Tacrine derivatives as acetylcholinesterase inhibitors

FIELD: chemistry.

SUBSTANCE: invention describes an amide of formula:

where A and B are independently selected from CH or N; D is H; Z is selected from hydrogen, unsubstituted C1-8alkyl, each L is independently selected from -CraRb-, -CRa=, -CO-, -O- or -NRa-; k, m, n, q, x and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, provided that k+m+n+q+x+w equals at least 4; R1-R6 are independently selected from hydrogen, CN or halogen; Ra and Rb are independently selected from hydrogen, unsubstituted C1-8alkyl, or its pharmaceutically acceptable salt. The invention describes a pharmaceutical composition, use of the compounds to treat AChE-mediated diseases, a treatment method, as well as an amide synthesis method and use of the formula (I) amide as a chemical agent for inhibiting acetylcholinesterase in biological research.

EFFECT: compounds have high acetylcholinesterase or butyrylcholinesterase inhibiting activity.

24 cl, 27 ex, 1 tbl

 

The technical field

This invention relates to a series of derivatives of tacrine, methods for their preparation, pharmaceutical compositions containing them and to their use in medicine. In particular, it relates to compounds and compositions that exhibit dvukhshagovoi inhibition of acetylcholinesterase, which is especially useful for the treatment of Alzheimer's disease.

Prior art

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is one of the most common causes of mental deterioration in the elderly, accounting for approximately 50-60% of all cases of dementia among people over 65 years of age. Demographic data indicate that the rate of cancer in the population of elderly is increasing.

Parts of the brain that are associated with higher mental functions, especially the neocortex and the hippocampus, are parts of the brain most affected by the characteristic pathology of AD. The characteristic pathology of AD include extracellular deposits of β-amyloid (derived from protein-amyloid precursor, APP) in senile plaques, intracellular formation of neurofibrillary plexus (containing abnormally phosphorylated form associated with microcannulae protein, Tau) and loss of neural what about the synapse and pyramidal neurons.

Current approaches to the treatment of this disease continue to be primarily symptomatic in nature with the main therapeutic strategy based on the cholinergic hypothesis and especially on the inhibition of acetylcholinesterase (AChE). During the last decades of the cholinergic hypothesis of AD has brought to the market various cholinergic drugs, mainly, AChE inhibitors, such as, for example, taken, donepezil or rivastigmine and most recently, galantamine, with a moderate improvement in cognitive function of patients suffering from Alzheimer's disease. These compounds, however, cause undesirable side effects such as nausea and vomiting.

Of the three-dimensional structure of AChE determined by x-ray crystallography, it follows that its active site, apparently, you can only penetrate through the deep and narrow catalytic pass. The AChE inhibitors affect two of the target site on the enzyme active site and the peripheral site. Inhibitors directed to the active site prevents the binding of the molecule-substrate, or hydrolysis, or occupying the site of a molecule with high affinity (taken)or irreversibly interacting with the catalytic serine (organophosphates and carbamates). Peripheral site consists of less than a certain teaching is TKA, localized at the entrance of the catalytic narrow passage. Inhibitors that are associated with this site include small molecules, such as propedy and peptide toxins, such as fasciculi. Bis-quaternion inhibitors, such as, for example, decamerone, at the same time associated with the active and peripheral sites, thereby occupying, in General, catalytic narrow passage.

In parallel with the development of drugs against dementia, research efforts have focused, among other things, on therapeutic potential of AChE inhibitors to slow the progression of such disorders. This fact was based on some data that clearly showed that AChE has secondary nehallenia functions.

New data show that AChE may play neposredstvennoy role in the differentiation of neurons. In addition, it was investigated the role of AChE in the adhesion of cells. The results indicate that AChE activates axonal growth in cell lines of neuroblastoma through effects on cell adhesion.

In addition, recent studies have shown that peripheral anionic site of AChE involved in the neurotrophic activity of the enzyme and lead to the conclusion that the function of adhesion AChE localized in the peripheral anionic site. This conclusion is not only to deepen our ponies the project for development of diseases of the nervous system and its disorders but also for the treatment of neuroblastoma, leukemia and, in particular, for the treatment of Alzheimer's disease.

As mentioned earlier, senile plaques are one of the pathological signs of AD, and their main component is β peptide. It is found in the form of a membrane not easily soluble aggregated form. In contrast, soluble β identified as normally circulating in the body fluids of a person. Structural studies β showed that synthetic peptides containing the sequence 1-40 and 1-42 β, can take two main conformational States in solution: amyloidogenic conformer (β ac) with a high content of β-pleated sheets, partially resistant to proteases, and neuroimagery conformer (β nac) with a disordered conformation of the ball or β-spiral-sensitive proteases. AChE together with localized deposits β peptide present in the brain of patients with Alzheimer's disease. Postulated that the AChE associated with form β nac, acting as a pathological chaperone and inducyruya conformational transition of the form β nac in the form β ac in vitro and, therefore, in amyloid fibrils. AChE directly stimulates the formation of amyloid fibrils from β peptide, forming stable complexes β-AChE.

Whereas nehallenia aspects the s cholinergic enzyme AChE, their relationship with symptoms of Alzheimer's disease and the role of the peripheral site of AChE in all of these functions reveals a promising target for developing new drugs against dementia. Peripheral or dvuhlitrovye AChE inhibitors can alleviate the impaired cognitive abilities in patients with Alzheimer's disease, and, more importantly, to avoid aggregation of β-amyloid, which is a new way to slow down the progression of the neurodegenerative process.

Thus, ligands capable of interacting simultaneously with the active and peripheral sites could have several advantages compared to the known inhibitors. On the one hand, they should significantly improve inhibitory efficiency, and, on the other hand, they should be involved in neurotropic activity.

Recently it was reported that some compounds with both activities, see Piazzi L. et al., J. Med. Chem.,2003,46, 2279, 2282.

In international patent publication WO 03033489 described derivatives of piperidine derivatives having an inhibitory action on acetylcholinesterase and on the aggregation of beta-amyloid.

In international patent publication WO 0117529 disclosed halogen-substituted derivatives of tacrine or mistaken for the treatment of disease Alzheime the and. One of the subgroups is the rest of the indole, coupled with tacrine through a short linker. For example, this publication describes the obtaining of N-[2-(3-indolyl)ethyl]-6-Cartagena formula:

In international patent publication WO 0117529 no assumptions about the website inhibition and no data was provided for the activity.

Castro, A.; Martinez, A. Mini Rev. Med. Chem.,2001, 1, 267-272 describes several families of AChE inhibitors with affinity to peripheral and simultaneously two types of the above sites, including some derivatives of tacrine.

International patent publication WO 04032929 discloses inhibitors of AChE with affinity simultaneously to two videopreteen sites (i.e., inhibitors of AChE dual action), containing the remainder of tacrine connected through a linker with certain heterocyclic compounds, such as the balance of tacrine, indanone or thiadiazolidine.

The invention

After careful research, the authors developed individual structural class of inhibitors of AChE dual-action, i.e. compounds which, following the above concepts, demonstrate the high activity of inhibiting AChE along with changes in the aggregation properties of β-amyloid due to the fact that they are simultaneously contacted with the catalytic and peripheral sites of AChE. In addition, electively can be modulated, and they are of low toxicity, which makes them promising for development on their basis of medicines.

The compounds of this invention are characterized by two basic heterocyclic components: the balance of tacrine and [6+5]heteroaromatic residue linked via an appropriate linker. The authors found that the selectivity and activity of the claimed compounds can be modulated by the nature and chain length of the linker, and the nature of substituents of the above-mentioned main components. As examples, these compounds show high inhibition of AChE, low toxicity, have high affinity for binding to the peripheral site and inhibit the aggregation of β-amyloid and the formation of the complex unit of β-amyloid-AchE and, if desired, exhibit high selectivity.

In one aspect this invention relates to the compound of formula (I):

Formula 1

where

A, B are independently selected from CH or N;

D is selected from CH, O, S, N;

provided that at least one of A, B or D is a heteroatom;

when D represents CH or N, then Z is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, and substituted and unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted, aryloxy;

when D represents O or S, then Z is absent;

each L is independently selected from-CRaRb-, -CRa=, -CO-, -O-, -S - or-NRa-;

k, m, n, q, x and w means, each an integer selected from 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10, provided that k+m+n+q+x+w is at least 4;

R1FOR R6independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -CORa, -C(O)ORa, -C(O)NRaRb,- (C=NRa, -CN, -ORa, -OC(O)Ra, -S(O)t-Ra, -NRaRb, -NRaC(O)Rb, -NO2,-N=CRaRbor halogen;

RaAnd Rbeach independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted, aryloxy or halogen; provided that they are not halogen when associated with N;

t is 0, 1 or 2;

the sludge is its tautomer, pharmaceutically acceptable salt, prodrug or MES.

The side chain of the formula:

it is accordingly a Deputy to a or b when a or b represents a carbon, which is then transformed into C instead of SN.

In another aspect this invention relates to pharmaceutical compositions that contain the compound according to formula (I) or its pharmaceutically acceptable salt, prodrug or MES and a pharmaceutically acceptable carrier, adjuvant or excipient. In a preferred embodiment, the composition is for oral administration.

In addition, the present invention relates to the use of videopreteen compounds to obtain medicines, preferably for the treatment of disorders of cognitive abilities, such as senile dementia, cerebrovascular dementia, mild decrease in cognitive function, attention deficit, and/or neurodegenerative diseases, accompanied by loss of reason, with abnormal protein aggregation, such as Alzheimer's disease or related condition, or prion diseases, such as disease Creutzfeldt-Jakob disease, or disease of Gerstman-Straussler-Sheinker, or Parkinson's disease, or parkinsonopodobnyh state, or polyglutamine disease, or tauopathy such as more is ery Peak fronto-temporal dementia, progressive supranuclear palsy, or familial amyotrophic lateral sclerosis, or systemic amyloidosis, or a related condition.

In another embodiment, this invention relates to the use of videopreteen compounds in the treatment of the aforementioned diseases or conditions.

In another aspect this invention relates to the use of videopreteen compounds as reagents for biological research.

In another aspect this invention relates to a method for producing the above compounds of formula I by linking two heterocyclic components via a linker.

Detailed description of the invention

In the above definition of the compounds of formula (I), the following terms have the following preferred values:

"Alkyl" refers to a hydrocarbon radical straight or branched chain consisting of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms and which is linked to the remainder of the molecule by a simple relationship, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl etc. Alkyl radicals may be optionally substituted by one or more substituents, such as halogen, hydroxy, alkoxy, carbon and, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio.

"Amino" refers to a radical of the formula-NH2-The otheraor-NRaRbwhere Raand Rbsuch as defined above.

"Aryl" refers to phenyl, naftalina, angenlina, phenanthridinone or anthracyclinone the radical, preferably phenyl or naftalina the radical. The aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halogen, alkyl, phenyl, alkoxy, halogenated, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl.

"Aralkyl" refers to an aryl group linked to an alkyl group. Preferred examples include benzyl and phenethyl.

"Acyl" refers to a radical of the formula-C(O)-Rcor-C(O)-Rdwhere Rcrepresents an alkyl radical and Rdrepresents an aryl radical, such as acetyl, propionyl, benzoyl and the like, there may be other acyl groups.

"Cycloalkyl" refers to (3-10)-membered monocyclic or bicyclic the radical, which is saturated or partially saturated and which consists of carbon and hydrogen atoms. Unless stated otherwise specifically in this description assumes that the term "cycloalkyl includes cycloalkyl radicals that long is Ino substituted by one or more substituents, such as alkyl, halogen, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl.

"Condensed aryl" refers to aryl group, especially phenyl or heteroaryl group condensed with another cycle.

"Alkoxy" refers to a radical of the formula-ORawhere Rarepresents a higher alkyl radical, for example methoxy, ethoxy, propoxy, etc.

"Gal-" or "Halo" refers to bromine, chlorine, iodine or fluorine.

"Heterocyclyl" refers to (3-15)-membered cyclic radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably (4-8)membered cycle with one or more heteroatoms, more preferably 5 to 6-membered cycle with one or more heteroatoms. For purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tricyclic structure, which may include a condensed cyclic structure; and atoms of nitrogen, carbon or sulfur in the heterocyclic radical may be optionally oxidized; the nitrogen atom may be optionally quaternion; and the heterocyclic radical may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, ephiny, the benzimidazole, benzothiazole, furan, isothiazol, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran.

References herein to substituted groups in the compounds of the present invention relate specifically to a particular residue, which can be substituted in one or more available positions by one or more suitable groups, for example halogen, such as fluorine, chlorine, bromine and iodine; cyano; hydroxyl; nitro; azido; alkanoyl, such as C1-6alcoolica group, such as acyl and the like; carboxamido; alkyl groups including those groups having from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenylamine and alkenylamine groups, including residues having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aryloxy groups such as phenoxy; alkylthio groups, including the remnants of which have one or more thioester linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groups, including the remnants of which have one or more sulfanilic St is sa and from 1 to about 12 carbon bonds or from 1 to about 6 carbon atoms; alkylsulfonyl groups, including the remnants of which have one or more sulfanilic linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; a carbocyclic aryl having 6 or more carbons, particularly phenyl or naphthyl and aralkyl, such as benzyl. Unless otherwise specified, optionally substituted group may have a substituent at each substitutable position of the group and each substitution is not dependent on another.

In the compounds according to this invention [6+5]heteroaromatic residue may be selected, among others, from indole, isoindole, benzimidazole, indazole, benzothiophene, benzothiazole, benzisoxazole, benzofuran, isobenzofuran.

A preferred class of compounds of formula (I) is the class in which a and preferably also represent CH. D preferably represents n

In a preferred variant of [6+5]heteroaromatic residue represents a structural unit of indole or indazole. In this case, good results were obtained when the linker is attached in position 2 or 3 of the indole, more preferably in position 3. More typically, in one embodiment of the present izobreteniya is located at the carbon of the heterocycle in position, located next to the benzene ring, which is, for example, position 3 of the indole. Such compounds have the formula:

Another preferred class of compounds of formula (I) represents the class in which the remnant of tacrine is substituted. More preferably, the remainder of tacrine was Deputy-halogen. In a preferred variant embodiment of the remainder of tacrine is Deputy-chlorine in position 6. This gives increased activity and selectivity for AChE.

The authors found that the linker between the two structural components plays an important role in the manifestation of activity and selectivity. Indeed, the linker containing a number of links L in the range from 4 to 18, more preferably from 7 to 13, gives good results. The most preferred values are from 8 to 12 and especially about 10 or 11.

In a preferred variant embodiment, the linker is -(L)to-(L)m-(L)n-(L)q-(L)x-(L)wis selected from the formula -(CH2)to-CO-NRa-(CH2)w-, -(CH2)k-NRa-CO-(CH2)w-, -(CH2)k-CO-NRa-(CH2)q-NRa-(CH2)w-, -(CH2)k-NRa-CO-(CH2)q-NRa-(CH2)w-, -(CH2)k-O-CO-NRa-(CH2)w-where k, q, w and Rasuch as the definition is prohibited above. More preferably the linker is -(L)to-(L)m-(L)n-(L)q-(L)x-(L)w- has the formula -(CH2)to-CO-NRa-(CH2)w- or -(CH2)to-O-CO-NRa-(CH2)w-. Rausually represents N. The integer k is 1 or 2, especially 2. Integer w is equal to, respectively, from 6 to 9, especially 6 or 7.

Preferably, the linker contain one or more amide links, they can be in any position in the linker.

It must be borne in mind that the present invention includes all combinations of the mentioned particular and preferred groups.

In one aspect, preferred compounds of this invention have the formula (II):

In a related aspect, preferred compounds have the formula (III):

In the compounds of the various formulas in this invention, Z is preferably selected from N and CH3especially H. R1, R3and R4are preferably N. R2preferably selected from H, -Gal and-CN, especially H. Preferably R5is a halogen and R6represents hydrogen.

In particular, the authors prefer to R1, R2, R3, R4, Z represents hydrogen; R5represented Galaga is, especially chlorine; and the linker has enabled amido, preferably an amido function, located between oligometastasis groups. In accordance with this, the linker preferably has the formula -(CH2)to-CONH-(CH2)w-where the sum of k and w is preferably in the range from 6 to 10, especially from 7 to 9. Accordingly, it is less than w, while q is 1, 2 or 3.

As options R1for R5independently selected from the group consisting of hydrogen, -CN, and halogen; and/or each L independently selected from the group consisting of-CRaRb-, -CO - and-NRa.

As an additional aspect of the present invention covers compounds of formula (A):

where:

L is independently selected from-C(R')(R")-, -CO-, -O - or-NR'-,

n is zero, one, two, three, four, five, six, seven, eight, nine or ten,

R' and R" are independently selected from hydrogen, alkyl, aryl, heteroaryl, halogen, halogenoalkane, alkoxy, alkylthio,

A is independently selected from-CO-, -C(R')(R”)-, =C(R')-, -N(R')-, =N-, -O-, -S(O)t-,

B is independently selected from-C(R')-, =C-, -N-,

C is independently selected from-C(R')(R")-, =C(R')-, -N(R')-, =N-,

R1, R2, R3, R4and R5independently selected from hydrogen, alkyl, alkoxy, alkylthio, cycloalkyl, halogenoalkane, halogen, aryl, -(Z)n-aryl, heteroaryl, -OR3, -C(O)Rsub> 3, -C(O)OR3, -S(O)t, cyano, nitro, mercapto,

t is zero, one or two,

Z is independently selected from C(R3)(R4)-, -C(O)-, -O-, -C(=NR3)-, -S(O)t-N(R3)-.

In a related aspect, compounds of this invention are in accordance with formula (I), and formula (A). Such compounds have the formula (B):

where appropriate definition selected, overlapping definitions as formulas (I)and formula (A).

Preferably, for formula (B) typically use the following definitions:

A represents CH or N;

B represents CH or N;

D represents CH, O, S or N;

at least one of A, B, and D is a heteroatom;

Z represents hydrogen, alkyl, alkoxy, cycloalkyl, halogenated, aryl, aralkyl, heteroaryl;

R1, R2, R3, R4, R5, R6represent hydrogen, alkyl, alkoxy, alkylthio, cycloalkyl, halogenated, halogen, aralkyl, heteroaryl, OR3, COR3, COOR3, SOtR3where t is 0, 1 or 2;

at least one of R1, R2, R3, R4represents hydrogen;

L represents CRaRr, CO, O, NRawhere Raand Rrrepresent hydrogen, alkyl, aryl, heteroaryl, halogen, halogenated, alcox is;

k, m, n, q, x, and w is from 0 to 10, provided that their amount is not more than 40 and preferably x and w are equal to 0.

Unless otherwise specified, it is assumed that the compounds according to this invention also include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, in the scope of the present invention includes compounds having the above structure, except for the replacement of the structure of hydrogen by deuterium or tritium, or the replacement of carbon13C - or14C-enriched carbon or15N-enriched nitrogen.

The term "pharmaceutically acceptable salt, derivative, solvate, prodrug" refers to any pharmaceutically acceptable salt, complex ether, MES or any other compound, which after administration to the recipient is capable of delivering (directly or indirectly) the compound described herein. However, it should be borne in mind that salt is not related to the pharmaceutically acceptable, are also within the scope of the invention because they can be used to obtain pharmaceutically acceptable salts. Obtaining salts, prodrugs and derivatives can be made by methods known in the art.

For example, pharmaceutically acceptable salts of compounds considered here, Sintesi the comfort of the starting compound, which contains a basic or acidic residue, conventional chemical methods. Generally, such salts receive, for example, the interaction of the free acid or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or a mixture of both. Usually the preferred non-aqueous environment, like ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of the additive salts of the acid include an additive salts of inorganic acids, such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and additive salts of organic acids, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluensulfonate. Examples of the additive salts of the base include inorganic salts such as, for example, salts of sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, and salts of organic bases, such as, for example, salts of Ethylenediamine, ethanolamine, N,N-dialkylacrylamide, triethanolamine, glucamine and salts of basic amino acids.

Especially preferred derivatives or prodrugs are those derivatives or prodrugs, which will help increase the bioavailability of the compounds according to this invention when such compounds in which W ill result to the patient (for example, giving oral input connection is easily absorbed into the blood) or which enhance delivery of the parent compound in a specific organ of a biological object (e.g., the brain or lymphatic system) in comparison with its source type.

Any compound that is a prodrug of compounds of formula (I), is not beyond the scope of this invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo into compounds according to this invention. The choice of such derivative obvious to a person skilled in the art, and they include, depending on the present in a given molecule functional groups and without limitation, derivatives offer the following compounds: esters, esters of amino acids, phosphate esters, metal salts, sulfate esters, carbamates and amides.

Compounds according to this invention may be in crystalline form or in the form of the free compounds or in the form of a solvate, and assumes that both forms are included in the scope of the present invention. Methods of solvation are well-known in this field. Suitable solvate are pharmaceutically acceptable solvate. In a specific embodiment, the MES p is ecstasy a hydrate.

The compounds of formula (I)or its salt, or a solvate are preferably in pharmaceutically acceptable or essentially pure form. Under a pharmaceutically acceptable form means the form, inter alia, with a pharmaceutically acceptable level of purity, including conventional pharmaceutical additives such as diluents and carriers, and not including any substance that is considered toxic at normal dose levels. The levels of purity for pharmaceutical substances are preferably more than 50%, more preferably more than 70%, most preferably more than 90%. In a preferred embodiment, the level of purity is more than 95% of the compounds of formula (I)or its salt, solvate or prodrugs.

The compounds of this invention represented by the above formula (I)may include enantiomers depending on the presence of chiral centers, or isomers, depending on the presence of multiple bonds (e.g., Z, E). Individual isomers, enantiomers or diastereoisomers and mixtures of them are all within the scope of the present invention.

The compounds of formula (I), defined above, can be obtained according to the strategy of the converging route by linking the two heterocyclic components that contain part of the linker. Synthetic methods for obtaining intermedi the tov, containing the remainder of tacrine or condensed with benzene, 5-membered heterocyclic system available from the literature and include conventional methods of organic synthesis. Specialist in the field of organic synthesis can easily develop a scheme to obtain for each connection, depending on the desired functionality of heterocycles and the nature of the linker that you want to receive. See, for example, international patent publication WO 0117529 and WO 04032929. Other intermediates reported in the literature.

9-alkylmethacrylamide can be synthesized following previously published methods [P.R. Carlier; Chow. E.S.-H; Han Y.; Liu, J.; El Yazal, J.; Pang Y.-P. J. Med. Chem.,1999, 42, 4225-4231]. General method for the synthesis of indole derivatives previously described in Padwa. A. et al., Synthesis,1994, 9, 993-1004. 5-Cyanoindole-3-propionic acid can be synthesized by the method reported in the literature [Agarwal A.; Jalluri R. K.; Dewitt C. Blanton; and Will Taylor E., Synthetic communications,1993, 23, 8, 1101-1110]. You can get and use alternative heterocycles. Conventional methods of organic synthesis can be found, for example, in "March''s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 5th Edition Wiley; Wiley series "The Chemistry of Heterocyclic Compounds"; Wiley Series Compendium of Organic Synthetic methods", etc.

Schemes 1 and 2 illustrate methods of preparing compounds according to this invention, when the linker contains amide or urethane link:

Alternative ways of obtaining compounds with a linker containing links Amin, simple ester, complex ester, and others apparent to the skilled in this field.

For example, to a solution of the corresponding derivative of indole in anhydrous THF added 1,1'-carbonyldiimidazole in the atmosphere N2and the resulting mixture is stirred for 4 hours at room temperature. Add a solution of the corresponding 9-alkylmethacrylamide in THF and stirring is continued for an additional 24 hours. After evaporation of the solvent under reduced pressure, water is added and the resulting mixture extracted with dichloromethane. The combined organic extracts are washed with saturated NaCl solution and dried Na2SO4. Evaporation of the solvent under reduced pressure gives a residue which is purified column flash chromatography on silica gel, as described below for each case.

The reaction products can be optionally purified by conventional methods such as crystallization or chromatography. In cases when the above-described methods for producing compounds according to this invention give a mixture of stereoisomers, these isomers may be separated by conventional methods such as preparative chromatography. If there are chiral CE the points that the compound can be obtained in racemic form, or individual enantiomers may be obtained either enantiospecific synthesis or by separation.

One preferred pharmaceutically acceptable form is a crystalline form, including a form of the pharmaceutical composition. In the case of salts and solvate additional ion part and part of the solvent should be non-toxic. Compounds according to this invention can provide various polymorphic forms, it is understood that the invention encompasses all such forms.

Typical compounds of this invention represented by the aforementioned formula (I), salt, MES or prodrug demonstrated excellent inhibitory activity against acetylcholinesterase. Therefore, another aspect of this invention relates to a method of treating, improving or preventing the disease or condition associated with AChE, and this method comprises the administration to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula (I) or pharmaceutical compositions containing it. Among the diseases that can be treated, disorders of cognitive abilities, such as senile dementia, cerebrovascular dementia, weak reduction cognition is athelney functions attention deficit disorder, and/or neurodegenerative, accompanied by loss of reason, a disease with abnormal protein aggregation, such as Alzheimer's disease or related condition, or prion disease, such as disease Creutzfeldt-Jakob or disease Gerstman-Straussler-Sheinker, or Parkinson's, or parkinsonopodobnyy state, or polyglutamine disease, or tauopathy, as, for example, the disease Peak, fronto-temporal dementia, progressive supranuclear palsy, or familial amyotrophic lateral sclerosis, or systemic amyloidosis, and related state.

In addition, the present invention provides pharmaceutical compositions containing a compound according to this invention or its pharmaceutically acceptable salt, derivative, prodrug or stereoisomer, along with a pharmaceutically acceptable carrier, adjuvant or excipient, for the introduction of the patient.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) a composition for oral, local or parenteral administration.

In a preferred embodiment, the pharmaceutical compositions are presented in oral form, either solid or liquid. Suitable dosage forms for pearling the injection can be in the form of tablets, capsules, syrups or solutions and may contain conventional excipients known in the art, such as binders, for example syrup, acacia, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for tableting, for example magnesium stearate; a disintegrator such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable humectants, such as sodium lauryl sulfate.

Solid oral compositions may be obtained by conventional methods of blending, filling or tableting. Multiple blending operation can be used to achieve adequate distribution of the active funds throughout the volume of the above compositions, uses large quantities of fillers. Such operations are common in the art. Tablets can be prepared with wet or dry granulation and optionally coated by methods well-known in this field, in particular intersolubility the floor.

The pharmaceutical composition may be adapted for parenteral administration such as sterile solutions, suspensions or liofilizovannye products to meet the total dosage form. Can be used adequate additional auxiliary means, such as fillers, buffering agents or surfactants.

The above drugs are usually obtained using standard methods, such as those described or referenced in the Pharmacopoeia of Spain and the United States and similar reference texts.

Introduction compounds or compositions according to this invention can be carried out by any suitable method, such as intravenous infusion with oral drugs and intraperitoneal and intravenous. Oral administration is preferred because of the convenience for the patient and chronic nature of the diseases to be treated.

Typically, the effective input the number of compounds in this invention generally depends on the relative efficiency of the selected connection, the severity of the disorder to be treated, and the body weight of the victim. However, the active compound is usually administered once or several times a day, for example 1, 2, 3 or 4 times a day, with a typical total daily dose range from 0.1 to 1000 mg/kg/day. Keep in mind that you may need to make some changes to the dosage depending on the age and condition of the patient and route of administration of the drug.

<> The compounds and compositions according to this invention can be used with other drugs, thereby providing a combination therapy. Other medicines can also be part of the same composition or may be provided as a separate composition for administration at the same time or at different points in time.

The following examples are provided as further illustration of this invention, and they should not be construed as limiting the scope of the invention.

EXAMPLES

General methods of making compounds of this invention have been described above.

Example 1:

N-[5-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)pentyl]-3-(1H-indol-3-yl)propionamide

Reagents: Indole-3-propionic acid (57 mg, 0.3 mmol), anhydrous THF (3 ml), 1,1'-carbonyldiimidazole (51 mg, 0.32 mmol) and 6-chloro-9-(5-aminophenylamino)-1,2,3,4-tetrahydropyridine (100 mg, 0.32 mmol).

Purification: column chromatography on silica gel using as eluent a mixture of DCM/MeOH (7:1). Yellow solid, yield: 121 mg (83%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,53 (Sirs, 1H), 7,87 (d, 1H, J=8,8 Hz), 7,88 (d, 1H, J=2.4 Hz), 7,55 (DD, 1H, J=8.0 Hz, J=1.2 Hz), 7,30 (DD, 1H, J=8.0 Hz, J=0.8 Hz), 7,21 (DD, 1H, J=8,8 Hz, J=2.4 Hz), 7,13 (TD, 1H, J=8 Hz, J=1.2 Hz), 7,06 (TD, 1H, J=8.0 Hz, J=0.8 Hz), 6.90 to (m, 1H), 5,61 (m, 1H), 4,24(Sirs, 1H), 3.43 points (t, 2H, J=6.4 Hz), and 3.16 (c, 2H, J=6.4 Hz), 3,10 (t, 2H, J=7,2 Hz), 3,01 (m, 2H), 2,52 (m, 2H), has 2.56 (t, 2H, J=7,2 Hz), of 1.84 (m, 4H), to 1.60 (2H, m)to 1.38 (m, 2H), 1,25 (m, 2H).

13C-NMR (CDCl3, 100 MHz, δ h/million): 172,9, 159,0, 151,4, 147,9, 136,5, 134,6, 127,2, 126,6, 124,9, 124,5, 122,0, 121,9, 119,4, 118,7, 118,2, 115,4, 114,8, 111,4, 49,5, 39,4, 37,7, 33,6, 31,5, 29,6, 24,9, 24,3, 23,1, 22,7, 21,8. ERIE-MS [M+H+]+489.

Example 2:

3-(1H-Indol-3-yl)-N-[5-(1,2,3,4-tetrahydropyridine-9 ylamino)-pentyl]propionamide

Reagents: Indole-3-propionic acid (63 mg, 0.33 mmol), anhydrous THF (3 ml), 1,1'-carbonyldiimidazole (57 mg, 0.35 mmol) and 9-(5-aminophenylamino)-1,2,3,4-tetrahydropyridine (100 mg, 0.35 mmol).

Purification: column chromatography on silica gel using a mixture of DCM/MeOH (3:1). Yellow solid. Yield: 147 mg (97%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,53 (Sirs, 1H), of 7.90 (t, 2H, J=8,4 Hz), 7,55 (t, 1H, J=8,4 Hz), 7,52 (DD, 1H, J=8.0 Hz, J=0.8 Hz), 7,35 (t, 1H, J=8,4 Hz), 7,30 (DD, 1H, J=8.0 Hz, J=0.8 Hz), 7,13 (TD, 1H, J=8 Hz, J=1.2 Hz), 7,05 (TD, 1H, J=8.0 Hz, J=0.8 Hz), 6.90 to (m, 1H), 5,61 (m, 1H), 3,90 (Sirs, 1H), 3,40 (m, 2H), 3,19 (c, 2H, J=6.4 Hz), 3,10 (t, 2H, J=7,2 Hz), 3,01 (m, 2H), 2,62 (m, 2H), has 2.56 (t, 2H, J=7,2 Hz), 1,80 is 2.00 (m, 4H), to 1.60 (m, 2H), 1,38 (m, 2H), 1,25 (m, 2H).

13C-NMR (CDCl3, 100 MHz, δ h/million): 172,9, 158,6, 150,8, 147,0, 136,5, 128,9, 128,8, 127,0, 123,8, 123,0, 122,1, 122,0, 120,1, 119,4, 118-8, 116,2, 114,8, 111,4, 49,6, 39,5, 37,8, 34,4, 31,7, 29,7, 25,2, 24,5, 23,5, 23,2, 21,8. ERIE-MS [M+H+]+455.

Example 3:

N-[6-(6-Chloro-1,2,3,4-tetrahydropyridine-9 is amino)hexyl]-3-(1H-indol-3-yl)propionamide

Reagents: Indole-3-propionic acid (70 mg, of 0.37 mmol), anhydrous THF (3 ml), 1,1'-carbonyldiimidazole (63 mg, 0,39 mmol) and 6-chloro-9-(6-aminobenzoylamino)-1,2,3,4-tetrahydropyridine (131 mg, 0,39 mmol).

Purification: column chromatography on silica gel using a mixture of DCM/MeOH(50:1, 25:1, 20:1). Yellow solid. Output: 143 mg (77%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,40 (Sirs, 1H), a 7.85 (d, 1H, J=2.4 Hz), to 7.84 (d, 1H, J=8,8 Hz), 7,55 (DD, 1H, J=8.0 Hz, J=1.2 Hz), 7,29 (DD, 1H, J=8.0 Hz, J=0.8 Hz), 7.23 percent (DD, 1H, J=8,8 Hz, J=2.4 Hz), to 7.15 (TD, 1H, J=8.0 Hz, J=1.2 Hz), 7,07 (TD, 1H, J=8.0 Hz, J=0.8 Hz), 6,97 (m, 1H), 5,41 (m, 1H), 4,42 (Sirs, 1H), 3,41 (t, 2H, J=6.4 Hz), 3,13 (s, 2H, J=6.4 Hz), to 3.09 (t, 2H, J=7,2 Hz), 3,01 (m, 2H), 2,64 (m, 2H), 2,54 (t, 2H, J=7,2 Hz), 1,91-of 1.88 (m, 4H), 1,59-of 1.53 (2H, m), 1,36-of 1.27 (m, 4H), 1,22-of 1.16 (m, 2H).

13C-NMR (CDCl3, 100 MHz, δ h/million): 172,7, 159,4, 150,7, 148,0, 136,4, 134,0, 127,3, 127,1, 124,6, 124,2, 121,8, 119,1, 118,6, 118,4, 115,7, 114,7, 111,3, 49,5, 39,4, 37,6, 34,1, 31,8, 29,6, 26,6, 26,6, 24,8, 23,1, 22,8, 21,7. ERIE-MS: m/z [M+H+]+503.

Example 4:

N-[7-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]-3-(1H-indol-3-yl)propionamide

Reagents: Indole-3-propionic acid (70 mg, of 0.37 mmol), anhydrous THF (3 ml), 1,1'-carbonyldiimidazole (63 mg, 0,39 mmol) and 6-chloro-9-(7-aminoethylamino)-1,2,3,4-tetrahydropyridine (135 mg, 0,39 mmol).

Purification: column chromatography on silica gel using a mixture of AcOEt/MeOH (50:1). Yellow solid. Yield: 151 mg (79%).

1H-NMR (CDCl3/sub> , 400 MHz, δ h/m): 8,10 (Sirs, 1H), 7,87 (d, 1H, J=8,8 Hz), the 7.85 (d, 1H, J=2.4 Hz), EUR 7.57 (DD, 1H, J=8.0 Hz, J=1.2 Hz), 7,32 (DD, 1H, J=8.0 Hz, J=0.8 Hz), 7,24 (DD, 1H, J=8,8 Hz, J=2.4 Hz), 7,16 (TD, 1H, J=8 Hz, J=1.2 Hz), to 7.09 (TD, 1H, J=8.0 Hz, J=0.8 Hz), 6,99 (m, 1H), 5,32 (m, 1H), 3,91 (Sirs, 1H), 3.45 points (t, 2H, J=6.4 Hz), 3,13 (s, 2H, J=6.4 Hz), 3,11 (t, 2H, J=7,2 Hz), to 3.02 (m, 2H), 2,65 (m, 2H), 2,55 (t, 2H, J=7,2 Hz), 1,92-of 1.88 (m, 4H), 1,64-of 1.57 (m, 2H), 1,36-1,14 (m, 8H).

13C-NMR (CDCl3, 100 MHz, δ h/million): 172,4, 159,3, 150,6, 147,9, 136,1, 133,8, 127,3, 126,9, 124,4, 124,0, 121,8, 121,6, 119,0, 118,5, 118,2, 115,6, 114,7, 111,0, 49,5, 39,3, 37,5, 34,0, 31,7, 29,4, 28,9, 26,7, 26,6, 24,6, 22,9, 22,7, 21,5. ERIE-MS: m/z [M+H+]+517.

Example 5:

N-[8-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)octyl]-3-(1H-indol-3-yl)propionamide

Reagents: Indole-3-propionic acid (70 mg, of 0.37 mmol), anhydrous THF (3 ml), 1,1'-carbonyldiimidazole (63 mg, 0,39 mmol) and 6-chloro-9-(8-aminoethylamino)-1,2,3,4-tetrahydropyridine (140 mg, 0,39 mmol).

Purification: column chromatography on silica gel using a mixture of AcOEt/MeOH (50:1). Yellow solid. Yield: 104 mg (53%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,21 (Sirs, 1H), 7,86 (d, 1H, J=8,8 Hz), the 7.85 (d, 1H, J=2.4 Hz), EUR 7.57 (DD, 1H, J=8.0 Hz, J=1.2 Hz), 7,24 (DD, 1H, J=8.0 Hz, J=0.8 Hz), 7,24 (DD, 1H, J=8,8 Hz, J=2.4 Hz), 7,16 (TD, 1H, J=8.0 Hz, J=1.2 Hz), to 7.09 (TD, 1H, J=8.0 Hz, J=0.8 Hz), 6,99 (m, 1H), 5,35 (m, 1H), 3,91 (Sirs, 1H), 3.46 in (t, 2H, J=6.4 Hz), 3,14 (s, 2H, J=6.4 Hz), 3,10 (t, 2H, J=7,2 Hz), 3,01 (m, 2H), 2,65 (m, 2H), 2,55 (t, 2H, J=7,2 Hz), 1,92-1,89 (m, 4H), 1,64 is 1.58 (m, 2H), 1,36 to 1.31 (m, 4H), 1,28-to 1.14 (m, 6H).

13C-NMR (CDCl3, 10 MHz, δ h/million): 172,6, 159,4, 150,8, 148,1, 136,4, 133,9, 127,4, 127,1, 124,6, 124,1, 121,9, 121,8, 119,1, 118,6, 118,4, 115,7, 114,8, 111,3, 49,7, 39,6, 37,7, 34,2, 31,9, 29,7, 29,3, 27,0, 26,8, 24,8, 23,1, 22,9, 21. ERIE-MS: m/z [M+H+]+531.

Example 6:

N-[9-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)nonyl]-3-(1H-indol-3-yl)propionamide

Reagents: Indole-3-propionic acid (28 mg, 0.15 mmol), anhydrous THF (3 ml), 1,1'-carbonyldiimidazole (25 mg, 0.15 mmol) and 6-chloro-9-(9-aminoaniline)-1,2,3,4-tetrahydropyridine (57 mg, 0.15 mmol).

Purification: column chromatography on silica gel using a mixture of DCM/MeOH (7:1). Yellow solid. Yield: 10 mg (14%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,53 (Sirs, 1H), 7,87 (d, 1H, J=8,8 Hz), 7,88 (d, 1H, J=2.4 Hz), EUR 7.57 (DD, 1H, J=8.0 Hz, J=1.2 Hz), 7,30 (DD, 1H, J=8.0 Hz, J=0.8 Hz), 7,21 (DD, 1H, J=8,8 Hz, J=2.4 Hz), 7,13 (TD, 1H, J=8 Hz, J=1.2 Hz), 7,06 (TD, 1H, J=8.0 Hz, J=0.8 Hz), 6.90 to (m, 1H), 5,61 (m, 1H), 4,24 (Sirs, 1H), 3,50 (m, 2H), 3,19 (s, 2H, J=6.4 Hz), 3,10 (t, 2H, J=7,2 Hz), 3,01 (m, 2H), 2,62 (m, 2H), has 2.56 (t, 2H, J=7,2 Hz), is 1.81 (m, 4H), of 1.52 (m, 2H), 1,01-of 1.40 (m, 13H).

13C-NMR (CDCl3, 100 MHz, δ h/million): 172,7, 159,0, 151,2, 147,8, 136,5, 134,3, 127,3, 127,2, 125,0, 124,4, 122,1, 122,0, 119,3, 118,8, 118,2, 115,3, 115,0, 111,4, 49,8, 39,8, 37,8, 34,0, 32,0, 29,8, 29,7, 29,5, 29,5, 27,2, 27,1, 25,0, 23,4, 23,0, 22,0. ERIE-MS [M+H+]+545.

Example 7:

N-[10-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)decyl]-3-(1H-indol-3-yl)propionamide

Reagents: Indole-3-propionic acid (47 mg, 0.25 mmol), anhydrous THF (4 is l), 1,1'-carbonyldiimidazole (44 mg, 0.27 mmol) and 6-chloro-9-(10-aminoethylamino)-1,2,3,4-tetrahydropyridine (105 mg, 0.27 mmol).

Purification: column chromatography on silica gel using a mixture of DCM/MeOH (10:1). Yellow solid. Yield: 21 mg (19%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,63 (Sirs, 1H), 7,89 (d, 1H, J=8,8 Hz), 7,87 (d, 1H, J=2.4 Hz), 7,56 (DD, 1H, J=8.0 Hz, J=1.2 Hz), 7,32 (DD, 1H, J=8.0 Hz, J=0.8 Hz), 7,21 (DD, 1H, J=8,8 Hz, J=2.4 Hz), 7,14 (TD, 1H, J=1.2 Hz, J=1.2 Hz), was 7.08 (TD, 1H, J=8.0 Hz, J=0.8 Hz), 6,97 (m, 1H), 5,61 (m, 1H), 4,24 (Sirs, 1H), 3,50 (m, 2H), 3,19 (s, 2H, J=6.4 Hz), 3,10 (t, 2H, J=7,2 Hz), 3,01 (m, 2H), 2.63 in (m, 2H), has 2.56 (t, 2H, J=7,2 Hz), 1,80-2,00 (m, 4H)and 1.51 (m, 2H), 1,01-of 1.40 (m, 14H).

13C-NMR (CDCl3, 100 MHz, δ h/million): 172,7, 159,0, 151,2, 147,8, 136,5, 1343, 127,3, 127,2, 125,0, 124,4, 122,1, 122,0, 119,3, 118,8, 118,2, 115,3, 115,0, 111,4, 49,8, 39,8, 37,8, 34,0, 32,0, 29,8, 29,7, 29,6, 29,5, 29,5, 27,2, 27,1, 25,0, 23,4, 23,0, 22,0. ERIE-MS [M+H+]+559.

Example 8:

N-(3-{[3-(1,2,3,4-tetrahydropyridine-9 ylamino)propyl]

methylamino}propyl)-3-(1H-indol-3-yl)propionamide

Reagents: Indole-3-propionic acid (56 mg, 0.29 mmol), anhydrous THF (4 ml), 1,1'-carbonyldiimidazole (50 mg, 0.31 mmol) and N1-[3-(1,2,3,4-tetrahydropyridine-9 ylamino)propyl]-N1-methylpropan-1,3-diamine (100 mg, 0.31 mmol).

Purification: column chromatography on silica gel using a mixture of DCM/MeOH (20:1+0.1%of NH3, 10:1+0,2%NH3, 10:1+0,4%NH3). Yellow solid. Yield: 70 mg (46%).

1H-NMR (CDClsub> 3, 400 MHz, δ h/m): 8,80 (Sirs, 1H), 7,86 (t, 2H, J=8,4 Hz), 7,51 (t, 1H, J=8,4 Hz), 7,46 (d, 1H, J=8,4 Hz), 7,27 (TD, 1H, J=7,0 Hz, J=2.0 Hz), 7,25 (d, 1H, J=7,0 Hz), 7,10 (TD, 1H, J=8.0 Hz, J=1.2 Hz), 7.03 is (TD, 1H, J=8.0 Hz, J=1.2 Hz), 6,85 (d, 1H, J=2.4 Hz), 6,37 (t, 1H, J=4.5 Hz), 5,00 (Sirs, 1H), 3.46 in (m, 2H), 3,19 (s, 2H, J=6.3 Hz), 3,07-a 3.01 (m, 4H), 2.63 in (m, 2H), 2,47 (t, 2H, J=7,0), a 2.36 (t, 2H, J=6,4 Hz), 2,24 (t, 2H, J=6.8 Hz), at 1.91 (s, 3H), 1,86-of 1.84 (m, 4H), 1.70 to to 1.67 (m, 2H), 1,54 of 1.50 (m, 2H).

13C-NMR (CDCl3, 100 MHz, δ h/million): 172,0, 158,3, 150,8, 147,2, 136,3, 128,4, 128,3, 127,1, 123,6, 122,8, 121,8, 121,8 120,2, 119,0, 118,5, 115,9, 114,7, 111,3, 56,6, 56,1, 48,7, 42,2, 38,5, 37,7, 34,0, 28,5, 26,6, 25,3, 23,2, 22,9, 22,7. ERIE-MS: m/z [M+H+]+498.

Example 9:

N-(3-{[3-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)propyl]-methylamino}propyl)-3-(1H-indol-3-yl)propionamide

Reagents: Indole-3-propionic acid (56 mg, 0.29 mmol), anhydrous THF (4 ml), 1,1'-carbonyldiimidazole (50 mg, 0.31 mmol) and N1-[3-(6-chloro-1,2,3,4-tetrahydropyridine-9 ylamino)-propyl]-N1-methylpropan-1,3-diamine (100 mg, 0.31 mmol).

Purification: column chromatography on silica gel using a mixture of DCM/MeOH (20:1+0.1%of NH3, 10:1+0,2%NH3, 10:1+0,4%NH3). Yellow solid. Yield: 70 mg (46%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,79 (width, 1H), 7,83 (d, 1H, J=8,8 Hz), 7,79 (d, 1H, J=2.4 Hz), 7,30 (DD, 1H, J=8.0 Hz, J=1.2 Hz), 7,24 (DD, 1H, J=8.0 Hz, J=0.8 Hz), 7,14 (DD, 1H, J=8,8 Hz, J=2.4 Hz), 7 08 (TD, 1H, J=8 Hz, J=1.2 Hz), 7,01 (TD, 1H, J=8.0 Hz, J=0.8 Hz), 6,86 (m, 1H), 6.30-in (m, 1H), 3,91 (Sirs, 1H), of 3.45 (m, 2H), 3,17 (s, 2H, J=7,2 Hz), 3,03 (t, 2H, =6.4 Hz), to 2.94 (m, 2H), 2,50 (m, 2H), 2,46 (t, 2H, J=7,2 Hz), 2,41-of 2.23 (m, 2H), 2,22-to 2.18 (m, 2H), 2,10 (s, 3H), of 1.18 (m, 4H), 1,73 is 1.60 (m, 2H), 1,59-1,49 (m, 2H).

13C-NMR (CDCl3, 100 MHz, δ h/million): 172,7, 159,5, 151,0, 148,0, 136,4, 134,0, 127,3, 127,2, 124,7, 124,1, 121,9, 122,0, 119,2, 118,6, 118,4, 115,7, 114,8, 111,4, 56,7, 56,21, 49,0, 42,3, 38,6, 37,8, 34,2, 28,5, 26,8, 25,2, 23,2, 23,0, 21,8. ERIE-MS: m/z [M+H+]+531.

Example 10:

[5-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)pentyl]amide of 1H-indole-3-carboxylic acid

Reagents: Indole-3-carboxylic acid (151 mg, of 0.94 mmol), anhydrous THF (4 ml), 1,1'-carbonyldiimidazole (153 mg, of 0.94 mmol) and 6-chloro-9-(8-aminophenylamino)-1,2,3,4-tetrahydropyridine (276 mg, 0.90 mmol).

Purification: column chromatography on silica gel (eluent: a mixture of EtOAc/MeOH (50:1)). Yellow solid. Yield: 198 mg (52%).

1H-NMR (CD3OD, 400 MHz, δ h/m): 8,07 (d, 1H, J=9.0 Hz), of 8.06 (dt, 1H, J=8.0 Hz and J=0.8 Hz), 7,80 (s, 1H), 7,69 (d, 1H, J=2.0 Hz), 7,41 (d, 1H, J=8.0 Hz), 7,22 (DD, 1H, J=9.0 Hz and J=2.0 Hz), 7,17 (TD, 1H, J=8.0 Hz and J=1.2 Hz), 7,12 (TD, 1H, J=8.0 Hz and J=1.2 Hz), to 3.58 (t, 2H, J=7.0 Hz), 3,37 (t, 2H, J=7.0 Hz), is 2.88 (t, 2H, J=6.2 Hz), to 2.65 (t, 2H, J=6.2 Hz), to 1.79 (m, 4H), 1,71 (m, 2H), and 1.63 (m, 2H), 1,45 (m, 2H).

13C-NMR (CD3OD, 100 MHz, δ h/million): 168,6, 160,3, 153,4, 148,6, 138,2, 135,6, 128,9, 127,2, 126,7, 126,6, 125,1, 123,5, 122,0, 121,8, 119,5, 116,7, 112,9, 112,0, 40,1, 34,3, 32,0, 30,7, 26,1, 25,4, 24,0, 23,6. ERIE-MS [M]+461,07.

Example 11:

[6-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)hexyl]amide of 1H-indole-3-carboxylic acid

eagency: Indole-3-carboxylic acid (153 mg, 0.95 mmol), anhydrous THF (10 ml), 1,1'-carbonyldiimidazole (154 mg, 0.95 mmol) and 6-chloro-9-(8-aminobenzoylamino)-1,2,3,4-tetrahydropyridine (300 mg, 0.90 mmol).

Purification: column chromatography on silica gel (eluent: a mixture of EtOAc/MeOH (50:1)). Yellow solid. Yield: 120 mg (28%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 10,24 (Sirs, 1H), 7,89 (m, 1H), a 7.85 (d, 1H, J=9.4 Hz), 7,83 (d, 1H, J=2.0 Hz), 7,71 (d, 1H, J=2,8 Hz), 7,39 (m, 1H), 7.18 in-7,22 (m, 3H), 6,13 (t, 1H, J=5.8 Hz), 4.0 (with Sirs, 1H), 3.46 in (m, 4H), of 2.97 (m, 2H), 2,60 (m, 2H), of 1.84 (m, 4H), to 1.60 (m, 4H), of 1.39 (m, 4H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 166,0, 159,6, 151,0, 148,1, 136,7, 134,2, 128,4, 127,2, 124,8, 124,7, 124,3, 122,8, 121,5, 119,7, 118,3, 115,7, 112,4, 112,1, 49,5, 39,4, 33,9, 31,7, 30,0, 26,7, 26,6, 24,6, 22,9, 22,6. ERIE-MS [M+H]+476.

Example 12:

[7-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]amide of 1H-indole-3-carboxylic acid

Reagents: Indole-3-carboxylic acid (147 mg, of 0.91 mmol), anhydrous THF (10 ml), 1,1'-carbonyldiimidazole (147 mg, of 0.91 mmol) and 6-chloro-9-(8-aminoethylamino)-1,2,3,4-tetrahydropyridine (300 mg, 0.87 mmol).

Purification: column chromatography on silica gel (eluent: a mixture of EtOAc/MeOH (50:1)). Yellow solid. Output: 226 mg (51%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 9,88 (Sirs, 1H), of 7.90 (DD, 1H, J=6.3 Hz, J=3.0 Hz), 7,87 (d, 1H, J=9 Hz), to 7.84 (d, 1H, J=2.0 Hz), 7,73 (d, 1H, J=2.7 Hz), 7,41 (DD, 1H, J=6.3 Hz, J=3.0 Hz), of 7.23 (d, 1H, J=9 Hz), 7.23 percent-7,19 (m, 2H), the 6.06 (t, 1H, J=5.5 Hz), 4.0 (with Sirs, 1H), 3.46 in (m, 4H), 2,98 (m, 2H), 2,61 (m, 2H), of 1.85 (m, 4H), to 1.59 (m, 4H), of 1.34 (m, 6).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 165,7, 159,6, 151,1, 148,2, 136,6, 134,2, 128,3, 127,4, 124,8, 124,7, 124,3, 122,8, 121,6, 119,8, 118,4, 115,8, 112,4, 112,3, 49,6, 39,5, 34,0, 31,8, 29,9, 29,1, 27,0, 26,9, 24,7, 22,9, 22,7. ERIE-MS [M]+489.

Example 13:

[8-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)octyl]amide of 1H-indole-3-carboxylic acid

Reagents: Indole-3-carboxylic acid (92 mg, or 0.57 mmol), anhydrous THF (3 ml), 1,1'-carbonyldiimidazole (92 mg, or 0.57 mmol) and 6-chloro-9-(8-aminoethylamino)-1,2,3,4-tetrahydropyridine (196 mg, 0.54 mmol).

Purification: column chromatography on silica gel (eluent: hexane/EtOAc 1:2+0,1%NH3, 1:3+0.2%of NH3). Yellow solid. Yield: 110 mg (40%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 10,51 (Sirs, 1H), a 7.85 (m, 1H), 7,79 (d, 1H, J=9.0 Hz), 7,76 (d, 1H, J=2.0 Hz), the 7.65 (d, 1H, J=1.6 Hz), 7,31 (m, 1H), 7,15 (DD, 1H, J=9.0 Hz, J=2.0 Hz), 7,10 (m, 2H), 6,09 (m, 1H), 3,9 (Sirs, 1H), 3,36 (c, 4H, J=7,3 Hz), 2.91 in (m, 2H), 2,53 (m, 2H), 1,78 (m, 4H), of 1.52 (m, 4H), 1.26 in-1,19 (m, 8H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 165,4, 158,9, 150,4, 147,5, 136,1, 133,5, 127,7, 126,6, 124,2, 123,6, 122,1, 122,0, 120,7, 119,1, 117,7, 115,0, 111,7, 111,4, 48,9, 38,9, 33,2, 31,1, 29,3, 29,1, 28,5, 26,3, 26,1, 23,9, 22,3, 22,0. ERIE-MS [M]+503.

Example 14:

N-[7-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]-2-(1H-indol-3-yl)ndimethylacetamide

Reagents: Indole-3-acetic acid (1.10 g, 6.3 mmol), anhydrous THF (50 ml), 1,1'-carbonyldiimidazole (1.07 g, 6.6 mmol) and 6-chloro-9-(8-aminoethylamino)-1,2,3,4-t is trihydroxide (to 2.29 g, 6.6 mmol).

Purification: column chromatography on silica gel (eluent: a mixture of EtOAc/MeOH (50:1)). Yellow solid. Output: 2,48 g (80%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 9,25 (Sirs, 1H), 7,79 (d, 1H, J=9 Hz), 7,79 (d, 1H, J=2.0 Hz), was 7.45 (d, 1H, J=8.0 Hz), 7,29 (d, 1H, J=8.0 Hz), and 7.6 (DD, 1H, J=9 Hz, J=2.0 Hz), 7,11 (t, 1H, J=8.0 Hz), 7.03 is (t, 1H, J=8.0 Hz), 7,03 (s, 1H), 5,71 (t, 1H, J=5.5 Hz), 3,82 (Sirs, 1H), the 3.65 (s, 2H), 3,34 (t, 2H, J=7.0 Hz), is 3.08 (c, 2H, J=6.6 Hz), 2,93 (Sirs, 2H), 2,56 (Sirs, 2H), is 1.81 (m, 4H), to 1.48 (m, 2H), 1,28 was 1.06 (m, 8H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 171,4, 159,4, 150,6, 148,0, 136,4, 133,7, 127,2, 126,8, 124,4, 123,9, 123,7, 122,2, 119,6, 118,4, 118,2, 115,5, 111,3, 108,5, 49,3, 39,2, 33,7, 33,3, 31,4, 29,1, 28,6, 26,5, 26,3, 24,3, 22,7, 22,4. ERIE-MS [M]+503.

Example 15:

N-[5-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)pentyl]-4-(1H-indol-3-yl)butyramide

Reagents: Indole-3-butyric acid (134 mg, 0.66 mmol), anhydrous THF (10 ml), 1,1'-carbonyldiimidazole (107 mg, 0.66 mmol) and 6-chloro-9-(5-aminophenylamino)-1,2,3,4-tetrahydropyridine (200 mg, to 0.63 mmol).

Purification: column chromatography on silica gel using a mixture of EtOAc/MeOH (100:1). Yellow solid. Yield: 220 mg (44%).

1H-NMR (CDCl3, 400 MHz, δ h/million): of 8.47 (Sirs, 1H), to 7.84 (d, 1H, J=1.9 Hz), 7,83 (d, 1H, J=10.0 Hz), 7,54 (d, 1H, J=7.4 Hz), 7,30 (d, 1H, J=7.4 Hz), 7,21 (DD, 1H, J=9.0 Hz, J=1.9 Hz), 7,13 (TD, 1H, J=7,4 Hz, J=1.2 Hz), 7,05 (TD, 1H, J=7,4 Hz, J=1.2 Hz), 6,10 (d, 1H, J=2.4 Hz), 5,52 (t, 1H, J=5.4 Hz), 3,91 (Sirs, 1H), 3,40 (m, 2H), 3,18 (s, 2H, J=6.4 Hz), 2,98 (Sirs, 2H), was 2.76 (t, 2H, J=7.0 Hz), 2,60 (width is, 2H), 2,18 (t, 2H, J=7.0 Hz), 2,02 (m, 2H), of 1.85 (m, 4H), to 1.61 (m, 2H), 1,45 (m, 2H), 1,36 to 1.31 (m, 2H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 173,3, 159,8, 150,8, 148,3, 136,5, 134,1, 127,6, 127,6, 124,7, 124,4, 122,0, 122,7, 119,2, 118,9, 118,6, 116,0, 115,6, 111,3, 49,5, 39,2, 36,4, 34,2, 31,4, 29,6, 26,3, 24,7, 24,7, 24,3, 23,0, 22,8. ERIE-MS [M]+503.

Example 16:

N-[6-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)hexyl]-4-(1H-indol-3-yl)butyramide

Reagents: Indole-3-butyric acid (134 mg, 0.66 mmol), anhydrous THF (8 ml), 1,1'-carbonyldiimidazole (107 mg, 0.66 mmol) and 6-chloro-9-(5-aminobenzoylamino)-1,2,3,4-tetrahydropyridine (200 mg, to 0.63 mmol).

Purification: column chromatography on silica gel using a mixture of DCM/MeOH(20:1, 20:1+0,01%NH3). Yellow solid. Yield: 163 mg (48%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,93 (Sirs, 1H), a 7.85 (d, 1H, J=1.9 Hz), to 7.84 (d, 1H, J=9.0 Hz), 7,51 (d, 1H, J=8.0 Hz), 7,29 (d, 1H, J=8.0 Hz), 7,20 (DD, 1H, J=9.0 Hz, J=2.0 Hz), 7,10 (t, 1H, J=7.5 Hz), 7,02 (t, 1H, J=7.5 Hz), 6.87 in (d, 1H, J=1.4 Hz), 5,80 (Sirs, 1H), 4,12 (Sirs, 1H), 3,41 (t, 2H, J=7,4 Hz), and 3.16 (c, 2H, J=6.6 Hz), 2,97 (Sirs, 2H), rating of 2.72 (t, 2H, J=7.4 Hz), 2,56 (Sirs, 2H), 2,17 (t, 2H, J=7.4 Hz), 1,99 (m, 2H)and 1.83 (m, 4H), and 1.56 (m, 2H), 1,41 (m, 2H), 1,35-to 1.21 (m, 4H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 173,6, 159,2, 151,4, 147,7, 136,7, 134,5, 127,6, 126,9, 125,1, 124,5, 122,0, 121,9, 120,0, 118,9, 118,3, 115,6, 115,4, 111,5, 49,5, 39,4, 36,5, 33,7, 31,8, 29,8, 26,7, 26,6, 26,4, 24,8, 24,7, 23,0, 22,7. ERIE-MS [M]+517.

Example 17:

N-[6-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)hexyl]-3-(1H-Indo) - Rev.-3-yl)acrylamide

Reagents: Indole-3-acrylic acid (88 mg, 0.47 mmol), anhydrous THF (6 ml), 1,1'-carbonyldiimidazole (76 mg, 0.47 mmol) and 6-chloro-9-(5-aminobenzoylamino)-1,2,3,4-tetrahydropyridine (150 mg, 0.45 mmol).

Purification: column chromatography on silica gel using a mixture of EtOAc/MeOH(100:1, 100:1+0,1%NH3). Yellow solid. Yield: 20 mg (8%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,93 (Sirs, 1H), 7,83-7,76 (m, 4H), 7,33-732 (m, 2H), 7,19-was 7.08 (m, 3H), 6.35mm (d, 1H, J=15,0 Hz), 5,79 (t, 1H, J=5,9 Hz), 3,92 (Sirs, 1H), 3,38 (t, 2H, J=7.0 Hz), 3.33 and (c, 2H, J=6.6 Hz), 2,94 (Sirs, 2H), 2,56 (Sirs, 2H), is 1.81 (m, 4H), 1,61-of 1.36 (m, 4H), 1,32 (m, 4H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 167,8, 159,4, 151,0, 147,9, 137,5, 134,8, 134,2, 129,0, 127,0, 125,4, 124,9, 124,3, 122,8, 120,9, 120,2, 118,3, 115,6, 113,1, 112,2, 49,4, 39,6, 33,8, 31,7, 29,8, 26,7, 26,6, 24,6, 22,9, 22,6. ERIE-MS [M]+501.

Example 18:

2-(5-Bromo-1H-indol-3-yl)-N-[7-(6-chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]ndimethylacetamide

Reagents: 5-Bromoindole-3-acetic acid (155 mg, 0.61 mmol), anhydrous THF (10 ml), 1,1'-carbonyldiimidazole (99 mg, 0.61 mmol) and 6-chloro-9-(8-aminoethylamino)-1,2,3,4-tetrahydropyridine (200 mg, of 0.58 mmol).

Purification: column chromatography on silica gel (eluent: a mixture of EtOAc/MeOH (50:1)). Yellow solid. Yield: 185 mg (54%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 9,36 (Sirs, 1H), 7,86 (d, 1H, J=9.0 Hz), 7,83 (d, 1H, J=2.3 Hz), 7,63 (t, 1H, J=0.8 Hz), 7.23 percent (m, 1H), 7,21 (m, 2H), to 7.09 (d, 1H, J=2.3 Hz), 5,72 (t, 1H, J=5.8 Hz), 3,95 (Sirs, 1H), 3,64 (C, 2), of 3.42 (t, 2H, J=7.2 Hz), 3.15 in (s, 2H, J=6.6 Hz), 2,98 (Sirs, 2H), 2,61 (Sirs, 2H), to 1.86 (m, 4H), and 1.56 (m, 2H), of 1.34 (m, 2H), 1.30 and at 1.17 (m, 4H), 1.14 in (m, 2H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 171,2, 159,5, 151,09, 148,1, 135,2, 134,2, 128,9, 127,3, 125,4, 125,3, 124,9, 124,3, 121,4, 118,4, 115,7, 113,2, 113,1, 108,6, 49,6, 39,6, 34,0, 33,5, 31,8, 29,5, 29,0, 26,8, 26,7, 24,6, 23,0, 22,7. ERIE-MS [M+1,79Br]+581, [M+1,81Br]+583.

Example 19:

N-[6-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)hexyl]-3-(5-isocyano-1H-indol-3-yl)propionamide

Reagents: 5-Cyanoindole-3-propionic acid (111 mg, 0.52 mmol), anhydrous THF (10 ml), 1,1'-carbonyldiimidazole (84 mg, 0.52 mmol) and 6-chloro-9-(8-aminoethylamino)-1,2,3,4-tetrahydropyridine (164 mg, 0.49 mmol).

Purification: column chromatography on silica gel (eluent: a mixture of EtOAc/MeOH (50:1)). Yellow solid. Yield: 60 mg (22%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 9,48 (Sirs, 1H), 7,89 (s, 1H), 7,87 (d, 1H, J=9.0 Hz), 7,82 (d, 1H, J=2.1 Hz), 7,33 (Sirs, 2H), 7.23 percent (DD, 1H, J=9.0 Hz, J=2.1 Hz), 7,10 (Sirs, 1H), 5,70 (t, 1H, J=5.6 Hz), 4.00 points (Sirs, 1H), 3,44 (t, 2H, J=7,2 Hz), 3,18 (s, 2H, J=6.6 Hz), is 3.08 (t, 2H, J=7,2 Hz), 2,98 (Sirs, 2H), 2,62 (Sirs, 2H), 2,52 (t, 2H, J=7.4 Hz), a 1.88 (m, 4H), 1,58 (m, 2H), 1,42-1,24 (m, 4H),1,40-1,24 (m, 4H), 1,23-of 1.18 (m, 2H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 172,5, 159,7, 151,2, 148,3, 138,3, 135,3, 134,42, 127,6, 127,4, 125,0, 124,9, 124,7, 124,6, 124,4, 121,1, 118,7, 116,2, 116,1, 112,4, 102,5, 49,6, 39,6, 37,6, 34,2, 31,9, 29,8, 26,7, 24,9, 23,2, 22,9, 21,3. ERIE-MS [M]+528.

Example 20:

[7-(6-Chloro-1,2,3,4-Tetra is hydrogren-9 ylamino)heptyl]amide of 1H-methylindol-3-carboxylic acid

Reagents: 1-Methylindol-3-carboxylic acid (212 mg, to 1.21 mmol), anhydrous THF (10 ml), 1,1'-carbonyldiimidazole (197 mg, to 1.21 mmol) and 6-chloro-9-(8-aminoethylamino)-1,2,3,4-tetrahydropyridine (400 mg, of 1.16 mmol).

Purification: column chromatography on silica gel (eluent: a mixture of EtOAc/MeOH (50:1)). Yellow solid. Yield: 45 mg (8%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 7,88 (d, 1H, J=7,0 Hz), 7,86 (d, 1H, J=9 Hz), to 7.84 (d, 1H, J=2.3 Hz), 7,63 (s, 1H), 7,33 (d, 1H, J=7,0 Hz), 7,28-7,20 (m, 3H), 5,97 (t, 1H, J=5.5 Hz), 3,9 (Sirs, 1H), 3,44 (m, 4H), to 2.99 (m, 2H), 2,62 (m, 2H), to 1.87 (m, 4H), to 1.59 (m, 4H), of 1.36 (m, 6H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 165,3, 159,7, 150,9, 148,3, 137,3, 134,0, 132,4, 127,7, 125,3, 124,7, 124,3, 122,6, 121,5, 120,0, 118,5, 115,9, 111,1, 110,2, 49,7, 39,5, 34,2, 33,4, 31,8, 30,0, 29,1, 27,0, 26,9, 24,7, 23,0, 22,8. ERIE-MS [M]+503.

Example 21:

[7-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]amide of 1H-indazol-3-carboxylic acid

Reagents: Indazol-3-carboxylic acid (162 mg, 1.00 mmol), anhydrous THF (5 ml), 1,1'-carbonyldiimidazole (170 mg, 1.05 mmol) and 6-chloro-9-(8-aminoethylamino)-1,2,3,4-tetrahydropyridine (364 mg, 1.05 mmol).

Purification: column chromatography on silica gel (eluent: a mixture of EtOAc/MeOH (50:1)). Yellow solid. Yield: 6 mg (1%).

1H-NMR (CDCl3, 400 MHz, δ h/million): of 11.26 (Sirs, 1H), 8.34 per (d, 1H, J=8.0 Hz), to 7.84 (d, 1H, J=2.0 Hz), 7,82 (d, 1H, J=9.0 Hz), the 7.43 (DD, 1H, J=8.0 Hz), 7.5 (t, 1H, J=7 Hz), 7.23 percent-7,17 (m, 2H), 7,03 (t, 1H, J=5.5 Hz), 3,9 (Sirs, 1H), 3,42 (m, 4H), 2,96 (Sirs, 2H), 258 (Sirs, 2H), equal to 1.82 (m, 4H), of 1.57 (m, 4H), 1,32 (m, 6H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 162,9, 159,6, 151,1, 148,2, 141,5, 139,6, 134,2, 127,5, 127,4, 124,8, 124,4, 124,9, 122,8, 122,1, 118,5, 115,8, 109,9, 49,7, 39,0, 34,1, 31,8, 29,8, 29,1, 26,9, 26,8, 24,7, 23,0, 22,7. ERIE-MS [M]+490.

Example 22:

Indole-taken urethane derivatives synthesized following the method similar to that described in the literature: Bruce A.; Spangle L.A.; Kaldor S.W.; Tetrahedron Letters,1996, 7, 937-940. Strategy synthesis is summarized in scheme 2.

Synthesis of intermediate compound, 2-(1H-indol-3-yl)ethyl, and 4-nitrophenylthio ester of carbonic acid:

To a solution of 2-(1H-indol-3-yl)ethanol (1600 mg, 9,92 mmol) in N-methylmorpholine (2000 mg, 19,84 mmol) is added p-nitrophenylphosphate (4000 mg, 19,84 mmol) and the mixture is stirred for 24 hours at room temperature. Water is added and the mixture extracted with dichloromethane. Evaporation of solvent gives a residue which is purified column chromatography on silica gel, using as eluent a mixture of DCM/Hx (3:1)getting 1034 mg (32%) indicated in the title compound as a yellow solid.

Total synthesis of urethane derivatives:

To a solution of 2-(1H-indol-3-yl)ethyl, and 4-nitrophenylthio ester of carbonic acid add a solution of the corresponding alkylmethacrylamide in DMF in the presence of DMAP and the mixture is stirred for 24 hours at room temperature. After you is Ariane solvent under reduced pressure, water is added and the mixture extracted with dichloromethane. Evaporation of solvent gives a residue which is purified column chromatography on silica gel, as described below for each case.

Example 23:

2-(1H-indol-3-yl)ethyl ester of [5-(6-chloro-1,2,3,4-tetrahydro-acridine-9-ylamino)pentyl]carbamino acid

Reagents: N1-(6-chloro-1,2,3,4-tetrahydropyridine-9-yl)pentane-1,5-diamine (500 mg, was 1.58 mmol), 2-(1H-indol-3-yl)ethyl, and 4-nitrophenyloctyl ester of carbonic acid (260 mg, 0.79, which mmol), DMAP (1930 mg, was 1.58 mmol).

Purification: chromatography on silica gel using as eluent a mixture of DCM/MeOH (7:0,5). Yield: 126 mg (32%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,51 (Sirs, 1H), 7,86 (m, 2H), EUR 7.57 (m, 1H, J=8.0 Hz), 7,28 (m, 1H,J=8.0 Hz), 7,21-of 7.23 (m, 1H), 7,14-7,10 (m, 1H), 7,07-7,03 (m, 1H), 6,97-PC 6.82 (m, 1H), 4,77 (Sirs, 1H), 4,33-4,30 (m, 2H), Android 4.04 (m, 2H), 3,14-3,13 (m, 2H), 3,05 are 2.98 (m, 4H), 2,58 (Sirs, 2H), 1,87 of-1.83 (m, 4H), 1,62-to 1.61 (m, 2H), 1,49 to 1.47 (m, 2H), of 1.37 and 1.35 (m, 2H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 165,7, 159,4, 151,3, 147,7, 136,5, 134,6, 127,7, 127,0, 124,9, 124,6, 122,3, 122,1, 119,4, 118,9, 118,3, 116,3, 115,8, 112,2, 49,5, 40,8, 33,7, 31,5, 30,0, 25,4, 24,7, 24,2, 23,0, 22,7. ERIE-MS [M+H]+505,1.

Example 24:

2-(1H-indol-3-yl)ethyl ester [6-(6-Chloro-1,2,3,4-tetrahydro-acridine-9-ylamino)hexyl]carbamino acid

Reagents: Reagents: N1-(6-chloro-1,2,3,4-tetrahydropyridine-9-yl)hexane-1,6-diamine (610 mg, of 1.84 mmol), 2-(1H-indol-3-yl)ethyl, and 4-nitrophenyloctyl ester of carbonic acid (30 mg, to 0.92 mmol), DMAP (225 mg, of 1.84 mmol).

Cleaning: a mixture of DCM/MeOH (7:0,5). Yield: 100 mg (21%).

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,25 (Sirs, 1H), of 7.90-7,87 (m, 2H), a 7.62 (d, 1H, J=8.0 Hz), 7,34 (d, 1H, J=8.0 Hz), 7,30-7,25 (m, 2H), 7,20-7,16 (m, 1H), 7,13-was 7.08 (m, 1H), 7.03 is-7,02 (m, 1H), 4,67 (Sirs, 1H), 4,36-to 4.33 (m, 2H,), 3.46 in (Sirs, 2H), 3,17-3,03 (m, 6H), 2,66 (Sirs, 2H), 1,92-1,90 (m, 4H), of 1.66 and 1.33 (m, 6N).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 159,5, 156,7, 150,7, 148,0, 136,1, 134,0, 127,5, 124,5, 124,2, 122,0, 119,3, 118,7, 118,3, 115,7, 112,1, 111,1, 65,0, 49,4, 40,6, 34,0, 31,6, 30,0, 26,4, 26,3, 25,2, 24,5, 23,0, 22,6. ERIE-MS [M+H]+519,1.

Example 25:

2-(1H-Indol-3-yl)ethyl ester [7-(3-chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]carbamino acid

Reagents: N1-(6-chloro-1,2,3,4-tetrahydropyridine-9-yl)heptane-1,7-diamine (344 mg, 1.0 mmol), 2-(1H-indol-3-yl)ethyl, and 4-nitrophenyloctyl ester of carbonic acid (166 mg, 0.5 mmol), DMAP (122 mg, 1.0 mmol).

Purification: purification by chromatography using as eluent a mixture of DCM/MeOH (7:0,5). Yield: 70 mg (40%) of crystalline solid amber color.

1H-NMR (CDCl3, 400 MHz, δ h/m): 8,25 (Sirs, 1H), of 7.90-7,88 (m, 2H), a 7.62 (d, 1H, J=8.0 Hz), 7,34 (d, 1H, J=8.0 Hz), 7,30-7,25 (m, 2H), 7,20-to 7.15 (m, 1H), 7,13-7,08, (m, 1H), 7.03 is-7,02 (m, 1H), 4,71 (Sirs, 1H), 4,35-4,32 (m, 2H), 3,5-of 3.45 (m, 2H), 3,17-of 3.12 (m, 2H), 3,09-of 3.06 (m, 2H), 3,03 (Sirs, 2H), 2,64 (Sirs, 2H), 1.91 a-a 1.88 (m, 4H), 1,64-to 1.60 (m, 2H), 1,47-of 1.44 (m, 2H), 1,31-1,25 (m, 6H).

13C-NMR (CD3Cl, 100 MHz, δ h/million): 159,6, 156,9, 151,2, 148,2, 136,4, 134,3, 127,7, 127,5, 124,9, 124,5, 122,3, 12,2, 119,0, 118,5, 115,8, 112,3, 111,4, 65,1, 49,8, 41,1, 34,0, 31,9, 30,2, 29,2, 27,0, 26,7, 25,4, 24,7, 23,1, 22,8. ERIE-MS [M+H]+533,10.

Example 26 Comparative example

N-[2-3(Indolyl)ethyl]-6-hartgring with a short linker, synthesized following a published method (Ming-Kuan H.U. and Jiajiu S., international publication WO 01/17529), and its identification methods1H-NMR and13C-NMR is consistent with the characteristics presented in the literature (same link).

Example 27:Biological test

Inhibition of acetylcholinesterase (AChE) (from bovine erythrocytes)

Inhibitory activity against AChE was evaluated at 30°C by the colorimetric method described by Almanim [Ellman G.L.; Courtney K.D.; Andres B.; Featherstone R. Biochem. Pharmacol. 1961, 7, 88-95]. The solution for analysis consisted of 0,1M phosphate buffer pH 8, 0.3 mm 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB reagent of Almana), 0,02 units AChE (Sigma Chemical; Co. from bovine erythrocytes) and 0.5 mm iodide of acetylthiocholine as a substrate for the enzymatic reaction. Compound was added to the solution for analysis and pre-incubated with the enzyme for 5 min at 30°C. after this period of time was added to the substrate. Changes in absorbance at 405 nm was recorded for 5 min using a microplate reader Digiscan 340T, comparing the reaction rate was calculated by the t inhibition, due to the presence of the test compound. The reaction rate was calculated on the basis of at least three measurements and the percent inhibition due to the presence of the test compounds was calculated relative to the control containing no connection. Determined the concentration of compound that causes 50% inhibition of AChE (IC50). The results are presented in table 1.

Inhibition butyrylcholinesterase (BuChE) (from human serum)

Inhibitory activity against BuChE was evaluated at 30°C by the colorimetric method described by Almana. The solution for analysis consisted of 0.01 units BuChE from human serum in 0.1m sodium phosphate buffer pH 8, 0.3 mm 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB reagent of Almana) and 0.5 mm iodide butyrylthiocholine as a substrate for the enzymatic reaction. Enzymatic activity was determined by measuring the absorption at 405 nm for 5 min using a microplate reader Digiscan 340T. Compound is pre-incubated with the enzyme for 10 minutes at 30°C. the reaction Rate was calculated on the basis of at least three measurements. Defined IC50as the concentration of each compound that reduces the enzymatic activity determined to not contain inhibitors of control, 50%. The results are presented in table 1.

<> Measuring toxicity

Cytotoxic molecules were tested on cell lines SH-SY5Y human neuroblastoma. These cells were cultured in 96-well tablets in modified according to the method of Dulbecco environment, Needle, supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin and were grown in 5% CO2-incubator at 37°C.

Cells were sown in tablets with 104cells/well for at least 48 hours before measurement of toxicity. Cells were exposed for 24 hours with compounds at various concentrations (from 10-5up to 10-9), quantitative assessment of cell death was performed by measuring the intracellular enzyme lactate-dehydrogenase (LDH) (kit for the detection of cytotoxicity, Roche). The amount of LDH were evaluated in a microplate reader Anthos 2010 at 492 and 620 nm. Controls were taken as 100% viability. The results are presented in table 1.

Competition with propidium

Propedy shows the increase in fluorescence upon binding to the peripheral site of AChE, making it a useful probe for competitive binding of the ligand to the enzyme.

Fluorescence was measured in the plate reader Fluostar optima (BMG). The measurements were carried out in 96-well tablets in volume (analyzed) solution 100 ál. Used buffer consisted of 1 mm Tris/HCl, pH 8.0. 10 μm AChE, incubi is ovali, at least 6 hours with molecules at various concentrations. 10 minutes before measuring the fluorescence was added to 20 μm iodide of propecia. The wavelength of excitation was 485 nm, and the wavelength of emission of 620 nm. The results are presented in table 1.

0,06
Table 1
ConnectionStructureIC50(nm) AChEIC50(μm) BuChEToxicity (µm)Competition of propecia (µm)
14100>100>100
2701>10010
30,02291001000
40,11010
50,5the 5.71010
64,49,6>100>100
7of 21.954>10010
81470,03>1001000
92,88EUR 7.57>10010
101809,5>10 100
11331,7>10100
123619>10100
134622,4>1010
140,1811,7>1010
150,343,2>1010
160,485,6>10100
17 1877>1010
180,631,7>10100
190,7211,7>10100
2010,9206>10100
219579>10100
231,513,6>10100
240,73,2 >10100
25359>1010
Comparative example537

Example 27:Inhibition of aggregation of β-amyloid

The formation of complexes AChE-Aβ was performed as previously described [A. Alvarez et al., J. Neurosci.,1998, 18, 3213-3223; Mufloz F.J.; N.C. Inestrosa FEBS Lett.,1999, 450, 205-209]. The original solutions of Aβ1-40(rPeptide, Georgia USA) with a 3.5 mm was dissolved in PBS (pH 7.4) after processing HFLP to get Monomeric original product, according to the manufacturer's recommendations. For joint experiments incubation of 0.1 mm peptide was mixed with human recombinant acetylcholinesterase (huAChE, Sigma-Aldrich) in the same buffer at a molar ratio of Aβ:huAChE 200:1 and stirred for 48 hours in the microtiter plate at room temperature. The resulting fibrils okharakterizovali binding of Congo Red (CR).

For inhibiting the aggregation of β-amyloid, a compound used with IC50defined in predtest the next paragraph biological assessment. 50 μm of iodide of propecia used as a reference [N.C. Inestrosa et al., J. Neuron, 1996, 16, 881-891].

For a quantitative estimation of aggregated fibril linking with CR were performed as described [Klunk WE.; Pettegrew JW.; Abraham DJ. J. Hystochem Cytochem.,1989, 8, 1293-1297]. Briefly, 5,5-ál aliquot of the aggregate mixture was added to 132 μl of 25 μm solution of CR (100 mm phosphate buffer pH 7.4, 150 mm NaCl) and incubated for 30 minutes at room temperature. The absorption was measured at 480 nm and 540 nm and was calculated by both molarity units according to CR (M)=(A540/25295)-(A480/46306).

In the above conditions derivatives 3 and 8 compounds indole showed 15% and 17% decrease, respectively, of the complex-Assembly of β-amyloid-huAChE. Peripheral inhibitor of iodide of propecia used as a reference, really showed a 10% decrease.

1. Amide of the formula (I):

where a, b are independently selected from CH or N;
D represents N;
Z is selected from hydrogen, unsubstituted With1-8of alkyl,
each L is independently selected from-CRaRb-, -CRa=, -CO-, -O - or-NRa-;
k, m, n, q, x and w means, each an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, provided that k+m+n+q+x+w is at least 4;
R1-R6independently selected from hydrogen, CN or halogen;
Raand Rbindependently selected from hydrogen, unsubstituted With-8 the alkyl, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where one of a and b is a C and the other represents CH.

3. The compound according to claim 1, having the formula (II):

where R1-R6, Z, L, k, m, n, q, x and w are such as defined in claim 1.

4. The compound according to claim 3, where Z is selected from N or CH3.

5. The compound according to claim 3 or 4, where R1, R3and R4represent N.

6. The compound according to claim 3 or 4, where R2selected from H, -Gal or-CN.

7. The compound according to claim 1, having the formula (III):

where R1-R5, L, k, m, n, q, x and w are such as defined in claim 1.

8. The connection according to claim 7, where R5selected from F, Cl, Br, I, preferably Cl.

9. The compound according to any one of claims 1 to 4, 7 and 8, where k+m+n+q+x+w is equal to the value selected from 7, 8, 9, 10, 11, 12 or 13, preferably 10 or 11.

10. The connection according to claim 9, where the linker -(L)k-(L)m-(L)n-(L)q-(L)x-(L)wis selected from the formula -(CH2)k-CO-NRa-(CH2)w-, -(CH2)k-CO-NRa-(CH2)q-NRa-(CH2)w-, -(CH2)k-O-CO-NRa-(CH2)w-where k, q, w and Rasuch as defined in claim 1.

11. The connection of claim 10, where the linker has the formula -(CH2)q-CO-NRa-(CH2)w- or -(CH2)q-O-CO-NRa-(CH2)w-.

12. Connect the tion in claim 11, where Rarepresents N.

13. The connection according to item 11 or 12, where q is 1 or 2, preferably 2.

14. The connection according to item 11 or 12, where w is 6, 7, 8 or 9, preferably 6 or 7.

15. A compound selected from the group consisting of
N-[5-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)pentyl]-3-(1H-indol-3-yl)propionamide;
3-(1H-Indol-3-yl)-N-[5-(1,2,3,4-tetrahydropyridine-9 ylamino)pentyl]propionamide;
N-[6-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)hexyl]-3-(1H-indol-3-yl)propionamide;
N-[7-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]-3-(1H-indol-3-yl)propionamide;
N-[8-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)octyl]-3-(1H-indol-3-yl)propionamide;
N-[9-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)nonyl]-3-(1H-indol-3-yl)propionamide;
N-[10-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)decyl]-3-(1H-indol-3-yl)propionamide;
N-(3-{[3-(1,2,3,4-tetrahydropyridine-9 ylamino)propyl]-methylamino}propyl)-3-(1H-indol-3-yl)propionamide;
N-(3-{[3-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)-propyl]methylamino}propyl)-3-(1H-indol-3-yl)propionamide;
[5-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)pentyl]amide of 1H-indole-3-carboxylic acid;
[6-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)hexyl]amide of 1H-indole-3-carboxylic acid;
[7-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]amide of 1H-indole-3-carboxylic acid;
[8-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)octyl]amide of 1H-indole-3-carboxylic what Islami;
N-[7-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]-2-(1H-indol-3-yl)ndimethylacetamide;
N-[5-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)pentyl]-4-(1H-indol-3-yl)butyramide;
N-[6-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)hexyl]-4-(1H-indol-3-yl)butyramide;
N-[6-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)hexyl]-3-(1H-indol-3-yl)acrylamide;
2-(5-Bromo-1H-indol-3-yl)-N-[7-(6-chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]ndimethylacetamide;
N-[6-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)hexyl]-3-(5-isocyano-1H-indol-3-yl)propionamide;
[7-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]amide of 1H-methylindol-3-carboxylic acid;
[7-(6-Chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]amide of 1H-indazol-3-carboxylic acid;
2-(1H-indol-3-yl)ethyl ester [5-(6-chloro-1,2,3,4-tetrahydropyridine-9 ylamino)pentyl]carbamino acid;
2-(1H-indol-3-yl)ethyl ether [6-(6-chloro-1,2,3,4-tetrahydropyridine-9 ylamino)hexyl]carbamino acid or
2-(1H-indol-3-yl)ethyl ester [7-(3-chloro-1,2,3,4-tetrahydropyridine-9 ylamino)heptyl]carbamino acid;
or its pharmaceutically acceptable salt.

16. The method of obtaining the amide according to any one of claims 1 to 15 General formula

where X is selected from CH or N;
L is selected from-CRaRb-, -CRa= or -(CRaRb)3N(Ra)(CRaRb)3-;
Raand Rbindependently selected from hydrogen or n is replaced With 1-8of alkyl;
and n is an integer selected from 0, 1, 2, 3, 5, 6, 7, 8, 9 or 10;
R2and R5independently selected from hydrogen, -CN or halogen;
including:
(i) obtaining a solution of a derivative of indole following formula

in anhydrous THF;
(ii) adding 1,1'-carbonyldiimidazole to the solution (i) in an inert environment;
(iii) obtaining the solution derived 9-alkylmethacrylamide following General formula:

in THF
(iv) the interaction of solution (iii) solution, obtained from (ii), at room temperature.

17. The pharmaceutical composition inhibiting the acetylcholinesterase or butyrylcholinesterase comprising the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier, adjuvant or excipient.

18. Pharmaceutical composition for 17 for oral administration.

19. The use of compounds according to any one of claims 1 to 15 for obtaining a medicinal product for the treatment of AChE-mediated diseases.

20. The application of claim 19, where the drug is intended to treat disorders of cognitive abilities, such as senile dementia, cerebrovascular dementia, mild decrease in cognitive function, attention deficit, and/or neurodegener the tive diseases, accompanied by loss of reason, with abnormal protein aggregation, such as Alzheimer's disease or related condition, or prion disease, or Parkinson's disease or parkinsonopodobnyh state, fronto-temporal dementia, systemic amyloidosis or a related condition.

21. The application of claim 20, where the drug is intended for treatment of Alzheimer's disease or an associated condition.

22. A method of treating a patient in need of such treatment, an effective amount of a compound according to any one of claims 1 to 15, where the method is aimed at the treatment of disorders of cognitive abilities, such as senile dementia, cerebrovascular dementia, mild decrease in cognitive function, attention deficit, and/or neurodegenerative diseases, accompanied by loss of reason, with abnormal protein aggregation, such as Alzheimer's disease or related condition, or prion disease, or Parkinson's disease or parkinsonopodobnyh state, fronto-temporal dementia, systemic amyloidosis or a related condition.

23. The method according to item 22 for the treatment of Alzheimer's disease or an associated condition.

24. The use of amide of the formula I

where A, B, D, Z, L, k, m, n, q, x, w, R1-R6defined in claim 1, or pharmaceutical the ski acceptable salt,
as a reagent for the inhibition of acetylcholinesterase in biological research.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: in embodiments of the invention, specific compounds are used to prepare a medicinal agent for treating, relieving and preventing conditions associated with dysfunction of monoamine transmission. The compounds have general formula (1) , where: R1 and R2 are identical or different and denote hydrogen, alkyl, alkenyl, alkynyl, aryl, thio or alkylthio, or R1 and R2 may have extra substitutes which are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkyloxy, morpholin-4-ylalkoxy, piperidin-1-ylalkyloxy, alkylamino, dialkylamino, arylamino.

EFFECT: more efficient use of compounds in preparing medicinal agents.

8 cl, 3 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline or quinazoline derivatives of general formula

Ib, where R1 is C1-6-alkyl or C1-6-alkoxy; X is N or CH; R3 and R4 independently denote hydrogen, C1-6-alkyl, C1-6-alkylsulphonyl or a group of formula (IIa), where A is oxygen or sulphur; D is -(CH2)t, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur, (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or a group of formula (IIb), where A is oxygen or sulphur; D is -(CH2)t-, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or R3 and R4 together with the nitrogen atom with which they are bonded form a 3-7-member ring or a 6-10-member bicyclic ring which can be saturated, partially saturated or unsaturated and contain 1, 2 or 3 heteroatoms selected from nitrogen, sulphur and oxygen, where each group is optionally substituted with 1 or 2 substitutes selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where aryl and aryl-C1-6-alkyl are also optionally substituted with 1 or 2 with C1-6-alkyls or C1-6-alkoxy). The invention also relates to use of formula Ib compounds in preparing a medicinal agent, to a pharmaceutical composition based on formula Ib compound and preparation method thereof.

EFFECT: obtaining novel quinoline and quinazoline derivatives having high affinity to 5-HT1-receptors.

12 cl, 171 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication, reducing desire for alcohol, which represents substituted 1H-benzimidazoles of general formula 1 or their pharmaceutically acceptable salts and/or hydrates, pharmaceutical composition, and medication on their basis. Compounds can be applied in treatment of alcohol abuse with application of ethanol-containing products, if necessary, together with antidepressants. In compounds of general formula 1 , where: W represents sulfur atom or group S=O; R1 represents one or more substituents, selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkyloxy, optionally substituted 5-6-member azaheterocyclyl with 1-2 atoms of nitrogen and/or oxygen in cycle; R2 represents atom of hydrogen or optionally substituted C1-C4alkyl; R3 and R4 independently on each other represent optionally similar substituents, selected from hydrogen, optionally substituted C1-C4alkyl, C3-C6cycloalkyl; R5 represents alkyl substituent, selected from hydrogen or optionally substituted C1-C7alkyl, C1-C7alkenyl, C1-C4alkynyl, optionally substituted phenyl, optionally substituted 5-6-member heterocyclyl with 1-3 heteroatoms, selected from nitrogen, oxygen and sulfur, possibly condensed with benzene ring; C1-C4-alkoxycarbonyl, optionally substituted amino carbonyl, or group CR3R4R together stands for group , where Alk stands for C1-C4alkyl.

EFFECT: medication allows to reduce symptoms of alcohol abuse considerably as compared with earlier known compounds and does not produce unfavorable effect on liver function.

12 cl, 3 tbl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of substituted 4-(benzimidazol-2-ylmethylamino)benzamidine of formula (I) or its physiologically compatible salt, in which R1 is a C1-C3alkyl group, R2 is a R21NR22 group, where R21 denotes a C1-C3alkyl group substituted with a C1-C3alkoxycarbonyl group, and R22 denotes a pyridinyl group, and R3 is a C1-C8alkoxycarbonyl group having thrombin inhibiting and thrombin clotting time prolonging activity. The method involves a step (a) where phenyldiamine of formula (II) in which R1 and R2 assume values given for formula (I), reacts with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid. At step (b), the obtained product of formula (III), in which R1 and R2 assume values given for formula (I), is hydrogenated and then at step (c), if necessary, the obtained product of formula (I), in which R3 is hydrogen, reacts with a compound of formula R3-X (IV), in which R3 assumes values given for formula (I), and X denotes an acceptable leaving group, and then converted to a physiologically compatible salt if necessary. The invention also relates to novel intermediate products - formula (III) compound, in which R1 and R2 assume values given for formula (I), as well as to 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, 4-(1,2,4-oxadiazol-5-on-3-yl)aniline and toluene sulphonate N-(2-pyridinyl)-N-(2-ethoxycarbonylethyl)amide 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl carboxylic acid.

EFFECT: agents are highly effective.

12 cl, 2 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives having FAK inhibitory activity of formula (I), where R0 is hydrogen; R1 is a 5- or 6-member heterocycle containing 1 or 2 nitrogen atoms substituted with (C1-C7)alkyl, hydroxyl group, dialkylamino group or a 6-member heterocycle containing one nitrogen atom; R2 is hydrogen; R3 is carbamoyl substituted once or twice with (C1-C7)alkyl; a 5-member heterocycle containing 4 nitrogen atoms; SO2N(R12)R13, where R12 is hydrogen or (lower)alkyl, and R13 is hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy(C1-C7)alkyl, di(C1-C7)alkylamino(C1-C7)alkyl, hydroxy(C1-C7)alkyl, or R12 and R13 together a nitrogen atom with which they are bonded form a 6-member heterocycle containing two nitrogen atoms, where the said heterocycle is not substituted or substituted with (C1-C7)alkyl; R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; (C1-C7)alkoxy; carbamoyl which is not substituted or substituted with (lower)alkyl; a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with di(C1-C7)alkylamino, (C1-C7)alkyl, hydroxy, 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms, unsubstituted or substituted with (C1-C7)alkyl; 6-member heterocycle-oxy containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms which is not substituted or substituted with (C1-C7)alkyl; R8 is hydrogen; halide; (C1-C7)alkoxy, carbamoyl unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5-member heterocycle containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with one or two substitutes independently selected from hydroxy, (C1-C7)alkyl, aminocarbonyl and (C1-C7)alkylamino; 6-member heterocycle-oxy, containing 1 nitrogen ring atom, unsubstituted or substituted 1-5 times with (C1-C7)alkyl or di(C1-C7)alkylamino; or R7 and R8 together with atoms with which they are bonded form a 6-member heterocycle containing two nitrogen or oxygen atoms, unsubstituted or substituted once or twice with (C1-C7)alkyl or oxo group; R9 is hydrogen; R10 is (C1-C7)alkoxy, as well as to their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and synthesis method.

EFFECT: novel compounds have useful biological activity.

4 cl, 167 ex

FIELD: medicine.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) or their pharmaceutically acceptable salts which possess inhibiting activity with respect to focal adhesion kinase (FAK), proteintyrosinekinase ZAP-70, receptor of insulin-like growth factor 1 (IGF-1R), tyrosinekinase activity of anaplastic lymphoma (ALK) and fusion protein NPM-ALK. In formula (I) , R0, R1 and R2 independently represent hydrogen, C1-C8 alkyl, 5- or 6-member heterocycle, containing 1,2 or 3 heteroatoms, selected from N, O and S, C1-C8alkoxy group, C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, halogen, carbamoyl, sulphamoyl, etc.; R3 represents C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, carbamoyl or sulphamoyl; R4 represents hydrogen or C1-C8alkyl; R5 represents chlorine or bromine; R6 represents hydrogen; R7, R8, R9 and R10 independently represent C1-C8alkyl, C5-C10aryl, possibly substituted by 5- or 6-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N, O and S, where substituents are selected from C1-C8alkyl, hydroxy, hydroxy-C1-C8alkyl, C1-C8alkoxy C1-C8alkyl, cyano, oxo, C1-C8alkylamino, diC1-C8alkylamino, carbamoyl, C1-C8alkylcaronyl, 5-10-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N and O, which is probably substituted by C1-C8alkyl; C1-C8alkoxy group, halogen- C1-C8alkoxy group, etc; A represents C. Invention also relates to pharmaceutical composition and to application of compounds of formula (I) for preparation of medication.

EFFECT: novel compounds possess useful biologic activity.

15 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline 1-[2-(4-benzyl-4-hydroxypiperidin-1-yl)-ethyl]-3-(2-methylquinolin-4-yl)-urea of formula I

,

in monosulphate trihydrate form. The invention also relates to a composition based on the said compound which has antagonistic effect on urotensin.

EFFECT: obtaining a novel compound and compositions based on said compound, which can be used in medicine as neurohormonal antagonists.

8 cl, 3 dwg, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acids. The substituted 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acids of general formula 1 and their pharmaceutically acceptable salts and/or hydrates , where: R1 is an amino group substitute selected from hydrogen; optionally substituted C1-C5 alkyl; optionally substituted C1-C5 alkylsulphonyl, optionally substituted arylsulphonyl or optionally substituted heterocyclylsulphonyl; acyl; R2 is an alkyl substitute selected from hydrogen, substituted amino group, optionally substituted hydroxy group, substituted mercapto group, substituted alkylamino group; R3 is hydrogen, C1-C3 alkyl; R4 is a substitute selected from hydrogen, C1-C3 alkyl substituted with an amino group, optionally substituted with phenyl or heterocyclyl; R5 is one or more substitutes of the cyclic system selected from trifluoromethyl, carboxyl, alkyloxycarbonyl, possibly substituted aryl, heterocyclyl, substituted aminomethyl, cyano group, or R5 is hydrogen provided that when R1 is a substitute selected from hydroxy-substituted C1-C3 alkyl, amino-substituted C1-C3 alkyl, and R2, R3, R4 and R6 are as described above, or R2 is an alkyl substitute selected from substituted amino group, optionally substituted hydroxy group, substituted mercapto group, substituted alkylamino group, and R1, R3, R4 and R6 are as described above; or R5 is fluorine.

EFFECT: obtaining novel substituted 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acids which have antiviral activity, especially against the influenza virus and hepatitis C virus (HCV).

19 cl, 3 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (1) , where substitutes are as defined in paragraph 1 of the invention. The compounds have fungicide properties. The method of obtaining formula (1) compounds is described, in which n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining novel compounds which can be used as fungicides.

24 cl, 312 tbl, 14 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel malonamide derivatives of general formula , to their pharmaceutically acceptable salts of acid bonding and to all forms of their optically pure enantiomers, racemates or diastereomers and diastereomer mixtures, possessing inhibiting activity with respect to γ-secretase, as well as to pharmaceutical preparation, containing one or more than one of claimed compounds, and to application of claimed compounds for manufacturing of drugs. Values of substituents R, R1, R2, R3, as well as X, n are given in invention formula.

EFFECT: obtaining compounds that can be applied in treatment of Alzheimer's disease.

19 cl, 6 dwg, 111 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, ophthalmology, and can be used for treatment of optic atrophy in children of age from 1 to 6 months. For this purpose regions of large and small fontanelles of head and upper sympathetic ganglia at the level of cervical spine at C1-C2 level are exposed to polarised light of apparatus "Bioptron". Exposures to light are carried out daily during 10 days in therapeutic dose 12 J/cm2 from the distance 5 cm from skin surface with light spot diametre 5 cm, irradiation intensity 40 mW/cm2 exposure duration 30 seconds on region of fontanelles and 1 minute on regions of ganglia. On finishing light impact nootropic medications cortexin and/or actovegin or cerebrolisin are introduced in age dose. Courses of treatment are carried out from 1 month to 6 month age until desired therapeutic effect is obtained.

EFFECT: method allows to improve cerebral and intraocular blood supply and metabolic processes of brain and optic nerve, improve delivery of nootropic medications to optic analyser, obtain therapeutic concentrations of medications without side effects.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention is aimed at dipyrazole compounds of formula I and their pharmaceutically acceptable salts, where radicals and groups are defined in claim 1 of the formula of invention. Disclosed compounds modulate AMPA and NMDA receptor functioning. A pharmaceutical composition based on formula I compounds and separate dipyrazole compounds are also part of the subject of invention.

EFFECT: possibility of using compounds as pharmaceutical agents, mainly for treating psychoneurological diseases.

16 cl, 2 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-alkylamino-3-sulfonyl-pyrazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and/or hydrates which have serotonin 5-HT6 receptor antagonist properties and can be used in treating or preventing development of various central nervous system diseases, whose pathogenesis is related to 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases, cognitive and anxiety disorders and obesity. In general formula (I):

R1 and R3 independently denote optionally identical C1-C3alkyl, R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3alkyl; R4 is C1-C3alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3alkyl; i is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3alkyloxycarbonyl, aminocarbonyl CONR6R7 or a NR6R7 amino group; R6 and R7 denote optionally identical hydrogen atom, optionally substituted C1-C3 alkyl, C3-C7cycloalkyl or an optionally substituted 5-7-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl; or R6 and R7 together with the nitrogen atom to which they are bonded form an optionally substituted 5-6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl.

EFFECT: obtaining new biologically active compounds.

26 cl, 12 dwg, 4 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely for teacheability and memory improvement in mammals. An infant takes a milk formula containing casein glycomacropeptide in amount sufficient to ensure introducing at least 100 mg/kg of sialic acid a day.

EFFECT: method extends the range of products for teacheability and memory improvement in an infant.

11 cl, 14 tbl, 13 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to bioorganic chemistry and medicine and can be used to prepare medicinal agents with neurotropic activity. The technical result is achieved due to creation of a peptide with neurotropic activity and having general formula: Ac-X-Met-Pro-Arg-Gly-NH2, where X-Met - L-Met or DL-Met.

EFFECT: obtaining a novel compound - analogues of the C-terminal end of vasopressin which are capable of selectively bonding with different subtypes of vasopressin receptors and, as a result, have different types of neurotropic activity, have low toxicity and are suitable for simple intranasal administration.

5 ex

FIELD: medicine.

SUBSTANCE: there is claimed application of dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor), vildagliptin or its salt for production of medication for prevention, retardation of progress or treatment of peripheral diseases such as peripheral neuropatia, neurodegenerative disorders, cognitive disorders, as well as for improvement of memory and ability to learn, and pharmaceutical composition for the same purpose. It is demonstrated: vildagliptin increases stage of wakefulness and response to external stimuli, increases REM sleep phase.

EFFECT: combination of vildagliptin with donepezil considerably improves disturbed ability to learn.

23 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound having the structural formula I , or its pharmaceutically acceptable salt, ester or amide, where A has the structure , where each bond in A, represented by a dotted and a solid line, represents a carbon-carbon single bond; each of a, b and c is a carbon atom; each of e, f, g and h is a carbon atom; X is nitrogen; X' is C; L is absent; each n equals 1; Y is nitrogen; W is nitrogen; R1 is hydrogen; each of R2, R3 and R4 is a hydrogen atom; each of R6, R8 and R9 is a hydrogen atom; R5 is selected from a group consisting of halogen, C1-6alkyl, optionally substituted with a hydroxy group, and C1-6alkoxy; R7 is selected from a group consisting of halogen, C1-6alkyl and perhalogenalkyl; Z is selected from a group consisting of NR11, oxygen and CH2; R11 is hydrogen; and each bond in formula I, represented by a dotted and a solid line, is a carbon-carbon double bond. The invention also relates to a method for synthesis of a formula V compound, a pharmaceutical composition based on a formula I compound, methods of treating psychoneurological disorders, a pharmaceutical composition containing a formula I compound and a psychoneurological agent.

EFFECT: obtaining novel compounds useful for modulating muscarine receptor activity.

37 cl, 1 tbl, 141 ex

FIELD: medicine.

SUBSTANCE: invention refers to psychoneurology, particularly to an agent for treating multiple sclerosis. A composition (solid or liquid dosage form) contains triiodide 1,3-diethylbenzimidazolium as an agent, low-molecular surgical polyvinylpyrrolidone, presented as a solubiliser, and an agent stabiliser, and in addition in the liquid dosage form - ethanol as a solvent.

EFFECT: composition under the invention exhibits high therapeutic effectiveness in treating multiple sclerosis, and is characterised by relieving undesirable by-effects.

2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. In general formula 1 , R1 and R3 independently denote optionally identical C1-C3 alkyl, and R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3 alkyl; R4 is C1-C3 alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3 alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3 alkyloxycarbonyl, aminocarbonyl CONR6R7 or amino group NR6R7; except compounds in which R3 is a -(CH2)nX group, where X is an amino group NR6R7 and n equals 0; R6 and R7 are optionally identical and denote a hydrogen atom, optionally substituted C1-C5 alkyl or R6 and R7 together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C1-C3 alkyl.

EFFECT: obtaining compounds which can be used in treating diseases of the central nervous system during prevention or treatment of cognitive disorders, neurodegenerative diseases, psychiatric disorders, have anxiolytic and nootropic effect and can be used to prevent and treat anxiety disorders and enhance mental capacity.

25 cl, 2 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncology and can be used for optimisation of Hodgkin's lymphoma of IIIA stage treatment in adults. Method is realised in the following way. In case there are no symptoms of intoxication, patients with histological subtype nodular sclerosis and with histological grade at which 75% and more of cellular nodules contain only dispersed Berezovsky-Stenberg cells located on rich in lymphocytes mixed cellular or fibrohistiocytic background, 2-3 cycles of introductory combined chemical therapy are carried out according to schemes MOPP, MOPPABV or ABVD. After that total or subtotal irradiation of lymphatic nodules is performed.

EFFECT: application of invention allows to determine indications for chemical-radiological therapy taking into account versions of histological structure of tumour, ensures long-term recurrence-free survival rate and reduces treatment toxicity.

2 ex

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