Arylaniline agonists of β2-adrenergic receptors, their using, pharmaceutical composition based on thereof and method for modulation of β2-adrenergic receptors

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): their pharmaceutically acceptable salts or solvates, or stereoisomers possessing properties of agonists of β2-adrenoreceptors, to pharmaceutical composition based on thereof, using the claimed compounds in manufacturing a medicinal agent, and to a method for modulation of β2-adrenergic receptors. In the formula (I) each among R1-R5 is chosen independently from group comprising hydrogen atom, (C1-C4)-alkyl and Ra wherein alkyl is substituted optionally with substituted chosen from Rb; or R4 and R5 are combined to form group of the formula: -NRdC(=O)C(Rd)=C(Rd)-; R6, R7 and R8 represent hydrogen atom; R9 represents (C1-C4)-alkyl; R10 represents hydrogen atom or (C1-C4)-alkyl; each among R11, R12 and R13 is chosen independently from group including hydrogen atom, (C1-C4)-alkyl, vinyl, cyclohexyl, phenyl, halogen atom, -CO2Rd, -ORd, -S(O)mRd, -N(NRdRe)Rd or -S(O)2NRdRe, 5-6-membered monocyclic heteroaryl comprising 1 or 2 heteroatoms chosen from nitrogen (N), sulfur (S) atoms, 9-membered bicyclic heteroaryl comprising N as a heteroatom and 5-membered heterocycle comprising N as a heteroatom; or R11 and R12 in common with atoms to which they are bound form 6- or 7-membered heterocyclic ring comprising oxygen (O) atom as a heteroatom and wherein for R11-R13 each phenyl or heteroaryl is substituted optionally with 1 or 2 substitutes chosen independently from Rc, and each heterocyclyl is substituted optionally with 1 or 2 substitutes chosen from Rb and Rc; alkyl is substituted optionally with substitute chosen from Rb, and vinyl is substituted optionally with substitute chosen from Rm; w = 0, 1, 2, 3 or 4. Values Ra, Rb, Rc, Rd, Rm and m are given in the invention claim.

EFFECT: improved method for modulation, valuable medicinal properties of compounds and pharmaceutical composition.

22 cl, 225 ex

 

This invention relates to new agonists β2adrenergic receptors. This invention also concerns pharmaceutical compositions containing such compounds, methods of using such compounds to treat diseases associated with the activity β2adrenergic receptors, and methods and intermediates useful for obtaining such compounds.

Agonists β2adrenergic receptorsrecognized as an effective medication for the treatment of pulmonary diseases such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema). Agonists β2adrenergic receptors are also suitable for treatment in case of premature birth and potentially useful for the treatment of neurological disorders and cardiac disorders. Despite the success achieved with specific agonists β2adrenergic receptors, modern agents have less than desirable, efficiency, selectivity, speed and/or duration of action. Thus, there is a need for additional agonists β2adrenergic receptors with improved properties. Preferred agents may possess, among other properties, increased duration of action which I, efficiency, selectivity and/or performance.

Summary of invention

This invention relates to new compounds, which have agonistic activity concerning β2adrenergic receptors. Thus, the invention relates to compounds of formula (I):

where each of R1-R5independently selected from the group comprising hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, cycloalkyl, heterocyclyl and Rand;

or R1and R2, R2and R3, R3and R4or R4and R5together with the formation of a group selected from the group comprising-C(Rd)=C(Rd)C(=O)NRd-, -CRdRd-CRdRd-C(=O)NRd-, -NRdC(=O)C(Rd)=C(Rd)-, -NRdC(=O)CRdRd-CRdRd-, -NRdC(=O)S-, -SC(=O)NRd-, -(CRdRd)p-, -S(CRdRd)q-, -(CRdRd)qS-, -S(CRdRd)rO-, -O(CRdRd)rS -, and-NHC(Rj)=C(Rk)-;

R6represents hydrogen, alkyl or alkoxy;

R7represents hydrogen or alkyl;

R8represents hydrogen or alkyl; or R8together with R9represents-CH2- or-CH2CH2-;

R9the independent is selected from the group includes alkyl, alkenyl, quinil, aryl, heteroaryl, cycloalkyl, heterocyclyl and Randor R9together with R8represents-CH2- or-CH2CH2-;

R10represents hydrogen or alkyl;

R11, R12and R13independently selected from the group comprising hydrogen, alkyl, cycloalkyl, alkenyl, quinil, aryl, heteroaryl, heterocyclyl, -NO2, halogen, -NRdRe, -C(=O)Rd, -CO2Rd, -OC(=O)Rd, -CN, -C(=O)NRdRe, -NRdC(=O)Re, -OC(=O)NRdRe, -NRdC(=O)ORe, -NRdC(=O)NRdRe, -ORd, -S(O)mRd, -NRd-NRd-C(=O)Rd, -NRd-N=CRdRd, -N(NRdReRdor-S(O)2NRdRe;

or R11and R12together with the atoms to which they are attached, form a condensed benzene ring which may be optionally substituted by 1, 2, 3 or 4 Rwith;

or R11and R12together with the atoms to which they are attached, form a heterocyclic ring;

where R1-R6, R9and R11-R13each alkyl, alkenyl and quinil optionally substituted Rmor one or more (e.g. 1, 2, 3, or 4) substituents independently selected from Rb; for R1-R6, R9and R11-R13each aryl and heteroaryl obazatelno substituted 1, 2, 3 or 4 substituents, independently selected from Rwith; and R1-R6, R9and R11-R13each cycloalkyl and heterocyclic ring optionally substituted by 1, 2, 3 or 4 substituents, independently selected from Rband Rwith;

each Randindependently is-ORd, -NO2, halogen, -S(O)mRd, -S(O)2ORd, -S(O)mNRdRe, -NRdRe, -O(CRfRg)nNRdRe, -C(=O)Rd, -CO2Rd, -CO2(CRfRg)nCONRdRe, -OC(=O)Rd, -CN, -C(=O)NRdRe, -NRdC(=O)Re, -OC(=O)NRdRe, -NRdC(=O)ORe, -NRdC(=O)NRdRe, -CRd(=N-ORe), -CF3or-OCF3;

each Rbindependently is Rand, oxo or =N-ORc;

each Rwithindependently represents Rand, alkyl, alkenyl or quinil; where each alkyl, alkenyl and quinil optionally substituted by 1, 2, 3 or 4 substituents, independently selected from Rb;

each Rdand Reindependently represents hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, cycloalkyl or heterocyclyl; where each alkyl, alkenyl, quinil, aryl, heteroaryl, cycloalkyl or heterocyclyl optionally substituted by one or more (e.g. 1, 2, 3, or 4) substituents independently selected the data of R h; or Rdand Retogether with the atoms to which they are attached, form a heterocyclic ring having from 5 to 7 ring atoms, with the specified heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;

each Rfand Rgindependently represents hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; where each alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from Rh; or Rfand Rgtogether with the carbon atoms to which they are attached, form a ring having from 5 to 7 ring atoms, with the specified ring optionally contains 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen;

each Rhindependently represents halogen, C1-8alkyl, C1-8alkoxy, -S-C1-8alkyl, aryl, (aryl)-C1-6alkyl, (aryl)-C1-8alkoxy, heteroaryl, (heteroaryl)-C1-6alkyl, (heteroaryl)-C1-8alkoxy, hydroxy, amino, -NHC1-6alkyl, -N(C1-6alkyl)2, -OC(=O)1-6alkyl, -C(=O)1-6alkyl, -C(=O)OS1-6alkyl, -NHC(=O)1-6alkyl, -C(=O)NHC1-6alkyl, carboxy, nitro, -CN or-CF3;

Rjand Rktogether with the carbon atoms to which it is attached, form a phenyl ring, which is optionally substituted by 1, 2, 3 or 4 Rwith;

each Rmindependently represents an aryl, heteroaryl, cycloalkyl or heterocyclyl, where each aryl or heteroaryl optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of Rwithand where every cycloalkyl and heterocyclyl optionally substituted by 1, 2, 3 or 4 substituents selected from Rb;

m is 0, 1 or 2;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

p is 3, 4 or 5;

q is 2, 3 or 4;

r is 1, 2 or 3;

w is 0, 1, 2, 3 or 4;

or their pharmaceutically acceptable salt, or solvate, or stereoisomer.

The invention also concerns the compounds of formula (II):

where R4represents-CH2HE or-NHCHO, and R5represents hydrogen; or R4and R5taken together are-NHC(=O)CH=CH-;

R11represents phenyl or heteroaryl, where each phenyl optionally substituted by 1 or 2 substituents selected from halogen, -ORd, -CN, -NO2, -SO2Rd, -C(=O)Rd, -C(=O)NRdReand C1-3of alkyl, where C1-3alkyl optionally substituted by 1 or 2 substituents selected from carboxy, hydroxy and amino, and each Rdand Reindependently denotes hydrogen or C1-3alkyl; and g is e every heteroaryl optionally substituted by 1 or 2 C 1-3alkyl substituents; and

R12represents hydrogen or-OS1-6alkyl;

or their pharmaceutically acceptable salt, or solvate, or stereoisomer.

This invention also concerns pharmaceutical compositions containing a compound of this invention and a pharmaceutically acceptable carrier.

This invention relates to a method of treatment of a disease or condition associated with the activity β2adrenergic receptors (e.g., lung diseases, such as asthma or chronic obstructive pulmonary disease, premature birth, neurological disturbance, cardiac disorders or inflammation), in mammals comprising the administration to a mammal a therapeutically effective amount of the compounds of this invention.

This invention relates to a method of treatment of a disease or condition associated with the activity β2adrenergic receptor (e.g., lung diseases, such as asthma or chronic obstructive pulmonary disease, premature birth, neurological disturbance, cardiac disorders or inflammation), in mammals comprising the administration to a mammal a therapeutically effective amount of the pharmaceutical composition of the present invention.

This invented the e also applies modulation method β 2adrenergic receptor, and the method includes stimulation β2adrenergic receptor using a modulating amount of a compound of this invention.

Separate and distinct aspect of the present invention also relates to synthetic methods and new intermediate products, including the ones described here, compounds of the formulas (III), (IV) and (VII), which are useful for preparing compounds of the present invention.

The invention also concerns the compounds of this invention, which is described here for use in drug therapy, and the use of the compounds of this invention in the manufacture of the drug or drugs for the treatment of a disease or condition associated with the activity β2adrenergic receptors (e.g., lung diseases, such as asthma or chronic obstructive pulmonary disease, premature birth, neurological disturbance, cardiac disorders or inflammation), in mammals.

When describing the compounds, compositions and methods of the present invention, the following terms have the following meanings, unless specified otherwise.

The term "alkyl" refers to monovalent saturated hydrocarbon group, which may be linear or branched, or a combination of both. Such alkyl grouppattern contain from 1 to 20 carbon atoms; more preferably from 1 to 8 carbon atoms; even more preferably from 1 to 4 carbon atoms. Typical alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term "alkenyl" refers to monovalent unsaturated hydrocarbon group containing at least one double bond in the carbon-carbon, usually 1 or 2 double bonds carbon-carbon bonds, which may be linear or branched, or a combination of both. Such alkeneamine groups preferably contain from 2 to 20 carbon atoms; more preferably from 2 to 8 carbon atoms; even more preferably from 2 to 4 carbon atoms. Typical alkeneamine groups include, for example, vinyl, allyl, Isopropenyl, but-2-enyl, n-Penta-2-enyl, n-Gex-2-enyl, n-hept-2-enyl, n-Oct-2-enyl, n-non-2-enyl, n-Dec-4-enyl, n-Dec-2,4-dienyl and the like.

The term "quinil" refers to monovalent unsaturated hydrocarbon group containing at least one triple bond of carbon-carbon, usually 1 triple bond carbon-carbon bonds, which may be linear or branched, or a combination of both. Such alkyline groups preferably contain from 2 to 20 carbon atoms; more preferably from 2 to 8 carbon atoms; even more predpochtitel is about 2 to 4 carbon atoms. Typical alkyline groups include, for example, ethinyl, propargyl, but-2-inyl and the like.

The term "alkoxy" refers to a group of the formula-OR, where R denotes an alkyl group as defined above. Typical alkoxygroup include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentox, n-hexose and the like.

The term "cycloalkyl" refers to a monovalent saturated carbocyclic group which may be monocyclic or cyclical. Each ring such cycloalkyl groups preferably contain from 3 to 10 carbon atoms. This term also includes cycloalkyl group condensed with aryl or heteroaryl group, with the attachment point is a non-aromatic (cycloalkyl) part of this group. Typical cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1,2,3,4-tetrahydronaphtyl-2-yl, decahydronaphthalene, indan-1-yl, substituted, norbornyl and the like.

The term "aryl" refers to a monovalent carbocyclic group which may be monocyclic or cyclical (e.g., condensed), where at least one ring is aromatic. Such aryl groups preferably contain from 6 to 20 atoms of carbon is a; more preferably from 6 to 10 carbon atoms. This term includes cyclical carbocyclic system of rings, where one or more of the rings are not aromatic, provided that the attachment point is in the aromatic ring. Typical aryl groups include, for example, phenyl, naphthyl, azulene, indan-5-yl, 1,2,3,4-tetrahydronaphtyl-6-yl and the like.

The term "heteroaryl" refers to a monovalent aromatic group which contains at least one heteroatom, preferably from 1 to 4 heteroatoms selected from N, S and O and which may be monocyclic or cyclical (e.g., condensed). Such heteroaryl groups preferably contain from 5 to 20 atoms; more preferably from 5 to 10 atoms. This term also includes heteroaryl group fused with cycloalkyl or aryl group, and the attachment point is aromatic (heteroaryl) part of the group. Typical heteroaryl groups include, for example, pyrrolyl, isoxazolyl, isothiazolin, pyrazolyl, pyridyl (or pyridinyl, which is equivalent), oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophene, China is l, indolyl, ethanolic and the like.

The term "heterocyclyl" or "heterocyclic ring" refers to a saturated or partially unsaturated cyclic non-aromatic group which may be monocyclic or cyclical (for example, condensed or linked by a bridge) and which contains at least one heteroatom, preferably from 1 to 4 heteroatoms, selected from N(X), S and O, where X independently denotes hydrogen or alkyl. Such heterocyclyl groups preferably contain from 3 to 20 atoms; more preferably from 3 to 10 atoms. This term also includes such heterocyclyl group fused with one or more cycloalkyl, aryl or heteroaryl group. The attachment point heterocyclyl group may be any carbon atom or nitrogen in heterocyclyl, cycloalkyl, aryl or heteroaryl part of this group. Typical heterocyclyl groups include, for example, pyrrolidinyl, piperidinyl, piperazinil, imidazolidinyl, morpholinyl, indolin-3-yl, 2-imidazolyl, 1,2,3,4-tetrahydroisoquinoline-2-yl, hinokitiol, 2-examintion and the like.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "oxo" refers to a group of the formula =O.

The expression "therapeutically effective amount" refers to the amount, the residual for the implementation of the treatment with the introduction of the needy in the treatment of the patient.

Used herein, the term "treatment" refers to treatment of disease or medical condition in a patient such as a mammal (in particular, human), and includes:

(a) the prevention of cases of a disease or medical condition, i.e prophylactic treatment of the patient;

(b) a decrease in the intensity of the disease or medical condition, i.e., the elimination or call back the development of the disease or medical condition in a patient;

(c) suppressing the disease or medical condition, that is, slow or delay development of a disease or medical condition in a patient; or

(d)relief of the symptoms of the disease or medical condition in a patient.

The phrase "disease or condition associated with the activity β2adrenergic receptor" includes all medical conditions and/or States, which, as recognized currently or will be discovered in the future, associated with the activity β2adrenergic receptors. Such painful conditions include, but are not limited to this, bronchostenosis or pulmonary diseases such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema), as well as neurological disorders and cardiac disorders. It is also known that the activity β2adrene the ecological receptors associated with preterm delivery (see, for example, U.S. patent No. 5872126) and some types of inflammation (see, for example, WO 99/30703 and U.S. patent No. 5290815).

The term "pharmaceutically acceptable salt" refers to salts derived from bases or acids, which is acceptable for administration to a patient such as a mammal. Such salts can be derived pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids.

Salt, derivative, pharmaceutically acceptable acids include derivatives of acetic acid, benzosulfimide, benzoic, campolongo, lemon, econsultancy, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, Pantothenic, phosphoric, succinic, sulfuric, tartaric, para-toluensulfonate, xinafoate (1-hydroxy-2-naphthoic) acid and the like. Particularly preferred salts, derivatives, fumaric, Hydrobromic, hydrochloric, acetic, sulfuric, phosphoric, methanesulfonic, para-toluensulfonate, xinafoate, tartaric, citric, lactic, maleic, succinic and benzoic acids.

Salt, derivative, pharmaceutically acceptable inorganic bases include salts of aluminum, ammonium, calcium, copper, iron trivalent, divalent iron, lithium, magnesium,manganese, trivalent, of divalent manganese, potassium, sodium, zinc and the like. Particularly preferred salts are the ammonium, calcium, magnesium, potassium and sodium. Salt, derivative, pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines, cyclic amines, naturally occurring amines and the like, such as salts of arginine, betaine, caffeine, choline, N,N'-dibenziletilendiaminom, diethylamine, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lysine, methylglucamine, research, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine and the like.

The term "MES" refers to a complex or aggregate formed by one or more molecules of the solute, namely the compounds of this invention or its pharmaceutically acceptable salt and one or more solvent molecules. Such solvate usually are solid crystalline substances, which is essentially a fixed molar ratio of solute and solvent. Typical solvents include, for example, water, methanol, ethanol, isopropanol, acetic acid and the like. If you dissolve elem is water, then we get the solvate is a hydrate.

The phrase "leaving group" refers to a functional group or atom which can be replaced with another functional group or atom in a substitution reaction, such as reaction of nucleophilic substitution. For example, a typical leaving groups include chlorine, bromine and iodine; sulfonic ester group, such as mesilate, toilet, brasilit, nosrat and the like; and acyloxy groups, such as acetoxy, triptoreline and the like.

The expression "aminosidine group" refers to a protective group suitable for preventing undesired interactions on the nitrogen of the amino group. Typical aminosidine groups include, but are not limited to, formyl; acyl groups, for example, alcoholnye groups, such as acetyl; alkoxycarbonyl group, such as tert-butoxycarbonyl (Vos); arylethoxysilanes groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr) and 1,1-di-(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

The expression "hidroxizina group" refers to a protective group suitable for preventing undesired interactions on the hydroxyl group. Typical hydroxyamine groups include, but are not limited to this, skinnie group, such as methyl, ethyl, tert-butyl; acyl groups, for example, alcoholnye groups, such as acetyl; arylmethyl groups, such as benzyl (Bn), para-methoxybenzyl (RMV), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

Listed below are the specific and preferred values for radicals, substituents, and ranges, are for illustration purposes only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.

A specific value for R1is hydrogen.

A specific value for R2is hydrogen.

A specific value for R3is hydroxy.

A specific value for R4is-CH2HE or-NHCHO.

A specific value for R5is hydrogen.

A specific value for R4together with R5is-NHC(=O)CH=CH -, or-SC(=O)NH-.

A specific value for R6is hydrogen.

A specific value for R7is hydrogen.

A specific value for R8is hydrogen.

A specific value for w is 0.

A specific value for w is 1 or 2.

A specific value for R9together with R8the two the is-CH 2- or-CH2CH2-.

A specific value for R10is hydrogen.

Another specific value for R10is alkyl.

A specific value for R11is hydrogen.

Another specific value for R11is alkyl, alkenyl, quinil, aryl, heteroaryl, heterocyclyl, -NO2, halogen, -NRdRe, -C(=O)Rd, -CO2Rd, -OC(=O)Rd, -CN, -C(=O)NRdRe, -NRdC(=O)Re, -OC(=O)NRdRe, -NRdC(=O)ORe, -NRdC(=O)NRdRe, -ORd, -S(O)mRd, -NRd-NRd-C(=O)Rd, -NRd-N=CRdRd, -N(NRdReRdor-S(O)2NRdRe.

Another specific value for R11is hydrogen, alkyl, heterocyclyl, -ORd, -S(O)mRdor-S(O)2NRdRe.

Another specific value for R11is heterocyclyl, -ORd, -S(O)mRdor-S(O)2NRdRe.

Another specific value for R11is-ORd.

Another specific value for R11is-S(O)mRd.

Another specific value for R12is hydrogen.

Another specific value for R12is alkyl, alkenyl, quinil, aryl, heteroaryl, heterocyclyl, -NO2g the lågen, -NRdRe, -C(=O)Rd, -CO2Rd, -OC(=O)Rd, -CN, -C(=O)NRdRe, -NRdC(=O)Re, -OC(=O)NRdRe, -NRdC(=O)ORe, -NRdC(=O)NRdRe, -ORd, -S(O)mRd, -NRd-NRd-C(=O)Rd, -NRd-N=CRdRd, -N(NRdReRdor-S(O)2NRdRe.

Another specific value for R12is hydrogen, alkyl, heterocyclyl, -ORd, -S(O)mRdor-S(O)2NRdRe.

A specific value for R12is heterocyclyl, -ORd, -S(O)mRdor-S(O)2NRdRe.

Another specific value for R12is-ORd.

Another specific value for R12is-S(O)mRd.

Another specific value for R12is-S(O)2NRdRe.

A specific value for R13is hydrogen.

Another specific value for R13is alkyl, alkenyl, quinil, aryl, heteroaryl, heterocyclyl, -NO2, halogen, -NRdRe, -C(=O)Rd, -CO2Rd, -OC(=O)Rd, -CN, -C(=O)NRdRe, -NRdC(=O)Re, -OC(=O)NRdRe, -NRdC(=O)ORe, -NRdC(=O)NRdRe, -ORd, -S(O)mRd, -NRd-NRd-C(=O)Rd, -NRd-N=CRdRd-N(NR dReRdor-S(O)2NRdRe.

Another specific value for R13is hydrogen, alkyl, heterocyclyl, -ORd, -S(O)mRdor-S(O)2NRdRe.

Another specific value for R13is heterocyclyl, -ORd, -S(O)mRdor-S(O)2NRdRe.

A specific value for R13is-ORd.

A specific value for R13is-S(O)mRd.

Specific group of compounds of this invention are compounds in which each R1-R4independently selected from the group comprising hydrogen, fluorine, chlorine, amino, hydroxy, N,N-dimethylaminocarbonylmethyl, -CH2HE and-NHCHO, and R5represents hydrogen; or R1denotes hydrogen, R2denotes hydrogen, R3denotes hydroxy and R4and R5together are-NHC(=O)CH=CH -, or-SC(=O)NH-.

Specific group of compounds of this invention are compounds in which R1denotes hydrogen, R2denotes chlorine, R3denotes amino, R4represents chlorine and R5denotes hydrogen.

Specific group of compounds of this invention are compounds in which R1denotes hydrogen, R2denotes N,N-dimethylaminocarbonylmethyl, R3about the mean hydrogen, R4denotes N,N-dimethylaminocarbonylmethyl and R5denotes hydrogen.

Specific group of compounds of this invention are compounds in which R1denotes hydrogen, fluorine, chlorine, R2denotes hydroxy, R3denotes hydrogen, R4denotes hydroxy and R5denotes hydrogen.

Specific group of compounds of this invention are compounds in which R1denotes hydrogen, R2denotes hydrogen, R3denotes hydroxy, R4denotes hydrogen and R5denotes hydrogen.

Specific group of compounds of this invention are compounds in which R1denotes hydrogen, R2denotes hydrogen, R3denotes hydroxy, R4is-CH2HE and R5denotes hydrogen.

Specific group of compounds of this invention are compounds in which R1denotes hydrogen, R2denotes hydrogen, R3denotes hydroxy, R4is-NHCHO, and R5denotes hydrogen.

Specific group of compounds of this invention are compounds in which R1denotes hydrogen, R2denotes hydrogen, R3denotes hydroxy and R4and R5together are-NHC(=O)CH=CH-.

Specific group connected to the deposits of the present invention are compounds, in which R1denotes hydrogen, R2denotes hydrogen, R3denotes hydroxy and R4and R5together are-SC(=O)NH-.

Specific group of compounds of this invention are compounds in which R11denotes hydrogen, R12means-SRd, R13denotes hydrogen and Rdis alkyl, aryl or heteroaryl.

Specific group of compounds of this invention are compounds in which R11means-SRd, R12denotes hydrogen, R13denotes hydrogen and Rdis alkyl, aryl or heteroaryl.

A specific value for Rdas part of the group-SRdis alkyl.

Another specific value for Rdas part of the group-SRdis1-6alkyl.

Another specific value for Rdas part of the group-SRdis1-3alkyl.

Another more specific value for Rdas part of the group-SRdis aryl, optionally substituted 1, 2, 3 or 4 substituents, independently selected from halogen, C1-6of alkyl, C1-6alkoxy, hydroxy, amino, -N(C1-6alkyl)2, nitro, -CN, and-CF3.

Another more specific value for Rdas part of the group-SRdis phenyl, optionally substituted by 1, 2, or 4 substituents, independently selected from fluorine and C1-3the alkyl.

Specific group of compounds of this invention are compounds in which R11or R12are methylthio, 2-methylphenylthio, 4-methyl-2-pyramidally, 4-forfinally or 4 methylphenylthio.

Specific group of compounds of this invention are compounds in which R11denotes hydrogen or alkyl, R12is-SO2NRdReand R13denotes hydrogen.

Specific group of compounds of this invention are compounds in which R11is-SO2NRdRe, R12denotes hydrogen or alkyl and R13denotes hydrogen.

A specific value for Rdas part of the group-SO2NRdReis alkyl, aryl or heteroaryl, and for Rehydrogen, alkyl, aryl or heteroaryl; where each alkyl, aryl or heteroaryl optionally substituted by one or more (e.g. 1, 2, 3, or 4) substituents independently selected from Rh; or Rdand Retogether with the nitrogen atom to which they are attached, represent a heterocyclic ring having from 5 to 7 ring atoms, which heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or and the PTA.

Specific values for Rdand Reas part of the group-SO2NRdReindependently are hydrogen, alkyl, aryl or heteroaryl; where each alkyl, aryl or heteroaryl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from Rh.

A specific value for Rhas part of the group-SO2NRdReis halogen, C1-8alkyl, -C1-8alkoxy, -S-C1-8alkyl, aryl, hydroxy, amino, -NHC1-6alkyl, -N(C1-6alkyl)2, -OC(=O)1-6alkyl, -C(=O)1-6alkyl, -C(=O)OS1-6alkyl, -NHC(=O)1-6alkyl, -C(=O)NHC1-6alkyl, carboxy, nitro, -CN, and-CF3.

Another specific value for Rhin the above context is halogen, C1-6alkyl, -C1-6alkoxy or-CF3.

A specific value for Rdand Retogether with the nitrogen atom to which they are attached as part of the group-SO2NRdReis a heterocyclic ring having from 5 to 7 ring atoms; this heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen.

A specific value for Rdand Reas part of the group-SO2NRdReindependently is alkyl; and each alkyl optionally Thames which n is 1 or 2 alkoxy-substituents.

A specific value for Rdor Reas part of the group-SO2NRdReis phenyl or naphthyl, each phenyl and naphthyl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, C1-6of alkyl, -C1-6alkoxy or-CF3.

A specific value for Rdor Reas part of the group-SO2NRdReis heteroaryl; and each heteroaryl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, C1-6of alkyl, -C1-6alkoxy or-CF3. The preferred heteroaryl is pyridyl, pyrimidyl or thiazolyl.

A preferred group of compounds are compounds in which R11or R12is-SO2NRdRewhere Rddenotes 4-heptyl-6-methyl-2-pyrimidyl, 5-methoxy-2-pyrimidyl, 2-pyridyl, phenyl, 2,6-dimetilfenil, 2-thiazolyl, 2-triptoreline or 3,5-dichlorophenyl and Redenotes hydrogen or ethyl.

Another preferred group of compounds are compounds of this invention in which R11or R12is-SO2NRdRewhere Rdand Retogether with the nitrogen atom to which they are attached, represent piperidino or morpholino.

Specific group of compounds of the present invention is predstavlyaet connection in which R11denotes hydrogen or alkyl; R12is-SO2Rd; and R13denotes hydrogen.

Another specific group of compounds of this invention are compounds in which R11is-SO2Rd; R12denotes hydrogen or alkyl; and R13denotes hydrogen.

A specific value for Rdas part of the group-SO2Rdis alkyl, aryl or heteroaryl.

A specific value for Rdas part of the group-SO2Rdis aryl, optionally substituted 1, 2, 3 or 4 substituents, independently selected from halogen, C1-6of alkyl, C1-6alkoxy, and-CF3.

A specific value for Rdas part of the group-SO2Rdis phenyl, optionally substituted by 1 or 2 substituents, independently selected from halogen and C1-6the alkyl.

A preferred group of compounds of this invention are compounds in which R11or R12is-SO2Rdwhere Rddenotes phenyl, 4-chlorophenyl, methyl or 4-forfinal.

Specific group of compounds of this invention are compounds in which at least one of R11, R12and R13is-ORdand each of the remaining two of R11, R12and R13independently you the wounds from the group includes hydrogen, alkyl, -O-alkyl and halogen, where any alkyl or-O-alkyl optionally substituted by aryl or one or more (e.g. 1, 2, 3, or 4) a halogen.

Specific group of compounds of this invention are compounds in which R11is-ORd.

Specific group of compounds of this invention are compounds in which R12is-ORd.

Specific group of compounds of this invention are compounds in which R13is-ORd.

Specific group of compounds of this invention are compounds in which R11denotes hydrogen, R12means-ORdand R13denotes hydrogen.

Specific group of compounds of this invention are compounds in which R11means-ORd, R12denotes hydrogen and R13denotes hydrogen.

A specific value for Rdas part of the group-ORdis alkyl, optionally substituted by one or more (e.g. 1, 2, 3, or 4) halogen and optionally substituted by 1, 2, 3 or 4 aryl substituents, where each aryl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, C1-6of alkyl, -C1-6alkoxy, hydroxy, amino, -NHC1-6of alkyl, -N(C1-6alkyl)2/sub> , -OC(=O)1-6of alkyl, -C(=O)1-6of alkyl, -C(=O)OS1-6of alkyl, -NHC(=O)1-6of alkyl, -C(=O)NHC1-6of alkyl, carboxy, nitro, -CN, and-CF3.

A specific value for Rdas part of the group-ORdis alkyl, optionally substituted by one or more (e.g. 1, 2, 3, or 4) halogen and optionally substituted by 1 or 2 phenyl substituents, where each phenyl optionally substituted by 1 or 2 substituents, independently selected from halogen, C1-6of alkyl, -C1-6alkoxy, hydroxy, -CN, and-CF3.

Specific group of compounds of this invention are compounds in which R11and R12together with the atoms to which they are attached, form a saturated or unsaturated 5-, 6 - or 7-membered ring containing one or more carbon atoms and 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen; and R13selected from the group comprising hydrogen, alkyl, -O-alkyl and halogen, where any alkyl or-O-alkyl optionally substituted by aryl or one or more (e.g. 1, 2, 3, or 4) a halogen.

More specific group of compounds of this invention are compounds in which R11and R12together are-co2O-, -och2CH2O-, -och2CH2CH2Oh.

Specific group of compounds of this izobreteny the present connection, in which R11, R12or R13denotes methoxy, ethoxy, benzyloxy or isopropoxy.

Specific group of compounds of this invention are compounds in which R11, R12and R13each denotes hydrogen.

Specific group of compounds of this invention are compounds in which at least one of R11, R12and R13is alkyl, and each of the remaining two of R11, R12and R13independently selected from the group comprising hydrogen, alkyl, cycloalkyl, hydroxy and halogen, where any alkyl optionally substituted with aryl, one or more (e.g. 1, 2, 3, or 4) halogen or 1 or 2-O-alkyl substituents; or R11and R12together with the atoms to which they are attached, form a saturated or unsaturated 5-, 6 - or 7-membered carbocyclic ring.

Specific group of compounds of this invention are compounds in which at least one of R11, R12and R13is alkyl, and each of the remaining two of R11, R12and R13independently selected from the group comprising hydrogen, alkyl, cycloalkyl, hydroxy and halogen, where any alkyl optionally substituted with aryl, one or more (e.g. 1, 2, 3, or 4) halogen or 1 or 2-O-alkyl substituents.

Peculiar is th group of compounds of this invention are compounds, in which R11and R12together with the atoms to which they are attached, form a saturated or unsaturated 5-, 6 - or 7-membered carbocyclic ring; and R13selected from the group comprising hydrogen, alkyl, cycloalkyl, hydroxy and halogen, where any alkyl optionally substituted with aryl, one or more (e.g. 1, 2, 3, or 4) halogen or 1 or 2-O-alkyl substituents.

A specific value for R13is hydrogen.

Specific group of compounds of this invention are compounds in which R11denotes hydrogen, R12denotes alkyl and R13denotes hydrogen.

Specific group of compounds of this invention are compounds in which R11denotes alkyl, R12denotes hydrogen and R13denotes hydrogen.

A preferred group of compounds of this invention are compounds in which R11or R12denotes methyl, ethyl, isopropyl or cyclohexyl; or R11or R12taken together, represent-CH2CH2CH2-.

Specific group of compounds of this invention are compounds in which at least one of R11, R12and R13is aryl; and each of the remaining two of R11, R12and R13independently selected from the group comprising hydrogen, alkyl, -O-alkyl and halogen, where any alkyl or-O-alkyl optionally substituted with aryl, one or more (e.g. 1, 2, 3, or 4) halogen or 1 or 2-O-alkyl substituents;

or in which R11and R12together with the atoms to which they are attached, form a condensed benzene ring, which optionally may be substituted by 1, 2, 3 or 4 Rwith; and R13independently selected from the group comprising hydrogen, alkyl, -O-alkyl and halogen, where any alkyl or-O-alkyl optionally substituted with aryl, one or more (e.g. 1, 2, 3, or 4) halogen or 1 or 2-O-alkyl substituents.

Specific group of compounds of this invention are compounds in which at least one of R11, R12and R13is aryl; and each of the remaining two of R11, R12and R13independently selected from the group comprising hydrogen, alkyl, -O-alkyl and halogen, where any alkyl or-O-alkyl optionally substituted with aryl, one or more (e.g. 1, 2, 3, or 4) halogen or 1 or 2-O-alkyl substituents.

Specific group of compounds of this invention are compounds in which R11is phenyl, optionally substituted by 1, 2, 3 or 4 alkilani, -ORd, -NO2, halogen, -NRdRe, -C(=O)Rd, -CO2Rd, -OC(=O)Rd, -CN, -C(=O)NRd Re, -NRdC(=O)Re, -OC(=O)NRdRe, -NRdC(=O)ORe, -NRdC(=O)NRdRe, -CRd(=N-ORe), -CF3or-OCF3; R12selected from the group comprising hydrogen and-O-alkyl, optionally substituted aryl or one or more (e.g. 1, 2, 3, or 4) a halogen; and R13denotes hydrogen.

Specific group of compounds of this invention are compounds in which R11is phenyl, optionally substituted by 1, 2, 3 or 4 alkilani, -ORd, halogen, -CF3or-OCF3; R12selected from the group comprising hydrogen and-O-alkyl, optionally substituted aryl or one or more (e.g. 1, 2, 3, or 4) a halogen; and R13denotes hydrogen.

Specific group of compounds of this invention are compounds in which R11or R12is phenyl.

Specific group of compounds of this invention are compounds in which R11and R12together with the atoms to which they are attached, form a condensed benzene ring.

Specific group of compounds of this invention are compounds in which at least one of R11, R12and R13means heterocyclyl; and each of the remaining two of R11, R12and R13independently selected from groups who, includes hydrogen, alkyl, -O-alkyl and halogen, where any alkyl or-O-alkyl optionally substituted with aryl, one or more (e.g. 1, 2, 3, or 4) halogen or 1 or 2-O-alkyl substituents;

or in which R11and R12together with the atoms to which they are attached, form a heterocyclic ring.

Specific group of compounds of this invention are compounds in which R11and R12together with the atoms to which they are attached, form a saturated or unsaturated 5-, 6 - or 7-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen, where the specified ring optionally may be substituted on carbon with one or two oxopropyl (=O), and where the specified ring condensed with the benzene ring, which optionally may be substituted by 1, 2, 3 or 4 Rwith; and R13independently selected from the group comprising hydrogen, alkyl, -O-alkyl and halogen, where any alkyl or-O-alkyl optionally substituted with aryl, one or more Halogens or 1 or 2-O-alkyl substituents.

Specific group of compounds of this invention are compounds in which R11or R12represents 2,3-dihydro-5-methyl-3-oxo-1-pyrazolyl; or R11or R12together with the atoms to which it is attached, form 2-examensarbete ring.

Another specific group of compounds of this invention are compounds in which R11or R12means of aniline, triptoreline or methoxycarbonyl.

A subgroup of compounds of this invention are compounds of formula (I), in which each of R1-R5independently selected from the group comprising hydrogen, alkyl and Rand; where each Randindependently is-ORd, halogen, -NRdRe, -NRdC(=O)OReor-OC(=O)NRdRe;

or R1and R2or R4and R5combined together, form a group selected from the group comprising-C(Rd)=C(Rd)C(=O)NRd, -CRdRd-CRdRd-C(=O)NRd-, -NRdC(=O)C(Rd)=C(Rd)-, -NRdC(=O)CRdRd-CRdRd-, -NRdC(=O)S -, and-SC(=O)NRd-;

R6, R8and R10each denotes hydrogen;

each of R11and R12independently selected from the group comprising hydrogen, alkyl, cycloalkyl, alkenyl, quinil, aryl, heteroaryl, heterocyclyl, -NO2, halogen, -NRdRe, -CO2Rd, -OC(=O)Rd, -CN, -C(=O)NRdRe, -NRdC(=O)Re, -ORd, -S(O)mRd, -NRd-NRd-C(=O)Rd, -NRd-N=CRdRd, -N(NRdReRdor-S(O)2NRd Re;

where R1-R5, R11and R12each alkyl optionally substituted by Rmor 1, 2, 3 or 4 substituents, independently selected from Rb; for R11and R12each aryl or heteroaryl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from Rwithand R11and R12each cycloalkyl and heterocyclyl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from Rband Rwith;

R13denotes hydrogen;

group containing-NR10located in the meta - or para-position relative to the group containing the R7; and

w is 0, 1 or 2.

Inside the above mentioned subgroups of compounds preferably, when each R11and R12independently selected from the group comprising hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, -ORd, -S(O)mRdand-S(O)2NRdRe; where each alkyl optionally substituted by 1 or 2 substituents independently selected from Rbeach aryl optionally substituted by 1 or 2 substituents independently selected from Rwithand every heterocyclyl optionally substituted by 1 or 2 substituents independently selected from Rband Rwith; and m is 0 or 2.

More preferably, such compounds, when R7denotes hydrogen;

each R11and R12independent is selected from the group including hydrogen, C1-6alkyl, cyclohexyl, phenyl, pyrazolyl, -ORd, -S(O)mRdand-S(O)2NRdRe;

w is 0; and

Rdand Reindependently selected from the group comprising hydrogen, C1-6alkyl, phenyl, -CF3and C1-3alkyl, pyridyl, thiazolyl, pyrimidinyl and pyrazolyl, where each phenyl optionally substituted by 1 or 2 substituents, independently selected from halogen, -CF3and C1-3of alkyl, each pyrimidinyl optionally substituted by 1 or 2 substituents, independently selected from C1-3the alkyl and OS1-3of alkyl, and each pyrazolyl optionally substituted by 1 or 2 substituents, independently selected from C1-3the alkyl and carboxy; or

Rdand Retogether with the nitrogen atom to which they are attached, form morpholino or piperidino.

In a more preferred subgroup of the preferred subgroup of compounds are compounds in which R11means-SRdand R12denotes hydrogen, or R11denotes hydrogen, and R12means-SRdwhere Rdselected from the group comprising From1-3alkyl, phenyl and pyrimidinyl, and where each phenyl optionally substituted by 1 or 2 substituents, independently selected from halogen and C1-3of alkyl, and each pyrimidinyl optionally substituted C1-3Alki the om.

Another preferred subgroup of compounds are compounds in which R11represents-S(O)2NRdReand R12denotes hydrogen or alkyl, or R11denotes hydrogen or alkyl, and R12represents-S(O)2NRdRewhere Rdand Reindependently selected from the group comprising hydrogen, C1-3alkyl, phenyl, pyridyl, thiazolyl and pyrimidinyl, and where each phenyl optionally substituted by 1 Deputy selected from halogen and C1-3of alkyl, and each pyrimidinyl optionally substituted by 1 Deputy, selected from C1-3the alkyl and OS1-3of alkyl; or Rdand Retogether with the nitrogen atom to which they are attached, represent morpholino or piperidino.

Another preferred subgroup of compounds are compounds in which R11represents-S(O)2Rdand R12denotes hydrogen, or R11denotes hydrogen, and R12is-S(O)2Rdwhere Rdrepresents a C1-3alkyl or phenyl where each phenyl optionally substituted by 1 Deputy selected from halogen and C1-3the alkyl.

Another preferred subgroup of compounds are compounds in which R11means-ORdand R12denotes hydrogen or-ORd; or R11about the means hydrogen, and R12means-ORdwhere Rdrepresents a C1-3alkyl.

Another preferred subgroup of compounds are compounds in which R11stands With1-3alkyl, and R12denotes hydrogen or C1-3alkyl; or R11represents cyclohexane, and R12represents hydroxy.

Another preferred subgroup of compounds are compounds in which R11denotes hydrogen or phenyl, and R12denotes OS1-3alkyl; or R11denotes phenyl, and R12denotes hydrogen.

Another preferred subgroup of compounds within the preferred subgroups, defined above, are compounds in which R12denotes hydrogen, and R11represents-S(O)2NRdRewhere-Rdand Retogether with the nitrogen atom to which they are attached, form morpholino or piperidino.

Another preferred group of compounds of formula (I) are compounds of the formula (II):

where R4denotes-CH2HE or-NHCHO, and R5represents hydrogen; or R4and R5taken together are-NHC(=O)CH=CH-;

R11denotes phenyl or heteroaryl, where each phenyl optionally substituted by 1 or 2 substituents, select nimi from halogen, -ORd, -CN, -NO2, -SO2Rd, -C(=O)Rd, -C(=O)NRdReand C1-3of alkyl, where C1-3alkyl optionally substituted by 1 or 2 substituents selected from carboxy, hydroxy and amino, and each Rdand Reindependently denotes hydrogen or C1-3by alkyl; and where each heteroaryl optionally substituted by 1 or 2 C1-3alkyl substituents; and

R12represents hydrogen or-OS1-6alkyl.

More preferably for compounds of formula (II)when R11represents phenyl, optionally substituted by 1 or 2 substituents selected from halogen, -ORd, -CN, -NO2, -SO2Rd, -C(=O)Rdand C1-3of alkyl, where C1-3alkyl optionally substituted by 1 or 2 substituents selected from carboxy, hydroxy and amino, and each Rddenotes hydrogen or C1-3by alkyl; or R11represents pyridyl, thiophenyl, furanyl, pyrrolyl, isoxazolyl or indolyl, each of which is optionally substituted by 1 or 2 C1-3alkyl substituents.

The most preferred compounds of formula (II)in which R11represents phenyl, pyridyl or thiophenyl, where each phenyl optionally substituted by 1 Deputy selected from the group comprising chlorine, -och3, -CN and CH2NH2; and R12denotes hydrogen, -och3 2H5. Among the preferred compounds, especially preferred compounds of formula (II)in which R4and R5taken together are-NHC(=O)CH=CH-, R11represents phenyl or pyridyl, wherein each phenyl optionally substituted by 1 Deputy selected from the group comprising chlorine, -och3, -CN and CH2NH2; and R12represents-och3.

The preferred compound is any of compounds 1-102, shown below in the examples.

The most preferred compounds of this invention include the following:

N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenylphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)chinoline-5-yl)ethylamine;

N-{2-[4-(4-methoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-formamido-4-HYDR shall xifei)ethylamine;

N-{2-[4-(3-phenylphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-methoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)chinoline-5-yl)ethylamine;

N-{2-[4-(3-phenylphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)chinoline-5-yl)ethylamine;

N-{2-[4-(4-methoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)chinoline-5-yl)ethylamine;

N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroc iphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenylphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-phenylphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(2-chlorophenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)chinoline-5-yl)ethylamine;

N-{2-[4-(3-(2-methoxyphenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(3-cyanophenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(4-aminomethylphenol)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(3-chlorophenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(4-aminomethylphenol)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(4-hydroxyphenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(3-pyridyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(4-pyridyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(thiophene-3-yl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine and

N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine.

The compounds of this invention contain one or more chiral centers. Thus, this invention includes racemic mixtures, pure stereoisomers (i.e. individual enantiomers or diastereoisomers and mixtures of such isomers enriched stereoisomers, unless specified differently. If you see a particular stereoisomer, the person skilled in the art will understand that the compositions of this invention may be present smaller amounts of other stereoisomers, unless differently provided that the applicability of the composition as a whole does not IP Luchesa the presence of isomers. In particular, the compounds of this invention contain a chiral center at Allenova carbon in formulas (I) and (II)that is attached to the hydroxy-group. If using a mixture of stereoisomers, it is useful to number stereoisomer with orientation (R) chiral center bearing a hydroxy-group, was greater than the number of the corresponding stereoisomer (S). If you compare the stereoisomers of the same compound, stereoisomer (R) is preferred over the stereoisomer (S).

General methods of synthesis

The compounds of this invention can be obtained by applying the described methods and techniques or similar methods and techniques. It is clear that when given a typical or preferred process conditions (namely, temperature of reaction, times, mole ratios of reactants, solvents, pressures, and other), you can also use other process conditions, unless otherwise noted. Optimum reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by a person skilled in the art using routine optimization techniques.

In addition, as it is clear to a person skilled in the art, it is possible to apply a conventional protective group for the protection of certain functional groups from unwanted interactions. The choice of the appropriate protections the first group for a particular functional group, as well as suitable conditions for the introduction and removal of protecting well-known in this field. Typical examples aminosidine groups and hydroxyamine groups above. Typical methods of removal include the following. Acyl aminosidine group or hydroxyamino group may conveniently be removed, for example, by treatment with an acid, such as triperoxonane acid. Arylmethyl group may conveniently be removed by hydrogenolysis with a suitable metal catalyst such as palladium on coal. Silyl hydroxyamino group can be conveniently removed by treatment with a source of fluoride ions, such as tetrabutylammonium, or by treatment with an acid, such as hydrochloric acid.

In addition, numerous protective group (including aminosidine group and hydroxyamine groups and their introduction and removal are described in Greene and Wuts,Protecting Groups in Organic Synthesis, 2ndEdition, John Wiley & Sons, NY, 1991 and McOmie,Protecting Groups in Organic Chemistry,Plenum Press, NY, 1973.

The method of obtaining compounds of this invention are presented in the following variants of the present invention and illustrated by the following methods.

The compound of formula (I) can be obtained by removing the protection from the following compounds of formula (III):

where R15represents aminosidine group. Thus, the data the invention concerns a method for obtaining compounds of formula (I), including the removal of protection from the corresponding compounds of the formula(III), where R15represents aminosidine group (for example, 1,1-(4-methoxyphenyl)methyl or benzyl).

The compound of formula (I), where R3denotes hydroxy, can be obtained by removing the protection from the corresponding compounds of formula (I), where R3is-OPg1and Pg1represents hydroxyamino group. Thus, this invention concerns a method for obtaining compounds of formula (I), where R3denotes hydroxy, including the removal of protection from the corresponding compounds of formula (I), where R3means-OPg1and Pg1means hydroxyamino group (e.g. benzyl).

The compound of formula (I), where R3represents hydroxy can be obtained by removing the protection from the corresponding compounds of the formula (III)in which R15is aminosidine group, and R3is-OPg1where Pg1means hydroxyamino group. Thus, this invention concerns a method for obtaining compounds of formula (I), including the removal of protection from the corresponding compounds of the formula (III)in which R15is aminosidine group (e.g. benzyl), and R3is-OPg1where Pg1means hydroxyamino group (e.g. benzyl).

This invention Casa is tsya also intermediate compounds of formula (III), in which R15is aminosidine group (for example, 1,1-di-(4'-methoxyphenyl)stands or benzyl); and the intermediate compounds of formula (I)in which R3is-OPg1and Pg1means hydroxyamino group; and the intermediate compounds of formula (III)in which R15is aminosidine group (e.g. benzyl), R3is-OPg1and Pg1means hydroxyamino group (e.g. benzyl).

The intermediate compound of formula (III) can be obtained by the interaction of the amine of formula (V) with the compound of the formula (IV), where R16denotes hydrogen or hydroxyamino group (e.g. tert-butyldimethylsilyl), and X is a suitable leaving group (e.g., bromine).

Thus, this invention concerns a method for obtaining compounds of formula (III), including the interaction of the corresponding aniline of formula (V) with an appropriate compound of formula (IV), where X is a suitable leaving group (e.g., bromine)and R15represents aminosidine group, in the presence of Katalizator-transition metal. If R16represents hydroxyamino group, then remove the protection from the intermediate product obtained by the reaction of the compounds of formula(V) with the compound of the formula (IV), about what adowanie intermediate product of the formula (III). Suitable conditions for this reaction, and suitable leaving groups are shown in the examples, as well known in this field.

The compounds of formula (III) can also be obtained in the interaction of an amine of formula (VII):

where R14represents hydrogen and R15represents aminosidine group (e.g. benzyl), with the compound of formula (VI), (VIII) or (IX):

where R16denotes hydrogen or hydroxyamino group (e.g. tert-butyldimethylsilyl), and Z is a suitable leaving group.

Thus, this invention concerns a method for obtaining compounds of formula (III), including the interaction of the amine of formula (VII), where R14denotes hydrogen, and R15means aminosidine group, with a corresponding compound of formula (VI), (VIII) or (IX), where R16denotes hydrogen or hydroxyamino group and Z is a suitable leaving group (e.g., bromine). If R16represents hydroxyamino group, then remove the protection from the intermediate product obtained by the reaction of the compounds of formula (VII) with the compound of the formula (VI), with formation of an intermediate product of the formula (III).

This invention relates to a method for obtaining compounds of the shape of the s (I), where R3is-OPg1and Pg1means hydroxyamino group, including the interaction of the compounds of the formula (VII), where R14and R15each denotes hydrogen, with an appropriate compound of formula (VI), where R3is-OPg1and Pg1means hydroxyamino group, and R16represents hydroxyamino group.

Depending on the specific values of the substituents is possible to use variations of the above described schemes of synthesis, in particular, in order reactions interaction and removal protection, receiving the compound of the present invention. For example, the compound of formula (I)in which R3denotes hydroxy, and R12and R13denote hydrogen, can be obtained by the interaction of the intermediate compounds of formula (I)in which R3is-OPg1where Pg1means hydroxyamino group, and R11is a suitable leaving group (for example, bromine), with Bronevoy acid, substituted appropriately, obtaining an intermediate product, which then removes the protection, as shown in the examples 65-102.

In addition, a useful intermediate compound to obtain a compound of formula (VII), where R14denotes hydrogen, and R15means aminosidine group, is the appropriate compound of formula (VII), where the R 14is aminosidine group that can be removed in the presence of R15. The compound of formula (VII), where R14denotes hydrogen, and R15means aminosidine group itself is also a useful intermediate compound to obtain a compound of formula (VII), where R14and R15both represent hydrogen. Thus, this invention relates to new intermediate compounds of formula (VII), where R14denotes hydrogen or aminosidine group, R15denotes hydrogen or aminosidine group, and where R7-R13and w have any of the specific values, or their salts.

The preferred compound of formula (VII) is a compound in which R14and R15both represent hydrogen. Another preferred compound of formula (VII) is a compound in which R14means alkoxycarbonyl protective group (e.g. tert-butoxycarbonyl), and R15means arylmethyl protective group (e.g. benzyl). Another preferred compound of formula (VII) is a compound in which R14denotes hydrogen, and R15means alkoxycarbonyl protective group (e.g. tert-butoxycarbonyl).

The pharmaceutical composition

This invention also concerns pharmaceutical compositions containing the connection of the present invention. Thus, connection, preferably in the form of pharmaceutically acceptable salts can be prepared in any form suitable for reception, such as oral or parenteral administration or introduction by inhalation.

To illustrate, the compound can be mixed with known pharmaceutical carriers and excipients and used in the form of powders, tablets, capsules, elixirs, suspensions, syrups, wafers and the like. Such pharmaceutical compositions contain from about 0.05 to 90 wt.% the active compounds, more often from about 0.1 to 30%. The pharmaceutical compositions may contain conventional carriers and excipients, such as corn starch or gelatin, lactose, magnesium sulfate, magnesium stearate, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid. Disintegrant commonly used in the compositions according to the invention include croscarmellose, microcrystalline cellulose, corn starch, starch glycolate, sodium and alginic acid.

Liquid composition usually consists of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid medium (media), for example, ethanol, glycerine, sorbitol, non-aqueous solvent such as polyethylene glycol, oils or water, optional with suspendiruemye, agent that promotes dissolution (such as cyclodextrin), preservative, surface-active agent, wetting agent, flavoring or coloring. Differently, the liquid preparation may be obtained from the recovered powder.

For example, you can restore the preparation of the powder containing the active compound, suspendisse agent, sucrose and sweetening agent, with water with the formation of the suspension; syrup can be obtained from a powder containing the active ingredient, sucrose and sweetening agent.

The composition in the form of tablets can be obtained using any suitable pharmaceutical carrier (s), usually used for solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and a binder such as polyvinylpyrrolidone. You can also get the pill with a colored film coated or enable the dye as part of the holder (s). In addition, the active compound can be prepared in dosage forms with controlled release formulation such as a tablet, containing hydrophilic or hydrophobic matrix.

It is possible to prepare a composition in the form of capsules, using routine methods, encapsulation, for example through active compound and excipients in hard gelatin to which Palu. Differently, you can get a semi-solid matrix of the active compounds and high molecular weight polyethylene and filled hard gelatin capsule; or you can prepare a solution of active compound in polyethylene glycol or a suspension in an edible oil such as vaseline oil or fractionated coconut oil, and filled soft gelatin capsule.

Binder tablets that can be included are of Arabian gum, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone (Povidone, hypromellose, sucrose, starch and ethylcellulose. Lubricants that can be included are magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silicon dioxide.

You can also apply flavoring agents such as peppermint taste, the taste of Grushenka, cherry flavor or similar. In addition, for a more attractive appearance dosage forms or for assistance in identifying the product, it may be desirable to add the dye.

The compounds of this invention and their pharmaceutically acceptable salts which are active when parenteral administration can be prepared in the form of a form for intramuscular, vnutriobolochechnoe or intravenous injection.

A typical composition is La intramuscular or vnutriobolochechnoe introduction consist of a suspension or solution of the active ingredient in oil, for example, peanut oil or sesame oil. A typical composition for intravenous or vnutriobolochechnoe introduction consist of a sterile isotonic aqueous solution containing, for example, the active ingredient and dextrose or sodium chloride, or a mixture of dextrose and sodium chloride. Other examples are aktirovannye ringer's solution for injection, aktirovannye ringer solution plus dextrose injection, Normosol-M and dextrose, Isolyte E, acetylated ringer's solution for injection and the like. In the preparation may optionally include a co-solvent, for example, polyethylene glycol; a chelating agent, such as Ethylenediamine tetraoxane acid; solubilizers agent such as cyclodextrin; and an antioxidant, such as sodium metabisulfite. Alternatively, the solution can be dried by freezing and then restore using a suitable solvent just prior to administration.

The compounds of this invention and their pharmaceutically acceptable salts which are active when applied topically, can be prepared in the form of compositions for transdermal applications or devices for transdermal delivery ("patches"). Such compositions include, for example, a lining, a reservoir for active compounds that regulate membrane, gasket and contact adhesive agent. Such transdermal the major patches can be used to provide continuous or intermittent introduction of the compounds of the present invention in controlled amounts. Construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in this field. See, for example, U.S. patent No. 5023252. Such patches can be designed for continuous, pulsed delivery of the pharmaceutical agent or delivery upon request.

One preferred method of introducing the compounds of this invention is inhalation. Inhalation is an effective means of delivery of the agent directly into the respiratory tract. There are three main types of pharmaceutical inhalation devices such as inhalers-sprays, inhalers dry powder (DPI) and dose inhalers (MDI). Spray devices provide air flow high speed, which provides dispersion of therapeutic agent in the form of an aerosol spray which is deposited in the respiratory tract of the patient. therapeutic agent is prepared in liquid form such as solution or suspension of the particles milled in the micron mill, with a size suitable for inhalation, where "ground to micron mill" is generally defined as containing about 90% or more of particles with a diameter of less than about 10 microns. A typical formulation for use in a conventional spray device is an isotonic aqueous solution of pharmaceutical salts of the active agent concentration is iej active agent from about 0.05 mg/ml to 10 mg/ml

DPI is usually injected therapeutic agent in the form of a free current of powder that can be dispersed with the air flow during inhalation by the patient. To obtain a free current of powder it is possible to prepare a therapeutic agent with a suitable carrier, such as lactose or starch. Medication in the form of a dry powder can be obtained, for example, combining the dry lactose with a particle size of about 1 to 100 microns with particles of pharmaceutical salts of the active agent, milled on the micron mill, and conducting dry mixing. Alternatively, the agent can be prepared without filler. The drug is loaded into a dispenser for dry powder or in cartridges or capsules inhaler for use with a device for delivery of a dry powder.

Examples of commercially available devices for delivery include DPI Diskhaler (GlaxoSmithKline, Research Triangle Park, NC) (see, for example, U.S. patent No. 5035237); Diskus (GlaxoSmithKline) (see, for example, U.S. patent No. 6378519); Turbuhaler (AstraZeneca, Wilmington, DE) (see, for example, U.S. patent No. 4524769) and a Rotahaler (GlaxoSmithKline) (see, for example, U.S. patent No. 4353365). Additional examples of suitable DPI devices described in U.S. patent No. 5415162, 5239993 and 5715810 and links to them.

MDI is usually emit a measured amount of a therapeutic agent, using a compressed carrier gas. Preparations for MDI-introduction include a solution or suspension of the active ingred the enta in a liquefied gas carrier. Despite the fact that usually as a compressed carrier gas used chlorofluorocarbons, such as CCl3F, because of the harmful effects of such agents on the ozone layer developed drugs that use hydrofluroalkane (HFA), such as 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptathlon-n-propane (HFA 227). Additional components of the preparations for MDI HFA-introduction include co-solvents such as ethanol or pentane, and surfactants, such as sarbatorile, oleic acid, lecithin and glycerin (see, for example, U.S. patent No. 5225183, EP 0717987 A2 and WO 92/22286).

Thus, a suitable drug for MDI-introduction may include from about 0.01 to wt.% pharmaceutical salts of the active ingredient, from about 0 to 20 wt.% ethanol and from about 0 wt.% surfactants, when that rest is compressed HFA-carrier gas. In one embodiment, the receipt of this drug chilled or compressed hydrofluroalkane added to a test tube containing a pharmaceutical salt of the active compound, ethanol (if present) and surfactant (if present). To obtain suspensions provide a pharmaceutical salt in the form of particles, milled on the micron mill. The drug is loaded into the canister aerosol, which is part of the MDI device. Examples of MDI devices, once Botanik specifically for use with compressed HFA-gas-carriers, are given in U.S. patent No. 6006745 and 6143277.

An alternative obtain prepare the drug in suspension by coating the surface-active substance is micronized particles of pharmaceutical salts of the active compounds, ground to micron mill, the method of spray drying (see, for example, WO 99/53901 and WO 00/61108). Additional examples of methods for producing particles suitable for inhalation, and drugs and devices that are suitable for inhalation dosing, see U.S. patent No. 6268533, 5983956, 5874063 and 6221398, and WO 99/55319 and WO 00/30614.

It is clear that discussed above pharmaceutical compositions can be applied to any form of compounds of this invention (i.e. free base, the pharmaceutical salt or MES)that is appropriate for the particular method of administration.

The active compound is effective in a wide range of doses and is normally administered in therapeutically effective amounts. However, it is clear that actually enter the amount of coupling is determined by the physician in light of the relevant circumstances, including the subject of the treatment of the condition, the route of administration, in fact, entered the compound and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms and the like.

The appropriate dose of a therapeutic agent for the introduction of Ingulets the her are in the usual range of from about 0.05 to 1000 mg/day, preferably from about 0.5 to 500 μg/day. Connection, you can enter periodic doses: weekly, several times a week, daily, or several times a day. The treatment regimen may require the introduction for extended periods of time, for example within a few weeks or months or treatment regimen may require continuous administration. Suitable for oral administration doses are in the usual range of from about 0.05 mg/day to 100 mg/day, preferably from 0.5 to 1000 μg/day.

These active agents can jointly host with one or more other therapeutic agents. For example, for the treatment of asthma or chronic obstructive pulmonary disease, these agents can be administered in combination with antagonists of muscarinic receptors (for example, ipatropium or Tiotropium) or steroid anti-inflammatory agent (for example, fluticasonealmeterol, beclomethasone, budesonide, mometazon, ciclesonide or triamcinolone). In addition, these active agents can jointly host with the agent having anti-inflammatory and/or bronchodilators, or other useful activity, including, but not limited to, an inhibitor of phosphodiesterase (PDE) (e.g., theophylline); PDE4 inhibitor (for example, cilomilast or R is FluMist); the antibody immunoglobulin (-antibody); a leukotriene antagonist (e.g., monteleukast); therapy with cytokine antagonist such as an antibody interleukin (-antibody), in particular, (-4)-therapy (-13)therapy, or a combination; a protease inhibitor such as an inhibitor of elastase or tryptase; chromosonally; medicamenti and nutritionalist. In addition, these agents can jointly be taken with anti-infective agent, or antihistamines. Suitable doses for other therapeutic agents, taken in combination with the compound of the present invention are in the range of from about 0.05 mg/day to 100 mg/day.

Thus, the compositions of this invention may optionally contain a compound of this invention and another therapeutic agent, as described above.

Additional suitable carriers for drugs active compounds of the present invention can be found inRemington: The Science and Practice of Pharmacy, 20thEdition, Lippincott Williams & Wilkins, Philadelphia, PA, 2000. The following non-restrictive examples illustrate typical pharmaceutical compositions of the present invention.

The example of the drug And

This example illustrates the obtaining of a typical pharmaceutical composition for oral administration the compounds of this invention are:

IngredientsQuantity per tablet (mg)
Active connection2
Lactose, spray dried148
Magnesium stearate2

The above ingredients are mixed and contribute in a gelatin capsule with a hard shell.

Example drug

This example illustrates the obtaining another typical pharmaceutical composition for oral administration the compounds of this invention are:

IngredientsQuantity per tablet (mg)
Active connection4
Corn starch50
Lactose145
Magnesium stearate5

The above ingredients are homogeneously mixed and pressed into the form of a single tablet of groove.

Example drug

This example illustrates the obtaining of a typical pharmaceutical composition for oral administration the compounds of this invention.

Receive a suspension for oral administration having the following structure.

/tr>
Ingredients
Active connection0.1 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methylparaben0.1 g
Granulated sugar25,5 g
Sorbitol (70% solution)is 12.85 g
Veegum K (Vanderbilt Co.)1.0 g
Flavoring agenta 0.035 ml
Dyes0.5 ml
Distilled waterHow much you want to 100 ml

Example D drug

This example illustrates the obtaining of a typical pharmaceutical compositions containing the compound of the present invention.

Get the drug for injection, pH is increased using a buffer to 4, having the following structure.

Ingredients
Active connection0.2 g
Buffer solution of sodium acetate (0.4 M)2.0 ml
HCl (1N)How much you want to pH 4
Distilled waterAs needed up to 20 ml

An example of a drug

This example illustrates the obtaining of a typical pharmaceutical HDMI is tion for injection, the compounds of this invention.

Receive the recovered solution by adding 20 ml of sterile water to 1 g of compound of the present invention. Before use the solution was diluted using 200 ml of liquid for intravenous administration, which is compatible with the active connection. Such fluid selected from a 5% solution of dextrose, 0.9% sodium chloride or a mixture of 5% dextrose and 0.9% sodium chloride. Other examples are aktirovannye ringer's solution for injection, aktirovannye solution ringer's plus 5% dextrose injection, Normosol-M and 5% dextrose, Isolyte E, and acetylated ringer's solution for injection.

Sample preparation F

This example illustrates the obtaining of a typical pharmaceutical compositions containing the compound of the present invention.

Get the drug for injection having the following composition:

Ingredients
Active connection0.1 to 5.0 g
Hydroxypropyl-β-cyclodextrin1-25 g
5% aqueous solution of dextrose (sterile)How much you want to 100 ml

The above ingredients are mixed and adjusted pH to 3.5±0,5 using 0,5N HCl or 0,5N NaOH.

Sample preparation G

This example illustrates the obtaining of a typical pharmaceutical com is osili for local application of the compounds of this invention.

IngredientsGrams
Active connection0,2-10
Span 602
Tween 602
Mineral oil5
Petrolatum10
Methylparaben0,15
Propylparaben0,05
BHA (butylhydroxyanisole)0,01
WaterHow much you want to 100

All of the above ingredients, except water, are combined and heated to 60°under stirring. Then add a sufficient quantity of water at 60°With vigorous stirring to emulsify the ingredients and add water to 100 g

Example preparation H

This example illustrates the obtaining of a typical pharmaceutical compositions containing the compounds of this invention.

Receive aqueous aerosol formulation for use in the spray by dissolving 0.1 mg of pharmaceutical salts of the active compounds in 0.9% sodium chloride solution, acidified with citric acid. The mixture is stirred and irradiated with ultrasound to dissolve the active salt. the pH of the solution is regulated to a value of from 3 to 8, medl the NGOs adding NaOH.

Example I drug

This example illustrates the obtaining of the preparation of a dry powder containing the compound of the present invention, for use in inhalation cartridges.

Gelatin inhalation cartridges fill pharmaceutical composition having the following ingredients:

Ingredientsmg/cartridge
Pharmaceutical salt active connections0,2
Lactose25

Pharmaceutical salt of the active compound grind on the micron mill before mixing with lactose. The contents of the cartridge is injected using a powder inhaler.

Example of drug J

This example illustrates the obtaining of the preparation of a dry powder containing the compound of the present invention, for use in the device for inhalation of a dry powder.

Get a pharmaceutical composition having a volumetric ratio of pharmaceutical salts, ground to micron mill, to the lactose of 1:200. This song fills the device for inhalation of a dry powder capable of delivering about 10 to 100 micrograms of the active medicinal ingredient per dose.

The example of the drug K

This example illustrates the obtaining of the drug, containing the connection of the present invention, for use in dose inhaler.

Receive a suspension containing 5% pharmaceutical salt of the active compound, 0.5% lecithin and 0.5% trehalose, by dispersing 5 g of the active compound in the form of particles, milled on the micron mill, with an average particle size less than 10 microns in colloidal solution prepared from 0.5 g of trehalose and 0.5 g of lecithin dissolved in 100 ml of demineralized water. The suspension is spray dried and the resulting material is milled into the micron mill to particles with an average diameter of less than 1.5 μm. Particles are loaded into canisters of compressed 1,1,1,2-Tetrafluoroethane.

The example of the drug L

This example illustrates the obtaining of the preparation containing the compound of the present invention, for use in dose inhaler.

Receive a suspension containing 5% pharmaceutical salts of the active compounds and 0.1% lecithin, by dispersing 10 g of the active compound in the form of particles, milled on the micron mill, with an average particle size less than 10 μm in a solution prepared from 0.2 g of lecithin dissolved in 200 ml of demineralized water. The suspension is spray dried and grind the material obtained at the micron mill to particles with an average diameter of less than 1.5 μm. Particles are loaded into canisters of compressed 1,1,1,2,3,3,3-heptathlon-n-propane.

Biological research is

The compounds of this invention and their pharmaceutically acceptable salts exhibit biological activity and are useful for medical applications. The ability of compounds to bind adrenergic receptor β2and its selectivity, agonistic effect and inherent activity can be demonstrated usingin vivotests a-C, below,in vivotest D below, or can be demonstrated using other tests which are well known in this field.

Abbreviations

%Eff

ATCC

BSA

cAMP

DMEM

DMSO

EDTA

Emax

FBS

Gly

HEK-293

PBS

rpm

Tris
% efficiency

American collection tissue cultures

Bovine serum albumin

Adenosine 3':5'-cyclic monophosphate

Modified by way of Dulbecco Wednesday Needle

The sulfoxide

Ethylenediaminetetraacetic acid

Maximum efficiency

Serum fetal cow

Glycine

Primary human kidney - 293

Phosphate-saline buffer solution

The revolutions per minute

Tris(hydroxymethyl)aminomethan

Membrane preparation from cells expressing

β1or β2adrenergichesky the receptors person

Cell lines derived HEK-293 stably expressingcloned β1or β2adrenergic receptors person, accordingly, is cultivated almost to confluence in DMEM with 10% cialisbuynow FBS in the presence of 500 μg/ml Geneticin. Remove the monolayer of cells using Versene 1:5000 (0.2 g/l EDTA in PBS)using a cell scraper. Cells precipitated by centrifugation at 1000 rpm and or store cellular precipitation frozen at -80°With or immediately receive membrane. To obtain the cell sediments re-suspended in buffer for lysis (10mm Tris/HCl pH 7.4, 4°With one tablet of complete cocktail of protease inhibitors, 2 mm EDTA Complete Protease Inhibitor Cocktail Tablets with 2 mm EDTA 50 ml buffer (Roche cat.# 1697498, Roche Molecular Biochemicals, Indianapolis, IN)) and homogenized using a glass homogenizer downs of fit (20 strokes) on ice. The homogenate was centrifuged at 20000×g, the precipitate is washed once with a buffer for lysis, re-suspending and centrifuger, as described above. The final precipitate is re-suspended in membrane buffer (75 mm Tris/HCl pH 7.4, 12.5 mm MgCl2, 1 mm EDTA, 25°). The protein concentration in the membrane suspension is determined by the Bradford method (Bradford M.M.,Analytical Biochemistry, 1976, 72, 248-54). The membrane should be stored frozen in aliquot at -80°C.

Test And

Study of the binding of radio-on

β 1andβ2adrenergic receptors person

Research associate conducted on 96-cell tablets for micrometrology in General the investigated volume of 100 μl with 5 µg of protein for membranes containing the β2adrenergic receptor human, or 2.5 μg of protein for membranes containing the β1adrenergic receptor, in a buffer for the study (75 mm Tris/HCl, pH 7.4, 25°S, 12.5 mm MgCl2, 1 mm EDTA, 0.2% BSA). The study saturating binding to determine the values of Kdradioligand perform using the [3H]dihydroalprenolol (NET-720, 100 Kiu/mmol, PerkinElmer Life Sciences Inc., Boston, MA) at 10 different concentrations in the range from 0.01 to 200 nm. Studies of substitution to determine the values pKiconnections comply with [3H]dihydroalprenolol at 1 nm and 10 different concentrations of the compounds in the range 40 PM - 10 μm. Compounds are dissolved to a concentration of 10 mm in the buffer for dilution (25 mm Gly-HCl, pH 3.0, with 50% DMSO), then diluted to 1 mm in 50 mm Gly-HCl, pH 3.0, and then generate serial dilution buffer for the study. The nonspecific binding determined in the presence of 10 μm of unlabeled alprenolol. The analyzed material is incubated for 90 min at room temperature, binding assays are terminated by rapid filtration through filtroventilation glass fiber GF/B (Packard BioScience Co., Meriden, CT)pre-soaked in 0.3% polyethylenimine. The filter plate was washed three times filtration buffer (75 mm Tris/HCl, pH 7.4, 4°S, 12.5 mm MgCl2, 1 mm EDTA), removing unbound radioactivity. The plate is dried, add 50 μl of scintillation fluid Microscint-20 (Packard BioScience Co., Meriden, CT)and measured by liquid scintillation counter Packard measurement limit values (Packard BioScience Co., Meriden, CT). Data binding analyzed by nonlinear regression analysis using the software package GraphPad Prism Software (GraphPad Software, Inc., San Diego, CA), using the 3-parameter model for a single competition. The minimum of the curve corresponds to the value for nonspecific binding, which was determined in the presence of 10 μm of alprenolol. Values of Kifor compounds calculated from the observed values of the IC50and values of Kdradioligand using the equation of Cheng-Prusoff (Cheng Y. and W.H. Prusoff,Biochemical Pharmacology, 1973, 22, 23, 3099-108). The selectivity of receptor subtype calculated as the ratio of Ki(1)/Ki(2). All investigated compounds show greater binding on β2adrenergic receptor than β1adrenergic receptor,that is, Ki(1)>Ki(2). The most preferred compounds of this invention demo which illustrate the selectivity of more than about 20.

Test

cAMP Flashplate-the study of whole cells on cell lines, heterological expressing β2adrenergic receptor person

To determine the agonistic abilities cultured cell line HEK-293 stably expressing cloned β2adrenergic receptor human (clone N) to confluence in medium containing DMEM supplied with 10% FBS and 500 μg/ml Geneticin. The day before the study is removed from the culture medium antibiotics.

cAMP Study is conducted in radioimmuno research format, using the system Flashplate Adenylyl Cyclase Activation Assay System with125I-cAMP (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, MA) according to the manufacturers instructions.

The day of the test cells washed once with PBS, removed with the use of versene 1:5000 (0.2 g/l EDTA in PBS) and shall count. Cells precipitated by centrifugation at 1000 rpm and re-suspended in stimulation buffer, preheated to 37°C, at a final concentration of 800,000 cells/ml In this study, the cells used at a final concentration of 40,000 cells per cell. Compounds are dissolved to a concentration of 10 mm in the buffer for dilution (25 mm Gly-HCl, pH 3.0, with 50% DMSO), then diluted to 1 mm in 50 mm Gly-HCl, pH 3.0, and then generate serial dilution buffer for the study (75 mm Tris/HCl, pH 7.4, 25°S, 12.5 m is MgCl 2, 1 mm EDTA, 0.2% BSA). Compounds tested in this study at 10 different concentrations in the range from 2.5 μm to 9.5 PM. The reaction mixture incubated for 10 min at 37°and stop the reaction by adding 100 ál of ice buffer for detection. Tablets are close, incubated over night at 4°and the next morning spend the measurement on a liquid scintillation counter with a measurement limit value (Packard BioScience Co., Meriden, CT). Calculate the amount of cAMP produced per ml of the reaction mixture, on the basis of the observed counter for samples and cAMP standards, as described in the guidelines of the manufacturers. Data analyzed by nonlinear regression analysis using the software package GraphPad Prism Software (GraphPad Software, Inc., San Diego, CA), using the 4-parameter model for the S-shaped response to dose with a variable slope. Agonistic ability expressed as values RES50. In this test all the investigated compounds show activity on β2adrenergic receptor, which is obvious from the values RES50that is more than about 5. The most preferred compounds of this invention demonstrate values RES50more about 7.

Test C

cAMP Flashplate-the study of whole cells on epithelial cell line is agcih, endogenous expressingβ2adrenergic receptor person

To determine the agonistic abilities and efficiencies (specific activities) in cell lines expressing endogenous levels β2adrenergic receptor, using epithelial cell line of the human lung (BEAS-2B) (ATSS CRL-9609, American Type Culture Collection, Manassas, VA) (January B. and others,British Journal of Pharmacology, 1998,123, 4, 701-11). Cells were cultured up to 75-90% confluence in complete medium containing no serum (LHC-9 MEDIUM containing epinephrine and retinoic acid, cat#181-500, Biosource International, Camarillo, CA). The day before the test environment switch on the LHC-8 (without epinephrine or retinoic acid, cat#141-500, Biosource International, Camarillo, CA).

cAMP Study is conducted in radioimmuno research format, using the system Flashplate Adenylyl Cyclase Activation Assay System with125I-cAMP (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, MA) according to the manufacturers instructions.

The day of the test cells washed with PBS, removed by the scraper using 5 mm EDTA in PBS and shall count. Cells precipitated by centrifugation at 1000 rpm and re-suspended in stimulation buffer, preheated to 37°C, at a final concentration of 600,000 cells/ml In this study, the cells used at a final concentration of 30,000 cells per cell. Compounds are dissolved prior to the centration of 10 mm in the buffer for dilution (25 mm Gly-HCl, pH 3.0, with 50% DMSO), then diluted to 1 mm in 50 mm Gly-HCl, pH 3.0, and then generate serial dilution buffer for the study (75 mm Tris/HCl, pH 7.4, 25°S, 12.5 mm MgCl2, 1 mm EDTA, 0.2% BSA).

Compounds tested in this study at 10 different concentrations in the range from 10 μm to 40 PM. Determine the maximum reaction in the presence of 10 μl of isoproterenol. The reaction mixture incubated for 10 min at 37°and stop the reaction by adding 100 ál of ice buffer for detection. Tablets are close, incubated over night at 4°and the next morning spend the measurement of scintillation counter with a measurement limit value (Packard BioScience Co., Meriden, CT). Calculate the amount of cAMP produced per ml of the reaction mixture, on the basis of the observed counter for samples and camp standards, as described in the guidelines of the manufacturers. Data analyzed by nonlinear regression analysis using the software package GraphPad Prism Software (GraphPad Software, Inc., San Diego, CA), using the 4-parameter model for the S-shaped response to dose with a variable slope. The compounds of this invention tested in this study demonstrate the values RES50more about 7.

The transfer efficiency (%Eff) is calculated from the ratio of the observed Emax (high point suitable the curve) and the maximum response, obtained for the 10 µm isoproterenol and expressed as %Eff relative to isoproterenol. The investigated compounds show values %Eff more than about 20.

Test D

The study bronchospastic against acetylcholine-induced bronchoconstriction model Guinea pigs

Groups of 6 male Guinea pigs (Duncan-Hartley (HsdPoc:DH) Harlan, Madison, WI) weighing 250 to 350 g identify individually on cards belonging to the cells. Throughout the study the animals are allowed access to food and water without restrictions.

Tested compound is administered by inhalation for 10 minutes in the dosing chamber, where it kept the animal as a whole (R&S Molds, San Carlos, CA). The dosing chamber is designed in such a way that the aerosol from the Central pipeline enters simultaneously into 6 individual chambers. After 60-minute acclimatization period and a 10-minute exposure to sprayed water for injection (WFI) of Guinea pigs exposed to aerosol the compounds or media (WFI). These aerosols generated by applying the spray LC Star (Model 22F51, PARI Respiratory Equipment, Inc. Midlothian, VA), from aqueous solutions, portable gas mixture (CO2=5%, O2=21% N2=74%) at a pressure of 1,547 kg/cm2(22 lb/in2). The gas flow through the nozzle at a given pressure is applied is 3 l/min The generated aerosol is transferred into a chamber under positive pressure. Upon delivery of aerosol solutions do not apply thin air. For 10 min spray is sprayed approximately 1.8 ml. It is measured gravimetrically by comparing the mass of the filled dispenser before and after spraying.

Bronchosan effects of compounds, administered by inhalation, evaluate, applying plethysmography whole body, 1.5, 24, 48 and 72 hours after dose. For forty-five minutes prior to the evaluation of the lung, each Guinea pig give anesthesia by intramuscular injection of ketamine (43,75 mg/kg), xylazine (3,50 mg/kg) and acepromazine (1,05 mg/kg). Place of operative intervention is shaved and washed with 70% ethanol, then do the middle section 2-5 cm ventral part of the neck. Then allocate the cervical vein and injected polyethylene catheter (PE-50, Becton, Dickinson, Sparks, MD), filled with a saline solution for intravenous infusion solution (0.1 mg/ml), acetylcholine (Ach) (Sigma-Aldrich, St. Louis, MO) in saline. Then expose the trachea and enter the cannula in the form of a Teflon tube 14G (#NE-014, Small Parts, Miami Lakes, FL). If you want to continue anesthesia using additional intramuscular injection of the above anesthetic cocktail. The depth of anesthesia monitor and regulate, if the animal responds to the compression of La is s or if the respiratory rate becomes greater than 100 breaths/min

When kanalirovanie completed, the animal is placed in plethysmograph (#PLY3114, Buxco, Electronics, Inc., Sharon, CT) and enter the esophageal catheter, working under pressure, to measure the stimulating pressure in the pulmonary artery (pressure). Teflon tracheal tube attached to the opening plethysmograph, giving a Guinea pig opportunity to breathe room air from the space outside the cell. Then the chamber is closed. To maintain the temperature of the body use a heating lamp and into the lungs of the Guinea pig is blown into 3 times in 4 ml of air using a calibration syringe 10 ml (#5520 Series, Hans Rudolph, Kansas City, MO)to ensure that the lower airway is not spachina and that the animal does not suffer from hyperventilation.

Having determined that the original values are within the range of 0.3-0.9 ml/cm H2About to change the amount of light within the range of 0.1-0,199 cm H2O/ml / sec for resistance begin its evaluation of the lungs. Computer program Buxco for pulmonary measurements are able to collect data and to obtain pulmonary evaluation. Run this program initiates an experimental Protocol and data collection. Volume changes over time that occur within plethysmograph with every breath, measured by the pressure transducer Buxco. Integrating this signal over time, calculate the flow rate for each wsdomain signal together with changes in the lung stimulating pressure, collecting, using the Sensym pressure transducer (#TRD4100), connected through a preamplifier Buxco (MAX 2270) interface data collection (#SFT3400 and #SFT3813). All other parameters of the lungs obtained from these two input data.

The original value is collected for 5 min, after which the Guinea pigs injected Ach. Ach administered intravenously for 1 minute from a syringe pump (sp210iw, World Precision Instruments, Inc., Sarasota, FL) at the following doses and prescribed times from the start of the experiment: 1.9 µg/min over 5 min to 3.8 mcg/min over 10 min, and 7.5 μg/min after 15 min of 15.0 µg/min over 20 min, 30 µg/min after 25 min and 60 µg/min after 30 minutes If the resistance or the change in volume of the lungs is not returned to baseline values after 3 min after each dose of Ach, in light of the Guinea pig is blown into 3 times in 4 ml of air from the calibration syringe 10 ml Logged options include lung breathing frequency (breaths/min), the volume change of the lung (ml/cm H2About) and pulmonary resistance (cm H2O/ml / sec) (Giles and others, 1971). When the measurement of lung function is completed 35 min this Protocol, a Guinea pig is removed from plethysmograph and death by CO2-asphyxia.

Value PD2which is defined as the amount of Ach, which is needed to cause a doubling of the initial pulmonary resistance, calculated using the pulmonary resistance is tulemast, obtained from flow and pressure above the range of samples Ach using the following equation. This value is obtained from the equation used for calculating quantities PC20in clinical practice, (Am. Thoracic Soc., 2000).

where C1= concentration of Ach from the second to the last (concentration prior To2);

With2= final concentration of Ach (concentration giving a 2-fold increase in pulmonary resistance (RL);

R0= the initial value of RL;

R1= the value of RLafter1;

R2= the value of RLafter2.

Statistical analysis of data is conducted by applying a unidirectional (one-way) analysis of variance followed by post-hoc analysis using the Bonferroni test/Dunn. Significant consider the value of P<0,05.

Curves dose-response describe chetyrehmetrovy logistic logistic equation using GraphPad Prism, version 3.00 for Windows (GraphPad Software, San Diego, California)

Y=Min+(Max-Min)/(1+10^((logED50-X)*Hillslope)),

where X is the logarithm of dose, Y is the response (PD2and Y starts at Min and asymptotically approaches Max S-shaped form.

Found that the typical compounds of this invention possess significant bronchospastic activity at time points after 24 hours after a dose.

The following PR the steps of the synthesis offered to illustrate this invention and are in no way intended to limit the scope of the present invention.

Examples

In the following examples, the abbreviations have the following meanings. Any acronyms that are not defined have a common value. While nothing else is stated, all temperatures are given in degrees Celsius.

Bn =Benzil
Vos =tert-butoxycarbonyl
DMSO =The sulfoxide
EtOAc =The ethyl acetate
TFA =Triperoxonane acid
THF =Tetrahydrofuran
MgSO4=Anhydrous magnesium sulfate
NaHMDS =Matrikelstyrelsen
TMSCl =Trimethylsilane
DMF =Dimethylformamide
TBS =Tert-butyldimethylsilyl

General:While nothing else is stated, reagents, starting materials and solvents purchase from commercial sources such as Sigma-Aldrich (St.Louis, MO), J.T.Baker (Phillipsburg, NJ), Honeywell Burdick and Jackson (Muskegon, MI), Trans World Chemicals, Inc. (TCI) (Rockville, MD), Mabybridge plc (Cornwall, UK), Peakdale Molecular Limited (High Peak, UK), Avocado Research Chemicals Limited (Lancashire, UK) and Bionet Research (Cornwall, UK) and used without further purification; the interaction is carried out in the atmosphere of AZ is the same; the reaction mixture is controlled by thin layer chromatography (TLC) on silica), analytical high performance liquid chromatography analysis (HPLC) or mass spectrometry; typically the reaction mixture is purified by the method column flash chromatography on silica gel or preparative HPLC, as described below; the samples for NMR dissolved in deuterated solvent (CD3OD, CDCl3or DMSO-d6) and the spectra obtained by the instrument Varian Gemini 2000 (300 MHz), using as an internal standard of residual protons of the listed solvents, unless specified differently; mass spectrometric identification carried out by the method with ionization elektrorazpredelenie (ESMS) on the instrument Perkin Elmer (PE SCIEX API 150 EX).

Example 1

Synthesis of compounds 1

To 62 mg (0.1 mmol) of the compoundbband 0.1 mmol of N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide (Sigma-Aldrich Library of Rare Chemicals) in 0.15 ml of toluene, add 9,3mg (0.015 mmol) of racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (Aldrich) in 0.15 ml of toluene, and 4.6 mg (0.05 mmol) of Tris(dibenzylidineacetone)diplegia(0) (Aldrich) in 0.1 ml of toluene and 29 mg (0.3 mmol) of tert-butyl sodium, suspended in 0.4 ml of toluene. The mixture is shaken and heated at 80°C for 5 hours. Add acetic acid (80% water, 0.6 ml) and the mixture is shaken and heated is up at 80° C for 5 hours. The crude reaction mixture is diluted with DMF to a total volume of 2 ml, filtered and purified by HPLC with reversed phase, using the automatic acquisition device, responsive to the mass. The fractions containing the product, analyzed by analytical / mass spectrometer LC-MS and dried by freezing, receiving TFA salt and compound 1 in the form of powder.

The intermediate connectionbbobtained as follows.

a. Synthesis of compoundXX

To 5-bromo-2-hydroxybenzylidene alcohol (93 g, 0.46 mol, from Aldrich) in 2.0 l 2.2-dimethoxypropane add 700 ml of acetone, then 170 g ZnCl2. After stirring for 18 h add 1.0m aqueous NaOH until then, until the aqueous phase becomes alkaline. To the suspension is added 1.5 liters of diethyl ether and the organic phase is decanted into a separating funnel. The organic phase is washed with saturated salt solution, dried over Na2SO4, filtered and concentrated under reduced pressure, obtaining the compound XX in the form of a light orange oil.1H NMR (300 MHz, DMSO-d6) : 7,28 (m, 2H), 6.75 in (d, 1H), 4,79 (s, 2H), 1,44 (C, 6N).

b. Synthesis of compoundyy

To 110 g (0.46 mol) of the compoundXXin 1.0 l of THF at -78°With added using a dropping funnel 236 ml (0.51 mol) 2,14M n-BuLi in hexane. After 30 minutes add 71 g (0.6 mol) of N-methyl-N-methoxyacetate (TCI). After 2 h the reaction is quenched with water, diluted with 2.0 l 1.0m aqueous phosphate buffer (pH=7.0) and extracted once with diethyl ether. Phase diethyl ether, washed once with saturated salt solution, dried over Na2SO4, filtered and concentrated under reduced pressure, getting a light orange oil. This oil was dissolved in minimum amount of ethyl acetate, diluted with hexane and crystallized product receiving connectionyyin the form of a white solid.1H NMR (300 MHz, CDCl3): 7,79 (m, 1H), 7,65 (m, 1H), 6,85 (d, 1H), 4,88 (s, 2H), 2,54 (s, 3H), and 1.56 (s, 6N).

C. Synthesis of compoundzz

To 23,4 g (0,113 mol) of the compoundyyin 600 ml of THF at -78°add 135 ml of 1.0m NaHMDS in THF (Aldrich). After 1 hour add to 15.8 ml (0,124 mol) of TMSCl. After another 30 min type of 5.82 ml (0,113 mol) of bromine. After 10 min the reaction is quenched by adding diethyl ether and pouring 500 ml of 5% aqueous Na2SO3pre-mixed with 500 ml of 5% aqueous NaHCO3. The phases are separated and the organic phase is washed with saturated salt solution, dried over Na2SO4, filtered and concentrated under reduced pressure, obtaining the connection zz in the form of a light orange oil which utverjdayut in the refrigerator.1H NMR (300 MHz, CDCl3): 7,81 (m, 1H), 7,69 (m, 1H), to 6.88 (d, 1H), 4,89 (s, 2H), 4,37 (s, 2H), and 1.56 (s, 6N).

d. Synthesis b> aa

To 32 g (0,113 mol) of the compoundzzin 300 ml of methylene chloride at 0°add to 31.6 ml (0.23 mol) of triethylamine, and then of 16.0 ml (0.10 mol) of 4-bromophenethylamine (Aldrich). After 2 hours add 27 g (0.10 mol) of 4,4'-dimethoxyphenethylamine. After 30 min, the suspension is partitioned between 50% saturated aqueous NaHCO3and diethyl ether and separated phases. The organic phase is washed once with water and once with saturated salt solution, dried over K2CO3, filtered and concentrated to an orange oil. This oil is purified by chromatography on silica gel (1400 ml of silica gel, elute with a mixture of acetonitrile/triethylamine/methylene chloride=3:0,5:96,5), receiving the connectionAAas an orange foam. 1H NMR (300 MHz, DMSO-d6) δ: the 7.65 (m, 1H), EUR 7.57 (m, 1H), 7,38 (d, 2H), 7,19 (d, 4H), to 6.95 (d, 2H), 6,78 (m, 5H), 5,09 (s, 1H), 4,82 (s, 2H), 3,98 (s, 2H), to 3.73 (m, 1H), 3,66 (s, 6H), 2,71 (m, 4H), 1,45 (s, 6H).

e. Synthesis of compoundbb

To 41 g (65 mmol) of the compoundAAin 120 ml of THF, add 200 ml of methanol, and then 2,46 g (65 mmol) of sodium borohydride. After 1 hour, the solution is partitioned between 1.0m aqueous phosphate buffer (pH=7.0) and diethyl ether and separated phases. Phase diethyl ether, washed with saturated salt solution, dried over K2CO3, filtered and concentrated to oil. This oil is purified by chromatography on si is imagele (1200 ml of silica gel, elute with a mixture of acetone/triethylamine/hexane=18:0,5:81,5), receiving the connectionbbin the form of a white foam. 1H NMR (300 MHz, DMSO-d6) δ: 7,37 (d, 2H), 7,13 (m, 4H), 6,95 to 6.75 (m, 8H), of 6.68 (d, 1H), 4.95 points (d, 1H), a 4.83 (s, 1H), 4,74 (s, 2H), 4,56 (m, 1H), 3,67 (2, 6H), to 2.55 (m, 4H), of 1.42 (s, 6H).

Example 2

The synthesis of compounds 2

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace the N1-(5-methoxy-2-pyrimidinyl)sulfanilamide (sulfamyl, available from Aldrich), get a TFA salt and connection2. m/z: [M+H+] calculated for C28H31N5O6S 566,2; found 566,2.

Example 3

Synthesis of compound 3

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace the N1-(4,6-dimethyl-2-pyrimidinyl)sulfanilamide (sulfamethazine, available from Aldrich), get a TFA salt and connection3. m/z: [M+H+] calculated for C29H33N5O5S 564,2; found 564,2.

Example 4

The synthesis of compounds 4

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-PI is imaginal)sulfanilamide replace 2-sulfanilamidnaya (sulfapiridin available from Aldrich), get a TFA salt and connection4. m/z: [M+H+] calculated for C28H30N4O5S 535,2; found 535,2.

Example 5

Synthesis of compound 5

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide substituted 5-amino-ortho-toluensulfonyl (para-toluidine, ortho-sulfanilic, available from Sigma-Aldrich Library of Rare Chemicals), get a TFA salt and connection5. m/z: [M+H+] calculated for C30H33N3O5S 548,2; found 548,2.

Example 6

Synthesis of compound 6

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-aminotoluene-2-sulfochlorides (available from Sigma-Aldrich Library of Rare Chemicals), get a TFA salt and connection6. m/z: [M+H+] calculated for C32H37N3O5S 576,3; found 576,2.

Example 7

Synthesis of compound 7

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-(piperidinomethyl)aniline (available on the Maybridge), get a TFA salt and connection7. m/z: [M+H+] calculated for C28H35N3O5S 526,2; found 526,2.

Example 8

Synthesis of compound 8

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-(morpholinomethyl)aniline (available from Maybridge), get a TFA salt and connection8. m/z: [M+H+] calculated for C27H33N3O6S 528,2; found 528,2.

Example 9

Synthesis of compound (9)

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace the N1-(2,6-dimetilfenil)-4-aminobenzoyl-1-sulfonamide (available from Maybridge), get a TFA salt and connection9. m/z: [M+H+] calculated for C31H35N3O5S 562,2; found 562,2.

Example 10

Synthesis of compound 10

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace the N1-(2-thiazolyl)sulfanilamide (sulfathiazole, available from Aldrich), get a TFA salt and connection10.

b> Example 11

Synthesis of compound (11)

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace the N1-[2-(trifluoromethyl)phenyl]-4-aminobenzoyl-1-sulfonamide (available from Maybridge), get a TFA salt and connection11.

Example 12

The synthesis of compounds 12

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace the N1-(3,5-dichlorophenyl)-4-aminobenzoyl-1-sulfanilamide (available from Maybridge), get a TFA salt and connection12.

Example 13

Synthesis of compound 13

To the mixture 0,69 g (1,83 mmol) of crude compoundherin 4 ml of methanol added 70 mg of 10% palladium on coal in a stream of nitrogen and the reaction mixture is shaken at 3,515 kg/cm2(50 lb/in2) H2within 2 days. The reaction mixture is filtered and the residue purified by HPLC with reversed phase (gradient from 10 to 50% acetonitrile in 0.1% aqueous TFA). The fractions containing pure product are combined and lyophilized, receiving TFA salt and connection12in powder form. m/z: [M+H+] calculated for C27H32N4O6S 541,2; n is Geno to 541.5.

The intermediate connectionherobtained as follows.

a. Synthesis of compoundAnd

To 10.7 g (to 53.0 mmol) of 4-bromophenethylamine (from Aldrich) in 100 ml of toluene added to 6.80 g (64 mmol) of benzaldehyde. After stirring for 10 min, the cloudy mixture was concentrated under reduced pressure. The residue is twice re-concentrated from toluene and dissolved transparent oil in 50 ml of tetrahydrofuran. Added to a solution of 2.0 g (53 mmol) of sodium borohydride, and then 20 ml of methanol and stirred contents of the flask in a water bath at ambient temperature for one hour. Add 1.0m HCl up until the pH is below 1. The suspension is stirred in a bath with ice for 30 min and the solids separated by filtration, washed with cold water and dried in the air, getting the hydrochloride salt of the compoundAndin the form of a colorless solid.1H NMR (300 MHz, DMSO-d6) : 9,40 (s, 2H), 7,50-to 7.32 (m, 7H), 7,14 (d, 2H), 4,07 (s, 2H), 3,03 (m, 2H), 2,92 (m, 2H).

b. Synthesis of compoundIn

To 5.0 g (15 mmol) of the compound in 100 ml of methanol added 1.70 g (16.5 mmol) of triethylamine. The solution is cooled in a bath of water and ice and add 3,66 g (16,8 mmol) di-tert-BUTYLCARBAMATE. After 3.5 hours the solution is concentrated under reduced pressure and the residue partitioned between 1.0m is one NaHSO 4and diethyl ether, the phases are separated. Phase diethyl ether, washed with water and then with saturated salt solution, dried over Na2SO4filter and concentrate, receiving the connectionIn(of 6.1 g, 93%) as a colourless oil.1H NMR (300 MHz, DMSO-d6) : 7,38 (d, 2H), 7,28-7,13 (m, 5H),? 7.04 baby mortality (m, 2H), 4,29 (users, 2H), 3,20 (m, 2H), 2,62 (m, 2H), 1,25 (s, N).

C. Synthesis of compounddd

Into the flask containing 3.4 g (8,8 mmol) of the compoundIn,2.8 g (11 mmol) of 4-(morpholinomethyl)aniline (from Maybridge), 0,41 g (0.45 mmol) of Tris(dibenzylidineacetone)diplegia(0), or 0.83 g (1.3 mmol) of racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 1.1 g (11 mmol) of tert-butyl sodium, add 40 ml of toluene and the mixture is heated at 95°C for 6 hours in nitrogen atmosphere. The mixture is diluted with 200 ml diethyl ether and washed twice with 100 ml 1.0m aqueous NaHSO4and then with 100 ml of saturated aqueous NaHCO3. Phase diethyl ether dried over MgSO4, filtered and concentrated to a dark oil. This oil is purified by chromatography on silica gel (gradient from 30 to 40% ethyl acetate in hexane)to give compoundddas a yellow foam (2.5 g, 51%).

d. Synthesis of compoundher.

To 0.56 g (0.6 mmol) of the compoundddin 6 ml of CH2Cl2add 4 ml of TFA. After 15 minutes the solution is concentrated and R is izbavlyayut 30 ml ethyl acetate and washed with double-1,0N aqueous sodium hydroxide. An ethyl acetate layer is dried over MgSO4, filtered, concentrated to an oil and dissolved in 8 ml of a mixture methanol:THF=1:1. Add bromohydrinGG(340 mg, 0.96 mmol) and K2CO3(370 mg, 2.7 mmol) and the reaction mixture was stirred at room temperature for 1.5 hour. The reaction mixture was concentrated, the residue is diluted with 30 ml of water and extracted twice with 30 ml of toluene. Toluene extracts are combined, dried over Na2SO4filter and concentrate. The residue is heated to 120°C. After 13 h, the reaction mixture was cooled to room temperature and the crude product compoundddtransferred to the next stage without purification.

Intermediate bromohydrinGGcan be obtained, as described in U.S. patent No. 6268533 B1 and in the work of R. Hett, and others,Organic Process Research and Development, 1998, 2, 96-99. Intermediate bromohydrinGGcan also be obtained using a technique similar to that described by Hong and others,Tetrahedron Lett., 1994, 35, 6631; or similar to those described in U.S. patent No. 5495054.

Example 14

Synthesis of compound 14

To a mixture of 0.6 g (0.83 mmol) of the compoundiiin 25 ml of ethanol is added 200 mg of 10% palladium on coal in a stream of nitrogen and the reaction mixture is allowed to mix under H2at atmospheric pressure for 5 days. The reaction mixture is filtered and the residue purified by HPLC with bresennol phase (gradient from 10 to 50% acetonitrile in 0.1% aqueous TFA). The fractions containing pure product are combined and lyophilized, receiving TFA salt and connection14in powder form. m/z: [M+H+] calculated for C28H29N5O5S 548,2; found 548,3.

The intermediate productiiobtained as follows.

A. Synthesis of compoundhh

Into the flask containing 3.4 g (8,8 mmol) of the compoundIn(example 13, part b), 2.0 g (8.0 mmol) sulfapiridina (from Aldrich), and 0.37 g (0.40 mmol) of Tris(dibenzylidineacetone)diplegia(0), 0.75 g (1.2 mmol) of racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 2,31 g (24,0 mmol) tert-butyl sodium, add 40 ml of toluene and the mixture is heated at 90°C for 18 h under nitrogen atmosphere. The mixture is diluted with 200 ml of methylene chloride and washed with 100 ml saturated aqueous NaHCO3and then with 100 ml saturated aqueous NaCl. The organic phase is dried over MgSO4filter and concentrate. The oil is purified by chromatography on silica gel (gradient from 0 to 5% methanol in methylene chloride)to give compoundhhin the form of an orange solid.

b. Synthesis of compoundii

To 4.5 g (8.1 mmol) of the compoundhhin 20 ml of CH2Cl2add 1.5 ml of TFA. After 1 hour the solution is concentrated and alkalinized 1,0N aqueous sodium hydroxide and extracted twice with methylene chloride and then with ethyl acetate. Organic is such layers combine, dried over MgSO4, filtered and concentrated to oil. This oil is purified by chromatography on silica gel (gradient from 2 to 10% methanol in methylene chloride). The purified product is dissolved in 10 ml of a mixture methanol:THF=1:1. Add bromohydrinGG(example 13, part d) (364 mg, 1.04 mmol) and K2CO3(378 mg, 2,73 mmol) and the reaction mixture was stirred at room temperature for 1.5 hour. The reaction mixture was concentrated, the residue is diluted with 30 ml of water and extracted twice with 30 ml of toluene. Toluene extracts are combined, dried over Na2SO4filter and concentrate. The residue is heated to 120°C. After 2 h the reaction mixture was cooled to room temperature and the crude product is purified by chromatography on silica gel (gradient from 5% to 10% methanol in methylene chloride)to give compound ii in the form of a reddish-brown solid.

Example 15

Synthesis of compound 15

To 610 mg (0.82 mmol) of the compoundffin 5.0 ml of acetic acid added 92 mg of 10% palladium on coal. The reaction mixture was shaken at 2,812 kg/cm2(40 lb/in2) H2within 20 hours. The mixture is filtered and the filtrate purified by HPLC with reversed phase (gradient from 10 to 40% acetonitrile in 0.1% aqueous TFA). The fractions containing pure product are combined and lyophilized, getting the ol TFA and connection 15in powder form. m/z: [M+H+] calculated for C29H32N4O6S 565,2; found 565,3.

The intermediate connectionffobtained as follows.

a. Synthesis of compoundff

To 0,91 g (1.6 mmol) of the compounddd(example 13, part C) in 8 ml of CH2Cl2add 6 ml of TFA. After 15 minutes the solution is concentrated, diluted with 30 ml ethyl acetate and washed with double-1,0N aqueous sodium hydroxide. An ethyl acetate layer is dried over MgSO4, filtered, concentrated to a brown oil. This oil is dissolved in 6.0 ml of isopropanol and added 375 mg (1.3 mmol) of the epoxideP. The solution is heated to 70°C. After 24 hours the solution is concentrated and the product purified by chromatography on silica gel (3% methanol in CH2Cl2). Pure fractions are combined and concentrated, obtaining the connectionffin the form of a yellow foam.

The intermediate epoxidePcan be obtained, as described in published international patent application no WO 95/25104; and in EP 0147719 A2 and ER Century

Example 16

Synthesis of compound 16

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 3-(methylthio)aniline (Aldrich), get a TFA salt and connection16. m/z: [M+H+] races Chicano for C 24H28N2O3S 425,2; found 425,1.

Example 17

Synthesis of compound 17

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-(methylthio)aniline (Aldrich), get a TFA salt and connection17. m/z: [M+H+] calculated for C24H28N2O3S 425,2; found 425,1.

Example 18

Synthesis of compound 18

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-(meta-tolylthio)aniline (Sigma-Aldrich Library of Rare Chemicals), get a TFA salt and connection18. m/z: [M+H+] calculated for C30H32N2O3S 501,2; found 501,2.

Example 19

Synthesis of compound 19

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-[(4-methylpyrimidin-2-yl)thio]benzoylamino (from Peakdale), get a TFA salt and connection19. m/z: [M+H+] calculated for C28H30N4O3S 503,2; found 503,1.

Example 20

Synthesis of compound 20

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-[(4-forfinal)sulfonyl]aniline (Bionet), get a TFA salt and connection20.

Example 21

Synthesis of compound 21

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-[(4-were)sulfonyl]aniline (Bionet), get a TFA salt and connection21.

Example 22

Synthesis of compound 22

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 3-aminodiphenylamine (from Sigma-Aldrich Library of Rare Chemicals), get a TFA salt and connection22. m/z: [M+H+] calculated for C29H30N2O5S 519,2; found 519,2.

Example 23

The synthesis of compounds 23

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-(4-chlorobenzenesulfonyl)phenylamine (from Sigma-Aldrich Library of Rare Chemicals), get a TFA salt and b> 23. m/z: [M+H+] calculated for C29H29ClN2O5S 553,2; found 553,1.

Example 24

Synthesis of compound 24

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-(methylsulphonyl)aniline (from Maybridge), get a TFA salt and connection24. m/z: [M+H+] calculated for C24H28N2O5S 457,2; found 457,1.

Example 25

The synthesis of compounds 25

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-(phenylsulfonyl)aniline (from Maybridge), get a TFA salt and connection25. m/z: [M+H+] calculated for C29H30N2O5S 519,2; found 519,2.

Example 26

Synthesis of compound 26

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-[(4-forfinal)sulfonyl]aniline (from Maybridge), get a TFA salt and connection26. m/z: [M+H+] calculated for C29H29FN2O5S 537,2; found 537,1.

Example 27

Sin is ez connection 27

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 3,4-etilendioksitiofenom (from Aldrich), get a TFA salt and connection27.

Example 28

Synthesis of compound 28

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-methoxyaniline (pair-anisidin, available from Aldrich), get a TFA salt and connection28.

Example 29

Synthesis of compound 29

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 3-ethoxyaniline (meta-anisidin from Aldrich), get a TFA salt and connection29.

Example 30

Synthesis of N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine (30)

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide substituted 1-amino-4-ethoxybenzene (pair-fenetidin, available from Aldrich), get with the ü TFA and connection 30.

Example 31

Synthesis of compound 31

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 3-chloro-4-methoxyaniline (from Aldrich), get a TFA salt and connection31.

Example 32

Synthesis of compound 32

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 3,4,5-trimethoxyaniline (from Aldrich), get a TFA salt and connection32. m/z: [M+H+] calculated for C26H32N2O6469,2; found 469,2.

Example 33

Synthesis of compound 33

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace hydrochloride 4-benzyloxyaniline (from Aldrich), get a TFA salt and connection33. m/z: [M+H+] calculated for C30H32N2O4485,2; found 485,2.

Example 34

Synthesis of compound 34

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl--methyl-2-pyrimidinyl)sulfanilamide replace 3,4-dimethoxyaniline (from Aldrich), get a TFA salt and connection34. m/z: [M+H+] calculated for C25H30N2O5439,2; found 439,2.

Example 35

Synthesis of compound 35

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 3,4-(trimethylenediamine)aniline (from Maybridge), get a TFA salt and connection35. m/z: [M+H+] calculated for C26H30N2O5451,2; found 451,2.

Example 36

Synthesis of compound 36

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-isopropoxyaniline (from TCI America), get a TFA salt and connection36. m/z: [M+H+] calculated for C26H32N2O4437,2; found 437,2.

Example 37

Synthesis of N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine (37)

To a mixture of 3.0 g (to 4.98 mmol) of the compoundF,obtained below in part C, 70 ml of ethanol is added 1.0 g of 10% palladium on coal in a stream of nitrogen. To the flask is connected to the tank with gaseous hydrogen and the reaction mixture is vigorously stirred for 5 hours. The reaction mixture was filtered through celite using methanol for washing, and the filtrate concentrated under reduced pressure. The residue is dissolved in 40 ml of a mixture of isopropanol/methanol = 1/1 add to 2.74 ml of 4M HCl in dioxane and the product precipitated in the form of a di-HCl salt by adding the solution to a large volume of EtOAc. A solid substance was separated by filtration, obtaining the di-HCl salt of compound37in the form of a white solid.1H NMR (300 MHz, DMSO-d6) δ: 8,94 (users, 1H), 8,63 (users, 1H), 6,97 is 6.67 (m, 11H), was 4.76 (m, 1H), 4,39 (s, 2H), 4,29 (user, 4H), a 3.87 (DD, 2H), 3,02 was 2.76 (m, 6H), to 1.22 (t, 3H); m/z: [M+H+] calculated for C25H30N2O4423,2; found 423,2.

The intermediate connectionFobtained as follows.

a. Synthesis of compoundC

Into the flask containing 3.0 g (7.7 mmol) of the compoundIn(example 13, part b),1.26 g (9.1 mmol) of para-phenetidine (4-ethoxyaniline, available from Aldrich), 0.32 g (0.35 mmol) of Tris(dibenzylidineacetone)diplegia(0), 0.65 g (1.05 mmol) of racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 0.88 g (9.1 mmol) of tert-butyl sodium, add 35 ml of toluene and the mixture is heated at 95°C for 5.5 hours under nitrogen atmosphere. The mixture is partitioned between 1.0m aqueous NaHSO4and diethyl ether and separated phases. Phase diethyl ether diluted with one volume of hexane and washed once 1.0m aqueous NaHSO4 and once with saturated salt solution, dried over Na2SO4, filtered and concentrated to a dark oil. This oil is purified by chromatography, using as eluent a mixture of 15% EtOAc/85% hexane and receiving 2,52 g (73%) of compoundWithin the form of a dark orange oil.1H NMR (300 MHz, DMSO-d6) δ: to 7.64 (s, 1H), 7,28-7,13 (m,5H), 6,91-6,72 (m, 8H), 4,27 (s, 2H), 3,92 (kV, 2H), 3,25 (s, 2H), 3.15 in (m, 2H), 2,52 (m, 2H), 1,31 (s, 9H), to 1.21 (t, 3H); m/z: [M+H+] calculated for C28H34N2O3447,3; found 447,8.

b. Synthesis of compoundE

To of 2.93 g (6,56 mmol) of the compoundWithin 15 ml of CH2Cl2when 0°add 15 ml triperoxonane acid. After 40 minutes the solution is concentrated under reduced pressure and the residue partitioned between 1M NaOH and EtOAc. The phases are separated and the EtOAc phase was washed once with water and once with saturated salt solution, dried over Na2SO4, filtered and concentrated to an orange oil. This oil was dissolved in 20 ml of isopropanol, add 1.86 g (6,56 mmol) of epoxideandand the solution is heated at 78aboutWith during the night. The mixture is cooled to room temperature and concentrated under reduced pressure, obtaining the connectionEin the form of an orange oil, which is used in the next stage without purification.

c. Synthesis of compoundF

To 6,56 mmol crude compound E with predigested in 40 ml of tetrahydrofuran at 0° To add to 16.4 ml (16.4 mmol) of 1M sociallyengaged in tetrahydrofuran. After 2 h the reaction is quenched by slowly adding decahydrate sodium sulfate. The suspension was diluted with diethyl ether, dried over Na2SO4, filtered and concentrated to an orange oil. This oil is purified by chromatography, using as eluent a mixture of 50% EtOAc/50% hexane and receiving the connectionFas not quite white foam.1H NMR (300 MHz, DMSO-d6) δ: to 7.61 (s, 1H), 7,37-of 6.71 (m, 21H), 5,02 (s, 2H), 4,94 (m, 1H), 4,67 (m, 1H), 4,55 (m, 1H), 4,48 (d, 2H), 3,85 (DD, 2H), 3,63 (DD, 2H), 2,53 (m, 6H), to 1.21 (t, 3H).

The intermediate epoxideandcan be obtained, as described by R. Hett, and others,Tetrahedron Lett., 1994, 35, 9357-9378.

Example 38

Synthesis of N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (38)

To a solution of 200 mg (0.36 mmol) of the compoundQ5.0 mlmethanol add 45 mg of 10% palladium on coal. The reaction mixture is placed in an atmosphere of gaseous H2at 1 atmosphere. After 20 h add another 25 mg of 10% palladium on coal and the reaction mixture is stirred under 1 atmosphere of H2within 24 hours, after which the reaction mixture is filtered. The filtrate is concentrated and purified by the method of preparative HPLC with reversed phase (gradient 15-50% acetonitrile in 0.1% TFA). The fractions containing the solid product of the joint is complementary and lyophilized, receiving TFA salt and connection6in powder form. Sample TFA salt (and 39.7 mg) dissolved in acetonitrile (1.0 ml), diluted with water (2.0 ml) and then 0,1N HCl (5.0 ml). The solution is frozen and lyophilized, receiving the hydrochloride salt of the compound38(to 38.3 mg) as a yellow powder.1H NMR (300 MHz, DMSO-d6) δ: 10,5 (users, 2H), 9,20 (users, 1H), 8,75 (users, 1H), they were 8.22 (d, 1H), 7,15 (d, 1H), 6,95-7,05 (m, 5H), 6,80-of 6.90 (m, 4H), 6,56 (d, 1H), of 5.40 (DD, 1H), 3,95 (kV, 2H), 2.95 and outstanding 3.18 (m, 4H), 2,80-2,95 (m, 2H), 1,29 (t, 3H); m/z: [M+H+] calculated for C27H29N3O4460,22; found 460,2.

The intermediate connectionQobtained as follows.

a. Synthesis of compoundX

To 7,03 g (of 35.1 mmol) of 4-bromophenethylamine (Sigma-Aldrich) in 60 ml THF added 8.6 g (39,4 mmol) di-tert-BUTYLCARBAMATE. After 10 minutes the solution is concentrated under reduced pressure and distribute the residue between saturated aqueous sodium bicarbonate and ethyl acetate. An ethyl acetate phase is washed with saturated salt solution, dried over MgSO4filter and concentrate, receiving the connectionXin the form of a white solid.

b. Synthesis of compoundY

Into the flask containing 1.2 g (4.1 mmol) of the compoundX, 0,72 g (5.3 mmol) of para-phenetidine (4-ethoxyaniline, Sigma-Aldrich), 0,19 g (0.35 mmol) of Tris(dibenzylidineacetone)diplegia(0), 0,38 g (0.61 mmol) racemic the ski 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 0.51 g (5.3 mmol) of tert-butyl sodium, add 35 ml of toluene and the mixture is heated at 95°C for 16 h under nitrogen atmosphere. The mixture is partitioned between 1.0m aqueous NaHSO4and diethyl ether. Phase diethyl ether, washed once with saturated NaHCO3and once with saturated salt solution, dried over MgSO4, filtered and concentrated to a dark oil. This oil is purified by chromatography on silica gel, using as eluent a mixture of 15% EtOAc/85% hexane and receiving compound Y in the form of a dark orange oil.

C. Synthesis of compoundQ

To 1.0 g (2.8 mmol) of the compoundYin 5 ml of CH2Cl2add 4 ml of TFA. After 15 minutes the solution is concentrated, diluted with 50 ml isopropylacetate and washed twice 1.0m aqueous NaOH. Isopropylacetate layer is dried over MgSO4, filtered, concentrated to a brown oil. This oil was dissolved in 5.0 ml of isopropanol and added 390 mg (1.3 mmol) of the epoxideP(example 15, part a). The solution is heated to 70°C. After 36 hours, the solution concentrate and purify the product by HPLC with reversed phase gradient of 20-70% acetonitrile in 0.1% TFA). The fractions containing pure product are combined and concentrated by removing the acetonitrile. The aqueous residue was diluted with saturated salt solution and extracted with ethyl acetate. An ethyl acetate layer is dried over MgSO4and concentrate, getting connected is e Qin the form of a yellow foam.

Example 39

Synthesis of compound 39

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 3,4-dimethylaniline (Aldrich), get a TFA salt and connection39.

Example 40

Synthesis of compound 40

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 5-aminoindane (from Aldrich), get a TFA salt and connection40.

Example 41

Synthesis of compound 41

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace meta-toluidine (Aldrich), get a TFA salt and connection41.

Example 42

Synthesis of compound 42

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-aminodiphenylamine (from Aldrich), get a TFA salt and connection42.

Example 43

Synthesis of compound 43

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 3-ethylaniline (from Aldrich), get a TFA salt and connection43. m/z: [M+H+] calculated for C25H30N2O3407,2; found 407,2.

Example 44

Synthesis of compound 44

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace the hydrochloride of 3-methyl-4-isopropylaniline (from Avocado Chemicals), get a TFA salt and connection44. m/z: [M+H+] calculated for C27H34N2O3435,3; found 435,2.

Example 45

Synthesis of compound 45

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-(triptoreline)aniline (Aldrich), get a TFA salt and connection45. m/z: [M+H+] calculated for C24H25F3N2O4463,2; found 463,2.

Example 46

Synthesis of compound46

Applying the methodology of interaction, similar to that described in example 1, except that N1 -(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide substituted 4-amino-2-cyclohexylphenol (from Sigma-Aldrich Library of Rare Chemicals), get a TFA salt and connection46. m/z: [M+H+] calculated for C29H36N2O4477,3; found 477,2.

Example 47

Synthesis of compound 47

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 2-naphthylamine (from Aldrich), get a TFA salt and connection47.

Example 48

Synthesis of N-{2-[4-(3-phenylphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine (48)

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 3-aminobiphenyl (from Trans World Chemicals, Inc.), get a TFA salt and connection48.

Example 49

Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine (49)

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace hydrochloride 3-phenyl-para-anisidine (from Trans World Chemicals, Inc.), p is get a TFA salt and connection 49.

Example 50

Synthesis of compound 50

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide substituted 6-amino-3,4-benzocoumarin (from Aldrich), get a TFA salt and connection50. m/z: [M+H+] calculated for C30H28N2O5497,2; found 497,1.

Example 51

Synthesis of compound 51

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 4-aminobiphenyl (from Aldrich), get a TFA salt and connection51. m/z: [M+H+] calculated for C29H30N2O3to 455.2; found to 455.2.

Example 52

Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine (52)

To 2.0 g (3.10 mmol) of the compoundNin 50 ml ethanol add 0,70 g 10% palladium on coal in a stream of nitrogen. To the flask is connected to the tank with gaseous hydrogen and the reaction mixture was vigorously stirred for 1.5 hours. The reaction mixture was filtered through celite using methanol for washing, and the filtrate concentrated under reduced pressure. The remainder of the process is Aut in 20 ml of isopropanol, type of 1.65 ml 4,0N HCl in dioxane and the product precipitated by adding this solution to a large volume of diethyl ether. A solid substance was separated by filtration, getting 1,43 g (80%) of the hydrochloride salt of the compound52in the form of a white solid.1H NMR (300 MHz, DMSO-d6) δ: 9,4 (user, 1H), 9,01 (users, 1H), 8,65 (users, 1H), 7,39-7,22 (m, 6H), 6,99-6,83 (m, 8H), 6,69 (d, 1H), 5,45 (user, 4H), of 4.77 (m, 1H), 4,39 (s, 2H), 3,62 (s, 3H), 3,02-2,78 (m, 6H); m/z: [M+H+] calculated for C30H32N2O4485,2; found 485,4.

The intermediate connectionNobtained as follows.

A. Synthesis of compoundD

Into the flask containing 3,91 g (10 mmol) of the compoundIn(example 13, part b),of 3.06 g (13 mmol) of the hydrochloride of 4-methoxy-3-phenylaniline (from TCI), and 0.46 g (0.5 mmol) of Tris(dibenzylidineacetone)diplegia(0), 0,93 g (1.5 mmol) of racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and of 2.21 g (23 mmol) of tert-butyl sodium, add 50 ml of toluene and the mixture is heated at 95°C for 5.5 hours under nitrogen atmosphere. The mixture is partitioned between 1.0m aqueous NaHSO4and diethyl ether and separated phases. Phase diethyl ether diluted with one volume of hexane and washed once 1.0m aqueous NaHSO4and once with saturated salt solution, dried over Na2SO4, filtered and concentrated to a dark oil. This oil is purified by chromatography is as silica gel, using as eluent a mixture of 12% EtOAc/88% hexane and receiving the connectionDin the form of a yellow foam.1H NMR (300 MHz, DMSO-d6) δ: 7,76 (s, 1H), 7,38-7,13 (m, 10H), 6,95-for 6.81 (m, 7H), 4,28 (s, 2H), 3,61 (s, 3H), and 3.16 (m, 2H), 2,53 (m, 2H), 1,29 (s, N).

b. Synthesis of compoundG

To 2,60 g (5,11 mmol) of the compoundDin 15 ml of CH2Cl2when 0°add 15 ml triperoxonane acid. After 40 minutes the solution is concentrated under reduced pressure and distribute the balance between 1M aqueous NaOH and EtOAc. The phases are separated and the EtOAc phase was washed once with water and once with saturated salt solution, dried over Na2SO4, filtered and concentrated to an orange residue. This residue is dissolved in 15 ml of isopropanol, add 1.45 g (5,11 mmol) of epoxideand(example 37, part (b) and heat the solution at 78°With during the night. The mixture is cooled to room temperature and concentrated under reduced pressure, obtaining the connectionGin the form of an orange oil, which is used in the next stage without purification.

c. Synthesis of compoundH

To 5,11 mmol raw connectionGwith the previous stage in 40 ml of tetrahydrofuran at 0°add to 12.7 ml (12.7 mmol) of 1.0m of sociallyengaged in tetrahydrofuran. After 2 h the reaction is quenched by slowly adding decahydrate sodium sulfate. Suspen the July diluted with diethyl ether, dried over Na2SO4, filtered and concentrated to an orange oil. This oil is purified by chromatography, using as eluent a mixture of 50% EtOAc/50% hexane and receiving 20 g of compoundNin the form of a white foam (61%, stage 2).1H NMR (300 MHz, DMSO-d6) :7,72 (s, 1H), 7,38-6,77 (m, 25H), to 5.00 (s, 2H), 4.92 in (m, 1H)and 4.65 (m, 1H), 4,55 (m, 1H), 4,45 (d, 2H), 3,62 (s, 2H), 3,61 (s, 3H), 2,52 (m, 6H).

Example 53

Synthesis of N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine (53)

To a mixture of 825 mg (1,22 mmol) of the compoundNin 15 ml ofethanol added 260 mg of 10% palladium on coal in a stream of nitrogen. To the flask is connected to the tank with gaseous hydrogen and the reaction mixture was vigorously stirred for 3 hours. The reaction mixture was filtered through celite using methanol for washing, and the filtrate concentrated under reduced pressure. The residue is dissolved in 10 ml of isopropanol, add to 0.67 ml of 4.0m HCl in dioxane and precipitated the product, adding this solution to a large volume of EtOAc. A solid substance was separated by filtration, obtaining the hydrochloride salt of the compound53in the form of a white solid. m/z: [M+H+] calculated for C31H32N2O4499,3; found 499,3.

The intermediate connectionNobtained as follows.

a. Synthesis of compoundJ

4,84 g of 20.5 mmol) of the hydrochloride of 4-methoxy-3-phenylaniline (TCI) partitioned between diethyl ether and 1.0m aqueous NaOH and separated phases. Phase diethyl ether, washed once with water and once with saturated salt solution, dried over K2CO3, filtered and concentrated to a brown solid. This solid is dissolved in 100 ml of CH2Cl2the solution is cooled to 0°and type of 21.2 g (84,6 mmol) tribromide boron. After 20 min the reaction mixture was poured onto 500 ml of ice and stirred the mixture overnight. The mixture was twice washed with EtOAc to remove the oxidized substances and EtOAc, the phases of the throw. The acid phase is alkalinized solid NaHCO3and twice extracted with EtOAc. The combined EtOAc phase was washed once with saturated salt solution, dried over Na2SO4filter and concentrate, receiving 2,48 g connectionJin the form of a brown solid.1H NMR (300 MHz, DMSO-d6) δ: of 8.37 (s, 1H), 7,41-7,14 (m, 5H), 6,57-6,32 (m, 3H), of 4.45 (s, 2H).

b. Synthesis of compoundK

To 2.28 g (12.2 mmol) of the compoundJin 45 ml of dimethylformamide at 0°add 734 mg (18.4 mmol) of 60% NaH in oil. After 10 minutes add 1,90 g (12.2 mmol) of iodata. After 20 min the solution is partitioned between diethyl ether and 5% aqueous Na2SO3and share phase. Phase diethyl EPE is and washed once 1.0m aqueous NaOH, once with water and once with saturated salt solution, dried over Na2SO4and concentrate, receiving the connectionToin the form of a dark brown oil.1H NMR (300 MHz, DMSO-d6) δ: 7,37-7,19 (m, 5H), 6.73 x (d, 1H), 6,47-6.42 per (m, 2H)and 4.65 (s, 2H), of 3.73 (Quartet, 2H), with 1.07 (t, 3H).

c. Synthesis of compoundL

Into a flask containing of 3.97 g (of 10.7 mmol) of the compoundIn(example 13, part b),of 2.27 g (12.2 mmol) of the compoundTo, and 0.46 g (0.5 mmol) of Tris(dibenzylidineacetone)diplegia(0), 0.95 g (1.5 mmol) of racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 1.27 g (13.3 mmol) of tert-butyl sodium, add 48 ml of toluene and the mixture is heated at 95°C for 5.5 hours under nitrogen atmosphere. The mixture is partitioned between 1.0m aqueous NaHSO4and diethyl ether and separated phases. Phase diethyl ether diluted with one volume of hexane and washed once 1.0m aqueous NaHSO4and once with saturated salt solution, dried over Na2SO4, filtered and concentrated to a dark oil. This oil is purified by chromatography on silica gel, using as eluent a mixture of 10% EtOAc/90% hexane and receiving of 4.13 g (77%) of compound L as a yellow foam.1H NMR (300 MHz, DMSO-d6) δ: 7,76 (s, 1H), 7,42-7,13 (m, 10H), 6,93-for 6.81 (m, 7H), 4,27 (s, 2H), 3,86 (kV, 2H), 3,25 (m, 2H), 2,53 (m, 2H), 1.28 (in s, 9H), of 1.13 (t, 3H).

d. Synthesis of compoundM

p> To 1.40 g (2.68 mmol) of the compoundLin 15 ml of CH2Cl2when 0°add 15 ml triperoxonane acid. After 40 minutes the solution is concentrated under reduced pressure and distribute the balance between 1.0m aqueous NaOH and EtOAc. The phases are separated and the EtOAc phase was washed once with water and once with saturated salt solution, dried over Na2SO4, filtered and concentrated to an orange residue. This residue is dissolved in 15 ml of isopropanol, add 1.45 g (2.68 mmol) of the epoxideand(example 37, part (b) and heat the solution at 78°With during the night. The mixture is cooled to room temperature and concentrated under reduced pressure, obtaining an orange oil which is used without further analysis.

E. Synthesis of compoundsN

To 2.68 mmol raw connectionMin 20 ml of tetrahydrofuran at 0°add to 7.0 ml (7.0 mmol) of 1.0m of sociallyengaged in tetrahydrofuran. After 2 h the reaction is quenched by slowly adding decahydrate sodium sulfate. The suspension was diluted with diethyl ether, dried over Na2SO4, filtered and concentrated to an orange oil. This oil is purified by chromatography on silica gel, using as eluent a mixture of 50% EtOAc/50% hexane and getting 835 mg connectionNin the form of a white foam.1H NMR (300 MHz, DMSO-d6) :7,73 (s, 1H), 7,42-6,77 (m, 25H), to 5.00 (s, 2H), is 4.93 (m, 1H), 4,66 (who, 1H), 4,51 (m, 1H), 4,47 (m, 2H), 3,86 (kV, 2H), 3,62 (m, 2H), by 2.55 (m, 6H), of 1.13 (t, 3H).

Example 54

Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine (54)

To a mixture of 1.24 g (1,83 mmol) of the compoundIin 30 mlethanol and 20 ml of methanol is added 400 mg of 10% palladium on coal in a stream of nitrogen. To the flask is connected to the tank with gaseous hydrogen and the reaction mixture was vigorously stirred for 1.5 hours. The reaction mixture was filtered through celite using methanol for washing, and the filtrate concentrated under reduced pressure. The residue is dissolved in 20 ml of isopropanol, add to 0.21 ml of 4.0m HCl in dioxane and precipitated the product, adding this solution to a large volume of EtOAc. A solid substance was separated by filtration, getting 447 mg of the hydrochloride salt of the compound54in the form of a white solid.1H NMR (300 MHz, DMSO-d6) :there is a 10.03 (users, 1H), of 9.55 (s, 1H), 8,81 (users, 1H), 8,59 (users, 1H), to 8.20 (d, 1H), 8,07 (d, 1H), 7,39-7,20 (m, 5H), 6,99-6,79 (m, 10H), and 4.75 (m, 1H), 3,62 (s, 3H), 3,03-of 2.72 (m, 6H); m/z: [M+H+] calculated for C30H31N3O4498,2; found 498,5.

The intermediate connectionIobtained as follows.

a. Synthesis of compoundI

To 944 mg (of 1.85 mmol) of the compoundD(example 52, part a) in 6 ml of CH2Cl2at 0aboutWith doba is given in 6 ml triperoxonane acid. After 40 minutes the solution is concentrated under reduced pressure and distribute the balance between 1.0m aqueous NaOH and EtOAc. The phases are separated and the EtOAc phase was washed once with water and once with saturated salt solution, dried over Na2SO4, filtered and concentrated to an orange oil.

The above residue is dissolved in 5 ml of isopropanol, is added 500 mg (of 1.85 mmol) of the epoxideband heat the solution at 78°With during the night. The mixture is cooled to room temperature and concentrated under reduced pressure, obtaining an orange oil. This oil is purified by chromatography on silica gel, using as eluent a mixture of 50% EtOAc/50% hexane and getting 825 mg (66%) of compoundIin the form of a white foam.1H NMR (300 MHz, DMSO-d6) δ: of 9.45 (s, 1H), 8,24 (d, 1H), of 8.09 (d, 1H), 7,72 (s, 1H), 7,42-6,77 (m, 25H), 5,09 (s, 2H), 4,49 (m, 1H), to 3.67 (m, 2H), 3,61 (s, 3H), of 2.50 (m, 6H).

The intermediate epoxidebcan be obtained, as described in U.S. patent No. 6268533 B1 and in the work of R. Hett, and others,Organic Process Research and Development, 1998, 2, 96-99.

Example 55

Synthesis of N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine (55)

To a mixture of 746 mg (1.07 mmol) of the compoundAboutin 15 ml of ethanol and 5 ml of EtOAc added 260 mg of 10% palladium on coal in a stream of nitrogen. To the flask is connected to the tank with gaseous hydrogen and the reaction mixture is firm is about is stirred for 3 hours. The reaction mixture was filtered through celite using methanol for washing, and the filtrate concentrated under reduced pressure. The residue is dissolved in 20 ml of isopropanol, add of 0.58 ml of 4.0m HCl in dioxane and the product precipitated by adding this solution to a large volume of EtOAc. A solid substance was separated by filtration, obtaining the hydrochloride salt of the compound55as not quite white solid.1H NMR (300 MHz, DMSO-d6) δ: 10,12 (users, 1H), 9,62 (s, 1H), 8,90 (users, 1H), 8,67 (users, 1H), 8,27 (d, 1H), 8,14 (d, 1H), 7,25 (m, 5H), 6,85-was 7.08 (m, 9H), 4,80 (DD, 1H), 3,94 (kV, 2H), 2,75 is 3.15 (m, 6H), to 1.21 (t, 3H); m/z: [M+H+] calculated for C31H33N3O4512,25; found 512,5.

The intermediate connectionAboutobtained as follows.

a. Synthesis of compoundAbout

To 1.4 g (2.68 mmol) of the compoundL(example 53, part C) in 6 ml of CH2Cl2when 0°add 6 ml triperoxonane acid. After 40 minutes the solution is concentrated under reduced pressure and distribute the balance between 1.0m aqueous NaOH and EtOAc. The phases are separated and the EtOAc phase was washed once with water and once with saturated salt solution, dried over Na2SO4, filtered and concentrated to an orange oil. This residue is dissolved in 5 ml of isopropanol, add 721 mg (2.68 mmol) of the epoxideb(example 54, part a) and heat the solution at 78°during the course the e night. The mixture is cooled to room temperature and concentrated under reduced pressure, obtaining an orange oil. This oil is purified by chromatography on silica gel, using as eluent a mixture of 50% EtOAc/50% hexane and getting 756 mg connectionAboutin the form of a white foam.1H NMR (300 MHz, DMSO-d6) δ: of 9.45 (d, 1H), of 8.25 (d, 1H), 8,14 (d, 1H), 7,72 (s, 1H), 7,45-6,76 (m, 25H), 5,10 (s, 2H), 5,04 (m, 1H), 3,94 (kV, 2H), 3,61 (s, 2H), 2,50 (s, 6H), of 1.13 (t, 3H).

Example 56

Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (56)

To a solution of 840 mg (1.2 mmol) of compound Sin 40 ml of a mixture methanol:THF=1:1 add 170 mg of 10% palladium on coal. The reaction mixture is shaken in an atmosphere of H2when 2,461 kg/cm2(35 lb/in2). After 24 hours the reaction mixture is filtered and the filtrate purified by HPLC with reversed phase (gradient from 10 to 70% acetonitrile in 0.1% aqueous TFA). The fractions containing pure product are combined and lyophilized, receiving TFA-salt of the compound56in powder form.

Sample TFA-salt (75 mg) was dissolved in acetonitrile (1.0 ml) and diluted with water (2.0 ml), and then 0,1N HCl (3.0 ml). The solution becomes turbid. Add 1.5 ml of acetonitrile gives a clear solution which is frozen and lyophilized. The residue re-dissolved in acetonitrile (1.0 ml) and diluted with water (2.0 ml), is then 0,1N HCl (4.0 ml). The solution becomes turbid. Add 1.0 ml of acetonitrile gives a clear solution which is frozen and lyophilized. Get the hydrochloride salt of the compound56(50 mg) as a gray solid.1H NMR (300 MHz, DMSO-d6) δ: 10,55 (users, 1H), of 9.30 (users, 1H), 8,80, (users, 1H), 8,24 (d, 1H), 7,25-of 7.48 (m, 5H), 6,92-to 7.18 (m, 9H), 6,55 (d, 1H), of 5.55 (d, 1H), 3,69 (s, 3H) 2,80-3,20 (m, 6N); m/z: [M+H+] calculated for C32H31N3O4522,24; found 522,3.

The intermediate connectionSobtained as follows.

a. Synthesis of compoundS

A solution of compoundD(800 mg, 1.6 mmol, example 52, part a) in 5 ml of CH2Cl2cooled to 0°and add 5 ml of TFA. After 20 min the reaction mixture was concentrate and dissolve the residue in ethyl acetate. An ethyl acetate solution is washed twice 1.0m aqueous NaOH and then with water and dried over MgSO4, filtered and concentrated to oil. This oil is dissolved in 3 ml of DMF and add BrattonR(800 mg, 2.1 mmol) and K2CO3(650 mg, 4.7 mmol). The reaction mixture is heated to 40°C. After 1 hour the reaction mixture is cooled and diluted with 5 ml of methanol. Added NaBH4(150 mg, 4.0 mmol) and vigorously stirred the reaction mixture for 10 min. the Reaction mixture is quenched, prokopeva suspension in 100 ml of rapidly stirred saturated aqueous NH4Cl. Sdeposited, and select by filtration, washed with water and dried.

Intermediate BrattonRcan be obtained as described in example V, parts a-d. Cm. also EP W.

Example 57

Synthesis of compound 57

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace methyl-4-aminobenzoate (from Aldrich), get a TFA salt and connection57. m/z: [M+H+] calculated for C25H28N2O5437,2; found 437,2.

Example 58

Synthesis of compound 58

Applying the methodology of interaction, similar to that described in example 1, except that N1-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide replace 2-(4-AMINOPHENYL)-3-methyl-3-pyrazolin-5-one (from Sigma-Aldrich Library of Rare Chemicals), get a TFA salt and connection58. m/z: [M+H+] calculated for C27H30N4O4475,2; found 475,2.

Example 59

Synthesis of compound 59

To a mixture of compoundjj(0.2 g, 0.27 mmol) in 6 ml of a mixture of DMF/EtOH (1:1) add 50 mg of 10% palladium on coal. The reaction mixture was stirred under H2when 2,812 kg/cm2(40 lb/in2within 8 hours. The suspension is filtered and cleaned metadomain with reversed phase (gradient from 10 to 50% acetonitrile in 0.1% aqueous TFA). The fractions containing pure product are combined and lyophilized, receiving the connection59as TFA-salt. The obtained TFA salt dissolved in a mixture of acetonitrile/water (1:1, 2 ml), to which is added 1.5 ml 0,1N aqueous HCl. The solution is frozen and lyophilized, receiving the connection59in the form of a salt with HCl. m/z: [M+H+] calculated for C30H29N5O5S 572,7; found 572,3.

The intermediate productjjobtained as follows.

a. Synthesis of compoundjj

ConnectionNN(4.5 g, 8.1 mmol) (example 14, part a) in 20 ml of CH2Cl2add 1.5 ml of TFA. After 1 hour the solution is concentrated and alkalinized 1,0N aqueous sodium hydroxide and twice extracted with CH2Cl2and then with ethyl acetate. The organic layers are combined, dried over MgSO4, filtered and concentrated to oil. This oil is purified by chromatography on silica gel (gradient from 2 to 10% methanol in methylene chloride). To the purified product (0,42 g to 0.92 mmol) is added epoxideP(example 15, part a) (0,22 g, from 0.76 mmol) and isopropanol (410 ml). The suspension is stirred at 70°C. Add the methylene chloride until you get a homogeneous solution. After 40 hours the reaction mixture is cooled to room temperature and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica gel (2% methanol in the stands who chloride), receiving the connectionjj.

Example 60

Synthesis of compound 60

To a mixture of compoundPP(0.3 g, 0.45 mmol) in 10 ml of anhydrous EtOH was added 100 mg of 10% palladium on coal. The reaction mixture was stirred under H2when 2,812 kg/cm2(40 lb/in2for 18 hours. The reaction mixture is filtered and the residue purified by HPLC with reversed phase (gradient from 10 to 50% acetonitrile in 0.1% aqueous TFA). The fractions containing pure product are combined and lyophilized, receiving the connection60as TFA-salt. The obtained TFA salt dissolved in a mixture of acetonitrile/water (1:2, 100 ml), to which add 6 ml 0,1N aqueous HCl. The solution is frozen and lyophilized, receiving the connection60in the form of a salt with HCl. m/z: [M+H+] calculated for C27H29N5O4488,6; found 488,3.

The intermediate connectionPPobtained as follows.

a. Synthesis of compoundSS

Into the flask containing the connectionIn(example 13, part b) (3.75 g, 9.6 mmol), 2-(4-AMINOPHENYL)-3-methyl-3-pyrazolin-5-Oh (2.0 g, 10.6 mmol) (from Sigma-Aldrich Library of Rare Chemicals), Tris(dibenzylideneacetone)dipalladium(0) (0,44 g, 0.48 mmol), racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0,90 g, 1.44 mmol) and tert-butyl sodium (2.20 g, 12.5 mmol), add toluene (50 ml). The mixture was stirred at 95°C for 6 hours in at the osphere nitrogen. The mixture is diluted with 200 ml diethyl ether and washed twice with 100 ml 1.0m aqueous NaHSO4,then 100 ml of saturated aqueousNaHCO3. Phase diethyl ether dried over MgSO4, filtered and concentrated to a dark oil. This oil is purified by chromatography on silica gel (gradient from 30 to 40% ethyl acetate in hexano), receiving the connectionSSas an orange foam.

b. Synthesis of compoundPP

ConnectionSS(0,99 g, 1,99 mmol) in 5 ml of CH2Cl2add 2 ml of TFA. After 1 hour the solution is concentrated, diluted with 15 ml of CH2Cl2and washed 1,0N aqueous sodium hydroxide. The aqueous phase is collected and washed again CH2Cl2(10 ml)and then ethyl acetate (10 ml). The organic layers are combined, dried over MgSO4filter and concentrate under reduced pressure. The crude product is purified by chromatography on silica gel (gradient of 2-10% MeOH in CH2Cl2), getting an oil (2.1 g). Part of this product (0.5 g, of 1.26 mmol) dissolved in 10 ml of a mixture methanol:THF=1:1. Add bromohydrinGG(example 13, part d) (0,42 g, 1.20 mmol) and K2CO3(0,44 g and 3.15 mmol) and the suspension is stirred at room temperature for 1.5 hour. The reaction mixture was concentrated, the residue is diluted with 30 ml of water and extracted twice with 30 ml of toluene. Toluene is xtracta unite, dried over Na2SO4filter and concentrate. The residue is heated to 120°C. After 2 h the reaction mixture was cooled to room temperature and the crude product is purified by chromatography on silica gel (gradient of 5-10% MeOH in CH2Cl2), receiving the connectionPPin the form of a reddish-brown solid (0.7 g).

Example 61A

Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (61)

To a solution of 200 mg (0.28 mmol) of the compoundTin 4 ml of acetic acid was added 100 mg of 10% palladium on coal. The reaction mixture is shaken in an atmosphere of H2when 2,812 kg/cm2(40 lb/in2). After 17 h, the reaction mixture was filtered and the filtrate purified by HPLC with reversed phase (gradient from 10 to 70% acetonitrile in 0.1% aqueous TFA). The fractions containing pure product are combined and lyophilized, receiving the connection61in powder form.

The intermediate connectionTobtained as follows.

a. Synthesis of compoundT

To 1.13 g connectionD(2.2 mmol, example 52, part a) in 4 ml of CH2Cl2add 4 ml of TFA. After 30 minutes the solution is concentrated and diluted with 20 ml ethyl acetate and 20 ml of water. Raise the pH to 11 by adding 6,0N aqueous sodium hydroxide, and separate the layers. Ethyl is attny layer is washed once with 1,0N aqueous solution of sodium hydroxide, dried over MgSO4, filtered, concentrated to a brown oil. This oil was dissolved in 7.0 ml of isopropanol and added 600 mg (2.0 mmol) of epoxideP(example 15, part a). The solution is heated to 70°C. After 34 hours the solution is concentrated and the product is partially purified by chromatography on silica gel (gradient from 1% to 2% methanol in CH2Cl2). The fractions containing the product are combined and concentrated, obtaining the compound T in the form of a yellow oil.

Example V

Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (61)

To a solution of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (PP) (4.0 g, 6.5 mmol) in tetrahydrofuran (100 ml) and water (16 ml) is added 10% palladium on coal (800 mg). The reaction mixture was vigorously stirred under hydrogen atmosphere for 6.5 hours. Solids filtered and washed with tetrahydrofuran (4×25 ml) and then with a mixture of 50% methanol/tetrahydrofuran (2×25 ml). Combined fractions are evaporated to dryness and purify the crude product by HPLC with reversed phase. The fractions containing pure product are combined and lyophilized. Combine the product of several cycles, getting 4.68 g, which is dissolved in acetonitrile (200 ml) and water (200 ml). Add 1,0N HCl (18.7 ml) and the solution liophilization again dissolved in acetonitrile (125 ml) and water (125 ml). Add 1,0N HCl and the solution lyophilized, receiving the hydrochloride salt of the compound61as not quite white powder.1H NMR (300 MHz, DMSO-d6) δ: 10,55 (users, 1H), 9,40 (users, 1H), 8,80, (users, 1H), compared to 8.26 (d, 1H), 7,60, (users, 2H) 7,25 was 7.45 (m, 5H), 6,92-7,16 (m, 10H), 6,55 (d, 1H), the 5.45 (d, 1H), 3,69 (s, 3H) 2,80 is 3.15 (m, 6H); m/z [M+H+] calculated for C32H31N3O4522,24; found 522,4.

The intermediate productPPobtained as follows.

A. Synthesis of 8-acetoxy-2(1H)-Hinayana (SS)

8-Hydroxyquinoline-N-oxide (160,0 g, 1.0 mol) and acetic acid (800 ml, 8.4 mol) is heated at 100°C for 3 h and then cooled on ice. The product is collected on a Buechner funnel, washed with acetic anhydride (2×100 ml) and dried under reduced pressure, obtaining 8-acetoxy-2(1H)-chinoline (SS) (144 g) as a reddish brown solid.

b. Synthesis of 5-acetyl-8-hydroxy-2(1H)-Hinayana (DD)

A suspension of aluminium chloride (85,7 g, 640 mmol) in 1,2-dichloroethane (280 ml) cooled on ice and add the connectionSS(56,8 g, 280 mol). The mixture is heated to room temperature, and then heated to 85°C. After 30 minutes add acetylchloride (1.5 ml, 21 mmol) and the mixture is heated for 60 minutes and Then the reaction mixture is cooled and add 1N HCl (3 l) at 0°and With good stirring. On the Le stirring for 2 hours, collect the solid on a Buechner funnel, washed with water (3×250 ml) and dried under reduced pressure. The crude product isolated from several parties (135 g), are combined and triturated in dichloromethane (4 l) for 6 hours. The product is collected on a Buechner funnel and dried under reduced pressure, obtaining 5-acetyl-8-hydroxy-2(1H)-chinoline (DD) (121 g).

C. Synthesis of 5-acetyl-8-benzyloxy-2(1H)-Hinayana (HER)

5-acetyl-8-hydroxy-2-chinolone (37,7 g, 186 mmol) is added dimethylformamide (200 ml) and potassium carbonate (34,5 g, 250 mol), and then benzylbromide (31.8 g, 186 mmol). The mixture is stirred at room temperature for 2.25 hours and then poured into a saturated solution of sodium chloride (3.5 l) at 0°C and well stirred for 1 hour. The product is collected and dried on the Buchner funnel for 1 hour, the obtained solid substance was dissolved in dichloromethane (2 l) and dried over sodium sulfate. The solution is filtered through a layer of celite and washed with dichloromethane (5×200 ml). The combined filtrate is concentrated to dryness and the resulting solid triturated in ether (500 ml) for 2 hours. The product is collected on a Buechner funnel, washed with ether (2×250 ml) and dried under reduced pressure, obtaining 5-acetyl-8-benzyloxy-2(1H)-chinoline (HER) (44 g) as a white powder.

d. Synthesis of 5-(2-bromo-1-hydroxy)ethyl-8-benzyloxy-2(1H)-Hinayana (R)

5-Acetyl-8-benzyloxy-2(1H)-chinoline (HER) (20,0 g, 68.2 mmol) dissolved in dichloromethane (200 ml) and cooled to 0°C. Added by syringe diethylether of boron TRIFLUORIDE (10.4 ml, 82,0 mmol) and the mixture is heated to room temperature, obtaining a thin slurry. This suspension is heated at 45°C (oil bath) and add a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 ml) for 40 minutes, the Mixture is maintained at 45°With a further 15 min and then cooled to room temperature. The mixture is concentrated under reduced pressure and then triturated in 10% aqueous sodium carbonate (200 ml) for 1 hour. Solids are collected on a Buechner funnel, washed with water (4×100 ml) and dried under reduced pressure. The product of two cycles combine to clear. The crude product (52 g) is triturated in 50% methanol in chloroform (500 ml) for 1 hour. The product is collected on a Buechner funnel and washed with 50% methanol in chloroform (2×50 ml) and methanol (2×50 ml). The solid is dried under reduced pressure, obtaining 5-(2-bromo-1-hydroxy)ethyl-8-benzyloxy-2(1H)-chinoline (R) (34,1 g) as a white powder.

E. Synthesis of 5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-Hinayana (FF)

Applying the methodology described in Mathre, etc., J. Org. Chem., 1991, 56, 751-762, prepare the catalyst as follows. (R)-(+)--Diphenylprop the ol (10.0 g, 39 mmol) and trimethylboroxine of 3.7 ml, 26 mmol) are combined in toluene (200 ml) and stirred at room temperature for 30 minutes the mixture is placed in an oil bath (150° (C) and 150 ml of distilled liquid. Add toluene (50 ml) and collected another 50 ml of distillate. Add another portion of toluene (50 ml) and collected another 50 ml of distillate. An aliquot of the material (1,00 ml)remaining in the tank is evaporated to dryness and weighed (241,5 mg), determining that the concentration of catalyst is 0,87M.

5-(2-Bromo-1-hydroxy)ethyl-8-benzyloxy-2(1H)-chinoline (R) (30.0 g, 81 mmol) suspended in tetrahydrofuran (1.2 l) under nitrogen atmosphere and add the above catalyst (13 ml, 11 mmol). The suspension is cooled to -5°in a bath of ice/isopropanol and added borane (1.0m in THF, 97 ml, 97 mmol) for 3 hours. The reaction mixture is stirred for further 45 min at -5°With, then slowly add methanol (200 ml). The mixture was concentrated in vacuo, obtaining 5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-chinoline (FF).

f. Synthesis of 5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-Hinayana (HH)

ConnectionFF(15 g, 40 mmol) and 2,6-lutidine (9.3 ml, 80 mmol) is suspended in dichloromethane at 0°C. Add one drop of tert-butyldimethylsilyl triftorbyenzola (18.5 ml, 80 mmol). Mixture is allowed to warm to room temperature is ture and stirred over night. The reaction mixture was diluted with dichloromethane (200 ml) and washed twice 1N hydrochloric acid and then three times with saturated solution of salt. The organic fractions are dried over magnesium sulfate and reduce the volume in vacuo to 100 ml of Organic matter contribute to a column of silica gel, balanced 30% ethyl acetate in hexane, and elute the product with 50% ethyl acetate in hexane. Removal of the solvent under reduced pressure gives 5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-chinoline (HH) (10.3 g). There is also unreacted starting material (compoundFF, 2 g).

g. Synthesis of N-tert-butoxycarbonyl-2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethylamine (LL)

Under a nitrogen compoundX(from example 38, part a) (5.0 g, and 16.7 mmol) is mixed with toluene (80 ml) and add hydrochloride 4-methoxy-3-phenylaniline (4.3 g, and 18.3 mmol)to give a suspension. Add 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.6 g, 2.5 mmol), and then Tris(dibenzylideneacetone)dipalladium(0) (760 mg, 0.83 mmol) and finally tert-butyl sodium (5,3 g, 55 mmol). The mixture is heated at 90°C for 150 min and then cooled to room temperature. Add water (150 ml)and then ethyl acetate (150 ml) and the combined organic phases are washed three times with 0.5m-sodium bisulfate (200 ml), once with a saturated solution of bicarbonate NAT is s (150 ml) and twice with a saturated solution of sodium chloride (150 ml). The organic phase is dried over magnesium sulfate (50 g) and remove volatiles in vacuum, obtaining N-tert-butoxycarbonyl-2-[4-(3-[phenyl-4-methoxyphenyl)AMINOPHENYL]ethylamine (LL) (8,4 g), which is used without further purification.

h. Synthesis of 2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethylamine (MM)

Under a nitrogen compoundLL(94,6 g) triturated in dichloromethane (500 ml) and cooled in a bath with ice. Add hydrogen chloride (4M in dioxane, 125 ml, 500 mmol) in 10 portions over 20 minutes the Reaction mixture was kept at room temperature for 130 minutes, during this time the product precipitates. Solids filtered off, washed with dichloromethane (350 ml) and dried under vacuum in the dark, getting dihydrochloride salt of 2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethylamine (MM).1H NMR (300 MHz, DMSO-d6):8,29 (users, 2H), 8,04 (users, 1H), 7,25 is 7.50 (m, 5H), 6.90 to-was 7.08 (m, 7H), of 3.69 (s, 3H), of 2.93 (m, 2H), 2,75 (m, 2H); m/z: [M+H+] calculated for C21H22N2O 319,18; found 319,3.

i. Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-tert-butyldimethylsilyl-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (NN)

Salt is the dihydrochloride of compoundMMdistribute between isopropylacetate and 1,0N sodium hydroxide. The organic layer is dried over sodium sulfate, concentri the comfort, getting free base in the form of a dark oil.

Weighed in the flask sodium iodide (4,2 g, 28 mmol), compoundNN(9,1 g of 18.6 mmol) and sodium bicarbonate (4.7 grams of 55.9 mmol). Under nitrogen add connectionMM(7 g, 22 mmol) in dimethyl sulfoxide (20 ml) and the mixture was stirred at 140°C (oil bath) for 30 min, and then cooled to room temperature. Add ethyl acetate (200 ml) and the mixture is washed three times with 1N hydrochloric acid, then 1N sodium hydroxide, saturated sodium bicarbonate and finally with a saturated solution of sodium chloride (each 200 ml). The organic phase is dried over sodium sulfate and evaporated to dryness, obtaining N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-tert-butyldimethylsilyl-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (NN) (13,9 g), which is used in the next stage without additional purification.

j. Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (PP)

ConnectionNN(13,9 g) are combined with methanol (200 ml) and add parts of concentrated hydrochloric acid (170 ml) (exothermic reaction). The solution after the addition becomes orange and muddy, add methanol (100 ml) to obtain a clear solution. The mixture is stirred at room temperature for the eyes, during this time formed a brown resin. Remove the solvent in vacuo and add ethyl acetate (300 ml). The resulting mixture is cooled in a bath with ice and neutralized (pH 7) 10N sodium hydroxide. Then raise the pH to 10 1M sodium hydroxide, getting a clear two-phase mixture. The phases are separated and the aqueous layer was extracted with ethyl acetate (300 ml). The combined organic layers dried over sodium sulfate and evaporated to dryness. The crude product is purified by the method of flash chromatography on silica gel (500 g, 0-10% methanol in dichloromethane)to give N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (PP) (5.6 g).

Example 61C

Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (PP)

The intermediate connectionPPobtained as follows.

A. Synthesis of 5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-Hinayana (FF)

(R)-(+)--Diphenylprolinol (30.0 g, 117 mmol) and trimethylboroxine (11,1 ml, 78 mmol) are combined in toluene (300 ml) and stirred at room temperature for 30 minutes the Mixture is placed in an oil bath (150° (C) and distilled liquid. Add toluene an aliquot of 20 ml and continue the distillation for 4 hours. Add 300 ml of toluene. In conclusion, the mixture is cooled to room temperature. An aliquot 500 the CL is evaporated to dryness, weigh (246 mg), determining that the concentration of the catalyst is 1,8M.

5-(2-Bromo-1-hydroxy)ethyl-8-benzyloxy-2(1H)-chinoline (R) (90.0 g, 243 mmol) was placed under nitrogen, add tetrahydrofuran (900 ml), and then the above catalyst (1.8m in toluene, 15 ml, 27 mmol). The suspension is cooled to -10±5°in a bath of ice/isopropanol. Add borane (1.0m in THF, 294 ml, 294 mmol) for 4 hours. The reaction mixture is stirred for further 45 min at -10°With, then slowly add methanol (250 ml). The mixture was concentrated in vacuo. The residue is dissolved in boiling acetonitrile (1.3 l), filtered hot and cooled to room temperature. The crystals are filtered, washed with acetonitrile and dried under reduced pressure, obtaining 5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-chinoline (FF) (72.5 g, 196 mmol, yield 81%, 95%, purity 95% by the ratio of areas in HPLC).

b. Synthesis of 5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-Hinayana (HH)

ConnectionFF(70,2 g, 189 mmol) is treated with N,N-dimethylformamide (260 ml) and cooled in a bath under nitrogen. Added 2,6-lutidine (40,3 ml, 376 mmol) for 5 min, and then slowly added tert-butyldimethylsilyl triftorbyenzola (99,8 ml, 378 mmol), keeping the temperature below 20°C. the Mixture is allowed to warm to room temperature over 45 minutes To this mixture is added drop by drop meta is ol (45 ml) for 10 min and distribute this mixture between a mixture of ethyl acetate/hexane (1:1, 500 ml) and the mixture of water/saturated salt solution (1:1, 500 ml). The organic fraction is washed twice with a mixture of water/saturated salt solution (1:1, each time in a 500 ml). The combined organic fraction is evaporated under reduced pressure, obtaining a light yellow oil. Add to butter two separate parts of cyclohexane (400 ml) and continue the distillation until the formation of thick white suspension. Add to suspension of cyclohexane (300 ml) and the resulting white crystals are filtered off, washed with cyclohexane (300 ml) and dried under reduced pressure, obtaining 5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-chinoline (HH) (75,4 g, 151 mmol, yield 80%, 98.6% of it).

C. Synthesis of N-[2-(4-bromophenyl)ethyl]-(R)-2-tert-butyldimethylsiloxy-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (JJ)

ConnectionNN(136,5 g, 279 mmol), 4-bromophenethylamine (123 g, 615 mmol) and dimethylsulfoxide (180 ml) is mixed at room temperature under nitrogen. Add 40 ml of dimethyl sulfoxide. The mixture is heated to 85°C for 5 hours. The reaction mixture is distributed between ethyl acetate (1 l) and 10% aqueous acetic acid (500 ml). The organic fraction was washed with 10% aqueous acetic acid (3×500 ml), then 1N sodium hydroxide (3×500 ml). The last wash was filtered through celite (100 g). The organic layer is concentrated to 300 ml and dobavlaut cyclohexane (2× 500 ml), the solution is concentrated to 300 ml Add sufficient cyclohexane to a final volume of 1.8 liters, which is filtered through celite (50 g). To the crude product add a solution of HCl in isopropanol obtained by slow addition of concentrated HCl (23,5 ml) isopropanol (180 ml) at 10°With (inside)and the reaction mixture is stirred for 5 hours, washed with cyclohexane (2×500 ml) and dried under reduced pressure for 24 hours, obtaining the hydrochloride of N-[2-(4-bromophenyl)ethyl]-(R)-2-tert-butyldimethylsiloxy-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (JJ) (145 g, 80% molar, 106 wt.%, HPLC-purity 97,9%).

d. Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-tert-butyldimethylsilyl-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (NN)

The hydrochloride of the compoundJJ(73,7 g, 114 mmol) and 4-methoxy-3-phenylenedimethylene (32,4 g, 137 mmol) is added toluene (380 ml) under moderate stirring for 5 min, and then add parts of tert-butyl sodium (49,3 g, 513 mmol) for 1 min and finally 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (10,65 g, 17 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (5,22 g, 5.7 mmol). The resulting mixture is stirred and heated to 85-89°With (inside) for 2.5 hours. The solution is cooled to room temperature, add water (400 ml) and the mixture is stirred for 5 min, filtered through celite (80 g) and distribute, COI is lsua toluene (100 ml). The organic layer is collected and concentrated under reduced pressure on a steam bath (40° (C)to give N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-tert-butyldimethylsilyl-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (NN) as a dark viscous oil.

E. Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (PP)

ConnectionNNwith the previous stage is dissolved in 280 ml of THF. Add to the solution trihydrated of triethylamine (27,6 g, 171 mmol), to wash the remnants of the reagent is used for another 20 ml THF and the reaction mixture is stirred at 25°C under nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure at a bath (25° (C)to give a dark viscous oil, to which is added dichloromethane (400 ml)and then 1N aqueous NaOH (200 ml). The reaction mixture is stirred for 5 hours. The upper layer is discarded, and the organic layer concentrated to a viscous oil.

This oil is dissolved in dichloromethane, receiving a total of 630 ml Take an aliquot 60 ml) and concentrated to 30 ml Add toluene (60 ml)and the mixture is then concentrated hydrochloric acid (2.7 ml) and methanol (4.5 ml)to give a thick paste, closed free-flowing liquid. The liquid is carefully removed and the paste is washed with toluene (50 ml). The resin is distributed between dichloromethane (40 ml) and 1N aqueous hydroxide NAT the Oia (40 ml) and remove the organic solvents under reduced pressure. The residue is purified by chromatography on silica gel, using a gradient of 0-10% methanol in dichloromethane)to give N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-chinoline-5-yl)ethylamine (PP).

Example 62

Synthesis of compound 62

To a solution of 70 ml of connectionnn(0,09mmol) in 5 ml of glacial acetic acid added 21 mg of 10% palladium on coal. The reaction mixture is shaken in an atmosphere of H2when 2,812 kg/cm2(40 lb/in2). After 18 h, the reaction mixture was filtered and the filtrate purified by HPLC with reversed phase (gradient from 10 to 50% acetonitrile in 0.1% aqueous TFA)to give compound62(10 mg, 0,0126 mmol)as TFA-salt.1H NMR (300 MHz, DMSO-d6) : to 1.21 and 1.33 (m, 2H), 1,39-of 1.52 (m, 4H), to 2.74 (m, 4H), 2,82 (m, 2H), 2,96-3,20 (m, 4H), 5.25 in (m, 1H), 6,13 (m, 1H), 6,51 (m, 1H), 6.90 to (d, 1H, J=8,2 Hz), 7,01 (d, 2H, J=8,8 Hz), 7,07-to 7.15 (m, 5H), 7,43 (d, 2H, J=9.1 Hz), 8,07 (d, 2H, J=9.9 Hz), 8,61 (users, 2H), 8,76 (s, 1H), accounted for 10.39 (s, 1H), 10,46 (s, 1H); m/z: [M+H+] calculated for C30H34N4O5S 563,7; found 563,3.

The intermediate connectionnnobtained as follows.

a. Synthesis of compoundkk

Into the flask containing 4,51 g (11.6 mmol) of the compoundIn(primer, part b), 3,61 g (15.0 mmol) of 4-piperidinemethanol)aniline (from Meybridge), of 0.53 g (of 0.58 mmol) of Tris(dibenzylidineacetone)diplodia), 1.19 g (1,91 mmol) of racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 1.45 g (15.1 mmol) of tert-butyl sodium, add toluene (60 ml) and the mixture was stirred at 95°C for 6 hours in nitrogen atmosphere. The mixture is diluted with 200 ml diethyl ether and washed twice with 100 ml 1.0m aqueous NaHSO4and then with 100 ml of saturated aqueous NaHCO3. Phase diethyl ether dried over MgSO4, filtered and concentrated to a dark oil. This oil is purified by chromatography on silica gel (gradient from 30 to 40% ethyl acetate in hexane)to give compoundkkas an orange foam.

b. Synthesis of compoundmm

A solution of compoundkk(2,88 g of 5.24 mmol) in 20 ml of CH2Cl2cooled to 0°and add 20 ml of TFA. After 20 min the reaction mixture was concentrate and dissolve the residue in isopropylacetate. Isopropylacetate solution is washed twice 1,0N aqueous NaOH and then with water and dried over MgSO4, filtered and concentrated to oil. This oil is dissolved in 2 ml DMF and add the intermediate productAA(Mg, 0.69 mmol), diethylethanolamine (179 mg, 1.38 mmol) and potassium iodide (172 mg, 1.04 mmol). The reaction mixture is heated to 100°C. After 18 h, the reaction mixture is cooled and added to vigorously stirred water. Saducees connectionmmseparated by filtering and purifying HRO what ecografia on silica gel (ethyl acetate/hexane=1:1), getting 544 mg of solids.

C. Synthesis of compoundnn

To a solution of compoundmm(83 mg, 0.01 mmol) in CH2Cl2(0.9 ml) and triethylamine (0,09 ml) add trihydrated of triethylamine (313 mg, 1.94 mmol). The solution was stirred at room temperature in an atmosphere of N2. After 18 h, the reaction mixture was diluted with CH2Cl2and washed 1,0N aqueous HCl and then twice with a saturated solution of NaCl. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure, obtaining the connectionnn(70 mg).

Example 63

Synthesis of compound 63

To a solution of 70 ml of connectionrr(1,05mmol) in 10 ml of glacial acetic acid was added 100 mg of 10% palladium on coal. The reaction mixture was stirred in an atmosphere of H2. After 65 hours, the reaction mixture was filtered and the filtrate purified by HPLC with reversed phase (gradient from 10 to 50% acetonitrile in 0.1% aqueous TFA)to give 90 mg (0.14 mmol) of the TFA-salt. The obtained TFA salt dissolved in a mixture of acetonitrile/water (1:2, 10 ml), to which is added 3 ml 0,1N aqueous HCl. The solution is frozen and lyophilized, receiving the connection63in the form of HCl salt.m/z: [M+H+] calculated for C29H29N5O4512,6; found 512,3.

The intermediate connectionrrreceive the following about the time.

a. Synthesis of compoundqq

To 0,99 g (1,99 mmol) of the compoundSS(example 60, part a) in 5 ml of CH2Cl2add 2 ml of TFA. After 1 hour the solution is concentrated, diluted with 15 ml of CH2Cl2and washed 1,0N aqueous sodium hydroxide. The aqueous phase is collected and washed again CH2Cl2(10 ml)and then ethyl acetate (10 ml). The organic layers are combined, dried over MgSO4filter and concentrate under reduced pressure. The crude product is purified by chromatography on silica gel (gradient of 2-10% MeOH in CH2Cl2), obtaining the intermediate productqqin the form of oil.

b. Synthesis of compoundrr

To a solution of compoundqq(to 2.06 mg, 5.0 mmol) in 27 ml of DMF add BrattonR(example 56, part a) (1,71 g, 4.5 mmol) and K2CO3(1,91 g of 13.8 mmol). The reaction mixture is heated to 5°C. After 1 hour the reaction mixture is allowed axladitsa to room temperature and filtered K2CO3. The filtrate is diluted with CH2Cl2(50 ml) and washed with 0,1N HCl (30 ml). The organic layer is washed once with a saturated solution of sodium bicarbonate, then saturated aqueous sodium chloride, dried over Na2SO4and concentrate under reduced pressure, obtaining oil. This product (1,14 g of 1.65 mmol) dissolved in 12 ml of THF/EtOH (11) and added NaBH 4(380 mg, 10.0 mmol). After 20 min of vigorous stirring, the reaction mixture was quenched with saturated aqueous NH4Cl, which is added to the cessation of gas in the reaction mixture. The reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate solution. The organic layer is washed twice with a saturated solution of sodium bicarbonate, then saturated sodium chloride solution, dried over Na2SO4and concentrate under reduced pressure. The crude product is purified by chromatography on silica gel (2% Meon in CH2Cl2)to give 230 mg of the intermediate connectionrr.

Example 64

Synthesis of N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine (64)

To a mixture of 580 mg (0,93 mmol) of the compoundVin 25 ml of ethanol is added 173 mg of 10% palladium on coal in a stream of nitrogen. To the flask is connected to the tank with gaseous hydrogen and the reaction mixture is vigorously stirred for 4 days. The reaction mixture is filtered and the filtrate concentrated under reduced pressure. The residue is purified by HPLC with reversed phase, using a gradient from 10 to 50% acetonitrile in 0.1% aqueous TFA. The fractions containing pure product are combined and lyophilized, receiving TFA-salt of the compound64as not quite white solid.

The way the TFA-salt of compound 64 (150 mg) dissolved in acetonitrile (2.0 ml) and water (2.0 ml). Add 0,1N HCl (7.0 ml, 0.70 mmol) and the resulting residue re-dissolved in acetonitrile. The resulting solution lyophilizer obtaining a solid substance, which is again dissolved in acetonitrile (5.0 ml) and water (5.0 ml). Add 0,1N HCl (7.0 ml, 0.7 mmol) and the resulting solution lyophilized, receiving the hydrochloride salt of the compound64as not quite white powder.1H NMR (300 MHz, DMSO-d6) δ: 10,10 (users, 1H), 9,62 (s, 1H), 8,80 (users, 1H), 8,65 (users, 1H), 8,27 (d, 1H), 8,15 (d, 1H), 6,80-to 7.15 (m, 11H), 4,78 (DD, 1H), 3,94 (kV, 2H), 2,80 is 3.15 (m, 6H), of 1.29 (t, 3H); m/z: [M+H+] calculated for C25H29N3O4436,22; found 436,3.

The intermediate connectionVobtained as follows.

a. Synthesis of compoundV

To 0,60 g (1.3 mmol) of the compoundWith(example 37, part a) in 20 ml of CH2Cl2when 0°add 2.0 ml triperoxonane acid. After 1 hour the solution is concentrated under reduced pressure and the residue partitioned between 1,0N aqueous NaOH and EtOAc. The phases are separated and the EtOAc phase is dried over MgSO4, filtered, concentrated to an oil and dissolved in 10 ml of a mixture methanol:THF=1:1. Add bromohydrinGG(example 13, part d) (360 mg, 1.0 mmol) and K2CO3(380 mg, 2.7 mmol) and the reaction mixture was stirred at room temperature for 1.5 hour. The reaction mixture is diluted with 30 ml of water and extracted twice on the operations in 30 ml of toluene. Toluene extracts are combined, dried over MgSO4filter and concentrate. The residue is heated to 120°C. After 2 h, the residue is cooled to room temperature and purified by chromatography on silica gel (gradient from 5% to 10% methanol in CH2Cl2). The fractions containing pure product are combined and concentrated, obtaining the connectionVin the form of a reddish-brown solid.

Example 65

Synthesis of N-{2-[4-(3-phenylphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (65)

ConnectionW(55,2 mg, 0,094 mmol), phenylboronic acid (13.2 mg, 0,113 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (PdCl2(dppf)-DHM) (5.0 mg, 0,006 mmol) are combined in a small vial to work under pressure and purge N2. Add 1,2-dimethoxyethane (1.0 ml) and 2,0N cesium carbonate (150 μl, 0.3 mmol). The test tube is sealed and then placed in an oil bath at 90°With over 4 hours. Next, the solution is cooled to room temperature and add DHM (10 ml). The solution is filtered and concentrated to dryness. To the residue add DMF (1.0 ml), 10% Pd/C (100 mg) and ammonium formate (200 mg) and heat the solution to 50°C for 1.5 hours. At this time, add a mixture of water:acetonitrile=1:1 and 200 μl of TFA and the solution is filtered to remove the catalyst. The filter is t purified by HPLC with reversed phase. The fractions containing pure product are combined and lyophilized, receiving the connection65as TFA-salt.1H NMR (300 MHz, DMSO-d6) δ: 10,46 (s, 1H), accounted for 10.39 (s, 1H), 8,60 (users, 2H), 8,19 (s, 1H), 8,07 (d, 1H), 7,50 (d, 2H), 7,37 (t, 2H), 7,15-7,30 (m, 3H), 6,85-7,10 (m, 9H), 6,51 (DD, 1H), 6,11 (d, 1H), 5,23 (d, 1H), 2,70 is 3.15 (m, 6H); m/z: [M+H+] calculated for C31H29N3O3492,23; found 492,3.

a. Synthesis of compoundU

ConnectionNN(example V, part f) (9,1 g, 18,62 mmol), 4-aminopenicillin (9.8 ml, 74,8 mmol) and sodium iodide (4,2 g, 27,93 mmol) is placed in a flask and rinsed with nitrogen. Add methylsulfoxide (25 ml) and the solution was placed in an oil bath at 140°C. the Solution is stirred for 20 min at 140°C. the Reaction mixture is allowed to cool to room temperature, then add ethyl acetate (300 ml) and N2O (300 ml). Distribute phase and the organic layer washed with water (4×200 ml) and saturated sodium chloride solution (4×200 ml). The organic phase is dried over sodium sulfate, filtered, concentrated in vacuo, receiving the connectionU(10.5 g).

b. Synthesis of compoundW

ConnectionU(5,18 g, at 9.53 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0,44 g, 0.48 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0,63 g, 0.95 mmol) and tert-butyl sodium (1,83 g, 19,06 mmol) are combined in a flask and about obaut nitrogen. Add 1-bromo-3-iadanza (2.0 ml, 11,44 mmol) and the flask is rinsed again. Add ortho-xylene (50 ml) and the solution is heated at the boil under reflux for 2.5 hours, at this time, HPLC analysis indicates complete reaction. Ortho-xylene is removed under vacuum while heating and add dichloromethane (200 ml). After dissolving the residue add celite (30 g) and the mixture is filtered and the filter residue is washed with dichloromethane until you collect the whole product. The solution is concentrated to dryness in vacuo, re-dissolved in THF (20 ml) and purge with nitrogen. Added by syringe tetrabutylammonium (20 ml, 1.0m in THF, 20 mmol) and stirred solution at room temperature for 18 hours. Then remove THF and the residue re-dissolved in DHM and washed with water (1×200 ml) and polysystem solution of sodium chloride (1×200 ml). The organic phase is dried over sodium sulfate, concentrated and chromatographic on silica gel (50 g, 0-10% methanol in dichloromethane)to give compoundWin the form of a yellow solid.

The synthesis of compounds of formula (X) compounds 66-93:

Examples 66-69

The synthesis of compounds 66-69

Using a technique similar to that described in example 65, except that phenylboronic acid substitute the appropriate substituted phenylboronic acid,receive TFA-salt compounds 66-69.

Connection66:N-{2-[4-(3-(2-chlorophenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (Formula (X), where R11denotes 2-chlorophenyl):1H NMR (300 MHz, DMSO-d6) :of 10.47 (s, 1H), 10,37 (s, 1H), 8,55, (users, 2H), by 8.22 (s, 1H), of 8.06 (d, 1H), 7,46 (m, 1H), 7,32 (m, 3H), 7,22 (m, 1H), 7,01 (m, 8H), 6.89 in (d, 1H), 6,74 (DD, 1H), 6,51 (d, 1H), 6,10 (d, 1H), 3,18 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C31H28ClN3O3526,19; found to 526.4.

Connection67: N-{2-[4-(3-(2-methoxyphenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (Formula (X), where R11represents 2-methoxyphenyl):1H NMR (300 MHz, DMSO-d6) :10,46 (s, 1H), the 10.40 (s, 1H), 8,60 (users, 2H), 8,12 (s, 1H), of 8.06 (d, 1H), 7,16 (m, 13H), to 6.80 (d, 1H), 6,51 (d, 1H), 6,11 (s, 1H), 5,24 (d, 1H), 3,69 (s, 3H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C32H31N3O4522,24; found RUR 522.7.

Connection68:formula (X), where R11denotes 4-hydroxymethylene:1H NMR (300 MHz, DMSO-d6):of 10.47 (s, 1H), accounted for 10.39 (s, 1H), 8,60 (users, 2H), 8,18 (s, 1H), 8,07 (d, 1H), 7,46 (d, 2H), 7,30 (m, 2H), 7,20 (m, 2H), 7,00 (m, 8H), 6,51 (DD, 1H), 6,11 (s, 1H), 5,23 (d, 1H), of 4.44 (s, 2H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C32H31N3O4522,24; found 522,4.

Connection69:formula (X), where R11represents 4-methoxyphenyl:1H NMR (300 MHz, DMSO-d6) :of 10.47 (s, 1H), accounted for 10.39 (s, 1H), 8,60 (users, 2H), 8,16 (s, 1H), 8,07(d, 1H), 7,44 (d, 2H), 6,85-7,20 (m, N), 6,51 (DD, 1H), 6,12 (d, 1H), 5,23 (d, 1H), 3,70 (s, 3H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C32H31N3O4522,24; found 522,4.

Example 70

Synthesis of compound 70

Connection70:formula (X), where R11represents 4-chlorophenyl.

Compound W (84,0 mg, 0,143 mmol), 4-Chlorfenvinphos acid to 27.2 mg, 0,172 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (PdCl2(dppf)-DHM) (5.9 mg, 0,007 mmol) are combined in a small vial to work under pressure and purge N2. Add 1,2-dimethoxyethane (2.0 ml) and 2,0N cesium carbonate (150 μl, 0.3 mmol). The test tube is sealed and then placed in an oil bath at 90°With over 4 hours. Next, the solution is cooled to room temperature and add DHM (10 ml). The solution is filtered and concentrated to dryness. To the residue add DMF (1.0 ml), 10% palladium on coal (10 mg) and the reaction mixture is stirred at a hydrogen pressure of 1 ATM for 4 hours. At this time, add a mixture of water:acetonitrile=1:1 and 200 μl of TFA and the solution is filtered to remove the catalyst. The filtrate is purified by HPLC with reversed phase. The fractions containing pure product are combined and lyophilized, receiving the connection70as TFA-salt.1H NMR (300 MHz, DMSO-d6) δ: 10,46 (s, 1H), the 10.40 (s, 1H), 8,61 (users, 2H), by 8.22 (s, 1H), 8,07 (d, 1H), 7,53 (d, 2H), 7,42 (d, 2H), 7.23 percent (t, 1H), 7,14 (1H), 6,85-7,10 (m, 8H), 6,51 (d, 1H), 6,12 (s, 1H), 5,24 (d, 1H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C31H28ClN3O3526,19; found to 526.4.

Examples 71-72

The synthesis of compounds 71-72

Using a technique similar to that described in example 70, except that 4-Chlorfenvinphos acid substitute the appropriate substituted Bronevoy acid, receive TFA-salt compounds71-72.

Connection71:formula (X), where R11denotes 5-indolyl:1H NMR (300 MHz, DMSO-d6) δ:11,07 (s, 1H), 10,47 (s, 1H), the 10.40 (s, 1H), 8,60 (users, 2H), 8,15 (s, 1H), 8,11 (d, 1H), 7,65 (s, 1H), 7,15-7,40 (m, 5H), 7,00-to 7.15 (m, 5H), 6.89 in (d, 2H), 6,51 (DD, 1H), to 6.39 (s, 1H), 6,11 (s, 1H), 5,24 (d, 1H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C33H30N4O3531,24; found 531,4.

Connection72:formula (X), where R11represents 4-pyridyl:1H NMR (300 MHz, DMSO-d6):10,48 (s, 1H) 10,38 (s, 1H), 8,60 (osirm, 4H), 8,32 (s, 1H), 8,07 (d, 1H), 7,69 (d, 2H), 7,31 (m, 2H), 7,16 (d, 1H) 7,05 (m, 6H), 6.90 to (d, 1H), of 6.52 (DD, 1H), 6,11 (s, 1H), 5,24 (d, 1H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C30H28N4O3493,23; found 493,5.

Example 73

Synthesis of compound 73

Connection73: formula (X), where R11denotes hydrogen. Get a TFA salt of compound 73:1H NMR (300 MHz, DMSO-d6):10,48 (s, 1H), accounted for 10.39 (s, 1H), 8,59 (users, 2H), 8,07 (DD, 2H), 6,85-7,17 (m, 10H), 6,72 (t, 1H), of 6.52 (DD, 1H), 6,11 (d, 1H), 5,22 (d, 1H), 3,0 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C25H25N3O3416,20; found 416,3.

Example 74

Synthesis of N-{2-[4-(3-(3-cyanophenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (74)

Connection74:formula (X), where R11denotes 3-cyanophenyl.

ConnectionW(example 65, part b) (58,1 mg, 0,100 mmol), 3-cyanoaniline acid (17.6 mg, 0,120 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (PdCl2(dppf)-DHM) (about 6 mg to 0.007 mmol) are combined in a small vial to work under pressure and purge N2. Add 1,2-dimethoxyethane (2.0 ml) and 2,0N cesium carbonate (200 μl, 0.4 mmol), the tube sealed and then placed in an oil bath at 90°With over 5 hours. Next, the solution is cooled to room temperature and add DHM (10 ml). The solution is dried (Na2SO4) for 30 min, then filtered, concentrated and dried in vacuum. The residue is dissolved in DHM (2 ml) and cooled to 0aboutWith, then add trichloride boron (1,0N in DHM, 1.0 ml, 1.0 mmol). After 10 min the reaction mixture was quenched with methanol (10 ml) and concentrate under reduced pressure. The residue is purified by HPLC with reversed phase. The fractions containing pure product are combined and lyophilized, receiving the connection74as TFA-salt.1H NMR (300 MHz, DMSO-d6) δ: 1,45 (s, 1H), the 10.40 (s, 1H), 8,70 (user, 2H), 8.34 per (m, 1H), of 8.09 (d, 1H), of 7.97 (s, 1H), a 7.85 (dt, 1H), 7,74 (dt, 1H), 7,58 (t, 1H), 7,20-7,30 (m, 2H), 6,95-7,10 (m, 7H), 6.90 to (d, 1H), 6,50 (d, 1H), 6,12 (s, 1H), 5.25 in (d, 1H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C32H28N4O3517,23; found 517,4.

Examples 75-93

The synthesis of compounds 75-93

Using a technique similar to that described in example 74, except that 3-cyanoaniline acid substitute the appropriate substituted Bronevoy acid, receive TFA-salt compounds75-93.

Connection75:formula (X), where R11denotes TRANS-2-fineliner m/z: [M+H+] calculated for C33H31N3O3518,25; found 518,3.

Connection76:N-{2-[4-(3-(3-pyridyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine(formula (X), where R11denotes 3-pyridyl):1H NMR (300 MHz, DMSO-d6) :10,38 (users, 2H), 8,84 (s, 2H), 8,67 (s, 1H), 8,58 (d, 1H), of 8.25 (s, 1H), 8,14 (d, 1H), 8,11 (d, 1H), to 7.59 (DD, 1H), 7,27 (m, 2H), 7,05 (m, 7H), 6.90 to (d, 1H), 6,50 (d, 1H), 5,28 (d, 1H), 3,10 (m, 4H), 2,83 (m, 2H); m/z: [M+H+] calculated for C30H28N4O3493,23; found 493,5.

Connection77: formula (X), where R11denotes 4-cyanophenyl:1H NMR (300 MHz, DMSO-d6) :10,45 (users, 1H), the 10.40 (s, 1H), 8,62 (users, 2H), of 8.27 (s, 1H), 8,07 (d, 1H), to 7.84 (d, 2H), 7,72 (d, 2H), 7,27 (m, 2H), 7,18 (m, 7H), 6,91 (d, 1H), of 6.52 (d, 1H), 6,12 (s, 1H), 5,24 (m, 1H), 3,12 (m, 4H), 2,81 (m, 2H); m/z: [M+H+] Asciano for C 32H28N4O3516,60; found 517,4.

Connection78: formula (X), where R11indicates 3,5-dimethylisoxazol-4-yl: m/z: [M+H+] calculated for C30H30N4O4511,24; found 511,5.

Connection79: formula (X), where R11denotes 2-furanyl:1H NMR (300 MHz, DMSO-d6):of 11.15 (s, 1H), 10,47 (s, 1H), 10,41 (s, 1H), 8,64 (users, 1H), 8,10 (t, 2H), was 7.08 (m, 9H), 6,77 (s, 1H), 6,74 (s, 1H), of 6.52 (d, 1H), 6.30-in (s, 1H), 6,12 (s, 1H), 6,02 (kV, 1H), 5.25 in (d, 1H), 3,10 (m, 4H), 2,85 (m, 2H); m/z: [M+H+] calculated for C29H27N3O4482,21; found 481,4.

Connection80: formula (X), where R11means thiophene-2-yl:1H NMR (300 MHz, DMSO-d6) :of 10.47 (s, 1H), 10,38 (s, 1H), 8,62 (users, 2H), by 8.22 (s, 1H), 8,07 (d, 1H), 7,44 (d, 1H), 7,33 (d, 1H), 7,35 (m, 2H), 7,06 (m, 7H), 6.90 to (d, 2H), 6,50 (d, 1H), 6,10 (d, 1H), 5,23 (m, 1H), 3,10 (m, 4H), 2,85 (m, 2H); m/z: [M+H+] calculated for C29H27N3O3S 498,19; found 498,5.

Connection81: formula (X), where R11denotes 3-nitrophenyl: m/z: [M+H+] calculated for C31H28N4O5537,22; found 537,3.

Connection82: formula (X), where R11denotes 4-formylphenyl: m/z: [M+H+] calculated for C32H29N3O4520,23; found 520,5.

Connection83:formula (X), where R11denotes 2-pyrrolyl. Using a technique similar to that described in example 74, except that 3-CANopen Bronevoy acid substituted 1-(tert-butoxycarbonyl)pyrrol-2-Bronevoy acid, get the TFA-salt of the compound83. Remove protective BOC-group occurs under reaction conditions.1H NMR (300 MHz, DMSO-d6) :11,13 (s, 1H), 10,46 (s, 1H), 10,37 (s, 1H), 8,58 (users, 2H), 8,08 (s, 1H), with 8.05 (s, 1H), 7,05 (m, 9H), 6.75 in (s, 1H), 6.73 x (s, 1H), 6,51 (d, 1H), 6,23 (s, 1H), between 6.08 (s, 1H), 6,01 (s, 1H), 5,22 (m, 1H), 3,12 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C29H28N4O3481,23; found 481,3.

Connection84:formula (X), where R11denotes 4-carboxylphenyl: m/z: [M+H+] calculated for C32H29N3O5536,22; found 536,3.

Connection85:formula (X), where R11denotes 4-methylsulfinylphenyl:1H NMR (300 MHz, DMSO-d6):10,45 (s, 1H), 10,38 (s, 1H), 8,58 (users, 1H), of 8.27 (s, 1H), with 8.05 (d, 1H), of 7.90 (d, 2H), to 7.77 (d, 2H), 7,26 (m, 2H),? 7.04 baby mortality (m, 7H), to 6.88 (d, 1H), 6,50 (d, 1H), 6,11 (s, 1H), 5,22 (d, 1H), and 3.16 (s, 3H), 3,11 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C32H31N3O5S 570,21; found 570,3.

Connection86:formula (X), where R11denotes 4-hydroxyphenyl. Using a technique similar to that described in example 74, except that 3-cyanoaniline acid to replace 4-benzyloxyaniline acid, receive TFA-salt of the compound86.1H NMR (300 MHz, DMSO-d6) :10,46 (s, 1H), the 10.40 (s, 1H), for 9.47 (s, 1H), 8,71 (users, 2H), 8,12 (m, 2H), 7,32 (d, 2H), 7,02 (m, 9H), 6.75 in (d, 2H), 6,51 (d, 1H), 6,10 (s, 1H), 5.25 in (d, 1H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C31H N3O4508,23; found 508,3.

Connection87:N-{2-[4-(3-(4-aminomethylphenol)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (formula (X), where R11denotes 4-(aminomethyl)phenyl): m/z: [M+H+] calculated for C32H32N4O3521,26; found 521,3.

Connection88:formula (X), where R11denotes 4-ethoxyphenyl: m/z: [M+H+] calculated for C33H33N3O4536,26; found 536,3.

Connection89:formula (X), where R11means thiophene-3-yl: m/z: [M+H+] calculated for C29H27N3O3S 498,19; found 498,3.

Connection90: formula (X), where R11denotes 2-indolyl: m/z: [M+H+] calculated for C33H30N4O3531,24; found 531,3.

Connection91:N-{2-[4-(3-(3-chlorophenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (formula (X), where R11denotes 3-chlorophenyl):1H NMR (300 MHz, DMSO-d6) δ:10,45 (s, 1H), 10,38 (s, 1H), 8,58 (users, 2H), to 8.20 (s, 1H), 7,21 (m, 14N), 6,51 (d, 1H), 6,10 (s, 1H), 5,23 (d, 1H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C31H28ClN3O3526,03; found 526,3.

Connection92:formula (X), where R11denotes 3-methoxyphenyl: m/z: [M+H] calculated for C32H31N3O4522,24; found 522,0.

Connection93:formula (X),where R 11denotes 3-forfinal:1H NMR (300 MHz, DMSO-d6) :10,42 (s, 1H), accounted for 10.39 (s, 1H), 8,60 (users, 2H), to 8.20 (s, 1H), 8,15 (d, 1H), 7,2 (m, 14H), 6,51 (d, 1H), 6,11 (s, 1H), 5,23 (d, 1H), 3,10 (m, 4H), of 2.81 (m, 2H); m/z: [M+H+] calculated for C31H28FN3O3509,58; found 510,3.

The synthesis of compounds of formula (XI) compounds 94-101

Example 94

Synthesis of N-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (94)

Connection94:formula (XI), where R11denotes 3-pyridyl

A. Synthesis of 4-iodination

4-Iodinecatalysed (4,80 g of 19.7 mmol) was dissolved in tetrahydrofuran (25 ml) under nitrogen and added dropwise via syringe 1.0m borane in tetrahydrofuran (up 29.6 ml, 29.6 mmol). The reaction mixture is heated at the boil under reflux for 1 hour, then cooled in ice and quenched with excess borane, adding methanol (100 ml). When is the formation of hydrogen, the solvent is removed under reduced pressure. The residue is dissolved in tetrahydrofuran (25 ml) and added 4N HCl in dioxane (6.0 ml, 24 mmol)and then ether (75 ml). The hydrochloride salt of 4-iodination collected on a Buechner funnel, washed with ether (2×50 ml) and dried under reduced pressure. To obtain the free base solid partitioned between dichloromethane (200 ml) and 1N NaOH(100 ml). The aqueous layer was extracted with dichloromethane (2×100 ml). The combined organic layers are dried (Na2SO4and concentrate, receiving 4-iodination (4.52 g) as a colourless oil.

b. Synthesis of compoundQQ

To a solution of 4-iodination (4.5 g, 22 mmol) in methylsulfoxide (13 ml) under nitrogen add connectionNN(example V, part f) (7,3 g, 15 mmol), sodium bicarbonate (3.7 g, 44 mmol) and sodium iodide (3.3 g, 22 mmol). The mixture is heated at 140°C in oil bath for 25 minutes After cooling to room temperature, add water (100 ml) and the resulting mixture extracted with ethyl acetate (2·150 ml). The combined extracts are washed with 1N HCl (2×50 ml), water (50 ml), 10% sodium thiosulfate (50 ml), saturated sodium bicarbonate solution (50 ml) and saturated salt solution (50 ml). The solution is dried (Na2SO4) and concentrate. The crude product is distilled in two parts by the method of flash chromatography on silica gel (75 g), elwira 0-5% methanol in dichloromethane containing 0.5% triethylamine. ConnectionQQ(6,1 g) was isolated as a dark yellow oil.

C. Synthesis of 4-amino-2-bromoanisole

To a mixture of 2-bromo-4-nitroanisole (5.0 g, 21.5 mmol, Lancaster), ethanol (25 ml) and water (25 ml) was added iron powder (4.8 g, 86 mmol) and 12N HCl (0.5 ml). The solution is heated at the boil under reflux for 20 is in. Add 1N NaOH (10 ml) and the reaction mixture while it is still hot, filtered through a layer of celite and washed with ethanol (2×50 ml). The ethanol is removed under reduced pressure and the residue is extracted with dichloromethane (2×100 ml). The organic extracts are dried (Na2SO4) and concentrate. The crude product is purified by the method of flash chromatography on silica gel (75 g), elwira dichloromethane and receiving 4-amino-2-bromoanisole in the form of a light reddish-brown solid.

d. Synthesis of compoundRR

The flask containing the connectionQQ(0,966 g, 1.48 mmol)in,4-amino-2-bromoanisole (0.35 g, 1.78 mmol), Tris(dibenzylideneacetone)dipalladium(0), (0,068 g 0,074 mmol), BINAP (0,092 g, 0,148 mmol) and tert-butyl sodium (0,569 g of 5.92 mmol), rinsed with nitrogen and then added anhydrous ortho-xylene (30 ml). The mixture is heated at 115°C in an oil bath for two hours. Next, the reaction mixture is cooled to room temperature and remove the solvent under reduced pressure. A brownish precipitate re-dissolved in dichloromethane and filtered through a layer of celite. The filtrate is concentrated to dryness under reduced pressure, dissolved in THF (20 ml) and purge with nitrogen. Add tetrabutylammonium (1,0N in THF, 4.5 ml, 4.5 mmol) and the solution stirred for 18 h at room temperature. The solvent is removed, propanganda pressure and distribute the balance between water and DHM. The organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. The crude product is purified by the method of flash chromatography on silica gel (1-10% Meon in DHM), receiving the connectionRR.

e.Synthesis of compound94

In purged with nitrogen tube for studies with screw cap place the connectionRR(73 mg, 0.12 mmol), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane (10 mg) and 3-pyridylamino acid (18 mg, 0.14 mmol). Add dimethoxyethane (2.5 ml), and then 2,0N cesium carbonate (0,20 ml, 0.40 mmol). The mixture is heated at 90°With over 4 hours. Next, the solution is cooled to room temperature and add DHM (20 ml). The solution is dried (Na2SO4) for 30 min, then filtered, concentrated and dried in vacuum. The residue is dissolved in DHM (2 ml) and cooled to 0°and then add trichloride boron (1,0N in DHM, 1.0 ml, 1.0 mmol). After 10 min the reaction is quenched with methanol (10 ml) and concentrate under reduced pressure. The residue is purified by HPLC with reversed phase. The fractions containing pure product are combined and lyophilized, receiving TFA-salt of N-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine(94).1Mr. YAM is (300 MHz, DMSO-d6) δ: 10; m/z: [M+H+] calculated for C31H30N4O4523,24; found 523,3.

The sampleTFA-salt (25 mg) dissolved in acetonitrile (0.5 ml) and water (0.5 ml) followed by addition of 1N HCl (0.10 ml, 0.10 mmol). The solution lyophilized in powder, which is re-dissolved in acetonitrile (0.5 ml) and water (0.5 ml). Add 1N HCl (0.10 ml, 0.10 mmol). Lyophilization gives the hydrochloride salt of the compound94in the form of a white powder.1H NMR (300 MHz, DMSO-d6) δ: 10,49 (users, 1H), 9,44 (users, 1H), 8,97 (d, 1H), 8,78 (d, 1H), 8,77 (users, 1H), 8,61 (dt, 1H), to 8.20 (d, 1H), 8,01 (DD, 1H), 6.90 to-to 7.15 (m, 8H), 6,47 (d, 1H), 5,39 (d, 1H), 3,70 (s, 3H), to 3.02 (m, 4H), 2,82 (m, 2H); m/z: [M+H+] calculated for C31H30N4O4523,24; found 523,6.

Example 95

Synthesis of N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (95)

Connection95:formula (XI), where R11denotes 3-cyanophenyl.

In purged with nitrogen tube for studies with screw cap place the connectionRR(from example 94, part d) (100 mg, 0,163 mmol), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane (10 mg) and 3-cyanoaniline acid (35 mg, 0.20 mmol). Add dimethoxyethane (3 ml), and then 2,0N cesium carbonate (0,30 ml of 0.60 mmol). The mixture is heated at 90°With over 4 hours. Next, the solution is cooled to room temp the atmospheric temperature and distributed between ethyl acetate and water. The organic layer is dried (Na2SO4), concentrated and dried under reduced pressure. The residue is dissolved in DHM (5 ml) and cooled to 0°and then add trichloride boron (1,0N in DHM, 2.0 ml, 2.0 mmol). After 10 min the reaction mixture was quenched with methanol (20 ml) and concentrate under reduced pressure. The residue is purified by HPLC with reversed phase. The fractions containing pure product are combined and lyophilized, receiving TFA-salt of the compound95.1H NMR (300 MHz, DMSO-d6) δ: of 10.47 (s, 1H), 10,38 (s, 1H), 8,57 (users, 2H) with 8.05 (d, 1H), 7,89 (m, 1H), 7,82 (m, 1H), of 7.70 (m, 2H), 7,53 (t, 2H), 7,07 (d, 1H), 6,95-7,00 (m, 4H), 6,85-6,92 (m, 3H), of 6.50 (DD, 1H), 6,09 (d, 1H), with 5.22 (d, 1H), the 3.65 (s, 3H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C33H30N4O4547,24; found 547,5.

Examples 96-102

The synthesis of compounds 96-102

Using a technique similar to that described in example 95, except that 3-cyanoaniline acid substitute the appropriate substituted phenylboronic acid, receive TFA-salt compounds96-102.

Connection96:N-{2-[4-(3-(4-aminomethylphenol)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine(formula (XI), where R11denotes 4-(aminomethyl)phenyl):1H NMR (300 MHz, DMSO-d6):of 10.47 (s, 1H), the 10.40 (s, 1H), 8,58 (users, 2H), 8,07 (m, 4H), 7,87 (s, 1H), 7,40 (DD, 4H), 7,07 (d, 1H), 6,84-7,05 (m, 8H), of 6.50 (DD, 1H), 6,11 (d, 1H), 5,23 (d, 1H), 3,98 (m, H), 3,62 (s, 3H), 3,05 (m, 2H), 2.95 and (m, 2H), 2,75 (m, 2H); m/z: [M+H+] calculated for C33H34N4O4551,27; found 551,5.

Connection97:N-{2-[4-(3-(4-pyridyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine(formula (XI), where R11represents 4-pyridyl):1H NMR (300 MHz, DMSO-d6) :10,46 (s, 1H), 10,42 (s, 1H), 8,65 (d, 2H), 8,62 (users, 1H), of 8.06 (d, 2H), 7,97 (users, 1H), 7,73 (d, 2H) 6,95-7,10 (m, 7H), 6.90 to (DD, 2H), 6,12 (users, 1H), 5,23 (d, 1H), 3,69 (s, 3H), 3,10 (m, 4H), 2,80 (m, 2H); m/z: [M+H+] calculated for C31H30N4O4523,24; found 523,6.

Connection98:formula (XI), where R11denotes 4-formylphenyl:1H NMR (300 MHz, DMSO-d6) :10,46 (s, 1H), accounted for 10.39 (s, 1H), 9,95 (s, 1H), 8,57 (users, 2H), with 8.05 (d, 1H), to $ 7.91 (users, 1H), a 7.85 (d, 2H), to 7.61 (d, 2H), 6,95-7,10 (m, 7H), 6.89 in (DD, 2H), 6,50 (DD, 1H), 6,10 (s, 1H), 5,22 (d, 1H), the 3.65 (s, 3H), of 3.05 (m, 4H), to 2.75 (m, 2H); m/z: [M+H+] calculated for C33H31N3O5550,24; found 550,6.

Connection99:formula (XI), where R11denotes 4-methylsulphonyl:1H NMR (300 MHz, DMSO-d6) δ:10,46 (s, 1H), 10,38 (s, 1H), 8,55 (users, 2H), with 8.05 (d, 1H), to $ 7.91 (s, 1H), 7,86 (d, 2H), 6,74 (d, 2H), 6,93-7,10 (m, 6N), 6,85-6,92 (m, 3H), 6,51 (DD, 1H), 6,09 (d, 1H), 5,22 (d, 1H), the 3.65 (s, 3H), 3,17 (s, 3H)), was 3.05 (m, 4H), to 2.75 (m, 2H); m/z: [M+H+] calculated for C33H33N3O6S 600,22; found 600,5.

Connection100:N-{2-[4-(3-(4-hydroxyphenyl)-4-methoxyphenyl)AMINOPHENYL]those who}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (formula (XI), where R11denotes 4-hydroxyphenyl). Using a technique similar to that described in example 95, except that 3-cyanoaniline acid to replace 4-benzyloxyaniline acid, receive TFA-salt of the compound100.1H NMR (300 MHz, DMSO-d6):10,46 (s, 1H), 10,38 (s, 1H), 9,34 (s, 1H), 8,57 (users, 2H), of 8.06 (d, 1H), 7,80 (s, 1H), 7,18 (d, 2H), 7,07 (d, 1H), 6,97 (d, 2H), 6,80-of 6.90 (m, 6H), 6,69 (d, 2H), 6,51 (DD, 1H), 6,09 (s, 1H), 5,23 (d, 1H), of 3.60 (s, 3H), 3,05 (m, 4H), 2,78 (m, 2H); m/z: [M+H] calculated for C32H31N3O5538,24; found 538,5.

Connection101:N-{2-[4-(3-(thiophene-3-yl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine(formula (XI), where R11means thiophene-3-yl).1H NMR (300 MHz, DMSO-d6) :of 10.47 (s, 1H), 10,38 (s, 1H), 8,57 (users, 2H), of 8.06 (d, 1H), 7,83 (s, 1H), 6,74 (DD, 1H), of 7.48 (DD, 1H), 7,31 (DD, 1H), 7,13 (s, 1H), 7,06 (d, 1H), 6,80-7,00 (m, 7H), 6,51 (DD, 1H), 6,01 (s, 1H), 5,23 (d, 1H), 3,70 (s, 3H), of 3.07 (m, 4H), 2,77 (m, 2H); m/z: [M+H+] calculated for C30H29N3O4S 528,20; consists 528.3 found.

Connection102:N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine(formula (XI), where R11denotes 3-chlorophenyl).1H NMR (300 MHz, DMSO-d6) :10,46 (s, 1H), 10,38 (s, 1H), 8,76 (users, 1H), 8,62 (users, 1H), 8,10 (s, 1H), 7,88 (users, 1H), 7,15-of 7.23 (m, 5H), 6,85-7,10 (m, 11H), of 6.50 (d, 1H), 6,09 (users, 1H), 5,27 (d, 1H), the 3.65 (s, 3H), 3,10 (m, 4H), 2,8 (m, 2H); m/z: [M+H+] calculated for C32H30ClN3O4556,20; found 556,2.

Example 103

Synthesis of N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (95)

Using a technique similar to that described in example 61C and at the stage of removal protection example V, except that the hydrochloride of 4-methoxy-3-phenylaniline replace 3-(3-cyanophenyl)-4-methoxyaniline in example 61C, part d, get the connection95.

The intermediate compound 3-(3-cyanophenyl)-4-methoxyaniline obtained as follows.

A. Synthesis of 2-(3-cyanophenyl)-4-nitroanisole

The complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane (1:1) (1,43 g) is added to a stirred mixture of 3-cyanophenylacetic acid (10.0 g, to 61.8 mmol) and 2-bromo-4-nitroanisole (14,35 g, 62 mmol) in 2,0N solution of cesium carbonate (92,7 ml, 185,4 mmol) and dimethyl ether of ethylene glycol (200 ml). The flask is rinsed with nitrogen and heated at 90°C (oil bath) for 4 hours. The mixture is allowed to cool to room temperature during the night, this time from the solution precipitates the product. The solid is collected on a Buechner funnel, washed with water and dried under reduced pressure, obtaining 2-(3-cyanophenyl)-4-nitroanisole (15.7 g).

b. Synthesis of 3-(3-cyanophenyl)-4-methoxyaniline

Zinc dust (20,26 g, 310 mmol) add cha the authorities over 5 min to a solution of 2-(3-cyanophenyl)-4-nitroanisole (15.7 g, 62 mmol) and ammonium formate (19,48 g, 310 mmol) in methanol (500 ml) and tetrahydrofuran (500 ml). The reaction is finished after 1 hour stirring at room temperature. The resulting mixture was filtered and concentrated the filtrate under reduced pressure. The residue is purified by the method of flash chromatography on silica gel, elwira 5% methanol in dichloromethane and receiving 3-(3-cyanophenyl)-4-methoxyaniline (10 g, 44 mmol) as a yellow oil.

Example 104

Synthesis of N-{2-[4-(3-(4-aminomethylphenol)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine (96)

Using a technique similar to that described in example 61C and at the stage of removal protection example V, except that the hydrochloride of 4-methoxy-3-phenylaniline replace 3-(4-aminomethylphenol)-4-methoxyaniline in example 61C, part d, get the connection96.

The intermediate compound 3-(4-aminomethylphenol)-4-methoxyaniline obtained as follows.

A. Synthesis of 2-(4-aminomethylphenol)-4-nitroanisole

A mixture of 2-bromo-4-nitroanisole (5,80 g 25,0 mmol) and hydrochloride 4-(aminomethyl)phenylboronic acid (4,96 g of 26.6 mmol) is stirred in 1-propanol (50 ml) under nitrogen. Add triphenylphosphine (315 mg, 1.20 mmol) and palladium(II) acetate (90 mg, 0.40 mmol)and then 2,0N sodium carbonate (33 ml, 66 mmol). The mixture is heated at 95°C (oil bath) under nitrogen for 3 hours, during this time, aimogasta ends, that estimate by TLC. Add water (25 ml) and the mixture is stirred in open air for 2 hours at room temperature. The mixture is extracted with ethyl acetate (100 ml, 2·50 ml) and the combined extracts washed with sodium bicarbonate solution (25 ml) and saturated salt solution (25 ml). This solution is dried with sodium sulfate and concentrated to an oil, which was purified by the method of flash chromatography on silica gel (100 g), elwira mixture of 0-4% methanol/0.5% triethylamine/dichloromethane. Pure fractions are combined and concentrated, obtaining 2-(4-aminomethylphenol)-4-nitroanisole (4.6 g) as a yellow solid.

b. Synthesis of 3-(4-aminomethylphenol)-4-methoxyaniline

A solution of 2-(4-aminomethylphenol)-4-nitroanisole (4,50 g) in methanol (200 ml) is treated with 10% palladium on coal (200 mg). The reaction mixture was stirred at a hydrogen pressure equal to one atmosphere for 2.5 hours. The reaction mixture was filtered through celite and the filter residue washed with methanol (3·25 ml). The filtrate is concentrated to dryness and the residue purified by the method of flash chromatography on silica gel (80 g), elwira mixture of 0-6% methanol/0.5% triethylamine/dichloromethane. Pure fractions are combined and concentrated, obtaining 3-(4-aminomethylphenol)-4-methoxyaniline in the form of a white powder.

Example 105

Synthesis of N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydrox is -2(1H)-chinoline-5-yl) - ethylamine (102)

Using a technique similar to that described in example 61C and at the stage of removal protection example V, except that the hydrochloride of 4-methoxy-3-phenylaniline replace 3-(3-chlorophenyl)-4-methoxyaniline in example 61C, part d, get the connection102.

The intermediate compound 3-(3-chlorophenyl)-4-methoxyaniline obtained as follows.

A. Synthesis of 2-(3-chlorophenyl)-4-nitroanisole

Into a flask containing a two-phase mixture of 2-bromo-4-nitroanisole (15.0 g, a 64.6 mmol) and 3-Chlorfenvinphos acid (12.1 g, and 77.6 mmol) in dimethyl ether of ethylene glycol (187.5 ml) and 2,0N cesium carbonate (97 ml), add complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane (1:1) (1.5 g). The mixture is heated at the boil under reflux for 4 hours in nitrogen atmosphere. The crude reaction mixture is distributed between ethyl acetate (350 ml) and saturated salt solution (250 ml) and then filtered through a Buechner funnel. The layers are separated and the organic layer was washed with saturated salt solution (250 ml). The organic phase is dried over Na2SO4, filtered and concentrated to a dark oil. The crude residue purified by the method of flash chromatography on silica gel, using as eluent dichloromethane and getting 2-(3-chlorophenyl)-4-nitroanisole in the form of a yellow solid (13,9 g, to 59.4 mmol).

b. Synthesis of 3-(3-chlorophenyl)-4-methoxyaniline

To a mixture of 2-(chlorphenyl)-4-nitroanisole (0.5 g, 1.9 mmol) in tetrahydrofuran (5 ml) and methanol (5 ml) is added platinum oxide (IV) (1mg). The reaction mixture was stirred at room temperature and hydrogen pressure equal to one atmosphere for 4.5 hours. The suspension is filtered through celite and concentrated under reduced pressure, obtaining 3-(3-chlorophenyl)-4-methoxyaniline in the form of a light yellow oil (405 mg, 1.7 mmol).

Despite the fact that the present invention is described with reference to specific options, specialists in this field it is clear that it is possible to make various changes and produce an equivalent replacement, not deviating from the true spirit and scope of this invention. In addition, many possible modifications to adapt a particular situation, material, consider the composition, method, stage or stages of the ways to the objectives, spirit and scope of the present invention. It is implied that all such modifications are included in the area enclosed here the claims. In addition, all references cited here above publications, patents and patent documents are fully incorporated herein by reference, even if individually incorporated by reference.

>8
BIOLOGICAL ACTIVITY
exampletest

β2agonistic activity

RES
tests

β2agonistic activity

RES
test

β2agonistic efficacy

% effect.
1>8
2>8
3>8
4>8>7.5>30
5>8
6>8
7>8
8>8
9>8
10>8
11>8
12>8
13>9.5>9>30
14>8>7.5>30
15>9.5>7.5>60
16>8
17>8
18>8
19>8
20>8
21>8
22>8
23>8>7.5>30
24>8
25>8
26>8
27>8
28>8
29>8
30>8>7.5>30
31>8
32>8
33>8
34>8
35>8
36>8
37>8>7.5>30
38>9.5>7.5>80
39>8
40>8
41>8
42>8
43>8
44>8
45>8
46>8
47>8
48>8
49>8>7.5>60
50>8
51>8
52>7.5>80
53>8>7.5>60
54>9.5>9>80
55>8>7.5>30
56>8>7.5>60
57>8
58>8>7.5>60
59>9.5>7.5>30
60>8>7.5>60
61>9.5>9>80
62>8>7.5>30
63>9.5>9>80
64>8>7.5>30
65>9.5>9>80
66>8>7.5>80
67>8>7.5>80
68>8>9>80
69>8>7.5>80
>8>7.5>80
71>8>9>80
72>9.5>9>80
73>8>9>80
74>9.5>9>80
75>8>7.5>60
76>9.5>9>80
77>8>7.5>60
78>9.5>9>80
79>9.5>9>80
80>9.5>9>80
81>9.5>9>60
82>9.5>9>80
83>9.5>9>80
84>8>7.5>80
85>9.5>9>80
86>9.5>9>80
87>9.5>9>80
88>8>7.5>80
89>9.5>9>80
90>8>7.5>80
91>9.5>7.5>80
92>8>7.5>80
93>9.5>9>80
94>9.5>9>60
95>9.5>9>80
96>9.5>9>80
97>9.5>9>60
98>9.5>9>80
99>9.5>7.5>80
100>9.5>9>80
101>9.5>9>80
102>9.5>9>80

1. The compound of formula (I)

where each of R1-R5independently selected from the group comprising hydrogen, C1-4alkyl, and Rawhere as the keel optionally substituted Deputy selected from Rb;

or R4and R5together with the formation of the group-NRdC(=O)C(Rd)=C(Rd)-;

R6represents hydrogen;

R7represents hydrogen;

R8represents hydrogen;

R9represents a C1-4alkyl;

R10represents hydrogen or C1-4alkyl;

each R11, R12and R13independently selected from the group comprising hydrogen, C1-4alkyl, vinyl, cyclohexyl, phenyl, halogen, -CO2Rd, -ORd, -S(O)mRd, -N(NRdReRdor-S(O)2NRdReA 5 - or 6-membered monocyclic heteroaryl comprising 1 or 2 heteroatoms selected from N, S and O, 9-membered bicyclic heteroaryl, including N as a heteroatom, and 5-membered heterocycle including N as heteroatom;

or R11and R12together with the atoms to which they are attached, form a 6-or 7-membered heterocyclic ring including O as heteroatom;

where R11-R13each phenyl or heteroaryl optionally substituted by 1 or 2 substituents independently selected from Rc; each heterocyclyl optionally substituted by 1 or 2 substituents selected from Rband Rc;

alkyl of neobythites is but replaced by Deputy, selected from Rband vinyl optionally substituted by a Deputy selected from Rm;

each Raindependently is-ORd, -NO2, halogen, -S(O)mRd, -NRdRe, -C(=O)Rd, -CO2Rd, -CN, or-NRdC(=O)Re;

each Rbindependently is-OH, -NH2or oxo;

each Rcindependently represents Ra, vinyl or1-3alkyl, where each alkyl optionally substituted by a Deputy selected from Rb;

each Rdand Reindependently represents hydrogen, C1-3alkyl, phenyl, or 5 - or 6-membered monocyclic heteroaryl comprising 1 or 2 heteroatoms selected from N, S; wherein each alkyl, phenyl or heteroaryl optionally substituted by 1, 2 or 3 substituents, independently selected from Rh; or Rdand Retogether with the atoms to which they are attached, form a heterocyclic ring having 6 ring atoms, and specified heterocyclic ring optionally contains 1 additional heteroatom selected from oxygen;

each Rhindependently represents halogen, C1-8alkyl, C1-4alkoxy, phenyl, or-CF3;

each Rmrepresents phenyl;

m is 0, 1 or 2;

w is 0, 1, 2, 3 or 4;

or in pharmaceutical preparations is automatic acceptable salt, or MES, or the stereoisomer.

2. The compound according to claim 1, where R1denotes hydrogen; R2denotes hydrogen; R3represents hydroxy; R4and R5together are-NHC(=O)CH=CH-.

3. The compound according to claim 1, where each of R11and R]2independently selected from the group comprising hydrogen, C1-4alkyl, cyclohexyl, phenyl, pyrazolyl, -ORd, -S(O)mRdand-S(O)2NRdRe; where pyrazolyl optionally substituted by 1 or 2 substituents, independently selected from C1-3the alkyl and oxo;

R13denotes hydrogen;

w is 0;

Rdand Reindependently selected from the group comprising hydrogen, C1-3alkyl, phenyl, -CF3, pyridyl, thiazolyl, pyrimidinyl, where each phenyl optionally substituted by 1 or 2 substituents, independently selected from halogen, -CF3and C1-3of alkyl, each pyrimidinyl optionally substituted by 1 or 2 substituents, independently selected from C1-3the alkyl and OS1-3the alkyl, or

Rdand Retogether with the nitrogen atom to which they are attached, form morpholino or piperidino.

4. The compound according to claim 3, where R11denotes hydrogen or phenyl, and R12means-OS1-3alkyl; or R11denotes phenyl, and R12denotes hydrogen.

5. The compound according to claim 1, constituting with the Association of the formula (II):

where R4denotes-CH2HE or-NHCHO, and R5represents hydrogen or R4and R5taken together are-NHC(=O)CH=CH-;

R11denotes phenyl or heteroaryl, where phenyl optionally substituted by 1 or 2 substituents selected from halogen, -ORd, -CN, -NO2, -SO2Rd, -C(=O)Rdand C1-3of alkyl, where C1-3alkyl optionally substituted hydroxy or amino group, where Rddenotes hydrogen or C1-3alkyl; heteroaryl denotes pyridyl, pyrrolyl, indolyl, furanyl or thiophenyl and every heteroaryl optionally substituted by 1 or 2 C1-3alkyl substituents;

R12represents hydrogen or-OS1-3alkyl;

or its pharmaceutically acceptable salt, or MES, or the stereoisomer.

6. The compound according to claim 5, where R11represents phenyl, optionally substituted by 1 Deputy selected from halogen, -ORd, -CN, -NO2, -SO2Rd, -C(=O)Rd, -CH2OH, -CH2NH2where Rddenotes hydrogen or C1-3alkyl.

7. The compound according to claim 5, where R11represents phenyl, pyridyl or thiophenyl, where each phenyl optionally substituted by 1 Deputy selected from the group comprising chlorine, -och3, -CN, and-CH2NH2and R1 denotes hydrogen, -och3and-OS2H5.

8. The compound according to claim 5, where R4and R5taken together are-NHC(=O)CH=CH-; R11represents phenyl, optionally substituted by 1 Deputy selected from the group comprising chlorine, -och3, -CN, and-CH2NH2and R12represents-och3.

9. The compound according to claim 5, where the compound is a mixture of stereoisomers, in which the amount of the stereoisomer having the (R)-the orientation of the chiral center that is attached to the hydroxy-group, more than the amount of the stereoisomer having the (R)-the orientation of the chiral center that is attached to the hydroxy-group.

10. The compound according to claim 5, where the compound is a stereoisomer having the (R)-the orientation of the chiral center that is attached to the hydroxy-group.

11. The compound according to claim 5, where the specified connection is selected from a group including:

N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxy-methyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenylphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxy-methyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)chinoline-5-yl)ethyl is in;

N-{2-[4-(4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxy-methyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenylphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)chinoline-5-yl)ethylamine;

N-{2-[4-(3-phenylphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)chinoline-5-yl)ethylamine;

N-{2-[4-(4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)chinoline-5-yl)ethylamine;

N-{2-[4-(3-(2-chlorophenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)chinoline-5-yl)ethylamine;

N-{2-[4-(3-(2-methoxyphenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-is)ethylamine;

N-{2-[4-(3-(3-cyanophenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(4-aminomethylphenol)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(3-chlorophenyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(4-aminomethylphenol)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(4-hydroxyphenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(3-pyridyl)phenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(4-pyridyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine;

N-{2-[4-(3-(thiophene-3-yl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine and

N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine.

12. The compound according to claim 5, representing N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-guide is hydroxy-2-(8-hydroxy-2-(1H)-chinoline-5-yl)ethylamine.

13. The compound according to claim 5, representing N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine.

14. Pharmaceutical composition having the properties Anisimovna β2adrenergic receptors, comprising a therapeutically effective compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to 14, where the composition is prepared for administration by inhalation.

16. The pharmaceutical composition according to 14, where the composition further comprises a therapeutically effective amount of a steroid anti-inflammatory agent.

17. The compound according to any one of claims 1 to 13, having the properties Anisimovna β2adrenergic receptors

18. The use of compounds according to any one of claims 1 to 13 in the manufacture of medicinal products for the treatment of a disease or condition associated with the activity β2adrenergic receptors in mammals.

19. Use p, where the disease or condition is a pulmonary disease.

20. The application of claim 19, where the pulmonary disease is asthma or chronic obstructive pulmonary disease.

21. Use p, where the disease or condition selected from the group including premature birth, neurological disorders, serdechnosti and inflammation.

22. The modulation method β2adrenergic receptors, including stimulation β2adrenergic receptor modulatory amount of a compound according to any one of claims 1 to 13.

Priority items:

13.11.2001 on para.12;

28.12.2001 according to claims 1-11, 13-22.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (1): wherein R1 means (C1-C6)-alkyl that can be substituted with phenyl; R2, R3, R4 and R5 represent independently each of other hydrogen halogen atom, nitro-group, (C1-C4)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyloxy-, (C6-C10)-aryloxy-group, (C6-C10)-aryl that can be mono-, di- or tri-substituted with halogen atom; 2-oxopyrrolidine-1-yl, 2,5-dimethylpyrrole-1-yl or -NR6-A-R7 under condition that R2, R3, R4 and R5 can't mean simultaneously hydrogen atom and at least one residue among R2, R3, R4 and R5 represents 2-oxopyrrolidine-1-yl, 2,5-dimethylpyrrole-1-yl or -NR6-A-R7 at value R6 - hydrogen atom, (C1-C4)-alkyl or (C6-C10)-aryl-(C1-C4)-alkyl wherein aryl can be substituted with halogen atom; A means a simple bond, -COn, -SOn or -CONH; n = 1 or 2; R7 means hydrogen atom; (C1-C18)-alkyl or (C2-C18)-alkenyl that can be substituted from one to three times with (C1-C4)-alkyl, (C1-C4)-alkyloxy-group, -N-((C1-C4)-alkyl)2-group, -COOH, (C1-C4)-alkyloxycarbonyl, (C6-C12)-aryl, (C6-C12)-aryloxy-group, (C6-C12)-arylcarbonyl, (C6-C10)-aryl-(C1-C4)-alkoxy-group, halogen atom, -CF3 or oxo-group wherein aryl, in turn, can be substituted with halogen atom, (C1-C)-alkyl, aminosulfonyl- or methylmercapto-group; (C6-C10)-aryl-(C1-C4)-alkyl, (C5-C8)-cycloalkyl-(C1-C4)-alkyl, (C5-C8)-cycloalkyl, (C6-C10)-aryl-(C2-C6)-alkenyl, (C6-C10)-aryl, diphenyl, diphenyl-(C1-C4)-alkyl, indanyl that can be mono- or di-substituted with (C1-C18)-alkyl, (C1-C18)-alkyloxy-group, (C3-C8)-cycloalkyl, hydroxy-group, (C1-C4)-alkylcarbonyl, (C6-C10)-aryl-(C1-C4)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyloxy-group, (C6-C10)-aryloxy-group, nitro-, cyano-group, (C6-C10)-aryl, fluorosulfonyl, (C1-C6)-alkyloxycarbonyl, (C6-C10)-arylsulfonyloxy-group, pyridyl, -NHSO2-(C6-C10)-aryl, halogen atom, -CF3 or -OCF3 wherein alkyl can be substituted once again with halogen atom, -CF3 or (C1-C4)-alkyloxy-group; or group Het-(CH2)r wherein r = 0, 1, 2 or 3 wherein Het means saturated or unsaturated 5-7-membered heterocycle comprising atoms nitrogen (N), oxygen (O) or sulfur (S) and can be condensed with benzene and substituted with (C1-C4)-alkyl, (C6-C10)-aryl, halogen atom, (C1-C4)-alkyloxy-group, (C6-C10)-aryl-(C1-C4)-alkyl, (C6-C10)-aryl-(C1-C)-alkylmercapto- or nitro-group and wherein aryl condensed with benzene can be, in turn, substituted with halogen atom, (C1-C4)-alkyloxy-group; and to their pharmacologically acceptable salts and additive salts of acids, and to a method for their preparing. Proposed compounds show inhibitory effect on activity of hormone-sensitive lipase.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 199 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to derivatives of piperazine and piperidine of the formula (I): wherein ---Z represents =C or -N; Q means benzyl or 2-, 3- or 4-pyridylmethyl that can be substituted with one or more substitutes taken among group comprising halogen atom, cyano-group, (C1-C3)-alkoxy-group, CF3, OCF3, SCF3, (C1-C4)-alkyl, (C1-C3)-alkylsulfonyl and their salts, and to a method for their preparing also. It has been found that these compounds elicit valuable pharmacological properties owing to combination of (partial) agonism with respect to members of dopamine receptors subtype and affinity with respect to corresponding serotonin and/or noradrenergic receptors and can be useful in preparing compositions used in treatment of fear and/or depression or Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: substituted benzoylisoxazols of general formula I are described, wherein R1 is cycloalkyl; R2 is hydrogen, alkoxycarbonyl; R3 is halogen, substituted alkyl, alkoxyl; R4 is halogen, alkoxil; Z is substituted 5-membered saturated or unsaturated heterocycle having 1-3 nitrogen atoms and additionally including one oxogroup (C=O). Also disclosed is herbicidal agents, containing compounds of formula I.

EFFECT: effective suppression of weeds in such cultures as maize and wheat.

16 cl, 6 tbl, 4 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

The invention relates to new derivatives of arylpiperazines General formula I, where X Is O or S1- C1-C4alkoxy, CF3, R2- C1-C6alkyl, saturated WITH3-C6cycloalkyl; heteroseksualci of 3-6 ring atoms, heteroatom of which is O, S or N, optionally N-substituted WITH1-C6by alkyl; phenyl, optionally substituted by F, Cl, Br, NH2CH3CF3or OCH3; 5-6-membered heteroaryl, the heteroatom of which is O, S or N, possibly substituted, or condensed heteroaromatic system containing 9 atoms

The invention relates to new arylpyrimidines compounds of formula I having the effect of antagonist 5HT2B-receptor, and pharmaceutical compositions

The invention relates to a new method of production (its variants) aminophenylalanine formula I, having the properties of plant growth regulators or herbicides, as well as intermediate products for their production

The invention relates to novel acylated to aminophenylacetylene General formula I which possess herbicide action and selectivity of action in comparison with the previously known compounds of this series

The invention relates to new substituted pyrimidinediamine or alkylating compounds, their pharmaceutically acceptable salts, hydrates, N-oxides and method for inhibition of reverse transcriptase of the virus

The invention relates to the technical field of herbicides and plant growth regulators, in particular of herbicides for selective control of weeds in cultivated plants

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

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing inhibitory effect on activity of dipeptidyl peptidase IV (DPP IV) that can be used, for example, in treatment of diabetes mellitus type 2. In compounds of the formula (I) X means nitrogen atom (N) or -C-R5; R1 and R2 mean independently hydrogen atom, (C1-C6)-alkyl; R3 means saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, or perfluoro-(C1-C6)-alkyl; R4 means (lower)-alkyl, (lower)-alkoxy-, (lower)-alkylthio-group, saturated or aromatic 7-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-, amino-group or perfluoro-(C1-C6)-alkyl, 4-fluorophenyloxy-(C1-C6)-alkyl or (C3-C6)-cycloalkyl; R5 means hydrogen atom or (C1-C6)-alkyl. Also, invention relates to methods for synthesis of compounds of the formula (I), pharmaceutical compositions and their using for preparing medicaments used in treatment and/or prophylaxis of DPP IV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

21 cl, 93 ex

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