Derivatives of indole order as p38 kinase inhibitors

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (1): and their pharmaceutically acceptable salts wherein represents a double bond; Z1 represents nitrogen atom (N), -CR5 wherein R5 represents hydrogen atom (H), (C1-C6)-alkyl, hydroxy-group (OH),(C1-C6)-alkoxy-group or halogen atom; Z2 at position 2 represents CR1 and at position it represents CA wherein each R1 means independently (C1-C6)-alkyl; A represents -Wi-COXjY wherein Y means -COR2 wherein R2 means -OR, -NR2, -NRNR2 or -NROR wherein each R represents independently hydrogen atom (H), (C1-C6)-alkyl, or (C5-C6)-heteroaryl comprising one or two heteroatoms in ring chosen from atoms N, O and S wherein each of them is substituted with one or some groups chosen from -NR'2, -OR', -COOR', (C1-C6)-alkyl, -CN, =O, and -SR' wherein each R' represents hydrogen atom (H) or (C1-C6)-alkyl and wherein two R or R' jointed to the same nitrogen atom (N) can form 3-8-membered ring chosen from the group comprising piperazine ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrrolidine ring, piperidine ring, azacyclopropane ring, azacyclobutane ring and azacyclooctane ring and wherein indicated ring can be substituted additionally with (C1-C6)-alkyl or -COO-(C1-C6)-alkyl; X represents unsubstituted (C1-C6)-alkylene, or Y means imidazole substituted with methyl group; i = 0; j = 0 or 1; R7 means hydrogen atom (H) or (C1-C6)-alkyl, -SOR, -SO2R, -RCO, -COOR, (C1-C6)-alkyl-COR, -CONR2, -SO2NR2,-CN, -OR, (C1-C6)-alkyl-SR, (C1-C6)-alkyl-OCOR, (C1-C6)-alkyl-COOR, (C1-C6)-alkyl-CN, or (C1-C6)-alkyl-CONR2 wherein each R represent independently hydrogen atom (H), (C1-C6)-alkyl or aryl that is substituted optionally with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; or R7 represents methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R3 represent independently halogen atom, (C1-C6)-alkyl, -OR, -SR or -NR2 wherein R represents hydrogen atom (H) or (C1-C6)-alkyl; n = 0-3; L1 means -CO; L2 means (C1-C4)-alkylene optionally substituted with one or two groups of (C1-C4)-alkyl; each R4 is chosen independently from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2, -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl; or R4 represents =O; m = 0-4; Ar means aryl group substituted with from 0 to 5 substitutes chosen from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2 and -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl. Compounds of the formula (I) possess the inhibitory activity with respect to p38-α kinase that allows their using as components of the pharmaceutical composition.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

63 cl, 3 tbl, 9 sch, 16 ex

 

This application has a priority claim in accordance with section 35, United States Code, § 119(e) according to the application U.S. serial No. 60/154594 (register No. 21900-30290 .20), filed may 9, 2000, and application U.S. serial No. 60/154594, filed September 17, 1999. Priority is claimed in accordance with section 35, United States Code § 120 according to the application U.S. serial No. 09/316761 21 may 1999. The contents of these applications are fully incorporated in this description as a reference.

The technical field

This invention relates to the treatment of various diseases associated with increased kinase activity R36-α. More specifically, it relates to compounds which are derivatives of indole number of related groups pieperazinove or piperidino type, as suitable in the present treatment methods.

The level of technology

It was found that a significant number of chronic and acute conditions associated with the occurrence of inflammatory reactions. In this reaction involved a huge number of cytokines, including IL-1, IL-6, IL-8 and TNF. It was found that the activity of these cytokines in the regulation of inflammation, at least in part caused by the activation of the enzyme in the path of signal transmission cells, a member of the family of MAP kinases, known as R and alternative, known as CSBP and RK. This kinase is activated volym phosphorylation after stimulation physiochemical stress, treatment with LPS or proinflammatory cytokines, such as IL-1 and TNF. Therefore, inhibitors of activity R kinase are useful anti-inflammatory agents.

Eye diseases associated with fibroproliferative condition include reconstructive retina, accompanied by proliferative vitreoretinopathy, and cataract surgery with implantation of intraocular lenses and postglucose drainage.

In PCT applications WO 98/06715, WO 98/07425 and WO 96/40143, which are included here as reference, describes the relationship of inhibitors R kinase with various painful conditions. As noted in these applications, the inhibitors R kinase suitable for the treatment of various diseases associated with chronic inflammation. In these applications are listed rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, sepsis caused by gram-negative microorganisms, toxic shock syndrome, asthma, respiratory distress syndrome in adults, stroke, reperfusion damage, CNS damage, such as neural trauma and ischemia, psoriasis, restenosis, cerebral malaria, chronic pneumonia, silicosis, multiple tumors in the lung tissues, bone resorption, such as osteoporosis homologous disease (Rea is of graft-versus-host), Crohn's disease, ulcerative colitis, including inflammation of the digestive tract (IBD) and Pires.

In the above PCT application describes compounds that are inhibitors R kinase and may be suitable for treatment of the above disease conditions. Such compounds are either imidazoles, or indoles substituted in positions 3 or 4 piperazinone ring, attached via carboxamido communication. Additional compounds which are conjugates of piperazine with indoles described as insecticides in WO 97/26252, is also included here as a reference.

Some aroyl/phenyl-substituted piperazines and piperidine that inhibit Rkinase, as described in published PCT application WO 00/12074, opublikovannoi March 9, 2000. In addition, indolizidine piperidine and piperazines, which inhibit the specified enzyme, as described in published PCT application WO 99/61426, published on 2 December 1999. Karbolinovye derivatives of piperidine and piperazine used as inhibitors Rkinase described in PCT/US00/07934, filed March 24, 2000.

None of the above patents discloses indole derivatives described in this application, which specifically inhibit R.

Description of the invention

This invention relates to methods and compounds suitable PR is the treatment of conditions characterized by increased activity R. Such conditions include inflammation, proliferative disorders and some cardiovascular disorders and Alzheimer's disease, are described below.

Found that the compounds of this invention inhibit R kinase, in particular, itsα-the isoforms, and thus may be useful for treatment of diseases, mediasound activities specified kinase. The compounds of this invention are the compounds of formula

and their pharmaceutically acceptable salts or pharmaceutical compositions, in which the

represents a single or double bond;

one Z2is CA or CR8A and the other is CR1, CR12, NR6or N, where each R1, R6and R8independently are hydrogen or is not affecting Deputy;

But it is Wi-COXjY, where Y is COR2or isosteres and R2is hydrogen or is not affecting Deputy, each of W and X is dividing the link length 2-6and each of i and j is independently 0 or 1;

Z3is NR7or;

each R3independently is not affecting to sweep elem;

n is 0-3;

each of the L1and L2is the link;

each R4independently is not affecting Deputy;

m is 0-4;

Z1is CR5or N, where R5is hydrogen or is not affecting Deputy;

each of l and k is an integer from 0 to 2, where the sum of l and k is from 0 to 3;

Ar is an aryl group substituted by from 0 to 5 do not influence substituents, where the two are not affecting the substituent may form a condensed ring; and

the distance between the Ar atom attached to the L2and α ring is 4.5-24.

This invention relates to methods for treating inflammatory or proliferative conditions using these compounds. This invention also relates to the treatment of conditions associated with heart failure, and Alzheimer's disease using the compounds of this invention.

Ways of implementation of the present invention

The compounds of formula (I) suitable for the treatment of conditions characterized by increased activity R kinase, in particular, itsα-isoforms. State characterized by increased Ractivity" include those in which the specified enzyme is present in asenna number, or in which the enzyme is modified to increase its usual activity, or both. Thus, the "increased activity" refers to any condition in which the effectiveness of these proteins is undesirable high, regardless of the reason.

The compounds of this invention are suitable for conditions under which Rkinase demonstrates increased activity. Such conditions include those in which fibrosis and sclerosis of bodies caused by, or accompanied by inflammation, oxidative damage, hypoxia, altered temperature or extracellular osmolarity, conditions that cause cellular stress, apoptosis or necrosis. Such conditions include ischemic-reperfusion injury, congestive heart failure, progressive pulmonary and bronchial fibrosis, hepatitis, arthritis, inflammation of the digestive tract, glomerular sclerosis, interstitial renal fibrosis, chronic scarring of the eyes, the bladder and the genital tract dysplasia of bone marrow, chronic infection or autoimmune condition and traumatic or surgical wounds. These States, of course, can be treated with compounds that inhibit R. Methods of treatment with compounds of this invention are described below.

The compounds of this invention

Compounds suitable for this innovation is the invention, are derivatives of a number of indole compounds containing binding Deputy And in a position corresponding to position 2 or 3 of the indole. In General, the preferred kernel indole series, although the alternatives included in the scope of the present invention, also illustrated below.

In the following description, certain provisions of the molecule is described as a possible "without effect deputies". This term is used as the substituents in these positions in General do not affect the main activity of the molecule, taken as a whole. These provisions can be used many deputies, and the person skilled in the art will easily determine whether any particular arbitrary Deputy "impact" or "no effect".

In the context of this description, the term "not affecting the Deputy" refers to the Deputy, which leaves the ability of the compounds of formula (I) inhibit the activity Rqualitatively unchanged. Thus, the Deputy may alter the degree of inhibition R. However, since the compound of the formula (I) retains the ability to inhibit the activity Rthe Deputy can be defined as "no effect". The results of the many experimental the tov, conducted to determine the ability of some compounds to inhibit the activity Ravailable in the art. Undertaken with this aim, the study of whole blood are presented below: was cloned gene for Rrecombinant method was cooked protein and assessed its activity, including the assessment of the ability of randomly selected compounds to affect its activity. Were clearly identified the main characteristics of the molecule. Provisions that are "not affecting substituents may be substituted organic groups, as is customary in the art. For the present invention is not important to determine the outer limits of such substitution. A clear definition of the main characteristics of the compounds are given below. In addition, L1and L2described in this invention as links. The nature of such links is less important than the distance that they establish between parts of the molecule. Ordinary links include alkylene, ie, (CH2)n-R; albaniles, ie, alkylenes group, which contains a double bond, including the double bond at one end. Other suitable linkages include, for example, substituted alkylene or Alcanena, carbonyl group and the like.

In the context given to the CSOs description, the term "hydrocarbonyl residue" refers to the residue, which contains only atoms of carbon and hydrogen. The balance can be aliphatic or aromatic, having a straight chain, be cyclic, branched, saturated or unsaturated. Hydrocarbonyl balance, so certain, however, may contain heteroatoms in addition to carbon and hydrogen members of the remnant of the Deputy. Thus, if it is determined that it contains such heteroatoms, hydrocarbonyl residue may also contain a carbonyl group, amino group, hydroxyl group and the like, or may contain heteroatoms in the main chain" hidrocarburos balance.

In the context of this description, the term "inorganic residue" refers to the residue, which does not contain carbon. Examples include, but not limited to, halogen, hydroxy, NO2or NH2.

In the context of this description, the term "alkyl", "alkenyl" and "quinil" includes straight, branched and cyclic monovalent substituents. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylmethyl, 2-propenyl, 3-butenyl and the like. Typically, alkyl, alkeline and alkyline substituents contain 1-10C(alkyl) or 2-10C(alkenyl or quinil). Preferably they contain 1-6(alkyl) or 2-6S(alkenyl or quinil). Heteroalkyl, heteroalkyl and heteroalkyl defined in the same way, but may contain 1-2 heteroatoms O, S or N combinations thereof in the main chain of the residue.

In the context of this description, the term "acyl" encompasses the definitions of alkyl, alkenyl, quinil and their waterform that are attached to additional residue through a carbonyl group.

"Aromatic" group refers to monocyclic or bicyclic group, such as phenyl or naphthyl; "heteroaromatic" also refers to a monocyclic or condensed bicyclic ring system, containing one or more heteroatoms selected from O, S and N. the Introduction of a heteroatom allows the inclusion of 5-membered rings as well as 6-membered rings. Thus, conventional aromatic systems include pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, ethanolic, hinely, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl and the like. Any monocyclic or condensed bicyclic ring system, which are characterized by aromaticity in the distribution of electrons in the ring system, are included in this definition. Typically, the ring system contains 5-12 atoms in the ring.

Similarly, "arylalkyl and heteroalkyl" refer to aromatic and heteroaromatic systems that are attached to another residue through a carbon chain, including substituted or unsubstituted, saturated or unsaturated of operon the e-chain, usually containing 1-6P. Such carbon chain may also include a carbonyl group, which makes them capable to give such substituents as acyl group.

If the compound of formula 1 contains one or more chiral centers, the invention includes optically pure forms as well as mixtures of stereoisomers or enantiomers.

As for the connection parts between the Ar atom attached to the L2and the ring α, L1and L2are the connecting links, which are separated Deputy Ar from rings α at a distance of 4.5-24preferably 6-20more preferably, 7.5 to 10. The distance is measured from the center of the ring α to Ar atom to which is attached a link L2. Usually, but not limited to, L1and L2are WITH and their isostere, or optionally substituted isostere, or shape with a longer chain L2in particular, it may be alkylene or Alcanena, optionally substituted without effect deputies, or L1or L2may be, or may include a heteroatom such as N, S or O. Such substituents include, but are not limited to, a group selected from the group comprising alkyl, alkenyl, quinil, aryl, arylalkyl, acyl, aroyl, heteroaryl, GE is aralkyl, heteroalkyl, heteroalkyl, heteroallyl, NH-aroyl, halogen, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOR, SO3R, CONR2, SO2NR2, NRSO2NR2CN, CF3, R3Si and NO2where each R independently is H, alkyl, alkenyl or aryl or heterogamy, and where two of the substituents on L2can be combined with the formation of non-aromatic saturated or unsaturated ring which comprises 0 to 3 heteroatoms such as O, S and/or N, and which contains from 3 to 8 members, or specified two Deputy can be combined with the formation of carbonyl group or oxime, simple ester oxime, complex ether of the oxime or Catala specified carbonyl group.

Isostere CO and CH2include SO, SO2or SNAN. Preferred CO and CH2. Thus, L2substituted by 0-2 substituents. Where it is valid, two optional substituent on L2can be combined with the formation of non-aromatic saturated or unsaturated hidrocarburos ring which comprises 0 to 3 heteroatoms such as O, S and/or N, and which contains from 3 to 8 members. Two optional substituent can be combined with the formation of carbonyl groups, which can be sequentially converted into the oxime, a simple ester oxime, with whom you can ether oxime or ketal.

Ar is aryl, heteroaryl, including 6-5 condensed heteroaryl, cycloaliphatic or collegerelations, which may be optionally substituted. Preferably Ar is optionally substituted phenyl. Every Deputy in Ar independently is hydrocarbonyl the remainder (1-20C)containing 0-5 heteroatoms selected from O, S and N, or the inorganic residue. Preferred substituents are selected from the group consisting of alkyl, alkenyl, quinil, aryl, arylalkyl, acyl, Arola, heteroaryl, heteroalkyl, heteroalkyl, heteroalkyl, heteroallyl, NH-Arola, halogen, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOR, SO3R, CONR2, SO2NR2, NRSO2NR2CN, CF3, R3Si and NO2where each R independently is H, alkyl, alkenyl or aryl or heterogamy, and where the two specified substituent can be combined with the formation of condensed optionally substituted aromatic or nonaromatic, saturated or unsaturated ring, which contains from 3 to 8 members. More preferred substituents include halogen, alkyl (1-4C), and more preferably fluorine, chlorine and methyl. These substituents may occupy any available position of the aryl ring Ar, preferably, 1-2 state is, most preferably one position. These substituents can be optionally substituted by substituents, the same as listed above. Of course, some substituents, such as halogen, may not be further substituted, as is well known to specialists in this field.

Two of the substituents on Ar can be combined with the formation of condensed, optionally substituted, aromatic or non-aromatic, saturated or unsaturated ring which contains 3-8 members.

Between the L1and L2there is a group of piperidino range of the following formula:

Z1is CR5or N, where R5is N or no effect Deputy. Each of l and k is an integer from 0 to 2, where the sum of l and k is from 0 to 3. Not affecting the substituents R5include, but are not limited to, halogen, alkyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, acyl, carboxy or hydroxy. Preferably, R5is H, alkyl, OR NR2, SR, or halogen, where R is H or alkyl. In addition, R5can be combined with R4Deputy education optionally substituted non-aromatic, saturated or unsaturated hidrocarburos ring which contains 3-8 members and 0-3 heteroatoms such as O, N and/or S. Site is citicoline options include connection in which Z1is CH or N, and such that both l and k are equal to 1.

R4is not affecting Deputy, such as hydrocarbonyl the remainder (1-20C)containing 0-5 heteroatoms selected from O, S and N. Preferably, R4is alkyl, alkoxy, aryl, arylalkyl, aryloxy, heteroalkyl, heteroaryl, heteroallyl, RCO, =O, acyl, halogen, CN, OR, NRCOR, NR where R is H, alkyl (preferably 1-4C), aryl or heteroborane. Each of the suitable substituents itself is unsubstituted or substituted by 1-3 substituents. The substituents are preferably selected from the group which consists of alkyl, alkenyl, quinil, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkyl, hetaeras alkynyl, heteroalkyl, NH-aroyl, halogen, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOR, SO3R, CONR2, SO2NR2, NRSO2NR2CN, CF3, R3Si and NO2where each R independently is H, alkyl, alkenyl or aryl or heterogamy, and where two of the substituents on R4in adjacent positions can be combined with the formation of condensed, optionally substituted aromatic or non-aromatic saturated or unsaturated ring, which contains from 3 to 8 members, or R4is =O or his ox the IOM, simple ether oxime, complex ether of the oxime or Cetelem. R4can be contained in the ring m times; and m is an integer from 0 to 4. Preferred options R4include alkyl (1-4C), especially the two alkyl substituent and the carbonyl. Most preferably, R4contains two methyl groups in positions 2 and 5 or 3 and 6 piperidinyl or piperazinilnom rings, or =O preferably in position 5 of the ring. Substituted forms can be chiral and can be preferably single enantiomer.

R3also is not affecting Deputy. These substituents include gidrolabilna residues (1-6C)containing 0-2 heteroatoms selected from O, S and/or N, and inorganic residues; n is an integer from 0 to 3, preferably 0 or 1. Preferably, Deputy represented by R3independently is halogen, alkyl, heteroalkyl, OCOR, OR, NRCOR, SR or NR2where R is an alkyl, aryl or heteroborane. Most preferably, R3substituents selected from alkyl, alkoxy or halogen, and most preferably, from methoxy, methyl and chlorine. Most preferably n is 0 and the ring α not substituted, with the exception of L1or n is 1 and R3is halogen or methoxy.

In the ring, designated as β, Z3can be NR7ilio, i.e. compounds may refer to indole or benzofuran. If Z3is NR7preferred options R7include H or optionally substituted alkyl, alkenyl, quinil, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkyl, heteroalkyl, heteroalkyl, or is SOR, SO2R, RCO, COOR, alkyl-OOR, SO3R, CONR2, SO2NR2CN, CF3, NR2, OR, alkyl-SR, alkyl-SOR, alkyl-SO2R, alkyl-OCOR, alkyl-COOR, alkyl-CN, alkyl-CONR2or R3Si, where each R is independently H, alkyl, alkenyl or aryl or heteroborane. More preferably R7is hydrogen or alkyl (1-4C), preferably, stands, or acyl (1-4C), or COOR, where R is H, alkyl, alkenyl or aryl or heteroborane. R7also preferably is substituted by alkyl, where preferred substituents or form of communication or contain groups sulfinol or sulfonic acid. Other preferred substituents include sulphidization alkyl substituents. Other preferred substituents include CONR2where R is as defined above.

Preferably, if the dotted line represents a double bond; however, compounds that contain saturated β ring, also included in the scope of this image is the shadow.

Preferably, mandatory Deputy CA or CR8A is in position 3; regardless of the position that is specified by the Deputy, another position is substituted by CR1, CR12, NR6or N. Preferably CR1. Preferred options R1include alkyl, alkenyl, quinil, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkyl, heteroalkyl, heteroallyl, NH-aroyl, halogen, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOR, SO3R, CONR2, SO2NR2, NRSO2NR2CN, CF3, R3Si and NO2where each R independently is H, alkyl, alkenyl or aryl or heterogamy, and where two Deputy R1can be combined with the formation of condensed, optionally substituted aromatic or non-aromatic saturated or unsaturated ring, which contains from 3 to 8 members. Most preferably, R1is alkyl, such as methyl, most preferably, ring α contains a double bond and CR1is CH or C-alkyl. Other preferred forms of R1include H, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl, halogen, OR, NR2, SR, NRCOR, alkyl-OOR, RCO, COOR, and CN, where each R independently is H, alkyl or aryl, or their heteroge the Mami.

Although in the preferred embodiment, the position not occupied by CA, includes CR1this provision can also be N or NR6. Although NR6the least preferred (as in this case, the ring marked βwill be saturated), if NR6present, the preferred options R6are H or alkyl, alkenyl, quinil, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkyl, heteroalkyl, heteroallyl, or SOR, SO2R, RCO, COOR, alkyl-COR, SO3R, CONR2, SO2NR2CN, CF3or R3Si, where each R is independently H, alkyl, alkenyl or aryl or heteroborane.

Preferably, CR8A or SA occupies position 3 and preferably Z2this position is CA. However, if the ring β saturated and there is R8preferred options R8are H, halogen, alkyl, alkenyl and the like. Preferably R8is relatively small Deputy, corresponding, for example, H or lower alkyl 1-4C.

But it is Wi-COXjY, where Y is COR2or isosteres and R2is without effect by the Deputy. Each of W and X is the separation element and may be, for example, optionally substituted alkyl, alkenyl or quinil, each of i and j is equal to 0 or 1. Site is preferably, W and X is not substituted. Preferably, j is equal to 0, such that the two carbonyl groups were nearby. Preferably, also, i 0, so that the closest WITH were outside the ring. However, compounds in which the closest WITH is separated from the ring, can be easily obtained by selective regeneration of the original glocalization β rings. In the most preferred embodiments of the present invention, the system rings α/β an indole containing CA in position 3, where a is the COCR2.

No effect of the substituent R2if R2different from N is hydrocarbonyl the remainder (1-20C)containing from 0 to 5 heteroatoms selected from O, S and/or N, or inorganic residue. Preferred options, in which R2is H or a straight or branched alkyl, alkenyl, quinil, aryl, arylalkyl, heteroalkyl, heteroaryl or heteroallyl, each of which is optionally substituted with halogen, alkyl, heteroalkyl, SR, OR, NR2, OCOR, NRCOR, NRCONR2, NRSO2R, NRSO2NR2, OCONR2, CN, COOR, CONR2, COR, or R3Si, where each R is independently H, alkyl, alkenyl or aryl or containing a heteroatom forms, or where R2is OR, NR2, SR, NRCONR2, OCONR2or NRSO2NR2where each R independently is H, alkyl, al is anilam or aryl or containing a heteroatom forms, and where two R attached to the same atom may form a 3-8 membered ring, and where the specified ring may be further substituted by alkyl, alkenyl, quinil, aryl, arylalkyl, heteroalkyl, heteroaryl or heteroallyl, each of which is optionally substituted with halogen, SR, OR, NR2, OCOR, NRCOR, NRCONR2, NRSO2R, NRSO2NR2, OCONR2or R3Si, where each R is independently H, alkyl, alkenyl or aryl or containing a heteroatom forms, where two R attached to the same atom may form a 3-6-membered ring, substituted by the above substituents.

Other preferred options R2include N, heteroallyl, -NR2heteroaryl, -COOR, -NHRNR2heteroaryl-COOR, heteroaromatic, -OR, heteroaryl-NR2, -NROR, and alkyl. Most preferably, R2is isopropylpiperazine, methylpiperazine, dimethylamine, piperazinil, isobutylacetate, oxycarbonate, morpholinium, aminotrimethylene, isobutylbarbituric, oxypiperidine, ethylcarboxylate, methoxy, ethoxy, hydroxy, stands, amino, annoation, pyrrolidinium, aminopropanol, piperidinium, pyrrolidinyl-piperidinium or methylpiperidine.

Isostere COR2represented by Y, is determined to follow the way.

Isostere have a variable lipophilicity and can contribute to improved metabolic stability. Thus, Y, as shown, may be replaced by isostere presented in table 1.

Table 1

Isotherms acid
The name of the groupChemical structureReplacement group (ZG)
tetrazoln/a
1,2,3-triazoleN; SCH3; COCH3; Br, SOCH3; SO2CH3; NO2; CF3: CN; COOMe
1,2,4-triazoleN; SCH3; COCH3; Br; SOCH3; SO2CH3; NO2
the imidazoleN; SCH3; COCH3; Br; SOCH3; SO2CH3; NO2

Thus, isostere include tetrazole, 1,2,3-triazole, 1,2,4-triazole and imidazole.

The compounds of formula (I) can be in the form of their pharmaceutically acceptable acid additive salts, including salts of inorganic acids such as hydrochloric, sulfuric, Hydrobromic or f is sforna acid, or salts of organic acids such as acetic, tartaric, succinic, benzoic, salicylic, and the like. If in the compound of formula (I) is a carboxyl group, the compound can also be in the form of salts with pharmaceutically acceptable cation.

The synthesis of compounds in accordance with this invention

The following scheme of reactions illustrate the transformation of 4-benzylpiperidine-5-carboxamide in connection glyoxalase acid of this invention and their derivatives.

Of course, illustrative 4-benzylpiperidine in position 5 can be generalized as

and Deputy glyoxalase type at position 3 can be generalized to WiCOXjY.

Also in the above schemes can be used ways in which the group a number of indole is a

Methods of synthesis of compounds in accordance with this invention is primarily known in this field.

Such methods may be illustrated by the following General schemes.

Substituted esters of aminobenzoic acids, such as I, can be treated with reagents such as dimethylacetal of dimethylacetamide and N-chlorosuccinimide in methylene chloride at low temperature is ur, followed by treatment with a base, such as triethylamine at boiling point under reflux in methylene chloride, dichloroethane or chloroform with getting indoles II, scheme 1. Treatment with reagents such as Raney Nickel, in a suitable solvent, such as ethanol, methanol or isopropanol, gives the corresponding ester of carboxylic acid, which upon hydrolysis in basic conditions gives the desired derivative indolocarbazoles acid.

Alternatively, the substituted esters of aminobenzoic acid I can be turned into ketals IV, scheme 2, treatment with the appropriate aldehyde under conditions of reductive alkylation reagent such as triacetoxyborohydride sodium in acetic acid in the presence of sodium sulfate. Then amines can be treated with Lewis acids such as aluminum chloride, titanium chloride, BF3-apiret in dichloromethane or dichloroethane, at the boiling point under reflux to obtain the corresponding substituted methyl esters of indole with appropriate substituents.

Another method may include processing a substituted esters aminobenzoic acid I with iodine and periodates sodium in a suitable solvent, such as dimethylformamide, to obtain the corresponding stanilov V, with the EMA 3. They can be subjected to interaction with acetylene, such as trimethylsilylacetamide or athletically simple ether in the presence of a suitable catalyst, such as palladium and copper, and base, such as triethylamine, to obtain cellspacing products, such as VI. Subsequent cyclization in a solvent such as dimethylformamide, in the presence of a catalyst such as copper iodide, gives an appropriately substituted indoles VII.

The synthesis of the required piperidino can be carried out by treatment of a suitable piperidone, such as VIII, scheme 4, substituted esters benzylphosphonate in the presence of a base such as sodium hydride, to obtain the alkenes, which can be restored to the corresponding substituted 4-benzylpiperidine, such as IX. The hydrogenation is usually carried out in the presence of catalytic metals, solvents, such as methanol, ethanol and ethyl acetate.

An alternative method may include the use of isonipecotamide, such as X, for acylation appropriately substituted benzene (ArH) in the presence of a Lewis acid such as aluminum chloride, to obtain the ketone XI, scheme 5. Further modification of the carbonyl group in XI using methods and techniques well known in the Anna area, give the desired compound XII.

Substituted piperazines can be subjected to interaction with various appropriate ArL2X in the presence or absence of a base or other catalytic reagent with obtaining substituted piperazines XV, scheme 6. They can be further divided to chiral components using chiral separating agent such as tartaric acid, obtaining any enantiomer of the substituted piperazines XV.

Compound III can be treated with halides, anhydrides or other electrophilic compounds (I), scheme 7, containing a variety of substituents, in the presence of a base such as sodium hydride, in many different solvents, to obtain the compounds XVI. They can be converted into the corresponding acid XVII by treatment with suitable reagents, such as aqueous base. Acid can then be subjected to interaction with substituted amines IX, XII or XV, when using a condensing agent such as EDAC.HCl, in different solvents, including methylene chloride, dimethylformamide, to obtain the compounds XVIII.

Compound XVIII can be first treated with acid chlorides, such as oxalicacid, in methylene chloride in bezpodmiotowej with the subsequent processing of various nucleophiles WH obtaining compounds XIX, scheme 8.

Compound XXIV can be synthesized from appropriately substituted benzofuran XX through their interaction with amines IX, XII or XV in the presence of an appropriate condensing agent to obtain compounds XXI, scheme 9. Further acylation to XXII can be carried out using Alliluyeva agent such as acetic anhydride, in the presence of a catalyst, such as Fe(III). The oxidation of acetyl groups XXII to group glyoxalase acid XXIII can be carried out using an oxidizing agent such as selenium dioxide (reference: F Da Settimo et al., Eur. J. Med. Chem (1996), 31, 951-956; Mssoc et al., (1975) patent of great Britain 1399089; E. Campaigne et al., J. Med. Chem (1965), 136-137). Finally, the combination of the acid with an appropriate nucleophile in WH may be carried out using any of the many known condensing agents in different solvents with the formation of compounds XXIV.

Studies of inhibition Rα kinase

For each of the research methods described below, the production of TNF-α correlated with activity R-α kinase.

A. the Study of inhibition R-α kinase using whole human blood.

Venous blood of healthy male volunteers collected in heparinised syringe and used for the tion 2 hours after blood collection. Test compounds dissolved in 100% DMSO and 1 μl aliquot of the drug in concentrations from 0 to 1 mm is placed in the four repeats in cell 24-cell titrations of microplates (Nunclon Delta SI, Applied Scientific, So. San. Francisco, CA). Add whole blood in a volume of 1 ml/cell, and the mixture incubated for 15 minutes with constant shaking (Titer Plate Shaker, Lab-Line Instruments, Inc., Melrose Park, IL) in a humidified atmosphere of 5% CO2at a temperature of 37°C. Whole blood cultured either in undiluted form or final dilution 1:10 with RPMI 1640 (Gibco 31800 + NaHCO3, Life Technologies, Rockville, MD, and Scios, Inc., Sunnyvale, CA). At the end of the incubation period in each cell add 10 μl of LPS [E. coli 0111:B4, Sigma Chemical Co., St. Louis, MO) to a final concentration of 1 or 0.1 μg/ml of undiluted or 1:10 diluted whole blood, respectively. Incubation continued for another 2 hours. The reaction is stopped by the room titration microplate in an ice bath, and plasma or containing no cells nasadochnye fluid collected by centrifugation at 3000 rpm for 10 minutes at a temperature of 4°C. the plasma Samples stored at a temperature of -80°With prior studies of the levels of TNF-α using ELISA according to the instructions attached to the kit for research Quantikine Human TNF-α assay kit (R&D Systems, Minneapolis, MN).

The values of the IC50calculated using concentration the AI inhibitor, which give a 50% reduction compared to control.

Century, the Study of inhibition R kinase enriched in mononuclear cells

In the study using enriched mononuclear cells, the Protocol of which is presented below, as the original use of cryopreserved mononuclear cells from peripheral human blood (OKCC) (Clonetics Corp.), which are washed and re-suspended in a mixture of warm environment for cell growth. Re-suspended cells are then calculate and seeded at 1×106cells/cell 24-cell titration the microplate. Then the tablets are placed in the incubator for one hour to precipitate the cells in each cell. After sedimentation of the cells, the medium is sucked off and in each cell tiralongo microplate, add a new medium containing 100 ng/ml stimulatory cytokine factor lipopolysaccharide (LPS) and the test chemical compound. Thus, each cell contains OKCC, LPS and test chemical compound. The cells are then incubated for 2 hours and the number of cytokine alpha Tumor Necrosis Factor (TNF-α) is measured using a solid-phase enzyme-linked immunosorbent assay (ELISA). One of these ELISA to determine the levels of TNF-α commercially available from R&D Systems. The amount of TNF-αproduced OKCC in each cell is then compared to the control the cell to determine does a chemical compound as an inhibitor of cytokine production.

Induced LPS synthesis of the cytokine in OKCC

Cryopreserved OKCC (cat no CC-2702 Clonetics Corp.)

Wednesday LGM-3 (cat No. SS-3212 Clonetics Corp.)

The original LPS solution 10 g/ml (cat No. L 2630 serotype 0111:B4 (Sigma)

ELISA kit for human TNF (R&D Systems)

Tnkase I (10 mg/ml of the original solution)

Obtaining cells

LGM-3 medium heated to 37°

5 μl of the original solution Gnkazy I add 10 ml of medium.

Cells are rapidly thawed and dispersed in the above environment

Centrifuge HD × 10 min @ CT

The precipitate after centrifugation was diluted to 10 ml of sterile saline solution with phosphate buffer

Centrifuge HD × 10 min @ CT

The residue after centrifuge re-suspended in 10 ml of LGM-3, then diluted to 50 ml medium LGM-3.

Conduct the counting of cells

Bring to 1×106cells/cell.

Sow 1 ml/cell 24-cell tablet

Place the tablet in the incubator for deposition within 1 hour

Getting incubation medium

LGM-3 containing 100 ng/ml LPS (for example, 50 ml of medium plus 0.5 ml of the original solution LPS)

Divided without remainder into 2 ml aliquots and add 1000X diluted inhibitor

Incubation

After sedimentation of the cells, the medium is sucked off and cover with 1 ml of the appropriate incubation medium. Planches the t returned to the incubator for 2 hours or 24 hours. After incubation nasadochnye liquid is transferred into a labeled test tube, or just spend ELISA TNF (or other), or freeze for later studies.

The values of the IC50calculated using the concentration of inhibitor that gives a 50% reduction compared to control.

Introduction and application

The compounds of this invention are suitable, among other indications for the treatment of conditions associated with inflammation. Thus, the compounds of formula (I) or their pharmaceutically acceptable salts are used for the production of pharmaceuticals for the prophylaxis or therapeutic treatment of mammals, including humans, in the event of conditions characterized by excessive production of cytokines and/or inappropriate or unregulated activity of cytokines in these cells, as cardiomyocytes, cardioballistic and macrophages.

Compounds in accordance with this invention inhibit the production of cytokines, such as TNF, IL-1, IL-6 and IL-8, cytokines, which are important Pro-inflammatory components in many different painful conditions and syndromes. Thus, inhibition of these cytokines is important for control and mitigation of many diseases. The compounds of this invention, as shown herein, inhibit the collection CI is the basics of MAP, also called R MARK (or R), CSBP or SAPK-2. Activates a specific protein, has been shown to be accompanied by exacerbation of disease in response to stress caused, caused, for example, by the action of lipopolysaccharide or cytokines, such as TNF and IL-1. The inhibition activity R, therefore, determines the ability of drugs to have a beneficial effect in the treatment of diseases such as Alzheimer's disease, ischemic heart disease, congestive heart failure, cardiomyopathy, myocarditis, vasculitis, restenosis, which may occur after plastic surgery on the coronary vessels, atherosclerosis, IBD, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, multiple sclerosis, acute respiratory distress syndrome (ARDS), asthma, chronic obstruction lung (CLD), silicosis, excrescence of the lung tissue, sepsis, septic shock, endotoxic shock, sepsis caused by gram-negative microorganisms, toxic shock syndrome, cardiac and cerebral insufficiency (shock), which are characterized by ischemia and reperfusion injury, surgical intervention, such as transplantation and graft rejection, cardiopulmonary bypass, coronary artery bypass graft, corruption TSN is, including open and closed head injuries, inflammatory diseases of the eye such as conjunctivitis and uveitis, acute renal failure, glomerulonephritis, inflammatory diseases of the digestive tract, such as Crohn's disease or ulcerative colitis, homologous disease, bone resorption, such as osteoporosis, diabetes type II, Pires, psoriasis, cachexia, viral infections such as caused by HIV, cytomegalovirus (CMV) and herpes, and cerebral malaria.

During the last seven years it has been shown that R contains a group of MAP kinases, designated as R-α, R-β, R-γ and R-δ. Y Jiang, Y et al, J. Biol Chem (1996) 271:17920-17926 p38-β characterized as a protein that contains 372-amenability, closely related R-α. When comparing activity R-α activity R-β the authors found that although both are activated by proinflammatory cytokines and external stress, R-βmainly activated this MAP kinase like kinase 6 (MCC) and mainly activated by a transcription factor 2, thus, we can assume that different mechanisms of action may be associated with these forms.

In Kumar, S., et al., Biochem Blophys Res Comm (1997) 235:533-538 and Stein, et al., J. Biol Chem (1997) 272:19509-19517 described second isoform R-β, R-β2, containing 364 amino acids with 73% identity to R-α. From all these references it is obvious that R-β aktiviruetsya proinflammatory cytokines and external stress, although the second specified isoform R-β, R-β2, presumably mainly expressed in the Central nervous system, heart and skeletal muscle, in contrast to having the place almost everywhere in the tissue expression R-α. Moreover, as indicated by the observations, activated factor-2 transcription (ATF-2) is the best substrate for R-β2 than for R-αthus, I believe that the different mechanisms of action may be associated with these forms. Physiological role R-β1 questioned in two recent studies, as it was not found in human tissues and does not demonstrate significant activity kinase C substrates R-α.

Identification R-γ presented at Li, Z. et al., Biochem Blophys Res Comm (1996) 228:334-340 and R-δ Wang, X. et al., J Biol Chem (1997) 272:23668-23674 and Kumar, S. et al., Biochem Biophys Res Comm (1997) 235:533-538. Data suggest that the two isoforms R (γ and δ) represent a unique subpopulation of family MARK, based on their forms of expression of tissue, using soil response to direct and indirect stimulation and sensitivity to kinase inhibitors.

Various results related to reactions to medicines designed for family R in respect of R-α and any alleged R-β1 or R-β2, or both are presented in Jiang, Kumar and Stein, above, and Eyers, P. A. et a., Chem and Biol (1995) 5:321-328. In another work, Wang, Y. et al., J Biol Chem (1998) 273:2161-2168 assumes the significance of such a differential action. As noted in Wang, a variety of incentives, such as myocardial infarction, hypertension, valvular heart disease, viral myocarditis, and advanced cardiomyopathy lead to increased work of the heart and increased mechanical pressure on the cardiomyocytes. Indicates that this leads to adaptive hypertrophic response, which, if not controlled, will have undoubtedly negative consequences. Wang refers to earlier studies, which show that in ischemic reperfusion injury in the heart, the activity R MARK increases due to hypertrophy and programmed cell death. In the link, Wang shows that the activation steps of the p-38β leads to hypertrophy, whereas activation steps R-α leads to apoptosis of myocytes. Thus, selective inhibition activity R-α compared with the activity R-β will be predominant in the treatment of conditions caused by cardiac insufficiency. Such conditions include congestive heart failure, cardiomyopathy, myocarditis, vasculitis, restenosis of blood vessels, heart valve disease, conditions associated with extracorporeal circulation, coronary bypass surgery, transplant and and vascular grafts. Further, given that α-isoform is toxic in other types of muscle cells, α-selective inhibitors can be used in conditions associated with cachexia, characterized TNF or other conditions, such as cancer, infection or autoimmune disease.

Thus, the invention encompasses the use of compounds that selectively inhibit the activity R-α isoforms, for the treatment of conditions associated with activation of R-αin particular those associated with cardiac hypertrophy, ischemia, and other external stresses, such as oxidative damage, hyperosmolarity or other agents or factors that activate R-α kinase or heart failure, for example, congestive heart failure, cardiomyopathy, and myocarditis.

The route of administration and formulation of compounds suitable in the present invention, and related compounds depend on the nature of the condition, severity of condition, of a specific subject, which is treated and assessment practitioner; preparative form depends on the method of introduction. Since connections in accordance with this invention are small molecules, they are conveniently introduced orally by mixing them with suitable pharmaceutical excipients to obtain tablets, capsules, syrups and the like. Suitable compositions for oral administration can also include auxiliary components, such as buffers, flavoring and the like. Usually the amount of active ingredient in the composition is from 5% to 95% by weight of the total composition, but depending on the media can be used over wide intervals. Suitable carrier materials include sucrose, pectin, magnesium stearate, lactose, peanut butter, olive oil, water and the like.

Compounds useful in this invention can also be entered by using suppositories or other crosslisted media. Typically, such compositions include excipients that facilitate the passage of compounds through the mucous membrane, such as pharmaceutically acceptable detergents.

Compounds can also be administered locally, for local conditions, such as psoriasis, or preparative form, intended to pass through the skin. Such preparative forms include lotions, creams, ointments and the like, which may be obtained by known methods.

Compounds can also be administered by injection, including intravenous, intramuscular, subcutaneous or intraperitoneal injection. Ordinary composition for this method of administration include liquid formulation in isotonic diluents, such as a solution of Khanka or R is the target ringer.

Alternative preparative forms include intranasal sprays, liposomal formulation, formulation with delayed release and the like, such that known in this field.

Can be used with any suitable preparative form. Summary known in the field of preparative forms can be found in Remington''s Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, PA. The link to this guide is usual in this field.

The dosage of the compounds of this invention depends on many factors, which vary from patient to patient. However, I believe that in General, daily perorally dose should be 0.001 to 100 mg/kg body weight, preferably from 0.01 to 50 mg/kg and more preferably from about 0.01 mg/kg to 10 mg/kg dosage regimen may vary depending on the condition, treating, and evaluating practitioner.

It should be noted that the compounds of formula (I) can be entered as a separate active ingredients, and mixtures of several such compounds of formula I. in Addition, inhibitors R kinase can be used as individual therapeutic agents or in combination with other therapeutic agents. Medicines that can be usefully combined with such compounds include natural and synthetic the systematic corticosteroids, especially prednisone and its derivatives, monoclonal antibodies directed to cells of the immune system, antibodies or soluble receptors or receptor fused protein, aimed at immune or non-immune cytokines and inhibitors of cell division, protein synthesis or transcription or translation of mRNA with small molecules or inhibitors of differentiation or activation of immune cells.

As mentioned above, although the compounds of this invention can be used for a person, they can also be used in veterinary medicine for the treatment of animals.

The following examples are intended to illustrate, but not limit this invention, and illustrate the use of the above reaction schema.

Example 1

6-Methoxy-(4-benzylpiperidine)indole-5-carboxamide-3-glossalia acid

0,348 mg (1 mmol) 6-methoxy-(4-benzylpiperidine)indole-5-carboxamide are dissolved in 15 ml of dry dichloromethane and cooled to a temperature of 0°in an ice bath. With a syringe added dropwise 0.6 ml 2-molar solution of oxalicacid in dichloromethane (Aldrich) in an inert atmosphere, and the mixture is stirred at a temperature of 0°within hours. The ice bath removed and the mixture is stirred for another hour at room temperature. The solvent is evaporated, and the STATCOM is dried in vacuum for 30 minutes. The obtained solid is dissolved in a mixture of THF/water and alkalinized with 20% aq. NaOH. The solvents are removed, and the residue is dissolved in water and acidified with conc. HCl. Precipitated solid is collected by filtration, dried and recrystallized from ethanol/water to obtain 350 mg specified in the connection header.

ASS 421, M+

Example 2

4-methylpiperazine 6-methoxy-(4-benzylpiperidine)-5-carboxamido-3-glyoxalase acid

This compound is obtained using the techniques described above for the corresponding acid, but substituting aqueous NaOH 4-methylpiperazine and carrying out the reaction in dry dichloromethane instead of THF/water.

ASS 503, M+

Example 3

1-(2-aminomethylpyrrolidine)amide 6-methoxy-(4-benzylpiperidine)-5-carboxamido-3-glyoxalase acid

This compound is obtained using the techniques described above, but replacing 4-methylpiperazin 1-(2-amino-ethyl)-pyrrolidine.

MS M+, 517

Example 4

amide 4-benzylpiperidine-5-carboxamido-3-glyoxalase acid

0,318 mg, 1 mmol, 4-benzylpiperidine-5-carboxamide are dissolved in dry dichloromethane and subjected to interaction with 0.6 ml 2-molar solution of oxalicacid at a temperature of 0°in ECENA 1 hour in nitrogen atmosphere. The cooling bath removed and the mixture is stirred for another hour at room temperature. The solvent is evaporated, and the residue is dried in vacuum for 30 minutes. The product re-dissolved in THF and added an excess of conc. ammonium hydroxide. After stirring for 1 hour the solvent is removed and the residue is recrystallized from ethyl acetate-hexane.

Yield: 220 mg, MS. M+, 389; 345, M+-CONH2

Example 5

4-methylpiperazine 6-chloro-(4'-fluoro-4-benzylpiperidine)-5-carboxamido-3-glyoxalase acid

Get by the above method.

MS M+, 524

Example 6

Obtain methyl ester of 6-methoxy-(4-benzylpiperidine)indole-5-carboxamide-3-glyoxalase acid

This connection receive according to the method described for the original glyoxalase acid but replacing sodium hydroxide with methanol, THF/water.

ESMS M+, 435

Example 7

Obtain methyl ester of 1-methyl-6-methoxy-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-glyoxalase acid

0,435 g of methyl ester of 6-methoxy-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-glyoxalase acid dissolved in 10 ml dry DMF and cooled to a temperature of 0°in an ice bath. Add the 80 mg NaH (60% dispersion) and the mixture is stirred for 15 minutes at a temperature of 0° With and for 30 minutes at room temperature in an inert atmosphere. The reaction mixture is cooled to a temperature of 0°and add 200 ál of iodomethane. After 30 minutes at a temperature of 0°the mixture is heated to room temperature and stirring is continued for another 4 hours. The reaction mixture was poured into water and extracted with dichloromethane (3×50 ml). The extract is dried, evaporated and purified by chromatography on a column of silica gel and ethyl acetate-hexane (50-90% ethyl acetate gradient).

Yield: 70%.

MS M+, 466

Example 8

Obtain 1-methyl-6-methoxy-[4 ftor-(4-benzylpiperidine)]indole-5-carboxamide-3-glyoxalase acid

0.24 g (0.51 mmol) of the methyl ester of 1-methyl-6-methoxy-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-glyoxalase acid dissolved in THF (10 ml), add 1 ml of 20% aq. sodium hydroxide and stirred for 4 h the Mixture was diluted with water (5 ml) and stirring is continued for 1 hour. THF is removed under reduced pressure and the remaining solution was diluted with water and acidified with conc. HCl, and the product collected by filtration. It is dried in vacuum and recrystallized from ethyl acetate.

Yield: 180 mg

ESMS M+, 453

Example 9

3-(Methoxybenzoyl)-(4-benzylpiperidine)indole-5-carboxamide

The acylation in p the Annex 3 of the indole ring is carried out according to the method Schuepp et al. (Synth. Commun, 27 (12), 2125 (1997). To a solution of 0,318 g (1.0 mmol) 5-(4-benzylpiperidine)-indocarbocyanine in dichloromethane added 2.2 ml (2.2 mmol) of 1M solution of ZnCl2in ether, followed by adding dropwise EtMgBr (1.0 mmol). The mixture is stirred for 1 hour and add p-antillarum (180 mg, 1.1 mmol). The suspension is stirred for 1 hour and add AlCl3(0.05 mmol). The resulting mixture is stirred for 2 hours and quenched with a feast upon. a solution of NB4Cl. The organic layer was washed with aq. NaHCO3and saturated salt solution, dried over MgSO4and filtered. The solvent is evaporated and the product purified by chromatography on a column of silica gel.

MS M+, 452

Example 10

3-Benzoyl-5-(4-benzylpiperidine)indolocarbazole

Receive, using the procedure described above but replacing p-Antillid with benzoyl chloride.

MS M+, 422

Example 11

3-Acetyl-5-(4-benzylpiperidine)indole-5-carboxamide

Receive, using the procedure described above but replacing p-Antillid acetylchloride.

MS M+, 360

Example 12

Obtaining 3-(2-hydroxyacyl)-5-(4-benzylpiperidine)-indocarbocyanine

3-(2-Chloroacetyl)-5-(4-benzylpiperidine)indolocarbazole obtained using the techniques described in the above Oh, but replacing p-Antillid chloroacetylation.

Hydrolysis chloroceryle group to hydroxyazetidine performed using published methods (J. Org. Chem., 1988, 53, 5446). To a solution of 50 mg (0.13 mmol) of 3-(2-chloroacetyl)-5-(4-benzylpiperidine)indocarbocyanine in dioxane (3 ml) add 5 ml of formamide-water (10:1). The reaction mixture is heated to a temperature of 110°C for 5 hours and cooled to room temperature. The reaction mixture was quenched with a feast upon. a solution of NH4Cl, extracted with dichloromethane, dried (MgSO4) and concentrate. The residue is purified preparative TLC carried out with dichloromethane-methanol (20:1) to obtain 20 mg (42%) specified in the connection header.

MS M+, 376

Example 13

5-(4-Benzylpiperidine)carboxamido-3-(3'-oxo)-ethylpropane

The acylation in position 3 of the indole ring is done according to published methods [Synth. Commun, 1977, 27 (12), 2125]. To a solution of 3, 6 ml ZnCl2(3.6 mmol, 1M solution in diethyl ether) in THF are added dropwise n-BuLi (2.2 ml, 3.6 mmol) at a temperature of 0°C. During the addition of formed white suspension. The reaction mixture is heated to room temperature, stirred for 1 hour and add a solution of 5-(4-benzylpiperidine)indocarbocyanine in dichloromethane (10 ml). The resulting mixture was stirred for 1 hour dobavlaut ethyl 3-chloro-3-oxopropionate (585 mg, 3.9 mmol). After 1 hour the reaction mixture was quenched with saturated NH4Cl, extracted with dichloromethane, dried (MgSO4) and concentrate. The residue is purified by chromatography on a column of silica gel to obtain 200 mg of the desired product.

MC> M+, 431

Connection 1-55 table 2, we obtain by the same method.

Example 14

Synthesis of (2S,5R) - N-4-Terbisil-TRANS-2,5-dimethylpiperazine

(+/-)N-Benzyl-TRANS-2,5-dimethylpiperazine synthesized as follows

50 g of TRANS-2,5-Dimethylpiperazine dissolved in 300 ml of ethanol and treated 26,36 ml (1/2 equivalent) benzylbromide. The mixture is stirred at room temperature for 12 hours and concentrated. The residue is placed in ethyl acetate and washed with 10% aqueous sodium bicarbonate and saturated sodium chloride; dried over anhydrous magnesium sulfate and concentrated to obtain crude 1-benzyl-TRANS-2,5-dimethylpiperazine in the form of oil.

The material obtained is subjected to chromatography using DHM/Meon 95/5 to remove dialkylamino product, and then DHM/Meon/tea 90/10/0,1 for elution benzyl-TRANS-2,5-dimethylpiperazine. Get a 19.6 g of the product as oil.

To a solution of (+/-)N-benzyl-TRANS-2,5-dimethylpiperazine (59 g, 0.29 mol) in methanol (150 ml) was added dropwise a solution of (+) tartaric acid (87 g of 0.58 mol is) in methanol (250 ml) over 5 minutes. The crystallization is carried out while maintaining the resulting mixture at a temperature at level 0°With in 48-72 hours. Mashing solution through 12-16 hours promotes the crystallization process. The mixture is filtered and washed with cold methanol and dried to obtain salt devinney acid (75,9 g) as white crystals. A single recrystallization from methanol, cooled to room temperature gives a salt in the form of white crystals. (58 g) [α]D=+47 (=to 1.00, methanol).

31 g, 15,27 mmol, dimethylphenylpiperazinium handle 43, 19,85 mmol, di-tert-BUTYLCARBAMATE in 250 ml of THF for 4 hours. Reaction control TLC and it almost ends upon completion of the addition of (BOC)2O. the Solvent is removed and the residue is placed in ethyl acetate and washed with 10% aqueous sodium carbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain 39,3 g connection with the BOC-protecting group. The compound obtained is used in the next stage without further purification.

to 39.3 mg, 131 mmol, benzylpiperazine with the BOC-protective group is treated 3,93 g of catalyst Perlman in 150 ml of methanol with 3 ml of acetic acid for 4 hours under hydrogen pressure 2,812 kg/cm2(40 f/d2in mixer Parra. The reaction mixture was filtered through celite and concentrate the t with obtaining balance, which is dried in a high vacuum and then dissolved in 250 ml of dry ethanol and treated with 1.2 equivalents, 158 mmol, 4-ftorangidridy and 2 equivalents, 262 mmol of triethylamine in 5 hours. The reaction mixture control TLC, which shows completion of the reaction by this time. The solvent is removed and the residue is placed in ethyl acetate and washed with 10% aqueous sodium carbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain 47 g of the crude product. The crude product is subjected to chromatography on a column of silica gel using hexane/ethyl acetate 95/5 to elution of the product. After chromatography obtain 29 g of 4-terbisil-TRANS-2,5-dimethyl-piperazine. 20 g of 1-(4-Fluoro)benzyl-TRANS-2,5-dimethyl-piperazine, 62 mmol, treated with a mixture of 200 ml of 4N HCl/Dioxane/2M HCl/ether (1:3) for 1 hour. Mass spectrometry with electron impact confirms the formation of the product and the disappearance of starting materials. The reaction mixture was concentrated to obtain a solid substance. This material is again washed with hexane and simple ether to remove residual dioxane and then long dried in vacuum before use. Get to 17.6 g of the final product as a white fluffy solid.

Example 15

Synthesis of chiral compounds

6-Clorinda-5-carboxylic acid (1.56 g, 7,44 mmol) dissolved in dry methylene chloride, 60 ml, the resulting solution was added EDAC.HCl (1,57 g, 8,18 mmol) and DMAP (10% mol). After stirring under nitrogen atmosphere for 10 min add Amin (2,19 g, 7.5 mmol) followed by the addition of triethylamine (3 ml, 21,52 mmol). After maturation over night at room temperature the reaction mixture was concentrated and the residue is placed in ethyl acetate and washed with 10% aq. sodium carbonate, saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives the crude product which is subjected to chromatographie on a column of silica gel using a gradient of EtOAc/hexane 2/8-6/4. TLC Rf0,435 (EtOAc:hexane, 1:1), EUMS M+ 413.

The product from the previous stage of 1.02 g dissolved in 30 ml of dry DHM. The reaction mixture is blown with nitrogen and placed in an ice bath. To the resulting mixture add 4 ml of 2M oxalicacid in DHM. The reaction mixture was stirred at room temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was concentrated on a rotary evaporator. After drying in vacuum for 15 min, the residue (yellow solid) was dissolved in DHM, 30 ml, to which is added 4 ml of a 2M solution of dimethylamine in THF. After 30 minutes the reaction to shift the ü concentrated and the residue is placed in ethyl acetate and washed with 10% aq. sodium carbonate, saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives the crude product, which was subjected to chromatography on a column of silica gel using a gradient of EtOAc To 100% EtOAc/MeOH 9:1. TLC Rf0/5 (EtOAc:MeOH, 9:1), EUMS M+ 513.

White solid from the previous stage is dissolved in 10 ml of dry DHM. To the resulting solution was added 2M HCl in ether and the precipitate discarded. The mixture is then concentrated on a rotary evaporator to dryness and then dried overnight under high vacuum to obtain the final product (1.08 g).

Additional examples

Synthesis of compound 2: Methyl 4-amino-2-chlorobenzoate (1) (18,5 g) dissolved in dichloromethane (350 ml) and add dimethylacetal of methylthiazolidine (13,6 g). The mixture is cooled DC temperature -45°With (bath of dry ice/acetonitrile). Added dropwise N-chlorosuccinimide (16.0 g) in 350 ml of dichloromethane for 1 hour 30 minutes, maintaining the bath temperature at the level of -45°C. the Reaction mixture was stirred for further 1 hour, then dropwise added triethylamine (16 ml, 100 mmol) in 30 ml of dichloromethane for 5 minutes, the reaction mixture is heated to room temperature, then refluxed for 16 hours. The solvent is removed, and the residue is placed in 500 ml of carbon tetrachloride,the triethylamine hydrochloride acid is removed by filtration, the filtrate is heated at boiling temperature under reflux for 2 hours. The solvent is removed on a rotary evaporator.

The residue is dissolved in 250 ml of tetrahydrofurane and add 250 ml of 10% hydrochloric acid. The mixture is stirred over night at room temperature until complete disappearance of starting material. The solvent is removed in vacuum, the acidic aqueous solution is extracted with ethyl acetate (3×125 ml). The combined ethyl acetate extracts are washed with 10% hydrochloric acid, water and dried over anhydrous sodium sulfate. The solvent is removed in vacuum. A mixture of the crude product was then purified on a column of silica gel, elwira with ethyl acetate:hexane (15:85) to give 6.4 g of the desired product 2.

Synthesis of compound 3: Methyl 6-chloro-3-thiomethyl-5-indolocarbazoles (5,2 g) dissolved in 150 ml of ethanol:tetrahydrofuran (9:3) and treated with Raney Nickel. Reaction controls mass spectrasystem analysis with 30-minute intervals, followed by the addition of Raney Nickel until the completion of the reaction. After completion of the reaction, the reaction mixture was carefully filtered through celite, the celite washed with methanol several times and the filtrate is evaporated. The residue is placed in ethyl acetate, washed with water, dried over anhydrous sodium sulfate. The solvent is removed to obtain compound 3 (3.2 g).

Synthesis Conn is in 4: Methyl ether, 1.5 g, dissolved in 30 ml of methanol/water 50:50. The reaction mixture is heated to a temperature of 50°C for 2 hours with 4 molar equivalents of sodium hydroxide. The reaction mixture was cooled in an ice bath, acidified to pH 3 with 5M hydrochloric acid. The ethanol is removed on a rotary evaporator, and the residue is extracted with ethyl acetate. The extract was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Evaporation of the solvent gives the desired acid 4 (1/48 g).

Synthesis of compound 5:

STAGE A: Phosphonate And (of 38.4 g) and piperidine (35.4 g) was dissolved in anhydrous dimethylformamide (400 ml). To the resulting solution was added in several portions sodium hydride (60% suspension in oil), keeping the temperature of the reaction mixture at 0°C. After complete addition of sodium hydride, the reaction mixture is stirred for 30 minutes and then the ice bath is removed, the reaction mixture is stirred for 6 hours and slowly heated to ambient temperature. The reaction mixture was again cooled in an ice bath and quenched with methanol. To the reaction mixture, water is added and the product extracted with ethylacetate. The ethyl acetate layer was washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. The solvent is removed to obtain the crude alkene which purify the chromatograph is her column, elwira with ethyl acetate/hexane (1:9) to obtain 21/8 g of the desired product C.

STAGE: 10,1 g connection is dissolved in 50 ml of methanol. After blowing solution nitrogen add the catalyst is 5% palladium on carbon (1 g) followed by addition of 1 ml of acetic acid. The reaction mixture hydronaut in a Parr apparatus for 4 hours at 2,812-3,515 kg/cm2(40-50 f/d2). The reaction mixture was filtered through celite and concentrated. The residue is treated with 2 M hydrochloric acid in ether to obtain a salt with hydrochloric acid. The obtained white solid long dried in vacuum, obtaining of 7.8 g of compound 5 in the form of hydrochloride.

Synthesis of compound 6: a Mixture of 6-Clorinda-5-carboloy acid (1,95 g), hydrochloride 4-verbesserten (2.76 g) was placed in 50 ml of dry dichloromethane and treated with triethylamine (1.7 ml). The mixture is stirred to obtain a clear solution. Add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g) and dimethylaminopyridine (0.25 g) and the mixture is stirred for 20 hours at ambient temperature. The mixture was poured into water and the organic layer separated. The aqueous solution is then extracted twice with dichloromethane. The combined extract was washed with 10% hydrochloric acid. The organic layer is dried over magnesium sulfate and Privat. The product was then purified by chromatography on a column of silica gel, elwira with ethyl acetate:hexane (3:7) to give compound 6 (2,78 g).

Synthesis of compound 7: 8,61 g of 6-chloro-(4-F-benzylpiperidine)indole-5-carboxamide (6) is dissolved in about 100 ml of dry DMF and the solution cooled in an ice bath. To the cold solution was added 30 ml of a 1M solution of bis(trimethylsilyl)amide sodium in tetrahydrofuran in an inert atmosphere. The reaction mixture is stirred at a temperature of 0°C for 15 minutes and at ambient temperature for another 30 minutes. The reaction mixture was again cooled in an ice bath and add 2.5 ml of iodomethane. After stirring for 30 minutes at a temperature of 0°the mixture is heated to ambient temperature and stirring is continued for 18 hours at ambient temperature. The mixture is diluted with water or saturated salt solution) and the product extracted with ethyl acetate (4×75 ml). The combined extract washed with water and dried over bezw. MgSO4. The solvent is removed and the product purified by chromatography on a column of silica gel, elwira with ethyl acetate:hexane (1:4) to give 8.0 g of the desired product 7.

Synthesis of compound 8: 8 g of compound 7 was dissolved in about 100 ml of anhydrous dichloromethane and cooled in an ice bath. To the resulting solution slowly via syringe add 2M solution is calilfornia (20,8 ml) in dichloromethane, and the mixture is stirred at a temperature of 0°C for 1 hour. The ice bath is removed and stirring is continued for a further 2 hours at ambient temperature. The solvent is removed under reduced pressure, and the residue pumped for 15 minutes to remove excessively present oxalicacid. The product immediately re-dissolved in betw. dichloromethane (150 ml), cooled in an ice bath, rapidly via syringe add 30 ml of a 2M solution of dimethylamine in tetrahydrofuran. After 15 minutes stirring, the stirring is continued for a further 15 minutes at ambient temperature. The solution is washed with water to remove salts and dried. After evaporation the residue is purified on a column of silica gel, elwira chloroform:methanol (99:1) to give 9.3 g of compound 8.

Synthesis of compound 10:

STAGE A: TO a solution of dimethylpiperazine 9 (25 g) in 300 ml of absolute ethanol, add 400 ml of 2N hydrogen chloride in diethyl ether. The solution is heated to a temperature of 70°C in oil bath for 20 minutes. Then the solution is cooled to room temperature and stand overnight at a temperature of 6°C. Receive solid, which is collected by filtration. The output of 39.8 g (dihydrochloride, TRANS-2,5-dimethylpiperazine) after drying overnight under high vacuum.

STAGE: This is Doliny a solution of 42.9 g of the dihydrochloride of dimethylpiperazine from the STAGE AND and 26.1 g of TRANS-2,5-dimethylpiperazine vigorously stirred on an oil bath at a temperature of 80° C to dissolve all of the original connections. The oil bath temperature is reduced to 65°and add 33.1 g of 4-formanilide. After stirring at this temperature for 30 minutes the solution was placed overnight in a refrigerator with a temperature of 6°C. the Solid is removed from the solution by filtration and to the filtrate is added 2N hydrogen chloride in diethyl ether. The filtrate is kept at a temperature of 6°C overnight and the solid collected. The solid is suspended in 5% aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The organic layer is dried over sodium sulfate and dried to obtain yellow oil.

STAGE C: a Solution of 50.7 g (L)-tartaric acid in 130 ml of boiling methanol is added to 70 ml of hot methanol solution of 37.5 g of the product from step C. the Solution stand at a temperature of 6°C for 96 hours, then white crystals are collected by filtration. The compound obtained is recrystallized from boiling methanol. The product is collected by filtration after maturation at a temperature of 6°With during the night. Yield 30.5 g of salt devinney acid ([α]=+43,2°, s=1).

Synthesis of compound (11): ester indole 3 (0,526 g) dissolved in 10 ml of acetone (dry) and put in an ice bath. To the resulting solution was added powdered potassium hydroxide(0.7 g, 12.5 mmol), after stirring for 5 minutes at a temperature of 0°to the reaction mixture add methyliodide (400 μl, 6,272 mmol). The reaction mixture is stirred at a temperature of 0°C for 10 minutes and then at room temperature for 30 minutes. After removal of solvent the residue is placed in ethyl acetate and washed with saturated sodium chloride. After drying over anhydrous sodium sulfate, filtration and evaporation on a rotary evaporator receive solid, 0,7, Chromatography on a column of silica gel with ethyl acetate:hexane (2:8) gives the methyl ester of compound 11 as a white solid. 0.52 g of the Obtained product is dissolved in 50 ml of methanol and treated with 5 ml of 10N sodium hydroxide, the reaction mixture is heated to a temperature of 50°C for 2 hours. The reaction mixture is cooled to room temperature and concentrated to a solid on a rotary evaporator. The residue is placed in 50 ml of water, washed with simple ether and placed in an ice bath. The basic solution is acidified with 10% hydrochloric acid to pH 2. The precipitate is extracted with ethyl acetate and the ethyl acetate layer was washed with a saturated solution of sodium chloride. Drying over anhydrous sodium sulfate, filtration and concentration on a rotary evaporator to give compound 11 (0,48 g) as a white solid.

Synthesis connected to the I 12: 1.56 g of the acid (11) was dissolved in dry methylene chloride, 10 ml, and the resulting solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1,57 g) and dimethylaminopyridine (catalytic). After stirring under nitrogen atmosphere for 10 min add 2,19 g amine (10) followed by the addition of triethylamine (3 ml). After stirring over night at room temperature the reaction mixture was concentrated and the residue is placed in ethyl acetate and washed with 10% aq. sodium carbonate, aq. saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives the crude product, which was subjected to chromatography on a column of silica gel using ethyl acetate:hexane (4:6) as eluent with the receipt of 1.02 g of the desired product.

Synthesis of compound 13: 1,02 g of compound 12 from the previous stage is dissolved in 30 ml of dry dichloromethane. The reaction mixture is blown with nitrogen and placed in an ice bath. To the resulting mixture add 4 ml of 2M oxalicacid in dichloromethane. The reaction mixture is stirred at a temperature of 0°C for 1 hour and then at room temperature for 2 hours. The reaction mixture was concentrated on a rotary evaporator. After drying in vacuum for 15 minutes, the residue (yellow solid) was dissolved in dry dichloromethane (30 ml), to which is added 4 ml of a 2M solution of dimethylamine in tetrahydrofuran. After 30 minutes, the reactions is nnow the mixture is concentrated and the residue is placed in ethyl acetate and washed with 10% aq. sodium carbonate, saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives the crude product, which was subjected to chromatography on a column of silica gel with ethyl acetate:methanol (9:1). The obtained white substance dissolved in 10 ml of dry dichloromethane. To the resulting solution was added a sufficient amount of 2M hydrochloric acid until then, until a precipitate. The mixture is then concentrated on a rotary evaporator to dryness and further dried overnight under high vacuum to obtain compound 13 (1.08 g).

Synthesis of compound 15: To a solution of aniline 1 (a 9.25 g, 0.05 mol) and dimethylacetal pyruvic aldehyde 14 (11.8 g, 0.1 mol) in 200 ml glacial acetic acid add anhydrous sodium sulfate (71,0 g, 0.5 mol) and the mixture is stirred for 30 minutes. Then added in several portions powder triacetoxyborohydride sodium (31.8 g, 0.15 mol) over 5 minutes. The reaction mixture is stirred for a further 2 hours. Acetic acid is removed under reduced pressure and the residue is alkalinized by adding a sufficient amount of saturated sodium bicarbonate solution. Then the product is extracted with ethyl acetate, dried with sodium sulfate and evaporated to obtain an oil. The oil obtained is subjected to chromatography on a column of silica gel, ISOE is isua ethyl acetate:hexane (3:7) to give compound 15 (14 g) as a colourless oil.

The synthesis of compounds 16 and 17): To a suspension of fresh aluminum chloride (18.5 g) in 200 ml of dry chloroform at a temperature of 0°slowly add a solution of ketala 15 (13.3 g) in 100 ml of chloroform, and the mixture is heated to room temperature and stirred over night. Aluminium chloride is cautiously quenched by adding ice water and the organic layer is separated and washed with sodium bicarbonate solution, dried and evaporated to obtain white solids. The isomers are separated using chromatography on a column of silica gel using ethyl acetate:hexane (1:9). First elute 6-chlorinda 17 (2.0 g), then 4-chloro isomer 16 (3.8 g).

Synthesis of compound 18: To a solution of 1.3 g of indole 17 in 15 ml of methanol is added a solution of 0.9 g of sodium hydroxide in 20 ml of water. The reaction mixture is heated at a temperature of 50°C for 4 hours to obtain a transparent solution. The mixture is cooled and the methanol is evaporated, the residue diluted with water and acidified with 10% hydrochloric acid. The product is extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated to obtain acid indole 18 (1.2 g) as a white solid.

2-Methyl-6-methoxyindol-5-carboxylic acid synthesized by the method described above.

Synthesis of compound 21: To a solution of methyl 4-amino-6-methoxy 5-benzoate 19 (6.0 g,0,033 mol) and dimethylacetal 20 (7.0 g, of 0.066 mol) in 150 ml of glacial acetic acid add anhydrous sodium sulfate (47,0 g, 0.33 mol) and the mixture is stirred for 30 minutes. Portions add the powder triacetoxyborohydride sodium (20,1 g 0,099 mol) over 5 minutes. The reaction mixture is stirred for a further 2 hours. Acetic acid is removed under reduced pressure and the residue is alkalinized by adding a sufficient amount of saturated sodium bicarbonate solution. Then the product is extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate and evaporated to obtain an oil. The oil obtained is subjected to chromatography on a column of silica gel using ethyl acetate:hexane (3:7) as eluent, and get the desired product 21 (5,2 g) in the form of oil.

Synthesis of compound 22: To a solution of compound 21 (3.6 g) and iodomethane (5.7 g) in 50 ml of anhydrous dimethylformamide added tert-butoxyd potassium (1.0 M in tetrahydrofuran, 20 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 0.5 hour and poured into 250 ml of ethyl acetate, washed with water (4×100 ml), saturated salt solution (50 ml) and dried over magnesium sulfate. Evaporation of solvent gives 3/26 g of compound 22. The product is used in the next stage without purification.

Synthesis of compound 23: To a suspension of anhydrous aluminium chloride 0.71 g) in 20 ml of anhydrous 1,2-dichloroethane is added dropwise a solution of compound 22 (1 g) in 10 ml of 1,2-dichloroethane with stirring. The reaction mixture is heated to a temperature of 80°C for 0.5 hour. After this time the reaction mixture was quenched with methanol, the solvent is evaporated, then add ethyl acetate (100 ml). The organic phase is washed with water, aq. a sodium bicarbonate solution and saturated salt solution and concentrated. The crude product is purified by chromatography on a column of silica gel using ethyl acetate:hexane (3:7), to obtain compound 23 (0,22 g).

Synthesis of compound 24: To a suspension of 1.2 g of acid indole 18 and 1.6 g of compound 5 in 30 ml of dichloromethane added 0.7 g of triethylamine followed by the addition of 1.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The obtained clear solution is stirred for 4 hours. The solvent is evaporated, and the residue is placed in ethyl acetate and washed with water, Rabb. hydrochloric acid and saturated salt solution. The organic layer is dried with sodium sulfate and evaporated. Product highlight (1.3 g) as a white solid after chromatography on a column of silica gel using ethyl acetate:hexane (1:4).

Synthesis of compound 25: to a Solution of 1.3 g of compound 24 in 20 ml of dichloromethane cooled to a temperature of 0°and add 2 M solution of oxalicacid in dichloromethane (3.4 ml, 6.8 mmol), the reaction mixture is stirred at a temperature of 0°St for 1 hour. The temperature was raised to room temperature and stirring is continued for another 1 hour. The solvent is evaporated and the residue is dried in vacuum. The acid chloride was dissolved in dichloromethane (25 ml) and add all at once a solution of 6.8 ml (to 13.6 mmol) 2 M N,N-dimethylamine in tetrahydrofuran. The solvent is removed and the product purified by chromatography on a column of silica gel using methanol:chloroform (2:98). The product is obtained as a white solid (1.4 g).

Synthesis of compound 27: to a Solution of compound 26 (130 mg) in anhydrous dimethylformamide (5 ml) is stirred at a temperature of 0°C in nitrogen atmosphere. Add sodium hydride (25 mg, 60% dispersion in oil) and stirred for 5 minutes, then at room temperature for 30 minutes. The mixture is cooled to a temperature of 0°and add chloromethyl metilsulfate (70 μl). The reaction mixture is stirred for 20 hours at room temperature and then extracted with ethyl acetate. The organic layer is dried over sodium sulfate, concentrated in vacuo. Clean off the residue on chromatotron using methanol: chloroform (2:98) to give 100 mg of the compound 27.

Synthesis of compound 28: to a Solution of oxone (120 mg) in water (1 ml) are added to a suspension of compound 27 (100 mg) in glacial acetic acid (4 ml). The reaction mixture was stirred at room the temperature for 18 hours, washed with water and concentrated in vacuo. The residue is purified on chromatotron using methanol: chloroform (2:98) to give 60 mg of compound 28.

Synthesis of compound 30: To a solution of compound 29 (200 mg) in tetrahydrofuran (20 ml) added dropwise bis(trimethylsilyl)amide, sodium (0.51 ml, 0.51 mmol) at a temperature of 0°C. the Mixture turned light yellow solution was slowly heated to ambient temperature and stirred for 30 minutes. Then add methoxymethane and the reaction mixture was stirred over night. The reaction mixture was quenched with ammonium chloride and extracted with dichloromethane. The combined organic layer was washed with saturated salt solution, dried and concentrated. The residue is purified by chromatography on a column of silica gel, elwira methanol:dichloromethyl (5:95) to obtain 190 mg of compound 30.

Synthesis of compound 31: to a solution of compound 29 (200 mg) in tetrahydrofurane (10 ml) was added dropwise bis (trimethylsilyl) amide, sodium (0,56 ml of 0.56 mmol) at a temperature of 0°C. the Mixture is slowly heated to ambient temperature, stirred for 30 minutes and then added to a solution of tailland (115 mg) in tetrahydrofuran (10 ml). The resulting mixture is stirred for 2 hours at room temperature, quenching the ammonium chloride and extracted with dichloromethane. The combined organic layer was washed with saturated salt solution, dried and concentrated. The residue is purified by chromatography on a column of silica gel, elwira methanol:dichloromethane (5:95) to obtain 90 mg of compound 31.

Synthesis of compound 34: Piperidone 33 is added slowly to a solution of 4-terbisil of magnesium chloride (32) (33 ml, 8.3 mmol, 0.25 M in ethyl ether) at a temperature of 0°C. the Reaction mixture is heated to ambient temperature and then at the boiling point under reflux for 6 hours. The obtained turbid solution is treated with chloride ammonia (saturated) and extracted with simple ether. The combined organic layer was washed with saturated salt solution, dried and concentrated. The residue is purified by chromatography on a column of silica gel, elwira hexane:ethyl acetate (4:1) to give 990 mg of compound 34.

Synthesis of compound 35: Alcohol 34 (670 mg) in dichloromethane (10 ml) are added to a solution of the TRIFLUORIDE diethylaminoethyl (0.5 ml, 4/34 mmol) in dichloromethane (20 ml) at a temperature of -78°C. the Reaction mixture is slowly heated to ambient temperature and stirred for 2 hours, and then treated with sodium carbonate (saturated) and extracted with dichloromethane. The combined organic layer was washed with saturated solutions of salts, dried and concentrate their. The residue is purified by chromatography on a column of silica gel, elwira hexane:ethyl acetate (8:1) to obtain 300 mg of compound 35.

Synthesis of compound 36: a Mixture of compound 35 (456 mg) and 4 M hydrochloric acid in dioxane (10 ml) is stirred for 4 hours. The reaction mixture is neutralized with sodium carbonate, extracted with ethyl acetate. The combined organic layer was washed with saturated salt solution, dried and concentrated. The crude product used in the next reaction without further purification.

Synthesis of compound 38: suspension indolocarbazoles acid 37 (475 mg) in anhydrous dichloromethane (20 ml) is added piperidine 36 (350 mg, of 1.66 mmol). The mixture is stirred for 10 minutes and then add 1-[3-(dimethylaminopropyl)1-3-ethylcarbodiimide hydrochloride (475 mg) and dimethylaminopyridine (202 mg). The reaction mixture becomes transparent, and it is continuously stirred over night. Then the reaction mixture was treated with 10% hydrochloric acid solution and extracted with dichloromethane. The combined organic extracts washed with sodium bicarbonate, saturated salt solution, dried and concentrated. The residue is purified by chromatography on a column of silica gel, elwira dichloromethane:ethyl acetate (9:1) to obtain 300 mg of compound 38 as a white foam.

Synthesis of compound 3: To a suspension of compound 38 (200 mg) added dropwise oxalicacid (0,52 ml, 1.04 mmol, 2M in dichloromethane) at a temperature of 0°C. the Reaction mixture is stirred at a temperature of 0°C for 30 minutes, then warmed to room temperature and stirred for 5 hours. Formed a yellow suspension. The solvent and excess oxalicacid removed under reduced pressure. The resulting yellow solid is dried in vacuum and dissolved in dichloromethane, and then cooled in an ice bath. Add dimethylamine (1,04 ml of 2.08 mmol, 2 M in tetrahydrofuran). After 30 minutes the reaction mixture is treated with water and extracted with dichloromethane. The organic extracts washed with water, saturated salt solution, dried and concentrated. The residue is purified by chromatography on a column of silica gel, elwira 3% Meon in dichloromethane to obtain 190 mg of compound 39 as a white solid.

Synthesis of compound 40: To a solution of compound 39 (75 mg) in tetrahydrofuran (10 ml) added dropwise KHMDS (and 0.46 ml, 0.23 mmol, 0.5 M in toluene) at a temperature of 0°C. the Mixture is slowly warmed to room temperature and stirred for 30 minutes. To the reaction mixture slowly add methyliodide (33 mg, 0.23 mmol), then stirred for 2 hours. The reaction mixture was quenched with ammonium chloride and extracted with dichloromethane. The combined organic extracts washed with saturated salt solution, dried and will centerour. The residue is purified by chromatography on a column of silica gel, elwira methanol:dichloromethane (2:98) to give 50 mg of compound 40.

Synthesis of compound 41: To a solution of compound 40 (75 mg) in tetrahydrofuran (10 ml) added dropwise KHMDS (and 0.46 ml, 0.23 mmol, 0.5 M in toluene) at a temperature of 0°C. the Mixture is slowly warmed to room temperature and stirred for 30 minutes. To the reaction mixture slowly add methoxymethane (18 mg, 0.23 mmol), then stirred overnight. The reaction mixture was quenched with ammonium chloride and extracted with dichloromethane. The combined organic extracts washed with saturated salt solution, dried and concentrated. The residue is purified by chromatography on a column of silica gel, elwira methanol:dichloromethane (2:98) to obtain 65 mg of compound 41.

Synthesis of compound 43: To a suspension of 6-methoxy-5-indolocarbazoles acid (37) (200 mg) in dichloromethane (5 ml) in one portion add the hydrochloride of 1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide (258 mg, 1.35 mmol). The reaction mixture was stirred to dissolve all solids. Add 4-benzyl-4-hydroxypiperidine (42) (258 mg)obtained by removing the protective group from the compound 34 by the method of synthesis of compounds 36, and the resulting mixture stirred at ambient temperature. The reaction mixture gets is muddy. Add a catalytic amount of dimethylaminopyridine (10 mg) and stirred at ambient temperature overnight. The reaction mixture is treated with water and extracted with dichloromethane. The combined organic layer washed with 10% hydrochloric acid solution, sodium bicarbonate (saturated) and saturated salt solution, then dried and concentrated to obtain 300 mg (82%) of compound 43 as a yellow foam.

Synthesis of compound 44: Oxalicacid (0,41 ml of 1.65 mmol, 2 M in dichloromethane) is added dropwise to a solution of 6-methoxy-(4-benzyl-4-hydroxypiperidine)indole-5-carboxamide (300 mg) in dichloromethane (20 ml) at a temperature of 0°C. the Reaction mixture is stirred at a temperature of 0°C for 30 minutes and then slowly heated to ambient temperature. 2 hours is formed yellow precipitate. The reaction mixture was concentrated under reduced pressure and dried for 1 hour under reduced pressure. The obtained yellow solid is suspended in dichloromethane (20 ml). At room temperature add methylpiperazine (0.2 ml) and diisopropylethylamine (0.2 ml). The mixture is stirred for 1 hour, treated with water and extracted with dichloromethane. The residue is purified by chromatography on a column of silica gel, elwira dichloromethane:methanol (10:1) to give 180 mg of a white solid. 20 m the obtained solid substance was dissolved in methanol (1 ml). To the resulting solution was added dropwise a saturated solution of hydrochloric acid to achieve a pH of about 3. Then the solvents removed, and the product is dried to obtain compound 44.

Synthesis of compound 45: To a solution of compound 44 (65 mg) in anhydrous tetrahydrofuran (10 ml) was added dropwise bis(trimethylsilyl)amide, sodium (0.25 ml, 0.25 mmol, 1.0 M solution in tetrahydrofuran) at ambient temperature. The mixture was stirred at ambient temperature for 30 minutes and then to the reaction mixture add ethylchloride (0,024 ml, 0.25 mmol). After 1 hour the reaction mixture was quenched with ammonium chloride (saturated) and extracted with ethyl acetate. The combined organic layer was washed with saturated salt solution, dried (magnesium sulfate) and concentrate under reduced pressure. The residue is purified by chromatography on a column of silica gel, elwira dichloromethane: methanol (10:1) to give 15 mg specified in the title compound 45 as a white solid. The obtained solid substance was dissolved in methanol (1 ml) and the resulting solution was added dropwise a saturated solution of hydrochloric acid in methanol until until the pH becomes about 3. Then the solvent is removed, and the product is dried to obtain hydrochloride of compound 45.

Synthesis of compound 47:

STAGE b: 10 g of the product from stage a is dissolved in anhydrous acetone and the reaction mixture is cooled in an ice tank. To the resulting solution was added powdered potassium hydroxide (14,02 g). After stirring at a temperature of 0°C for 10 minutes add 4-florantyrone (23,5 g) and the reaction mixture is stirred at a temperature of 0°C for 20 minutes and at room temperature for 1 hour. After removal of solvent on a rotary evaporator the residue is placed in ethyl acetate and washed with 10% aqueous sodium carbonate, saturated salt solution and dried over anhydrous sodium sulfate. Filtration and concentration gives the crude product which is purified by chromatography on a column of silica gel using ethyl acetate:hexane, to obtain 14 g of compound 47.

Synthesis of compound 48: 14 g of compound 47 was dissolved in 100 ml of methylene chloride and treated with 100 ml of 2 M hydrochloric acid in ether for 2 hours. The solvent is removed and the resulting solid is washed with simple ether is hexane and dried in high vacuum to obtain compound 48 (11/3 g) in the form of hydrochloride salt.

Synthesis of compound 49: 1 g of compound 48 was dissolved in 20 ml of methylene chloride and treated with 6-methoxy-5-indolocarbazoles acid (37) (0.87 g), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.95 g), triethylamine (700 μl) and dimethyl-aminopyridine (catalytic) and the reaction mixture was stirred over night. The reaction mixture was concentrated and the residue is placed in ethyl acetate, washed with 10% aqueous sodium carbonate, saturated salt solution and dried over anhydrous sodium sulfate. Filtration and concentration to give the crude material that is purified by chromatography on a column of silica gel using ethyl acetate/hexane, to obtain the compound 49 (1.6 g).

Synthesis of compound 50: 1,6 g of compound 49 was dissolved in 25 ml of dry dichloromethane. The reaction mixture is blown with nitrogen and placed in an ice bath. To the resulting solution add 5 ml of 2M oxalicacid in dichloromethane. The reaction mixture was stirred at room temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was concentrated on a rotary evaporator and then dried in vacuum for 15 minutes, the residue (yellow solid) was dissolved in dry dichloromethane. To the obtained residue is added a 2M solution of dimethylamine in THF (5 ml) and the reaction mixture stirred for 0.5 hour. Then the reaction mixture conc the Ute, and the residue is placed in ethyl acetate and washed with 10% aq. sodium carbonate, saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives the crude product, which was subjected to chromatography on a column of silica gel using ethyl acetate/hexane, to obtain compound 50 (1.45 g).

Synthesis of compound 52: 2R,5S-transdetermination 51 (5.0 g) is dissolved in 15 ml of ethanol, the resulting solution was added 2-primatives (4.4 g). The resulting mixture is stirred at a temperature of 40°C for 30 minutes, cooled to room temperature and concentrated to dryness on a rotary evaporator. The residue is placed in ethyl acetate and washed with 10% aqueous sodium carbonate, saturated salt solution and dried over anhydrous sodium sulfate. Filtration and concentration gives the crude material which is purified by chromatography on a column of silica gel using ethyl acetate/hexane, to obtain the compound 52 (5,4 g).

Synthesis of compound 53: 5 g of compound 52 was dissolved in 60 ml of methylene chloride and treated with 60 ml of 2 M hydrochloric acid in ether for 3 hours. The solvent is removed and the resulting solid is washed with simple ether and hexane and dried in high vacuum to obtain compound 53 in the form of a hydrochloride salt (3.6 g).

Synthesis of compound 54 compound 53 (1,32 g) was dissolved in 20 ml of methylene chloride and treated with 6-methoxy-5-indolocarbazoles acid (37) (0.9 g) in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (1.04 g), 800 μl of triethylamine, and catalytic DMAP, during the night. The reaction mixture was concentrated and the residue is placed in ethyl acetate, washed with 10% aqueous sodium carbonate, saturated salt solution and dried over anhydrous sodium sulfate. Filtration and concentration to give the crude material that is purified by chromatography on a column of silica gel using ethyl acetate/hexane, to obtain the compound 54 (0.95 g).

Synthesis of compound 55: 0,6 g of compound 54 was dissolved in 20 ml of methylene chloride. The reaction mixture is blown with nitrogen and placed in an ice bath. To the resulting solution was added 2 ml of 2M oxalicacid in methylene chloride. The reaction mixture was stirred at room temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was concentrated on a rotary evaporator and then dried in vacuum for 15 minutes. The residue (yellow solid) was dissolved in 15 ml of dry methylene chloride, the resulting solution was added 2 ml of 2M solution of dimethylamine in tetrahydrofuran. After 30 minutes the reaction mixture was concentrated and the residue is placed in ethyl acetate and washed with 10% aq. sodium carbonate, saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives the crude product which is purified by chromatography on a column of silica gel, use the Zuya ethyl acetate/hexane, getting connection 55 (0,78 g).

Synthesis of compound 57: 7,65 g (19,97 mmol) of indole 56 dissolved in 80 ml of anhydrous dimethylformamide and cooled in an ice bath. In an inert atmosphere is added dropwise 40 ml (2M solution in dichloromethane) oxalicacid for 20 minutes. After stirring for 15 minutes at a temperature of 0°the reaction mixture is heated to ambient temperature and stirring is continued for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (3×100 ml). The combined extract is washed with water, dried over sodium sulfate and evaporated. The product is then purified by chromatography on a column of silica gel, elwira with ethyl acetate:hexane (30:70) to give 8 g (97,5%) of aldehyde 57.

Synthesis of compound 58: To a solution of 1-methylimidazole (149 mg) in tetrahydrofuran (10 ml) was added dropwise n-utility (1/14 ml, 1.82 mmol, 1.6 M in hexane) at a temperature of -78°C. the Reaction mixture was stirred at -40°C for 30 minutes. Add connection 57 (500 mg) in tetrahydrofuran (10 ml). The reaction mixture is heated to ambient temperature and stirred overnight. The reaction mixture was quenched with ammonium chloride (saturated), extracted with ethyl acetate. The combined organic layer was washed with a saturated solution of salt, sushi is t and concentrate. The crude mixture is refluxed with phenylhydrazine (0.6 ml) in ethanol (10 ml) to remove the connection 57 which has not trashdolls in the reaction. After removal of solvent the residue is purified by chromatography on a column of silica gel, elwira with ethyl acetate:hexane (4:1) to give 120 mg of compound 58.

Using the above techniques, receive connections from tables 2 and 3, which are tested to determine its ability to inhibit R-α kinase. It was found that the compounds in tables 2 and 3 have values IC50for inhibition R-α in the range from 0.1 to 1.5 mcmol.

Table 2
Conn. No.StructureMM (RASSC.)MM (calc.)
1466466
2452453
3535534
4573573
5480480

Conn. No.StructureMM (RASSC.)MM (calc.)
6418418
7551551
8524523
9590590

Conn. No.StructureMM (RASSC.)MM (calc.)
10521520
11620620
12592592
13579580

Conn. No.StructureMM (RASSC.)MM (calc.)
14523522
15 509509
16484484
17567567

Conn. No.StructureMM (RASSC.)MM (calc.)
18593592
19537537
20526525
21678678

Conn. No.StructureMM (RASSC.)MM (calc.)
22579578
23522522
24650650
25480480

Conn. No.StructureMM (RASSC.)MM (calc.)
26648648
27549548
28620620
29597596

Conn. No.StructureMM (RASSC.)MM (calc.)
30539538
31519519
32553553
33513513

Conn. No.StructureMM (RASSC.)MM (calc.)
34609 609
35592591
36596595
37542541

Conn. No.StructureMM (RASSC.)MM (calc.)
38571571
39541541
40494494
41548548

Conn. No.StructureMM (RASSC.)MM (calc.)
42570570
43514513
44490490
45 595595

Conn. No.StructureMM (RASSC.)MM (calc.)
46566566
47537537
48573573
49536536

Conn. No.StructureMM (RASSC.)MM (calc.)
50543543
51509509
52507507
53572572

Conn. No.StructureMM (RASSC.)MM (calc.)
54 565565
55599599
56537537
57513513
58456456

Conn. No.StructureMM (RASSC.)MM (calc.)
59485485
60551551
61511511
62499500

Conn. No.StructureMM (RASSC.)MM (calc.)
63543543
64584584
65493493
66494494

Conn. No.StructureMM (RASSC.)MM (calc.)
67477477
68542542
69584584
70530529
71512511

Conn. No.StructureMM (RASSC.)MM (calc.)
72523522
73539539
74495495
75 512511
76528528

Conn. No.StructureMM (RASSC.)MM (calc.)
77499499
78552551
79512511
80498497
81496495

Conn. No.StructureMM (RASSC.)MM (calc.)
82525525
84510509
85540539
86485486
87495495

Conn. No.StructureMM (RASSC.)MM (calc.)
88552551
89508508
90562562
91558558
92539539

Conn. No.StructureMM (RASSC.)MM (calc.)
93542542
94590590
95528528
96555555

Conn. No.StructureMM (RASSC.)MM (calc.)
97510509
98497497
99527527
100550550
101569569

Conn. No.StructureMM (RASSC.)MM (calc.)
102527527
103526525
104528528
105526525
106540539

Conn. No.Structure MM (RASSC.)MM (calc.)
107538537
108498498
109524523
110542541
111530529

Conn. No.StructureMM (RASSC.)MM (calc.)
112499500
113508508
114542541
115504504
116492504

Table 3

Conn. No.StructureMM (RASSC) MM (calc.)
117472.5858472.5858
118404.4636404.4636
119390.4368390.4368
120502.6116502.6116

Conn. No.StructureMM (RASSC.)MM (calc.)
121558.6752558.6752
122458.559458.559
123389.4527389.4527
124420.4626420.4626
125516.6384516.6384

Conn. No.StructureMM (RASSC.)MM (calc.)
126 504.6027504.6027
127422.4537422.4537
128525.021525.021
129434.4894434.4894
130422.4537422.4537

Conn. No.StructureMM (RASSC.)MM (calc.)
131438.4527438.4527
132452.4795452.4795
133408.4269408.4269
134420.4626420.4626
135391.4249391.4249
136528.5582528.5582

Conn. No. StructureMM (RASSC.)MM (calc.)
137435.4775435.4775
138419.4785419.4785
139486.6126486.6126
140511.547511.547
141507.559507.559

Conn. No.StructureMM (RASSC.)MM (calc.)
142505.5868505.5868
143574.6931574.6931
144465.5222465.5222
145437.4686437.4686

Conn. No.StructureMM (RASSC.)MM (calc.)
146 480.9931480.9931
147518.6106518.6106
148535.0845535.0845
149460.5748460.5748

Conn. No.StructureMM (RASSC.)MM (calc.)
150548.6553548.6553
151520.6017520.6017
152446.548446.548
153450.4677450.4677

Conn. No.StructureMM (RASSC.)MM (calc.)
154494.5639494.5639
155511.0189511.0189
156606.6911606.6911
157521.5858521.5858

Conn. No.StructureMM (RASSC.)MM (calc.)
158490.6006490.6006
159506.5749506.5749
160490.6006490.6006
161536.6007536.6007
162498.9832498.9832

Conn. No.StructureMM (RASSC.)MM (calc.)
163469.9415469.9415
164541.02541.02
165511.9783511.9783/td>
166497.9951497.9951
167497.9951497.9951
168483.9683483.9683

Conn. No.StructureMM (RASSC.)MM (calc.)
169539.0478539.0478
170549.6434549.6434
171476.5738476.5738
172476.5738476.5738

Conn. No.StructureMM (RASSC.)MM (calc.)
173476.5738476.5738
174469.9415469.9415
175479.549 479.549
176513.01513.01
177494.5639494.5639

Conn. No.StructureMM (RASSC.)MM (calc.)
178534.6285534.6285
179508.5907508.5907
180522.6175522.6175
181483.5123483.5123

1. Derivatives of indole of the formula

and their pharmaceutically acceptable salt,

whererepresents a double bond;

Z1is N or CR5where R5represents H, C1-C6alkyl, hydroxy, C1-C6alkoxy or halogen;

Z2in position 2 is CR1and Z2in position 3 represents SA,

where each R1independently is hydrogen or C1/sub> -C6by alkyl;

But it is Wi-COXjY, where Y is COR2where R2is OR, NR2, NRNR2or NROR, where each R independently represents H, C1-C6alkyl or C5-C6heteroaryl containing in the ring one or two heteroatoms selected from N, O and S, each of which is optionally substituted by one or more groups selected from NR'2, OR', COOR', C1-C6of alkyl, CN, =O, SR', where each R' represents H or C1-C6alkyl, and where two R or R'attached to the same N atom may form a 3-8-membered ring selected from the group comprising pieperazinove ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrolidine ring, piperidine ring, azacycloheptane ring, azacycloheptane ring and azacycloheptane ring; and where the specified ring may be optionally substituted C1-C6the alkyl or COO-C1-C6the alkyl, and X is unsubstituted alkylene (1-6C), or Y is an imidazole, substituted stands, i is 0, j is 0 or 1;

R7is N or C1-C6the alkyl, SOR, SO2R, RCO, COOR, C1-C6alkyl-COR, CONR2, SO2NR2, CN, OR, C1-C6alkyl-SR, C1-C6alkyl-OCOR, C1-C6alkyl-COOR, C1-C6Ala is l-CN or C 1-C6alkyl-CONR2where each R independently represents H, C1-C6alkyl or aryl, which is optionally substituted with halogen, C1-C4the alkyl or C1-C4alkoxy, or R7is methoxymethyl, methoxyethyl, ethoxymethyl, benzoyloxymethyl or 2-methoxyethoxymethyl;

each R3independently is halogen, C1-C6the alkyl, OR, SR or NR2where R is H or C1-C6alkyl;

n is 0-3;

L1CO;

L2is alkylene (1-4C), optionally substituted by one or two groups C1-C4of alkyl;

each R4independently selected from the group including C1-C6alkyl, halogen, OR, NR2, SR, SOR, SO2R, RCO, COOR, CONR2, SO2NR2where each R independently represents H or C1-C6alkyl,

or R4is =O;

m is 0-4;

Ar is an aryl group substituted by from 0 to 5 substituents selected from the group comprising C1-C6alkyl, halogen, OR, NR2, SR, SOR, SO2R, RCO, COOR, CONR2and SO2NR2where each R independently represents H or C1-C6alkyl.

2. The compound according to claim 1, where Z1is N.

3. The compound according to claim 1, where j is equal to 0.

4. Connection p., where R7is H, C1-C6the alkyl or C1-C6the acyl.

5. The compound according to claim 1, where Z1is SN.

6. The compound according to claim 1, where L2is unsubstituted C1-C4alkylene.

7. The compound according to claim 1, where L2is unsubstituted methylene or methylene substituted C1-C4the alkyl.

8. The compound according to claim 1, where Ar is optionally substituted phenyl.

9. The connection of claim 8, where the specified optional Deputy represents halogen, or, or C1-C6alkyl, where each R is independently H or C1-C6the alkyl.

10. The connection of claim 8, where the specified phenyl is unsubstituted or substituted by one Deputy.

11. The compound according to claim 1, where each R4is halogen, C1-C6alkoxy or C1-C6the alkyl.

12. Connection to item 11, where m is 0, 1 or 2.

13. The connection section 12, where m is 2 and both R4are C1-C6the alkyl.

14. The compound according to claim 1, where R3is halogen or C1-C6alkoxy.

15. The connection 14, where n is 0, 1 or 2.

16. The compound according to claim 1, where L1associated with the ring α 4-, 5 - or 6-position.

17. Connection P16, where L1associated with the ring α 5-position.

18. The compound according to claim 1, where R1is N.

19. The connection 17, g is e, Z 1is N.

20. The connection 17, where Z1is SN.

21. The compound according to claim 1 or its pharmaceutically acceptable salt as an active component of the medicinal product for the treatment of pathological conditions characterized by increased activity R-α.

22. Connection item 21, where the pathological condition is rheumatoid arthritis.

23. The connection according to claim 19, where a represents COCOR2and R2matter specified in claim 1.

24. Connection item 23, where Z2in position 2 is CH.

25. Connection claim 20, where a is COCOR2where R2matter specified in claim 1.

26. Connection A.25, where Z2in position 2 is CH.

27. The connection point 24, where n is equal to 0 or 1.

28. Connection item 27, where Ar is substituted phenyl.

29. Connection item 27, where L2is unsubstituted C1-C4alkylene.

30. The connection clause 29, where n is equal to 1 and R3is halogen or methoxy.

31. Connection item 30, where R7represents N or C1-C6alkyl, C1-C6alkyl-COR, C1-C6alkyl-SR, C1-C6alkyl-OCOR, C1-C6alkyl-COOR, C1-C6alkyl-CN, or C1-C6alkyl-CONR2where R has the meanings indicated in claim 1.

32. Connection p, where R7presented AET methyl or methoxymethyl, methoxyethyl, ethoxymethyl, benzoyloxymethyl or 2-methoxyethoxymethyl.

33. Connection p, where Ar is a para-florfenicol.

34. Connection p, where R2is or or NR2where each R independently is H or C1-C6the alkyl, and where two R attached to the same N atom, may form a 6-membered ring selected from morpholino rings, piperidino rings and piperazinovogo ring.

35. The connection 34, where R2is NR2where each R independently is H or C1-C6the alkyl, and where two R attached to the same N atom, may form a 6-membered ring selected from morpholino rings, piperidino rings and piperazinovogo ring.

36. The compound according to claim 1, selected from the group including

td align="left"> {5-[4-(4-Terbisil)piperidine-1-carbonyl]-1H-indol-3-yl)-Okrokana acid;
Conn. no.Connection name
1{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}octoxynol acid methyl ester;
2{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}Okrokana acid;
31-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
45-(4-B is sulpiride-1-carbonyl)-1-(4-chlorobenzoyl)-6-methoxy-1H-indol-3-yl]octoxynol acid methyl ester;
5{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}octoxynol acid ethyl ester;
6[5-(4-Benzylpiperidine-1-carbonyl)-1-methyl-1H-indol-3-yl]-octoxynol acid methyl ester;
71-{5-[4-(4-Chlorobenzyl)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
85-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-3-

methoxyaniline-1-carboxylic acid ethyl ester;
95-(4-Benzyl-4-hydroxypiperidine-1-carbonyl)-6-methoxy-3-[2-(4-methylpiperazin-1-yl)-2-oxoacyl]indole-1-carboxylic acid ethyl ester;
101-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-2-piperazine-1-ilatan-1,2-dione;
114-(2-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-2-oxoacyl)piperazine-1-carboxylic acid tert.-butyl ether;
124-(2-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-2-oxoacyl)piperazine-1-carboxylic acid ethyl ester;
135-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-3-(2-morpholine-4-yl-2-oxoacyl)indole-1-carboxylic acid ethyl ester;
14N-(2-Dimethylaminoethyl)-2-{5-[4-(4-terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-2-oxoacetate;
151-methyl-6-methoxy-[4'-fluoro-(4-benzyl-2,5-dimethyl-piperazinil)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
162-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetate;
171-Etoxycarbonyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
185-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-3-[2-(4-methylpiperazin-1-yl)-2-oxoacyl]indole-1-carboxylic acid ethyl ester;
193-Dimethylaminoacetyl-5-[4-(4-terbisil)piperidine-1-carbonyl]-6-methoxyindol-1-carboxylic acid ethyl ester;
201-{6-Chloro-5-[4-(4-Terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-morpholine-4-ilatan-1,2-dione;
213-[2-(4-tert.-butoxycarbonylmethyl-1-yl)-2-oxoacyl]-5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxyindol-1-carboxylic acid ethyl ester;
225-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-3-(2-oxo-2-piperazine-1-ylacetic)-indole-1-carboxylic acid ethyl ester;
23 1-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-2-morpholine-4-ilatan-1,2-dione;
243-[2-(4-Ethoxycarbonylmethyl-1-yl)-2-oxoacyl]-5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxyindol-1-carboxylic acid ethyl ester;
252-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
264-(2-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-2-oxoacyl)-2,5-TRANS-dimethylpiperazine-1-carboxylic acid tert.-butyl ether;
271-(2,5-TRANS-Dimethylpiperazine-1-yl)-2-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}ethane-1,2-dione;
284-(2-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl }-2-oxoacyl)-2,5-TRANS-dimethylpiperazine-1-carboxylic acid ethyl ester;
296-Chloro-5-[4-(4-Terbisil)piperidine-1-carbonyl]-3-[2-(4-methylpiperazin-1-yl)-2-oxoacyl]indole-1-carboxylic acid ethyl ester;
301-{6-Chloro-5-[4-(4-Terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
311-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-1,2-dimethyl-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)this is -1,2-dione;
321-{6-Chloro-5-[4-(4-Terbisil)piperidine-1-carbonyl]-1,2-dimethyl-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)-ethane-1,2-dione;
331-methyl-6-chloro-[4'-fluoro-(4-benzyl-2,5-dimethylpiperazine)]-indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
346-Methoxy-5-[4-(4-Terbisil)-2,5-dimethylpiperazine-1-carbonyl]-3-[2-(morpholine-4-yl)-2-oxoacyl]indole-1-carboxylic acid ethyl ester;
355-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-3-[2-(4-methylpiperazin-1-yl)-2-oxoacyl]indole-1-carboxylic acid dimethylamide;
366-Chloro-5-[4-(4-Terbisil)piperidine-1-carbonyl]-3-[2-(4-methylpiperazin-1-yl)-2-oxoacyl]-indole-1-carboxylic acid dimethylamide;
372-{6-Chloro-1-etoxycarbonyl-5-[4-(4-Terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
381-Etoxycarbonyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethyl-piperazinil)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
392-{6-Chloro-1-dimethylaminoethyl-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
402-{6-Chloro-1-cyano-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
412-{6-Chloro-5-[4-(4-Terbisil)piperidine-1-carbonyl]-1-methanesulfonyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
426-Chloro-3-dimethylaminoacetyl-5-[4-(4-Terbisil)piperidine-1-carbonyl]-indole-1-carboxylic acid tert.-butyl ether;
432-{6-Chloro-5-[4-(4-Terbisil)piperidine-1-carbonyl]-1-methoxymethyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
442-{1-Cyano-5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
451-tert.-Butoxycarbonyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
462-{6-Methoxy-1-dimethylaminoethyl-5-[4-(4-Terbisil)-2R,5S-dimethylpiperazine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
471-Acetyl-6-methoxy-[4'-fluoro-(4-benzyl-2,5-dimethylpiperazine)]-indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
481-Methanesulfonyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
493-Dimethylaminoacetyl-5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxyindol-1-carboxylic acid dimethylamide;
50512-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methoxymethyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
522-{1-Acetyl-5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
532-{1-Dimethylsulphamoyl-5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl]-N,N-dimethyl-2-oxoacetate;
543-Dimethylaminoacetyl-5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxyindol-1-carboxylic acid tert.-butyl ether;
551-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-1-methanesulfonyl-6-methoxy-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
561-Acetyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethyl-piperazinil)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
571-Methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]-indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
582-{6-Chloro-5-[4-(4-Terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-oxoacetate;
591-Methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]-indole-5-carboxamide-3-the foreign Ministry Glyoxylic acid;
601-Acetyl-2-methyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]-indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
612-{6-Chloro-5-[4-(4-formanilide)piperidine-1-carbonyl]-1-methoxymethyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetate;
622-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methoxymethyl-1H-indol-3-yl}-N-methyl-2-oxoacetate;
631-Methoxymethyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
642-{1-tert.-Butoxycarbonylmethyl-6-chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
652-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-N-ethyl-N-methyl-2-oxoacetate;
662-{6-Ethoxy-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
672-{5-[4-(4-Formanilide)-6-methoxypiperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
68{6-Chloro-3-dimethylaminoacetyl-5-[4-(4-terbisil)-piperidine-1-carbonyl]-indol-1-yl}acetic acid methyl ester;
696-Chloro-3-dimethylaminoacetyl-5-[4-(4-FPO is benzyl)piperidine-1-carbonyl]-indol-1-ymetray ether of 2,2-dimethylpropionic acid;
702-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methylthiomethyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
712-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N,N-diethyl-2-oxoacetate;
722-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-(2-cyanoethyl)-N-methyl-2-oxoacetate;
732-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-oxo-1H-thiazol-2-ylacetamide;
741 Azetidin-1-yl-2-{6-chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-N-indol-3-yl}ethane-1,2-dione;
752-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-isopropyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
762-[6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-(2-methoxyethyl)-1H-indol-3-yl]-N,N-dimethyl-2-oxoacetate;
771-Methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N-methylamide;
782-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-cyclopropylmethyl-N-propyl-2-oxoacetate;
792-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-isopropyl-N-methyl-2-oxoacetate;
802-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-ethyl-N-methyl-2-oxoacetate;
812-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-cyclopropyl-2-oxoacetate;
822-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-oxo-N-pyrrolidin-1-ylacetamide;
841-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-pyrrolidin-1-ilatan-1,2-dione;
852-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N,N-aminobutiramida 2-oxoacetate;
862-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-methoxy-2-oxoacetate;
871-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-(2-methylaziridine-1-yl)ethane-1,2-dione;
881-Asokan-1-yl-2-{6-chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}ethane-1,2-dione;
891-Methyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
902-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methanesulfonyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
91 2-[6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-(2-methoxyethoxymethyl)-1H-indol-3-yl]-N,N-dimethyl-2-oxoacetate;
921-Methoxymethyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
932-{1-Acetoxymethyl-6-chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
942-{1-Benzoyloxymethyl-6-chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
952-{6-Chloro-1-ethoxymethyl-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
961-methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid morpholine;
972-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-cyclopropyl-N-methyl-2-oxoacetate;
982-{5-[4-Fluoro-4-(4-terbisil)piperidine-1-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
992-{5-[4-Fluoro-4-(4-terbisil)piperidine-1-carbonyl]-6-methoxy-1-methoxymethyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
1001-methyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamid the-3-Glyoxylic acid morpholine;
1012-{6-Chloro-1-(2-diethylaminoethyl)-5-[4-(4-terbisil)-piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
1021-Methyl-6-chloro-[4-(1-4'-florfenicol)piperazinil]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1032-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-ethyl-2-oxo-N-propylacetamide;
1041-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-thiazolidin-3-ilatan-1,2-dione;
1052-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-ethyl-N-isopropyl-2-oxoacetate;
1061-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-(4,4-dimethyloxazolidine-3-yl)ethane-1,2-dione;
1071-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-(2,5-dimethylpiperidin-1-yl)ethane-1,2-dione;
108{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}octoxynol acid N',N'-dimethylhydrazide;
1091-{6-Chloro-5-[4-(4-Terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-2-piperidine-1-ilatan-1,2-dione;
1102-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-ethyl-N-(2-metoxi who yl)-2-oxoacetate;
1112-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-(2-methylsulfonylamino)-2-oxoacetate;
1122-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-methoxy-N-methyl-2-oxoacetate;
1132-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl}-N-cyanomethyl-N-methyl-2-oxoacetate;
114[(2-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1-methyl-1H-indol-3-yl)-2-oxoacyl)methylamino]acetic acid methyl ester;
1152-{1-Cyanomethyl-5-[4-(4-terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl} - N,N-dimethyl-2-oxoacetate;
116[6-Chloro-1-methyl-3-(1-methyl-1H-imidazole-2-carbonyl)-1H-indol-5-yl]-[4-(4-terbisil)piperidine-1-yl]-methanon;
1171-[5-(4-Benzylpiperidine-1-carbonyl)-1H-indol-3-yl]-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
118[5-(4-Benzylpiperidine-1-carbonyl)-1H-indol-3-yl]-octoxynol acid methyl ester;
119[5-(4-Benzylpiperidine-1-carbonyl)-1H-indol-3-yl]-Okrokana acid;
1201-[5-(4-Benzylpiperidine-1-carbonyl)-6-methoxy-1H-indol-3-yl]-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
1214-{2-[5-(4-Benzyl shall piperidin-1-carbonyl)-1H-indol-3-yl]-2-oxoacyl}piperazine-1-carboxylic acid tert.-butyl ether;
1221-[5-(4-Benzylpiperidine-1-carbonyl)-1H-indol-3-yl]-2-piperazine-1-ilatan-1,2-dione;
1232-[5-(4-Benzylpiperidine-1-carbonyl)-1H-indol-3-yl]-2-oxoacetate;
124[5-(4-Benzylpiperidine-1-carbonyl)-6-methoxy-1H-indol-3-yl]Okrokana acid;
1252-[5-(4-Benzylpiperidine-1-carbonyl)-6-methoxy-1H-indol-3-yl]-2-oxo-N-(2-pyrrolidin-1-retil)ndimethylacetamide;
1261-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-2-methyl-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
127{5-[4-(4-Terbisil)piperidine-1-carbonyl]-2-methyl-1H-indol-3-yl}octoxynol acids;
1281-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
129[5-(4-Benzylpiperidine-1-carbonyl)-6-methoxy-1H-indol-3-yl]octoxynol acid methyl ester;
130{5-[4-(4-Terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-octoxynol acid methyl ester;
131{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}Okrokana acid;
132{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}octoxynol acid methyl ester;
133
134[5-(4-Benzylpiperidine-1-carbonyl)-4-methoxy-1H-indol-3-yl]Okrokana acid;
135{5-[4-(4-Terbisil)-piperazine-1-carbonyl]-1H-indol-3-yl}Okrokana acid;
136[5-(4-Benzylpiperidine-1-carbonyl)-4-methoxy-1H-indol-3-yl]octoxynol acid 2-methyl-4-oxo-4H-Piran-3-silt ether;
1376-Methoxy-(4-benzylpiperazine)indole-5-carboxamide-3-Glyoxylic acid methyl ester;
138[4-(1-Phenylethyl)piperazinil]indole-5-carboxamide-3-Glyoxylic acid methyl ester;
1391-{5-[4-(4-Terbisil)piperazine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-2-(4-methylpiperidin-1-yl)ethane-1,2-dione;
140N-(2,3-Dihydroxypropyl)-2-{5-[4-(4-terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-2-oxoacetate;
1411-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-2-morpholine-4-ilatan-1,2-dione;
1421-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-2-piperidine-1-ilatan-1,2-dione;
1431-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-2-(4-pyrrolidin-1-reparacin-1-yl)ethane-1,2-dione;
1442-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
1452-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl)-2-oxoacetate;
146[3'-Chloro-(4-benzyl-2,5-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1471-[5-(4-Benzyl-4-hydroxypiperidine-1-carbonyl)-6-methoxy-1H-indol-3-yl]-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
1481-{5-[4-(3'-Chloro-4-benzyl-2,5-dimethylpiperazine)-1-carbonyl]-1H-indol-3-yl}-2-(4-methylpiperidin-1-yl)ethane-1,2-dione;
149[4-(3'-Chloro-1-phenylethyl)-2,5-dimethylpiperazine]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1501-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-2-(4-isopropylpiperazine-1-yl)ethane-1,2-dione;
1511-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)-ethane-1,2-dione;
152(4-Benzyl-2R,5S-piperazinil)indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
153(4-Benzyl-oxopiperidin)indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1546-Methoxy-[4'-fluoro-(4-benzyl-2,5-di is ethylpiperazine)]-indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1556-Methoxy-[3'-chloro-(4-benzyl-2R,5S-dimethylpiperazine)]-indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1564-(2-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-2-oxoacyl)-piperazine-1-carboxylic acid tert.-butyl ether;
1571-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-2-(4-hydroxypiperidine-1-yl)ethane-1,2-dione;
1584-Methoxy-[4-(1-phenylethyl)piperazinil]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1591-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-2-piperazine-1-ilatan-1,2-dione;
1606-Methoxy-[4-(1-phenylethyl)piperazinil]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1616-Methoxy-[4'-fluoro-(4-benzyl-2,5-dimethylpiperazine)]-indole-5-carboxamide-3-pixelboy acid morpholine;
1626-Chloro-[4'-fluoro-(4-benzyl-2,5-dimethylpiperazine)]-indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1632-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
1646-Chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]-indole-5-carboxamide-3-piccilo the second acid N,N-dimethylamide;
1651-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-2-morpholine-4-ilatan-1,2-dione;
1662-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-diethyl-2-oxoacetate;
1672-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N-isopropyl-N-methyl-2-oxoacetate;
1682-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-2-methyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
1691-{6-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-2-methyl-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
1706-Methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]-indole-5-carboxamide-3-Glyoxylic acid 4-methylpiperazine;
1716-Methoxy-(4-benzyl-2,5-dimethylpiperazine)indole-5-carboxamide-3-Glyoxylic acid N-dimethylamide;
1726-Methoxy-(4-benzyl-2S,5R-dimethylpiperazine)indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1736-Methoxy-(4-benzyl-2R,5S-dimethylpiperazine)indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1742-{4-Chloro-5-[4-(4-terbisil)piperidine-1-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
1752-{5-[4-4-Terbisil)piperidine-1-carbonyl]-6-methoxy-2-methyl-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate;
1766-Chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]-2-methylindol-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1776-Methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]-indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1781-{5-[4-(4-Terbisil)piperidine-1-carbonyl]-6-methoxy-2-methyl-1H-indol-3-yl}-2-(4-methylpiperazin-1-yl)ethane-1,2-dione;
1796-Methoxy-[4-(4'-terbisil)-2R,5S-dimethylpiperazine]-2-methylindol-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1806-Methoxy-{4-[1-(4'-forfinal)ethyl]-2R,5S-dimethylpiperazine}-2-methylindol-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide;
1812-{5-[4-Fluoro-4-(4-terbisil)piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-N,N-dimethyl-2-oxoacetate

and their pharmaceutically acceptable salts.

37. The compound according to claim 1, selected from the group including

6-methoxy-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 144);

1-methyl-6-chloro-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 58);

1-methyl-6-methoxy-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-Glyoxylic acid N,N-DIMET lamed (compound 25);

1-methyl-6-chloro-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-Glyoxylic acid morpholine (compound 20);

1-methyl-6-methoxy-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-Glyoxylic acid morpholine (compound 23);

6-methoxy-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-Glyoxylic acid morpholine (compound 141);

6-chloro-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-Glyoxylic acid morpholine (compound 165);

6-methoxy-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-Glyoxylic acid amide (compound 145);

6-chloro-[4'-fluoro-(4-benzylpiperidine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 163),

and their pharmaceutically acceptable salts.

38. The compound according to claim 1, selected from the group including

1-methyl-6-methoxy-[4'-fluoro-(4-benzyl-2,5-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 15);

1-methyl-6-chloro-[4'-fluoro-(4-benzyl-2,5-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 33);

1-methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 57);

1-methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-amide piccilo the Oh of the acid (compound 59);

1-methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N-methylamide (compound 77);

1-methyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 89);

1-methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid morpholine (compound 96);

1-methyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-

5-carboxamide-3-Glyoxylic acid morpholine (compound 100),

and their pharmaceutically acceptable salts.

39. Connection § 38, where the specified compound is 1-methyl-6-methoxy-[4'-fluoro-(4-benzyl-2,5-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 15) or its pharmaceutically acceptable salt.

40. Connection § 38, where the specified compound is 1-methyl-6-chloro-[4'-fluoro-(4-benzyl-2,5-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 33) or its pharmaceutically acceptable salt.

41. Connection § 38, where the specified compound is 1-methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 57) or its pharmaceutically acceptable salt.

42. Connection § 38, where is the th compound is 1-methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid amide (compound 59) or its pharmaceutically acceptable salt.

43. Connection § 38, where the specified compound is 1-methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N-methylamide (compound 77) or its pharmaceutically acceptable salt.

44. Connection § 38, where the specified compound is 1-methyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 89) or its pharmaceutically acceptable salt.

45. Connection § 38, where the specified compound is 1-methyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid morpholine (compound 96) or its pharmaceutically acceptable salt.

46. The compound according to claim 1, where the specified compound is 6-chloro-[4'-fluoro-(4-benzyl-2,5-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 144) or its pharmaceutically acceptable salt.

47. Connection § 38, where the specified compound is 1-methyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid morpholine (compound 100) or its pharmaceutically acceptable salt.

48. The compound according to claim 1, where the specified connection is 1-etoxycarbonyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethyl who MFA (compound 34), or its pharmaceutically acceptable salt.

49. The compound according to claim 1, where the specified connection is 1-etoxycarbonyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 38) or its pharmaceutically acceptable salt.

50. The compound according to claim 1, where the specified connection is 1-tert-butoxycarbonyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 45) or its pharmaceutically acceptable salt.

51. The compound according to claim 1, where the specified compound is 1-acetyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 56) or its pharmaceutically acceptable salt.

52. The compound according to claim 1, where the specified compound is 1-acetyl-2-methyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 60) or its pharmaceutically acceptable salt.

53. The compound according to claim 1, where the specified connection is 1-methoxymethyl-6-chloro-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 63) or its pharmaceutically acceptable salt.

54. The compound according to claim 1, where the specified connection is 1-methoxymethyl-6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 92) or its pharmaceutically acceptable salt.

55. The compound according to claim 1, where the specified compound is 1-methyl-6-chloro-[4-(1-(4'-forfinal)ethyl)-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 102) or its pharmaceutically acceptable salt.

56. The compound according to claim 1, where the specified connection is methyl ester of 6-methoxy-(4-benzylpiperazine)indole-5-carboxamide-3-Glyoxylic acid (compound 137) or its pharmaceutically acceptable salt.

57. The compound according to claim 1, where the specified connection represents methyl ester [4-(1-phenylethyl)piperazinil]indole-5-carboxamide-3-Glyoxylic acid (compound 138) or its pharmaceutically acceptable salt.

58. The compound according to claim 1, where the specified compound is (4-benzyl-2R,5S-piperazine)indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 152) or its pharmaceutically acceptable salt.

59. The compound according to claim 1, where the specified compound is 6-methoxy-[4'-fluoro-(4-benzyl-2,5-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid morpholine (compound 161) or its pharmaceutically acceptable salt.

60. The compound according to claim 1, where the specified compound is 6-methoxy-[4'-fluoro-(4-benzyl-2R,5S-dimethylpiperazine)]indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 177) or its pharmaceutically acceptable salt.

61. The connection is about to claim 1, where the specified connection is (6-methoxy-2-methyl-[4-(1-(4'-forfinal)ethyl)-2R,5S-dimethylpiperazine)indole-5-carboxamide-3-Glyoxylic acid N,N-dimethylamide (compound 180) or its pharmaceutically acceptable salt.

62. Derivatives of indole of the formula

and their pharmaceutically acceptable salt,

where

represents a double bond;

Z1represents N, CH, SLEEP or CF;

Z2in position 2 is CR, where R is H or alkyl (C1-6);

Z2at position 3 is C-C(=O)-C(=O)-or, or C-C(=O)-C(=O)-NR2where each R is independently H or alkyl(C1-6), or NR2is morpholino, piperidino or pieperazinove ring, each of which may be substituted by up to 3 groups selected from R' and-OR', where R' is alkyl (C1-6);

R7is H or is C1-C6the alkyl, SO2R, RCO, COOR, C1-C6alkyl-COR, CONR2, SO2NR2CN, CF3, NR2, OR, C1-C6alkyl-SR, C1-C6alkyl OR C1-C6alkyl-COOR or C1-C6alkyl-CN, where each R independently is H or C1-C6the alkyl, or R7is methoxymethyl, methoxyethyl, ethoxymethyl;

each R3/sup> independently is halogen, C1-C6the alkyl, OR, SR or N(R)2where R is H or C1-C6by alkyl;

n is 0-3;

m is 0-4;

L1CO;

L2is alkylene (1-4C), optionally substituted by one or two groups of C1-C4of alkyl;

each R4independently selected from the group comprising C1-C6alkyl, halogen, OR, SR, SOR, SO2R, RCO, COOR, CONR2and SO2NR2,

where each R independently is H or C1-C6by alkyl;

Ar is an aryl group substituted by 0-5 substituents selected from the group comprising C1-C6alkyl, halogen, OR, SR, SOR, SO2R, RCO, COOR, CONR2and SO2NR2where each R independently is H or C1-C6the alkyl.

63. Pharmaceutical composition having inhibitory activity against R-α kinase, containing at least one pharmaceutically acceptable excipient and derived indole of the formula (I)

and its pharmaceutically acceptable salt,

whererepresents a double bond;

Z1is N or CR5where R5represents H, C1-C6alkyl, hydroxy, C1-C6alkoxy legalage;

Z2in position 2 is CR1and Z2at position 3 is SA;

where each R1independently is hydrogen or C1-C6by alkyl;

But it is Wi-COXjY, where Y is COR2,

where R2is OR, NR2, NRNR2or NROR, where each R independently represents H, C1-C6alkyl or C5-C6heteroaryl containing in the ring one or two heteroatoms selected from N, O and S, each of which is optionally substituted by one or more groups selected from NR'2, OR', COOR', C1-C6of alkyl, CN, =O, SR', where each R' represents H or C1-C6alkyl, and where two R or R'attached to the same N atom may form a 3-8-membered ring selected from the group comprising pieperazinove ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrolidine ring, piperidine ring, azacycloheptane ring, azacycloheptane ring and azacycloheptane ring; and where the specified ring may be optionally substituted C1-C6the alkyl or COO-C1-C6the alkyl, and X is unsubstituted alkylene (1-6C), or Y is an imidazole, substituted stands, i is 0, j is 0 or 1;

R7is N or C1-C6the alkyl, SOR, SO 2R, RCO, COOR, C1-C6alkyl-COR, CONR2, SO2NR2, CN, OR, C1-C6alkyl-SR, C1-C6alkyl-OCOR, C1-C6alkyl-COOR, C1-C6alkyl-CN, or C1-C6alkyl-CONR2where each R independently represents H, C1-C6alkyl or aryl, which is optionally substituted with halogen, C1-C4the alkyl or C1-C4alkoxy, or R7is methoxymethyl, methoxyethyl, ethoxymethyl, benzoyloxymethyl or 2-methoxyethoxymethyl;

each R3independently is halogen, C1-C6the alkyl, OR, SR or NR2where R is H or C1-C6alkyl;

n is 0-3;

L1CO;

L2is alkylene (1-4C), optionally substituted by one or two groups With1-C4of alkyl;

each R4independently selected from the group including C1-C6alkyl, halogen, OR, NR2, SR, SOR, SO2R, RCO, COOR, CONR2, SO2NR2where each R independently represents H or C1-C6alkyl, or R4is =O;

m is 0-4;

Ar is an aryl group substituted by from 0 to 5 substituents selected from the group comprising C1-C6alkyl, halogen, OR, NR2, SR, SOR, SO2R, RCO, COOR, CONR2and SO2NR2where each R independently represents H or C 1-C6alkyl.

Priority points and features:

21.05.1999 according to claims 1, 2-6, 8-35, 62, 65, for compounds of formula I or their pharmaceutically acceptable salts, where Z1represents N or CH, L2is unsubstituted alkylene (1-4C), Ar is an aryl group substituted by from 0 to 5 substituents selected from the group comprising C1-C6alkyl, halogen, OR, NR2, SR, RCO, COOR, CONR2and where Z2, R, R1, A, R2, R', R3, R4, R7L1, W, X, Y, I, j, n and m have the meanings indicated in claim 1;

17.09.1999 according to claims 1, 7, 37-61, 62, 63 for compounds of formula I or their pharmaceutically acceptable salts, where Z1is CR5where R5represents C1-C6alkyl, hydroxy, C1-C6alkoxy or halogen; L2is alkylene (1-4C)substituted with one or two groups C1-C4of alkyl; Ar is an aryl group substituted by from 0 to 5 substituents selected from the group including SOR, SO2R, SO2NR2; and where Z2, R, R1, A, R2, R', R3, R4, R7L1, W, X, Y, I, j, n and m have the meanings indicated in claim 1;

09.05.2000 in § 38.



 

Same patents:

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperazine oxime of the general formula (I): wherein X means phenyl or pyridyl substituted with 1 or 2 substitutes; Y means 2- or 3-indolyl, phenyl, 7-azaindole-3-yl, 3-indazolyl, 2-naphthyl, 3-benzo[b]thiophenyl or 2-benzofuranyl that can be substituted; n = 0-3; m = 0-2; R1 means -NH2, morpholino-, thiomorpholino-group, 2-, 3- or 4-pyridyl or 4-CH3-piperazinyl. Compounds possess antagonistic activity with respect to neurokinine receptors and can be used in treatment of anxiety states. Also, invention describes a pharmaceutical composition based on compounds of the formula (I), method for its preparing and using.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 16 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of sulfonylpyrrolidine of the formula (I): wherein R1 means aryl optionally substituted with halogen atom; R2 means aryl optionally substituted with halogen atom or (lower)-alkyl; R3 means -OR', cyano-group, halogen atom, N-hydroxyamidino-group, -C(O)-OR, -C(O)NR'R'', -N(R')-C(O)-R4, -N(R')-S(O)2-R, -N(R')-C(S)-NR'R, or 5- or 6-membered heteroaryl group comprising from 1 to 4 heteroatoms one of that represents oxygen atom and others represent nitrogen atom, or all heteroatoms represent nitrogen atom only and optionally substituted with (lower)-alkyl or (C3-C7)-cycloalkyl; R4 means (C3-C7)-cycloalkyl, phenyl or (lower)-alkyl that are optionally substituted with halogen atom; R means (lower)-alkyl; R' means hydrogen atom (H), (lower)-alkyl or (C3-C7)-cycloalkyl-(lower)-alkyl being independently of one another if above one R' presents; R'' means H, (lower)-alkyl; n means a whole number from 0 to 5, and to their pharmaceutically acceptable salts under condition that 1-[4-(methylphenyl)sulfonyl]-5-phenylpyrrolidinemethanol is excluded. Compounds of the formula (I) possess affinity to metabotropic glutamate receptors of group I that allows their using as a medicinal agent in treatment, prophylaxis of acute and/or chronic neurological disturbances and states that result to development of glutamate insufficiency taken among the following disorders: damage of spinal cord, head trauma, hypoxia caused by pregnancy, hypoglycemia, Alzheimer's disease, Huntington chorea, amyotrophic lateral sclerosis, disturbance in cognitive ability, memory disturbance and chronic and acute pain, schizophrenia, idiopathic parkinsonism and parkinsonism caused by medicinal agents, convulsions, anxiety (fear) and depressions.

EFFECT: valuable medicinal properties of compounds.

21 cl, 6 sch, 1 tbl, 153 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new ortho-substituted and N-substituted indoles of the formula (α): or (β): or their pharmaceutically acceptable salts wherein Z1 represents -CR4 or nitrogen atom (N); R4 means hydrogen atom (H), (C1-C6)-alkyl comprising optionally oxygen atom (O) or nitrogen atom (N) possibly substituted with halogen atom, keto-group, 5-6-membered cycloaliphatic radical possibly comprising 1-2 oxygen atoms (O) or nitrogen atom (N); Z2 represents -CH or -CR wherein R means (C1-C6)-alkyl; R1 means compound of the formula: wherein X1 means -CO or its isostere; m = 0, 1; Y represents alkyl that can be substituted; or two Y form in common (C2-C3)-alkylene; n = 0, 1 or 2; Z3 represents -CH; X2 represents -CH, -CH2 or their isostere; Ar represents one or two phenyl groups bound with X2 wherein phenyl can be substituted; R2 represents hydrogen atom (H), (C1-C6)-alkyl or aryl wherein each aryl comprises, possibly, oxygen atom (O) or nitrogen atom (N) and can be substituted. Proposed compounds are selective inhibitors of p38α kinase.

EFFECT: valuable biochemical properties of compounds.

34 cl, 5 tbl, 23 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

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

4 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted indole compounds of Mannich bases of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C10)-alkyl, unsubstituted phenyl or naphthyl bound through (C1-C2)-alkylene group or that monosubstituted at least with hydroxy group (-OH), halogen atom, -CF3, -CN, (C1-C6)-alkyl, (C1-C6)-alkoxy group; R2 means atoms H, F, Cl, Br, groups -CF3, -CN, -OR10, -CO(OR11), -CH2CO(OR12), -COR19, (C1-C10)-alkyl, unsubstituted phenyl or naphthyl, or that monosubstituted at least with -OH, halogen atom, -CF3, -CN, (C1-C6)-alkyl and (C1-C6)-alkoxy group; R3 means -CH(R13)N(R14)(R15); R4, R5, R6 and R7 can have similar or different values and mean atoms H, F, Cl, Br and groups -CF3, -CN, -NO2, -OR10 and others; R10 means H, -COR17, (C1-C6)-alkyl and others; R13 means unsubstituted phenyl or phenyl monosubstituted with at least (C1-C4)-alkyl, halogen atom, -CF3, -CN and -OH; R14 and R15 can have similar or different values and mean unbranched or branched (C1-C6)-alkyl, or R14 and R15 represent in common (CH2)n wherein n means a whole number from 3 to 6, or (CH2)O(CH2)2; R17 means (C1-C6)-alkyl; R19 means -NHR20, (C1-C6)-alkyl and others; R20 means H, (C1-C6)-alkyl and others, and/or their racemates, enantiomers, diastereomers and/or corresponding bases, and/or corresponding salts of physiologically acceptable acids with exception of racemates of some compounds given in claim 1. Also, invention describes method for their preparing and using as a medicinal agent possessing analgesic effect.

EFFECT: valuable medicinal properties of compounds.

42 cl, 2 dwg, 3 tbl, 103 ex

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

SUBSTANCE: invention relates to new derivatives of 1-aziridino-1-hydroxyiminomethyl of the general formula (I):

wherein R means a single bond or organic radical that can bind aziridinoxime groups by a covalent bond and taken among the group including saturated or unsaturated alkanes with normal or branched chain and comprising up to 6 carbon atoms, substituted azino-group -(R')C=N-N=C(R'') wherein R' and R'' represent independently of one another hydrogen atom or lower alkyl, heterocyclic compounds comprising from 3 to 6 atoms in ring and up to 4 heteroatoms taken among -N- and -O-, and aromatic compounds comprising up to 8 atoms in ring; R1 and R2 mean independently of one another -H, -COOH, -COOCH3, -COOC2H5 or -CONH2; n means a whole number 2 or 3; with exception the compound wherein R represents a single bond and R1 and R2 are both hydrogen atom, and also with exception the compound wherein R represents a single bond and one of substitutes is hydrogen atom among the group R1 and R2. Also, invention describes a method for their preparing and medicinal preparations comprising these compounds that possess an antitumor effect.

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

7 cl, 3 tbl, 19 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-phenylpyridine of the general formula: (I) wherein R means halogen or halogen atom; R1 means -(C≡C)mR1' or -(CR'=CR'')mR1'; X means -C(O)N(R8)-, -N(R8)C(O)- or -N(R8)-(CH2)p- wherein m = 0-4 and p = 1-2; values of radicals R1', R2, R3', R3, R4, R4', R8, R' and R'' are given above, and to their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. New compounds are neurokinine-1 antagonists and can be used as medicinal agents in treatment of diseases mediated by neurokinine-1 receptors.

EFFECT: valuable medicinal properties of derivatives.

13 cl, 119 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to a new biologically active compound of 4-oxoquinoline that is useful as an anti-HIV agent and to its pharmaceutically acceptable salt. Invention describes an anti-HIV agent comprising compound of 4-oxoquinoline represented by the following formula [I] or its pharmaceutically acceptable salt as an active component wherein ring Cy represents phenyl group, naphthyl group or pyridyl group and each this group is substituted optionally with 1-5 substituted chosen from the following group A wherein A represents the group consisting of cyano-group, phenyl group, nitro-group, halogen atom, (C1-C4)-alkyl group, halogen-(C1-C4)-alkyl group, halogen-(C1-C4)-alkoxy-group, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3 and -COORa1 wherein Ra1 and Ra2 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or benzyl group, and Ra3 represents (C1-C4)-alkyl group; R1 represent a substitute chosen from the following group B, or (C1-C10)-alkyl group optionally substituted with 1-3 substitutes chosen from halogen atom and the following group B wherein the group B represents the group consisting of phenyl group optionally substituted with phenyl group or 1-5 halogen atoms; (C3-C6)-cycloalkyl group, imidazolyl group, benzothiophenyl group, thiazolyl group optionally substituted with 1-3 (C1-C6)-alkyl groups, morpholinyl group, pyridyl group, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4 and -NRa5COORa6 wherein Ra4 and Ra5 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or phenyl group; Ra6 represents (C1-C4)-alkyl group; R2 represents hydrogen atom or (C1-C4)-alkyl group; R31 represents hydrogen atom, cyano-group, hydroxy-group, halogen atom or (C1-C4)-alkoxy-group; X represents -C-R32, and Y represents -C-R33 or nitrogen atom wherein R32 and R33 are similar or different and each represents hydrogen atom, cyano-group, halogen atom, pyrrolidinyl group, (C1-C10)-alkyl group optionally substituted with 1-3 halogen atoms, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10 or -N=CH-NRa10Ra11 wherein Ra7 and Ra8 are similar or different and each represents hydrogen atom, phenyl group or (C1-C10)-alkyl group optionally substituted with (C3-C6)-cycloalkyl group or hydroxy-group; Ra9 represents (C1-C4)-alkyl group and Ra10 and Ra11 are similar or different and each represents hydrogen atom or (C1-C4)-alkyl group. Also, invention describes compound of the formula (III) given in the invention description, integrase inhibitor, antiviral agent, ant-HIV composition, anti-HIV agent, using compound of 4-oxoqionoline, method for inhibition of integrase activity, method for prophylaxis or treatment of viral infectious disease, pharmaceutical composition used for inhibition of integrase activity, antiviral composition and commercial package (variants). Invention provides the development of a pharmaceutical agent possessing inhibitory effect on activity of integrase.

EFFECT: valuable medicinal properties of compound, agent and composition.

40 cl, 7 tbl, 250 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

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

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I): or its pharmaceutically acceptable salt. Indicated compounds stimulate release of growth hormone from hypophysis and can be used in medicine.

EFFECT: improved stimulating method, valuable medicinal property of compound and composition.

4 cl, 1 dwg, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

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

11 cl, 2 tbl, 27 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new improved method for preparing derivatives of 3,3-diarylpropylamines of the general formula (I) and sterically highly pure stable intermediate substances and their using for preparing pharmaceutical compositions. Method for preparing 3,3-diarylpropylamines of the general formula (I) wherein R means hydrogen atom, linear or branched (C1-C6)-alkyl but preferably methyl or isopropyl; R' and R'' can be similar or different and mean linear or branched (C1-C6)-alkyl but preferably methyl or isopropyl. Method involves condensation of cinnamic acid with compound of the general formula (1) to form compound of the general formula (2a) and the following reaction of the latter with chiral tertiary amine - cinchonidine to yield the corresponding salt of compound of the general formula (2b): and then from this compound the crystalline form of compound of the formula (3): is isolated followed by its either direct reduction with equivalent excess of hydride to yield lactol of the formula (5a) or via intermediate step by formation of corresponding acid chloroanhydride to form ester with alcohols of type R-OH wherein R is given above and the following conversion to compound of the formula (4): and the latter is hydrogenated with diisobutylaluminum-hydride or tri-tert.-butoxyaluminum-hydride to yield lactol of the formula (5) . Prepared lactols of the formula (5a) or (5) after reductive amination with secondary amine form compounds of the formula (I).

EFFECT: improved preparing method.

10 cl, 1 sch, 1 tbl, 13 ex

Muscarinic agonists // 2269523

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein Z1 represents -CR1 or nitrogen atom (N); Z2 represents -CR2; Z3 represents -CR3 or N; Z4 represents -CR4; W1 represents oxygen (O), sulfur (S) atom or -NR5; one of W2 and W3 represents N or -CR6 and another among W2 and W3 represents CG; W1 represents NG; W2 represents -CR5 or N; W3 represents -CR6 or N; or W1 and W3 represent N and W2 represents NG; G represents compound of the formula (II): wherein Y represents oxygen atom (O), -C(O)- or absent; p = 1, 2, 3, 4 or 5; Z is absent; each t = 2. Also, invention describes a method for enhancing activity of the muscarinic cholinergic receptor and a method for treatment of morbid states when modification of cholinergic and, especially, muscarinic receptors m1, m4 or both m1 and m4 offers the favorable effect.

EFFECT: valuable medicinal properties of agonists.

14 cl, 2 tbl, 101 ex

FIELD: medicine, pharmaceutical industry.

SUBSTANCE: the suggested preparation for treating inflammatory skin diseases contains mud volcano mud as an active substance to be introduced into polymeric mixture, moreover, the mud should be introduced into swollen polymers during mixing and homogenization till the development of homogeneous gel mass at the ratio of 15-30:1.5-2.5 in weight portions, and, also, a conservant and a pharmaceutically acceptable solvent. Additionally, the preparation contains plant and/or mineral oils and an emulsifier.

EFFECT: higher efficiency of therapy.

4 cl, 4 ex

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