Heterocyclic compounds and compositions on their basis, showing antagonistic activity against receptors tachykinin

 

(57) Abstract:

The compounds of formula I and their Quaternary ammonium derivatives of formula Ia (symbols, see p. 1 f-crystals of the invention and a composition based on them show antagonistic activity against neirokinina 1 and neirokinina 2 in the treatment or prevention of Central nervous system diseases, respiratory diseases, allergies. 5 C. and 90 C. p. F.-ly, 10 PL.

The present invention relates to a series of new heterocyclic compounds with antagonistic towards tachykinins activity. It also relates to methods and compositions on their basis for therapeutic and preventive purposes, as well as to methods of their production and intermediate products used in their production.

The presence in mammals of different species tachykinin associated with various diseases and disorders, including respiratory diseases such as asthma, bronchitis, rhinitis and cough; allergies; eye inflammatory diseases, such as conjunctivitis, spring catarrh, skin diseases such as contact dermatitis, allergic dermatitis and urticaria; inflammatory diseases such as rheumatism is istemi; such as fear and Alzheimer's disease; gastrointestinal diseases such as colitis; and cystitis; and many others. The inhibition activity of these forms tachykinin will thus result a new treatment and/or prevention of these diseases and disorders.

The compound of the present invention exhibit antagonism, mainly to tachykinin receptors, but, especially in relation to the receptors for substance P (these receptors are typically specified as "receptors neirokinina 1" - HK1) and receptors for neirokinina A (these receptors are typically specified as "receptors neirokinina 2" - HK2). The particular advantage of the compounds of the present invention is that they exhibit antagonism to both of these receptors, the so-called "dual effect".

Compounds that are structurally similar to the present invention, is described in FR 2729952, FR 2729953 and FR 2729954. However, they are selective with respect to HK1receptors and none of these compounds does not have the dual effect of the compounds of the present invention.

It is known that non-peptide compounds slightly lower molecular weight are antagonism to both this recipe is the effect. Typical examples of the compounds described in these documents are:

< / BR>
However, oral absorption of these compounds is weak. As a result, these known compounds can not be introduced through the mouth and must be injected parenterally, for example by injection. In medicine it is well known that the introduction of any drug by injection is undesirable, since the patient must be trained (and some patients are in principle not trainees) or the drug should be entered by trained personnel, which is expensive and inconvenient for the patient and staff alike.

Thus, there is a need for a new receptor antagonist tachykinin, which has the above-mentioned dual effect and which has good oral absorption and low toxicity.

Currently, applicants have developed new compounds that have activity against receptors HK1that are at least equal to the compounds known from the prior art, showing the dual effect and which unexpectedly show a much stronger activity against receptors HK2.

Thus, the volume of ncrete, the object of the present invention are such compounds that are antagonistic towards the receptors tachykinin.

Another and more specific, object of the present invention are such compounds, that possess the antagonism of such receptors tachykinin, which are known as receptors HK1and HK2.

Another and more specific, object of the present invention are such compounds that have significantly improved activity.

Other objects and advantages of the present invention are the compounds of formula (I):

< / BR>
and their Quaternary ammonium derivatives of formula (Ia):

< / BR>
where

R1and R2are the same or different from each other and each represents a carbocyclic aryl group or aromatic heterocyclic group, the aryl group and the said heterocyclic group is unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of the substituents defined below:

A represents A methylene group, carbonyl group or sulfonyloxy group;

B about 4 carbon atoms, or alkenylamine group containing from 2 to 4 carbon atoms;

D represents an oxygen atom or sulfur;

E represents alkylenes group containing from 1 to 6 carbon atoms, halogenosilanes group containing from 1 to 6 carbon atoms, a group cycloalkane-1,1-diyl containing from 3 to 6 carbon atoms, cycloalkane-1,1-Dimethylol group containing from 3 to 6 carbon atoms in cycloalkanones part, or group cycloalkane-1,1-di(ylmethyl) containing from 3 to 6 carbon atoms in cycloalkanones part;

G represents alkylenes group containing from 1 to 4 carbon atoms, or alkenylamine group containing from 2 to 4 carbon atoms;

L represents a group of formula-N(R3)- or a group of the formula-C(R4)(R5)-

where R3represents a carbocyclic aryl group or aromatic heterocyclic group, the aryl group and the above aromatic heterocyclic group is unsubstituted or substituted by at least one Deputy, selected from the group consisting of the substituents defined hereinafter,

R4represents a hydrogen atom, a carbocyclic aryl group or aromatic heterocyclic group specified Arilla least one Deputy, selected from the group consisting of the substituents defined hereinafter,

R5represents a group of formula-CO-R6, alkyl group containing from 1 to 6 carbon atoms, alkoxygroup containing from 1 to 6 carbon atoms, amino group, allmenalp, alkyl group containing from 1 to 6 carbon atoms, which is substituted by allmineral, allmenalp, a nitrogen atom which is substituted by an alkyl group containing from 1 to 6 carbon atoms, a hydroxy-group, hydroxyalkyl group containing from 1 to 6 carbon atoms, alkoxyalkyl the group in which the alkoxy and alkyl parts have from 1 to 6 carbon atoms, kalkylarksmall group, containing from 1 to 6 carbon atoms in oxyalkylene parts and in which kalkilya part presents alkyl group which has from 1 to 4 carbon atoms and which is substituted by from 1 to 3 carbocyclic aryl groups which are unsubstituted or substituted by at least one Deputy, selected from the group steriade substituents defined hereinafter,

where R6represents an alkyl group containing from 1 to 6 carbon atoms, alkoxygroup containing from 1 to 6 carbon atoms, a group of the formula - NRaRbcarbocycle the Skye group are unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of the substituents defined hereinafter, where Randrepresents a hydrogen atom, alkyl group containing from 1 to 6 carbon atoms, alkoxygroup containing from 1 to 6 carbon atoms, aliphatic carbocyclic acyl group containing from 1 to 6 carbon atoms, alkanesulfonyl group containing from 1 to 6 carbon atoms, halogenoacetyl group containing from 1 to 6 carbon atoms, cycloalkyl group containing from 3 to 8 carbon atoms, carbocyclic aryl group which is unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of the substituents defined hereinafter, or aracelio group in which an alkyl group containing from 1 to 4 carbon atoms, a substituted from 1 to 3 carbocyclic aryl groups mentioned above, and

Rbrepresents a hydrogen atom, alkyl group containing from 1 to 6 carbon atoms, alkoxygroup containing from 1 to 6 carbon atoms, aliphatic carbocyclic acyl group containing from 1 to 6 carbon atoms, alkanesulfonyl group containing from 1 to 6 carbon atoms, halogenoacetyl GRU is practical aryl group or aromatic heterocyclic group, and the above aryl group and the said heterocyclic group is unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of the substituents defined hereinafter, or aracelio group in which an alkyl group containing from 1 to 4 carbon atoms, a substituted from 1 to 3 carbocyclic aryl groups mentioned above, or

Raand Rbtogether with the nitrogen atom to which they are attached, represent a nitrogen-containing heterocyclic group, or

R4and R5together with the nitrogen atom to which they are attached, represent cycloalkyl or heterocyclic group containing from 5 to 10 ring atoms of the specified group is unsubstituted or substituted by at least one Deputy, selected from the group consisting of the substituents defined hereinafter, and the said heterocyclic group contains a single heteroatom which is selected from the group comprising nitrogen atoms, oxygen, or sulfur, or R4and R5together with the carbon atom to which they are attached, represent cycloalkyl or heterocyclic group mentioned above, which is condensed with carbocyclic aryl ECA group are unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of the substituents listed below;

R7represents an alkyl group containing from 1 to 6 carbon atoms; and

these substituents selected from the group consisting of halogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogenoalkane group having from 1 to 6 carbon atoms, alkoxygroup having from 1 to 6 carbon atoms, aliphatic carbocyclic acyl group having from 1 to 6 carbon atoms, alkanesulfonyl group having from 1 to 6 carbon atoms, galogenzameshchennye group having from 1 to 6 carbon atoms, hydroxy-group, carboxypropyl, alkoxycarbonyl group having from 1 to 6 carbon atoms in the CNS part, alluminare, having from 1 to 6 carbon atoms, alkanesulfonyl having from 1 to 6 carbon atoms, halogensulphonylphenyl having from 1 to 6 carbon atoms, amino group, ceanography, alkylene group having from 1 to 8 carbon atoms (with the formation of cycloalkyl group condensed with aryl or heteroaryl ring);

and these substituents are:

with the substitution of the carbon atom, oxoprop, with the substitution of the nitrogen atom, you is carbon, alkyl groups having from 1 to 6 carbon atoms, which are unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of the substituents listed next, carbocyclic aryl groups which are unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of the substituents listed above, and kalkilya group in which an alkyl group containing from 1 to 4 carbon atoms, a substituted from 1 to 3 carbocyclic aryl groups mentioned above;

and with the substitution of the sulfur atom by one or two atoms of oxygen form sulfoxide or sulfonic group; and these substituents selected from the group consisting of halogen atoms, alkoxygroup having from 1 to 6 carbon atoms, aliphatic carbocyclic acyl group having from 1 to 6 carbon atoms, alkanesulfonyl group having from 1 to 6 carbon atoms, galogenzameshchennye group having from 1 to 6 carbon atoms, hydroxy-group, carboxypropyl, alkoxycarbonyl group having from 1 to 6 carbon atoms in the CNS part, acylamino group, having from 1 to 6 carbon atoms, amino group and cyanopropyl;
the AI for the treatment or prevention of diseases of the Central nervous system, neurodegenerative diseases, respiratory diseases, inflammatory diseases, allergies, hypersensitivity, eye inflammatory diseases, skin diseases, alcoholism, somatic diseases, stress-induced attenuation of sympathetic reflexes, dysthymia, unwanted immune reactions, diseases associated with immunostimulating, diseases associated with food intake, vomiting, functional disorders of the bladder, eosinopenia, diseases caused by impaired blood flow, and pain, which contains an effective amount of the compounds of formula (I) or (Ia) or its pharmaceutically acceptable salt or a complex ester, in a mixture with a pharmaceutically acceptable carrier or diluent.

The invention relates also to a method of treatment or prevention of diseases or disorders selected from the group comprising diseases of the Central nervous system, neurodegenerative diseases, respiratory diseases, inflammatory diseases, allergies, hypersensitivity, eye diseases, skin diseases, alcoholism, physical illness, stress-induced attenuation of sympathetic reflexes, the e with eating, vomiting, functional diseases of the bladder, eosinopenia, diseases caused by impaired blood flow, and pain, which includes the introduction of the animal (which may be a human) suffering from specified diseases or disorders, an effective amount of the compounds of formula (I) or (Ia) or its pharmaceutically acceptable salt or a complex ester.

The invention also relates to the compound of formula (Iz):

< / BR>
where J represents alkylenes group containing from 1 to 6 carbon atoms;

Ar represents a carbocyclic aryl group or aromatic heterocyclic group condensed with a ring containing J or S, and the above aryl group and the said heterocyclic group is unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of the substituents listed above;

R14represents a hydrogen atom or aminosilane group; and

S*_ O is sulfoxide group in which the sulfur atom has the S-configuration.

Detailed description of the invention

When R1, R2, R3, R4, R6, Ra, Rb, Ar or Deputy are curbline from 6 to 10 carbon atoms, and most preferably from 6 to 10 carbon atoms, ring carbon atoms. The group may have a single aromatic ring or it may contain two or more condensed aromatic rings. The group may be unsubstituted or may be substituted by one or more Deputy selected from the group consisting of the substituents listed above and shown in the examples below. There is no special limitation in the number of substituents, except such which can be caused by a number of capable of substitution provisions and sometimes steric hindrance. However, usually when a group is substituted, preferred are 1 to 3 substituents. Examples of the unsubstituted groups include the phenyl, 1-naphthyl, 2-naphthyl, angenlina, penetrelia and antarctilyne group, which phenyl and naftalina groups are substituted, the phenyl group is most preferred.

Examples of the substituted groups include 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-acid, 2,3-acid, 2,5-acid, 3,4-acid, 2,6-acid, 3,4,5-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxyphenyl, 2,4,6-trimethoxyaniline, 3-were, 4-were, 2,4-dimetilfenil, 2,3-dimetilfenil, 2,5-dimetilfenil, 3,4-dimetilfenil, 3, 5dimethylphenyl, 2,6-dimetilfenil, 3,4,5-trimetilfenil, 2,4,5-trimetilfenil, 2,3,4-trimetilfenil, 2,3,5-trimetilfenil, 2,3,6-trimetilfenil, 2,4,6-trimetilfenil, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4,5-trichlorophenyl, 2,4,5-trichlorphenol, 2,3,4-trichlorophenol, 2,3,5-trichlorophenol, 2,3,6-trichlorophenol, 2,4,6-trichlorphenol, 2-forfinal, 3-forfinal, 4-forfinal, 2,4-differenl, 2,3-differenl, 3,4-differenl, 3,5-differenl, 2,6-differenl, 3,4,5-tryptophanyl, 2,4,5-tryptophanyl, 2-triptoreline, 3-triptoreline, 4-triptoreline, 2,4-bis(trifluoromethyl)phenyl, 2,3-bis-(trifluoromethyl)phenyl, 3,4-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 2,6-bis(trifluoromethyl)phenyl, 3,4,5-Tris(tricritical)phenyl, 2,4,5-Tris(tricritical)phenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 2-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl and 4-ethoxycarbonylphenyl.

When the Deputy is alkalinous group containing from 1 to 8 carbon atoms, it forms together with the two carbon atoms aryl group to which it is attached, cycloalkyl group is owned by the group.

When R1, R2, R3, R4, R6, Rbor Ar are aromatic heterocyclic group, it is the one ring, having from 5 to 7 ring atoms, of which from 1 to 3 atoms are heteroatoms selected from the group consisting of nitrogen atom, oxygen and sulfur, or a condensed ring system in which at least one of the rings is aromatic heterocyclic group mentioned above, and every other ring is the same as the aromatic heterocyclic group or carbocyclic aryl group mentioned above. When the aromatic heterocyclic group include a 3 heteroatoms, they are preferably all nitrogen atoms or one or two are nitrogen atoms and respectively two or one are the atoms of oxygen and/or sulfur.

Examples of such aromatic heterocyclic groups include furyl group, thienyl, pyrrolyl, azepine, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, tiadiazol, pyranyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. The preferred groups are 5-7-membered aromatic geterotsiklicheskikh or sulfur. Examples of such groups include groups pyrrolyl, azepine, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, tiadiazol, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. Of these, the most preferred groups are pyridyl, imidazolyl, oxazolyl, pyrazinyl and thiazolyl.

Such aromatic heterocyclic group may form a condensed ring with another cyclic group, and examples of the condensed ring systems include indolyl group, benzofuran, benzothiazyl, benzoxazolyl, benzimidazolyl, ethanolic, chinosol and Minoxidil.

These aromatic heterocyclic groups may be unsubstituted, or they can be substituted by one or more substituents selected from the group consisting of the substituents listed above and shown in the examples below. There is no special limitation in the number of substituents, except such which can be caused by a number of capable of substitution provisions and sometimes steric hindrance. However, usually when a group is substituted, preferred are 1 to 3 substituents.

Alternative, R6can be represented NEA can be heteroatoms, selected from the group consisting of nitrogen atom, oxygen and sulfur, at least one is nitrogen atoms. Examples of such groups include groups pyrrolidinyl, piperidinyl, piperazinil, N-methylpiperazine, morpholine, thiomorpholine, oxazolidinyl, diazolidinyl, oxolane, tylenol and targetability.

When B and G are alkylenes group containing from 1 to 4 carbon atoms, this may be a straight or branched group containing from 1 to 4 carbon atoms, and examples include a methylene group, METROTILE, ethylene, propylene, trimethylene, tetramethylene, 1-metallisation, 2-metallisation and 3-metallisation, of which preferred are straight or branched chain group having from 1 to 3 carbon atoms, more preferred are straight or branched chain group having from 2 to 3 carbon atoms, and the most preferred are ethylene group or trimethylene.

When B and G are alkenylamine group containing from 2 to 4 carbon atoms, this may be a straight or branched group containing from 2 to 4 carbon atoms, and examples include group ethenylene, 2-propanole, 1-methyl-2-propanole, 2-methyl-2-propanole, 2-ethyl-2-propanole and 2-butenyl are group ethenylene or 2-propanole.

When E or J are alkylenes group containing from 1 to 6 carbon atoms, this may be a straight or branched group containing from 1 to 6 carbon atoms, and examples include a methylene group, METROTILE, ethylene, propylene, trimethylene, tetramethylene, 1-metallisation, 2-metallisation, 3-metallisation, pentamethylene, hexamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,1-dimethyltrimethylene and 2,2-dimethyltrimethylene, of which preferred are straight or branched chain group having from 1 to 4 carbon atoms, more preferred are a methylene group or ethylene.

E can also be halogenosilanes group containing from 1 to 6 carbon atoms and substituted by 1 to 3 halogen atoms, preferably selected from the group consisting of fluorine atoms, chlorine, bromine and iodine, in which Allenova group can be any of the unsubstituted alkilinity groups, are presented as examples above.

When E is cycloalkane-1,1-dialnow group containing from 3 to 6 carbon atoms, it is a group of the formula

< / BR>
where m is an integer from 2 to 5. When E is cycloalkane-1,1-Dimethylol group containing from 3 and E represents cycloalkane-1,1-di(ylmethylene) group, containing from 3 to 6 carbon atoms in cycloalkanones part, it is a group of the formula

< / BR>
where m above.

Examples of these groups include groups cyclopropane-1,1-diyl, CYCLOBUTANE-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cyclopropane-1,1-dimetil, CYCLOBUTANE-1,1 - dimethyl, cyclopentane-1,1-dimetil, cyclohexane-1,1-dimetil, cyclopropane-1,1-di(ylmethyl), CYCLOBUTANE-1,1-di(ylmethyl), cyclopentane-1,1-di(ylmethyl), cyclohexane-1,1-di(ylmethyl), of which preferred are cyclopropane-1,1-diyl. CYCLOBUTANE-1,1-diyl, cyclopropane-1,1-dimetil and CYCLOBUTANE-1,1-dimetil.

When R5, R6, R7, Raand Rb, assistant or Deputy represent an alkyl group containing from 1 to 6 carbon atoms, this may be a straight or branched group containing from 1 to 6 carbon atoms, and examples include methyl groups, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl, of which the preferred means isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, of which preferred are a methyl group or ethyl.

When R5, R6, Raand Rb, assistant or Deputy represent alkoxygroup containing from 1 to 6 carbon atoms, this may be a straight or branched group containing from 1 to 6 carbon atoms, and examples include methoxy group, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentane, 2-methylbutoxy, neopentylene, 1 ethylpropoxy, hexyloxy, isohexyl, 4-methylpentylamino, 3 methylpentane, 2-methylpentane, 1 methylpentylamine, 3,3-Dimethylbutane, 2,2-Dimethylbutane, 1,1-Dimethylbutane, 1,2-Dimethylbutane, 1,3-Dimethylbutane, 2,3-Dimethylbutane and 2 ethylbutane, of which preferred are straight or branched chain group having from 1 to 4 carbon atoms, such as methoxy group, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butyl and tert-butoxy, of which preferred are a methoxy group or ethoxy.

When R5is allmenalp, acyl part of this group may be selected from various acyl groups, well known to specialists in this biteline containing from 1 to 21 carbon atoms, more preferably from 1 to 6 carbon atoms, and most preferably from 2 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoic, 8-methylnonanoic, 3-ethyloctanoic, 3,7-dimethyloctane, undecanoyl, dodecanoyl, tridecanol, deletion, pentadecanol, hexadecanol, 1-methylpentanol, 14-methylpentadiene, 13,13-dimethylcarbamoyl, heptadecanoyl, 15-methylhexadecanoic, octadecanoyl, 1-methylheptadecyl, nonadecanoic, emosanal or geekosaur;

halogenalkyls group, in which alcoolica part can be any of alkanoyl groups given as examples above, other than formyl group, but preferred is a group containing from 2 to 6 carbon atoms, and which preferably contains from 1 to 3 halogen atoms, for example, chloroacetyl group, dichloroacetyl, trichloroacetyl or TRIFLUOROACETYL;

alkoxyalkanols group in which the alkoxy portion contains from 1 to 6 carbon atoms and may be any of the alkoxy groups given as examples above in relation to R5and so on, and alcoolica part can be any of alkanols groupdelay from 2 to 6 carbon atoms, for example, methoxyacetyl group;

alcoolica or alcoolica group, preferably containing from 3 to 6 carbon atoms, for example, the group acryloyl, propiolic, methacryloyl, crotonoyl, isocrotonic or (E)-2-methyl-2-butanol; aromatic acyl group in which the aryl part may be as described above and shown in the examples above in relation to R1and so on, for example, unsubstituted arylcarbamoyl group such as benzoyl, 1-napolina or 2-napolina group;

halogensubstituted arylcarbamoyl group in which the aryl part may be as described above and shown in the examples above in relation to R1and so on, for example, 2-brombenzene or 4-chlorbenzoyl group;

alkyl substituted arylcarbamoyl group in which the aryl part may be as described above and shown in the examples above in relation to R1and so on , and the alkyl part may be as described above and shown in the examples above and in the relation R5and so on, for example, 2,4,6-trimethylbenzoyl or 4-toluene group;

alkoxy-substituted arylcarbamoyl group in which the aryl part may be as described above and shown in it is about as examples above in relation to R5and so on, for example, 4-ansorena group;

nitrosamine arylcarbamoyl group in which the aryl part may be as described above and shown in the examples above in relation to R1and so on, for example, 4-nitrobenzene or 2-nitrobenzoyl group;

alkoxycarbonylmethyl arylcarbamoyl group in which the aryl part may be as described above in relation to R1and so on, and alkoxy part arylcarboxylic groups may be the same as described above and shown in the examples above in relation to R5and so on, for example, 2-(methoxycarbonyl)benzene group; aryl-substituted arylcarbamoyl group, in which each aryl part may be as described above in relation to R1and so on, for example, 4-phenylbenzyl group;

alkoxycarbonyl group having from 1 to 6, preferably from 1 to 4 carbon atoms in the alkoxy part (for a total of up to 2 to 7, preferably from 2 to 5 carbon atoms), for example, group methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl, isopentylamine, 2-methylbutadiene, neopentyl the 3-methylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 1-methylbenzyloxycarbonyl, 3,3-dimethylbutyryl, 2,2-dimethylbutyryl, 1,1-dimethylethoxysilane, 1,2-dimethylbutadiene, 1,3-dimethylbutadiene, 2,3-dimethylbutadiene and 2-ethylbutanol, preferably, the group methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl and tert-butoxycarbonyl, of which preferred are group methoxycarbonyl, etoxycarbonyl, tertbutoxycarbonyl and isobutoxide;

alkoxycarbonyl group substituted by a halogen atom or trialkylsilyl group containing from 1 to 6 carbon atoms in the alkyl part, such as 2,2,2-trichlorocarbanilide or 2-trimethylsilylethynyl group;

alkenylamine group containing from 2 to 6 carbon atoms in alkenylphenol parts, such as vinylcarbazole and allylcarbamate group;

arylcarbamoyl group, aryl ring which may be substituted by 1 or 2 alkoxygroup containing from 1 to 6 carbon atoms or nitro groups, such as group benzylcarbamoyl, phenacyl, 4-methoxybenzylamine, 3,4-dimethoxybenzophenone, 2-nitrobenzylidene methanesulfonyl, econsultancy and 1-propanesulfonyl; fluorinated alkanesulfonyl group containing from 1 to 6 carbon atoms, such as groups trifloromethyl and pentafluoroethanesulfonyl;

arylsulfonyl group in which the aryl part may be as described above and shown in the examples above in relation to R5and so on, such as benzolsulfonat and p-toluensulfonyl group.

Of them, preferred are aliphatic acyl group, aromatic acyl group and alkanesulfonyl group.

When R5represents an alkyl group containing from 1 to 6 carbon atoms and which is substituted by allmineral, the alkyl part may be any of alkyl groups, such as described above and shown in the examples above in relation to R5and so on, and acyl groups such as described above and shown in the examples above in relation to R5.

When R5represents a hydroxyalkyl group containing from 1 to 6 carbon atoms, this may be any of the above alkyl groups that are substituted with at least one hydroxy-group, such as hydroxymethyl group, hydroxyethyl, hydroxypropyl, hydroxyl is coxi and alkyl parts can be independently selected from the respective groups, such as described above and shown in the examples above in relation to R5. Examples of such alkoxyalkyl groups include groups methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl, isobutoxide, second-butoxymethyl, tert-butoxymethyl, petrochemical, isopentylamine, neopentylglycol, hexyloxymethyl, isohexadecane, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxide, butoxide, isobutoxide, second-butoxyethyl, tert-butoxyethyl, pentyloxide, isobutylacetate, neopentylglycol, hexyloxymethyl, isohexadecane, methoxypropyl, ethoxypropan, propoxyphen, isopropoxyphenyl, butoxypropyl, isobutoxide, second-butoxypropyl, tert-butoxypropyl, pentyloxide, isopentylamine, neopentylglycol, hexyloxymethyl, isohexadecane, methoxybutyl, ethoxymethyl, propoxymethyl, isopropoxide, butoxymethyl, isobutoxide, second-butoxymethyl, tert-butoxymethyl, pentyloxide, isobutylacetate, neopentylglycol, hexyloxymethyl, isohexanoate, methoxyphenyl, ethoxyphenyl, propoxyphenyl, isopropoxyphenyl, butoxyphenyl, isobutoxide, verb ntil, isohexadecane, methoxyacetyl, atoxigenic, propoxyethyl, isopropoxyphenyl, butoxyethyl, isobutoxide, second-butoxyethyl, tert-butoxyethyl, pentylhexyl, isopentylamine, neopentylglycol, hexyloxyphenyl and isohexadecane.

When R5is kalkylarksmall group, kalkilya part represents an alkyl group containing from 1 to 4 carbon atoms and which is substituted by from 1 to 3 carbocyclic aryl groups which are unsubstituted or which is substituted by at least one Deputy, preferably selected from the group consisting of the substituents listed above and shown in the examples below, and the alkyl part oxyalkylene group contains from 1 to 6 carbon atoms. The alkyl parts may be any of the alkyl groups shown by examples in relation to R5. Kalkilya part of the group can be any of Uralkalij groups, specified and shown in the examples below in relation to deputies . Specific examples of such groups include groups benzoyloxymethyl-aftermatket-aftermatket, penetrometer, 2-benzyloxyethyl, 2 - naphthylmethyl, 2 - naphthylmethyl, 2-penetracion 3-b is timeconsistent, 4- -naphthylmethyl, 4-penetrometer, 5-benzyloxyphenyl, 5- -naphthylmethyl, 5- -naphthylmethyl, 5-penetrateinto, 6-benzyloxyethyl, 6 - naphthylmethyl, 6 - naphthylmethyl and 6-penetrometer. Aryl portion of these groups may be substituted or unsubstituted and, if substituted, the substituents selected from the group consisting of the substituents listed above.

When Raor Rb, assistant or Deputy represent an aliphatic acyl group, this may be any of the aliphatic acyl groups, halogenalkyls groups, alkoxyalkanols groups, alkenols groups, alkenol groups, alkoxycarbonyl groups, alkoxycarbonyl groups substituted by a halogen atom, and alkenylboronic groups, specified and shown in the examples above in relation to R5in particular, groups are formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl and isovaleryl.

When Raor Rb, assistant or Deputy are alkanesulfonyl group or halogenoacetyl group, it can be any of those as described above and shown in the examples above in relation to R5or Deputy

When Raor Rbtogether with the nitrogen atom to which they are attached, represent a nitrogen-containing heterocyclic group, it may contain from 5 to 7 ring atoms, of which from 1 to 3 can be heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, at least one is nitrogen. The heterocyclic group preferably is a saturated (non-aromatic) group. Examples of such groups include groups pyrrolidino, piperidino, piperazine derivatives, N-methylpiperazine, morpholine, thiomorpholine.

When Raor Rbtogether with the carbon atom to which they are attached, represent cycloalkyl or heterocyclic group containing from 5 to 10 ring atoms, this group is unsubstituted or substituted by at least one Deputy, selected from the group consisting of the substituents listed above. Heterocyclic group contains only one heteroatom which is selected from the group comprising nitrogen atoms, oxygen or sulfur. Alternative, R4and R5together with the, above, which is condensed with carbocyclic aryl group or aromatic heterocyclic group, the aryl group and the said heterocyclic group is unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of the substituents listed above. Examples of such groups include aromatic and saturated heterocyclic groups represented in the examples above in relation to Raand Rb, R1etc., and R6, respectively, and cycloalkyl group are presented as examples above in relation to Raand Rb.

Especially preferred group, which may presented together R4or R5is a group of the formula:

< / BR>
in which Ar, J and S*_ O above.

When Deputy or Deputy represent a halogen atom, this may be a fluorine atom, chlorine or iodine, preferably fluorine atom or chlorine.

When the Deputy is halogenating group, the alkyl part may be a straight or branched group containing from 1 to 6, preferably from 1 to 3 carbon atoms. There is no special limitation the provisions; however, generally, preferred are 1 to 3 halogen atoms. Examples of such groups include trifluoromethyl, trichloromethyl, deformity, dichloromethyl, dibromoethyl, vermeil, chloromethyl, methyl bromide, iodomethyl, 2,2,2-trichloroethyl, 2,2,2-triptorelin, 2-bromacil, 2-chloroethyl, 2-foretel, 2-Iodate, 2,2-dibromoethyl, 3-bromopropyl, 3-chloropropyl, 3-forproper, 3-improper, 4-bromobutyl, 4-chlorobutyl, 4-terbutyl, 4-iodobutyl, 5-bromopentyl, 5-chloropentyl, 5-terpencil, 5-iopentol, 6-bromohexyl, 6-chlorhex, 6-forexer and 6-iohexol, of which preferred are the groups are trifluoromethyl, 2-bromacil, 2-chloroethyl and 2-feratel.

When Deputy or Deputy is alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy part, this can be any of the groups listed and presented as examples above in relation to R5.

When the Deputy or the Deputy represents allmenalp, acyl part of this group may be any of the groups listed as examples above in relation to R5and so on, Specific preferred examples of such groups include aliphatic carbocyclic of alluminare, such as formamido, acetamido, propionamido, butyramide is cetamide, propionamido.

When the Deputy is alkanesulfonyl group containing from 1 to 6 carbon atoms, this may be a straight or branched group containing from 1 to 6, preferably from 1 to 4 carbon atoms, and examples include groups methanesulfonyl, econsultancy, propanesulfonyl, isopropylphenyl, butanesulfonyl, isobutylphenyl, second-butanesulfonyl, tert-butanesulfonyl, pentanesulfonic, isointensity, neopentylene, 2-methylbutanol, 1-ethylpropylamine, 4-methylphenylsulfonyl, 3-methylphenylsulfonyl, 2-methylphenylsulfonyl, 1-methylphenylsulfonyl, 3,3-dimethylbutanol, 2,2-dimethylbutanol, 3,3-dimethylbutanol, 1,1-dimethylbutanol, 1,2-dimethylbutadiene, 1,3-dimethylbutadiene, 2,3-dimethylbutadiene, 2-ethylbutanol, hexanesulfonic and isohexanol. Of them, preferred are such alkanesulfonyl groups that contain from 1 to 4 carbon atoms, preferably groups methanesulfonyl, econsultancy, propanesulfonyl, isopropylphenyl, butanesulfonyl and isobutylphenyl, and the most preferred group methanesulfonyl.

When Raor Rbor Deputy are aracelio the selected groups, it is the same as above, and examples include a benzyl group, naphthylmethyl - naphthylmethyl, intermetal, phenantrolinate, anthranilates, diphenylmethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1 - naphtalate, 2 - naphtalate, 1 - naphtalate, 2 - naphtalate, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,

1- -naftilamin, 2 - naftilamin, 3 - naftilamin, 1 - naftilamin, 2 - naftilamin, 3 - naftilamin, 1 - phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1 - naphthylmethyl, 2 - naphthylmethyl, 3 - naphthylmethyl, 4 - naphthylmethyl, 1 - naphthylmethyl, 2 - naphthylmethyl, 3 - naphthylmethyl, 4 - naphthylmethyl, 1-fenilpentil, 2-fenilpentil, 3-fenilpentil, 4-fenilpentil, 5-fenilpentil, 1- -naphthylmethyl, 2- -naphthylmethyl, 3- -naphthylmethyl, 4 - naphthylmethyl, 5- -naphthylmethyl, 1- -naphthylmethyl, 2- -naphthylmethyl, 3- -naphthylmethyl, 4- -naphthylmethyl, 5 - naphthylmethyl, 1-phenylhexa, 2-phenylhexa, 3-phenylhexa, 4-phenylhexa, 5-phenylhexa, 6-phenylhexa, 1 - nattinger, 2 - nattinger, 3 - nattinger, 4 - nattinger, 5- -nattinger, 6 - nattinger, 1 - nattinger, 2 - nattinger, 3 - nattinger, 4 - nattinger, 5 - nattinger and 6-nattinger, of which preferred are such kalkilya groups in which the aryl part of the group assetsfinancial group.

When the Deputy is alkanesulfonyl group or halogenated.sulphonated, alkanesulfonyl or halogensulphonylphenyl part of it can be any of such groups, which are listed and presented as examples above in relation to R5or Deputy .

When R14is aminosidine group, it can be any of the aliphatic acyl groups, aromatic acyl groups, and alkoxycarbonyl groups, which are listed and presented as examples above in relation to R5and so on , or altneratively groups, aracelikarsaalyna groups and silyl groups, which are listed and presented as examples later in relation to the ether groups, preferably alkoxycarbonyl group. Of them, particularly preferred is tert-butoxycarbonyl group.

Each connection according to the present invention in its molecule contains a basic group, and may, thus, to form the salt of the addition of acids. Examples of such salts of addition of the acid include salts of mineral acids, especially halogen acids such as hydrofluoric acid, Hydrobromic acid, idiscoveri acid and phosphoric acid; salts with lower alkylsulfonyl acids such as methanesulfonate acid, triftormetilfullerenov acid or econsultancy acid; salts with arylsulfonic acids, such as benzolsulfonat acid or n-toluensulfonate acid; salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid; and salts with amino acids such as glycine, ornithine, lysine, glutamic acid or aspartic acid.

Since the compounds of formula (I) according to the present invention can be converted into a Quaternary amine by modifying the nitrogen atom piperidine or piperazine derivatives group in the molecule with a group R7such salts of compounds of formula (I) containing the cation and the anion (which may be any atom or group capable of forming anion, and examples include a halogen ion such as chlorine ion and iodine ion) is also included in the present invention.

The compounds of formula (I) according to the present invention can sometimes be transformed into a Hydra is uceni in the present invention.

The compounds of formula (I) according to the present invention can form esters, which are also part of the present invention. When connections are intended for therapeutic use, ester should be pharmaceutically acceptable, which, as is well known, means that it must be not more toxic (or most unacceptable toxicity) than the ancestral connection, and not less active (or less unacceptable activity) than the generic connection. Such esters may be regarded either as "General" ethers or "biodegradable" esters, or they can act as a protective group.

Common esters are esters that can be cleaved by a chemical method, such as hydrogenation, hydrolysis, electrolysis, photolysis, etc., Examples of such groups which can form esters with hydroxy-group include:

the above aliphatic acyl group;

the above aromatic acyl group;

tetrahydropyranyl or tetrahydropyranyl groups, such as groups tetrahydropyran-2-yl, 3-bromotetradecane-2-yl, 4-methoxyacridine-4-yl, tetrathiophene-2-yl and 4-methoxyacridine-2-yl and tetrathiophene-2-yl;

silyl groups such as trialkylsilyl group containing from 1 to 6 carbon atoms in each alkyl part (for example, trimethylsilyl group, triethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, methyldiisopropanolamine, methyldi-tert-Boticelli and triisopropylsilyl), trialkylsilyl group containing from 1 to 6 carbon atoms in each alkyl part and in which one or two alkyl groups, substituted aryl groups, which are listed and presented as examples above in relation to R1and so on (for example, group diphenylmethylsilane, diphenylbutyric, diphenylethylene and phenyldimethylsilane); optionally substituted alkoxymethyl group containing from 1 to 6 carbon atoms in the alkoxy part, such as alkoxymethyl group (for example, group methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl and tributoxyethyl), alkoxysilane alkoxymethyl group containing from 1 to 6 carbon atoms in each alkoxy part (for example, 2-methoxyethoxymethyl group), halogenoacetyl group, containing from 1 to 6 carbon atoms in the alkoxy part [e.g., 2,2,2-trichloroethylene and bis(2-chlorates the s from 1 to 6 carbon atoms in the alkoxy part (for example, 1-ethoxyethylene and 1-isopropoxyaniline group), halogenation group (for example, 2,2,2-trichlorethylene group);

kalkilya groups, such as described above with respect to the Deputy , preferably alkyl groups, substituted from 1 to 3 aryl groups (for example, benzyl group, -naphthylmethyl-naphthylmethyl, diphenylmethyl, triphenylmethyl-naphthaleneacetic and 9-antimetal), lower alkyl groups substituted by from 1 to 3 aryl groups, the aryl ring of which is substituted by lower alkyl, lower alkoxy, nitro, halogen or cyano (for example, group 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylalanine, 2-nitrobenzyl, 4-nitrobenzyl, 4-Chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl);

the above alkoxycarbonyl group;

altneratively groups, such as group vinyloxycarbonyl and allyloxycarbonyl;

aracelikarsaalyna group, aryl ring which may be substituted by 1 to 2 lower alkoxy or nitro groups, such as group benzyloxycarbonyl, 4-methoxybenzenesulfonyl, 3,4-dimethoxyphenylacetone, 2-nitrobenzenesulfonyl, and 4-nitrobenzenesulfonyl.

Biodegradable the decomposition, with the formation of the free acid or a salt thereof. It may be determined whether ester biodegradable with the introduction of the experimental animal (e.g., rat or mouse) by intravenous infusion, exploring the body fluid after the introduction and definition of parent compound or its pharmaceutically acceptable salt.

Examples of biodegradable esters include:

1-(acyloxy)lower alkyl groups such as 1-(alifaticheskii acyloxy)a lower alkoxy group (for example, group formyloxyethyl, acetoxymethyl, dimethylaminoacetonitrile, propionylacetate, butyraldoxime, pivaloyloxymethyl, valerolactone, isovalerylglycine, hexaniacinate, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl, 1-valeriansee, 1-isovalerianic, 1-hexaniacinate, 1-formylacetate, 1-acetoxymethyl, 1-propionyloxy, 1-butyryloxy, 1-pivaloyloxymethyl, 1-alariaceae, 1-isovalerylglycine, 1-hexanolactone, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl and 1-is urbanrocker, cyclohexylcarbodiimide, 1-cyclopentanecarboxylate, 1-cyclohexylcarbodiimide, 1-cyclopentanecarboxylate, 1-cyclohexylcarbodiimide, 1-cyclopentanecarboxylate and 1-cyclohexyloxycarbonyloxy);

1-(aromatic acyloxy)lower alkyl groups (for example, benzoyloxymethyl group);

carbonylcyanide groups, such as (alkoxycarbonyl)alkyl groups and (cycloalkylcarbonyl)alkyl groups (for example, group methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonylmethyl, msobuttoniconandcaption, ventilatsioonisusteemi, hexyloxybenzoyl, cyclohexyloxycarbonyloxy, cyclohexyloxycarbonyloxy(cyclohexyl)methyl, 1-(methoxycarbonylamino)ethyl, 1-(ethoxycarbonyl)ethyl, 1-(propoxycarbonyl)ethyl, 1-(isopropoxycarbonyl)ethyl, 1-(butoxycarbonylamino)ethyl, 1-(isobutoxyethene)ethyl, 1-(ventilatsioonile)ethyl, 1-(hexyloxyethoxy)ethyl, 1-(cyclopentanecarbonyl)ethyl, 1-(cyclopentanecarbonyl)propyl, 1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentanecarbonyl)butyl, 1-(cyclohexyloxy)-ethyl, 2-(ethoxycarbonyl)ethyl, 2-(propoxycarbonyl)ethyl, 2-(isopropoxycarbonyl)ethyl, 2-(butoxycarbonylamino)ethyl, 2-(isobutoxyethene)ethyl, 2-(ventilatsioonile)ethyl, 2-(hexyloxyethoxy)ethyl, 1-(methoxycarbonylamino)propyl, 1-(ethoxycarbonyl)propyl, 1-(propoxycarbonyl)propyl, 1-(isopropoxycarbonyl)propyl, 1-(butoxycarbonylamino)propyl, 1-(isobutoxyethene)propyl, 1-ventilatsioonile)propyl, 1-(hexyloxyethoxy)propyl, 1-(methoxycarbonyl)butyl, 1-(ethoxycarbonyl)butyl, 1-(propoxycarbonyl)butyl, 1-(isopropoxycarbonyl)butyl, 1-(butoxycarbonylamino)butyl, 1-(isobutoxyethene)butyl, 1-(methoxycarbonylamino)pentyl, 1-(ethoxycarbonyl) pentyl, 1-(methoxycarbonyl)hexyl and 1-(ethoxycarbonyl)hexyl);

exodeoxyribonuclease group (for example, group (5-phenyl-2-oxo-1,3-dioxolan-4-yl)methyl, [5-(4-were)-2-oxo-1,3-dioxolan-4-yl] methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolan-4-yl] methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolan-4-yl] methyl, (2-oxo-1,3-dioxolan-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolan-4-yl)methyl and (5-butyl-2-oxo-1,3-dioxolan-4-yl)methyl);

Caligastia acyl group,

the above aromatic acyl group;

polovinye salt residues of succinic acid;

phosphate salt residues;

epioblasma residues, such as amino acids;

1-(acyloxy)allyloxycarbonyl groups, such as pivaloyloxymethyl group.

Of them, preferred are carbonylcyanide group.

The compounds of formula (I) according to the present invention have an asymmetric carbon atom in the molecule, and the stereoisomers, in which the asymmetric carbon atom has the R and S configuration. The stereoisomers, in which the asymmetric carbon atom has the R and S configurations, and their mixture, with any ratio, are also included in the present invention.

Preferred classes of compounds of the present invention are those compounds of formula (I) and its salts and esters, in which E represents a methylene group and

(A1) R1and R2are the same or different and each represent a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 groups selected from the group consisting of the Deputy is displaced from 1 to 3 groups selected from the group containing substituents ;

(B1) A represents A carbonyl group;

(G1) B is a single bond;

(1) D is an oxygen atom;

(E1) G is alkylenes group having from 1 to 4 carbon atoms;

(W1) G is alkylenes group having 2 or 3 carbon atoms;

(Z1) R3represents an aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 groups selected from the group containing substituents ;

(I1) L represents a group of formula-C(R4)(R5)-;

(K1) R4represents a carbocyclic aryl group or aromatic heterocyclic group;

(C1) R5represents a group of the formula-COR6(where R6represents an alkyl group having from 1 to 6 carbon atoms or a group of the formula-NRaRb)-;

(M1) R5represents an amino group, alluminare or hydroxy-group;

(N1) R4and R5together with the carbon atom to which they are attached, represent cycloalkyl or heterocyclic group having from 5 to 10 ring atoms, and is unsubstituted or substituted by at least one Deputy, selected from groups group, containing atoms of nitrogen, oxygen and sulfur, or R4or R5together with the carbon atom to which they are attached, represent cycloalkyl or heterocyclic group mentioned above, which is condensed with carbocyclic aryl group or aromatic heterocyclic group, the aryl group and the said heterocyclic group is unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of substituents .

Further preferred classes of compounds of the present invention are those compounds of formula (I) and their salts and esters, in which E represents a group of formula -(CH2)nin which n is an integer from 2 to 4, and

(A2) R1and R2are the same or different and each represent a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 groups selected from the group containing substituents ;

(B2) R2represents a carbocyclic aryl group or a carbocyclic aryl group substituted by from 1 to 3 groups selected from the group, the
(D2) D is an oxygen atom;

(E2) G is alkylenes group having from 1 to 4 carbon atoms;

(I) G is alkylenes group having 2 to 3 carbon atoms;

(Z2) R3represents an aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 groups selected from the group containing substituents ;

(I2) L represents a group of General formula-C(R4)(R5)-;

(K2) R4represents a carbocyclic aryl group or aromatic heterocyclic group;

(C2) R5represents a group of formula-CO-R5(where R6represents an alkyl group having from 1 to 6 carbon atoms or a group of the formula-NRaRb)-;

(M2) R5represents an amino group, alluminare or hydroxy-group;

(H2) n is 2 or 3;

(O2) n = 2;

(P2) R4and R5together with the carbon atom to which they are attached, represent cycloalkyl or heterocyclic group having from 5 to 10 ring atoms, and the specified group is unsubstituted or substituted by at least one Deputy, selected from the group containing substituents , the heterocyclic group, R5together with the carbon atom to which they are attached, represent cycloalkyl or heterocyclic group mentioned above, which is condensed with carbocyclic aryl group or aromatic heterocyclic group, the aryl group and the said heterocyclic group is unsubstituted or substituted by at least one Deputy, preferably selected from the group consisting of substituents .

Even among preferred classes of compounds of the present invention are those compounds of formula (I) and their salts and esters in which R4and R5together with the carbon atom to which they are attached, represent a group of the formula:

< / BR>
and

(A3) R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 groups selected from the group containing substituents ;

(B3) R1represents a carbocyclic aryl group or a carbocyclic aryl group substituted by from 1 to 3 groups selected from the group consisting of substituents1;

deputies1selected from the group consisting of alkylen the represents a carbocyclic aryl group or a carbocyclic aryl group, substituted from 1 to 3 groups selected from the group containing substituents ;

(G3) R2represents a carbocyclic aryl group or a carbocyclic aryl group substituted by from 1 to 3 halogen atoms;

(3) A represents A carbonyl group;

(E3) B is a single bond;

(I) D is an oxygen atom;

(Z2) E represents C1-4alkylenes group or a C3-8alkylenes group that contains C3-6cycloalkane-1,1-dialnow group;

(I3) E represents a methylene group, ethylene, dimethylmethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, cyclopropane-1,1-diyl, CYCLOBUTANE-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cyclopropane-1,1-dimetil, CYCLOBUTANE-1,1-dimetil, cyclopentane-1,1-dimetil or cyclohexane-1,1-dimetil;

(K3) G represents C1-4alkylenes group;

(L3) G represents C2-3alkylenes group;

(M3) J represents C1-4alkylenes group;

(H3) J is methylene or ethylene group;

(O3) the ring A represents A carbocyclic aryl group, carbocyclic aryl group substituted by from 1 to 3 groups selected from the group consisting of substituents or aromatic heterocyclics is substituted by from 1 to 3 groups selected from the group consisting of substituents .

Examples of some compounds of the present invention, which can be obtained as described in the examples shown in the following formulas (I-1), (I-2) and (I-3). Deputies are these relevant groups in tables 1, 2 and 3, i.e. table 1 relates to formula (I-1), etc.

Each of the compounds shown in these tables, covers 2 connections, one of which G is dimethylene group (which may be indicated in the table by the suffix "a" after the number) and in the other G is trimethylene group (which may be indicated in the table by the suffix "b" after the number).

Moreover, each of the compounds from 2-1537 to 2-3072 also encompasses compounds in which B may represent a single bond or CH2group. They can be marked with additional suffix, or , respectively, for example, the connection 2-1537, where G is dimethylene group and B represents a single bond, may be known as compound 2-1537a , the connection 2-1537, where G is dimethylene group and B represents CH2the group may be known as compound 2-1537a , the connection 2-1537, where G is trimed G is trimethylene group and B represents CH2the group may be known as compound 2-1537b .

Some abbreviations of the names of the substituents in the tables indicate the following:

cBu - CYCLOBUTANE-1,1-diyl

cHx - cyclohexyl-1,1-diyl

Me - methyl

Ph - phenyl

cPn - cyclopentane-1,1-diyl

cPr - cyclopropane-1,1-diyl

In addition, the group has provided at the end of the description of the formula, labeled Conn.-XX.

1. The compounds of formula I

< / BR>
and their Quaternary ammonium derivatives of formula Ia

< / BR>
where R1represents a carbocyclic aryl group containing from 6 to 10 carbon atoms in a single ring or two condensed rings, where this aryl group is unsubstituted or substituted by at least one of the substituents , as defined below, or an aromatic heterocyclic group containing from 5 to 7 ring atoms, of which from 1 to 3 atoms are a heteroatom of nitrogen and/or sulfur;

R2represents a phenyl group which may be substituted by one or more halogen atoms;

A represents A carbonyl group or sulfonyloxy group;

B represents a single bond between groups represented by A and R1alkylene
D represents an oxygen atom or sulfur;

E represents alkylenes group containing from 1 to 6 carbon atoms;

G represents alkylenes group containing from 1 to 4 carbon atoms, or alkynylamino group containing from 2 to 4 carbon atoms;

L represents a group of formula-N(R3)- or a group of the formula-C(R4)(R5)-, where R3represents a phenyl group which may be unsubstituted or substituted aliphatic carboxylic acyl group containing from 1 to 6 carbon atoms; R4represents a hydrogen atom, phenyl group or pyridyloxy group, and R5represents a group of formula-CO-R6alkoxygroup containing from 1 to 6 carbon atoms, amino group, alluminare where indicated acyl group is a carboxylic acyl group containing from 1 to 6 carbon atoms, phenylcarbonylamino group or phenalkylamine group where the specified acylcarnitine group contains from 1 to 6 carbon atoms, the nitrogen atom of the specified alluminare optionally substituted alkyl group containing from 1 to 6 carbon atoms, a hydroxy-group, kalkylarksmall group containing from 1 to 6 carbon atoms in oxyalkylene part and the cat is Jena phenyl group, which may be substituted by one or more halogenoalkane groups containing from 1 to 6 carbon atoms, where R6represents an alkyl group containing from 1 to 6 carbon atoms, a group of the formula-NRaRb, phenyl group which may be optionally substituted by a halogen atom, where Rarepresents a hydrogen atom, alkyl group containing from 1 to 6 carbon atoms, phenyl group or phenylalkyl group where the specified alkyl portion contains from 1 to 6 carbon atoms and Rbrepresents a hydrogen atom, alkyl group containing from 1 to 6 carbon atoms, phenyl group or phenylalkyl group where the specified alkyl portion contains from 1 to 6 carbon atoms, or Raand Rbtogether with the nitrogen atom to which they are attached, represent a nitrogen-containing heterocyclic group containing from 5 to 7 ring atoms, of which from 1 to 3 can be heteroatoms nitrogen and/or oxygen and/or sulfur and at least one is nitrogen, R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group containing 5 to 10 ring atoms, and the specified group is unsubstituted or Deputy is specified heterocyclic group contains one or more heteroatoms, selected from the group consisting of nitrogen atoms, oxygen, or sulfur, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group;

R7represents an alkyl group containing from 1 to 6 carbon atoms;

these substituents selected from the group comprising halogen atoms, alkyl groups containing from 1 to 6 carbon atoms, halogenoalkane group containing from 1 to 6 carbon atoms, hydroxy-group and alkoxygroup containing from 1 to 6 carbon atoms;

these alternates are: the substitution of the carbon atom, carbonyl group, with the substitution of the nitrogen atom selected from alkanesulfonyl groups containing from 1 to 6 carbon atoms, phenyl groups and phenylalkyl groups where the specified alkyl portion contains from 1 to 6 carbon atoms, and the substitution of the sulfur atom by one or two atoms of oxygen form sulfoxide or sulfonic group,

and their pharmaceutically acceptable salts and esters.

2. The compound of formula I under item 1, where R1represents a carbocyclic aryl group containing from 6 to 10 carbon atoms in a single ring or two one Deputy , as defined below, or an aromatic heterocyclic group containing from 5 to 7 ring atoms, of which from 1 to 3 atoms are heteroatoms nitrogen and/or oxygen and/or sulfur, R2represents a phenyl group which may be substituted by one or more halogen atoms, A represents A carbonyl group or sulfonyloxy group; B represents a single bond between groups represented by A and R1, alkylenes group containing from 1 to 4 carbon atoms, or alkenylamine group containing from 2 to 4 carbon atoms; D represents an oxygen atom or sulfur, E is a methylene group, G is alkylenes group containing from 1 to 4 carbon atoms, or alkenylamine group containing from 2 to 4 carbon atoms, L represents a group of formula-N(R3)- or a group of the formula-C(R4)(R5)-, where R3represents a phenyl group which may be unsubstituted or substituted aliphatic carboxylic acyl group containing from 1 to 6 carbon atoms; R4represents a hydrogen atom, phenyl group or pyridyloxy group, and R5represents a group of formula-CO-R6, an amino group, alluminare where specified the acyl Grupo phenalkylamine group, where specified acylcarnitine portion contains from 1 to 6 carbon atoms, the nitrogen atom of the specified alluminare optionally substituted alkyl group containing from 1 to 6 carbon atoms, a hydroxy-group or kalkylarksmall group containing from 1 to 6 carbon atoms in oxyalkylene parts and in which kalkilya part is an alkyl group containing from 1 to 4 carbon atoms and which is substituted by phenyl group which may be substituted by one or more halogenoalkane groups containing from 1 to 6 carbon atoms, where R6represents an alkyl group containing from 1 to 6 carbon atoms, a group of the formula-NaRb, phenyl group which may be optionally substituted by a halogen atom, where Rarepresents a hydrogen atom, alkyl group containing from 1 to 6 carbon atoms, phenyl group or phenylalkyl group, where this alkyl group contains from 1 to 6 carbon atoms, and Rbrepresents a hydrogen atom, alkyl group containing from 1 to 6 carbon atoms, phenyl group or phenylalkyl group where the specified alkyl portion contains from 1 to 6 carbon atoms, or Raand Rbtogether with the nitrogen atom to which, of which from 1 to 3 can be heteroatoms nitrogen and/or oxygen and/or sulfur and at least one is nitrogen, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group selected from the group comprising group: pyrrolidine, tetrahydrofuran, piperidine, tetrahydrothiophene, imidazole, oxazolidin, thiazolidin where the specified heterocyclic group is unsubstituted or substituted by at least one Deputy, selected from the group including substituents , as defined hereinafter, or R4and R5together with the carbon atoms to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group, and these substituents selected from the group comprising halogen atoms, alkyl groups containing from 1 to 6 carbon atoms, halogenoalkane group containing from 1 to 6 carbon atoms, and alkoxygroup containing from 1 to 6 carbon atoms; the said substituents are: the substitution of a carbon atom, carbonyl group, with the substitution of the nitrogen atom selected from alkanesulfonyl groups containing from 1 to 6 carbon atoms, phenyl groups and phenylalkyl groups, where oksanaberzul sulfoxide or sulfonic group, and their pharmaceutically acceptable salts and esters.

3. The compound of formula I under item 1 and its Quaternary ammonium derivatives of formula Ia under item 1, where R1represents a carbocyclic aryl group containing from 6 to 10 carbon atoms in a single ring or two condensed rings, where this aryl group is unsubstituted or substituted by at least one Deputy , as defined hereinafter, or an aromatic heterocyclic group containing from 5 to 7 ring atoms, of which from 1 to 3 heteroatoms of nitrogen and/or oxygen and/or sulfur, R2represents a phenyl group which may be substituted by one or more halogen atoms, A represents A carbonyl group or sulfonyloxy group: B represents a single bond between groups represented by A and R1, alkylenes group containing from 1 to 4 carbon atoms, or alkenylamine group containing from 2 to 4 carbon atoms, D represents an oxygen atom or sulfur, E represents a group of formula -(CH2)nwhere n is an integer from 2 to 4, G is alkylenes group containing from 1 to 4 carbon atoms, or alkenylamine group containing from 2 to 4 carbon atoms, L predst group, which may be unsubstituted or substituted aliphatic carboxylic acyl group containing from 1 to 6 carbon atoms; R4represents a hydrogen atom, phenyl group or pyridyloxy group, and R5represents a group of formula-CO-R6alkoxygroup containing from 1 to 6 carbon atoms, amino group, alluminare where indicated acyl group is a carboxylic acyl group containing from 1 to 6 carbon atoms, phenylcarbonylamino group or phenalkylamine group where the specified acylcarnitine portion contains from 1 to 6 carbon atoms, the nitrogen atom of the specified alluminare optionally substituted alkyl group containing from 1 to 6 carbon atoms, a hydroxy-group, kalkylarksmall group containing from 1 to 6 carbon atoms in oxyalkylene parts and in which kalkilya part is an alkyl group containing from 1 to 4 carbon atoms, and which is substituted by phenyl group which may be substituted by one or more halogenoalkane groups containing from 1 to 6 carbon atoms, where R6represents an alkyl group containing from 1 to 6 carbon atoms, a group of the formula-NRaRb, phenyl group which may biaduo from 1 to 6 carbon atoms, phenyl group or phenylalkyl group where the specified alkyl portion contains from 1 to 6 carbon atoms, and Rbrepresents a hydrogen atom, alkyl group containing from 1 to 6 carbon atoms, phenyl group or phenylalkyl group where the specified alkyl portion contains from 1 to 6 carbon atoms, or Raand Rbtogether with the nitrogen atom to which they are attached, represent a nitrogen-containing heterocyclic group containing from 5 to 7 ring atoms, of which from 1 to 3 can be heteroatoms nitrogen and/or oxygen and/or sulfur and at least one is nitrogen, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group selected from the group comprising group: pyrrolidine, tetrahydrofuran, piperidine, tetrahydrothiophene, imidazole, oxazolidin, thiazolidin where the specified heterocyclic group is unsubstituted or substituted by at least one Deputy, selected from the substituents as defined below, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group, and R7p include halogen atoms, alkyl groups containing from 1 to 6 carbon atoms, halogenoalkane group containing from 1 to 6 carbon atoms, and alkoxygroup containing from 1 to 6 carbon atoms, such substituents are: the substitution of the carbon atom of the carbonyl group, with the substitution of the nitrogen atom selected from alkanesulfonyl groups containing from 1 to 6 carbon atoms, phenyl groups and phenylalkyl groups where the specified alkyl portion contains from 1 to 6 carbon atoms, and the substitution of the sulfur atom by one or two atoms of oxygen form sulfoxide or sulfonic group, and their pharmaceutically acceptable salts and esters.

4. Connection on p. 1, where E represents a methylene group.

5. Connection on p. 4, where R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 substituents , and R2represents a phenyl group or a phenyl group substituted by 1 to 3 halogen atoms.

6. Connection on p. 2, where R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 substituents , and RObedinenie by p. 3, where R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 substituents , and R2represents a phenyl group or a phenyl group substituted by 1 to 3 halogen atoms.

8. Connection on p. 4, where R2represents a phenyl group or a phenyl group substituted by 1 to 3 halogen atoms.

9. Connection on p. 2 where R2represents a phenyl group or a phenyl group substituted by 1 to 3 halogen atoms.

10. Connection on p. 3, where R2represents a phenyl group or a phenyl group substituted by 1 to 3 halogen atoms.

11. Connection on p. 4, where A represents A carbonyl group.

12. Connection on p. 2, where A represents A carbonyl group.

13. Connection on p. 3, where A represents A carbonyl group.

14. Connection on p. 4, where B represents a single bond.

15. Connection on p. 2, where B represents a single bond.

16. Connection on p. 3, where B represents a single bond.

17. Connection on p. 4, where D represents an oxygen atom.

18. Connection on p. 2, where D Ave is unity under item 4, where G represents alkylenes group containing from 1 to 4 carbon atoms.

21. Connection on p. 2, where G is alkylenes group containing from 1 to 4 carbon atoms.

22. Connection on p. 3, where G is alkylenes group containing from 1 to 4 carbon atoms.

23 Connection on p. 4, where G is alkylenes group containing from 2 to 3 carbon atoms.

24. Connection on p. 2, where G is alkylenes group containing from 2 to 3 carbon atoms.

25. Connection on p. 3, where G is alkylenes group containing from 2 to 3 carbon atoms.

26. Connection on p. 4, where R3represents a phenyl group, substituted aliphatic carboxylic acyl group containing from 1 to 6 carbon atoms.

27. Connection on p. 2, where R3represents a phenyl group, substituted aliphatic carboxylic acyl group containing from 1 to 6 carbon atoms.

28. Connection on p. 3, where R3represents a phenyl group, substituted aliphatic carboxylic acyl group containing from 1 to 6 carbon atoms.

29. Connection on p. 4, where L represents a group of formula-C(R4)(R54)(R5)-.

32. Connection on p. 4, where R4represents a phenyl group or pyridyloxy group.

33. Connection on p. 2, where R4represents a phenyl group or pyridyloxy group.

34. Connection on p. 3, where R4represents a phenyl group or pyridyloxy group.

35. Connection on p. 4, where R5represents a group of formula-CO-R6where R6represents an alkyl group containing from 1 to 6 carbon atoms, or a group of the formula-NRaRb.

36. Connection on p. 2, where R5represents a group of formula-CO-R6where R6represents an alkyl group containing from 1 to 6 carbon atoms, or a group of the formula-NRaRb.

37. Connection on p. 3, where R5represents a group of formula-CO-R6where R6represents an alkyl group containing from 1 to 6 carbon atoms, or a group of the formula-NRaRb.

38. Connection on p. 4, where R5represents an amino group, alluminare or hydroxy-group.

39. Connection on p. 2, where R5represents an amino group, alluminare or hydroxy-group.

40. Link on p. 4, where R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group containing 5 to 10 ring atoms, and the specified group is unsubstituted or substituted by at least one of the substituents of the heterocyclic group has a single heteroatom selected from nitrogen atoms, oxygen and sulfur, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group.

42. Connection on p. 2, where R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group selected from the group comprising group: pyrrolidine, tetrahydrofuran, piperidine, tetrahydrothiophene, imidazole, oxazolidin, thiazolidin specified heterocyclic group is unsubstituted or substituted by at least one Deputy, selected from the substituents defined in paragraph 2, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group.

43. Connection on p. 3, where R4
and R5together with the carbon atom to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group.

44. Connection on p. 4, where R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 substituents , R2represents a phenyl group which is optionally substituted from 1 to 3 halogen atoms, A represents A carbonyl group, B represents a single bond, D represents an oxygen atom, G represents alkylenes group containing from 1 to 4 carbon atoms, L represents a group of formula-C(R4)(R5)-, R4represents phenyl group, and R5represents a group of formula-CO-R6where R6represents an alkyl group containing from 1 to 6 carbon atoms, or a group of the formula-NRaRb heterocyclic group or carbocyclic aryl group, substituted from 1 to 3 substituents , R2represents a phenyl group which is optionally substituted from 1 to 3 halogen atoms, A represents A carbonyl group, B represents a single bond, D represents an oxygen atom, G represents alkylenes group containing from 1 to 4 carbon atoms, L represents a group of formula-C(R4)(R5)-, R4represents phenyl group, and R5represents a group of formula-CO-R6where R6represents an alkyl group containing from 1 to 6 carbon atoms, or a group of the formula-NRaRb.

46. Connection on p. 3, where R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 substituents , R2represents a phenyl group which is optionally substituted from 1 to 3 halogen atoms, A represents A carbonyl group, B represents a single bond, D represents an oxygen atom, G represents alkylenes group containing from 1 to 4 carbon atoms, L represents a group of formula-C(R4)(R5)-, R4represents phenyl group, and R5represents a group of formula-CO-R6where R6predstave. Connection on p. 4, where R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 substituents , R2represents a phenyl group optionally substituted by 1 to 3 halogen atoms, A represents A carbonyl group, B represents a single bond, D represents an oxygen atom, G represents alkylenes group containing from 1 to 4 carbon atoms, L represents a group of formula-C(R4)(R5) and R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group containing 5 to 10 ring atoms of the specified group is unsubstituted or substituted by at least one of the substituents of the heterocyclic group has a single heteroatom selected from nitrogen atoms, oxygen, or sulfur, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group.

48. Connection on p. 2, where R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic amestoy from 1 to 3 halogen atoms, A represents A carbonyl group, B represents a single bond, D represents an oxygen atom, G represents alkylenes group containing from 1 to 4 carbon atoms, L represents a group of formula-C(R4)(R5) and R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group selected from the group comprising group: pyrrolidine, tetrahydrofuran, piperidine, tetrahydrothiophene, imidazole, oxazolidin, thiazolidin, and the said heterocyclic group is unsubstituted or substituted by at least one Deputy, selected from the group including substituents , as defined hereinafter, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group.

49. Connection on p. 3, where R1represents an aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 substituents , R2represents a phenyl group optionally substituted by 1 to 3 halogen atoms, A represents A carbonyl group, B represents a single bond, D represents an oxygen atom, G presented the )-, R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group selected from the group comprising group: pyrrolidine, tetrahydrofuran, piperidine, tetrahydrothiophene, imidazole, oxazolidin, thiazolidin, and the said heterocyclic group is unsubstituted or substituted by at least one Deputy, selected from the group including substituents , as defined hereinafter, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group.

50. Connection on p. 1, where E represents a group of formula -(CH2)n-, where n is an integer from 2 to 4.

51. Connection on p. 50, where R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 substituents , and R2represents a phenyl group optionally substituted by 1 to 3 halogen atoms.

52. Connection on p. 50, where R2represents a phenyl group optionally substituted by 1 to 3 halogen atoms.

53. Connection on p. 50, where A is carbopol p. 50, where D represents an oxygen atom.

56. Connection on p. 50, where G is alkylenes group containing from 1 to 4 carbon atoms.

57. Connection on p. 50, where G is alkylenes group containing from 2 to 3 carbon atoms.

58. Connection on p. 50, where R3represents a phenyl group, substituted aliphatic carbocyclic acyl group containing from 1 to 6 carbon atoms.

59. Connection on p. 50, where L represents a group of General formula-C(R4)(R5)-.

60. Connection on p. 50, where R4represents a phenyl group or pyridyloxy group.

61. Connection on p. 50, where R5represents a group of General formula-CO-R6where R6represents an alkyl group containing from 1 to 6 carbon atoms, or a group of the formula-NRaRb.

62. Connection on p. 50, where R5represents an amino group, alluminare or hydroxy-group.

63. Connection on p. 50, where R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group containing 5 to 10 ring atoms, and the specified group is unsubstituted or substituted by at least one and the same oxygen, or sulfur, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group.

64. Connection on p. 50, where n is 2 or 3.

65. Connection on p. 51, where n is 2 or 3.

66. Connection on p. 50, where n is equal to 2.

67. Connection on p. 51, where n is equal to 2.

68. Connection on p. 50, where R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 substituents , R2represents a phenyl group optionally substituted by 1 to 3 halogen atoms, A represents A carbonyl group, B represents a single bond, D represents an oxygen atom, G represents alkylenes group containing from 1 to 4 carbon atoms, L represents a group of General formula C(R4)(R5)-, R4represents a phenyl group, R5represents a group of formula-CO-R6where R6represents an alkyl group containing from 1 to 6 carbon atoms, or a group of the formula-NRaRband n is 2 or 3.

69. Connection on p. 51, where R1is carbochemistry from 1 to 3 substituents , R2represents a phenyl group optionally substituted by 1 to 3 halogen atoms, A represents A carbonyl group, B represents a single bond, D represents an oxygen atom, G represents alkylenes group containing from 1 to 4 carbon atoms, L represents a group of General formula-C(R4)(R5)-, R4represents a phenyl group, R5represents a group of formula-CO-R6where R6represents an alkyl group containing from 1 to 6 carbon atoms, or a group of the formula-NRaRband n is 2 or 3.

70. Connection on p. 50, where R1represents a carbocyclic aryl group, aromatic heterocyclic group or carbocyclic aryl group substituted by from 1 to 3 substituents , R2represents a phenyl group optionally substituted by 1 to 3 halogen atoms, A represents A carbonyl group, B represents a single bond, D represents an oxygen atom, G represents alkylenes group containing from 1 to 4 carbon atoms, L represents a group of General formula-C(R4)(R5)-, R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group containing from 5 to 1 is th , and the said heterocyclic group has a single heteroatom selected from the group comprising nitrogen atoms, oxygen, or sulfur, or R4and R5together with the carbon atom to which they are attached, represent a heterocyclic group mentioned above, which is condensed with the phenyl group.

71. Connection on p. 1, where R1represents a carbocyclic aryl group containing from 6 to 10 carbon atoms in a single ring or two condensed rings, mentioned aryl group is unsubstituted or substituted by at least one of the substituents , as defined below, or an aromatic heterocyclic group containing from 5 to 7 ring atoms, of which from 1 to 3 atoms are heteroatoms nitrogen and/or oxygen and/or sulfur, R2represents a phenyl group which may be substituted by one or more halogen atoms, A represents A carbonyl group or sulfonyloxy group, B represents a single bond between groups represented by A and R1, alkylenes group containing from 1 to 4 carbon atoms, or alkenylamine group containing from 2 to 4 carbon atoms, D represents an oxygen atom or sulfur, E is the carbon atoms, or alkenylamine group containing from 2 to 4 carbon atoms, L represents a group of formula-C(R4)(R5)-, where R4and R5together with the carbon atom to which they are attached, represent a group of the formula

< / BR>
where J represents alkylenes group containing from 1 to 6 carbon atoms;

Ar represents a phenyl group;

S*_ O is sulfoxide group in which the sulfur atom has the configuration;

these substituents selected from the group comprising halogen atoms, alkyl groups containing from 1 to 6 carbon atoms, halogenoalkane group containing from 1 to 6 carbon atoms and alkoxygroup containing from 1 to 6 carbon atoms; the said substituents are: the substitution of the carbon atom of the carbonyl group, with the substitution of the nitrogen atom selected from phenyl groups and phenylalkyl groups where the specified alkyl portion contains from 1 to 6 carbon atoms, and the substitution of the sulfur atom, one or two atoms of oxygen form sulfoxide or sulfonic group, and their pharmaceutically acceptable salts and esters.

72. Connection on p. 71, where R1represents a phenyl group, optionally substituted from 1 to 3 substituents selected from 1 to 6 carbon atoms.

73. Connection on p. 71, where R2represents a phenyl group substituted by 1 to 3 halogen atoms.

74. Connection on p. 71, where A represents A carbonyl group.

75. Connection on p. 71, where B represents a single bond.

76. Connection on p. 71, where D represents an oxygen atom.

77. Connection on p. 71, where E represents C1-4alkylenes group.

78. Connection on p. 71, where E represents a methylene group or ethylene.

79. Connection on p. 71, where G represents C1-4alkylenes group.

80. Connection on p. 71, where G represents C2-3alkylenes group.

81. Connection on p. 71, where J represents C1-4alkylenes group.

82. Connection on p. 71, where J represents a methylene or ethylene group.

83. Connection on p. 71, where R1represents a phenyl group substituted by from 1 to 3 substituents selected from the group including alkoxygroup containing from 1 to 6 carbon atoms, and halogenoalkane group containing from 1 to 6 carbon atoms; R2represents a phenyl group substituted by 1 to 3 halogen atoms; A represents A carbonyl group, B represents a single bond is a new group and J represents C1-4alkylenes group.

84. Connection on p. 71, where R1represents a phenyl group substituted by from 1 to 3 substituents selected from the group including alkoxygroup containing from 1 to 6 carbon atoms, and halogenoalkane group containing from 1 to 6 carbon atoms; R2represents a phenyl group substituted by 1 to 3 halogen atoms; A represents A carbonyl group, B represents a single bond, D represents an oxygen atom, E represents a methylene group or ethylene, G represents C2-3alkylenes group, and J represents a methylene or ethylene group.

85. Connection on p. 1, selected from the group including:

1-{ 2-[5-(3,4-dichlorophenyl)-3-(3,4,5-trimethoxybenzoyl)-oxazolidin-5-yl] ethyl}-4-(2-pyridyl)piperidine-4-carboxamide,

1-{ 2-[5-(3,4-dichlorophenyl)-3-(3,4,5-trimethoxybenzoyl)-oxazolidin-5-yl] ethyl}-4-(3-pyridyl)piperidine-4-carboxamide and

1-{ 2-[5-(3,4-dichlorophenyl)-3-(3,4,5-trimethoxybenzoyl)-oxazolidin-5-yl] ethyl}-4-(4-pyridyl)piperidine-4-carboxamide,

and its salts and esters.

86. Connection on p. 2, selected from the group including:

1-{ 2-[5-(3,4-dichlorophenyl)-3-(3,4,5-trimethoxybenzoyl)-oxazolidin-5-yl] ethyl}-4-phenylpiperidine-4-carboxamide and

1BR>
and its salts and esters.

87. Connection on p. 3, selected from the group including:

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-morpholine-2-yl] ethyl}-4-phenylpiperidine-4-carboxamide;

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-morpholine-2-yl] ethyl}-4-phenylpiperidine-4-(N,N-dimethylcarbamate);

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-morpholine-2-yl] ethyl}-4-phenyl-4-(pyrrolidin-1-ylcarbonyl)-piperidine;

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-morpholine-2-yl] ethyl}-4-morpholinomethyl-4-phenylpiperidine;

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3-methoxybenzoyl)morpholine-2-yl] ethyl} -4-phenylpiperidine-4-carboxamide;

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3-methoxybenzoyl)morpholine-2-yl] ethyl} -4-phenylpiperidine-4-(N,N-dimethylcarbamate);

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-morpholine-2-yl] ethyl}Spiro[benzo[C]thiophene-1(3H), 4'-piperidine];

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-morpholine-2-yl] ethyl}Spiro[isoquinoline-1(2H),4'-piperidine]-3(4H)-he;

1-{2-[2,3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-morpholine-2-yl]ethyl} Spiro[benzofuran-1(3H), 4'-piperidine];

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-morpholine-2-yl] ethyl}Spiro[isobenzo[C]thiophene-1(3H),4'-piperidine)-2-oxide;

1-{ 2-[2-(3,4-dichlorophenyl)-4-(benzoyl)morpholine-2-yl] ethyl} Spiro[benzo[C]thiophene-1(3H),4'-piperidine];

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3-methoxybenzoyl)morpholine-2-yl] ethyl} Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-2-oxide and

1-{ 2-[2-(3,4-dichlorophenyl)-4-(3-methoxybenzoyl)morpholine-2-yl] ethyl} Spiro[isoquinoline-1(2H),4'-piperidine]-3(4H)-he;

and its salts and esters.

88. Connection on p. 71, selected from the group including:

1-{ 2-[(5R)-(3,4-dichlorophenyl)-3-(3,4,5-trimethoxybenzoyl)-oxazolidin-5-yl]ethyl}Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-(2S)-oxide;

1-(2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-morpholine-2-yl] ethyl)Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-(2S)-oxide;

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-hexahydro-1,4-oxazepine-2-yl]ethyl)Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-(2S)-oxide;

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3-isopropoxyphenyl)morpholine-2-yl] ethyl}Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-(2S)-oxide;

1-{ 2-[(2R)-(3,4-dichlorophenyl)-5,5-dimethyl-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl]ethyl}Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-(2S)-oxide,

and its salts and esters.

89. Composition exhibiting antagonistic activity against receptors neirokinina 1 and neirokinina 2 in the treatment or prevention of Central nervous system diseases, neurodegenerative diseases, respiratory Zab is th, skin diseases, alcoholism, somatic diseases, stress-induced attenuation of sympathetic reflexes, dysthymia, unwanted immune reactions, diseases associated with immunostimulating, diseases associated with food intake, vomiting, functional disorders of the bladder, eosinopenia, diseases caused by impaired blood flow, and pain, which contains an effective amount of the active compounds of formula I or Ia, or its pharmaceutically acceptable salt, or a complex ester according to any one of paragraphs.1, 4, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 51-64, 66, 68, 70 and 85, in a mixture with a pharmaceutically acceptable carrier or diluent.

90. Composition exhibiting antagonistic activity against receptors neirokinina 1 and neirokinina 2 in the treatment or prevention of Central nervous system diseases, respiratory diseases, inflammatory diseases, allergies, eye diseases, skin diseases, diseases associated with food intake, and pain, which contains an effective amount of the active compounds of formula I or Ia, or its pharmaceutically acceptable salt, or a complex ester according to any one of paragraphs.2, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48 and 86, in a mixture with farmac the op perate receptor neirokinina 1 and neirokinina 2 in the treatment or prevention of diseases of the Central nervous system, respiratory diseases, inflammatory diseases, allergies, eye diseases, skin diseases, diseases associated with food intake, and pain, which contains an effective amount of the active compounds of formula I or Ia, or its pharmaceutically acceptable salt, or a complex ester according to any one of paragraphs.3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 65, 67, 69 and 87, in a mixture with a pharmaceutically acceptable carrier or diluent.

92. Composition exhibiting antagonistic activity against receptors neirokinina 1 and neirokinina 2 in the treatment or prevention of Central nervous system diseases, respiratory diseases, inflammatory diseases, allergies, eye diseases, skin diseases, diseases associated with food intake, and pain, which contains an effective amount of the active compounds of formula I or Ia, or its pharmaceutically acceptable salt, or a complex ester according to any one of paragraphs.71-84 and 88, in a mixture with a pharmaceutically acceptable carrier or diluent.

93. The compound of formula I or Ia, or its pharmaceutically acceptable salt or ester according to any one of paragraphs.1, 4, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 51-64, 66, 68, 70 and 85 used when the floor is neirokinina 2 in the treatment or prevention of diseases or disorders, selected from diseases of the Central nervous system, neurodegenerative diseases, respiratory diseases, inflammatory diseases, allergies, hypersensitivity, eye diseases, skin diseases, alcoholism, somatic diseases, stress-induced attenuation of sympathetic reflexes, dysthymia, unwanted immune reactions, diseases associated with immunostimulating, diseases associated with food intake, vomiting, functional disorders of the bladder, eosinopenia, diseases caused by impaired blood flow, and pain.

94. The compound of formula I or Ia, or its pharmaceutically acceptable salt or ester according to any one of paragraphs.2, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48 and 86 used to obtain drugs exhibiting antagonistic activity against receptors neirokinina 1 and neirokinina 2 in the treatment or prevention of diseases or disorders selected from diseases of the Central nervous system, respiratory diseases, inflammatory diseases, allergies, eye diseases, skin diseases, diseases associated with food intake, and pain.

95. The compound of formula I or Ia, and is, 9 and 87 used to obtain drugs exhibiting antagonistic activity against receptors neirokinina 1 and neirokinina 2 in the treatment or prevention of diseases or disorders selected from diseases of the Central nervous system, respiratory diseases, inflammatory diseases, allergies, eye diseases, skin diseases, diseases associated with food intake, and pain.

96. The compound of formula I or Ia, or its pharmaceutically acceptable salt or ester according to any one of paragraphs.71-84 and 86 used to obtain drugs exhibiting antagonistic activity against receptors neirokinina 1 and neirokinina 2 in the treatment or prevention of diseases or disorders selected from diseases of the Central nervous system, respiratory diseases, inflammatory diseases, allergies, eye diseases, skin diseases, diseases associated with food intake, and pain.

Priority points:

01.12.95 - PP.2, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 86, 90 and 94;

25.12.95 - PP.3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 65, 67, 69, 87, 91 95

08.11.96 - PP.71 - 84, 88, 92 and 96;

29.11.96 - PP.1, 4, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 3

 

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