3 is selected from -(CH2)2-COOH, -(CH2)3-COOH, -CH2-CHCH3-COOH, -CH2-C(CH3)2-COOH, -CHCH3-CH2-COOH, -(CH2)2-PO3H2, -(CH2)3-PO3H2and -(CH2)2-OPO3H2; and R4 denotes N. Preferably R1 and -(CH2)n-together denote a linear octillo group. Further preferably, R3 represents -(CH2)2-PO3H2. In another preferred embodiment of the X denotes-O-.

The term halogen refers to fluorine, chlorine, bromine or iodine. Preferred ha�ohanami are fluorine and chlorine, and in particular chlorine.

The term (1-4C)alkyl means a branched or unbranched alkyl group having 1-4 carbon atoms, for example methyl, ethyl, propyl, isopropyl and butyl. The preferred alkyl group is methyl.

The term (1-4C)alkoxy means alkoxygroup having 1-4 carbon atoms in which the alkyl group is as defined above. Preferred alkoxygroup is methoxy.

The term (1-4C)alkylene means a branched or unbranched alkylenes group having 1-4 carbon atoms, e.g., methylene, -CCH3CH2etc. In the definition of R3, which stands for (1-4C)alkylene-R5, one or more of the carbon atoms in alkalinous group can (among other things) to be independently substituted (CH2)2with obrazovanie cyclopropyl group, i.e., forming the group R3, such as

The term (2-4C)alkynyl means a branched or unbranched alkylamino group having 2-4 carbon atoms, in which the triple bond may be present in the group in various positions, for example, ethinyl, propargyl, 1-butynyl, 2-butynyl, etc.

The term (3-6C)cycloalkyl means a cyclic alkyl group having 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Preferred are cyclopentyl and cyclohexyl.

The term (4-6C)cycloalkenyl means a cyclic alkenyl group having 4-6 carbon atoms and comprising one or two double bonds, for example cyclohexenyl.

The term (3-6C)cycloalkyl means a cyclic alkyl group having two attachment points. Preferred is 1,3-CYCLOBUTANE having the structure

The term (6-8C)bicycloalkyl means of a condensed ring system of two cycloalkyl groups, together with 6-8 carbon atoms, such as bicyclo[3.1.1]hept-2-yl.

The term (8-10C)bicyclic group means a condensed ring system of aromatic and non-aromatic ring structure, together with 8-10 carbon atoms, for example indane.

The term monocyclic of heterocycl covers monocyclic heteroaryl groups and non-aromatic heterophilically group, for example, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxane, morpholinyl, etc.

The term bicyclic heterocycle covers bicyclic heteroaryl groups and non-aromatic heterobicyclic group, for example, indole, indazole, isoindole, indolizine, benzimidazole�, imidazothiazoles, imidazopyridines, benzofuranyl, dihydrobenzofuranyl, benzodioxolyl, chinoline, ethenolysis, hemolysins, tetrahydroisoquinoline, etc.

In relation to substituents, the term "independently" means that the substituents may be the same or different from each other in the same molecule.

Compounds according to the invention can accordingly be obtained by the methods available in the art, and as illustrated in the experimental section of this description.

Compounds according to the present invention can contain one or more centers of asymmetry and may thus constitute racemate and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. More centres of asymmetry may be present depending on the nature of the various substituents on the molecule. Each centre of asymmetry independently of proizvode two optical isomers, and all possible optical isomers and diastereomers in mixtures as pure or partially purified compounds are included in the scope of this invention. The present invention includes all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be carried out, as known in the art, �metodologia appropriate modification, disclosed here. Their absolute stereochemistry may be determined by x-ray crystallography of crystalline products or crystalline intermediates which derivatized, if necessary, a reagent containing the center of asymmetry of known absolute configuration. If desired, racemic mixtures of compounds can be separated so that have been allocated to individual enantiomers. The separation can be carried out by methods known in the art, such as reaction of a combination of racemic mixtures of compounds with enantiomerically pure compound with the formation of diastereomeric mixture, followed by separation of the individual diastereomers by conventional methods such as fractional crystallization or chromatography.

Compounds may exist as polymorphs, which are also included in the present invention. In addition, the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also within the scope of this invention.

Isotope labeled compound of formula (I) or its pharmaceutically acceptable salts, including the compounds of formula (I) isotopically-labeled to be detectable by PET or SPECT, also is within the scope of the invention. The same applies to compounds of formula� (I), labeled with [13C]-, [14C]-, [3H]-, [18F]-, [125I]- or other isotopically enriched atoms, suitable for binding with the receptor or of metabolic studies.

The term "pharmaceutically acceptable salt" refers to those salts which are, within the normal medical judgment, are suitable for use in contact with tissues of humans and animals without unwanted toxicity, irritation, allergic response and the like, and are commensurate with a reasonable ratio of benefit/risk. Pharmaceutically acceptable salts are known in the art. They can be obtained by the in situ isolation and purification of the compounds according to the invention or separately, by introducing them into the reaction with pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.

Compounds of the invention may be administered enterally or parenterally. The exact dose and mode of administration of these compounds and their compositions depend on the biological activity of the compound per se, the age, body weight and sex of the patient, the individual patient's needs, who administered the drug, the degree of disorder or the needs and judgment of the doctor. In General, parenteral administration requires lower dosages than other LMS�Oba introduction, which are more dependent on adsorption. However, the dosage for humans preferably is from 0.001 to 10 mg per kg of body weight. In General, enteral and parenteral introduction in case of a dosage ranging from 0.1 to 1000 mg a day full of active ingredients.

Mixed with pharmaceutically suitable auxiliary means, for example, as described in the standard reference “Remington, The Science and Practice of Pharmacy” (21stedition, Lippincott Williams & Wilkins, 2005, see especially Part 5: Pharmaceutical Manufacturing), the compounds can be extruded into solid dosage forms such as pills or tablets, or processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension or emulsion.

In order to obtain dosage forms, for example tablets, possible to use conventional additives such as fillers, colorants, polymeric binders, etc., In General, may be any pharmaceutically suitable additive, which counteracts the function of active connections.

Suitable carrier materials which may be administered compounds of the invention include, for example, lactose, starch, cellulose derivatives, etc., or mixtures thereof, used in suitable amounts. Compositions for intravenous administration can be solutions connect�tions according to the invention in sterile isotonic aqueous buffer. If necessary, intravenous compositions may include, for example, solubilizers agents, stabilizers and/or local anesthetic to reduce pain at the injection site.

The pharmaceutical compositions according to the invention can be formulated for any route of administration, and may include at least one compound according to the present invention and its pharmaceutically acceptable salts with any pharmaceutically suitable ingredient, excipient, carrier, adjuvant or carrier.

"Pharmaceutically suitable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the composition and not to be harmful to the recipient.

In a variant implementation of the invention relates to a pharmaceutical pack or kit comprising one or more containers filled with one or more pharmaceutical compositions according to the invention. To such container(s) can be applied to various written materials such as instructions for use or notice in the form prescribed by the state body regulating the manufacture, use or sell body regulating the manufacture, use or sale, for medical or veterinary administration.

Unless otherwise indicated, all technical and scientific terms used here have the same �the value, as is commonly understood by a specialist in the field of technology to which this invention relates. Although methods and materials similar or equivalent described herein can be used in the practice or testing of the present invention, suitable methods and materials described in this document.

Description of the DRAWINGS

Figure 1. The percentage of alternatie in young and old male mice C57BL/6J in the T-maze, treated with either vehicle (control group), or the connection34b(10 mg/kg; oral).

The following examples are intended to further a more detailed illustration of the invention.

EXAMPLES

§1. MATERIALS AND METHODS:

The spectra of nuclear magnetic resonance (1H NMR) were determined in the indicated solvent using a Bruker Avance-400 I with a 9.4 T magnet (1H: 400 MHz,13C: 100 MHz), equipped with a broadband inverse BBI head with Z-gradient and ATM, or a Bruker Avance DRX 600 with a 14.1 T magnet equipped with inverse triple resonance grigorovka TXI Z-gradient and ATM, at 300 K, unless otherwise noted. Spectra were determined in deuteronom chloroform(CDCl3) with 99.8% atom D; ordimethylsulfoxide-d6(DMSO-d6) containing 0.03 vol./about. % tetramethylsilane; both obtained from Aldrich Chemical; shifts (δ) are given in ppm slabovolnogo shift from tetramethylsilane. Binding constants J are given� in Hz. The shape of the peaks in the NMR spectra marked with the symbol 'square' (Quartet), 'CAD.' (doublet of quartets), 't' (triplet), 'dt' (doublet of triplet), 'd' (doublet), 'DD' (doublet of doublet), 's' (singlet), 'br.with' (broadened singlet) and 'm' (multiplet). NH and HE signals were identified after mixing the sample with a drop of D2O.

Melting point was recorded on the instrument for measuring the Büchi melting point B-545.

All reactions involving moisture-sensitive compounds or conditions carried out in an anhydrous atmosphere of nitrogen.

The reactions were checked using thin-layer chromatography (TLC) on tablets covered with a plastic with silica gel (pre-coated with silica gel Merck 60 F254) with the indicated eluent. Spots were visualized with UV light (254 nm) or I2.

Liquid chromatography - Mass spectrometry (LC-MS)

System A: Column: Acquity UPLC BEH C18 1.7 μm, 50 × 2.1 mm with 1.7 µm particles. Column thermostating in a drying oven column oven at 45°C.

Detection: Diode array from 210 to 260 nm

stagetotal time (min)flow (µl/min)A(%)B(%)
00 800955
10,1800955
24,58001090
358001090
45,01800955

A=a 99.9% water with 0.1% CH3COOH

B=99.9% of CH3CN with 0.1%CH3COOH

System B: Column: Waters Sunfire C18, 30 × 4.6 mm with 2.5 µm particles. Column thermostating in a drying Cabinet for speakers at 23°C.

Detection: UV/VIS-meter with a wavelength of 254 nm + evaporative light scattering detector operating at 70° Celsius and a pressure ofN21.7 bar.

stagetotal time (min)flow (µl/min)A(%)B(%)
00 1800955
11,818000100
22,618000100
32,81800955
43,01800955

A=a 99.9% water with 0.1% HCOOH

B=99.9% of CH3CN with 0.1% HCOOH

Marked retention time (Rtfor System B is given for the peak in the chromatogram of the full ion current (TIC), which showed a mass for [M+H]+within 0.5 amu accuracy accurate calculation of the MW and had an associated peak in the chromatogram of evaporative light scattering (ELS) % relative area (cleanliness) >85%.

§2. GENERAL ASPECTS of SYNTHESES

Suitable synthesis of the claimed compounds and intermediate compounds containing 2-allmotiongroup, consistent ways, as described below; see figure 1.

Scheme 1

Q1denotes groups�, equivalent to R1-A, or a group which can be converted into R1-A.Q2refers to a group, equivalent to R3, or a group which can be converted into R3. For details, see the complete details given below.

The synthesis begins with the appropriately substituted methylvinylketone (II). Appropriately substituted methylvinylketone commercially available or can be obtained from other commercially available methylvinylketone, for example, O-alkylation (not)substituted 4-hydroxyacetophenone. This O-alkylation can be carried out with a suitable alkylating agent such as 1-bromooctane or benzyl bromide, in solvents, such as dimethylsulfoxide (DMSO), acetone or acetonitrile, in the presence of base, such as potassium hydroxide or potassium carbonate, at temperatures from 0°C to 60°C. As another example, 1-(4-benzyloxy-3-trifluoromethyl-phenyl)-atanan was obtained from 4'-fluoro-3'-(trifluoromethyl)methylvinylketone reaction with benzyl alcohol in the presence of strong bases, such as tert-butoxide potassium in a solvent such as tetrahydrofuran, at a temperature of approximately 70°C.

Appropriately substituted methylvinylketone (II) bromilow, yielding 2'-bromoacetophenone (III). Bromination can be carried out with copper bromide (II) in a suitable solvent, such as utilizata�, with heating to reflux; the reaction of the corresponding similaralcohol ether, obtained with DIPEA and TMSOTf, 0°C, with NBS in a solvent such as dichloro methane at ambient temperature; or with Tetra-N-butylammonium tribromide, in a solvent such as methanol, at ambient temperature.

The reaction of 2'-bromoacetophenone (III) with benzyl amine, in a solvent such as ethanol and chloroform, at temperatures from 0°C to ambient temperature gives aminoketone (R4=H), which directly reduced with a reducing agent such as sodium borohydride, in a solvent such as ethanol and chloroform, at temperatures from 0°C to ambient temperature, yielding the alcohols (IV, R4=H). Alternatively, 2'-bromoacetophenone (III) can be restored with a suitable reducing agent, such asNaBH4, in a solvent such as 1,4-dioxane, at ambient temperature, followed by treatment with base such as KOH in a mixture of water and a suitable solvent, such asEt2O, getting 2-aryloxyalkyl, which, when treated with benzylamine at 80°C, to give the amino alcohols (IV, R4=H). Another method for the synthesis of amino alcohols (IV, R4=Me) is performed by reaction of the appropriately substituted methylvinylketone with trimethylsilyl cyanide in the presence of a Lewis acid, such as Jodi� zinc, at ambient temperature, in pure form, followed by reduction of intermediate compounds of cyanohydrin reducing agent such as lithium-aluminiumhydride, in a solvent such as tetrahydrofuran, and subsequent formation of imina with benzaldehyde in the presence of an acid catalyst such as p-toluensulfonate acid, in a solvent such as toluene, and finally the restoration of the intermediate imina sodium borohydride, in a solvent such as methanol, at temperatures from -15°C to ambient temperature.

Aminoalcohols (IV) can be introduced into the reaction with the activated monochloroacetic acid or bromoxynil acid in a solvent such as dichloro methane, with a base, such as triethylamine, and then cyklinowanie in a solvent such as 2-propanol, with a base, such as potassium hydroxide, to obtain the morpholine-3-ones. These morpholine-3-ones can then be restored by the reducing agent such as boron hydride, in a solvent such as tetrahydrofuran, at temperatures from 0°C to ambient temperature, to obtain N-benzyl and morpholines (V). Some of the N-benzyl and morpholines (V) can be converted to other N-benzyl morpholines (V), see Scheme 2. For example, N-benzyl-2-(4-bromophenyl)-morpholine (V-Br) was used as the starting material in the following sequence:

Thus�Ohm, treatment V-Br n-butyl lithium at -75°C in a solvent such as tetrahydrofuran or a simple diethyl ether, followed by quenching with formamide such as N,N-dimethylformamide or N-formylmorpholine, leads to the formation of V-CHO. If the intermediate lithium quenched with a suitable isocyanate, then the image of the corresponding amides V-CONHG.

Recovery V-CHO reducing agent such as sodium borohydride, in a solvent such as methanol, at temperatures from 0°C to ambient temperature, gave benzyl alcohols V-CH2OH.

Connection type V-CH2OH may be subjected to reaction combination in the conditions of the Mitsunobu reaction with phenols in a solvent such as tetrahydrofuran or dichloro methane at ambient temperature.

Connection type V-CHO can also be subjected to reaction combination with a suitable fosfoserina, in a solvent such as tetrahydrofuran, at a temperature of about 70°C, giving compounds of the type V-CHCHG. This ylid can be obtained from a suitable phosphonium salt with a strong base such as sodium hydride, in a solvent such as tetrahydrofuran, at temperatures of about 0°C.

V-Br can also be turned into V-OH with a suitable palladium catalyst in a solvent such as 1,4-dioxane (Anderson, K. W.; T. Ikawa, Tundel, R. E., S. L. Buchwald J. Am. Chem. Soc. 2006 128(33), 10694-10695). Compounds V-OH can alkylaromatic, n�example, in terms of the transfer phase in a solvent such as water and 1,4-dioxane, with a base, such as potassium hydroxide, and a catalyst transfer phases, such as tetrabutylammonium bromide, at temperatures around the boiling point of the solvent.

Scheme 2

G denotes a group, which is part of a R1-A in the final compounds I.

In the conditions of palladium catalysis IV-Br can also be turned into V-CH2G with a suitable ORGANOMETALLIC reagent, such as reagent boron (Suzuki reaction) or zinc reagent (Negishi reaction), in a solvent such as toluene or tetrahydrofuran, at temperatures around the boiling point of the solvent. Also V-Br may be subjected to reaction combination with a suitable amine donor, such as benzophenone Yiming, in the conditions of palladium catalysis in the presence of base, such as tert-butoxide sodium, in a solvent such as toluene, at temperatures of about 100°C. Subsequent treatment with an aqueous solution of acid, such as hydrochloric acid, at ambient temperature leads to intermediate compounds V-NH2. V-NH2 may be introduced into reaction with a suitable alkylating agent and a base, such as N-ethyldiethanolamine, in a solvent such as methanol, at ambient temperature, to obtain secondary amines V-NHCH2G. V-NH2 can�e to be introduced into reaction with a suitable reagent the acylation, such as acyl chloride, with a suitable base, such as N-ethyldiethanolamine, in a solvent such as acetonitrile, at temperatures from 0°C to ambient temperature, to obtain amides V-NHCOG.

Removal of the N-benzyl group at N-benzyl the morpholines (V) can be carried out by hydrogenation in a solvent such as ethanol, and a catalyst such as palladium hydroxide, or alternatively by reaction with ACE-Cl in a solvent such as 1,2-dichloroethane, followed by reaction of the intermediate carbamate with methanol. Received morpholines (VI) can be converted into other morpholines (VI) sequence of stages. Cm. scheme 3. For example, (VI-OH) may be protected with a suitable nitrogen protective group (P. G. M. Wuts, T. W. Greene, Protective groups in organic synthesis, 4th ed., John Wiley & Sons, 2006), such as tert-butyloxycarbonyl (BOC), by reaction with di-tert-butyl bicarbonate in a solvent such as acetonitrile, at ambient temperature. Then the phenolic group may be introduced into reaction with a suitable alkylating reagent in a solvent such as acetonitrile, in the presence of base such as potassium carbonate, at ambient temperature. After that, tert-butyloxycarbonyl (BOC) group can be removed by treatment with acid such as hydrogen chloride, in a solvent such as ethanol, at temperatures from temperature environment�th environments up to 60°C, giving modified morpholine (VI-OG).

Scheme 3

Morpholines (VI) can be introduced into the reaction with ether (meth)acrylic acid, in the so-called Michael reaction, in a solvent such as acetonitrile, methanol or N,N-dimethylformamide, at temperatures from ambient temperature up to 85°C, and eventually with the addition of a certain amount of base, such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-s, to obtain the esters morpholine-4-yl-propionic acid (VIIa, Q2=CH2CH2COOR'). If these ethers, morpholine-4-yl-propionic acid (VIIa, Q2=CH2CH2COOR') contain a phenolic group (VIIA-HE), these compounds can be modified as follows: by reaction with a suitable alkylating reagent such as alkyl bromide or alkyl chloride, in the presence of base such as potassium carbonate or cesium carbonate, in a solvent, such as acetonitrile and/or tetrahydrofuran, at ambient temperature, to produce a compound type VIIa-OG. Alternative, VIIA-IT can be turned into VIIa-OG reaction with a suitable alcohol in the presence of triphenylphosphine and a suitable azo-reagent, such as diisopropyl azodicarboxylate, in a solvent such as tetrahydrofuran or dichloro methane. In addition, VII-IT can be converted into the corresponding ether triptime�sulfonovoj acid by reaction with N-phenylbis(perform-sulfonamide) in the presence of base, such as Et3N, in a solvent, such asCHCl3at a temperature of from ambient temperature to 60°C. the Ether triftormetilfullerenov acid can be Wedn react with thioacetate under palladium catalysis in a solvent such as toluene, at 110°C, giving the thioethers VIIA-SAc. Hydrolysis in alkaline medium thioether with a base, such as NaOH, in a solvent such as EtOH and water, at 0°C, directly followed by alkylation with a suitable alkylating agent at ambient temperature gives the thioethers VIIa-SG.

Connection type VIIa-OG and VIIa-SG can be converted into a final compound I is a basic or acidic hydrolysis of the ester, depending on the nature of the group E. for Example, complex tert-butyl ester (E=C(CH3)3) may be treated with acid such as trifluoroacetic acid or hydrogen chloride, in a solvent, such asCH2Cl2or 1,4-dioxane, at ambient temperature. As a further example, a complex of ethyl esters (E=CH2CH3) may be treated with base, such as sodium hydroxide or lithium hydroxide, in solvents such as ethanol, THF and/or water, at temperatures ranging from ambient temperature to 70°C.

Compounds of type VI can also be substituted on the nitrogen by reaction with a suitable alkylating reagent such as alkyl, bromo� or alkyl chloride, in the presence of base such as potassium carbonate, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, if necessary in the presence of sodium iodide, in a solvent such as acetonitrile or DMF, at temperatures ranging from ambient temperature to 100°C. alternatively, compounds of type VI can also be allroutes on the nitrogen of the acid chloride acid or other activated allermuir reagent, in the presence of base, such as N-ethyldiethanolamine, in a solvent such as acetonitrile, at ambient temperature.

Compounds of type VI can also be modified at the nitrogen group of the ether of 2,2-debtor-propionic acid, in accordance with the sequence of stages (Cheguillaume A., Lacroix S., Marchand-Brynaert J. Tetrahedron Letters 2003, 44, 2375): First reaction with 1H-benzotriazole-1-methanol in a solvent such as ethanol, at temperatures of about 50°C; followed by reaction with a zinc reagent derived from zinc dust, trimethylsilylpropyne and bromodifluoroacetate, in a solvent such as tetrahydrofuran, at temperatures of about 70°C.

Morpholines type VI can also be modified at the nitrogen by reaction with vinylphosphonate the diester in a solvent such as acetonitrile, at temperatures of about 85°C.

Compounds of type I, in which R3=(CH2)2OPO3H2can be synthesized as shown in scheme 4.

Diagram 4

Thus a suitable substituted morpholine VI is introduced into reaction with 2-(2-chloroethoxy)tetrahydro-2H-PYRAN in the presence of base such as potassium carbonate and sodium iodide, in a solvent such as DMF, at a temperature of about 100°C. Tetrahydro-2H-PYRANOVA group is removed by treatment with an acid such as p-toluensulfonate acid, in a solvent such as methanol, at ambient temperature. The formed alcohol is then treated phosphoramidite reagent, such as di-tert-butyl-N,N-diisopropylphosphoramidite, in the presence of tetrazole, in a mixture of solvents such as THF, CH2Cl2andCH3CN, at ambient temperature and then oxidized with an oxidizing reagent such as hydrogen peroxide or tert-butylhydroperoxide, in the same solvent at ambient temperature. The partial hydrolysis of phosphate esters can be carried out in conditions that depend on the nature of groups E. g di-tert-butyl esters can be hydrolysed by treatment with an acid, such as TFA, in a solvent, such asCH2Cl2at ambient temperatures. As another example, a complex of diethyl esters can be introduced into the reaction with bromotrimethylsilane in a solvent, such asCH2Cl2at a temperature of environ�happening, with subsequent treatment with methanol to affect hydrolysis.

Compounds in which W represents-S-, -SO - or-SO2-, can be prepared as described below and shown in scheme 5.

Scheme 5

Q1refers to a group equivalent to R1-A, or a group which can be converted into R1-A. Q2refers to a group, equivalent to R3, or a group which can be converted into R3. For details, see the complete details given below.

The synthesis begins with the appropriately substituted ester brompheniramine acid. Appropriately substituted esters brompheniramine acids are commercially available or can be obtained according to methods known from the literature. Ether brompheniramine acid is introduced into reaction with 2-aminoethanethiol in the presence of base such as potassium carbonate, in a solvent such as ethanol, at ambient temperature, yielding 2-aryl-thiomorpholine-3-ones (VIII). These thiomorpholine-3-ones can then be restored by the reducing agent such as boron hydride, in a solvent such as tetrahydrofuran, at temperatures from 0°C to ambient temperature, to obtain 2-aryl-thiomorpholine (IX). Thiomorpholine (IX) can be introduced into the reaction with ether (meth)acrylic acid in the so-called Michael reaction in solvent�, such as acetonitrile, methanol or N,N-dimethylformamide, at temperatures from ambient temperature up to 85°C and eventually with the addition of a certain amount of base, such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, leading to ethers, morpholine-4-yl-propionic acid (X, Q2=CH2CH2COOR'). If these esters thiomorpholine-4-yl-propionic acid (X, Q2=CH2CH2COOR') substituted by bromine (X, Q1=bromine, the bromine may be replaced by iodine (X, Q1=I) in the reaction with sodium iodide catalyzed by copper iodide (I), in the presence of N,N-dimethylethylenediamine, in a solvent such as 1,4-dioxane, at temperatures of about 130°C, in a closed vessel. Then iodine (X, Q1=I), can be replaced with a suitable alcohol in the presence of base, such as cesium carbonate, and kataliziruetsa copper iodide (I) and 1,10-phenanthroline in a solvent such as toluene, at a temperature of about 110°C, to obtain compounds in which Q1 is equivalent to R1-A, and Q2=CH2CH2COOR'. If R' is tert-butyl, the ester may be hydrolysed by acid, such as hydrochloric acid, in a solvent such as 1,4-dioxane, at temperatures ranging from ambient temperature to 80°C, giving a compound (I, W=S). Thiomorpholine (X, W=S, Q1=R1-A, Q2=CH2CH2COOR') can be oxidized oxidizing reagent, such as peroxymonosulfate potassium (Oxone®), �rastvoritele, such as methanol/water, at temperatures from 0°C to ambient temperature, to obtain thiomorpholine-1-oxide (X, W=SO, Q1=R1-A, Q2=CH2CH2COOR'). If R' is tert-butyl, acid hydrolysis, as described for thiomorpholine, gives compounds (I, W=SO).

Thiomorpholine (IX) can be protected with a suitable nitrogen protective group (P. G. M. Wuts, T. W. Greene, Protective groups in organic synthesis, 4th ed., John Wiley & Sons, 2006), such as tert-butyloxycarbonyl (BOC), by reaction with di-tert-butyl bicarbonate in a solvent such as acetonitrile, at ambient temperature. Then thiomorpholine can be oxidized oxidizing reagent such as 3-chloroperoxybenzoic acid, in a solvent such as dichloro methane, at temperatures from 0°C to ambient temperature, to obtain thiomorpholine-1,1-dioxide (XI). Then the tert-butyloxycarbonyl (BOC) group can be removed by treatment with acid such as hydrogen chloride, in a solvent such as ethanol, at temperatures from ambient temperature up to 60°C, giving a modified thiomorpholine-1,1-dioxide (XII). Thiomorpholine-1,1-dioxide may then be introduced into the reaction in the so-called Michael reaction as described above for thiomorpholine, to produce a compound XIII (Q2=CH2CH2COOR'). In case of compound XIII is substituted by bromine (Q1=Br), they can be replaced with a suitable Speer�ohms in the presence of base, such as cesium carbonate, and kataliziruetsa a catalyst based on palladium, such as Pd(AcO)2and a suitable phosphine ligand, in a solvent such as toluene, at a temperature of about 100°C, to obtain compounds XIII (W=SO2, Q1=R1-A, Q2=CH2CH2COOR'). If R' is tert-butyl, acid hydrolysis, as described for thiomorpholine, gives compounds (I, W=SO2).

Abbreviations

ACE-Cl1-Chloroethyl chloroformate
AcClAcetyl chloride
AlCl3Aluminum chloride
9-BBN9-Borabicyclo[3.3.1]nonane dimer
BH3∙THFComplex boron hydride-tetrahydrofuran
n-BuLin-Butyl lithium
nBu4NBrTetrabutylammonium chloride
CHCl3Chloroform
CH2Cl2Dichloro methane
CH3CNAcetonitrile
Cs2CO3Sodium carbonate, cesium
CuBr2The copper bromide (II)
CuIThe copper iodide (I)
DBU1,8-Diazabicyclo[5.4.0]undec-7-ene
DIADDiisopropyl azodicarboxylate
DIPEAN,N-Diisopropylethylamine
DMFN,N-Dimethylformamide
DMSODimethyl sulfoxide
Et3NTriethylamine
Et2OSimple diethyl ether
EtOHEthanol
EtOAcThe ethyl acetate
HClHydrogen chloride
H2SO4Sulfuric acid
K2CO3Potassium carbonate
KHCO3Bicarbonate Cali�
KIPotassium iodide
KOHPotassium hydroxide
KOtBuTert-butoxide potassium
LiAlH4Lithium-aluminiumhydride
LiHMDSLithium bis(trimethylsilyl)amide
LiOHThe lithium hydroxide
MeIMethyl iodide
MeMgBrMetalmania bromide
MeOHMethanol
minMinutes
NaBH4Borohydride sodium
NaHCO3Sodium bicarbonate
NaISodium iodide
NaN3Sodium azide
NaOHSodium hydroxide
NaOtBuTert-butoxide sodium
Na2SO4 Sodium sulphate
NBSN-Bromosuccinimide
PBr3Tribromide phosphorus
Pd2dba3Tris(dibenzylideneacetone)dipalladium (0)
Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
PdCl2(PPh3)2Bis(triphenylphosphine)palladium (II) dichloride
Pd(PPh3)4Tetrakis(triphenylphosphine)palladium (0)
iPr2ODiisopropyl ether
RTAmbient temperature
SiO2Silica
TFATrifluoroacetic acid
THFTetrahydrofuran
TMSClChlorotrimethylsilane
TMSOTfTrimethylsilyl triftormetilfullerenov
p-TsOH Monohydrate p-toluensulfonate acid
ZrCl4The zirconium tetrachloride

§3. SYNTHESES of the INTERMEDIATE COMPOUNDS

ARYL(thio)MORPHOLINES

1-(4-Octyloxy-phenyl)-atanan: To a solution of 4'-hydroxyacetophenone (25,0 g; 183,6 mmol) in DMSO (300 ml) was added KOH (11.3 g; 201,9 mmol) and the reaction mixture was stirred for 1 hour at ambient temperature. After 1 hour the reaction mixture was cooled (0°C) and added 1-bromooctane (34,9 ml; 201,9 mmol). A ice bath was removed, and the reaction mixture was stirred over night at ambient temperature. The reaction mixture was extracted with a mixture of EtOAc/5% aqueous solutionNaHCO3. The organic layer was driedNa2SO4and concentrated in vacuum. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:3) to give 1-(4-octyloxy-phenyl)-Etalon (43,08 g)

1-(4-benzyloxy-2-methylphenyl)-atanan: a mixture of 4'-hydroxy-2'-methylacetophenone (are 24.88 g; 165,7 mmol)), KI (5,50 g; 33,1 mmol), K2CO3(34.3 g; 248,5 mmol) and benzyl bromide (21,7 ml; 182,2 mmol) in acetone (200 ml) was stirred overnight at ambient temperature. Then, the resulting mixture was filtered and separated between EtOAc and 5% aqueous solution�ω NaHCO3. The organic layer was dried(Na2SO4), filtered and concentrated under vacuum to give 1-(4-benzyloxy-2-methylphenyl)-Etalon, which was used as such.

1-(4-benzyloxy-3-methylphenyl)-atanan: a mixture of 4'-hydroxy-3'-methylacetophenone (10.00 g; 66.6 per mmol) and K2CO3(13,80 g, 99.9 mmol) in acetone (100 ml) was stirred at ambient temperature for 40 minutes. Was then added benzyl bromide (7.9 ml; 66.6 per mmol) and the mixture was heated to reflux for 2.5 hours. After cooling to ambient temperature the mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with 5% aqueous ammonium hydroxide solution, water and brine, dried(MgSO4), filtered and concentrated under vacuum to give 1-(4-benzyloxy-3-methylphenyl)-Etalon (15,86 g).

The following compound was obtained in a similar way:

1-(4-Benzyloxy-3-methoxy-phenyl)-atanan

1-(4-Benzyloxy-3-trifluoromethyl-phenyl)-atanan: a mixture of benzyl alcohol (10,9 ml; 104,98 mmol) and KOtBu (12,96 g; 115,5 mmol) in THF (500 ml) was heated to reflux for 10 minutes. Then added 4'-fluoro-3'-(trifluoromethyl)methylvinylketone (21,64 g; 105 mmol) and the mixture was heated to reflux for another 2 �aces. After cooling to ambient temperature, the mixture was separated between EtOAc and 5% aqueous solutionNaHCO3. The organic layer was separated, dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:2,5), obtaining 1-(4-Benzyloxy-3-trifluoromethyl-phenyl)-Etalon (22,37 g).

4-acetyl-3-trifluoromethyl-phenyl ester methanesulfonic acid: To a solution of 1-(4-hydroxy-2-trifluoromethyl-phenyl)-ethanone (29,74 g; resulting gain of 145.7 mmol) in CH2Cl2(300 ml) and THF (120 ml) at 0°C was added aEt3N (24,4 ml; 174,8 mmol). To this mixture at 0°C was added dropwise a solution of methanesulfonyl chloride (12.5 ml; 160,3 mmol) inCH2Cl2(60 ml). Then the mixture was stirred over night at ambient temperature, and poured into ice water. The layers were separated, and the organic layer was washed with 1 M aqueous HCl solution and water, dried(MgSO4), filtered and concentrated under vacuum to give 4-acetyl-3-trifluoromethyl-phenyl ester methanesulfonic acid (40,47 g), which was used as such.

The following compounds were obtained in a similar way:

4-acetyl-2-chloro-phenyl ester methanesulfonic acid

4-acetyl-3-fluoro-phenyl ester methanesulfonic acid

1-(2-chloro-4-methoxy-phenyl)-atanan

To a mixture ofAlCl3(42,08 g; 315,60 mmol) inCH2Cl2(300 ml) at -30°C was added dropwise 3-chloroanisole (22,50 g; 157,80 mmol). To this mixture was added dropwise a solution of AcCl (10,50 ml; 147,63 mmol) inCH2Cl2(100 ml) at such a speed as to keep the temperature below -15°C. the resulting mixture was stirred for 4 hours at -10°C. the mixture is Then poured on ice and extractedCH2Cl2. The combined organic layers were dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O/hexane 1:9) to give 1-(2-chloro-4-methoxy-phenyl)-Etalon (17,68 g).

2-Bromo-1-(4-octyloxy-phenyl)-atanan: To a solution of 1-(4-octyloxy-phenyl)-ethanone (43,0 g; 173,1 mmol) in EtOAc (200 ml) was added aCuBr2(77,3 g; 346,2 mmol) and heated to reflux for 2 hours. The reaction mixture was filtered through diatomaceous Earth. The reaction mixture was washed with 10% aqueous sodium thiosulfate solution and brine. The organic layer was dried overNa2SO4,concentrated in vacuo and purified by chromatography on a column (SiO2,Et2O:hexane 1:7)) to obtain 2-bromo-1-(4-octyloxy-phenyl)-Etalon (36,3 g)

1-(4-Benzyloxy-2-methyl-phenyl)-2-bromo-atanan: To a solution of 1-(4-benzyloxy-2-methylphenyl)-ethanone (42,00 g; 174,8 mmol) in MeOH (300 ml) was added Tetra-N-butylammonium tribromide (84,28 g; 174,8 mmol) and the mixture was stirred overnight at ambient temperature. Then MeOH was evaporated in vacuo, and the residue separated between EtOAc (300 ml) and 5% aqueous solutionNaHCO3. The organic layer was dried(Na2SO4), filtered, concentrated in vacuo and purified by chromatography on a column (SiO2,Et2O:hexane 1:1), obtaining 1-(4-benzyloxy-2-methyl-phenyl)-2-bromo-Etalon (49,93 g).

The following compound was obtained in a similar way:

1-(4-Benzyloxy-3-trifluoromethyl-phenyl)-2-bromo-atanan

1-(4-Benzyloxy-3-methyl-phenyl)-2-bromo-atanan: To a solution of 1-(4-benzyloxy-3-methyl-phenyl)-ethanone (12,89 g; 53,1 mmol) in CH2Cl2was added dropwise at 0°C, DIPEA (10,9 ml; 63,7 mmol) and trimethylsilyl triftormetilfullerenov (11,1 ml; 61,1 mmol). The resulting mixture was stirred at 0°C for 1 hour and was then added in one part of the NBS (10,87 g; 61,1 mmol). The mixture was allowed to warm to ambient temperature, stirred over night. The mixture is then concentrated under vacuum, the residue was dissolved in EtOAc, washed twice with water and brine, dried(MgSO4), filter�and and concentrated in vacuo, obtaining 1-(4-benzyloxy-3-methyl-phenyl)-2-bromo-Etalon (11,90 g).

The following compound was obtained in a similar way:

1-(4-Benzyloxy-3-methoxy-phenyl)-2-bromo-atanan

4-(2-bromoacetyl)-3-trifluoromethyl-phenyl ester methanesulfonic acid

4-(2-bromoacetyl)-2-hlorfenilovy ester methanesulfonic acid

4-(2-bromoacetyl)-3-forfinally ester methanesulfonic acid

1-(3-Benzyloxy-phenyl)-2-bromo-atanan

2-Bromo-1-(2-chloro-4-methoxy-phenyl)-atanan

2-Bromo-1-(5-bromo-pyridin-2-yl)-Etalon

2 Azido-1-(4-benzyloxy-phenyl)-atanan

To a mixture of 1-(4-benzyloxy-phenyl)-2-bromo-ethanone (28,55 g; 93,6 mmol) in CH2Cl2(300 ml) and water (30 ml) was added ain one part of the nBu4NBr (1,51 g; 4.7 mmol), andNaN3(6,69 g; 102,9 mmol). After 4 h at ambient temperature the layers were separated. The organic layer was washed with water, dried(Na2SO4), filtered and concentrated under vacuum to give 2-azido-1-(4-benzyloxy-phenyl)-Etalon (23,64 g).

4-oxiranyl-3-trifluoromethyl-phenyl ester methanesulfonic acid: To a solution of 4-(2-bromoacetyl)-3-trifluoromethyl-phenyl ester methanesulfonic acid (33,95 g; to 89.3 mmol) in 1,4-dioxane (150 ml) was added dropwise a solution ofNaBH4(2,37 g; of 62.5 mmol) in water (47 ml). �must register the mixture was stirred at ambient temperature for 2.5 hours, then quenched with 0.5 M aqueous HCl solution (125 ml) and was extracted with EtOAc. The combined organic layers were washed with water, dried(MgSO4), filtered and concentrated in vacuo. The residue was dissolved inEt2O (500 ml) and treated with a solution of KOH (4,19 g; 74,7 mmol) in water (100 ml). The mixture was heated to reflux for 4 hours. After cooling to ambient temperature the volatile components were removed under vacuum and the residue separated between EtOAc and water. The organic layer was washed with water, dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column(CH2Cl2) to obtain 4-oxiranyl-3-trifluoromethyl-phenyl ester methanesulfonic acid (of 23.54 g).

The following compounds were obtained in a similar way:

4-oxiranyl-3-fluoro-phenyl ester methanesulfonic acid

4-oxiranyl-2-chloro-phenyl ester methanesulfonic acid

2-(2-chloro-4-methoxy-phenyl)-oxirane

2-Amino-1-(4-benzyloxy-phenyl)-ethanol: SuspensionLiAlH4(8,18 g; 215,6 mmol) in THF (100 ml) at 0°C was added dropwise a solution of 2-azido-1-(4-benzyloxy-phenyl)-ethanone (23,05 g; of 86.2 mmol) in THF (200 ml). The mixture was stirred at 0°C for 20 min and then 2 hours at ambient temperature. Then p�therefore added water (50 ml) and 2 M aqueous NaOH (150 ml). The formed precipitate was removed by filtration through diatomaceous earth and washed with MeOH. The filtrate was concentrated in vacuo and the remaining aqueous layer was extracted withCH2Cl2. The combined organic layers were dried(Na2SO4), filtered and concentrated under vacuum to give 2-amino-1-(4-benzyloxy-phenyl)-ethanol (20,10 g)

2 Benzylamino-1-(4-octyloxy-phenyl)-ethanol: To a cooled (0°C) suspension of 2-Bromo-1-(4-octyloxy-phenyl)-ethanone (36,1 g; 110,3 mmol) in EtOH (500 ml) andCHCl3(100 ml) was added benzylamine (48,2 ml; 441,2 mmol). After 30 minutes the bath with ice was removed and the mixture was stirred for a further 2 hours at ambient temperature. Then the reaction mixture was cooled again to 0°C and added in small portionsNaBH4(6,26 g; 165,5 mmol). The resulting mixture was stirred at 0°C for 1 hour and then a further 4 hours at ambient temperature. The reaction mixture was quenched with 1 M aqueous HCl solution (750 ml) at 0°C and stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was separated between EtOAc and 2 n aqueous NaOH. The organic layer was dried(Na2SO4), filtered, concentrated in vacuo and purified by chromatography on a column (SiO2, EtOAc) to give 2-benzylamino-1-(4-OK�yloxy-phenyl)-ethanol (22,58 g)

The following compounds were obtained in a similar way:

2 Benzylamino-1-(4-bromophenyl)-ethanol

2 Benzylamino-1-(4-benzyloxy-phenyl)-ethanol

2 Benzylamino-1-(4-benzyloxy-2-methyl-phenyl)-ethanol

2 Benzylamino-1-(4-benzyloxy-3-methyl-phenyl)-ethanol

2 Benzylamino-1-(4-benzyloxy-3-trifluoromethyl-phenyl)-ethanol

2 Benzylamino-1-(4-benzyloxy-3-methoxy-phenyl)-ethanol

2 Benzylamino-1-(3-benzyloxy-phenyl)-ethanol

2-(Benzhydryl-amino)-1-(5-bromo-pyridin-2-yl)-ethanol

4-(2-benzylamino-1-hydroxy-ethyl)-3-trifluoromethyl-phenyl ester methanesulfonic acid: 4-oxiranyl-3-trifluoromethyl-phenyl ester methanesulfonic acid (of 23.54 g, 79.2 mmol) was dissolved in benzylamine (26 ml). The resulting mixture was stirred at 80°C for 4 h. After cooling to ambient temperature, was added aEt2O and the mixture was cooled to 0°C. the Formed precipitate was collected by filtration, washed withEt2O, and dried under vacuum at 40°C, receiving 4-(2-benzylamino-1-hydroxy-ethyl)-3-trifluoromethyl-phenyl ester methanesulfonic acid in the form of white solids (26,87 g), which was used as such.

The following compounds were obtained in a similar way:

4-(2-benzylamino-1-hydroxy-ethyl)-3-forfinally ether of methanesulfonic�th acid

4-(2-benzylamino-1-hydroxy-ethyl)-2-hlorfenilovy ester methanesulfonic acid

2 Benzylamino-1-(2-chloro-4-methoxy-phenyl)-ethanol

1-Amino-2-(4-benzyloxy-phenyl)-propan-2-ol: a mixture of 1-(4-benzyloxy-phenyl)-ethanone (18.50 g; is 81.8 mmol), zinc iodide (0.52 g; 1.6 mmol) and trimethylsilyl cyanide (33,8 ml; amounted to 269.8 mmol), stirred overnight at ambient temperature. Then an excess of trimethylsilyl cyanide was removed under vacuum and the residue was dissolved in THF (100 ml). The resulting solution was added dropwise to a mixture of lithium-aluminiumhydride (12,7 g; 335,2 mmol) in THF (200 ml). The mixture was heated to reflux for 2 hours. Then the mixture was cooled to 0°C and treated successively with water (13 ml), 2 M aqueous NaOH (26 ml) and water (13 ml). After that, the mixture was heated to reflux for 15 minutes, cooled again to ambient temperature, filtered through diatomaceous earth and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2, MeOH) to obtain 1-amino-2-(4-benzyloxy-phenyl)-propan-2-ol (18,15 g).

1 Benzylamino-2-(4-benzyloxy-phenyl)-propan-2-ol: A mixture of 1-amino-2-(4-benzyloxy-phenyl)-propan-2-ol (1.26 g; 4.9 mmol), benzaldehyde (0.55 ml; 5.4 mmol) and p-toluensulfonate acid (0.04 g; 0,24 mmol) in toluene (30 ml) heating�and to reflux in the apparatus of Dean-stark overnight. The mixture is then cooled to ambient temperature and the solvent was removed in vacuum. The residue was suspended in MeOH (30 ml), cooled to -15°C and treatedNaBH4(0.74 g; 19,6 mmol), adding parts. After completion of the addition the mixture was warmed to ambient temperature and stirred for one hour. Then MeOH was removed under vacuum. The residue was divided betweenEt2O and 5% aqueous solutionNaHCO3. The organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 2:1), obtaining 1 benzylamino-2-(4-benzyloxy-phenyl)-propan-2-ol (1,07 g).

4-Benzyl-6-(4-octyloxy-phenyl)-morpholine-3-one: To a solution of 2-benzylamino-1-(4-octyloxy-phenyl)-ethanol (22,50 g; 63,3 mmol) and Et3N (9,7 ml; to 69.6 mmol) inCH2Cl2(500 ml) at 0°C was added dropwise a solution of chloroacetyl chloride (5.5 ml; to 69.6 mmol) inCH2Cl2(25 ml). After 1 hour at 0°C the reaction was quenched with 1 M aqueous HCl solution (200 ml). The layers were separated, and the organic layer was washed with 5% aqueous solutionNaHCO3, dried(Na2SO4) and concentrated in vacuo. The residue was dissolved in 2-propanol (250 ml) was added KOH (4.26 g; 76 mmol). The resulting mixture was stirred p�and ambient temperature for 1 hour and then concentrated in vacuo. The crude product was separated between EtOAc and 0.5 M aqueous HCl solution. The layers were separated, and the organic layer was washed with 5% aqueous solutionNaHCO3, dried(Na2SO4) and evaporated under vacuum to give 4-benzyl-6-(4-octyloxy-phenyl)-morpholine-3-one (22,30 g), which was used as such in next step.

The following compounds were obtained in a similar way:

4-Benzyl-6-(4-bromophenyl)-morpholine-3-one

4-Benzyl-6-(4-benzyloxy-phenyl)-morpholine-3-one

4-Benzyl-6-(4-benzyloxy-2-methyl-phenyl)-morpholine-3-one

4-Benzyl-6-(4-benzyloxy-3-methyl-phenyl)-morpholine-3-one

4-Benzyl-6-(4-benzyloxy-3-methoxy-phenyl)-morpholine-3-one

4-Benzyl-6-(4-benzyloxy-3-trifluoromethyl-phenyl)-morpholine-3-one

4-Benzyl-6-(4-benzyloxy-phenyl)-6-methyl-morpholine-3-one

4-Benzyl-6-(3-benzyloxy-phenyl)-morpholine-3-one

4-Benzyl-6-(2-chloro-4-methoxy-phenyl)-morpholine-3-one

4-Benzhydryl-6-(5-bromo-pyridin-2-yl)-morpholine-3-one

The following compounds are obtained similarly from phenyl esters of methanesulfonic acid using 2.5 equivalent of KOH instead of 1.25 equivalent.

4-Benzyl-6-(4-hydroxy-2-trifluoromethyl-phenyl)-morpholine-3-one

4-Benzyl-6-(2-fluoro-4-hydroxy-phenyl)-morpholine-3-one

4-Benzyl-6-(3-chloro-4-hydroxy-phenyl)-morpholine-3-one

N-[2-(4-Benzyloxy�-phenyl)-2-hydroxyethyl]-2-chloracetamide : To a mixture of 2-amino-1-(4-benzyloxy-phenyl)-ethanol (20,10 g; 82,6 mmol), Et3N (13,82 ml; 99,1 mmol),CH2Cl2(200 ml) and MeOH (20 ml) was added dropwise at -10°C, chloroacetyl chloride (7,24 ml; at 90.9 mmol). The resulting mixture was allowed to warm to ambient temperature and stirred overnight and then concentrated in vacuo. The residue was purified by flash chromatography (SiO2, EtOAc) to give N-[2-(4-benzyloxy-phenyl)-2-hydroxyethyl]-2-chloracetamide (17,45 g).

6-(4-Benzyloxy-phenyl)-morpholine-3-one: To a solution of KOtBu (6,68 g; 59.5 mmol) in 2-methyl-2-butanol (100 ml) was added dropwise a solution of N-[2-(4-benzyloxy-phenyl)-2-hydroxyethyl]-2-chloracetamide (17,30 g; for 54.1 mmol) in THF (100 ml). The resulting mixture was stirred for 1 hour at ambient temperature and then concentrated in vacuo. The residue was dissolved in CH2Cl2and was treated with 1 M aqueous HCl solution at 0°C. the Layers were separated, and the aqueous layer was extracted withCH2Cl2. The combined organic layers were dried(Na2SO4), filtered and concentrated under vacuum to give 6-(4-benzyloxy-phenyl)-morpholine-3-one (14,10 g).

4-Benzyl-6-(4-benzyloxy-phenyl)-2,2-dimethyl-morpholine-3-one and 4-Benzyl-6-(4-benzyloxy-phenyl)-2-methyl-morpholine-3-one: To a solution of 4-benzyl-6-(4-benzyloxy-phenyl)-morpholine-3-it (,90 g; 18,5 mmol) in THF (100 ml) at -78°C was added dropwise a solution of LiHMDS in THF (18.5 ml; 1.00 mol/l; 18.5 mmol). The resulting mixture was stirred at -78°C for 15 minutes, then added MeI (1,15 ml; 18.5 mmol) and the resulting mixture was stirred for 1 hour at -78°C. the Sequence of addition of LiHMDS and MeI was repeated three times. After the last addition of MeI the mixture was allowed to warm to ambient temperature and stirred over night. Then 5% aqueous solutionNaHCO3was added to the mixture and was extracted with EtOAc. The combined organic layers were dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O/hexane 1:1) to give two compounds. Less polar compound was a 4-benzyl-6-(4-benzyloxy-phenyl)-2,2-dimethyl-morpholine-3-one (1.90 g), and more polar compound was a 4-benzyl-6-(4-benzyloxy-phenyl)-2-methyl-morpholine-3-one (3,81 g).

2-(4-bromophenyl)-thiomorpholine-3-one: To a solution of 2-aminoethanethiol hydrochloride (6,93 g; 61 mmol) in EtOH (400 ml) at ambient temperature was added K2CO3(16,86 g; 122 mmol), followed, after 15 minutes, ethyl ether bromo-(4 Poslednij fenelli)-acetic acid (12 ml, 61 mmol). The resulting mixture was stirred at ambient temperature within t�e two days then water was added, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried(MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from EtOH, yielding 2-(4-bromophenyl)-thiomorpholine-3-one (12.8 g).

4-Benzyl-2-(4-octyloxy-phenyl)-morpholine: To a solution of 4-benzyl-6-(4-octyloxy-phenyl)-morpholine-3-she (22,22 g; 56,2 mmol) in THF (400 ml) dropwise at 0°C was added a complex of boron hydride-THF (1M, 140,4 ml; 140,4 mmol). After 1 hour the mixture was allowed to warm to ambient temperature and stirred for another 2 hours. To the reaction mixture at 0°C was added MeOH (30 ml) and the resulting mixture was stirred at ambient temperature for 30 minutes and then concentrated in vacuo. The residue was suspended in MeOH (300 ml) and was added 1 M aqueous NaOH solution (112 ml) and heated to reflux for 1 hour. The mixture was concentrated in vacuo, and the residue was separated between EtOAc and 5% aqueous solution of NaHCO3. The organic layer was dried(Na2SO4), filtered and concentrated under vacuum to give 4-benzyl-2-(4-octyloxy-phenyl)-morpholine (20,33 g), which was used as such in next step.

The following compounds were obtained in a similar way:

4-Benzyl-6-(4-bromophenyl)-morpholine

4-Benzyl-2-(4-benzyloxy�-phenyl)-morpholine

4-Benzyl-2-(4-benzyloxy-2-methyl-phenyl)-morpholine

4-Benzyl-2-(4-benzyloxy-3-methyl-phenyl)-morpholine

4-Benzyl-2-(4-benzyloxy-3-methoxy-phenyl)-morpholine

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

4-Benzyl-2-(4-benzyloxy-phenyl)-2-methylmorpholin

4-Benzyl-6-(4-benzyloxy-phenyl)-2,2-dimethylmorpholine

4-Benzhydryl-2-(5-bromo-pyridin-2-yl)-morpholine

4-(4-benzyl-morpholine-2-yl)-3-trifluoromethyl-phenol: To a solution of 4-benzyl-6-(4-hydroxy-2-trifluoromethyl-phenyl)-morpholine-3-she (26,18 g; to 67.3 mmol) in THF (600 ml) at 0°C was added dropwise BH3∙THF in THF (235,4 ml; 1.00 mol/l; 235,4 mmol). The resulting mixture was stirred for 1 hour at 0°C and then for 18 hours at ambient temperature. Then was added 1 M HCl aqueous solution (550 ml) and the mixture was stirred overnight at ambient temperature. The resulting mixture was separated between EtOAc and 2 M aqueous NaOH (350 ml), organic layers were dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,CH2Cl2/MeOH 98:2) to give 4-(4-benzyl-morpholine-2-yl)-3-trifluoromethyl-phenol.

The following compounds were obtained in a similar way:

4-(4-benzyl-morpholine-2-yl)-3-forfinal

4-Benzyl-2-(3-benzyloxy-phenyl)-morpholine

Benzyl-2-(2-chloro-4-methoxy-phenyl)-morpholine

2-(4-bromophenyl)-thiomorpholine

4-(4-benzyl-morpholine-2-yl)-2-chlorophenol: To a solution of 4-benzyl-6-(3-chloro-4-hydroxy-phenyl)-morpholine-3-she (13,05 g; 39,0 mmol) in THF (600 ml) at 0°C was added partsLiAlH4(4,44 g; 117,04 mmol). The resulting mixture was allowed to warm to ambient temperature and stirred over night. Then the mixture was cooled to 0°C was added sequentially water (4.5 ml), 2 M aqueous NaOH (9,0 ml) and water (9,0 ml). Thereafter, the mixture was stirred for 1 h. the Formed precipitate was removed by filtration through diatomaceous earth and washed with EtOAc. The organic solution was concentrated in vacuo, and the residue was purified by chromatography on a column (SiO2,CH2Cl2/MeOH 98:2) to give 4-(4-benzyl-morpholine-2-yl)-2-chlorophenol (9,10 g).

4-(4-benzyl-morpholine-2-yl)-3-chlorophenol: To a solution of 1 dodecanthiol (12,7 ml; wins with 52.86 mmol) in dry DMF (50 ml) at 0°C was added KOtBu (5,93 g; wins with 52.86 mmol). After completion of the addition the mixture was allowed to slowly warm to ambient temperature (~30 minutes) and then were added 4-benzyl-2-(2-chloro-4-methoxy-phenyl)-morpholine (5,60 g; 17,62 mmol). The resulting mixture was stirred at 110°C for 6 hours. After cooling to ambient temperature, EtOAc was added and the mixture was washed with 5% aqueousNaHCO3, water and sole�first solution; dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,CH2Cl2/MeOH 99:1) to give 4-(4-benzyl-morpholine-2-yl)-3-chlorophenol (4,56 g).

4-Benzyl-2-(4-benzyloxy-phenyl)-5,5-dimethylmorpholine

To a solution of 4-benzyl-6-(4-benzyloxy-phenyl)-morpholine-3-she (7,14 g, 19,1 mmol) in THF (100 ml) at -10°C was added aZrCl4(4,46 g, 19,1 mmol). The resulting mixture was stirred for 30 min at -10°C, was then added dropwise a solution of MeMgBr in Et2O (the 38.2 ml of 3.00 mol/l; 114,6 mmol), maintaining the temperature below 10°C. After complete addition the resulting mixture was stirred at ambient temperature for 1 hour. After cooling the mixture to 0°C was added dropwise 2 M aqueous NaOH. The resulting suspension was filtered, and the filtrate was extracted with three timesCH2Cl2. The combined organic layers were dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O/hexane 1:3) to give 4-benzyl-2-(4-benzyloxy-phenyl)-5,5-dimethylmorpholine (3.6 g).

4-(4-benzyl-morpholine-2-yl)-phenol: To a suspension of 4-benzyl-6-(4-bromophenyl)-morpholine (8,70 g; 26,19 mmol) in water (25 ml) and 1,4-dioxane (25 ml) was added KOH (3,23 g; 57,61 mmol), three�(dibenzylideneacetone)dipalladium (0) (479,6 mg; 0,52 mmol) and di-tert-butyl-(2',4',6'-triisopropyl-biphenyl-2-yl)-Foshan (444,8 mg; 1.05 mmol). The mixture was heated to reflux for two hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuo. The residue was separated between EtOAc and 5% aqueous solutionNaHCO3. The organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O:hexane 1:1) to give 4-(4-benzyl-morpholine-2-yl)-phenol (3,67 g).

6-(4-Benzhydryl-morpholine-2-yl)-pyridin-3-olreceived a similar fashion.

4-Benzyl-2-(4-hexyloxy-phenyl)-morpholine: To a mixture of 4-(4-benzyl-morpholine-2-yl) phenol (1.33 g; 4,94 mmol) in water (10 ml) and 1,4-dioxane (10 ml) was added KOH (0.55 g; for 9.88 mmol), 1-bromhexin (1,04 ml; 7,41 mmol) and tetrabutylammonium bromide (0.16 g; 0.49 mmol), the mixture was heated to reflux over night. After cooling to ambient temperature the mixture was concentrated in vacuo and separated between EtOAc and 5% aqueous solutionNaHCO3. The organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O:hexane 1:1) to give 4-benzyl-2-(4-hexyloxy-phenyl)-Mor�Olin (1.31 g).

4-Benzyl-2-(4-heptyloxy-phenyl)-morpholinewas obtained in a similar manner.

4-Benzyl-2-[3-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine: a mixture of 4-(4-benzyl-morpholine-2-yl)-2-chlorophenol (0.50 g; 1.56 mmol), 2,6-dichlorobenzyl bromide (0,39 g of 1.64 mmol) and Cs2CO3(2.55 g; of 7.82 mmol) in CH3CN (20 ml) was heated to reflux over night. After cooling to ambient temperature the mixture was separated between EtOAc and water. The layers were separated and the organic layer was dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,CH2Cl2:MeOH 98:2) to give 4-benzyl-2-[3-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0.74 g).

The following compounds were obtained in a similar way:

4-Benzyl-2-[3-chloro-4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-morpholine

4-Benzyl-2-[3-chloro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine

4-Benzyl-2-(4-octylphenyl)-morpholine: To a solution of 1-ökten (2,12 ml, 13.5 mmol) in THF (50 ml) at 0°C was added 9-BBN (4.3 g, a 17.6 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred over night. Was then added K3PO4(7.6 g, a 35.8 mmol), then after 45 minutes, 4-benzyl-6-(4-bromophenyl)-morpholine (3.0 g, 9 mmol), palladium acetate (II) (8 mg; 4 mol. %) and DICYCLOHEXYL-(2',6'-dimethoxy-biphenyl-2-yl)-Foshan (296 mg; 8 mol. %). The mixture was heated to reflux for 2 hours. After cooling to ambient temperature the mixture was concentrated in vacuo, the residue was dissolved in EtOAc and washed with 5% aqueous solutionNaHCO3. The organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O:hexane, 1:1) to give 4-benzyl-2-(4-octylphenyl)-morpholine (2,58 g).

4-(4-benzyl-morpholine-2-yl)-benzaldehyde: To a solution of 4-benzyl-6-(4-bromophenyl)-morpholine (1,73 g, to 5.21 mmol) in THF (25 ml) was added dropwise at -78°C n-BuLi (2.08 ml; 2.50 mol/l; to 5.21 mmol). The resulting mixture was stirred for one hour and was then added dropwise at -78°C a solution of N-formylmorpholine (0,90 g, 7,81 mmol) in THF (5 ml). The reaction mixture was quenched by adding 5% aqueous solution ofNaHCO3at -70°C. the resulting mixture was extracted withEt2O. the combined organic layers were dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O:hexane 1:1) to give 4-(4-benzyl-morpholine-2-yl)-benzaldehyde (1.21 g).

[4-(4-benzyl-morpholine-2-yl)-Fe�yl]-methanol : To a solution of 4-(4-benzyl-morpholine-2-yl)-benzaldehyde (1.19 g; 4,23 mmol) in MeOH (25 ml) in small portions at 0°C was added aNaBH4(0.16 g; 4,23 mmol). After completion of the addition the mixture was allowed to warm to ambient temperature and stirred for one hour. Then the mixture was cooled to 0°C, water was added and MeOH was evaporated in vacuum. To water solution was added 5% aqueous solutionNaHCO3and EtOAc. The layers were separated, and the organic layer was dried(Na2SO4), filtered and concentrated under vacuum to give [4-(4-benzyl-morpholine-2-yl)-phenyl]-methanol (1.16 g), which was used as such.

4-Benzyl-2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine: To a solution of 2,6-dichlorphenol (0,68 g; 4,19 mmol) in THF (20 ml) at ambient temperature was added DIAD (1,13 ml; 5,72 mmol) and triphenylphosphine (1,50 g, 5,72 mmol), then after 30 minutes, [4-(4-benzyl-morpholine-2-yl)-phenyl]-methanol (1,08 g, 3,81 mmol). Then, the resulting mixture was stirred at ambient temperature for 1 hour and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:1) to give 4-benzyl-2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine (2.35 g) which was used as such in next step.

The following compound was obtained in a similar way:

4-�ensil-2-[2-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine

4-(4-benzyl-morpholine-2-yl)-N-(2,6-dichlorophenyl)-benzamide: To a solution of 4-benzyl-6-(4-bromophenyl)-morpholine (1.01 g; of 3.04 mmol) in THF (25 ml) was added dropwise at -78°C n-BuLi (1.2 ml; 2.5 mol/l in hexano; of 3.04 mmol). After 1 hour at -78°C was added dropwise a solution of 2,6-dichlorophenyl isocyanate (0,63 g, to 3.34 mmol) in THF (5 ml). The mixture was allowed to warm to ambient temperature and was then added 5% aqueous solutionNaHCO3. Then the mixture was extracted withEt2O. the Organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on columns (Et2O:hexane 1:1) to give 4-(4-benzyl-morpholine-2-yl)-N-(2,6-dichlorophenyl)-benzamide (0,68 g).

4-Benzyl-2-{4-[2-(2,6-dichlorophenyl)-vinyl]-phenyl}-morpholine: To a suspension of (2,6-dichlorobenzyl)-triphenyl-phosphonium bromide (2,06 g; 4.1 mmol) (see: A. Schmidpeter, H. Noeth, G. Jochem, H.-P. Schroedel, K. Karaghiosoff; Chem. Ber., 1995, 128, 379) in THF (25 ml) at 0°C was added sodium hydride (60% dispersion in mineral oil) (215 mg; 4.5 mmol). After stirring for 1 hour was added, at 0°C, 4-(4-benzyl-morpholine-2-yl)-benzaldehyde (1.05 g; 3.7 mmol). Then the mixture was heated to reflux for 1 hour. After cooling to ambient temperature was added 5% aqueousNaHCO3and the mixture of extras�in addition, they delegated Et2O. the Organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:1) to give 4-benzyl-2-{4-[2-(2,6-dichlorophenyl)-vinyl]-phenyl}-morpholine (1.15 g).

4-Benzyl-2-[4-(2,6-dichlorobenzyl)-phenyl]-morpholine: To a mixture of chloride of 2,6-dichloraniline (7.95 ml; 0.50 mol/l in THF; at 3.97 mmol) and tetrakis(triphenylphosphine)palladium (0) (83,48 mg; 0.07 mmol) in THF (25 ml) was added 4-benzyl-6-(4-bromophenyl)-morpholine (1.20 g; 3,61 mmol). The resulting mixture was stirred at ambient temperature for 2 hours and then heated to reflux for 2 hours. After cooling to ambient temperature the mixture was concentrated in vacuo. The residue was divided between 5% aqueousNaHCO3and EtOAc. The organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:1) to give 4-benzyl-2-[4-(2,6-dichlorobenzyl)-phenyl]-morpholine (1.40 g).

2-[4-(4-benzyl-morpholine-2-yl)-phenyl]-1-phenyl-atanan: To a degassed solution of 4-benzyl-2-(4-bromophenyl)-morpholine (205 mg; 0,62 mmol) and methylvinylketone (87 ml, 0.74 mmol) in toluene (4 ml) was added NaOtBu (of 148.3 mg; 1.54 mmol), 2,2'-bis (�ebenisterie)-1,1'-binaphthyl (38,4 mg; Of 0.06 mmol) and Tris(dibenzylideneacetone)dipalladium (0) (28,3 mg; 0.03 mmol). The mixture was heated to 110°C for 30 min in a microwave reactor. After cooling to ambient temperature was added 5% aqueous solution of NaHCO3and the mixture was extracted with EtOAc. The combined organic layers were dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O/hexane 1:1), obtaining 2-[4-(4-benzyl-morpholine-2-yl)-phenyl]-1-phenyl-Etalon (110,00 mg).

Benzhydrylidene-[4-(4-benzyl-morpholine-2-yl)-phenyl]-amine: To a degassed solution of 4-benzyl-6-(4-bromophenyl)-morpholine (4,00 g; 12,04 mmol) in toluene (50 ml) was added Yiming benzophenone (2,42 ml; 14,45 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0,60 g; 0.96 mmol), Tris(dibenzylideneacetone)-dipalladium (0) (0.22 g; 0,24 mmol) and NaOtBu (1.62 g; 16,86 mmol). The mixture was heated to 100°C for 16 hours. After cooling to ambient temperature was added 5% aqueous solutionNaHCO3and the product was extracted with EtOAc. The combined organic layers were dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:1), getting benzhydrylidene-[4-(4-benzyl-morpholine-2-yl)-phenyl]-amine (3,30 g).

4-(4-benzyl-morpholine-2-yl)-phenylamine: To a solution of benzhydrylidene-[4-(4-benzyl-morpholine-2-yl)-phenyl]-amine (3,30 g, 7,63 mmol) in THF (50 ml) was added hydrochloric acid (30,5 ml; 1.00 mol/l in water; 30,5 mmol). The resulting mixture was stirred over night at ambient temperature. The reaction mixture was divided between 1 M aqueous HCl solution and EtOAc. The aqueous layer was podslushivaet 1 M aqueous NaOH (pH>10) and was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated under vacuum to give 4-(4-benzyl-morpholine-2-yl)-phenylamine (1.85 g).

[4-(4-benzyl-morpholine-2-yl)-phenyl]-(2,6-dichlorobenzyl)-amine: a mixture of 4-(4-benzyl-morpholine-2-yl)-phenylamine (0,82 g; 3,06 mmol), DIPEA (1,57 ml; 9,17 mmol) and 2,6-dichlorobenzyl bromide (0.88 g; 3,67 mmol) in MeOH (25 ml) was stirred at ambient temperature overnight. The mixture was divided between a 5% aqueous solutionNaHCO3and EtOAc. The organic layer was dried(Na2SO4), filtered and concentrated under vacuum to give [4-(4-benzyl-morpholine-2-yl)-phenyl]-(2,6-dichlorobenzyl)-amine (1.25 g).

N-[4-(4-benzyl-morpholine-2-yl)-phenyl]-2,6-dichlorobenzamide: To a mixture of 4-(4-benzyl-morpholine-2-yl)-phenylamine (0,48 g; 1.8 mmol) and N-ethyldiethanolamine (0,92 ml; 5.4 mmol) in CH3CN (10 ml) at 0°C was added 2,6-dichlorobenzoyl chloride (0,31 ml; 2.2 mmol). The resulting mixture was allowed to warm to ambient temperature, stirred for 1 hour and was divided betweenEt2O and 5% aqueous solutionNaHCO3. The organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O), receiving N-[4-(4-benzyl-morpholine-2-yl)-phenyl]-2,6-dichlorobenzamide (0,61 g).

4-Benzyl-2-{4-[2-(2,6-dichlorophenyl)-ethyl]-phenyl}-morpholine: To a degassed solution of [2-(2,6-dichlorophenyl)ethyl]triptoreline potassium (0.28 g; 1 mmol) and tribasic potassium phosphate (0,58 g; 2.7 mmol) in toluene (20 ml) and water (4 ml) was added 4-benzyl-6-(4-bromophenyl)-morpholine (0.30 g; 0,90 mmol), palladium acetate (II) (6,1 mg; 0.03 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxide-1,1'-biphenyl (to 25.3 mg; 0.05 mmol). The mixture was heated to reflux over night. After cooling to ambient temperature the mixture was concentrated in vacuo and separated between EtOAc and 5% aqueous solutionNaHCO3. The organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:1) to give 4-benzyl-2-{4-[2-(2,6-dichlorophenyl)-ethyl]-phenyl}-morpholine (0,21 g).

Required[2-(2,6-d�chlorophenyl)ethyl]triptorelin potassium was prepared as follows: To a solution of 2,6-dichlorostyrene (1,58 ml; 11.6 mmol) in THF (15 ml) was added dimer chloro(1,5-cyclooctadiene)iridium (I) (38,8 mg; 0.06 mmol), 1,2-bis(diphenylphosphino)ethane (46,1 mg; 0.12 mmol) and pinacolborane (to 11.6 ml; 1M in THF; 11.6 mmol). The resulting mixture was stirred at ambient temperature overnight, then concentrated in vacuo and purified by chromatography on a column (SiO2Et2O:hexane 1:3). The resulting product was treated with MeOH (56 ml), water (14 ml) and potassium bifluoride (3,43 g; to 43.9 mmol) and stirred at ambient temperature overnight. Then the solvent was removed under vacuum, and the residue treated with toluene and concentrated in vacuo. The last stage was repeated three times to remove all the water. The obtained solid substance was treated withCH3CN and heated at 50°C. the Precipitate was removed by filtration and washed withCH3CN. Merged layersCH3CN was concentrated in vacuo, and the residue treated withEt2O. the Formed precipitate was collected by filtration and dried under vacuum to give [2-(2,6-dichlorophenyl)ethyl]triptorelin potassium (1.12 g) which was used as such.

tert-butyl ether 3-[2-(4-benzyloxy-phenyl)-5-oxo-morpholine-4-yl]-propionic acid: To a mixture of 6-(4-benzyloxy-phenyl)-morpholine-3-she (13,40 g; 47,3 mmol) and Ismail�in Chennai NaOH powder (of 3.78 g; A 94.6 mmol) in THF (250 ml) was added tert-butyl acrylate (13,7 ml; and 94.6 mmol). The resulting mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O) to obtain tert-butyl ether 3-[2-(4-benzyloxy-phenyl)-5-oxo-morpholine-4-yl]-propionic acid (14,20 g).

2-(4-octyloxy-phenyl)-morpholine: To a solution of 4-benzyl-2-(4-octyloxy-phenyl)-morpholine (20,22 g; 53 mmol) in MeOH (400 ml) was added palladium hydroxide (0.74 g; 5,30 mmol). The mixture was treated withH2at normal pressure overnight. The reaction mixture was filtered through diatomaceous earth. The drained precipitate was washed with a solution of ammonia in MeOH. Evaporation of the solvent gave 2-(4-octyloxy-phenyl)-morpholine (14,80 g), which was used as such in next step.

The following compounds were obtained in a similar way:

3-Methyl-4-morpholine-2-yl-phenol

4-Morpholine-2-yl-phenol

2-(4-octylphenyl)-morpholine

2-(4-Hexyloxy-phenyl)-morpholine

2-(4-Heptyloxy-phenyl)-morpholine

4-Morpholine-2-yl-2-trifluoromethyl-phenol

4-(2-methyl-morpholine-2-yl)-phenol

2-Methyl-4-morpholine-2-yl-phenol

2-Methoxy-4-morpholine-2-yl-phenol

4-(5,5-dimethyl-morpholine-2-yl)-phenol

4-Morpholine-2-yl-3-trifluoromethyl-Fe�ol

3-Fluoro-4-morpholine-2-yl-phenol

tert-butyl ether 3-[2-(4-hydroxyphenyl)-5-oxo-morpholine-4-yl]-propionic acid:

4-(6,6-dimethyl-morpholine-2-yl)-phenol

3-Morpholine-2-yl-phenol

6-Morpholine-2-yl-pyridine-3-ol

2-(4-Phenethyl-phenyl)-morpholine: a mixture of 4-benzyl-2-{4-[2-(2,6-dichlorophenyl)-vinyl]-phenyl}-morpholine (0.54 g; 1.27 mmol) and palladium hydroxide (0.04 g; 0.25 mmol) in MeOH (25 ml) was treated withH2at normal pressure overnight. The resulting mixture was filtered through diatomaceous earth and the solvent was evaporated, yielding 2-(4-phenethyl-phenyl)-morpholine (0,34 g).

(+)-2-(4-octyloxy-phenyl)-morpholine and (-)-2-(4-octyloxy-phenyl)-morpholine:

Racemic2-(4-octyloxy-phenyl)-morpholinedivided into two optical isomer preparative chiral HPLC at ambient temperature on a column CHIRALPAK® IA 20 µm to 250 H (76 mm), using as mobile phase99.9% of CH3CN/0.1% diethylamine (about./about.) at a volumetric flow rate of 270 ml/min and with UV detection at 240 nm. This gave, after evaporation of the solvents, the(+)-2-(4-octyloxy-phenyl)-morpholine(e.e. 98,3%; [α]D25=+24 (c of 1.0, MeOH)) and(-)-2-(4-octyloxy-phenyl)-morpholine(e.e. 99,0%, [α]D25=-28 (c of 1.0, MeOH)).

2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine: To a solution of 4-benzyl-2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpho�in (2.25 g; The 3.7 mmol) in 1,2-dichloroethane (10 ml) was added dropwise at 0°C 1-chloroethyl chloroformate (of 0.44 ml; 4.0 mmol). After 15 minutes, the cooling was removed, and then the mixture was heated to reflux over night. After cooling to ambient temperature the mixture was concentrated in vacuo. To the residue was added toluene, and the mixture was concentrated in vacuo. This last stage was repeated twice. To the final residue was added MeOH (10 ml) and the mixture was stirred over night at ambient temperature. The mixture is again concentrated under vacuum. The residue was separated between EtOAc and 2 M aqueous NaOH. The layers were separated, and the organic layer was dried(Na2SO4), filtered and concentrated under vacuum to give 2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine (0.98 g), which was used as such in next step.

The following compounds were obtained in a similar way:

N-(2,6-dichlorophenyl)-4-morpholine-2-yl-benzamide

2-{4-[2-(2,6-dichlorophenyl)-vinyl]-phenyl}-morpholine

(2,6-dichlorobenzyl)-(4-morpholine-2-yl-phenyl)-amine

2,6-Dichloro-N-(4-morpholine-2-yl-phenyl)-benzamide

2-{4-[2-(2,6-dichlorophenyl)-ethyl]-phenyl}-morpholine

2-[4-(2,6-dichlorobenzyl)-phenyl]-morpholine

2-[3-Chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine

2-[3-Chloro-4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-morpholine

2-[3-Chloro-4-(2-Cryptor�ethyl-benzyloxy)-phenyl]-morpholine

2-[2-Chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine

2-(4-Morpholine-2-yl-phenyl)-1-phenyl-atanan

tert-butyl ether 2-(4-hydroxyphenyl)-morpholine-4-carboxylic acid: a mixture of 4-morpholine-2-yl-phenol (0,99 g; 5,41 mmol) and di-tert-butyl bicarbonate (1.18 g; 5,41 mmol) in CH3CN (50 ml) was stirred at ambient temperature for 3 days. Then the mixture was concentrated in vacuo, and the residue was purified by chromatography on a column (SiO2,CH2Cl2:CH3OH 97:3) to obtain tert-butyl ether 2-(4-hydroxyphenyl)-morpholine-4-carboxylic acid (1.15 g).

The following compound was obtained in a similar way:

tert-butyl ether 2-(4-bromophenyl)-thiomorpholine-4-carboxylic acid

tert-butyl ether 2-(4-bromophenyl)-1,1-diokso-1λ6-thiomorpholine-4-carboxylic acid: To a solution of tert-butyl methyl ether 2-(4-bromophenyl)-thiomorpholine-4-carboxylic acid (3.60 g; 10.05 mmol) inCH2Cl2(100 ml) at 0°C was added 3-chloroperoxybenzoic acid (5,20 g; 30,14 mmol). The resulting mixture was stirred overnight at ambient temperature and then was added a saturated aqueous solution of sodium thiosulfate, and the mixture was stirred for another 30 min. the Layers were separated, and the aqueous layer was extracted with EtOAc twice. About�yedinenye EtOAc layers were washed twice with an aqueous solution Na2CO3. The combined organic layers were dried(MgSO4), filtered and concentrated in vacuum, obtaining tert-butyl ether 2-(4-bromophenyl)-1,1-diokso-1λ6-thiomorpholine-4-carboxylic acid (4,06 g), which was used as such in next step.

2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine hydrochloride: Acetyl chloride (1.35 ml, 8,9 mmol) was added to ethanol (60 ml). The obtained solution was added at ambient temperature to tert-butyl ether 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-carboxylic acid (1,54 g; 3.4 mmol). The resulting mixture was stirred at 60°C for 3 hours and then at ambient temperature for three days. The resulting suspension was concentrated in vacuo and treated with iPr2O. the Formed precipitate was collected by filtration and dried under vacuum to give 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine hydrochloride (1.31 g).

The following compound was obtained in a similar way:

2-(4-bromophenyl)-thiomorpholine-1,1-dioxide

tert-butyl ether 3-[2-(4-hydroxy-2-methyl-phenyl)-morpholine-4-yl]-propionic acid: a mixture of 3-methyl-4-morpholine-2-yl-phenol (14.26 g; of 73.8 mmol) and tert-butyl acrylate (21,4 ml; was 147.6 mmol) in CH3CN (250 ml) was heated to reflux over night. On�Le cooling to ambient temperature the mixture was concentrated in vacuum and the residue separated between EtOAc and 5% aqueous solution NaHCO3. The organic layer was dried(Na2SO4), filtered, concentrated in vacuo and purified by chromatography on a column (SiO2,CH2Cl2>Et2O/hexane 1:1> Ether) to give tert-butyl ether 3-[2-(4-hydroxy-2-methyl-phenyl)-morpholine-4-yl]-propionic acid (22,62 g).

The following compounds were obtained in a similar way:

tert-butyl ether 3-[2-(4-hydroxyphenyl)-morpholine-4-yl]-propionic acid

Isomer 1 tert-butyl ether 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acidfrom (+)-2-(4-octyloxy-phenyl)-morpholine.

Isomer 2 tert-butyl ether 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acidfrom (-)-2-(4-octyloxy-phenyl)-morpholine.

tert-butyl ether 3-[2-(4-octylphenyl)-morpholine-4-yl]-propionic acid.

tert-butyl ether 3-[2-(4-hexyloxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-[2-(4-heptyloxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-[2-(4-hydroxy-3-trifluoromethyl-phenyl)- morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-phenylcarbamoyl)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-(2-{4-[2-(2,6-�chlorphenyl)-vinyl]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-[2-(4-phenethyl-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzylamino)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzoylamino)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-hydroxyphenyl)-2-methyl-morpholine-4-yl]-propionic acid.

tert-butyl ether 3-(2-{4-[2-(2,6-dichlorophenyl)-ethyl]-phenyl}-morpholine-4-yl)-propionic acid.

tert-butyl ether 3-[2-(4-hydroxy-3-methyl-phenyl)-morpholine-4-yl]-propionic acid.

tert-butyl ether 3-[2-(4-hydroxy-3-methoxy-phenyl)-morpholine-4-yl]-propionic acid.

tert-butyl ether 3-{2-[4-(2,6-dichlorobenzyl)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-[2-(4-hydroxyphenyl)-5,5-dimethyl-morpholine-4-yl]-propionic acid.

tert-butyl ether 3-[2-(4-hydroxy-2-trifluoromethyl-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-[2-(2-fluoro-4-hydroxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-[6-(4-hydroxyphenyl)-2,2-dimethyl-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[3-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[3-chloro-4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-morpholine-4-yl}-p�pianoboy acid

tert-butyl ether 3-{2-[3-chloro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(3-hydroxyphenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[2-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-bromophenyl)-thiomorpholine-4-yl]-propionic acid

tert-butyl ether 3-[2-(4-bromophenyl)-1,1-diokso-1λ6-thiomorpholine-4-yl]-propionic acid

tert-butyl ether 3-[2-(5-hydroxy-pyridin-2-yl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(2-oxo-2-phenyl-ethyl)-phenyl]-morpholine-4-yl}-propionic acid

3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionitrilewith the use of Acrylonitrile instead of tert-butyl acrylate.

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid: a mixture of tert-butyl ether 3-[2-(4-hydroxyphenyl)-morpholine-4-yl]-propionic acid (5,00 g; 16.3 mmol) and K2CO3(6,74 g; and 48.8 mmol) inCH3CN (100 ml) was stirred for one hour at ambient temperature. Was then added 2,6-dichlorobenzyl bromide (4,29 g of 17.9 mmol) and the resulting mixture was stirred over night at ambient temperature. The reaction mixture was again�elali between EtOAc (250 ml) and 5% aqueous solution NaHCO3(100 ml). The layers were separated, and the organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O/hexane 1:1), obtaining tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid (7,40 g).

The following compounds were obtained in a similar way:

tert-butyl ether 3-(2-(4-octyloxy-phenyl)-morpholine-4-yl)-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-forbindelse)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-debtor-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-3-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-methyl-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-2-methyl-morpholine-4-yl}-propionic acid

tert-butilovyi 3-{2-[4-(2-trifluoromethyl-benzyloxy)-phenyl]-2-methyl-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-methyl-2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-carboxylic acid

tert-butyl ether 3-{2-[3-methoxy-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-3-methoxyphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-3-methoxyphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[3-methyl-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-3-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-3-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-5-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

3-{2-[4-(3-phenyl-allyloxy)-phenyl]-morpholine-4-yl}-propionic acid tert-butyl ester

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-5-oxo-�orfelin-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-octyloxy-phenyl)-5-oxo-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-5,5-dimethyl-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[5,5-dimethyl-2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{6-[4-(2,6-dichloro-benzyloxy)-phenyl]-2,2-dimethyl-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2,2-dimethyl-6-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-2-fluorophenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-fluoro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-2-fluorophenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-octyloxy-2-trifluoromethyl-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-3-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed2-methyl bromide-1,3-dichloro-4-ethyl-benzenewas obtained as follows: To a mixture of 2',4'-dichloroacetophenone (4,85 g; 25,66 mmol) suspended in diethylene glycol (20 ml) was added KOH 2,37 g; 35,92 mmol) and hydrazine hydrate (2,9 ml). The mixture was heated at 100°C (for 1 hour) and then overnight at 200°C. After cooling to ambient temperature the mixture was divided betweenEt2O and water. The layers were separated, and the organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2hexane), obtaining the product: 2,4-dichloro-1-ethylbenzene (2,24 g). To a solution of 2,2,6,6-tetramethylpiperidine (2,36 ml; 14 mmol) dissolved in THF (40 ml) at -78°C was added a solution of n-BuLi in hexano (5,6 ml; 2.50 mol/l; 14 mmol). The reaction mixture was stirred for 90 minutes, giving the temperature to reach 0°C. Then at -78°C was added a solution of 2,4-dichloro-1-ethylbenzene (2,23 g; by 12.74 mmol) dissolved in THF (5 ml). The resulting mixture was stirred for 2.5 hours. Was then added dropwise DMF (1,48 ml; 19,11 mmol) and the resulting mixture was stirred for 30 minutes. The reaction mixture was quenched by adding at -50°C a saturated aqueous solutionNH4Cl. The resulting mixture was extracted withEt2O. the combined organic layers were dried(Na2SO4), filtered and concentrated under vacuum to give crude 2,6-dichloro-3-ethylbenzaldehyde, which was re-dissolved in MeOH (100 ml). Was then added in small portions at 0°CNaBH4(1.45 g; 38,22 mmol). After completion of the addition, the mixture was allowed to warm to ambient temperature and stirred for one hour. Then the mixture was cooled to 0°C, water was added and MeOH was evaporated in vacuum. To water solution was added 5% aqueous solutionNaHCO3andEt2O. the Layers were separated, and the organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:7, then 1:1) to give (2,6-dichloro-3-ethylphenyl)methanol (2.11 g). To a solution of (2,6-dichloro-3-ethylphenyl)methanol (0.79 g; a 3.85 mmol) inEt2O (25 ml) was added dropwise at 0°CPBr3(Of 0.47 ml; 5,01 mmol) and the resulting mixture was stirred over night at ambient temperature. Then at 0°C was added water, then EtOAc to 5% aqueous solutionNaHCO3. The layers were separated, and the organic layer was dried(MgSO4), filtered and concentrated under vacuum to give 2-methyl bromide-1,3-dichloro-4-ethyl-benzene (0,57 g), which was used as such.

tert-butyl ether(+)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid tert-butyl ester(-)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid: Racemic tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid� (7,1 grams) were divided into two optical isomer preparative chiral HPLC at 24°C on a column CHIRALPAK® T304 20 µm 270 H 110 mm using as mobile phase of 60% n-heptane/40% isopropanol (vol./about.) at a volumetric flow rate of 570 ml/min and UV irradiation at 225 nm. This gave, after evaporation of the solvents, thetert-butyl ether(+)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid(3,38 g; e.e. > 99,5%, [α]D25=+13 (c of 1.0, MeOH)) andtert-butyl ether(-)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid(3,38 g; e.e. 99,0%, [α]D25=-12 (c of 1.0, MeOH)).

tert-butyl ether 3-{2-[4-(2,6-dimethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid: To a solution of tert-butyl ether 3-[2-(4-hydroxyphenyl)-morpholine-4-yl]-propionic acid (0.45 g; 1.5 mmol) in THF (10 ml) was added 2,6-dimethylbenzylamine alcohol (0.22 g; 1.6 mmol) then DIAD (0,43 ml; 2.2 mmol) and triphenylphosphine (0,58 g; 2.2 mmol). The resulting mixture was stirred at ambient temperature for 3 days. Then the reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 2:1), obtaining tert-butyl ether 3-{2-[4-(2,6-dimethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid (0,38 g).

The following compounds were obtained in a similar way:

tert-butyl ether 3-{2-[4-(3,5-dichloro-pyridin-4-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl�first aired 3-(2-{4-[1-(2,6-dichlorophenyl)-ethoxy]-phenyl}-morpholine-4-yl)-propionic acid.

tert-butyl ether 3-{2-[4-(2,3-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(2,3,6-trichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(2-chlor-6-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(2,4-dichloro-pyridin-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2,4-dichloro-pyridine-3-yl)-methanolwas obtained as follows: To a solution of 2,4-dichloropyridine (3,00 ml; 27.8 mmol) in THF (25 ml) was added dropwise at -78°C a solution of LDA (15,3 ml; 2.00 mol/l in a mixture of THF/heptane/ethylbenzene; 30,6 mmol). The resulting mixture was stirred at -78°C for 1 hour. Was then added dropwise at -78°C a solution of ethyl chloroformate (3.2 ml; 33,33 mmol) in THF (5 ml) and the mixture was stirred for another 1 hour at the same temperature. To the resulting mixture dropwise at -78°C was added a 5% aqueous solution of NaHCO3. The mixture was allowed to warm to ambient temperature and was extracted with EtOAc. The organic layer was dried(Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:3), obtaining the ethyl ester of 2,4-dichloro-nicotinic acid (2,45 g). To a solution of ethyl 2,4-dichloro-nicotinic acid (2.35 g; is 10.68 mmol) in THF (50 ml) add�Yali dropwise at 4°C diisobutylaluminium hydride (32.0 ml; A 1.00 mol/l in THF, 32,0 mmol). After 15 minutes, remove the tub of ice, and the reaction mixture was stirred at ambient temperature overnight. Then the mixture was concentrated in vacuo and separated between 5% aqueous solutionNaHCO3and EtOAc. The layers were separated, and the organic layer was dried(Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on columns (Et2O:hexane 1:1) to give (2,4-dichloro-pyridine-3-yl)-methanol (0.40 g).

tert-butyl ether 3-{2-[4-(2-chloro-5-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2-chloro-5-methylphenyl)methanolwas obtained as follows: To a solution of 2-chloro-5-methylbenzoic acid (2.05 g; 12.2 mmol) in THF (20 ml) was added dropwise a complex connectionBH3∙THF in THF (1 mol/l, 24,0 ml; 24.0 mmol) and then stirred for 2 hours at 60°C. To the reaction mixture were added at 0°C 1 M HCl aqueous solution (30 ml) and the resulting mixture was stirred at ambient temperature for 10 minutes. The mixture was concentrated in vacuo, and the residue was separated between EtOAc and 5% aqueous solutionNaHCO3. The organic layer was dried(Na2SO4), filtered and concentrated under vacuum to give the product (1.8 g) which was used as such in next step.

tert-butyl EF�p 3-{2-[4-(2-chloro-5-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid . The required (2-chloro-5-ethylphenyl)methanol was obtained as follows: To a purified nitrogen to a solution of 5-bromo-2-chlorethylene (4,3 ml of 25.1 mmol) in THF (100 ml) was added lithium chloride (2,12 g, a 50.1 mmol) and Pd(dppf)Cl2(0,82 g, 1 mmol). The mixture is then cooled to -78°C and added dropwise a solution of diethylzinc in heptane (37,6 ml; 1.00 mol/l; of 37.6 mmol). The reaction mixture was allowed to warm to ambient temperature over night. The obtained reaction mixture was cooled to -10°C and diluted withEt2O (300 ml). Then gently added 1 M HCl aqueous solution (150 ml). The layers were separated, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O:hexane 5:95) to give ethyl 2-chloro-5-ethylbenzoic (4,61 g). To a purified nitrogen to a solution of ethyl 2-chloro-5-ethyl-benzoate (1 g, 4,70 mmol) in THF (25 ml) was added at -5°C diisobutylaluminium (14,11 ml; 14,11 mmol) in toluene. The reaction mixture was allowed to warm to ambient temperature and stirred over night. The obtained reaction mixture was cooled to -10°C and added 5% aqueous solutionNaHCO3(10 ml). The layers were separated, and the organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:g�ksana 1:3, thenEt2O:hexane 1:1), obtaining (2-chloro-6-ethylphenyl)methanol (0.59 g), which was used as such.

tert-butyl ether 3-{2-[4-(2-chloro-5-propyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2-chloro-5-propylphenyl)methanolreceived in a manner similar to used to (2-chloro-5-ethylphenyl)methanol, bromide using N-propyltin instead of diethylzinc.

tert-butyl ether 3-{2-[4-(2-chloro-5-isopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2-chloro-5-isopropylphenyl)methanolreceived in a manner similar to used to (2-chloro-5-ethylphenyl)methanol using diisopropyl zinc instead of diethylzinc.

tert-butyl ether 3-{2-[4-(2,4,6-trichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(2,6-dichloro-4-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.Needed[2,6-dichloro-4-(trifluoromethyl)phenyl]methanolwas obtained as follows: To a solution of 1,3-dichloro-5-(trifluoromethyl)benzene (4,73 g; 22 mmol) in THF (40 ml) at -78°C was added n-BuLi in hexano (8 ml; 2.50 mol/l; 20 mmol). The resulting mixture was stirred for 15 minutes and poured on the dry ice in THF. The reaction mixture was acidified with to pH 3 (5 M aqueous solution of HCl and was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and the end�was tarawali in a vacuum. The residue was purified by chromatography on a column (SiO2,CH2Cl2/MeOH 8:2) to give 2,6-dichloro-4-(trifluoromethyl)benzoic acid (1.2 g). To this solution 2,6-dichloro-4-(trifluoromethyl)benzoic acid (1.7 g; 6,6 mmol) in THF (20 ml) was added dropwise a solution of the complex hydride of boron-THF in THF (1 mol/l and 13.3 ml; 13,3 mmol). Then, the resulting mixture was stirred over night at 60°C. To the reaction mixture at 0°C was added 1 M HCl aqueous solution (30 ml) and the resulting mixture was stirred at ambient temperature for 10 minutes. The mixture was concentrated in vacuo, and the residue was separated between EtOAc and 5% aqueous solutionNaHCO3. The layers were separated, and the organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:3, thenEt2O:hexane 1:1) to give [2,6-dichloro-4-(trifluoromethyl)phenyl]-methanol (1.3 g) which was used as such in next step.

tert-butyl ether 3-{2-[4-(2,6-dichloro-4-iodine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2,6-dichloro-4-itfinal)methanolwas prepared as follows: To a solution of 3,5-dichlorodibenzo (2.72 g; 10 mmol) in THF (25 ml) at -78°C was added a solution of lithium diisopropylamide in a mixture of THF/heptane/ethyl benzene (5.5 ml; 2.00 mol/l; 11 mmol). Received�th mixture was stirred for 4.5 hours at -78°C and was then added dropwise at -78°C a solution of DMF (1.2 ml, 15 mmol) in THF (5 ml). The obtained reaction mixture was stirred for 2 hours at -40°C. Then the reaction mixture was quenched by adding at -20°C in a 5% aqueous solutionNH4Cl. The resulting mixture was extracted with Et2O. the combined organic layers were dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O:hexane 1:3) to give 2,6-dichloro-4-benzaldehyde (0.7 g, 23%). To a solution of 2,6-dichloro-4-benzaldehyde (450 mg, 1.3 mmol) in MeOH (15 ml) in small portions at 0°C was added NaBH4(72,14 mg; 1.9 mmol). After completion of the addition the mixture was allowed to warm to ambient temperature and stirred for one hour. Then the mixture was cooled to 0°C, water was added and MeOH was evaporated in vacuum. To water solution was added 5% aqueous solutionNaHCO3and EtOAc. The layers were separated, and the organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (CH2Cl2/acetone 95:5) to give (2,6-dichloro-4-itfinal)methanol (0.42 g) which was used as such.

tert-butyl ether 3-(2-{4-[3-(2-fluorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-(2-{4-[3-(2-trifluoromethyl-phenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid�

tert-butyl ether 3-(2-{4-[3-(2-chloro-6-fluoro-phenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-(2-{4-[3-(2,6-dichlorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-(2-{4-[3-(4-chlorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-(2-{4-[3-(2-chlorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-(2-{4-[3-(2,3-debtor-phenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-(2-{4-[3-(4-chlorophenyl)-allyloxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-{2-[4-(3-phenyl-prop-2-ynyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-(2-{4-[3-(4-chlorophenyl)-prop-2-enyloxy]-phenyl}-morpholine-4-yl)-propionic acid

3-{2-[4-(indane-1-yloxy)-phenyl]-morpholine-4-yl}-propionic acid

3-{2-[4-(7-methyl-indane-1-yloxy)-phenyl]-morpholine-4-yl}-propionic acid.Needed7-methoxy-indane-1-olwas prepared as follows: To a solution of 7-methyl-1-indanone (0,94 g; 6,43 mmol) in EtOH (50 ml) at 0°C was added aNaBH4(0.78 g; 20.6 mmol). The resulting mixture was stirred at ambient temperature overnight, then was added water (5 ml) and the resulting mixture was stirred for 10 min. the Mixture was concentrated in vacuo the residue was dissolved in EtOAc and washed with water and brine, dried(MgSO4), filtered and concentrated under vacuum to give 7-methoxy-indane-1-ol (0.85 g) which was used as such.

tert-butyl ether 3-{2-[4-(2,3-dihydro-benzofuran-3-yloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed2,3-dihydro-benzofuran-3-olreceived according to: Ghosh, S. et al Tetrahedron, 1989, 45, 1441-1446.

3-{2-[4-(2,6-dichloro-4-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2,6-dichloro-4-methyl-phenyl)-methanolwas obtained as follows: To 1-bromo-3,5-dichlorobenzene (2,50 g; 11.1 mmol) was added a solution of LiCl in THF (44,3 ml; 0.50 mol/l; 22,2 mmol) and Pd(dppf)Cl2(0,32 g; 0.44 mmol). The resulting mixture was cooled to -78°C and added dropwise a solution of chloride medicine in THF (11,1 ml; 2 mol/l; 22,2 mmol), the mixture is then slowly heated to 50°C for 4 hours. After cooling to ambient temperature, was added 1 M aqueous solution of HCl and Et2O, and the layers were separated. The organic layer was dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,hexane/CH2Cl295:5) to obtain 1,3-dichloro-5-methyl-benzene.

To a solution of 1,3-dichloro-5-methyl-benzene (0.95 g; 5,90 mmol) in THF (20 ml) was added dropwise at -78°C a solution of n-BuLi in hexane (2.4 ml; 2.5 mol/l; 6 mmol). After 15 minutes at -78°C, the mixture was poured on dry ice in THF and Yes�Ali to warm to ambient temperature over night. Then the reaction mixture was acidified using 1 M aqueous HCl solution and was extracted with CH2Cl2. The combined organic layers were dried(MgSO4), filtered and concentrated under vacuum to give 2,6-dichloro-4-methyl-benzoic acid (1.35 g), which was used as such.

To a solution of 2,6-dichloro-4-methyl-benzoic acid (1.35 g; to 6.58 mmol) in THF (13.5 ml) was added dropwise at 0°C a solution of BH3∙THF in THF (19,8 ml; 1.00 mol/l; 19,8 mmol). After complete addition the mixture was heated to reflux over night. Then the mixture was cooled to 0°C was added 1 M aqueous HCl solution (40 ml) then, after 10 min, Et2O (100 ml). The layers were separated; the aqueous layer was extracted withEt2O, and the combined organic layers were washed with brine, dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O/hexane 1:2) to give 2,6-dichloro-4-methyl-phenyl)-methanol (0.80 g).

tert-butyl ether 3-{2-[4-(2-chloro-6-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid; required(2-chloro-6-ethyl-phenyl)-methanolwas obtained as follows: To a solution of 2-chloro-6-ethylbenzaldehyde (1.8 g, of 10.67 mmol), obtained according to US2007/197621, (see also WO2007/85556 and US6380387) in MeOH (50 ml) in small portions at 0°C was added aNaBH4(1.21 g; 32,02 mmol). Last� completion of the addition, the mixture was allowed to warm to ambient temperature and stirred for one hour. Then the mixture was cooled to 0°C, water was added and MeOH was evaporated in vacuum. To water solution was added 5% aqueous solutionNaHCO3and EtOAc. The layers were separated, and the organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:7, then aEt2O:hexane 3:1), obtaining (2-chloro-6-ethylphenyl)methanol (1.2 g).

tert-butyl ether 3-{2-[4-(2-chloro-6-isopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid; required(2-chloro-6-isopropyl-phenyl)-methanolgot a restore usingNaBH42-chloro-6-isopropyl-benzaldehyde in MeOH, which was obtained similarly to 2-chloro-6-ethylbenzaldehyde.

tert-butyl ether 3-{2-[4-(2-chloro-6-cyclopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid; required(2-chloro-6-cyclopropyl-phenyl)-methanolgot a restore usingNaBH42-chloro-6-cyclopropyl-benzaldehyde in MeOH, which was obtained similarly to 2-chloro-6-ethylbenzaldehyde.

tert-butyl ether 3-{2-[4-(2-chloro-6-isobutyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid; required(2-chloro-6-isobutyl-phenyl)-methanolgot a restore usingNaBH 42-chloro-6-isobutyl-benzaldehyde in MeOH, which was obtained similarly to 2-chloro-6-ethylbenzaldehyde.

tert-butyl ether 3-[2-(3-benzyloxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-[2-(3-octyloxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[3-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[3-(2-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-4-prop-1-inyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2,6-dichloro-4-prop-1-inyl-phenyl)-methanolwas obtained as follows: To a degassed solution of (2,6-dichloro-4-itfinal)methanol (3.00 g; 9,90 mmol) in Et3N (80 ml) in a microwave reactor pressure was added CuI (0.19 g; 0.99 mmol) and PdCl2(PPh3)2(0.35 g; 0.50 mmol). The reactor was washed with gaseous nitrogen was loaded with propina to a pressure of 5 bar. The vessel is then heated in a microwave reactor at 50°C for 15 min and then at 80°C for 10 min. After cooling to ambient temperature the pressure was released, and volatile components were removed under vacuum. The residue was dissolved inCH2Cl2and washed with water. The organic layer was concentrated in vacuo, and the residue was purified by chromatography on columns, obtaining 2,6-dichloro-4-prop-1-inyl-phenyl)-methanol (1,79 g).

tert-butyl ether 3-{2-[4-(2,6-dichloro-4-propyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2,6-dichloro-4-propyl-phenyl)-methanolwas obtained as follows: a mixture of (2,6-dichloro-4-prop-1-inyl-phenyl)-methanol (800 mg; 3.72 mmol) and Raney Nickel (20 mg) in EtOH (15 ml) was treated with hydrogen gas (1 ATM.) over night at ambient temperature. Then the catalyst was removed by filtration, and the filtrate was concentrated under vacuum to give (2,6-dichloro-4-propyl-phenyl)-methanol (790,0 mg).

tert-butyl ether 3-{2-[4-(2,6-dichloro-4-isopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2,6-dichloro-4-isopropyl-phenyl)-methanolreceived from (2,6-dichloro-4-Isopropenyl-phenyl)-methanol in a manner similar to used to (2,6-dichloro-4-propyl-phenyl)-methanol.(2,6-dichloro-4-Isopropenyl-phenyl)-methanolwas prepared as follows: To a degassed mixture of (2,6-dichloro-4-itfinal)methanol (1.50 g; 4.95 mmol), Cs2CO3(9,68 g; 29,71 mmol) and 2-Isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.85 ml; 9,90 mmol) in 1,2-dimethoxyethane (20 ml) and water (5 ml) was added Pd(dppf)Cl2(0.36 g; 0.50 mmol). The resulting mixture was stirred at ambient temperature for three days and was then added EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,CH2Cl2/hexane 2:1) to give (2,6-dichloro-4-Isopropenyl-phenyl)-methanol (0.96 g)

tert-butyl ether 3-{2-[4-(2-chloro-6-triptoreline-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. The required (2-chloro-6-triptoreline-phenyl)-methanol was obtained as follows: To a solution of 2,2,6,6-tetramethylpiperidine (2,35 ml; 14. mmol) in THF (25 ml) at -78°C was added dropwise a solution of n-BuLi in hexano (5,60 ml; 2.50 mol/l; 14 mmol). The resulting mixture was stirred for 60 min at -78°C and was then added dropwise at -78°C a solution of 3-(triptoreline)chlorobenzene (2,50 g; 12,72 mmol) in THF (10 ml). After 2.5 hours at -78°C was added dropwise DMF (1,48 ml, 19,11 mmol), and stirring was continued for another 30 min, then was added a saturated aqueous solutionNH4Cl followed by the addition ofEt2O. After heating to ambient temperature, the layers were separated, and the organic layer was washed with water, dried(Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in MeOH (25 ml) and added partsNaBH4(1.44 g; 38,16 mmol). After complete addition the mixture was allowed to warm to ambient temperature and stirred for 30 minutes. Was then added water (5 ml), and volatile components�patients under stood was removed under vacuum. Added Et2O and 5% aqueous solutionNaHCO3and the organic layer was separated, dried (Na2SO4), filtered and concentrated under vacuum to give (2-chloro-6-triptoreline-phenyl)-methanol (2.10 g), which was used as such.

tert-butyl ether 3-{2-[4-(2-chloro-4-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2-chloro-4-methyl-phenyl)-methanolwas obtained as follows: To a solution of 2-chloro-4-methylbenzoic acid (2.18 g; 12.8 mmol) in THF (22 ml) was added dropwise at 0°C a solution of BH3∙THF in THF (25,6 ml; 1.00 mol/l; 25,6 mmol). After complete addition the mixture was heated to reflux for 3 hours. Then the mixture was cooled to 0°C, was added dropwise 1 M aqueous HCl solution (30 ml) and the mixture was stirred for 10 min.Added Et2O (100 ml) and the layers were separated. The organic layer was washed with 1 M aqueous HCl solution (2×), 5% aqueous solutionNaHCO3(2H) and brine, dried(Na2SO4), filtered and concentrated under vacuum to give (2-chloro-4-methyl-phenyl)-methanol (1.80 g), which was used as such.

tert-butyl ether 3-{2-[4-(2-chloro-3-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2-chloro-3-methyl-phenyl)-methanolwas obtained in a similar manner as described for (2-chloro-4-methylphenyl)-methanol

tert-butyl ether 3-{2-[4-(2,4-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(4-methoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(2-methoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(4,4-dimethyl-cyclohexyloxy)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(2-deformedarse-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(2,6-diethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2,6-diethylphenyl)-methanolwas obtained as follows: To a mixture of 2,6-diferentialglea (25,00 g; 175,93 mmol) and p-TsOH (0,67 g; 3,52 mmol) in toluene (150 ml) was added 1-aminobutane (16,5 ml; 167,1 mmol). The resulting mixture was stirred at ambient temperature for 24 hours, then washed with 5% aqueous solution of NaHCO3, water and brine, dried(Na2SO4), filtered and concentrated under vacuum to give butyl-(2,6-debtor-benzylidene)-amine (RUB 35.36 g).

To a solution of butyl-(2,6-debtor-benzylidene)-amine (1.10 g; is 5.58 mmol) in THF (25 ml) at -10°C was added dropwise a solution of etimani bromide in Et2O (4,1 ml of 3.00 mol/l; 12,3 mmol). After completion of the addition the reaction mixture was stirred at the�ture environment for 4 hours. The reaction mixture was quenched by adding dropwise a 5% aqueous solutionNaHCO3and then was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum to give butyl-(2,6-diethyl-benzylidene)-amine (1.10 g).

To a solution of butyl-(2,6-diethyl-benzylidene)-amine (1.10 g; of 5.06 mmol) in water (20 ml) was added H2SO4(5.00 ml; 93,80 mmol) and the mixture was heated to reflux for 2 hours. After cooling to ambient temperature the mixture was diluted with EtOAc and washed with water, 5% aqueous solutionNaHCO3and saline solution. The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give 2,6-diethylbenzamide (0,72 g).

To a solution of 2,6-diethylbenzamide (0,68 g; 4,19 mmol) in THF (15 ml) was added dropwise at 0°C a solution of BH3∙THF in THF (to 8.38 ml; 1.00 mol/l; to 8.38 mmol). After complete addition the mixture was heated to reflux for 3 hours. Then the mixture was cooled to 0°C and added dropwise 1 M aqueous HCl solution (10 ml). The mixture was allowed to warm to ambient temperature (~10 min) and treatedEt2O. the Layers were separated, the organic layer was washed with 1 M aqueous HCl solution (2×), 5% aqueous solution of NaHCO3(2H) and brine, dried(Na2SO4/sub> ), filtered and concentrated under vacuum to give (2,6-diethylphenyl)-methanol (0,67 g), which was used as such.

tert-butyl ether 3-{2-[4-(3-trifluoromethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-ethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-triptoreline-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-isopropyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-trifluoromethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-cyclopropyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[5-(2,6-dichloro-benzyloxy)-pyridin-2-yl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-deformedarse-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Needed(2-chloro-6-deformedarse-phenyl)-methanolwas obtained as follows: To a solution of 2-chloro-6-hydroxy-benzaldehyde (1.00 g; 6,39 mmol) and KOH (7.1 g; 127,7 mmol) in CH3CN (20 ml) and water (20 ml) at -15°C was added bromodifluoromethyl diethylphosphonate (1.25 ml; of 7.03 mmol). After 30 minutes the mixture was allowed to warm to ambient temperature, stirred for another 30 min and then treated with 1 M aqueous HCl solution and was extracted withEt2O. the combined organic layers were dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O/hexane 1:3) to give 2-chloro-6-deformedarse-benzaldehyde (0,68 g).

To a solution of 2-chloro-6-deformedarse-benzaldehyde (0.65 g; 3,15 mmol) in MeOH (10 ml) at -15°C was added NaBH4(357,13 mg; 9,44 mmol). After complete addition the mixture was allowed to warm to ambient temperature and stirred for 30 minutes. Was then added water (5 ml), and volatiles were removed under vacuum. The residue was divided between the Et2O and 5% aqueous solutionNaHCO3. The layers were separated, and the organic layer was dried (Na2SO4), filtered and concentrated under vacuum to give (2-chloro-6-deformedarse-phenyl)-methanol (0.52 g) which was used as such.

tert-butyl ether 3-{2-[4-(2-chloro-6-deformedarse-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid.

4-[4-(2-tert-butoxycarbonyl-ethyl)-morpholine-2-yl]-phenyl �fir 2,6-dichlorobenzoyl acid : To a solution of tert-butyl ether 3-[2-(4-hydroxyphenyl)-morpholine-4-yl]-propionic acid (0,39 g; 1.27 mmol) and N-ethyldiethanolamine (0.65 ml, 3,81 mmol) in CH3CN (5 ml) at 0°C was added 2,6-dichlorobenzoyl chloride (of 0.44 ml; 3.0 mmol). Then the mixture was allowed to warm to ambient temperature and was stirred for 2 days at ambient temperature. The mixture was divided between the Et2O and 5% aqueous solutionNaHCO3. The layers were separated, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O) to give 4-[4-(2-tert-butoxycarbonyl-ethyl)-morpholine-2-yl]-phenyl ester 2,6-dichlorobenzoyl acid (0,51 g).

tert-butyl ether 4-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-butyric acid: 2-(4-Octyloxy-phenyl)-morpholine (1,50 g; 5.2 mmol), tert-butyl ether 4-pamakani acid (1,38 g; 6.2 mmol) (obtained according to C. Morin, M. Vidal Tetrahedron,1992, 48(42), 9277), potassium iodide (1.03 g; 6.2 mmol), K2CO3(1.42 g; 10,29 mmol) and CH3CN (15 ml) were mixed and heated to reflux for 2 hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuo, dissolved in EtOAc, washed with 5% aqueous solutionNaHCO3, dried (Na2SO4 ), concentrated in vacuo and purified by chromatography on a column (SiO2Et2O:hexane 1:1), obtaining tert-butyl ether 4-[2-(4-octyloxy-phenyl)-morpholine-4-yl]- butyric acid (1.90 g), TLC (SiO2Rf. 0,20 EtOAc:hexane 1:1).

The following compounds were obtained in a similar way:

tert-butyl ether 4-[2-(4-octylphenyl)-morpholine-4-yl]-butyric acid

tert-butyl ether 4-[2-(4-hexyloxy-phenyl)-morpholine-4-yl]-butyric acid

tert-butyl ether 4-[2-(4-heptyloxy-phenyl)-morpholine-4-yl]-butyric acid

diethyl ether {3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propyl}-phosphonic acid

tert-butyl ether 4-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-butyric acid

tert-butyl ether 2,2-dimethyl-3-(2-(4-octyloxy-phenyl)-morpholine-4-yl)-propionic acid.Neededtert-butyl ether 3-chloro-2,2-dimethyl-propionic acidwas prepared as follows. To a solution of 3-chloro-2,2-dimethylpropionic acid (5,00 g; 36.6 mmol) in DMF (25 ml) was added N,N'-carbonyldiimidazole (5,94 g, 36.6 mmol) and the resulting mixture was stirred for 1 hour at 40°C. was Then added tert-butyl alcohol (7,1 ml; 73 mmol) and DBU (5.5 ml; 36.6 mmol) and the mixture was stirred overnight at 40°C. After cooling to ambient temperature, 5% aqueous solutionNaHCO3(50 ml) was added to smexii was stirred for another 15 minutes. The reaction mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by chromatography on a column (SiO2Et2O:hexane 1:1), obtaining tert-butyl ether 3-chloro-2,2-dimethyl-propionic acid (3,34 g).

tert-butyl ether 3-[2-(4-triftormetilfullerenov-phenyl)-morpholine-4-yl]-propionic acid: To a solution of tert-butyl methyl ether [2-(4-hydroxyphenyl)-morpholine-4-yl]-propionic acid (2,07 g; 6,73 mmol) inCHCl3(50 ml) was added aEt3N (1,40 ml; 10,10 mmol), DMAP (82,3 mg; 0.67 mmol) and N-phenylbis(triptorelin-sulfonamid) (2,89 g; 8,08 mmol). The mixture was heated at 60°C for 3 hours. After cooling to ambient temperature the mixture was washed with 5% aqueous Na2CO3and water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O) to obtain tert-butyl ether 3-[2-(4-triftormetilfullerenov-phenyl)-morpholine-4-yl]-propionic acid (2.30 g).

tert-butyl ether 3-[2-(4-acetylmethadol-phenyl)-morpholine-4-yl]-propionic acid: To a degassed solution of tert-butyl ether 3-[2-(4-triftormetilfullerenov-phenyl)-morpholine-4-yl]-propionic acid (2.55 g; 5.8 mmol) in toluene (50 ml) was added Pd 2dba3(0.27 g; 0.29 mmol) and (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]-ethyl]-2-(dicyclohexylphosphino)ferrocene (0,32 g, of 0.58 mmol) followed, after 5 min, thioacetic potassium (1.33 g; 11.6 mmol). The mixture was heated to reflux over night. After cooling to ambient temperature the mixture was diluted with CH2Cl2, filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2, CH2Cl2/acetone 95:5) to obtain tert-butyl ether 3-[2-(4-acetylmethadol-phenyl)-morpholine-4-yl]-propionic acid (1.70 g).

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzolsulfonat)-phenyl]-morpholine-4-yl}-propionic acid: a mixture of tert-butyl ether 3-[2-(4-acetylmethadol-phenyl)-morpholine-4-yl]-propionic acid (0.31 g; 0.85 mmol) and NaOH (37 mg, 0.93 mmol) in EtOH (10 ml) and water (1 ml) was stirred for 30 minutes at 0°C. Then was added 2,6-dichlorobenzyl bromide (0.22 g; 0.93 mmol) dissolved in EtOH (2.5 ml), and the mixture was allowed to warm to ambient temperature. After 90 min the mixture was separated between EtOAc and 5% aqueous solution of NaHCO3. The layers were separated, and the organic layer was washed with 5% aqueous NaHCO3and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,CH2Cl 2/acetone 95:5) to obtain tert-butyl ether 3-{2-[4-(2,6-dichloro-benzolsulfonat)-phenyl]-morpholine-4-yl}-propionic acid (0.20 g).

The following compounds were obtained in a similar way:

tert-butyl ether 3-{2-[4-(2-chlorine-benzolsulfonat)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(2-chloro-6-fluoro-benzolsulfonat)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-[2-(4-octylsilane-phenyl)-morpholine-4-yl]-propionic acid.

tert-butyl ether 3-[2-(4-itfinal)-thiomorpholine-4-yl]-propionic acid: To a solution of tert-butyl ether 3-[2-(4-bromophenyl)-thiomorpholine-4-yl]-propionic acid (22,15 g; to 57.33 mmol), 1,4-dioxane (250 ml) was added N,N'-dimethylethylene-diamine (3,05 ml; 28,67 mmol). After the resulting mixture was barbotirovany gaseous nitrogen for 1 hour and then was added CuI (1,09 g, 5,73 mmol) and NaI (21,48 g; 143,33 mmol). The mixture was heated at 130°C in a closed vessel for 4 days. After cooling to ambient temperature the mixture was concentrated in vacuo, and the residue was purified by chromatography on a column (SiO2Et2O/hexane 2:3) to obtain tert-butyl ether 3-[2-(4-itfinal)-thiomorpholine-4-yl]-propionic acid (g Jn 19: 30).

tert-butyl ether 3-[2-(4-benzyloxy-phenyl)-thiomorpholine-4-yl]-PR�pianoboy acid : (All solutions were degassed.) To a suspension of 1,10-phenanthroline (183,0 mg; 1.02 mmol) in toluene (15 ml) was added CuI (96.7 mg; 0.51 mmol), Cs2CO3(Of 3.31 g; 10,15 mmol) and a solution of tert-butyl ether 3-[2-(4-itfinal)-thiomorpholine-4-yl]-propionic acid (2.20 g; 5.08 mmol) and benzyl alcohol (1.05 ml; 10,15 mmol) in toluene (20 ml). The mixture was heated for three days at 100°C. After cooling to ambient temperature was added EtOAc and water. The layers were separated, and the organic layer was dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2, EtOAc/CH2Cl21:6) to obtain tert-butyl ether 3-[2-(4-benzyloxy-phenyl)-thiomorpholine-4-yl]-propionic acid (1.85 g).

The following compounds were obtained in a similar way:

tert-butyl ether 3-{2-[4-(2-chlorine-benzyloxy)-phenyl]-thiomorpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-thiomorpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-octyloxy-phenyl)-thiomorpholine-4-yl]-propionic acid.

tert-butyl ether 3-[2-(4-benzyloxy-phenyl)-1-oxo-thiomorpholine-4-yl]-propionic acid: To a solution of tert-butyl ether 3-[2-(4-benzyloxy-phenyl)-thiomorpholine-4-yl]-propionic acid (0.85 g; 1,77 mmol) in MeOH (25 ml) to�alali dropwise at 0°C a solution of oxone® (0.54 g; 0,89 mmol) in water (25 ml). The resulting mixture was stirred for 2 hours at 0°C and then overnight at ambient temperature. The resulting mixture was treated with water and 25% aqueous solution of NH4OH and was extracted with EtOAc. The combined organic layers were dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,CH2Cl2/MeOH 97,5:2,5), obtaining tert-butyl ether 3-[2-(4-benzyloxy-phenyl)-1-oxo-thiomorpholine-4-yl]-propionic acid (0.65 g).

The following compounds were obtained in a similar way:

tert-butyl ether 3-{2-[4-(2-chlorine-benzyloxy)-phenyl]-1-oxo-thiomorpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-1-oxo-thiomorpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-octyloxy-phenyl)-1-oxo-thiomorpholine-4-yl]-propionic acid.

ethyl ester {2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-acetic acid: a mixture of 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine hydrochloride (0.65 g; 1.68 mmol), Et3N (of 0.58 ml; 4.2 mmol) and ethyl bromo acetate (0,24 ml; 2,19 mmol) inCH3CN (65 ml) was stirred at 85°C overnight. After cooling to ambient temperature the mixture was concentrated in vacuo, and the residue was separated between water�th and CH2Cl2. The layers were separated, and the aqueous layer was again extracted with CH2Cl2. The combined organic layers were concentrated in vacuo, and the residue was purified by chromatography on a column (SiO2Et2O:hexane 2:1), obtaining the ethyl ester {2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-acetic acid (0,62 g).

ethyl ether of 2,2-debtor-3-(2-(4-octyloxy-phenyl)-morpholine-4-yl)-propionic acid

To a solution of 2-(4-octyloxy-phenyl)-morpholine (0.75 g; 2.6 mmol) in EtOH (10 ml) was added 1H-benzotriazole-1-methanol (0,38 g; 2.6 mmol) and the reaction mixture was heated at 50°C for 20 minutes. After cooling to ambient temperature the solvent was removed under vacuum to give 1-[2-(4-octyloxy-phenyl)-morpholine-4-ylmethyl]-1H-benzotriazole; which was used as such.

To a suspension of zinc dust (0,34 g; 5.2 mmol) in dry THF (10 ml) was added chlorotrimethylsilane (0.33 ml; 2.6 mmol) and ethyl bromodifluoroacetate (0.50 ml; 3.9 mmol), the mixture was heated to reflux for 10 min and then cooled to ambient temperature. To this mixture was added dropwise a solution of 1-[2-(4-octyloxy-phenyl)-morpholine-4-ylmethyl]-1H-benzotriazole in THF (5 ml). After completion of the addition the mixture was heated to reflux for 2 hours. After cooling to ambient temperature�environment setup portion of the reaction mixture was filtered through diatomaceous earth, and filtered the precipitate was washed with ethanol. The solvent was removed under vacuum, and the residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:1), obtaining the ethyl ester of 2,2-debtor-3-(2-(4-octyloxy-phenyl)-morpholine-4-yl)-propionic acid (0,58 g).

ethyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2,2-debtor-propionic acidreceived a similar manner.

ethyl ester of 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-3-oxo-propionic acid: To a suspension of 2-(4-octyloxy-phenyl)-morpholine (0,97 g; 3.3 mmol) and N-ethyldiethanolamine (1,14 ml; 6.7 mmol) in CH3CN (10 ml) was added dropwise ethyl malonyl chloride (0,51 ml; 4.0 mmol). The resulting mixture was stirred for one hour at ambient temperature and then separated between 5% aqueous solutionNaHCO3and Et2O. the Organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O), obtaining the ethyl ester of 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-3-oxo-propionic acid (0.50 g).

ethyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-3-oxo-propionic acidreceived a similar manner.

tert-butyl ether 2-methyl-3-[2-(4-octyloxy-phenyl)-morpholine-4-�l]-propionic acid . To a suspension of 2-(4-octyloxy-phenyl)-morpholine hydrochloride (0.17 g; 0.5 mmol) in DMF (5.00 ml) was added tert-butyl methacrylate (0,17 ml; 1.0 mmol) and DBU (0,23 ml; 1.5 mmol), the mixture was heated at 140°C in a sealed flask overnight. After cooling to ambient temperature the reaction mixture was divided between 5% aqueous solution of NaHCO3and EtOAc. The layers were separated, and the organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on a column (SiO2,Et2O:hexane 1:1), obtaining tert-butyl ether 2-methyl-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid (0.11 g).

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2-methylpropionic acidreceived a similar manner.

tert-butyl ether 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-butyric acid: a mixture of 2-(4-octyloxy-phenyl)-morpholine (0.24 gram, 1.1 mmol), tert-butyl ether 3-pamakani acid (0.24 g; 1.1 mmol), sodium iodide (27,4 mg; 0.2 mmol) and DBU (0.4 ml; 2.7 mmol) in CH3CN (10 ml) was heated in a closed vessel at 120°C. After cooling to ambient temperature the reaction mixture was divided between 5% aqueous solution of NaHCO3and EtOAc. The layers were separated, and the organic layer was dried(Na2SO4), filtered and the end�was tarawali. The residue was purified by chromatography on a column (SiO2Et2O) to obtain tert-butyl ether 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-butyric acid (0.15 g).

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-butyric acidreceived in this way. Neededtert-butyl ether 3-bromeley acidwas prepared as follows. To a solution of 3-pamakani acid (5.0 ml; 47,0 mmol) in tetrahydrofuran (50 ml) was added dropwise at -40°C trifluoroacetic anhydride (13.7 ml; of 98.7 mmol). After 1 hour at -40°C was added tert-butyl alcohol (20 ml). The resulting mixture was allowed to warm to ambient temperature and stirred over night. Then the reaction mixture was concentrated in vacuo. The residue was treated with 2 M aqueous NaOH and was extracted with Et2O. the Organic layer was dried(Na2SO4) and concentrated in vacuum, obtaining tert-butyl ether 3-pamakani acid (6,05 g), which was used as such.

methyl ester 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2,2-dimethylpropionic acid: To a solution of methyl ester of 2,2-dimethyl-3-oxo-propionic acid (WHSS0374-001) (0,90 g, 5,44 mmol) in 1,2-dichloroethane (20 ml) was added 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0,91 g, 2.7 mmol) and NaBH(OAc)3(1.62 g; a 7.62 mmol). The resulting mixture was stirred for �eyes at ambient temperature and then treated with 5% aqueous solution of NaHCO 3(10 ml) and was extracted with CH2Cl2(3×30 ml). The combined organic layers were dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2,Et2O/hexane 1:1), obtaining methyl ester 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2,2-dimethylpropionic acid (1.12 g) in the form of a pure colorless oil. Neededmethyl ether of 2,2-dimethyl-3-oxo-propionic acidwas prepared as follows. To a solution of methyl ester of 2,2-dimethyl-3-hydroxypropionic acid (10.00 g; the 75.7 mmol) inCH2Cl2(200 ml) in small portions at 0°C was added pyridine chloroformiate (28,54 g; to 132.4 mmol). The reaction mixture gave to slowly warm to ambient temperature and stirred over night. Then the mixture was dilutedCH2Cl2was filtered through diatomaceous earth and concentrated in vacuo. The remaining oil was purified by chromatography on a column (SiO2,hexane/Et2O 7:3), obtaining the methyl ester of 2,2-dimethyl-3-oxo-propionic acid (5,59 g).

The following compound was obtained according to a similar manner:

tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-cyclobutanecarbonitrile acid. Neededtert-butyl ether 3-oxo-cyclobutanecarbonitrile acidreceived, ka� described in R. P. Lemieux, G. B. Schuster, J. Org. Chem.,1993, 58, 100.

tert-butyl ether 3-{2-[4-(benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid: a mixture of tert-butyl ether 3-[2-(4-hydroxyphenyl)-morpholine-4-yl]-propionic acid (76,8 mg; 0.25 mmol), Cs2CO3(241 mg; 0.74 mmol) and NaI (3.7 mg, 25 μmol) inCH3CN/THF (6:4; 2.5 ml) was stirred for three hours at ambient temperature. Was then added benzyl chloride (35 μl; 0.3 mmol) in CH3CN (1 ml), and the mixture was heated at 60°C for 20 h. After cooling to ambient temperature the solvent was removed under vacuum. The residue was divided between CH2Cl2and 1 M aqueous solution of K2CO3. The layers were separated, and the aqueous layer was washed withCH2Cl2. The combined organic layers were concentrated in vacuo, and the residue was dried under vacuum at 40°C over night. The resulting product was used as such in next step.

The following compounds were obtained in a similar way:

tert-butyl ether 3-{2-[4-(6-methyl-imidazo[1,2-a]pyridine-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-(2-{4-[3-(2-propyl-thiazole-5-yloxy)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-{2-[4-(2-benzyloxy-ethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-phenoxy-ethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-hex-5-ynyloxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(4-acetoxy-butoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-(2-{4-[3-(4-pertenece)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-(2-{4-[2-(naphthalene-2-yloxy)-ethoxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-[2-(4-phenylcarbamoyloxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(4-pyrazol-1-yl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(1-methyl-1H-pyrazol-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(6-cyano-hexyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-venetjoki-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(3-phenyl-propoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3-benzyloxy-propoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(7-methoxy-heptyloxy)-phenyl]-morph�Lin-4-yl}-propionic acid

tert-butyl ether 3-(2-{4-[3-(4-tert-butyl-phenyl)-[1,2,4]oxidiazol-5-ylethoxy]-phenyl}-morpholine-4-yl)-propionic acid

tert-butyl ether 3-{2-[4-(5-oxo-hexyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-phenyl-butoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3-methoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-cyclohexylmethoxy-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(2-benzolsulfonat-ethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3-phenoxy-propoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-[1,2,4]triazole-1-yl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,3-dihydro-benzofuran-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-biphenyl-4-yl-2-oxo-ethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-phenoxy-butoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-oxo-2-phenyl-ethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl�first aired 3-{2-[4-(3-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-(2-{4-[2-(1H-indol-3-yl)-ethoxy]-phenyl}-morpholine-4-yl)-propionic acid.

tert-butyl ether 3-{2-[4-(3-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid: To a solution of 3-methoxybenzylamine alcohol (0.25 M, 450 μl) in THF was added a solution of tert-butyl ether 3-[2-(4-hydroxy-2-methyl-phenyl)-morpholine-4-yl]-propionic acid (0.25 M, 360 μl) in THF. To this mixture was added a solution of DIAD in THF (0.25 M, 360 μl). Finally added triphenylphosphine on a polystyrene substrate (~190 mg, 1,2 mmol/g), then THF (1 ml). The reaction mixture was stirred at intervals for 20 hours at 30°C. was Then added a new amount of DIAD (360 μl, 0.25 M in THF) and triphenylphosphine on a polystyrene substrate (95 mg, 1,2 mmol/g). The mixture was stirred again at intervals for 20 hours at 30°C. To this mixture was added macroporous carbonate resin (~90 mg, 3,06 mmol/g, Argonaut Technologies), and the mixture was stirred again at intervals for 20 hours at 50°C.

The mixture was transferred into air-conditioned with methanol and THF in a strong cation exchange cartridge (IST, 0.5 g, 0.6 mmol/g), washed sequentially THF (6 ml) and CH3CN (8 ml), after which he suirable 1 n of NH4OH in CH3CN (6 ml). Concentration in vacuo gave tert-butyl ether 3-{2-[4-(3-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid (~15 mg), which is used�exercise as such.

The following compounds were obtained in a similar way:

tert-butyl ether 3-{2-[4-(5-bromo-2-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,4-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,3-dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-cyclopentyloxy-2-methyl-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[4-(2,5-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(pyridin-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(naphthalene-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(6-methyl-pyridin-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chlorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,5-dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tre�-butyl ether 3-{2-[4-(2-bromine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(2-methyl-benzyloxy)- phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(biphenyl-2-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3,5-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(3-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-chlorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-isopropyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(3-phenoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(2-phenethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3,4-Dimitar�-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3,5-dimethyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-benzyloxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(thiophene-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3-fluorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3-benzyloxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-fluorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(biphenyl-4-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(pyridin-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-butoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-[2-(4-cyclohexylmethoxy-2-methyl-phenyl)-morpholine-4-yl]-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(tetrahydro-furan-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(3-methyl-BAA�siloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,3-debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(4-triptoreline-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3-chlorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(tetrahydro-Piran-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(4-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3,4-debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(2,3,4-trimethoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(cyclohex-3-animetake)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-butyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(4-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3-dimethylamino-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(pyridin-4-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2-iodine-benzo�loksi)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3,5-dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,4-debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(2,4,5-trimethoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(3-bromine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-bromine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(4-tert-butyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[4-(2,5-debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid

tert-butyl ether 3-{2-[2-methyl-4-(tetrahydro-furan-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid.

tert-butyl ether 3-{2-[4-(2,6-dichloro-4-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid: tert-butyl ether 3-{2-[4-(2,6-dichloro-4-iodine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid (0,34 g; 0,57 mmol) and Pd(dppf)Cl2(14,70 mg; 0.02 mmol) was added to a solution of lithium chloride (4,59 ml; 0.50 mol/l; 2,30 mmol) in THF; 0.04 EQ.). The mixture was cooled to 0°C and added dropwise a solution of diethylzinc in n-heptane (1,15 ml; 1.00 mol/l; 1.15 mmol). The mixture on�revali to 60°C over night. After cooling to ambient temperature was added a saturated aqueous solution of NH4Cl. The mixture was extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2, EtOAc:hexane 1:1), obtaining tert-butyl ether 3-{2-[4-(2,6-dichloro-4-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid (115,00 mg).

2-(4-Octyloxy-phenyl)-4-[2-(tetrahydro-Piran-2-yloxy)-ethyl]-morpholine: a mixture of 2-(4-octyloxy-phenyl)-morpholine (1,99 g; 6.8 mmol), 2-(2-chloroethoxy)tetrahydro-2H-PYRAN (1,21 ml; 8.2 mmol), K2CO3(1.89 g; 13,7 mmol) and NaI (0.20 g; 1.4 mmol) in DMF (15 ml) was heated to 100°C over night. After cooling to ambient temperature the reaction mixture was divided between a 5% aqueous solutionNaHCO3and Et2O. the Organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2, EtOAc) to give 2-(4-octyloxy-phenyl)-4-[2-(tetrahydro-Piran-2-yloxy)-ethyl]-morpholine (2,04 g).

2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-[2-(tetrahydro-Piran-2-yloxy)-ethyl]-morpholinereceived a similar manner.

diethyl ether {2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethyl}-phosphonic acid: a mixture of 2-(4-octyloxy-f�Neal)-morpholine (0,83 g; The 2.9 mmol) and diethyl vinylphosphonate (of 0.53 ml; 3.4 mmol) in CH3CN (10 ml) was heated to reflux for 3 days. After cooling to ambient temperature the mixture was concentrated in vacuo, and the residue was purified by chromatography on a column (SiO2, EtOAc:MeOH 90:10) to give diethyl ether {2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethyl}-phosphonic acid (0.42 g).

Di-tert-butyl ether phosphoric acid 2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethyl ester: To a solution of 2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethanol (1.33 g; 4.0 mmol) in a mixture of THF (15 ml) and CH2Cl2(15 ml) at ambient temperature was added a solution of tetrazole in CH3CN (17.6 ml; 0,45 mol/l; 7.9 mmol). The resulting mixture was stirred for 30 minutes and then di-tert-butyl N,N-diisopropylphosphoramidite (2.00 ml; 6.3 mmol) was added and stirred overnight at ambient temperature. Was then added an aqueous solution of hydrogen peroxide (1,80 ml; 300 g/l; 15,9 mmol) and the mixture stirred at ambient temperature for another 15 min. the Reaction mixture was quenched by adding 5% aqueous solution of NaHCO3and was extracted with EtOAc. The organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2Et2O) to give di-tert-butile�th phosphoric acid ester 2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethyl ester (0.71 g).

Di-tert-butyl ether phosphoric acid 2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-ethyl ester: To a solution of 2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-ethanol (0.74 g; 1,94 mmol) in a mixture of THF (10 ml) and CH2Cl2(10 ml) at ambient temperature was added a solution of tetrazoleCH3CN ((8,60 ml; 0,45 mol/l; a 3.87 mmol). The resulting mixture was stirred for 30 minutes and then di-tert-butyl N,N-diisopropylphosphoramidite (0,98 ml, 3.10 mmol) was added and stirred overnight at ambient temperature. The mixture is then cooled to 4°C and added a solution of tert-butyl hydroperoxide in nonane (0,31 ml; ~of 5.5 mol/l, 2,90 mmol). Thereafter, the mixture was stirred at ambient temperature for another 30 min. the Reaction mixture was quenched by adding 5% aqueous solution ofNaHCO3and was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2, EtOAc) to give di-tert-butyl ether phosphoric acid 2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-ethyl ester (0.66 g).

Diethyl ether {2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propyl}-phosphonic acid: a mixture of 2-(4-octyloxy-phenyl)-morpholine (1.04 g; 3.6 mmol), diethyl(3-bromopropyl), phospho�ATA (0,82 ml; The 4.3 mmol), NaI (0.11 g; 0.7 mmol) and K2CO3(0,99 g; 7.1 mmol) in CH3CN (10 ml) was heated to reflux for 2 hours. After cooling to ambient temperature the mixture was divided between a 5% aqueous solutionNaHCO3and Et2O. the Organic layer was dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on a column (SiO2, EtOAc:MeOH 90:10) to give diethyl ether {2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propyl}-phosphonic acid (1.13 g).

Diethyl ether(3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propyl)-phosphonic acidreceived a similar manner.

§4. SYNTHESES of SPECIFIC COMPOUNDS

(Cm. Table)

Method A:

Connection 1(3-{2-[4-(benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid)crude tert-butyl ether 3-{2-[4-(benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid (see §3) was treated with a mixture of TFA, water and CH2Cl2(30:3:67; 3 ml) and stirred at ambient temperature for 2 h. Then the volatile components were removed under vacuum, and the crude product was purified preparative HPLC, obtaining a salt of trifluoroacetic acid 3-{2-[4-(benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid;Rt=1,86 min (System A), [M+H]+Found: 342,19; Hop: 342,17. Conditions preparative LC-MS: Injection damp�about product was dissolved in 600 ml DMSO/CH 3CN 1:2; column Waters Sunfire C mm 5 µm 45°C, mobile phase water/CH3CN/TFA 0,1% 25 ml/min, acceleration 20 min. 10% -90% CH3CN, detection with UV 210-260 nm.

The following compounds were obtained similarly.

Compound 2;Salt of trifluoroacetic acid 3-{2-[4-(6-methyl-imidazo[1,2-a]pyridine-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=0,76 min (System A), [M+H]+Found: 396,23; Hop.: 396,19.

Connection 3;Salt of trifluoroacetic acid 3-(2-{4-[3-(2-propyl-thiazole-5-yloxy)-propoxy]-phenyl}-morpholine-4-yl)-propionic acidRt=2,04 min (System A), [M+H]+Found: 435,21; Hop.: 435,20.

Connect 4;Salt of trifluoroacetic acid 3-{2-[4-(2-benzyloxy-ethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,89 min (System A), [M+H]+Found: 386,22; Hop.: 386,20.

Connection 5;Salt of trifluoroacetic acid 3-{2-[4-(2-phenoxy-ethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,91 min (System A), [M+H]+Found: 372,21; Hop.: 372,18.

Connection 6;Salt of trifluoroacetic acid 3-[2-(4-hex-5-ynyloxy-phenyl)-morpholine-4-yl]-propionic acidRt=1,77 min (System A), [M+H]+Found: 332,21; Hop.: 332,19.

Connection 7;Salt of trifluoroacetic acid 3-{2-[4-(4-acetoxy-butoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,51 min (System A), [M+H]sup> +Found: 366,21; Hop.: 366,19.

Compound 8;Salt of trifluoroacetic acid 3-(2-{4-[3-(4-pertenece)-propoxy]-phenyl}-morpholine-4-yl)-propionic acidRt=2,16 min (System A), [M+H]+Found: 404,22; Hop.: 404,19.

Compound 9;Salt of trifluoroacetic acid 3-(2-{4-[2-(naphthalene-2-yloxy)-ethoxy]-phenyl}-morpholine-4-yl)-propionic acidRt=2,35 min (System A), [M+H]+Found: 422,24; Hop.: 422,20.

Compound 10;Salt of trifluoroacetic acid 3-[2-(4-phenylcarbamoyloxy-phenyl)-morpholine-4-yl]-propionic acidRt=1,48 min (System A), [M+H]+Found: 385,20; Hop.: 385,18.

Compound 11;Salt of trifluoroacetic acid 3-{2-[4-(4-pyrazol-1-yl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,83 min (System A), [M+H]+Found: 408,22; Hop.: 408,19.

Compound 12;Salt of trifluoroacetic acid 3-{2-[4-(1-methyl-1H-pyrazol-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,14 min (System A), [M+H]+Found: 346,20; Hop.: 346,18.

Compound 13;Salt of trifluoroacetic acid 3-{2-[4-(4-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=2,14 min (System A), [M+H]+Found: 376,13; Hop.: 376,13.

Compound 14;Salt of trifluoroacetic acid 3-{2-[4-(6-cyano-hexyloxy)-phenyl]-morpholine-4-yl}-propionic acid t=1,68 min (System A), [M+H]+Found: 361,24; Hop.: 361,21.

Compound 15;Salt of trifluoroacetic acid 3-[2-(4-venetjoki-phenyl)-morpholine-4-yl]-propionic acidRt=1,93 min (System A), [M+H]+Found: 356,23; Hop.: 356,19.

Compound 16;Salt of trifluoroacetic acid 3-{2-[4-(3-phenyl-propoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=2,11 min (System A), [M+H]+Found: 370,24; Hop.: 370,20.

Compound 17;Salt of trifluoroacetic acid 3-{2-[4-(3-benzyloxy-propoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,97 min (System A), [M+H]+Found: 400,26; Hop.: 400,21.

Compound 18;Salt of trifluoroacetic acid 3-{2-[4-(7-methoxy-heptyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=2,04 min (System A), [M+H]+Found: 380,27; Hop.: 380,24.

Compound 19;Salt of trifluoroacetic acid 3-(2-{4-[3-(4-tert-butyl-phenyl)-[1,2,4]-oxadiazol-5-ylethoxy]-phenyl}-morpholine-4-yl)-propionic acidRt=2,67 min (System A), [M+H]+Found: 466,27; Hop.: 466,23.

Compound 20;Salt of trifluoroacetic acid 3-{2-[4-(5-oxo-hexyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,35 min (System A), [M+H]+Found: 350,22; Hop.: 350,20.

Connection 21;Salt of trifluoroacetic acid 3-{2-[4-(4-phenyl-butoxy)-phenyl]-morpholine-4-yl}-impregnated�new acid Rt=2,38 min (System A), [M+H]+Found: 384,25; Hop.: 384,22.

Compound 22;Salt of trifluoroacetic acid 3-{2-[4-(3-methoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,75 min (System A).

Compound 23;Salt of trifluoroacetic acid 3-{2-[4-(2-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,99 min (System A), [M+H]+Found: 376,18; Hop.: 376,13.

Compound 24;Salt of trifluoroacetic acid 3-[2-(4-cyclohexylmethoxy-phenyl)-morpholine-4-yl]-propionic acidRt=2,26 min (System A), [M+H]+Found: 348,27; Hop.: 348,22.

Compound 25;Salt of trifluoroacetic acid 3-{2-[4-(2-benzolsulfonat-ethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,45 min (System A), [M+H]+Found: 420,18; Hop.: 420,15.

Compound 26;Salt of trifluoroacetic acid 3-{2-[4-(3-phenoxy-propoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=2,12 min (System A), [M+H]+Found: 386,21; Hop.: 386,20.

Compound 27;Salt of trifluoroacetic acid 3-{2-[4-(4-[1,2,4]triazole-1-yl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,46 min (System A), [M+H]+Found: 409,22; Hop.: 409,19.

Compound 28;Salt of trifluoroacetic acid 3-{2-[4-(2,3-dihydro-benzofuran-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidR =1,94 min (System A), [M+H]+Found: 384,21; Hop.: 384,18.

Compound 29;Salt of trifluoroacetic acid 3-{2-[4-(2-biphenyl-4-yl-2-oxo-ethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=2,30 min (System A), [M+H]+Found: 446,23; Hop.: 446,20.

The connection 30;Salt of trifluoroacetic acid 3-{2-[4-(4-phenoxy-butoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=2,25 min (System A), [M+H]+Found: 400,24; Hop.: 400,21.

The connection 31;Salt of trifluoroacetic acid 3-{2-[4-(2-oxo-2-phenyl-ethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,60 min (System A), [M+H]+Found: 370,18; Hop.: 370,17.

Compound 32;Salt of trifluoroacetic acid 3-{2-[4-(3-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=2,09 min (System A), [M+H]+Found: 376,16; Hop.: 376,13.

Compound 33;Salt of trifluoroacetic acid 3-(2-{4-[2-(1H-indol-3-yl)-ethoxy]-phenyl}-morpholine-4-yl)-propionic acidRt=1,99 min (System A), [M+H]+Found: 395,22; Hop.: 395,20.

Method B:

The connection 34;3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. Tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid (0.59 g; 1.27 mmol) was dissolved in 4 M HCl solution in 1,4-dioxane (6,33 ml, 25,30 mmol) and stirred overnight at those�ture of the environment. Then the solvent was removed under vacuum, and the residue was treated with iPr2O, the precipitate was collected by filtration and dried over night under reduced pressure, obtaining hydrochloride 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]- morpholine-4-yl}-propionic acid (0.50 g).1H NMR (400 MHz, DMSO-d6) δ ppm 2,88-of 2.97 (2H, m), 3,11 (1H, t, J=11,7 Hz), 3,15-3,23 (1H, m), 3,30-of 3.43 (2H, m), 3,49 (1H, d, J=12,0 Hz), 3,55-to 3.64 (1H, m), 4,01-4,20 (2H, m) of 4.88 (1H, d, J=12,0 Hz), 5,24 (2H, C) to 7.04-7,12 (2H, m), 7,35 (2H, d, J=8,7 Hz), 7,40-7,49 (1H, m), 7,49-7,56 (2H, m).

The following compounds were obtained in a similar way:

Compound 34a; Hydrochloride(+)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid([α]D25=+7 (c of 1.0, MeOH)).1H NMR (400 MHz, DMSO-d6) δ ppm 2,82-2,96 (m, 2H) 3,09 (d, J=0,37 Hz, 2H) 3,34 (ush. S., 2H) 3.43 points-3,52 (m, 1H) 3,95-4,07 (m, 1H) of 4.09-4,20 (m, 1H) 4,78-of 4.88 (m, 1H) 5,24 (s, 2H) 7,06-7,14 (m, 2H) 7,30-7,39 (m, 2H) 7,43-7,51 (m, 1H) 7,54-of 7.62 (m, 2H)

Compound 34b; Hydrochloride(-)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid([α]D25=-7 (c of 1.0, MeOH)).1H NMR (400 MHz, DMSO-d6) δ ppm 2,84-2,96 (m, 2H) 3,09 (s, 2H) 3,34 (ush. S., 2H) 3.43 points-3,52 (m, 1H) 3,97-4,08 (m, 1H) of 4.09-4,18 (m, 1H) 4,79-4,89 (m, 1H) 5,24 (s, 2H) 7,07-7,15 (m, 2H) 7,31-7,38 (m, 2H) 7,43-7,51 (m, 1H) 7,54-to 7.60 (m, 2H).

The connection 35; Hydrochloride 3-(2-(4-octylphenyl)-morpholine-4-yl)-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 0,55-0,71 (m, 3H) 1,04 (ush., 10H) 1,25-1,43 (m, 2H) 2,23-2,44 (m, 2H) 2,55-2,73 (m, 2H) 2,78-of 3.04 (m, 2H) 3,08-of 3.53 (m, 4H) 367-4,07 (m, 2H) 4,48-4,69 (m, 1H) 6,90-7,25 (m, 4H).

The connection 36; Hydrochloride 4-[2-(4-octylphenyl)-morpholine-4-yl]-butyric acid.1H NMR (600 MHz, DMSO-d6) δ ppm 0,86 (t, J=6,8 Hz, 3H) 1.19 and 1.33 (m, 10H) of 1.52 to 1.60 (m, 2H) 1,94-2,02 (m, 2H) a 2.36 (t, J=7,2 Hz, 2H) of 2.57 (t, J=7,7 Hz, 2H) 3,03-3,18 (m, 4H) 3,58-3,68 (m, 2H) 4,10-4,19 (m, 2H) 4,84-4,89 (m, 1H) 7,22 (d, J=8,6 Hz, 2H) 7,30 (d, J=8,6 Hz, 2H).

Compound 37; Hydrochloride 3-[2-(4-hexyloxy-phenyl)-morpholine-4-yl]-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 0,84-0,91 (m, 3H) 1,27-1,34 (m, 4H) 1,36-of 1.46 (m, 2H) 1,66-of 1.74 (m, 2H) 2,84-of 2.91 (m, 2H) 3,02-3,18 (m, 2H) 3,30 is 3.40 (m, 2H) 3,44-3,51 (m, 1H) 3,52-3,61 (m, 1H) of 3.91-was 4.02 (m, 3H) of 4.09-4,17 (m, 1H) 4,74-to 4.81 (m, 1H) 6,95 (d, J=to 8.7 Hz, 2H) 7,29 (d, J=to 8.7 Hz, 2H) 11,10-12,90 (m, 2H).

The connection 38; Hydrochloride 4-[2-(4-hexyloxy-phenyl)-morpholine-4-yl]-butyric acid.1H NMR (400 MHz, DMSO-d6) δ ppm 0,63-0,71 (m, 3H) 1,05-1,15 (m, 4H) 1,15-1,25 (m, 2H) 1,44-of 1.53 (m, 2H) 1,70-of 1.81 (m, 2H) 2,14 (t, J=7,1 Hz, 2H) 2,78-2,95 (m, 2H) 3,11-3,39 (m, 4H) of 3.75 (t, J=6,4 Hz, 2H) 3,78-3,84 (m, 1H) 3,87-to 3.96 (m, 1H) 4,56-a 4.64 (m, 1H) 6.75 in (d, J=to 8.7 Hz, 2H) to 7.09 (d, J=to 8.7 Hz, 2H) 10,70-11,00 (ush.with., 1H).

The connection 39; Hydrochloride 3-[2-(4-heptyloxy-phenyl)-morpholine-4-yl]-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm of 0.59 to 0.68 (m, 3H) 0,96-1,22 (m, 8H) 1,40-of 1.52 (m, 2H) 2,61-of 2.72 (m, 2H) 2,78-2,96 (m, 2H) 3,02-3,39 (m, 4H) 3,67-3,81 (m, 3H) 3,84-3,94 (m, 1H) 4,57 (d, J=10,8 Hz, 1H) 6,71 (d, J=to 8.7 Hz, 2H) 7,05 (d, J=to 8.7 Hz, 2H) Of 10.67-12,94 (m, 2H).

The connection 40; Hydrochloride 4-[2-(4-heptyloxy-phenyl)-morpholine-4-yl]-butyric acid.1H NMR (400 MHz, DMSO-d6/sub> ) δ ppm of 0.87 (t, J=7,0 Hz, 3H) 1,22-of 1.35 (m, 6H) 1,36-1,44 (m, 2H) 1,66-of 1.74 (m, 2H) 1,94-2,05 (m, 2H) 2,34 (t, J=7,4 Hz, 2H) 2,99-3,17 (m, 4H) 3,43 is 3.57 (m, 2H) 3,95 (t, J=6,4 Hz, 2H) 4,03-to 4.14 (m, 2H) 4,87 (d, J=10,2 Hz, 1H) 6,94 (d, J=to 8.7 Hz, 2H) 7,29 (d, J=to 8.7 Hz, 2H) 10,80-11,20 (ush.with., 1H) 12,00-12,40 (ush.with., 1H).

The connection 41; Hydrochloride 3-(2-(4-octyloxy-phenyl)-morpholine-4-yl)-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 1,22-of 1.36 (8H, m), 1,37-of 1.46 (2H, m), 1,66-to 1.77 (2H, m), 2,85-of 2.92 (2H, m), is 3.08 (1H, t, J=11,7 Hz) 3,13-3,21 (1H, m), 3,29-to 3.41 (2H, m), 3,48 (1H, d)to 3.56 (1H, d, J=12,3 Hz), 3,95 (2H, t, J=6,5 Hz), 4,01 (1H, t, J=12,2 Hz), 4,07-4,17 (1H, m), 4,80 (1H, d, J=10,8 Hz) at 6.92 (2H, dt, J=8,5, 0.7 Hz) to 7.28 (2H, d, J=9,0 Hz).

Compound 41a; Hydrochloride(+)-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acidfrom isomer 2 tert-butyl ether 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid, [α]D25=+5 (c of 1.0, MeOH);1H NMR (400 MHz, DMSO-d6) δ ppm 0,81 is 0.92 (m, 3H) 1,19 was 1.47 (m, 10H) 1,64-to 1.77 (m, 2H) 2,83-2,96 (m, 2H) 3,03-3,21 (m, 2H) 3,29-3,40 (m, 2H) 3,48 (d, J=12,34 Hz, 1H) 3,56 (d, J=12,34 Hz, 1H) 3,95 (t, J=6,47 Hz, 2H) 3,98-4,08 (m, 1H) 4,08-4,18 (m, 1H) 4,75-of 4.87 (m, 1H) to 6.88-6,97 (m, 2H) 7,28 (d, J=8,73 Hz, 2H).

Compound 41b; Hydrochloride(-)-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acidfrom isomer 1 tert-butyl ether 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid, [α]D25=-5 (c of 1.0, MeOH);1H NMR (400 MHz, DMSO-d6) δ ppm of 0.57 to 0.76 (m, 3H) of 0.93 to 1.31 (m, 10H) 1,40-1,58 (m, 2H) 2,61-2,80 (m, 2H) 2,80-3,01 (m, 2H) 3,13 (t, J=7,83 Hz, 2H) 3,20 is-3.45 (m, 2H) 3,65-4,01 (m, 4H) 4,63 (m, 1H) 6,65-6,87 (m, 2H) to 7.09 (d, =8,73 Hz, 2H)

The connection 42; Hydrochloride 4-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-butyric acid.1H NMR (600 MHz, DMSO-d6) δ ppm 0,86 (t, J=6,8 Hz, 3H) 1,21-1,34 (m, 8H) 1,36-1,44 (m, 2H) 1,66-of 1.74 (m, 2H) 1,95-2,05 (m, 2H) a 2.36 (t, J=7,2 Hz, 2H) 3,03-3,19 (m, 4H) 3,47-3,59 (m, 2H) 3,95 (t, J=6,4 Hz, 2H) 4,02-4,20 (m, 2H) with 4.86 (d, J=10,2 Hz, 1H) 6,93 (d, J=to 8.7 Hz, 2H) 7,30 (d, J=to 8.7 Hz, 2H) at 11.23-11,40 (ush.with., 1H).

The connection 43; Hydrochloride of 2,2-dimethyl-3-(2-(4-octyloxy-phenyl)-morpholine-4-yl)-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm and 0.64 (t, J=6.32 per Hz, 3H) 0,86-1,25 (m, 17H) 1,42-of 1.53 (m, J=6,96, of 6.96, of 6.85, to 6.62 Hz, 2H) 3,68-3,99 (m, 4H) 4,73 (d, J=10,53 Hz, 1H) 6,72 (d, 2H) 7,06 (d, J=7,83 Hz, 2H).

The connection 44; hydrochloride 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-butyric acid.1H NMR (400 MHz, DMSO-d6) δ ppm 0,79-0,86 (m, 4H) 1,17-of 1.42 (m, 16H) 1,63-1,72 (m, 2H) 3,93 (t, J=6,47 Hz, 3H) 4,11-4,19 (m, 1H) 4,65-4,73 (m, 1H) 6,91 (d, J=8,73 Hz, 2H) 7,31 (d, J=of 8.43 Hz, 2H).

The connection 45; Hydrochloride 2-methyl-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm of 0.67 (t, J=6,47 Hz, 2H) of 1.05 (DD, J=7,22, of 3.91 Hz, 4H) 1,03 (ush. S., 2H) 1,09 (ush. S., 3H) 1,19 (d, J=7,52 Hz, 2H) 1,50 (square d, J=at 6.92, to 6.62 Hz, 1H) 2,31 (ush. S., 3H) 2,85-of 2.93 (m, 2H) 2,95 (ush. S., 1H) 3,18 (ush. S., 7H) 3,26 (ush. S., 2H) 3,29 (ush. S., 1H) 3,37 (s, 1H) 3,76 (t, J=6,47 Hz, 1H) 3,90 (ush. S., 1H) 6.75 in (d, J=of 8.43 Hz, 1H) was 7.08 (DD, J=8,43, 6.32 per Hz, 1H).

The connection 46; Hydrochloride 3-{2-[4-(2-chloro-6-forbindelse)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 142 (C, 1H) 2,82-2,98 (m, 2H) 3,02-3,20 (m, 2H) 3,26-3,40 (m, 2H) 3,47 (d, J=12,04 Hz, 1H) 3,93-4,07 (m, 1H) 4,08-is 4.21 (m, 1H) 4,75-4,91 (m, 1H) 5,16 (DD, J=1.35 V, and 0.75 Hz, 2H) 7,02-7,17 (m, 1H) 7,28-7,39 (m, 2H) 7,40-of 7.46 (m, 1H) Of 7.48-EUR 7.57 (m, 1H).

Compound 47; Hydrochloride 3-{2-[4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm of 1.41 (s, 1H) 2,81-2,96 (m, 2H) 3,01-3,20 (m, 2H) 3,24-3,39 (m, 2H) 3,47 (d, J=12,64 Hz, 1H) 3,53-to 3.64 (m, 1H) 3,92-4,06 (m, 1H) 4,08-4,19 (m, 1H) 4,80 (d, J=11,14 Hz, 1H) 5,24 (s, 2H) 7,00-to 7.09 (m, 2H) 7,28-7,38 (m, 2H) 7,54-of 7.64 (m, 1H) 7,68-7,84 (m, 2H).

The connection 48; Hydrochloride 3-{2-[4-(2,6-debtor-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm of 1.41 (s, 1H) 2,85-to 2.99 (m, 2H) 3,03-up 3.22 (m, 2H) 3,25-3,40 (m, 2H) 3,47 (d, J=12,04 Hz, 1H) 3,95-4,08 (m, 1H) 4,10-4,19 (m, 1H) 4,78-4,91 (m, 1H) 5,13 (s, 2H) was 7.08 (d, J=8,73 Hz, 2H) 7,15-7,25 (m, 2H) 7,34 (d, J=8,73 Hz, 2H) of 7.48-to 7.60 (m, 1H).

The connection 49; Hydrochloride 3-{2-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,83-to 2.94 (1H, m), 3,02-3,19 (1H, m), 3,26-3,37 (1H, m), 3,47 (1H, d, J=12,4 Hz), only 3.57 (1H, DD, J=12,4, 0,8 Hz), 3,93-of 4.05 (1H, m, J=12,3, 12,3, 1,3, 1.0 Hz) 4,07-4,18 (1H, m), 4,80 (1H, d), 5,23 (1H, C), 7,07 (1H, d) to 7.33 (1H, d) of 7.64 (1H, t), 7,68-7,74 (1H, m), to 7.77 (1H, d, J=7,6 Hz), of 7.82 (1H, s).

The connection 50; Hydrochloride 3-{2-[4-(2,6-dimethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,32 (s, 6H) 2,83-to 2.94 (m, 2H) 3,02-3,21 (m, 2H) 3,26 is 3.40 (m, 3H) 3,41-3,51 (m, 1H) 3,51-3,61 (m, 1H) of 3.91-4,06 (m, 1H) 4,06-4,19 (m, 1H) and 4.82 (DD, J=9,85, of 1.01 Hz, 1H) 5,5 (C, 2H) 6,74-is 6.81 (m, 0H) to 7.04-7,11 (m, 2H) 7,17 (DD, J=of 8.34, of 6.06 Hz, 2H) 7,29-value of 7, 37 (m, 2H).

The connection 51; Hydrochloride 3-{2-[4-(3,5-dichloro-pyridin-4-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid:1H NMR (400 MHz, DMSO-d6) δ ppm 2,81-2,98 (m, 2H) 3,01-up 3.22 (m, 2H) 3,24-of 3.42 (m, 2H) 3,42-3,70 (m, 2H) 3,92-4,19 (m, 2H) 4,85 (DD, J=11,17, of 1.13 Hz, 1H) 5.25 in (s, 2H) 7,03-7,14 (m, 2H) 7,26-7,41 (m, 2H) 8,61-of 8.79 (m, 2H)

The connection 52; Hydrochloride 3-{2-[4-(2,4-dichloro-pyridin-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid:1H NMR (400 MHz, DMSO-d6) δ ppm 2,83-2,98 (2H, m), 3,01-up 3.22 (2H, m), 3,23-of 3.53 (3H, m), 3,52-3,65 (1H, m), 3,94-4,07 (1H, m), 4,08-is 4.21 (1H, m), 4,84 (1H, dt, J=11,1, 0.7 Hz) 5,21-5,31 (2H, m) 7,04-to 7.18 (2H, m), 7,29-7,44 (2H, m), 7,74 (1H, d, J=5.3 Hz) To 8.45 (1H, d, J=5.3 Hz).

The connection 53; Hydrochloride 3-{2-[4-(2,6-dichloro-phenylcarbamoyl)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,85-2,98 (1H, m), 3,02-of 3.25 (1H, m), 3,35 (1H, t, J=8,1 Hz), 3,51 (1H, d, J=12,6 Hz), 3,67-of 3.77 (1H, m), 4,07 (1H, t, J=12,4 Hz), 4,15-of 4.26 (1H, m), 4,96-5,07 (1H, m), 7,41 (1H, t, J=8,1 Hz), 7,51-of 7.64 (2H, m) 8,06 (1H, d, J=8,3 Hz).

The connection 54; Hydrochloride 3-{2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,86-to 2.99 (2H, m) 3,00-3,25 (2H, m), 3,24-of 3.42 (2H, m), 3,50 (1H, d, J=12.1 Hz) 3,65 (1H, d, J=12,6 Hz), 4,00-of 4.12 (1H, m), 4,12-4,24 (1H, m), 4,89-4,99 (1H, m), of 5.03 (2H, C), 7,22 (1H, t, J=8,1 Hz), of 7.36-7,49 (2H, m) 7,49-7,63 (3H, m).

The connection 55; Hydrochloride 3-(2-{4-[2-(2,6-dichlorophenyl)-vinyl]-phenyl}-morpholine-4-yl)-propionic acid.1H NMR(400 MHz, DMSO-d6) δ ppm 2,85-2,95 (1H, m), of 3.07 (1H, t, J=1 1.5 Hz) 3,12-3,21 (1H, m), 3,35 (1H, t, J=7,8 Hz), 3,43-3,55 (1H, m), 3,60-3,70 (1H, m), 3,97-4,07 (1H, m), 4,14-4,22 (1H, m), 4,90 (1H, DD, J=11,0, 0,6 Hz), 7,07-7,14 (1H, m) Made 7.16 interest of 7.24 (1H, m), 7,34 (1H, t, J=8,1 Hz), the 7.43 (1H, d, J=8,3 Hz), 7,55 (1H, d, J=8,1 Hz), to 7.68 (1H, d, J=8,3 Hz).

The connection 56; Hydrochloride 3-[2-(4-phenethyl-phenyl)-morpholine-4-yl]-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm: 2,80-3,23 (7H, m), 3,24-of 3.80 (4H, m), 3,96-be 4.29 (2H, m), 4.80 to-5,04 (1H, m), 7,10-7,52 (9H, m).

Compound 57; Hydrochloride 3-{2-[4-(2,6-dichloro-benzylamino)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,86-2,98 (2H, m), 3,01-3,18 (2H, m), 3,26-3,36 (2H, m), 3,40-of 3.53 (2H, m), 3,94-of 4.05 (1H, m), 4,05-to 4.14 (1H, m), 4,35-4,43 (2H, m), 4.72 in (1H, dt, J=10,9, 1,1 Hz), 6,72 (2H, d, J=8,6 Hz), 7,07-7,20 (2H, m), 7,12 (1H, d, J=8,8 Hz), 7,35-7,45 (1H, m), 7,51 (1H, d, J=7,8 Hz).

The connection 58; Hydrochloride 3-{2-[4-(2,6-dichloro-benzoylamino)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,87-of 2.97 (2H, m), 2,99-up 3.22 (2H, m) 3,27-3,42 (3H, m), 3,49 (1H, d, J=11,9 Hz), 3,60 (1H, DD, J=11,9, and 1.0 Hz), 3,98-4,10 (1H, m), 4,10-to 4.23 (1H, m) of 4.88 (1H, DD, J=11,0, 0,6 Hz), 7,38 (2H, d, J=8,6 Hz) of 7.46 and 7.55 (1H, m) 7,55-7,63 (1H, m), 7,72 (1H, d, J=8,6 Hz).

Compound 59; Hydrochloride 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-methyl-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 1,21-of 1.84 (m, 3H) 2,95 (m, 2H) 3,02-of 3.42 (m, 6H) 3,70-4,20 (m, 2H) 5,24 (s, 2H) 7,10 (d, J=7,6 Hz, 2H) 7,43-7,52 (m, 3H) 7,56-to 7.60 (m, 2H) 11,41 (ush. S., 1H) 12,85 (ush. s, 1H).

The connection 60; Hydrochloride 3-{2-[4-(2-�ENT-6-fluoro-benzyloxy)-phenyl]-2-methyl-morpholine-4-yl}-propionic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1,21-of 1.93 (m, 3H) 2,86-3,01 (m, 2H) 3,02-3,44 (m, 6H) 3,60-4,20 (m, 2H) 5,16 (s, 2H) to 7.09 (d, J=7,8 Hz, 2H) 7,34 (t, J=8,8 Hz, 1H) 7,41-7,49 (m, 3H) 7,49-7,56 (m, 1H) 11,36 (ush. S., 1H) 12,72 (ush. s, 1H).

The connection 61; Hydrochloride 3-{2-[4-(2-trifluoromethyl-benzyloxy)-phenyl]-2-methyl-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 1,21-1,90 (m, 3H) 2,86-3,00 (m, 2H) 3,02-of 3.46 (m, 6H) 3,52-4,22 (m, 2H) to 7.04 (d, J=7,3 Hz, 2H) 7,44 (d, J=8,6 Hz, 2H) 7,60 (t, J=7,3 Hz, 1H) 7,69-a 7.85 (m, 3H) 11,33 (m, 1H) 12,71 (ush. s, 1H).

The connection 62; Hydrochloride 3-[2-methyl-2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm of 0.80 is 0.92 (m, 3H) 1,20-1,89 (m, 13H) 1,71 (Quin., J=6,9 Hz, 2H) 2,85-to 2.99 (m, 2H) 3,00-of 3.43 (m, 6H) 3,53-4,16 (m, 2H) 3,95 (t, J=6,4 Hz, 2H) 6,94 (d, J=to 8.7 Hz, 2H) 7,39 (d, J=to 8.7 Hz, 2H) MK 11: 23 (ush. S., 1H) 12,72 (ush. s, 1H).

Compound 63; Hydrochloride 4-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-butyric acid.1H NMR (400 MHz, DMSO-d6) δ ppm 1,92-2,04 (m, 2H) of 2.35 (t, J=7,20 Hz, 2H) 3,02-3,18 (m, 4H) 3,45-to 3.64 (m, 2H) 4,00-4,18 (m, 2H) 4,83-4,91 (m, 1H) 5,23 (s, 2H) 7,07-7,13 (m, 2H) 7,32-7,38 (m, 2H) 7,45-7,51 (m, 1H) 7,58 (d, J=7 Hz, 2H) 11,3 (ush. S., 1H) 12,3 (ush. s, 1H).

Connection 64; Hydrochloride 3-(2-{4-[1-(2,6-dichlorophenyl)-ethoxy]-phenyl}-morpholine-4-yl)-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 1,71 (d, J=6,6 Hz, 3H) 2,82-of 2.91 (m, 2H) 2,96-3,13 (m, 2H) 3,21-3,35 (m, 2H) 3,39-to 3.56 (m, 2H) 3,96 (t, J=12.0 Hz, 1H) 4,08 (d, J=11,1 Hz, 1H) 4,74 (d, J=a 10.6 Hz, 1H) 6,04 (kV, J=6,6 Hz, 1H) 6,84 (d, J=to 8.7 Hz, 2H) of 7.24 (d, J=to 8.7 Hz, 2H) 7,31 (t, J=8,1 Hz, 1H) 7,44 (d, J=8,1 Hz, 2H) 11,51 (ush. S., 1H) 12,69 (ush. s, 1H).

Compound 65; Hydrochloride 3-(2-{4-[2-(2,6-dichlorophenyl)-ethyl]-phenyl}-morpholine-4-yl)-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,76-2,83 (m, 2H) 2,85-of 2.93 (m, 2H) 3,01-3,20 (m, 4H) to 3.34 (t, J=8,0 2H) 3,45-3,66 (m, 2H) 3,95-4,05 (m, 1H) 4,16 (d, J=11,6 Hz, 1H) 4,84 (d, J=10.1 Hz 1H) 7,27-of 7.36 (m, 5H) of 7.48 (d, J=8,1 Hz, 2H) 11,31 (ush. S., 1H) 12,67 (ush. s, 1H).

The connection 66; Hydrochloride 3-{2-[3-methoxy-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.So a MP 170-172°C.

Compound 67; Hydrochloride 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-3-methoxyphenyl]-morpholine-4-yl}-propionic acid.So a MP 169-171°C.

The connection 68; Hydrochloride 3-{2-[4-(2,6-dichloro-benzyloxy)-3-methoxyphenyl]-morpholine-4-yl}-propionic acid.So a MP 214-216°C.

Compound 139: Hydrochloride 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2-methylpropionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 1,20-of 1.26 (m, 3H) 3,01-up 3.22 (m, 4H) 3,41-3,63 (m, 3H) 3,97-4,08 (m, 1H) of 4.09-4,16 (m, 1H) 4,81-of 4.90 (m, 1H) 5,24 (s, 2H) 7,10 (d, J=8,6 Hz, 2H) 7,31-value of 7, 37 (m, 2H) 7,45-7,51 (m, 1H) EUR 7.57 (d, J=8,3 Hz, 2H) The 10.2 to 10.9 (ush.with., 1H) from 12.5 to 13.1 (ush.with., 1H).

The connection 140: Hydrochloride 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-butyric acid.1H NMR (400 MHz, DMSO-d6) δ ppm of 1.34 (d, J=6,6 Hz, 3H) 2,54-of 2.64 (m, 1H) 3,03-3,24 (m, 2H) 3,33 is 3.76 (m, 4H) 4,01-4,22 (m, 2H) with 4.86-4,94 (m, 1H) 5,23 (s, 2H) 7,10 (d, J=8,6 Hz, 2H) 7,38 (d, J=8,6 Hz, 2H) 7,45-7,51 (m, 1H) EUR 7.57 (d, J=8,3 Hz, 2H) 10,9-11,4 (ush.with., 1H 12,5-13,0 (ush.with., 1H).

Compound 142:The mono hydrochloride-(2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-ethyl) ether phosphoric acid.1H NMR (400 MHz, DMSO-d6) δ ppm 3,03-3,19 (m, 2H) 3,30-to 3.41 (m, 2H) 3.43 points-3,51 (m, 1H) 3,52-3,65 (m, 1H) 3,94-of 4.05 (m, 1H) of 4.09-4,24 (m, 3H) 4,82 (d, J=a 10.6 Hz, 1H) 5,23 (s, 2H) 7,10 (d, J=8,6 Hz, 2H) 7,34 (d, J=8,6 Hz, 2H) 7,44-7,51 (m, 1H) EUR 7.57 (d, J=8,3 Hz, 2H) 10,1-11,5 (ush.with., 1H).

Compound 143:Hydrochloride 3-{2-[3-methyl-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidSo a MP 191-194°C.

Compound 144:Hydrochloride 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-3-methylphenyl]-morpholine-4-yl}-propionic acidSo a MP 194-196°C.

Compound 145:Hydrochloride 3-{2-[4-(2,6-dichloro-benzyloxy)-3-methylphenyl]-morpholine-4-yl}-propionic acidSo a MP 198-200°C.

Compound 147: Hydrochloride 3-{2-[4-(2,3-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 222-227°C.

Compound 148: Hydrochloride 3-{2-[4-(2-chloro-5-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidT. PL 218,5-222°C.

The connection 152: Hydrochloride 3-{2-[4-(2-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. T. PL. 223-228°C.

Compound 153: Hydrochloride 3-{2-[4-(2-chloro-6-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. T. PL. 185,5-190,5°C.

The connection 154: Hydrochloride 3-{2-[4-(2,3,6-trichloro-benzyloxy)-phenyl]-morpholine-yl}-propionic acid . So a MP 213-216°C.

Compound 155: Hydrochloride 3-{2-[4-(2-chlor-6-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 215-218°C.

Compound 156: Hydrochloride 3-{2-[4-(2-chloro-5-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 209-213°C.

Compound 157: Hydrochloride 3-{2-[4-(2-chloro-5-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 198-202°C.

Compound 158: Hydrochloride 3-{2-[4-(2-chloro-5-propyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 199-203°C.

Compound 159: Hydrochloride 3-{2-[4-(2-chloro-5-isopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 203-207°C.

The connection 160: Hydrochloride 3-{2-[4-(2,4,6-trichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 215-218°C.

Compound 161: Hydrochloride 3-{2-[4-(2,6-dichloro-4-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. T. PL. 221-226°C.

The connection 162: Hydrochloride 3-{2-[4-(2,6-dichloro-4-iodine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 210-215°C.

Compound 163: Hydrochloride 3-(2-{4-[3-(2-fluorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 1,96-2,05 (m, 2H) 2,76-of 2.81 (m, 2H) 2,83-2,96 (m, 2H) 3,04-3,17 (m, 2H), or 3.28-3,37 (m, 2H) 3,47 (d, J=12.2 Hz, 1H) 3,56 (d, J=12.2 Hz, 1H) 3,94-of 4.04 (m, 3H) 4,08-4,16 (m, 1H) 4,78 (d, J=a 10.6 Hz, 1H) 6,95 (J=8,6 Hz, 2H) 7,10-7,17 (m, 2H) 7,22-,34 (m, 4H) of 11.0 and 11.6 (ush.with., 1H) 12,1-12,9 (ush.with., 1H).

Compound 164: Hydrochloride 3-{2-[4-(2,6-dichloro-4-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 198-202°C.

Compound 165: Hydrochloride 3-{2-[4-(2,6-dichloro-4-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. T. PL. 197-204°C.

The connection 166: 3-[2-(4-Benzyloxy-phenyl)-5-oxo-morpholine-4-yl]-propionic acid.1H NMR (400 MHz, CDCl3) δ ppm 2,71-2,79 (m, 2H) 3,41-3,49 (m, 1H) 3,56-and 3.72 (m, 3H) 4,28-4,45 (m, 2H) 4,70-to 4.76 (m, 1H) 5,07 (s, 2H) 6,98 (d, J=8,8 Hz, 2H) 7,27-7,45 (m, 7H).

Compound 167: 3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-5-oxo-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, CDCl3) δ ppm 2,67-2,83 (m, 2H) 3.43 points-3,51 (m, 1H) 3,57-3,66 (m, 1H) 3,67-of 3.75 (m, 2H) 4,29-4,47 (m, 2H) 4,72-4,79 (m, 1H) 5,27 (s, 2H) 7,03 (d, J=8,8 Hz, 2H) 7,22-7,29 (m, 1H) 7,30-7,40 (m, 4H).

Compound 168: 3-[2-(4-Octyloxy-phenyl)-5-oxo-morpholine-4-yl]-propionic acid1H NMR (400 MHz, CDCl3) δ ppm 0,85-0,93 (m, 3H) 1,22-of 1.39 (m, 8H) 1,39-1,50 (m, 2H) 1,72-to 1.82 (m, 2H) 2,67-of 2.81 (m, 2H) 3,41-3,48 (m, 1H) 3,61 (t, J=12.3 Hz, 1H) 3,69 (t, J=6,6 Hz, 2H) 3,94 (t, J=6,6 Hz, 2H) 4,27-4,45 (m, 2H) 4,69-4,74 (m, 1H) 6,89 (d, J=8,8 Hz, 2H) 7,28 (d, J=8,8 Hz, 2H).

Connection 169: Hydrochloride 3-(2-{4-[3-(2-trifluoromethyl-phenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 1,97-2,07 (m, 2H) 2,84-2,95 (m, 4H) 3,04-3,19 (m, 2H) 3,29-to 3.38 (m, 2H) 3,47 (d, J=11,9 Hz, 1H) 3,53-of 3.60 (m, 1H) 3,94-4,08 (m, 3H) of 4.09-4,17 (m, 1H) 4,80 (d, J=9,3 Hz, 1H) of 6.96 (d, J=to 8.7 Hz, 2H) 7,30 (d, J=to 8.7 Hz, 2H) 7,39-of 7.46 (m, 1H) 7,52 (d, J=7,8 Hz, 1H) 7,58-7,65 (m, 1H) 7,68 (d, J=7,8 Hz, 1H) 11,2 (ush.with., 1H) 12,8 (ush.with., 1H).

The connection 170: Hydrochloride 3-(2-{4-[3-(2-chloro-6-fluoro-phenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 1,90-2,02 (m, 2H) 2,83-2,95 (m, 4H) 3,04-3,18 (m, 2H) of 3.33 (t, J=7.9 Hz, 2H) 3,47 (d, J=11,9 Hz, 1H) 3,57 (d, J=11,9 Hz, 1H) 3,95-4,05 (m, 3H) 4.13 in (d, J=11,9 Hz, 1H) 4,78 (d, J=10.0 Hz, 1H) 6,96 (J=8,6 Hz, 2H) Made 7.16 interest-7.23 percent (m, 1H) 7,27-7,35 (m, 4H) 10,9-11,4 (ush.with., 1H) 12,1-12,9 (ush.with., 1H).

Compound 171: Hydrochloride 3-(2-{4-[3-(2,6-dichlorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 1,92-2,01 (m, 2H) 2,84-of 2.91 (m, 2H) 3,01-3,16 (m, 3H), or 3.28-3,38 (m, 2H) 3,47 (d, J=12.2 Hz, 2H) 3,58 (d, J=12.2 Hz, 1H) 3,93-4,01 (m, 1H) 4,03-4,08 (m, 2H) 4.13 in (d, J=12.1 Hz, 1H) to 4.77 (d, J=10.4 Hz, 1H) 6,95 (d, J=8,9 Hz, 2H) 7,25-to 7.33 (m, 3H) of 7.46 (d, J=8,1 Hz, 2H) 10,8-11,4 (ush.with., 1H) of 12.2 to 12.9 (ush.with., 1H).

The connection 172: Hydrochloride 3-(2-{4-[3-(4-chlorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 1,95-2,05 (m, 2H) 2,69 is 2.76 (m, 2H) 2,84-to 2.94 (m, 2H) 3,04-3,16 (m, 2H), or 3.28-3,37 (m, 2H) 3,47 (d, J=12.3 Hz, 1H) 3,56 (d, J=12,3, 1H) 3,92-of 4.04 (m, 3H) 4,15 (d, J=12.3 Hz, 1H) 4,80 (d, J=9,6 Hz, 1H) 6,95 (d, J=to 8.7 Hz, 2H) 7.24 to of 7.36 (m, 6H) 10,9-11,9 (ush.with., 1H) of 12.2 to 12.9 (ush.with., 1H).

Compound 173: Hydrochloride 3-(2-{4-[3-(2-chlorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 1,97-of 2.09 (m, 2H) 2,83-2,95 (m, 4H) 3,04-3,17 (m, 2H) of 3.33 (t, J=7.9 Hz, 2H) 3,47 (d, J=12.1 Hz, 1H) 3,56 (d, J=12.1 Hz, 1H) 3,96-of 4.05 (m, 3H) 4.13 in (d, J=12.1 Hz, 1H) 4,79 (d, J=10.0 G�, 1H) 6,96 (J=8,6 Hz, 2H) 7,20-7,31 (m, 4H) to 7.33-value of 7, 37 (m, 1H) 7,40 was 7.45 (m, 1H) 11,0-11,4 (ush.with., 1H) 12,1-12,9 (ush.with., 1H).

Connection 174: Hydrochloride 3-(2-{4-[3-(2,3-debtor-phenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 1,98-of 2.08 (m, 2H) 2,82-is 2.88 (m, 2H) 2,88-to 2.94 (m, 2H) 3,01-3,16 (m, 2H), or 3.28-3,38 (m, 2H) 3,47 (d, J=12.2 Hz, 1H) 3,58 (d, J=12.2 Hz, 1H) 3,93-4,08 (m, 3H) 4.13 in (d, J=12.1 Hz, 1H) 4,82 (d, J=10.4 Hz, 1H) 6,95 (d, J=8,9 Hz, 2H) 7,11-7,18 (m, 2H) 7,22-7,32 (m, 3H) 11,2-11,9 (ush.with., 1H) of 12.2 to 12.9 (ush.with., 1H).

Compound 175: Hydrochloride 3-{2-[3-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidSo a MP 179-181°C.

Compound 176: hydrochloride 3-{2-[3-Chloro-4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidSo a MP 178-180°C.

Compound 177; Hydrochloride 3-{2-[3-chloro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 199-201°C.

Compound 178; Hydrochloride 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-2-fluorophenyl]-morpholine-4-yl}-propionic acidSo a MP 189-190°C.

Compound 179; 3-{2-[4-(2,6-dichloro-benzyloxy)-2-fluorophenyl]-morpholine-4-yl}-propionic acid hydrochloride.T. PL. 174,5-178°C.

Connection 180; Hydrochloride 3-{2-[2-fluoro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidT. PL. 201-201,5°C.

Compound 181; Hydrochloride 3-{2-[4-(2,6-dichloro-3-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (40 MHz, DMSO-d6) δ ppm 1,19 (t, J=7.5 Hz, 3H) 2,75 (sq, J=7.5 Hz, 2H) 2,83-2,95 (m, 2H) 2,99-3,18 (m, 2H) 3,30-to 3.38 (m, 2H) 3,48 (d, J=a 12.7 Hz, 1H) 3,57-3,65 (m, 1H) 3,95-of 4.04 (m, 1H) 4,10-4,17 (m, 1H) to 4.81 (d, J=11,9 Hz, 1H) and 5.26 (s, 2H) 7,11 (d, J=to 8.7 Hz, 2H) 7,34 (d, J=to 8.7 Hz, 2H) of 7.46 (d, J=8.4 Hz, 1H) 7,52 (d, J=8.4 Hz, 1H) 10,9-11,9 (ush.with., 1H) of 12.2 to 12.9 (ush.with., 1H).

Connection 182; Hydrochloride 3-{2-[4-(2-chloro-6-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm of 1.17 (t, J=7.5 Hz, 3H) 2,72 (sq, J=7.5 Hz, 2H) 2,83-2,95 (m, 2H) 3,05-3,18 (m, 2H) 3,29-to 3.38 (m, 2H) 3,48 (d, J=11,9 Hz, 1H) 3,55-3,65 (m, 1H) 3,96-of 4.04 (m, 1H) 4,11-4,18 (m, 1H) 4,82 (d, J=11,9 Hz, 1H) 5,17 (s, 2H) 7,10 (d, J=to 8.7 Hz, 2H) 7,27-7,39 (m, 5H) 11,1-11,9 (ush.with., 1H) of 12.2 to 12.9 (ush.with., 1H).

Compound 183; Hydrochloride 3-{2-[4-(2-chloro-6-isopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm to 1.21 (d, J=6,8 Hz, 6H) 2,84-2,96 (m, 2H) 3,08-3,22 (m, 3H) 3,29-to 3.38 (m, 2H) 3,48 (d, J=12,8 Hz, 1H) 3,58 (d, J=12,8 Hz, 1H) 3,95-was 4.02 (m, 1H) 4,10-4,18 (m, 1H) 4,82 (d, J=10.1 Hz, 1H) to 5.21 (s, 2H) 7,10 (d, J=to 8.7 Hz, 2H) 7,31-7,44 (m, 5H) of 11.0 to 11.8 (ush.with., 1H) of 12.2 to 12.9 (ush.with., 1H).

Compound 184; Hydrochloride 3-{2-[4-(2-chloro-6-cyclopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 0,64-0,76 (m, 2H) from 0.87 to 0.96 (m, 2H) 2,02-2,11 (m, 1H) 2,85-of 2.97 (m, 2H) 3,06-3,18 (m, 2H) 3,32-to 3.41 (m, 2H) 3,48 (d, J=12,4 Hz, 1H) 3,55-3,61 (m, 1H) 3,97 is 4.03 (m, 1H) 4,10-to 4.14 (m, 1H) a 4.83 (d, J=a 10.6 Hz, 1H) Is 5.33 (s, 2H) 7,10 DD, J=6,9, 1.6 Hz, 1H) 7,12 (d, J=8,8 Hz, 2H) 7,30-value of 7, 37 (m, 4H) 11,1-11,8 (ush.with., 1H) 12,4-13,0 (ush.with., 1H).

Compound 185; Hydrochloride 3-{2-[4-(2-chloro-6-isobut�-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid 1H NMR (400 MHz, DMSO-d6) δ ppm of 0.85 (d, J=6,6 Hz, 6H) 1,78-1,90 (m, 1H) 2,58 (d, J=7,2 Hz, 2H) 2,84-2,92 (m, 2H) 3,06-3,18 (m, 2H) 3,32-to 3.41 (m, 2H) 3,41-of 3.53 (m, 2H) 3,97-4,07 (m, 1H) 4,10-4,18 (m, 1H) a 4.83 (d, J=10.5 Hz, 1H) 5,13 (s, 2H) 7,06 (d, J=8,8 Hz, 2H) 7.23 percent (DD, J=7,1, of 1.8 Hz, 1H) 7,30-7,41 (m, 4H) 11,1-11,8 (ush.with., 1H) 12,4-12,9 (ush.with., 1H).

Compound 186; Hydrochloride 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-5,5-dimethyl-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 1,37 was 1.47 (m, 6H) 2,91-3,03 (m, 3H) 3,12-3,23 (m, 1H) 3,51-to 3.64 (m, 2H) 3,79-3,88 (m, 1H) 3,92-4,01 (m, 1H) is 4.93 (d, J=11,9 Hz, 1H) 5,24 (s, 2H) 7,11 (d, J=8,8 Hz, 2H) 7,38 (d, J=8,8 Hz, 2H) 7,45-7,52 (m, 1H) 7,58 (d, J=7,8 Hz, 2H) 10,9-11,3 (ush.with., 1H) 12,6-13,1 (ush.with., 1H).

Compound 187; Hydrochloride 3-[5,5-dimethyl-2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 0,81-0,89 (m, 3H) 1,17-1,47 (m, 16H) 1,63-of 1.75 (m, 2H) 2,91-of 3.04 (m, 3H) 3,12-3,23 (m, 1H) 3,47-to 3.64 (m, 2H) 3,74-3,84 (m, 1H) of 3.91 is 4.03 (m, 3H) is 4.93 (d, J=11,9 Hz, 1H) 6,95 (d, J=8,8 Hz, 2H) to 7.33 (d, J=8,8 Hz, 2H) 11,1 (ush.with., 1H) 12,8 (ush.with., 1H).

Compound 188; Hydrochloride 3-{2-[4-(2,6-dichloro-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acidSo a MP 195-197°C.

Compound 189; Hydrochloride 3-[2-(4-octyloxy-2-trifluoromethyl-phenyl)-morpholine-4-yl]-propionic acidT. PL. 178,5-of 180.5°C.

Connection 190; Hydrochloride 3-{6-[4-(2,6-dichloro-benzyloxy)-phenyl]-2,2-dimethyl-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm of 1.27 (s, 3H) 1,53 (s, 3H) 2,85-of 2.97 (m, 4H) 3,29-3,35 (m, 2H) 3.46 in-,53 (m, 2H) is 4.93 (d, J=11,9 Hz, 1H) 5,24 (s, 2H) 7,10 (d, J=8,8 Hz, 2H) to 7.33 (d, J=8,8 Hz, 2H) 7,44-7,52 (m, 1H) EUR 7.57 (d, J=7,8 Hz, 2H) of 10.5 to 10.9 (ush.with., 1H) 12,5-13,0 (ush.with., 1H).

Compound 191; Hydrochloride 3-[2,2-dimethyl-6-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 0,86 (t, J=6,8 Hz, 3H) 1,19-of 1.45 (m, 13H) a 1.54 (s, 3H) 1,64-of 1.75 (m, 2H) 2,84-3,02 (m, 4H) 3,24-3,36 (m, 2H) 3,39-3,51 (m, 2H) 3,95 (t, J=6,5 Hz, 2H) to 4.92 (d, J=a 10.6 Hz, 1H) 6,94 (d, J=8,5 Hz, 2H) 7,27 (d, J=8,5 Hz, 2H) 10,9-11,4 (ush.with., 1H) 12,5-13,0 (ush.with., 1H).

Connection 192; Hydrochloride 3-{2-[4-(2,6-dichloro-4-propyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 101-103°C.

Compound 193; Hydrochloride 3-{2-[4-(2,6-dichloro-4-isopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 108-110°C.

Connection 194; Hydrochloride 3-{2-[4-(2,6-dichloro-4-prop-1-inyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid. So a MP 220-224°C.

Compound 195; Hydrochloride 3-{2-[4-(2-chloro-6-triptoreline-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,85-of 2.97 (m, 2H) 3,06-3,18 (m, 2H) 3,29-to 3.38 (m, 1H) 3,48 (d, J=11,9 Hz, 1H) 3,59 (d, J=11,9, 1H) 3,95-4,07 (m, 1H) of 4.09-4,18 (m, 1H) a 4.83 (d, J=a 10.6 Hz, 1H) 5,16 (s, 2H) to 7.09 (d, J=8,8 Hz, 2H) 7,35 (d, J=8,8 Hz, 2H) of 7.48-7,52 (m, 2H) 7,58-to 7.68 (m, 2H) 11,2-11,9 (ush.with., 1H) 12,4-13,0 (ush.with., 1H).

Connection 196; Hydrochloride 3-{2-[4-(2-chloro-4-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,32 (s, 3H) 2,83-2,92 (�, 2H) 3,04-3,17 (m, 2H), or 3.28 is 3.40 (m, 2H) 3,47 (d, J=a 10.6 Hz, 1H) 3,57 (d, J=a 10.6 Hz, 1H) 3,94-of 4.05 (m, 1H) 4,08-4,16 (m, 1H) a 4.83 (d, J=10,2 Hz, 1H) 5,12 (s, 2H) to 7.04 (d, J=8,8 Hz, 2H) 7,18 (d, J=7,8 Hz, 1H) 7,27-7,39 (m, 3H) of 7.46 (d, J=7,8 Hz, 1H) and 11.2 to 12.0 (ush.with., 1H) 12,3-13,0 (ush.with., 1H).

Compound 197; Hydrochloride 3-{2-[4-(2-chloro-3-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm of 2.38 (s, 3H) 2,81-2,89 (m, 2H) 3,04-3,18 (m, 2H) 3,30-3,52 (m, 3H) 3,55-3,61 (m, 1H) 3,92-was 4.02 (m, 1H) 4.13 in (d, J=12,6 Hz, 1H) 4,78 (d, J=10,2 Hz, 1H) to 5.17 (s, 2H) 7,06 (d, J=8,8 Hz, 2H) 7,27-the 7.43 (m, 5H) 10,8-11,5 (ush.with., 1H) 12,3-13,0 (ush.with., 1H).

The connection 198; Hydrochloride 3-{2-[4-(2,4-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,85-of 2.97 (m, 2H) 3,04-3,17 (m, 2H), or 3.28-3,38 (m, 2H) 3,42-3,51 (m, 1H) 3,52-3,62 (m, 1H) 3,96-4,06 (m, 1H) of 4.09-4,17 (m, 1H) a 4.83 (d, J=10.4 Hz, 1H) 5,16 (s, 2H) 7,06 (d, J=8,8 Hz, 2H) 7,32 (d, J=8,8 Hz, 2H) 7,49 (DD, J=8,3, and 2.1 Hz, 1H) 7,61 (d, J=8,3 Hz, 1H) of 7.70 (d, J=2.1 Hz, 1H) and 11.2 to 12.0 (ush.with., 1H) 12,3-12,9 (ush.with., 1H).

Compound 199; Hydrochloride 4-[4-(2-carboxy-ethyl)-morpholine-2-yl]-phenyl ester 2,6-dichlorobenzoyl acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,89-2,96 (m, 2H) 3,09-up 3.22 (m, 2H) 3,30-to 3.41 (m, 2H) 3,51 (d, J=12.0 Hz, 1H) 3,70 (d, J=12.0 Hz, 1H) 4,01-4,11 (m, 1H) 4,15-to 4.23 (m, 1H) 4,96 (d, J=10.5 Hz, 1H) of 7.36 (d, J=to 8.7 Hz, 2H) 7,55 (d, J=to 8.7 Hz, 2H) 7,61-7,73 (m, 3H) 11,2-11,9 (ush.with., 1H) of 12.1 to 12.7 (ush.with., 1H).

The connection 200; Hydrochloride 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-cyclobutanecarbonitrile acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,40-2,53 (�, 2H) 2,81-3,00 (m,H) 3,32-3,50 (m, 4H) 3,54-3,66 (m, 1H) 3,89-4,01 (m, 1H) 4,10-4,20 (m, 1H) to 4.75 (d, J=10,8 Hz, 1H) 5,20 (s, 2H) 7,10 (d, J=8,8 Hz, 2H) value of 7, 37 (d, J=8,8 Hz, 2H) 7,45-7,50 (m, 1H) 7,55-members, 7.59 (m, 2H) 11,1 (ush.with., 1H) 12,6 (ush.with., 1H).

Connection 201; Hydrochloride 3-{2-[4-(2,6-dichloro-benzolsulfonat)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,84-2,96 (m, 2H) 3,05-3,09 (m, 1H) 3,11-3,18 (m, 1H) of 3.33 (t, J=7.9 Hz, 1H) 3,49 (d, J=11,0 Hz, 1H) to 3.64 (d, J=11,0 Hz, 1H) 3,97-4,06 (m, 1H) 4,12-4,20 (m, 1H) to 4.41 (s, 2H) 4,87 (1H) with 4.86 (d, J=10.4 Hz, 1H) 7,31-7,39 (m, 3H) of 7.42-7,52 (m, 4H) 11,0-12,0 (ush.with., 1H) 12,3-13,0 (ush.with., 1H).

The connection 202; Hydrochloride 3-{2-[4-(2-chlorine-benzolsulfonat)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,84-2,96 (m, 2H) 3,00-3,18 (m, 2H), or 3.28-3,37 (m, 2H) 3,47 (d, J=12.0 Hz, 1H) 3,61 (d, J=12.0 Hz, 1H) 3,96-4,07 (m, 1H) 4,10-4,18 (m, 1H) 4,32 (s, 2H) with 4.86 (d, J=11,4 Hz, 1H) 7.23 percent-7,35 (m, 4H) value of 7, 37-the 7.43 (m, 3H) 7,43-of 7.48 (m, 1H) 11,2-11,9 (ush.with., 1H) 12,3-12,9 (ush.with., 1H).

Compound 203; Hydrochloride 3-{2-[4-(2-chloro-6-fluoro-benzolsulfonat)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,84-of 2.91 (m, 2H) 3,01-3,18 (m, 2H) 3,30-to 3.38 (m, 2H) 3,48 (d, J=12.0 Hz, 1H) 3,63 (d, J=12.0 Hz, 1H) 3,93-of 4.05 (m, 1H) 4,12-4,19 (m, 1H) 4,29 (s, 2H) 4,80-of 4.88 (m, 1H) 7,17-7,24 (m, 1H) 7,32-7,45 (m, 6H) Of 11.0 and 11.6 (ush.with., 1H) of 12.1 to 12.7 (ush.with., 1H).

Connection 204; Hydrochloride 3-[2-(4-octylsilane-phenyl)-morpholine-4-yl]-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 0,81-0,89 (m, 3H) of 1.19 to 1.31 (m, 8H) 1,32-of 1.43 (m, 2H) 1,51-to 1.61 (m, 2H) 2,86-2,92 (m, 2H) 2,94-to 2.99 (m, 2H) 3,01-3,18 (m, 2H) 3,27-3,3 (m, 2H) and 3.46 (d, J=12.1 Hz, 1H) of 3.60 (d, J=12.1 Hz, 1H) 3,96-4,06 (m, 1H) 4,10-4,18 (m, 1H) 4,84 (d, J=10.4 Hz, 1H) 7,28-of 7.36 (m, 4H) 11,0-12,9 (ush.with., 2H).

The connection 205; Hydrochloride 3-{2-[4-(4,4-dimethyl-cyclohexyloxy)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm of 0.93 (d, J=3.3 Hz, 6H) 1,22-1,32 (m, 2H) 1,39 was 1.47 (m, 2H) 1,50-to 1.61 (m, 2H) 1,75-of 1.84 (m, 2H) 2,82-2,90 (m, 2H) 3,02-3,16 (m, 2H) 3,26-3,59 (m, 4H) 3,94 (t, J=11,4, 1H) 4,12 (d, J=11,4 Hz, 1H) 4,30-4,39 (m, 1H) 4,73 (d, J=11,4 Hz, 1H) 6,95 (d, J=to 8.7 Hz, 2H) 7,27 (d, J=to 8.7 Hz, 2H) 10,9 (ush.with., 1H) 12,9 (ush.with., 1H).

The connection 206; Hydrochloride 3-{2-[4-(2-deformedarse-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 2,84-2,92 (m, 2H) 3,04-3,16 (m, 2H), or 3.28-3,38 (m, 2H) 3.43 points-3,51 (m, 1H) 3,53-3,61 (m, 1H) 3,97 (t, J=11,4, 1H) 4.13 in (DD, J=11,4, 2.4 Hz, 1H) 4,78 (d, J=11,4 Hz, 1H) 5,12 (s, 2H) 7,02-to 7.09 (m, 2H) 7,25 (t, J=75 Hz, 1H) 7.24 to 7,35 (m, 4H) of 7.42-of 7.48 (m, 1H) EUR 7.57 (DD, J=to 7.6, 1.9 Hz, 1H) 11,1 (ush.with., 1H) 12,9 (ush.with., 1H).

The connection 207; Hydrochloride 3-{2-[4-(3-trifluoromethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acidSo a MP 209-211°C.

The connection 208; Hydrochloride 3-{2-[4-(2-chloro-6-ethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acidSo a MP 214-215°C.

Compound 209; Hydrochloride 3-{2-[4-(2-chloro-6-triptoreline-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acidSo a MP 179-182°C.

The connection 210; Hydrochloride 3-{2-[4-(2-chloro-6-isopropyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-and�}-propionic acid So a MP 206-210°C.

Connection 211; Hydrochloride 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acidT. PL. 171,5-172,5°C.

The connection 212; Hydrochloride 3-{2-[4-(2-chloro-6-trifluoromethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acidSo a MP 200-201°C.

The connection 213; Hydrochloride 3-{2-[4-(2-chloro-6-cyclopropyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acidSo a MP 203-204°C.

The connection 214; Hydrochloride 3-{2-[4-(2,6-diethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm to 1.15 (t, J=7.5 Hz, 6H) to 1.88 (d, J=11.3 Hz, 1H) 2,01-2,10 (m, 3H) 2,45 is 2.55 (m, 2H) 2,66 (sq, J=7,4 Hz, 4H) 2,71-of 2.75 (m, 1H) 2,80-2,85 (m, 1H) 3,58-to 3.67 (m, 1H) 3,87-3,92 (m, 1H) 4,37-4,42 (m, 1H) of 5.01 (s, 2H) 7,01 (d, J=to 8.7 Hz, 2H) 7,11 (d, J=7,8 Hz, 2H) 7.23 percent-7,31 (m, 3H).

The connection 215; Hydrochloride 3-{2-[2-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 2,87-of 2.93 (m, 2H) 3,04-3,20 (m, 2H) 3,30-to 3.38 (m, 2H) 3.46 in-3,55 (m, 2H) 4,02-4,11 (m, 1H) 4,12-4,20 (m, 1H) 5,19-a 5.25 (m, 1H) 5,27 (s, 2H) 7,15 (DD, J=8,8, 2,6 Hz, 1H) 7,28 (d, J=2,6 Hz, 1H) of 7.46-7,53 (m, 2H) Members, 7.59 (d, J=8,8 Hz, 2H) 11,8-12,9 (ush.with., 2H).

Compound 216: Hydrochloride 3-{2-[4-(2,6-dichlorobenzyl)-phenyl]-morpholine-4-yl}-propionic acid:1H NMR (400 MHz, DMSO-d6) δ ppm 2,83-of 2.93 (m, 2H) 2,97-3,20 (m, 2H) 3,22-3,39 (m, 2H) 3,47 (d, J=12,38 Hz, 1H) 3,55-3,66 (m, 1H) 3,94-4,06 (m, 1H) 4,08-4,19 (m, 1H) 4,28 (s, 2H) 4,78-4,89 (m, 1H) 7,15 (d, J=of 8.34 Hz, 2H) 7,267,40 (m, 3H) 7,53 (d, J=8,08 Hz, 2H).

Compound 217: Hydrochloride 3-{2-[4-(2-chloro-6-deformedarse-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid:1H NMR (400 MHz, DMSO-d6) δ ppm 2,88-2,95 (m, 2H) 3,05-3,18 (m, 2H), or 3.28-3,39 (m, 2H) 3,42-3,51 (m, 1H) 3,53-3,62 (m, 1H) 3,97 (t, J=11,4, 1H) 4.13 in (d, J=11,4 Hz, 1H) 4,84 (d, J=11,4 Hz, 1H) 5,13 (s, 2H) was 7.08 (d, J=to 8.7 Hz, 2H) to 7.33 (t, J=85 Hz, 1H) 7,26-value of 7, 37 (m, 3H) 7,47 (d, J=7,6 Hz, 1H) 7,56 (d, J=to 7.6, 1.9 Hz, 1H) 1 1,8 (ush.with., 1H) 12,8 (ush.with., 1H).

Connection 218: Hydrochloride 3-{2-[4-(2-chloro-6-deformedarse-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid: T a MP 192-193°C.

Connection 230; Hydrochloride 3-[2-(3-benzyloxy-phenyl)-morpholine-4-yl]-propionic acidSo a MP 222-225°C.

Compound 231; Hydrochloride 3-[2-(3-octyloxy-phenyl)-morpholine-4-yl]-propionic acidSo a MP 218-220°C.

Connection 232; Hydrochloride 3-{2-[3-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidSo a MP 229-230°C.

Compound 233; Hydrochloride 3-{2-[3-(2-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidSo a MP 233-234°C.

Compound 234; 3-[2-(4-Benzyloxy-phenyl)-thiomorpholine-4-yl]-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 a-1,99 (m, 2H) 2,11-2,19 (m, 1H) 2,25-2,33 (m, 1H) 2,47-of 2.54 (m, 3H) 2,72-2,83 (m, 1H) 2,91-of 3.04 (m, 2H) 3,81-3,88 (m, 1H) of 5.01 (s, 2H) to 6.88 (d, J=8,8 Hz, 2H) 7,18-7,39 (m, 7H).

Connection 235; Hydrochloride 3-{2-[4-(2-chlorine-benzyloxy)-phenyl]-thiomorpholine-4-yl}-propionic acid/b> So a MP 178-182°C

Compound 236; Hydrochloride 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-thiomorpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 2,89-to 2.99 (m, 3H) 3,10-3,20 (m, 1H) 3,33-3,54 (m, 4H) 3,71-3,83 (m, 2H) of 4.54-4,60 (m, 1H) 5,23 (s, 2H) 7,11 (d, J=to 8.7 Hz, 2H) 7,32 (d, J=to 8.7 Hz, 2H) of 7.46-7,52 (m, 1H) 7,55-members, 7.59 (m, 2H) 11,4 (ush.with., 1H) 12,8 (ush.with., 1H).

Compound 237; 3-[2-(4-Octyloxy-phenyl)-thiomorpholine-4-yl]-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 0,84-of 0.90 (m, 3H) 1,23-1,34 (m, 8H) 1,35-of 1.42 (m, 2H) 1,64-of 1.73 (m, 2H) 2,26-2,34 (m, 1H) 2,35-2,41 (m, 2H) 2,41-2,48 (m, 1H) 2,57-2,63 (m, 1H) 2,64-2,70 (m, 2H) 2,81-2,89 (m, 1H) 3,02-3,14 (m, 2H) 3,89-to 3.96 (m, 3H) 6,86 (d, J=8,8 Hz, 2H) 7,26 (d, J=8,8 Hz, 2H).

Compound 238; hydrochloride 3-{2-[5-(2,6-dichloro-benzyloxy)-pyridin-2-yl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 2,88-of 2.97 (m, 2H) 3,11-3,26 (m, 2H) 3,32-3,44 (m, 2H) 3,52 (d, J=11,9 Hz, 1H) 3,74 (d, J=11,9 Hz, 1H) 4,06-is 4.21 (m, 2H) 5,01 (d, J=11,9 Hz, 1H) of 5.34 (s, 2H) 7,38 (ush.with., 1H) 7,47-to 7.55 (m, 2H) 7,56-7,61 (m, 2H) 7,69 (DD, J=8,7, and 3.0 Hz, 1H) 8,40 (d, J=3.0 Hz, 1H) 11,8 (ush.with., 1H).

Compound 239; hydrochloride 3-{2-[4-(2-oxo-2-phenyl-ethyl)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, DMSO-d6) δ ppm 2,84-2,92 (m, 2H) 3,00-3,18 (m, 2H), or 3.28-3,38 (m, 2H) 3,42-3,51 (m, 1H) 3,58-3,66 (m, 1H) 3,94-of 4.04 (m, 1H) 4,11-4,19 (m, 1H) 4,42 (s, 2H) 4,79-of 4.87 (m, 1H) 7,28-value of 7, 37 (m, 4H) 7,54 (t, J=7,6 Hz, 2H) 7,65 (t, J=7,0 Hz, 1H) 8,05 (t, J=7,6 Hz, 2H) 11,2 (ush.with., 1H) 12,8 (ush.with., 1H)

Method C:

Compound 69; 3-{2-[4-(3-methoxy-benzyloxy)-methylphenyl]-morpholine-4-yl}-propionic acid : tert-butyl ether 3-{2-[4-(3-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid was dissolved in 4 M HCl solution in 1,4-dioxane (1 ml, 4 mmol) and stirred overnight at ambient temperature. Then the solvent was removed under vacuum. The residue was purified preparative HPLC, receiving 3-{2-[4-(3-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid Rt=1,00 min (System B). Conditions preparative LC-MS: Injection of crude product was dissolved in 2700 ál of the mixtureDMSO/CH3CN 1:2; column Waters SunFire Prep C18 OBD 5 μm 30×100 mm, mobile phase water/CH3CN/HCOOH 0.1% of 40 ml/min, acceleration of 8.5 min 5% -100% CH3CN, detection: UV 225 nm.

The following compounds were obtained in a similar way:

The connection 70; 3-{2-[4-(5-bromo-2-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,26 min (System B).

The connection 71; 3-{2-[4-(2,4-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,61 min (System B).

The connection 72; 3-{2-[4-(2,3-Dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRtD =0.99 min (System B).

Compound 73; 3-[2-(4-Cyclopentyloxy-2-methyl-phenyl)-morpholine-4-yl]-propionic acidRt=1,05 min (System B).

The connection 74; 3-{2-[4-(2,5-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidR t=1,10 min (System B).

The connection 75; 3-{2-[2-Methyl-4-(pyridin-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=0,68 min (System B).

The connection 76; 3-{2-[2-Methyl-4-(naphthalene-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,10 min (System B).

Compound 77; 3-{2-[4-(Benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,01 min (System B).

The connection 78; 3-{2-[4-(2-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=0,92 min (System B).

Compound 79; 3-{2-[2-Methyl-4-(6-methyl-pyridin-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=0,71 min (System B).

Compound 80; 3-{2-[4-(2-chlorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,04 min (System B).

Compound 81; 3-{2-[4-(2,5-Dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=0,93 min (System B).

The connection 82; 3-{2-[4-(2-bromine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,05 min (System B).

The connection 83; 3-{2-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,04 min (System B).

The connection 84; 3-{2-[4-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,21 min (Syst�mA (B).

Connection 85; 3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,03 min (System B).

The connection 86; 3-{2-[4-(the biphenyl-2-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,13 min (System B).

Compound 87; 3-{2-[2-Methyl-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,06 min (System B).

The connection 88; 3-{2-[4-(3,5-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,13 min (System B).

Compound 89; 3-{2-[2-Methyl-4-(3-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,09 min (System B).

Connection 90; 3-{2-[4-(4-chlorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,06 min (System B).

The connection 91; 3-{2-[4-(4-isopropyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,14 min (System B).

The connection 92; 3-{2-[2-Methyl-4-(3-phenoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,15 min (System B).

Compound 93; 3-{2-[4-(4-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=0,92 min (System B).

The connection 94; 3-{2-[2-Methyl-4-(2-phenethyl-benzyloxy)- phenyl]-morpholine-4-yl}-propionic acidRt=1,19 min (System B).

To connect�Linux 95 ; 3-{2-[4-(3,4-Dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=0,86 min (System B).

Connection 96; 3-{2-[4-(3,5-dimethyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,08 min (System B).

Compound 97; 3-{2-[4-(4-Benzyloxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,05 min (System B).

Connection 98; 3-{2-[2-Methyl-4-(thiophene-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=0,90 min (System B).

Connection 99; 3-{2-[4-(3-fluorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,03 min (System B).

Connection 100; 3-{2-[4-(3-Benzyloxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,15 min (System B).

Connection 101; 3-{2-[4-(4-fluorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,01 min (System B).

The connection 102; 3-{2-[4-(biphenyl-4-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,14 min (System B).

The connection 103; 3-{2-[4-(2,3-Dihydro-benzo [1,4] dioxin-2-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,03 min (System B).

The connection 104; 3-{2-[2-Methyl-4-(pyridin-2-ylethoxy)- phenyl]-morpholine-4-yl}-propionic acidRt=0,75 min (System B).

The connection 105; 3-{2-4-(4-Butoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid Rt=1,05 min (System B).

The connection 106; 3-[2-(4-Cyclohexylmethoxy-2-methyl-phenyl)-morpholine-4-yl]-propionic acidRt=1,10 min (System B).

Connection 107; 3-{2-[2-Methyl-4-(tetrahydro-furan-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=0,83 min (System B).

Connection 108; 3-{2-[2-Methyl-4-(3-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,05 min (System B).

The connection 109; 3-{2-[4-(2,3-Debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,03 min (System B).

The connection 110; 3-{2-[2-Methyl-4-(4-triptoreline-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,12 min (System B).

The connection 111; 3-{2-[4-(3-chlorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,05 min (System B).

The connection 112; 3-{2-[2-Methyl-4-(tetrahydro-Piran-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=0,91 min (System B).

The connection 113; 3-{2-[2-Methyl-4-(4-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,08 min (System B).

The connection 114; 3-{2-[4-(3,4-Debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,05 min (System B).

The connection 115; 3-{2-[2-Methyl-4-(2,3,4-trimethoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic �Isleta Rt=0,91 min (System B).

The connection 116; 3-{2-[4-(Cyclohex-3-animetake)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,07 min (System B).

The connection 117; 3-{2-[4-(4-butyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,22 min (System B).

The connection 118; 3-{2-[2-Methyl-4-(4-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=1,05 min (System B).

The connection 119; 3-{2-[4-(3-Dimethylamino-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=0,86 min (System B).

The connection 120; 3-{2-[2-Methyl-4-(pyridin-4-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=0,66 min (System B).

The connection 121; 3-{2-[4-(2-iodine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,07 min (System B).

The connection 122; 3-{2-[4-(3,5-Dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,00 min (System B).

The connection 123; 3-{2-[4-(2,4-Debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,03 min (System B).

The connection 124; 3-{2-[2-Methyl-4-(2,4,5-trimethoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acidRt=0,88 min (System B).

The connection 125; 3-{2-[4-(3-bromine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,08 min(System B).

The connection 126; 3-{2-[4-(4-bromine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,07 min (System B).

The connection 127; 3-{2-[4-(4-tert-Butyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,18 min (System B).

Connection 128; 3-{2-[4-(2,5-Debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acidRt=1,02 min (System B).

Compound 129; 3-{2-[2-Methyl-4-(tetrahydro-furan-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acidRt=0,83 min (System B).

Method D:

The connection 130; salt of trifluoroacetic acid 3-{2-[4-(2,6-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid: tert-butyl ether 3-{2-[4-(2,6-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid (1,23 g; 2.6 mmol) was dissolved in CH2Cl2(15 ml). Was added TFA (5 ml) and the resulting mixture was stirred over night at ambient temperature. The reaction mixture was concentrated in vacuo, and the residue treated withiPr2O. the Precipitate was collected by filtration, obtaining a salt of trifluoroacetic acid 3-{2-[4-(2,6-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,27-of 2.38 (2H, m), 2,83 (2H, t, J=7,6 Hz), of 3.07 (1H, t, J=11,7 Hz), 3,13 -, or 3.28 (1H, m), 3,39 (2H, t, J=7,7 Hz), 3,48-of 3.69 (2H, m), 3,83-3,98 (1H, m), 4,18 (1H, d), 4,90 (1H, d, J=10,6 Hz), with 5.22 (2H, d), To 6.88 ó 7.1 (2H, m), 7,34 (1H, d, J=8,3 Hz), 7,43-7,52 (1H, m), 7,58 (2H, d).

The following compound was obtained in a similar way:

Compound 131; salt of trifluoroacetic acid 3-{2-[4-(2,6-dichloro-benzyloxy)-3-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,73-2,90 (m, 2H) 3,07-3,26 (m, 2H), or 3.28 is-3.45 (m, 2H) 3,51 (d, J=12.1 Hz, 1H) 3,71 (d, J=12.1 Hz, 1H) 3,90 (t, J=12.1 Hz, 1H) 4,20 (d, J=10.7 Hz, 1H) to 4.81 (d, J=10.7 Hz, 1H) 5,38 (s, 2H) 7,47-7,53 (m, 1H) 7,56-7,63 (m, 3H) 7,65-of 7.75 (m, 2H) 10,84 (ush. S., 1H) 12,42 (ush. s, 1H).

Method E:

The connection 132; {2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-acetic acid: a mixture of ethyl ether {2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-acetic acid (0,62 g; 1.5 mmol), 2 M aqueous NaOH solution (5 ml) and ethanol (25 ml) was stirred for 3 hours at ambient temperature. Then was added 1 M HCl aqueous solution (9.8 ml), and the mixture was concentrated in vacuo. The residue was treated with saturated solution of NH4ClCH2Cl2. The formed precipitate was collected by filtration, washed with small amounts of water and ethanol, and dried under vacuum to give {2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-acetic acid (0,41 g).1H NMR (400 MHz, DMSO-d6) δ ppm of 2.23 (t, J=10 Hz, 1H) 2,40 (dt, J=10 Hz, J=3 Hz, 1H) 2,76-2,83 (m, 1H) 2,86-of 2.93 (m, 1H) 3,13-3,25 (m, 2H) to 3.67 (dt, J=11 Hz, J=2 Hz, 1H) 3,87-3,95 (m, 1H) to 4.46 (DD, J=10 Hz, J=2 Hz, 1H) to 5.21 (s, 2H) 6,99-7,06 (m, 2H) 7,26-7,32 (m, 2H) 7,44-7,50 (m, 1H) 757 (d, J=7 Hz, 2H) 12,3 (ush. s, 1H).

The following compounds were obtained in a similar way:

Compound 219; 3-{2-[4-(indane-1-yloxy)-phenyl]-morpholine-4-yl}-propionic acidT. PL. 124 - 129,5°C.

Connection 220; 3-{2-[4-(7-methyl-indane-1-yloxy)-phenyl]-morpholine-4-yl}-propionic acidT. PL. 134 - 139°C.

Compound 221; 3-{2-[4-(2,3-Dihydro-benzofuran-3-yloxy)-phenyl]-morpholine-4-yl}-propionic acid. T. PL 141,5-144,5°C.

Connection 222; 3-(2-{4-[3-(4-chlorophenyl)-allyloxy]-phenyl}-morpholine-4-yl)-propionic acid1H NMR (400 MHz, CDCl3) δ ppm of 2.33 (t, J=11,7 Hz, 1H) 2,47-2,59 (m, 3H) 2,74-2,86 (m, 2H) 2,98-3,10 (m, 2H) 3,87 (TD, J=11,9, 2.4 Hz, 1H) 4.13 in (DD, J=11,9, 2.4 Hz, 1H) 4,55 (DD, J=10,5, 2.5 Hz, 1H) 4,69 (DD, J=5,7, 1.6 Hz, 2H) 6.32 per-to 6.42 (m, 1H) 6,68 (d, J=16,0 1H) 6,95 (d, J=8,8 Hz, 2H) 7.23 percent-of 7.36 (m, 6H).

Compound 223; 3-{2-[4-(3-phenyl-prop-2-ynyloxy)-phenyl]-morpholine-4-yl}-propionic acid1H NMR (400 MHz, CDCl3) δ ppm of 2.33 (t, J=11,7 Hz, 1H) 2,47-2,60 (m, 3H) 2,74-2,86 (m, 2H) 2,98-3,11 (m, 2H) 3,87 (TD, J=11,9, 2.5 Hz, 1H) 4.13 in (DD, J=11,9, 2.4 Hz, 1H) 4,55 (DD, J=10,5, 2.5 Hz, 1H) 4,91 (s, 2H) 7,03 (d, J=8,8 Hz, 2H) 7,25-of 7.36 (m, 5H) 7,40-of 7.46 (m, 2H).

The connection 224; 3-(2-{4-[3-phenyl-allyloxy]-phenyl}-morpholine-4-yl)-propionic acid1H NMR (400 MHz, CDCl3) δ ppm 2,32 (t, J=11,7 Hz, 1H) 2,47-2,59 (m, 3H) 2,75-2,87 (m, 2H) 2,98-3,11 (m, 2H) 3,87 (TD, J=11,9, 2.5 Hz, 1H) 4,14 (DD, J=10,5, 2.4 Hz, 1H) 4,55 (DD, J=10,5, 2.4 Hz, 1H) 4,70 (DD, J=5,7, 1.6 Hz, 2H) 6,36-6,44 (m, 1H) 6,69 (d, J=15,9, 1H) 6,95 (d, J=8,8 Hz, 2H) 7,22-the 7.43 (m, 7H).

Compound 225; 3-(2-{4-[3-(4-�lorgeril)-prop-2-enyloxy]-phenyl}-morpholine-4-yl)-propionic acid 1H NMR (400 MHz, CDCl3) δ ppm 2,28-2,36 (m, 1H) 2,47-2,59 (m, 3H) 2,73-2,86 (m, 2H) 3,01 (d, J=11.5 Hz, 1H) is 3.08 (d, J=11.5 Hz, 1H) 3,86-of 3.91 (m, 1H) 4,11-4,16 (m, 1H) a 4.53-4,58 (m, 1H) 4,89 (s, 2H) 7,03 (d, J=to 8.7 Hz, 2H) 7,25-value of 7, 37 (m, 6H).

Connection 226; 3-{2-[4-(4-methoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 2,03-2,12 (m, 1H) 2,20-of 2.28 (m, 1H) 2,41-2,48 (m, 2H) 2,63-2,71 (m, 2H) 2,82-2,87 (m, 1H) 2,88-2,96 (m, 1H) 3,58-3,71 (m, 1H) 3,75 (s, 3H) 3,89-to 3.96 (m, 1H) 4,35-of 4.44 (m, 1H) 5,00 (C, 2H) to 6.88-of 6.99 (m, 4H) 7,25 (d, J=to 8.7 Hz, 2H) value of 7, 37 (d, J=to 8.7 Hz, 2H) 12,3 (ush.with., 1H).

Compound 227; 3-{2-[4-(2-methoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.1H NMR (400 MHz, DMSO-d6) δ ppm 1,90-1,98 (m, 1H) 2,08-2,17 (m, 1H) 2,36-2,44 (m, 2H) 2,54-2,61 (m, 2H) 2,73-2,79 (m, 1H) 2,82-2,88 (m, 1H) 3,55-3,65 (m, 1H) 3,82 (s, 3H) 3,87-3,93 (m, 1H) 4,35-to 4.40 (m, 1H) 5,03 (s, 2H) 6,91-of 6.99 (m, 3H) 7,05 (d, J=7,8 Hz, 1H) 7,27 (d, J=to 8.7 Hz, 2H) 7,30-7,40 (m, 2H) 12,1-12,6 (ush.with., 1H).

Method F:

Compound 133; 3-[2-(4-Octyloxy-phenyl)-morpholine-4-yl]-3-oxo-propionic acid: To a solution of ethyl ester of 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-3-oxo-propionic acid (0.46 g; 1.1 mmol) in tetrahydrofuran (4 ml) and water (1 ml) was added lithium hydroxide (54,3 mg; 2.3 mmol) and the mixture was stirred at 70°C for 3 hours. After cooling to ambient temperature the mixture was loaded on the column RE-AH [ISOLUTE (AB biotage AB); of 0.58 mmol/g, 10 g]. The column was washed with CH3CN and then the desired compound was suirable with 20 vol./about. % TFA in CH3 CN. The fractions containing the compound were concentrated under vacuum to give 3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-3-oxo-propionic acid (0.40 g).1H NMR (400 MHz, DMSO-d6) δ ppm with 0.83 to 0.89 (m, 3H) 1.22 m of 1.34 (m, 8H) of 1.39 (d, J=7,52 Hz, 2H) 1,65-of 1.73 (m, 2H) 3,75 (d, J=1,20 Hz, 1H) of 3.91-3,99 (m, 3H) 4,27 (ush. S., 1H) 6,89 (DD, J=8,58, 3,16 Hz, 2H) 7,28 (DD, J=8,43, of 3.91 Hz, 2H).

Compound 151: 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-3-oxo-propionic acidreceived in this way.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2,71-2,79 (m, 2H) 3,41-3,49 (m, 1H) 3,56-and 3.72 (m, 3H) 4,28-4,45 (m, 2H) 4,70-to 4.76 (m, 1H) 5,07 (s, 2H) 6,98 (d, J=8,8 Hz, 2H) 7,27-7,45 (m, 7H).

Method G:

The connection 134; Triethylammonium salt of 2,2-debtor-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid: To a solution of the ethyl ester of 2,2-debtor-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid (0.55 g; 1.3 mmol) in THF (5 ml) and water (1 ml) was added lithium hydroxide (0.06 g; 2.6 mmol) and stirred at 70°C for 3 hours. After cooling to ambient temperature the reaction mixture was loaded on a SCX column-3 [ISOLUTE (AB biotage AB); 0.61 mmol/g, 15 g]. The column was washed with CH3CN (4×15 ml), and then the desired compound was suirableCH3CN+10% Et3N (2×15 ml). The fractions containing the compound were concentrated under vacuum to give 2,2-debtor-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid in the form triethylammonium salt (0.45 g).1H NMR (00 MHz, Chloroform-d) δ ppm 0,85-0,92 (m, 1H) 0,88 (s, 1H) and 1.13 (d, J=6.32 per Hz, 5H) of 1.30 (t, J=value of 7, 37 Hz, 10H) 1,43 (square d, J=7,22, at 6.92 Hz, 1H) 1,72-to 1.79 (m, J=7,30, 7,30, 7,07, to 6.62 Hz, 1H) 2,99-of 3.04 (m, 1H) 3,06 (s, 1H) 3,09 (ush. S., 1H) 3,09-3,15 (m, 2H) 3,11 (d, J=7,52 Hz, 2H) of 3.77 to 3.85 (m, 1H) of 3.92 (t, J=to 6.62 Hz, 2H) 6,84 (d, J=8,73 Hz, 1H) 7,24 (d, J=8,73 Hz, 1H).

The connection 150; Triethylammonium salt 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2,2-debtor-propionic acid: got this way.1H NMR (400 MHz, DMSO-d6) δ ppm of 2.18 (t, J=10,8 Hz, 1H) 2,32-2,42 (m, 1H) 2,77-to 2.94 (m, 4H) 3,56-3,65 (m, 1H) 3,82-3,90 (m, 1H) 4,34-to 4.41 (m, 1H) to 5.21 (s, 2H) 7,02 (d, J=8,6 Hz, 2H) 7,27 (d, J=8,6 Hz, 2H) 7,44-7,50 (m, 1H) 7,56 (d, J=8,3 Hz, 2H) 10,4 (ush.with., 1H).

Method N:

The connection 135; 2-[2-(4-Octyloxy-phenyl)-morpholine-4-yl]-ethanol: To a solution of 2-(4-octyloxy-phenyl)-4-[2-(tetrahydro-Piran-2-yloxy)-ethyl]-morpholine (1.85 g; 4.4 mmol) in MeOH (10 ml) was added monohydrate p-toluensulfonate acid (0.84 g; 4.4 mmol) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was divided between 5% aqueous solution of NaHCO3and EtOAc. The organic layer was dried(Na2SO4), filtered and concentrated under vacuum to give 2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethanol (1.44 g).1H NMR (400 MHz, CDCl3) δ ppm 0,85-0,92 (m, 3H) 1,23-of 1.37 (m, 7H) 1,39-1,48 (m, 2H) 1,71-of 1.81 (m, 2H) 2,05 (s, 1H) 2,15-of 2.24 (m, 1H) a 2.36 (TD, J=11,44, and 3.31 Hz, 1H) 2,53-2,62 (m, 2H) to 2.79 (DD, J=11,44, of 1.50 Hz, 1H) 3,32 (d, J=1.50 Hz, 1H) 3,61-3,68 (m, 2H) 3,76-3,88 (m, 1H) 3,94 (t, J=6,2 Hz, 2H) 4,03 (DD, J=11,44, of 1.81 Hz, 1H) 4,48 (DD, J=10,23, 2,11 Hz, 1H) 6,84-6,89 (m, 2H) 7.24 to 7,30 (m, 2H).

Compound 141; 2-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-ethanol was obtained in a similar way.1H NMR (400 MHz, DMSO-d6) δ ppm to 3.06 -, or 3.28 (m, 4H) 3,48-3,66 (m, 2H) 3,81 (t, J=4,6 Hz, 2H) 3,98 of 4.09 (m, 1H) 4,10-4,19 (m, 1H) with 4.86 (d, J=a 10.6 Hz, 1H) 5,24 (s, 2H) 5,42 (ush.with., 1H) 7,11 (d, J=8,6 Hz, 2H) 7,34 (d, J=8,6 Hz, 2H) 7,45-7,51 (m, 1H) EUR 7.57 (d, J=8,3 Hz, 2H) to 10.9 (s, 1H).

Method I:

The connection 136; {3-[2-(4-Octyloxy-phenyl)-morpholine-4-yl]-propyl}-phosphonic acid: To a solution of diethyl ether {3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propyl}-phosphonic acid (1,06 g; 2,26 mmol) in CH2Cl2(10 ml) was added bromotrimethylsilane (2,38 ml; 18,06 mmol) and the reaction mixture was stirred at ambient temperature overnight. Then the mixture was concentrated in vacuo, re-dissolved in MeOH (10 ml) and stirred for 2 hours at ambient temperature. The mixture was concentrated in vacuo and treated with iPr2O. the Precipitate was collected by filtration and dried under vacuum to give {3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propyl}-phosphonic acid (0,82 g; 69,8%).1H NMR (400 MHz, DMSO-d6) δ ppm of 0.75 (t, 3H) 1,06-1,25 (m, 8H) 1,24-of 1.35 (m, 2H) of 1.42 to 1.68 (m, 4H) 1,73-1,94 (m, 2H) 2,83-of 3.04 (m, 2H) 3,10 (t, 2H) 3,37 (d, J=12,04 Hz, 1H) 3,43 (d, J=12,04 Hz, 1H) 3,72-of 3.91 (m, 3H) of 4.04 (d, J=12,34 Hz, 1H) a 4.64 (d, J=10,83 Hz, 1H) 6,83 (d, J=of 8.43 Hz, 2H) 7,20 (d, J=of 8.43 Hz, 2H).

The following link� were obtained in a similar way:

Compound 137; {2-[2-(4-Octyloxy-phenyl)-morpholine-4-yl]-ethyl}-phosphonic acid1H NMR (400 MHz, DMSO-d6) δ ppm 0,79-of 0.90 (m, 3H) 1,15-1,45 (m, 9H) 1,62-of 1.74 (m, 2H) 2,04-of 2.20 (m, 2H) 3,03 is 3.23 (m, 2H) 3,25-3,39 (m, 2H) 3,57 (d, J=11,74 Hz, 1H) to 3.67 (d, J=12,04 Hz, 1H) 3,84-3,99 (m, 3H) of 4.09-4,22 (m, 1H) 4.72 in (d, J=10,53 Hz, 1H) 6,94 (d, J=of 8.43 Hz, 2H) 7,29 (d, J=8,73 Hz, 2H).

Compound 146; (3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propyl)-phosphonic acid;1H NMR (400 MHz, DMSO-d6) δ ppm from 1.57 to 1.69 (m, 2H) 1,86-2,00 (m, 2H) 3,05-3,27 (m, 4H) 3,47-3,65 (m, 2H) 3,90 (d, J=12,8 Hz, 1H) 4,18 (d, J=12,8 Hz, 1H) 4.72 in (d, J=10,9 Hz, 1H) 5,24 (s, 2H) 7,11 (d, J=8,6 Hz, 2H) value of 7, 37 (d, J=8,6 Hz, 2H) 7,45-7,52 (m, 1H) 7,58 (d, J=8,3 Hz, 2H) 9,80-10,20 (ush.with., 1H).

Method J:

Connection 138; Mono-{2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethyl}ester of phosphoric acid: a solution of 2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethyl ester di-tert-butyl ether phosphoric acid (0,69 g, 1,31 mmol) in TFA (3 ml) and CH2Cl2(3 ml) was stirred at ambient temperature for 1 hour. Then the reaction mixture was concentrated in vacuo, and the residue was treated with iPr2O. the Precipitate was collected by filtration and dried under vacuum over night, getting a salt of trifluoroacetic acid mono-{2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethyl}ester of phosphoric acid (0.42 g).1H NMR (400 MHz, DMSO-d6) δ ppm of 0.63-0.79 in (m, 3H) 0,98-1,32 (m, 9H) 1,45-1,58 (m, 2H) 2,86-of 3.07 (m, 2H) 3,13 -, or 3.28 (m, 2H) 3,29-3,47 (m, 2H) 3,68-3,83 (m, 3H)3,89-4,06 (m, 3H) is 4.57 (d, J=10,53 Hz, 1H) was 6.77 (d, J=of 8.43 Hz, 2H) 7,10 (d, J=of 8.43 Hz, 2H).

Method K:

Compound 149; 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-(1(2)H-tetrazol-5-ylmethyl)-morpholine hydrochloride: To 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine hydrochloride (0.30 g; 0,80 mmol) was added 2 M aqueous NaOH and EtOAc. The layers were separated, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The obtained 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine was mixed with NaI (24,0 mg; 0.16 mmol), 5-chloromethyl-1(2)N-tetrazole (0.11 g; 0.96 mmol), K2CO3(0.33 g; 2,40 mmol) and CH3CN (10 ml) in a closed cylinder of Pyrex. The mixture was heated at 100°C overnight. After cooling to ambient temperature the mixture was concentrated in vacuo, and the residue was purified by chromatography on a column (SiO2, EtOAc:MeOH 1:1), obtaining 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-(1(2)H-tetrazol-5-ylmethyl)-morpholine. This is the free base was dissolved in 4 M HCl solution in 1,4-dioxane (4 ml, 16 mmol) and stirred at ambient temperature for one hour. Then the mixture was concentrated in vacuo, and the residue was treated with iPr2O. the Precipitate was collected by filtration and dried under vacuum to give 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-(1(2)H-tetrazol-5-ylmethyl)-morpholine hydrochloride (0.13 g).1H NMR (400 MHz, DMSO-d6) δ ppm of 1.96 (t, J=10,9 Hz, 1H) 2,13-of 2.21 (m, 1H) 2,73-2,79 (m, 1H) 2,84-,90 (m, 1H) 3,55-to 3.64 (m, 3H) 3,84-of 3.91 (m, 1H) 4,34-4,39 (m, 1H) to 5.21 (s, 2H) 7,00 (d, J=8,6 Hz, 2H) 7,24 (d, J=8,6 Hz, 2H) 7,44-7,50 (m, 1H) 7,56 (d, J=8,3 Hz, 2H).

Method L:

The connection 228; 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-[2-(2H-tetrazol-5-yl)-ethyl]-morpholine hydrochloride: To a solution of 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionitrile (0.30 g; 0.77 mmol) in xylene (10 ml) was added tributyltin chloride (0.46 ml; 1.7 mmol) andNaN3(110 mg; 1.7 mmol). The mixture was heated at 120°C for two days. After cooling to ambient temperature the mixture was treated with methanol (10 ml) and concentrated in vacuo. The residue was purified by chromatography on a column (EtOAc:MeOH 90:10 to 50:50) to give 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-[2-(2H-tetrazol-5-yl)-ethyl]-morpholine in the form of the free base (0.30 g), the free base was treated with HCl solution in 1,4-dioxane, after stirring at ambient temperature for 4 hours, precipitated salt. The salt was collected by filtration, washed with Et2O, and dried under vacuum to give 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-[2-(2H-tetrazol-5-yl)-ethyl]-morpholine hydrochloride (0.30 g).1H NMR (400 MHz, DMSO-d6) δ ppm 3,15-3,29 (m, 2H) 3,53-of 3.75 (m, 6H) 4,06-4,22 (m, 2H) 4,94 (d, J=11,0 Hz, 1H) 5,24 (s, 2H) 7,11 (d, J=8,6 Hz, 2H) of 7.36 (d, J=8,6 Hz, 2H) 7,45-7,52 (m, 1H) 7,58 (d, J=8,3 Hz, 2H) 12,31 (ush.with., 1H).

Method M:

Connection 229; 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-Mohali�-4-yl}-2,2-dimethylpropanoate acid : To a suspension of methyl ester 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2,2-dimethylpropionic acid (1.05 g; 2,32 mmol) in THF (21 ml) and water (5,25 ml) was added LiOH (111,2 mg; a 4.64 mmol). The resulting mixture was stirred for two days at 50°C. After cooling to ambient temperature the reaction mixture was neutralized (pH 7) with 1 M aqueous HCl solution (a 4.64 ml), diluted with water (50 ml) and was extracted with CH2Cl2(3×50 ml). The combined organic layers were dried(Na2SO4), filtered and concentrated in vacuo. The solid residue was triturated with iPr2O (10 ml) and collected by filtration, receiving 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2,2-dimethylpropionic acid (0,72 g) in the form of white powder.

§5. The PHARMACEUTICAL COMPOSITION

Suitable example of the pharmaceutical compositions according to the present invention are presented below.

The tablet obtained by direct compression of the next song:

The power of pills: 2, 10, and 30 mg of compound 34b/unit. Weight of tablet: 500 mg.
connectionfunctionnumber
compound 34bactive pharmaceutical ingredient0.4 to 6%
Ac-di-Sol® (= sodium croscarmellose)disintegrator3%
PRUV® (sodium stearyl fumarate)lubricant2%
Aerosil® (=silicon dioxide)glidant2%
MCC (=microcrystalline cellulose)filler30%
lactose monohydrate DCL 15fillerelse

§6. PHARMACOLOGICAL TESTS AND DATA

Functional activity (agonism) in vitro receptors on the human S1P5

The test of the CHO-human-S1P5-Aeqorin was purchased from Euroscreen, Brussels (Eurosite, Technical dossier, human receptor lysophospholipid S1P5 (Edg8), clone DNA and the recombinant cell line CHO AequoScreenTM, catalog Number ES-593-A, September 2006). Cells Human-S1P5-Express Aequorin mitochondria targeted apo-Aequorin. Cells were loaded with coelenterazine to reconstitute active Aequorin. After binding of agonists to the human receptor S1P5 intracellular calcium concentration is increased and the binding of calcium to the complex apo-Aequorin/coelenterazine leads to the oxidation reaction coelenterazine that leads to the production of apo-Aequorin, Coelenterata, CO2and light (λmax469 nm). This luminescent reaction depends on the concentration of agonist. Luminescence was measured using a MicroBeta Jet (Perkin Elmer). Agonistic effects of the compounds expressed as pEC50. Compounds were tested in 10-point range of polylogarithm concentrations, and three independent experiments were carried out at each measurement point.

Functional activity (agonism) in vitro receptors on the human S1P3

The test of the CHO-human-S1P3-Aeqorin (CHO/Gα16/AEQ/h-S1P3) was carried out in Solvay Pharmaceuticas. Plasmid DNA that encodes the receptor S1P3 (access number in GenBank NM_005226), was purchased from cDNA Resource Center UMR (Rolla, MO). Design with pcDNA3.1/hS1P3 bearing mitochondria targeted apo-Aeqorin and protein Gα16, transtitional the cell line CHO K1.

Cells Human-S1P3-Express Aequorin mitochondria targeted apo-Aequorin. Cells were loaded with coelenterazine to reconstitute active Aequorin. After binding of agonists to the human receptor S1P3 intracellular calcium concentration is increased and the binding of calcium to the complex apo-Aequorin/coelenterazine leads to the oxidation reaction coelenterazine that leads to the production of apo-Aequorin, Coelenterata, CO2and light (λmax469 nm). This luminescent reaction depends on the concentration of agonist. Luminescence was measured using a MicroBeta Jet (Perkin Elmer). Agonistic effects of the compounds expressed as pEC50. Compounds were tested in 10-point range of polylogarithm concentrations, and three independent experiments were carried out at each measurement point.

Functional activity (agonism) in vitro on the human receptors S1P1

Test CHO-K1-Human S1P1-c-AMP was implemented in Euroscreenfast, Brussels (Euroscreen, communicating with human S1P1 Gi/0, (Edg1) receptor, a number of FAST-0197C, December 2009).

Recombinant cells CHO-K1 expressing human S1P1 grown in average logarithmics�phase in nutrient media without antibiotics, detached, centrifuged and re-suspended. For testing agonistic activity of the cells was mixed with compound, Forskolin and incubated at ambient temperature. Cells were literally, and the concentration of camp was assessed according to the manufacturer's specifications, using the HTRF kit from CIS-BIO International (cat no62AM2PEB).

Agonistic effects of compounds were expressed as percentage activity of the reference compound in its concentration EC100, was calculated EC50and the results were indicated as pEC50. Compounds were tested in 10-point range of polylogarithm concentrations, replicating experiment 1.

Pharmacological data (agonist to the receptor) for the selected ports:

Therapeutic in vivo model; T-maze {T-confusion}

Age-related memory deficits found in people and rodents. Spontaneous alternation is an inherent tendency in rodents to alternate free elections in the T-maze in a series of consecutive passes. This sequential procedure is based on memory and is sensitive to various pharmacological manipulations that affect memory processes (Aging and the physiology of spatial memory. Barnes C. A. Neurobiol. Aging1988: 563-8; Dember WN, Fowler H. Spontaneous alternation behavior. Psychol. Bull.1958, 55(6):412-427; Gerlai R. A new continuous alternation task i T-maze detects hippocampal dysfunction in mice. A strain comparison and lesion study. Behav Brain Res199895(1):91-101).

For this study, male mice with C57BL/6J aged 2 months or 12 months were used in the test of spontaneous alternatie in the T-maze. Briefly, mice were subjected to 1 procedure, including 15 trials consisting of 1 test "forced-choice" accompanied by 14 trials of "free choice". Animals were considered as held in one of the arms of the maze when all four paws were within this sleeve. The procedure is completed, and the animal was removed from the maze as soon as 14 free choice trials were carried out, or 15 minutes has elapsed, regardless of what came before. The percentage of alternatie of 14 free choice trials was determined for each mouse and used as an index of the strength of RAM. Connection34badministered orally for 21 days prior to the test T-maze and T-maze at t=-30 min, it Was shown that the compound34bin the dose of 10 mg/kg/day drew age-related decline in cognitive function in C57BL6J mice 12 months of age with 100% efficiency. Thus, the treated mice 12 months of age were identical in performance, the treated carrier mice aged 2 months.

Conclusion: compounds according to the present invention have a positive effect on the targeted age�deleterious decline in cognitive function.

1. The compound, which is a derivative of (thio)morpholine of formula (I)

in which
R1 is selected from
cyano,
(2-4C)alkynyl,
(1-4C)alkyl,
(3-6C)cycloalkyl,
(4-6C)cycloalkenyl,
(6-8C)bicycloalkyl, (8-10C)bicyclic group, each of which may be substituted (1-4C)alkyl,
phenyl, biphenyl, naftel, each of which can be substituted one to three substituents, independently selected from halogen, (1-4C)alkyl, if necessary substituted by one or more fluorine atoms, (2-4C)alkynyl, (1-4C)alkoxy, if necessary substituted by one or more fluorine atoms, amino, di(1-4C)alkylamino and (3-6C)cycloalkyl,
phenyl, substituted phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle, each of which may be substituted (1-4C)alkyl,
5-6-membered monocyclic heterocycle containing 1-3 heteroatom selected from N, O and S, if necessary substituted by halogen, (1-4C)alkyl or phenyl, if necessary substituted (1-4C)alkyl,
and
9-10-membered bicyclic heterocycle, containing 1-2 heteroatom selected from N and O, if necessary substituted (1-4C)alkyl;
And selected from-CO-O-, -NH-CO-, -CO-NH, -C=C-, -CLO3-O - linking group-Y-(CH2)n-X-, in which
Y is attached to R1 and selected from-O-, -SO2-, -CH2 -O-, -CO-, -CO-O-, -CO-NH-, -NH-CO-, -C=C - and-C≡C-;
n means an integer from 1 to 7; and
X is attached to the phenylene group selected from-O-, -S-, and-NH;
the ring structure represents a phenylene;
R2 denotes H, (1-4C)alkyl, if necessary substituted by one or more fluorine atoms, (1-4C)alkoxy or halogen; and
R3 represents (1-4C)alkylene-R5, in which Allenova group may be substituted by one or two halogen atoms, or R3 denotes a (3-6C)cycloalkyl-R5 or-CO-CH2-R5, in which R5 represents-OH, -PO3H2, -OPO3H2, -COOH or tetrazol-5-yl;
R4 denotes H or (1-4C)alkyl;
R6 represents one or more substituents independently selected from H, (1-4C)alkyl or oxo;
W denotes-O - or-S-;
or its pharmaceutically acceptable salt; provided that the derivative of formula (I) is not 2-(4-ethylphenyl)-4-morpholinoethyl, 4-[4-(2-hydroxyethyl)-2-morpholinyl]benzoylacetonitrile or 3-methyl-2-[4-(phenylmethoxy)phenyl]-4-morpholinoethyl hydrochloride.

2. The compound according to claim 1, having structure (II)

3. The compound according to claim 1, wherein R3 is selected from -(CH2)2-HE, -CH2-COOH, -(CH2)2-COOH, -(CH2)3-COOH, -CH2-SNSN3-COOH, -CH2- (CH3)2-COOH, -SNSN3-CH2-COOH, -CH2-CF2-COOH, -CO-CH2-COOH, 1,3-�clobutinol-COOH, -(CH2)2-PO3H2, -(CH2)3-PO3H2, -(CH2)2-ORO3N2, -(CH2)3-OPO3H2, -CH2-tetrazol-5-yl, -(CH2)2-tetrazol-5-yl and (CH2)3-tetrazol-5-yl.

4. The compound according to claim 1, in which R2 denotes H, methyl, methoxy, trifluoromethyl, deformity, Cl or F; and R4 denotes H or methyl.

5. The compound according to claim 1, wherein A is selected from-CO-O-, -NH-CO-, -CO-NH, -C=C-, -CLO3Oh - and a linking group-Y-(CH2)n-X-, and Y is attached to R1 and selected from-O-, -SO2-, -CH2-O-, -CO-, -CO-O-, -NH-CO-, -C=C - and-C≡C-; n is an integer from 1 to 7; and X is attached to the phenylene group selected from-O-, -S - and-NH.

6. The compound according to claim 1, wherein R1 is selected from cyano, ethinyl, (1-4C)alkyl, cyclopentyl, cyclohexyl, cyclohexenyl, 6,6-dimethyl-bicyclo[3.1.1]hept-2-yl, indanyl, if necessary substituted bromide, biphenyl, naftel, phenyl, if necessary substituted one, two or three substituents, independently selected from chlorine, fluorine, bromine, (1-4C)alkyl, (2-4C)alkynyl, (1-4C)alkoxy, dimethylamino, trifloromethyl, triptoreline and (3-6C)cycloalkyl,
phenyl, monosubstituted phenoxy, benzyl, benzyloxy, phenylethyl, pyrazolyl or triazolyl,
pyrazolyl, thiazolyl, oxadiazolyl, teinila, tetrahydrofuranyl, Piri�of inila, tetrahydropyranyl, each of which can be substituted by chlorine, (1-4C)alkyl or phenyl, substituted (1-4C)alkyl, and
indolyl, imidazopyridine, dihydrobenzofuranyl and benzodioxane, each of which may be substituted (1-4C)alkyl.

7. The connection according to claim 6, in which R1 is selected from (1-4C)alkyl, cyclopentyl, cyclohexyl, pyridinyl and phenyl, and pyridinyl may be substituted with one or two substituents, independently selected from chlorine, fluorine, bromine, and (1-4C)alkyl, and phenyl may be substituted by one or two substituents, independently selected from chlorine, fluorine, bromine, (1-4C)alkyl, (1-4C)alkoxy and trifloromethyl.

8. The connection according to claim 7, in which R1 is selected from (1-4C)alkyl and dichlorophenyl.

9. The compound according to claim 1, having structure (II) in which R1 represents 2,6-dichlorophenyl; A denotes a connecting group,- Y-(CH2)n-X-, and Y is attached to R1 and denotes a bond, n=1, and X is attached to the phenylene group and a represents-O-; R2 represents H; R3 represents -(CH2)2-COOH, and R4 denotes N.

10. The compound according to claim 1, having structure (II) in which R1 represents (1-4C)alkyl; A denotes a connecting group,- Y-(CH2)n-X-, and Y is attached to R1 and denotes a bond, n is an integer selected from the integers from 1 to 6, and X is attached to the phenylene group and a represents-O - or a bond; R2 denotes H; R3 is selected from -(�N 2)2-COOH, -(CH2)3-COOH, -CH2-SNSN3-COOH, -CH2- (CH3)2-COOH, -SNSN3-CH2-COOH, -(CH2)2-PO3H2, -(CH2)3-PO3H2and -(CH2)2-OPO3H2; and R4 denotes N.

11. The compound according to claim 1, having structure (II)

in which
R3 is selected from -(CH2)2-HE, -CH2-COOH, -(CH2)2-COOH, -(CH2)3-COOH, -CH2-SNSN3-COOH, -CH2- (CH3)2-COOH, -SNSN3-CH2-COOH, -CH2-CF2-COOH, -CO-CH2-COOH, 1,3-cyclobutyl-COOH, -(CH2)2-PO3H2, -(CH2)3-PO3H2, -(CH2)2-OPO3H2, -(CH2)3-OPO3H2, -CH2-tetrazol-5-yl, -(CH2)2-tetrazol-5-yl and -(CH2)3-tetrazol-5-yl;
R2 denotes H, methyl, methoxy, trifluoromethyl, deformity, Cl or F;
R4 denotes H or methyl;
And selected from-CO-O-, -NH-CO-, -CO-NH, -C=C-, -CLO3-O - linking group-Y-(CH2)n-X-, and Y is attached to R1 and selected from-O-, -SO2-, -CH2-O-, -CO-, -CO-O-, -NH-CO-, -C=C - and-C≡C-; n is an integer from 1 to 7; and X is attached to the phenylene group selected from-O-, -S - and-NH;
and in which R1 is selected from cyano, ethinyl, (1-4C)alkyl, cyclopentyl, C�of clavecilla, cyclohexenyl, 6,6-dimethyl-bicyclo[3.1.1]hept-2-yl, indanyl, if necessary substituted bromide, biphenyl, naftel,
phenyl, if necessary substituted one, two or three substituents, independently selected from chlorine, fluorine, bromine, (1-4C)alkyl, (2-4C)alkynyl, (1-4C)alkoxy, dimethylamino, trifloromethyl, triptoreline and (3-6C)cycloalkyl,
phenyl, monosubstituted phenoxy, benzyl, benzyloxy, phenylethyl, pyrazolyl or triazolyl,
pyrazolyl, thiazolyl, oxadiazolyl, teinila, tetrahydrofuranyl, pyridinyl, tetrahydropyranyl, each of which can be substituted by chlorine, (1-4C)alkyl or phenyl, substituted (1-4C)alkyl, and
indolyl, imidazopyridine, dihydrobenzofuranyl and benzodioxane, each of which may be substituted (1-4C)alkyl.

12. The compound according to claim 11 in which R1 and -(CH2)n- together denote a linear octillo group, X denotes-O-, and R3 denotes - (CH2)2-PO3H2.

13. The compound according to claim 1, selected from the following compounds:
3-{2-[4-(benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(6-methyl-imidazo[1,2-a]pyridine-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid;
3-(2-{4-[3-(2-propyl-thiazole-5-yloxy)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-{2-[4-(2-benzyloxy-ethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-phenoxy-ethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-[2-(4-hex-5-ynyloxy-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[4-(4-acetoxy-butoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-(2-{4-[3-(4-pertenece)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-(2-{4-[2-(naphthalene-2-yloxy)-ethoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-[2-(4-phenylcarbamoyloxy-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[4-(4-pyrazol-1-yl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(1-methyl-1H-pyrazol-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(6-cyano-hexyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-[2-(4-venetjoki-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[4-(3-phenyl-propoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-benzyloxy-propoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(7-methoxy-heptyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-(2-{4-[3-(4-tert-butyl-phenyl)-[1,2,4]oxidiazol-5-ylethoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-{2-[4-(5-oxo-hexyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-phenyl-butoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-methoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chlorine-benzyloxy)-phenyl]-mo�folin-4-yl}-propionic acid,
3-[2-(4-cyclohexylmethoxy-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[4-(2-benzolsulfonat-ethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-phenoxy-propoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-[1,2,4]triazole-1-yl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,3-dihydro-benzofuran-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-biphenyl-4-yl-2-oxo-ethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-phenoxy-butoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-oxo-2-phenyl-ethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-(2-{4-[2-(1H-indol-3-yl)-ethoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
(+)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
(-)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-(2-(4-octylphenyl)-morpholine-4-yl)-propionic acid,
4-[2-(4-octylphenyl)-morpholine-4-yl]-butyric acid,
3-[2-(4-hexyloxy-phenyl)-morpholine-4-yl]-propionic acid,
4-[2-(4-hexyloxy-phenyl)-morpholine-4-yl]-butyric acid,
3-[2-(4-heptyloxy-phenyl)-morpholine-4-yl]-propionic acid,
4-[2-(4-heptyloxy-phenyl)-morpholine-4-yl]-butyric acid,
3-(2-(4-octyloxy-phenyl)-morpholine-4-�l)-propionic acid,
(+)-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid,
(-)-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid,
4-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-butyric acid,
2,2-dimethyl-3-(2-(4-octyloxy-phenyl)-morpholine-4-yl)-propionic acid,
3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-butyric acid,
2-methyl-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[4-(2-chloro-6-forbindelse)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-debtor-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dimethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3,5-dichloro-pyridin-4-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,4-dichloro-pyridin-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-phenylcarbamoyl)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine-4-yl}-propionic acid,
3-(2-{4-[2-(2,6-dichlorophenyl)-vinyl]-phenyl}-morpholine-4-yl)-propionic acid,
3-[2-(4-phenethyl-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[4-(2,6-dichloro-benzylamino)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-benzoylamino)-phenyl]-morpholine-4-yl}-propionic acid;
3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-methyl-morpholine-4-yl}-propionic acid,
3-{2- [4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-2-methyl-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-trifluoromethyl-benzyloxy)-phenyl]-2-methyl-morpholine-4-yl}-propionic acid,
3-[2-methyl-2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid,
4-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-butyric acid,
3-(2-{4-[1-(2,6-dichlorophenyl)-ethoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-(2-{4-[2-(2,6-dichlorophenyl)-ethyl]-phenyl}-morpholine-4-yl)-propionic acid,
3-{2-[3-methoxy-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-3-methoxyphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-3-methoxyphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(5-bromo-2-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,4-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,3-dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-[2-(4-cyclopentyloxy-2-methyl-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[4-(2,5-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(pyridin-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid, 3-{2-[2-methyl-4-(naphthalene-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(6-methyl-pyridin-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chlorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,5-dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-bromine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(2-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(biphenyl-2-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3,5-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(3-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-chlorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-isopropyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(3-phenoxy-benzyloxy)-phenyl]-morpholine-4-yl}-PR�peony acid,
3-{2-[4-(4-methoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(2-phenethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3,4-dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3,5-dimethyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-benzyloxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(thiophene-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-fluorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-benzyloxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-fluorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(biphenyl-4-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylethoxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(pyridin-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-butoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-[2-(4-cyclohexylmethoxy-2-methyl-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[2-methyl-4-(tetrahydro-furan-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(3-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,3-debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-�Rodionova acid,
3-{2-[2-methyl-4-(4-triptoreline-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-chlorine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(tetrahydro-Piran-2-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(4-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3,4-debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(2,3,4-trimethoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(cyclohex-3-animetake)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-butyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid;
3-{2-[2-methyl-4-(4-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-dimethylamino-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(pyridin-4-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-iodine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3,5-dimethoxy-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,4-debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(2,4,5-trimethoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-bromine-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(4-bromine-benzyloxy)-2-methylphenyl]-morpholine-4-�l}-propionic acid,
3-{2-[4-(4-tert-butyl-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,5-debtor-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-methyl-4-(tetrahydro-furan-3-ylethoxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-2-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-3-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid,
{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-acetic acid,
3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-3-oxo-propionic acid,
2,2-debtor-3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid,
2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethanol,
2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-ethanol,
{3-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-propyl}-phosphonic acid,
{2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethyl}-phosphonic acid,
mono-{2-[2-(4-octyloxy-phenyl)-morpholine-4-yl]-ethyl}ester of phosphoric acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2-methylpropionate acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-butyric acid,
mono-(2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-ethyl)ether phosphoric acid,
3-{2-[3-methyl-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-3-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-4-(2,6-dichloro-benzyloxy)-3-methylphenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,3-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-5-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,3,6-trichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chlor-6-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-5-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-5-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-5-propyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.
3-{2-[4-(2-chloro-5-isopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,4,6-trichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-4-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-4-iodine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-(2-{4-[3-(2-fluorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-{2-[4-(2,6-dichloro-4-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-4-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-[2-(4-benzyloxy-phenyl)-5-oxo-morpholine-4-yl]-propionic acid,
3-{2-[4-(2,6-dichloro-benzy�oxy)-phenyl]-5-oxo-morpholine-4-yl}-propionic acid,
3-[2-(4-octyloxy-phenyl)-5-oxo-morpholine-4-yl]-propionic acid,
3-(2-{4-[3-(2-trifluoromethyl-phenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-(2-{4-[3-(2-chloro-6-fluoro-phenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-(2-{4-[3-(2,6-dichlorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-(2-{4-[3-(4-chlorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-(2-{4-[3-(2-chlorophenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-(2-{4-[3-(2,3-debtor-phenyl)-propoxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-{2-[3-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[3-chloro-4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[3-chloro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-2-fluorophenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-2-fluorophenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-fluoro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-3-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-ethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-isopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-cyclopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[-(2-chloro-6-isobutyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-5,5-dimethyl-morpholine-4-yl}-propionic acid,
3-[5,5-dimethyl-2-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid,
3-[2-(4-octyloxy-2-trifluoromethyl-phenyl)-morpholine-4-yl]-propionic acid,
3-{6-[4-(2,6-dichloro-benzyloxy)-phenyl]-2,2-dimethyl-morpholine-4-yl}-propionic acid,
3-[2,2-dimethyl-6-(4-octyloxy-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[4-(2,6-dichloro-4-propyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-4-isopropyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-4-prop-1-inyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-triptoreline-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-4-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-3-methyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,4-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
4-[4-(2-carboxy-ethyl)-morpholine-2-yl]-phenyl ester 2,6-dichlorobenzoyl acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-cyclobutanecarbonyl acid,
3-{2-[4-(2,6-dichloro-benzolsulfonat)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chlorine-benzolsulfonat)-phenyl]-morpholine-4-yl}-propionic acid, 3-{2-[4-(2-chloro-6-fluoro-benzolsulfonat)-phenyl]-morpholine-4-yl}-propionic acid,
3-[2-(4-octylsilane-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[4-(4,4-dimethyl-cyclohexyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-deformedarse-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(3-trifluoromethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-ethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-triptoreline-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-isopropyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-fluoro-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-trifluoromethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-cyclopropyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-diethyl-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[2-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichlorobenzyl)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-deformedarse-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-chloro-6-deformedarse-benzyloxy)-2-trifluoromethyl-phenyl]-morphol�n-4-yl}-propionic acid,
3-[2-(3-benzyloxy-phenyl)-morpholine-4-yl]-propionic acid,
3-[2-(3-octyloxy-phenyl)-morpholine-4-yl]-propionic acid,
3-{2-[3-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[3-(2-chlorine-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-[2-(4-benzyloxy-phenyl)-thiomorpholine-4-yl]-propionic acid,
3-{2-[4-(2-chlorine-benzyloxy)-phenyl]-thiomorpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-thiomorpholine-4-yl}-propionic acid,
3-[2-(4-octyloxy-phenyl)-thiomorpholine-4-yl]-propionic acid,
3-{2-[5-(2,6-dichloro-benzyloxy)-pyridin-2-yl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(indane-1-yloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(7-methyl-indane-1-yloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,3-dihydro-benzofuran-3-yloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-(2-{4-[3-(4-chlorophenyl)-allyloxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-{2-[4-(3-phenyl-prop-2-ynyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-(2-{4-[3-phenyl-allyloxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-(2-{4-[3-(4-chlorophenyl)-prop-2-enyloxy]-phenyl}-morpholine-4-yl)-propionic acid,
3-{2-[4-(4-methoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2-methoxy-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-3-oxo-propion�Wai acid,
3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2,2-debtor-propionic acid,
(3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propyl)-phosphonic acid,
2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-(1(2)N-tetrazol-5-ylmethyl)-morpholine,
3-{2-[4-(2-oxo-2-phenyl-ethyl)-phenyl]-morpholine-4-yl}-propionic acid;
2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-[2-(2H-tetrazol-5-yl)-ethyl]-morpholine and
3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-2,2-dimethylpropanoate acid,
or its pharmaceutically acceptable salt.

14. The compound according to claim 1, which is an(-)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-yl}-propionic acid.

15. The compound according to any one of claims. 1-14 for use in therapy as a modulator of sphingosine-1-phosphate (S1P).

16. Pharmaceutical composition having the properties of a modulator of sphingosine-1-phosphate (S1P), comprising a compound according to any one of claims. 1-14 and at least one pharmaceutically acceptable auxiliary substance.

17. Use of a compound according to any one of claims. 1-14 to obtain medicines for the treatment, relief or prophylaxis of diseases and conditions in which participates the receptor S1P1, S1P3 and/or S1P5 or which involve modulation of the endogenous system signal transduction S1P1, S1P3 and/or S1P5 via receptor S1P1, S1P3 and/or S1P5.

18. The use according to claim 17, wherein the disease is a violations� CNS, such as neurodegenerative violation, in particular selected from cognitive disorders, Alzheimer's disease, (vascular) dementia, disease, Niemann-pick and cognitive deficits in schizophrenia, obsessive-compulsive behavior, major depression, autism, multiple sclerosis and pain, and, in particular, the disease is a cognitive disorder such as age-related decline in cognitive function.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula

,

or its pharmaceutically acceptable salt. In claimed formula each symbol has values, determined in formula of invention. Versions of formula [I] compound and particular compounds are also objects of invention. In addition, invention relates to pharmaceutical composition, ITK inhibitor and means for treatment or prevention of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection and other diseases and methods of treating said diseases.

EFFECT: claimed compounds inhibit induced T-cellular kinase (ITK).

32 cl, 86 tbl, 387 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining 7-R-pyrido[1,2-a]benzimidazoles of general formula, , where a) R=CF3, R'=H; b) R=CN, R'=H; c) R=COOH, R'=H; d) R=COOCH3, R'=H; e) R=COOC2H5, R'=H; f) R=COOPh, R'=H; g) R=CF3, R'=CH3; h) R=CN, R'=CH3, which consists in the fact that reduction of N-(2-nitro-4-R-phenyl)-3,5-R'-pyridinium chlorides is carried out in mixture of alcohol and 4% hydrochloric acid, taken in ratio 1:1, by means of electric current in electrolyser without diaphragm in galvanostatic mode at temperature 40°C on lead cathode, with passing charge in 4 F for 0.5 h, current power 0.4 A through electrolytic cell, with application of platinum anode, target products are extracted by filtration of precipitated sediment after processing reaction mixture with ammonium hydroxide.

EFFECT: method of obtaining derivatives of pyrido[1,2-a]benzimidazoles, which can be applied as semi-products for synthesis of biologically active substances, demonstrating antioxidant activity, which finds application in field of optoelectronics, for example non-linear optics, has been elaborated.

8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula

,

having Aβ42 secretion inhibiting activity. In formula I , hetaryl I is a five- or six-member heteroaryl group containing 1-3 heteroatoms selected from O, S or N, hetaryl II is a five- or six-member heteroaryl group containing 1-3 heteroatoms as defined above for hetaryl I, or is a bicyclic ring system containing 1-4 heteroatoms selected from S, O or N, where at least one ring is aromatic by nature, R1 is C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl substituted with a halogen, or a halogen; R2 is a halogen, C1-7-alkyl, C1-7-alkoxy, hydroxy, C1-7-alkyl substituted with a halogen, C1-7-alkyl substituted with a hydroxy, or benzo[1,3]dioxolyl or is -(CHR)p-phenyl, optionally substituted with a halogen, C1-7-alkyl, C1-7-alkoxy, S(O)2-C1-7-alkyl, cyano, nitro, C1-7-alkoxy substituted with a halogen, dimethylamino, -(CH2)p-NHC(O)O-C1-7-alkyl or C1-7-alkyl, substituted with a halogen. The values of radicals R, R3, R4,p, n, m, o are given in the claim.

EFFECT: invention relates to a method of producing said compounds, a medicinal agent containing said compounds and a method of treating Alzheimer's disease, cerebral amyloid angiopathy, Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), vascular dementia, dementia pugilistica or Down syndrome, associated with β amyloid activity.

21 cl, 283 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds, which possess an inhibiting activity with respect to anti-apoptotic Bcl-2 proteins. The invention also relates to a pharmaceutical composition, containing the said compounds, and to a method of treating urinary bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukaemia, colorectal cancer, oesophageal cancer, hepatocellular cancer, lymphoblast leukosis, follicular lymphoma, lymphoid malignant diseases of a T-cell or B-cell origin, melanoma, myelogenous leukaemia, myeloma, oral cavity cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small-cell lung cancer or spleen cancer.

EFFECT: obtaining the compounds, possessing the inhibiting activity with respect to anti-apoptotic Bcl-2 proteins.

4 cl, 5 tbl, 405 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel N-containing heteroaryl derivatives of formula I or II or their pharmaceutically acceptable salts, which possess properties of JAK kinase, in particular JAK3, and can be applied for treating such diseases as asthma and chronic obstructive pulmonary disease (COPD). In formulae A represents carbon and B represents nitrogen or A represents nitrogen and B represents carbon; W represents CH or N; R1 and R2, independently represent hydrogen, C1-4alkyl, halogenC1-4alkyl, -CN; R3 represents C1-4alkyl, R9-C1-4alkyl, Cy1, where Cy1 is optionally substituted with one or several substituents R10; R4 represents hydrogen, C1-4alkyl, R12R7N-C0alkyl, where one of R7 and R12 represents hydrogen, and the other represents C1-4alkyl or group R13, which is selected from C1-5alkyl, Cy2-C0alkyl; R5 represents hydrogen; R6 represents hydrogen, C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0alkyl, Cy1; R7 represents hydrogen or C1-4alkyl; R9 represents halogen, -CN, -CONR7R12, -COR13, CO2R12, -OR12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12; R10 represents C1-4alkyl or R9-C0-4alkyl; R11 represents C1-4alkyl, halogen, -CN, -NR7R14; R12 represents hydrogen or R13; R13 represents C1-5alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, Cy2-C0alkyl or R14R7N-C1-4alkyl; where Cy2 is optionally substituted with one or several constituents R11; R14 represents hydrogen or C1-4alkyl; R16 represents C1-4alkyl, halogenC1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl or cyanoC1-4alkyl; Cy1 represents monocyclic carbocyclic unsaturated or saturated ring, selected from C3-C6cycloalkyl, phenyl, or saturated monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or partially unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available C atom, and where one or several ring C or S atoms are optionally oxidised with formation of CO or SO2; and Cy2 represents monocyclic carbocyclic unsaturated ring, selected from C3-C6cycloalkyl, or aromatic monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available atom C or N.

EFFECT: obtaining novel heteroaryl derivatives.

27 cl, 41 ex

Ethinyl derivatives // 2553461

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to ethinyl derivatives of formula I, where X represents N or C-R1; Y represents N or C-R2; Z represents CH or N; R4 represents 6-membered ring, containing 0, 1 or 2 nitrogen atoms, possibly substituted with 1-2 groups, selected from halogen, lower alkyl, lower alkoxy or NRR'; R1 represents hydrogen, lower alkyl, lower hydroxyalkyl, lower cycloalkyl or represents 5-6-membered heterocycloalkyl, containing 1-2 heteroatoms, selected from O and N; R2 represents hydrogen, CN; R and R' independently on each other represent hydrogen; or their pharmaceutically acceptable salts or acid-addition salts. Invention also relates to pharmaceutical composition, possessing activity of positive allosteric modulator of mGluR5 receptor, including effective quantity of at least one invention compound, and to application of invention compounds for manufacturing medication for treatment or prevention of diseases, associated with positive allosteric modulators of mGluR5 receptor.

EFFECT: obtained are novel compounds, which can be applied as positive allosteric modulator of mGluR5 receptor.

14 cl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I), their pharmaceutically acceptable salts, tautomers or stereoisomers. In formula R1 represents benzimidazolyl optionally substituted by C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, dimethylaminoC1-4alkyl or oxo group; benzioxazolyl optionally substituted by C1-4alkyl or amino group; benzotriazolyl optionally substituted by C1-4alkyl; dihydrobenzisothiazol-1,1-dionyl; pyrimidyl; dihydroisoquinolinonyl optionally substituted by oxo group; imidazopyridyl; indazolyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, tetrahydropyranylamino, piperidinylamino, halogen, trifluoromethyl or amino group; indolinyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, carboxylate or oxo group; isoindolinyl optionally substituted by C1-4alkyl, aminoC1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl or oxo group; phenyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, trifluoromethyl, carbamoyl, methylcarbamoyl, piperidinylcarbamoyl, methylpiperidinylcarbamoyl, aminoC1-4alkyl, carboxyl, amino, dialkylamino, imidazolyl, pyrrolidin-2-one, triazolyl, morpholinyl, C1-4alkylcarbonylamino, C1-4alkoxyC1-4alkoxy or hydroxyC1-4alkyl; pyrazolopyridyl optionally substituted by C1-4alkyl; pyridyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, hydroxy, amino, morpholinyl, carbamoyl, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkoxy, aminoC1-4alkylamino, hydroxypiperidinyl, hydroxyC1-4alkyl, hydroxyC1-4alkoxy, pyrrolidinylC1-4alkylamino, pyrrolidinylC1-4alkoxy; pyrrolopyridinyl optionally substituted by oxo group; quinolinyl optionally substituted by amino or hydroxy group; or triazolopyridyl substituted by C1-4alkyl. The other radical values are presented in the patent claim. The invention also refers to individual compounds, to a pharmaceutical composition, possessing kinase inhibitory activity and containing an effective amount of the compound of the invention, to a method for kinase inhibition in a cell, to a method of treating or preventing inflammatory conditions, immunological conditions, allergic conditions, rheumatic conditions, cancer, and neuroinflammatory diseases.

EFFECT: there are prepared new compounds possessing Syk, FLT3, JAK1, JAK2 inhibitory activity.

21 cl, 1 tbl, 133 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.

EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.

15 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 5,6-dihydropyrrolo[2,1-a]isoquinoline derivatives 1-4 having the general structural formula: , where 1 - R=CH3, 2 - R=CH2CH3, 3 - R=CH2CF3, 4 - R=CH(CH3)2, characterised by that 6,7-diethoxy-3,4-dihydro-1-(3,4-diethoxybenzoyl)isoquinoline is mixed with methyl propiolate and methane, or ethanol, or 2,2,2-trifluoroethanol, or isopropanol and stirred at temperature of +50°C, the precipitate obtained at the end of the reaction and after removing reagents, is crystallised in ether.

EFFECT: method of producing derivatives which can be used as intermediate compounds when producing biologically active compounds.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

The invention relates to new heterocycles compounds, more particularly to a new heterocycles compounds which are inhibitors of the enzyme 5-lipoxygenase (5-LO)

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula A-I, where G1 stands for hydrogen atom or R'; G2 stands for halogen atom, CN, CF3, isopropyl or phenyl, where said isopropyl or phenyl is optionally substituted with up to three substituents, independently selected from WRW; G3 stands for isopropyl or (C3-C10)cycloaliphatic ring, where said G3 is optionally substituted with up to three substituents, independently selected from WRW; W stands for bond or (C1-C6)alkylidene chain, where up to two methylene groups of W residue are optionally and independently substituted for -CO2- or -O-; RW stands for R'; and R' is independently selected from hydrogen atom or (C1-C8)alkyl group. Invention also relates to method of obtaining compound of formula FF (stands for bromine atom, fluorine atom or tret-butyl; G3 stands for tret-butyl) by hydrogenation of respective nitrocompound in presence of palladium catalyst and to methods of obtaining C-9 and 433 compounds, which include stage of hydrogenation of respective nitrocompound in presence of palladium catalyst as intermediate stage.

EFFECT: formula A-I compounds, which are intermediate for synthesis of modulators of ATP-binding cassette ("ABC") transporters.

35 cl, 4 tbl, 80 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics, namely, deals with compounds of formula , suitable for reduction of regulation of biological activity of melanocortin-5 receptor (MC5R). Such diseases and/or conditions include, but are not limited by, acne, seborrhoea, seborrheic dermatitis, cancer and inflammatory diseases.

EFFECT: compounds of claimed invention can be applied for treatment of diseases and/or conditions, in which reducing regulation of MC5R is favourable.

3 cl, 109 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-(1,2,5-oxadiazol-3-yl)benzamides of formula , in which R stands for an alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, cyano, nitro, methylsulphenyl, acetylamino, methoxycarbonyl, methylcarbonyl, piperidinylcarbonyl, halogen, amino, or heteroaryl, selected from the group, including 1,2,3-triazolyl, 1,2,4-triazolyl, benzisoxazolyl, thiophenyl, pyridinyl and benzimidazol-2-yl, or heterocyclyl, selected from the group, including piperidinyl, respectively selected with s residues, selected from the group, including methyl, ethyl, methoxy and halogen; X and Z independently on each other respectively stand for nitro, halogen, cyano, alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, OR1, S(O)nR2, alkyl-OR1 with 1-6 carbon atoms in alkyl, or heteroaryl, selected from the group, including 1,2,4-triazolyl; Y stands for nitro, halogen, OR1, S(O)nR2, NR1COR1, O-alkylheterocyclyl with 1-6 carbon atoms in the alkyl, and where heterocyclyl is selected from 1,4-dioxan-2-yl, O-alkyl heteroaryl with 1-6 carbon atoms in the alkyl, and where the heteroaryl is selected from pyrazolyl, alkyl-OR1 with 1-6 carbon atoms in the alkyl, alkyl-NR1SO2R2 with 1-6 carbon atoms in the alkyl, NR1R2, tetrahydrofuranyloxymethyl, tetrahydrofuranylmethoxymethyl, O(CH2)-3,5-dimethyl-1,2-oxazol-4-yl, O(CH2)2-O(3,5-dimethoxypyrimidin-2-yl, O(CH2)-5-pyrrolidin-2-one, O(CH2)-5-2,4-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one, or heteroaryl, selected from the group, including 1,2,3-triazolyl and pyrazolyl, or heterocyclyl, selected from the group, including 4,5-dihydro-1,2-oxazol-3-yl and tetrahydropyrimidi-2(1H)-on-1-yl, respectively substituted with s residues, selected from the group, including methyl, methoxy and cyanomethyl; R1stands for hydrogen, alkyl with 1-6 carbon atoms, alkinyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, cycloalkylalkyl with 2-6 carbon atoms in the cycloalkyl and 1-6 carbon atoms in the alkyl, phenyl or phenylalkyl with 1-6 carbon atoms in the alkyl, with six last residues being substituted with s residues, selected from the group, including a halogen, OR3 and CON(R3)2; R2 stands for alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl or phenyl with 1-6 carbon atoms alkyl, with the five last residues being substituted with s residues, selected from the group, including a halogen, OR3, OCOR3, CO2R3, COSR3 and CON(R3)2; R3 stands for hydrogen or alkyl with 1-6 carbon atoms; n stands for 0, 1 or 2; s stands for 0, 1, 2 or 3. The invention also relates to the application of N-(1,2,5-oxadiazol-3-yl)benzamides of formula (I), as a herbicidal preparation and for fighting undesirable plants.

EFFECT: N-(1,2,5-oxadiazol-3-yl)benzamides, possessing herbicidal activity.

9 cl, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of treatment or relieving the severity of cystic fibrosis in a patient, where the patient has the cystic fibrosis transmembrane receptor (CFTR) with R117H mutation, including a stage of introduction to the said patient of an effective quantity of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

EFFECT: elaborated is the method of treating cystic fibrosis, based on the application of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

3 cl, 4 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to azetidine-substituted isoxazoline derivatives of formula (1), where A represents phenyl, naphtyl or heteroaryl, where said heteroaryl represents 5-6-membered aromatic monocyclic ring and contains 1 N heteroatom; each of R1a, R1b and R1c independently represents hydrogen, halogen, cyano, nitro or C1-C6halogenalkyl; R2 represents halogen, cyano or nitro; R3 represents hydrogen, halogen, hydroxyl, cyano, N3 or -NHR4; R4 represents hydrogen, -C(O)R5, -C(S)R5, -C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5 or -C(NR7)R5; R5 represents hydrogen, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C6cycloalkyl, C0-C6alkylphenyl, C0-C6alkylheteroaryl, representing 5-6-membered aromatic monocyclic ring, containing from 1 to 3 heteroatoms, each of which is independently selected from N, O and S, or C0-C6alkylheterocycle, where said heterocycle represents 4-membered monocyclic ring, containing 1 heteroatom, selected from N, O and S; R6 represents C1-C6halogenalkyl; R7 represents cyano; Ra represents hydrogen, C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl; Rb represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; Rc represents C1-C6alkyl, C1-C6halogenalkyl, C1-C6halogenalkylC3-C6cycloalkyl, C0-C3alkylC3-C6cycloalkyl or C0-C3alkylphenyl, each of which is possibly substituted with at least one substituent, selected from cyano or halogen, each of groups C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl ad R5 can be possibly and independently substituted with at least one substituent, selected from cyano, halogen, hydroxyl, C1-C6alkoxy, C1-C6halogenalkoxy, C1-C6halogenalkyl, -S(O)pRc, -SH, -S(O)pNRaRb, -NRaC(O)Rb, -SC(O)Rc and -C(O)NRaRb; and where grouping C0-C6alkylheteroaryl or C1-C6alkylheterocycle as R5 can be possibly additionally substituted with at least one substituent, selected from halogen, oxo, hydroxyl, C1-C6alkyl and -SH; n represents integer number 0 or 1, and p represents integer number 0, 1 or 2 and its stereoisomers. Invention also relates to pharmaceutical or veterinary composition, possessing parasiticidal activity, containing therapeutic amount of formula (I) derivative and pharmaceutically or veterinarily acceptable excipient, diluents or carrier.

EFFECT: azetidine-substituted isoxazoline derivatives of formula (1), intended for manufacturing means for treatment or control of parasitic infection or invasion in animal.

20 cl, 5 tbl, 225 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

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