Derivative of carboxylic acid, pharmaceutical composition and medicine of preventing and/or curing diseases, caused by activation of dp receptor, use of such derivative for making such medicine, method of preventing and/or curing diseases, caused by activation of dp receptors

FIELD: chemistry.

SUBSTANCE: description is given of a derivative of carboxylic acid with general formula , where R1 represents a hydrogen atom, C1-4alkyl, benzyl, E represents C(=O)-, -SO2- or -CH2-;R2 represents a halogen atom, C1-6 alkyl, C1-6 alkoxy, hydroxyl, C1-4 alkyl, substituted -OR8 , R3 represents a halogen atom, C1-6 alkyl, C1-6 alkoxy; R4 represents a hydrogen atom, C1-6alkyl; R5 represents C1-6 alkyl, C1-10 alkoxy, R8 represents C1-4 alkyl, phenyl; represents a benzol ring; G represents (1) C1-6 alkylene; represents dihydrobenzoxazine; m and n represent 0 or an integer from 1 to 4; I represents 0 or an integer from 1 to 8, where, when m is more or equal to 2, R2 is the same or different; when n is more or equal to 2, R3 is the same of different; when i is more or equal to 2, R5 is the same of different, or its pharmaceutical salt. Since the compound with formula (I), is linked to the DP receptor and has antagonistic effect to the DP receptor.

EFFECT: it is useful for preventing and/or curing such diseases as allergic rhinitis, allergic conjunctivitis, bronchial asthma, malt cell disease, migraine, contact dermatitis, stroke, ulcerative colitis, thrombocyte aggregration or sleep disorder.

 

The scope of the invention

The invention relates to carboxylic acid derivative.

More specifically, this invention relates to:

(1) carboxylic acid derivative represented by the formula (I)

(symbols in the formula are set up which will be described below), and its non-toxic salt,

(2) the method of obtaining the specified connection,

(3) a pharmaceutical agent containing the specified connection as the active ingredient.

Background of the invention

Prostaglandin D2(abbreviated PGD2known as one of the metabolites produced in the arachidonic acid cascade, and is considered one of the chemical mediators involved in allergic diseases such as allergic rhinitis, bronchial asthma and allergic conjunctivitis. It is known that PGD2mainly is produced and released from mastocytes and that released PGD2provides bronchial stenosis, stimulation of vascular permeability, expansion and contraction of blood vessels, stimulation of mucus secretion and inhibition of platelet aggregation. It was also reported that PGD2causes bronchostenosis, and nasal obstructionin vivoandabout producing PGD2in higher amounts in pathological since the position of the patient, suffering from systemic mastocytosis, allergic rhinitis, bronchial asthma, atopic dermatitis, urticaria, etc. (N. Engl. J. Med.1989;303: 1400-4,Am. Rev. Respir. Dis.1983;128: 597-602,J. Allergy Clin. Immunol. 1991;88: 33-42,Arch. Otolaryngol. Head Neck Surg. 1987;113: 179-83,J. Allergy Clin. Immunol. 1988;82: 869-77,J. Immunol. 1991;146: 671-6,J. Allergy Clin. Immunol.1989;83: 905-12,N. Eng. J. Med.1986;315: 800-4,Am. Rev. Respir. Dis.1990;142, 126-32,J. Allergy Clin. Immunol. 1991;87: 540-8,J. Allegry Clin. Immunol. 1986;78: 458-61). It was also reported that PGD2involved in nervous activity, in particular of sleep, hormone secretion, and pain. In addition, it was reported that he is involved in platelet aggregation, glycogen metabolism and the regulation of intraocular pressure.

PGD2exerts its biological activity through binding to DP receptor, which is one of the PGD2the receptors. Since DP receptor antagonists bind with its receptor and exhibit antagonistic activity, it is believed that antagonists DP receptor useful for the prophylaxis and/or treatment of diseases such as allergic diseases (e.g. allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and food Allergy), systemic mastocytosis, disorders accompanied by activation system mastocytes, anafile the political shock, bronchostenosis, urticaria, eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch (such as atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis and contact dermatitis), diseases (such as cataract, retinal detachment, inflammation, infection, and sleep disorders), which are generated secondarily as a result of conduct accompanying itching (for example, abrasion and pulsating reduction), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, stroke, autoimmune disease, traumatic brain disorder, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, etc. He is also involved in the sleep process and platelet aggregation and is considered useful for these diseases as well.

For example, in the description of WO 86/05779 indicated that the compounds represented by the formula (T)which are useful as antagonists for SRS-A (slow reacting substance of anaphylaxis):

(in the formula AndTrepresents a hydrogen atom, phenyl or what enocsi; nT is an integer from 3 to 10; R1Trepresents a hydrogen atom or lower alkoxy; X1Trepresents-CH2-Y1T- (where Y1Trepresents-O-, -S - or-NH-), -CO-Y2T- (where Y2Trepresents-O-, -S - or-NH -), etc.;

represents a group represented by the formulaetc.; R2Trepresents a hydrogen atom, halogen atom, nitro, hydroxyl, lower alkoxy, cyano, lower alkyl, lower alkoxy-lower alkyl, halogen-lower alkyl or a group represented by the formula-NR4TR5T- etc.;

X2Tis a group-Y3T-Y4T- (where Y3Trepresents a single bond, -O-, -S - or-NH-, and Y4Trepresents a C1-6alkylene, which may contain a sulfur atom) and so on; and

DTrepresents a carbonyl or lower alkoxycarbonyl etc).

Among prostaglandin receptors have a large number of receptors, including subtypes, and each of them has different pharmacological effects. Thus, the development of new compounds that specifically bind to the DP receptor and weakly communicating with other prostaglandin receptors, may lead to the development of pharmaceuticals with minor side effects is om, since such compounds do not show any other functions. Therefore, there is a need to find such pharmaceuticals.

Description of the invention

The authors of the present invention conducted a serious investigation to find compounds that are specifically associated with DP receptors and exhibit antagonistic activity, and as a result, it was found that derivatives of carboxylic acids represented by the formula (I), solve the task to implement the present invention.

Thus, the present invention relates to:

(1) carboxylic acid derivative represented by the formula (I):

where in the formula, R1represents (1) hydrogen atom, (2)1-4alkyl, (3)2-4alkenyl or (4) benzyl;

E represents-C(=O)-, -SO2- or-CH2-;

R2represents (1) halogen atom, (2)1-6alkyl, (3)1-6alkoxy, (4) hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8) pyridyl, (9) nitro, (10) -NR6R7or (11)1-4alkyl, substituted OR8;

R3represents (1) halogen atom, (2)1-6alkyl, (3)1-6alkoxy, (4) hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8) pyridyl, (9) nitro, (10) -NR6R7or (11)1-4alkyl, substituted OR8;

<> R6and R7each independently represents a hydrogen atom or a C1-4alkyl;

R8represents a C1-4alkyl, phenyl or pyridyl;

R4represents (1) hydrogen atom, (2)1-6alkyl or (3) benzyl;

R5represents (1)1-6alkyl, (2)1-10alkoxy, (3)1-6alkyl, substituted C1-6alkoxy, (4) halogen atom, (5) hydroxyl, (6) trihalomethyl, (7) nitro, (8) -NR9R10, (9) phenyl, (10) phenoxy, (11) oxo, (12)2-6acyl, (13) cyano or (14) -SO2R11;

R9and R10each independently represents a hydrogen atom or a C1-4alkyl,

R11represents a C1-6alkyl;

represents a C5-12monocyclic or bicyclic carbocycle or 5-12-membered monocyclic or bicyclic a heterocycle;

G represents (1)1-6alkylene containing from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, (2)2-6albaniles containing from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, or (3) (C2-6akinyan containing from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom;

represents a C5-12monocyclic or bicyclic shall arbocel or 5-12-membered monocyclic or bicyclic a heterocycle;

m represents 0 or an integer from 1 to 4;

n represents 0 or an integer from 1 to 4; and

i represents 0 or an integer from 1 to 11;

where, when m is 2 or more, R2are the same or different; when n is 2 or more, R3are the same or different; when i is 2 or more, R5are the same or different,

or its pharmaceutically acceptable salt,

(2) the method of production of the specified connection and

(3) a pharmaceutical agent containing the specified connection as the active ingredient.

Detailed description of the invention

In this description, the term "C1-4alkyl" includes linear and branched C1-4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

In this description, the term "C1-6alkyl" includes linear and branched C1-6alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl.

In this description, the term "C1-6alkoxy" includes linear and branched C1-6alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, hexyloxy, etexilate.

In d nom description, the term "C 1-10alkoxy" includes linear and branched C1-10alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, hexyloxy, etexilate, heptyloxy, octyloxy, nonyloxy, decyloxy.

In this description, the term "C2-6acyl" includes linear and branched C1-6acyl, such as ethanol, propanol, butanol, 2-methylpropanol, pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl, hexanoyl, 2-methylpentanol, 3-methylpentanol, 4-methylpentanol, 2-ethylbutanol and 2,3-dimethylbutanol.

In this description, the term "halogen atom" includes fluorine atom, chlorine, bromine and iodine.

In this description, trihalomethyl represents methyl substituted by three halogen atoms.

In this description, the term "C1-4alkylene" includes linear or branched C1-4alkylene, such as methylene, ethylene, propylene, isopropylene, butylene, and isobutylene.

In this description, the term "C2-4albaniles" includes linear or branched C2-4albaniles, such as vinile, propylene, 1 - or 2-butylen and butadiene.

In this description, the term "C2-4akinyan" includes linear or branched C2-4akinyan, such as ethynylene, 1 - or 2-propylen and 1 - or 2-Butyrin.

In this description of t is pmin "C 1-6alkylene containing from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom" includes

linear or branched C1-6alkylene, such as methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentile, hexylen or

linear or branched C1-6alkylene, in which one or two carbon atoms in the methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentylene and hexylene substituted(s) one or two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, such as linear or branched alkylene containing one or two heteroatom(s)selected(x) of nitrogen atom, oxygen atom and sulfur atom, for example, -(CH2)2-NH-, -(CH2)2-N(CH3)-, -(CH2)2-O-, -(CH2)2-S-, -(CH2)3-NH-, -(CH2)3-N(CH3)-, -CH2-CH(CH3)-CH2-NH-, -CH2-CH(CH3)-CH2-N(CH3)-, -(CH2)3-O - (CH2)3-S-,

where alkylene only the carbon atom linked to the adjacent-O-.

In this description, the term "C2-6albaniles containing from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom" includes

linear or branched C2-6albaniles, such as vinile, propylen, 1 - or 2-butylen, butadienyl, penttinen and hexarelin or

<> With2-6albaniles, in which one or two carbon atoms in vinylene, propylene, 1 - or 2-butylene, butadiene, pentylene and hexanite substituted(s) one or two heteroatoms, selected(and) from nitrogen atom, oxygen atom and sulfur atom, such as a linear or branched C2-6albaniles containing one or two heteroatom(s)selected(x) of nitrogen atom, oxygen atom and sulfur atom, for example, -CH=CH-NH-, -CH=CH-N(CH3)-, -CH=CH-O-, -CH=CH-S-, -CH=CH=CH2-NH-, -CH=CH-CH2-NH(CH3)-, -CH=CH-CH2-O - and-CH=CH-CH2-S-,

where alkeneamine only atom of carbon is connected with the adjacent-O-.

In this description, the term "C2-6akinyan containing from 0 to 2 heteroatom selected from nitrogen atom, oxygen atom and sulfur atom" includes

linear or branched C2-6akinyan, such as ethynylene, 1 - or 2-propylen, 1 - or 2-Butylin, pentikinen and geksanalem or

With2-6akinyan, in which one or two carbon atoms in the ethynylene, 1 - or 2-propylene, 1 - or 2-butenolide, pentylidene, hexylamine and hexanite substituted(s) one or two heteroatom(s)selected(s) from nitrogen atom, oxygen atom and sulfur atom, such as a linear or branched C2-6akinyan containing one or two heteroatom(s)selected(x) of nitrogen atom, oxygen atom and sulfur atom, such as- ≡NH-, -C≡N(CH 3)-, -C≡O-, -C≡S-, -C≡CH2-NH-, -C≡CH2-N(CH3)-, -C≡CH2-O - and-C≡CH2-S-,

where alkylamine only the carbon atom linked to the adjacent-O-.

In this description and examples With5-12monocyclic or bicyclic carbocycle include monocyclic or bicyclic5-12carbocyclic aryl or carbocycle, which is partially or fully saturated, such as cyclopentane, cyclohexane, Cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, benzene, pentalene, perhydroanthracene, azulene, pergerson, inden, palikonda, indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene and peritonealis.

In this description, the term "5-to 12-membered monocyclic or bicyclic a heterocycle" include 5-to 12-membered monocyclic or bicyclic heterocyclic aryl containing heteroatom(s)selected(s) from one to four nitrogen atoms, from one to two oxygen atoms and/or one or two sulfur atoms, such as a heterocycle, which is a partially or fully saturated. Examples of such groups are, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, thiopyran, tiepin, isoxazol, thiazole, isothiazol, who Sasin, teasin, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, ditionally, indazole, quinoline, isoquinoline, hinaidi, phthalazine, naphthylidine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, chrome, benzocain, benzoxazepin, benzothiophen, benzodiazepin, benzazepin, benzodiazepine, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydroacetic, tetrahydroazepine, perhydroxyl, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyran, dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrooxazolo, tetrahydrooxazolo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydrothiazine, tetrahedr is teasin, dihydrothiazine, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, dioxolane, dioxane, indolin, isoindoline, dihydrobenzofuran, perhydroanthracene, dihydroisobenzofuran, peligrosamente, dihydrobenzofuran, targetobjecttype, dihydroisobenzofuran, peligrosamente, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, benzocain, dihydroisoxazole, dihydrobenzofuran, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, benzodioxepin, dihydroisoxazole and tetrahydrobenzoic.

In this description, the term "C5-6rich carbocycle" includes such courses as cyclopentane and cyclohexane.

In this description, the term "5-6-membered saturated, a heterocycle, containing from one to the two nitrogen atoms, from one to two oxygen atoms and/or one sulfur atom" includes such heterocycles as pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, targetability, targetability, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydrooxazolo (oxazolidine), tetrahydrocortisol (isoxazolidine), tetrahydrothieno (thiazolidin), tetrahydrocortisol (isothiazolin), tetrahydrooxazolo, tetrahydrothiophene, morpholine, thiomorpholine, Ossetian, dioxolane and dioxane.

In this description, the term "C5-6carbocycle" includes such carbocycle as cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

In this description, the term "5-6-membered heterocycle containing one to two nitrogen atoms, from one to two oxygen atoms and/or one sulfur atom" includes such heterocycles as pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, furan, Piran, thiophene, thiopyran, oxazol, isoxazol, thiazole, isothiazol, oxazin, teasin, pyrrolin, pyrrolidin, imidazolin, imidazolidin, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dihydrofuran, tetr hydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyran, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrooxazolo, tetrahydroxide, dihydrothiazine, tetrahydrothiophene, morpholine, thiomorpholine, Ossetian, dioxolane and dioxane.

Unless specifically stated another condition, all isomers are included in this description. For example, alkyl, alkoxy and alkylene include linear and branched isomers. In addition, all isomers due to the presence of a double bond, ring and condensed ring (E-, Z-, CIS - and TRANS-compounds), isomers due to asymmetric carbon atom, and so on (R-, S-, αand β-compounds, enantiomers and diastereoisomers), optically active compounds with having optical rotation (D-, L-, d - and l-compounds), polar compounds obtained by chromatographic separation (high-polar compound and iskopaemoe connection), equilibrium compounds, rotary isomers and their mixtures in any ratio, as well as racemic mixtures are included in this invention.

If this description specifically States otherwise condition symbolOsnach is that the connection, located on the reverse side of the plane of the paper (i.e. α-configuration), symbolmeans the link located on this side of the plane of the paper (i.e. β-configuration) and the symbolmeans a mixture of αand β-configurations that will be apparent to a person skilled in this field.

The compounds of this invention are transformed into pharmaceutically acceptable salts known methods. As to pharmaceutically acceptable salts, preferred are non-toxic and soluble in water. Examples of suitable salts are the alkali metal salt (such as potassium, sodium and lithium), alkaline earth salt of a metal (such as calcium and magnesium), ammonium salts (such as Tetramethylammonium salt and tetrabutylammonium salt), salt with organic amine (such as triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Tris(hydroxymethyl)methylamine, lysine, arginine and N-methyl-D-glucamine) and an acid additive salt such as a salt of an inorganic acid (e.g. hydrochloride, the hydrobromide, hydroiodide, sulfate, phosphate and nitrate) and salt of organic acid (for example, acetate, triptorelin, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, etancelin is t, bansilalpet, toluensulfonate, isothionate, glucuronate and gluconate)).

Salt of the compounds of the present invention includes a solvate, as well as a solvate with the above salt of the alkali (alkaline earth) metals, ammonium salt, salt with organic amine and an acid additive salt.

MES preferably is non-toxic and soluble in water. Examples of suitable solvate is a solvate with water and an alcohol solvent (such as ethanol).

R1in the formula (I) preferably represents a hydrogen atom, a C1-4alkyl or benzyl and, more preferably, a hydrogen atom or a C1-4alkyl.

R2in the formula (I) preferably represents a halogen atom, a C1-6alkyl, C1-6alkoxy, hydroxyl, trihalomethyl, cyano, phenyl, pyridyl, nitro or NR6R7and, more preferably, a halogen atom, a C1-6alkyl, C1-6alkoxy or hydroxyl.

R3in the formula (I) preferably represents a halogen atom, a C1-6alkyl, C1-6alkoxy, hydroxyl, trihalomethyl or cyano, more preferably, a halogen atom, a C1-6alkyl, C1-6alkoxy or hydroxyl.

R8in the formula (I) preferably represents a C1-4alkyl or phenyl.

R4in the formula (I) preferably represents an atom in which aroda, With1-4alkyl or benzyl, more preferably a hydrogen atom or a C1-4alkyl.

R5in the formula (I) preferably represents a C1-6alkyl, C1-10alkoxy, halogen atom, hydroxyl, trihalomethyl, phenyl or cyano, more preferably, From1-6alkyl, C1-10alkoxy or halogen atom.

Ringin the formula (I) preferably represents a C5-6monocyclic carbocycle or 5-6-membered monocyclic heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or one sulfur atom. In particular, the preferred cyclopentane, cyclohexane, benzene, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, furan, Piran, thiophene, thiopyran, oxazol, isoxazol, thiazole, isothiazol, pyrrolidin, imidazolidine, piperidine or piperazine, the preferred benzene or pyridine. Especially preferred With5-6monocyclic carbocycle, in particular, benzene ring represented by the formula

G in formula (I) preferably represents (1)1-6alkylene containing from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, (2)2-6albaniles or (3) (C2-6akinyan, more preferably, (1) C1-6alkylene containing from 0 to 2 Goethe is of oetomo, selected from nitrogen atom, oxygen atom and sulfur atom, (2)2-4alkynylamino group, or (3) (C2-4akinyan, particularly preferably, (1) C1-4alkylene, (2)2-4albaniles or (3) (C2-4akinyan.

Ringin the formula (I) preferably represents

(in the formularepresents a C5-6rich carbocycle or 5-6-membered saturated, a heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or one sulfur atom; and

represents a C5-6carbocycle or 5-6-membered heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or one sulfur atom).

Ringpreferably represents a 5-6-membered saturated, a heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or one sulfur atom, more preferably 5-6-membered saturated, a heterocycle containing one or two nitrogen atom and/or one or two oxygen atom. For example, preferred are a morpholine, dioxane, Ossetian, tetrahydrofuran, pyrrolidine, tetrahydrooxazolo (oxazolidine) and imidazolidin, and especially preferred are morpholine, tetrahydrofuran and pyrrolidine.

preferably represents C5-6carbocycle or 5-6-membered heterocycle containing one or two nitrogen atom, one or two oxygen atom and, more preferably, From5-6carbocycle or 5-6-membered heterocycle containing one or two nitrogen atom. For example, preferred are cyclopentane, cyclohexane, cyclopentadiene, benzene, pyridine, pyrazin, pyrimidine, pyridazine, oxazin, piperidine and piperazine, more preferred are cyclohexane, benzene, pyridine, pyrazin and pyrimidine, and particularly preferred is a benzene ring.

preferably represents dihydroisoxazole, benzodioxan, benzocain, dihydrobenzofuran or indolin, more preferably dihydroisoxazole, dihydrobenzofuran or indolin, and particularly preferred dihydroisoxazole.

Preferably m is 0, 1 or 2.

Preferably n is 0, 1 or 2.

Preferably i is 0 or is an integer from 1 to 5.

As for the compounds represented by formula (I), a preferable compound is a compound represented by formula (I-a)

(all the symbols in the formula take the values defined above), a compound represented by formula (I-b)

(all the symbols in the formula take the values defined above), or the compound represented by formula (I-c)

(all the symbols in the formula take the values defined above).

Specific compounds of this invention are compounds listed in tables 1-35, compounds described in the examples and their pharmaceutically acceptable salts.

The compounds of this invention specifically associated with DP receptors and little contact with other prostaglandin receptors. In addition, the compounds of this invention are compounds with high solubility. Such properties are important for their development as pharmaceuticals, and believe that the compounds of the present invention satisfy the requirements especially useful pharmaceutical remedies [The Merck Manual of Diagnosis and Therapy(17thEd.), published by Merck&Co.].

The method of obtaining compounds of this invention

The compounds of this invention represented by formula (I)can be obtained, for example, by the method described below.

[1] Among the compounds represented by formula (I), compounds in which R1represents a C1-4alkyl, C2-4alkenyl or benzyl, i.e. compounds represented by formula (IA)

(in the formula, R1Ais the th 1-4alkyl, C2-4alkenyl or benzyl, other characters take the values defined above)can be obtained according to the method described below.

(a) Compound in which E represents a-C(=O)- or-S(O)2in the formula (IA), i.e. the compound of formula (IA-1)

(in the formula EAndrepresents-C(=O)- or-S(O)2,and other characters take the values defined above), can be obtained from compounds of formula (II-1)

(in the formula, R2-1takes on the values defined for R2,and a hydroxyl or amino group, R2-1protected, if necessary; R4-1represents a hydrogen atom; and other symbols take the values defined above) or from compounds of formula (II-2)

(in the formula, R4-2represents a C1-6alkyl or benzyl, and other characters take the values defined above) by amidation reaction with the compound of the formula (III)

(in the formula E1represents-COOH or-SO3H; R3-1and R5-1take the values defined for R3and R5, respectively, and a hydroxyl or amino group, R3-1and R5-1are protected, if necessary; and other symbol is take the values defined above) with the subsequent removal of the protection, if necessary.

The amidation reaction is a known reaction, and examples of the amidation reaction are

(1) the method using gelegenheid acid,

(2) the method using mixed acid anhydride

(3) the method using a condensing agent.

Next will be described in detail these methods.

(1) the Method using gelegenheid acid is, for example, so that the carboxylic acid reacts with a reagent (such as oxacillin and thionyl chloride) in an organic solvent (such as chloroform, dichloromethane, diethyl ether, tetrahydrofuran, dimethoxyethane and toluene) or without solvent at a temperature in the range from -20°C to the boiling temperature to obtain gelegenheid acid, and the resulting gelegenheid acid interacts with the amine in the presence of a base (such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine and diisopropylethylamine) in an inert organic solvent (such as chloroform, dichloromethane, diethyl ether and tetrahydrofuran) at a temperature of from 0 to 40°C. in Addition, interaction with galogenangidridy acid can be carried out at a temperature from 0 to 40°in an organic solvent (such as dioxane, tet is hydrofuran, dichloromethane and toluene) in the presence of a catalyst phase transfer (such as Quaternary ammonium salt, such as tetrabutylammonium chloride, chloride of triethylenediamine, chloride, tri-n-octylacrylamide, chloride of triethyltetramine and bromide of Tetramethylammonium) or without catalyst using an aqueous alkali solution (such as aqueous solution of sodium bicarbonate and an aqueous solution of sodium hydroxide).

(2) the Method using mixed acid anhydride is carried out, for example, so that the carboxylic acid is subjected to interaction with galogenangidridy acid (such as pivaloyloxy, taillored or methylchloride) or acid derivative (such as ethylchloride and isobutylparaben) at a temperature in the range from 0 to 40°in the presence of an organic solvent (such as chloroform, dichloromethane, diethyl ether and tetrahydrofuran) or without a solvent, in the presence of a base (such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine and diisopropylethylamine), and the resulting mixed acid anhydride is subjected to interaction with the amine at a temperature in the range from 0 to 40°in an organic solvent (such as chloroform, dichloromethane, diethyl ether and tetrahydrofuran).

(3) the Method using a condensing agent is carried out, the for example, in such a way that carboxylic acid and amine are interacting at a temperature in the range from 0 to 40°With 1-hydroxybenzotriazole (HOBt) or without using a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide and cyclic anhydride 1-propylphosphonic acid) in the presence of a base (such as pyridine, triethylamine, dimethylaniline and dimethylaminopyridine) or without base, in an organic solvent (such as chloroform, dichloromethane, dimethylformamide, diethyl ether and tetrahydrofuran) or without a solvent.

Preferably, all of the reactions (1), (2) and (3) are carried out in an atmosphere of inert gas (such as argon and nitrogen) in anhydrous conditions.

The reaction of removal of protecting a hydroxyl or amino group is a well known reaction, and examples of such reactions are the following:

(1) hydrolysis with alkali;

(2) the reaction of removing the protective group under acidic conditions;

(3) the reaction of removing the protective group by hydrogenolysis;

(4) the reaction of removing the protective silyl group;

(5) the reaction of removing the protective group using metal; and

(6) the reaction of removing the protective group using ORGANOMETALLIC compounds.

Next will detail the OPI is Ana these methods.

(1) the Reaction of removing the protective group using alkali is carried out, for example, at a temperature in the range from 0 to 40°using a hydroxide of alkaline metal (such as sodium hydroxide, potassium hydroxide and lithium hydroxide), a hydroxide of alkaline earth metal (such as barium hydroxide and calcium hydroxide), a carbonate (such as sodium carbonate and potassium carbonate), an aqueous solution or mixture in an organic solvent (such as methanol, tetrahydrofuran and dioxane).

(2) the Reaction of removing the protective group under acidic conditions is carried out, for example, at a temperature in the range from 0 to 100°in an organic acid (such as acetic acid, triperoxonane acid, methanesulfonate acid and p-toluensulfonate), inorganic acid (hydrochloric acid and sulfuric acid) or mixtures thereof (such as a mixture of Hydrobromic acid/acetic acid) in an organic solvent (such as dichloromethane, chloroform, dioxane, ethyl acetate and anisole).

(3) the Reaction of removing the protective group by hydrogenolysis is carried out, for example, at a temperature in the range from 0 to 200°in hydrogen atmosphere of normal pressure or high pressure or in the presence of ammonium formate and catalyst [such as palladium on carbon, palladium black, palladium hydroxide, platinum hydroxide, oxide PLA the ins and Raney Nickel] in a solvent [such as the solvent of the ether type (for example, tetrahydrofuran, dioxane, dimethoxyethane and diethyl ether), an alcohol type (e.g., methanol and ethanol), a benzene type (for example, benzene and toluene), a ketone type (for example, acetone and methyl ethyl ketone), a nitrile type (for example acetonitrile), an amide type (for example dimethylformamide), water, ethyl acetate, acetic acid or a mixed solvent comprising two or more solvents].

(4) the Reaction of removing the protective silyl group is, for example, at a temperature in the range from 0 to 40°using tetrabutylammonium fluoride in an organic solvent miscible with water (such as tetrahydrofuran and acetonitrile).

(5) the Reaction of removing the protective group using the metal is, for example, at a temperature in the range from 0 to 40°using ultrasound or without him in the presence of powdered zinc in an acidic solvent (such as a buffer of acetic acid with a pH in the range from 4.2 to 7.2, or a mixture of buffer and organic solvent, such as tetrahydrofuran).

(6) the Reaction of removing the protective group using complex metal is, for example, at a temperature in the range from 0 to 40°With out using complex metal such as tetranitropentaerithrite (0), bis(triphenylphosphine)palladium (II) dichloride, palladium (II) acetate and Tr is C(triphenylphosphine)rhodium (I) chloride, in the presence of a phosphine derivative (such as triphenylphosphine), or without it, in the presence of reagent-traps (such as the anti-hydride, triethylsilane, dimedone, morpholine, diethylamine and pyrrolidine), organic acids (such as acetic acid, formic acid and 2-ethylhexanoate acid and/or salts of organic acids (such as 2-ethylhexanoate, sodium 2-ethylhexanoate and potassium) in an organic solvent (such as dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane and ethanol), water or mixtures thereof.

The protective group for hydroxyl include such groups as methyl, trityl, methoxymethyl (IOM), 1-ethoxyethyl (IT), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (TNR), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (AC), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc) and 2,2,2-trichlorocyanuric (Troc).

The protective group for the amino group includes groups such as benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)etoxycarbonyl (Rooted), TRIFLUOROACETYL, 9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl, benzoyloxymethyl (CMV), 2-(trimethylsilyl)ethoxymethyl (SEM), etc.

As for the protective group for hydroxyl and amino groups, specific restrictions for what it is not, in addition, this group should be able to easily and selectively be chipped off. For example, the reaction of removing the protective group can be carried out by the method described in T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999".

A qualified technician can easily understand that the target compound of this invention can be easily obtained using suitable reactions of these reactions the removal of the protective groups.

(b) a Compound of formula (IA)in which E represents-CH2-or, in other words, the compound of formula (IA-2)

(in the formula, all symbols take the values defined above) can be obtained from compounds of formula (II-1) or formula (II-2) and the compounds of formula (IV)

(in the formula, all symbols take the values defined above) by the reaction of reductive amination.

The reaction of reductive amination is a known reaction and can be, for example, at a temperature in the range from 0 to 40°in the presence of a reducing agent (such as triacetoxyborohydride sodium, cyanoborohydride sodium and sodium borohydride) in an organic solvent such as dichloroethane, dichloromethane, dimethylformamide, acetic acid and their mixture).

(C) a Compound of formula (IA) can also be obtained from compounds which ia of the formula (V)

(in the formula, all symbols take the values defined above) and compounds of formula (VI)

(in the formula, Z represents a removable group or a hydrogen atom, and other symbols take the values defined above) by the reaction of esterification.

The esterification reaction is a well known reaction and, in the case of the compounds of formula (VI), where Z is a leaving group, is carried out, for example, at a temperature in the range from 0°C to the boiling temperature in the presence of alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide and lithium hydroxide), a hydroxide of alkaline earth metal (such as barium hydroxide and calcium hydroxide), a carbonate (such as cesium carbonate, sodium carbonate and potassium carbonate), alkali metal hydride (such as sodium hydride and potassium hydride), water the solution or mixture in an organic solvent (such as dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, and methyl tert-butyl ether).

When using a compound of the formula (VI)in which Z represents a hydrogen atom, the reaction is carried out, for example, at a temperature in the range from 0 to 60°in the presence of azo-compounds (such as diethylazodicarboxylate, diisopropylsalicylic the lat, 1,1'-(azodicarbon)piperidine and 1,1'-azobis(N,N-dimethylformamide)and phosphine compounds such as triphenylphosphine, tributylphosphine, triethylphosphine and triphenylphosphine on a polymer basis) in an organic solvent (such as dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene and toluene).

(d) a Compound in which R4is an R4-2or, in other words, the compound of formula (IA-3)

(in the formula, all symbols take the values defined above) can also be obtained from compounds of formula (IA-4)

(all the symbols in the formula take the values defined above) by the reaction of N-alkylation.

The reaction of N-alkylation is a known reaction and may be carried out by the interaction of, for example, at a temperature in the range from 0 to 40°using alkyl(C1-6) halide or benzylchloride in the presence of carbonate (such as cesium carbonate, sodium carbonate and potassium carbonate) in an organic solvent (such as dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether and tetrahydrofuran).

In the case of compounds in which E in the formula (IA-4) represents-SO2-, the reaction can also be carried out, for example, at a temperature in the range from 0 to 60°using the-W 1-6Olkiluoto alcohol or benzyl alcohol in the presence of azo compounds (such as diethylazodicarboxylate, diisopropylperoxydicarbonate, 1,1'-(azodicarbon)piperidine and 1,1'-azobis(N,N-dimethylformamide)and phosphine compounds such as triphenylphosphine, tributylphosphine, triethylphosphine and triphenylphosphine on a polymer basis) in an organic solvent (such as dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene and toluene).

[II] In the case of compounds in which R1in the formula (I) represents a hydrogen atom or, in other words, the compounds of formula (IB)

(in the formula, all symbols take the values defined above), it can also be obtained from compounds of formula (IA) by reaction of removing the protective group carboxyl with the subsequent removal of the protective group of the hydroxyl or amino groups, if necessary.

The reaction removal protection carboxyla is a well-known reaction, examples of which are the following reaction:

(1) Hydrolysis with alkali,

(2) the reaction of removing the protective group under acidic conditions,

(3) the reaction of removing the protective group by hydrogenolysis,

(4) the reaction of removing the protective group using metal.

These methods will be described in detail.

(1) the Reaction remove protection using alkali Prov is out, for example, at a temperature in the range from 0 to 40°using a hydroxide of alkaline metal (such as sodium hydroxide, potassium hydroxide and lithium hydroxide), a hydroxide of alkaline earth metal (such as barium hydroxide and calcium hydroxide), a carbonate (such as sodium carbonate and potassium carbonate), an aqueous solution or mixture in an organic solvent (such as methanol, tetrahydrofuran and dioxane).

(2) the Reaction of removing the protective group under acidic conditions is carried out, for example, at a temperature in the range from 0 to 100°in an organic acid (such as acetic acid, triperoxonane acid, methanesulfonate acid and p-talouselama acid), inorganic acid (hydrochloric acid and sulfuric acid) or mixtures thereof (such as a mixture of Hydrobromic acid/acetic acid) in an organic solvent (such as dichloromethane, chloroform, dioxane, ethyl acetate and anisole).

(3) the Reaction of removing the protective group by hydrogenolysis is carried out, for example, at a temperature in the range from 0 to 200°in hydrogen atmosphere of normal pressure or high pressure or in the presence of ammonium formate in the presence of a catalyst (such as palladium on carbon, palladium black, palladium hydroxide, platinum oxide and Raney Nickel) in a solvent (such as ether solvent type (in the example, tetrahydrofuran, dioxane, dimethoxyethane and diethyl ether), an alcohol type (e.g., methanol and ethanol), a benzene type (for example, benzene and toluene), a ketone type (for example, acetone and methyl ethyl ketone), a nitrile type (for example acetonitrile), an amide type (for example dimethylformamide), water, ethyl acetate, acetic acid or a mixed solvent comprising two or more solvents).

(4) the Reaction of removing the protective group using the metal is, for example, at a temperature in the range from 0 to 40°using ultrasound or without it, in the presence of powdered zinc in an acidic solvent (such as a buffer of acetic acid with a pH in the range from 4.2 to 7.2, or a mixture of buffer and organic solvent, such as tetrahydrofuran).

Qualified it is clear that the target compound of this invention can be easily obtained by using appropriate reactions from the list of reactions for the removal of the protective group.

The reaction of removing the protective group of the hydroxyl or amino group can be carried out using the methods described above.

Compounds represented by formulas (II-1), (II-2), (III), (IV), (V) and (VI)are known compounds and can be easily obtained by known methods.

For example, the compounds of formulas (II-1) and (II-2) can be is Holocene way shown in the following diagram the sequence of reactions produce compounds of formula 1.

On the diagram, X represents a halogen atom, R4-3represents a C1-5alkyl or phenyl, and the other characters take the values defined above.

The diagram above for obtaining compounds of formula 1, compounds of formulas (VII) and (XII)used as starting substances are known compounds and can be easily obtained by the known methods.

In each of the reactions described in this description, the reaction product can be purified standartnym method of purification, such as distillation under normal pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, and recrystallization. Cleaning may be performed after each reaction or after several reactions.

Pharmacological activity of the compounds of this invention

Hereinafter will be described in the experimental examples evaluate the activity of compounds of this invention in relation to DP receptor. Although the methodology for determining the activity described in the literature, for example, in the publication WO 96/23066, the authors of the present invention implemented a number of improvements to determine is whether the activity of the test compounds in relation to DP receptor is simple and accurate. In particular, as shown in the following experimental examples, the determination made using ovary cells Chinese hamster (Chinese hamster ovary CHO)stably expressing the DP receptor human.

(i) Ligand binding using cells expressing prostanoid DP receptor

Cultured cells of Chinese hamster ovary (Cho)expressing the DP receptor, and in accordance with the usual method, prepare a membrane fraction.

Membrane fraction (50 μl) (protein content: 40 to 150 mcg), 100 ál of the experimental buffer (25 mmol/l HEPES-NaOH containing 1 mmol/l EDTA, 5 mmol/l of Mg2+and 10 mmol/l Mn2+; pH 7.4), 1 μl of vehicle (dimethyl sulfoxide: DMSO) or compounds of the present invention (the final concentration of DMSO: 0.5%) and 50 μl of [3H]-PGD2c concentration of 10 nmol/l (final concentration: 2.5 nmol/l) is added to a polyethylene tube, and received the incubation mixture is incubated at room temperature. Instead of the media in nonspecific binding group is added 2 mmol/l PGD2(the final concentration of PGD2: 10 umol/l). Twenty minutes to complete the reaction in a test tube add 1 ml ice wash buffer (10 mmol/l Tris-HCl buffer containing 0.01% bovine serum albumin (BSA) and 100 mmol/l NaCl; pH 7.4). Immediately after this memb annoy fraction collected on a glass fiber filter (GF/B) by filtration under reduced pressure. Membrane fraction on the glass fiber filter was washed once with approximately 2 ml of washing buffer and the glass fiber filter is dried. The dried glass fiber filter is placed in a glass vessel, there also add liquid scintillation cocktail for counting, and using a scintillation counter to measure radioactivity.

Specific binding of [3H]-PGD2c PD receptor is calculated by subtracting the radioactivity in nonspecific binding group and the radioactivity in groups other than non-specific binding group. The inhibition produced by the connection of the present invention, calculated on the basis of specific binding of [3H]-PGD2in the media and in the groups of the present invention. The value of Ki(dissociation constants of the compounds of this invention) is calculated in accordance with the following formula, using the obtained value of the IC50(the concentration of the compounds of this invention required for inhibition of specific binding in the group of media at 50%).

Ki= IC50/(1+([L]*/Kd))

[L]*: Concentration of [3H]-PGD2(2.5 nmol/l)

Kd: The dissociation constant of [3H]-PGD2.

The value of Kd[3H]-PGD2determine by the method of nonlinear regression analysis after calculating the special is practical bind [ 3H]-PGD2after addition of [3H]-PGD2at various concentrations in accordance with the method described above.

From the measurement results described above, it was found that the compounds of this invention are strongly linked with DP receptor when the values of Kinot exceeding 10 µmol/L.

(ii) Quantitative determination of antagonistic activity against DP receptor using cells expressing prostanoid DP receptor

Create Cho cells, stably expressing the DP receptor human, plated on 24-hole culture plate at a density of cells 1x105cells/well and incubated at 37°C for 2 days in 5% CO2. Each well was washed with 500 μl of MEM (minimum essential medium)and the cells incubated at 37°within 10 minutes after adding 500 μl of MEM containing 2 mmol/l of diclofenac. After removal of the supernatant by aspiration add 450 μl of MEM containing 1 mmol/l 3-isobutyl-1-of methylxanthines, 2 µmol/l diclofenac and 1% BSA (experienced medium), and the mixture was incubated at 37°C for 10 minutes. The reaction is initiated by adding 50 ál of the experimental environment containing PGD2and media, or power environment containing PGD2and the compound of the present invention, (final concentration PGD2: 10 nmol/l), followed by incubation at 37°the. After 10 minutes to complete the reaction, add 500 ál of ice trichloroacetic acid (TCA, 10% wt./vol.). After freezing (-80° (C) and thawing of the reaction mixture, the cells are separated using a cell scraper and subsequent centrifugation speed 13000 rpm for 3 minutes. The obtained supernatant is collected and the concentration of camp in the supernatant determined by radioimmunoassay analysis using the analytical camp set (camp assay kit,production Amersham). Thus, the buffer of [125I]camp analytic set is added to 125 μl aliquot of the supernatant obtained as described above, to obtain the total volume of 500 μl, and the resulting solution is mixed with 1 ml of 0.5 mol/l tri-n-octylamine in chloroform. After extraction with TCA in the chloroform layer, the amount of camp in the water layer is calculated in accordance with the methods listed in the analytical set of [125I]cAMP.

The value of the antagonistic activity of the compounds of this invention in relation to DP receptor is expressed as the values of the IC50(the concentration of the compounds of this invention required to inhibit the production of camp observed in the absence of the compounds of this invention, 50%). The value of the IC50calculate the value of inhibiting the production of camp, expressed in percent, shall receive the frame with 10 nmol/l PGD 2where PGD2shows submaximal production of camp.

Based on the results of the measurements found that the compounds of this invention exhibit a great deal of antagonism in relation to DP receptor, when values of the IC50not exceeding 10 µmol/L.

[Toxicity]

The toxicity of the compounds of this invention represented by formula (I)is sufficiently low and, as it was confirmed that the connection is secure enough to use as pharmaceuticals.

Industrial applicability

[Use as pharmaceuticals]

Since the compounds of this invention of formula (I) contact DP receptors and exhibit antagonistic activity, it is believed that they are useful for prevention and/or treatment of diseases such as allergic disease (such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and food Allergy), systemic mastocytosis, disorders accompanied by activation system mastocytes, anaphylactic shock, bronchostenosis, urticaria, eczema, pimples, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases, soprovozhdayas the itching (for example, atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis and contact dermatitis), diseases (such as cataract, retinal detachment, inflammation, infection, and sleep disorders), which are generated secondarily as a result of conduct accompanying itching (for example, abrasion and pulsating reduction), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, stroke, autoimmune disease, traumatic brain disorder, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis and irritable bowel syndrome. They are also involved in the sleep process and platelet aggregation, and are considered useful for these diseases.

Among the compounds of this invention of formula (I) compounds that are weakly associated with compounds other than DP receptors do not show other activity, such compounds can be used as pharmaceutical drugs with little side effects.

The compound of this invention represented by formula (I)may be administered as a combined preparation by combining with other medications order

(1) complement and/or enhance prevention is nd and/or therapeutic activity of a compound,

(2) improvement of pharmacokinetics and absorption and reduce the dose of connections

and/or

(3) reduction of side-effect connection.

Combined preparation of the compounds of this invention represented by formula (I), with other pharmaceuticals may be in the form of a composite pharmaceutical agents, in which both components are introduced in the preparation, or may be entered in the form when the components are entered as separate drugs. Separate introduction in the form of individual drugs involves the simultaneous introduction and introduction at different times. In the case of the introduction at different times of the compound of this invention represented by formula (I)may be administered first followed by the introduction of other pharmaceutical agents or other pharmaceutical agent may be administered first followed by the introduction of the compounds of this invention represented by formula (I). How each injection may be the same or different.

There are no specific limitations to diseases, which shows a prophylactic and/or therapeutic effect of the above combined drug, if it is a disease in which the preventive and/or therapeutic effect of the compounds of this invention of formula (I) is complemented and/or enhanced.

Another pharmaceutical is redtwo to complement and/or enhance the preventive and/or therapeutic action of the compounds of this invention of formula (I) for allergic rhinitis include antihistamines means, suppressor of release of mediators, a thromboxane synthetase inhibitor, antagonist thromboxane A2 receptor antagonist of leukotriene receptor, steroid, stimulant α-adrenaline receptor xantinove derivative, an anticholinergic agent and suppressor synthase nitric monoxide.

Another pharmaceutical agent to complement and/or enhance the preventive and/or therapeutic action of the compounds of this invention of formula (I) for allergic conjunctivitis includes antagonist of leukotriene receptor, antihistaminic agent, suppressor of release of mediators, non-steroidal anti-inflammatory agent, prostaglandins, steroid and synthase inhibitor of nitric monoxide.

Antihistaminic agent include pharmaceutical agents, as ketotifenum, mequitazine, azelastine hydrochloride, oxatomide, terfenadine, emedastine, epinastine hydrochloride, astemizole, Bastin, cetrizine hydrochloride, bepotastine, Fexofenadine, loratadine, desloratadine, olopatadine hydrochloride, 427, ZCR-2060, NIP-530, mometazon furoate, mizolastine, BP-294, andrast, auranofin, acrivastine.

Suppressor of release of mediators include pharmaceutical agents, as tranilast, cromoglicate sodium, amlexanox, reprint, ibudilast, casinolist and pemirolast potassium.

Examples of PMPs who quarrel enzymes for the synthesis of thromboxane are ozagrel hydrochloride and imfortant sodium.

Antanovich thromboxanes And2receptor include pharmaceutical agents, as seratrodast, ramatroban, Dimitrova calcium hydrate and KT-2-962.

Antagonist leucotrienos receptor include farmatsevticheskii means as pranlukast hydrate, montelukast, zafirlukast, MCC-847, KCA-757, CS-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284 and ONO-4057.

Steroid agent for external use include pharmaceutical agents, as clobetasol propionate, diflorasone acetate, fluocinonide, mometasone furancarboxylic, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, budesonide, valerate, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, depradine propionate, prednisolone valerate, propionate, fluoqinolona acetonide, beclomethasone propionate, triamcinolone acetonide, flumetazon pivalate, alklometazon propionate, clobetasol valerate, prednisolone, beclomethasone propionate and fludroxycortide.

Pharmaceutical agent for oral administration and for injection includes tools such as cortisone acetate, hydrocortisone, hydrocortisone nutrifaster, hydrocortisone, nutrisource is at, fludrocortisone acetate, prednisolone, prednisolone accept, prednisolone nutriceutical, butyl acetate prednisolone, prednisolone nutrifaster, halopedia acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone nutriceutical, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone nutrifaster, dexamethasone palmitate, paramethasone acetate and betamethasone.

Means for inhalation include pharmaceutical agents, such as beclomethasone propionate, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasone palamecia, mometasone frankenbot, prasterone sulfonate, deflazacort, methylprednisolone, sulatan and methylprednisolone nutriceutical.

Xantinove derived include pharmaceutically funds, as aminophylline, theophylline, doxofylline, cipamfylline, diprophylline.

Anticholinergic agent include pharmaceutical agents, as ipratropium bromide, oxitropium bromide, flutropium bromide, cimetropium bromide, temiverine, Tiotropium bromide and revatropate (UK-112166).

Non-steroidal anti-inflammatory agent include pharmaceutical agents, as aspirin, sodium salicylate, aspirin, aspirin-dealuminated mixture, diflunisal, indomitus is h, suprofen, openmath, dimethylethanolamine, bufexamac, felbinac, diclofenac, Tomatin sodium, clinoril, fenbufen, nabumeton, proglumetacin, indometacin farnesyl, acemetacin, proglumetacin maleate, amfenac sodium, movetalk, etodolac, ibuprofen, ibuprofen of Picanol, naproxen, flurbiprofen, flurbiprofen aksetil, Ketoprofen, fenoprofen calcium, cuprofen, oxaprozin, pranoprofen, loxoprofen sodium, alminoprofen, zaltoprofen, marennikova acid, aluminum mefenamic, taftalenovaya acid, floctafenine, ketovinylation, oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, ointment Mapagana (Napageln), epirizole, tiaramide hydrochloride, tinoridine hydrochloride, emorfazone, sulpirid, Amigrenin, Caledon, Sedes G, Amipylo-N, Solbon tool from a cold pirazolonovogo type, acetaminophen, phenacetin, dimethocaine mesilate, a drug based on simetrica and remedy against common cold separationof type.

Prostaglandins (hereinafter referred to as PG) include pharmaceutical agents, as agonist PG receptor and antagonist PG receptor.

PG receptor include receptors, as PGE receptors (ER, AR, ER and ER), PGD receptor (DP and CRTH2), PGF receptor (FP), PGI receptor (IP) and TX receptor (TP).

There is no special limit of the mass ratio of the compounds of formula (I) and other pharmaceuticals.

That cases others pharmaceuticals, any two or more pharmaceutical agents may be combined in the product and entered.

As for other pharmaceutical products that complement and/or enhance the preventive and/or therapeutic effect of the compounds of formula (I)include not only already developed at present, pharmaceutical agents, but also those that will be developed in the future with the above-described mechanism of action.

When the above purpose, the compound of formula (I) of this invention or its non-toxic salt or combined preparation of compounds of formula (I) with another pharmaceutical agent, it (he) is normally administered systemically or locally in oral or parenteral form.

Although the dose varies depending on age, body weight, symptom, therapeutic effect, the route of administration, the treatment time and the like, the connection usually is administered orally in an amount of from 1 mg to 1000 mg per one introduction to the adult from one to several times a day; parenteral (preferably as a nasal remedies, eye drops or ointments) in an amount of from 1 mg to 100 mg per one introduction to the adult from one to several times per day; or intravenously for 1 to 24 hours per day in a continuous manner.

Of course, in different conditions, the dose is changed as described above, and according to the respectively, in some cases, sufficient can be a smaller dose than described above, while in some other cases it may be necessary dose superior to that of the above-described interval.

With the introduction of the compounds of formula (I) or its non-toxic salts or the combined preparation of the compounds of formula (I) with another pharmaceutical agent, it is used in the form of solid compositions, liquid compositions or other compositions for oral administration, or injections, medicines for external use, suppositories etc. for parenteral administration.

Solid composition for oral administration includes such compositions such as tablets, pills, capsules, powders with filler and granules.

Capsules include hard capsules and soft capsules.

In such solid compositions one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and metasilicates magnesium. The composition may contain an additive which is not a standard inert diluent, such as lubricants, for example magnesium stearate, disintegrity agent, such as glycolate, calcium cellulose, a stabilizer such as lactose, and solubilizers agent, for example, glutam the new acid and aspartic acid. Tablet or pill can, if necessary, covered with a film of soluble substances inside the stomach or inside of the small intestine, such as sugar, gelatin, hydroxypropylcellulose and phthalate of hydroxypropylmethylcellulose, or can be covered by two or more layers of coating. Such compositions also include a capsule capable of absorbed substances, such as gelatin.

Liquid composition for oral administration includes such compositions as pharmaceutically acceptable emulsion/suspension, solution, syrup and elixir. In such liquid compositions, one or more active compounds introduced(s) generally used inert diluent (such as clean water and ethanol). In addition to the inert diluent, the composition may contain an adjuvant such as a humidifier or suspendisse agent, sweetener, flavoring agent, an aromatic agent and antiseptic agent.

Another composition for oral administration includes a means for sputtering, which contains one or more active compounds and are produced in a known manner. In addition to the inert diluent, the composition may contain a stabilizer, such as hydrosulfite sodium, and buffer to give isotonicity such as isotherwise tool (for example, sodium chloride, sodium citrate and citric acid). The way production is odstv means for spraying are described in detail, for example, in U.S. patent No. 2868691 and No. 3095355.

Parenteral injection according to this invention include aseptic aqueous and/or nonaqueous solution, suspension and emulsion. Aqueous solution and the aqueous suspension includes components such as distilled water for injection and physiological saline. Non-aqueous solution or non-aqueous suspension includes components such as propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohol such as ethanol, and Polysorbate 80 (registered trade mark). You can also mix and aseptic aqueous or non-aqueous solution, suspension and emulsion, and the use of the drug received. Such a composition may further contain adjuvants, such as an antiseptic, moisturizer, emulsifier, dispersing agent, a stabilizer (such as lactose) and solubilizers agent (such as glutamic acid and aspartic acid). They are sterilized, for example, by filtration through a bacterial filter, mixed with a disinfectant or irradiation. They can also be used in a manner that is aseptic solid composition and before use, for example, in the form of a lyophilized product they are dissolved in sterilized or aseptic distilled water for injection or other rest is ritesh.

The form of the introduction of eye drops for parenteral administration include eye drops, eye drops, suspension-type eye drops emulsion type, eye drops that dissolve in the process of applying, and eye ointment.

These eye drops can be produced in accordance with the known method. For example, in the case of eye drops isotonic vehicle such as sodium chloride and concentrated glycerin), a buffer (such as sodium phosphate and sodium acetate), a surfactant (such as Polysorbate 80 (trade name), polyxystra 40 and polyoxyethylenesorbitan castor oil), a stabilizer (such as sodium citrate and edetate sodium), an antiseptic (such as benzalkonium chloride and paraben), etc. are selected and prepared as necessary. They are sterilized in the final stage or prepared by aseptic operations.

Inhalation means for injecting includes aerosol drug powder for inhalation and liquid for inhalation. Liquid for inhalation may be so shaped that when applied directly ingredient is dissolved or suspendered in water or other suitable medium.

Such inhalation receive funds in accordance with the known method.

For example, in the case of inhalation liquid with which estva antiseptic agent (such as benzalkonium chloride and paraben), dye, a buffer (such as sodium phosphate and sodium acetate), an isotonic vehicle such as sodium chloride and concentrated glycerin), thickener (such as carboxyvinyl polymer), an absorption promoter, etc. are selected and prepared as necessary.

In the case of powder for inhalation lubricant such as stearic acid and its salt), binders (such as starch and dextrin), excipient (such as lactose and cellulose), a coloring agent, an antiseptic (such as benzalkonium chloride and paraben), absorption promoter, etc. are selected and prepared as necessary.

With the introduction of liquid for inhalation are typically used dispersal devices (such as the atomizer and the atomizer), while with the introduction of powder for inhalation is commonly used device for the inhalation of powdered pharmaceuticals.

Other compositions for parenteral administration include one or more active substances and the solution is for external use, ointments, liniments, suppositories for rectal administration, pessary for intravaginal administration and the like, which are prepared in the usual way.

The best way of carrying out the invention

The following reference examples and examples illustrate the invention but do not restrict it.

In all SC is bkah the above solvents, used for synthesis or for elution, and the ratio of solvents used in the chromatographic separations or TLC, is based on volume. In the NMR data in parentheses are the solvents used to obtain the NMR spectrum.

Reference example 1: N-formyl-2-ftoranila

In an argon atmosphere at 0°With acetic anhydride (15,5 ml) was added dropwise formic acid (6,1 ml). The mixture was stirred at 50°C for 2 hours. After cooling the reaction mixture to room temperature it was diluted with tetrahydrofuran (THF; 10 ml). To the diluted solution was added 2-ftoranila (5,56 g) in THF (20 ml) at room temperature, after which the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, obtaining mentioned in the title compound, physical data which is presented below. Received specified in the header of the connection used in the next reaction without further purification.

TLC: Rf0,70 (hexane: ethyl acetate = 2:1).

Reference example 2: N-methyl-2-ftoranila

To a solution of the compound obtained in reference example 1, in anhydrous THF (25 ml) was added borane-tertrahydrofuran ring complex (1M THF solution; 125 ml) in an argon atmosphere, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to room for the Noah temperature. To the reaction mixture is added methanol (30 ml) and 4 n solution of hydrogen chloride in dioxane (10 ml) under cooling in an ice bath, and the mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated, added 2n aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate. The solution is filtered through Celite (trade mark)and the filtrate concentrated. To the residue is added a mixed solvent (hexane:ethyl acetate = 10:1) and the resulting solution was filtered through silica gel. The filtrate is concentrated and receiving specified in the header connection (6,45 g), the physical data which is presented below.

TLC: Rf 0,85 (hexane:ethyl acetate = 5:1);

NMR (CDCl3): δ 7,00-6,91 (m, 2H), 6,80-6,55 (m, 2H), 3,90 (users, 1H), 2,82 (s, 3H).

Reference example 3: (2S)-3-(N-(2-forfinal)-N-methylamino)-1,2-propandiol

A mixture of the compound obtained in reference example 2 (1.24 g), (R)-(+)-glycidol (1,11 g, Aldrich, 98%) and ethanol (1 ml) was stirred at 50°C for 12 hours in an argon atmosphere. The reaction mixture was concentrated, obtaining mentioned in the title compound, physical data which is presented below. The compound obtained is used in the next reaction without further purification.

TLC: Rf of 0.40 (hexane:ethyl acetate = 1:1).

A DSS is adjustment example 4: (2S)-2-hydroxymethyl-4-methyl-3,4-dihydro-2H-1,4-benzoxazin

To a solution of the compound obtained in reference example 3, in anhydrous dimethylformamide (DMF; 10 ml) is added tert-piperonyl potassium (1.68 g) in aqueous solution, the mixture was stirred at 80°C for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated. The residue is purified column chromatography on silica gel (hexane: ethyl acetate = 3:1), obtaining mentioned in the title compound (1.55 g, which is 97.6%), physical data which is presented below.

TLC: Rf of 0.35 (hexane:ethyl acetate = 2:1);

NMR (CDCl3): δ of 7.90-6,79 (m, 2H), 6,70-6,60 (m, 2H), 4,33 (m, 1H), 3,82 (DD, J=13,0, 4,2 Hz, 1H), 3,79 (DD, J=13,0, 4,2 Hz, 1H), 3,19 (DD, J=10,2, 2.1 Hz, 1H), 3,17 (DD, J=11,4, a 5.4 Hz, 1H), 2,86 (s, 3H).

Optical purity specified in the header connections that determine high performance liquid chromatography (HPLC).

Column: CHIRALCEL OD (Daicel Chemical Industries Ltd.), 0,46 cmφ x 25 cm

Flow rate: 1 ml/min

Solvent: hexane: 2-propanol = 93:7,

The wavelength of detection: 254 nm,

Retention time: 30,70 minutes

Temperature: 24°C.

Reference example 5: (2S)-2-methyloxime-4-methyl-3,4-dihydro-2H-1,4-benzoxazin

To a solution of the compound obtained in reference example 4 (20 g)in toluene (80 ml) was added triethylamine (23 ml). See the camping cooled to 5° C. To the mixture are added dropwise methanesulfonanilide (9,5 ml) and the resulting mixture was stirred at 5°C for 30 minutes. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer is washed successively with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solution is filtered through Celite (trade mark). The filtrate is concentrated and receiving specified in the header of the connection, the physical data of which are presented below. The connection used in the next reaction without further purification.

TLC: Rf of 0.55 (hexane:ethyl acetate - 1:1);

NMR (CDCl3): δ to 6.88 (m, 1H), for 6.81 (DD, J=8,4, 1.5 Hz, 1H), 6.75 in-6,65 (m, 2H), 4,54 (m, 1H), and 4.40 (d, J=5.4 Hz, 2H), 3.27 to (DD, J=11,7, 2.7 Hz, 1H), 3,17 (DD, J=11,7, 6.3 Hz, 1H), of 3.07 (s, 3H), 2,88 (s, 3H).

Reference example 6: methyl ester of 4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoic acid

To a solution of the compound obtained in reference example 5, and the methyl ester of 4-hydroxybenzoic acid (23,2 g) in DMF (200 ml) is added potassium carbonate (38,3 g) at room temperature and the resulting mixture was stirred at 80°C for 15 hours. The reaction mixture was poured into water and then extracted with a mixed solvent (ethyl acetate: hexane = 1:2). The organic layer is washed successively 1 N. aqueous sodium hydroxide solution, water and saturated in the s ' solution of sodium chloride and dried over anhydrous sodium sulfate. The solution is filtered through Celite (trade mark). The filtrate is concentrated and receiving specified in the header of the connection, the physical data of which are presented below. The connection used in the next reaction without further purification.

TLC: Rf and 0.62 (hexane: ethyl acetate = 2:1);

NMR (CDCl3): δ to 7.99 (d, J=9.0 Hz, 2H), of 6.96 (d, J=9.0 Hz, 2H), 6,94-6,79 (m, 2H), 6,70 (d, J=7.5 Hz, 1H), of 6.68 (t, J=7.5 Hz, 1H)and 4.65 (m, 1H), 4,27 (DD, J=9,9, 4.8 Hz, 1H), 4,17 (DD, J=9,9, and 6.6 Hz, 1H), 3,89 (s, 3H), 3,39 (DD, J=11,7, 2.7 Hz, 1H), 3,25 (DD, J=11,7, and 6.6 Hz, 1H), 2,90 (s, 3H).

Reference example 7: 4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoic acid

The compound obtained in reference example 6, is dissolved in methanol (150 ml) and THF (150 ml). To the solution add 5 N. aqueous sodium hydroxide solution (100 ml) at room temperature, and the mixture is stirred at room temperature for 15 hours. The reaction mixture was poured into water and washed with a mixed solvent (ethyl acetate: hexane = 1:2). The aqueous layer was acidified by adding 2 N. hydrochloric acid (260 ml) and the resulting crystalline material is collected by filtration. The filtered substance was washed with water, dried under reduced pressure for 2 days, getting mentioned in the title compound (39 g), the physical data which is presented below.

TLC: Rf of 0.13 (hexane: ethyl acetate = 2:1).

Reference example 8: 4-((2S)-4-methyl-3,4-dihydro-2H-1,4-b is isoxazine-2-ylethoxy)benzoyl chloride

In an argon atmosphere to a solution of the compound obtained in reference example 7 (5 g), dimethoxyethane (21 ml) add oxalicacid (2,75 ml)and the resulting mixture was stirred at 40°C for 1 hour. The reaction mixture was concentrated, obtaining mentioned in the title compound (4.7 g), the physical data which is presented below.

NMR (CDCl3): δ to 8.12 (d, J=8.7 Hz, 2H), 7,50 (DD, J=8,1, 1.5 Hz, 1H), 7,35 (dt, J=1.5 and 8.1 Hz, 1H), 7,16-to 6.95 (m, 4H), 5,07-4,96 (m, 1H), to 4.52-and 4.40 (m, 2H), a 3.87 (DD, J=12,9, and 2.1 Hz, 1H), 3,68 (DD, J=12,9, and 10.5 Hz, 1H), 3,29 (s, 3H).

Reference example 9. methyl ester of 3-aminophenylacetic acid

Methanol (20 ml) cooled to -10°C in argon atmosphere. The solvent is added dropwise thionyl chloride (or 4.31 ml) and a solution of 3-aminophenylacetic acid (3.00 g) in methanol (25 ml)and the resulting mixture is stirred at a temperature in the range -10 to 0°C for 1 hour. To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated. The residue is purified column chromatography on silica gel (ethyl acetate:hexane = 1:1), obtaining specified in the header connection (3,90 g), the physical data which is presented below.

TLC: Rf of 0.43 (hexane:ethyl acetate = 1:1);

NMR (CDCl3): δ 7,1 (t, J=7.8 Hz, 1H), 6,69-to 6.57 (m, 3H), of 3.69 (s, 3H), 3,53 (s, 2H).

Example 1: methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)phenylacetic acid

In an argon atmosphere to a solution of the compound obtained in reference example 9 (165 mg)in methylene chloride (2 ml) is added pyridine (161 μl). To the mixture is added dropwise a solution of the compound obtained in reference example 8 (350 mg)in methylene chloride (2.5 ml) under ice cooling, and the mixture was stirred at 0°C for 15 minutes. To the mixture is added methanol and water. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated, obtaining mentioned in the title compound (447 mg), physical data which is presented below.

TLC: Rf of 0.23 (hexane:ethyl acetate =2:1).

Example 1(1) ˜ 1(15)

The following compounds produced by the method described in example 1, using the corresponding amine instead of the compound obtained in reference example 9.

Example 1 (1): methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-chlorophenylalanine acid

TLC: Rf of 0.27 (ethyl acetate: hexane = 3:7);

NMR (CDCl3): δ 8,51 (s, 1H), at 8.36 (s, 1H), 7,88 (d, J=6,9 Hz, 2H), 7,37 (d, J=8,1 Hz, 1H), 7,10-6,98 (m, 3H), 6,94-to 6.80 (m, 2H), ,78-6,66 (m, 2H), 4,73-4,63 (m, 1H), 4,30 (DD, J=of 9.6, 4.8 Hz, 1H), 4,21 (DD, J=a 9.6, 6.3 Hz, 1H), 3,71 (s, 3H), 3,66 (s, 2H), 3,40 (DD, J=12,0, 3.0 Hz, 1H), 3.27 to (DD, J=12,0, 6,6 Hz, 1H), 2.91 in (s, 3H).

Example 1(2): methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methylphenylacetic acid

TLC: Rf of 0.15 (ethyl acetate: hexane = 3:7);

NMR (CDCl3): δ 7,86 (d, J=8.7 Hz, 2H), 7,72 (d, J=8,4 Hz, 1H), to 7.59 (s, 1H), 7,22 (t, J=7.8 Hz, 1H), 7,10 (d, J=7.8 Hz, 1H), 7,06-of 6.96 (m, 2H), 6,93-for 6.81 (m, 2H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=9,9, 4.8 Hz, 1H), 4,19 (DD, J=a 9.9, 6.3 Hz, 1H), 3,71 (s, 2H), 3,70 (s, 3H), 3,40 (DD, J=11,4, 2.7 Hz, 1H), 3.27 to (DD, J=11,4, and 6.6 Hz, 1H), 2,92 (s, 3H), and 2.26 (s, 3H).

Example 1(3): methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-methylphenylacetic acid

TLC: Rf to 0.17 (ethyl acetate: hexane = 3:7);

NMR (CDCl3): δ 7,89 (users, 1H), a 7.85 (d, J=8.7 Hz, 2H), 7,58 (s, 1H), 7,19 (d, J=7.8 Hz, 1H), 7,07-of 6.96 (m, 3H), 6,92-to 6.80 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=of 9.6, 4.8 Hz, 1H), 4,19 (DD, J=of 9.6, 6.3 Hz, 1H), 3,69 (s, 3H), of 3.64 (s, 2H), 3,40 (DD, J=11,7, 3.0 Hz, 1H), 3.27 to (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H), 2,31 (s, 3H).

Example 1(4): methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-methylphenylacetic acid

TLC: Rf 0,68 (ethyl acetate: hexane = 1:1);

NMR (CDCl3): δ 7,83 (d, J=8.7 Hz, 2H), 7,69 (s, 1H), 7,44 (s, 1H), 7,33 (s, 1H), 7,06-6,94 (m, 2H), 6,92-to 6.80 (m, 3H), 6,75 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4,29 (DD, J=9,0, 4,2 Hz, 1H), 4,18 (DD, J =9,0, 6,6 Hz, 1H), 3,70 (s, 3H), 3,62 (s, 2H), 3,40 (DD, J=12,0, 2.7 Hz, 1H), 3.27 to (DD, J=12,0, 6.3 Hz, 1H), 2.91 in (s, 3H), of 2.35 (s, 3H).

<> Example 1(5): methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-chlorophenylalanine acid

TLC: Rf of 0.29 (ethyl acetate: toluene = 1:9);

NMR (CDCl3): δ and 8.50 (DD, J=8,7, 1.8 Hz, 1H), 8,42 (s, 1H), 7,89 (d, J=9.0 Hz, 2H), 7,31 (t, J=8,1 Hz, 1H), 7,10-7,00 (m, 3H), 6,92-for 6.81 (m, 2H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=9,9, 4.8 Hz, 1H), 4,20 (DD, J=a 9.9, 6.3 Hz, 1H), 3,82 (s, 2H), and 3.72 (s, 3H), 3,40 (DD, J=11,4, 2.7 Hz, 1H), 3.27 to (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 1(6): methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-hydroxyphenylarsonic acid

TLC: Rf of 0.56 (ethyl acetate: hexane = 1:1);

NMR (CDCl3): δ with 8.05 (s, 1H), 7,88 (d, J=8.7 Hz, 2H), 7,13 (d, J=1.8 Hz, 1H), 7,08-7,00 (m, 4H), of 6.96-to 6.80 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=of 9.6, 4.8 Hz, 1H), 4,20 (DD, J=a 9.6, 6.3 Hz, 1H), 3,70 (s, 3H), of 3.56 (s, 2H), 3,40 (DD, J=11,7, 2.7 Hz, 1H), 3.27 to (DD, J=11,7, 6.3 Hz, 1H), 2,92 (s, 3H).

Example 1(7): methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-methoxyphenylacetic acid

TLC: Rf of 0.55 (ethyl acetate: hexane =1:1);

NMR (CDCl3): δ 8,50-8,42 (m, 2H), 7,86 (d, J=8.7 Hz, 2H), 7,06-of 6.96 (m, 3H), 6,92-for 6.81 (m, 3H), 6,76 of 6.68 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=9,9, a 5.4 Hz, 1H), 4,19 (DD, J=a 9.9, 6.3 Hz, 1H), 3,92 (s, 3H), 3,70 (s, 3H), 3,63 (s, 2H), 3,40 (DD, J=11,4, 2.7 Hz, 1H), 3.27 to (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 1(8): methyl ester 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-chlorophenylalanine acid

TLC: Rf 0,61 (ethyl acetate: hexane = 1:1);

NMR (CCl 3): δ 7,83 (d, J=9.0 Hz, 2H), of 7.75 (s, 1H), 7.62mm (d, J=2.7 Hz, 1H), 7,54 (DD, J=9,0, 2.4 Hz, 1H), 7,37 (d, J=9.0 Hz, 1H), 7,02 (d, J=9.0 Hz, 2H), 6,93-to 6.80 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), the 4.29 (dd, J=9,9, 5,1 Hz, 1H), 4,19 (DD, J=a 9.9, 6.3 Hz, 1H), 3,79 (s, 2H), of 3.73 (s, 3H), 3,40 (DD, J=11,7, 6.3 Hz, 1H), 3.27 to (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 1(9): methyl ester 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methoxy-3-methylphenylacetic acid

TLC: Rf of 0.50 (ethyl acetate: hexane =1:1);

NMR (CDCl3): δ of 7.82 (d, J=8.7 Hz, 2H), 7,65 (s, 1H), 7,45 (d, J=2.7 Hz, 1H), 7,30 (d, J=2.7 Hz, 1H), 7,01 (d, J=9.0 Hz, 2H), 6,92-for 6.81 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,29 (DD, J=of 9.6, 4.8 Hz, 1H), 4,18 (DD, J=a 9.6, 6.3 Hz, 1H), and 3.72 (s, 3H), 3,71 (s, 3H), 3,70 (s, 2H), 3,40 (DD, J=11,7, 2.7 Hz, 1H), 3.27 to (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H), 2,32 (s, 3H).

Example 1(10): methyl ester 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-hydroxy-3-methylphenylacetic acid

TLC: Rf 0.21 in (ethyl acetate: hexane =1:1);

NMR (CDCl3): δ 8,66-8,58 (m, 1H), 7,81 (d, J=9.0 Hz, 2H), 7,58 (s, 1H), 7,38 (d, J=2.4 Hz, 1H), 7,21 (d, J=2.4 Hz, 1H), 7,07-of 6.96 (m, 2H), 6,93-to 6.80 (m, 2H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,29 (DD, J=9,9, a 5.4 Hz, 1H), 4,18 (DD, J=a 9.9, 6.3 Hz, 1H, in), 3.75 (s, 3H), 3,68 (s, 2H), 3,40 (DD, J=11,4, 2.7 Hz, 1H), 3.27 to (DD, J=11,4, 6.3 Hz, 1H), 2.91 in (s, 3H), to 2.29 (s, 3H).

Example 1(11): methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-phenoxymethylpenicillin acid

TLC: Rf 0,59 (ethyl acetate: hexane =1:1).

Example 1(12): methyl ester 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxa is n-2-ylethoxy)benzoylamine)-4-chloro-2-florfenicol acid

TLC: Rf of 0.71 (ethyl acetate: hexane =1:1);

NMR (CDCl3): δ and 8.50 (d, J=7.2 Hz, 1H), 8,21 (s, 1H), 7,87 (d, J=9.0 Hz, 2H), 7,18 (d, J=9.0 Hz, 1H), 7,08-6,98 (m, 2H), 6,92-to 6.80 (m, 2H), 6,76-only 6.64 (m, 2H), 4,72-to 4.62 (m, 1H), or 4.31 (DD, J=9,9, 5,1 Hz, 1H), 4,21 (DD, J=9,9, and 6.6 Hz, 1H), of 3.73 (s, 2H), 3,40 (DD, J=11,7, 3.0 Hz, 1H), 3.27 to (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 1(13): methyl ester 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-florfenicol acid

TLC: Rf of 0.47 (ethyl acetate: hexane =1:1);

NMR (CDCl3): δ 7,83 (d, J=8,4 Hz, 2H), of 7.70 (s, 1H), 7,60-of 7.48 (m, 2H), 7,10-6,98 (m, 3H), 6,92-to 6.80 (m, 2H), 6.75 in-6,65 (m, 2H), 4,72-to 4.62 (m, 1H), 4,29 (DD, J=9,6, a 5.4 Hz, 1H), 4,19 (DD, J=a 9.6, 6.3 Hz, 1H), 3.72 points s, 3H), of 3.69 (s, 2H), 3,40 (DD, J=12,0, 2.7 Hz, 1H), 3.27 to (DD, J=12,0, 6,6 Hz, 1H), 2.91 in (s, 3H).

Example 1(14): methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-florfenicol acid

TLC: Rf 0.21 in (ethyl acetate: hexane =3:7);

NMR (CDCl3): δ 7,83 (d, J=8,4 Hz, 2H), 7,76 (s, 1H), 7,60-7,52 (m, 1H), 7,20 (s, 1H), 7,02 (d, J=8,4 Hz, 2H), 6,92 to 6.75 (m, 3H), 6,75 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,29 (DD, J=of 9.6, 4.8 Hz, 1H), 4,19 (DD, J=of 9.6, 6.6 Hz, 1H), and 3.72 (s, 3H), 3,62 (s, 2H), 3,40 (DD, J=11,4, 2.7 Hz, 1H), 3.27 to (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 1(15): methyl ester of 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-ethoxymethylenemalonic acid

TLC: Rf 0.26 (ethyl acetate: hexane =1:1);

NMR (CDCl3): δ 7,83 (d, J=8.7 Hz, 2H), 7,74 (s, 1H), 7,54 (s, 2H), 7,08-6,97 (m, 3H), 6,93-to 6.80 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,46 (s, 2H), 4,29 (DD, J=9,9, 5,1 Hz, 1H), 4,19 (DD, J9,9, 6.3 Hz, 1H), 3,70 (s, 3H), of 3.64 (s, 2H), 3,44-to 3.33 (m, 4H), of 3.27 (DD, J=11,7, 6.3 Hz, 1H), 2.91 in (s, 3H).

Example 2: 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)phenylacetic acid

To a solution of the compound obtained in example 1 (224 mg)in a mixed solvent consisting of tetrahydrofuran (2.5 ml) and methanol (2.5 ml), add 2 N. aqueous sodium hydroxide solution (2 ml). The mixture is stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and then washed with tert-butylmethylamine ether. The aqueous layer was acidified by addition of 1 N. hydrochloric acid, then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue is purified column chromatography on silica gel (ethyl acetate:hexane = 1:1 ˜ ethyl acetate:methanol = 10:1), obtaining mentioned in the title compound (123 mg), physical data is described below.

TLC: Rf value of 0.52 (ethyl acetate: methanol = 19:1);

NMR (CDCl3): δ of 7.90 for 7.78 (m, 3H), EUR 7.57 (s, 1H), 7,54 (d, J=8,1 Hz, 1H), 7,29 (m, 1H), 7,06-to 6.95 (m, 3H), 6,91-PC 6.82 (m, 2H), 6.75 in of 6.66 (m, 2H)and 4.65 (m, 1H), 4,27 (DD, J=of 9.6, 4.8 Hz, 1H), 4,16 (DD, J=9,6, and 6.6 Hz, 1H), 3,63 (s, 2H), 3,38 (DD, J=11,4, 2.7 Hz, 1H), 3,25 (DD, J=11,4, and 6.6 Hz, 1H), 2,90 (s, 3H).

Example 2(1)˜2(15)

The following compound is produced by way of sunnym in example 2, using the compounds obtained in example 1(1)-1(15).

Example 2(1): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-chlorophenylalanine acid

TLC: Rf of 0.38 (chloroform: methanol = 9:1);

NMR (CDCl3): δ 8,53 (d, J=1.8 Hz, 1H), at 8.36 (s, 1H), 7,88 (d, J=8.7 Hz, 2H), 7,37 (d, J=8,1 Hz, 1H), 7,08-6,98 (m, 3H), 6,92-PC 6.82 (m, 2H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=of 9.6, 4.8 Hz, 1H), 4,19 (DD, J=a 9.6, 6.3 Hz, 1H), 3,69 (s, 2H), 3,40 (DD, J=12,0, 3.0 Hz, 1H), 3.27 to (DD, J=12,0, 6,9 Hz, 1H), 2.91 in (s, 3H).

Example 2(2): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methylphenoxy acid

TLC: Rf of 0.37 (chloroform: methanol = 9:1);

NMR (CDCl3): δ a 7.85 (d, J=8.7 Hz, 2H), 7,71 (d, J=8,4 Hz, 1H), to 7.61 (s, 1H), 7,28-7,19 (m, 1H), 7,11 (d, J=7.5 Hz, 1H), 7,02 (d, J=8.7 Hz, 2H), 6,92-to 6.80 (m, 2H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=9,6, 5,1 Hz, 1H), 4,19 (DD, J=a 9.6, 6.3 Hz, 1H), 3,74 (s, 2H), 3,40 (DD, J=11,4, 3.3 Hz, 1H), 3.27 to (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H), and 2.26 (s, 3H).

Example 2(3): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-methylphenoxy acid

TLC: Rf of 0.34 (chloroform: methanol = 9:1);

NMR (CDCl3): δ 7,89 (s, 1H), to 7.84 (d, J=8.7 Hz, 2H), to 7.61 (s, 1H), 7,20 (d, J=7.8 Hz, 1H), 7,07-of 6.99 (m, 3H), 6,92-for 6.81 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=9,9, 5,1 Hz, 1H), 4,19 (DD, J=to 9.9, 6.6 Hz, 1H), 3,66 (s, 2H), 3,40 (DD, J=11,4, 2.7 Hz, 1H), 3.27 to (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H), and 2.26 (s, 3H).

Example 2(4): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-methylphenoxy acid

TLC: Rf 0.39 to (chlorine the product: methanol = 9:1);

NMR (CDCl3): δ of 7.82 (d, J=9.0 Hz, 2H), 7,74 (s, 1H), 7,41 (s, 1H), 7,37 (s, 1H), 7,00 (d, J=9.0 Hz, 2H), 6,92-for 6.81 (m, 3H), 6,76 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4,28 (DD, J=9,9, a 5.4 Hz, 1H), 4,18 (DD, J=9,9, 6,6 Hz, 1H), 3,62 (s, 2H), 3,39 (DD, J=11,7, 3.3 Hz, 1H), 3,26 (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H), of 2.34 (s, 3H).

Example 2(5): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-chlorophenylalanine acid

TLC: Rf and 0.46 (chloroform: methanol =9:1);

NMR (CDCl3): δ charged 8.52 (d, J=8,4 Hz, 1H), 8,42 (s, 1H), 7,89 (d, J=9.0 Hz, 2H), 7,32 (t, J=8,4 Hz, 1H), 7,12-7,00 (m, 3H), 6,93-PC 6.82 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=9,9, a 5.4 Hz, 1H), 4,20 (DD, J=a 9.9, 6.3 Hz, 1H), a 3.87 (s, 2H), 3,40 (DD, J=11,4, 2.7 Hz, 1H), 3.27 to (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 2(6): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-hydroxyphenylarsonic acid

TLC: Rf 0.28 in (chloroform: methanol =9:1);

NMR (CDCl3): δ 8,10 (s, 1H), 7,86 (d, J=9.0 Hz, 2H), 7,14 (d, J=1.8 Hz, 1H), 7,08-6,97 (m, 4H), 6,92-PC 6.82 (m, 2H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,29 (DD, J=9,6, 5,1 Hz, 1H), 4,19 (DD, J=a 9.6, 6.3 Hz, 1H), to 3.58 (s, 2H), 3,40 (DD, J=11,7, 3.0 Hz, 1H), 3.27 to (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 2(7): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-methoxyphenylalanine acid

TLC: Rf of 0.45 (chloroform: methanol = 9:1);

NMR (CDCl3): δ 8,51-8,44 (m, 2H), a 7.85 (d, J=9.0 Hz, 2H), 7,06-6,97 (m, 3H), 6,92-PC 6.82 (m, 3H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=9,9, 5,1 Hz, 1H), 4,18 (DD, J=9,9, and 6.6 Hz, 1H), 3,92 (s, 3H), 3,66 (s, 2H), 3,40 (DD, J=11,7, 2.7 Hz, 1H), 3.27 to (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 2(8): 5-(4-((2S)-4-methyl-,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-chlorophenylalanine acid

TLC: Rf and 0.62 (chloroform: methanol = 4:1);

NMR (CDCl3): δ 7,86-7,76 (m, 3H), 7,66 (d, J=2.4 Hz, 1H), 7,52 (DD, J=8,4, 2.4 Hz, 1H), was 7.36 (d, J=8,4 Hz, 1H), 7,00 (d, J=9.0 Hz, 2H), 6,94-to 6.80 (m, 2H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,28 (DD, J=9,9, a 5.1 Hz, 1H), 4,18 (DD, J=a 9.9, 6.3 Hz, 1H), 3,81 (s, 2H), 3,39 (DD, J=11,4, 2.7 Hz, 1H), 3,26 (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 2(9): 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methoxy-3-methylphenoxy acid

TLC: Rf 0,70 (chloroform: methanol = 4:1);

NMR (CDCl3): δ of 7.82 (d, J=8.7 Hz, 2H), 7,65 (s, 1H), 7,45 (d, J=2.7 Hz, 1H), 7,34 (d, J=2.7 Hz, 1H), 7,01 (d, J=8.7 Hz, 2H), 6,94-PC 6.82 (m, 2H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,29 (DD, J=9,9, 5,1 Hz, 1H), 4,18 (DD, J=a 9.9, 6.3 Hz, 1H), 3,76 (s, 3H), 3,71 (s, 2H), 3,40 (DD, J=11,7, 3.0 Hz, 1H), 3.27 to (DD, J=11,7, 6.3 Hz, 1H), 2.91 in (s, 3H), of 2.33 (s, 3H).

Example 2(10): 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-hydroxy-3-methylphenoxy acid

TLC: Rf is 0.22 (chloroform: methanol = 4:1);

NMR (CDCl3): δ 7,81 (d, J=9.0 Hz, 2H), 7,74-to 7.64 (m, 1H), was 7.36-7,26 (m, 1H), 7,20-7,14 (m, 1H), 6,99 (d, J=9.0 Hz, 2H), 6,93-PC 6.82 (m, 2H), 6,76 of 6.66 (m, 2H), 4,71-br4.61 (m, 1H), 4,28 (DD, J=9,9, a 5.4 Hz, 1H), 4,17 (DD, J=a 9.9, 6.3 Hz, 1H), the 3.65 (s, 2H), 3,40 (DD, J=11,4, 2.4 Hz, 1H), 3,26 (DD, J=11,4, 6,9 Hz, 1H), 2.91 in (s, 3H), of 2.28 (s, 3H).

Example 2(11): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-phenoxymethylpenicillin acid

TLC: Rf of 0.47 (chloroform: methanol = 9:1);

NMR (CDCl3): δ 7,83 (d, J=9,3 Hz, 2H), 7,78 (s, 1H), 7,66-of 7.60 (m, 2H), 7,34-7,20 (m, 2H), 7,15 (s, 1H), 7,05-6,92 (m, 5H), 6,92-to 6.80 (m, 2H), 6,74 of 6.66 (m, 2H),5,07 (s, 2H), 4,72-to 4.62 (m, 1H), 4,29 (DD, J=9,9, a 5.4 Hz, 1H), 4,18 (DD, J=9,9, and 6.6 Hz, 1H), 3,70 (s, 2H), 3,40 (DD, J=11,7, 2.7 Hz, 1H), 3.27 to (DD, J=11,7, 6,9 Hz, 1H), 2.91 in (s, 3H).

Example 2(12): 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-chloro-2-ftorhinolona acid

TLC: Rf of 0.37 (chloroform: methanol = 9:1);

NMR (CDCl3): δ charged 8.52 (d, J=7.8 Hz, 1H), they were 8.22 (s, 1H), 7,86 (d, J=8.7 Hz, 2H), 7,19 (d, J=9.0 Hz, 1H),? 7.04 baby mortality (d, J=8.7 Hz, 2H), 6,92-to 6.80 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=9,6, 5,1 Hz, 1H), 4,20 (DD, J=9,6, and 6.6 Hz, 1H, in), 3.75 (s, 2H), 3,40 (DD, J=11,7, 3.0 Hz, 1H), 3.27 to (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 2(13): 5-(4-((2S)-4-methyl-3,4-dihydro-2H-l,4-benzoxazin-2-ylethoxy)benzoylamine)-2-ftorhinolona acid

TLC: Rf of 0.50 (chloroform: methanol = 9:1);

NMR (CDCl3): δ of 7.82 (d, J=8.7 Hz, 2H), 7,76 (s, 1H), 7,63-7,56 (m, 1H), 7,54-7,46 (m, 1H), 7,06 (t, J=8.7 Hz, 1H), 7,01 (d, J=8.7 Hz, 2H), 6,93-for 6.81 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,71-br4.61 (m, 1H), 4,29 (DD, J=of 9.6, 5.4 Hz, 1H), 4,18 (DD, J=a 9.6, 6.3 Hz, 1H), and 3.72 (s, 2H), 3,40 (DD, J=12,0, 2.7 Hz, 1H), 3.27 to (DD, J=12,0, 6,6 Hz, 1H), 2.91 in (s, 3H).

Example 2(14): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-ftorhinolona acid

TLC: Rf 0.28 in (chloroform: methanol = 9:1);

NMR (CDCl3): δ 7,86-to 7.77 (m, 3H), EUR 7.57-to 7.50 (m, 1H), 7,28-7,22 (m, 1H), 7,01 (d, J=9.0 Hz, 2H), 6,92-6,76 (m, 3H), 6,74 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,29 (DD, J=9,9, 4.8 Hz, 1H), 4,18 (DD, J=a 9.9, 6.3 Hz, 1H), the 3.65 (s, 2H), 3,40 (DD, J=11,7, 2.7 Hz, 1H), 3.27 to (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 2(15): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-ethoxymethylene Usna acid

TLC: Rf of 0.33 (chloroform: methanol = 9:1);

NMR (CDCl3): δ 7,83 (d, J=8.7 Hz, 2H), 7,78 (s, 1H), 7,58 (s, 1H), 7,53 (s, 1H), 7,07-6,97 (m, 3H), 6,92-PC 6.82 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,46 (s, 2H), 4,29 (DD, J=9,9, 4.8 Hz, 1H), 4,18 (DD, J=a 9.9, 6.3 Hz, 1H), to 3.67 (s, 2H), 3,44-to 3.36 (m, 4H), of 3.27 (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Reference example 10, methyl ester 3-(N-ethylamino)phenylacetic acid

In an argon atmosphere to a solution of the compound obtained in reference example 9 (820 mg)in methylene chloride (5 ml) is added pyridine (802 μl) and acetic anhydride (517 μl) and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture, water is added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated give crude acetyl derivatives.

A solution of crude acetyl derivatives in anhydrous THF (3 ml) is cooled by the ice in the atmosphere of argon. To the solution was added borane-dimethylsulfide complex (2M solution in THF; equal to 4.97 ml), the mixture is stirred at room temperature for 1 hour and then stirred at 60°C for 15 hours. The reaction mixture is cooled with ice, and then added to the mixture methanol and hydrogen chloride in dioxane. The mixture was stirred at 60°C for 30 minutes. The reaction mixture was neutralized by saturated in the s ' solution of sodium bicarbonate and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate = 8:1), obtaining mentioned in the title compound (320 mg), physical data is given below.

TLC: Rf 0,49 (hexane:ethyl acetate = 2:1);

NMR (CDCl3): δ for 7.12 (t, J=7.5 Hz, 1H), 6,59 (d, J=7.5 Hz, 1H), 6,55-6.48 in (m, 2H), 3,68 (s, 3H), of 3.54 (s, 2H), 3.15 in (sq, J=7.2 Hz, 2H), 1,25 (t, J=7.2 Hz, 3H).

Example 3: methyl ester of 3-(N-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoyl)-N-ethylamino)phenylacetic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 1 using the compound obtained in reference example 10, instead of the compound obtained in reference example 9.

TLC: Rf of 0.20 (hexane:ethyl acetate = 2:1).

Example 3 (1): methyl ester of 3-(N-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoyl)-N-methylamino)phenylacetic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 1 using methyl ester of 3-(N-methylamino)phenylacetic acid instead of the compound obtained in reference example 9.

TLC: Rf of 0.33 (hexane:ethyl acetate = 1:1).

Example 4: 3-(N-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoyl)-N-ethylamino)phenylacetic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 2 using the compound obtained in example 3 instead of the compound obtained in example 1.

TLC: Rf to 0.63 (ethyl acetate:methanol = 19:1),

NMR (CDCl3): δ 7,30-to 7.18 (m, 3H), 7,12-7,02 (m, 2H), 6,92 of 6.66 (m, 7H), of 4.54 (m, 1H), 4,30 (DD, J=10,8, and 4.8 Hz, 1H), a 4.03 (DD, J=10,8, 7.5 Hz, 1H), 3,99 (DQC., J=2,4, 7.2 Hz, 2H), 3,41 (s, 2H), 3,39 (DD, J=11,7, 2.4 Hz, 1H), of 3.07 (DD, J=11,7, and 7.8 Hz, 1H), 2,86 (s, 3H), 1,22 (t, J=7.2 Hz, 3H).

Example 4(1): 3-(N-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoyl)-N-methylamino)phenylacetic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 2 using the compound obtained in example 3(1), instead of the compound obtained in example 1.

TLC: Rf is 0.49 (ethyl acetate: methanol = 19: 1);

NMR (CDCl3): δ 7,29-7,20 (m, 4H), 7,10-7,02 (m, 2H), 6,91-6,69 (m, 6H), 4,55 (m, 1H), 4,28 (DD, J=10,8, and 4.8 Hz, 1H), Android 4.04 (DD, J=10,8, 7.2 Hz, 1H), 3,49 (s, 3H), 3.43 points (s, 2H), 3,38 (DD, J=11,4, 2.4 Hz, 1H), 3,09 (DD, J=11,4, 7.2 Hz, 1H), 2,86 (s, 3H).

Example 5: methyl ester 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)phenylacetic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 1, using 2-methyl-4-((2S)-4-methyl-3,4-Digi the ro-2H-1,4-benzoxazin-2-ylethoxy)of benzoyl chloride instead of the connection obtained in reference example 8.

TLC: Rf 0.14 (ethyl acetate:hexane = 3:7);

NMR (CDCl3): δ 7,60-7,38 (m, 4H), 7,32 (t, J=7.8 Hz, 1H), 7,06 (d, J=7.5 Hz, 1H), 6,92-6,77 (m, 4H), 6,74 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,6, a 5.4 Hz, 1H), 4,14 (DD, J=9,6, and 6.6 Hz, 1H), 3,71 (s, 3H)as the 3.65 (s, 2H), 3,39 (DD, J=11,4, 3.0 Hz, 1H), 3,26 (DD, J=11,4, and 7.8 Hz, 1H), 2.91 in (s, 3H), of 2.51 (s, 3H).

Example 5(1)-5(14)

The following compounds of the present invention receive in accordance with the method of example 5 using the corresponding derivative instead of the compound obtained in reference example 8 and using the compound obtained in reference example 9, or a corresponding derivative instead.

Example 5(1): methyl ester 3-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)phenylacetic acid

TLC: Rf of 0.45 (hexane: ethyl acetate = 1:1);

NMR (CDCl3): δ of 8.04 (s, 1H), 7,83 (d, J=8,4 Hz, 1H), 7,62-7,52 (m, 2H), 7,33 (t, J=7.8 Hz, 1H), to 7.09 (d, J=7.8 Hz, 1H), 7,02 (d, J=2.4 Hz, 1H), 6,99-for 6.81 (m, 3H), 6,76 of 6.66 (m, 2H), 4,71-br4.61 (m, 1H), 4,27 (DD, J=9,9, 5,1 Hz, 1H), 4,17 (DD, J=9,9, 6.0 Hz, 1H), 3,71 (s, 3H), of 3.65 (s, 2H), 3,38 (DD, J=11,4, 2.7 Hz, 1H), 3,25 (DD, J=11,4, 6.3 Hz, 1H), 2.91 in (s, 3H).

Example 5 (2): methyl ester 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methylphenylacetic acid

TLC: Rf and 0.46 (hexane: ethyl acetate = 1:1);

NMR (CDCl3): δ 7,80-of 7.70 (m, 1H), 7,50 (d, J=7.8 Hz, 1H), 7,30-to 7.18 (m, 2H), to 7.09 (d, J=7.8 Hz, 1H), 6,92-of 6.78 (m, 4H), 6,75 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths(DD, J=9,6, 5,1 Hz, 1H), 4,14 (DD, J=9,6, and 6.6 Hz, 1H), 3,71 (s, 2H), 3,69 (s, 3H), 3,39 (DD, J=11,4, 2.7 Hz, 1H), 3,26 (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H), of 2.53 (s, 3H), 2,24 (s, 3H).

Example 5(3): methyl ester 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-chlorophenylalanine acid

TLC: Rf of 0.68 (hexane: ethyl acetate = 1:1);

NMR (CDCl3): δ 8,49 (s, 1H), to 7.99 (s, 1H), 7,54 (d, J=8,1 Hz, 1H), was 7.36 (d, J=8,1 Hz, 1H),? 7.04 baby mortality-6,98 (m, 1H), 6,92-to 6.80 (m, 4H), 6,74 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4,27 (DD, J=9,6, 5,1 Hz, 1H), 4,15 (DD, J=of 9.6 and 6.9 Hz, 1H), and 3.72 (s, 3H), to 3.67 (s, 2H), 3,40 (DD, J=11,7, 2.1 Hz, 1H), 3,26 (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H), of 2.56 (s, 3H).

Example 5(4): methyl ester 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-florfenicol acid

TLC: Rf of 0.54 (hexane: ethyl acetate = 1:1);

NMR (CDCl3): δ 7,56-7,42 (m, 3H), 7,17 (s, 1H), 6,92-6,76 (m, 5H), 6.75 in of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=of 9.6, 4.8 Hz, 1H), 4,15 (DD, J=9,6, a 5.4 Hz, 1H), 3,71 (s, 3H), 3,61 (s, 2H), 3,39 (DD, J=11,7, 2,7 Hz, 1H), 3,26 (DD, J=11,7, 6.3 Hz, 1H), 2.91 in (s, 3H), of 2.51 (s, 3H).

Example 5(5): methyl ester 5-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-florfenicol acid

TLC: Rf of 0.47 (hexane: ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ 7,60-7,35 (m, 4H), 7,06 (t, J=9.0 Hz, 1H), 6,93 to 6.75 (m, 4H), 6,75 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=of 9.6, 4.8 Hz, 1H), 4,14 (DD, J=a 9.6, 6.3 Hz, 1H), and 3.72 (s, 3H), of 3.69 (s, 2H), 3,39 (DD, J=11,4, 2.7 Hz, 1H), 3,25 (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H), of 2.51 (s, 3H).

Example 5(6): methyl ester 5-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzac Azin-2-ylethoxy)benzoylamine)-2-methoxyphenylacetic acid

TLC: Rf of 0.38 (hexane: ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ EUR 7.57-of 7.48 (m, 1H), of 7.48 and 7.36 (m, 3H), 7,31 (s, 1H), 6,93-6,76 (m, 5H), 6,74 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4,25 (DD, J=9,9, 4.8 Hz, 1H), 4,14 (DD, J=9,9, and 6.6 Hz, 1H), 3,82 (s, 3H), 3,70 (s, 3H), the 3.65 (s, 2H), 3,39 (DD, J=11,1, 2.4 Hz, 1H), 3,25 (DD, J=11,1, 6,6 Hz, 1H), 2.91 in (s, 3H), of 2.50 (s, 3H).

Example 5(7): methyl ester 3-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-chlorophenylalanine acid

TLC: Rf of 0.53 (hexane: ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ 8,68 (users, 1H), 8,54 (users, 1H), 7,87 (d, J=8,4 Hz, 1H), was 7.36 (d, J=8,4 Hz, 1H), 7,10-to 6.80 (m, 5H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,27 (DD, J=9,6, a 5.4 Hz, 1H), 4,18 (DD, J=9,6, 6.0 Hz, 1H), 3,71 (s, 3H), 3,66 (s, 2H), 3,39 (DD, J=12,0, 2.7 Hz, 1H), 3,25 (DD, J=12,0, 6,6 Hz, 1H), 2.91 in (s, 3H).

Example 5(8): methyl ester 5-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-florfenicol acid

TLC: Rf of 0.44 (hexane: ethyl acetate =1:1);

NMR (300 MHz, CDCl3): δ 8,03 (s, 1H), 7,83 (d, J=8,4 Hz, 1H), 7,62-7,56 (m, 1H), 7,56-of 7.48 (m, 1H), 7,07 (t, J=9,3 Hz, 1H), 7,02 (d, J=2.4 Hz, 1H), 6,98-to 6.80 (m, 3H), 6,76 of 6.66 (m, 2H), 4,71-br4.61 (m, 1H), 4,27 (DD, J=of 9.6, 4.8 Hz, 1H), 4,17 (DD, J=9,6, 6.0 Hz, 1H), of 3.73 (s, 3H), 3,70 (s, 2H), 3,38 (DD, J=11,4, 2.7 Hz, 1H), 3,25 (DD, J=11,4, 6.3 Hz, 1H), 2.91 in (s, 3H).

Example 5(9): methyl ester 5-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methoxyphenylacetic acid

TLC: Rf of 0.30 (hexane: ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ to 7.93 (s, 1H), 7,82 (d, J=8.7 Hz, 1H), EUR 7.57 (DD, J=8,7, 2.7 Hz, 1H), 7,43 (d, J=2 Hz, 1H), 7,01 (d, J=2.7 Hz, 1H), 6,98-for 6.81 (m, 4H), 6,76 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,6, 5,1 Hz, 1H), 4,16 (DD, J=a 9.6, 6.3 Hz, 1H), 3,82 (s, 3H), 3,70 (s, 3H), of 3.65 (s, 2H), 3,38 (DD, J=11,4, 2,7 Hz, 1H), 3,25 (DD, J=11,4, 6.3 Hz, 1H), 2.91 in (s, 3H).

Example 5(10): methyl ester 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-methylphenylacetic acid

TLC: Rf of 0.38 (hexane: ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ 7,93 (users, 1H), 7,49 (d, J=8,1 Hz, 1H), 7,28-7,22 (m, 1H), 7,18 (d, J=8,1 Hz, 1H), 7,06-7,01 (m, 1H), 6,92-of 6.78 (m, 4H), 6,74 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=of 9.6, 4.8 Hz, 1H), 4,15 (DD, J=a 9.6, 6.6 Hz, 1H), 3,70 (s, 3H), of 3.64 (s, 2H), 3,40 (DD, J=11,7, 2.7 Hz, 1H), 3,26 (DD, J=11,7, 6.3 Hz, 1H), 2.91 in (s, 3H), of 2.54 (s, 3H), and 2.27 (s, 3H).

Example 5(11): methyl ester 5-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-chloro-2-florfenicol acid

TLC: Rf 0,70 (hexane: ethyl acetate =1:1);

NMR (300 MHz, CDCl3): δ 8,48 (d, J=7.5 Hz, 1H), a 7.85 (s, 1H), 7,53 (d, J=8,1 Hz, 1H), 7,17 (d, J=9.0 Hz, 1H), 6,92-to 6.80 (m, 4H), 6,75 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4,27 (DD, J=of 9.6, 4.8 Hz, 1H), 4,15 (DD, J=9,6, 6,6 Hz, 1H), of 3.73 (s, 3H), 3,71 (s, 2H), 3,39 (DD, J=11,7, 2.7 Hz, 1H), 3,26 (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H), by 2.55 (s, 3H).

Example 5(12): methyl ester 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-methylphenylacetic acid

TLC: Rf of 0.51 (hexane: ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ 7,44 (d, J=8,4 Hz, 1H), 7,41 (users, 1H), was 7.36 (users, 1H), 7,30 (users, 1H), 6,92-6,76 (m, 5H), 6,74 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=of 9.6, 4.8 Hz, 1H), 4,14 (DD, J=9,6, 6.6 G is, 1H), 3,70 (s, 3H), of 3.60 (s, 2H), 3,39 (DD, J=11,4, 2.7 Hz, 1H), 3,26 (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H), of 2.51 (s, 3H), of 2.35 (s, 3H).

Example 5(13): methyl ester 3-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-methylphenylacetic acid

TLC: Rf of 0.40 (hexane: ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ 8,00 (s, 2H), of 7.90 (d, J=8,4 Hz, 1H), 7,19 (d, J=7.5 Hz, 1H), 7,07-7,01 (m, 2H), 7,00-6,93 (m, 1H), 6,93-for 6.81 (m, 2H), 6.75 in is 6.67 (m, 2H), 4,71-br4.61 (m, 1H), 4,27 (DD, J=9,9, 5.7 Hz, 1H), 4,18 (DD, J=a 9.9, 6.3 Hz, 1H), 3,70 (s, 3H), of 3.65 (s, 2H), 3,39 (DD, J=11,7, 2.7 Hz, 1H), 3,25 (DD, J=11,7, 6.3 Hz, 1H), 2.91 in (s, 3H), 2,32 (s, 3H).

Example 5(14): methyl ester 3-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-methylphenylacetic acid

TLC: Rf 0,49 (hexane: ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ 7,98 (s, 1H), 7,81 (d, J=9.0 Hz, 1H), 7,41 (s, 1H), was 7.36 (s, 1H), 7,02 (d, J=2.4 Hz, 1H), 6,99-for 6.81 (m, 4H), 6,76 is 6.67 (m, 2H), 4,71-br4.61 (m, 1H), 4.26 deaths (DD, J=9,9, a 5.4 Hz, 1H), 4,17 (DD, J=9,9, 6.3 Hz, 1H), 3,70 (s, 3H), of 3.60 (s, 2H), 3,38 (DD, J=11,4, 2.4 Hz, 1H), 3,25 (DD, J=11,4, 6.3 Hz, 1H), 2.91 in (s, 3H), of 2.36 (s, 3H).

Example 6: 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)phenylacetic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 2 using the compound obtained in example 5.

TLC: Rf of 0.40 (chloroform: methanol = 9:1);

NMR (CDCl3): δ a 7.62 7,40 (m, 4H), 7,33 (t, J=8,1 Hz, 1H), 7,10? 7.04 baby mortality (m, 1H), 6,92-6,76 (m, 4H), 6,74 of 6.66 (m, 2H), 4,70-4,60(m, 1H), 4.26 deaths (DD, J=of 9.6, 4.8 Hz, 1H), 4,14 (DD, J=9,6, and 6.6 Hz, 1H), 3,68 (s, 2H), 3,39 (DD, J=11,4, 2.7 Hz, 1H), 3,25 (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H), of 2.50 (s, 3H).

Example 6(1)-6(14)

Below obtain the connection according to the method of example 6 using the compounds obtained in example 5(1)˜5(14).

Example 6(1): 3-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)phenylacetic acid

TLC: Rf of 0.29 (chloroform: methanol =9:1);

NMR (CDCl3): δ of 8.06 (s, 1H), 7,82 (d, J=8,4 Hz, 1H), 7.62mm (s, 1H), 7,55 (d, J=8,4 Hz, 1H), 7,34 (t, J=7.5 Hz, 1H), to 7.09 (d, J=7.5 Hz, 1H), 7,01 (d, J=1.8 Hz, 1H), 6,98-to 6.80 (m, 3H), 6,76 is 6.67 (m, 2H), 4,71-br4.61 (m, 1H), 4.26 deaths (DD, J=9,9, 5,1 Hz, 1H), 4,17 (DD, J=9,9, 6.0 Hz, 1H), 3,68 (s, 2H), 3,38 (DD, J=11,7, 3.0 Hz, 1H), 3,25 (DD, J=11,7, 6.0 Hz, 1H), 2.91 in (s, 3H).

Example 6(2): 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methylphenoxy acid

TLC: Rf of 0.38 (chloroform: methanol = 9:1);

NMR (CDCl3): δ 7,82-to 7.68 (m, 1H), 7,54-7,44 (m, 1H), 7,38-to 7.18 (m, 2H), 7,10 (d, J=8,1 Hz, 1H), 6,92-6,77 (m, 4H), 6,75 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,9, a 5.4 Hz, 1H), 4,14 (DD, J=a 9.9, 6.3 Hz, 1H), to 3.73 (s, 2H), 3,39 (DD, J=11,4, 2.7 Hz, 1H), 3,25 (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H), 2,52 (s, 3H), 2,24 (s, 3H).

Example 6(3): 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-chlorophenylalanine acid

TLC: Rf of 0.41 (chloroform: methanol = 9:1);

NMR (CDCl3): δ 8,49 (users, 1H), to 7.99 (s, 1H), 7,53 (d, J=7.8 Hz, 1H), 7,37 (d, J=7.8 Hz, 1H), 7,01 (DD, J=7,8, 1.8 Hz, 1H), 6,93-of 6.78 (m, 4H), 6,76 of 6.66 (m, 2H), 4,7-4,60 (m, 1H), 4,27 (DD, J=9,9, 4.8 Hz, 1H), 4,16 (DD, J=9,9, and 6.6 Hz, 1H), 3,70 (s, 2H), 3,40 (DD, J=11,7, 2.7 Hz, 1H), 3,25 (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H), by 2.55 (s, 3H).

Example 6(4): 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-ftorhinolona acid

TLC: Rf of 0.41 (chloroform: methanol = 9:1);

NMR (CDCl3): δ 7,56-7,40 (m, 3H), 7,20 (users, 1H), 6,93 to 6.75 (m, 5H), 6,76 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,6, 5,1 Hz, 1H), 4,14 (DD, J=9,6, and 6.6 Hz, 1H), to 3.64 (s, 2H), 3,39 (DD, J=11,7, 2.4 Hz, 1H), 3,25 (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H), 2.49 USD (s, 3H).

Example 6(5): 5-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-ftorhinolona acid

TLC: Rf 0.31 in (chloroform: methanol = 9:1);

NMR (300 MHz, CDCl3): δ to 7.61 (users, 1H), 7,52-7,38 (m, 3H), 7,07 (t, J=8.7 Hz, 1H), 6,92-6,76 (m, 4H), 6,76 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,3, 5,1 Hz, 1H), 4,14 (DD, J=9,3, 6.3 Hz, 1H), of 3.73 (s, 2H), 3,39 (DD, J=11,7, 2.7 Hz, 1H), 3,25 (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H), of 2.50 (s, 3H).

Example 6(6): 5-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methoxyphenoxy acid

TLC: Rf of 0.36 (chloroform: methanol = 9:1);

NMR (300 MHz, CDCl3): δ 7,58-7,39 (m, 3H), 7,34 (users, 1H), 6,93-6,76 (m, 5H), 6,74 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,3, 4.8 Hz, 1H), 4,14 (DD, J=9,3, 6.3 Hz, 1H), 3,85 (s, 3H), of 3.69 (s, 2H), 3,39 (DD, J=11,4, 2,7 Hz, 1H), 3,25 (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H), of 2.50 (s, 3H).

Example 6(7): 3-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-chlorophenylalanine acid

TLC: Rf of 0.41 (chloroform: IU is anal = 9:1);

NMR (300 MHz, CDCl3): δ 8,70 (users, 1H), 8,56 (users, 1H), 7,87 (d, J=8,4 Hz, 1H), 7,38 (d, J=8,4 Hz, 1H), 7,07-7,00 (m, 2H), of 6.96 (DD, J=9,0, 2.4 Hz, 1H), 6,93-to 6.80 (m, 2H), 6,76 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4,28 (DD, J=9,9, a 5.4 Hz, 1H), 4,18 (DD, J=a 9.9, 6.3 Hz, 1H), 3,71 (s, 2H), 3,39 (DD, J=11,7, 2.7 Hz, 1H), 3,25 (DD, J=11,7, 6.3 Hz, 1H), 2.91 in (s, 3H).

Example 6(8): 5-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-ftorhinolona acid

TLC: Rf of 0.41 (chloroform: methanol = 9:1);

NMR (300 MHz, CDCl3): δ of 8.06 (s, 1H), 7,82 (d, J=8.7 Hz, 1H), to 7.67-of 7.60 (m, 1H), 7,56-7,47 (m, 1H), was 7.08 (t, J=9.0 Hz, 1H), 7,02 (d, J=2.1 Hz, 1H), 6,99-for 6.81 (m, 3H), 6,76 is 6.67 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,9, a 5.4 Hz, 1H), 4,17 (DD, J=9,9, 6.0 Hz, 1H), 3,74 (s, 2H), 3,38 (DD, J=11,7, 2.7 Hz, 1H), 3,25 (DD, J=11,7, 6.3 Hz, 1H), 2.91 in (s, 3H).

Example 6(9): 5-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methoxyphenoxy acid

TLC: Rf of 0.41 (chloroform: methanol = 9:1);

NMR (300 MHz, CDCl3): δ of 7.96 (s, 1H), 7,82 (d, J=8,4 Hz, 1H), EUR 7.57 (DD, J=8,4, 2.7 Hz, 1H), of 7.48 (d, J=2.7 Hz, 1H), 7,01 (d, J=2.7 Hz, 1H), 6,97-for 6.81 (m, 4H), 6,75 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,9, 5,4 Hz, 1H), 4,16 (DD, J=a 9.9, 6.3 Hz, 1H), 3,86 (s, 3H), 3,70 (s, 2H), 3,38 (DD, J=11,7, 3.0 Hz, 1H), 3,25 (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H).

Example 6(10): 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-methylphenoxy acid

TLC: Rf of 0.35 (chloroform: methanol = 9:1);

NMR (300 MHz, CDCl3): δ 8,04-7,86 (user., 1H), 7,53-7,42 (m, 1H), 7,34-7,22 (m, 1H), 7,19 (d, J=7.8 Hz, 1H), 7,07-6,99 (m, 1H), 6,92-6,76 (m, 4H), 6,75 of 6.66 (m, 2H), 4,70-4,60 (m, H), 4,27 (DD, J=9,9, 4.8 Hz, 1H), 4,15 (DD, J=9,9, and 6.6 Hz, 1H), 3,66 (s, 2H), 3,39 (DD, J=11,7, 2.7 Hz, 1H), 3,25 (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H), 2,52 (s, 3H), of 2.28 (s, 3H).

Example 6(11): 5-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-chloro-2-ftorhinolona acid

TLC: Rf of 0.35 (chloroform: methanol =9:1);

NMR (300 MHz, CDCl3): δ 8,54-8,43 (m, 1H), 7,86 (s, 1H), 7,52 (d, J=8,4 Hz, 1H), 7,18 (d, J=9.0 Hz, 1H), 6,92-to 6.80 (m, 4H), 6,75 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4,27 (DD, J=9,9, 4.8 Hz, 1H), 4,15 (DD, J=9,9, and 6.6 Hz, 1H), of 3.75 (s, 2H), 3,38 (DD, J=11,7, 3.0 Hz, 1H), 3,25 (DD, J=11,7, and 6.6 Hz, 1H), 2.91 in (s, 3H), of 2.54 (s, 3H).

Example 6(12): 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-methylphenoxy acid

TLC: Rf of 0.35 (chloroform: methanol = 9:1);

NMR (300 MHz, CDCl3): δ of 7.48-7,28 (m, 4H), 6,92-6,76 (m, 5H), 6,74 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,9, 5,1 Hz, 1H), 4,14 (DD, J=9,9, and 6.6 Hz, 1H), 3,63 (s, 2H), 3,39 (DD, J=11,4, 2.7 Hz, 1H), 3,25 (DD, J=11,4, 6,6 Hz, 1H), 2.91 in (s, 3H), of 2.50 (s, 3H), of 2.35 (s, 3H).

Example 6(13): 3-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-methylphenoxy acid

TLC: Rf is 0.42 (chloroform: methanol =9:1);

NMR (300 MHz, CDCl3): δ 8,02 (s, 2H), of 7.90 (d, J=8.7 Hz, 1H), 7,19 (d, J=8,1 Hz, 1H), 7,09-7,00 (m, 2H), 7,00-6,93 (m, 1H), 6,93-for 6.81 (m, 2H), 6,76 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4,27 (DD, J=9,6, 5,1 Hz, 1H), 4,18 (DD, J=a 9.6, 6.3 Hz, 1H), 3,68 (s, 2H), 3,39 (DD, J=11,7, 2.7 Hz, 1H), 3,25 (DD, J=11,7, 6.3 Hz, 1H), 2.91 in (s, 3H), 2,32 (s, 3H).

Example 6(14): 3-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-5-MetLife ilocana acid

TLC: Rf to 0.39 (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ 8,00 (s, 1H), 7,81 (d, J=8.7 Hz, 1H), 7,41 (s, 2H), 7,01 (d, J=2.4 Hz, 1H), 6,98-for 6.81 (m, 4H), 6.75 in is 6.67 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,9, 5,1 Hz, 1H), 4,17 (DD, J=a 9.9, 6.3 Hz, 1H), 3,64 (s, 2H), 3,38 (DD, J=11,4, 2.7 Hz, 1H), 3,25 (DD, J=11,4, 6.3 Hz, 1H), 2.91 in (s, 3H), of 2.36 (s, 3H).

Reference example 11: 2-methoxy-5-nitrophenylacetonitrile

To a solution of 2-methoxy-5-nitrobenzylamine (984 mg) in dimethyl sulfoxide (5 ml) is added sodium cyanide (216 mg), and the mixture was stirred at 80°C for 10 minutes. To the reaction mixture, water is added, and the mixture was extracted with ethyl acetate. The organic layer is washed successively with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated, obtaining specified in the header of the connection, the physical data of which are given below. Received specified in the header of the connection used in the next stage without additional purification.

TLC: Rf of 0.30 (ethyl acetate:hexane =3:7).

Reference example 12: ethyl ester of 2-methoxy-5-nitrophenylacetic acid

To the compound obtained in reference example 11, add concentrated sulfuric acid (10 ml), water (10 ml), ethanol (10 ml) and dimethoxyethane (10 ml)and the resulting mixture is refluxed over night. The reaction mixture was diluted with water and ethyl acetate and then extracted with what dilatatum. The organic layer is washed successively 1 N. aqueous sodium hydroxide solution, water, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated, obtaining mentioned in the title compound (500 mg), physical data is given below.

TLC: Rf of 0.44 (ethyl acetate:hexane =3:7);

NMR (CDCl3): δ 8,21 (DD, J=9,0, 2.7 Hz, 1H), 8,12 (d, J=2.7 Hz, 1H), 6,93 (d, J=9.0 Hz, 1H), 4,18 (sq, J=7.2 Hz, 2H), 3,93 (s, 3H), to 3.67 (s, 2H), 1.26 in (t, J=7.2 Hz, 3H).

Reference example 13: ethyl ester of 2-methoxy-5-aminophenylarsonic acid

The compound obtained in reference example 12 (250 mg), dissolved in a mixed solvent comprising ethyl acetate (3 ml), methanol (3 ml) and THF (3 ml)in an argon atmosphere. To the mixture is added 10% palladium on carbon (65 mg), and the mixture is stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade mark). The filtrate is concentrated and the resulting residue is purified column chromatography on silica gel (hexane: ethyl acetate = 7:3), getting mentioned in the title compound (90 mg), the physical data is given below.

TLC: Rf of 0.55 (ethyl acetate:hexane =1:1).

Reference example 14: ethyl ester of 2-hydroxy-5-nitrophenylacetic acid

To a solution of the compound obtained in reference example 12 (250 mg)in methylene chloride (4 ml) to relax the individual tribromide boron (1M solution in methylene chloride; 3,1 ml) at -15°C, and the mixture is stirred at room temperature overnight. To the reaction mixture add crushed ice. The resulting mixture was extracted with ethyl acetate. The organic layer is washed successively with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane: ethyl acetate = 7:3), getting mentioned in the title compound (100 mg), physical data is given below.

TLC: Rf is 0.49 (ethyl acetate: hexane = 1:1);

NMR (CDCl3): δ 8,88 (s, 1H), 8,12 (DD, J=8,7, 2.7 Hz, 1H), of 8.06 (d, J=2.7 Hz, 1H), 7,02 (d, J=8.7 Hz, 1H), 4,25 (sq, J=7.2 Hz, 2H), 3,76 (s, 2H), 1,33 (t, J=7.2 Hz, 3H).

Reference example 15: ethyl ester of 2-hydroxy-5-aminophenylarsonic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of reference example 13 using the compound obtained in reference example 14, instead of the compound obtained in reference example 12.

TLC: Rf of 0.29 (ethyl acetate: hexane =1:1);

NMR (CDCl3): δ 6,79 (d, J=8,4 Hz, 1H), 6,56 (DD, J=8,4, 3.0 Hz, 1H), 6.48 in (d, J=3.0 Hz, 1H), 4,19 (sq, J=7.2 Hz, 2H), to 3.58 (s, 2H), 1,29 (t, J=7.2 Hz, 3H).

Example 7: ethyl ester of 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methoxyphenylacetic acid

Specified in reception the e connection physical data of which are given below are in accordance with the method of example 1 using the compound obtained in reference example 13, instead of the compound obtained in reference example 9.

TLC: Rf of 0.51 (ethyl acetate:hexane =1:1);

NMR (CDCl3): δ of 7.82 (d, J=8.7 Hz, 2H), 7,63 (s, 1H), 7,30-7,24 (m, 1H), 7,08-to 6.80 (m, 5H), 6.75 in-6,65 (m, 2H), 4,70-4,60 (m, 1H), 4,36-of 4.05 (m, 4H), 3,83 (s, 3H), of 3.69 (s, 2H), 3,40 (DD, J=11,7, 2.7 Hz, 1H), 3.27 to (DD, J=11,7, 6,9 Hz, 1H), 2.91 in (s, 3H), of 1.30 (t, J=7.2 Hz, 3H).

Example 7(1): ethyl ester of 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-hydroxyphenylarsonic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 1 using the compound obtained in reference example 15, instead of the compound obtained in reference example 9.

TLC: Rf 0,68 (ethyl acetate:hexane =1:1).

Example 8: 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methoxyphenoxy acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 2 using the compound obtained in example 7, instead of the compound obtained in example 1.

TLC: Rf of 0.38 (chloroform:methanol =9:1);

NMR (CDCl3): δ of 7.82 (d, J=8.7 Hz, 2H), 7,71 (s, 1H), 7,55 (DD, J=8,7, 2.7 Hz, 1H), 7,44 (d, J=2.7 Hz, 1H), 6,99 (d, J=8,7 the C, 2H), 6,94-to 6.80 (m, 3H), 6,75 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,28 (DD, J=9,9, 5,1 Hz, 1H), 4,17 (DD, J=a 9.9, 6.3 Hz, 1H), 3,83 (s, 3H), to 3.67 (s, 2H), 3,39 (DD, J=11,4, 2.7 Hz, 1H), 3,26 (DD, J=11,4, and 6.6 Hz, 1H), only 2.91 (s, 3H).

Example 8(1): 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-hydroxyphenylarsonic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 2 using the compound obtained in example 7(1), instead of the compound obtained in example 1.

TLC: Rf of 0.29 (chloroform:methanol = 5:1);

NMR (CDCl3): δ 7,86-7,72 (m, 3H), 7,43-7,35 (m, 1H), 7.24 to 7,16 (m, 1H),? 7.04 baby mortality-6,92 (m, 2H), 6,92-of 6.78 (m, 3H), 6,74-only 6.64 (m, 2H), 4,70-4,56 (m, 1H), 4,30-4,20 (m, 1H), 4,20-4,10 (m, 1H), 3,63 (s, 2H), 3,42-of 3.32 (m, 1H), 3,30-3,20 (m, 1H), 2,89 (s, 3H).

Reference example 16: benzyl ether of 2-methyl-5-nitrophenylacetic acid

In an argon atmosphere to a solution of 2-methyl-5-nitrobenzoic acid (2,45 g) in toluene (10 ml) add oxalicacid (1,88 ml), and the mixture is stirred at room temperature for 5 hours. The mixture is concentrated and the residue is dissolved in a mixed solvent comprising THF (25 ml) and acetonitrile (25 ml). To this mixture trimethylsilyldiazomethane (2M solution in hexane; 12.5 ml) under ice cooling, and the mixture was stirred at 0°C for 1 hour. The solvent is removed, to the obtained residue, add benzyl alcohol (15 ml) and kallidin (15 ml) and the mixture is stirred is at 180° C for 2 hours. The reaction mixture is cooled to room temperature. To the mixture is added 1N hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer is washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate = 9:1), obtaining mentioned in the title compound (1.4 g), the physical data is given below.

TLC: Rf of 0.60 (ethyl acetate:hexane = 3:7).

Reference example 17: benzyl ether of 2-methyl-5-aminophenylarsonic acid

The compound obtained in reference example 16 (1.4 g), dissolved in a mixed solvent comprising acetic acid (100 ml) and water (10 ml). To the solution was added iron powder (3.77 g) and the mixture was stirred at 60°C for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered through Celite (trade mark). The filtrate is concentrated. The obtained residue was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane: ethyl acetate = 9:1), obtaining mentioned in the title compound (1.1 g), the physical is their information is below.

TLC: Rf 0.31 in (ethyl acetate:hexane =3:7);

NMR (CDCl3): δ 7,40-of 7.24 (m, 5H), to 6.95 (d, J=7.8 Hz, 1H), 6,60-6,50 (m, 2H), 5,13 (s, 2H), 4,00-3,60 (user., 2N), to 3.58 (s, 2H), 2,17 (s, 3H).

Example 9: benzyl ether of 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methylphenylacetic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 1 using the compound obtained in reference example 17, instead of the compound obtained in reference example 9.

TLC: Rf to 0.19 (ethyl acetate:hexane = 3:7);

NMR (CDCl3): δ of 7.82 (d, J=9.0 Hz, 2H), 7,66 (s, 1H), 7,52 (d, J=8,1, 2.4 Hz, 1H), 7,41 (d, J=2.1 Hz, 1H), 7,40-of 7.24 (m, 5H), 7,17 (d, J=8,1 Hz, 1H), 7,01 (d, J=9.0 Hz, 2H), 6,92-for 6.81 (m, 2H), 6,74 of 6.66 (m, 2H,), of 5.15 (s, 2H), 4,72-to 4.62 (m, 1H), 4,29 (DD, J=9,6, 5,1 Hz, 1H), 4,18 (DD, J=9,6, and 6.6 Hz, 1H), 3,68 (s, 2H), 3,40 (DD, J=11,7, 2.7 Hz, 1H), 3.27 to (DD, J=11,7, 6.3 Hz, 1H), 2.91 in (s, 3H), and 2.26 (s, 3H).

Example 9(1)˜9(5)

Below obtain the connection according to the method of example 9 using the appropriate connection.

Example 9(1): benzyl ester 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-florfenicol acid benzyl

TLC: Rf 0.28 in (ethyl acetate:hexane = 3:7);

NMR (CDCl3): δ 8,43 (DD, J=7,2, 2.1 Hz, 1H), 8,00-7,94 (m, 1H), a 7.85 (d, J=9.0 Hz, 2H), 7,50-7,20 (m, 5H), 7,14-6,92 (m, 4H), 6,92-to 6.80 (m, 2H), 6,76-only 6.64 (m, 2H), further 5.15 (s, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=9,6 of 4.8 Hz, 1H), 4,19 (DD, J=9,6, and 6.6 Hz, 1H), 3,69 (s, 2H, 3,40 (DD, J=12,0, 3.3 Hz, 1H), 3.27 to (DD, J=12,0, 6,6 Hz, 1H), 2.91 in (s, 3H).

Example 9(2): benzyl ether of 5-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methylphenylacetic acid

TLC: Rf to 0.63 (ethyl acetate:hexane = 1:1);

NMR (CDCl3): δ 7,50-7,24 (m, 9H), 7,16 (d, J=8,4 Hz, 1H), 6,92-6,76 (m, 4H), 6,75 of 6.66 (m, 2H), further 5.15 (s, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,9, 5,1 Hz, 1H), 4,15 (DD, J=9,9, and 6.6 Hz, 1H), 3,68 (s, 2H), 3,39 (DD, J=11,4, 2.7 Hz, 1H), 3,26 (DD, J=11,4, 6.3 Hz, 1H), 2.91 in (s, 3H), of 2.50 (s, 3H), and 2.26 (s, 3H).

Example 9(3): benzyl ester 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-florfenicol acid

TLC: Rf 0,66 (hexane:ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ 7,68-of 7.60 (m, 1H), 7,50 (d, J=8,4 Hz, 1H), 7,40-7,28 (m, 6H), 7,10-6,76 (m, 6H), 6,76-only 6.64 (m, 2H), further 5.15 (s, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,9, 5,1 Hz, 1H), 4,15 (DD, J=9,9, and 6.6 Hz, 1H), 3,70 (s, 2H), 3,39 (DD, J=11,1, 2.4 Hz, 1H), 3,26 (DD, J=11,1, 6,6 Hz, 1H), 2.91 in (s, 3H), of 2.53 (s, 3H).

Example 9(4): benzyl ester 3-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-florfenicol acid

TLC: Rf and 0.61 (hexane:ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ 8,50-to 8.40 (m, 1H), 7,87 (d, J=8.7 Hz, 1H), 7,44-7,24 (m, 6H), 7,13-to 6.80 (m, 6H), 6,76 of 6.66 (m, 2H), further 5.15 (s, 2H), 4,70-4,60 (m, 1H), 4,27 (DD, J=9,6, a 5.4 Hz, 1H), 4,19 (DD, J=9,6, 6.0 Hz, 1H), 3,69 (s, 2H), 3,38 (DD, J=12,0, 2.7 Hz, 1H), 3,25 (DD, J=12,0, 6,6 Hz, 1H), 2.91 in (s, 3H).

Example 9(5): benzyl ether of 5-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methylphenylazo sour is s

TLC: Rf of 0.58 (hexane:ethyl acetate = 1:1);

NMR (300 MHz, CDCl3): δ 7,94 (s, 1H), 7,81 (d, J=8.7 Hz, 1H), 7,54-7,47 (m, 1H), 7,46-7,42 (m, 1H), 7,40-7,28 (m, 5H), 7,17 (d, J=8.7 Hz, 1H), 7,02 (d, J=2.1 Hz, 1H), 6,98-to 6.80 (m, 3H), 6.75 in is 6.67 (m, 2H), further 5.15 (s, 2H), 4,71-br4.61 (m, 1H), 4.26 deaths (DD, J=9,9, 5,1 Hz, 1H), 4,17 (DD, J=a 9.9, 6.3 Hz, 1H), 3,69 (s, 2H), 3,38 (DD, J=11,4, 2.7 Hz, 1H), 3,25 (DD, J=11,4, 6.3 Hz, 1H), 2.91 in (s, 3H), and 2.26 (s, 3H).

Example 10: 5-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methylphenoxy acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 2 using the compound obtained in example 9 instead of the compound obtained in example 1.

TLC: Rf of 0.37 (chloroform:methanol = 9:1);

NMR (CDCl3): δ 7,81 (d, J=8.7 Hz, 2H), 7,78 (s, 1H), 7,52-7,41 (m, 2H), 7,15 (d, J=8,4 Hz, 1H), 6,98 (d, J=8.7 Hz, 2H), 6,92-for 6.81 (m, 2H), 6.75 in of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4,27 (DD, J=of 9.6, 4.8 Hz, 1H), 4.16 the (DD, J=a 9.6, 6.3 Hz, 1H), the 3.65 (s, 2H), 3,39 (DD, J=12,0, 3.0 Hz, 1H), 3,26 (DD, J=12,0, 6.3 Hz, 1H), 2.91 in (s, 3H), of 2.28 (s, 3H).

Example 10(1)˜10(5)

Below obtain the connection according to the method of example 10, using appropriate derivative instead of the compounds obtained in example 9(1)˜9(5).

Example 10(1): 3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-ftorhinolona acid

TLC: Rf of 0.29 (chloroform:methanol =9:1);

NMR (CDCl3): δ to 8.45 (DD, J=7,5, and 2.1 Hz, 1H), 7,98 (d, J=2.1 Hz, 1H), a 7.85 (d, J=,0 Hz, 2H), 7,16-6,93 (m, 4H), 6,93-to 6.80 (m, 2H), 6,76 of 6.66 (m, 2H), 4,72-to 4.62 (m, 1H), 4,30 (DD, J=of 9.6, 4.8 Hz, 1H), 4,19 (DD, J=9,6, and 6.6 Hz, 1H), 3,69 (s, 2H), 3,40 (DD, J=12,0, 3.3 Hz, 1H), 3.27 to (DD, J=12,0, 6,6 Hz, 1H), only 2.91 (s, 3H).

Example 10(2): 5-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H - 1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methylphenoxy acid

TLC: Rf of 0.32 (chloroform:methanol = 9:1);

NMR (CDCl3): δ 7,56-7,34 (m, 4H), 7,18 (d, J=8,4 Hz, 1H), 6,92-6,76 (m, 4H), 6,75 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,6, and 4.5 Hz, 1H), 4,14 (DD, J=a 9.6, 6.3 Hz, 1H), 3,69 (s, 2H), 3,39 (DD, J=11,4, and 2.1 Hz, 1H), 3,25 (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H), of 2.50 (s, 3H), of 2.30 (s, 3H).

Example 10(3): 3-(2-methyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-ftorhinolona acid

TLC: Rf 0.31 in (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ to 7.67 (d, J=2.7 Hz, 1H), 7,50 (d, J=8,4 Hz, 1H), 7,37 (s, 1H), 7,14-6,76 (m, 6H), 6,76 of 6.68 (m, 2H), 4,70-4,60 (m, 1H), 4,27 (DD, J=9,3, 5,1 Hz, 1H), 4,15 (DD, J=9,3, and 6.6 Hz, 1H), 3,69 (s, 2H), 3,40 (DD, J=11,7, 2.7 Hz, 1H), 3,26 (DD, J=11,7, 6,9 Hz, 1H), 2,92 (s, 3H), of 2.53 (s, 3H).

Example 10(4): 3-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-4-ftorhinolona acid

TLC: Rf of 0.43 (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ 8,51-8,42 (m, 1H), 7,88 (d, J=9.6 Hz, 1H), 7,15-to 6.80 (m, 7H), 6,76 of 6.66 (m, 2H), 4,71-br4.61 (m, 1H), 4.26 deaths (DD, J=9,6, a 5.4 Hz, 1H), 4,18 (DD, J=a 9.6, 6.3 Hz, 1H), 3,70 (s, 2H), 3,40 (DD, J=12,0, 3,3 Hz, 1H), 3,25 (DD, J=12,0, 6,6 Hz, 1H), 2,9l (s, 3H).

Example 10(5): 5-(2-chloro-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)-2-methylphenoxy acid/p>

TLC: Rf of 0.47 (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ 8,00 (s, 1H), 7,81 (d, J=9.0 Hz, 1H), EUR 7.57-7,52 (m, 1H), 7,49-7,42 (m, 1H), 7,19 (d, J=8,4 Hz, 1H), 7,01 (d, J=2.4 Hz, 1H), 6,98-for 6.81 (m, 3H), 6,76 of 6.66 (m, 2H), 4,70-4,60 (m, 1H), 4.26 deaths (DD, J=9,9, 5,1 Hz, 1H), 4,17 (DD, J=a 9.9, 6.3 Hz, 1H), 3,69 (s, 2H), 3,38 (DD, J=11,4, 2.7 Hz, 1H), 3,25 (DD, J=11,4, and 6.6 Hz, 1H), 2.91 in (s, 3H), 2,31 (s, 3H).

Reference example 18: the pyridine salt of 4-(atomic charges)benzosulfimide acid

A solution of 4-(hydroxy)benzosulfimide acid (3 g) in pyridine (10 ml) and acetic anhydride (10 ml) was stirred at room temperature for 3 hours. The resulting crystalline material is collected by filtration and washed with hexane, getting mentioned in the title compound (4 g) physical data of which is given below.

NMR (300 MHz, CDCl3): δ 8,95 (d, J=6.0 Hz, 2H), 8,42 (t, J=7.5 Hz, 1H), 8,02-7,89 (m, 4H), 7,12 (d, J=8.7 Hz, 2H).

Reference example 19: 4-(chlorosulfonyl)phenylacetate

In an argon atmosphere to a solution of the compound obtained in reference example 18 (4 g), dimethoxyethane (20 ml) is added thionyl chloride (2.5 ml). The mixture was stirred at 0°C for 1 hour. To the reaction mixture poured water, and the resulting mixture extracted with ethyl acetate. The organic layer is washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel, is the learn specified in the title compound (2.76 g), physical data of which is given below.

TLC: Rf of 0.50 (hexane:ethyl acetate = 7:3).

Reference example 20: methyl ether 3-((((4 atomic charges)phenyl)sulfonyl)amino)phenylacetic acid

Specified in the header of the connection, the physical data shown below are in accordance with the method of example 1 using the compound obtained in reference example 9 (300 mg)and the compound obtained in reference example 19 (426 mg).

TLC: Rf 0,11 (hexane:ethyl acetate = 7:3).

Reference example 21: methyl ether 3-((((4-hydroxy)phenyl)sulfonyl)amino)phenylacetic acid

To a solution of the compound obtained in reference example 20 in methanol (10 ml) and dimethoxyethane (5 ml) is added potassium carbonate (354 mg) at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was filtered through Celite (trade mark)and the filtrate concentrated. The residue is purified column chromatography on silica gel, getting mentioned in the title compound (370 mg), physical data is given below.

TLC: Rf is 0.22 (hexane:ethyl acetate = 1:1).

Example 11: the methyl ester of 3-(((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)phenyl)sulfonyl)amino)phenylacetic acid

To a solution of the compound obtained in reference example 21 (370 mg)in DMF (15 ml) was added (2S)-2-tosyloxy-4-meth is l-3,4-dihydro-2H-1,4-benzoxazin (384 mg), received in accordance with the methods described above in the following sequence: reference example 1 → reference example 2 → reference example 3 → reference example 4, → reference example 5, using a corresponding compound in the presence of cesium carbonate (750 mg) at room temperature. The mixture was stirred at 60°C for 2 hours. To the reaction mixture, water is added and the resulting mixture extracted with ethyl acetate. The organic layer is washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue is purified column chromatography on silica gel, getting mentioned in the title compound (282 mg), physical data is given below.

TLC: Rf and 0.46 (hexane:ethyl acetate =1:1);

NMR (300 MHz, CDCl3): δ 7,74-7,66 (m, 2H), 7,19 (t, J=8,1 Hz, 1H), 7,06-of 6.78 (m, 7H), 6,75-of 6.65 (m, 2H), 6,41 (s, 1H), 4,68-4,58 (m, 1H), 4,23 (DD, J=of 9.6, 4.8 Hz, 1H), 4,13 (DD, J=9,6, 6.0 Hz, 1H), to 3.67 (s, 3H), 3,55 (s, 2H), 3,36 (DD, J=11,7, 2.7 Hz, 1H), 3,23 (DD, J=11,7, and 6.6 Hz, 1H), 2,89 (s, 3H).

Example 12: 3-(((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)phenyl)sulfonyl)amino)phenylacetic acid

Specified in the title compound (90 mg), the physical data shown below are in accordance with the method of example 2 using the compound obtained in reference example 11 (111 mg).

TLC: Rf of 0.33 (chloroform is:methanol =9:1);

NMR (300 MHz, CDCl3): δ 7,63 (d, J=9,3 Hz, 2H), 7.24 to 7,17 (m, 1H), 7,13-7,06 (m, 1H),? 7.04 baby mortality-6,97 (m, 1H), 6,94-6,70 (m, 8H), 4,67-of 4.57 (m, 1H), 4,27 (DD, J=10,2, 5,1 Hz, 1H), 4,14 (DD, J=10,2, 5.7 Hz, 1H), 3,53 (s, 2H), 3,37 (DD, J=11,4, 2.4 Hz, 1H), 3,17 (DD, J=11,4, 7.2 Hz, 1H), 2,88 (s, 3H).

Example 12(1)˜12(6)

Below connection receive in accordance with the methods described above in the following sequence: reference example 18 → reference example 19 → reference example 20 → reference example 21 → example 11 → example 12, using an appropriate connection.

Example 12(1): 3-(N-((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)phenyl)sulfonyl)-N-methylamino)phenylacetic acid

TLC: Rf of 0.47 (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ 7,46-7,39 (m, 2H), 7,28 (t, J=7.5 Hz, 1H), 7,21 for 7.12 (m, 2H), of 6.96-6,72 (m, 7H), 4,72-to 4.62 (m, 1H), or 4.31 (DD, J=10,5, a 5.4 Hz, 1H), 4,20 (DD, J=10,5, 6.0 Hz, 1H), 3,54 (s, 2H), 3,41 (DD, J=11,7, 2.4 Hz, 1H), 3,19 (DD, J=11,7, 7.2 Hz, 1H), 3.15 in (s, 3H), 2,90 (s, 3H).

Example 12(2): 3-(N-((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)phenyl)sulfonyl)-N-ethylamino)phenylacetic acid

TLC: Rf of 0.56 (chloroform:methanol =9:1);

NMR (300 MHz, CDCl3): δ 7,52-7,44 (m, 2H), 7,30 (t, J=7.8 Hz, 1H), 7,21-7,10 (m, 2H), of 6.96-to 6.80 (m, 4H), 6,80-of 6.71 (m, 3H), 4,74 with 4.64 (m, 1H), 4,32 (DD, J=10,8, a 5.4 Hz, 1H), 4,20 (DD, J=10,8, 6.0 Hz, 1H), 3,70-to 3.50 (m, 4H), to 3.41 (DD, J=11,7, 2.4 Hz, 1H), 3,20 (DD, J=11,7, 7.2 Hz, 1H), 2,90 (s, 3H), of 1.07 (t, J=7.2 Hz, 3H).

Example 12(3): 3-(N-((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-and the methoxy)phenyl)sulfonyl)-N-propylamino)phenylacetic acid

TLC: Rf of 0.56 (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ 7,47 (d, J=8.7 Hz, 2H), 7,32-7,26 (m, 1H), 7,20-to 7.09 (m, 2H), 6,97-of 6.71 (m, 7H), 4,73-4,63 (m, 1H), or 4.31 (DD, J=a 10.5, 5.7 Hz, 1H), 4,20 (DD, J=10,5, 6.0 Hz, 1H), 3,55 (s, 2H), 3,54-3,44 (m, 2H), 3,41 (DD, J=11,7, 2.7 Hz, 1H), 3,20 (DD, J=11,7, 6,9 Hz, 1H), 2,90 (s, 3H), 1,50-of 1.36 (m, 2H), 0,89 (t, J=7.5 Hz, 3H).

Example 12(4): 3-(N-((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)phenyl)sulfonyl)-N-butylamino)phenylacetic acid

TLC: Rf of 0.56 (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ 7,47 (d, J=9.0 Hz, 2H), 7,34-7,27 (m, 1H), 7,22-to 7.09 (m, 2H), 7,00-6,70 (m, 7H), 4,73-4,60 (m, 1H), 4,32 (DD, J=10,2, 5,1 Hz, 1H), 4,20 (DD, J=10,2, 6.3 Hz, 1H), 3,60 is-3.45 (m, 4H), 3,42 (DD, J=11,4, 2,4 Hz, 1H), 3,20 (DD, J=11,4, 7.5 Hz, 1H), 2,90 (s, 3H), 1,45-1,20 (m, 4H), of 0.85 (t, J=6.9 Hz, 3H).

Example 12(5): 3-(N-((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)phenyl)sulfonyl)-N-isopropylamino)phenylacetic acid

TLC: Rf of 0.50 (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ 7,63 (d, J=9.0 Hz, 2H), 7,35-7,22 (m, 2H), 7,11-7,05 (m, 1H), 7,00-for 6.81 (m, 5H), 6,79-6,69 (m, 2H), 4,72-to 4.52 (m, 2H), or 4.31 (DD, J=10,2, a 5.4 Hz, 1H), 4,18 (DD, J=10,2, 6.3 Hz, 1H), only 3.57 (s, 2H), 3,41 (DD, J=11,4, 2.4 Hz, 1H), 3,23 (DD, J=11,4, 6,9 Hz, 1H), 2,90 (s, 3H), of 1.05 (d, J=6.9 Hz, 6H).

Example 12(6): 3-(N-((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)phenyl)sulfonyl)-N-isobutylamino)phenylacetic acid

TLC: Rf of 0.51 (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ was 7.45 (d, J=9.0 Hz, 2H), 7,29 (t, J=7.2 Hz, 1H), 7,20-7,11 (m, 2H), of 6.96-to 6.80 (m, 4H), 6,80-of 6.71 (m, 3H), 4,73-4,63 (m, 1H), 4,32 (DD, J=10,8, a 5.4 Hz, 1H), 4,20 (DD, J=10,8, ,0 Hz, 1H), 3,54 (s, 2H), 3,42 (DD, J=12,0, 2.4 Hz, 1H), 3,38-3,24 (m, 2H), 3,19 (DD, J=12,0, 7.5 Hz, 1H), 2,90 (s, 3H), 1,63-1,50 (m, 1H), 0,90 (d, J=6.6 Hz, 3H), 0,89 (d, J=6.6 Hz, 3H).

Reference example 22: 4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzaldehyde

Specified in the title compound (270 mg), physical data shown below are in accordance with the method of example 11, using 4-hydroxybenzaldehyde (150 mg).

TLC: Rf of 0.43 (hexane:ethyl acetate = 7:3).

Example 13: methyl ester of 3-((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzyl)amino)phenylacetic acid

To a solution of the compound obtained in reference example 22 (270 mg)and the compound obtained in reference example 9 (180 mg)in dichloroethane (5 ml) is added acetic acid (0,097 ml) and triacetoxyborohydride sodium (462 mg) at room temperature, and the mixture was stirred for 1 hour. To the reaction mixture, water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated, obtaining mentioned in the title compound (330 mg), physical data is given below.

TLC: Rf 0,46 (toluene:ethyl acetate = 1:9);

NMR (300 MHz, CDCl3): δ 7,32-7,24 (m, 2H), 7,12 (t, J=7.8 Hz, 1H), 6,91 (d, J=9.0 Hz, 2H), 6,88-to 6.80 (m, 2H), 6,72-6,60 (m, 3H), 6,58-6,50 (m, 2H), 4,68-4,58 (m, 1H), 4,25 (s, 2H), 4.26 deaths-4,17 (m, 1H), 4,15-of 4.05 (m, 1H) 4,00-to 3.92 (m, 1H), to 3.67 (s, 3H), 3,53 (s, 2H), 3,39 (DD, J=11,7, 2.7 Hz, 1H), 3,25 (DD, J=11,7, and 6.6 Hz, 1H), 2,90 (s, 3H).

Example 14: 3-((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzyl)amino)phenylacetic acid

Specified in the title compound (48 mg), physical data shown below are in accordance with the method of example 2 using the compound obtained in example 12 (110 mg).

TLC: Rf of 0.47 (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ 7,32-7,24 (m, 2H), 7,12 (t, J=7.8 Hz, 1H), 6,94-to 6.80 (m, 4H), 6,70 (d, J=7.8 Hz, 2H), only 6.64 (t, J=7.2 Hz, 1H), 6,57-6,51 (m, 2H), 4,67-of 4.57 (m, 1H), 4,30-4,19 (m, 3H), 4,17-of 4.05 (m, 1H), 3,55 (s, 2H), 3,38 (DD, J=11,4, 2.7 Hz, 1H), 3,23 (DD, J=11,4, 6,9 Hz, 1H), 2,89 (s, 3H).

Example 14(1)˜14(2)

Below connection receive in accordance with the methods described above in the following sequence: reference example 22 → example 13 → example 14, using the appropriate connection.

Example 14(1): 3-(N-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzyl)-N-methylamino)phenylacetic acid

TLC: Rf of 0.50 (chloroform:methanol = 9:1);

NMR (300 MHz, CDCl3): δ 7,22-7,10 (m, 3H), 6,94-6,79 (m, 4H), 6.75 in-6,60 (m, 5H), 4,66-4,56 (m, 1H), 4,46 (s, 2H), 4,22 (DD, J=9,6, 5,1 Hz, 1H), 4,08 (DD, J=9,6, and 6.6 Hz, 1H), only 3.57 (s, 2H), 3,38 (DD, J=11,4, 2.4 Hz, 1H), 3,22 (DD, J=11,4, 6,9 Hz, 1H), 2,98 (s, 3H), 2,89 (s, 3H).

Example 14(2): 3-(N-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzyl)-N-ethylamino)phenylacetic acid

TLC: Rf 0,49 (chlorine the product:methanol = 9:1);

NMR (300 MHz, CDCl3): δ 7,19-to 7.09 (m, 3H), 6,92-6,79 (m, 4H), 6,74-only 6.64 (m, 2H), 6,64-6,55 (m, 3H), 4,65-4,55 (m, 1H), of 4.44 (s, 2H), 4,22 (DD, J=of 9.6, 4.8 Hz, 1H), 4,08 (DD, J=9,6, and 6.6 Hz, 1H), 3,54 (s, 2H), 3,44 (sq, J=7,2 Hz, 2H), 3,38 (DD, J=11,7, 2.7 Hz, 1H), 3,21 (DD, J=11,7, 6,9 Hz, 1H), 2,88 (s, 3H), of 1.18 (t, J=7.2 Hz, 3H).

Example compositions 1

Below the components are mixed in a standard way and pressed to obtain 100 tablets each containing 50 mg of active ingredient.

3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)phenylacetic acid5.0 g
Carboxymethylcellulose, calcium salt (disintegrity agent)0.2 g
Magnesium stearate (lubricant)0.1 g
Microcrystalline cellulose4.7 grams

Example composition 2

Below the components are mixed in a standard way, the solution is sterilized in a standard way and poured into a 5 ml ampoule, then lyophilizer standard way, thus obtaining 100 ampoules each containing 20 mg of active ingredient.

3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylethoxy)benzoylamine)phenylacetic acid2.0 g
M is NIT 20 g
Distilled water1000 ml

1. Carboxylic acid derivative represented by the formula (I)

where R1represents (1) hydrogen atom, (2)1-4alkyl or (4) benzyl;

E represents-C(=O)-, -SO2- or-CH3-;

R2represents (1) halogen atom, (2) C1-6alkyl, (3) C1-6alkoxy, (4) hydroxyl, or (11)1-4alkyl, substituted OR8;

R3represents (1) halogen atom, (2) C1-6alkyl, (3) C1-6alkoxy;

R4represents (1) hydrogen atom, (2) C1-6alkyl;

R5represents (1) C1-6alkyl, (2) C1-10alkoxy,

R5represents a C1-4alkyl, phenyl;

represents a benzene ring;

G represents (1) C1-6alkylen;

is dihydroisoxazole;

m represents 0 or an integer from 1 to 4;

n represents 0 or an integer from 1 to 4 and

i represents 0 or an integer from 1 to 8;

where, when m is greater than or equal to 2, R2are the same or different; when n is greater than or equal to 2, R3 are the same or different; when i is greater than or equal to 2, R5are the same or different,

or its pharmaceutically acceptable salt.

2. Pharmaceutical composition having antagonistic activity against the DP receptor containing the compound according to claim 1 or its pharmaceutically acceptable salt.

3. The remedy for the prevention and/or treatment of diseases caused by activation of the DP receptor, which contains a compound according to claim 1 or its pharmaceutically acceptable salt.

4. The remedy for the prevention and/or treatment of diseases related to allergic Renita, allergic conjunctivitis, bronchial asthma, systemic mastocytosis, migraine, contact dermatitis, stroke, ulcerative colitis, platelet aggregation or sleep disorders, which contains a compound according to claim 1 or its pharmaceutically acceptable salt.

5. The use of compounds according to claim 1 for the manufacture of pharmaceutical products for the prevention and/or treatment of diseases related to allergic Renita, allergic conjunctivitis, bronchial asthma, systemic mastocytosis, migraine, contact dermatitis, stroke, ulcerative colitis, platelet aggregation or sleep disorders.

6. The method of prevention and/or treatment of diseases related to allergic Renita, allergic to is injuctive, bronchial asthma, systemic mastocytosis, migraine, contact dermatitis, stroke, ulcerative colitis, platelet aggregation or sleep disorders, which includes an introduction to the mammal an effective amount of a compound according to claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: compounds with the formula are described and its pharmaceutically acceptable salts, where Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, m, n, p and q are as specified in the invention. The obtained compounds have the modulating activity regarding the 5-HT receptors. The pharmaceutical composition which contains the compounds with formula (I) and used in treatment of certain central nervous system diseases is also described.

EFFECT: novel compound group with useful biological properties is obtained.

10 cl, 2 dwg, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a method for preparing derivatives of benzoxazine and describes a method for preparing compound represented by the formula . Method involves of compound represented by the formula (I): with compound represented by the formula (II-1-a): in the presence of a base to form compound represented by the formula (III-1-a): followed by reduction of this compound to compound represented by the formula (IV-a): , interaction of this compound with compound represented by the following formula: to form compound represented by the formula (V-a): and the following treatment of this compound in the presence of a base to obtain compound represented by the formula (VI-a): , treatment of this compound with compound of boron trifluorine and its conversion by this manner to the boron chelate compound represented by the following formula: followed by reaction of this compound with 4-methylpiperazine to obtain compound represented by the following formula: followed by cleavage and elimination of boron chelate of this compound. In each of above given formulas X1, X2 and X3 represents independently halogen atom; R1 represents a leaving group; R3 represents hydrogen atom or carboxyl-protecting group; R4 represents hydroxyl-protecting group; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms; R7 represents carboxyl-protecting group; Y represents alkoxy-group comprising 1-6 carbon atoms, halogen atom or dialkylamino-group (wherein alkyl groups can be similar or different and each represents alkyl group comprising 1-6 carbon atoms). Also, invention describes variants above described method, methods for preparing intermediate compounds and intermediate compound. Invention provides industrially favorable methods for preparing intermediate compounds that are useful for preparing compounds with antibacterial properties.

EFFECT: improved preparing methods, valuable properties of compounds.

96 cl, 102 ex

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

SUBSTANCE: invention relates to derivatives of aryl carboxylic acids and describes a compound of the formula (I):

, wherein groups R1, R2, R3, R4 and groups R5 and R6 when they are joined to carbon atom can be similar or different and mean hydrogen, halogen atom, hydroxy-group or optionally substituted group taken among alkyl, alkoxy-group, phenyl, carboxylic acid or sulfonic acid; one or both substitutes R5 and R6 can mean oxo-group also if they are joined to carbon atom; if R5 and R are joined to nitrogen atom then they mean hydrogen atom, hydroxy-group or optionally substituted alkyl or benzyl; X means heteroatom taken among oxygen and sulfur atom or NH; Ar means optionally substituted bivalent a single or condensed aromatic or heterocyclic group wherein aromatic ring represents phenyl, naphthyl and heterocyclic group represents furan; R7 means hydrogen, halogen atom, alkoxy-group, alkyl, or it forms a bond with the adjacent group R8; R8 means hydrogen atom, hydroxy-, alkoxy-group, alkyl or optionally substituted benzyl; or R8 forms a bond in common with R7; R9 means hydrogen atom or optionally substituted group taken among alkyl, phenyl or benzyl group; R10 means hydrogen atom or optionally substituted group taken among alkyl, phenyl or benzyl group; Y means oxygen atom or NR12 wherein R12 means hydrogen atom, alkyl or benzyl; R10 and R12 can form in common five- or six-membered cyclic structure comprising carbon atoms that involves optionally one or some heteroatoms taken among oxygen, sulfur or nitrogen atoms; a binding group represented by the formula: -(CH2)n-(O)m- can be joined through nitrogen atom or through carbon atom and wherein n means a whole number from 1 to 4; m means a whole number from 0 to 1 under condition that when a binding group is joined through carbon atom then R5 either R6 represents oxo-group; Y means oxygen atom; R9 doesn't mean hydrogen atom; or its derivatives, analogs, its tautomeric forms, its stereoisomers, its polymorphic forms, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates. Also, invention describes methods for preparing compounds of the general formula (I), intermediate compounds and methods for their preparing, a pharmaceutical composition eliciting activity with respect to hPPRα, hPPRγ and inhibitory activity with respect to HMG-CoA-reductase and involving compound of the formula (I). Also, invention relates to methods for prophylaxis and treatment of different diseases caused by above said activity, a method for reducing the total cholesterol level and a method for reducing the glucose level. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

27 cl, 64 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

The invention relates to new benzoxazine and piridokshinom compounds of formula I, where part of the Q - condensed phenyl, or condensed pyridyl; Z1is hydrogen, halogen, C1-C6alkyl, phenyl, nitro, sulfonylamino or trifluoromethyl; Z2is hydrogen or halogen; X is hydrogen or oxygen; And - C1-C6-alkyl, C1-C6-alkylaryl or C1-C6-Alkylglucoside, where aryl and heterocyclyl described in the claims, n = 0 to 3; Y is the portion described in the claims, and their pharmaceutically acceptable salts, esters and proletarienne forms

The invention relates to the derivatives of colchicine formula (I), where R denotes methoxy or methylthiourea; R1means a linear or branched C1- C6alkyl, provided that when R is methoxy, R1cannot be methyl; and compounds of formula II, where R is methylthio; R1means a linear or branched C1- C6-alkyl

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns application of 3-hydroxi-7-hydroxysteroid for protection from ischemic affection of peripheral organs and for treatment of spinal cord affection caused by spinal cord damage, where steroid is compound of formula and its pharmaceutically accepted salts and esters. Method of mammal protection from ischemia-induced tissue affection in peripheral organs or from damage-induced spinal cord affection by introduction of effective amount of 3-hydroxy-7-hydroxysteroid or its pharmaceutically accepted esters is also disclosed.

EFFECT: given invention extends range of means for protection from ischemic tissue affection in peripheral organs where each of R1, R2, Ra, Rb, A and n has values specified in description.

17 cl, 6 dwg, 14 tbl, 23 ex

FIELD: medicine; neurology.

SUBSTANCE: within 8 days from treatment beginning 1% emoxypin solution dosed 20 ml and 20% pyracetam solution are drop-by-drop introduced simultaneously intravenously daily, dissolved in 200 ml of physiological saline, once a day in the morning, combined with sermyon of single dosage 4 mg intramuscularly in the afternoon. From 9th day 1% emoxypin solution is injected intramuscularly daily dosed 5 ml once a day within 7 days, and capsulated eikonol is dosed 2 g 5 times a day within 20 days. Course of treatment continues 28 days.

EFFECT: method provides optimum scheme of treatment for the given group of patients and decrease in by-effects of medical agents.

5 tbl, 3 ex

FIELD: medicine; neurology.

SUBSTANCE: method includes pharmacotherapy added with preparations of salt-water fish oil, containing "ПHЖК" of omega-3 class - "ЭПК" and "ДГК". For this purpose patient having had stroke, 6 months after hospitalisation is prescribed to take pyracetam 5 ml intramuscularly in daily single dosage in first half of day and capsulated eikonol in dosed 2 capsules of eikonol content 1 g, daily 4 times a day within 3 weeks. For the next 2 weeks eikonol is prescribed as protein dietary caviar daily once a day dosed 45 g during meal. Then there follows a break for 5 months. Thereafter therapy course is repeated.

EFFECT: method enables to stabilise patient condition; to lower his psychological stress due to exception of collateral by-effects of therapy; to lower total cholesterol and triglyceride level for the given group of patients without special lipostatic agent application.

5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the crystal forms of methanesulfonate (A, B and C forms), methanesulfonate hydrate (F form), solvate with the acetic acid of methanesulfonate (I form), ethanesulfonate (α and β forms), hydrochloride, hydrobromide, n-toluenesulfonate or sulfate 4-(3-chlorine-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, to the methods of their production, to the pharmaceutical compositions based on them and showing the angiogenesis related activity, to the method of prevention or treatment of the disease where inhibiting angiogenesis is effective and to the application of the crystal forms in producing the pharmaceutical agent for prevention or treatment of the disease where inhibiting angiogenesis is effective.

EFFECT: producing the pharmaceutical agent for prevention or treatment of the disease where inhibiting angiogenesis is effective.

45 cl, 21 dwg, 27 tbl, 13 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns medicinal agent reducing cholesterol content in blood serum or medicinal agent for prevention and treatment of atherosclerosis consisting of combined compound of general formula 1 and inhibitors of cholesterol biosynthesis, medicinal set including this agent, and method of cholesterol reduction in blood serum or prevention and treatment of atherosclerosis.

EFFECT: effective cholesterol reduction in blood serum or prevention and effective treatment of atherosclerosis.

13 cl, 14 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention can be used for treatment of inferior limb trophic ulcers caused by postthrombotic disease. For this purpose vein blood is sampled in amount 400-500 ml with following centrifugation during 15 mines at rate 2000 rotations per minute. Produced erythromass is dissolved with 200 ml of 0.9% physiologic saline and intravenously introduced to patient. Patient plasma in amount 200 ml is placed in thermostat and incubated within 20 mines at temperature 37C°. Then incubated plasma is added with 20 mg of agent Vasaprostan and produced received mix is slowly intravenously introduced to patient drop-by-drop within 2-3 hours once a day throughout 10 days.

EFFECT: increased efficiency of treatment of trophic ulcers and prolonged agent circulation in blood.

8 dwg, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: application 2-ethyl-6-methyl-3-oxpyridine succinate (Mexicor) as agent for accelerated physical rehabilitation of patients suffering from myocardium heart attack is offered. Agent application allows to accelerate physical rehabilitation of patients, to raise tolerance (to adapt muscles), and to restore vascular endothelium reaction to physical activity for patients suffering from myocardium heart attack.

EFFECT: medicinal agent has improved efficiency.

2 tbl

FIELD: medicine; neurology.

SUBSTANCE: occupational therapy is accompanied by application of 2-6 leeches within liver, spleen planes and paraanal area. 4-5 leeches are also applied to umbilicus area.

EFFECT: reduction and normalisation of increased thrombocyte activation; reduction of anxiety and depression.

5 ex, 6 tbl

FIELD: medicine; cardiology.

SUBSTANCE: invention can be applied for prevention of immunodependant complications for cardiosurgery patients in postoperative period. For this purpose 7-10 days before operation self-restricted bone marrow cells (BMC) are sampled. Mononuclear fraction BMC is marked out in vitro. It is cultivated in gas medium within 7 to 10 days and introduced to patient during operation intramyocardially or intracoronary.

EFFECT: invention provides reparative regeneration of myocardium and reduction of infection-septic complications and organ dysfunctions.

2 tbl, 4 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: 2,4,6-trimethyl-3-oxypyridine succinate (trimexidine) is offered as specified agent. Agent is applied for treatment of acute and chronic strokes including ischemic and hemorrhagic stokes, abnormalities caused by other conditions and diseases accompanied with cognitive function reduction and neurodegeneration. Improved neurologic deficit, high muscular tonus, and improved coordination of movements after stroke, restored memory impairments and reduced number of animal death caused by stroke.

EFFECT: antihypoxic action of trimexidine surpasses one of mexidol.

4 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: invention refers to biochemistry and medicine, namely to method of production of capture physiologically active substances, specifically blood anticoagulants used for prevention and treatment of thromboses, thrombophlebitis, thromboembolism, thromboembolic complications etc. Method of production of capture physiologically active substances is realised by reaction of physiologically active substance and N- acryloylhygidroxyphthamylide copolymer, of lower critical mixing temperature. Heparin and hirudin are used as physiologically active substance while N-acryloylhygidroxyphthamylide copolymer is copolymer of 1-5% mole N-acryloylhygidroxyphthamylide, 88-98% mole N- isopropylacrylamide or N,N-diethylacrylamide and 1-7 % mole acrylamide of molecular weight 8900-18000.

EFFECT: method provides possibility to produce polymeric derivatives of blood anticoagulants of lowered molecular weight.

24 ex, 3 tbl, 1 dwg

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