Amid derivative

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to new amide derivative, useful as pharmaceuticals, in particular for the prophylaxis and therapeutic treatment of diseases that involve the herpes virus.

RATIONALE INVENTIONS

Viruses belonging to the family Herpesviridae, cause various diseases in humans and animals. For example, it is known that varicella zoster virus (VZV) causes chickenpox and herpes zoster, and herpes simplex viruses type 1 and 2 (HSV-1 and HSV-2) cause infections such as mouth herpes, genital herpes, etc., respectively. In addition, in recent years have been identified infectious disease caused by herpes viruses, such as cytomegalovirus (CMV), EB virus (Epstein-Barr; EBV), human herpes viruses 6, 7 and 8, and so on.

Currently, the quality of medicines against herpes viruses, such as VZV and HSV, use pharmaceutical medicines of the number of nucleic acids, such as acyclovir (ACV), and the corresponding prodrugs, such as valacyclovir (VCV), famciclovir (FCV), and so on. These pharmaceutical medicines of the number of nucleic acids monophosphorylated to nukleotidfosfatazu under the action of viral timedancing encoded by VZV or HSV, and subsequently prevrashajutsja trifosfatnogo compounds under the action of cellular enzymes. Finally, triphosphorylated nucleoside analogs are incorporated during replication of viral genomes in DNA polymerase of herpesvirus, suppressing the reaction of elongation of viral DNA chains. Since the reaction mechanism of the existing antiherpesvirus funds based on the effect of "competitive inhibition" in respect of deoxynucleosides, as indicated above, these drugs must be used at high concentrations to ensure manifestations of anti-virus activity. Actually, these antiherpesvirus medicines of the number of nucleic acids clinically administered at high dose component from a few hundred mg to several grams per day. Because such medicines number of nucleic acids are easily included in the genomic DNA of the host by the DNA polymerase of the host, further raises concerns their mutagenicity.

On the other hand, recently there have been reports of some pharmaceutical drugs of some nucleic acids, have antiherpesvirus activity. For example, described amide or sulfonamidnuyu derived, blocking the enzyme complex HSV helicase - primase exhibiting anti-HSV-1 activity and anti-CMV activity, represented by the following formula (G), where the N atom substituted thiazolidenediones gr is POI or the like (patent reference 1). However, missing information, particularly regarding anti-VZV activity of these compounds.

(in the formula, R denotes hydrogen, lower alkyl, amino, lower alkylamino or the like; R2means hydrogen or lower alkyl; Q may be absent, but when present, Q means methylene; R3means hydrogen, lower alkyl or the like; R4means unsubstituted or substituted phenyl(lower)alkyl, 1-indanyl, 2-indanyl, (lower cycloalkyl)-(lower alkyl), (Het)-(lower alkyl) or the like; R5means phenylsulfonyl, 1 - or 2-naphthylmethyl, (Het)-sulfonyl, (unsubstituted or substituted phenyl)-Y-(CH2)nC(O), (Het)-(CH2)nC(O) or the like, where Y denotes O or S and n is 0, 1 or 2; see more link.)

In addition, the above amide or sulfonamidnuyu derivative having anti-HSV-1 activity and anti-CMV activity, represented by the following formula (H), where the nitrogen atom is substituted by thiazolidenediones group (patent reference 2). However, missing information, particularly regarding anti-VZV activity of these compounds.

(in the formula, R1mean NH2; R2means H; R3means H; R4means CH2Ph, CH2-(4-pyridyl), CH2-cyclohexyl, or the like, and R 5means CO-(substituted phenyl), CO-(unsubstituted or substituted heterocycle), or the like; see more link.)

Previously, the present applicants found amide compound, substituted thiazolidenediones group and having a suitable anti-VZV activity, represented by the following formula, where the nitrogen atom of amide group substituted directly by an aromatic aryl group or heteroaryl group, or a corresponding salt. Based on this, the authors filed a patent application (patent reference 3).

(in the formula, R1and R2denote - H, -lower alkyl, -NRaRb, or the like; A is aryl which may have a Deputy (deputies), -heteroaryl, which may have a Deputy (deputies), or the like; R3means-aryl, which may have a Deputy (deputies), -heterocycle, which may have a Deputy (deputies), or the like; X is CO or SO2; see more publication).

[Reference patent 1] the text of the international publication WO 97/24343

[Reference patent 2] the text of the international publication WO 00/29399

[Link to patent 3] the text of the international publication WO 02/38554

Still, it is highly desirable to obtain antiherpesvirus medicinal product with satisfactory Antiherpes what usnei activity related to the number of non-nucleic acids, extremely safe at low doses and is suitable for oral administration.

Description of the INVENTION

Applicants conducted intensive research on the connection with antiherpesvirus action. As a result, the applicants discovered that, unexpectedly, a new amide derivative represented by the following General formula (I), where a group of 1,2,4-oxadiazol-3-yl, 4-oxazolyl, 1,2,3-triazole-2-yl or 2-pyridyl entered as Z in a cyclic structure instead of the conventional amino-substituted thiazole cycle, has excellent antiherpesvirus activity. Thus, the purpose of the invention was achieved. Compared with conventional antiherpesvirus medicines connection according to the invention has excellent pharmacokinetics in biological organisms and exhibits excellent antiviral activity when administered orally even at low dose. In addition, the connection according to the invention is less cause for concern in relation to mutagenicity and high performance security profile unlike pharmaceuticals number of nucleic acids.

In other words, the invention relates to new amide derivative represented by following General formula (I), or according to stuudy salt.

where in the formula the symbols have the following meanings:

Z: 1,2,4-oxadiazol-3-yl, 4-oxazolyl, 1,2,3-triazole-2-yl or 2-pyridyl,

A: aryl which may have a Deputy (deputies), heteroaryl, which may have a Deputy (deputies), aryl group condensed with a saturated hydrocarbon cycle, which may have a Deputy (deputies) or aryl group fused with a saturated heterocyclic cycle, which may have a Deputy (deputies), provided that the aryl group condensed with a saturated hydrocarbon cycle, or aryl group fused with a saturated heterocyclic cycle, linked to the nitrogen atom through a carbon atom in the aromatic cycle,

X: CO or SO2,

R3: alkyl which may have a Deputy (deputies), alkenyl, which may have a Deputy (deputies), quinil, which may have a Deputy (deputies), cycloalkyl, which may have a Deputy (deputies), cycloalkenyl, which may have a Deputy (deputies), aryl which may have a Deputy (deputies), or heterocyclic group which may have a Deputy (deputies), or NRaRb,

Ra and Rb, which are identical or different from each other signify H, lower ALK is l, lower alkenyl, lower quinil, cycloalkyl, cycloalkenyl, aryl, 5 - or 6-membered monocyclic heteroaryl containing from 1 to 4 heteroatoms selected from the group comprising N, S and O, or lower alkylenedioxy group; the same values are applicable and forth.

Further, the invention relates to pharmaceutical compositions containing the amide derivative represented by the General formula (I), and pharmaceutically acceptable carrier, more specifically, antiherpesvirus medicines and therapeutic treatment of diseases that involve the herpes virus.

The BEST WAY of carrying out the INVENTION

Amide derivative of General formula (I) defined below.

The term "lower" in this specification means a linear or branched hydrocarbon chain with 1 to 4 carbon atoms. Examples of "lower alkyl" groups preferably include an alkyl group with 1-4 carbon atoms, particularly preferably methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, isobutylene and tertbutylphenol group. Examples of "lower alkenyl" groups preferably include alkenylphenol group with 2-5 carbon atoms, particularly preferably such a group as vinyl, allyl, 1-propenyl, Isopropenyl, 1-butenyl, 2-butenyl and 3-butenyl. Examples of "lower etkinlik" groups preferably include alkene is inuu group with 2-5 carbon atoms, particularly preferably such a group as ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl and 1-methyl-2-PROPYNYL. In addition, examples of the "lower alkilinity" groups preferably include alkylenes group with 1-3 carbon atoms, particularly preferably such a group as methylene, ethylene, trimethylene, propylene and dimethylmethylene.

Examples of "alkyl" groups preferably include linear or branched alkyl group with 1-10 carbon atoms, particularly preferably such a group as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2,2-diethylpropane, n-octyl and n-decyl. Examples of "alkenyl" and "etkinlik" groups preferably include a linear or branched group with 2-10 carbon atoms.

"Aryl" group means an aromatic hydrocarbon cyclic group, preferably aryl group with 6 to 14 carbon atoms, more preferably phenyl and naftalina group.

Examples of "cycloalkyl" groups include cycloalkyl group with 3-10 carbon atoms, which can form cross-links, preferably such a group as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and substituted. Examples of "cycloalkenyl" groups preferably include cycloalkenyl group with 3-10 carbon atoms, in which bennoti preferably such a group, as cyclopentenyl and cyclohexenyl. Examples of "aryl group condensed with a saturated hydrocarbon cycle preferably includes a condensed cyclic group of the benzene cycle or naphthalene cycle and C5-6-saturated hydrocarbon cycle, preferably such a group as indanyl and tetrahydronaphthyl.

Examples of "heterocyclic group" include saturated or unsaturated 5-8-membered heterocyclic group with 1-4 heteroatoms selected from N, S and O, which may be a monocyclic ring or may form a bicyclic or tricyclic condensed ring by condensation with a heterocycle (cycles) or hydrocarbon cycle (cycles). The heterocyclic group preferably means "heteroaryl", "5-8-membered saturated heterocyclic group" and "aryl condensed with a saturated heterocyclic cycle.

"Heteroaryl" preferably includes a 5-6-membered monocyclic heteroaryl group with 1-4 heteroatoms selected from N, S and O, and bicyclic or tricyclic heteroaryl group formed through condensation of the monocyclic heteroaryl group with the benzene ring or heteroaryl cycle (cycles). Examples of monocyclic heteroaryl groups preferably include such a group, the AK furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl, and examples of bicyclic or tricyclic heteroaryl groups preferably include such a group as benzofuranyl, benzothiazol, benzothiadiazoles, benzothiazolyl, benzoxazolyl, benzoxadiazole, benzimidazolyl, indolyl, isoindolyl, indazoles, hinely, ethanolic, cinnoline, hintline, honokalani, benzodioxolyl, imidazopyridine, indolizinyl, carbazolyl, dibenzofurans and dibenzothiazyl.

"5-8-membered saturated heterocyclic group" is a 5-8-membered saturated heterocyclic group with 1-4 heteroatoms selected from N, S and O, and may contain cross-links. Examples of such groups preferably include tetrahydro-2H-pyranyl, tetrahydro-2H-dipiradol, tepanil, ciocanel, diabetico[3.1.0]hexenyl, perhydro-1,3-thiazines, pyrrolidinyl, imidazolidinyl, pyrazolidine, piperidinyl, azepane, diazepan, piperidinyl, morpholinyl and thiomorpholine. More preferred examples are a 5-7-membered heterocyclic group. In addition, examples of the "nitrogen-containing saturated heterocyclic group" include groups, from among the above-mentioned "5-8-membered saturated heterotic the practical group", containing at least one nitrogen atom in the cycle. Examples of such groups preferably include piperidino, morpholino, 1-piperazinyl and 1-pyrrolidinyl.

"Aryl group fused with a saturated heterocyclic cycle include a condensed cyclic group formed by condensation 5-8-membered saturated heterocyclic cycle with the benzene ring cycle or naphthalene cycle. Preferred examples of the above aryl groups include 3,4-dihydro-2H-1,4-benzoxazine, 3,4-dihydro-2H-1,4-benzothiazine, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxin, bromanil, isopropanol, 3,4-dihydro-2H-1-benzothiophene, 3,4-dihydro-1H-2-benzothiophene, indolinyl, isoindolyl, 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline.

When the cycle A means aryl condensed with a saturated hydrocarbon cycle" or "aryl condensed with a saturated heterocyclic cycle", the Deputy linked to the nitrogen atom of amide group through a carbon atom in the aromatic cycle.

According to the invention examples of atoms "halogen" includes atoms of F, Cl, Br and I. "halogen-substituted lower alkyl" group means the above lower alkyl group substituted by one or more of the abovementioned halogen atoms, preferably CF3.

Substituents for the alkyl groups, which may be for Estatal (deputies)", "alkenylphenol group which may have a Deputy (deputies)and alkenylphenol group which may have a Deputy (deputies)" primarily represents 1-4 substituent selected from the following group C.

Group C: cycloalkyl, cycloalkenyl, aryl, NRaRb, NRc-NRaRb, (nitrogen-containing saturated heterocyclic group which may have a Deputy (deputies), selected from such groups as the lower alkyl, lower alkylene-COORa and NRaRb), NRc-(nitrogen-containing saturated heterocyclic group which may have a Deputy (deputies), selected from such groups as the lower alkyl, lower alkylene-COORa and NRaRb), NRc-lower alkylene-ORa, NRc-lower alkylene-NRaRb, NRc-lower alkylene-(nitrogen-containing saturated heterocyclic group which may have a Deputy (deputies), selected from such groups as the lower alkyl, lower alkylene-COORa and NRaRb), - O-lower alkylene-NRaRb, - O-lower alkylene-(nitrogen-containing saturated heterocyclic group which may have a Deputy (deputies), selected from such groups as the lower alkyl, lower alkylene-COORa and NRaRb), - O-lower alkylene-ORa, - O-lower alkyl-COORa, COORa, - halogen atoms, CORa, NO2, CN, ORa, O-(halogen-substituted lower alkyl), SRa, SORa, SO2Ra, CO-NRaRb, CO-(nitrogen-containing saturated heterocyclic group which may have a Deputy (deputies)selected from the same the groups, as the lower alkyl, lower alkylene-COORa and NRaRb), NRa-CORb, SO2NraRb and =O(oxo) group (where Ra and Rb accept above values and Re denotes H or a lower alkyl group).

The substituents for "cycloalkyl group which may have a Deputy (deputies)", "cycloalkenyl group which may have a Deputy (deputies)", "aryl group which may have a Deputy (deputies)", "heteroaryl group which may have a Deputy (deputies)", "aryl condensed with a saturated hydrocarbon cycle, which may have a Deputy (deputies)", "aryl condensed with a saturated heterocyclic cycle, which may have a Deputy (deputies)" and "heterocyclic group which may have a Deputy (deputies)" primarily represents 1-5 substituents selected from the following group D.

Group D: [lower alkyl group which may have 1-3 substituent selected from groups such as ORa, SRa, CN, COORa, CONRa, NRaRb and (nitrogen-containing saturated heterocyclic group which may have a Deputy (deputies), selected from such groups as the lower alkyl, lower alkylene-COORa and NRaRb)], lowest alkenyl, lower quinil, halogen-substituted lower alkyl, 5 - or 6-membered monocyclic heteroaryl and deputies belonging to the above group C.

the preferred substituents of the above are 1-5 groups, selected from the following group D1.

Group D1: lower alkyl, phenyl, halogen-substituted lower alkyl, COOH, COO-lower alkyl, CO-lower alkyl, halogen atoms, NO2, CN, OH, lower alkylene-OH, lower alkylene-O-lower alkyl, O-lower alkyl, halogen-substituted lower alkyl, O-lower alkylene-OH, O-lower alkylene-O-lower alkyl, O-lower alkylene-COOH,-lower alkylene-COO-lower alkyl, O-lower alkylene-NH2, O-lower alkylene-NH-lower alkyl, O-lower alkylene-N(lower alkyl)2About lowest alkylene-(nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group (groups)), O-phenyl, O-lower alkylene-phenyl, NH2, NH-lower alkyl, NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, NH-lower alkylene-NH2, NH-lower alkylene-NH-lower alkyl, NH-lower alkylene-N(lower alkyl)2, NH-lower alkylene-(nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group (groups)), N(lower alkyl)2, (nitrogen-containing saturated heterocyclic group which may have a Deputy (deputies), selected from such groups as the lower alkyl and lower alkylene-COORa), NHCO-lower alkyl, N(lower alkyl)CO-lower alkyl, CONH2, CONH-lower alkyl, CON(lower alkyl)2, =O(oxo), SH, S-lower alkyl, SO-lower alkyl and SO2is lower alkyl.

In soy is ininii, having saturated heterocyclic loop containing a sulfur atom, the sulfur atom of the cycle can form the oxide (SO) or dioxide (SO2).

Preferred compounds belonging to the compound (I) according to the invention, is presented below.

(1) Compounds where A denotes aryl, which may have 1-5 substituents selected from group D, heteroaryl, which may have 1-5 substituents selected from group D, aryl condensed with a saturated hydrocarbon cycle, which may have 1-5 substituents selected from group D or aryl group fused with a saturated heterocyclic cycle, which may have 1-5 substituents selected from group D; and R3means cycloalkyl, which may have 1-5 substituents selected from group D, cycloalkenyl, which may have 1-5 substituents selected from group D, aryl which may have 1-5 substituents selected from group D, aryl fused with a saturated heterocyclic cycle, which may have 1-5 substituents selected from group D, heteroaryl, which may have 1-5 substituents selected from group D, or a 5-8-membered monocyclic saturated heterocyclic group which may have 1-5 substituents selected from group D.

(2) Compounds where X is CO.

(3) Compounds, where A denotes the aryl group selected from f Niley and naftilos group; heteroaryl group selected from the group comprising a pyridyl, pyrimidinyl, benzofuranyl, benzothiazol, benzothiadiazoles, benzothiazolyl, benzoxazolyl, benzoxadiazole, benzimidazolyl, indolyl, isoindolyl, indazoles, imidazopyridine and indolizinyl; aryl group condensed with a saturated hydrocarbon cycle, selected from the group comprising 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydronaphthalen-1-yl and 5,6,7,8-tetrahydronaphthalen-2-yl; or an aryl group fused with a saturated heterocyclic cycle selected from the group comprising 3,4-dihydro-2H-1,4-benzoxazine, 3,4-dihydro-2H-1,4-benzothiazine, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxin, bromanil, isopropanol, 3,4-dihydro-2H-1-benzothiophene, 3,4-dihydro-1H-2-benzothiophene, indolinyl, isoindolyl, 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline; each group including aryl, heteroaryl, aryl condensed with a saturated hydrocarbon cycle, aryl fused with a saturated heterocyclic cycle, can have 1-5 substituents selected from group D1; R3means cycloalkyl selected from the group including cyclopentyl, cyclohexyl and cycloheptyl, cycloalkenyl selected from the group comprising cyclopentenyl and cyclohexenyl, aryl selected from the group comprising phenyl and naphthyl, aryl fused with a saturated is heterocyclics cycle, selected from the group comprising 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxin, 3,4-dihydro-2H-1-benzothiophene and 3,4-dihydro-1H-2-benzothiophene, heteroaryl selected from the group comprising a pyridyl, pyrimidinyl, benzofuranyl, benzothiazol, benzothiadiazoles, benzothiazolyl, benzoxazolyl, benzoxadiazole, benzimidazolyl, indolyl, isoindolyl, indazoles, imidazopyridine and indolizinyl, or 5-8-membered saturated heterocyclic group selected from the group comprising tetrahydro-2H-pyranyl, tetrahydro-2H-dipiradol, tepanil, ciocanel, diabetico[3.1.0]hexenyl, perhydro-1,3-thiazines, pyrrolidinyl, imidazolidinyl, pyrazolidine, piperidinyl, azepane, diazepan, piperidinyl, morpholinyl and thiomorpholine, each group including cycloalkyl, cycloalkenyl, aryl, aryl fused with a saturated heterocyclic cycle, heteroaryl and 5-8-membered saturated heterocyclic group may have 1-5 substituents selected from group D1 and the sulfur atom of the cycle can form the oxide or dioxide.

(4) Compounds, where A denotes a group selected from the group comprising phenyl, pyridyl, benzothiazolyl, indazole, 5-indanyl, 1,3-benzodioxolyl and indolinyl, each of these groups may have 1-3 substituent selected from the group comprising lower alkyl, lower alkylene-O-lower alkyl, CF3- halogen atoms, CO-n is SSI alkyl, OH, O-lower alkyl, CN, OCF3, O-lower alkylene-OH, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N(lower alkyl)2, NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl and O-lower alkylene-phenyl; and R3means a group selected from the group including cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, diabetico[3.1.0]hexenyl, tetrahydro-2H-pyranyl, thiomorpholine, tetrahydro-2H-dipiradol, perhydro-1,3-thiazines, all these groups may be substituted by 1 or 2 substituents selected from the group including halogen atoms, CN, =O, OH, O-lower alkyl, lower alkylene-OH and CONH2and the sulfur atom of the cycle can form the oxide or dioxide.

(5) Compounds, where A denotes a group selected from the group comprising phenyl, benzothiazolyl, indolyl, 5-indanyl and 1,3-benzodioxolyl, all of these groups can have 1-3 substituent selected from the group comprising lower alkyl, lower alkylene-O-lower alkyl, CF3atoms of halogen, O-lower alkyl, CN, O-CF3, O-lower alkylene-OH, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkylene-OH and NH-lower alkylene-O-lower alkyl.

(6) R3means a group selected from the group including cyclohexyl, phenyl, naphthyl, benzoxadiazole, diabetico[3.1.0]hexenyl, tetrahydro-2H-pyranyl, thiomorpholine, tetrahydro-2H-dipiradol, perhydro-1,-triazinyl, which may be substituted by 1 or 2 substituents selected from the group including halogen atoms, CN, =O, OH or O-lower alkyl, and the sulfur atom of the cycle can form the oxide or dioxide;

(7) Compounds where Z means 1,2,3-triazole-2-ilen group.

(8) Compounds where Z means 1,2,4-oxadiazol-3-ilen group.

(9) Compounds where Z denotes 4-oxazolidinyl group.

(10) Compounds, where A denotes a group selected from the group comprising phenyl and 5-indenolol group, all of these groups can have 1-5 substituents selected from the group comprising lower alkyl, O-lower alkyl, and halogen atoms; X is CO and R3means 1,1-dissidocerida-2H-thiopyran-4-yl.

(11) Compounds, where A denotes phenyl, which is substituted by a methyl group and may further have 1 or 2 substituent selected from the group comprising methyl and halogen atoms.

(12) Compounds, where A denotes the 5-indenolol group.

(13) Compounds selected from the group including

N-(2,6-dimetilfenil)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(4-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2-were)-N-(2-{[4-(1,3-oxa the ol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,4-dimetilfenil)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3,4-dimetilfenil)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,3-dihydro-1H-inden-5-yl)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(4-chloro-3-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3-fluoro-4-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3-fluoro-2,4-dimetilfenil)-N-(2-{[4-(l,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3,5-debtor-4-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2-fluoro-4-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,3-dimetilfenil)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,4-dimetilfenil)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,6-dimetilfenil)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(4-fluoro-2,6-dimetilfenil)-N-(2-{[4-(1,2,4-OK is diazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,3-dihydro-1H-inden-5-yl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3-fluoro-4-were)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(4-chloro-3-were-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide and

N-(3-fluoro-2,4-dimetilfenil)-N-(2-{[4-(l,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide.

The compound of the present invention may form a salt, depending on kinds of the substituting groups. Salts of the compounds of the present invention are pharmaceutically acceptable salts. As the acid additive salts, and specific examples of such salts include salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, aspartic acid, glutamic acid, and so what. In addition, as a salt with a base, examples of such salts include salts with inorganic bases containing metals such as sodium, potassium, magnesium, calcium, aluminum, etc., or with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, etc., and ammonium salts and the like.

The connection according to the invention covers various isomers depending on the type of substituent. For example, when there are geometric isomers, such as CIS-TRANS and the like, and the tautomers, such as keto-enol and the like, the present invention covers these isomers as in isolated form and as mixtures. In addition, the connection according to the invention may contain asymmetric carbon atom and can exist as isomers based on the asymmetric carbon atom. The invention includes such isomers both in isolated form and as mixtures. In addition, depending on the structure of the connection according to the invention can form N-oxides. Such N-oxides are also included in the scope of the invention. Also included are a variety hydrate, solvate and polymorph forms. The invention also covers all connections becoming in the process of metabolism in vivo into compounds according to the invention or the corresponding salts, so-called prodrugs. Examples of groups obrazowe is such prodrugs, include groups described in Prog. Med. 5: 2157-2161 (1985), and the groups described in "Drug Design", 163-198 in "Pharmaceutical Research and Development", Vol. 7, published by Hirokawa Publishing Co. in 1990.

Below is a typical way of obtaining the compounds according to the invention.

The following methods of obtaining sometimes effectively from the point of view of production technology to replace, at the stage of starting material or intermediate product, a specific functional group, depending on its type, suitable protective group, namely the group, easily transforms into a functional group. Subsequently, the protective group can be removed, if necessary, which allows to obtain the desired compound. Examples of such functional groups include amino group, hydroxyl group, carboxyl group and the like. Appropriate protective groups are described, for example, in Protective Groups in Organic Synthesis, third edition (T. W. Green and P. G. M. Wuts, eds., 15 JOHN WILLY & SONS, INC.). Such groups can be appropriately used depending on the reaction conditions. For the introduction and removal of such protective groups can be used the methods described in the link.

The first way to obtain

The compound (I) can be easily obtained by the implementation of the amidation reaction in the interaction of compounds of carboxylic acid (III) and aniline p is vizvolnogo (II).

The amidation reaction can be performed in conventional ways. For example, it is possible to apply the method described in "Courses in Experimental Chemistry" edited by the Chemical Society of Japan, fourth edition (Maruzen), Vol.22, pp.137-173. Preferably, the interaction is carried out, making the connection carboxylic acid (III) in a reactive derivative, such as galoyanized (acid chloride etc.) or the acid anhydride, and subsequent implementation of the interaction obtained reactive derivative with an aniline derivative (II). In the case of the use of a reactive carboxylic acid derivative, it is preferable to add the base [inorganic base such as potassium carbonate, sodium hydroxide, etc., or organic base, such as triethylamine (TEA), diisopropylethylamine, pyridine, etc.]. In addition, the amidation reaction can be carried out by engagement with a carboxylic acid in the presence of a condensing agent [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), 1,1'-carbonylbis-1H-imidazole (CDI), etc]. In this case, can be entered excipients, such as 1-hydroxybenzotriazole (HOBt), etc. the Reaction temperature can be appropriately selected depending on the original connection. Suitable solvents include solvents which are inert to the mutually is deystviy, for example, the number of aromatic hydrocarbon solvents, such as benzene, toluene, etc.; a number of solvents ethers, such as tetrahydrofuran (THF), 1,4-dioxane, etc.; solvents of a number of halogenated hydrocarbons such as dichloromethane, chloroform, etc.; solvents, amide series such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, etc.; basic solvents such as pyridine, etc.; and the like. The solvent is accordingly selected depending on the type of the initial compounds and the like, and can be used as solvent thereof, or a mixture of two or more solvents.

The second way to obtain

The compound (I) receive, exposing aminosilane represented by the General formula (IV) and the compound of carboxylic acids or sulfonic acids (V) the amidation reaction or reactions sulfonmethane.

The amidation can be carried out in the same way as in the first method.

The reaction sulfonmethane may be conducted according to generally accepted way interaction of amino compounds (IV) with a reactive derivative of sulfonic acid compound (V). Examples of the reactive derivative of sulfonic acid include galodamadruga (acid chloride, bromohydrin etc), acid anhydrides (EN is igrid sulfonic acid derived from two molecules sulfonic acid), azides acids and the like. This reaktsionnosposobnykh derived sulfonic acids can be obtained from the corresponding sulfonic acid using conventional techniques. When galoyanized used as reactivepower derived, the interaction is preferably carried out in the presence of a base (inorganic bases, such as sodium hydroxide, sodium hydride, etc., or organic bases, such as pyridine, TEA, diisopropylethylamine etc). In the case of using such reactivepower derived as the acid anhydride, acid azide, etc., the interaction may be carried out in the absence of base. In some cases, the interaction may be carried out in the presence of inorganic bases such as sodium hydride, etc. or an organic base such as TEA, pyridine, 2,6-lutidine, etc. the Reaction temperature is accordingly selected depending on the kind of the reactive derivative of sulfonic acids and the like. The solvent can be used which is inert to interaction solvents, such as solvents, are given as examples for amidation on the above-mentioned first method.

In addition, depending on the type of substituent, the desired compound (I) can be obtained by the reaction of modification is the", well-known specialists in this field. For example, can be applied successfully known interactions, such as the aforementioned amidation, sulfenamidovy, N-alkylation, as described in "Courses in Experimental Chemistry" edited by the Chemical Society of Japan (Maruzen)and the like. The procedure of interactions can be changed depending on the desired connection and interaction.

The above starting compound can easily be obtained by the use of known interactions, for example, described in "Courses in Experimental Chemistry" edited by the Chemical Society of Japan (Maruzen), in international publication WO 02/38554 and the like. Typical ways of obtaining the source compounds are described below.

The method of obtaining the compound (III)

The method of obtaining the compound (IV)

(in the formula, R means a group capable of forming ester residue, such a group as lower alkyl, aralkyl etc.; and P is a protective group for the amino group, such a group as fluorenylmethoxycarbonyl (Fmoc), and so on).

According to the above reaction scheme, the amidation can be carried out in the same manner as in the above first method of obtaining and sulfenamidovy - in the same way as in the above storespace receipt.

N-alkylation of compound (VI) can be performed using the halogenated alkyl compound (VII) according to standard techniques, for example by the method described in the above "Courses in Experimental Chemistry", fourth edition (Maruzen), Vol.20, pp.279-318. The interaction may be carried out in the temperature range of from cooling to heating.

Examples of acceptable solvents include solvents which are inert to interaction, such as solvents, are given as examples for amidation according to the above first method, etc. Interaction preferably carried out in the presence of a base such as potassium carbonate, sodium hydroxide, sodium hydride, etc. There may be first performed the amidation and subsequently conducted N-alkylation. Removing protection with the aim of obtaining compounds of carboxylic acid (III) may be carried out using appropriate conventional method, depending on the type of ester. In the case of complex alilovic esters, such as complex ethyl ester, etc., removing protection, it is preferable to carry out the processing of the above esters by base, such as aqueous solution of sodium hydroxide, etc. In the case of complex Arakelova esters, such as benzyl ether, etc., removing the protection can be done by restoring these esters with Pallady the coal (Pd-C) in an atmosphere of hydrogen. Interactions can be carried out according to the method described in the aforementioned "Protective Groups in Organic Synthesis", third edition.

Removing protection in order to obtain the amino compounds (IV) is carried out by application of the General methods depending on the type of the protective group. For example, there may be used a method described in the aforementioned "Protective Groups in Organic Synthesis", third edition, pp. 503-572.

The required initial connection can be obtained by the reaction of modification of the substituent in connection with a specific type of substituent, a well-known specialist in this field.

Various isomers can be isolated by conventional methods, based on differences in the physicochemical properties of the isomers. For example, a racemic compound can be reduced to pure stereochemical isomer by a commonly used method of separation of optical isomers [for example, the implementation of the method of obtaining diastereomeric salts with conventional optically active acid (tartaric acid, etc. and optical selection of salt or by other methods]. In addition, diastereomer mixture can be separated, for example, fractionated crystallization, chromatography or the like, and optically active compounds can be obtained using a suitable optically active source Mat is the Rial.

The connection according to the invention obtained by the above method, isolate and purify in free form or in the form of a corresponding salt after the salt formation according to the standard technique. Isolation and purification carried out using conventional chemical techniques, such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various chromatographic techniques and the like.

The pharmaceutical composition according to the invention contains as an effective component, one type or two types or more types of the compounds according to the invention can be obtained according to generally used in this field method using pharmaceutical carriers, fillers, and similar General use. The introduction of specified composition can be orally by tablets, pills, capsules, granules, powders, liquids, etc. or parenteral dosing by injection, such as intravenous injection, intramuscular injection, etc., external preparations such as ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments etc., suppositories, inhalations and the like.

As solid compositions for oral administration using tablets, powders, granules and the like. In what aka solid compositions one or more active substances are mixed with, at least one inert filler, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate-magnesium aluminate, etc. According to conventional methods, the composition may contain inert excipients, such as lubricants, for example magnesium stearate, etc.; disintegrators, such as natrocarbonatite etc.; and contributing to the dissolution of funds. Tablets or pills may be coated with a sugar shell or soluble in the acorn or intersolubility the floor.

Examples of liquid compositions for oral administration include pharmaceutically acceptable emulsions, liquids, suspensions, syrups, elixirs, etc. that can be included inert solvents for General use, such as purified water, ethanol and so on. In addition to the inert solvent, the composition may further contain auxiliary agents such as solubilizing agents, humectants and suspendresume means; sweeteners; corrigentov; flavourings and preservatives.

Examples of the injections for parenteral administration include sterile aqueous or non-aqueous liquids, suspensions and emulsions. Aqueous solvents include, for example, distilled water for injection and physiologically the RCM solution. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (trade mark) and the like. Such compositions can optionally contain isotonic means, preservatives, humectants, emulsifiers, dispersing funds, stabilizers and contributing to the dissolved substances. These injections are sterilized by filtration through a retaining bacteria filters, activate the sterilizing means, or by irradiation. Alternatively, these injections may be issued in the form of sterile solid compositions and dissolved or suspended in sterile water or a sterile solvent for injection immediately before use.

Examples of external preparations include ointments, plasters, creams, jellies, compresses (poultice), sprays, lotions, eye drops, eye ointments etc. An external agent contains commonly used ointment bases, the base for lotions, aqueous or nonaqueous liquids, suspensions, emulsions and the like. As examples of bases for ointments or lotions can be mentioned polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, utverjdenie a polyoxyethylene castor oil, glycerylmonostearate, stearyl alcohol, cetyl alcohol, euromac ogol, serviceservice and the like.

Typically, a suitable daily dose of a compound according to the invention is from about 0.001 to 50 mg/kg/body weight, preferably from 0.01 to 30 mg/kg/body weight, more preferably from 0.05 to 10 mg/kg/body weight, for oral administration. For intravenous administration, the daily dose is from about 0.0001 to 10 mg/kg/body weight, preferably from 0.001 to 1.0 mg/kg/body weight. The dose is administered once or divided portions during the day, and accordingly shall be chosen in each case depending on the symptom, age, sex, and the like. When the connection according to the invention is intended for use as an external tool, it is desirable that the tool contained a compound according to the invention in amounts of from 0.0001 to 20%, preferably from 0.01 to 10%. An external agent is applied topically once or separate portions during the day depending on the symptom.

The connection according to the invention can be suitably used in combination with other pharmaceutical agents. The examples used in combination means include other antiherpesvirus tools such as ACV, VCV, FCV, penciclovir (PCV), vidarabine (ara-A), BVDU (brainydictionary), foscarnet (PFA), ganciclovir (GCV), etc.; pain from neuralgia after chickenpox, such as amitriptyl is n (a tricyclic antidepressant), gabapentin (antispasmodic remedy), lidocaine and meksiletin (antiarrhythmic agent), capsicin, etc.; and anti-inflammatory analgesics, such as indomethacin, ibuprofen, celecoxib, etc.

Action of the compounds according to the invention is confirmed by the following pharmacological tests.

The test example 1: test for anti-VZV activity

This test is carried out according to the method described Shigeta S. (The Journal of Infectious Diseases, 147, 3, 576-584 (1983). Namely embryonic fibroblasts (HEF) are seeded in 96-well titration the microplate using a nutrient medium for the cultivation of crops [Eagle MEM (Nissui)supplemented with 10% (V/o) fetal calf serum (FBS; Sigma)], growing in 5% CO2at 37°C for 4 days before the formation of the monolayer. After washing cells supporting environment cells inoculant using 100 µl/well VZV (strain CaQu), diluted to 20-30 boe/100 μl of the supporting medium (Eagle MEM supplemented with 2% FBS). Tablet centrifuged at 2000 rpm for 20 minutes at room temperature and then incubated at 37°C for 3 hours in an atmosphere of 5% CO2for VZV infection. After triple washing supportive environment, to each well add 100 ál each of the test drugs, diluted to the appropriate concentration supports what redoy. After growing the cells at 37°C for 3-4 days in an atmosphere of 5% CO2the cells fixed with the help of a mixture of 10% formalin/PBS at a concentration of 100 μl/well for 2-3 hours. After growing the cells in 5% CO2at 37°C for 3-4 days add a mixture of 10% formalin/PBS at 100 μl/well to fix the cells for 2-3 hours. After discarding waste fixing solution and the culture supernatant and the subsequent washing of the plate with water, add a coloring solution (0.025% of crystal violet) at a concentration of 50 µl/well for coloring within 2-3 minutes, the tablet then washed with water and dried at 37°C. induce cell Death in HEF cells infected with VZV, so that plaques of dead cells formed a monolayer HEF cells. The number of plaques counted using a microscope, counting the value of EC50the test drug as concentration, inhibitory 50% of plaques.

Compared with acyclovir, relevant EC50equal to 3.4 μm, the values of EC50for connection examples 1, 11, 13, 27, 37, 39, 98 and 125 according to the invention comprise 0,075, 0,060, 0,033, 0,10, 0,095, 0,082, 0,14 and to 0.19 μm, in the same order. This confirms that the compounds according to the examples have high anti-VZV activity.

The test example 2: test for anti-HSV-1 activity

10000 MRC-5 cells seeded and virusiv the Ute in 96-well titration the microplate, using a nutrient medium for the cultivation of crops [Eagle MEM (Nissui)supplemented with 10% FBS], in 5% CO2at 37°C for 4-5 days before the formation of the monolayer. After washing cells support culture medium [Eagle MEM supplemented with 2% (V/o) FBS] to each well add 100 ál of supporting culture medium with the appropriate concentration of dissolved test reagent. Immediately after addition of the test drug solution HSV-1 (strain KOS) inoculant at 50 TCID50(50% tissue culture infectious dose)/100 ál.

After growing cells in an atmosphere of 5% CO2at 37°C for 5 days to each well was added 20 μl of MTT solution [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium; Sigma] (diluted with PBS to 7.5 mg/ml)for further 24-h incubation. After discarding waste in culture medium to each well add 100 ál of solvent (obtained by adding 10% Triton × 100 (o/o) and 0.4% hydrochloric acid to isopropanol) to solubilize the formed of parmasan. The absorption at 540 nm or 690 nm was measured with a spectrophotometer to read the microplate. Based on suppression ratio (%) cell death MRC-5 cells through replication of HSV-1 count value EC50for the test drug.

Comparedwith aciclovir, relevant EC50equal to 0.48 μm, the values of EC50for connection examples 1, 11, 13, 27, 37, 39, 98 and 125 according to the invention comprise 0,075, 0,040, 0,0060, 0,060, 0,026, 0,029, 0,042 and 0,028 μm, in the same order. This confirms that the compounds according to the examples have high anti-HSV activity.

The test example 3

Using the model in mice with cutaneous HSV-1 infection, obtained by the method of H. Machida'a and others (Antiviral Res., 1992, 17, 133-143), investigate the activity of the compounds according to the invention in vivo. The skin of each devoid of wool mouse HR-1 [female, age 7 weeks] scarificial and down several times using a needle, and viral suspension(WT-51 strain of HSV-1, 1,5×104PFU/15 μl) put drops on scarification area for contamination, anestesia diethyl ether.

Compound is administered orally in the form of a suspension in methylcellulose, except for compounds marked with an asterisk, which is dissolved in a solution of 20% Cremophor EL (Nakarai Tesuku)/20% polyethylene glycol (PEG) 400/60% H2O, since that meets 3 hours after infection, and then at a dose of 10 mg/kg twice daily for 5 days. The symptom of damage to the skin caused by infection with HSV-1, classified according to the following scale for 17 days:

Grade 0: no signs of infection.

Point 1: localized, barely noticeable small bubbles.

Grade 2: slight spreading their bubbles.

Grade 3: large "foci" of the formed bubbles.

Point 4: herpetiformis bubbles.

Score 5: large "foci" formed ulcers.

Point 6: herpetiformis, with strong large ulcers.

Point 7: hind limb paralysis or death.

AUC is calculated from the average disease score for each group and using AUC, calculate the degree of suppression of the disease group with the introduction of each of the test compounds in relation to the group with placebo. The results are shown below in table 1.

Table 1
Test connectionInhibitory activity (%)Test connectionInhibitory activity (%)
Example 1*93Example 1498
Example 692Example 2489
Example 1192Example 37100
Example 98*95Example 125*80
Connection comparison And38Connection comparison2
Connection compare With44Connection compare D43

Link is a comparison of:

Connection example 49, Ref 3

Connection comparison:

Connection example 85, the link 3

Connection compare With:

Connection example 87, Ref 3

Compound comparison D:

Connection example 119, link 3

The degree of inhibition of damage in the groups receiving the connection according to the invention is high, which proves that the connection according to the invention is characterized by greater activity in suppressing acute damage than the tested compound comparisons, described in reference 3.

Based on the above it can be concluded that the compounds according to the invention, administered orally to groups of experimental models in vivo in animals, have good antiherpesvirus activity at low dose.

In addition, the compounds having a weak inhibitory activity against CYP-enzymes, from among the compounds according to the invention is very convenient for the reason that practically does not cause concern in terms of drug-drug interactions with other medicines.

An example of a pharmaceutical composition in tablet form

Weigh five grams of the compound of the present invention and mixed with 63,6 the lactose and 27.2 g of corn starch. The resulting mixture granularit using 10% aqueous solution of hydroxypropylcellulose (for example, HPC-SL (product name) manufactured by Shin-Etsu Chemical Co., Ltd.), using a granulator, fluidized bed, and the obtained granules are dried. The dried granules are mixed with 2 g of hydroxypropylcellulose with a low degree of substitution (for example, L-HPC (product name) manufactured by Shin-Etsu Chemical Co., Ltd.) and further mixed with 0.2 g of the magnesium stearate, obtaining a powder mixture for the production of tablets. The powder mixture was placed in a rotary tablet press machine (for example, car production Kikusui Seisakusyo Ltd.) with a pestle and molar (diameter: 7 mm), with 100 mg tablets containing 5 mg of the drug.

Examples

Below, examples of the preparation of compounds according to the invention are indicated as examples. Here many of the original compounds used in subsequent interactions, known from the text of the international W0 02/38554 and the like, and therefore can be easily obtained by methods described in these references. Examples of obtaining new compounds from starting materials, the following standard examples.

The standard example 1:

An aqueous solution of sodium carbonate and tetranitropentaerithrite add to DME-solution of 3-bromothiophene and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, and the mixture is of ipatt under reflux under heating for 6 hours in an argon atmosphere. After cooling to room temperature, to the reaction mixture are added ethyl acetate and water to separate the organic layer, which is then washed and dried. The solvent is evaporated under reduced pressure. The resulting crude product was then purified by chromatography on a column of silica gel, receiving 4-(3-thienyl)aniline (light yellow solid product).

Electron impact - MS (M)+: 175.

The standard example 2:

Achilleifolia add to dodecanol suspension of 5-(4-nitrophenyl)-1,3,4-oxadiazol-2-she and the mixture is refluxed under heating for 3 hours. After cooling the reaction mixture to room temperature, the precipitate was separated by filtration and washed with hexane. The resulting crude product was then purified by chromatography on a column of silica gel, receiving ethyl-3-(4-nitrophenyl)-1,2,4-thiadiazole-5-carboxylate (light yellow solid product). To an ethanol suspension of this product add water and sodium hydroxide and heated to 85°C for 40 minutes under stirring. After cooling to room temperature the mixture podkalyvayut by adding 1 M hydrochloric acid. The resulting mixture was heated for one hour under stirring on an oil bath at 95°C. After which the mixture is cooled to room temperature and add chloroform and aqueous sodium bicarbonate for the Department of organic the sky layer, which is then washed and dried. The solvent is evaporated under reduced pressure, obtaining 3-(4-nitrophenyl)-1,2,4-thiadiazole (light yellow solid product). To an ethanol suspension of this product add water and 1 M hydrochloric acid, heated to 80°C and add reduced iron. The reaction mixture is optionally heated to 80°C for 50 minutes with stirring and then filtered through celite. After evaporation of the resulting filtrate ethanol under reduced pressure to the residue is added chloroform and aqueous sodium bicarbonate to separate the organic layer, which is then washed and dried. The solvent is evaporated under reduced pressure, obtaining 4-(1,2,4-thiadiazole-3-yl)aniline (light yellow solid product).

Electron impact - MS (M)+: 177.

The standard example 3:

To an ethanol suspension of 3-(4-nitrophenyl)isoxazol add water and 1 M hydrochloric acid. The mixture is heated to 80°C and added iron. After heating the mixture up to 80°C for 40 minutes under stirring, the mixture was filtered through celite and evaporated from the filtrate of the ethanol under reduced pressure. To the obtained residue is added chloroform and aqueous sodium hydrogen carbonate solution to separate the organic layer, which is washed and dried. By evaporation of the solvent under reduced Yes the relocation receive a 4-isoxazol-3-ranelin (light yellow solid product). FAB-MS [(M+H)+]: 161.

The standard example 4:

5% palladium on coal in the powder added to a mixed ethanol-tetrahydropyranol suspension of 4-(4-nitrophenyl)-1,3-oxazole and stirred for 12 hours at room temperature in a hydrogen atmosphere. The reaction solution is filtered through celite and the filtrate evaporated under reduced pressure. The resulting crude product was then purified by chromatography on a column of silica gel, receiving [4-(1,3-oxazol-4-yl)phenyl]amine (light yellow solid product).

Electron impact-MS (M)+: 160.

The standard example 5:

Carboxylate potassium and ethylbromoacetate added to the DMF-solution of 4-methylaniline and heated under stirring. To the reaction mixture are added water and ethyl acetate. Then the organic layer was separated, washed and dried, the solvent is evaporated under reduced pressure to give crude product. The crude product is dissolved in methylene chloride and the resulting solution was added pyridine, tetrahydro-2H-thiopyran-4-carbonylchloride-1,1-dioxide and stirred. Then the reaction solution is concentrated and add 1 M hydrochloric acid and chloroform. The separated organic layer is washed and dried, and the solvent is evaporated under reduced pressure. The resulting crude product was then purified by chromatography on a column of silica gel, receiving ethyl-{[(1,1-dixarit what-2H-thiopyran-4-yl)carbonyl](4-were)amino}acetate (colorless oily product). FAB-MS [(M+H)+]: 354.

Standard examples 6-30:

Connection standard examples 6-30, are shown in tables 2 and 3 below, receive the same manner as in example 5.

Example 1:

To ethanol (10 ml) solution of ethyl-{(2,6-dimetilfenil)[(1,1-dioxymethylene-2H-thiopyran-4-yl)carbonyl]amino]acetate (735 mg) was added 1 M aqueous sodium hydroxide solution (2.3 ml). The mixture is stirred at room temperature for 5 hours. Then to the reaction mixture was added 1 M hydrochloric acid to podkashlivanija solution, water and chloroform to separate the organic layer. After which the organic layer is dried over anhydrous sodium sulfate and filtered, then the solvent is evaporated under reduced pressure. Then the resulting crude product carboxylic acid is dissolved in chloroform (15 ml), the resulting solution was successively added WSC·HCl (422 mg) and [4-(1,3-oxazol-4-yl)phenyl]amine (320 mg) and stirred at room temperature for 4 hours. Then to the reaction solution was added saturated sodium hydrogen carbonate solution and chloroform, the organic layer separated. The organic layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered, the solvent is evaporated from the filtrate under reduced pressure. The resulting crude product with the floor is nodding with a mixture of hexane-ethyl acetate (= 3/2), and then recrystallized from ethanol, receiving N-(2,6-dimetilfenil)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide (colorless crystal) output 610 mg.

Examples 2-125:

Connection standard examples 2-125 shown in table 4-24 below, receive the same manner as in example 1.

Physico-chemical properties of the compounds according to the standard examples are shown in tables 2 and 3, while in table 4-24 presents the structure and physico-chemical properties of the compounds according to the examples.

In tables 25-26 presents typical examples of other compounds covered by the invention. These compounds can easily be obtained by the means indicated in the above examples, or methods of production, or by some modification of the methods well known to specialists in this field.

Abbreviations in the tables have the following meanings. Ref: standard example; Ex: example; Co: connection number; Str: structural formula; Dat: physicochemical properties of {F+: FAB-MS [(M+H)+]; F: FAB-MS [(M-H)-]}; ESI+: ESI (electrospray ionization) - MS [(M+H)+]; N1: δ ppm characteristic peak in1H-NMR (DMSO-d6, TMS internal standard); Ph: phenyl; Me: methyl; Et: ethyl; Pr: propyl and Bn: benzyl. Here the number in front of each replacement group indicates the position of substitution. the example 3,4-(Cl)2-5-F-Ph means 3,4-dichloro-5-florfenicol group.

Table 4

Etc.AndData
12,6-(Me)2-PhF+: 482

N1: 1,87-to 2.42 (5H, m), 2,13 (6H×0,1, s), 2,33 (6N×0,9, C), 2,97-of 3.27 (4H, m), 4,19 (2N×0,9, C), 4,48 (2N×0,1, s), 7,07-of 7.25 (3H, m), 7,62-7,66 (2H, m), 7,72 to 7.75 (2H, m), 8,43 (1H, d), 8,54 (1H, d), 10,15 (1H, users)
24-Me-PhF+: 468

N1: 1,98-to 2.06 (4H, m), of 2.34 (3H, s), 2,68-2,70 (1H, m), 2,97-to 3.02 (4H, m), 4,35 (2H, s), 7,28 (2H, d), of 7.36 (2H, d), 7,63-7,66 (2H, m), 7,72-7,76 (2H, m), 8,43 (1H, s), 8,54 (1H, s), 10,14 (1H, s)
33-Me-PhF+: 468

N1: 2,01-of 2.09 (4H, m)to 2.35 (3H, s), 2,71 (1H, m), 2.93 which is a 3.06 (4H, m), 4,36 (2H, s), 7,17-7,38 (4H, m), of 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, d), 8,54 (1H, d), 10,15 (1H, s)
42-Me-PhF+: 468

N1: 1,88-of 2.15 (4H, m), of 2.15 (3H×0,1, C), and 2.26 (3H×0,9, C), 2,41 is 2.46 (1H, m), 2,83 was 3.05 (4H, m), 3,86 (1H×0,9, d), 4,20 (1H×0,1, d), 4,74 (1H×0,9, d), 4,84 (1H×0,1, d), 7,09-to 7.77 (8H, m), 8,43 (1H, d), 8,53 (1H, d), 10,14 (1H×0,9, C), 10,19 (1H×0,1, C)
52,3-(Me)2-PhF+: 482

N1: 1,85-2,12 (4H, m), 2,03 (3H×0,1, C)to 2.15 (3H×0,9, in), 2.25 (3H×0,1, C)2,31 (3H×0,9, C), 2,42-2,47 (1H, m), 2,83-2,90 (1H, m)3,00-up 3.22 (3H, m), a-3.84 (1H×0,9, d), 4,16 (1H×0,1, d), 4.72 in (1H×0,9, d), 4,84 (1 is× 0,1, d), 7,07 and 7.36 (3H, m), 7,62-7,66 (2H, m), 7,71-7,76 (2H, m), 8,43 (1H, users), 8,54 (1H, d), 10,12 (1H×0,9, C)10,16 (1H×0,1, C)

Table 5
62,4-(Me)2-PhF+: 482

N1: 1,88-of 2.50 (5H, m), is 2.09 (3H×0,1, C)of 2.21 (3H×0,9, in), 2.25 (3H×0,1, C)of 2.30 (3H×0,9, C), 2,85-3,20 (4H, m), 3,81 (1H×0,9, d), 4,17 (1H×0,1, d), 4.72 in (1H×0,9 d), to 4.81 (1H×0,1, d), 6,97-7,39 (3H, m), 7,62-7,66 (2H, m), 7,72-7,76 (2H, m), 8,43 (1-H, s), 8,54 (1H, s), 10,11 (1H×0,9, C), 10,17 (1H×0,1, C)
72,5-(Me)2-PhF+: 482

N1: 1,86 is 2.51 (5H, m), of 2.08 (3H×0,1, C)of 2.20 (3H×0,9, C), 2,22 (3H×0,1, C)of 2.30 (3H×0,9, C), 2,87-3,26 (4H, m), a-3.84 (1H×0,9, d), is 4.21 (1H×0,1, d), 4,70 (1H×0,9 d), 4,80 (1H×0,1, d), 6,92-to 7.32 (3H, m), 7,63-the 7.65 (2H, m), 7,72-7,76 (2H, m), 8,43 (1H, s), 8,54 (1H, s), 10,12 (1H×0,9, C), 10,17 (1H×0,1, C)
83,4-(Me)2-PhF+: 482

N1: 1,92-of 2.08 (4H, m), is 2.09 (3H, s), 2,24 (3H, s), 2,71 (1H, s), 2,94-of 3.06 (4H, m)to 4.33 (2H, s), 7,17-7,24 (3H, m), of 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,12 (1H, s)
93,5-(Me)2-PhF+: 482

N1: 1,96-2,14 (4H, m), is 2.30 (6H, s), 2,73 (1H, m), 2.95 and totaling 3.04 (4H, m)to 4.33 (2H, s), 7,02 (1H, s), was 7.08 (2H, s), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,12 (1H, s)
102,4,6-(Me)3-PhF+: 496

N1: 1,87-of 2.45 (5H, m), of 2.08 (3H×0,1, C)2,09 (6N×0,1, C), and 2.27 (3H×0,9, C), 2,28 (6N×0,9, C), 3,01-3,26 (4H, m), 4.16 the (2N×09, C)of 4.44 (2H×0,1, C)to 6.88 (2H×0,1, s), 7,01 (2N×0,9, C)to 7.61-the 7.65 (2H, m), 7,71 to 7.75 (2H, m), 8,43 (1H, s), 8,54 (1H, s), 10,12 (1H×0,9, C), 10,14 (1H×0,1, C)
11F+: 494

N1: 2,01-of 2.08 (6H, m), 2,70-3,06 (9H, m), 4,34 (2H, s), 7,13-to 7.32 (3H, m), of 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,13 (1H, s)

Table 6
123-Cl-4-Me-PhF+: 502

N1: 2,01-to 2.06 (4H, m), a 2.36 (3H, s), 2,68 is 2.75 (1H, m), 3,01-of 3.06 (4H, m), 4,37 (2H, s), 7,37-7,40 (1H, m), 7,46 (1H, d), 7,60-7,66 (3H, m), 7,74 (2H, d), 8,44 (1H, s), 8,55 (1H, s), 10,18 (1H, s)
134-Cl-3-Me-PhF+: 502

N1: 2,00 e 2.06 (4H, m), a 2.36 (3H, s), 2,68 is 2.75 (1H, m), 3,01 totaling 3.04 (4H, m), 4,36 (2H, s), 7,33 and 7.36 (1H, m), of 7.48-7,52 (2H, m), of 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,18 (1H, s)
143-F-4-Me-PhF+: 486

N1: 2,00-of 2.05 (4H, m), and 2.26 (3H, s), 2,70-2,77 (1H, m), 3,01-3,03 (4H, m), 4,36 (2H, s), 7.24 to 7,26 (1H, m), 7,32-7,41 (2H, m), of 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,17 (1H, s)
153-Br-4-Me-PhF+: 546, 548

N1: 2,00 e 2.06 (4H, m), of 2.38 (3H, s), 2,68-to 2.74 (1H, m), 3,01 totaling 3.04 (4H, m), 4,36 (2H, s), 7,41-7,47 (2H, m), of 7.64 (2H, d), 7,73-7,76 (3H, d), 8,43 (1H, s), 8,54 (1H, s), 10,18 (1H, s)
165-F-2-Me-PhF+: 486

N1: 1,88-of 2.15 (4H, m), 2,11 (3H×0,1, C)of 2.23 (3H×0,9, C), a 2.45-2.49 USD (1H, m), 2,96-and 3.16 (4H, m), 3,92 (1H×0,9, d), 4,27 (1H×0,1, d), 4,70 (1H×0,9, d), 4,82 (1H×0,1, d), 6,95-6,98 (1H×,1, m), 7,06-7,10 (1H×0,1, m), 7,20-of 7.25 (1H×0,9, m), 7,29-7,33 (1H×0,1, m), 7,37-7,40 (1H×0,9, m), 7,42-7,46 (1H×0,9 m), the 7.65 (2H, d), 7,74 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,18 (1H×0,9, C), 10,23 (1H×0,1, C)
173-F-2,4-(Me)2-PhF+: 500

N1: 1,88-of 2.23 (4H, m), 2,03 (3H×0,1, C)of 2.16 (3H×0,9, C)of 2.20 (3H×0,1, C), and 2.26 (3H×0,9, C), 2,47-of 2.54 (1H, m), 2,87-3,17 (4H, m), 3,91 (1H×0,9, d), 4,25 (1H×0,1, d), of 4.66 (1H×0,9, d), 4,80 (1H×0,1, d), to 6.88 (1H×0,1, e), 7,10 (1H×0,1, DD), 7,21 (1H×0,9, DD), 7,28 (1H×0,9, d), to 7.64 (2H, d), 7,73 (2H, s), 8,43 (1H, s), 8,54 (1H, s), 10,14 (1H×0,9,) and 10.20 (1H×0,1, C)

Table 7
184-F-3,5-(Me)2-PhF+: 500

N1: 2,00-of 2.05 (4H, m), 2,24 (6H, s), 2,67-to 2.74 (1H, m), 3.00 and totaling 3.04 (4H, m)to 4.33 (2H, c), of 7.23 (2H, d), the 7.65 (2H, d), 7,74 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,15 (1H, s)
19the 3.5-F2-4-Me-PhF+: 504

N1: 1,99-of 2.05 (4H, m), 2,17 (3H, s), 2,75-2,82 (1H, m), 2,99-3,10 (4H, m), 4,37 (2H, s), 7,28 (2H, d), the 7.65 (2H, d), 7,74 (2H, d), 8,44 (1H, s), 8,55 (1H, s)of 10.21 (1H, s)
202-F-4-Me-PhF+: 486

N1: 1,89-2,11 (4H, m), 2,30 (3H×0,1, C), a 2.36 (3H×0,9, C), 2,60 of 2.68 (1H, m), 3,01-3,26 (4H, m), of 3.94 (1H×0,9, d), was 4.02 (1H×0,1, d)4,50 (1H×0,1, d), was 4.76 (1H×0,9, d), 7,00 (1H×0,1, d), to 7.09 (1H×0,1, d), 7,12 (1H×0,9, d), 7,24 (1H×0,9, d), 7,38 (1H×0,1, DD), to 7.50 (1H×0,9, DD), 7,63 (2H, d), 7,73 (2H, d), 8,44 (1H, s), 8,55 (1H, s), 10,17 (1H×0,9, C), 10,23 (1H×0,1, C)/td>

Table 8

Etc.AndData
214-Me-PhF+: 469

N1: 1,94-2,11 (4H, m), of 2.34 (3H, s), 2,65 is 2.75 (1H, m), 2,92-is 3.08 (4H, m), to 4.38 (2H, s), 7,28 (2H, d), 7,37 (2H, d), 7,79 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), 10,38 (1H, s)
223-Me-PhF: 467

N1: 1,96-2,11 (4H, m)to 2.35 (3H, s), 2,65 was 2.76 (1H, m), 2,92-to 3.09 (4H, m), 4,39 (2H, s), 7,20-7,39 (4H, m), 7,79 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s),10,38 (1H, s)
232-Me-PhF+: 469

N1: 1,88-of 2.26 (4H+3H, m), 2,42-2,52 (1H, m), 2,84-3,18 (4H, m), 3,91 (1H×0,9, d), of 4.44 (1H×0,1, d), and 4.75 (1H×0,9, d), to 4.87 (1H×0,1, d), 7,08-rate of 7.54 (4H, m), 7,75-7,81 (2H, m), 7,97-8,04 (2H, m), to 9.66 (1H×0,9, C), 9,67 (1H×0,1, s), 10,37 (1H×0,9, C), 10,41 (1H×0,1, C)
242,3-(Me)2-PhF: 481

N1: 1,83-2,31 (4H+3H+3H, m), 2,42-of 2.54 (1H, m), 2,82-and 3.16 (4H, m), 3,88 (1H×0,9, d), 4,19 (1H×0,1, d), 4.72 in (1H×0,9, d), to 4.87 (1H×0,1, d), 7,05-7,37 (3H, m), 7,75-7,80 (2H, m), 7,97-8,03 (2H, m), to 9.66 (1H×0,9, C)to 9.66 (1H×0,1, s), 10,35 (1H×0,9, C), 10,38 (1H×0,1, C)
252,4-(Me)2-PhF: 481

N1: 1,84 is 2.33 (4H+3H+3H, m), 2,42-2,52 (1H, m), 2,84-3,19 (4H, m), 3,86 (1H×0,9, d), is 4.21 (1H×0,1, d), to 4.73 (1H×0,9, d), 4,84 (1H×0,1, d), 6,95-7,40 (3H, m), 7,75-7,81 (2H, m), 7,98-8,02 (2H, m), to 9.66 (1H×0,9, C)to 9.66 (1H×0,1, s), 10,35 (1H×0,9, C), accounted for 10.39 (1H×0,1, C)
/p>

Table 9
262,5-(Me)2-PhF: 481

N1: 1,84 of-2.32 (4H+3H+3H, m), 2,42-2,52 (1H, m), 2,87-3,18 (4H, m)to 3.89 (1H×0,9, d), 4,25 (1H×0,1, d), 4.72 in (1H×0,9, d), a 4.83 (1H×0,1, d), 6,92-7,34 (3H, m), 7,76-of 7.82 (2H, m), 7,98-8,04 (2H, m), to 9.66 (1H×0,9, C), 9,67 (1H×0,1, s), 10,37 (1H×0,9, C), accounted for 10.39 (1H×0,1, C)
272,6-(Me)2-PhF: 481

N1: 1,88-2,42 (5H+6H, m), 2,98-of 3.27 (4H, m), 4,22 (2N×0,86,) 4,51 (2N×0,14, C), 7,1-7,3 (3H, m), 7,76-7,81 (2H, m), 7,99-8,03 (2H, m), to 9.66 (1H, s), 10,38 (1H, s)
283,4-(Me)2-PhF+: 483

N1: 1,97-of 2.20 (4H, m), 2,24 (6H, s), 2,67 was 2.76 (1H, m), 2,96-3,30 (4H, m), 4,37 (2H, s), 7,17-7,27 (3H, m), 7,79 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), 10,36 (1H, s)
293,5-(Me)2-PhF+: 483

N1: 1,98-2,12 (4H, m), is 2.30 (6H, s), 2,65-2,78 (1H, m), 2,93-3,10 (4H, m), 4,36 (2H, s), 7,00 for 7.12 (3H, m), 7,79 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), 10,37 (1H, s)
30F: 495

N1: 1,83-2,52 (4H+9H+1H, m), 2,99-3,26 (4H, m), 4,18 (2N×0,9, C), 4,48 (2N×0,1, C)to 6.88 (2H×0,1, s), 7,01 (2N×0,9, C), 7,74-of 7.82 (2H, m), 7,94-8,03 (2H, m), to 9.66 (1H, s), 10,36 (1H with)
31F: 499

N1: 1,82 is 2.44 (6H+5H, m), 2,98-3,30 (4H, m), is 4.21 (2H×0,85, C)4,50 (2N×to 0.15, (C), to 6.95 (2H×0,15, d), was 7.08 (2H×0,85, d), of 7.75-of 7.82 (2H, m), 7,97-of 8.04 (2H, m), to 9.66 (1H×0,85, s), to 9.66 (1H×0,15, C)of 1.40 (1H, users)
32F+: 487

N1: 1,97-2,11 (4H, m), and 2.26 (3H, users), 2,63-to 2.74 (1H, m), 2.95 and-of 3.07 (4H, m), to 4.38 (2H, s), 7,21 was 7.45 (3H, m), 7,79 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), accounted for 10.39 (1H, s)
33F: 493

N1: 1,96-of 2.20 (6H, m), 2,70-2,78 (1H, m), 2,84-is 3.08 (8H, m), 4,37 (2H, s),? 7.04 baby mortality-7,33 (3H, m), 7,79 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), 10,37 (1H, s)

Table 10
344-Me-3-Br-PhF: 546

N1: 1,96-of 2.16 (4H, m), of 2.38 (3H, s), 2,66-2,77 (1H, m), 2,96-is 3.08 (4H, m), 4,39 (2H, s), 7,40-7,49 (2H, m), 7,73-of 7.82 (3H, m), of 8.00 (2H, d), to 9.66 (1H, s), 10,41 (1H, s)
353-F-4-Me-PhF+: 487

N1: 1,97-2,07 (4H, m), and 2.26 (3H, s), 2,69-2,77 (1H, m), 2,99-3,03 (4H, m), 4,39 (2H, s), 7,22-7,28 (1H, m), 7,31-7,42 (2H, m), 7,80 (2H, d), to 7.99 (2H, d), to 9.66 (1H, s), the 10.40 (1H, s)
363-Cl-4-Me-PhF+: 503

N1: 1,97-2,11 (4H, m), a 2.36 (3H, s), 2,65-2,78 (1H, m), 2,97-is 3.08 (4H, m), 4,39 (2H, s), 7,39 (1H, DD), was 7.45 (1H, d), 7,60 (1H, d), 7,80 (2H, d), to 7.99 (2H, d), 9,65 (1H, s), the 10.40 (1H, s)
374-Cl-3-Me-PhF+: 503

N1: 1,95-of 2.09 (4H, m), a 2.36 (3H, s), 2,65 was 2.76 (1H, m), 2.95 and-of 3.07 (4H, m), 4,39 (2H, s), of 7.36 (1H, DD), of 7.48 (1H, d), 7,51 (1H, d), 7,80 (2H, d), to 7.99 (2H, d), to 9.66 (1H, s), the 10.40 (1H, s)
384-F-3,5-(Me)2-PhF+: 501

N1: 1,94-2,12 (4H, m), 2,24 (6H, s), 2,64-to 2.74 (1H, m), 2,94-is 3.08 (4H, m), 4,35 (2H, s), 7.23 percent (2H, d), 7,79 (2H, d), to 7.99 (2H, d), to 9.66 (1H, s)to 1.38 (1H, C)
393-F-2,4-(Me)2-PhF+: 501

N1: 1,84-of 2.34 (4H+3H+3H, m), 2,48 is 2.55 (1H, m), 2,85-up 3.22 (4H, m), 3,98 (1H×0,9, d), 4,30 (1H×0,1, d)and 4.65 (1H×0,9, d), to 4.81 (1H×0,1, d), 7,22 (1H, t), 7,27 (1H, d), 7,78 (2H, d), 7,98 (2H, d), to 9.66 (1H, s), 10,37 (1H×0,9, C), 10,51 (1H×0,1, C)
402-F-4-Me-PhF+: 487

N1: 1,90-to 2.18 (4H, m), 2,30 (3H×0,1, C), a 2.36 (3H×0,9, C), 2,62 of 2.68 (1H, m), 3,01 is 3.23 (4H, m), 3,99 (1H, d), of 4.77 (1H, d), 7,13 (1H, d), 7,25 (1H, d), to 7.50 (1H, DD), to 7.77 (2H, d), to 7.99 (2H, d), to 9.66 (1H, s), the 10.40 (1H×0,9, C), 10,45 (1H×0,1, C)

Table 11
414-F-PhF: 471

N1: 1,97-2,22 (4H, m), 2,61-2,70 (1H, m), 2.95 and-3,30 (4H, m), and 4.40 (2H, s), 7,21-to 7.35 (2H, m), 7,53-7,58 (2H, m), 7,78 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), the 10.40 (1H, s)
423-F-PhF: 471

N1: 1,96-of 2.24 (4H, m), 2,65 is 2.80 (1H, m), 2,97-up 3.22 (4H, m), 4,43 (2H, s), 7,10-7,56 (4H, m), 7,80 (2H, d), 8,01 (2H, d), to 9.66 (1H, s), 10,44 (1H, s)
433,4-F2-PhF: 489

N1: 1,94-of 2.25 (4H, m), 2,65 is 2.75 (1H, m), 2,97-3,30 (4H, m)to 4.41 (2H, s), 7,37-of 7.69 (3H, m), 7,88 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), 10,43 (1H, s)
443,5-(CI)2-PhF: 522

N1: 1,95-2,12 (4H, m), 2,66-of 2.81 (1H, m), 2.95 and-3,20 (4H, m), 4,42 (2H, s), to 7.64 (2H, s), of 7.70 (1H, s), 7,79 (2H, d), 8,01 (2H, d), to 9.66 (1H, s), 10,46 (1H, s)
454-Pr-PhF+: 497

N1: of 0.91 (3H, t), 1,55-of 1.66 (2H, m), 1,95 and 2.13 (4H, m)at 2.59 (2H,t), 2,65 is 2.75 (1H, m), 2,90-3,20 (4H, m), 4,39 (2H, s), 7,29 (2H, d), 7,39 (2H, d), 7,79 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), 10,37 (1H, s)
46F: 483

N1: 1,94-of 2.09 (4H, m), 2,62-by 2.73 (1H, m), 2.91 in-is 3.08 (4H, m), of 3.78 (3H, s), 4,37 (2H, s), 7,02 (2H, d), 7,41 (2H, d), 7,78 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), 10,37 (1H, s)
47F+: 499

N1: 1,95-to 2.13 (4H, m), 2,65-2,78 (1H, m), 2,97-of 3.06 (4H, m), 4,35 (2H, s)6,09 (2H, s), 6,97-to 7.09 (3H, m), 7,78 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), 10,37 (1H, s)
48F+: 535

N1: 1,95-2,11 (4H, m), 2,64 is 2.75 (1H, m), 2,96-3,20 (4H, m)to 4.41 (2H, s), 7,39 (1H, DD), 7,51 (1H, d), to 7.61 (1H, d), 7,79 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), 10,42 (1H, s)

Table 12
494-F-3-Cl-PhF: 505

N1: 1,94-of 2.30 (4H, m), 2,64 was 2.76 (1H, m), 2,92-3, 20 (4H, m)to 4.41 (2H, s), 7,46 to 7.62 (2H, m), 7,74-7,83 (3H, m), 8,01 (2H, d), to 9.66 (1H, s), 10,44 (1H, s)
503-F-2-Me-PhF: 485

N1: 1,86-2,22 (4H+3H, m), 2,44-of 2.54 (1H, m), 2,84-3,20 (4H, m), a 4.03 (1H×0,9, d), 4,34 (1H×0,1, d), of 4.67 (1H×0,9, d), a 4.83 (1H×0,1, d), 6,98-the 7.43 (3H, m), 7,74-of 7.82 (2H, m), of 7.96-8,04 (2H, m), 9,65 (1H×0,9, C), 9,65 (1H×0,1, s), 10,38 (1H×0,9, C), 10,42 (1H×0,1, C)
515-F-2-Me-PhF: 485

N1: 1,84-2,24 (4H+3H, m), 2,44-2,52 (1H, m), 2,92-up 3.22 (4H, m), 3,99 (1H×0,9, d)to 4.33 (1H×0,1, d), 4,69 (1H×0,9, d), 4,81 (N× 0,1, d), 6,93-7,47 (3H, m), 7,76-7,81 (2H, m), 7,97-of 8.04 (2H, m), to 9.66 (1H×0,9, C)to 9.66 (1H×0,1, C), the 10.40 (1H×0,9, C), 10,43 (1H×0,1, C)
523,5-(Br)2-4-Me-PhF: 625

N1: 1,95-2,10 (4H, m), of 2.54 (3H, s), 2,68-2,82 (1H, m), 2.95 and-and 3.16 (4H, m), and 4.40 (2H, s), 7,80 (2H, d), to 7.84 (2H, s), to 7.99 (2H, d), to 9.66 (1H, s), 10,44 (1H, s)
533,4,5-F3-PhF: 507

N1: 1,88-2,12 (4H, m), 2,65 is 2.80 (1H, m), 2.95 and-of 3.07 (4H, m)to 4.41 (2H, s), of 7.48 to 7.62 (2H, m), 7,80 (2H, d), to 7.99 (2H, d), to 9.66 (1H, s), 10,46 (1H, s)
542,3,5,6-F4-4-Br-PhF-: 605

N1: 1,90-of 2.28 (4H, m), 2,78-is 2.88 (1H, m), 2,98 of 3.28 (4H, m), 4,46 (2N×0,85, C), 4,70 (2N×0,15, C), 7,72-7,79 (2H, m), 7,94-8,03 (2H, m), to 9.66 (1H×0,85, C)to 9.66 (1H×0,15, C), 10,44 (1H×0,85, (C), of 10.47 (1H×0,15, C)
553-F-4-MeO-PhF: 501

N1: 1,96-2,07 (4H, m), 2,65 was 2.76 (1H, m), 2,96-of 3.06 (4H, m), a 3.87 (3H, s), to 4.38 (2H, s), 7,21 was 7.45 (3H, m), 7,80 (2H, d), to 7.99 (2H, d), to 9.66 (1H, s), accounted for 10.39 (1H, s)

Table 13
563-CF3-4-Cl-PhF-: 555

N1: 1,94-2,11 (4H, m), 2,62 was 2.76 (1H, m), 2.95 and-of 3.12 (4H, m), to 4.46 (2H, s), 7,75-7,87 (4H, m), 7,97-with 8.05 (3H, m), to 9.66 (1H, s), of 10.47 (1H, s)
573-CN-4-Me-PhES+: 494

N1: 1,95-2,07 (4H, m), 2,52 (3H, s), 2,65 is 2.75 (1H, m), 2,98 totaling 3.04 (4H, m)to 4.41 (2H, s), 7,58 (1H, d), 7,73 (1H, DD), 7,79 (2H, d), to $ 7.91 (1H, d), to 7.99 (2H, d), to 9.66 (1H, s), 10,43 (1H, s)
583-CN-4-Cl-PhF-: 512

N1 1,94 is 2.10 (4H, m), 2,65 is 2.80 (1H, m), 2,94-3,11 (4H, m), of 4.44 (2H, s), 7,80 (2H, d), 7,82-a 7.92 (2H, m), of 8.00 (2H, d), 8,13 (1H, s), to 9.66 (1H, s), of 10.47 (1H, s)
593-Br-4-F-PhF+: 553

N1: 1,96-of 2.08 (4H, m), 2,63 is 2.75 (1H, m), 2.95 and-3,10 (4H, m), and 4.40 (2H, s)to 7.50 (1H, t), 7,55-7,63 (1H, m), 7,80 (2H, d), to $ 7.91 (1H, DD), to 7.99 (2H, d), to 9.66 (1H, s), 10,43 (1H, s)
60the 3.5-F2-4-Br-PhF+: 569

N1: 1,92-2,12 (4H, m), was 2.76-2,90 (1H, m), 2,94-and 3.16 (4H, m), 4,43 (2H, s), 7,49 (2H, d), 7,80 (2H, d), to 7.99 (2H, d), to 9.66 (1H, s), of 10.47 (1H, s)
61F: 468

N1: 1,92-of 2.27 (4H, m), 2,64 was 2.76 (3H+1H, m), 2,94-to 3.38 (4H, m), 4,50 (2H, s), 7,75-of 7.90 (3H, m), to 7.99 (2H, d), 8,20-to 8.40 (1H, m), 8,68-of 8.90 (1H, m), to 9.57 (1H, s), as 10.63 (1H, s)
62ES+: 538

N1: 1,96-to 2.18 (4H+3H, m), 2,69 is 2.80 (1H, m), 2,96-3,10 (4H, m), and 3.16 (2H, t), 4,14 (2H, t), 4,37 (2H, s), 7,10 (1H, DD), 7,29 (1H, d), 7,79 (2H, d), 7,98 (2H, d), of 8.09 (1H, d), to 9.66 (1H, s), accounted for 10.39 (1H, s)

Table 14
63F+: 554

CDCl3: 2,11-of 2.21 (2H, m), 2,33 is 2.46 (2H, m), 2,75-2,87 (3H, m), a 3.01 (2H, t), 3,16-to 3.35 (4H, m), 3,37 (3H, s), 3,50-3,61 (4H, m), to 4.38 (2H, s), 6,36 (1H, d), of 6.50 (1H, DD), 7,02 (1H, d), 7,63 (2H, d), 8,02 (2H, d), 8,66 (1H, s), 8,73 (1H, s)
64F: 494

N1: 1,98-to 2.13 (4H, m), 2,73-of 2.86 (1H, m), 2,90-of 3.12 (4H+2H, m), 3,49 (2H, t)to 4.33 (2H, s), 6,59-6,72 (2H, m), 10 (1H, d), 7,80 (2H, d), to 7.99 (2H, d), to 9.66 (1H, s), 10,36 (1H, s)
65F: 510

N1: 1,98-2,14 (4H, m), 2,69 is 2.80 (1H, m), 2,92 totaling 3.04 (4H, m), 4,48 (2H, s), to 7.68 (1H, DD), 7,80 (2H, d), of 8.00 (2H, d), 8,18 (1H, d), 8,32 (1H, d), for 9.47 (1H, s), to 9.66 (1H, s), 10,43 (1H, s)
66ESI+: 512

N1: 1,99-2,14 (4H, m), 2,71 is 2.80 (1H, m), 2,92 was 3.05 (4H, m), 4,50 (2H, s), to 7.64 (1H, DD), 7,80 (2H, d), of 8.00 (2H, d), 8,24 (1H, d), of 8.28 (1H, d), 9,49 (1H, s), to 9.66 (1H, s), 10,43 (1H, s)

Table 15

Etc.AData
674-F-PhF+: 472

N1: 1,99-of 2.05 (4H, m), 2,62-2,69 (1H, m), 2,98-to 3.02 (4H, m), 4,37 (2H, s), 7,29-7,34 (2H, m), 7,54-EUR 7.57 (2H, m), of 7.64 (2H, d), 7,74 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,17 (1H, s)
683,4-F2-PhF+: 490

N1: 1,99-2,02 (4H, m), 2,69 (1H, m), 2,98 totaling 3.04 (4H, m), to 4.38 (2H, s), 7,39 to 7.75 (7H, m), 8,43 (1H, s), 8,54 (1H, s), and 10.20 (1H, s)
693-Me-4-F-PhF+: 486

N1: 2,00-of 2.05 (4H, m), and 2.26 (3H, s), 2,64-a 2.71 (1H, m), 2,99-3,03 (4H, m), 4,35 (2H, s), 7,22-7,44 (3H, m), the 7.65 (2H, d), 7,74 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,16 (1H, s)
702-Me-3-F-PhF+: 486

N1: 1,89-of 2.20 (4H, m), is 2.05 (3H×0,1, C)to 2.18 (3H×0,9, C), 2,45 is 2.51 (1H, m), 2,85-and 3.16 (4H, m), of 3.96 (1H×0,9, d), 4,28 (1H×0,1, d), of 4.67 (1H×0,9, d), 4,84 (1H×0,1, d) 6,99-7,41 (3H, m)to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,16 (1H×0,9, C), 10,22 (1H×0,1, C)
713,5-Br2-4-Me-PhF+: 625

N1: 2,00-of 2.05 (4H, m), of 2.54 (3H, s), 2,70-2,77 (1H, m), 3,01-of 3.12 (4H, m), 4,37 (2H, s), the 7.65 (2H, d), 7,74 (2H, d), to 7.84 (2H, s), 8,44 (1H, s), 8,55 (1H, s), 10,22 (1H, s)
723,4,5-F3-PhF+: 508

N1: 1,93-2,04 (4H, m), 2,71 was 2.76 (1H, m), 3,01-is 3.08 (4H, m), to 4.38 (2H, s), 7,56 (2H, DD), the 7.65 (2H, d), of 7.75 (2H, d), 8,44 (1H, s), 8,55 (1H, s), 10,24 (1H, s)

Table 16
733-BnO-PhF+: 560

N1: 1,95-of 2.08 (4H, m), 2,66-to 2.74 (1H, m), 2.91 in was 3.05 (4H, m), 4,36 (2H, s)to 5.13 (2H, s), 7,07 (2H, d), to 7.15 (1H, s), 7,31-7,47 (6H, m), the 7.65 (2H, d), 7,74 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,16 (1H, s)
744-Et-PhF+: 482

N1: of 1.20 (3H, t), 1,99-of 2.09 (4H, m), 2,62-of 2.72 (3H, m), 2,94-of 3.06 (4H, m), 4,36 (2H, s), 7,31 (2H, d), 7,39 (2H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,14 (1H, s)
753-CF3-4-Cl-PhF+: 556

N1: 1,99-of 2.05 (4H, m), 2,65-of 2.72 (1H, m), 3,02-of 3.06 (4H, m), 4,43 (2H, s), the 7.65 (2H, d), 7,74 (2H, d), to 7.84 (2H, s), 8,02 (1H, s), 8,43 (1H, s), 8,54 (1H, s), 10,24 (1H, s)
763-Cl-4-F-PhF+: 506

N1: 1,99-2,04 (4H, m), 2,65-of 2.72 (1H, m), 3,01 totaling 3.04 (4H, m), to 4.38 (2H, s), 7,50-7,58 (2H, m), the 7.65 (2H, d), 7,74 (2H, d), 7,79-7,81 (1H, m), 8,43 (1H, s), 8,54 (1H, s), and 10.20 (1H, s)
773-F-4-MeO-PhF+: 502

N1: 2,00-of 2.05 (4H, m), 2,67-to 2.74 (1H, m), 3.00 and-3,03 (4H, m), a 3.87 (3H,s), of 4.35 (2H, s), 7,22-the 7.43 (3H, m), of 7.64 (2H, d), 7,74 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,16 (1H, s)
78F+: 498

N1: 2,00 e 2.06 (4H, m), 2,69 was 2.76 (1H, m), 3,01 totaling 3.04 (4H, m)to 4.33 (2H, s)6,09 (2H, s), 6,98 (2H, s), to 7.09 (1H, s), to 7.64 (2H, d), 7,74 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,14 (1H, s)

Table 17
79F+: 534

N1: 2,00-of 2.05 (4H, m), 2,67-to 2.74 (1H, m), 3.00 and was 3.05 (4H, m), to 4.38 (2H, s), 7,39 (1H, DD), 7,49 (1H, d), a 7.62 (1H, d), of 7.69 (2H, d), 7,74 (2H, d), 8,44 (1H, s), 8,55 (1H, s), 10,19 (1H, s)
803-CN-4-Cl-PhF-: 511

N1: 1,94-of 2.16 (4H, m), 2,67-to 2.74 (1H, m), 2,98 totaling 3.04 (4H, m)to 4.41 (2H, s), the 7.65 (2H, d), 7,74 (2H, d), 7,84-of 7.90 (2H, m)to 8.12 (1H, s), 8,43 (1H, s), 8,55 (1H, s), 10,24 (1H, s)
813-CN-4-Me-PhF: 491

N1: 2,00-2,04 (4H, m), 2,52 (3H, s), 2,67-a 2.71 (1H, m), 3.00 and-3,03 (4H, m), to 4.38 (2H, s), EUR 7.57 (1H, d), to 7.64 (2H, d), 7,73 to 7.75 (3H, m), to $ 7.91 (1H, s), 8,43 (1H, s), 8,54 (1H, s), and 10.20 (1H, s)
823-F-4-CF3-PhF+: 540

N1: 2,00 e 2.06 (4H, m), 2,80-and 2.83 (1H, m), 3.00 and-of 3.07 (4H, m), to 4.46 (2H, s), 7,55 (1H, s)of 7.64-7,76 (5H, m), of 7.90 (1H, DD), 8,44 (1H, s), 8,55 (1H, s), 10,27 (1H, s)
834-CF3-PhF+: 522

N1: 2,01-2,07 (4H, m), 2,70-2,77 (1H, m), 3.00 and was 3.05 (4H, m), of 4.44 (2H, s), of 7.64-a 7.85 (6H, m), a 7.85 (2H, d), 8,44 (1H, s), 8,54 (1H, s), 10,23 (1H, s)
84the 3.5-F2-4-Br-PhF+: 568, 570

N1 1,94-of 2.08 (4H, m), 2,79-2,84 (1H, m), 3,01-3,11 (4H, m)to 4.41 (2H, s), 7,49 (2H, d), the 7.65 (2H, d), 7,74 (2H, d), 8,44 (1H, s), 8,55 (1H, s), of 10.25 (1H, s)
853-Br-4-F-PhF+: 550

N1: 2,01-2,04 (4H, m), 2,65-of 2.72 (1H, m), 2,98 totaling 3.04 (4H, m), to 4.38 (2H, s), 7,49 (1H, DD), EUR 7.57-to 7.61 ()1H, m), the 7.65 (2H, d), 7,74 (2H, d), to $ 7.91 (1H, DD), 8,44 (1H, s), 8,55 (1H, s)of 10.21 (1H, s)
86F: 509

N1: 1,99-to 2.13 (4H, m), 2,68-and 2.79 (1H, m), 2.91 in was 3.05 (4H, m), to 4.46 (2H, s), 7,63-to 7.77 (5H, m), 8,17 (1H, d), 8,31 (1H, d), 8,43 (1H, s), 8,53 (1H, s), 9,46 (1H, s), 10,19 (1H, s)

Table 18
87F: 509

N1: 1,99-to 2.13 (4H, m), 2,70-and 2.79 (1H, m), 2.91 in was 3.05 (4H, m), 4,47 (2H, s), to 7.61-7,76 (5H, m), 8,21-8,30 (2H, m), 8,43 (1H, s), 8,54 (1H, s), 9,49 (1H, s), 10,19 (1H, s)
88F: 493

N1: 1,98-2,12 (4H, m), was 2.76-and 2.83 (1H, m), of 2.92 (2H, DD), 2,97-to 3.09 (4H, m), of 3.46 (2H, DD), the 4.29 (2H, s), of 5.75 (1H, s), 6,54-6,56 (2H, m), 7,05 (1H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,11 (1H, s)
89F+: 537

N1: 1,98-of 2.09 (4H, m)of 2.16 (3H, s), 2.71 to 2,78 (114, m), 2,96-of 3.07 (4H, m)and 3.15 (2H, DD), 4,14 (2H, DD), 4,34 (2H, s), to 7.09 (1H, d), 7,30 (1H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,13 (1H, s)
903-HE-4-Me-PhF+: 484

N1: 1,96-of 2.09 (4H, m), 2,12 (3H, s), 2,74-2,78 (1H, m), 3,01 was 3.05 (4H, m), 4,32 (2H, s), is 6.78 (1H, d), 91 (1H, C)7,13 (1H, d), the 7.65 (2H, d), 7,74 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 9,65 (1H, s), 10,13 (1H, s)
91F+: 542

N1: 2,02-2,07 (4H, m), 2,17 (3H, s), 2,73 is 2.80 (1H, m), 3.00 and totaling 3.04 (4H, m)to 3.33 (3H, s), of 3.69 (2H, t), 4,11 (2H, t), 4,36 (2H, s), 6,97 (1H, DD), 7,05 (1H, d), 7,22 (1H, d), the 7.65 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,14 (1H, s)
923-NH2-4-Me-PhF+: 483

N1: 1,98-of 2.09 (4H, m), is 2.05 (3H, s), was 2.76-2,82 (1H, m), 2,97-is 3.08 (4H, m), the 4.29 (2H, s), 5,09 (2H, s), 6,51 (1H, DD), of 6.68 (1H, d), 6,97 (1H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, d), 8,54 (1H, d), 10,10 (1H, s)

Table 19
93ESI+: 555

N1: 2,01-2,07 (4H, m)of 2.16 (3H, s), and 2.26 (614, (C), 2,70 (2H, t), 2,74-2,78 (1H, m), 3,01 totaling 3.04 (4H, m), 4,07 (2H, t), 4,36 (2H, s), of 6.96 (1H, d), 7,06 (1H, s), 7,21 (1H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,14 (1H, s)
94ESI+: 528

N1: 1,96-2,12 (4H, m)to 2.18 (3H, s), 2,72 is 2.80 (1H, m), 2.95 and-is 3.08 (4H, m), 3,68-of 3.80 (2H, m), 3,94-4,06 (2H, t), 4,35 (2H, s), is 4.85 (1H, t), of 6.96 (1H, d), the 7.65 (2H, d), 7,74 (2H, d), 8,44 (1H, s), 8,54 (1H, C), 10,14 (1H, s)
95F+: 541

N1: 2,00-2,10 (4H, m)2,07 (3H, s), was 2.76-2,82 (1H, m), 2,97-is 3.08 (4H, m), 3,24-of 3.27 (2H, m)of 3.25 (3H, s)to 3.49 (2H, t)to 4.33 (2H, s), free 5.01 (1H, t), to 6.58 (1H, d), 6,63 (1H, s), 7,02 (1H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,10 (1H, s)
96F+: 508

N1: 2,00-2,14 (4H, m), 2,74-2,84 (1H, m), 2.91 in was 3.05 (4H, m)4,06 (3H, s), of 4.45 (2H, s), 7.23 percent-7,30 (1H, m), 7,63-of 7.70 (2H, m), 7,71 for 7.78 (3H, m), to 7.84 (1H, d), 8,10 (1H, s), 8,43 (1H, s), 8,54 (1H, s), 10,18 (1H, s)
97F+: 509

N1: 1,97-2,14 (4H, m), 2,70 (3H, s), 2,73-and 2.83 (1H, m), 2,89 (2H, t), 2,95-3,10 (4H, m), 4,32 (2H, s), is 6.54 (1H, d), of 6.65 (1H, DD), 7,07 (1H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, d), 8,54 (1H, d), 10,11 (1H, s)

Table 20
Etc.AData
98F+: 482

N1: 1,84 is 2.44 (6H+5H), 2,96-3,30 (4H, m), 4,20 (2N×0,85, C)4,50 (2N×0,15, C), 7,06-7,27 (3H, m), 7,73-7,81 (2H, m), 7,94 shed 8.01 (2H, m), 8,08 (2H, usher.), 10,30 (1H, s)
99F+: 446

N1: of 3.69 (3H, s), br4.61 (2H, s), 6,83 (2H, d)? 7.04 baby mortality? 7.04 baby mortality (6H, m), 7,80 (2H, d), 7,98 (2H, d), of 8.09 (2H, s), accounted for 10.39 (1H, s)
100F+: 473

N1: of 4.77 (2H, s), 7,07 (2H, t), 7,34 was 7.45 (3H, m), 7,81 (2H, d), 7,95-8,12 (6H, m), 9,40 (1H, s), 10,46 (1H, s)
101F+: 456

N1: rate 4.79 (2H, s), 7,29 (2H, s), 7,45 (1H, d), 7,71 (2H, d), 7,94-8,13 (6H, m), to 8.45 (2H, users), 9,41 (1H, s), 10,50 (1H, s)

Table 21
Etc.AData
102F-: 443

N1: 2,30 (6H, s), 4,39 (2H, s), 7,01-7,16 (5H, m), 7.24 to 7,33 (2H, m), to 7.84 (2H, d), 8,01 (2H, d), 9,67 (1H, s), 10,48 (1H, s)
103F+: 474

N1: rate 4.79 (2H, s),? 7.04 baby mortality-7,11 (2H, m), 7,34 was 7.45 (3H, m), 7,83 (2H, d), 7,98-8,08 (4H, m), 9,40 (1H, s), 9,67 (1H, s), 10,55 (1H, s)
104F+: 444

N1: 1,10-1,30 (2H, m), 1,33-of 1.52 (2H, m), 1,62 to 1.76 (2H, m), 1,88 is 2.01 (2H, m), 2,24-is 2.37 (3H +1H, m), 2,59-2,70 (1H, m), 4,36 (2H, s), 7,27 (2H, d), 7,34 (2H, d), 7,78 (2H, d), to 7.99 (2H, d), to 9.66 (1H, s), 10,34 (1H, s)
105F+: 443

N1: 1,12 of 1.28 (2H, m), 1,34 of 1.50 (2H, m), 1,62-of 1.74 (2H, m), 1,88 is 2.01 (2H, m), 2,23-is 2.37 (3H +1H, m), 2,59-2,70 (1H, m)to 4.33 (2H, s), 7,27 (2H, d), 7,34 (2H, d), to 7.64 (2H, d), 7,72 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,11 (1H, s)
106F+: 421

N1: 1,40-1,72 (4H, m), of 2.34 (3H, s), 2,46-to 2.57 (1H, m), 2,96-3,10 (2H, m), 3,70-3,82 (2H, m), to 4.38 (1H, s), 7,27 (2H, d), of 7.36 (2H, d), 7,78 (2H, d), to 7.99 (2H, d), to 9.66 (1H, s), 10,35 (1H, s)
107F+: 420

N1: 1,40-1,72 (4H, m), of 2.33 (3H, s), 2,46-to 2.57 (1H, m), 2.95 and-3,10 (2H, m), 3,70-3,82 (2H, m), 4,35 (1H, s), 7,27 (2H, d),of 7.36 (2H, d), to 7.64 (2H, d), 7,73 (2H, d),8,43 (1H, s), 8,54 (1H, s), 10,12 (1H, s)

Table 22
108F: 450

N1: 1,67-of 1.75 (2H, m), 1,95-of 2.05 (2H, m), of 2.34 (3H, s), 2.40 a at 2.45 (2H, m), to 2.57 (1H, m), 3,17-is 3.21 (2H, m), to 4.46 (2H, s), 7,28 (2H, d), 7,38 (2H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,44 (1H, s), 8,54 (1H, s), 10,13 (1H, s)
109F+: 438

N1: a 2.12 (3H, s), 2,36 is 2.43 (4H, m), 3,35-of 3.42 (4H, m), 4,39 (2H, s), 7,07 (2H, d), 7,17 (2H, d), 7,80 (2H, d), of 8.00 (2H, d), to 9.66 (1H, s), 10,35 (1H, s)
110F+: 437

N1: and 2.27 (3H, s), 2,37 is 2.43 (4H, m), 3,36-of 3.42 (4H, m), 4,36 (2H, s), 7,06 (2H, d), 7,17 (2H, d), 7,66 (2H, d), 7,74 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,12 (1H, s)
111F+: 469

N1: to 2.29 (3H, s), 2,96-of 3.06 (4H, m), 3,48-3,51 (4H, m)to 4.41 (2H, s), 7,14 (2H, d), 7,20 (2H, d), 7,66 (2H, d), of 7.75 (2H, d), 8,44 (1H, s), 8,54 (1H, s), 10,18 (1H, s)
112F+: 466

N1: is 1.81 (1H, t), 2,11-2,19 (2H, m), of 2.34 (3H, s), 2,78 (2H, d), 3,45-of 3.53 (2H, m), 4,42 (2H, s), 7,28 (2H, d), 7,35 (2H, d), 7,63 (2H, d), 7,73 (2H, d), 8,43 (1H, d), 8,54 (1H, d), 10,15 (1H, s)
113F+: 451

N1: 1,45-to 1.60 (2H, m), 1,87-of 1.97 (1H, m), 2,13-of 2.36 (6H, m), 2,58-only 2.91 (2H, m), 3,03-3,17 (1H, m), 3,82-to 4.73 (4H, m),? 7.04 baby mortality-to 7.25 (3H, m), to 7.61-to 7.68 (2H, m), 7,71-7,76 (2H, m), 8,43 (1H, s), 8,54 (1H, s), 10,13-of 10.25 (1H, m)

Table 23
114F+: 413

N1: of 2.21 (3H, s), 4,63 (2H, s), 7,00-7,28 (6H, m), 7,63 for 7.78 (4H, m), 8,42-8,51 (3H, m), 8,55 (1H, s), 10,29 (1H, s)
115F+: 432

N1: 1,71-of 1.85 (2H, m), 1,88 is 2.00 (2H, m), 2,08 was 2.25 (4H, m), of 2.34 (3H, s), 2.70 height is 2.80 (1H, m), 4,37 (2H, s), 7,29 (2H, d), 7,41 (2H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,13 (1H, s)
116F+: 434

N1: 0,72-0,88 (2H, m), 1,05-1,20 (1H, m), of 1.28 to 1.48 (2H, m)and 1.51-of 1.85 (4H, m), 2,08-to 2.18 (1H, m), 2,30-of 2.36 (3H, m)to 4.33 (2H, s), 7,27 (2H, d), 7,34 (2H, d), to 7.64 (2H, d), 7,72 (2H, d), 8,43 (1H, s), 8,54 (1H, s), of 10.09 (1H, s)
117F+: 454

N1: 1,46-1,78 (6N, m), 1,90-of 2.05 (2H, m), of 2.33 (3H, s), 2,37-2,48 (1H, m), 4,35 (2H, s), 7,27 (2H, d), 7,37 (2H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,12 (1H, s)
118F+: 448

N1: 0,68-0,81 (1H, m), 1,02-2,01 (7H, m), 2.13 and of-2.32 (1H, m), 2,32 to 2.35 (3H, m)to 4.33 (2H, s),of 7.23-7.29 trend (2H, m), 7,34 (2H, d), to 7.64 (2H, d), 7,72 (2H, d), 8,43 (1H, s), 8,54 (1H, s), of 10.09 (1H, s)
119F+: 461

N1: 0,95-1,08 (2H, m), 1,30-1,45 (2H, m), 1,63 is 1.75 (4H, m), 1,96-of 2.08 (1H, m), 2,14-of 2.24 (1H, m), of 2.34 (3H, s), 4,35 (2H, s), is 6.61 (1H, s), to 7.15 (1H, s), 7,27 (2H, d), 7,35 (2H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, s), 8,54 (1H, s), 10,11 (1H, s)

Table 24
120F+: 448

N1: 0,52-0,66 (2H, m), 1,20-of 1.44 (3H, m), 1.60-to around 1.74 (4H, m), 2,12-2,22 (1H, m), of 2.33 (3H, s), 3,11 (2H, t), 4,28 (1H, t), 4,34 (2H, s) 7,26 (2H, d), 7,34 (2H, d), to 7.64 (2H, d), 7,73 (2H, d), 8,43 (1H, d), 8,54 (1H, d), 10,10 (1H, s)
121F+: 486

N1: 2,31 (3H, s), 2,34-2,70 (4H, m), 3,05-3,15 (4H, m) 4,36 (2H, s), 7,20 (2H, d), 7,33 (2H, d), to 7.64 (2H, d), 7,74 (2H, d), 8,43 (1H, s),8,54 (1H, s), 10,16 (1H, s)
122F+: 454

N1: 2,19 (3H, s), and 4.68 (2H, s), was 7.08 (2H, d), 7,25 (2H, d), of 7.48 (1H, d), 7,65-7,79 (4H, m), of 7.90-of 8.04 (2H, m), 8,44 (1H, s), 8,56 (1H, s)
123F+: 469

N1: 2,18 (3H, s), of 4.66 (2H, s),? 7.04 baby mortality (2H, d), to 7.15 (2H, d), 7,39 (2H, d), of 7.69 (2H, d), of 7.75 (2H, d), of 7.90 (2H, d), 8,21 (1H, s), 8,44 (1H, s), 8,56 (1H, s), 9,43 (1H, s), 10,29 (1H, s)
124F+: 480

of 2.08 (3H, s), 4.72 in (2H, s), 6.89 in (2H, d), 7,08-of 7.23 (3H, m), 7,37-the 7.43 (1H, m), 7,58-of 7.82 (6H, m), to 7.99 (1H, d), at 8.36 (1H, d), to 8.45 (1H, s), to 8.57 (1H, s), 10,38 (1H, s)
125F+: 492

N1: 1,87 is 2.44 (6H+5H, m), 2,97-of 3.27 (4H, m), is 4.21 (2H×0,85, C)4,50 (2N×0,15,, 7,07-7,33 (4H, m), 7.68 per-7,73 (2H, m), 7,83-a 7.92 (2H, m), 8,05-8,08 (2H, m), 8,63-8,64 (1H, m), 10,22 (1H, s)

Table 25

Table 26/p>

INDUSTRIAL APPLICABILITY

Because the connection according to the invention has a suitable antiherpesvirus activity and shows the superior antiviral activity when administered orally even at low dose, compared with the conventional antiherpesvirus drugs specified compound useful as a pharmaceutical drug, in particular for the prevention or therapeutic treatment of various diseases, including infectious diseases caused by viruses of the family of herpesvirus, in particular, of various herpesvirus infections, such as chickenpox (varicella birds), caused by the varicella-zoster virus, chickenpox, mediated by recurrent infections associated with latent varicella-zoster virus, lip herpes and herpes encephalitis caused by HSV-1-infection, and genital herpes caused by HSV-2 infection, as antiherpesvirus drugs with high security profile.

1. Amide derivative represented by following General formula (I), or a corresponding salt,

where in the formula the symbols have the following meanings:

Z: 1,2,4-oxadiazol-3-yl, 4-oxazolyl, 1,2,3-triazole-2-yl or 2-feast of the deal,

A: phenyl which may have a Deputy (deputies)selected from the group comprising lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene-IT, CN, IT, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2, NH-lower alkylene-HE, NH-lower alkylene-O-lower alkyl, O-lower alkylene-NH2About lowest alkylene-NH-lower alkyl and lower alkylene-N(lower alkyl)2; heteroaryl, which represents a monocyclic 6-membered ring containing the nitrogen atom as the heteroatoms, or a bicyclic 9-membered ring containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which may have a Deputy (deputies)selected from lower alkyl; or phenyl group condensed with a saturated 5-membered hydrocarbon cycle; or phenyl group condensed with a saturated 5-membered heterocyclic cycle containing 1-2 heteroatoms selected from nitrogen and/or oxygen, which may have a Deputy (deputies)selected from the group comprising lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, provided that the aryl group condensed with a saturated hydrocarbon cycle or aryl group fused with a saturated heterocyclic cycle is linked to the nitrogen atom is via the carbon atom in the aromatic cycle,

X: WITH,

R3: C3-C6cycloalkyl, which may have a Deputy (deputies)selected from the group comprising oxo, HE, halogen, CN, O-lower alkyl, -C(O)-NH2-C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2lowest alkylen-HE lower alkylene-O-lower alkyl; aryl selected from phenyl, naphthyl, which may have a Deputy (deputies)selected from halogen; pyridyl; 9-membered bicyclic heteroaryl containing 1-3 heteroatoms selected from S, N, and O; or a saturated heterocyclic group, which represents a monocyclic 6-membered group containing 1-2 heteroatoms selected from S, SO, SO2, N, and O, which may have a Deputy (deputies)selected from halogen.

2. Amide derivative or salt of a specified derivative according to claim 1, where a represents phenyl which may have a Deputy (deputies)selected from the group comprising lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene-IT, CN, IT, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2, NH-lower alkylene-HE, NH-lower alkylene-O-lower alkyl, O - lower alkylene-NH2About lowest alkylene-NH-lower alkyl and lower alkylene-N(lower alkyl)2; heteroaryl group selected from the group comprising a pyridyl, Ben is thiazolyl, indazoles, which may have a Deputy (deputies)selected from lower alkyl; phenyl group condensed with a saturated 5-membered hydrocarbon cycle, selected from the group comprising 4-indanyl, 5-indanyl, or phenyl group condensed with a saturated 5-membered heterocyclic cycle selected from the group comprising 1,3-benzodioxolyl, indolinyl, isoindolyl, which may have a Deputy (deputies)selected from the group comprising lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl;

R3means cycloalkyl selected from the group including cyclopentyl and cyclohexyl, which may have a Deputy (deputies)selected from the group comprising oxo, HE, halogen, CN, O-lower alkyl, -C(O)-NH2-C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2lowest alkylen-HE lower alkylene-O-lower alkyl; aryl selected from phenyl and naphthyl, which may have a Deputy (deputies)selected from halogen; heteroaryl selected from the group comprising a pyridyl, benzothiazolyl and benzoxazolyl; or a saturated heterocyclic group selected from the group comprising tetrahydro-2H-pyranyl, tetrahydro-2H-dipiradol, diabetico[3.1.0]hexenyl, perhydro-1,3-thiazines, piperidinyl, piperidinyl, morpholinyl and thiomorpholine, which may have replaced the Deputy (deputies), selected from halogen and sulfur atom cycle can form the oxide or dioxide.

3. Amide derivative or salt of a specified derivative according to claim 2, where a represents a group selected from phenyl, which may have 1-3 substituent selected from the group consisting of alkyl, CF3, halogen, HE, O-lower alkyl, CN, O-lower alkylene-HE, NH2, NH-lower alkylene-O-lower alkyl, O-lower alkylene-phenyl; pyridyl, which may have 1-3 substituent selected from lower alkyl; benzothiazolyl, which may have 1-3 substituent selected from lower alkyl; 5-indanyl, 1,3-benzodioxolyl, which may have 1-3 substituent selected from halogen; and indolinyl, which may have 1-3 substituent selected from the group consisting of lower alkyl, lower alkylene-O-lower alkyl and lower alkyl, and

R3represents a group selected from cyclohexyl, CN, =O, HE, O-lower alkyl, lower alkylene HE CONH2; phenyl which may be substituted by 1-2 substituents selected from halogen; naphthyl, pyridyl; benzothiazolyl, benzoxadiazole, diabetico[3.1.0]hexane, tetrahydro-2H-pyranyl, thiomorpholine, tetrahydro-2H-dipiradol, which may be substituted by 1-2 substituents selected from halogen and perhydro-1,3-teinila, and the sulfur atom of the cycle in R3may form on the led or dioxide.

4. Amide derivative or salt of a specified derivative according to claim 1, where Z represents a 1,2,4-oxadiazol-3-ilen group.

5. Amide derivative or salt of a specified derivative according to claim 1, where Z is a 4-oxazolidinyl group.

6. Amide derivative or salt of a specified derivative according to claim 1, where a represents a group selected from phenyl which may have 1 to 4 substituent selected from the group consisting of lower alkyl, O-lower alkyl and halogen atoms; and 5-indanernas group; X represents CO; and R3means 1,1-dissidocerida-2H-thiopyran-4-yl.

7. Amide derivative or salt of a specified derivative according to claim 6, where a represents phenyl, which is substituted by a methyl group and may further have 1 or 2 substituent selected from the group consisting of methyl and halogen atoms.

8. Amide derivative or salt of a specified derivative according to claim 6, where a represents a 5-indenolol group.

9. Amide derivative according to claim 1, selected from the group including

N-(2,6-dimetilfenil)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(4-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)those whom rehydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,4-dimetilfenil)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3,4-dimetilfenil)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,3-dihydro-1H-inden-5-yl)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(4-chloro-3-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3-fluoro-4-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3-fluoro-2,4-dimetilfenil)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3,5-debtor-4-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2-fluoro-4-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,3-dimetilfenil)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,4-dimetilfenil)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-CT is the oksamid-1,1-dioxide;

N-(2,6-dimetilfenil)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(4-fluoro-2,6-dimetilfenil)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(2,3-dihydro-1H-inden-5-yl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(3-fluoro-4-were)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide;

N-(4-chloro-3-were)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide, and

N-(3-fluoro-2,4-dimetilfenil)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide.

10. Pharmaceutical composition having Antiherpes effect, containing an effective amount of the amide derivative according to claim 1 and a pharmaceutically acceptable carrier.

11. Amide derivative according to claim 1, as antiherpesvirus medicines.

12. The method of treatment of diseases that involve the herpes virus, including the introduction in need of such treatment to the patient a therapeutically effective amount of an amide derivative or salt of a specified derivative according to claim 1.

13. Amide derivative according to claim 1, with representing the th N-(4-were)-N-(2-{[4-(1,3-oxazol-4-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide.

14. Amide derivative according to claim 1, which represents the N-(4-were)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide.

15. Amide derivative according to claim 1, which represents the N-(2,6-dimetilfenil)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide.

16. Amide derivative according to claim 1, which represents the N-(3-fluoro-4-were)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide.

17. Amide derivative according to claim 1, which represents the N-(4-chloro-3-were)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide-1,1-dioxide.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to method for obtaining 5-{2-[5-{2-[1,3,5-ditiazinan-5-il]ethyl}-4-methyl-1,3,5-tiadiazinan-3-il]ethyl} 1,3,5-ditiazinan with formula including interaction of methyltriethyltetaraamin with water solution of formaldehide saturated with hydrogen sulphide. The given compound can find application as selective sorbents and extragents of precious metals and special reagents for inhibition of vital functions of bacteria in various technological media.

EFFECT: efficient method for obtaining 5-{2-[5-{2-[1,3,5-ditiazinan-5-il]ethyl}-4-methyl-1,3,5-tiadiazinan-3-il]ethyl} 1,3,5-ditiazinan.

1 cl, 1 ex

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

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds of the formula (I) and their pharmaceutically acceptable salts in the capacity of modulators of receptors CB1 and to the pharmacological composition on their basis. Bonds can be used for treatment and prophylaxis of diseases, which are associated with the modulation of receptor CB1, for example, obesity and diabetes of type II. In the general formula (I) R1 means hydrogen or the lowest alkyl; R2 means hydrogen, the lowest alkyl, the lowest alkenyl, the lowest alkoxy-lowest alkyl, the lowest alkoxycarbonilamino-group or - (CH2)m-R2a; or R1 and R2 form together with atom of nitrogen to which they are attached, a 5-or 6-member saturated heterocyclic ring; R2a means cycloalkyl, which is not necessarily mono- or tetra-substituted independently by hydroxy-group, the lowest alkyl; C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen; 5- or 6-member monovalent heteroaromatic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heteroaromatic ring is not necessarily mono-substituted independently with the lowest alkyl; or phenyl which is not necessarily mono- or di-substituted independently with the lowest of the alkoxy group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy group or nitro-group; R3 means the lowest alkyl, the lowest alkoxy-lowest alkyl, diphenyl-lowest alkyl or - (CH2)n-R3a; R3a means C3-6cycloalkyl which can be not necessarily condensed with the phenol ring; or C3-6cycloalkyl, which can be not necessarily mono-, di- or trisubstituted independently hydroxy-group, the lowest alkyl, C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heterocyclic rings are not necessarily mono-substituted independently by the lowest alkyl, 5- or 6-member monovalent heteroaromatic ring containing one heteroatom, independently selected from oxygen and sulfur, the aforesaid heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, or the phenyl, which can be not necessarily mono-, di- or trisubstituted independently by the hydroxy-group, lowest alkyl, lowest alkoxy-group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; R4 means the lowest alkyl the lowest alkoxycarbonyl; C3-6 cycloalkyl, 5- or 6-member monovalent heteroaromatic ring, which contains one or two heteroatoms, independently selected from nitrogen, the said heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, lowest alkoxy-group; phenoxy-lowest alkyl, in which the phenyl part is not necessarily mono-, di- or trisubstituted independently by the lowest alkoxy-group; or the phenyl, which not necessarily can be mono-, di- or trisubstituted independently, by the lowest alkyl, by the lowest alkoxy-group, by halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; or two adjusted substitutes of the said phenyl remainder indicate together -O-(CH2)p-O- or -(CH2)2-O-; R5 and R6 each indicates a substitute independently selected from hydrogen of lowest alkyl; R7 indicates hydrogen; m indicates 0,1 or 2; n indicates 1.

EFFECT: new bonds possess useful biological properties.

28 cl, 4 dwg, 380 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents phenyl group, containing 1-3 substitutes, selected from halogen and cyano group; R2 represents pyridyl group, which has 1-3 substitutes, selected from monocyclic or polycyclic heterocyclic group, which can have 1-3 substitutes, selected from halogen atoms, cyanogroup, as well as other values of R2 radical, given in formula of invention, R3 represents phenyl group or pyridyl group, which has 1-2 substitutes, selected from halogen and trihalogenmethyl group; R4 represents hydrogen atom; and X represents -SO2-; its salt or its solvate. As well as to medication and pharmaceutical composition, inhibiting production or secretion of β-amyloid protein, and containing compound of formula (I), and to application of compound of pt.1 in order to obtain medication.

EFFECT: obtaining novel compounds, inhibiting production or secretion of β-amyloid protein.

14 cl, 1 tbl, 296 ex

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

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine of the general formula (I), which possess properties of the inhibitor of CDK-kinase. In the general formula (I) R1 designates hydrogen, halogen, C1-C6alkyl, R2 designates C1-C10alkyl, C1-C10alkenyl, or C3-C10cycloalkyl which can be mono-, bi- or tricyclic or denotes one- or polysubstituted by identical or different substitutes from the number of hydroxy-group, halogen, C1-C6alkoxygroup, C1-C6kalkylthiogroup, -NH-(CH2)n-C3-C10cycloalkyl, C3-C10 cycloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, C1-C6alkanoil, -CONR3R4, -COR5, C1-C6alkylOAc, where Ac indicates C1-C4alkylCO-group, carboxygroups, phenyl, 5-6-member heteroaryl, containing 1-2-heteroatom in the ring, selected from nitrogen, -(CH2)n- phenyl, -(CH2)n-5-6-member heteroaryl containing 1-2-heteroatom in a ring, selected from nitrogen, phenyl-(CH2)n-R5, -(CH2)nPO3(R5)2 and -R6 and -NR3R4C1-C10alkyl, or C3-C10cycloalkyl, in this case phenyl, C3-C10 cycloalkyl, heteroaryl, -(CH2)n-phenyl and -(CH2)n heteroaryl can be one or polysubstituted by identical or different substitutes from halogens, hydroxygroup, C1-C6alkyl, C1-C6alkoxygroup, benzoxy-group and -CF3 groups, and ring of C3-C10 cycloalkyl and C1-C10alkyl can be separated by one or several nitrogen atoms, oxygen and/or sulfur and/or the said ring can be interrupted by one or two groups of =C=O or R2 designates the group X designates oxygen or group-NH-, and one of A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, X designates oxygen or group-NH-, either one from A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, values of R3 -R10 are specified in the formula of the invention.

EFFECT: connections can be used for the treatment of cancer, autoimmune diseases caused by chemotherapeutic means of alopecia and inflammations of mucous membrane, cardiovascular diseases, infectious diseases, chronic neurodegenerative and viral infections.

13 cl, 1 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula (I) where: X is O; Y represents a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(O)2R34), CH2O or CH2S; Z is C(O), or if Y is a bond, then Z can also be S(O)2; R1 could be substituted with phenyl; R4 is hydrogen, C1-6-alkyl (substituted possibly by C3-6-pilkoalkyl) or C3-6-cycloalkyl; R2, R3, R5, R6, R7 and R8 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; type independently indicate 0 or 1; R9 could possibly be substituted with an aryl or heterocycle; R10, R32 and R35 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; R33 and R34 are C1-6-alkyl or C3-6-cycloalkyl; where the aforesaid aryl and heterocyclic groups, when possible, can be substitute with: halogen cyanogens, nitro, hydroxyl, oxo, S(O)Kr12, OC(O)NR13R14, NR15R16, NR17C(O)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, by C1-6-alkyl (which itself can be monosubstituted with NHC(O)phenyl), C1-6-halogenalkyl, C1-6-alkoxy(C1-6)alkyl, C1-6-alkoxy, C1-6-halogenaloxy, C1-6-alkoxy(C1-6)-alkoxy, C1-6-alkylthio, C2-6-alkenyl, C2-6-alkinil, C3-10-cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkyl, morpholinyl, heteroaryl, heteroaryl(C1-4)alkyl, heteroarylhydroxy of heteroaryl(C1-4)alkoxy, where any of the said phenyl and heteroaryl groups can be substituted by halogen, hydroxyl, nitro, S(O)r(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-.4-alkyl)2, cyanogens, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), CO2H, CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3; k and r independently mean 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 independently represent hydrogen, C1-6-alkyl (probably replaced by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), C3-6-cycloalkyl, phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), NH(C1-4-alkyl)2, S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, S(O)2)(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H5 CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3); alternatively, NR13R14, NR15R16, NR20R21, NR22R23, NR26R27 can independently form 4-7-member heterocyclic ring, selected from the group, which includes: azetidine (which can be substituted by hydroxyl or C1-4-alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter is probably substituted by C1-4-alkyl on the peripheral nitrogen; R12, R25, R28 and R31 are independently C1-6-alkyl (possibly substituted by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4- alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connec to form a ring as described hereabove for R13 and R14), cyanogen, C1-4- alkyl, C1-4- alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), NHC(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3); or its N-oxide; or its pharmaceutically acceptable salt, solvate or solvate of its salt, which are modulators of activity of chemokines (especially CCR3); also described is the pharmaceutical composition on their basis and the method of treating the chemokines mediated painful condition.

EFFECT: obtaining new compounds possessing useful biological properties.

13 cl, 238 ex

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: medicine; pharmacology.

SUBSTANCE: invention is related to the compounds of general formula (I) and their pharmaceutically acceptable salts with properties β2-adrenoreceptor agonists, to the method of their production and based on them pharmaceutical composition. The compounds can be used for treatment of conditions when the symptomatic severity can be reduced by β2- adrenoreceptor activation, e.g., obstructive or inflammatory respiratory diseases. In the general formula (I) , X means -R1-Ar-R2 or -Ra-Y; Ar means phenylen, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, phenyl, C1-C10 alcoxy, substituted by phenyl group or phenyl, substituted by C1-C10 alcoxy group; R1 and R2 are bound to the adjacent carbon atoms within Ar group, and either R1 means C1-C10alkylen, and R2 means hydrogen, C1-C10alkyl or halogen, Ra means the bond or C1-C10 alkylen optionally substituted by group of the row: hydroxy, C1-C10 alcoxy, C6-C10aryl or C7-C14aralkyl; Y means C1-C10alkyl, or C2-C10alkynil, optionally substituted by hydroxyl group, C3-C10cycloalkyl, optionally condensed with one or more benzene rings and optionally substituted by group of the row: C1-C10alkyl, C1-C10alcoxy, C3-C10cycloalkyl, C7-C14aralkyl, C7-C14aralkyloxy or C6-C10aryl, where groups C7-C14aralkyl, C7-C14aralkyloxy or C6-C10 aryl are optionally substituted by group of the row: halogen, C1-C10alkyl, C1-C10alcoxy; C6-C10aryl, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, C1-C10halogenalkyl, phenoxy, C1-C10alkylthio, C6-C10aryl, 5-6-term saturated heterocyclic ring, containing one nitrogen atom in cycle; phenoxy, optionally substituted by C1-C10alcoxy group; 5-6-term heterocyclic ring, containing one or two nitrogen or oxygen atoms in cycle, and the described heterocyclic ring is optionally substituted by group of the row: C1-C10alkyl, C6-C10aryl, C7-C14aralkyl, C1-C10alcoxycarbonil or 5-7-term heterocyclil (C1-C10)alkyl, containing one nitrogen atom in cycle; -NRdRe, where Rd means hydrogen or C1-C10alkyl, and Re means C1-C10alkyl, or Re means C6-C10aryl, or Re means 5-6-term heterocyclic ring, containing one nitrogen or sulfur atom in cycle, and the ring is optionally substituted by halogen-substituted phenyl group or Re means C6-C10arylsypfonil, optionally substituted by groups C1-C10alkylamino or di(C1-C10alkyl)amino; -SRf, where Rf means C6-C10aryl or C7-C14aralkyl, optionally substituted by group of row: halogen or C1-C10halogenalkyl; or -CONHRg, where Rg means C6-C10aryl, provided, if Ra means the bond, then Y doesn't mean C1-C5alkyl.

EFFECT: compound can prevent or reduce symptom's intensity.

15 cl, 4 tbl, 157 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel compounds with formula (I) and their pharmaceutically acceptable salts. The compounds of this invention has the properties of the NPY receptor antagonists and can be used fortreatment of such diseases as arthritis, diabetes, malnutrition, obesity. In general formula (I) , R1 means phenyl or 6-term nitrogen-containing heteroaryl, where in at least one of two meta-positions each phenyl group or 6-term nitrogen-containing heteroaryl group is substituted by group R5; R2 means hydrogen; R3 means C3-C6cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, where in at least one of two ortho-positions each group of C3-C6 cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, substituted by group R6; R4 means hydrogen, C1-C6alkyl; R5 means hydrogen, cyano, trifluoromethyl, C1-C6alkyl-SO2-, amino-SO2-, halogen, C1-C6alcoxy, C1-C6alkylcarbonil or aminocarbonil; R6 means hydrogen, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C1-C6 alcoxy or hydroxy, provided, one R5 group, and R6 doesn't mean hydrogen.

EFFECT: described compounds and based on them pharmaceutical agents are efficient in treatment and prevention of above listed diseases.

19 cl, 2 tbl, 2 dwg, 130 ex

FIELD: organic chemistry, medicine, pharmacy, cosmetology.

SUBSTANCE: invention relates to novel biphenylmethylthiazolidinedions of the general formula (I): , their salts, and to their optical and geometrical isomers possessing agonistic activity with respect to PPARγ receptors, to pharmaceutical and cosmetic compositions based on thereof, and to their using for preparing composition used in treatment of different cutaneous diseases. In compound of the formula (I) R1 means radical of the following formula (a): or (b): ; R2 and R3 mean hydrogen atom; X means binding groups showing the following structures: -CH2-N(R8)-CO-, -N(R8)-CO-N(R9)- that can be read from left to right or vice versa; R4 means phenyl substituted with group R10, pyrrolyl, naphthyl, biphenyl, indenyl, benzothienyl and all these groups can be mono- or di-substituted with group R11 and/or R12, group -(CH2)n-(CO)qR13, adamantyl, cyclopentylethyl, group -(CH2)n-O-R13; R5 means hydroxyl or alkoxyl with 1-19 carbon atoms; R6 means group -OR14. Values R8, R9, R10, R11, R12, R13, n and q are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

25 cl, 2 dwg, 37 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazole derivatives of general formula I and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and based medicinal product. Compounds can be applied for treatment and prevention of diseases mediated by adenosine receptors, e.g., epilepsy, depressions, narcomania, Parkinson's disease. In general formula I R denotes phenyl unsubstituted or substituted with halogen or -SN2N(CH3) (CH2)nOCH3, or denotes benzyl, lower alkyl, lower alkoxy-group, - (CH2)nOCH3, or denotes pyridine-3- or -4-yl unsubstituted or substituted with lower alkyl, halogen, morpholinyl, - (CH2)n-halogen, - (CH2)nOCH3, - (CH2)n-diethylene-imide oxide-4-yl, or (CH2)n-tetrahydropyrrole-1-yl; R1 denotes phenyl unsubstituted or substituted with halogen tetrahydropyran-4-yl, 3,6-2H-2n-pyran-4-yl or morpholine-4-yl; n denotes mutually independent 1 or 2.

EFFECT: production of benzothiazole derivatives which can be applied for treatment and prevention of diseases mediated by adenosine receptors.

9 cl, 4 dwg, 27 ex

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