Substituted acrylamide derivative and pharmaceutical composition based on said derivative

FIELD: chemistry.

SUBSTANCE: in formula (I') , R5 is any group selected from a group comprising C1-C6 alkoxy group, which can be substituted with one group selected from a group of β substitutes, phenyloxy group which can be substituted with one group selected from a group of γ substitutes, C1-C6 halogenalkoxy group and C3-C6 cycloalkyloxy group; R6 is a substitute in a benzene ring which is selected from a group of α substitutes; R7 is a hydrogen atom, C1-C6 halogenalkyl group, C1-C6 hydroxyalkyl group which can be substituted with a hydroxy-protective group, C1-C6 alkyl group which can be substituted with one group selected from a group of β substitutes, or a phenyl group which can be substituted with one hydroxy group; m equals 1; n equals 1 or 2; numbers in each benzene ring denote the number of the position of each substitute; the group of substitutes includes hydroxyl groups, nitro groups, cyano groups, C1-C6 dialkylamino groups, acetamide groups, halogen atoms, C1-C6 alkyl groups, which can be substituted with one group selected from a group of β substitutes, C1-C6 halogen alkyl groups, C3-C10 cycloalkyl groups, 6-member heterocyclic groups with an N atom or O atom as a heteroatom, C3-C6 cycloalkenyl groups, phenyl group which can be substituted with one group selected from a group of γ substitutes, 5-6-member heteroaryl groups with 1-3 N atoms as heteroatoms which can be substituted wit one or more groups selected from a group of γ substitutes, C1-C6 alkoxy groups, C1-C6 halogenalkoxy groups, C3-C10 cycloalkoxy groups, phenyloxy group, C1-C6 alkylthio groups, C1-C6 halogenalkylthio groups, C1-C6 alkylsulphonyl groups and C1-C6 alkylcarbonyl groups; the group of β substitutes includes C1-C6 alkoxycarbonyl groups, C3-C10 cycloalkyl groups which can be substituted with one group selected from a group of γ substitutes, C3-C6 cycloalkenyl groups, C6-C10 aryl groups which can be substituted with one or more groups selected from a group of γ substitutes, 5-6-member heteroaryl groups with one N, O or S heteroatom, 9-member heteroaryl groups with two heteroatoms selected from N and S, C1-C6 alkoxy group and C6-C10 aryloxy group; and the group of γ substitutes include cyano groups, C1-C6 dialkylamino groups, C1-C6 cyclic amino groups, halogen atoms, C1-C6 alkyl groups, C3-C10 cycloalkyl grous, C1-C6 halogenalkyl groups, C1-C6 alkoxy groups and C1-C6 alkylenedioxy groups. The invention also relates to compounds or pharmaceutically acceptable salts thereof, selected from: 4-(2-cyclopropylethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}-vinyl)-benzamide. Other compounds are given in the formula of invention. The invention also relates to a pharmaceutical composition which can inhibit bone resorption, which contains the disclosed compound, to use of the disclosed compound as a medicinal agent for inhibiting bone resorption, for preparing a medicinal agent for lowering concentration of calcium in the blood, for preparing a medicinal agent for inhibiting reduction of bone mass, to a medicinal agent for inhibiting bone resorption in form of the disclosed compound, to a method of inhibiting bone resorption, a method of lowering concentration of calcium in the blood, a method of inhibiting reduction of bond mass, involving addition of an effective amount of the disclosed compound.

EFFECT: more effective use of the compounds.

22 cl, 6 tbl, 116 ex

 

The technical field

The present invention relates to amide derivatives or their pharmaceutically acceptable salts which are useful as a drug with high activity against osteoporosis, anti-inflammatory activity, activity against rheumatoid arthritis and activity against hypercalcemia, etc.

The level of technology

Previously, compounds represented by following formula (a) disclosed in the documents listed below.

Patent document 1 discloses compounds, for example, presented below, which, as has been demonstrated, are useful as antiviral agents.

Patent document 2 discloses compounds, for example, presented below, which, as has been demonstrated, are useful as therapeutic agents for the treatment of Alzheimer's disease.

ExampleL1The position of substitution of the double bond
14-forfinalE
2+4-forfinalZ
32,4-differenlE
42,4-differenlZ
53-chlorophenylE
63-chlorophenylZ
72-chlorophenylE
82-chlorophenylZ
94-methoxyphenylE
104-methoxyphenylZ

Patent document 3 discloses compounds, for example, presented below, describes the method of synthesis Rev-suppressing compounds and a method of screening for such compounds.

cyclohexyl
ABC
2,4-dichlorophenylphenyl
2-naphthylα,α,α-Cryptor-m-toluyl1,2,3,4-tetrahydronaphtyl-1-yl
2-naphthylα,α,α-Cryptor-m-toluyldiphenylmethyl
2,4-dichlorophenylα,α,α-Cryptor-m-toluyldiphenylmethyl
2-naphthylα,α,α-Cryptor-m-toluyl2-(p-toluyl)ethyl
2-naphthylα,α,α-Cryptor-p-toluyldiphenylmethyl
p-toluyl2,4-differenl2-hydroxyphenethyl
2-naphthyl3-genolini(1-naphthyl)methyl
2-naphthylα,α,α-Cryptor-p-toluyl4-phenylbut-2-yl
2,4-dichlorophenyl4-biphenylyldiphenylmethyl

Patent document 4 discloses compounds, for example, presented below, which, as has been demonstrated, are useful in ka is este anti-hypertensive funds.

However, none of the above Patent documents 1 to 4 does not specify the activity in respect of metabolic bone disease and inflammation, and therefore indications for use of such compounds is quite different from the compounds of the present invention. In addition, for compounds below were known only patterns and their application were not known.

Typically, under normal bone metabolism bone resorption under the action of osteoclasts balanced by osteoarthritis by osteoblasts to maintain homeostasis. It is believed that the metabolic bone diseases occur when the balance between bone resorption and osteogenesis is broken. Bones retain about 99% of the total amount of calcium in vivo and play an important role in the maintenance of a constant concentration of calcium in the blood by osteoarthri and bone resorption. If there is an abnormal formation or activation of osteoclasts, which are primarily responsible for bone resorption, bone resorption is accelerated, increasing the concentration of calcium in the blood, and thus, there are metabolic bone diseases, such as hypercalcemia.

It is known that the metastases Kostya is in cancer cause abnormal secretion of cytokines, leading to the development of hypercalcemia. In this process, bone resorption under the action of osteoclasts is accelerated, thus, the concentration of calcium in the blood (non-Patent document 1). Predictions for cancer patients with cancer hypercalcemia, usually bad.

Moreover, it is known that in rheumatoid arthritis, osteoarthritis and other abnormal formation or activation of osteoclasts is one of the main causes of various symptoms in the bones and joints (non-Patent document 2). Patients with rheumatoid arthritis, osteoarthritis and the like, suffer from severe pain that makes a significant shortcomings in the lives of patients.

In addition, when the balance between bone resorption and osteogenesis steadily inclined in the direction of bone resorption by reducing the secretion of female hormones after menopause or due to aging, bone density decreases and osteoporosis. In this case, the osteoclasts are responsible for bone resorption.

When older patients with a high risk of osteoporosis fractures, the high possibility that they will be bedridden, what is a social problem (non-Patent document 3).

Usually under such conditions diseases held hormone replacement therapy with estrogen or the like, or the input is whether a therapeutic tool, such as a bisphosphonate or calcitonin to inhibit the activity of osteoclasts (non-Patent document 4). However, none of these existing tools is not satisfactory for significant hypercalcemia or metabolic bone disease, and, therefore, it is necessary to develop tools with high therapeutic efficacy.

[Patent document 1]

International publication number WO 2004/002977

[Patent document 2]

International publication number WO 00/24392

[Patent document 3]

Japanese Publication of International Patent Application No. 2001-506965

[Patent document 4]

Patent of great Britain No. 1113569

[Non-patent document 1]

Jean-Jacques Body, CANCER Supplement, vol. 88, p. 3054 (2000)

[Non-patent document 2]

E. Romas, et al., Bone, vol. 30, p. 340 (2002)

[Non-patent document 3]

Bruno Fautrel, et al., Current Opinion in Rheumatology, vol. 14, p. 121 (2002)

[Non-patent document 4]

Mohammad M. Iqbal, et al., Missouri Medicine, vol. 99, p. 19 (2002)

Disclosure of invention

The problems solved by the present invention

The purpose of this invention is the provision of medicines, which are excellent tools for improvement, prevention or treatment of osteoporosis, inflammation, rheumatoid arthritis, hypercalcemia, etc.

Means of solving problems

The authors of the present invention conducted the in-depth research of medicines, having a high activity, decrease in the concentration of calcium in the blood and suppressive activity against reduction of bone mass, and it was found that the medicinal product comprising the compound of formula (I) according to the present invention (hereinafter indicated as the compound of the present invention, have low toxicity, excellent suppressive activity against bone resorption activity, decrease in the concentration of calcium in the blood and suppressive activity against the decrease in bone mass associated with it, and are useful for prevention or treatment of metabolic bone diseases such as osteoporosis, hypercalcemia, metastatic bone cancer, periodontal disease, deforming ostos and osteoarthritis. Thus was created the present invention. The present invention is described below.

The present invention includes

(1) a pharmaceutical composition for suppression of bone resorption, comprising a compound of formula (I) or its pharmacologically acceptable salt as an active ingredient:

[where R1represents a C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents α, or 5-10-membered heteroaryl group which may be substituted by one the or more groups, selected from the group of substituents α;

R2represents a C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents α, 5-10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents α, or a 3-6-membered heterocyclic group which may be substituted by one or more groups selected from the group of substituents α; and

X represents a hydroxyl group, With1-C6alkoxygroup,1-C6alkoxygroup, which is substituted by a hydroxyl group, or a group of formula N(R3R4(where R3represents a hydrogen atom, a C1-C6halogenating group1-C6hydroxyalkyl group which may be protected hydroxyamino group1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, C1-C6alkoxygroup, which may be substituted by a hydroxyl group, With3-C10cycloalkyl group which may be substituted by one or more groups selected from the group of substituents α, C6-C10aryl group which may be substituted by one or more groups, who swear from the group of substituents α, or 5-10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents α, and R4represents a hydrogen atom or a C1-C6alkyl group; or R3and R4together with the nitrogen atom associated with R3and R4form a 3-6-membered heterocyclic group which may be substituted by one or more groups selected from the group of substituents β), and

the group of substituents α represents a group containing a hydroxyl group, a nitro group, ceanography, amino, C1-C6alkylamino, C1-C6dialkylamino, C3-C6cycloalkylation, acetamidoxime, halogen atoms, C1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenoalkane group, C3-C10cycloalkyl group, 3-6 membered heterocyclic group, a C3-C6cycloalkenyl group, C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents γ, 5-10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents γ, C1-C6alkoxygroup,which may be substituted by one or more groups, selected from the group of substituents β, C1-C6halogenlampe, C1-C6alkoxy, C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C1-C6alkenylacyl, which may be substituted by one or more groups selected from the group of substituents β, C1-C6alkenylacyl, which may be substituted by one or more groups selected from the group of substituents β, C3-C10cycloalkylcarbonyl, 3-6-membered geterotsiklicheskikh, C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ, C1-C6accelerometry, C1-C6alkylenedioxy, C1-C6allylthiourea, which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenation, C1-C6alkylsulfonyl group which may be substituted by one or more groups selected from the group of substituents β, C1-C6galogenzameshchennye group, C1-C6acylcarnitine group which may be substituted by one or more groups selected from the group of substituents β, C1-C6g is loyaltyonline group and C 6-C10arylcarbamoyl group which may be substituted by one or more groups selected from the group of substituents γ;

the group of substituents β represents a group containing a hydroxyl group, a carboxyl group, a C1-C6alkoxycarbonyl group, carbamoyl group, ceanography, amino, acetamidoxime, N-C6-C10arylacetamides, C1-C6alkoxycarbonylmethyl, urea group, a C3-C10cycloalkyl group which may be substituted by one or more groups selected from the group of substituents γ, C3-C6cycloalkenyl group, 3-6 membered heterocyclic group, a C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents γ, 5-10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents γ, C1-C6alkoxygroup, C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ, and C3-C10cycloalkylcarbonyl; and

the group of substituents γ represents a group containing a hydroxyl group, ceanography, amino, C1-C6alkylamino, C1 6dialkylamino, C2-C6cyclic amino groups, halogen atoms, C1-C6alkyl group, a C3-C10cycloalkyl group, C1-C6halogenoalkane group, C1-C6alkoxygroup, C3-C10cycloalkylcarbonyl, C1-C6alkylenedioxy and phenyl group].

Preferred compositions as above compositions are the following:

(2) the composition according to the above item (1), where R1represents a phenyl group which may be substituted by one or more groups selected from the group of substituents α, or pyridyloxy group which may be substituted by one or more groups selected from the group of substituents α;

(3) the composition according to the above item (1), where R1represents a phenyl group which may be substituted by one or more groups selected from the group of substituents α;

(4) the composition according to the above item (1), where R1represents a phenyl group substituted with any group selected from the group comprising C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C6-C10alloctype, which can be substituted one or nekolkupati, selected from the group of substituents γ, and C1-C6halogenlampe;

(5) the composition according to the above item (1), where R1is a 4-isobutylphenyl group, 4-(cyclopropylmethoxy)phenyl group, 4-(2-cyclopropylmethoxy)phenyl group, 4-(1-methylcyclopropyl)phenyl group, 4-(3,3,3-triplications)phenyl group, 4-(4,4,4-triptoreline)phenyl group, 4-(2-phenylethane)phenyl group, 4-(2-(4-methoxyphenyl)ethoxy)phenyl group, 4-(2-(3-methoxyphenyl)ethoxy)phenyl group, 4-(2-(4-chlorophenyl)ethoxy)phenyl group, 4-(2-(4-(N,N-dimethylamino)phenyl)ethoxy)phenyl group, 4-(4-chlorophenoxy)phenyl group or 4-(4-triptoreline)phenyl group;

(6) the composition according to any one of the above items (1)to(5), where R2represents a C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents α;

(7) the composition according to any one of the above items (1)to(5), where R2represents a phenyl group which may be substituted by one or more groups selected from the group of substituents α;

(8) the composition according to any one of the above items (1)to(5), where R2represents a phenyl group substituted with any group selected from the group comprising halogen atoms, C1 -C6alkyl group, a C1-C6halogenoalkane group, C3-C6cycloalkyl group, C1-C6alkoxygroup, C3-C6cycloalkylcarbonyl, C1-C6halogenlampe, C1-C6ancilliary and 5-10-membered heteroaryl group;

(9) the composition according to any one of the above items (1)to(5), where R2is a 4-florfenicol group, 4-chloraniline group, 4-triftormetilfullerenov group, 4-isopropylphenyl group, 4-cyclopropylamino group, 4-isopropoxyphenyl group, 4-deformationally group, 4-triphtalocyaninine group, 4-(2,2,2-triptoreline)phenyl group, 4-(2,2-diflorasone)phenyl group, 4-cyclopropylacetylene group, 4-ethoxyphenyl group, 4-methylthiophenyl group or 4-(1H-pyrrol-1-yl)phenyl group;

(10) the composition according to any one of the above items (1)to(9), where X represents a group of formula N(R3R4(where R3represents a C1-C6halogenating group1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, or C1-C6hydroxyalkyl group which may be protected hydroxyamino group, and R4represents a hydrogen atom);

(11) composers who s on any of the above items (1)to(9), where X represents a group of formula N(R3R4(where R3represents a C2-C3halogenating group2-C3hydroxyalkyl group which may be protected hydroxyamino group, or With1-C3alkyl group, a substituted 1-hydroxyisopropyl group, and R4represents a hydrogen atom);

(12) the composition according to any one of items (1)to(9), where X is a 2-foretelling, 2,2-diferentiating, 2-hydroxyethylamino, 1-(2-hydroxypropyl)amino group, 1-hydroxycyclophosphamide, 2-acetoxyethylamine, 2-(morpholine-4-RECETOX)ethylamino or 2-(3-carboxyphenoxy)ethylamino; and

(13) the composition according to any one of the above items (1)to(12), where the chemical structure in relation to the position acrylamide group in the formula (I) represents Z.

In addition, the present invention includes

(14) the compound of the formula (I') or its pharmacologically acceptable salt:

[where R5and R6each independently represents a substituent in the benzene ring, which is selected from the group of substituents α;

R7represents a hydrogen atom, a C1-C6halogenating group1-C6hydroxyalkyl group which may be asimina hydroxyamino group, With1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents α, or C3-C10cycloalkyl group which may be substituted by one or more groups selected from the group of substituents α;

m is an integer having a value of from 1 to 3;

n is an integer having a value of from 1 to 3;

the numbers in each benzene ring indicate the position number of each substituent;

the group of substituents α represents a group containing a hydroxyl group, a nitro group, ceanography, amino, C1-C6alkylamino, C1-C6dialkylamino, C3-C6cycloalkylation, acetamidoxime, halogen atoms, C1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenoalkane group, C3-C10cycloalkyl group, 3-6 membered heterocyclic group, a C3-C6cycloalkenyl group, C6-C10aryl group which may be substituted by one or more groups selected from the group for whom estately γ, 5-10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents γ, C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenlampe, C1-C6alkoxy, C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C1-C6alkenylacyl, which may be substituted by one or more groups selected from the group of substituents β, C1-C6alkenylacyl, which may be substituted by one or more groups selected from the group of substituents β, C3-C10cycloalkylcarbonyl, 3-6-membered geterotsiklicheskikh, C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ, C1-C6accelerometry, C1-C6alkylenedioxy, C1-C6allylthiourea, which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenation, C1-C6alkylsulfonyl group which may be substituted by one or more groups selected from the group Zam is stitely β, C1-C6galogenzameshchennye group, C1-C6acylcarnitine group which may be substituted by one or more groups selected from the group of substituents β, C1-C6galogenirovannyie group and C6-C10arylcarbamoyl group which may be substituted by one or more groups selected from the group of substituents γ;

the group of substituents β represents a group containing a hydroxyl group, a carboxyl group, a C1-C6alkoxycarbonyl group, carbamoyl group, ceanography, amino, acetamidoxime, N-C6-C10arylacetamides, C1-C6alkoxycarbonylmethyl, urea group, a C3-C10cycloalkyl group which may be substituted by one or more groups selected from the group of substituents γ, C3-C6cycloalkenyl group, 3-6 membered heterocyclic group, a C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents γ, 5-10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents γ, C1-C6alkoxygroup, C6-C10alloctype, which can be substituted one or several and groups selected from the group of substituents γ, and C3-C10cycloalkylcarbonyl; and

the group of substituents γ represents a group containing a hydroxyl group, ceanography, amino, C1-C6alkylamino, C1-C6dialkylamino, C2-C6cyclic amino groups, halogen atoms, C1-C6alkyl group, a C3-C10cycloalkyl group, C1-C6halogenoalkane group, C1-C6alkoxygroup, C3-C10cycloalkylcarbonyl, C1-C6alkylenedioxy and phenyl groups]where the compounds of formula (I') are the following compounds:

The above compound or its pharmacologically acceptable salt, preferably, are:

(15) the compound or its pharmacologically acceptable salt according to the above item (14), where R5represents any group selected from the group comprising halogen atoms, C1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenoalkane group, C3-C6cycloalkyl group, C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group replace what she β, C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ, C1-C6halogenlampe and C3-C6cycloalkylcarbonyl;

(16) the compound or its pharmacologically acceptable salt according to the above item (14), where R5represents any group selected from the group comprising C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ, and C1-C6halogenlampe;

(17) the compound or its pharmacologically acceptable salt according to the above item (14), where R5is isobutylacetate, cyclopropylmethoxy, 2-cyclopropylethyl, 1-methylcyclopropene, 3,3,3-cryptocomplexity, 4,4,4-cryptosporiosis, 2-venlafaxinum, 2-(4-methoxyphenyl)ethoxypropan, 2-(3-methoxyphenyl)ethoxypropan, 2-(4-chlorophenyl)ethoxypropan, 2-(4-(N,N-dimethylamino)phenyl)ethoxypropan, 4-chlorphenoxy or 4-triftormetilfosfinov;

(18) the compound or its pharmacologically acceptable salt according to any one of the above items (14)to(17), where R6represents ubuu group, selected from the group comprising halogen atoms, C1-C6alkyl group, a C1-C6halogenoalkane group, C3-C6cycloalkyl group, C1-C6alkoxygroup, C3-C6cycloalkylcarbonyl, C1-C6halogenlampe, C1-C6ancilliary and 5-10-membered heteroaryl group;

(19) the compound or its pharmacologically acceptable salt according to any one of the above items (14)to(17), where R6represents a fluorine atom, a chlorine atom, triptorelin group, isopropyl group, cyclopropyl group, isopropylamino, dipterocarp, cryptometer, 2,2,2-triptracker, 2,2-dipterocarp, cyclopropylamino, ethoxypropan, metalcorp or 1H-pyrrol-1-ilen group;

(20) the compound or its pharmacologically acceptable salt according to any one of the above items (14)to(17), where R6is ethoxypropan, triptorelin group, cyclopropyl group, cyclopropylamino, dipterocarp, cryptometer or 2,2-dipterocarp;

(21) the compound or its pharmacologically acceptable salt according to any one of the above items (14)to(20), where R7represents a C1-C6halogenating group1-C6alkyl group which may be substituted by the one or more groups, selected from the group of substituents β, or C1-C6hydroxyalkyl group which may be protected hydroxyamino group;

(22) the compound or its pharmacologically acceptable salt according to any one of the above items (14)to(20), where R7represents a C2-C3halogenating group2-C3hydroxyalkyl group which may be protected hydroxyamino group, or With1-C3alkyl group, a substituted 1-hydroxyisopropyl group;

(23) the compound or its pharmacologically acceptable salt according to any one of the above items (14)to(20), where R7is a 2-foretelling group, 2,2-deperately group, 2-hydroxyethylene group, 2-hydroxypropyl group, 1-hydroxyisopropyl group, 2-acetoxyethyl group, 2-(morpholine-4-RECETOX)ethyl group, or 2-(3-carboxyphenoxy)ethyl group;

(24) the compound or its pharmacologically acceptable salt according to any one of the above items (14)to(23), where m and n each represents 1;

(25) the compound or its pharmacologically acceptable salt according to the above item (24), where R5is a substituent in the 4-position of the benzene ring in the formula (I') and R6is a substituent in the 4'-position of the benzene ring in the formula (I'); and

(26) the compound or E. what about the pharmacologically acceptable salt, where the compound is selected from the following groups:

4-(2-cyclopropylmethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-(2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-(2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

4-(2-cyclopropylmethoxy)-N-(2-[4-(2,2-diflorasone)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

2-{[(2Z)-2-{[4-(2-cyclopropylmethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}acetic acid ethyl ester

2-{[(2Z)-2-{[4-(2-cyclopropylmethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}ethylsuccinate,

4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,

4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}benzamide,

N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylmethoxy)benzamide,

N-[1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

N-(2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4[2-(4-methoxyphenyl)ethoxy]benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide,

4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)be same,

4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(4,4,4-triptoreline)benzamid,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(4,4,4-triptoreline)benzamid,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-{1-{[(2,2-dottorati)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-{1-({[(2S)-2-hydroxypropyl]amino}carbonyl)-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-(2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[4-(trifluoromethyl)phenoxy]benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide,

4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide and

4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}is ansamed; and

(27) the compound or its pharmacologically acceptable salt according to any one of the above items (14)to(26), where the chemical structure in relation to the position acrylamide group represents Z.

In addition, the present invention provides

(28) a pharmaceutical composition comprising one or more compounds or their pharmacologically acceptable salt according to any one of the above items (14)to(27) as an active ingredient;

(29) the composition according to the above item (28), which is a tool of suppression of bone resorption;

(30) the composition according to any one of the above items(1)-(13), (28) and (29), where the composition is used to reduce the concentration of calcium in the blood; and

(31) the composition according to any one of the above items(1)-(13), (28) and (29), where the composition is used to suppress the decrease in bone mass.

In addition, the present invention provides

(32) the composition according to any one of the above items(1)-(13), (28) and (29), where the composition is used for the improvement of bone metabolism;

(33) the composition according to any one of the above items(1)-(13), (28) and (29), where the composition is used for preventing or treating metabolic bone disease;

(34) the composition according to the above item (33), where metabolic bone disease is a osteoporosis;

(35) composers who, s in the above item (33), where metabolic bone disease is a risk; and

(36) the composition according to any one of the above items(1)-(13), (28) and (29), where the composition is used for the suppression of metastases in the bones in cancer.

In addition, the present invention provides

(37) a method for improving bone metabolism, where the mammal is administered an effective amount of a composition according to any one of the above items(1)-(13), (28) and (29);

(38) a method of preventing or treating metabolic bone disease where the mammal is administered an effective amount of a composition according to any one of the above items(1)-(13), (28) and (29);

(39) a method of prevention or treatment of osteoporosis, where the mammal is administered an effective amount of a composition according to any one of the above items(1)-(13), (28) and (29);

(40) a means of suppression of bone resorption, where the tool significantly reduces the concentration of calcium in the serum of a mammal, which enter the tool; and

(41) a means of suppression of bone resorption in the above item (40), where the dose of the tools used as the active ingredient is from about 0.001 mg/kg to 100 mg/kg

Determine the preferred groups, etc.

Regarding the group of substituents α, preferred substituents are included in the group comprising halogen atoms, C1-C 6alkyl group which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenoalkane group, C3-C10cycloalkyl group, 5-10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents γ, C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenlampe, C3-C10cycloalkylation and C1-C6allylthiourea, which may be substituted by one or more groups selected from the group of substituents β.

Regarding the group of substituents β, preferred substituents are in the group, including C3-C10cycloalkyl group which may be substituted by one or more groups selected from the group of substituents γ, C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents γ, 5-10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents γ, and C6-C10alloctype, which may be substituted by one or more groups selected from the group Deputy is γ.

Regarding the group of substituents γ, preferred substituents are a group that contains a hydroxyl group, ceanography, C1-C6dialkylamino, halogen atoms, C1-C6alkyl group, a C1-C6halogenoalkane group, C3-C10cycloalkyl group, C1-C6alkoxygroup, C1-C6alkylenedioxy and C3-C10cycloalkylation.

Of the compounds of formula (I) compounds of formula (I') are preferred. Of the compounds of formula (I) compounds in which each of m and n is 1 are preferred. Compounds in which R5represents the substituent in 4-position and R6represents the substituent in the 4'-position, are preferred.

C6-C10aryl group in "C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents α" in the above definitions of R1, R2, R3and R7and "C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents γ" in the definition of the groups of substituents α and β, can be condensed with other cyclic groups. Examples of such C6-C10aryl groups include f is nalinie group, Ingenierie group, indanamine group, raftiline group and chromaline groups and phenyl groups are preferred.

The term "may be substituted" in the above "C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents α"preferably means substitution of one or two groups, and the term "may be substituted" in the "C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents γ"preferably means no substitution or replacement of one group.

5-10-membered heteroaryl group "5-10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents α" in the definition of R1, R2and R3and 5-10-membered heteroaryl group "5-10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents γ" in the definition of the groups of substituents α and β denote the cyclic group containing from 3 to 6 carbon atoms, a nitrogen atom, an oxygen atom and/or sulfur atom. Examples 5-10-membered heteroaryl groups include foreline group, thienyl group, pyrrolidine group, pyrazolidine group, imidazo the ilen group, oxazolidine group, isoxazolyl group, thiazolidine group, isothiazolinone group, triazolyl group, tetrazolyl group, perylene group, peredelnye group, pyridazinyl group, pyrimidinyl group and personilnya group. Of them 5 - or 6-membered heteroaryl group are preferred. The above "5-to 10-membered heteroaryl group" may be fused with another cyclic group, such as indlela group, benzofuranyl group, benzothiazoline group, kinolinna group, izochinolina group, chinadaily group, tetrahydroquinoline group or tetrahydroisoquinoline group. R1preferably represents pyridyloxy group, R2preferably represents pyridyloxy group, triazolyl group or pyrrolidinyl group, and R3preferably represents pyridyloxy group. From the group of substituents β benzothiazoline group, Peregrina group and pyrrolidine group are preferred.

The term "may be substituted" in the above "5-to 10-membered heteroaryl group which may be substituted by one or more groups selected from the group of substituents α"preferably means substitution of one or two groups, and the term "may be substituted" in the "5-to 10-membered g is tervailing group, which may be substituted by one or more groups selected from the group of substituents γ"preferably means no substitution or replacement of one group.

"3-6-membered heterocyclic group" in "3-6-membered heterocyclic group which may be substituted by one or more groups selected from the group of substituents α" in the definition of R2in "3-6-membered heterocyclic group which may be substituted by one or more groups selected from the group of substituents β" in the definition of R3and R7and in "3-6-membered heterocyclic group" in the definitions of groups of substituents α and β can represent, for example, azetidine group, pyrrolidinyl group, pyrrolidino group, imidazolidinyl group, imidazolidinyl group, pyrazolidine group, pyrazolidine group, oxazolidinyl group, diazolidinyl group, piperidino group, tetrahydropyranyloxy group, dihydropyridine group, piperazinilnom group, morpholinyl group, thiomorpholine group, homopiperazine group, tetrahydrofuryl group, tetrahydropyranyl group, 2,5-dioxopiperazinyl group and 2,6-dioxopiperazinyl group. In the group of substituents β pyrrolidinyl group, piperideine group, morpholinyl group and Tetra is hydroporinae group are preferred.

"3-6-membered heterocyclic group" in "3-6-membered heterocyclic group" in the definitions of groups of substituents α and β can be condensed with other cyclic groups, such as 1,3-dioxo-2,3-dihydro-1H-isoindolyl group or 2,4-dioxo-1,2,3,4-tetrahydroquinazoline group.

C1-C6alkoxygroup in "C1-C6alkoxygroup" in the definitions of X and groups of substituents β, and γ and C1-C6alkoxygroup, which may be substituted by a hydroxyl group or a C1-C6alkoxygroup, substituted hydroxyl group" in the definitions of R3and X and C1-C6alkoxygroup in "C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β" in the definition of the groups of substituents α can, for example, represent a linear or branched alkoxygroup containing 1-6 carbon atoms; and preferred are a methoxy group, ethoxypropan, propoxylate, isopropoxide, butoxypropan or isobutoxy.

The term "substituted" in the above "C1-C6alkoxygroup, substituted hydroxyl group" means the substitution of one to three groups and, preferably, substitution of one or two groups.

C1-C6alkyl groups in the above "C1-C6 alkyl group" in the definitions of R3, R4and groups of substituents γ and C1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β" in the definition of R3, R7and groups of substituents α can, for example, represent a linear or branched alkyl groups containing 1-6 carbon atoms; and the preferred are methyl group, ethyl group, through the group, isopropyl group or bucilina group.

The term "may be substituted" in the above "C1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β," preferably means substitution of one or two groups.

Examples of "hydroxyamino group" in the definitions of R3and R7include "aliphatic acyl group", for example alkylcarboxylic groups, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoic, 8-methylnonanoic, 3-ethyloctanoic, 3,7-dimethyloctane, undecanoyl, dodecanoyl, tridecanol, deletion, pentadecanol, hexadecanol, 1-methylpentanol, 14-methylpentadiene, 13,13-dimethylcarbamoyl, heptadecanoyl, 15-methylhexadecanoic, octadecanoyl, 1-meth is heptadecanoyl, nonadecanoic, eicosanoic, and heneicosanol; aminirovanie alkylcarboxylic groups that are above acylcarnitine group substituted by a substituted amino group, such as morpholine-4-ylacetic, piperidine-1-ylacetic and pyrrolidin-1-ylacetic; karboksilirovanie alkylcarboxylic groups, such as succinoyl, glutaryl and adipoyl; halogen-substituted C1-C6alkylcarboxylic groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and TRIFLUOROACETYL; C1-C6alkoxy, C1-C6alkylcarboxylic groups, such as methoxyacetyl; unsaturated alkylcarboxylic groups, such as (E)-2-methyl-2-butanol; "aromatic acyl group", for example arylcarbamoyl groups such as the benzoyl, α-naphtol and β-naphtol; halogen-substituted arylcarbamoyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl; containing lower alkyl arylcarbamoyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl; containing lower alkoxy arylcarbamoyl groups such as 4-anisoyl; karboksilirovanie arylcarbamoyl groups such as 2-carboxybenzoyl 3-carboxybenzoyl and 4-carboxybenzoyl; nitrified arylcarbamoyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl; contains the lowest alkoxycarbonyl arylcarbamoyl groups such as 2-(methoxycarbonyl)benzoyl; and arriraw is installed arylcarbamoyl group, such as 4-phenylbenzyl; "tetrahydropyranyl or tetrahydropyranyl groups, such as tetrahydropyran-2-yl, 3-bromotetradecane-2-yl, 4-methoxyacridine-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytryptamine-4-yl; "tetrahydrofuranyl or tetrahydrofuranyl groups, such as tetrahydrofuran-2-yl and tetrahydrofuran-2-yl; "silyl groups", for example three(lower alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, methyldiisopropanolamine, Matilde-tert-Boticelli and triisopropylsilyl; and three(lower alkyl)silyl group, substituted by 1 or 2 aryl groups, such as diphenylmethylene, diphenylbutyric, diphenylethylene and phenyldimethylsilane; "alkoxymethyl group", for example (lower alkoxy)methyl group, such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl and tert-butoxymethyl; containing lower alkoxy (lower alkoxy)methyl group, such as 2-methoxyethoxymethyl; and halogen-substituted (lower alkoxy) methyl group, such as 2,2,2-trichloroacetyl and bis(2-chloroethoxy)methyl; "substituted ethyl groups, for example, contains the lowest alkoxyethyl groups such as 1-ethoxyethyl and 1-(isopropoxy)ethyl; and halogenated ethyl g is uppy, such as 2,2,2-trichloroethyl; "kalkilya groups, for example lower alkyl groups, substituted 1-3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthylmethyl and 9-antimetal; and lower alkyl groups, substituted 1-3 aryl groups, the aryl ring of which is substituted by lower alkyl, lower alkoxy, halogen or cyano, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylalanine, 2-nitrobenzyl, 4-nitrobenzyl, 4 Chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, methyl, piperonyl; "alkoxycarbonyl group", for example (lower alkoxy)carbonyl group, such as methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and isobutoxide; and (lower alkoxy)carbonyl group, substituted by halogen or three(lower alkyl)silyl group such as 2,2,2-trichlorocyanuric and 2-trimethylsilylethynyl; "altneratively groups, such as vinyloxycarbonyl and allyloxycarbonyl; "arylaminomethylene groups, such as phenylenecarbonyl group; and "aracelikarsaalyna groups in which the aryl ring may be substituted by 1 or 2 groups, lower alkoxy or nitro, such as benzyloxycarbonyl, 4-methoxybenzenesulfonyl, 3,4-dimethoxyphenylacetone, 2-nitrobenzyloxy is of IMT and 4-nitrobenzenesulfonyl. "Protective group for a hydroxy-group"preferably represents an aliphatic acyl group, more preferably, alkylcarboxylic group, zaminirovannoy alkylcarboxylic group or carboxypropanoyl alkylcarboxylic group and, more preferably, acetyl, morpholine-4-ratetylenol or succinoyl group.

C1-C6hydroxyalkyl group "C1-C6hydroxyalkyl group which may be protected hydroxyamino group" in the definitions of R3and R7may, for example, represent a hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxyphenyl or 6-hydroxyhexyl and, preferably, is hydroxymethylene, 2-hydroxyethylene or 3-hydroxypropyl group.

C3-C10cycloalkyl group "C3-C10cycloalkyl group which may be substituted by one or more groups selected from the group of substituents α" in the definition of R3and R7and C3-C10cycloalkyl group "C3-C10cycloalkyl group" in the definition of the groups of substituents α and C3-C10cycloalkyl group which may be substituted by one or more groups selected from the group of substituents γ" in the definition of the groups of substituents β are, in the example, cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group or adamantly group.

The term "may be substituted" in the above "C3-C10cycloalkyl group which may be substituted by one or more groups selected from the group of substituents α" and "C3-C10cycloalkyl group which may be substituted by one or more groups selected from the group of substituents γ" means that this group is unsubstituted or mono-to tri-substituted.

"C1-C6alkylamino" in the definitions of groups of substituents α and γ represents the amino group, substituted one of the above C1-C6alkyl groups, such as amino group, a substituted linear or branched alkyl group containing from 1 to 6 carbon atoms; and preferably is methylaminopropyl, ethylamino, propylamino, isopropylamino or butylamino and, more preferably, methylaminopropyl, ethylamino or propylamino.

"C1-C6dialkylamino" in the definitions of groups of substituents α and γ represents an amino group substituted by two of the above C1-C6alkyl groups, and may, for example, be an amino group, amestoy two linear or branched alkyl groups, each of which contains from 1 to 6 carbon atoms; and preferably is dimethylaminopropyl, diethylaminopropyl, dipropylamino, diisopropylamino or dibutylamino and, more preferably, dimethylaminopropyl or diethylaminopropyl.

"C3-C6cycloalkylation" in the definition of the groups of substituents α may, for example, be cyclopropylamino, cyclobutylamine, cyclopentylamine or cyclohexylamino and, preferably, is cyclopentylamine or cyclohexylamino.

"C1-C6halogenation group" in the definitions of R3, R5, R6and groups of substituents α and γ represents the above C1-C6alkyl group, a substituted maximum possible number of halogen atoms. Examples of C1-C6halogenoalkanes groups include pharmacylow group, deformational group, triptorelin group, foretelling group, deperately group, triptorelin group, forproperty group, deferrability group, triptorelin group, terbutaline group, deformational group, triptorelin group, formentino group, diferently group, cryptocotyle group, perhexiline group, divergenceline group, t is everexisting group, panafcortelone group, geksaftorpropilenom group, nonafterburning group, chloromethylene group, dichloromethylene group, trichlorethylene group, chlorethylene group, dichlorethylene group, trichlorethylene group, chloropropylene group, dichloropropylene group, trichlorpropane group, chlorbutanol group, dichloroethylene group, trichlorobutylene group, chloraniline group, dichloraniline group, trichlorethylene group, chlorhexidine group, dichlorethylene group, trichlorethylene group, pentachloroaniline group, HEXAFLUOROPROPYLENE group and nonachlorobiphenyl group. C1-C6halogenation group, preferably represents pharmacylow group, deformational group, triptorelin group, foretelling group, deperately group, triptorelin group, forproperty group, deferrability group or triptorelin group and, more preferably, formeterol group, deformational group, triptorelin group, foretelling group, deperately group or triptorelin group.

"C3-C6cycloalkenyl group" in the definitions of groups of substituents α and β may, for example, be cyclopropylamino group, cyclobutenyl group, cyclopentenyl group or tsiklogeksilnogo group, and preferably, represents cyclopentadienyl group or tsiklogeksilnogo group.

"C1-C6halogenlampe" in the definition of the groups of substituents α represents the above C1-C6halogenating group, the alkyl end of which is substituted by an oxygen atom, and may, for example, be formatexpr, dipterocarp, cryptometer, peritonsillar, dipterocarp, triptracker, forproposals, gettoctopichref, cryptocracy, formatexpr, dipterocarpus, tripcomputer, forinteractive, differentialsysteme, cryptocontroller, forexbroker, deforestcloseup, trytoreconnectyou, pentafluoropropyl, hexadecyloxypropyl, nonafterburning, chlorotoxin, dichloromethoxy, trichlormethiazide, chlorethoxyfos, declarationthree, trichlorethene, chloropropoxy, dichloropropane, trichloropropane, chlorotoxin, dichloromethoxy, trichlorbenzene, Globetrotter, dichlorphenoxy, trichlormethiazide, chlorhexiderm, dichlorohexane, trihloretilamina, pentachloroethane, hexachloropropane or nonabsorbency and, preferably, the stand is made by formatexpr, dipterocarp, cryptometer, peritonsillar, dipterocarp, triptracker, forproposals, gettoctopichref or cryptocracy and, more preferably, formatexpr, dipterocarp, cryptometer, peritonsillar, dipterocarp or triptracker.

C1-C6alkoxy, C1-C6alkoxygroup in "C1-C6alkoxy, C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β" in the definition of the groups of substituents α represents the above C1-C6alkoxygroup, replaced by one of the above C1-C6alkoxygroup, and may, for example, be methoxyethoxy, 2-methoxyethoxy, 3-methoxypropyl, 4-methoxybutyl, 5-methoxybenzyloxy, 6-methoxyphenylacetate, ethoxyethoxy, 2-ethoxyethoxy, 3-ethoxypropane, 4-toxinotype, 5-ethoxyethylacetate or 6-amoxicillinum and, preferably, is a 2-methoxyethoxy, 3-methoxypropyl, 4-methoxybutyl or 5-methoxybenzyloxy.

C1-C6alkenylacyl in "C1-C6alkenylacyl, which may be substituted by one linescale groups, selected from the group of substituents β" in the definition of the groups of substituents α may, for example, be vinyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 4-pentyloxy, 1-hexaniacinate, 2-hexaniacinate, 3-hexaniacinate, 4-hexaniacinate or 5-hexaniacinate and, preferably, is a 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy or 3-butenyloxy.

C1-C6alkenylacyl in "C1-C6alkenylacyl, which may be substituted by one or more groups selected from the group of substituents β" in the definition of the groups of substituents α may, for example, be a 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 4-pentyloxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 4-hexyloxy or 5-hexyloxy and, preferably, is a 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy or 3-butenyloxy.

The term "may be zames is on" I "C 1-C6alkoxy, C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C1-C6alkenylacyl, which may be substituted by one or more groups selected from the group of substituents β" and "C1-C6alkenylacyl, which may be substituted by one or more groups selected from the group of substituents β" means that the group is unsubstituted or mono-to tri-substituted.

"C3-C10cycloalkylation" in the definitions of groups of substituents α and β represents the above C3-C10cycloalkyl group, which is linked to the oxygen atom, and may, for example, be cyclopropane, cyclobutanes, cyclopentyloxy or cyclohexyloxy and, preferably, is cyclopropane, cyclobutanes or cyclopentyloxy.

"3-6-membered geterotsiklicheskikh" in the definition of the groups of substituents α represents a cyclic group containing a nitrogen atom, an oxygen atom and/or sulfur atom and containing from 3 to 6 carbon atoms, which is linked to the oxygen atom; and may, for example, be aziridination, azetidinone, pyrrolidinyloxy, piperidinyloxy, Taranaki is the Rupp, taylortype, tetrahydropyranyloxy, tetrahydropyranyloxy, oxiranylmethyl, acetamidoxime, tetrahydropyranyloxy or tetrahydropyranyloxy and, preferably, is tetrahydropyranyloxy or tetrahydropyranyloxy.

C6-C10alloctype in "C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ" in the definition of the groups of substituents α and β represents the above C6-C10aryl group, which is linked to the oxygen atom, and may, for example, be fenoxaprop, ingenjorsfirma or naphthyloxy and, preferably, is fenoxaprop.

The term "may be substituted" in the above "C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ"means that the group is unsubstituted or mono-to tri-substituted.

"C1-C6accelerograph" in the definitions of groups of substituents α and γ may, for example, be melanochroa, ethylenoxy, trimethylaluminum, tetramethylthiourea, pentamethylene or hexadecyloxypropyl and, preferably, is ethylenoxy the PUF or trimethylaluminum.

"C1-C6alkylenedioxy" in the definitions of groups of substituents α and γ may, for example, be methylendioxy, Ethylenedioxy, trimethylenediamine, Tetramethylammonium, pentamethylchroman or hexamethylendiamine and, preferably, is methylenedioxy or Ethylenedioxy.

C1-C6allylthiourea in "C1-C6allylthiourea, which may be substituted by one or more groups selected from the group of substituents β" in the definition of the groups of substituents α represents the above C1-C6alkyl group, which is linked to the sulfur atom, and preferably represents metalcorp, ethylthiourea, PropertyGroup, isopropylthio or butylthiourea and, more preferably, metalcorp or ethylthiourea.

The term "may be substituted" in the above "C1-C6allylthiourea, which may be substituted by one or more groups selected from the group of substituents β" means that the group is unsubstituted or mono-to tri-substituted.

"C1-C6halogenlampe" in the definition of the groups of substituents α represents the above C1-C6allylthiourea, substituted maximum possible number of halogen atoms, which may for example, to represent formattertype, deformationof, triptoreline, foretelltarotve, diferitilor, triptoreline, afterpropertiesset, deformability, Cryptosporidium, ferrocytochrome, deformalities, Cryptosporidium, perpetuitygroup.com, differentition, Cryptosporidium, perhexiline, divergenceline, tripolaxity, pentafluoropropyl, geksaftorpropilenom, nonafterburning, chloromethylthiazole, dichloromethylsilane, trichloromethylthio, chloroethylthio, dichloraniline, trichloracetic, chlorpropamide, dichloropropionate, trichloroethane, chloroethylthio, dichlorobutadiene, trichloromethylthio, chlorphentermine, dichlorophenylthio, trichloromethylthio, chlorhexidine, dichloracetic, trichloracetic, pentachloroaniline, hexachloroplatinum or nonabsorption and, preferably, is formattertype, deformationof, triptoreline, foretelltarotve diferitilor, triptoreline, afterpropertiesset, deformability or Cryptosporidium.

C1-C6alkylsulfonyl group "C 1-C6alkylsulfonyl group which may be substituted by one or more groups selected from the group of substituents β" in the definition of the groups of substituents α represents the above C1-C6alkyl group, which is connected sulfonylurea group, and preferably represents methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylphenyl group or butylsulfonyl group and, more preferably, methylsulfonyl group or ethylsulfonyl group.

The term "may be substituted" in the "C1-C6alkylsulfonyl group which may be substituted by one or more groups selected from the group of substituents β" means that the group is unsubstituted or mono-to tri-substituted.

"C1-C6halogenated.sulphonated group" in the definition of the groups of substituents α represents the above C1-C6alkylsulfonyl group, substituted maximum possible number of halogen atoms, and may, for example, be hermetically group, diplomatically group, triftormetilfullerenov group, veratraldehyde group, diferentialgfeichung group, triftormetilfullerenov group, forprofessionals group, di is compromisingly group, triphosphopyridine group, terbutylazine group, deformationally group, triftormetilfullerenov group, perpendicularily group, diferentialgfeichung group, cryptocontroller group, forensically group, diferencialniho group, cryptolicensing group, pentafluoroethanesulfonyl group, geksaftorpropilenom group, nonafterburning group, chloromethanesulfonyl group, dichlorocarbanilide group, trichlorocarbanilide group, Kharatishvili group, dichlorocarbanilide group, trichlorocarbanilide group, chloropropanesulfonyl group, dichloropropionanilide group, trichloroethylene group, CHLOROTHALONIL group, dichlorobenzenesulfonyl group, trichlorocarbanilide group, Carpentersville group, dichlorobenzenesulfonyl group, trichloromethylsulfuryl group, chloroxylenol group, declaresymbolfont group, trichloroethylene group, pentafluoroethanesulfonyl group, HEXAFLUOROPROPYLENE group or nonachlorobiphenyl group, and preferably represents hermetically group, diplomatically group, triform tilslutning group, veratraldehyde group, diferentialgfeichung group, triftormetilfullerenov group, forprofessionals group, deformabilities group or triphosphopyridine group.

C1-C6acylcarnitine group "C1-C6alkylcarboxylic group which may be substituted by one or more groups selected from the group of substituents β" in the definition of the groups of substituents α represents the above C1-C6alkyl group that is linked to the carbonyl group, and may, for example, represent an acetyl group, ethylcarbitol group, propelleronline group, butylcarbamoyl group, internabonal group or paxilonline group, and preferably represents an acetyl group, ethylcarbitol group or propelleronline group.

The term "may be substituted" in the above "C1-C6alkylcarboxylic group which may be substituted by one or more groups selected from the group of substituents β" means that the group is unsubstituted or mono-to tri-substituted.

"C1-C6halogencarbonic group" in the definition of the groups of substituents α represents the above C1-C6halogenating group that is linked to the carbonyl of the Naya group, and may, for example, be ftormetilirovaniya group, deformational group, triftormetilfullerenov group, forecastability group, diftormetilirovaniya group, triftormetilfullerenov group, forprofessionals group, deformationally group, triphosphopyridine group, ferrocenecarboxylic group, deformational group, triftormetilfullerenov group, perpendicularily group, diftormetilirovaniya group, cryptocontroller group, forexternal group, diftormetilirovaniya group, cryptolicensing group, pentafluorothiophenol group, geksaftorpropilenom group, nonafterburning group, chlorocarbonyl group, dichlorocarbanilide group, trichlorocarbanilide group, chlorotalonil group, dichlorocarbanilide group, trichlorocarbanilide group, chloropropionyl group, dichloropropionanilide group, trichloropyridinol group, chlorocarbonyl group, dichlorocarbanilide group, trichlorocarbanilide group, chlorphentermine group, dichlorophenylamino group, trichloromethylcarbinol group, chloroxylenol group, dichloroxylenol group, rechargecolorado.com group, pentachlorothiophenol group, HEXAFLUOROPROPYLENE group or nonachlorobiphenyl group, and preferably represents ftormetilirovaniya group, deformational group, triftormetilfullerenov group, forecastability group, diftormetilirovaniya group, triftormetilfullerenov group, forprofessionals group, deformationally group or triphosphopyridine group.

C6-C10arylcarbamoyl group "C6-C10arylcarbamoyl group which may be substituted by one or more groups selected from the group of substituents γ" in the definition of the groups of substituents α represents the above C6-C10aryl group, which is connected to the carbonyl group, and may, for example, be benzoyloxy group, interkabel group or afterburning group, and preferably represents benzoyloxy group.

The term "may be substituted" in the above "C6-C10arylcarbamoyl group which may be substituted by one or more groups selected from the group of substituents γ" means that the group is unsubstituted or mono-to tri-substituted.

"C1-C6alkoxycarbonyl group" in the definition of the groups of substituents β pre who is above C 1-C6alkoxygroup, which is connected to the carbonyl group, and may, for example, represent a linear or branched alkoxycarbonyl group containing from 1 to 6 carbon atoms and, preferably, is methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group or butoxycarbonyl group and, more preferably, methoxycarbonyl group or ethoxycarbonyl group.

"N-C6-C10arylacetamide" in the definition of the groups of substituents β represents acetaminoph containing the above C6-C10aryl group on the nitrogen atom, and may, for example, be an N-phenylacetamide, N-indenyltitanium or N-naphthylacetamide and preferably represents N-phenylacetamido.

"C1-C6alkoxycarbonylmethyl" in the definition of the groups of substituents β represents the above C1-C6alkoxycarbonyl group containing a carbonyl group is linked to the amino group and may, for example, represent a linear or branched alkoxycarbonylmethyl containing from 1 to 6 carbon atoms and, preferably, is methoxycarbonylamino, ethoxycarbonylmethoxy, the PCC is xtabulator, isopropoxycarbonyl or butoxycarbonylamino and, more preferably, methoxycarbonylamino or ethoxycarbonylmethoxy.

"C2-C6cyclic amino group" in the definition of the groups of substituents γ, for example, be aziridinyl group, azetidinone group, pyrolidine group or piperidino group, and preferably represents a pyrolidine group or piperidino group.

In the compounds of formula (I) according to the present invention R1preferably represents a phenyl group which may be substituted by one or more groups selected from the group of substituents α, or pyridyloxy group which may be substituted by one or more groups selected from the group of substituents α; more preferably, phenyl group which may be substituted by one or more groups selected from the group of substituents α; even more preferably, phenyl group, substituted with any group selected from the group comprising C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ, and C1-C6/sub> halogenlampe; and, particularly preferably, 4-isobutylphenyl group, 4-(cyclopropylmethoxy)phenyl group, 4-(2-cyclopropylmethoxy)phenyl group, 4-(1-methylcyclopropyl)phenyl group, 4-(3,3,3-triplications)phenyl group, 4-(4,4,4-triptoreline)phenyl group, 4-(2-phenylethane)phenyl group, 4-(2-(4-methoxyphenyl)ethoxy)phenyl group, 4-(2-(3-methoxyphenyl)ethoxy)phenyl group, 4-(2-(4-chlorophenyl)ethoxy)phenyl group, 4-(2-(4-(N,N-dimethylamino)phenyl)ethoxy)phenyl group, 4-(4-chlorophenoxy)phenyl group or 4-(4-triptoreline)phenyl group.

R2preferably represents C6-C10aryl group which may be substituted by one or more groups selected from the group of substituents α; more preferably, phenyl group which may be substituted by one or more groups selected from the group of substituents α; even more preferably, phenyl group, substituted with any group selected from the group comprising halogen atoms, C1-C6alkyl group, a C1-C6halogenoalkane group, C3-C6cycloalkyl group, C1-C6alkoxygroup, C3-C6cycloalkylcarbonyl, C1-C6halogenlampe, C1-C6ancilliary and 5-10-membered heteroa the global group, and, particularly preferably, 4-florfenicol group, 4-chloraniline group, 4-triftormetilfullerenov group, 4-isopropylphenyl group, 4-cyclopropylamino group, 4-isopropoxyphenyl group, 4-deformationally group, 4-triphtalocyaninine group, 4-(2,2,2-triptoreline)phenyl group, 4-(2,2-diflorasone)phenyl group, 4-cyclopropylacetylene group, 4-ethoxyphenyl group, 4-methylthiophenyl group or 4-(1H-pyrrol-1-yl)phenyl group.

X preferably represents a group of formula N(R3R4where R4represents a hydrogen atom, and R3represents a C1-C6halogenating group1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, or C1-C6hydroxyalkyl group which may be protected hydroxyamino group; more preferably a group of formula N(R3R4where R4represents a hydrogen atom, and R3represents a C2-C3halogenating group2-C3hydroxyalkyl group which may be protected hydroxyamino group, or With1-C3alkyl group, a substituted 1-hydroxyisopropyl group; and more preferably, 2-foretelling is the SCP, 2,2-diferentiating, 2-hydroxyethylamino, 1-(2-hydroxypropyl)amino group, 1-hydroxycyclophosphamide, 2-acetoxyethylamine, 2-(morpholine-4-RECETOX)ethylamino or 2-(3-carboxyphenoxy)ethylamino.

In the compounds of formula (I') according to the present invention R5preferably represents any group selected from the group comprising halogen atoms, C1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenoalkane group, C3-C6cycloalkyl group, C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ, C1-C6halogenlampe and C3-C6cycloalkylcarbonyl; more preferably, any group selected from the group comprising C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ, and C1-C6 halogenlampe; and, even more preferably, isobutylacetate, cyclopropylmethoxy, 2-cyclopropylethyl, 1-methylcyclopropene, 3,3,3-cryptocomplexity, 4,4,4-cryptosporiosis, 2-venlafaxinum, 2-(4-methoxyphenyl)ethoxypropan, 2-(3-methoxyphenyl)ethoxypropan, 2-(4-chlorophenyl)ethoxypropan, 2-(4-(N,N-dimethylamino)phenyl)ethoxypropan, 4-chlorphenoxy or 4-triftormetilfosfinov.

R6preferably represents any group selected from the group comprising halogen atoms, C1-C6alkyl group, a C1-C6halogenoalkane group, C3-C6cycloalkyl group, C1-C6alkoxygroup, C3-C6cycloalkylcarbonyl, C1-C6halogenlampe, C1-C6ancilliary and 5-10-membered heteroaryl group; more preferably a fluorine atom, a chlorine atom, triptorelin group, isopropyl group, cyclopropyl group, isopropylamino, dipterocarp, cryptometer, 2,2,2-triptracker, 2,2-dipterocarp, cyclopropylamino, ethoxypropan, metalcorp or 1H-pyrrol-1-ilen group and, more preferably, ethoxypropan, triptorelin group, cyclopropyl group, cyclopropylamino, dipterocarp, cryptometer the 2.2-dipterocarp.

R7preferably represents C1-C6halogenating group1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, or C1-C6hydroxyalkyl group which may be protected hydroxyamino group; more preferably, From2-C3halogenating group2-C3hydroxyalkyl group which may be protected hydroxyamino group, or With1-C3alkyl group, a substituted 1-hydroxyisopropyl; and even more preferably 2-foretelling group, 2,2-deperately group, 2-hydroxyethylene group, 2-hydroxypropyl group, 1-hydroxyisopropyl group, 2-acetoxyethyl group, 2-(morpholine-4-RECETOX)ethyl group, or 2-(3-carboxyphenoxy)ethyl group.

In a preferred combinations of the substituents in the compound of formula (I') according to the present invention R5represents any group selected from the group comprising halogen atoms, C1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenoalkane group, C3-C6cycloalkyl group, C1-C6alkoxygroup, which can the be substituted by one or more groups, selected from the group of substituents β, C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ, C1-C6halogenlampe and C3-C6cycloalkylcarbonyl; R6represents any group selected from the group comprising halogen atoms, C1-C6alkyl group, a C1-C6halogenoalkane group, C3-C6cycloalkyl group, C1-C6alkoxygroup, C3-C6cycloalkylcarbonyl, C1-C6halogenlampe, C1-C6ancilliary and 5-10-membered heteroaryl group; and R7represents a C1-C6halogenating group1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, or C1-C6hydroxyalkyl group which may be protected hydroxyamino group. In more preferred combinations of the substituents R5represents any group selected from the group comprising C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C6-C10alloctype, which can be substituted by one or more groups selected the C group of substituents γ, and C1-C6halogenlampe; R6represents a fluorine atom, a chlorine atom, triptorelin group, isopropyl group, cyclopropyl group, isopropylamino, dipterocarp, cryptometer, 2,2,2-triptracker, 2,2-dipterocarp, cyclopropylamino, ethoxypropan, metalcorp or 1H-pyrrol-1-ilen group; and R7represents a C2-C3halogenating group2-C3hydroxyalkyl group which may be protected hydroxyamino group, or With1-C3alkyl group, a substituted 1-hydroxyisopropyl. In more preferred combinations of the substituents R5is isobutylacetate, cyclopropylmethoxy, 2-cyclopropylethyl, 1-methylcyclopropene, 3,3,3-cryptocomplexity, 4,4,4-cryptosporiosis, 2-venlafaxinum, 2-(4-methoxyphenyl)ethoxypropan, 2-(3-methoxyphenyl)ethoxypropan, 2-(4-chlorophenyl)ethoxypropan, 2-(4-(N,N-dimethylamino)phenyl)ethoxypropan, 4-chlorphenoxy or 4-triftormetilfosfinov; R6is ethoxypropan, triptorelin group, cyclopropyl group, cyclopropylamino, dipterocarp, cryptometer or 2,2-dipterocarp; and R7is a 2-foretelling group, 2,2-gift ratelow group, 2-hydroxyethylene group, 2-hydroxypropyl group, 1-hydroxyisopropyl group, 2-acetoxyethyl group, 2-(morpholine-4-RECETOX)ethyl group, or 2-(3-carboxyphenoxy)ethyl group.

The compounds of formula (I') according to the present invention, preferably, are the following:

4-(2-cyclopropylmethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-(2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-(2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

4-(2-cyclopropylmethoxy)-N-(2-[4-(2,2-diflorasone)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

2-{[(2Z)-2-{[4-(2-cyclopropylmethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}acetic acid ethyl ester

2-{[(2Z)-2-{[4-(2-cyclopropylmethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}ethylsuccinate,

4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,

4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}benthami is,

N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylmethoxy)benzamide,

N-[1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

N-(2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide,

4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}in the Nile)benzamid,

4-[2-(4-chlorophenyl)ethoxy]-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(4,4,4-triptoreline)benzamid,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(4,4,4-triptoreline)benzamid,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-{1-{[(2,2-dottorati)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-{1-({[(2S)-2-hydroxypropyl]amino}carbonyl)-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-(2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[4-(trifluoromethyl)phenoxy]benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]Ben who amide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide,

4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide and

4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide;

more preferably:

4-(2-cyclopropylmethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-(2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-(2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

4-(2-cyclopropylmethoxy)-N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

2-{[(2Z)-2-{[4-(2-cyclopropylmethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}acetic acid ethyl ester

4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,

N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylmethoxy)benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]be same,

4-[2-(4-chlorophenyl)ethoxy]-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(4,4,4-triptoreline)benzamid,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(4,4,4-triptoreline)benzamid,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-{1-{[(2,2-dottorati)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-{1-({[(2S)-2-hydroxypropyl]amino}carbonyl)-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

N-(2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[4-(trifluoromethyl)phenoxy]benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide,

N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-[4-(cryptomite is)phenoxy]benzamide,

4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide and

4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide.

The term "metabolic bone disease" in the present invention means a disease characterized by a significant decrease in bone mass or increasing the concentration of calcium in the blood, and diseases in which it is necessary suppression of bone resorption or the rate of bone resorption for their prevention or treatment.

Examples of such metabolic bone diseases include osteoporosis, hypercalcemia, metastatic bone cancer, periodontal disease, deforming ostos and osteoarthritis.

As mentioned above, the term "osteoporosis" means a systemic disease, in which due to the reduction in bone mass of the microfabrics of the bone is interrupted and the mechanical strength of bone are reduced, leading to an increased risk of fractures. Examples of osteoporosis includes postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis caused by steroid funds or immunosuppressants, osteoclasia or osteopenia caused by rheumatoid arthritis and osteopenia as a result of replacement of the artificial knee joint.

As mentioned above, the term "treatment" means the treatment or alleviation of disease Il the symptom or suppression of symptom.

As mentioned above, the term "substantial decrease in the concentration of calcium in the blood" usually means a decrease in the concentration of calcium in the blood, strictly supported at a constant level to below normal. The rate of decrease, preferably, 0.1% or more, more preferably 0.5% or more, still more preferably 1% or more and, particularly preferably, 5% or more.

As mentioned above, the term "its pharmacologically acceptable salt" means ό salt or acid salt, obtained by the interaction of the compounds of formula (I) according to the present invention, when the compound contains an acidic group or a basic group, with a base or acid.

Pharmacologically acceptable "ό salt of compounds of formula (I) according to the present invention preferably is a salt of an alkali metal such as sodium salt, potassium salt or lithium salt; salt alkaline-earth metal, such as salt or magnesium salt, calcium salt and an organic base, such as salt N methylmorpholine, salt, triethylamine salt of tributylamine, salt diisopropylethylamine, salt dicyclohexylamine, salt N methylpiperidine, salt, pyridine salt of 4-pyrrolidinedione or picoline salt; or a salt of the amino acids, such as salt of glycine, lysine salt, salt arginine, salt, ornithine salt of glutamic acid or a salt TSA is rainaway acid and preferably, the salt of an alkali metal.

Pharmacologically acceptable acid salt of compound of formula (I) according to the present invention preferably is a salt of an inorganic acid, such as hydrohalogen, such as hydroptere, hydrochloride, hydrobromide or hydroiodide, nitrate, perchlorate, sulfate or phosphate; salt of organic acid, for example (lower alkane)sulfonate such as methanesulfonate, triftorbyenzola or econsultant, arylsulfonate, such as bansilalpet or p-toluensulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate or maleate; or a salt of the amino acids, such as salt of glycine, salt, lysine salt, arginine salt, ornithine salt of glutamic acid or a salt of aspartic acid and, most preferably, hydrogenogenic.

The compound of formula (I) or its pharmacologically acceptable salt according to the present invention may be converted to hydrate upon absorption of water or to connect with water when salt is left on the air or recrystallized, and this hydrate is included in the present invention.

The compound of formula (I) or its pharmacologically acceptable salt according to the present invention has acrylamido structure in its molecule and, thus, may be present in the form of two regioisomers, namely (E)-isomer and Z-isomer, thanks to the double bond. In the compound of the present invention both such regioisomer and mixtures thereof are represented by a single formula (I). Therefore, the present invention includes such as regioisomers, and mixtures containing these regioisomers in any proportion and preferably consists mostly of (Z)-isomer. The isomer mixtures can be divided by known separation processes.

The compound of formula (I) or its pharmacologically acceptable salt according to the present invention include optical isomers, when contain asymmetric carbon atom in the molecule. In the compound of the present invention, all optical isomers and mixtures thereof are represented by a single formula (I). Therefore, the present invention encompasses all such optical isomers and mixtures containing optical isomers in any proportion.

The compounds of formula (I) according to the present invention, labeled with an isotope (for example,3H,14C or35S)are also included in the present invention.

Preferred examples of compounds of formula (I) according to the present invention are the compounds of formula (I-1), (I-2) or (I-3), described in the following tables 1, 2 and 3, but the present invention is not limited to these compounds.

In the presented tables substituents indicated by the following abbreviations. If the Deputy is represented by several abbreviations it consists of interconnected substituents, denoted by these abbreviations. For example, 2-cPrEtO denotes 2-cyclopropylmethoxy.

didi
Memethyl group
Etethyl group
Prthrough group
cPrcyclopropyl group
iPrthe isopropyl group
cBucyclobutyl group
iBuisobutylene group
tButert-bucilina group
Pnpencilina group
cPncyclopentolate group
cHxtsiklogeksilnogo group
cHpcycloheptyl group
Ph phenyl group
diEtNdiethylaminopropyl
diMeNdimethylaminopropan
Thithiophene-2-ilen group
Pyrrpyrrol-1-ilen group
Indinden-2-ilen group
1-cPencyclopenten-1-ilen group
2-cPencyclopenten-2-ilen group
αNpnaphthalene-1-ilen group
βNpnaphthalene-2-ilen group
Acacetyl group
Adaadamantly group
Bnbenzyl group
Boctert-butoxycarbonyl group
Bun3-butene-1-ilen group
Bzbenzoline group
BDO2-benzo[1,3]dioxol-5-ilen group
CF3Pr4,4,4-triptorelin group
CF3CF2Pr4,4,4,5,5-pentecontaetia group
Chr2,2-DIMETHYLPROPANE-6-ilen group
DDQZ2,4-dioxo-1,4-dihydro-2H-hinzelin-3-ilen group
2-DHBD2,3-dihydrobenzo[1,4]dioxin-2-ilen group
6-DHBD2,3-dihydrobenzo[1,4]dioxin-6-ilen group
MEDOmethylendioxy
Furfuran-2-ilen group
Mormorpholine-4-ilen group
Phtlcalolina group
Pippiperidine-4-ilen group
Pizpiperazine-1-ilen group
Pre2-the prop is-1-ilen group
Pry2-propyne-1-ilen group
Phthizbenzothiazole-2-ilen group
2-Pypyridine-2-ilen group
3-Pypyridine-3-ilen group
4-Pypyridine-4-ilen group
Pyrdpyrrolidin-1-ilen group
DOPyrd2,5-dioxopiperidin-1-ilen group
Pyrrpyrrol-1-ilen group
Quinthe quinoline-3-ilen group
HFtetrahydrofuran-2-ilen group
THPtetrahydropyran-4-ilen group
Triztriazole-1-ilen group

Table 1

Illustrative compounds of table 1

In the above table 1 preferred examples of compounds of formula (I-1) according to the present invention are listed as illustrative compound No. 1-58 by 1-110, 1-128 on 1-144, 1-162 on 1-178, 1-196 on 1-212, 1-274 on 1-282, 1-438 on 1-443, 1-504 on 1-506 and 1-517 on 1-519; and more preferable examples are illustrative compound No. 1-58: (example 15) 4-(2-cyclopropylmethoxy)-N-((Z)-2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

illustrative compound No. 1-60: (example 16) 4-(2-cyclopropylmethoxy)-N-((Z)-2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

illustrative compound No. 1-61: (example 10) 4-(2-cyclopropylmethoxy)-N-((Z)-2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

illustrative compound No. 1-62: (example 11) 4-(2-cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

illustrative compound No. 1-64: (example 12) 4-(2-cyclopropylmethoxy)-N-((Z)-2-[4-(2,2-diflorasone)phenyl]-1-{[(2-hydroxyethyl)amino]carb is nil}vinyl)benzamide,

illustrative compound No. 1-68: (example 9) 4-(2-cyclopropylmethoxy)-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

illustrative compound No. 1-69: (example 19) 4-(2-cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,

illustrative compound No. 1-72: (example 18) 4-(2-cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}benzamide,

illustrative compound No. 1-109: (example 14) N-((Z)-2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylmethoxy)benzamide,

illustrative compound No. 1-129: (example 7) N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

illustrative compound No. 1-130: (example 6) N-((Z)-2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

illustrative compound No. 1-132: (example 3) N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

illustrative compound No. 1-138: (example 5) N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

illustrative compound No. 1-141: (example 8) N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

illustrative connection # 1-144: (example 1) N-((Z)-2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,

illustrative compound No. 1-163: (example 27) 4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide,

illustrative compound No. 1-166: (example 23) 4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

illustrative compound No. 1-172: (example 25) N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide,

illustrative compound No. 1-196: (example 83) 4-[2-(4-chlorophenyl)ethoxy]-N-((Z)-2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

illustrative connection # 1-198 (example 81) 4-[2-(4-chlorophenyl)ethoxy]-N-((Z)-2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

illustrative compound No. 1-199: (example 78) 4-[2-(4-chlorophenyl)ethoxy]-N-((Z)-2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

illustrative compound No. 1-200: (example 79) 4-[2-(4-chlorophenyl)ethoxy]-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

illustrative compound No. 1-206: (example 80) 4-[2-(4-chlorophenyl)ethoxy]-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,

illustrative compound No. 1-212: (example 82) 4-[2-(4-chlorophenyl)ethoxy]-N-((Z)-2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}in the Nile)benzamid,

illustrative connection # 1-277: (example 108 N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,

illustrative compound No. 1-440: (example 104) 4-(cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,

illustrative compound No. 1-506: (example 107 N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(4,4,4-triptoreline)benzamide and

illustrative compound No. 1-519: (example 112 N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide.

Table 2

Illustrative compounds of table 2

In the above table 2, the preferred examples of compounds of formula (I-2) according to the present invention are

illustrative compound No. 2-6: N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(2-naphthyl)vinyl]-4-isobutoxide,

illustrative compound No. 2-16: N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[6-(trifluoromethyl)pyridin-3-yl]vinyl}-4-isobutoxide,

illustrative compound No. 2-19: N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-6-isobutoxyethene and

illustrative compound No. 2-21: 2-fluoro-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl is)vinyl]-4-isobutoxide.

Table 3

Illustrative compounds of table 3

In the above table 3 preferred examples of compounds of formula (I-3) according to the present invention are listed as illustrative compound No. 3-48 on 3-77, 3-88 on 3-117, 3-128 on 3-157, 3-168 on 3-197, 3-208 on 3-237 and 3-248 on 3-277; and more preferable examples are

illustrative compound No. 3-92: 2-({(2Z)-2-{[4-(2-cyclopropylmethoxy)benzoyl]amino}-3-[4-(cyclopropylamino)phenyl]propen-2-oil}amino)acetic acid ethyl ester

illustrative compound No. 3-102: 2-{[(2Z)-2-{[4-(2-cyclopropylmethoxy)benzoyl]amino}-3-[4-(triptoreline)phenyl]propen-2-oil]amino}acetic acid ethyl ester

illustrative compound No. 3-112: (example 20) 2-{[(2Z)-2-{[4-(2-cyclopropylmethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}acetic acid ethyl ester

illustrative compound No. 3-172: 2-{[(2Z)-3-[4-(cyclopropylamino)phenyl]-2-({4-[2-(4-methoxyphenyl)ethoxy]benzoyl}amino)propen-2-oil]amino}acetic acid ethyl ester

illustrative compound No. 3-182: 2-({(2Z)-2-({4-[2-(4-methoxyphenyl)ethoxy]benzoyl}amino)-3-[4-(triptoreline)phenyl]propen-2-oil}amino)acetic acid ethyl ester

illustrative compound No. 3-192:2-{[(2Z)-3-(4-cyclopropylmethyl)-2-({4-[2-(4-methoxyphenyl)ethoxy]benzoyl}amino)propen-2-oil]amino}acetic acid ethyl ester

illustrative compound No. 3-212: 2-({(2Z)-3-[4-(cyclopropylamino)phenyl]-2-[(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)amino]propen-2-oil}amino)acetic acid ethyl ester

illustrative compound No. 3-222: 2-({(2Z)-2-[(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)amino]-3-[4-(triptoreline)phenyl]propen-2-oil}amino)acetic acid ethyl ester

illustrative compound No. 3-232: 2-({(2Z)-3-(4-cyclopropylmethyl)-2-[(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)amino]propen-2-oil}amino)acetic acid ethyl ester

illustrative compound No. 3-252: 2-({(2Z)-2-({4-[2-(4-chlorophenyl)ethoxy]benzoyl}amino)-3-[4-(cyclopropane)phenyl]propen-2-oil}amino)acetic acid ethyl ester

illustrative compound No. 3-262: 2-({(2Z)-2-({4-[2-(4-chlorophenyl)ethoxy]benzoyl}amino)-3-[4-(triptoreline)phenyl]propen-2-oil}amino)ethyl acetate and

illustrative compound No. 3-272: 2-{[(2Z)-2-({4-[2-(4-chlorophenyl)ethoxy]benzoyl}amino)-3-(4-cyclopropylmethyl)propen-2-oil]amino}ethyl acetate.

A common way to obtain

The compound of formula (I) according to the present invention can be obtained in the following ways :

The following methods of obtaining, as a rule, is carried out in accordance with known methods described, for example, in "ORGANIC FUNCTIONAL GROUP PREPARATIONS", 2nd edition, ACADEMIC PRESS, INC. (1989) or "Comprehensive Organic Transformations", VCH Publishers Inc. (1989).

Some functional groups on the stage from the original substances to intermediate compounds for obtaining require protection of approaching what they are protective groups, which can be easily converted into the functional group. In this case, the desired compound can be obtained by removal of the protective groups, if necessary.

Examples of such functional groups include hydroxyl group, carboxyl group, carbonyl group and the amino group. Protective groups for these functional groups are described, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, Inc. (1999), and they are not necessary can be used in accordance with the reaction conditions.

Use carboxyl-protective group, for example, C1-C6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl and tert-butyl), C7-C11aralkyl (e.g., benzyl), phenyl, trityl, silyl (for example, trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl and tert-butyldimethylsilyl) and C2-C6alkenyl (e.g., 1-allyl). These groups can be substituted, for example, one to three halogen atoms (e.g. fluorine, chlorine, bromine and iodine), C1-C6alkoxy (e.g. methoxy, ethoxy and propoxy), or nitro.

Use hydroxyl-protective group, for example, C1-C6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl and tert-butyl), phenyl, trityl, C7-C11aralkyl (e.g., benzyl), formyl, C1-C6alkylsulphonyl (for example, acetyl and propionyl), Ben is oil, C7-C11aralkylamines (for example, benzylcarbamoyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (for example, trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl and tert-butyldimethylsilyl) and C2-C6alkenyl (e.g., 1-allyl). These groups can be substituted, for example, one to three halogen atoms (e.g. fluorine, chlorine, bromine and iodine), C1-C6the alkyl (for example, stands, ethyl, n-propylene), C1-C6alkoxy (e.g. methoxy, ethoxy and propoxy), or nitro.

Using carbonyl-protective group, for example a cyclic acetal (e.g., 1,3-dioxane) and non-cyclic acetal (e.g., di-C1-C6alkylaryl).

Use of amino-protective group, such as formyl, C1-C6alkylsulphonyl (for example, acetyl and propionyl), C1-C6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl), benzoyl, C7-C11aralkylamines (for example, benzylcarbamoyl), C7-C14Uralelectromed (for example, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl), trityl, phthaloyl, N,N-dimethylaminomethylene, silyl (for example, trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl and tert-butyldimethylsilyl) and C2-C6alkenyl (e.g., 1-allyl). These groups can be substituted, for example, one is W hen halogen atoms (for example, fluorine, chlorine, bromine and iodine), C1-C6alkoxy (e.g. methoxy, ethoxy and propoxy), or nitro.

The above protective group is removed by known methods such as a method using acid, base, ultraviolet light, hydrazine, phenylhydrazine, N-methyldithiocarbamate sodium, tetrabutylammonium fluoride, palladium acetate or trialkylsilyl (for example, trimethylsilylmethyl or trimethylsilylpropyne) or recovery method.

As described below, method A is a method for obtaining compounds of formula (I).

The way A

In the above formula, R1, R2and X have the above values.

Method A1 is a method for obtaining compounds of formula (I), and it is carried out by reacting the compounds of formula (II) and compounds of formula (III) in the presence of a solvent.

The compound of formula (III)used in the above reaction, preferably, represents a primary or secondary aliphatic amine, such as methylamine, ethylamine, Propylamine, Isopropylamine, butylamine, isobutylamine, 2-foreteller, 2-methoxyethylamine, ethanolamine, amoxilin, aminoacetonitrile, 1-amino-2-propanol, 2-amino-2-methyl-1-propanol, 2-amino-1-propanol, 3-amino-1-propanol, N-acetylethylenediamine, benzylamine, furfurylamine, thiophene-2-m is tillin, 2-(aminomethyl)pyridine, 1-phenylethylamine, 2-phenylethylamine, dimethylamine, diethylamine, pyrrolidine, piperidine, morpholine, piperazine or 2-(methylamino)ethanol; or an aromatic amine such as aniline, 2-aminophenol, 3-aminophenol, 4-aminophenol, 4-ftoranila, 4-Chloroaniline or 4-methoxyaniline; more preferably a primary aliphatic amine; and particularly preferably ethanolamine.

Examples of the solvent used in the above reaction include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as toluene, benzene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; amides such as N,N-dimethylacetamide and triamide hexamethylphosphoric acid; and lower alkalemia alcohols, such as methanol, ethanol, propanol and butanol. To obtain (Z)-isomer a isomer provisions alcohols and ethers are preferred alcohols are more preferred, and particularly preferred is ethanol. To obtain (E)-isomer a isomer position preferred are aromatic hydrocarbons, and toluene is more preferable.

The reaction temperature varies depending on, for example, parent compounds, dissolve the I and type founding and usually is in the range from 0°C to 200°C and preferably, from 25ºC to 80ºC.

The reaction time varies depending on, for example, the starting compounds, solvent, base and reaction temperature and is usually from 1 minute to 24 hours and preferably from 10 minutes to 6 hours.

After completion of the reaction, the target compound in this way is collected from the reaction mixture in accordance with the traditional way. For example, the reaction mixture is optionally neutralized or filtered to remove insoluble substances, if they are present. The reaction solution is extracted with an organic solvent that is not miscible with water, such as toluene, and washed with water. The organic layer containing the target compound are concentrated under reduced pressure to remove solvent to obtain the target compounds.

The obtained target compound can be isolated and purified, if necessary, a conventional method such as recrystallization, pereosazhdeniya, or method, which is widely used for separation and purification of organic compounds (for example, adsorption column chromatography using a carrier such as silica gel, alumina or Florisil consisting of magnesium-silica gel; distribution column chromatography using a carrier such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas) or Diaion HP-20(Mitsubihi Chemical Company); ion-exchange chromatography or normal-phase and reversed-phase column chromatography using silica gel or alkylated silica gel and preferably column chromatography on silica gel).

The isomers can be separated, if necessary, any of the above methods of separation/purification at a suitable stage after completion of the reaction of each of the above methods or after completion of the desired method.

When the compound having the structure of formula (I)is present in the form of isomers, such as regioisomers, rotary isomers or diastereomers, these isomers can be separated, if desired, at their respective isomeric forms of the above methods of separation/purification. In this method, (E)-isomer and the (Z)-isomer get regioisomers, and can be separated from one another above methods of separation/purification.

When the compound having the structure of formula (I), exists as a racemic mixture, this mixture can be divided into (S)-isomer and (R)-isomer traditional method of optical separation.

As described below, method B is a method for obtaining compounds of formula (II).

Method In

In the above formula, R1and R2have the above values.

Method B1 is a JV is a method for obtaining compounds of formula (II), and it is carried out by reacting the compounds of formula (IV) and compounds of formula (V) in the presence or in the absence of solvent.

Examples of the solvent used in the above reaction include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as toluene, benzene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; amides such as N,N-dimethylacetamide and triamide hexamethylphosphoric acid; and acid anhydrides such as acetic anhydride. In particular, the anhydrides of the acids are preferred, and acetic anhydride is more preferable.

The reaction temperature varies depending on, for example, the starting compounds, solvent, and the type of Foundation and usually ranges from 25ºC to 200ºc is manageable and, preferably, from 80ºC to 120ºC.

The reaction time varies depending on, for example, the starting compounds, solvent, base and reaction temperature and is usually from 1 minute to 1 hour and preferably from 10 minutes to 6 hours.

The compound of formula (II)obtained in this way are in the form of a mixture of regioisomers, (E)-isomer and the (Z)-isomer, in which (Z)-isomer, as a rule, is preferred. To generate is to obtain (E)-isomer, the proportional content of (E)-isomer can be increased by further processing of the compounds of formula (II)obtained in this way, acid.

Examples of the acid used in the above acid treatment include acid Branstad, for example inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, Perlina acid and phosphoric acid, and organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid, camphorsulfonic acid, triperoxonane acid and triftormetilfullerenov acid; a Lewis acid such as zinc chloride, tin tetrachloride, trichloride boron TRIFLUORIDE boron and tribromide boron; and acidic ion-exchange resin. Inorganic acids are preferred, and Hydrobromic acid is preferred.

The solvent used in the above acid treatment, preferably, is an acetic acid.

The reaction temperature varies depending on, for example, the starting compounds and the type of acid and solvent, and typically ranges from-20ºC to 100ºC and, preferably, from 0ºC to 25ºC.

The reaction time varies depending on the reaction temperature, the starting compounds and the type is used in the reaction of the reactants or solvent and is usually from 10 minutes to 10 hours and, preferably, from 30 minutes to 2 hours.

After completion of the reaction, the target compound of this method is collected from the reaction mixture in accordance with the same method as described in method A.

Following method C is a method for obtaining compounds of formula (IV).

Way

In the above formula, R1has the above meaning. Y represents a halogen atom or a group represented by formula-O-S(O)2RC(where RCrepresents a methoxy group or a phenyl group which may be substituted by one to three groups selected from the group comprising C1-C6alkyl group which may be substituted by one to three halogen atoms, and halogen atoms).

Method C1 is a method of obtaining the compounds of formula (VII).

This method is realized by the interaction of the compounds of formula (VI) and halogenation agent or sulfonylurea agent in a solvent in the presence or in the absence of base.

In the above reaction, you can use any of halogenation agent, which is typically used for halogenation of primary alcohols, without any limitation, and examples of such agents include oxalicacid; thionylchloride, such as thionyl chloride and thienylboronic; trihalogen fo the handicap, such as trichloride phosphorus and tribromide phosphorus; pentachloride phosphorus, such as pentachloride phosphorus and pentabromide phosphorus; oxychloride phosphorus, such as phosphorus oxychloride and oxybromide phosphorus; reagents of Vilsmeier (Vilsmeier), such as N,N-dimethylchlorosilane and N,N-dimethylpropanediamine; combination of phosphines, such as triphenylphosphine, and Halogens or metatarsalgia and combinations of phosphines, esters of azodicarboxylic acids and halides of metals such as a mixture of triphenylphosphine, diethylazodicarboxylate and lithium bromide. Oxalicacid is preferred, and a combination of oxalicacid and catalytic amounts of dimethylformamide is preferred. The addition of dimethylformamide increases the reaction rate.

In the above reaction, you can use any sulfonyloxy agent, which is typically used for sulfonylamine, without any limitation, and examples of such agents include sulphonylchloride, such as methanesulfonate and p-toluensulfonate, and a sulfonic acid anhydride. Methanesulfonate and p-toluensulfonate are preferred.

The base used in the above reaction varies depending on, for example, used reagent, but is not specifically limited. For example, the you can use an organic base, such as imidazole, pyridine, triethylamine and N-Mei, with imidazole, pyridine and triethylamine are preferred.

Examples of the solvent used in the above reaction include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; esters such as ethyl acetate and butyl acetate; ethers such as tetrahydrofuran, diethyl ether and tert-butyl methyl ether; and amides such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide and N,N-dimethylacetamide. Halogenated hydrocarbons are preferable, and dichloromethane is preferable.

The reaction temperature varies depending on, for example, the source of the substances used reagent and the type of solvent and typically ranges from-20ºC to 100ºC and, preferably, from 0ºC to 25ºC.

The reaction time varies depending on the reaction temperature, the starting compounds used in the reaction of the reagents and solvent, and is usually from 10 minutes to 12 hours and preferably from 2 hours to 3 hours.

The way C2 is a method of obtaining the compounds of formula (IV).

This method is carried out by reacting the compounds of formula (VII) and glycine in a solvent in the presence of the first.

The base used in the above reaction, may be different depending on, for example, used reagent, but is not specifically limited. For example, use organic bases such as imidazole, pyridine, triethylamine, N-Mei and diisopropylethylamine, and triethylamine is preferred.

Examples of the solvent used in the above reaction include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; water and solvent mixtures such as a mixture of water and the above organic solvents. Solvent mixtures of ethers and water are preferred, and a solvent mixture of tetrahydrofuran and water is more preferred.

The reaction temperature varies depending on, for example, the source of the substances used reagent and the type of solvent and typically ranges from-20ºC to 100ºC and, preferably, from 0ºC to 25ºC.

The reaction time varies depending on the reaction temperature, the starting compounds used in the reaction of the reagent and the type of solvent and usually the leaves from 10 minutes to 24 hours and, preferably, from 1 hour to 12 hours.

After completion of the reaction, the target compound of this method is collected from the reaction mixture in the same manner as described in method A.

As described below, method D is an alternative to method C to obtain the compounds of formula (IV).

Method D

In the above formula, R1has the above meaning. Rpis carboxyl-protective group, and has the above value.

Method D1 is a method of obtaining the compounds of formula (IX), and it is carried out by reacting the compounds of formula (VI) and compounds of formula (VIII) in the presence of a condensing agent in a solvent in the presence or in the absence of base.

In the above reaction, you can use any condensing agent without any limitation, and examples of such agents include di-lower alkalemia esters of azodicarboxylic acid-triphenylphosphine, such as the diethyl ester of azodicarboxylic acid-triphenylphosphine; carbodiimide derivatives, such as N,N'-dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); halides 2-halogen-1-(lower alkyl)pyridinium, such as iodide, 2-chloro-1-methyl pyridinium; directorrelated, such as diphenylphosphoryl (DPPA); esters of Harborview acid, t is the cue as ethylchloride and isobutylparaben; phosphorylchloride, such as diethylphosphate; imidazole derivatives such as N,N'-carbodiimide (CDI); derivative benzotriazole, such as hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (HATU) and hexaflurophosphate (1H-benzotriazol-1 yloxy)triprolidine (PyBOP); and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium (DMT-MM). DMT-MM is preferred.

The base used in the above reaction may be different, depending on, for example, used reagent, but is not specifically limited. Examples of the base include organic bases such as imidazole, pyridine, triethylamine, N-Mei and diisopropylethylamine. The triethylamine is preferred.

Examples of the solvent used in the above reaction include halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; and water. Alcohols and water are preferred, and more preferred is ethanol.

The reaction temperature varies in the head of the dependence from, for example, the source of the substances used reagent and the type of solvent and typically ranges from-20ºC to 100ºC and, preferably, from 0ºC to 50ºC.

The reaction time varies depending on the reaction temperature, the starting compounds used in the reaction reagents and the type of solvent, and is usually from 10 minutes to 24 hours and preferably from 1 hour to 12 hours.

After completion of the reaction, the target compound of this method is collected from the reaction mixture in the same manner as described in method A.

Method D2 is a method of obtaining the compounds of formula (IV), and it is carried out by hydrolysis of the compounds of formula (IX) in a solvent in the presence of a base.

Examples of the base used in the above reaction include carbonates of alkali metals such as lithium carbonate, sodium carbonate and potassium carbonate; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides of alkali metals such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium. Hydroxides of alkali metals are preferred, and more preferred are the I the lithium hydroxide and sodium hydroxide.

Examples of the solvent used in the above reaction include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; lower alternately, such as acetonitrile and propionitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and triamide hexamethylphosphoric acid; lower alkalemia alcohols, such as methanol, ethanol, propanol and butanol; and water. Alcohols, ethers, and water are preferred, and ethanol is preferred.

The reaction temperature varies depending on, for example, the source of the substances used reagent and the type of solvent and is usually in the range from 0ºC to 100ºC and, preferably, from 25ºC to 80ºC.

The reaction time varies depending on the reaction temperature, the starting compounds used in the reaction of the reagent and the type of solvent, and is usually from 10 minutes to 12 hours and preferably from 2 to 3 hours.

After completion of the reaction, the target compound of this method is collected from the reaction mixture in the same manner as described in method A.

Following method E is an alternative method D2 from method D to obtain the compounds of formula (IV) from compounds of formula (IX).

Method E

In specified you the e formula R 1has the above meaning. Rprepresents a protective group which can be removed by acid from the above carboxyl-protective groups.

"Protective groups which can be removed with acid, preferably represent THP (tetrahydropyranyl) group, tetrahydrofuranyl group, MEM (methoxyethoxymethyl) group, BOM (benzoyloxymethyl) group, tertiary boutelou (tert-boutelou) group, diphenylmethylene group, 9-antiloitering group and 5-dibenzosuberyl group.

Method E1 is a method of obtaining the compounds of formula (IV), and it is carried out by hydrolysis of the compounds of formula (IX) in a solvent in the presence of acid.

Examples of the acid used in the above reaction include acid Branstad, for example inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, Perlina acid and phosphoric acid, and organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid, camphorsulfonic acid, triperoxonane acid and triftormetilfullerenov acid; a Lewis acid such as zinc chloride, tin tetrachloride, trichloride boron TRIFLUORIDE boron and tribromide boron; acid and the ion-exchange resin. Inorganic acids and organic acids are preferred, and more preferred is triperoxonane acid.

Examples of the solvent used in the above reaction include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as toluene, benzene and xylene; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; lower alternately, such as acetonitrile and propionitrile; and amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and triamide hexamethylphosphoric acid. Halogenated hydrogeology are preferred, and more preferred is dichloromethane.

The reaction temperature varies depending on, for example, the source of the substances used reagent and the type of solvent and is usually in the range from 0 to 100ºC and, preferably, from 0 to 50ºC.

The reaction time varies depending on the reaction temperature, the starting compounds used in the reaction of the reagent and the type of solvent, and is usually from 10 minutes to 6 hours and preferably from 1 to 3 hours.

After completion of the reaction, the target compound e is th way collected from the reaction mixture in the same way, as shown in method A.

As described below, method F is a method of obtaining the compounds of formula (VI'), which can be used as the compounds of formula (VI) in method C or D.

Method F

In the above formula, RPhas the value shown in the above-described method D or E, and Rxrepresents a group selected from the group comprising C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C1-C6halogenlampe, C1-C6alkoxy, C1-C6alkoxygroup, which may be substituted by one or more groups selected from the group of substituents β, C1-C6alkenylacyl, which may be substituted by one or more groups selected from the group of substituents β, C1-C6alkenylacyl, which may be substituted by one or more groups selected from the group of substituents β, C3-C6cycloalkylcarbonyl, 3-6-membered geterotsiklicheskikh, C6-C10alloctype, which may be substituted by one or more groups selected from the group of substituents γ, C1-C6allylthiourea, which may be substituted by one or more groups selected from g is uppy of substituents β, and C1-C6halogenation group selected from the group of substituents α.

The way F1 is a method of obtaining the compounds of formula (XII), and it is carried out by reacting the compounds of formula (X) and the compounds of formula (XI) in a solvent using reagent Mitsunobu or similar

The reagent Mitsunobu or the like used in the above reaction, preferably, is a combination of azo compounds, such as lower Olkiluoto ether diazocarbonyl acid, such as diethylazodicarboxylate or diisopropylcarbodiimide, or azodicarbonamide, such as 1,1'-(azodicarbon)dipiperidino, with a phosphine, such as triarylphosphines, such as triphenylphosphine or tri-(lower alkyl)phosphine, such as tributylphosphine; or tributylphosphorotrithioate, more preferably, a combination of lower Olkiluoto ether diazocarbonyl acid with triarylphosphines or tributylphosphorotrithioate and, particularly preferably, a combination of diethylazodicarboxylate with triphenylphosphine or tributylphosphorotrithioate.

(1) the Case where the reagent Mitsunobu or the like is tributylphosphorotrithioate

Examples of the solvent include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromati the definition hydrocarbons, such as toluene, benzene and xylene; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol. Aromatic hydrocarbons are preferable, and toluene is more preferable.

The reaction temperature varies depending on, for example, the source of the substances used reagent and the type of solvent and is usually in the range from 0 to about 150ºc and, preferably, from 50 to 120ºC.

The reaction time varies depending on the reaction temperature, the starting compounds used in the reaction of the reagent and the type of solvent, and is usually from 30 minutes to 12 hours and preferably from 2 to 5 hours.

(2) the Case where the reagent Mitsunobu or the like is a combination of azo compounds and phosphine

Examples of the solvent include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as toluene, benzene and xylene; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol. Ethers are preferred and, and more preferred is tetrahydrofuran.

The reaction temperature varies depending on, for example, the source of the substances used reagent and the type of solvent, and is usually from -20 to 80°C and, preferably, from 0 to 50ºC.

The reaction time varies depending on the reaction temperature, the starting compounds used in the reaction of the reagent and the type of solvent, and is usually from 30 minutes to 24 hours and preferably from 1 to 3 hours.

After completion of the reaction, the target compound of this method is collected from the reaction mixture in the same manner as described in method A.

Method F2 is a method of obtaining the compounds of formula (VI'), and it is carried out by hydrolysis of the compounds of formula (XII) in a solvent in the presence of base or acid in the same manner as the method of D2 from method D or method E1 of method E.

Description applicability

Aminopropane, which is an active ingredient of a medicinal product according to the present invention or its pharmacologically acceptable salt have low toxicity and excellent activity suppression of bone resorption. Therefore, the drug of the present invention is particularly useful as a prophylactic or therapeutic agent (particularly, a therapeutic agent) from the OST is oporoza.

When the compound of formula (I), which is an active ingredient of a medicinal product according to the present invention or its pharmacologically acceptable salt is used as the above preventive or therapeutic agent (particularly, a therapeutic agent), the compound or salt as such or in a mixture with optional pharmaceutically acceptable excipient, diluent or the like can be entered, for example, orally in the form of tablets, capsules, granules, powders or syrups, or parenterally in the form of a preparation for injection or suppository.

Such compositions get well-known methods using additives such as fillers (for example, organic fillers: derivatives of sugars, such as lactose, white sugar, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, α-starch and dextrin; cellulose derivatives such as crystalline cellulose; Arabian gum; dextran and pullulan, and inorganic fillers: silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate and alumosilicate magnesium; phosphates such as calcium phosphate; carbonates, such as calcium carbonate; and sulfates such as calcium sulfate), lubricants such as, stearic acid, salts of stearic acid with metals such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and spermaceti; boric acid; adipic acid; salts of sulfuric acid, such as sodium sulfate; glycol; fumaric acid; sodium benzoate; D,L-leucine; sodium salts of fatty acids; salts euryceros acid, such as sodium lauryl sulfate and lauryl sulfate, magnesium; silicic acids such as silicic anhydride and silicothermic; and the aforementioned starch derivatives), binders (for example, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, macrogol and the compounds mentioned above as fillers), leavening agents (for example, cellulose derivatives such as nizkozameshhennoj hydroxypropylcellulose, carboxylmethylcellulose, calcium salt of carboxylmethylcellulose and internally-crosslinked sodium salt of carboxylmethylcellulose; and chemically modified starch/cellulose, for example carboxylmethyl, sodium carboxylmethyl and cross-linked polyvinylpyrrolidone), stabilizers (for example, esters of peroxybenzoyl acid, such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzylaniline; phenols such as phenol and cresol; Ty who has erocal; dehydroacetic acid and sorbic acid), flavors (e.g., sweeteners, podnikatel and traditionally used odorants) and thinners.

Dose scheme and the introduction vary depending on, for example, symptoms and age. Typically, the composition is administered as follows:

for oral administration, the dose per one introduction is from 0.001 to 100 mg/kg and preferably from 0.01 to 10 mg/kg

When intravenous dose per one introduction from 0.0001 to 10 mg/kg and preferably from 0.001 to 1 mg/kg

The frequency of injection and the interval between doses vary depending on the disease to be treated, and its severity or from the destination, i.e. therapeutic or prophylactic use, and typically range from one to three times per day, or from one to six times per week/month. The pharmaceutical composition of the present invention has satisfactory physical stability bioabsorable and pharmacokinetics and, thus, has the great advantage that the frequency of injection may be slow.

The advantages of the present invention

The authors of the present invention conducted in-depth studies of drugs with high activity, decrease in the concentration of calcium in the blood and suppressive activity, healthy lifestyles is authorized against the decline of bone mass, and drugs were found, including the compounds of formula (I) according to the present invention.

The compounds of formula (I) according to the present invention have low toxicity and excellent activity suppression of bone resorption and, therefore, the activity decrease in the concentration of calcium in the blood and suppressive activity directed against the decline of bone mass. Therefore, the compounds are useful as preventive or therapeutic agents (in particular, therapeutic agents) from the above metabolic bone disease.

The best way of carrying out the invention

EXAMPLES

The present invention will be described hereinafter in detail with reference to examples and examples of tests, but is not limited to them.

(Example 1) N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-144)

(1a) tert-Butyl ether N-(4-hydroxybenzoyl)glycine

Oxalicacid (8,7 ml of 99.7 mmol) and few drops of N,N-dimethylformaldehyde (hereinafter DMF) was added to a solution of dichloromethane (40 ml)containing 4-benzyloxybenzyl acid (11.1 g, to 48.6 mmol), while cooling with ice. The mixture was stirred at room temperature for 2 hours and then the solvent evaporated. The obtained residue RA is tarali in dichloromethane (100 ml) and then to the mixture was added the hydrochloride tert-butyl ester of glycine (8,20 g, for 48.9 mmol) and N-ethyl-N,N-Diisopropylamine (21 ml, 120 mmol) under cooling with ice. The mixture was stirred at room temperature for 19 hours and then to the mixture was added water to complete the reaction. The mixture was extracted with dichloromethane twice and the organic layers were combined and concentrated. The obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate, 9:1 to 2:1, vol/about.) obtaining tert-butyl ether N-[4-(benzyloxy)benzoyl]glycine. All the received quantity of ether was dissolved in methanol (165 ml) and to the mixture was added 20% palladium hydroxide on coal (926 mg). The mixture was intensively stirred in hydrogen atmosphere at room temperature for 3.5 hours. The reaction mixture was filtered through Celite and then concentrated to obtain 12.2 g specified in the title compound (colorless crystalline solid, yield: quantitative.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: becomes 9.97 (1H, s), 8,54 (1H, ushort, J=6 Hz), of 7.70 (2H, d, J=9 Hz), 6,78 (2H, d, J=9 Hz), 3,83 (2H, d, J=6 Hz), of 1.41 (9H, s).

(1b) N-{4-[2-(4-Methoxyphenyl)ethoxy]benzoyl}glycine

(Tributyl phosphoramidite)acetonitrile (428 μl, 1.50 mmol) was added to a solution of toluene (7 ml)containing tert-butyl ether N-(4-hydroxybenzoyl)glycine (264 mg, 1.05 mmol)obtained in example 1 (1a)and 2-(4-methoxyphenyl)ethanol (176 mg, of 1.16 mmol). The mixture is PE is amasyali at 100ºC for 3.5 hours and then to the mixture was added water. The mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent is then evaporated. The obtained residue was purified column chromatography on silica gel (hexane→hexane:ethyl acetate, 6:1, 4:1 and 3:1, vol/about.) to obtain an oily substance (358 mg). To a solution of dichloromethane (1 ml)containing this oily substance (358 mg, 0,929 mmol)was added triperoxonane acid (0.5 ml). The mixture was stirred at room temperature for 1 hour and then the solvent evaporated. To the obtained residue was added diisopropyl ether to suspension. The precipitate was collected by filtration and washed with diisopropyl ether to obtain 248 mg specified in the title compound (colorless crystalline solid, yield: 72%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 12,50 (1H, users), 8,67 (1H, t, J=5 Hz), 7,83 (2H, d, J=8 Hz), 7,24 (2H, d, J=8 Hz), 7,00 (2H, d, J=8 Hz), 6.87 in (2H, d, J=8 Hz), 4,20 (2H, t, J=6 Hz), with 3.89 (2H, d, J=5 Hz), and 3.72 (3H, ), 2,98 (2H, t, J=6 Hz).

(1c) (4Z)-4-(4-Chlorobenzylidene)-2-{4-[2-(4-methoxyphenyl)ethoxy]phenyl}-1,3-oxazol-5(4H)-he

A mixture of N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg, 1.00 mmol)obtained in example 1 (1b), 4-chlorobenzaldehyde (148 mg, 1.05 mmol), sodium acetate (111 mg, 1.35 mmol) and acetic anhydride (467 m is l, 5.00 mmol) was stirred at 120ºC for 20 minutes and then to the mixture was added water to complete the reaction. The mixture is then continuously intensively stirred until then, while the mixture was cooled to room temperature. The precipitate was collected by filtration, washed with water and hexane and dried by heating under reduced pressure to obtain 376 mg specified in the title compound (yellow powder, yield: 87%).

Next, the compound obtained in the cyclization reaction, indicated as oxazole.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,11 (2H, d, J=9 Hz), of 8.09 (2H, d, J=9 Hz), 7,42 (2H, d, J=9 Hz), 7,20 (2H, d, J=8 Hz), to 7.09 (1H, s), of 6.99 (2H, d, J=9 Hz), 6,86 (2H, d, J=8 Hz), 4,22 (2H, t, J=7 Hz), 3,80 (3H, ), is 3.08 (2H, t, J=7 Hz).

(1d) N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide

2-Aminoethanol (18 μl, 0.30 mmol) was added to a solution of ethanol (0.7 ml)containing (4Z)-4-(4-chlorobenzylidene)-2-{4-[2-(4-methoxyphenyl)ethoxy]phenyl}-1,3-oxazol-5(4H)-he obtained in example 1 (1c) (108 mg, 0.25 mmol). The mixture was stirred at 60ºC for 3 hours. The solvent is evaporated and the residue was purified by thin-layer chromatography for separation (ethyl acetate:methanol, 30:1, about./about., showed three times) to give 88 mg specified in the title compound (white amorphous solid, yield: 71%).

MS (FAB) m/z: 495 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ ppm: of 9.75 (1H, users), of 8.06 (1H, t, J=5 Hz), 7,94 (2H, d, J=8 Hz), 7,53 (2H, d, J=8 Hz), 7,39 (2H, d, J=7 Hz), 7,25 (2H, d, J=7 Hz), 7,14 (1H, s),? 7.04 baby mortality (2H, d, J=8 Hz), to 6.88 (2H, d, J=7 Hz), 4,63 (1H, t, J=6 Hz), to 4.23 (2H, t, J=7 Hz), to 3.73 (3H, s), 3,44 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), 2,99 (2H, t, J=6 Hz).

(Example 2) N-((Z)-2-[4-(Deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-131)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg)obtained in example 1 (1b)and 4-(deformedarse)benzaldehyde (139 μl) to obtain the corresponding oxazolone (334 mg). Then carried out the same reaction as in example 1 (1d), using 121 mg of this oxazolone to obtain 114 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 527 [M + H]+.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,89 (1H, users), to 7.77 (2H, d, J=9 Hz), 7,37 (2H, d, J=9 Hz), 7,20 (2H, d, J=9 Hz), 7,05 (2H, d, J=9 Hz), 7,00 (1H, s)6,91 (2H, d, J=9 Hz), 6.87 in (2H, d, J=9 Hz), 6,77 (1H, t, J=6 Hz), of 6.49 (1H, t, J=74 Hz), 4,17 (2H, t, J=7 Hz), 3,80 (3H, s), of 3.77 (2H, t, J=5 Hz), 3,49 (2H, q, J=5 Hz), 3,06 (2H, t, J=7 Hz).

(Example 3) N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-132)

<>

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg)obtained in example 1 (1b)and 4-(triptoreline)benzaldehyde (150 μl) to obtain the corresponding oxazolone (366 mg). Then carried out the same reaction as in example 1 (1d), using 160 mg of this oxazolone to obtain 126 mg specified in the title compound (white powder).

TPL: 139-141ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,80 (1H, users), 8,08 (1H, t, J=5 Hz), 7,95 (2H, d, J=8 Hz), to 7.64 (2H, d, J=7 Hz), 7,33 (2H, d, J=8 Hz), 7,25 (2H, d, J=7 Hz), 7,17 (1H, s),? 7.04 baby mortality (2H, d, J=8 Hz), to 6.88 (2H, d, J=8 Hz,), with 4.64 (1H, t, J=5 Hz)to 4.23 (2H, t, J=6 Hz), to 3.73 (3H, s), of 3.46 (2H, q, J=6 Hz), 3,24 (2H, q, J=6 Hz)of 3.00 (2H, t, J=6 Hz).

(Example 4) N-((Z)-2-[4-(2,2-Diflorasone)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-134)

(4a) 4-(2,2-Diflorasone)benzaldehyde

With reference to the document (J. Med. Chem. (1994), 37, 3977-3985) sodium hydride (3,36 g, 55%, 77,1 mmol) was added to a solution of DMF (100 ml)containing 2,2-differetial (5.75 g, 70,1 mmol)over 5 minutes under a stream of nitrogen gas while cooling with ice. The mixture was stirred at the same temperature for 10 minutes and then a solution of DMF (40 ml)containing 4-forbindelse (of 9.56 g of 77.0 mmol), doba is Lyali dropwise within 5 minutes. The mixture was stirred at room temperature for 4 hours and then poured into ice water (500 ml). The resulting mixture was extracted with a mixture of simple ether:hexane (300 ml, 1:1, vol/about.) three times. Extracted organic layer was washed with water (300 ml) three times and then with saturated saline and dried over anhydrous magnesium sulfate. The solvent is then evaporated to obtain the crude product. To the crude product was added a mixed solution of simple ether/hexane (20 ml, 1:10, vol/about.) and the supernatant was removed. This procedure was repeated, in General, four times for washing the crystals with getting the 10.1 g specified in the title compound (colorless crystalline solid, yield: 77%).

Range1H-nuclear magnetic resonance (500 MHz, CDCl3) δ ppm: 9,92 (1H, s), 7,87 (2H, d, J=8 Hz),? 7.04 baby mortality (2H, d, J=8 Hz), 6,13 (1H, TT, J=55 Hz, 4 Hz), 4,27 (2H, TD, J=13 Hz, 4 Hz).

(4b) N-((Z)-2-[4-(2,2-Diflorasone)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg)obtained in example 1 (1b)and 4-(2,2-diflorasone)benzaldehyde (196 mg)obtained in example 4 (4a), to obtain the corresponding oxazolone (306 mg). Then carried out the same reaction as in example 1 (1d), using 158 mg of the of isolona to obtain 144 mg specified in the title compound (white powder).

TPL: 172-174ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: RS 9.69 (1H, users), of 7.96 (2H, d, J=8 Hz), to 7.93 (1H, t, J=5 Hz), 7,51 (2H, d, J=8 Hz), 7,25 (2H, d, J=7 Hz), 7,20 (1H, s),? 7.04 baby mortality (2H, d, J=8 Hz), 6,97 (2H, d, J=8 Hz), to 6.88 (2H, d, J=7 Hz), 6,36 (1H, TT, J=55 Hz, 3 Hz), 4,63 (1H, t, J=7 Hz), 4,30 (2H, TD, J=14 Hz, 3 Hz)to 4.23 (2H, t, J=7 Hz), to 3.73 (3H, s), of 3.43 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz)of 3.00 (2H, t, J=7 Hz).

(Example 5) N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-138)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg)obtained in example 1 (1b)and 4-cyclopropylbenzene (which is a compound disclosed in Tetrahedron Lett. (2002), 43, 6987-6990, 154 mg) to obtain the corresponding oxazolone (300 mg). Then carried out the same reaction as in example 1 (1d), using 154 mg of this oxazolone to obtain 155 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 501 [M + H]+.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,79 (2H, d, J=9 Hz), 7,71 (1H, users), 7,28 (2H, d, J=8 Hz), 7,20 (2H, d, J=8 Hz), 7,05 (1H, s), 7,02 (2H, d, J=8 Hz), 6,93 (2H, d, J=9 Hz), 6.87 in (2H, d, J=9 Hz), of 6.65 (1H, t, J=5 Hz), 4,18 (2H, t, J=7 Hz), 3,80 (3H, s), of 3.78 (2H, t, J=5 Hz), 3,50 (2H, q, J=5 Hz), 3,06 (2H, t, J=7 Hz), 1,89 of-1.83 (1H, m), 1,01-to 0.96 (2H, m), 0,71-of 0.67 (2H, m).

(Example 6) N-((Z)-2-[4-(Cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-130)

(6a) 1-Bromo-4-(2-chloroethoxy)benzene

With reference to the document (J. Org. Chem. (2002), 67, 1093-1101), potassium carbonate (83,0 g, 600 mmol) was added to a solution of DMF (500 ml)containing 4-bromophenol (of 50.4 g, 291 mmol)at room temperature. The mixture was stirred at the same temperature for 30 minutes and then to the mixture was added 2-chloroethyl 4-methylbenzenesulfonate (70,2 g, 299 mmol). The mixture was stirred at 50ºC for 24 hours. The reaction solution was cooled to 10ºC and to the mixture was added water (500 ml) to precipitate a white solid. This white solid was collected by filtration, washed with water (500 ml) and were dried at 50ºC under reduced pressure to get to 58.6 g specified in the title compound (yield: 86%).

TPL: 54-56ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,39 (2H, d, J=9 Hz), for 6.81 (2H, d, J=9 Hz), 4,20 (2H, t, J=6 Hz), 3,80 (2H, t, J=6 Hz).

(6b) 1-Bromo-4-(vinyloxy)benzene

Tert-Butoxylate (33,7 g, 300 mmol) was added to a solution of tetrahydrofuran (hereinafter THF) (250 ml)containing 1-bromo-4-(2-chloroethoxy)benzene (58,6 g, 249 mmol)obtained in example 6 (6a), for 10 minutes at-10ºC. The mixture was stirred at room temperature for 21 hours and to the mixture is added water (500 ml). The resulting mixture was extracted with methyl tert-butyl ether (200 ml, 150 ml) twice. The organic layers were combined, washed with saturated saline (100 ml) twice and dried over anhydrous magnesium sulfate. The solvent is then evaporated. The obtained residue was dissolved in hexane (100 ml) and the precipitated insoluble substance was removed by filtration. The insoluble substance was then washed with hexane (5 ml) five times. The filtrates were combined, concentrated and was purified column chromatography on silica gel (hexane) to obtain the 39,0 g specified in the title compound (colorless oil, yield: 79%).

Range1H-NMR (400 MHz, CDCl3) δ ppm: the 7.43 (2H, d, J=9 Hz), 6.89 in (2H, d, J=9 Hz), 6,59 (1H, DD, J=14 Hz, 6 Hz), 4,78 (1H, DD, J=14 Hz, 2 Hz), 4,47 (1H, DD, J=6 Hz, 2 Hz).

(6c) 4-(Cyclopropylamino)benzaldehyde

With reference to the document (Tetrahedron Lett. (1998), 39, 8621-8624), has been cyclopropanation, as indicated below. Diethylzinc (a 1.0 M solution in hexane, 250 ml, 250 mmol) was added to dichloromethane (250 ml) and to the mixture was added a solution of dichloromethane (120 ml)containing triperoxonane acid (19.2 ml, 249 mmol)under ice cooling over a period of 100 minutes. The mixture then was stirred for 1 hour. Then to the mixture was added a solution of dichloromethane (100 ml)containing chloridometer (20,1 ml, 250 mmol)with ice cooling for 40 minutes, and then to the mixture after the Lyali a solution of dichloromethane (120 ml), containing 1-bromo-4-(vinyloxy)benzene (32,8 g, 165 mmol)obtained in example 6 (6b), at the same temperature for 20 minutes. The mixture was stirred at room temperature for 1.5 hours. Then to the reaction solution was added 0,1N. hydrochloric acid solution (400 ml). The mixture was stirred for 30 minutes, filtered through Celite and washed with hexane (200 ml). The hexane filtrate and wash solution were combined. The organic layer was washed with 0,1N. a solution of hydrochloric acid (100 ml) and then saturated brine (100 ml)containing about 1 g of sodium sulfite, twice. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated to obtain 36,0 g of 1-bromo-4-(cyclopropylamino)benzene (yellow oil).

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,37 (2H, d, J=9 Hz), 6,93 (2H, d, J=9 Hz), 3.72 points-3,68 (1H, m), 0.79, which is 0,73 (4H, m).

To a solution of THF (350 ml)containing the crude product (36,0 g, 165 mmol), was added n-utility (116 ml of 1.56 M solution in hexane, 181 mmol) at-66ºC for 40 minutes in a nitrogen atmosphere. The mixture was stirred at the same temperature for 1 hour. Then to the reaction solution was added dropwise DMF (23,6 g, 323 mmol) for 12 minutes. The mixture was stirred at the same temperature for 30 minutes and left to stand at room temperature is during the night, and then was added dropwise a saturated aqueous solution of ammonium chloride (150 ml) for 5 minutes. The organic layer was separated and washed with saturated aqueous solution of ammonium chloride (100 ml) and saturated saline (100 ml). The wash solution were combined and extracted with hexane (200 ml). All organic layers were combined and dried over anhydrous magnesium sulfate. The solvent is evaporated and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate, 9:1, vol/about.) to obtain 23.3 g specified in the title compound (light yellow oil, yield: 87%).

Range1H-NMR (400 MHz, CDCl3) δ ppm: 9,87 (1H, s)of 7.82 (2H, d, J=9 Hz), 7,14 (2H, d, J=9 Hz), 3,83-with 3.79 (1H, m), 0,87 is 0.81 (4H, m).

(6d) N-((Z)-2-[4-(Cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg)obtained in example 1 (1b)and 4-(cyclopropylamino)benzaldehyde (170 mg)obtained in example 6 (6c), to obtain the corresponding oxazolone (304 mg). Then carried out the same reaction as in example 1 (1d), using 159 mg of this oxazolone to obtain 159 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 517 [M + H]+.

Range1H-is the nuclear magnetic resonance (400 MHz, CDCl3) δ ppm: 7,81 (2H, d, J=9 Hz), 7,68 (1H, users), 7,35 (2H, d, J=9 Hz), 7,21 (2H, d, J=8 Hz), 7,10 (1H, s)to 7.00 (2H, d, J=9 Hz), 6,94 (2H, d, J=9 Hz), 6.87 in (2H, d, J=8 Hz), only 6.64 (1H, t, J=6 Hz), 4,19 (2H, t, J=7 Hz), 3,80 (3H, s), of 3.78 (2H, t, J=5 Hz), 3,71 (1H, Sept, J=3 Hz), 3,51 (2H, q, J=5 Hz), 3,06 (2H, t, J=7 Hz), 0,78-0,75 (4H, m).

(Example 7) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-129)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (248 mg)obtained in example 1 (1b)and 4-isopropoxybenzonitrile (131 μl) to obtain the corresponding oxazolone (227 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 122 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 519 [M + H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,67 (1H, users), of 7.97 (2H, d, J=8 Hz), 7,89 (1H, ushort, J=5 Hz), 7,47 (2H, d, J=8 Hz), 7,26 (2H, d, J=8 Hz), 7,18 (1H, s), 7,05 (2H, d, J=8 Hz), 6.89 in (2H, d, J=8 Hz), 6,86 (2H, d, J=8 Hz,), with 4.64-4,58 (2H, m)to 4.23 (2H, t, J=7 Hz), to 3.73 (3H, s), of 3.43 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz)of 3.00 (2H, t, J=7 Hz), of 1.23 (6H, d, J=6 Hz).

(Example 8) N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-141)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg)obtained in example 1 (1b)and 4-(methylthio)benzaldehyde (140 μl) to obtain the corresponding oxazolone (342 mg). Then carried out the same reaction as in example 1 (1d), using 156 mg of the specified oxazolone to obtain 134 mg specified in the title compound (white powder).

TPL: 61-63ºC.

Range1H-nuclear magnetic resonance (500 MHz, CDCl3) δ ppm: 7,79 for 7.78 (3H, m), 7,30 (2H, d, J=9 Hz), 7,21 (2H, d, J=9 Hz), 7,16 (2H, d, J=9 Hz), 7,02 (1H, s), 6,92 (2H, d, J=9 Hz), 6.87 in (2H, d, J=9 Hz), 6,70 (1H, t, J=6 Hz), 4,18 (2H, t, J=7 Hz), 3,80 (3H, s), of 3.77 (2H, t, J=5 Hz), 3,50 (2H, q, J=5 Hz), 3,06 (2H, t, J=7 Hz), a 2.45 (3H, s).

(Example 9) 4-(2-Cyclopropylmethoxy)-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-68)

(9a) 4-(2-Cyclopropylmethoxy)benzoic acid

Methyl 4-hydroxybenzoate (8,83 g, 58,0 mmol), 2-cyclopropylethanol (5,13 g, to 59.6 mmol) and triphenylphosphine (15.7 g, was 59.9 mmol) was dissolved in THF (250 ml). Then to the mixture was added diethylazodicarboxylate (29,8 ml, 40% solution in toluene, to 59.6 mmol) under ice cooling with stirring. The mixture was stirred at room temperature for 2 days and then to the reaction solution were added water (200 ml). The resulting mixture was extracted with ethyl acetate on the times. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and then the solvent evaporated. The obtained residue was dissolved in diethyl ether. The precipitate was removed by filtration and the diethyl ether evaporated. The specified filtering procedure was repeated twice and the residue was purified column chromatography on silica gel (hexane:ethyl acetate, 20:1, vol/about.) to obtain an oily substance (13,2 g). All the number specified oily substance was dissolved in ethanol (200 ml) and to the mixture was added 2 M aqueous solution of lithium hydroxide (60 ml, 120 mmol). The mixture was stirred at 60ºC for 50 minutes and then to the mixture was added with ice cooling 10% hydrochloric acid solution (40 ml). The resulting mixture two times were extracted with ethyl acetate. The organic layers were combined, washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is then evaporated. The resulting residue is suspended in diisopropyl ether, the precipitate was collected by filtration and dried under reduced pressure to obtain g 9.28 are specified in the connection header (powder, yield: 78%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 12,6 (1H, s), 7,88 (2H, d, J=9 Hz), 7,02 (2H, d, J=9 Hz), 4,10 (2H, t, J=7 Hz), 1,64 (2H, q, J=7 Hz), 0.88 to 0,79 (1H, m), 0,46 at 0.42 (2H, m), 0,15-0,11 (2H, m).

(9b) N-4-(2-Cyclopropylmethoxy)benzoyl]glycine

Oxalicacid (8,64 ml, a 99.0 mmol) and one drop of DMF was added under ice cooling to a solution of dichloromethane (30 ml)containing 4-(2-cyclopropylmethoxy)benzoic acid (9.28 are g, 45,0 mmol)obtained in example 9 (9a). The mixture was stirred at room temperature for 1.75 hours and the solvent evaporated. Then the resulting residue is suspended in THF (3 ml). The resulting suspension was added dropwise to a 50% aqueous solution of THF (120 ml)containing glycine (to 4.41 g of 58.7 mmol) and triethylamine (15.7 ml, 112 mmol), while cooling with ice. The mixture was stirred at room temperature for 1.5 hours and then to the mixture was added with ice cooling 10% hydrochloric acid solution (40 ml). The precipitate was collected by filtration, washed with water and dried by heating under reduced pressure to obtain 11.4 g specified in the connection header (powder, yield: 97%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 12,5 (1H, users), 8,64 (1H, ushort, J=6 Hz), 7,81 (2H, d, J=9 Hz), 6,98 (2H, d, J=9 Hz), 4,07 (2H, t, J=7 Hz), 3,88 (2H, d, J=6 Hz), and 1.63 (2H, q, J=7 Hz), 0.88 to 0,78 (1H, m), 0,46 at 0.42 (2H, m), 0,15-0,11 (2H, m).

(9c) (4Z)-4-(4-Cyclopropylbenzene)-2-[4-(2-cyclopropylmethoxy)phenyl]-1,3-oxazol-5(4H)-he

A mixture of N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (184 mg, 0,699 mmol)obtained in example 9 (9b), 4-cyclopropylbenzene (113 mg, 0,769 mmol)obtained in example 5, and is of Etat sodium (75 mg, 0,909 mmol) and acetic anhydride (660 μl, of 6.99 mmol) was stirred at 120ºC for 30 minutes and then allowed to cool to room temperature. To the resulting otverzhdennom product was added hexane (2 ml) and water (4 ml) and the product was washed using ultrasonic vibrations. The precipitate was collected by filtration, washed with water and hexane and dried by heating under reduced pressure to obtain 196 mg specified in the title compound (white powder, yield: 74%).

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,12 (2H, d, J=9 Hz), 8,10 (2H, d, J=8 Hz), 7,16 (1H, s), to 7.15 (2H, d, J=8 Hz), 7,03 (2H, d, J=9 Hz), 4,14 (2H, t, J=7 Hz), 1,99-of 1.93 (1H, m)of 1.73 (2H, q, J=6 Hz), 1,10-of 1.05 (2H, m), 0,93-0,83 (1H, m), 0,83-of 0.79 (2H, m), 0.55 to 0.50 in (2H, m), of 0.17 to 0.14 (2H, m).

(9d) 4-(2-Cyclopropylmethoxy)-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide

2-Aminoethanol (20 µl, 0.33 mmol) was added to a solution of ethanol (1.6 ml)containing (4Z)-4-(4-cyclopropylbenzene)-2-[4-(2-cyclopropylmethoxy)phenyl]-1,3-oxazol-5(4H)-he (95 mg, 0.25 mmol)obtained in example 9 (9c). The mixture was stirred at 60ºC for 1 hour and then the solvent was removed. The residue was washed with hexane:ethyl acetate (3:1, vol/vol.). The precipitate was collected by filtration and dried under reduced pressure to obtain 95 mg specified in the title compound (white powder, yield: 86%).

TPL: 195=200ºc is manageable (decomp.).

Range1H-nuclei the CSOs magnetic resonance (400 MHz, DMSO-d6) δ ppm: 9,67 (1H, users), 7,95-to $ 7.91 (3H, m), 7,39 (2H, d, J=8 Hz), to 7.15 (1H, users), 7,02 (2H, d, J=9 Hz), 7,00 (2H, d, J=9 Hz), to 4.62 (1H, t, J=5 Hz), 4,10 (2H, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), 3,22 (2H, q, J=6 Hz), 1,90 of-1.83 (1H, m), of 1.65 (2H, q, J=7 Hz), 0,95-of 0.91 (2H, m), 0,89-0,80 (1H, m), 0,68-of 0.64 (2H, m), 0,47-of 0.43 (2H, m), of 0.16 and 0.12 (2H, m).

(Example 10) 4-(2-Cyclopropylmethoxy)-N-((Z)-2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-61)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (150 mg)obtained in example 9 (9b)and 4-(deformedarse)benzaldehyde (83 μl) to obtain the corresponding oxazolone (188 mg). Then carried out the same reaction as in example 9 (9d), using 90 mg of the specified oxazolone to obtain 76 mg specified in the title compound (white powder).

TPL: 153-155ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,72 (1H, users), of 8.00 (1H, ushort, J=6 Hz), to 7.93 (2H, d, J=9 Hz), 7,56 (2H, d, J=9 Hz), 7.23 percent (1H, t, J=74 Hz), 7,16 (1H, s), 7,12 (2H, d, J=9 Hz), 7,02 (2H, d, J=9 Hz), to 4.62 (1H, t, J=5 Hz), 4,10 (2H, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 1,64 (2H, q, J=7 Hz), 0.88 to 0,81 (1H, m), 0,47-of 0.43 (2H, m), of 0.16 and 0.12 (2H, m).

(Example 11) 4-(2-Cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide (Illustrative compound No. 1-62)

Khujand what have been the same reaction, as in example 9 (9c), using N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (150 mg)obtained in example 9 (9b)and 4-(triptoreline)benzaldehyde (90 μl) to obtain the corresponding oxazolone (176 mg). Then carried out the same reaction as in example 9 (9d), using 80 mg of the specified oxazolone to obtain 74 mg specified in the title compound (white powder).

TPL: 142-144ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: of 9.75 (1H, users), of 8.04 (1H, t, J=6 Hz), to 7.93 (2H, d, J=9 Hz), a 7.62 (2H, d, J=9 Hz), 7,32 (2H, d, J=8 Hz), 7,14 (1H, users), 7,02 (2H, d, J=9 Hz), to 4.62 (1H, t, J=5 Hz), 4,10 (2H, t, J=7 Hz), of 3.43 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 1,64 (2H, q, J=7 Hz), 0,89-of 0.79 (1H, m), 0,47 at 0.42 (2H, m), of 0.16 and 0.12 (2H, m).

(Example 12) 4-(2-Cyclopropylmethoxy)-N-((Z)-2-[4-(2,2-diflorasone)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-64)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (212 mg)obtained in example 9 (9b)and 4-(2,2-diflorasone)benzaldehyde (170 mg)obtained in example 4 (4a), to obtain the corresponding oxazolone (281 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 164 mg specified in the title compound (pale yellow amorphous solid).

p> MS (FAB) m/z: 475 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: RS 9.69 (1H, s), 7,98 (2H, d, J=9 Hz), 7,94 (1H, ushort, J=5 Hz), 7,52 (2H, d, J=9 Hz), 7,20 (1H, s), 7,05 (2H, d, J=9 Hz), 6,98 (2H, d, J=9 Hz), 6,36 (1H, TT, J=54 Hz, 3 Hz), 4,63 (1H, t, J=5 Hz), or 4.31 (2H, TD, J=14 Hz, 3 Hz), 4,11 (2H, t, J=7 Hz), 3,44 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), of 1.65 (2H, q, J=7 Hz), 0,89 is 0.81 (1H, m), 0,47-of 0.43 (2H, m), of 0.16 and 0.12 (2H, m).

(Example 13) 4-(2-Cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(2,2,2-triptoreline)phenyl]vinyl}benzamide (Illustrative compound No. 1-65)

(13a) 4-(2,2,2-Triptoreline)benzaldehyde

Sodium hydride (787 mg, 55%, 18.0 mmol) suspended in DMF (10 ml) under nitrogen atmosphere and to the mixture was added dropwise a solution of DMF (5 ml)containing 4-hydroxybenzaldehyde (2.00 g, 16.4 mmol)for 5 minutes at room temperature. Immediately after this add was the deposition of a light yellow insoluble substances. After 5 minutes, was added dropwise a solution of DMF (5 ml)containing 2,2,2-triptorelin 4-methylbenzenesulfonate (4,00 g, and 17.2 mmol), to obtain a brown solution. This brown solution was stirred at room temperature for 1 hour and then to the mixture was added water (100 ml) and ethyl acetate (150 ml). The organic layer was separated, again washed with water (50 ml) five times, 10% aqueous sodium hydroxide solution (50 ml) three times and with saturated solely the solution and dried over anhydrous magnesium sulfate. The solvent is evaporated to obtain the crude product. This crude product was purified column chromatography on silica gel (hexane:ethyl acetate, 5:1, vol/about.) to obtain 1.40 g specified in the title compound (light yellow oil, yield: 42%).

Range1H-NMR (400 MHz, CDCl3) δ ppm: 9,94 (1H, s), 7,89 (2H, d, J=9 Hz), 7,07 (2H, d, J=9 Hz), of 4.44 (2H, q, J=8 Hz).

(13b) 4-(2-Cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(2,2,2-triptoreline)phenyl]vinyl}benzamide

Carried out the same reaction as in example 9 (9c), using N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (150 mg)obtained in example 9 (9b)and 4-(2,2,2-triptoreline)benzaldehyde (128 mg)obtained in example 13 (13a), to obtain the corresponding oxazolone (215 mg). Then carried out the same reaction as in example 9 (9d), using 96 mg of the specified oxazolone with getting 65 mg specified in the title compound (white powder).

TPL: 173-175 ° C.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: to 9.66 (1H, users), of 7.96-a 7.92 (3H, m), 7,51 (2H, d, J=9 Hz), 7,18(1H, s), 7,02 (2H, d, J=9 Hz), 7,00 (2H, d, J=9 Hz), 4,74 (2H, q, J=9 Hz), to 4.62 (1H, ushort, J=5 Hz), 4,10 (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 1,64 (2H, q, J=7 Hz), 0.88 to 0,81 (1H, m), 0,47-of 0.43 (2H, m), of 0.16 and 0.12 (2H, m).

(Example 14) N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylmethoxy)benzamide (illustrative connection # 1-109)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (213 mg)obtained in example 9 (9b)and 4-chlorobenzaldehyde (131 mg) to obtain the corresponding oxazolone (288 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 56 mg specified in the title compound (white powder).

TPL: 143-145ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: of 9.75 (1H, s), of 8.06 (1H, ushort, J=5 Hz), 7,95 (2H, d, J=9 Hz), 7,54 (2H, d, J=9 Hz), 7,40 (2H, d, J=8 Hz), 7,14 (1H, s),? 7.04 baby mortality (2H, d, J=8 Hz), with 4.64 (1H, t, J=5 Hz), 4,11 (2H, t, J=6 Hz), 3,44 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), of 1.65 (2H, q, J=6 Hz), 0.88 to 0,81 (1H, m), 0,47-of 0.43 (2H, m), of 0.16 and 0.12 (2H, m).

(Example 15) 4-(2-Cyclopropylmethoxy)-N-((Z)-2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-58)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (210 mg)obtained in example 9 (9b)and 4-ethoxybenzaldehyde (122 μl) to obtain the corresponding oxazolone (180 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 154 mg specified in the title compound (white amorphous substance).

<> MS (FAB) m/z: 439 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: for 9.64 (1H, s), 7,95 (2H, d, J=9 Hz), 7,87 (1H, ushort, J=5 Hz), 7,46 (2H, d, J=9 Hz), 7,17 (1H, s), 7,02 (2H, d, J=9 Hz), 6,85 (2H, d, J=9 Hz), br4.61 (1H, t, J=6 Hz), 4,10 (2H, t, J=7 Hz), to 3.99 (2H, q, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), of 1.65 (2H, q, J=7 Hz), of 1.29 (3H, t, J=7 Hz), 0.88 to 0,81 (1H, m), 0,47-of 0.43 (2H, m), of 0.16 and 0.12 (2H, m).

(Example 16) 4-(2-Cyclopropylmethoxy)-N-((Z)-2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-60)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (263 mg)obtained in example 9 (9b)and 4-(cyclopropylamino)benzaldehyde (170 mg)obtained in example 6 (6c), to obtain the corresponding oxazolone (235 mg). Then carried out the same reaction as in example 9 (9d), using 156 mg of the specified oxazolone to obtain 157 mg specified in the title compound (white powder).

TPL: 132-134ºC.

Range1H-nuclear magnetic resonance (500 MHz, CDCl3) δ ppm: 7,88 (1H, users), of 7.82 (2H, d, J=9 Hz), 7,34 (2H, d, J=8 Hz), 7,06 (1H, s), 6,98 (2H, d, J=9 Hz), 6,93 (2H, d, J=8 Hz), 6,79 (1H, ushort, J=6 Hz), 4,08 (2H, t, J=6 Hz in), 3.75 (2H, t, J=5 Hz), 3,70 (1H, Sept, J=3 Hz), 3,47 (2H, q, J=5 Hz), 1,71 (2H, q, J=6 Hz), 0,89-of 0.82 (1H, m), 0,78-0,73 (4H, m), 0,52-0,49 (2H, m), of 0.15 and 0.12 (2H, m).

(Example 17) 4-(2-Cyclopropylmethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}--(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-59)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (211 mg)obtained in example 9 (9b)and 4-isopropoxybenzonitrile (139 μl) to obtain the corresponding oxazolone (188 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone with getting to 90.0 mg specified in the title compound (white amorphous substance).

MS (FAB) m/z: 453 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,67 (1H, users), 7,98 (2H, d, J=9 Hz), 7,89 (1H, ushort, J=5 Hz), 7,47 (2H, d, J=9 Hz), 7,18 (1H, s), 7,05 (2H, d, J=9 Hz), 6,85 (2H, d, J=9 Hz), 4,65-4,59 (2H, m), 4,11 (2H, t, J=7 Hz), 3,41 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), of 1.65 (2H, q, J=7 Hz), of 1.23 (6H, d, J=6 Hz), 0,88-0,82 (1H, m), 0,47-of 0.43 (2H, m), of 0.16 and 0.12 (2H, m).

(Example 18) 4-(2-Cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}benzamide (Illustrative compound No. 1-72)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (212 mg)obtained in example 9 (9b)and 4-(1H-pyrrol-1-yl)benzaldehyde (153 mg) to obtain the corresponding oxazolone (328 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 113 mg specified the CSOs in the title compound (white amorphous substance).

MS (FAB) m/z: 460 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,78 (1H, s), 8,03-7,98 (3H, m), a 7.62 (2H, d, J=8 Hz), 7,58 (2H, d, J=9 Hz), 7,42-7,41 (2H, m), 7.23 percent (1H, s), 7,06 (2H, d, J=8 Hz), 6,26-of 6.25 (2H, m)and 4.65 (1H, t, J=6 Hz), of 4.12 (2H, t, J=6 Hz), of 3.45 (2H, q, J=6 Hz), 3,24 (2H, q, J=6 Hz), of 1.65 (2H, q, J=6 Hz), 0,88-0,82 (1H, m), 0,48-of 0.43 (2H, m), of 0.16 to 0.14 (2H, m).

(Example 19) 4-(2-Cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide (Illustrative compound No. 1-69)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-cyclopropylmethoxy)benzoyl]glycine (212 mg)obtained in example 9 (9b)and 4-(trifluoromethyl)benzaldehyde (122 μl) to obtain the corresponding oxazolone (235 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 163 mg specified in the title compound (white powder).

TPL: 174-176ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,80 (1H, s), 8,13 (1H, ushort, J=6 Hz), 7,92 (2H, d, J=9 Hz), 7,69 (2H, d, J=9 Hz), to 7.64 (2H, d, J=9 Hz), 7,14 (1H, s), 7,02 (2H, d, J=9 Hz), 4,63 (1H, t, J=5 Hz), 4,10 (2H, t, J=7 Hz), of 3.45 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), 1,64 (2H, q, J=7 Hz), 0,87 is 0.81 (1H, m), 0,47 at 0.42 (2H, m), of 0.16 and 0.12 (2H, m).

(Example 20) 2-{[(2Z)-2-{[4-(2-Cyclopropylmethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}ethyl acetate (Illustrative connected to the e No. 3-112)

Acetylchloride (97,0 μl, of 1.36 mmol) and 1,4-diazabicyclo[2,2,2]octane (287 mg, 2.56 mmol) was added to a solution of dichloromethane (2 ml)containing 4-(2-cyclopropylmethoxy)-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (197 mg, 0,453 mmol)obtained in example 9 (9d). The mixture was stirred at room temperature for 14 hours and then to the mixture was added water to complete the reaction. The mixture was extracted with dichloromethane and the organic layer was concentrated. The obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate, 1:3, vol/about.) to obtain 146 mg specified in the title compound (white powder, yield: 68%).

TPL: 80-82ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,80 (2H, d, J=9 Hz), the 7.65 (1H, users), 7,28 (2H, d, J=8 Hz),? 7.04 baby mortality (1H, s), of 6.99 (2H, d, J=8 Hz), 6,93 (2H, d, J=9 Hz), 6.73 x (1H, ushort, J=5 Hz), 4,20 (2H, t, J=5 Hz), 4,08 (2H, t, J=7 Hz), of 3.60 (2H, q, J=5 Hz), 2,03 (3H, s), 1,89-to 1.82 (1H, m)to 1.70 (2H, q, J=7 Hz), 1.00 and-of 0.96 (2H, m), 0,90-0,84 (1H, m), 0,71-of 0.67 (2H, m), 0,53-of 0.48 (2H, m), of 0.16 and 0.12 (2H, m).

(Example 21) 2-{[(2Z)-2-{[4-(2-Cyclopropylmethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}ethylmorpholine-4-ylacetic (Illustrative compound No. 3-116)

In accordance with the method disclosed in the document (J. Med. Chem. (1994), 37, 4538-4554), 73 mg specified in the title compound (white amorphous substance, yhod: 16%) was synthesized using 4-(2-cyclopropylmethoxy)-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (355 mg, 0,817 mmol)obtained in example 9 (9d).

MS (ESI) m/z: 562 [M+H]+.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: 9,71 (1H, s), 8,13 (1H, ushort, J=6 Hz), of 7.97 (2H, d, J=9 Hz), 7,42 (2H, d, J=8H), 7,13 (1H, s), 7,05 (2H, d, J=8 Hz), 7,03 (2H, d, J=8 Hz), 4,13-4.09 to (4H, m), 3,56-of 3.54 (4H, m), 3,41-to 3.38 (2H,, m), 3,19 (2H, s), 2,48-2,47 (4H, m), 1,90-of 1.85 (1H, m), of 1.65 (2H, q, J=6 Hz), 0,94-0,93 (2H, m), 0,87-0,82 (1H, m), 0,68 is 0.65 (2H, m), 0,47-of 0.43 (2H, m), of 0.15 to 0.14 (2H, m).

(Example 22) 2-{[(2Z)-2-{[4-(2-Cyclopropylmethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}ethyl succinate (Illustrative compound No. 3-117)

In accordance with the method disclosed in the document (Tetrahedron Lett. (1989), 30, 5045-5048), 198 mg specified in the title compound (white powder, yield: 88%) was synthesized using 4-(2-cyclopropylmethoxy)-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (182 mg, 0,817 mmol)obtained in example 9 (9d).

TPL: 118ºC (decomp.).

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: 12,22 (1H, s), 9,71 (1H, s), 8,15 (1H, ushort, J=6 Hz), 7,98 (2H, d, J=8 Hz), the 7.43 (2H, d, J=8 Hz), 7,14 (1H, s),? 7.04 baby mortality (2H, d, J=8 Hz), 7,02 (2H, d, J=8 Hz), 4,11 (2H, t, J=7 Hz), 4,06 (2H,, t, J=6 Hz), to 3.38 (2H, q, J=6 Hz), 2,52 is 2.46 (4H, m), 1,90-of 1.85 (1H, m), of 1.65 (2H, q, J=7 Hz), of 0.95 to 0.92 (2H, m), 0,89 is 0.81 (1H, m), 0,68-of 0.64 (2H, m), 0,47-of 0.43 (2H, m), of 0.16 to 0.13 (2H, m).

(Example 23) 4-{2-[4-(Dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide (Illus the administrative connection # 1-166)

(23a) 4-{2-[4-(Dimethylamino)phenyl]ethoxy}benzoic acid

Carried out the same reaction as in example 9 (9a), using 2-[4-(dimethylamino)phenyl]ethanol (567 mg, of 3.43 mmol) to give 567 mg specified in the connection header (powder, yield: 63%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 12,56 (1H, users), to 7.84 (2H, d, J=9 Hz), 7,11 (2H, d, J=9 Hz), 6,98 (2H, d, J=9 Hz), of 6.66 (2H, d, J=9 Hz), of 4.16 (2H, t, J=7 Hz), of 2.92 (2H, t, J=7 Hz), 2,84 (6H, s).

(23b) N-(4-{2-[4-(Dimethylamino)phenyl]ethoxy}benzoyl)glycine

N-Ethyl-N,N-Diisopropylamine (388 μl, of 2.23 mmol) and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium (615 mg, 2.22 mmol) was added to a solution of ethanol (10 ml)containing 4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoic acid (567 mg, 1,99 mmol)obtained in example 23 (23a), and methyl ether glycinate (280 mg, of 2.23 mmol). The mixture was stirred at room temperature for 18 hours, and to the mixture was added saturated aqueous sodium hydrogen carbonate solution to complete the reaction. The mixture was extracted with ethyl acetate twice and the organic layers were dried over anhydrous magnesium sulfate. The solvent is then evaporated. The obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate, 1:1 to 2:5, by vol./about.) obtaining oily compounds. To a solution of ethanol (6 ml)containing received from the connection, was added an aqueous solution of 2 M lithium hydroxide (1.60 ml, 3,20 mmol). The mixture was stirred at 60ºC for 40 minutes and then to the mixture was added 10% hydrochloric acid solution (3.5 ml) under cooling with ice. The mixture was extracted with ethyl acetate and the organic layers were combined, washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated to obtain 395 mg specified in the title compound (white powder, yield: 58%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 12,50 (1H, users), 8,65 (1H, ushort, J=6 Hz), 7,80 (2H, d, J=9 Hz), 7,11 (2H, d, J=9 Hz), 6,98 (2H, d, J=9 Hz), of 6.66 (2H, d, J=9 Hz), is 4.15 (2H, t, J=7 Hz), a 3.87 (2H, d, J=6 Hz), of 2.92 (2H, t, J=7 Hz), 2,84 (6H, s).

(23c) (4Z)-2-(4-{2-[4-(Dimethylamino)phenyl]ethoxy}phenyl)-4-[4-(triptoreline)benzylidene]-1,3-oxazol-5(4H)-he

A mixture of N-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (241 mg, 0,676 mmol)obtained in example 23 (23b), 4-(triptoreline)benzaldehyde (106 μl, 0,742 mmol), sodium acetate (83,9 mg of 1.02 mmol) and acetic anhydride (319 μl, to 3.38 mmol) was stirred at 120ºC for 15 minutes and then allowed to cool to room temperature. To the resulting otverzhdennom product was added saturated aqueous sodium hydrogen carbonate solution, hexane and ethanol and the solution was washed using ultrasonic vibrations. The precipitate was collected by filtration and dried by using nahrawan is under reduced pressure to obtain 234 mg specified in the connection header (orange solid, yield: 70%).

Range1H-NMR (400 MHz, CDCl3) δ ppm: of 8.25 (2H, d, J=9 Hz), 8,11 (2H, d, J=9 Hz), 7,31 (2H, d, J=9 Hz), 7,18 (2H, d, J=8 Hz), 7,13 (1H, s), 7,02 (2H, d, J=9 Hz), 6.73 x (2H, d, J=8 Hz), 4,22 (2H, t, J=7 Hz), 3,05 (2H, t, J=7 Hz), to 2.94 (6H, s).

(23d) of 4-{2-[4-(Dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide

2-Aminoethanol (57 μl, 0,944 mmol) was added to a solution of ethanol (0.5 ml)containing (4Z)-2-(4-{2-[4-(dimethylamino)phenyl]ethoxy}phenyl)-4-[4-(triptoreline)benzylidene]-1,3-oxazol-5(4H)-he (234 mg, 0,471 mmol)obtained in example 23 (23c). The mixture was stirred at 60ºC for 2.5 hours and then the solvent evaporated. The obtained residue was purified column chromatography on silica gel (ethyl acetate:methanol, 50:1, about./about.) to obtain 167 mg specified in the title compound (white amorphous solid, yield: 64%).

MS (FAB) m/z: 558 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,79 (1H, s), 8,07 (1H, ushort, J=5 Hz), 7,95 (2H, d, J=9 Hz), to 7.64 (2H, d, J=9 Hz), 7,34 (2H, d, J=8 Hz), 7,16 (1H, s), 7,14 (2H, d, J=8 Hz),? 7.04 baby mortality (2H, d, J=9 Hz), 6,69 (2H, d, J=9 Hz), with 4.64 (1H, t, J=5 Hz), 4,19 (2H, q, J=7 Hz), of 3.45 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), to 2.94 (2H, t, J=7 Hz), 2,85 (6H, s).

(Example 24) N-((Z)-2-[4-(Deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide (Illustrative compound No. 1-165)

<> Carried out the same reaction as in example 23 (23c), using N-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (230 mg)obtained in example 23 (23b), and 4-(deformedarse)benzaldehyde (93,8 μl) to obtain the corresponding oxazolone (387 mg). Then carried out the same reaction as in example 23 (23d), using the total number of the specified oxazolone to obtain 247 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 540 [M+H]+.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: 9,73 (1H, s), 8,02 (1H, ushort, J=5 Hz), 7,95 (2H, d, J=9 Hz), 7,58 (2H, d, J=9 Hz), 7,25 (1H, t, J=74 Hz), 7,18 (1H, s), 7,14 (2H, d, J=8 Hz), 7,13 (2H, d, J=9 Hz),? 7.04 baby mortality (2H, d, J=9 Hz), 6,69 (2H, d, J=9 Hz), 4,63 (1H, t, J=5 Hz), 4,19 (2H, t, J=7 Hz), 3,44 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), to 2.94 (2H, t, J=7 Hz), 2,85 (6H, s).

(Example 25) N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide (Illustrative compound No. 1-172)

Carried out the same reaction as in example 23 (23c), using N-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (324 mg)obtained in example 23 (23b), and 4-cyclopropylbenzene (170 mg)obtained in example 5, to obtain the corresponding oxazolone (360 mg). Then carried out the same reaction as in example 23 (23d), using only the number specified is oxazolone to obtain 293 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 514 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: RS 9.69 (1H, s), 7,97-to 7.93 (3H, m), 7,41 (2H, d, J=7 Hz), 7,17 (1H, s), to 7.15 (2H, d, J=8 Hz),? 7.04 baby mortality (2H, d, J=8 Hz), 7,02 (2H, d, J=8 Hz), 6,69 (2H, d, J=7 Hz), 4,63 (1H, t, J=5 Hz), 4,20 (2H, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), to 2.94 (2H, t, J=7 Hz), of 2.86 (6H, s), 1,90-of 1.84 (1H, m), 0,95-of 0.91 (2H, m), 0.67 and-of 0.64 (2H, m).

(Example 26) of the hydrochloride of N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide (Illustrative compound No. 1-172)

A mixed solution of 4n. hydrochloric acid in ethyl acetate (97 μl, 0,388 mmol) and methanol (680 ml) was added to a solution of methanol (3 ml)containing N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide (133 mg, 0,259 mmol)obtained in example 25. The resulting mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated and dried to obtain 150 mg specified in the title compound (white amorphous solid).

Elemental analysis (%) for C31H35N3O4·HCl·3/2H2O:

theoretical value: C, 64,52; H, for 6.81; N, 7,28; Cl, 6,14,

measured value: C, 64,47; H, 6,86; N, 6,82; Cl, 5,75.

(Example 27) 4-{2-[4-(Dimethylamino)phenyl]ethoxy}-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illus the administrative connection # 1-163)

Carried out the same reaction as in example 23 (23c), using N-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (255 mg)obtained in example 23 (23b), and 4-(isopropoxy)benzaldehyde (174 mg) to obtain the corresponding oxazolone (189 mg). Then carried out the same reaction as in example 23 (23d), using 185 mg of the specified oxazolone to obtain 89 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 532 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,63 (1H, users), 7,94 (2H, d, J=9 Hz), 7,86 (1H, ushort, J=5 Hz), 7,44 (2H, d, J=9 Hz), 7,16 (1H, s), 7,12 (2H, d, J=9 Hz), 7,02 (2H, d, J=9 Hz), at 6.84 (2H, d, J=9 Hz), to 6.67 (2H, d, J=9 Hz), 4,63-of 4.57 (2H, m), 4,18 (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), with 2.93 (2H, t, J=7 Hz), 2,85 (6H, s)to 1.22 (6H, d, J=6 Hz).

(Example 28) of the hydrochloride of 4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-163)

A mixed solution of 4n. hydrochloric acid in ethyl acetate (27 μl, to 0.108 mmol) and methanol (186 μl) was added to a solution of methanol (1 ml)containing 4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (of 37.7 mg, 0,071 mmol)obtained in example 27. The mixture was mixed in to the room temperature for 40 minutes. The reaction mixture was concentrated and dried to obtain 42,3 mg specified in the title compound (white powder, yield: 99%).

TPL: 103-105ºC.

Elemental analysis (%) for C31H37N3O5·HCl·2H2O:

theoretical value: C, 61,63; H, 7,01; N, Of 6.96; Cl, by 5.87,

measured value: C, 61,62; H, 6,74; N, 6,93; Cl, 5,67.

(Example 29) 4-{2-[4-(Dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide (Illustrative compound No. 1-173)

Carried out the same reaction as in example 23 (23c), using N-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (202 mg)obtained in example 23 (23b), and 4-(trifluoromethyl)benzaldehyde (90,6 μl) to obtain the corresponding oxazolone (241 mg). Then carried out the same reaction as in example 23 (23d), using the total number of the specified oxazolone to obtain 165 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 542 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,84 (1H, s), 8,16 (1H, ushort, J=6 Hz), to 7.93 (2H, d, J=8 Hz), of 7.70 (4H, s), 7,16 (1H, s), 7,14 (2H, d, J=8 Hz),? 7.04 baby mortality (2H, d, J=8 Hz), 6,69 (2H, d, J=8 Hz)and 4.65 (1H, t, J=5 Hz), 4,19 (2H,, t, J=7 Hz), of 3.45 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), to 2.94 (2H, t, J=7 Hz), 2,85 (6H, s).

(Example 30) N-((Z)-2-[4-(Deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-salutogenetic (Illustrative compound No. 1-4)

(30a) of N-(4-Isobutoxide)glycine

Carried out the same reaction as in example 9 (9b), using 4-isobutoxide acid (55,0 g, 283 mmol), obtained in accordance with the method disclosed in document J. Am. Chem. Soc., 61, 3050 (1939), with 50.2 g specified in the title compound (colorless crystalline solid, yield: 71%).

TPL: 140-142ºC.

(30b) of N-((Z)-2-[4-(Deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxide

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (184 mg)obtained in example 30 (30a)and 4-(deformedarse)benzaldehyde (165 mg) to give 195 mg of the corresponding oxazolone. Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 99 mg specified in the title compound (white powder).

TPL: 75-78ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,17 (1H, users), 7,78 (2H, d, J=9 Hz), 7,35 (2H, d, J=9 Hz), 7,02 (2H, d, J=9 Hz), 6,97 (1H, ushort, J=5 Hz), 6,94 (1H, s), 6.89 in (2H, d, J=9 Hz), 6,47 (1H, t, J=74 Hz in), 3.75 (2H, d, J=7 Hz), to 3.73-and 3.72 (2H, m), 3,44 (2H, q, J=5 Hz), 3,26 (1H, users), 2,10 (1H, Sept, J=7 Hz), was 1.04 (6H, d, J=7 Hz).

(Example 31) N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-isobutoxide (Illustrative compound No. 1-5)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (539 mg)obtained in example 30 (30a)and 4-(triptoreline)benzaldehyde (351 μl) to obtain the corresponding oxazolone (659 mg). Then carried out the same reaction as in example 9 (9d), using 106 mg of the specified oxazolone to obtain 58 mg specified in the title compound (white powder).

TPL: 170-171ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,76 (3H, userd, J=9 Hz), 7,39 (2H, d, J=9 Hz), to 7.15 (2H, d, J=8 Hz), 7,01 (1H, s)6,91 (2H, d, J=9 Hz), of 6.68 (1H, ushort, J=6 Hz), of 3.78 (2H, users), 3,76 (2H, d, J=7 Hz), 3,51 (2H, q, J=5 Hz), of 2.97 (1H, users), 2,11 (1H, Sept, J=7 Hz), was 1.04 (6H, d, J=7 Hz).

(Example 32) N-((Z)-2-[4-(2,2-Diflorasone)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxide (Illustrative compound No. 1-7)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (184 mg)obtained in example 30 (30a)and 4-(2,2-diflorasone)benzaldehyde (150 mg)obtained in example 4 (4a), to obtain the corresponding oxazolone (256 mg). Then carried out the same reaction as in example 9 (9d), using 122 mg of the specified oxazolone to obtain 63 mg specified in the title compound (white powder).

TPL: 150-151ºC.

Range1Yadernogo magnetic resonance (400 MHz, DMSO-d6) δ ppm: to 9.66 (1H, users), 7,97-of 7.90 (3H, m), 7,49 (2H, d, J=9 Hz), 7,18 (1H, s), 7,02 (2H, d, J=9 Hz), to 6.95 (2H, d, J=9 Hz), 6,34 (1H, TT, J=54 Hz, 4 Hz), to 4.62 (1H, ushort, J=5 Hz), the 4.29 (2H, dt, J=15 Hz, 3 Hz), 3,83 (2H, d, J=6 Hz), 3.43 points (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 2,04 (1H, Sept, J=7 Hz), and 1.00 (6H, d, J=7 Hz).

(Example 33) N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(2,2,2-triptoreline)phenyl]vinyl}-4-isobutoxide (Illustrative compound No. 1-8)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (500 mg)obtained in example 30 (30a)and 4-(2,2,2-triptoreline)benzaldehyde (447 mg)obtained in example 13 (13a), to obtain the corresponding oxazolone (592 mg). Then carried out the same reaction as in example 9 (9d), using 100 mg of the specified oxazolone to obtain 85 mg specified in the title compound (white solid).

TPL: 176-178ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,80 (2H, d, J=9 Hz), of 7.70 (1H, users), 7,38 (2H, d, J=9 Hz), was 7.08 (1H, s)6,94 (2H, d, J=9 Hz), make 6.90 (2H, d, J=9 Hz), 6,66 (1H, users), to 4.33 (2H, q, J=8 Hz), 3,80 is 3.76 (4H, m), 3,52 (2H, q, J=5 Hz), 2,10 (1H, Sept, J=7 Hz), of 1.05 (6H, d, J=7 Hz).

(Example 34) N-((Z)-2-(4-Ethylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxide (Illustrative compound No. 1-10)

Carried out the same reaction as in example 9 (9c), using N-4-isobutoxide)glycine (520 mg), obtained in example 30 (30a)and 4-ethylbenzaldehyde (312 μl) to obtain the corresponding oxazolone (442 mg). Carried out the same reaction as in example 9 (9d), using 122 mg of the specified oxazolone to obtain 110 mg specified in the title compound (white powder).

TPL: 174-176ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,81 (2H, d, J=9 Hz), to 7.61 (1H, users), 7,33 (2H, d, J=8 Hz), 7,19 (2H, d, J=8 Hz), 7,10 (1H, s), to 6.95 (2H, d, J=9 Hz), 6,56 (1H, t, J=6 Hz), 3,83-of 3.80 (2H, m), of 3.78 (2H, d, J=7 Hz), 3,53 (2H, q, J=5 Hz)of 2.64 (2H, q, J=7 Hz), 2,11 (1H, Quint, J=7 Hz), of 1.23 (3H, t, J=7 Hz), was 1.04 (6H, d, J=7 Hz).

(Example 35) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropylphenyl)vinyl]-4-isobutoxide (Illustrative compound No. 1-11)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (183 mg)obtained in example 30 (30a)and 4-isopropylbenzaldehyde (118 mg) to obtain the corresponding oxazolone (188 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 127 mg specified in the title compound (white powder).

TPL: 178-180ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: of 8.06 (1H, users), 7,80 (2H, d, J=9 Hz), 7,31 (2H, d, J=8 Hz), 7,16 (2H, d, J=8 Hz), 7,00 (1H, s), 6.90 to-to 6.88 (3H, m in), 3.75 (2H, d, J=6 Hz), 3,71 (2H, q, J=5 Hz), 3,43-3,40 3H, m)of 2.86 (1H, Sept, J=7 Hz), 2,10 (1H, Sept, J=7 Hz), to 1.22 (6H, d, J=7 Hz), was 1.04 (6H, d, J=7 Hz).

(Example 36) N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxide (Illustrative compound No. 1-12)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (215 mg)obtained in example 30 (30a)and 4-cyclopropylbenzene (135 mg)obtained in example 5, to obtain the corresponding oxazolone (215 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 126 mg specified in the title compound (white powder).

TPL: 180-181ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: RS 9.69 (1H, users), of 7.96 (2H, d, J=9 Hz), 7,94 (1H, ushort, J=6 Hz), 7,42 (2H, d, J=8 Hz), 7,17 (1H, s),? 7.04 baby mortality (2H, d, J=9 Hz), 7,02 (2H, d, J=8 Hz), to 4.62 (1H, t, J=5 Hz), a-3.84 (2H, d, J=6 Hz), of 3.43 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), was 2.05 (1H, Sept, J=7 Hz), 1,90-of 1.85 (1H, m), and 1.00 (6H, d, J=7 Hz), 0,95-of 0.91 (2H, m), 0.67 and-of 0.64 (2H, m).

(Example 37) N-((Z)-2-(4-Cyclopent-1-EN-1-ylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxide (Illustrative compound No. 1-14)

(37a) 4-Cyclopent-1-EN-1-ivansanchez

n-Utility (7.2 ml of 1.56 M solution in hexane, and 11.2 mmol) was added to a solution of 1-bromo-4-(dimethoxymethyl)benzene (to 2.29 g, to 9.91 mmol) in THF (25 ml) and-78ºC. The mixture was stirred at the same temperature for 2 hours and then to the mixture was added Cyclopentanone (of 1.34 ml, 15.1 mmol). The resulting mixture was heated to room temperature and then was stirred for 1 hour. The reaction was completed by addition of a saturated aqueous solution of ammonium chloride and three times was carried out by extraction with ethyl acetate. The obtained organic layers were washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate, 5:1, vol/about.) obtaining oily compounds. To a mixed solution of dichloromethane-water (9.1 ml, 100:1, vol/vol.), containing the obtained oily compound was added at room temperature triperoxonane acid (9 ml) and the mixture was continuously stirred for 20 minutes. The solvent is evaporated and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate, 10:1, vol/about.) to obtain 1.18 g specified in the connection header (light brown crystalline solid, yield: 90%).

Range1H-NMR (400 MHz, CDCl3) δ ppm: becomes 9.97 (1H, s), 7,83 (2H, d, J=8 Hz), 7,58 (2H, d, J=8 Hz), 6,41-6,40 (1H, m), 2.77-to 2,73 (2H, m), 2,60-of 2.56 (2H, m)to 2.06 (2H, Quint, J=7 Hz).

(37b) N-((Z)-2-(4-Cyclopent-1-EN-1-ylphenyl)-1-{[(2-hydroxide is)amino]carbonyl}vinyl)-4-isobutoxide

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (216 mg)obtained in example 30 (30a)and 4-cyclopent-1-EN-1-albenzaalbenza (157 mg)obtained in example 37 (37a), to obtain the corresponding oxazolone (194 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 128 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 449 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,72 (1H, s), 7,98-7,94 (3H, m), of 7.48 (2H, d, J=8 Hz), 7,39 (2H, d, J=8 Hz), 7,16 (1H, s), 7,02 (2H, d, J=8 Hz), of 6.31 (1H, users), to 4.62 (1H, ushort, J=5 Hz), 3,82 (2H, d, J=6 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 2,63 at 2.59 (2H, m), 2,47 is 2.44 (2H, m), 2,04 (1H, Sept, J=6 Hz), with 1.92 (2H, Quint, J=7 Hz), 0,99 (6H, d, J=6 Hz).

(Example 38) N-((Z)-2-(4-Ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxide (Illustrative compound No. 1-1)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (514 mg)obtained in example 30 (30a)and 4-ethoxybenzaldehyde (338 mg) to obtain the corresponding oxazolone (422 mg). Then carried out the same reaction as in example 9 (9d)using 102 mg of the specified oxazolone to obtain 54 mg specified in the title compound (white powder coated examination bed with is).

TPL: 124-125ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: for 9.64 (1H, users), 7,95 (2H, d, J=9 Hz), 7,86 (1H, ushort, J=5 Hz), 7,46 (2H, d, J=9 Hz), 7,17 (1H, s), 7,02 (2H, d, J=9 Hz), 6,85 (2H, d, J=9 Hz), br4.61 (1H, ushort, J=6 Hz), 4.00 points (2H, q, J=7 Hz), 3,83 (2H, q, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 2,04 (1H, Sept, J=6 Hz), of 1.29 (3H, t, J=7 Hz), and 1.00 (6H, d, J=7 Hz).

(Example 39) N-((Z)-2-[4-(Cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxide (Illustrative compound No. 1-3)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (155 mg)obtained in example 30 (30a)and 4-(cyclopropylamino)benzaldehyde (200 mg)obtained in example 6 (6c), to obtain the corresponding oxazolone (141 mg). Then carried out the same reaction as in example 9 (9d), using 126 mg specified oxazolone to obtain 126 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 439 [M+H]+.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,03 (1H, users), 7,79 (2H, d, J=9 Hz), 7,29 (2H, d, J=9 Hz), of 6.99(1H, s), 6,93 (2H, d, J=9 Hz), 6.89 in (1H, t, J=6 Hz), 6.87 in (2H, t, J=9 Hz), 3,74 (2H, d, J=6 Hz), 3,71-to 3.67 (3H, m), 3,42 (2H, q, J=5 Hz), to 3.38 (1H, users), is 2.09 (1H, Sept, J=7 Hz), was 1.04 (6H, d, J=7 Hz), 0,80-0,71 (4H, m).

(Example 40) N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]vinyl}-4-isobutoxide the ID (Illustrative compound No. 1-9)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (518 mg)obtained in example 30 (30a)and 4-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (375 μl) to obtain the corresponding oxazolone (715 mg). Then carried out the same reaction as in example 9 (9d), using 101 mg of the specified oxazolone to obtain 89 mg specified in the title compound (white solid).

TPL: 174-177ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,79 (2H, d, J=9 Hz), 7,66 (1H, users), 7,42 (2H, d, J=9 Hz), 7,19 (2H, d, J=8 Hz), 7,07 (1H, s), to 6.95 (2H, d, J=9 Hz), 6,62 (1H, ushort, J=6 Hz), 5,90 (1H, TT, J=53 Hz, 3 Hz), 3,83-with 3.79 (2H, m,), of 3.78 (2H, d, J=6 Hz), 3,53 (2H, q, J=5 Hz), only 2.91 (1H, users), 2,11 (1H, Quint, J=7 Hz), was 1.04 (6H, d, J=7 Hz).

(Example 41 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-isobutoxide (Illustrative compound No. 1-15)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (520 mg)obtained in example 30 (30a)and 4-(methylthio)benzaldehyde (303 μl) to obtain the corresponding oxazolone (594 mg). Then carried out the same reaction as in example 9 (9d), using 129 mg of the specified oxazolone to obtain 134 mg specified in the title compound (white powder).

TPL: 161-163ºC.

Range1 H-NMR (400 MHz, CDCl3) δ ppm: 8,30 (1H, users), 7,78 (2H, d, J=9 Hz), 7,24 (2H, d, J=9 Hz), to 7.09 (2H, d, J=9 Hz), was 7.08 (1H, ushort, J=5 Hz), to 6.88 (1H, s), 6.87 in (2H, d, J=9 Hz), 3,74 (2H, d, J=7 Hz), to 3.67 (2H, users), of 3.46 (1H, users), 3,39 (2H, q, J=5 Hz), 2,43 (3H, s), 2,10 (1H, Sept, J=7 Hz), was 1.04 (6H, d, J=7 Hz).

(Example 42 N-((Z)-2-[4-(Ethylthio)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxide (Illustrative compound No. 1-16)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (520 mg)obtained in example 30 (30a)and 4-(ethylthio)benzaldehyde (387 mg) to obtain the corresponding oxazolone (574 mg). Then carried out the same reaction as in example 9 (9d), using 100 mg of the specified oxazolone to obtain 82 mg specified in the title compound (white powder).

TPL: 153-155ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,80 (2H, d, J=9 Hz), of 7.70 (1H, users), 7,31 (2H, d, J=8 Hz), 7.23 percent (2H, d, J=9 Hz), 7,05 (1H, users), 6,94 (2H, d, J=9 Hz), of 6.65 (1H, users), 3,81 is 3.76 (4H, m), 3,51 (2H, q, J=5 Hz), 3,05 (1H, users), 2,95 (2H, q, J=7 Hz), 2,16-2,04 (1H, m)of 1.33 (3H, t, J=7 Hz), was 1.04 (6H, d, J=7 Hz).

(Example 43 N-((Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-{4-[(trifluoromethyl)thio]phenyl}vinyl)-4-isobutoxide (Illustrative compound No. 1-17)

Carried out the same reaction as in example 9 (9c), with the use of the N-(4-isobutoxide)glycine (512 mg), obtained in example 30 (30a)and 4-[(trifluoromethyl)thio]benzaldehyde (462 mg) to obtain the corresponding oxazolone (719 mg). Then carried out the same reaction as in example 9 (9d), using 101 mg of the specified oxazolone to obtain 101 mg specified in the title compound (pale yellow amorphous solid).

MS (FAB) m/z: 483 [M+H]+.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,39 (1H, users), 7,76 (2H, d, J=9 Hz), 7,53 (2H, d, J=8 Hz), 7,35 (2H, d, J=8 Hz), 7,07 (1H, ushort, J=5 Hz), 6.87 in (2H, d, J=9 Hz), 6,85 (1H, in), 3.75 (2H, d, J=7 Hz), 3,70 (2H, q, J=4 Hz), 3,40 (2H, q, J=5 Hz), or 3.28 (1H, ushort, J=5 Hz), 2,10 (1H, Sept, J=7 Hz), was 1.04 (6H, d, J=7 Hz).

(Example 44 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}-4-isobutoxide (Illustrative compound No. 1-18)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (520 mg)obtained in example 30 (30a)and 4-(1H-pyrrol-1-yl)benzaldehyde (390 mg) to obtain the corresponding oxazolone (723 mg). Then carried out the same reaction as in example 9 (9d), using 200 mg of the specified oxazolone to obtain 163 mg specified in the title compound (white powder).

TPL: 174-176ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,18 (1H, users), 7,76 (2H, d, J=9 Hz), 7,38 (2H, d, J=9 Hz), 7,26 (2H, d, J=9 Hz), 7,02 (2H, the, J=2 Hz), 6,99 (1H, ushort, J=6 Hz), of 6.96 (1H, users), at 6.84 (2H, d, J=9 Hz), of 6.31 (2H, t, J=2 Hz), 3,74 at 3.69 (4H, m), 3,44 (2H, q, J=4 Hz), 2,08 (1H, Sept, J=7 Hz), of 1.03 (6H, d, J=7 Hz).

(Example 45 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-isobutoxide (Illustrative compound No. 1-13)

Carried out the same reaction as in example 9 (9c), using N-(4-isobutoxide)glycine (524 mg)obtained in example 30 (30A)and 4-(trifluoromethyl)benzaldehyde (314 μl) to obtain the corresponding oxazolone (663 mg). Then carried out the same reaction as in example 9 (9d), using 95 mg of the specified oxazolone to obtain 43 mg specified in the title compound (colorless crystalline solid).

TPL: 207-210ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: of 7.82 (1H, users), 7,74 (2H, d, J=9 Hz), 7,56 (2H, d, J=8 Hz), 7,46 (2H, d, J=8 Hz), 7,00 (1H, s)6,91 (2H, d, J=9 Hz), of 6.68 (1H, ushort, J=6 Hz), 3,80 (2H, users), 3,76 (2H, d, J=7 Hz), 3,52 (2H,, kV, J=5 Hz), 2,92 (1H, users), 2,10 (1H, Sept, J=7 Hz), was 1.04 (6H, d, J=7 Hz).

(Example 46) 4-(Cyclobutylmethyl)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide (Illustrative compound No. 1-251)

(46a) N-[4-(Cyclobutylmethyl)benzoyl]glycine

Carried out the same reaction as in example 9 (9a) and (9b), using methyl 4-hydroxybenzoate (3.8 g, 25,0 mmol) and cyclobutylamine (2,36 ml to 25.0 mmol) to obtain the 6,41 g specified in the title compound (colorless oil, yield: 97%).

(46b) 4-(Cyclobutylmethyl)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide

Carried out the same reaction as in example 9 (9c), using N-[4-(cyclobutylmethyl)benzoyl]glycine (150 mg)obtained in example 46 (46a), and 4-(triptoreline)benzaldehyde (90 μl) to obtain the corresponding oxazolone (161 mg). Then carried out the same reaction as in example 9 (9d), with the use of 81 mg of the specified oxazolone to obtain 73 mg specified in the title compound (white powder).

TPL: 168-170ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: of 9.75 (1H, users), of 8.04 (1H, t, J=6 Hz), 7,92 (2H, d, J=9 Hz), a 7.62 (2H, d, J=9H), 7,32 (2H, d, J=8 Hz), 7,14 (1H, users), 7,02 (2H, d, J=9 Hz), to 4.62 (1H, ushort, J=6 Hz), was 4.02 (2H, d, J=7 Hz), of 3.43 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 2,73 (1H, Sept, J=7 Hz), 2,12-2,04 (2H, m), 1,96-to 1.79 (4H, m).

(Example 47) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenylethane)benzamide (Illustrative compound No. 1-112)

(47a) N-[4-(2-Phenylethane)benzoyl]glycine

Carried out the same reaction as in example 9 (9a) and (9b), using methyl 4-hydroxybenzoate (2,23 g, 14.7 mmol) and 2-phenylethanol (1.80 ml, 15.1 mmol) to obtain 3,23 g specified in the agolove compound (light yellow powder, yield: 74%).

[In this case used a 2H. aqueous sodium hydroxide solution instead of the aqueous solution of 2M lithium hydroxide.]

(47b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenylethane)benzamid

Carried out the same reaction as in example 9 (9c), using N-[4-(2-phenylethane)benzoyl]glycine (174 mg)obtained in example 47 (47a), and 4-isopropoxybenzonitrile (101 μl) to obtain the corresponding oxazolone (205 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 111 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 488 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: for 9.64 (1H, users), 7,95 (2H, d, J=9 Hz), 7,86 (1H, ushort, J=6 Hz), was 7.45 (2H, d, J=9 Hz), 7,34-7,28 (4H, m), 7.23 percent-7,20 (1H, m), 7,16 (1H, s), 7,03 (2H, d, J=9 Hz), at 6.84 (2H, d, J=9 Hz), 4.63 to-4,57 (2H, m), 4,28 (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz), to 1.22 (6H, d, J=7 Hz).

(Example 48 N-((Z)-2-[4-(Deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-phenylethane)benzamide (Illustrative compound No. 1-114)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-phenylethane)benzoyl]glycine (150 mg)obtained in example 47 (47a), and 4-(deformedarse)benzaldehyde (73 μl) to obtain sootvetstvuyuschego of oxazolone (181 mg). Then carried out the same reaction as in example 9 (9d), using 88 mg of the specified oxazolone to obtain 74 mg specified in the title compound (white powder).

TPL: 155-157ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,71 (1H, users), of 8.00 (1H, ushort, J=6 Hz), to 7.93 (2H, d, J=9 Hz), 7,56 (2H, d, J=9 Hz), 7,33-7,28 (4H, m), 7.23 percent (1H, t, J=74 Hz), 7,22-7,19 (1H, m), 7,16 (1H, s), 7,11 (2H, d, J=9 Hz), 7,03 (2H, d, J=9 Hz), to 4.62 (1H, ushort, J=5 Hz), 4,27 (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz).

(Example 49 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(2-phenylethane)benzamide (Illustrative compound No. 1-115)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-phenylethane)benzoyl]glycine (150 mg)obtained in example 47 (47a), and 4-(triptoreline)benzaldehyde (79 μl) to obtain the corresponding oxazolone (172 mg). Then carried out the same reaction as in example 9 (9d), using 80 mg of the specified oxazolone to obtain 64 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 515 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,76 (1H, users), of 8.04 (1H, ushort, J=6 Hz), 7,92 (2H, d, J=9 Hz), to 7.61 (2H, d, J=9 Hz), 7,34-7,28 (6H, m), 7.23 percent-7,20 (1H, m), 7,14 (1H, s), 7,03 (2H, d, J=9 Hz), to 4.62 (1H, ushort, J=5 Hz), 4,27 (2H, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz),up 3.22 (2H, kV, J=6 Hz), 3,06 (2H, t, J=7 Hz).

(Example 50 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(2,2,2-triptoreline)phenyl]vinyl}-4-(2-phenylethane)benzamide (Illustrative compound No. 1-118)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-phenylethane)benzoyl]glycine (150 mg)obtained in example 47 (47a), and 4-(2,2,2-triptoreline)benzaldehyde (113 mg)obtained in example 13 (13a), to obtain the corresponding oxazolone (186 mg). Then carried out the same reaction as in example 9 (9d), using 88 mg of the specified oxazolone to obtain 64 mg specified in the title compound (white solid).

TPL: 194 -196 ° C.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,68 (1H, users), 7,95-a 7.92 (3H, m)to 7.50 (2H, d, J=9 Hz), 7,34-7,28 (4H, m), 7.24 to 7,19 (2H, m), 7,03 (2H, d, J=9 Hz), of 6.99 (2H, d, J=9 Hz), 4,74 (2H, q, J=9 Hz), to 4.62 (1H, ushort, J=5 Hz), 4,27 (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz).

(Example 51 N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-phenylethane)benzamide (Illustrative compound No. 1-121)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-phenylethane)benzoyl]glycine (180 mg)obtained in example 47 (47a), and 4-cyclopropylbenzene (97 mg)obtained in example 5, to obtain the corresponding oxaz the womb (196 mg). Then carried out the same reaction as in example 9 (9d), using 95 mg of the specified oxazolone to obtain 67 mg specified in the title compound (light yellow powder).

TPL: 113-115ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: to 9.66 (1H, users), 7,94 (2H, d, J=9 Hz), 7,92 (1H, t, J=6 Hz), 7,39 (2H, d, J=8 Hz), 7,34-7,28 (4H, m), 7.24 to 7,20 (1H, m), 7,14 (1H, users), 7,03 (2H, d, J=9 Hz), 7,00 (2H, d, J=9 Hz), br4.61 (1H, t, J=6 Hz), 4,28 (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz), 1,90 of-1.83 (1H, m), 0,95-of 0.90 (2H, m), 0.67 and to 0.63 (2H, m).

(Example 52 N-((Z)-2-[4-(Cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-phenylethane)benzamide (Illustrative compound No. 1-113)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-phenylethane)benzoyl]glycine (185 mg)obtained in example 47 (47a), and 4-(cyclopropylamino)benzaldehyde (180 mg)obtained in example 6 (6c), to obtain the corresponding oxazolone (220 mg). Then carried out the same reaction as in example 9 (9d), using 101 mg of the specified oxazolone to obtain 58 mg specified in the title compound (pale yellow amorphous solid).

MS (FAB) m/z: 487 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,65 (1H, users), 7,95 (2H, d, J=9 Hz), 7,89 (1H, ushort, J=6 Hz), 7,47 (2H, d, J=9 Hz), 7,34-7,28 (4H, m), 7.23 percent-7,20 (1H, m), 7,17 (1H, s), 703 (2H, d, J=9 Hz), 6,98 (2H, d, J=9 Hz), br4.61 (1H, ushort, J=5 Hz), 4,27 (2H, t, J=7 Hz), 3,81 (1H, Quint, J=3 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz), 0,78-to 0.73 (2H, m), 0,63-of 0.59 (2H, m).

(Example 53) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropylphenyl)vinyl]-4-(2-phenylethane)benzamide (Illustrative compound No. 1-120)

Carried out the same reaction as in example 9 (9c), using N-[4-(2-phenylethane)benzoyl]glycine (187 mg)obtained in example 47 (47a), and 4-isopropylbenzaldehyde (104 μl) to obtain the corresponding oxazolone (147 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 114 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 473 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: RS 9.69 (1H, s), 7,95-of 7.90 (3H, m), 7,44 (2H, d, J=8 Hz), 7,34-7,28 (4H, m), 7,24-7,22 (1H, m), 7,18 (2H, d, J=9 Hz), 7,16 (1H, s),? 7.04 baby mortality (2H, d, J=9 Hz), br4.61 (1H, t, J=5 Hz), 4,28 (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz), and 2.83 (1H, Sept, J=7 Hz), of 1.16 (6H, d, J=7 Hz).

(Example 54) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(3,3,3-cryptocracy)benzamide (Illustrative compound No. 1-274)

(54a) N-[4-(3,3,3-Cryptocracy)benzoyl]glycine

Carried out the same reaction as in example 9 (9a) and (9b), with the use of what Finance methyl 4-hydroxybenzoate (1.52 g, 9,99 mmol) and 3,3,3-cryptochrome-1-ol (1,14 g of 9.99 mmol) to give 385 mg specified in the title compound (white powder, yield: 14%).

(54b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(3,3,3-cryptocracy)benzamid

Carried out the same reaction as in example 9 (9c), using N-[4-(3,3,3-cryptocracy)benzoyl]glycine (291 mg)obtained in example 54 (54a), and 4-isopropoxybenzonitrile (173 mg) to obtain the corresponding oxazolone (240 mg). Then carried out the same reaction as in example 9 (9d), using 76 mg of the specified oxazolone to obtain 69 mg specified in the title compound (white powder).

TPL: 84-86ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,76 (1H, users), 7,79 (2H, d, J=9 Hz), 7,32 (1H, ushort, J=6 Hz), 7,20 (2H, d, J=9 Hz), 6,78 (2H, d, J=9 Hz), 6,77 (1H, s), of 6.68 (2H, d, J=9 Hz), of 4.45 (1H, Sept, J=6 Hz), is 4.15 (2H, t, J=6 Hz), 3,74 (1H, users), of 3.54 (2H, users), 3,24 (2H, q, J=4 Hz), 2,66 is 2.55 (2H, m)of 1.28 (6H, d, J=6 Hz).

(Example 55) N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(3,3,3-cryptocracy)benzamide (Illustrative compound No. 1-279)

Carried out the same reaction as in example 9 (9c), using N-[4-(3,3,3-cryptocracy)benzoyl]glycine (1,46 g)obtained in example 54 (54a), and 4-cyclopropylbenzene (768 mg)obtained in example 5, to obtain compliance with the plans of oxazolone (1,72 g). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 1.22 g specified in the title compound (white powder).

TPL: 185-187ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: RS 9.69 (1H, users), of 7.96 (2H, d, J=9 Hz), to 7.93 (1H, ushort, J=5 Hz), 7,39 (2H, d, J=8 Hz), to 7.15 (1H, s), 7,06 (2H, d, J=9 Hz), 7,00 (2H, d, J=8 Hz), br4.61 (1H, t, J=5 Hz), the 4.29 (2H, t, J=6 Hz), of 3.43 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 2,88-2,77 (2H, m), 1,90 of-1.83 (1H, m), 0,95-of 0.91 (2H, m), 0.67 and-of 0.64 (2H, m).

(Example 56 N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenoxyethoxy)benzamide (Illustrative compound No. 1-313)

(56a) N-[4-(2-Phenoxyethoxy)benzoyl]glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (249 mg, 0,991 mmol)obtained in example 1 (1a)and 2-Phenoxyethanol (163 μl, 1,19 mmol) to obtain 241 mg specified in the title compound (white powder, yield: 78%).

(56b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenoxyethoxy)benzamid

Carried out the same reaction as in example 1 (1c), using N-[4-(2-phenoxyethoxy)benzoyl]glycine (241 mg)obtained in example 56 (56a), and 4-isopropoxybenzonitrile (133 μl) to obtain the corresponding oxazolone (250 mg). Then carried Taku the same response, as in example 1 (1d), using the total number of the specified oxazolone to obtain 129 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 505 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: to 9.66 (1H, users), of 7.97 (2H, d, J=9 Hz), 7,88 (1H, ushort, J=6 Hz), was 7.45 (2H, d, J=9 Hz), 7,29 (2H, DD, J=9 Hz, 7 Hz), 7,16 (1H, s), to 7.09 (2H, d, J=9 Hz), 6,98 (2H, d, J=9 Hz), 6,94 (1H, t, J=7 Hz), at 6.84 (2H, d, J=7 Hz), with 4.64-4,58 (2H, m), 4,42-and 4.40 (2H, m), 4,35-4,32 (2H, m), of 3.43 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), of 1.23 (6H, d, J=6 Hz).

(Example 57 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(2-phenoxyethoxy)benzamide (Illustrative compound No. 1-317)

Carried out the same reaction as in example 1 (1c), using N-[4-(2-phenoxyethoxy)benzoyl]glycine (157 mg)obtained in example 56 (56a), and 4-(triptoreline)benzaldehyde (69 μl) to obtain the corresponding oxazolone (176 mg). Carried out the same reaction as in example 1 (1d), using 175 mg specified oxazolone to obtain 58 mg specified in the title compound (white amorphous solid).

MS (ESI) m/z: 531 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,81 (1H, users), 8,08 (1H, ushort, J=6 Hz), of 7.97 (2H, d, J=9 Hz), the 7.65 (2H, d, J=9 Hz), 7,34 (2H, d, J=9 Hz), 7,31 (2H, d, J=8 Hz), 7,17 (1H, s), 7,11 (2H, d, J=8 Hz), 7,00 (2H, d, J=9 Hz), of 6.96 (1H, t, J=7 Hz) with 4.64 (1H, ushort, J=5 Hz), 4,43-to 4.41 (2H, m), 4,35-to 4.33 (2H, m), of 3.45 (2H, q, J=6 Hz), 3,24 (2H, q, J=6 Hz).

(Example 58) N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-phenoxyethoxy)benzamide (Illustrative compound No. 1-316)

Carried out the same reaction as in example 1 (1c), using N-[4-(2-phenoxyethoxy)benzoyl]glycine (157 mg)obtained in example 56 (56a), and 4-cyclopropylbenzene (71 mg)obtained in example 5, to obtain the corresponding oxazolone (166 mg). Carried out the same reaction as in example 1 (1d), using 165 mg of the specified oxazolone to obtain 62 mg specified in the title compound (pale yellow amorphous solid).

MS (ESI) m/z: 487 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,72 (1H, users), 8,00-7,94 (3H, m), 7,42 (2H, d, J=8 Hz), 7,32 (2H, t, J=8 Hz), 7,18 (1H, s), 7,11 (2H, d, J=8 Hz), 7,05-to 6.95 (5H, m), 4,63 (1H, ushort, J=5 Hz), 4,43-and 4.40 (2H, m), 4,36-to 4.33 (2H, m,), 3,44 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), 1,91-of 1.84 (1H, m), 0,96-of 0.91 (2H, m), 0,68-of 0.64 (2H, m).

(Example 59) 4-(3-Cyclopropylmethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-323)

(59a) N-[4-(3-Cyclopropylmethoxy)benzoyl]glycine

Carried out the same reaction as in example 9 (9a) and (9b), using methyl 4-hydroxybenzoate (6,09 g, 40.0 mmol) and 3-is ecoproperty-1-ol (which represents the connection disclosed in Helv. Chim. Acta (2003), 86, 865-893, to 4.41 g, to 44.0 mmol) to obtain the grade of 5.74 g specified in the title compound (white powder, yield: 51%).

(59b) 4-(3-Cyclopropylmethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

Carried out the same reaction as in example 9 (9c), using N-[4-(3-cyclopropylmethoxy)benzoyl]glycine (139 mg)obtained in example 59 (59a), and 4-isopropoxybenzonitrile (86 mg) to obtain the corresponding oxazolone (124 mg). Then carried out the same reaction as in example 9 (9d), using 91 mg of the specified oxazolone to obtain 63 mg specified in the title compound (white powder).

TPL: 64-66ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,29 (1H, users), 7,81 (2H, d, J=9 Hz), 7,28 (2H, d, J=9 Hz), 7,07 (1H, ushort, J=6 Hz), to 6.95 (1H, s)6,86 (2H, d, J=9 Hz), 6.75 in (2H, d, J=9 Hz), 4,50 (1H, Sept, J=6 Hz), to 4.01 (2H, t, J=6 Hz), to 3.64 (2H, t, J=5 Hz)to 3.36 (2H, q, J=5 Hz), 1,90 (2H, Quint, J=7 Hz), to 1.38 (2H, q, J=7 Hz), is 1.31 (6H, d, J=6 Hz), of 0.75 to 0.67 (1H, m), 0,47-of 0.43 (2H, m), of 0.07 to 0.04 (2H, m).

(Example 60) 4-(3-Cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide (Illustrative compound No. 1-327)

Carried out the same reaction as in example 9 (9c), using N-[4-(3-cyclopropylmethoxy)benzoyl]glycine (277 mg)obtained in example 59 (59a), and 4-(triptoreline)benzalde the guide (150 μl) to obtain the corresponding oxazolone (224 mg). Then carried out the same reaction as in example 9 (9d), using 151 mg of the specified oxazolone to obtain 123 mg specified in the title compound (colorless amorphous solid).

MS (FAB) m/z: 493 [M+H]+.

Range1H-nuclear magnetic resonance (500 MHz, CDCl3) δ ppm: to $ 7.91 (1H, users), 7,78 (2H, d, J=9 Hz), 7,40 (2H, d, J=9 Hz), 7,16 (2H, d, J=8 Hz), 7,01 (1H, s), 6,92 (2H, d, J=9 Hz), 6,78 (1H, t, J=5 Hz), of 4.05 (2H, t, J=6 Hz), of 3.78 (2H, userc, J=4 Hz), to 3.49 (2H, q, J=4 Hz), 3,05 (1H, ushort, J=6 Hz), with 1.92 (2H, Quint, J=7 Hz), of 1.39 (2H, q, J=7 Hz), 0.74 and is 0.67 (1H, m), 0,47-of 0.43 (2H, m), of 0.07 to 0.04 (2H, m).

(Example 61) 4-(3-Cyclopropylmethoxy)-N-((Z)-2-[4-(2,2-diflorasone)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-330)

Carried out the same reaction as in example 9 (9c), using N-[4-(3-cyclopropylmethoxy)benzoyl]glycine (277 mg)obtained in example 59 (59a), and 4-(2,2-diflorasone)benzaldehyde (196 mg)obtained in example 4 (4a), to obtain the corresponding oxazolone (244 mg). Then carried out the same reaction as in example 9 (9d), using 150 mg of the specified oxazolone to obtain 84 mg specified in the title compound (white powder).

TPL: 149-151ºC.

Range1H-nuclear magnetic resonance (500 MHz, CDCl3) δ ppm: 7,81-7,79 (3H, m), of 7.36 (2H, d, J=9 Hz), 7,06 (1H, s), 6,93 (2H, d, J=9 Hz), 6,86 (2H, d, J=8 Hz), 6,74 (1H, t, J=6 Hz), 6,07 (1H, TT, J=55 Hz, Hz), of 4.16 (2H, TD, J=13 Hz, 4 Hz), of 4.05 (2H, t, J=7 Hz), of 3.77 (2H, t, J=5 Hz), 3,50 (2H, q, J=5 Hz), with 1.92 (2H, Quint, J=7 Hz), of 1.39 (2H, q, J=7 Hz), 0,76 was 0.68 (1H, m), of 0.47 to 0.44 (2H, m), of 0.07 to 0.04 (2H, m,).

(Example 62 N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(3-cyclopropylmethoxy)benzamide (Illustrative compound No. 1-326)

Carried out the same reaction as in example 9 (9c), using N-[4-(3-cyclopropylmethoxy)benzoyl]glycine (277 mg)obtained in example 59 (59a), and 4-cyclopropylbenzene (154 mg)obtained in example 5, to obtain the corresponding oxazolone (260 mg). Then carried out the same reaction as in example 9 (9d), using 151 mg of the specified oxazolone to obtain 148 mg specified in the title compound (white powder).

TPL: 170-171ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,80 (2H, d, J=9 Hz), to 7.67 (1H, users), 7,29 (2H, d, J=8 Hz), 7,06 (1H, s), 7,03 (2H, d, J=9 Hz), 6,94 (2H, d, J=8 Hz), is 6.61 (1H, ushort, J=5 Hz), 4,06 (2H, t, J=7 Hz), with 3.79 (2H, users), 3,51 (2H,, kV, J=5 Hz)to 3.09 (1H, users), 1,96-of 1.84 (3H, m)of 1.39 (2H, q, J=7 Hz), 1,02 to 0.97 (2H, m), to 0.73 and 0.68 (3H, m), 0,47-of 0.43 (2H, m), of 0.07 to 0.04 (2H, m).

(Example 63 N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(2-tamilarasi)]benzamide (Illustrative compound No. 1-283)

(63a) N-{4-[2-(2-Thienyl)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 9 (9a) and(9b), using methyl 4-hydroxybenzoate (1.55 g, 10.2 mmol) and 2-(2-thienyl)ethanol (1.20 ml, about 10.8 mmol) to obtain 2,02 g specified in the title compound (white powder, yield: 65%).

[In this case used a 2H. aqueous sodium hydroxide solution instead of the aqueous solution of 2M lithium hydroxide.]

(63b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(2-tamilarasi)]benzamide

Carried out the same reaction as in example 9 (9c), using N-{4-[2-(2-thienyl)ethoxy]benzoyl}glycine (251 mg)obtained in example 63 (63a), and 4-isopropoxybenzonitrile (139 μl) to obtain the corresponding oxazolone (191 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 134 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 495 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,65 (1H, users), of 7.96 (2H, d, J=9 Hz), 7,87 (1H, ushort, J=6 Hz), was 7.45 (2H, d, J=9 Hz), 7,35 (1H, DD, J=5 Hz, 2 Hz), 7,16 (1H, s), 7,05 (2H, d, J=9 Hz), 6,99-to 6.95 (2H, m), at 6.84 (2H, d, J=9 Hz), 4,63-of 4.57 (2H, m), 4,27 (2H, t, J=6H), 3,42 (2H, q, J=6 Hz), or 3.28 (2H, t, J=6 Hz), 3,21 (2H, q, J=6 Hz), to 1.22 (6H, d, J=6 Hz).

(Example 64) N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(2-thienyl)ethoxy]benzamide (Illustrative compound No. 1-288)

Carried out akuu same response, as in example 9 (9c), using N-{4-[2-(2-thienyl)ethoxy]benzoyl}glycine (279 mg)obtained in example 63 (63a), and 4-cyclopropylbenzene (171 mg)obtained in example 5, to obtain the corresponding oxazolone (268 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 124 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 477 [M+H]+.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: 9,71 (1H, s), 7,98-7,94 (3H, m), 7,41 (2H, d, J=8 Hz), 7,37 (1H, DD, J=5 Hz, 1 Hz), 7,17 (1H, s), 7,07 (2H, d, J=9 Hz), 7,02 (2H, d, J=8 Hz), 7,00-6,97 (2H, m), 4,63 (1H, t, J=5 Hz), 4,29 (2H, t, J=6 Hz), 3.43 points (2H, q, J=6 Hz), 3,29 (2H, t, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 1,90-of 1.84 (1H, m), 0,95-of 0.91 (2H, m), 0.67 and-of 0.64 (2H, m).

(Example 65 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[2-(1H-pyrrol-1-yl)ethoxy]benzamide (Illustrative compound No. 1-295)

(65a) N-{4-[2-(1H-Pyrrol-1-yl)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 23 (23a), using methyl 4-hydroxybenzoate (913 mg, 6,00 mmol) and 2-(1H-pyrrol-1-yl)ethanol (692 μl, 6,60 mmol) to obtain the corresponding derivative of benzoic acid (1.23 g, yield: 89%). Then carried out the same reaction as in example 23 (23b)using 578 mg (2,50 mmol) of the specified derivative with getting mg specified in the title compound (colorless crystalline solid, yield: 79%).

(65b) N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[2-(1H-pyrrol-1-yl)ethoxy]benzamide

Carried out the same reaction as in example 23 (23c), using N-{4-[2-(1H-pyrrol-1-yl)ethoxy]benzoyl}glycine (120 mg)obtained in example 65 (65a), and 4-(triptoreline)benzaldehyde (63 μl) to obtain the corresponding oxazolone (128 mg). Then carried out the same reaction as in example 23 (23d), using the total number of the specified oxazolone to obtain 91 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 504 [M+H]+.

Range1H-NMR (400 MHz, CDCl3) δ ppm: at 8.36 (1H, users), of 7.75 (2H, d, J=8 Hz), 7,35 (2H, d, J=9 Hz), 7,10 (2H, d, J=8 Hz), 7,01 (1H, t, J=6 Hz), 6.87 in (1H, s), PC 6.82 (2H, d, J=9 Hz), 6.75 in (2H, t, J=2 Hz), 6,18 (2H, t, J=2 Hz), 4,28 (2H, t, J=5 Hz), 4,20 (2H, t, J=5 Hz), 3,70 (2H, t, J=5 Hz), 3,39 (2H, q, J=5 Hz), 3,26 (1H, users).

(Example 66) N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(1H-pyrrol-1-yl)ethoxy]benzamide (Illustrative compound No. 1-297)

Carried out the same reaction as in example 23 (23c), using N-{4-[2-(1H-pyrrol-1-yl)ethoxy]benzoyl}glycine (173 mg)obtained in example 65 (65a), and 4-cyclopropylbenzene (92 mg)obtained in example 5, to obtain the corresponding oxazolone (178 mg). Then carried out the same reacts the Yu, as in example 23 (23d), using the total number of the specified oxazolone to obtain 118 mg specified in the title compound (pale yellow amorphous solid).

MS (FAB) m/z: 460 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,67 (1H, users), to 7.93 (2H, d, J=9 Hz), 7,92 (1H, t, J=6 Hz), 7,38 (2H, d, J=9 Hz), 7,14 (1H, s), 7,01 (2H, d, J=9 Hz), of 6.99 (2H, d, J=9 Hz), PC 6.82 (2H, t, J=2 Hz), 5,98 (2H, t, J=2 Hz), br4.61 (1H, t, J=5 Hz), 4,32-4.26 deaths (4H, m), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 1,89 of-1.83 (1H, m), 0,95-of 0.90 (2H, m), 0.67 and to 0.63 (2H, m).

(Example 67) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(3-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-146)

(67a) N-{4-[2-(3-Methoxyphenyl)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 9 (9a) and (9b), using methyl 4-hydroxybenzoate (4.26 deaths grams of 28.0 mmol) and 2-(3-methoxyphenyl)ethanol (4,32 ml, was 31.0 mmol) to obtain the 8,54 g specified in the title compound (colorless crystalline substance, yield: 92%).

(67b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(3-methoxyphenyl)ethoxy]benzamide

Carried out the same reaction as in example 9 (9c), using N-{4-[2-(3-methoxyphenyl)ethoxy]benzoyl}glycine (264 mg)obtained in example 67 (67a), and 4-isopropoxybenzonitrile (138 mg) to obtain the corresponding oxazolone (236 mg). ZAT is m carried out the same reaction, as in example 9 (9d), using 151 mg of the specified oxazolone to obtain 138 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 519 [M+H]+.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,31 (1H, users), of 7.70 (2H, d, J=9 Hz), 7,17 for 7.12 (3H, m), 7,05 (1H, ushort, J=6 Hz), for 6.81 (1H, s), 6,78-6,69 (5H, m), 6,63 (2H, d, J=9 Hz), 4,39 (1H, Sept, J=6 Hz), 4,08 (2H, t, J=7 Hz), and 3.72 (3H, C)3,57 (1H, userd, J=5 Hz), 3,53 (2H, userd, J=4 Hz), 3,24 (2H, q, J=4 Hz), 2,98 (2H, t, J=7 Hz), to 1.21 (6H, d, J=6 Hz).

(Example 68 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[2-(3-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-149)

Carried out the same reaction as in example 9 (9c), using N-{4-[2-(3-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg)obtained in example 67 (67a), and 4-(triptoreline)benzaldehyde (200 mg) to obtain the corresponding oxazolone (416 mg). Then carried out the same reaction as in example 9 (9d), using 121 mg of the specified oxazolone to obtain 96 mg specified in the title compound (colorless amorphous solid).

MS (FAB) m/z: 545 [M+H]+.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: 9,80 (1H, users), 8,08 (1H, t, J=6 Hz), of 7.97 (2H, d, J=9 Hz), the 7.65 (2H, d, J=9 Hz), 7,34 (2H, d, J=8 Hz), 7.23 percent (1H, t, J=8 Hz), 7,18 (1H, s), 7,06 (2H, d, J=9 Hz), 6,93 (1H, s)6,91 (1H, d, J=9 Hz), for 6.81 (1H, DD, =8 Hz, 2 Hz)and 4.65 (1H, t, J=6 Hz), the 4.29 (2H, t, J=7 Hz), of 3.75 (3H, s), 3,47 (2H, q, J=6 Hz)at 3.25 (2H, q, J=6 Hz), totaling 3.04 (2H, t, J=7 Hz).

(Example 69) N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(3-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-155)

Carried out the same reaction as in example 9 (9c), using N-{4-[2-(3-methoxyphenyl)ethoxy]benzoyl}glycine (231 mg)obtained in example 67 (67a), and 4-cyclopropylbenzene (108 mg)obtained in example 5, to obtain the corresponding oxazolone (249 mg). Then carried out the same reaction as in example 9 (9d), using 101 mg of the specified oxazolone to obtain 97 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 501 [M+H]+.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: RS 9.69 (1H, users), of 7.96 (2H, d, J=9 Hz), 7,94 (1H, t, J=5 Hz), 7,41 (2H, d, J=8 Hz), 7.23 percent (1H, t, J=8 Hz), 7,17 (1H, s), 7,05 (2H, d, J=8 Hz), 7,02 (2H, d, J=8 Hz), 6,92-of 6.90 (2H, m), for 6.81 (1H, DD, J=8 Hz, 2 Hz), to 4.62 (1H, t, J=6 Hz), 4,28 (2H, t, J=7 Hz), of 3.75 (3H, s), 3,44 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), totaling 3.04 (2H, t, J=7 Hz), to 1.87 (1H, Sept, J=5 Hz), 0,95-of 0.91 (2H, m,), 0,67-of 0.64 (2H, m).

(Example 70) N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(3-methoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-161)

Carried out the same reaction as in example 9 (9c), using N-{4-[2-(methoxyphenyl)ethoxy]benzoyl}glycine (329 mg), obtained in example 67 (67a), and 4-chlorobenzaldehyde (148 mg) to obtain the corresponding oxazolone (396 mg). Then carried out the same reaction as in example 9 (9d), using 108 mg of the specified oxazolone to obtain 90 mg specified in the title compound (white powder).

TPL: 54-56ºC.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: 9,76 (1H, users), of 8.06 (1H, t, J=6 Hz), 7,95 (2H, d, J=9 Hz), 7,53 (2H, d, J=9 Hz), 7,39 (2H, d, J=8 Hz), 7.23 percent (1H, t, J=8 Hz), to 7.15 (1H, s), 7,05 (2H, d, J=9 Hz), 6,92 (1H, s)6,91 (1H, d, J=9 Hz), for 6.81 (1H, DD, J=8 Hz, 2 Hz), with 4.64 (1H, t, J=6 Hz), 4,28 (2H, t, J=7 Hz), of 3.75 (3H, s), of 3.45 (2H, q, J=6 Hz), 3,24 (2H, q, J=6 Hz), totaling 3.04 (2H, t, J=7 Hz).

(Example 71) 4-[2-(1,3-Benzodioxol-5-yl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-331)

(71a) N-{4-[2-(1,3-Benzodioxol-5-yl)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (300 mg, 1,19 mmol)obtained in example 1 (1a)and 2-(1,3-benzodioxol-5-yl)ethanol (which is a compound disclosed in Tetrahedron (2003), 59, 3369-3378, 239 mg, 1.44 mmol) to give 356 mg specified in the title compound (pale red powder, yield: 87%).

(71b) 4-[2-(1,3-Benzodioxol-5-yl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

p> Carried out the same reaction as in example 1 (1c), using N-{4-[2-(1,3-benzodioxol-5-yl)ethoxy]benzoyl}glycine (179 mg)obtained in example 71 (71a), and 4-isopropoxybenzonitrile (95 μl) to obtain the corresponding oxazolone (212 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 94 mg specified in the title compound (pale yellow amorphous solid).

MS (FAB) m/z: 533 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: for 9.64(1H, users), 7,95 (2H, d, J=9 Hz), 7,86 (1H, t, J=6 Hz), was 7.45 (2H, d, J=9 Hz), 7,16 (1H, s), 7,03 (2H, d, J=9 Hz), 6,93 (1H, d, J=2 Hz), 6,85 (1H, d, J=2 Hz), 6,83 (2H, s), 6,77 (1H, DD, J=8 Hz, 2 Hz), 5,96 (2H, s), 4,63-of 4.57 (2H, m), 4,22 (2H, t, J=7 Hz), 3,42 (2H, t, J=6 Hz), 3,21 (2H, q, J=6 Hz), 2,98 (2H, t, J=7 Hz), of 1.23 (6H, d, J=6 Hz).

(Example 72) 4-[2-(1,3-Benzodioxol-5-yl)ethoxy]-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-334)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(1,3-benzodioxol-5-yl)ethoxy]benzoyl}glycine (180 mg)obtained in example 71 (71a), and 4-cyclopropylbenzene (95 mg)obtained in example 5, to obtain the corresponding oxazolone (192 mg). Then carried out the same reaction as in example 1 (1d), using only the number specified is about oxazolone to obtain 123 mg specified in the title compound (white powder).

TPL: 113-115ºC.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: RS 9.69 (1H, users), 7,95 (2H, d, J=8 Hz), 7,94 (1H, t, J=6 Hz), 7,41 (2H, d, J=8 Hz), 7,17 (1H, s),? 7.04 baby mortality (2H, d, J=9 Hz), 7,02 (2H, d, J=8 Hz), to 6.95 (1H, d, J=1 Hz), 6,85 (1H, d, J=8 Hz,), 6,79 (1H, DD, J=8 Hz, 1 Hz), 5,98 (2H, s), to 4.62 (1H, ushort, J=5 Hz)to 4.23 (2H, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 2,98 (2H, t, J=7 Hz), to 1.87 (1H, Quint, J=3 Hz), 0,95-0,91 (2H, m), 0.67 and-of 0.64 (2H, m).

(Example 73) 4-[2-(4-Forfinal)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-214)

(73a) N-{4-[2-(4-Forfinal)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (249 mg, 0,991 mmol)obtained in example 1 (1a)and 2-(4-forfinal)ethanol (150 μl, 1.20 mmol) to obtain 241 mg specified in the title compound (yield: 91%).

(73b) 4-[2-(4-Forfinal)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-forfinal)ethoxy]benzoyl}glycine (250 mg)obtained in example 73 (73a), and 4-isopropoxybenzonitrile (137 μl) to obtain the corresponding oxazolone (215 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 122 mg of the criminal code the data in the title compound (white amorphous solid).

MS (FAB) m/z: 507 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: for 9.64 (1H, users), 7,95 (2H, d, J=9 Hz), 7,86 (1H, ushort, J=6 Hz), was 7.45 (2H, d, J=9 Hz), was 7.36 (2H, DD, J=9 Hz, 6 Hz), 7,16 (1H, s), 7,12 (2H, t, J=9 Hz), 7,03 (2H, d, J=9 Hz), at 6.84 (2H, d, J=9 Hz), 4,63-of 4.57 (2H, m), 4.26 deaths (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,05 (2H, t, J=7 Hz), to 1.22 (6H, d, J=6 Hz).

(Example 74) 4-[2-(4-Forfinal)ethoxy]-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide (Illustrative compound No. 1-217)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-forfinal)ethoxy]benzoyl}glycine (317 mg)obtained in example 73 (73a), and 4-(triptoreline)benzaldehyde (200 mg) to obtain the corresponding oxazolone (360 mg). Then carried out the same reaction as in example 1 (1d), using 109 mg of the specified oxazolone to obtain 92 mg specified in the title compound (colorless amorphous solid).

MS (FAB) m/z: 533 [M+H]+.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: 9,79 (1H, users), 8,07 (1H, t, J=5 Hz), 7,95 (2H, d, J=8 Hz), to 7.64 (2H, d, J=9 Hz), 7,38 (2H, DD, J=8 Hz, 6 Hz), 7,34 (2H, d, J=8 Hz), 7,16 (1H, s), 7,14 (2H, t, J=9 Hz), 7,05 (2H, d, J=9 Hz), with 4.64 (1H, t, J=5 Hz), 4,27 (2H, t, J=7 Hz), of 3.45 (2H, q, J=6 Hz), 3,24 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz).

(Example 75), N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-forfinal)e is the hydroxy]benzamide (Illustrative compound No. 1-223)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-forfinal)ethoxy]benzoyl}glycine (254 mg)obtained in example 73 (73a), and 4-cyclopropylbenzene (130 mg)obtained in example 5, to obtain the corresponding oxazolone (226 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 166 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 489 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,67 (1H, s), 7,95-to $ 7.91 (3H, m), 7,40-7,34 (4H, m), to 7.15 (1H, s), 7,13 (2H, t, J=9 Hz), 7,03 (2H, d, J=9 Hz), of 6.99 (2H, d, J=9 Hz), br4.61 (1H, t, J=5 Hz), 4.26 deaths (2H, t, J=7 Hz), 3,42 (2H, kV, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,05 (2H, t, J=7 Hz), 1,90 of-1.83 (1H, m), 0,95-of 0.90 (2H, m), 0.67 and to 0.63 (2H, m).

(Example 76) N-((Z)-2-[4-(Cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-forfinal)ethoxy]benzamide (Illustrative compound No. 1-215)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-forfinal)ethoxy]benzoyl}glycine (203 mg)obtained in example 73 (73a), and 4-(cyclopropylamino)benzaldehyde (116 mg)obtained in example 6 (6c), to obtain the corresponding oxazolone (179 mg). Then carried out the same reaction as in example 1 (1d), using the total number indicated the data of oxazolone to obtain 132 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 505 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,65 (1H, s), 7,95 (2H, d, J=9 Hz), 7,89 (1H, ushort, J=6 Hz), 7,47 (2H, d, J=9 Hz), was 7.36 (2H, DD, J=9 Hz, 6 Hz), 7,17 (1H, s), 7,12 (2H, t, J=9 Hz), 7,03 (2H, d, J=9 Hz), 6,98 (2H, d, J=9 Hz), to 4.62 (1H, t, J=5 Hz), 4.26 deaths (2H, t, J=7 Hz), 3,81 (1H, Sept, J=3 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,05 (2H, t, J=7 Hz), 0,78-to 0.73 (2H, m), 0,63-of 0.59 (2H, m).

(Example 77) N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-forfinal)ethoxy]benzamide (Illustrative compound No. 1-229)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-forfinal)ethoxy]benzoyl}glycine (317 mg)obtained in example 73 (73a), and 4-chlorobenzaldehyde (148 mg) to obtain the corresponding oxazolone (342 mg). Then carried out the same reaction as in example 1 (1d), using 110 mg of the specified oxazolone to obtain 98 mg specified in the title compound (white powder).

TPL: 60-63ºC.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: 9,76 (1H, users), of 8.06 (1H, t, J=5 Hz), 7,95 (2H, d, J=9 Hz), 7,54 (2H, d, J=8 Hz), 7,40-7,37 (4H, m), to 7.15 (1H, s), to 7.15 (2H, t, J=9 Hz), 7,05 (2H, d, J=9 Hz), with 4.64 (1H, t, J=5 Hz), 4,27 (2H, t, J=7 Hz), of 3.45 (2H, q, J=6 Hz), 3,24 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz).

(Example 78) 4-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-199)

(78a) N-{4-[2-(4-Chlorophenyl)ethoxy]benzoyl}glycine

(Tributylphosphine)acetonitrile (1.31 g, 4,89 mmol) was added to a solution of toluene (12 ml)containing ethyl ester of N-(4-hydroxybenzoyl)glycine (which is a compound disclosed in J. Med. Chem. (1999), 42, 1041-1052, 663 mg of 2.97 mmol) and 2-(4-chlorophenyl)ethanol (447 μl, 3,30 mmol). The mixture was stirred at 100ºC for 4 hours and then to the mixture was added ethyl acetate. The resulting mixture was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated and the obtained residue was purified column chromatography on silica gel (hexane→hexane:ethyl acetate, 4:1 to 3:1 and then ethyl acetate.about.) obtaining powder (1.23 g). All the number specified powder was dissolved in ethanol (12 ml), and then to the mixture was added an aqueous solution of 2 M lithium hydroxide (to 3.00 ml of 6.00 mmol). The resulting mixture was stirred at 60ºC for 30 minutes and then to the mixture was added 10% hydrochloric acid solution (2.1 ml) under cooling with ice. The precipitate was collected by filtration, washed successively with water and diisopropyl ether and then dried under reduced pressure to get 861 mg specified in the connection header (powder, yield: 87%).

(78b) 4-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide

Implementation of the conduct the same reaction, as in example 1 (1c), using N-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (267 mg)obtained in example 78 (78A), and 4-(deformedarse)benzaldehyde (111 μl) to obtain the corresponding oxazolone (333 mg). Then carried out the same reaction as in example 1 (1d), using 118 mg of the specified oxazolone to obtain 91 mg specified in the title compound (white powder).

TPL: 160-162ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,71 (1H, users), of 8.00 (1H, ushort, J=6 Hz), 7,92 (2H, d, J=9 Hz), 7,56 (2H, d, J=9 Hz), 7,35 (4H, s), 7.23 percent (1H, t, J=74 Hz), 7,16 (1H, s), 7,11 (2H, d, J=9 Hz), 7,02 (2H, d, J=9 Hz), to 4.62 (1H, t, J=5 Hz), 4.26 deaths (2H, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 3,05 (2H, t, J=7 Hz).

(Example 79) 4-[2-(4-Chlorophenyl)ethoxy]-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide (Illustrative compound No. 1-200)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (234 mg)obtained in example 78 (78A), and 4-(triptoreline)benzaldehyde (110 μl) to obtain the corresponding oxazolone (208 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 160 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 549 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,76 (1H, s), of 8.04 (1H, ushort, J=5 Hz), 7,92 (2H, d, J=9 Hz), to 7.61 (2H, d, J=9 Hz), 7,35 (4H, s), 7,31 (2H, d, J=9 Hz), 7,14 (1H, s), 7,02 (2H, d, J=9 Hz), to 4.62 (1H, t, J=5 Hz), 4.26 deaths (2H,, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz).

(Example 80) 4-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-206)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (238 mg)obtained in example 78 (78A), and 4-cyclopropylbenzene (124 mg)obtained in example 5, to obtain the corresponding oxazolone (215 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 173 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 505 [M+H]+.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: RS 9.69 (1H, s), 7,97-to 7.93 (3H, m), 7,41 (2H, d, J=8 Hz), 7,38 (4H, s), 7,17 (1H, s), 7,05 (2H, d, J=9 Hz), 7,01 (2H, d, J=8 Hz), 4,63 (1H, t, J=5 Hz), 4,28 (2H, t, J=6 Hz), 3,44 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), of 3.07 (2H, t, J=6 Hz), 1,89-of 1.84 (1H, m), 0,95-of 0.91 (2H, m), 0.67 and-of 0.64 (2H, m).

(Example 81) 4-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-198)

Did W the reaction, as in example 1 (1c), using N-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (267 mg)obtained in example 78 (78A), and 4-(cyclopropylamino)benzaldehyde (136 mg)obtained in example 6 (6s), to obtain the corresponding oxazolone (341 mg). Then carried out the same reaction as in example 1 (1d), using 115 mg of the specified oxazolone to obtain 79 mg specified in the title compound (light yellow powder).

TPL: 66-69ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,65 (1H, users), 7,95 (2H, d, J=9 Hz), 7,89 (1H, ushort, J=6 Hz), 7,47 (2H, d, J=9 Hz), was 7.36 (4H, s), 7,17 (1H, s), 7,03 (2H, d, J=9 Hz), 6,97 (2H, d, J=9 Hz), to 4.62 (1H, t, J=6 Hz), 4.26 deaths (2H,, t, J=7 Hz), 3,81 (1H, Sept, J=3 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz), 0,78-to 0.73 (2H, m), 0,63-of 0.59 (2H, m).

(Example 82) 4-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-212)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (267 mg)obtained in example 78 (78A), and 4-chlorobenzaldehyde (118 mg) to obtain the corresponding oxazolone (301 mg). Then carried out the same reaction as in example 1 (1d), using 110 mg of the specified oxazolone with receiving 50 mg specified in the title compound (colorless crystalline solid).

TPL 137-139ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,72 (1H, users), of 8.04 (1H, ushort, J=6 Hz), to $ 7.91 (2H, d, J=9 Hz), to 7.50 (2H, d, J=9 Hz), 7,37 (2H, d, J=9 Hz), 7,35 (4H, s), 7,11 (1H, s), 7,02 (2H, d, J=9 Hz), 4,63 (1H, t, J=5 Hz), 4.26 deaths (2H,, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz).

(Example 83) 4-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1-196)

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (236 mg)obtained in example 78 (78A), and 4-ethoxybenzaldehyde (107 μl) to obtain the corresponding oxazolone (183 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 124 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 509 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: for 9.64 (1H, s), 7,94 (2H, d, J=9 Hz), 7,87 (1H, ushort, J=6 Hz), was 7.45 (2H, d, J=9 Hz), was 7.36 (4H, s), 7,16 (1H, s), 7,02 (2H, d, J=9 Hz), 6,85 (2H, d, J=9 Hz), br4.61 (1H, t, J=6 Hz), 4,27 (2H,, t, J=7 Hz), 3,99 (2H, q, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), 3,06 (2H, t, J=7 Hz), of 1.28 (3H, t, J=7 Hz).

(Example 84) 4-[2-(4-Cyclopropylmethyl)ethoxy]-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (Illustrative compound No. 1 to 240)

(84a) of Methyl 4-[2-(4-bromophenyl)ethoxy]benzoate

Methyl 4-hydroxybenzoate (1,09 g, 7,14 mmol), 2-(4-bromophenyl)ethanol (1.44 g, 7,14 mmol) and triphenylphosphine (of 2.06 g, 7,86 mmol) was dissolved in THF (44 ml), and then to the mixture was added diethylazodicarboxylate (3,57 ml, 40% solution in toluene, 7,86 mmol) with stirring under ice cooling. The mixture was then stirred at room temperature for 2 days and then the reaction solution was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate 19:1 to 9:1, vol/about.) with the receipt of 1.75 g specified in the title compound (white powder, yield: 73%).

Range1H-NMR (400 MHz, CDCl3) δ ppm: to 7.95 (2H, d, J=9 Hz), 7,42 (2H, d, J=8 Hz), 7,14 (2H, d, J=9 Hz), 6.87 in (2H, d, J=9 Hz), 4,19 (2H, t, J=7 Hz), a 3.87 (3H, s), 3,06 (2H, t, J=7 Hz).

(84b) 4-[2-(4-Cyclopropylmethyl)ethoxy]benzoic acid

Cyclopropylamine carried out in accordance with the method, reskrim in Tetrahedron Lett. (2002), 43, 6987-6990. Cyclopropylboronic (298 mg, 3.46 mmol) was dissolved in a mixed solution of toluene (10 ml) and water (0.54 ml) and to the mixture was added methyl 4-[2-(4-bromophenyl)ethoxy]benzoate (893 mg, of 2.66 mmol)obtained in example 84 (84a), tricyclohexylphosphine (15% solution in toluene of 0.58 ml, 0,266 mmol), potassium phosphate (2.16 g, 9,86 mmol) and palladium acetate (45 mg, 0,200 mmol). The mixture was stirred at 100ºC for 2 hours and then cooled on the room temperature. After adding the above-mentioned ethyl acetate, and the mixture was washed successively with water (twice) and saturated saline and dried over anhydrous sodium sulfate. The solvent is then evaporated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate, 9:1, vol/about.) to obtain the corresponding cyclopropanes derived (544 mg, of 1.84 mmol).

All the number cyclopropene derivative was dissolved in ethanol (4.59 ml) and to the mixture was added an aqueous solution of 2 M lithium hydroxide (1,84 ml, to 3.67 mmol). The mixture was stirred at 60ºC for 1 hour and then cooled to room temperature and to the mixture was added water and 1N. hydrochloric acid solution (to 3.67 ml, to 3.67 mmol). The precipitate was collected by filtration and dried by heating under reduced pressure to obtain 448 mg specified in the title compound (yield: 60%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 12,68 (1H, users), 7,86 (2H, d, J=9 Hz), 7,19 (2H, d, J=8 Hz), 7,01 (2H, d, J=7 Hz), of 6.99 (2H, d, J=8 Hz), 4,22 (2H, t, J=7 Hz), 2,99 (2H, t, J=7 Hz), a 1.88 (1H, Quint, J=4 Hz), 0,93-0,89 (2H,, m), 0,64 is 0.60 (2H, m).

(84c) N-{4-[2-(4-Cyclopropylmethyl)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 9 (9b), using 4-[2-(4-cyclopropylmethyl)ethoxy]benzoic acid (444 mg, 1.57 mmol)obtained in example 84 (84b), with 492 mg specified in the header the compound (white powder, yield: 92%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 12,56 (1H, users), 8,67 (1H, ushort, J=6 Hz), 7,82 (2H, d, J=9 Hz), 7,20 (2H, d, J=8 Hz), 7,01 (2H, d, J=8 Hz), 7,00 (2H, d, J=8 Hz), is 4.21 (2H, t, J=7 Hz), 3,88 (2H, d, J=5 Hz)to 2.99 (2H, t, J=7 Hz), a 1.88 (1H, Quint, J=5 Hz), 0,93-0,89 (2H, m), 0,65-0,61 (2H, m).

(84d) 4-[2-(4-Cyclopropylmethyl)ethoxy]-N-((Z)-2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide

Carried out the same reaction as in example 9 (9c), using N-{4-[2-(4-cyclopropylmethyl)ethoxy]benzoyl}glycine (150 mg)obtained in example 84 (84c), and 4-cyclopropylbenzene (68 mg)obtained in example 5, to obtain the corresponding oxazolone (100 mg). Then carried out the same reaction as in example 9 (9d), using 97 mg of the specified oxazolone to obtain 77 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 511 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: to 9.66 (1H, users), 7,94-of 7.90 (3H, m), 7,39 (2H, d, J=8 Hz), 7,19 (2H, d, J=8 Hz), 7,14 (1H, s), 7.03 is-6,98 (6H, m), br4.61 (1H, t, J=5 Hz)to 4.23 (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, kV, J=6 Hz)of 3.00 (2H, t, J=7 Hz), 1,91 of-1.83 (2H, m), 0,95-0,89 (4H, m), 0.67 and-0,61 (4H, m).

(Example 85) N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-cyclopropylmethyl)ethoxy]benzamide (Illustrative compound No. 1-246)

Carried out the same reaction as in p is the emer 9 (9c), using N-{4-[2-(4-cyclopropylmethyl)ethoxy]benzoyl}glycine (150 mg)obtained in example 84 (84c), and 4-chlorobenzaldehyde (65 mg) to obtain the corresponding oxazolone (112 mg). Then carried out the same reaction as in example 9 (9d), using 109 mg of the specified oxazolone to obtain 90 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 506 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,72 (1H, users), 8,03 (1H, t, J=6 Hz), to $ 7.91 (2H, d, J=9 Hz), to 7.50 (2H, d, J=9 Hz), 7,37 (2H, d, J=9 Hz), 7,18 (2H, d, J=8 Hz), 7,12 (1H, s), 7,01 (2H, d, J=9 Hz), 7,00 (2H, d, J=8 Hz,), to 4.62 (1H, t, J=5 Hz), 4,22 (2H, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz)of 3.00 (2H, t, J=7 Hz), 1,91-of 1.84 (1H, m), 0,94-0,89 (2H, m), 0,65-0,61 (2H, m).

(Example 86) 4-{2-[3-(Dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide (Illustrative compound No. 1-183)

(86a) N-(4-{2-[3-(Dimethylamino)phenyl]ethoxy}benzoyl)glycine

Carried out the same reaction as in example 78 (78a), using the ethyl ester of N-(4-hydroxybenzoyl)glycine (which is a compound disclosed in J. Med. Chem. (1999), 42, 1041-1052, 666 mg, 2,98 mmol) and 2-[3-(dimethylamino)phenyl]ethanol (555 mg, to 3.36 mmol) to obtain 783 mg specified in the title compound (white powder, yield: 77%).

(86b) 4-{2-[3-(Dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide

Carried out the same reaction as in example 1 (1c), using N-(4-{2-[3-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (242 mg)obtained in example 86 (86a), and 4-(triptoreline)benzaldehyde (110 μl) to obtain the corresponding oxazolone (245 mg). Carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 192 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 558 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,76 (1H, s), with 8.05 (1H, ushort, J=6 Hz), 7,92 (2H, d, J=9 Hz), a 7.62 (2H, d, J=9 Hz), 7,31 (2H, d, J=8 Hz), 7,14 (1H, s), to 7.09 (1H, t, J=8 Hz), 7,03 (2H, d, J=9 Hz), of 6.68 (1H, users), 6,60 (1H, d, J=7 Hz), to 6.57 (1H, DD, J=8 Hz, 2 Hz), to 4.62 (1H, t, J=5 Hz), 4,25 (2H, t, J=7 Hz), 3,44 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 2,98 (2H, t, J=7 Hz), is 2.88 (6H, s).

(Example 87) N-((Z)-2-(4-Cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[3-(dimethylamino)phenyl]ethoxy}benzamide (Illustrative compound No. 1-189)

Carried out the same reaction as in example 1 (1c), using N-(4-{2-[3-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (242 mg)obtained in example 86 (86a), and 4-cyclopropylbenzene (126 mg)obtained in example 5, to obtain the corresponding oxazolone (222 mg). Carried out the same reaction as in example 1 (1d), using the entire amount of the decree of the aqueous oxazolone to obtain 145 mg specified in the title compound (pale yellow amorphous solid).

MS (FAB) m/z: 514 [M+H]+.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: RS 9.69 (1H, s), 7,97-to 7.93 (3H, m), 7,41 (2H, d, J=8 Hz), 7,17 (1H, s), 7,12 (1H, t, J=8 Hz), 7,05 (2H, d, J=9 Hz), 7,02 (2H, d, J=8 Hz), 6,70 (1H, users), 6,63 (1H, d, J=7 Hz), 6,60 (1H, DD, J=8 Hz, 2 Hz), to 4.62 (1H, t, J=5 Hz), 4,27 (2H, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz)of 3.00 (2H, t, J=7 Hz), 2,89 (6H, s), 1,90-of 1.84 (1H, m), 0,95-of 0.91 (2H, m), 0.67 and-of 0.64 (2H, m).

(Example 88) N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[3-(dimethylamino)phenyl]ethoxy}benzamide (Illustrative compound No. 1-195)

Carried out the same reaction as in example 1 (1c), using N-(4-{2-[3-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (241 mg)obtained in example 86 (86a), and 4-chlorobenzaldehyde (108 mg) to obtain the corresponding oxazolone (227 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 160 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 508 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,72 (1H, s), 8,03 (1H, ushort, J=6 Hz), to $ 7.91 (2H, d, J=9 Hz), to 7.50 (2H, d, J=9 Hz), 7,37 (2H, d, J=9 Hz), 7,11 (1H, s), to 7.09 (1H, t, J=7 Hz), 7,03 (2H, d, J=9 Hz), to 6.67 (1H, users), 6,60 (1H, d, J=7 Hz), to 6.57 (1H, DD, J=8 Hz, 2 Hz), to 4.62 (1H, t, J=6 Hz), 4,25 (2H, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 2,98 (2H, t, J=7 Hz), 2,87 (6H, s).

(Example 89) 4-(4-Atilano the si)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-335)

(89a) N-[4-(4-Ethylenoxy)benzoyl]glycine

The oxidation reaction (which is a method disclosed in Tetrahedron (1987), 43, 4767-4776) was performed using 4-(4-ethylenoxy)benzaldehyde (which is a compound disclosed in J. Med. Chem. (1996), 39, 3984-3997, 500 mg, 2.21 mmol). 2-Methyl-2-butene (940 μl, 8,84 mmol), dihydrate sodium dihydrophosphate (338 mg, of 2.16 mmol) and sodium chlorite (80%, 875 mg, 7,74 mmol) was added to a mixed solution of tert-butanol (3.6 ml) and water (1.0 ml)containing 4-(4-ethylenoxy)benzaldehyde. The resulting mixture was stirred at room temperature and the reaction was completed by addition of 1N. of hydrochloric acid. After extraction with ethyl acetate the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated to obtain 622 mg of 4-(4-ethylenoxy)benzoic acid (white powder, yield: quantitative). Then carried out the same reaction as in example 9 (9b), using the total number of the specified 4-(4-ethylenoxy)benzoic acid with getting 437 mg specified in the title compound (pale red powder, yield: 66%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 12,54 (1H, users), 8,73 (1H, ushort, J=6 Hz), a 7.85 (2H, d, J=9 Hz), 7,25 (2H, d, J=9 Hz), 7,01 (2H, d, J=9 Hz), 6,97 (2H, d, J=9 Hz), 3,90 (2H, d, J=6 Hz), and 2.6 (2H, kV, J=7 Hz), 1,19 (3H, t, J=7 Hz).

(89b) (4Z)-2-[4-(4-Ethylenoxy)phenyl]-4-(4-isopropoxyaniline)-1,3-oxazol-5(4H)-he

A mixture of N-[4-(4-ethylenoxy)benzoyl]glycine (200 mg, 0,668 mmol)obtained in example 89 (89a), and acetic anhydride (0,38 ml, a 4.03 mmol) was stirred at 80ºC for 20 minutes. To the reaction mixture were added ethyl acetate and then the mixture was cooled to room temperature. The solvent is evaporated and then the residue was purified column chromatography on silica gel (hexane:ethyl acetate, 3:1, vol/about.) obtaining 2-[4-(4-ethylenoxy)phenyl]-1,3-oxazol-5(4H)-she (120 mg, 0,427 mmol). The entire quantity of the specified 2-[4-(4-ethylenoxy)phenyl]-1,3-oxazol-5(4H)-it was dissolved in benzene (0.9 ml), and then to the mixture was added 4-isopropoxybenzonitrile (71 mg, 0,432 mmol) and triethylamine (24 μl, 0,172 mmol). The mixture was stirred at 90°C for 2 hours. After adding to the reaction solution of water the mixture was extracted with a mixture solvent of hexane and ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated to obtain 181 mg specified in the connection header (brown oil, yield: 99%).

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,13 (2H, d, J=9 Hz), 8,08 (2H, d, J=9 Hz), 7,22 (2H, d, J=9 Hz), to 7.15 (1H, s), 7,03 (2H, d, J=9 Hz), 7,00 (2H, d, J=9 Hz), 6,94 (2H, d, J=9 Hz), 4,69-to 4.62 (1H, m)to 2.67 (2H, q, J=7 Hz), to 1.38 (6H, d, J=6 Hz), of 1.27 (3H, t, J=7 Hz).

(89c) 4-(4-Ethylenoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

Carried out the same reaction as in example 9 (9d), with the use of (4Z)-2-[4-(4-ethylenoxy)phenyl]-4-(4-isopropoxyaniline)-1,3-oxazol-5(4H)-she (181 mg, 0,422 mmol)obtained in example 89 (89b), to obtain 115 mg specified in the title compound (pale yellow amorphous solid, yield: 56%).

MS (FAB) m/z: 489 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,73 (1H, users), of 8.00 (2H, d, J=9 Hz), 7,89 (1H, t, J=5 Hz), 7,46 (2H, d, J=9 Hz), 7,27 (2H, d, J=8 Hz), 7,18 (1H, s), 7,02 (2H, d, J=9 Hz), 7,01 (2H, d, J=8 Hz), 6,86 (2H, d, J=9 Hz), with 4.64-4,58 (2H, m), of 3.43 (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 2,62 (2H, q, J=7 Hz), of 1.23 (6H, d, J=6 Hz), of 1.20 (3H, t, J=8 Hz).

(Example 90) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(4-phenylmethoxy)benzamide (Illustrative compound No. 1-307)

(90a) N-[4-(4-Phenylmethoxy)benzoyl]glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (249 mg, 0,991 mmol)obtained in example 1 (1A)and 4-phenylbutane-1-ol (200 μl, of 1.30 mmol) to give 203 mg specified in the title compound (white powder, yield: 63%).

(90b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(4-phenylmethoxy)benzamid

The implementation of the Lyali the same reaction, as in example 1 (1c), using N-[4-(4-phenylmethoxy)benzoyl]glycine (203 mg)obtained in example 90 (90A), and 4-isopropoxybenzonitrile (108 μl) to obtain the corresponding oxazolone (167 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 110 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 517 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,63 (1H, s), 7,94 (2H, d, J=9 Hz), 7,86 (1H, ushort, J=6 Hz), was 7.45 (2H, d, J=9 Hz), 7,29-of 7.25 (2H, m), 7,21-7,14 (4H, m), 7,01 (2H, d, J=9 Hz), at 6.84 (2H, d, J=9 Hz), 4,63-of 4.57 (2H, m), 4,07 (2H, t, J=5 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), to 2.65 (2H, t, J=7 Hz), 1.77 in-1,71 (4H, m)to 1.22 (6H, d, J=6 Hz).

(Example 91 N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(3-phenylpropoxy)benzamide (Illustrative compound No. 1-301)

(91a) methyl ester of N-(4-hydroxybenzoyl)glycine

Oxytrichloride (4,0 ml, at 45.9 mmol) and few drops of DMF were added to a solution of dichloromethane (5 ml)containing 4-benzyloxybenzyl acid (to 2.29 g, 10.0 mmol)with ice cooling and then the mixture was again added dichloromethane (2.5 ml). The mixture was stirred at room temperature for 2.5 hours and the solvent evaporated. The obtained residue was dissolved in dichloromethane (20 ml) and to the mixture was added PR is ice cooling methyl ester of glycine hydrochloride (1.39 g, 11.1 mmol) and N-ethyl-N,N-Diisopropylamine (4,4 ml of 25.2 mmol). The mixture was stirred at room temperature for 18 hours and then to the mixture was added water to complete the reaction. The mixture was extracted with dichloromethane and the organic layers were combined and concentrated. The obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate, 3:4→0:1, vol/about.) obtaining methyl ester N-[4-(benzyloxy)benzoyl]glycine. Then, 1.66 g of the specified ether was dissolved in a mixture solvent of methanol (8 ml) and THF (8 ml). To the mixture was added 20% palladium hydroxide on carbon (168 mg). The mixture was intensively stirred at room temperature in a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite and then concentrated to obtain 1.19 g specified in the title compound (white powder, yield: 85%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm rating: 10.0 (1H, s), 8,65 (1H, ushort, J=6 Hz), 7,71 (2H, d, J=9 Hz), 6,79 (2H, d, J=9 Hz), 3,95 (2H, d, J=6 Hz), 3,63 (3H, s).

(91b) N-[4-(3-Phenylpropoxy)benzoyl]glycine

Methyl ester of N-(4-hydroxybenzoyl)glycine (0.34 g, and 1.63 mmol)obtained in example 91 (91a), 3-phenylpropane-1-ol (0,23 ml, 1.70 mmol) and triphenylphosphine (457 mg, of 1.74 mmol) was dissolved in THF (6.5 ml) and to the mixture was added diethylazodicarboxylate (0,88 ml, 40% solution in toluene of 1.76 mmol) under stirring while cooling Edom. The resulting mixture was stirred at room temperature for 3.5 hours and then the reaction solution was diluted with ethyl acetate, washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated and the obtained residue was purified column chromatography on silica gel (hexane→hexane:ethyl acetate, 5:1, 3:1, 2:1 and 1:1, vol/about.) to obtain 490 mg of an oily substance.

All the number specified oily substance was dissolved in ethanol (7.5 ml) and to the mixture was added 2n. an aqueous solution of sodium hydroxide (3,80 ml of 7.60 mmol). The mixture was stirred at 90ºC for 2 hours and then cooled with ice. The mixture was acidified using concentrated hydrochloric acid and then concentrated. After evaporation of ethanol, the precipitate was collected by filtration, washed with water and dried by heating under reduced pressure to obtain 318 mg specified in the title compound (yield: 63%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 12,6 (1H, users), 8,67 (1H, ushort, J=6 Hz), 7,83 (2H, d, J=9 Hz), 7,30-7,17 (5H, m), 7,01 (2H, d, J=9 Hz), a 4.03 (2H, t, J=7 Hz), 3,90 (2H, d, J=6 Hz), a 2.75 (2H, t, J=7 Hz), 2.06 to a 2.01 (2H, m).

(91c) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(3-phenylpropoxy)benzamid

Carried out the same reaction as in example 1 (1c), using the-W N-[4-(3-phenylpropoxy)benzoyl]glycine (227 mg), obtained in example 91 (91b), and 4-isopropoxybenzonitrile (125 μl) to obtain the corresponding oxazolone (244 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 130 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 503 [M + H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: for 9.64 (1H, s), 7,95 (2H, d, J=9 Hz), 7,86 (1H, ushort, J=5 Hz), was 7.45 (2H, d, J=9 Hz), 7,29-7,17 (5H, m), 7,16 (1H, s), 7,02 (2H, d, J=9 Hz), at 6.84 (2H, d, J=9 Hz), 4,63-of 4.57 (2H, m), Android 4.04 (2H, t, J=6 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), a 2.75 (2H, t, J=7 Hz), 2,08 is 2.01 (2H, m)of 1.23 (6H, d, J=6 Hz).

(Example 92) 4-(2,3-Dihydro-1H-inden-2-ylethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-341)

(92a) N-[4-(2,3-Dihydro-1H-inden-2-ylethoxy)benzoyl]glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (250 mg, 0,995 mmol)obtained in example 1 (1a), and 2,3-dihydro-1H-inden-2-ylmethanol (which is a compound disclosed in J. Med. Chem. (1989), 32, 1326-1334, 165 mg, 1.11 mmol) to obtain 263 mg specified in the title compound (colorless crystalline solid, yield: 85%).

(92b) 4-(2,3-Dihydro-1H-inden-2-ylethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)AMI is about]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

Carried out the same reaction as in example 1 (1c), using N-[4-(2,3-dihydro-1H-inden-2-ylethoxy)benzoyl]glycine (258 mg)obtained in example 92 (92A), and 4-isopropoxybenzonitrile (138 μl) to obtain the corresponding oxazolone (279 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 130 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 515 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,68 (1H, s), 7,98 (2H, d, J=9 Hz), 7,89 (1H, ushort, J=5 Hz), 7,47 (2H, d, J=9 Hz), 7,26-7,24 (2H, m), 7,18 (1H, s), 7,15 for 7.12 (2H, m), was 7.08 (2H, d, J=9 Hz), 6,86 (2H, d, J=9 Hz), with 4.64-4,59 (2H, m), 4,08 (2H, d, J=7 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 3,11 (2H, DD, J=16 Hz, 8 Hz), to 2.94 (1H, Sept, J=7 Hz), of 2.81 (2H, DD, J=16 Hz, 7 Hz), of 1.23 (6H, d, J=6 Hz).

(Example 93) 4-(2-Cyclopent-2-EN-1-ylethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-344)

(93a) N-[4-(2-Cyclopent-2-EN-1-ylethoxy)benzoyl]glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (157 mg, of 0.625 mmol)obtained in example 1 (1a)and 2-cyclopent-2-EN-1-retinol (which is a compound disclosed in J. Org. Chem. (2000), 65, 4241-4250, 85 mg, 0.75 mmol) to obtain 128 is g specified in the title compound (white powder, yield: 72%).

(93b) 4-(2-Cyclopent-2-EN-1-ylethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

Carried out the same reaction as in example 1 (1c), using N-[4-(2-cyclopent-2-EN-1-ylethoxy)benzoyl]-glycine (128 mg)obtained in example 93 (93A), and 4-isopropoxybenzonitrile (76 mg) to obtain the corresponding oxazolone (90 mg). Then carried out the same reaction as in example 1 (1d), using 75 mg of the specified oxazolone to obtain 77 mg specified in the title compound (white powder).

TPL: 67-70ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,94 (1H, users), of 7.82 (2H, d, J=9 Hz), 7,32 (2H, d, J=9 Hz),? 7.04 baby mortality (1H, s)6,91 (2H, d, J=9 Hz), 6,83 (1H, t, J=5 Hz), to 6.80 (2H, d, J=9 Hz), 5,80-USD 5.76 (1H, m), 5,74-5,71 (1H, m)to 4.52 (1H, Sept, J=6 Hz), of 4.05 (2H, t, J=6 Hz), to 3.73 (2H, t, J=5 Hz), of 3.45 (2H, q, J=5 Hz)to 3.33 (1H, users), is 2.88 (1H, ushort, J=6 Hz), 2,43-of 2.26 (2H, m), 2,17-2,07 (1H, m), with 1.92 (1H, Sept, J=7 Hz), 1,80 (1H, Sept, J=7 Hz), 1,54-of 1.45 (1H, m)of 1.32 (6H, d, J=6 Hz).

(Example 94) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenylpropoxy)benzamide (Illustrative compound No. 1-347)

(94a) N-[4-(2-Phenylpropoxy)benzoyl]glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (247 mg, 0,983 mmol)obtained in example 1 (1a)and 2-phenylpropane-1-ol (185 μl, of 1.32 mmol)to give 221 mg specified in the title compound (white powder, yield: 72%).

(94b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenylpropoxy)benzamid

Carried out the same reaction as in example 1 (1c), using N-[4-(2-phenylpropoxy)benzoyl]glycine (219 mg)obtained in example 94 (a), and 4-isopropoxybenzonitrile (121 μl) to obtain the corresponding oxazolone (185 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 134 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 503 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,63 (1H, s), to 7.93 (2H, d, J=9 Hz), the 7.85 (1H, ushort, J=6 Hz), 7,44 (2H, d, J=9 Hz), 7,35-7,29 (4H, m), 7.23 percent-7,20 (1H, m), to 7.15 (1H, s), 7,01 (2H, d, J=9 Hz), 6,83 (2H, d, J=9 Hz), 4.63 to-4,57 (2H, m), 4,21-4,10 (2H, m)to 3.41 (2H, q, J=6 Hz), 3.25 to 3,18 (3H, m)of 1.33 (3H, d, J=7 Hz), to 1.22 (6H, d, J=6 Hz).

(Example 95) 4-(4-Cyclopropylmethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-350)

(95a) of N-[4-(4-Cyclopropylmethoxy)benzoyl]glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (251 mg, 1.00 mmol)obtained in example 1 (1A)and 4-cyclopropylmethyl-1-ol (which is a compound disclosed in J. Med. Chem. (1998), 41, 1112-123, 137 mg, 1.20 mmol) to obtain 257 mg specified in the title compound (white powder, yield: 88%).

(95b) 4-(4-Cyclopropylmethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

Carried out the same reaction as in example 1 (1c), using N-[4-(4-cyclopropylmethoxy)benzoyl]glycine (146 mg)obtained in example 95 (95A), and 4-isopropoxybenzonitrile (86 mg) to obtain the corresponding oxazolone (94 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 55 mg specified in the title compound (white powder).

TPL: 53-55ºC.

Range1H-nuclear magnetic resonance (500 MHz, CDCl3) δ ppm: 8,14 (1H, users), 7,81 (2H, d, J=9 Hz), 7,30 (2H, d, J=9 Hz), of 6.99 (1H, s), 6,97 (1H, t, J=5 Hz), to 6.88 (2H, d, J=9 Hz), 6,77 (2H, d, J=9 Hz), 4,51 (1H, Sept, J=6 Hz), 3,98 (2H, t, J=6 Hz), 3,68 (2H, t, J=5 Hz), 3,40 (2H, q, J=5 Hz), a 1.88-1.77 in (2H, m), 1,62-is 1.51 (2H, m)is 1.31 (6H, d, J=6 Hz), 1,32-of 1.26 (2H, m), 0,73-0,65 (1H, m), 0,45-0,41 (2H, m), of 0.05-0.02 (2H, m).

(Example 96 N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(2-naphthyl)ethoxy]benzamide (Illustrative compound No. 1-353)

(96a) N-{4-[2-(2-Naphthyl)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (251 mg, 1.00 mmol)obtained in example 1 (1a)and 2-(2-what aftil)ethanol (207 mg, 1.20 mmol) to give 314 mg specified in the title compound (white powder, yield: 90%).

(96b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(2-naphthyl)ethoxy]benzamide

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(2-naphthyl)ethoxy]benzoyl}glycine (140 mg)obtained in example 96 (96A), and 4-isopropoxybenzonitrile (69 mg) to obtain the corresponding oxazolone (108 mg). Then carried out the same reaction as in example 1 (1d), with the use of 81 mg of the specified oxazolone to obtain 57 mg specified in the title compound (white powder).

TPL: 78-79ºC.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 8,03 (1H, users), 7,82 to 7.75 (5H, m), 7,69 (1H, s), 7,47-7,37 (3H, m), 7,27 (2H, d, J=9 Hz), 6,97 (1H, s), 6,88-6,86 (3H, m), 6,74 (2H, d, J=9 Hz), 4,47 (1H, Sept, J=6 Hz), 4.26 deaths (2H, t, J=6 Hz), to 3.67 (2H, t, J=5 Hz), 3,39 (2H, q, J=5 Hz)at 3.25 (2H, t, J=6 Hz), of 1.28 (6H, d, J=6 Hz).

(Example 97 N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-{2-[3-(trifluoromethyl)phenyl]ethoxy}benzamide (Illustrative compound No. 1-356)

(97a) of N-(4-{2-[3-(Trifluoromethyl)phenyl]ethoxy}benzoyl)glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (502 mg, 2.00 mmol)obtained in example 1 (1a)and 2-[3-(trifluoromethyl)phenyl]ethanol (330 μl, of 2.20 mmol) with recip is of 368 mg specified in the title compound (white powder, yield: 80%).

(97b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-{2-[3-(trifluoromethyl)phenyl]ethoxy}benzamide

Carried out the same reaction as in example 1 (1c), using N-(4-{2-[3-(trifluoromethyl)phenyl]ethoxy}benzoyl)glycine (368 mg)obtained in example 97 (97A), and 4-isopropoxybenzonitrile (174 μl) to obtain the corresponding oxazolone (338 mg). Carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone with getting 311 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 557 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,68 (1H, s), 7,98 (2H, d, J=7 Hz), 7,89 (1H, ushort, J=5 Hz), 7,74 (1H, s), to 7.68 (1H, d, J=7 Hz), 7,62-of 7.55 (2H, m), 7,47 (2H, d, J=9 Hz), 7,18 (1H, s), 7,06 (2H, d, J=8 Hz), 6,86 (2H, d, J=8 Hz), with 4.64-4,58 (2H, m), 4,34 (2H, d, J=6 Hz), 3.43 points (2H, q, J=6 Hz), 3,24-3,17 (4H, m)of 1.23 (6H, d, J=6 Hz).

(Example 98) 4-[2-(2-Forfinal)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-359)

(98a) N-{4-[2-(2-Forfinal)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (231 mg, 0,919 mmol)obtained in example 1 (1a)and 2-(2-forfinal)ethanol (137 μl, of 1.02 mmol) to give 214 mg of the indicated in the title the information of the compound (white powder, yield: 73%).

(98b) 4-[2-(2-Forfinal)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(2-forfinal)ethoxy]benzoyl}glycine (214 mg)obtained in example 98 (98A), and 4-isopropoxybenzonitrile (118 μl) to obtain the corresponding oxazolone (232 mg). Carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 168 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 507 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,68 (1H, s), 7,98 (2H, d, J=8 Hz), of 7.90 (1H, ushort, J=5 Hz), of 7.48-7,42 (3H, m), 7,34-7,29 (1H, m), 7,22-7,16 (3H, m), 7,05 (2H, d, J=8 Hz), 6,86 (2H, d, J=8 Hz), with 4.64-4,59 (2H, m), the 4.29 (2H, t, J=7 Hz), 3.43 points (2H, q, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 3,11 (2H, t, J=7 Hz), of 1.23 (6H, d, J=6 Hz).

(Example 99) 4-[2-(4-Cyanophenyl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide (Illustrative compound No. 1-362)

(99a) N-{4-[2-(4-Cyanophenyl)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (582 mg, a 3.83 mmol)obtained in example 1 (1A)and 4-(2-hydroxyethyl)benzonitrile (592 mg, 4.02 mmol) to obtain 226 mg specified in the header connect the FL (white powder, yield: 46%).

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 12,5 (1H, s), 8,65 (1H, t, J=9 Hz), 7,80 (2H, d, J=9 Hz), to 7.77 (2H, d, J=9 Hz), 7,53 (2H, d, J=9 Hz), 6,98 (2H, d, J=9 Hz), the 4.29 (2H, t, J=7 Hz), a 3.87 (2H, d, J=6 Hz)and 3.15 (2H, t, J=7 Hz).

(99b) 4-[2-(4-Cyanophenyl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-cyanophenyl)ethoxy]benzoyl}glycine (226 mg)obtained in example 99 (99), and 4-isopropoxybenzonitrile (121 μl) to obtain the corresponding oxazolone (217 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 128 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 514 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,65 (1H, s), 7,95 (2H, d, J=9 Hz), 7,87 (1H, ushort, J=5 Hz), 7,78 (2H, d, J=8 Hz), 7,55 (2H, d, J=8 Hz), 7,44 (2H, d, J=9 Hz), 7,16 (1H, s), 7,02 (2H, d, J=9 Hz), 6,83 (2H, d, J=9 Hz), 4,63-of 4.57 (2H, m), 4,32 (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), and 3.16 (2H, t, J=7 Hz), to 1.22 (6H, d, J=6 Hz).

(Example 100) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-{2-[4-(trifluoromethyl)phenyl]ethoxy}benzamide (Illustrative compound No. 1-365)

(100a) N-(4-{2-[4-(Trifluoromethyl)phenyl]ethoxy}benzoyl)glycine

Carried Taku the same response, as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (251 mg, 1.00 mmol)obtained in example 1 (1a)and 2-[4-(trifluoromethyl)phenyl]ethanol (209 mg, 1.10 mmol), obtained in accordance with the method disclosed in the document (J. Med. Chem. (2002), 45, 4321-4335), with 278 mg specified in the title compound (white powder, yield: quantitative).

(100b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-{2-[4-(trifluoromethyl)phenyl]ethoxy}benzamide

Carried out the same reaction as in example 1 (1c), using N-(4-{2-[4-(trifluoromethyl)phenyl]ethoxy}benzoyl)glycine (278 mg)obtained in example 100 (100A), and 4-isopropoxybenzonitrile (130 mg) to obtain the corresponding oxazolone (180 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone to obtain 28 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 557 [M+H]+.

Range1H-NMR (400 MHz, CDCl3) δ ppm: 7,79 (3H, userd, J=9 Hz), EUR 7.57 (2H, d, J=8 Hz), 7,39 (2H, d, J=8 Hz), 7,30 (2H, d, J=9 Hz), 7,03 (1H, s), 6.89 in (2H, d, J=9 Hz), 6,78 (2H, d, J=9 Hz), 6,72 of 6.68 (1H, m), 4,51 (1H, Sept, J=6 Hz), to 4.23 (2H, t, J=7 Hz), 3,74 (2H, users), of 3.46 (2H, q, J=5 Hz), 3,17 (3H, ushort, J=7 Hz), is 1.31 (6H, d, J=6 Hz).

(Example 101 N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-were)ethoxy]Ben the amide (Illustrative compound No. 1-368)

(101a) N-{4-[2-(4-Were)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 1 (1b), using tert-butyl ether N-(4-hydroxybenzoyl)glycine (275 mg, of 1.09 mmol)obtained in example 1 (1a)and 2-(4-were)ethanol (159 μl, to 1.14 mmol) to obtain 306 mg specified in the title compound (colorless crystalline solid, yield: 90%).

(101b) N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-were)ethoxy]benzamide

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-were)ethoxy]benzoyl}glycine (306 mg)obtained in example 101 (101A), and 4-isopropoxybenzonitrile (176 mg) to obtain the corresponding oxazolone (335 mg). Then carried out the same reaction as in example 1 (1d), using the total number of the specified oxazolone obtaining 300 mg specified in the title compound (pale yellow amorphous solid).

MS (FAB) m/z: 503 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,63 (1H, users), 7,94 (2H, d, J=9 Hz), 7,86 (1H, ushort, J=5 Hz), 7,44 (2H, d, J=9 Hz), 7,20 (2H, d, J=8 Hz), to 7.15 (1H, s), 7,11 (2H, d, J=8 Hz), 7,02 (2H, d, J=9 Hz), at 6.84 (2H, d, J=9 Hz), 4,63-of 4.57 (2H, m), 4,24 (2H, t, J=7 Hz), 3,42 (2H, q, J=6 Hz), 3,21 (2H, q, J=6 Hz), a 3.01 (2H, t, J=7 Hz), and 2.27 (3H, s)to 1.22 (6H, d, J=6 Hz).

(Example 102 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(t is aftermatket)phenyl]vinyl}-4-[2-(4-isopropoxyphenyl)ethoxy]benzamide (Illustrative compound No. 1-373)

(102a) N-{4-[2-(4-Isopropoxyphenyl)ethoxy]benzoyl}glycine

Carried out the same reaction as in example 78 (78a), using the ethyl ester of N-(4-hydroxybenzoyl)glycine (which is a compound disclosed in J. Med. Chem. (1999), 42, 1041-1052, 397 mg, of 2.20 mmol) and 2-(4-isopropoxyphenyl)ethanol (which is a compound disclosed in J. Chem. Soc. Perkin Trans. 1 (1983), 619-624, 447 mg, 2.00 mmol) to obtain the 636 mg specified in the title compound (white powder, yield: 82%).

(102b) N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[2-(4-isopropoxyphenyl)ethoxy]benzamide

Carried out the same reaction as in example 1 (1c), using N-{4-[2-(4-isopropoxyphenyl)ethoxy]benzoyl}glycine (228 mg)obtained in example 102 (102A), and 4-(triptoreline)benzaldehyde (96 μl) to obtain the corresponding oxazolone (207 mg). Then carried out the same reaction as in example 1 (1d), using 204 mg of the specified oxazolone to obtain 171 mg specified in the title compound (white amorphous solid).

MS (FAB) m/z: 573 [M+H]+.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,76 (1H, users), with 8.05 (1H, t, J=6 Hz), 7,92 (2H, d, J=9 Hz), a 7.62 (2H, d, J=9 Hz), 7,31 (2H, d, J=8 Hz), 7,20 (2H, d, J=9 Hz), 7,14 (1H, s), 7,02 (2H, d, J=9 Hz), 6,83 (2H, d, J=9 Hz), to 4.62 (1H, t, J=5 Hz), 4,55 (1H, Sept, J=6 Hz), 4,22 (2H, t, J=7 Hz), 3,44 (2H, to the, J=6 Hz), up 3.22 (2H, q, J=6 Hz), 2,98 (2H, t, J=7 Hz), 1,24 (6H, d, J=6 Hz).

(Example 103) N-[(E)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-isobutoxide

(103a) of 2-(4-Isobutoxy)-4-(4-isopropoxyaniline)-1,3-oxazol-5(4H)-he

Carried out the same reaction as in example 1 (1c), using N-(4-isobutoxide)glycine (of 5.00 g)obtained in example 30 (30A)and 4-isopropoxybenzonitrile (3,59 g) to obtain the corresponding oxazolone (4,21 g). Then 313 mg specified oxazole was dissolved in 33% solution of HBR in acetic acid (5.0 ml) at room temperature. The resulting solution was stirred for 0.5 hours and then poured into ice-cold water. Precipitated crystals were collected by filtration, washed with water and dried to obtain 282 mg specified in the title compound (yellow powder, yield: 84%, mixture of 4E isomer/4Z isomer = 4,6/1).

MS (FAB) m/z: 380 [M+H]+.

4E isomer: range1H-NMR (400 MHz, CDCl3) δ ppm: 8,18 (2H, d, J=9 Hz), to 7.99 (2H, d, J=9 Hz), 7,45 (1H, s), of 6.99 (2H, d, J=9 Hz), to 6.95 (2H, d, J=9 Hz), of 4.66 (1H, Quint, J=6 Hz), 3,80 (2H, d, J=6 Hz), 2,12 (1H, Sept, J=6 Hz), to 1.38 (6H, d, J=5 Hz), of 1.05 (6H, d, J=7 Hz).

(103b) of N-[(E)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-isobutoxide

2-Aminoethanol (50 μl, 0,828 mmol) was added to a solution of toluene (2.0 ml)containing 2-(4-isobutoxy is)-4-(4-isopropoxyaniline)-1,3-oxazol-5(4H)-he (151 mg, 0,398 mmol, mixture of 4E isomer/4Z isomer = 4,6/1)obtained in example 103 (103a). The mixture was stirred at 50°C for 15 minutes and then the resulting reaction solution was added water. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated and the obtained residue was purified by thin-layer chromatography for separation (ethyl acetate) to give 37 mg specified in the title compound (white solid, yield: 21%). [Also received 53 mg of the corresponding Z-isomer specified in the title compound (white solid, yield: 30%).]

MS (FAB) m/z: 441 [M+H]+.

Range1H-NMR (400 MHz, CDCl3) δ ppm: and 8.50 (1H, s), to $ 7.91 (1H, s)of 7.82 (2H, d, J=9 Hz), 7,27 (2H, d, J=9 Hz), 6,94 (2H, d, J=9 Hz), to 6.88 (2H, d, J=9 Hz), 6,17 (1H, ushort, J=6 Hz), 4,56 (1H, Sept, J=6 Hz), of 3.77 (2H, d, J=7 Hz), 3,61 (2H, t, J=5 Hz)to 3.36 (2H, q, J=5 Hz), 2,11 (1H, Sept, J=7 Hz), of 1.35 (6H, d, J=6 Hz), was 1.04 (6H, d, J=7 Hz).

(Example 104) 4-(Cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide (Illustrative compound No. 1-440)

Carried out the same reaction as in example 9 (9c), using N-[4-(cyclopropylmethoxy)benzoyl]glycine (499 mg)obtained in the same manner as in example 9 (9b)and 4-(three is timetake)benzaldehyde (300 μl) to obtain the corresponding oxazolone (668 mg). Carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone with getting 698 mg specified in the title compound (white powder).

TPL: 144-145ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,77 (1H, users), of 8.06 (1H, t, J=6 Hz), to 7.93 (2H, d, J=9 Hz), 7,63 (2H, d, J=9 Hz), 7,33 (2H, d, J=9 Hz), 7,16 (1H, s), 7,02 (2H, d, J=9 Hz), 4,63 (1H, t, J=6 Hz), 3,90 (2H, d, J=7 Hz), of 3.45 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), 1,28-to 1.21 (1H, m), and 0.61-0,57 (2H, m), 0,36-0,32 (2H, m).

(Example 105 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[(1-methylcyclopropyl)methoxy]benzamide (Illustrative compound No. 1-443)

Carried out the same reaction as in example 9 (9c), using N-{4-[(1-methylcyclopropyl)methoxy]benzoyl}glycine (363 mg)obtained in the same manner as in example 9 (9b)and 4-(triptoreline)benzaldehyde (207 μl) to obtain the corresponding oxazolone (532 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone with getting 545 mg specified in the title compound (white powder).

TPL: 170-173ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,77 (1H, users), of 8.06 (1H, t, J=6 Hz), to 7.93 (2H, d, J=9 Hz), 7,63 (2H, d, J=9 Hz), 7,33 (2H, d, J=9 Hz), to 7.15 (1H, s), 7,02 (2H, d, J=9 Hz), 4,63 (1H, t, J=6 Hz), a-3.84 (2H, s), of 3.45 (2H,, kV, J=6 Hz), 3,23 (2H, the, J=6 Hz), 1,19 (3H, s), 0.55 to about 0.53 (2H, m), 0,42-0,40 (2H, m).

(Example 106 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-isopropoxybenzoic (Illustrative compound No. 1-415)

Carried out the same reaction as in example 9 (9c), using N-(4-isopropoxybenzoic)glycine (which is a compound disclosed in Tetrahedron Lett. (1995), 36, 6193-6196, 380 mg) and 4-(triptoreline)benzaldehyde (240 μl) to obtain the corresponding oxazolone (548 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone with getting 588 mg specified in the title compound (white powder).

TPL: 142-146ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,77 (1H, users), with 8.05 (1H, t, J=6 Hz), to 7.93 (2H, d, J=9 Hz), to 7.64 (2H, d, J=9 Hz), 7,34 (2H, d, J=9 Hz), 7,16 (1H, s), 7,01 (2H, d, J=9 Hz), 4,74 (1H, Sept, J=6 Hz), 4,63 (1H, t, J=6 Hz), 3,44 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), of 1.29 (6H, d, J=6 Hz).

(Example 107 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(4,4,4-triptoreline)benzamide (Illustrative compound No. 1-506)

Carried out the same reaction as in example 9 (9c), using N-[4-(4,4,4-triptoreline)benzoyl]glycine (350 mg)obtained in the same manner as in example 9 (9b)and 4-(triptoreline)benzaldehyde (172 μl) with the teachings of the corresponding oxazolone (337 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone with getting 297 mg specified in the title compound (white powder).

TPL: 160-163ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,79 (1H, users), of 8.06 (1H, t, J=6 Hz), 7,95 (2H, d, J=9 Hz), to 7.64 (2H, d, J=9 Hz), 7,33 (2H, d, J=9 Hz), 7,19 (1H, s), 7,05 (2H, d, J=9 Hz), 4,63 (1H, t, J=6 Hz), of 4.13 (2H, t, J=6 Hz), of 3.45 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), 2,56-of 2.38 (2H, m), 2.00 in of 1.93 (2H, m).

(Example 108 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamide (Illustrative compound No. 1-277)

Carried out the same reaction as in example 9 (9c), using N-[4-(3,3,3-cryptocracy)benzoyl]glycine (291 mg)obtained in the same manner as in example 9 (9b)and 4-(triptoreline)benzaldehyde (150 μl) to obtain the corresponding oxazolone (390 mg). Carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 349 mg specified in the title compound (white powder).

TPL: 159-160ºC.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: 9,82 (1H, users), 8,08 (1H, t, J=6 Hz), of 7.97 (2H, d, J=9 Hz), to 7.64 (2H, d, J=9 Hz), 7,34 (2H, d, J=9 Hz), 7,17 (1H, s), was 7.08 (2H, d, J=9 Hz), with 4.64 (1H, t, J=6 Hz), 4,30 (2H, t, J=6 Hz), of 3.45 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), 2,87-2,78 (2H, m).

(Example 109) N-((Z)-2-[2-Fluoro-4-(trifluoromethyl)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(3,3,3-cryptocracy)benzamid

Carried out the same reaction as in example 9 (9c), using N-[4-(3,3,3-cryptocracy)benzoyl]glycine (300 mg)obtained in the same manner as in example 9 (9b), and 2-fluoro-4-triftormetilfullerenov (150 μl) to obtain the corresponding oxazolone (265 mg). Carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone with getting 286 mg specified in the title compound (white powder).

Tel: 203-205ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,83 (1H, s), compared to 8.26 (1H, t, J=5 Hz), of 7.90 (2H, d, J=9 Hz), 7,71 (2H, d, J=9 Hz), 7,54 (1H, d, J=8 Hz), 7,07 (2H, d, J=9 Hz), 7,06 (1H, s)and 4.65 (1H, t, J=5 Hz), the 4.29 (2H, t, J=6 Hz), of 3.46 (2H, q, J=6 Hz)at 3.25 (2H, q, J=6 Hz), 2,88-2,77 (2H, m).

(Example 110) N-((Z)-2-[3-Fluoro-4-(trifluoromethyl)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(3,3,3-cryptocracy)benzamid

Carried out the same reaction as in example 9 (9c), using N-[4-(3,3,3-cryptocracy)benzoyl]glycine (300 mg)obtained in the same manner as in example 9 (9b), and 3-fluoro-4-triftormetilfullerenov (208 mg) to obtain the corresponding oxazolone (274 mg). Then carried out the same reaction as in example 9 (9d), using the same quantities of the selected oxazolone to obtain 281 mg specified in the title compound (light yellow powder).

TPL: 185-186ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,90 (1H, s)8,23 (1H, t, J=6 Hz), 7,95 (2H, d, J=9 Hz), 7,76 (1H, t, J=8 Hz), to 7.59 (1H, d, J=13 Hz), 7,52 (1H, d, J=8 Hz), 7,14 (1H, s), to 7.09 (2H, d, J=9 Hz)and 4.65 (1H, t, J=6 Hz), 4,30 (2H, t, J=6 Hz), of 3.45 (2H, q, J=6 Hz), 3,24 (2H, q, J=6 Hz), 2,89-2,77 (2H, m).

(Example 111) N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-propoxybenzene

Carried out the same reaction as in example 9 (9c), using N-(4-propoxymethyl)glycine (which is a compound disclosed in Chem. Abstr. (1974), 80, 60167w, 403 mg) and 4-triphtalocyaninine (255 μl) to obtain the corresponding oxazolone (461 mg). Then carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone with getting 353 mg specified in the title compound (white amorphous solid).

TPL: 185-186ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,79 (1H, s), 8,07 (1H, t, J=6 Hz), 7,95 (2H, d, J=9 Hz), to 7.64 (2H, d, J=9 Hz), 7,34 (2H, d, J=9 Hz), 7,16 (1H, s), 7,03 (2H, d, J=9 Hz), with 4.64 (1H, t, J=6 Hz), was 4.02 (2H, t, J=6 Hz), 3,44 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz), 1,80-1,71 (2H, m), 0,99 (3H, t, J=7 Hz).

(Example 112 N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide (Illustrative compound No. 1-519)

ASU is actulaly the same reaction, as in example 9 (9c), using N-{4-[4-(trifluoromethyl)phenoxy]benzoyl}glycine (382 mg)obtained in the same manner as in example 9 (9b)and 4-triphtalocyaninine (169 μl) to obtain the corresponding oxazolone (256 mg). Carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone to obtain 256 mg specified in the title compound (white powder).

TPL: 84-86ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: 9,96 (1H, users), to 8.12 (1H, t, J=6 Hz), of 8.06 (2H, d, J=9 Hz), 7,80 (2H, d, J=9 Hz), 7,66 (2H, d, J=9 Hz), 7,35 (2H, d, J=9 Hz), 7,26-7,19 (5H, m), with 4.64 (1H, t, J=6 Hz), of 3.45 (2H, q, J=6 Hz), 3,24 (2H, q, J=6 Hz).

(Example 113) 4-(4-Chlorophenoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide

Carried out the same reaction as in example 9 (9c), using N-[4-(4-chlorophenoxy)benzoyl]glycine (333 mg)obtained in the same manner as in example 9 (9b)and 4-triphtalocyaninine (163 μl) to obtain the corresponding oxazolone (270 mg). Carried out the same reaction as in example 9 (9d), using the total number of the specified oxazolone with getting 248 mg specified in the title compound (white powder).

TPL: 77-82ºC.

Range1H-NMR (400 MHz, DMSO-d6) δ ppm: to 9.91 (1H, users), of 8.09 (1H, t, J=6 G is), 8,02 (2H, d, J=9 Hz), the 7.65 (2H, d, J=9 Hz), to 7.50 (2H, d, J=9 Hz), 7,35 (2H, d, J=9 Hz), 7,18 (1H, s), 7,13 (2H, d, J=9 Hz), 7,11 (2H, d, J=9 Hz), 4,63 (1H, t, J=6 Hz), of 3.45 (2H, q, J=6 Hz), 3,23 (2H, q, J=6 Hz).

(Example 114 N-{(Z)-1-{[(2,2-Dottorati)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid

Carried out the same reaction as in example 9 (9d), using oxazolone (223 mg)obtained in the production method of example 108, and 2,2-differetiation (49 mg) to obtain 180 mg specified in the title compound (white powder).

TPL: 142-143ºC.

Range1H-nuclear magnetic resonance (500 MHz, DMSO-d6) δ ppm: of 9.89 (1H, s), 8,53 (1H, t, J=6 Hz), 7,98 (2H, d, J=9 Hz), to 7.67 (2H, d, J=9 Hz), was 7.36 (2H, d, J=9 Hz), 7,20 (1H, s), to 7.09 (2H, d, J=9 Hz), 6,03 (1H, TT, J=56 Hz, 4 Hz), 4,30 (2H, t, J=6 Hz), 3,59-3,51 (2H, m), 2,87-2,78 (2H, m).

In addition to the above examples 1-114 were similarly synthesized compounds are presented in table 4. In table 4 rooms illustrative compounds similar to the above in tables 1, 2 and 3 mean the same connection.

td align="left"> /tr>
Table 4
Illustrative compound No.AppearanceMelting point (ºC)FABMS ([M+H] )
1-6colorless crystalline solid142-143
1-20colorless crystalline solid76-80
1-21colorless crystalline solid85-89
1-22colorless crystalline solid198-200
1-23colorless crystalline solid183-185
1-24colorless crystalline solid125-128
1-25colorless crystalline solid 177-179
1-26white amorphous solid465
1-27white amorphous solid439
1-28white amorphous solid477
1-29light yellow crystalline solid107-110
1-30colorless crystalline solid194-197
1-31colorless crystalline solid154-156
1-31(hydrochloride)yellow crystalline solid 162 to 165
1-32colorless crystalline solid138-140
1-33colorless crystalline solid191-193
1-34light yellow crystalline solid106-109
1-35light yellow crystalline solid93-96
1-36light yellow crystalline solid110-113
1-37light yellow amorphous solid476
1-38colorless crystallizes the e solid 194-196
1-39colorless crystalline solid208 (decomp.)
1-40colorless crystalline solid74-77
1-41light yellow amorphous solid70-80
1-42light yellow amorphous solid453
1-43colorless crystalline solid143-145
1-44colorless crystalline solid135-137
1-45light yellow is e amorphous solid 495
1-46colorless crystalline solid103-107
1-47colorless crystalline solid133-134
1-48white amorphous solid455
1-49colorless crystalline solid121-123
1-50colorless crystalline solid129-130
1-51light yellow amorphous solid467
1-52light yellow amorphous TV is Joe substance 477
1-53white amorphous solid495
1-54colorless crystalline solid166-168
1-55yellow amorphous solid66-78489
1-71colorless crystalline solid164-166
1-73light yellow amorphous solid471
1-110colorless crystalline solid156-158
1-126colorless crystalline solid is emesto 123-125
1-147white amorphous solid517
1-164white amorphous solid530
1-168colorless crystalline solid190-192
1-175white amorphous solid520
1-249colorless crystalline solid73-76
1-250colorless crystalline solid168-170
1-254colorless crystalline solids the 169-171
1-257colorless crystalline solid195-197
1-259colorless crystalline solid180-183
1-262white amorphous solid465
1-263colorless amorphous solid475
1-272colorless crystalline solid142-144
1-273white amorphous solid443
1-275colorless crystalline solid in the society 138-140
1-281colorless crystalline solid170-172
1-284colorless crystalline solid59-62
1-290colorless crystalline solid144-146
1-293white amorphous solid476
1-315white amorphous solid503
1-319white amorphous solid513
1-320colorless crystalline solids the 103-105
1-321colorless crystalline solid138-140
1-322colorless crystalline solid158-159
1-341white amorphous solid501
1-372white amorphous solid529
1-374colorless crystalline solid141-144
1-377light yellow crystalline solid112-114
1-380colorless crystallizes the e solid 120-122
1-383white amorphous solid412
1-386colorless crystalline solid82-85
1-389light yellow crystalline solid97-100
1-392colorless crystalline solid141-143
1-395colorless crystalline solid205-207
1-398colorless crystalline solid79-81
1-401the white Amorin the e solid 425
1-404white amorphous solid435
1-407white amorphous solid451
1-410light yellow crystalline solid81-84
1-413light yellow crystalline solid92-95
1-416white amorphous solid441
1-419light yellow crystalline solid75-78
1-422white amorphous solid 481
1-425colorless crystalline solid176-178
1-428colorless crystalline solid94-97
1-431white amorphous solid467
1-432white amorphous solid465
1-434colorless crystalline solid156-158
1-435colorless crystalline solid89-92
1-438white amorphous solid 439
1-441colorless crystalline solid90-92
1-444colorless crystalline solid165-167
1-447colorless crystalline solid79-81
1-450colorless crystalline solid94-96
1-451white amorphous solid465
1-453colorless crystalline solid191-193
1-454colorless crystalline solid vases is in 178-180
1-457white amorphous solid495
1-460white amorphous solid533
1-463white amorphous solid495
1-466light yellow amorphous solid481
1-467white amorphous solid479
1-468colorless crystalline solid144-145
1-469colorless crystalline solid 165-167
1-470colorless crystalline solid155-156
1-471colorless crystalline solid179-181
1-472colorless crystalline solid151-153
1-473colorless crystalline solid60-62
1-476colorless crystalline solid137-139
1-477colorless crystalline solid70-73
1-480colorless crystallizes the second solid 72-74
1-483colorless crystalline solid89-92
1-486white amorphous solid453
1-489white amorphous solid467
1-492white amorphous solid431
1-495colorless crystalline solid84-86
1-498white amorphous solid445
1-501colorless crystalline solid 86-88
1-504colorless crystalline solid70-73
1-507colorless crystalline solid71-74
1-510white amorphous solid399
1-513white amorphous solid461
1-515white amorphous solid469
1-517light yellow amorphous solid529
1-520colorless crystalline solid193-195
1-523yellow amorphous solid501
1-526light yellow amorphous solid499
1-529white amorphous solid531
1-532colorless crystalline solid87-88
1-535light yellow crystalline solid90-92
1-538white amorphous solid532
1-541colorless crystalline solid81-83
1-544light yellow amorphous solid549 (ESI+)
1-545white amorphous solid547
1-546white amorphous solid575
1-547light yellow amorphous solid557 (ESI+)
1-550colorless crystalline solid65-68
1-553white amorphous solid547
1-556colorless crystalline solid81-83
1-559white amorphous solid571
1-562white amorphous solid563
1-565white amorphous solid504
1-565(hydrochloride)colorless crystalline solid96-98
1-568(hydrochloride)colorless crystalline solid77-80
1-571light yellow crystalline solid64-68
1-574light yellow crystalline solid
1-577light brown amorphous solid510
1-580colorless crystalline solid61-64
1-583light yellow amorphous solid546
1-586colorless crystalline solid146-148
1-589white amorphous solid483
1-592white amorphous solid165-167465
1-593white amorphous solid 471
1-596white amorphous solid497
1-599colorless crystalline solid177-179
1-600colorless crystalline solid147
1-603white amorphous solid519
1-606light yellow amorphous solid533
1-609white amorphous solid467
1-612light yellow crystalline solid107-109
1-618colorless crystalline solid137-138
1-623yellow amorphous solid571
1-624white amorphous solid531
1-625white amorphous solid537
1-626yellow amorphous solid559
1-627white amorphous solid525
1-629brown crystalline solid89-93
1-630hot pink amorphous solid584
1-631colorless crystalline solid159-160
1-632white amorphous solid535
2-1colorless crystalline solid129-131
2-2white amorphous solid483
2-3colorless crystalline solid89-91413
2-4colorless amorphous solid441
2-5 colorless crystalline solid64-66
2-6colorless crystalline solid150-152
2-7light yellow crystalline solid147-149
2-8light yellow amorphous solid467
2-9colorless crystalline solid86-89
2-10colorless crystalline solid68-70
2-11colorless crystalline solid113-115
2-12white amorphous solid64-70595
2-13colorless crystalline solid155-158
2-14light yellow crystalline solid133-135
2-15colorless crystalline solid107-110
2-16colorless crystalline solid184-187
2-17colorless crystalline solid123-126
2-18light yellow crystalline solid
2-19light yellow crystalline solid74-76
2-20colorless crystalline solid80-83
2-21white amorphous solid51-54459
3-1colorless crystalline solid156-158
3-1(R isomer)colorless crystalline solid75-78
3-1(S isomer)colorless crystalline solid75-77
3-2colorless crystalline solid the second substance 76-78
3-3colorless crystalline solid144-146
3-4colorless crystalline solid182-184
3-5colorless crystalline solid88-90
3-6(R isomer)colorless crystalline solid82-85
3-6(S isomer)colorless crystalline solid82-84
3-7colorless crystalline solid85-87
3-8 light yellow amorphous solid70-75455
3-9colorless crystalline solid135-137
3-10colorless crystalline solid156-159
3-11light yellow crystalline solid151-153
3-12colorless crystalline solid123-125
3-13white amorphous solid481
3-14colorless crystalline solid156-158
3-15 yellow crystalline solid147-149
3-16colorless crystalline solid103-105
3-17light yellow crystalline solid101-103
3-18colorless crystalline solid112-115
3-19colorless crystalline solid186 to 190
3-20white amorphous solid477
3-21colorless crystalline solid488
3-22brown crystalline solid229-232
3-23colorless crystalline solid96-99
3-24colorless crystalline solid74-76
3-25colorless crystalline solid60-62
3-26colorless crystalline solid179-180
3-27colorless crystalline solid93-95
3-28light yellow crystalline solid195-197
3-29colorless crystalline solid176-177
3-30colorless crystalline solid83-85
3-31colorless crystalline solid240-241
3-32yellow crystalline solid208-211
3-33colorless crystalline solid98-101
3-34light yellow crystalline solid107-109
3-35white amorphous solid87-91540
3-36colorless crystalline solid134-136
3-37light yellow crystalline solid153 to 155
3-38colorless crystalline solid101-103
3-39light yellow amorphous solid86-101467
3-40white amorphous solid108-110566
3-41colorless crystalline solid224-226
3-42colorless amorphous solid3-43white amorphous solid442
3-44white amorphous solid441
3-45white amorphous solid457

In table 4, "decomp." means the decomposition temperature.

(Test example 1) evaluation of the activity to reduce the concentration of calcium in the blood

The concentration of calcium in the blood in a living organism is strictly controlled and is maintained by intestinal absorption and excretion of urine and release (bone resorption) and adhesion (osteoarthri) in the bone tissues. In immature rats, the activity of the processes of bone resorption and osteoarthri extremely high concentration of calcium in the blood decreases significantly with strong suppression of bone resorption. Activity suppression of bone resorption compounds of the present invention was evaluated by introducing compounds immature rats by observing the decrease in the concentration of calcium in the blood as pok is the indicator of such activity.

The test was performed using 4-week-old male Wistar rats that were starved for 12-24 hours. Each test compound suspended in 0.5% solution of methylcellulose (MC). The oral suspension was administered to rats at the dose of 5 ml/kg similarly to rats of normal control group was injected only 0.5% MC. Then the rats took the blood from the jugular vein under ether anesthesia after 6 hours after administration of each test compound or 0.5% MC. The blood was immediately centrifuged (10,000 rpm, 5 minutes) at room temperature to separate the serum. The calcium concentration in each serum sample was measured using an auto-analyzer (JEOL, JCA-BM2250). In each group of tests used five rats.

The test results presented in table 5 below. The evaluation was carried out using comparative tests relative to the normal control group on the basis of the rate of decrease in the concentration of calcium in serum (%)calculated according to the following formula:

the rate of decrease in the concentration of calcium in serum (%) = ([concentration of serum calcium in the normal control group] - [calcium concentration in serum in the group of injection of the test compound]/[concentration of serum calcium in the normal control group]) × 100.

Table 5
Test connectionInjected dose
(mg/kg)
The rate of decrease in the concentration of serum calcium (%)
Example 51027,6
Example 92029,3
Example 112030,6
Example 141033,2
Example 161027,2

Typically, the concentration of calcium in the blood must be maintained at a constant level, but the levels of calcium in the blood declined with the introduction of the compounds of the present invention. This result suggests that the activity to reduce the concentration of calcium in the blood of the compounds of the present invention is high.

(Test example 2) Evaluation of suppressive activity against reducing bone density and activity against arthritis

In rheumatoid arthritis there is not only the swelling and pain caused by arthritis, but also a systematic reduction m the chick bone and joint destruction, caused a significant increase in bone resorption. Suppressive effect of the compounds of the present invention versus the decrease of bone mass and increase the volume of the paw induced arthritis was evaluated by using the model of arthritis in rats with the use of adjuvant where rats showed arthritis similar to rheumatoid arthritis people.

The test was performed using 8-week-old female Lewis rats. Cells of Mycobacterium butyricum, who was killed by heating, were crushed in an agate mortar, suspended in liquid paraffin, sterilized by heating, to a concentration of 2 mg/ml and were treated by ultrasound with receiving adjuvant. Under ether anesthesia, the rats of the control group, different from the normal control group and the rats of group injection of the test compounds by subcutaneous injection was administered 0.05 ml of the indicated adjuvant each time (a total of 1.0 ml/rat) in two portions in the base of the tail. Starting on day 14 after injection, each rat adjuvant oral was administered 5 ml/kg of the test compounds suspended in 0.5% MC, once a day for 7 days. Similarly to the rats of the control group was injected only 0.5% MC. At the 21st day after the adjuvant injection was measured volumes of the hind legs using a device for measuring swelling of the legs (MUROMACHI KIKAI, TK-101CMP). Then took a biopsy of the thigh to the STI. Femur after removal of soft tissues adequately recorded, dehydrational and dried with ethanol. The density of the femur was measured using the analyzer bone density (Aloka, DOS-600 EX-IIIR). In each group of tests used five rats.

The test results presented in table 6 below. The evaluation was carried out using comparative tests relative to the normal control group and the control group on the basis of the indicator of suppressing the reduction of bone density (%) and rate of suppression of paw edema (%), calculated by the following formulas:

the rate of suppression of reduction of bone density (%) = (1-([density of the femur in the normal control group] - [density of the femur in the group injection of the test compounds])/[density of the femur in the normal control group] - [density of the femur in the control group]) × 100;

the rate of suppression of paw edema (%) = (1-([volume paws in the group introducing a test compound] - [volume paws in the normal control group])/[volume paws in the control group] - [volume paws in the normal control group]) × 100.

Table 6
Test connection Injected dose (mg/kg)The rate of suppression of reduction of bone density (%)The rate of suppression of paw edema (%)
Example 3105722
Example 5105425
Example 9103711
Example 11104029
Example 14108612
Example 16107035

Reduced bone density and increased swelling of the paws was significantly suppressed with the introduction of the compounds of the present invention. Thus, it was confirmed the beneficial effect of the compounds of the present invention as a preventive or therapeutic medicines for metabolic bone disease and inflammation.

Industrial is remenisant

Drugs of the present invention have the effect of reducing the concentration of calcium in the blood and suppressive effect against the reduction in bone mass due to their excellent suppressive effect on bone resorption and have low toxicity. That is why these drugs are useful as prophylactic or therapeutic drugs with metabolic bone diseases such as osteoporosis, hypercalcemia, metastatic bone cancer, periodontal disease, deforming ostos and osteoarthritis, in mammals such as human, monkey, dog, cat, horse and swine, especially people).

1. The compound of formula (I') or its pharmacologically acceptable salt:

[where R5represents any group selected from the group comprising C1-C6alkoxygroup, which is substituted by one group selected from the group of substituents β, fenoxaprop, which may be substituted with one group selected from the group of substituents γ, C1-C6halogenlampe and C3-C6cycloalkylcarbonyl;
R6represents a substituent in the benzene ring, which is selected from the group of substituents α;
R7represents a hydrogen atom, a C1-C6halogen is lilou group, C1-C6hydroxyalkyl group which may be protected hydroxyamino group, C1-C6alkyl group which may be substituted with one group selected from the group of substituents β, or phenyl group which may be substituted by one hydroxy-group;
m is an integer equal to 1;
n is an integer having a value of from 1 to 2;
the numbers in each benzene ring indicate the position number of each substituent;
the group of substituents α represents a group containing a hydroxyl group, a nitro group, ceanography, C1-C6dialkylamino, acetamidoxime, halogen atoms, C1-C6alkyl group which may be substituted with one group selected from the group of substituents β, C1-C6halogenoalkane group3-C10cycloalkyl group, 6-membered heterocyclic group, with the N atom and the atom is About as heteroatoms, With3-C6cycloalkenyl group, phenyl group which may be substituted with one group selected from the group of substituents γ, 5-6-membered heteroaryl group with 1 to 3 N atoms as heteroatoms which can be substituted by one or more groups selected from the group of substituents γ, C1-C6alkoxygroup, C1-C6Galaga is alkoxygroup, With3-C10cycloalkylcarbonyl, fenoxaprop, C1-C6allylthiourea, C1-C6halogenation, C1-C6alkylsulfonyl group and C1-C6acylcarnitine group;
the group of substituents β represents a group comprising C1-C6alkoxycarbonyl group3-C10cycloalkyl group which may be substituted with one group selected from the group of substituents γ, C3-C6cycloalkenyl group6-C10aryl group which may be substituted by one or more groups selected from the group of substituents γ, 5-6-membered heteroaryl group with one heteroatom N, O or S, 9-membered heteroaryl group with two heteroatoms, selected from N and S, C1-C6alkoxygroup and C6-C10alloctype; and
the group of substituents γ is a group, including ceanography, C1-C6dialkylamino,2-C6cyclic amino groups, halogen atoms, C1-C6alkyl group, a C3-C10cycloalkyl group, C1-C6halogenoalkane group, C1-C6alkoxygroup and C1-C6alkylenedioxy].

2. The compound or its pharmacologically acceptable salt according to claim 1, where R5represents l the buoy group, selected from the group comprising C1-C6alkoxygroup, which may be substituted with one group selected from the group of substituents β, fenoxaprop, which may be substituted with one group selected from the group of substituents γ, and C1-C6halogenlampe.

3. The compound or its pharmacologically acceptable salt according to claim 1, where R5is cyclopropylmethoxy, 2-cyclopropylethyl, 1-methylcyclopropene, 3,3,3-cryptocomplexity, 4,4,4-cryptosporiosis, 2-venlafaxinum, 2-(4-methoxyphenyl)ethoxypropan, 2-(3-methoxyphenyl)ethoxypropan, 2-(4-chlorophenyl)ethoxypropan, 2-(4-(N,N-dimethylamino)phenyl)ethoxypropan, 4-chlorphenoxy or 4-triftormetilfosfinov.

4. The compound or its pharmacologically acceptable salt according to any one of claims 1 to 3, where R6represents any group selected from the group comprising halogen atoms, C1-C6alkyl group, a C1-C6halogenoalkane group3-C6cycloalkyl group, C1-C6alkoxygroup,3-C6cycloalkylcarbonyl, C1-C6halogenlampe,1-C6ancilliary and 5-6-membered heteroaryl group with 1 to 3 N atoms as heteroatoms.

5. The compound or its pharmacologically acceptable salt according to any which one of claims 1 to 3, where R6represents a fluorine atom, a chlorine atom, triptorelin group, isopropyl group, cyclopropyl group, isopropylamino, dipterocarp, cryptometer, 2,2,2-triptracker, 2,2-dipterocarp, cyclopropylamino, ethoxypropan, metalcorp or 1H-pyrrol-1-ilen group.

6. The compound or its pharmacologically acceptable salt according to any one of claims 1 to 3, where R6is ethoxypropan, triptorelin group, cyclopropyl group, cyclopropylamino, dipterocarp, cryptometer or 2,2-dipterocarp.

7. The compound or its pharmacologically acceptable salt according to any one of claims 1 to 3, where R7represents a C1-C6halogenating group, C1-C6alkyl group which may be substituted by one or more groups selected from the group of substituents β, or C1-C6hydroxyalkyl group which may be protected hydroxyamino group.

8. The compound or its pharmacologically acceptable salt according to any one of claims 1 to 3, where R7represents a C2-C3halogenating group or3-C3hydroxyalkyl group which may be protected hydroxyamino group.

9. The compound or its pharmacologically acceptable salt according to any ISP-3, where R7is a 2-foretelling group, 2,2-deperately group, 2-hydroxyethylene group, 2-hydroxypropyl group, 2-acetoxyethyl group, 2-(morpholine-4-RECETOX)ethyl group, or 2-(3-carboxyphenoxy)ethyl group.

10. The compound or its pharmacologically acceptable salt according to any one of claims 1 to 3, where m and n each has the value 1.

11. The compound or its pharmacologically acceptable salt of claim 10, where R5is a substituent in the 4-position of the benzene ring in the formula (I'), and R6is a substituent in the 4'-position of the benzene ring in the formula (I').

12. The compound or its pharmacologically acceptable salt, where the compound is selected from the following compounds:
4-(2-cyclopropylmethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,
4-(2-cyclopropylmethoxy)-N-(2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,
4-(2-cyclopropylmethoxy)-N-(2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,
4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,
4-(2-cyclopropylmethoxy)-N-(2-[4-(2,2-diflorasone)phenyl]-1-{[(2-hydroxyethyl)amino] carbonyl}vinyl)benzamide,
4-(2-cyclopropylmethoxy)-N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,
2-{[(2Z)-2-{[4-(2-cycloprop is ylethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}acetic acid ethyl ester,
2-{[(2Z)-2-{[4-(2-cyclopropylmethoxy)benzoyl]amino}-3-(4-cyclopropylmethyl)propen-2-oil]amino}ethylsuccinate,
4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,
4-(2-cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}benzamide,
N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylmethoxy)benzamide,
N-[1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methoxyphenyl)ethoxy]benzamide,
N-(2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,
N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,
N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,
N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy] benzamide,
N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,
4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide,
4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,
N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide,
4-[2-4-chlorophenyl)ethoxy]-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,
4-[2-(4-chlorophenyl)ethoxy]-N-(2-[4-(cyclopropylamino)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,
4-[2-(4-chlorophenyl)ethoxy]-N-(2-[4-(deformedarse)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,
4-[2-(4-chlorophenyl)ethoxy]-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,
4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-cyclopropylmethyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,
4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,
4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide,
N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(4,4,4-triptoreline)benzamid,
N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,
N-{1-{[(2,2-dottorati)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-(3,3,3-cryptocracy)benzamid,
N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide and
4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(triptoreline)phenyl]vinyl}benzamide.

13. The compound or its pharmacologically acceptable salt according to any one of claims 1 to 3, where the chemical structure in relation to the position acrylamide group of the formula (I') represents Z.

14. The pharmaceutical composition, the region is surrounding the ability of suppression of bone resorption, comprising the compound or its pharmacologically acceptable salt according to any one of claims 1 to 13 as an active ingredient.

15. The use of compound or its pharmacologically acceptable salt according to any one of claims 1 to 13 as a drug for the suppression of bone resorption.

16. The use of compound or its pharmacologically acceptable salt according to any one of claims 1 to 13 for receiving drugs to reduce the concentration of calcium in the blood.

17. The use of compound or its pharmacologically acceptable salt according to any one of claims 1 to 13 for receiving drugs to suppress the decrease in bone mass.

18. Drug suppression of bone resorption, which significantly reduces the concentration of calcium in the serum of a mammal, which enter the specified medication, and specified drug suppression of bone resorption is a compound or its pharmacologically acceptable salt according to any one of claims 1 to 13.

19. Drug suppression of bone resorption by p, where the dose specified drugs used as active ingredient, is from 0.001 to 100 mg/kg

20. The method of suppression of bone resorption in an animal in need thereof, comprising the introduction of a specified animal an effective amount connected the I or its pharmacologically acceptable salt according to any one of claims 1 to 13.

21. The method of reducing the concentration of calcium in the blood of the animal, in need thereof, comprising the introduction of a specified animal an effective amount of the compound or its pharmacologically acceptable salt according to any one of claims 1 to 13.

22. The method of suppressing the decrease in bone mass in an animal in need thereof, comprising the introduction of a specified animal an effective amount of the compound or its pharmacologically acceptable salt according to any one of claims 1 to 13.



 

Same patents:

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns applications of compositions formulated as follows or its salt, solvate or prodrug of medical agent for treatment or prevention of disease state mediated by glucokinase (GLK). Besides, given invention concerns new group of composition formulated as (I) and to method of specified compositions production. The invention enables to widen range of agents used for treatment or prevention of disease conditions mediated by glucokinase (GLK) where each of R1, R2, R3, n and m has values specified in the description.

EFFECT: increased efficiency.

19 cl, 51 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

The invention relates to new biologically active compounds, in particular to derive orotovoy acid, and can be used in medicine, chemistry and agriculture

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of general formula (I) and its pharmaceutically acceptable salts. In general formula (I) , Y represents group -CONH(Q)- or -NHCONH(Q)-; Q represents 6-member aromatic ring or 5-10-member heteroaromatic ring, containing one or two N heteroatoms or two O heteroatoms; R represents hydrogen, halogen, linear or branched (C1-C6)alkyl; (C1-C6)alkoxy; di-(C1-C6)alkylamino, 5-member heteroaromatic ring, containing one O or S heteroatom; 6- or 9-member heteroaromatic ring, containing one or two N heteroatoms; phenyl, mono- or disubstituted with halogen, (C1-C6)alkyl, halogeno(C1-C6)alkyl, (C1-C6)alkoxy, acyl; hydroxy; piano; di-(C1-C6)alkylamino, acylamino' carbamoyl; X represents group : where Z represents CH2, N or O; m represents integer number from 1 to 3; p is equal 0, 1; R" is selected from group, consisting of di-( C1-C6)alkylaminocarbonyl, (C1-C6)alkyl, acyl. Invention also relates to pharmaceutical composition, containing as active ingredient, invention compound, to application of invention compound for manufacturing pharmaceutical composition, to method of inhibition of nicotinic acetylcholine receptor α7.

EFFECT: obtaining compound, which possesses agonistic activity with respect to nicotinic acetylcholine receptor (nAChR) α7.

7 cl, 2 tbl, 4 dwg, 270 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted derivatives of oxamic acid thiohydrazides of general formula: , where R and R1 denote H, unsubstituted or substituted Het, phenyl, Alk, wherein substitutes can be Alk, Hal, CF3, COOR3, SR3, or R+R1=C2H4OC2H4; R2 denotes H, Alk, OR3, Hal, where R3=Alk; Het denotes a 5- or 6-member ring which contains one or two heteroatoms selected from N and S. The invention also relates to a method for synthesis of said compounds.

EFFECT: obtaining novel compounds which exhibit antibacterial activity and can be used as antibacterial agents for inhibiting pathogenic bacteria, including Chlamydia.

4 cl, 21 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula 1: whereat : X is N or CH; R1 is selected from the group consisting of OSO2CH3, SOR4, SO2R4, SO2NH2, SO2NHCH3, SO2N(CH3)2, COR4, CN, OCF3, CF3, F, Cl, Br, I, CH(OH)CF3, CH2SO2CF3, CH2SO2CH3, CH2CF3, CH2COCH3, CH2COCF3; R2 is selected from the group consisting of CN, CF3, OH, OR4, F, CI, Br, I, CH3; R3 is selected from the group consisting of C1-C4 alkyls, allyl, CH2CH2OCH3, CH2CH2CH2F, CH2CH2CHF2, CH2CH2F, CH2CHF2, CH2CF3, 3,3,3-trifluoropropyl, 4,4,4-trifluorobuthyl; CH2CH2OH, CH2CH2CH2OH, CH2CH(OH)CH3, CH2CH2COCH3, , ;

R4 is selected from the group consisting of C1-C3 alkyls, CF3, CHF2, CH2F; provided that when R1 is CN, OCF3, CF3, F or Cl X is not CH, R2 is not F, CI, Br, CH3, and R3 is not C1-C3 alkyl or allyl; provided that when R1 is CF3 or CN, X is not CH, R2 is not F, CI, Br, CH3, and R3 is not C1-C2 alkyl; provided that when X is N: R1 is not Cl, when R2 is CH3, and R3 is CH2CH2OH; R1 is not Cl, when R2 is Cl, and R3 is CH3; R1 is not F, when R2 is CN, and R3 is CH3; R1 is not Cl, when R2 is Cl, and R3 is CH2CH2CH2OH; R1 is not Cl, when R2 is Cl, and R3 is CH2CH2OH; and provided that when R1 is SO2R4, SO2NH2, SO2NHCH3 or SO2N(CH3)2 R2 is not OH. The present invention refers also to the pharmaceutically acceptable salts of the said compounds, to the intermediate compounds, to their pharmaceutical composition as well as to the method of central nervous system abnormalities treatment.

EFFECT: obtaining of the new bioactive compounds active as modulators of dopamine neurotransmission.

43 cl, 79 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

Casr antagonist // 2315036

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel compound represented by the following formula (1) , its pharmaceutically acceptable salts or optically active isomers wherein each symbol is given in the invention description. Proposed compound possesses antagonistic effect with respect to calcium-sensitive receptor (CASR). Also, invention relates to a therapeutically medicinal agent used in treatment of osteoporosis based on this compound, to a method for treatment of osteoporosis, calcium receptor antagonist and to agent promoting secretion of parathyroid hormone (PTH).

EFFECT: valuable medicinal properties of antagonist.

33 cl, 66 tbl, 5 ex

FIELD: medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes dipeptide-nitrile inhibitors of cathepsin K, their pharmaceutically acceptable salts or their esters that are used in therapeutic or prophylaxis treatment of disease of morbid state mediated by cathepsin K.

EFFECT: valuable medicinal properties of inhibitors.

3 cl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.

EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

FIELD: catalyst preparation methods.

SUBSTANCE: invention relates to alumina-supported catalyst preparation method and employment thereof in reactions of nucleophilic substitution of aromatic halides containing electron-accepting group. In particular, alumina support impregnated with alkali selected from alkali metal hydroxides is prepared by treating alkali metal hydroxide aqueous solution with aluminum oxide in organic solvent followed by drying thus obtained catalyst mixture at temperature not lower than 150°C. Catalyst is, in particular, used to introduce electron-accepting protective groups into organic compounds comprising at least one of -OH, -SH, and -NH, as well as in reaction of substituting amino, thio, or ether group for halogen in a haloarene and in preparation of 2-puperidinobenzonitrile.

EFFECT: simplified preparation of catalyst and regeneration of spent catalyst, and avoided involvement of dangerous reactants.

11 cl, 20 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to biologically active compounds. Invention represents dipeptide nitrile inhibitors of cathepsin K, their pharmaceutically acceptable salts or their esters of the general formula:

wherein X means -CH or nitrogen atom (N); R means (C1-C7)-(lower)-alkyl, (C1-C7)-(lower)-alkoxy-(C1-C7)-(lower)-alkyl, (C5-C10)-aryl-(C1-C7)-(lower)-alkyl or (C3-C8)-cycloalkyl.

EFFECT: valuable biochemical properties of compounds.

6 cl, 12 ex

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes the novel derivatives of phenylalanine of the formula (I) and (II) possessing with antagonistic activity with respect to α4-integrin. Derivatives of phenylalanine are used as therapeutic agents in different diseases associated with α4-integrin.

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

The invention relates to a derivative of sulfoaluminate and sulphoniumhydroxide acid of formula I, its pharmaceutically acceptable salts, where W is-HE-or-NHOH; X denotes (a) a heterocyclic radical selected from the group comprising imidazolines, dihydrobenzofuranyl and so on, b) -NR1SO2R2where R1denotes a hydrogen atom, R2denotes an unsubstituted phenylalkyl and so on; Y represents carbon or sulfur, with the proviso that when Y represents carbon, n is equal to 2; Z represents phenyl, optionally substituted with halogen, unsubstituted alkoxy, phenyloxy, optionally substituted with halogen, phenylacetonitrile, 4-methylpiperazine, 4-phenylpiperidine, pyridyloxy, -NR'1COR'2, -SO2R'2where R'1denotes a hydrogen atom, R'2denotes phenyl, optionally substituted by hydroxy or phenyl, pyridinyl, substituted-CF3; m denotes an integer from 1 to 4, n represents an integer of 1 or 2

The invention relates to new derivatives of carboxylic acids of General formula I containing heterocyclic ring

The invention relates to 3-(mercaptoethyl)-hinzelin-2,4-(1H,3H)-diones of General formula I, where R1denotes hydrogen, 6-methyl, 6-fluoro, 6-chloro, 6-bromo or 6,7-dimethoxy; R2denotes hydrogen or methyl and n is 1 or 2, or their tautomers, method for their production and pharmaceutical compositions, in particular for the treatment of immune diseases and/or viral infections in humans and animals

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent having CXCR2 inhibiting properties. In formula I , X denotes -CR3=CR4-, -CR5=N-, -N=CR6-, -NR7- or -S-; R3, R4, R5 and R6 independently denote hydrogen, F, CI, Br, I; R7 denotes hydrogen; Y1, Y2, Y3 and Y4 independently denote -CR8- or nitrogen, provided that at least two of Y1, Y2, Y3 and Y4 denote -CR8-; where R8 denotes hydrogen, F, CI, Br, I; A denotes a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; a bicyclic partially saturated 9-member cycloalkyl; a bicyclic partially saturated 9-10-member heterocycle in which two atoms in the ring are oxygen atoms; phenyl; naphthyl; a 5-6-member heteroaryl in which 1-3 atoms in the ring are oxygen, sulphur and nitrogen atoms; a 9-10-member bicyclic heteroaryl in which 1-3 atoms in the ring are nitrogen, oxygen and sulphur atoms; a 6-member heterocycle in which one atom in the ring is a nitrogen atom and which can be unsubstituted or substituted with alkyl having 1, 2, 3 or 4 carbon atoms, -C(O)CH3, -C(O)CH2CH3, -C(O)cyclopropyl, -C(O)CF3 and -C(O)OC(CH3)3; where phenyl, heterocyclic or heteroaryl radical is substituted with 1, 2 or 3 radicals selected from a group consisting of F, O, Br, I, OH, CN, NO2, SCF3, SF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; cycloalkyl having 3, 4, 5 or 6 carbon atoms; alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -S-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -NR9R10, C(O)R44, S(O)SR47, -(CH2)k-phenyl, 5-6-member heteroaryl, in which 1-3 atoms in the ring are nitrogen and sulphur atoms; where the phenyl radical may be substituted with F, CI, Br, I; R9 is an alkyl having 1, 2, 3 or 4 carbon atoms; R10 is an alkyl having 1, 2, 3 or 4 carbon atoms; R44 is an alkyl having 1, 2, 3 or 4 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms; R47 is an alkyl having 1, 2, 3 or 4 carbon atoms; k equals 0, 1, 2 or 3; s equals 1 or 2; B is -O-C(R11R12), -C≡C-, -CR52=CR53-, -C(R13R14)C(R15R16), -NR17-C(R18R19); R11, R12, R13, R14, R15, R16, R17, R18, R19, R52, R53 independently denote hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D is C(O)OH, C(O)NHR21 or C(=NR58)NHR22; R21 and R22 independently denote hydrogen, -SO2-alkyl having 1, 2, 3 or 4 carbon atoms, -SO2-phenyl; R58 is OH; R1 and R2 independently denote an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where the alkyl radicals are unsubstituted or substituted with 1 radical selected from a group consisting of F, Cl, Br, I, phenyl substituted with OH; or R1 and R2, taken together with a carbon atom with which they are bonded form a 3-, 4-, 5- or 6-member carbocycle. The invention also relates to use of formula I compounds in preparing a medicinal agent which has CXCR2 inhibiting properties, to a medicinal agent which containing an effective amount of the disclosed compound and having CXCR2 inhibiting properties, as well as to use of formula II compounds (formula and values of radicals are given in the formula of invention) in preparing a medicinal agent having CXCR2 inhibiting properties.

EFFECT: high effectiveness of application.

10 cl, 384 ex

Up!