Arylethanolamine derivatives and pharmaceutical composition

 

(57) Abstract:

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine. In the compound of General formula I, Ar denotes phenyl which may be substituted by 1-3 substituents selected from the group: halogen, lower alkyl, possibly substituted by 1-3 substituents selected from halogen; lower alkoxy, lower alkoxycarbonyl, carboxypropyl, cyano; naphthyl, 5-, 6-membered heteroaryl selected from the group thienyl, furyl, thiazolyl, pyridyl, pyrimidyl, X is an oxygen atom, sulfur or the group-NH-, Y is an oxygen atom, R1-a lower alkyl which may be substituted by halogen atoms, cycloalkyl, phenyl which may be substituted by 1-3 substituents selected from lower alkyl, possibly substituted by 1-3 halogen atoms, lower alkoxyl, nitro, C1-C3-alkylenedioxy, 5-, 6-membered heterocycle selected from the group of pyridyl, pyrimidyl, thiazolyl, furil, teinila, each of which may be substituted by lower alkyl, possibly substituted by 1-3 halogen atoms, lower alkoxyl, R2- lower alkyl, lower quinil,alkoxygroup, halogen, cycloalkyl, R3is phenyl which may be substituted by 1-4 substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, R4and R5may be the same or different and mean hydrogen, lower alkyl, or pharmaceutically acceptable salt. The invention also relates to pharmaceutical compositions having the properties of endothelin antagonist and including arylethanolamine derivative or its pharmaceutically acceptable salt p. 1 and a pharmaceutically acceptable carrier. 2 S. and 1 C.p. f-crystals, 9 PL.

The present invention relates to medicines, more precisely, to the new arylethanolamine derivative with high affinity to the receptor endothelin, their pharmaceutically acceptable salts and containing pharmaceutical compositions, in particular to the receptor antagonist of endothelin.

Art

The endothelium is an endogenous physiologically active peptide consisting of 21 amino acids; it is known that endothelin there are three isopeptide ET-1, ET-2 and ET-3, in which the amino acid sequence is slightly different.

The endothelium exerts its FIA endothelin installed to date that there are at least two subtypes called ETAand ETB, respectively. These receptors differ in affinity for endothelin. ETAhas a higher affinity for ET-1 and ET-2 than for ET-3, whereas the receptor for ETBhas a similar degree of affinity to the three types of endothelin.

The endothelium and the endothelin receptor are produced and expressed, respectively, in different cells of different organs and there are many physiological effects, which are caused by them. For example, in blood vessel ET-1, which is produced and secreted in the endothelial cells of the vessel, binds to a receptor ETAon the smooth muscle cells of the blood vessel in the vicinity, and reduces blood vessel heavily and constantly. On the other hand, endothelial cells of the vessel themselves Express the receptor for ETBand, if ET-1 is associated with him, is produced and secreted nitrogen monoxide (NO). Nitrogen monoxide has the effect of relaxing the smooth muscles of the blood vessel. Indeed, if in the experiment ET-1 injected intravenously to rats after transient hypotension observed long-term hypertension.

As seen on the physiological action on the blood with the VNO reduces blood vessel, and, for this reason, its relationship with diseases, especially cardiovascular diseases, is a matter of debate since its discovery.

Today argue that there is a possibility that excessive secretion of endothelin, especially ET-1 (more specifically, the increase in the concentration of ET-1 or local, or in the tissues and circulating blood), is involved not only in cardiovascular diseases, but also in many other diseases. So, it is reported that this phenomenon occurs when the primary arterial hypertension, pulmonary hypertension, hypertension induced by erythropoietin, hypertension, caused by cyclosporine A, bronchial asthma, acute renal failure, chronic renal failure, glomerular nephritis, renal failure, caused by cyclosporine, acute myocardial infarction, unstable angina, congestive heart failure, cerebrovascular spasm, especially after subarachnoid hemorrhage, cerebrospinal disorder, urinary incontinence, benign prostatic hypertrophy, arteriosclerosis, Raynaud's syndrome, diabetic human peripheral blood circulation, diabetic renal zabolevania RTSA, chronic respiratory failure, chronic obstructive pulmonary disease, cor pulmonale, acute respiratory failure, pulmonary edema, ischemic renal disorders, respiratory distress syndrome, adult, interstitial pneumonia, pulmonary fibrosis, glaucoma, osteoarthritis, chronic rheumatoid arthritis, liver cirrhosis, inflammatory bowel disease, cancer, etc. (G. M. Rubanyi, M. A. Plokoff, Pharmacologioal Rewiews, vol. 46, N 3, 325 (1994); Saishin Igaku, vol. 49, N 3, 335 (1994); Kidney International, 37, 1487-1491 (1990); Lancet, 339, 381-385 (1992); Cell Mol. Neurobiol., 13, 15-23 (1993); J. Clin. Endocrinol. Metab., 76, 378-383 (1993); J. Clin. Pathol. , 48(6), 519-524 (1995); Chest. 104(2), 476-480 (1993); Am. J. Med, 99(3), 155-160 (1995); Hepatology, 16, 95-99 (1992); and so on).

Therefore, pharmaceutical preparations, which, by binding to the endothelin receptor, inhibit the binding of ET-1, endothelin receptor, i.e., antagonists of the endothelin receptor, can be an effective prophylactic and therapeutic means in respect of diseases mentioned above.

In respect of such antagonists of the endothelin receptor, in Japanese patent laid publication Hei-05/155864, Hei-05/222003, Hei-06/211810 and Hei-07/017972 described a number benzosulfimide derivatives. In particular, a compound which is represented by the following formula

is ntan), reported as effective, and digestible oral introduction of pathogenic models of the number of animals (J. Pharmacol. Exp. Ther., 270(1), 228-2345, 1994; Hypertension, 224, 183-188, 1994; Clin. Pharmacol. Ther., 60, 124-137, 1996).

Description of the invention

The purpose of the present invention is to provide new compounds having a much better antagonistic effect on the endothelin receptor.

The present inventors conducted a screening of compounds having a high affinity for endothelin receptor, and as a result have found that the new arylethanolamine derivatives, which differ from the known compounds in the sense that arelatively group substituted in the pyrimidine sulfonamide ring, exhibit high affinity for endothelin receptor, especially to the receptor ETAand have a strong antagonistic effect, resulting in the present invention is implemented.

Therefore, the present invention relates to a new arylaminomethylidene derivative represented by the following formula (I) or its pharmaceutically acceptable salt.

< / BR>
In the formula, Ar is optionally substituted aryl or optionally substituted 5-6-membered heteroaryl;

X is an oxygen atom, a sulfur atom or a group of the form is alkyl, cycloalkyl, possibly substituted aryl or possibly substituted 5-6-membered heteroaryl;

R2- lower alkyl, lower alkenyl or lower quinil, each of which may be substituted by 1-3 substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, cycloalkyl, halogen, carboxypropyl and lower alkoxycarbonyl;

R3is phenyl which may be substituted by 1-4 substituents selected from the group consisting of optionally halogen-substituted lower alkyl, lower alkoxygroup, halogen, lower allylthiourea, lower alkylsulfonyl, lower alkanesulfonyl, carboxypropyl, lower alkoxycarbonyl and carbamoyl; and

R4and R5that may be the same or different, is a hydrogen atom or lower alkyl).

The preferred compounds which are preferred in the present invention are arylethanolamine derivative represented by the above formula (I) in which:

Ar is aryl which may be substituted by 1-5 substituents selected from the group consisting of lower alkyl (the lower alkyl may be substituted by 1-4 substituents selected from the group consisting of halogen, lower alcohol of alkoxycarbonyl, carboxypropyl, halogen, nitro, ceanography, amino, lower mono - or dialkylamino, hydroxy-group and C1-C3-alkylenedioxy; or a 5-6-membered heteroaryl, which may be substituted by 1-4 substituents selected from the group consisting of lower alkyl (the lower alkyl may be substituted by 1-4 substituents selected from the group consisting of halogen, lower alkoxygroup, carboxypropyl, amino and lower mono - or dialkylamino), low alkoxygroup, lower alkoxycarbonyl, carboxypropyl, halogen, nitro, ceanography, amino and lower mono - or dialkylamino; and

R1is hydrogen; lower alkyl which may be substituted by halogen atoms; cycloalkyl; aryl which may be substituted by 1-5 substituents selected from the group consisting of lower alkyl (the lower alkyl may be substituted by 1-4 substituents selected from the group consisting of halogen, lower alkoxygroup, carboxypropyl, amino and lower mono - or dialkylamino), low alkoxygroup, lower alkoxycarbonyl, carboxypropyl, halogen, nitro, ceanography, amino, lower mono - or dialkylamino, hydroxy-group and C1s from the group consisting of lower alkyl (the lower alkyl may be substituted by 1-4 substituents selected from the group consisting of halogen, lower alkoxygroup, carboxypropyl, amino and lower mono - or dialkylamino), low alkoxygroup, lower alkoxycarbonyl, carboxypropyl, halogen, nitro, ceanography, amino, lower mono - or dialkylamino; or its pharmaceutically acceptable salt.

More preferred compounds are:

(1) arylethanolamine derivative represented by the above formula (I) or their salts, in which

Ar is aryl which may be substituted by 1-5 substituents selected from the group consisting of optionally halogen-substituted lower alkyl, lower alkoxygroup, lower alkoxycarbonyl, carboxypropyl, halogen, nitro and cyanopropyl; or a 5-6-membered heteroaryl, which may be substituted by 1-4 substituents selected from the group consisting of lower alkyl and lower alkoxygroup;

X is an oxygen atom or a group of the formula-NH-;

Y is an oxygen atom;

R1- optionally halogen-substituted lower alkyl; cycloalkyl; aryl which may be substituted by 1-5 substituents selected from the group, with whom, is carboxypropyl, halogen, nitro, ceanography and C1-C3-alkylenedioxy; or a 5-6-membered heteroaryl, which may be substituted by 1-4 substituents selected from the group consisting of optionally halogen-substituted lower alkyl, lower alkoxygroup, lower alkoxycarbonyl, carboxypropyl, halogen, nitro and cyanopropyl;

R3is phenyl which may be substituted by 1-4 substituents selected from the group consisting of optionally halogen-substituted lower alkyl, lower alkoxygroup, halogen, carboxypropyl and lower alkoxycarbonyl;

(2) arylethanolamine derivative represented by the formula (I) or their pharmaceutically acceptable salts, in which

Ar is a 5-6-membered heteroaryl, naphthyl or phenyl which may be substituted by 1-5 substituents selected from the group consisting of optionally halogen-substituted lower alkyl, lower alkoxygroup and halogen;

R1- optionally halogen-substituted lower alkyl; cycloalkyl; phenyl which may be substituted by 1-5 substituents selected from the group consisting of optionally halogen-substituted lower alkyl, lower alkoxygroup, nitro and C1-C3-alkylenedioxy is possible halogen-substituted lower alkyl and lower alkoxygroup;

R2lowest quinil or lower alkyl which may be substituted by 1-3 substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup of cycloalkyl and halogen;

R3is phenyl which may be substituted by 1-4 substituents selected from the group consisting of lower alkyl, lower alkoxygroup and lower alkoxycarbonyl;

(3) arylethanolamine derivative represented by the formula (I) or their pharmaceutically acceptable salts, in which

Ar is phenyl, possibly substituted lower alkyl, or thienyl;

X is an oxygen atom;

R1is phenyl which may be substituted by lower alkoxygroup, or 5-6-membered heteroaryl, which may be substituted by lower alkyl;

R2lowest quinil or lower alkyl which may be substituted by 1-3 substituents selected from the group consisting of hydroxy-group and halogen; and

R3is phenyl, which is substituted by lower alkoxygroup or groups;

(4) arylethanolamine derivative represented by the formula (I) or their pharmaceutically acceptable salts, in which

Ar is phenyl or thienyl;

R1- pyrimidinyl;

R2- a lower alkyl which may be substituted with halogen or halogenide alkyl; and

R5is hydrogen; or

(5) arylethanolamine derivative represented by the formula (I) or their pharmaceutically acceptable salt, selected from the group consisting of the following compounds and their salts:

N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2 - pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone,

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone,

N-[6-(2-floratone)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone,

N-[6-(2-propenyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone,

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -1-methyl-2-phenylacetophenone,

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -1-ethyl-2-phenylacetophenone, and

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2-thienyl) tinsulanond.

Further, the present invention relates to a pharmaceutical composition, which contains arylethanolamine derivative or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, and, particularly, it relates to antagonists of the endothelin receptor. More specifically, it otnositelino, such as primary arterial hypertension, pulmonary hypertension, hypertension induced by erythropoietin, hypertension, caused by cyclosporine A, bronchial asthma, acute renal failure, chronic renal failure, glomerular nephritis, renal failure, caused by cyclosporine, acute myocardial infarction, unstable angina, congestive heart failure, cerebrovascular spasm, especially after subarachnoid hemorrhage, cerebrosidase disorder, urinary incontinence, benign prostatic hypertrophy, arteriosclerosis, Raynaud's syndrome, diabetic human peripheral blood circulation, diabetic renal disease, preeclampsia, premature birth, stomach ulcers, liver failure, rheumatism, restenosis after RTSA, chronic respiratory failure, chronic obstructive pulmonary disease, cor pulmonale, acute respiratory failure, pulmonary edema, ischemic renal disorder, respiratory distress syndrome of adults, interstitial pneumonia, pulmonary fibrosis, glaucoma, osteoarthritis, chronic rheumatoid arthritis, cirrhosis, inflammatory bowel disease, cancer/P> The term "lower" used in the definitions of the groups in formula (I) of the present description, refers to a normal or branched carbon chain with 1-6 carbon atoms, unless otherwise stated.

Accordingly, examples of "lower alkyl" are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Among these groups with 1-4 carbon atoms are preferred, and methyl, ethyl, propyl and isopropyl are particularly preferred.

"Lower alkenyl" is a normal or branched alkenyl with 2-6 carbon atoms, and its specific examples are vinyl, allyl, 1-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methylallyl, 1-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 1-m is Teal-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,1-dimethyl-1-butenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 1-methyl-1-pentenyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 4-methyl-1-pentenyl, 4-methyl-2-pentenyl and 4-methyl-3-pentenyl and among them alkenyl with 3-4 carbon atoms is preferred.

"Lower quinil" is a normal or branched quinil with 2-6 carbon atoms, and its examples are ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-PROPYNYL, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 2-methyl-3-butynyl, 1-methyl-2-butenyl, 1-methyl-3-butynyl, 1,1-dimethyl-2-PROPYNYL, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. Among them quinil with 3-4 carbon atoms are preferred.

"Aryl" in the "optionally substituted aryl" is an aromatic hydrocarbon group. Preferably, this is aryl with 6-14 carbon atoms, and its examples are phenyl, naphthyl, indenyl, antril and tenantry. More preferably it is phenyl or naphthyl.

These groups may be substituted by one or more substituents or, preferably, 1-5 substituents. Any Deputy, therefore, mlney group. Preferred examples are lower alkyl (the lower alkyl may be substituted by 1-4 substituents selected from the group consisting of halogen, lower alkoxygroup, carboxypropyl, amino and lower mono - or dialkylamino), the lowest alkoxygroup, lower alkoxycarbonyl, carboxypropyl, halogen, the nitro-group, cyano, amino, lower mono - or dialkylamino, the hydroxy-group and C1-C3-alkylenedioxy.

The term "5-6-membered heteroaryl" in the "optionally substituted 5-6-membered heteroaryl" means a 5-6-membered monocyclic heteroaryl containing 1-4 heteroatoms selected from nitrogen atoms, sulfur and oxygen, and its typical examples are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Preferred examples of the "optionally substituted 5-6-membered heteroaryl" for Ar in the present invention are furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolin, oxazolyl and isoxazolyl, and especially preferred are furyl and thienyl. Examples of preferred groups GPI can be substituted by one or more of any substituents or preferably 1-4 substituents. You can use any Deputy, if it is a Vice, which is usually used as a substituent heteroaryl. Preferred examples are lower alkyl (the lower alkyl may be substituted by 1-4 substituents selected from the group consisting of halogen, lower alkoxygroup, carboxypropyl, amino and lower mono - or dialkylamino), the lowest alkoxygroup, lower alkoxycarbonyl, carboxypropyl, halogen, the nitro-group, cyano, amino or lower mono - or dialkylamino.

Preferred "cycloalkyl is cycloalkyl with 3-8 carbon atoms. Its typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and preferred examples are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Examples of "lower alkoxygroup" are methoxy group, ethoxypropan, propoxylate, isopropoxide, butoxypropan, isobutoxy, second-butoxypropan, tert-butoxypropan, pentyloxy (lilacchrome), isopentylamine, tert-pentyloxy group, neopentadactyla, 2-methylbutoxy, 1,2-DIMETHYLPROPANE, 1 particularly preferred methoxy group and ethoxypropan.

Examples of the "halogen atom" include fluorine, chlorine, bromine and iodine, the preferred examples are fluorine and chlorine.

Lower alkyl which is substituted by an atom or atoms of halogen in the "optionally halogen substituted lower alkyl" is a group in which one or more hydrogen atoms replaced by the abovementioned halogen atoms. Preferably is lower alkyl, substituted by 1-4 halogen atoms, such as chloromethyl, vermeil, methyl bromide, iodomethyl, dichloromethyl, deformity, dibromomethyl, trichloromethyl, trifluoromethyl, 2-chloroethyl, 2-foretel, 2-bromacil, 2-Iodate, 2,2-dichloroethyl, 2,2-dottorati, 2,2-dibromoethyl, 2,2,2-trichloroethyl, 2,2,2-triptorelin, 1-chloroethyl, 1-foretel, 1-bromacil, 1-Iodate, 1,2-dichloroethyl, 1,2-dottorati, 1,1-dibromoethyl, 1,2,2-trichloroethyl, 1,2,2-triptorelin, 1-bromo-2-chloroethyl, 3-chloropropyl, 3-forproper, 3,3-dichloropropyl, 3,3-direcror, 3,3,3-cryptochromes, 4-chlorobutyl and 5-terpencil. Among them, alkyl with 1-3 carbon atoms, substituted with 1-3 chlorine atoms or fluorine is preferred, especially preferred trifluoromethyl.

"Lower alkoxycarbonyl" is a group in which an ester is formed from carboxypropyl and normal or branched alcohol with 1 to 6 carbon atoms, and e is nil, isobutoxide, second-butoxycarbonyl", tert-butoxycarbonyl, pentyloxybenzoyl, isopentylamine, neopentylglycol, tert-pentyloxybenzoyl and hexyloxybenzoyl. Among these groups with 1-4 carbon atoms are preferred, particularly preferred methoxycarbonyl and etoxycarbonyl.

"The lowest allylthiourea" is a group in which a hydrogen atom of mercaptopropyl substituted by the above-mentioned "lower alkyl", and its typical examples are methylthiourea, ethylthiourea, PropertyGroup, isopropylthio, butylthiourea, isobutylthiazole, intelligroup, isopentype and vexillographer. Among them allylthiourea with 1-4 carbon atoms is preferred, and groups with 1-3 carbon atoms, such as methylthiourea, ethylthiourea, PropertyGroup and isopropyltoluene especially preferred.

Examples of "lower alkylsulfonyl are methylsulfinyl, ethylsulfinyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, isobutylphenyl, pentasulfide, isopentylamine, exisulind and isohexanol. Among them alkylsulfonyl with 1-4 carbon atoms is preferred, and groups with 1-3 atoms of carbon is.

Examples of "lower alkanesulfonyl are methanesulfonyl, econsultancy, propanesulfonyl, isopropylphenyl, butanesulfonyl, isobutylphenyl, pentanesulfonic, isointensity, hexanesulfonic and isohexanol. Among them alkanesulfonyl with 1-4 carbon atoms is preferred, and groups with 1-3 carbon atoms, such as methanesulfonyl, econsultancy, propanesulfonyl and isopropylphenyl especially preferred.

"Lower mono - or dialkylamino" is an amino group in which one or two hydrogen atoms replaced by the above alkilani. In the case of the lower dialkylamino two alkyl may be the same or different. Examples of the lower monoalkylamines are methylaminopropyl, atramentaria, propylamino, isopropylamino, butylamino, isobutylamino, second-butylamino, tert-butylamino and intellimorph, while examples of the lower dialkylamino are dimethylaminopropan, diethylaminopropyl, dipropylamino, methylaminopropyl, methylpropylamine, methylisoborneol, methylbutylamine, methylisobutylketone, ethylpropylamine and ethylisopropylamine, atlantoxerus and propyleneoxide.

In the compounds of the present invention include geometric isomers, such as CIS - and TRANS-compounds (or E-connection, and Z-connection), due to the double bonds and the present invention covers each of the separated isomers (E-connection or Z-connection) and their mixtures. In the present invention, the compound in which the group4and R5are in the TRANS configuration is preferred. In addition, geometrical isomers and tautomers may be present depending on the types of substituents and the present invention covers each of the separated isomers and mixtures thereof.

In addition, the compounds of the present invention may have asymmetric carbon atoms and optical isomers [(R)-compound and (S)-connection] due to the fact that there may be asymmetric carbon atoms. The present invention encompasses a mixture of such optical isomers and the compound obtained its division.

The compound (I) of the present invention may form a salt with acid or, depending on the type of substituent salt with a base as well. This salt is a pharmaceutically acceptable Sol is aristolochioides acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid and phosphoric acid) or organic acid (e.g. formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate, econsultation, aspartic acid and glutamic acid), and salt with a base such as an inorganic base (e.g. sodium, potassium, magnesium, calcium and aluminum salts) and organic base (for example, methylamine, ethylamine, ethanolamine, lysine and ornithine), and ammonium salt.

The present invention further covers various types of hydrate and solvate of the compounds (I) of the present invention and their salts and polymorphic crystals.

Ways to get

Compounds of the present invention and their pharmaceutically acceptable salts can be obtained by various known synthetic methods using the characteristics based on their basic skeleton or deputies. At the same time, sometimes effectively in the method of obtaining, A group, i.e. a group which can easily be converted into a specified functional group. Then, the protective group is removed, if necessary, and get the desired connection. Examples of such functional groups are hydroxy-group and carboxypropyl, while examples of the protective group include those described, for example, in "Protective groups in organic synthesis" (Greene and Wuts, Protective Groups in Organic Synthesis), 2-nd edition, and they can be appropriately used depending on the reaction conditions.

Typical methods of synthesis of compounds of the present invention will be given below.

The first way

< / BR>
(In the formulas, Z is a leaving group such as halogen and the remainder of the organic sulfonic acids; and M is hydrogen or alkali metal).

Examples of the residue of sulphonic acids are alkanesulfonyl, such as methanesulfonamido and econsultancy and aromatic sulfonyloxy, such as benzolsulfonate and toluensulfonate (especially p-toluensulfonate).

Examples of the alkali metal are sodium and potassium.

Compounds of the present invention (I) is obtained by reaction of the joint is proizvodnym formula (III) to carry out the esterification or N-alkylation.

Mainly carry out this reaction in such a way that the compound (II) is injected into the reaction with compound (III) in the number corresponding to the reaction, in the presence or absence of an inert solvent, such as benzene, xylene, tetrahydrofuran (THF), ether, dioxane, dimethylformamide (DMF), dimethyl sulfoxide, dichloromethane, dichloroethane and chloroform, in the presence of, if necessary, inorganic bases such as sodium, sodium hydride, sodium hydroxide, potassium hydroxide and potassium carbonate, or organic bases such as trimethylamine, triethylamine, pyridine, picoline, the lutidine and N, N-dimethylaniline, cooling, room temperature or heated, depending on the response.

The second way

< / BR>
The compound of the present invention (I) can be obtained by reaction of compounds of formula (IV) having a hydroxy-group, mercaptopropyl or their alkali metal derivative, with a compound of formula (V) having an appropriate leaving group.

The reaction can be carried out in the same way as in the First method of obtaining.

The third way

< / BR>
< / BR>
The compound of the present invention (I) can be obtained in the following way. Thus, the derived methansulfonate uly (VIII) is subjected to dehydration (second stage).

The first stage is mainly carried out in such a way that the derived methansulfonate (VI) enter into reaction with a derivative of benzaldehyde (VII) in an amount corresponding to the reaction, in an inert solvent, such as diethyl ether, THF, DMF and benzene, in the presence of a base such as sodium hydride, potassium carbonate, sodium carbonate, n-utillity and N,N,N',N'-tetramethylethylenediamine, at a temperature of from -60oC to heat.

The second stage is mainly carried out in such a way that the alcohol (VIII) maintained at room temperature or under heating in an inert solvent, such as benzene and dichloromethane.

If necessary, can be added to the reaction mixture dehydrating reagent, such as p-toluensulfonate pyrimidine, sulfuric acid and methylchloride-triethylamine.

Below, typical methods of obtaining raw materials will be described in detail.

How A

< / BR>
The original compound (II) from the First retrieval method can be obtained by reaction of pyrimidinediamine (IX) with arylethanolamine (X) or its salt. Pyrimidinediamine (IX) can be obtained by the method described in Japanese patent laid publication Hei-05/222003, or p is appropriate inorganic base.

The way IN

< / BR>
The compound (IV), which is the starting material for the Second method of production, is produced by reaction of the halide of formula (II) with sulfureous reagent, such as sodium hydrogen sulfide, hydroxide, such as sodium hydroxide, or aminimum reagent, such as ammonia.

The compound in which X is a sulfur atom in the above formula, obtained by reaction of sulfurylase.

Mostly the reaction is carried out in such a way that the halide (II) is injected into the reaction sulfureous reagent, such as hydrogen sulfide and sodium hydrosulfide in an amount corresponding to the reaction, in an inert solvent, such as toluene, benzene, chloroform, THF and DMF, at room temperature or when heated.

The method C

< / BR>
< / BR>
Source material (VI) in the Third method of obtaining obtained as follows. Thus, the compound (IX) enter into reaction with a derivative of methanesulfonamide (XI) (first stage) and the resulting compound (XII) enter into reaction with the compound (III) (second stage).

Regarding the first stage, the reaction is mainly carried out in the same conditions as in the production Method of A.

As for the second stage, the reaction prayasam of the above methods of obtaining, isolate and purify in the form of the free compounds or salts or its MES, such as a hydrate. Salt can be obtained by conventional salt-forming reaction.

Isolation and purification can be conducted by usual chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization and various chromatographic methods.

Each of the isomers can be isolated by conventional means, using physico-chemical differences between the isomers. In the case of optical isomers, for example, they can be separated by conventional means racemic cleavage, such as fractional crystallization and chromatography. As regards the optical isomer, it is also possible synthesis of the specified isomer from the appropriate optically active starting compound.

Industrial applicability

Compounds of the present invention have an affinity for the receptors of endothelin and they, in particular, have a high affinity receptor for ETAthat is one of the subtypes of endothelin receptors.

Therefore, the compounds of the present invention exhibit the effect of competitive inhibition of light which he takes part, such as cardiovascular disease. Examples of such diseases are the primary arterial hypertension, pulmonary hypertension, hypertension induced by erythropoietin, hypertension, caused by cyclosporine A, bronchial asthma, acute renal failure, chronic renal failure, glomerular nephritis, renal failure, caused by cyclosporine, acute myocardial infarction, unstable angina, congestive heart failure, cerebrovascular spasm, especially after subarachnoid hemorrhage, cerebrosidase disorder, urinary incontinence, benign prostatic hypertrophy, arteriosclerosis, Raynaud's syndrome, diabetic human peripheral blood circulation, diabetic renal disease, pre-eclampsia, premature birth, stomach ulcers, liver failure, rheumatism, restenosis after RTSA, chronic respiratory failure, chronic obstructive pulmonary disease, cor pulmonale, acute respiratory failure, pulmonary edema, ischemic renal disorder, respiratory distress syndrome of adults, interstitial pneumonia, pulmonary fibrosis, glaucoma, osteoarthritis, chronic rawmat the present invention show excellent absorption when administered orally and, also, good exposure duration.

The effect of the compounds of the present invention has established the following pharmacological tests.

(1) the Test for inhibition of binding of endothelin (ET-1) receptor ETAman

Test method

cDNA of the receptor ETAperson received from the mRNA of light through RT-PCR (polymerase chain reaction with reverse transcriptase) and then transferred into pEF-BOS (expression vector) to obtain the plasmid. The obtained plasmid was introduced into the cell culture COS-1 (strain cells derived from kidney cells of the African green monkey) with DEAE-dextran (diethylaminoethoxy) and receptor cDNA ETAthe man was transactionalist cells COS-1. After incubation for three days in normal DMEM (Wednesday Needle, modified by way of Dulbecco) (containing 10% FBS (serum fetal cow) is selected from among cells COS-1 suspended in hypotonic buffer (10 mm Tris-HCl and 5 mm EDTA; pH of 7.4) and homogenized in Polirone (transmitter station). Suspension with gomogenizirovannykh cells were subjected to ultracentrifugation (100000 g for 30 minutes at 4oC), the formed precipitate (fraction of cell membranes) re suspenderbelt protein: approximately 1 mg/ml).

For the experiment, binding of the receptor sample frozen cell membranes melted and suspended in incubation buffer (50 mm Tris-HCl, 10 mm MgCl2and 0.01% bovine serum albumin; pH 7,4). Suspension of membranes (200 μl) containing 1,25 µg protein membranes 25 ál of incubation buffer containing the test compound in various concentrations and 25 μl of [125I] ET-1 (specific radioactivity: 2200 CI/mm: final concentration: 25 μm), incubated at 25oC 3 hours and then filtered through a filter made of glass fiber with the use of the harvester of Brandes (Brandel). The measurement of the radioactivity on the filter stellanova fibers was performed using gamma counter (efficiency account: 81%). Nonspecific binding was determined using a test buffer containing 0.1 mm ET-1. Inhibitory activity of the test compounds in relation to [125I] ET-1 was calculated as the concentration (IR50) required to inhibit 50% of specific binding.

Results

Compounds of the present invention strongly inhibit the binding of ET-1 receptor ETAman. The result is shown in table 1.

(2) Test on the inhibition of the contraction induced by ET-1 who were given from the thoracic aorta of male Wistar rats (Wistar) (body weight: 300-350 g). The internal cavity of the ring easily hygienic wipe with cotton wool to remove the endothelium. Each of the annular mount preparations with a residual voltage of 1 g in the tub for bodies filled with 10 ml of Krebs-Henseleit (Krebs-Henseleit), via which it is barbotirovany a mixture of 95% CO2and 5% O2. The voltage generated by the ring preparation was registered isometrically. After incubation for 10 minutes with the test compound in the bath for organ was added ET-1 accumulation. Antagonistic activity of the test compound relative to the receptor ET-1 was calculated as the concentration (pA2) test the connections required to move the response curve for the concentration of ET-1 in two times to the right of the step (dose) move right response curve for the concentration of ET-1 test compounds at various concentrations.

Results

Compounds of the present invention strongly inhibited the reduction was caused by ET-1 in the annular sample arteries of rats.

(3) Test for inhibition of Pressor reactions caused by big ET-1, decapitated rats

Test method

Male Wistar rats (Wistar) (body weight: 25-350 g) was anestesiologi nutrinos destroyed by the introduction of the steel pin and the rat was then connected to the ventilator. Catheter for measurement of systemic arterial blood pressure was injected into the carotid artery, and the other catheter for the introduction of big ET-1 was inserted into the femoral vein. 30 minutes after oral administration of the test compounds at a dose of 0.1-10 mg/kg rat was decapitated and then injected intravenously big ET-1 at doses of 0.1-3.2 nmol/kg accumulation. The activity of test compounds was assessed by the dose (the amount DR2the reaction to the dose, RD2) at which the response curve on the dose Pressor responses to big ET-1 was shifted to the right two times.

Results

Oral administration of the compounds of the present invention exhibits an excellent inhibitory effect on the Pressor response caused by big ET-1, decapitated rats. The results are shown in table 2.

Table 2

Test connection - RD (mg/kg)

Example 2 - 0,61

Example 38 - 0,65

Example 42 - 1,85

Comparative compound*- 32

*comparative compound: the compound described in Example 67 Japanese patent laid publication Hei-05/222003 (generic name: Bosentan (Bosentan).

< / BR>
(4) Test for inhibition of Pressor reactions caused by big ET-1 in rats, nahodyaschiysya). Catheter for measurement of systemic arterial blood pressure was injected into the carotid artery, while the other catheter for the introduction of big ET-1 was inserted into the jugular vein. The experiment was carried out 2-3 days after surgery. So, big ET-1 was administered intravenously to rats, in consciousness, at a dose of 0.5 nmol/kg every hour. 30 minutes after the third injection, big ET-1 was administered orally with the test compound at doses of 0.3-3 mg/kg Activity of the test compounds was assessed by the inhibition of the Pressor reactions caused by big ET-1.

Results

The test found that the compounds of the present invention exhibit excellent inhibitory effect on the Pressor response caused by big ET-1, in rats, in consciousness.

The pharmaceutical composition containing the compound of the present invention (I) or its salt and a pharmaceutically acceptable carrier, can be obtained in the usual way of one or more compounds of the formula (I) or their salts and a pharmaceutical carrier, filler and other additives which are usually used for the preparation of a pharmaceutical product. The introduction can be either by oral administration using tablets,nutramigen injection, suppositories and transcutaneous funds.

As for the solid composition for oral administration according to the present invention, the use of tablets, powder, granules, etc., In such solid compositions one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and minimalistically. The composition may also contain additives other than the inert diluent, such as a lubricating substance (e.g., magnesium stearate), means causing raspadaemost (for example, calcicalathina), a stabilizer (e.g., lactose) and auxiliary solubilizer (e.g., glutamic acid and aspartic acid). Tablets and pills may be coated, if necessary, a sugar or a gastric or enteric film, such as sucrose, gelatin, hydroxypropylcellulose and phthalate of hydroxypropylmethylcellulose.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and contains a generally used inert diluents, such STV, such as wetting and suspendresume funds, as well as sweetening means, flavoring means, flavorings and preservatives.

Injections for parenteral administration include aseptic aqueous and non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, Polysorbate 80 (trade name), etc. Such compositions may also contain auxiliary agents such as antiseptics, wetting, emulsifying agents, dispersing agents, stabilizers (e.g., lactose) and auxiliary soljubilizatory (for example, glutamic acid and aspartic acid). They can be made aseptic, for example, by filtration through filter traps bacteria, mixed with aseptic means, or by irradiation. They can also be used to obtain aseptic solid composition after dilution in aseptic water or aseptic solvent for injection before use.

If lane is administered once or 2-4 times a day. In the case of intravenous appropriate daily dosage is about 0.001 to 30 mg/kg body weight and administered at once or in two or more times a day. The dose is usually determined in each case, taking into account the symptom, age, sex, etc.

The present invention is shown in more detail in the following examples. Compounds of the present invention is not limited to the compounds listed in the examples that follow. In this regard, the methods of obtaining the starting compounds used in the working examples will be described in reference examples.

Reference example 1

Sodium hydride (60%) (480 mg) was added to a solution of 1.00 g of 2-phenylethanolamine in 10 ml of dimethylformamide under ice cooling and stirred at room temperature for 15 minutes. To this reaction solution was added with stirring at 1.91 g of 4,6-dichloro-5-(2-methoxyphenoxy) -2-(2-pyrimidinyl)pyrimidine. The reaction mixture was stirred at room temperature for 2.5 hours and poured into a mixture of 1 N. hydrochloric acid and ice. The resulting crystals were collected by filtration and was received at 1.91 g of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2 - pyrimidinyl)-4-pyrimidinyl]-2-phenyl-Tinsulanonda.

Reference example 2

N-[is sravnitelnim example 1.

Reference example 3

N-[6-Chloro-5-(4-methoxycarbonyl-2-propylenoxide)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone was obtained as in Comparative example 1.

4,6-Dichloro-5-(4-methoxycarbonyl-2-propylenoxide)-2-(2 - pyrimidinyl)pyrimidine, which is a starting material for the above compound was prepared as follows.

To 3.00 g of 4,6-dihydroxy-5-(4-methoxycarbonyl-2-propylenoxide)-2-(2-pyrimidinyl)pyrimidine was added 10 ml of phosphorus oxychloride and 1.2 ml collidine and the mixture was heated at the boil under reflux for 4 hours under stirring. The reaction solution was poured into ice water and was extracted with chloroform. The chloroform layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum and the crystals in the residue suspended in ether and collected by filtration receipt of 1.76 g of 4,6-dichloro-5-(4-methoxycarbonyl-2-propylenoxide)-2-(2-pyrimidinyl)pyrimidine.

Connection subsequent Reference examples was synthesized as in Reference example 1.

Reference example 4

N-[6-Chloro-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl] -2-phenylacetophenone

>Reference example 6

N-[6-Chloro-5-(2-methoxyphenoxy)-2-phenyl-4-pyrimidinyl] -2 - phenylacetophenone

Reference example 7

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(4-triptoreline)-4-pyrimidinyl] -2-phenylacetophenone

Reference example 8

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-nitrophenyl)-4-pyrimidinyl]-2-phenylacetophenone

Reference example 9

N-[6-Chloro-2-(3,5-acid)-5-(2-methoxyphenoxy)-4-pyrimidinyl] -2-phenylacetophenone

Reference example 10

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-methoxyphenyl)-4-pyrimidinyl]-2-phenylacetophenone

Reference example 11

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3,4-methylenedioxyphenyl)-4-pyrimidinyl] -2-phenylacetophenone

Reference example 12

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl] -2-phenylacetophenone

Reference example 13

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl] -2-phenylacetophenone

Reference example 14

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl] -2-phenylacetophenone

Reference example 15

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-pyridyl)-4-pyrimidinyl] -2-phenylacetophenone

Reference example 16

N-[6-Chloro-2-(6-chloro-3-pyridyl)-5-(2-methoxyphenoxy-3-pyridyl)-4-pyrimidinyl]-2-phenylacetophenone

Reference example 18

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-thienyl)-4-pyrimidinyl] -2-phenylacetophenone

Reference example 19

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-thienyl)-4-pyrimidinyl] -2-phenylacetophenone

Reference example 20

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-methyl-4-triazolyl)-4-pyrimidinyl] -2-phenylacetophenone

Reference example 21

N-[6-Chloro-2-(3-furyl-5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-phenylacetophenone

Reference example 22

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -1-methyl-2-phenylacetophenone

Reference example 23

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -1-ethyl-2-phenylacetophenone

Reference example 24

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-were)atenolole

Reference example 25

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-tert-butylphenyl)atenolole

Reference example 26

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-chlorophenyl)atenolole

Reference example 27

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2-thienyl)atenolole

Reference example 28

N-[6-Chloro-5-(2-Mr> N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-methoxyphenyl)atenolole

Reference example 30

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2-naphthyl)atenolole

Reference example 31

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(1-naphthyl)atenolole

Reference example 32

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2-chlorophenyl)atenolole

Reference example 33

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-ethoxycarbonylphenyl)atenolole

Reference example 34

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(3-thienyl)atenolole

Reference example 35

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(3-chlorophenyl)atenolole

Reference example 36

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenyl-1-propylaminosulfonyl

Reference example 37

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-methyl-2-phenylacetophenone

Reference example 38

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2-were)atenolole

Reference example 39
their examples

Example 1

Sodium (230 mg) was dissolved in 5.6 ml of etilenglikola and while cooling with ice and stirring was added to 495 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone. The reaction mixture was stirred at 80oC 3 hours and was poured into a mixture of 1 N. hydrochloric acid and ice. The crystals formed were collected by filtration, and the obtained crystals were purified column chromatography on silica gel (chloroform-methanol = 20:1) to obtain 500 mg of N-[6-(2-hydroxyethoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone.

To a methanol solution of 104 mg of the resulting derived sulfonamida was added 2 ml of 0.1 N. ethanol solution of KOH and then concentrated in vacuum. The resulting solid material suspended in ether and collected by filtration to obtain 84 mg of N-[6-(2-hydroxyethoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylalaninamide potassium.

Example 2

Sodium (181 mg) was dissolved in 10 ml of methanol and, at room temperature and stirring was added 400 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone. The reaction mixture was stirred at room temperature for 3 hours and wiliwili column chromatography on silica gel (chloroform-methanol = 40: 1). The resulting yellow amorphous substance was led from the ether and collected by filtration to obtain 273 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2 - phenylacetophenone.

Compounds of the following examples 3-6 were obtained as in Example 2.

Example 3

N-[6-Ethoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone

Example 4

N-[5-(2-Methoxyphenoxy)-6-propoxy-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone

Example 5

N-[6-Cyclopropylmethoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone

Example 6

N-[6-(2-Methoxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone

Example 7

Sodium (181 mg) was added to 10 ml of isopropyl alcohol, and after 1 hour was added 100 ml of isopropyl alcohol and then heated at 60oC to dissolve. To this reaction solution was added 400 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylethanolamine under stirring at room temperature. The reaction mixture was stirred at room temperature for 1.25 hours, then at 60oC 45 minutes and was poured into a mixture of 1 N. hydrochloric acid and ice. RA is. iltram was concentrated in vacuum and the obtained residue was purified column chromatography on silica gel (eluent ethyl acetate). The obtained amorphous substance was led from the ether and collected by filtration to obtain 57 mg of N-[6-isopropoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone.

Example 8

To a solution of 258 mg of ftramadol in 20 ml of dimethylformamide was added 194 mg of sodium hydride (60%) while cooling with ice and then stirred for 30 minutes. To this reaction solution under stirring and ice cooling was added 400 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone and stirred 30 minutes. The reaction mixture was stirred at room temperature for 2 hours and poured into a mixture of 1 N. hydrochloric acid and ice. This solution was extracted with chloroform, the chloroform layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum and the obtained residue was purified column chromatography on silica gel (chloroform-methanol = 40:1). The obtained amorphous substance was led from the ether and collected by filtration to obtain 240 mg of N-[6-(2-floratone-5-(2-methoxyphenoxy)-2- (2-pyrimidinyl)-4-pyrimidinyl] -2-BR>
N-[6-(2,2-Diflorasone)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone

Example 10

N-[5-(2-Methoxyphenoxy)-2-(2-pyrimidinyl)-6-(2,2,2-triptoreline)-4-pyrimidinyl]-2-phenylacetophenone

Example 11

Sodium (693 mg) was added to 18.2 ml aminoethanol and dissolved in it. To this reaction solution was added under stirring at room temperature 3.00 g of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone. The reaction mixture was stirred at 60oC 1 hour, and then 2 hours at 80oC and poured into a mixture of 1 N. hydrochloric acid and ice. The solution was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum and the obtained residue was purified column chromatography on silica gel (chloroform-methanol = 20:1). The obtained amorphous substance suspended in ether and collected by filtration receipt of 2.40 g of N-[6-(2-hydroxyethylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone.

Example 12

Sodium (1,031 g) was dissolved in 20,130 g of 1,3-propane diol and under stirring at room temperature the mixture was stirred at room temperature for 50 minutes, then 50 minutes at 60oC and poured into a mixture of 1 N. hydrochloric acid and ice. The solution was extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum and the obtained residue was purified column chromatography on silica gel (chloroform-methanol= 100:1 - 20:1). The resulting syrup was led from the ether and collected by filtration to obtain 1,817 g of N-[6-(3-hydroxypropoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone.

Example 13

Sodium (185 mg) was dissolved in 5 ml of 2-propyne-1-ol and to this reaction solution was added under stirring at room temperature 390 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone. The reaction mixture was stirred at 60oC for 1 hour and was poured into a mixture of 1 N. hydrochloric acid and ice. The solution was extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum and the obtained residue was purified column chromatography on silica gel (chloroform-methanol= 100:1 - 30:1). The resulting syrup was led from the ether and collected by filtration to obtain 342 mg of N-[6-(2-propenyloxy)-5-(2-marks tarali 7.7 ml of ethylene glycol and to this reaction solution was added with stirring to 700 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(3-were)Tinsulanonda. The reaction mixture was stirred at 90oC for 30 minutes and poured into a mixture of 1 N. hydrochloric acid and ice. The crystals formed were collected by filtration, and the obtained crystals were purified column chromatography on silica gel (chloroform-methanol = 20:1). The obtained amorphous substance was led from the ether and collected by filtration to obtain 533 mg of N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(3-were)Tinsulanonda.

Example 15

(a) To 508 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone was added 10.3 ml 0.1 M ethanol solution of potassium hydroxide and then stirred overnight. The crystals formed were collected by filtration and recrystallized from a mixture of ethanol-water to obtain 330 mg of N-[6-methoxy-5-(2-methoxyphenoxy) -2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylalaninamide potassium.

(b) To 1.00 g of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2 - pyrimidinyl)-4-pyrimidinyl]-2-phenylethanolamine was added 10 ml of a mixture of ethanol-water (4:1) and 110 mg of sodium methoxide was heated at the boil under reflux. To this mixture was added 18 ml of a mixture of ethanol-water (4:1) to ensure that the crystals were completely dissolved. The mixture filtragem. The crystals were washed with a mixture of ethanol-water (4:1) to give 80 mg of the monohydrate of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenyl)idealhumidity sodium.

Example 16

Sodium (356 mg) was dissolved in 20 ml of methanol and to this reaction solution was added under stirring at room temperature to 900 mg of N-[6-chloro-5-(4-methoxycarbonyl)-2 - propylenoxide-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone. The reaction mixture was stirred at room temperature for 5 hours and 40 minutes, 1 hour and 50 minutes at 60oC and at room temperature over night. Then the reaction mixture was poured into a mixture of 1 N. hydrochloric acid and ice. The crystals formed were collected by filtration and was purified column chromatography on silica gel (chloroform-ethanol = 20:1). The obtained amorphous substance was led from the ether and collected by filtration to obtain 452 mg of N-[6-methoxy-5-(4-methoxycarbonyl-2-propylenoxide)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone.

Example 17

The sodium methoxide (336 mg) was added to a solution of 320 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl] -2 - phenylacetophenone in 10 ml of N, N-dimethylformamide and stirred over night. The reaction mixture howled the Rial was purified column chromatography on silica gel (chloroform) and the oil obtained was led from the ether and was obtained 210 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]-2-phenylacetophenone.

Compounds of the following Examples 18-25 received in the same way as in Example 17, except that, if necessary, the reaction was carried out at room temperature or at 110oC. Connection forming a salt, was synthesized salt-forming reaction as in Example 15.

Example 18

N-[2-Cyclopropyl-6-methoxy-5-(2-methoxyphenoxy)-4-pyrimidinyl] -2-phenylethanolamine potassium

Example 19

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-phenyl-4-pyrimidinyl] -2-phenylacetophenone

Example 20

N-[6-Methoxy-5-(2 - methoxyphenoxy)-2-(4-triptoreline)-4-pyrimidinyl]-2-phenylacetophenone

Example 21

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-nitrophenyl)-4-pyrimidinyl] -2-phenylacetophenone

Example 22

N-[2-(3,5-Acid)-6-methoxy-5-(2-methoxyphenoxy)-4-pyrimidinyl] -2-phenylacetophenone

Example 23

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-methoxyphenyl)-4-pyrimidinyl] -2-phenylacetophenone

Example 24

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3,4-methylenedioxyphenyl)-4-pyrimidinyl]-2-phenylacetophenone

Example 25

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]-2-phenylacetophenone

Compounds of the following Examples 26 and 27 were obtained as in Example 2.
Example 27

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl] -2-phenylacetophenone

Compounds of the following Examples 28 and 29 were obtained as in Example 17, except that, if necessary, the reaction was carried out at room temperature or at 110oC.

Example 28

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-pyridyl)-4-pyrimidinyl] -2-phenylacetophenone

Example 29

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(6-methoxy-3-pyridyl)-4-pyrimidinyl] -2-phenylacetophenone

Example 30

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(6-trifluoromethyl-3-pyridyl)-4-pyrimidinyl]-2-phenylacetophenone was obtained as in Example 2.

Compounds of the following Examples 31-34 received in the same way as in Example 17, except that the reaction was carried out at room temperature or at 110oC.

Example 31

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-thienyl)-4-pyrimidinyl]-2-phenylacetophenone

Example 32

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-thienyl)-4-pyrimidinyl]-2-phenylacetophenone

Example 33

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-methyl-4-triazolyl)-4-pyrimidinyl] -2-phenylacetophenone

Example 34

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-furyl)-4-pyrimidinyl] -2-phenylen] -2-phenylacetophenone received as well as in Example 13.

Example 36

N-[6-(2-Hydroxyethoxy-5-(2-methoxyphenoxy)-2-(6-trifluoromethyl-3-pyridyl)-4-pyrimidinyl]-2-phenylacetophenone was obtained as in Example 1.

Compounds of the following Examples 37-42 was obtained as in Example 17, except that, if necessary, the reaction was carried out at room temperature or at 110oC. Connection forming a salt, was synthesized salt-forming reaction as in Example 15.

Example 37

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2 - pyrimidinyl)-4-pyrimidinyl]-1-methyl-2-phenylacetophenone.

Example 38

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -1-ethyl-2-phenylethanolamine potassium

Example 39

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-were)atenolole

Example 40

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-tert-butylphenyl)Tinsulanonda potassium

Example 41

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-chlorophenyl)atenolole

Example 42

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2-thienyl)atenolole

Compounds of the following Examples 43-48 received so tx2">

Example 43

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-tryptophanyl)Tinsulanonda potassium

Example 44

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-methoxyphenyl)atenolole

Example 45

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2-naphthyl)atenolole

Example 46

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4 - pyrimidinyl]-2-(1-naphthyl)atenolole

Example 47

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2-chlorophenyl)atenolole

Example 48

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-carboxyphenyl)atenolole

Example 49

Concentrated sulfuric acid (0.1 ml) was added to a solution of 150 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(4-carboxyphenyl)Tinsulanonda in 10 ml of methanol and was stirred over night while boiling under reflux. The reaction mixture was concentrated under vacuum, was added 1 N. hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and obrazu)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-ethoxycarbonylphenyl)Tinsulanonda.

Compounds of the following Examples 50 and 51 was obtained as in Example 2.

Example 50

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(3-thienyl)atenolole

Example 51

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(3-chlorophenyl)atenolole

Example 52

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenyl-1-propylaminosulfonyl potassium was obtained as in Example 17 and Example 15(a).

Compounds of the following Examples 53-55 was obtained as in Example 2.

Example 53

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-methyl-2-phenylacetophenone

Example 54

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2-were)atenolole

Example 55

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2,4,6-trimetilfenil)atenolole

Structural formulas and physical-chemical properties of the above compounds of reference Examples are shown in Tables 3 and 4, and the structural formulas and physical-chemical properties of the compounds of the working Examples in Tables 5-8.

Abbreviations used in the tables have the following meanings.

Ref: config magnetic resonance (DMSO-d6, TMS internal standard, unless otherwise specified) :

ana: the data of elemental analysis

tho: theoretical value

fou: found

m/z: mass spectroscopy (m/z)

N. P.: used in the next stage without purification

Ph: phenyl

Pmy: pyrimidinyl

cPr: cyclopropyl

nPr: n-propyl

The: Teenel

Naph: naphthyl

tBu: tert-butyl

Py: pyridyl

Thi: thiazolyl

Fur: furyl

triMeO: trimethoxypropane,

diMeO: dimethoxypropane

triMe: trimethyl

FAB: fast atom bombardment

Indicate in NMR spectra in tables 3-8: s - singlet, d - d, doublet, t - t, triplet, m - m, multiplet, brs - CL. broad singlet, brd - sm, broad doublet, dd = DD, doublet of doublets, dt - dt, doublet of triplets.

Compounds, chemical structural formulas of which are given in table 9, can be easily obtained almost the same methods that are described in the Examples or the Methods of Obtaining the above, or some of their modifications which are obvious to experts in the given field of technology.

Abbreviations in table 9 are the same values that have already been specified. The column "Co" in table 9 indicates the connection number.

An example of the composition is given at the end of oformula I

< / BR>
where Ar is phenyl which may be substituted by 1-3 substituents selected from the group: halogen, lower alkyl, possibly substituted by 1-3 substituents selected from halogen; lower alkoxy, lower alkoxycarbonyl, carboxypropyl, cyano; naphthyl, 5-, 6-membered heteroaryl selected from the group thienyl, furyl, thiazolyl, pyridyl, pyrimidyl;

X is an oxygen atom, sulfur or the group-NH-;

Y is an oxygen atom;

R1-a lower alkyl which may be substituted by halogen atoms, cycloalkyl, phenyl which may be substituted by 1-3 substituents selected from lower alkyl, possibly substituted by 1-3 halogen atoms, lower alkoxyl, nitro, C1-C3-alkylenedioxy, 5-, 6-membered heterocycle selected from the group of pyridyl, pyrimidyl, thiazolyl, furil, teinila, each of which may be substituted by lower alkyl, possibly substituted by 1-3 halogen atoms, lower alkoxyl;

R2-lower alkyl, lower quinil, each of which may be substituted by 1-3 groups selected from the group consisting of hydroxy-group, the lower alkoxygroup, halogen, cycloalkyl,

R3is phenyl which may be substituted by 1-4 substituents selected from the group consisting of lower alkyl, mean hydrogen, lower alkyl,

or their pharmaceutically acceptable salt.

2. Connection on p. 1, which is chosen from the group comprising the following compounds and their salts:

N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone,

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-phenylacetophenone,

N-[6-(2-floratone)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone,

N-[6-(2-propenyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylacetophenone,

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -1-methyl-2-phenylacetophenone,

N-6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -1-ethyl-2-phenylacetophenone,

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] -2-(2-thienyl) tinsulanond.

3. Pharmaceutical composition having the properties of endothelin antagonist, including arylethanolamine derivative or its pharmaceutically acceptable salt p. 1 and a pharmaceutically acceptable carrier.

 

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