Amides of 3-substituted 5- and 6-aminoalkylindole-2-carboxylic acid and related analogues such as casein kinase iΕ inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

 

Background of invention

1. The scope of the invention

The present invention relates to a group of substituted amides of 5-aminoalkyl-1H-indole-2-carboxylic acid and 6-aminoalkyl-1H-indole-2-carboxylic acid. More precisely, the invention relates to Amida 3-aristotlean and 3-heterocyclization 5-aminoalkyl-1H-indole-2-carboxylic acid and 6-aminoalkyl-1H-indole-2-carboxylic acids and their related counterparts. Connection, which is the object of the invention are inhibitors of the phosphorylation time human protein Period (hPER) under the action of caseinline Iε person and are therefore useful as pharmaceutical agents, especially for the treatment and/or prevention of diseases and disorders related to the Central nervous system.

2. The preceding technical field

Rhythmic changes in behavior characteristic of many living organisms, from single cell to man. If the rhythm under constant conditions is saved and has a period of about a day, while only weakly dependent on temperature, this rhythm is called the "circadian" (Konopka, R.J. and Benzer, S. (1971) Proc. Nat. Acad. Sci. USA 68, 2112-2116).

Circadian rhythms are generated by an endogenous biological pacemakers (circadian clock), which exist in most living organisms, including humans, fungi, insects and bacteria is (Dunlap, J.C. (1999) Cell 96, 271-290; Hastings, J.W. et al. Circadian Rhythms, The discrimination of Biological Timing. In: Prosser, C.L. ed. Neural and Integrative Animal discrimination, New York: Wiley-Liss (1991) 435-546; Allada, R. et al. (1998) Cell 93, 791-804; Kondo et al. (1994) Science 266, 1233-1236; Crosthwaite, S.K. et al. (1997) Science 276, 763-769; Shearman, L.P., et al. (1997) Neuron, 19, 1261-1269). Circadian rhythms are self-sustaining and remain constant even in total darkness, but can be synchronized with the new regime shifts day/night (to adapt) the signals of the external environment, such as light and temperature cycles (Pittendrigh, C.S. (1993) Annu. Rev. Physiol., 55, 16-54; Takahashi, J.S. (1995) Annu. Rev. Neurosci. 18, 531-553; Albrecht, U. et al. (1997) Cell 91, 1055-1064). Circadian clocks play a key role in maintaining many biological rhythms and regulate many circadian manifestations, such as daily fluctuations in behavior, eating, cycles of sleep and wakefulness, as well as physiological changes, such as hormone production and fluctuations in body temperature (Hastings, M. (1997) Trends Neurosci. 20, 459-464; Reppert, S.M. and Weaver, D.R. (1997) Cell 89, 487-490).

Genetic and molecular studies of fruit fliesDrosophila melanogasterclarify the role of some genes involved in circadian rhythm. Such studies led to the identification of the path, which is rigidly autoregulated and includes the transcriptional/translational feedback (Dunlap, J.C. (1999) Cell,96, 271-290; Dunlap, J.C. (1996) Annu. Rev. Genet.30, 579-601; Hall, J.C. (1996) Neuron,17, 799-802). Acronymically circadian oscillator in Drosophilaare two stimulating protein dCLOCK/dBMAL (CYCLE) and two inhibitory protein dPERIOD (dPER) and dTIMELESS (dTIM). dCLOCK and dBMAL heterodimerizes with the formation of the transcription factor dCLOCK/dBMAL, which promotiom the expression of two genes, calledDrosophilaPeriod(dperandDrosophilaTimeless(dtim). Ultimately, reading the mRNA of these genes to ensure protein synthesis dPER and dTIM respectively. Within a few hours in cytoplasm synthesis and phosphorylation of protein derivatives dPER and dTIM, then reaches a critical level, they form heterodimer and translucida in the core. Once in the nucleus, dPER and dTIM function as negative regulators of their own transcription and accumulation of dPER and dTIM inhibited, and again starts the activation of thedperanddtimdue to the presence of dCLOCK/dBMAL (Zylka, M.J. et al. (1998) Neuron 20, 1103-1110; Lowrey, P.L. et al. (2000) 288, 483-491). It was shown that genedperan indispensable element in the control of circadian rhythms hatching adult (the emergence of adult flies from pupae), behavior and locomotor activity (Konopka, R.J., & Benzer, S. (1971) Proc. Natl. Acad. Sci. USA, 68, 2112-2116). Missense mutations of the genepercan either be shortened (perS)or lengthen (perLthe period of the circadian rhythm, whereas nonsense mutations (pero) generate arrhythmia in their behavior (Hall, J.C. (1995) Trends Neurosci. 18, 20-240).

In mammals, the suprachiasmatic nucleus (SHA) of the anterior hypothalamus is the site of major biological clock (see review Panda et al, (2002) Nature 417, 329-335; Reppert, S.M. and Weaver, D.R. (1997) Cell, 89, 487-490). Watch SHE included in the 24-hour day cycle due to the daily cycle of day and night, and the light acts through direct and indirect transmission channels retin-SHA (Klein, D.C. et al. (1991) Suprachiasmatic Nuclei: The Mind's Clock, Oxford University Press, New York). In SHA rodents identified and cloned three genesPerthat are referred to as murine genesPer1(mPer1),mPer2andmPer3. Proteins, these mammalian genes (mPER1, mPER2, mPER3), have some common areas of homology with each other, and each gene mammalsPerencodes a protein with a domain dimerization of the protein, which is represented as PAS (PAS is an abbreviation consisting of the first letters of the three proteins PER, ARNT and SIM, which has been found to have such a functionally important domain dimerization), which is highly homologous to the PAS domain PER insect. Levels of messenger RNAPer(mRNA) and protein fluctuate during the circadian day and, ultimately, participate in positive and negative regulation of the biological clock, but only mPER1 and mPER2 oscillate in response to exposure to light (Zylka, M.J. et al. (1998) Neuron 20, 1103-1110.; Albrecht, U. et al., (1997) Cell 91, 1055-1064; Shearman, L.P., et al. (1997) Neuron, 19, 1261-1269). Homolog geneDrosophilatim in mammals have been cloned and designated as mTim. However, there has been no evidence of interactions mPER-mTIM similar is recorded inDrosophilaand it has been suggested that interactions PER-PER can be replaced by a function of dimers PER-TIM for the molecular action of the circadian clock of mammals (Zylka, M.J. et al., (1998) Neuron 21, 1115-1122). Another possibility is that the rhythms in PER1 and PER2 form a negative feedback loop that regulates the transcriptional activity of the protein Clock (through their PAS domains), which in turn activates the expression of either or both genesPer(Shearman, L.P., et al. (1997) Neuron, 19, 1261-1269).

Views about the role of the three genesmPerin step clockwork mammals have been the subject of many studies. Structural homology mPER proteins in relation to dPER permitted to hope that the mPER proteins will function as negative elements in the feedback circuit mammals. It is assumed that PER1 is involved in the negative regulation of its own transcription in the feedback circuit, but recent evidence indicates that it is involved in the input stage (Hastings, M.H. et al. (1999) Proc. Natl. Acad. Sci. USA 26, 15211-15216). PER2 is the most well-studied protein, and the mutant protein mouse mPER2 (mPer2Brdm1), no 87 residues at the carboxyl side of the domain dimerization PAS, today is a shortened circadian cycle in normal conditions, day or night, but shows arrhythmia in complete darkness. The mutation also reduces the oscillating expression of bothmPer1andmPer2in SHA, showing thatmPer2can be adjusted bymPer1"in vivo" (Zheng, B. et al. (1999) Nature 400, 169-173). It was shown that PER2 has a dual function in the regulation of the "wheels" in the Central hours (Shearman, L.P., et al. (2000) Science 288, 1013-1018). In this study, it was demonstrated that PER2 is associated with cryptochrome (CRY) proteins and translocases in the core, which is negatively regulated the transcription of CRY is driven positive transcriptional complexes CLOCK and BMAL1. After penetration into the core of PER2 initiates a positive lever hours due to positive regulation of transcription of BMAL1 by yet unknown mechanism. Function PER3 poorly known, but inmPer3knockout mice observed a weak effect on the circadian activity, and therefore it was assumed that the PER3 participates in circadian regulated output channels (Shearman, L.P., et al. (2000) Mol. Cell. Biol. 17, 6269-6275). It was reported that the mPER proteins interact with each other and that mPER3 can serve as a carrier of mPER1 and mPER2 to deliver them into the kernel, which is critical for the generation of circadian signals in SHA (Kume, K. et al. (1999) Cell 98, 193-205; Takano, A. et al. (2000), FEBS Letters, 477, 106-112).

Theoretically justified that the phosphorylation of components of the circadian clock regulates the duration of the cycle. The first genetic evidence that a specific protein kinase regulates circadian rhythmDrosophilait was the discovery of a new gene doubletime (dbt)encoding a protein serine-threonine kinase (Price J.L. et al. (1998) Cell 94, 83-95; B. Kloss et al. (1998) Cell 94, 97-107). Missense mutations indbtlead to altered circadian rhythm. Null allelesdbtcause hypophosphorylation dPER and arrhythmias.

The kinases mammals, most closely related to DBT are caseinline Iε (CKIε) and caseinline Iδ (CKIδ). It is shown that both kinases are associated with mPER1, and in several studies it was demonstrated that CKIε phosphorylates and mouse, and human PER1 (Price J.L. et al. (1998) Cell 94, 83-95; B. Kloss et al. (1998) Cell 94, 97-107). In the study of the embryo cells of human kidney 293T, transfection together with hCKIε wild type, hPER1 demonstrated a significant increase in phosphorylation (shown in the example of the shift in molecular weight). In this study, phosphorylated hPER1 has a half-life of approximately twelve hours, while nefosfaurilirovanna hPER1 remains stable in the cell for more than 24 hours, indicating that phosphorylation of hPER1 leads to a fall in the stability of the protein (Kessler, G.A. et al. (2000) NeuroReport, 11, 951-955). In another study it was also shown that the sequence of the phosphorylation of PER1 hCKIε includes cytoplasmic FIC is the situation and the instability of the protein (Vielhaber, E. et al. (2000) Mol. Cell. Biol. 13, 4888-4899; Takano, A. et al. (2000) FEBS Letters 477, 106-112).

There was no biochemical reason to choose between CKIε or CKIδ as a potential regulator in mammals as long as the work Lowery et al. [(2000) Science 288, 483-491] not detected that the Syrian Golden hamster predominantly mutations in CKIε (mutationtau, Ralph, M.R. and Menaker, M. (1988) Science 241, 1225-1227) caused a reduction of circadian day as heterozygous (22 h), and homozygous (20 h) animals. In this case, reduced activity levels of CKIε led to decreased phosphorylation of PER at presumably higher levels tsitoplazmaticheskogo protein PER, which caused increased penetration into the nucleus and change circadian cycles. Recently, it was assumed that CKIδ may also participate in the regulation of circadian rhythm due to posttranslational modification of proteins hours mammals hPER1 and hPER2 [Camacho, F. et al., (2001) FEBS Letters 489(2,3), 159-165]. Therefore inhibitors, including inhibitors of the number of small molecules, CKIε and/or CKIδ human or mammalian provide new opportunities phase shift or reset the circadian clock. As shown below, the change in the circadian rhythm can be useful for the treatment of sleep disorders or mood.

In the patent US 6555328 B1 disclosed methods of screening cells to identify compounds that modify the circus is derivative rhythms, based on the test connection, changing the ability of the human caseinline 1ε and/or human caseinline 1δ to fosforilirovanii human clock proteins hPER1, hPER2 and hPER3. For example, HEK293T cells transfections together with hCKIε and Per1 or Per2. In order to assess the significance of inhibition of CKIε and inhibitors CKIε for circadian biology was established highly productive cell culture (33rdAnnual Meeting, Soc. for Neurosci., November 8-12, 2003, Abstract numbers 284.1, 284.2, and 284.3), in which circadian rhythms can be monitored in a standard way. In this assay, fibroblasts Rat-1 stably Express the constructMper1-lucthat allows you to define the rhythmic activation of the promoter ofMper1in living cells, repeatedly evaluating the luciferase activity according to the change of light output within a few days. The format of the periodic control culture provides accurate and reproducible assessment of the concentration-dependent effects of inhibitors CKIε on circadian rhythm and gives the opportunity to communicate inhibition of CKIε with changes in the circadian period.

Sleep disorders were divided into four main categories, which include primary sleep disorders (dyssomnia and parasomnias, sleep disorders associated with medical/psychiatric disorders, and the category of suspected sleep disorders for those with sleep disorders, which nebo, which can be classified because of insufficient data. It is believed that primary sleep disorders arise from deviations directly in the systems responsible for the generation of sleep-Wake (homeostatic system) or time (circadian system). Dyssomnia relate to violations of forming or maintaining sleep, and include primary insomnia, hypersomnia (excessive sleepiness, narcolepsy, sleep disorders associated with breathing, sleep disorders associated with circadian rhythm, and dyssomnia not included in these categories. Primary insomnia is characterized by a continuing (>1 month) problems initiating and maintaining sleep or nevosstanovlenie sleep. Sleep problems associated with primary insomnia, leading to significant impairment or disorders, including irritable in the daytime, loss of attention and concentration, fatigue and malaise, worsening of mood and motivation. Sleep disorders associated with circadian rhythm include syndrome desynchronize when travelling syndrome sleep disorders in shift work syndrome premature sleep phase syndrome and delayed sleep phase (J. Wagner, M.L. Wagner and W.A. Hening, Annals of Pharmacotherapy (1998) 32, 680-691). Persons with a regime of forced sleep demonstrate a higher level of vigilance in the percentage of time of sleep at certain times of the circadian day (Dijk and Lockley, J. Appl. Physiol. (2002) 92, 852-862). It is believed that with age there is a shift of circadian rhythm sleep which often leads to less quality of sleep (Am J Physiol Endocrinol Metab. (2002) 282, E297-E303). Thus, sleep, arising out of, circadian phase, may be flawed from the point of view of quantity and quality, backed up with additional examples of changes in sleep during shift work and desynchronosis in the flights. The change in the circadian clock of humans can cause sleep disturbances, and agents that modulate the circadian rhythm, for example, the inhibitor CKIε and/or CKIδ, can be useful for the treatment of sleep disorders, particularly sleep disorders associated with circadian rhythm.

Mood disorders are divided into depressive disorder ("unipolar depression"), bipolar disorders, and two disorders based on etiology, which include mood disorders due to a General state of health and mood disturbance under the influence of drugs. Depressive disorders additionally classified as major depressive disorder, estimatesa disorder and depressive disorder, not classified in other categories. Bipolar disorder is additionally subdivided into bipolar disorder type I and II. It was noted that the definition of "seasonal" can be applied to large depressive disorders, which are periodic in nature is, and in the case of large attacks depressive disorders bipolar disorders I and type II. Notable anergy, hypersomnia, overeating, weight gain and the need for carbohydrates is often characterized by large depressive symptoms, which are seasonal. It is unclear if there is seasonal in nature is more likely in large depressive disorders, which are periodic in nature, or bipolar disorders. However, in the framework of bipolar disorder seasonal nature seems to be more likely in bipolar disorder type II than in bipolar disorder type I. In some individuals the manifestation of mania or hypomania may also be associated with a specific time of the year. The seasonality of the winter type, as a rule, varies depending on latitude, age and gender. Prevalence increases at higher latitudes, the exposure of the winter manifestations of depression decreases with age, women are from 60% to 90% of the total number of seasonal dependent people. Seasonal affective disorder (SAD), a term widely used in the literature, are a subtype of mood disorders, which in the diagnostic and statistical Manual of mental disorders (DSM-IV) (American Psychiatric Association: “Diagnostic and Statistical Manual of Menta Disorders”, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000) are indicated by the term "seasonal" when describing the seasonal nature of the attacks big depressive disorders in bipolar disorder type I, bipolar disorder type II or periodic large depressive disorders (E. M. Tam et al., Can. J. Psychiatry (1995) 40, 457-466). Characteristics and diagnoses of depressive disorders, major depressive disorders, seizures of large major depressive disorder, bipolar disorder type I, bipolar disorder type II and seasonal effects described in the DSM-IV.

Patients suffering from great depressive disorders, including SAD, which are characterized by periodic bouts of depression, usually in winter, showed a positive response to light therapy (Kripke, Journal of Affective Disorders (1998) 49(2), 109-117). The success of therapy based on the use of bright light, for patients suffering from SAD and great depression, allowed us to propose several hypotheses to explain the fundamental mechanism of action of therapeutic effect of light. Such hypothesis is the hypothesis of circadian rhythm", which suggests that the antidepressant effects of bright light can be related to a phase shift of the circadian pacemaker in relation to sleep (E. M. Tam et al., Can. J. Psychiatry (1995) 40, 457-466). Confirmed the m relationship between light therapy and circadian rhythm was the fact, what is clinically effective light therapy at high depressive disorders causes a concomitant shift in circadian phase, and clinical efficacy of light therapy, obviously, depends on the ability of light therapy to provide light shift (Czeisler et al., The Journal of discrimination (2000) 526 (Part 3), 683-694; Terman et al., Arch. Gen. Psychiatry (2001) 58, 69-75). In addition, it was shown that light therapy accelerates and enhances the effectiveness of the pharmacological treatment of large major depressive disorder (Benedetti et al., J. Clin. Psychiatry (2003) 64, 648-653). Therefore, it can be expected that inhibition caseinline Iε and/or caseinline Iδ will cause a shift circadian phase and this inhibition is a potentially clinically effective mono - or combination therapy for mood disorders.

It should be noted that sleep disturbance is a critical symptom of many psychiatric disorders (W.V. McCall, J. Clin. Psychiatry (2001) 62 (suppl 10), 27-32). Sleep disturbances are a common feature of depressive disorders, and insomnia is a sleep disorder, which is often associated with depression, being present in more than 90% of patients with depression (M.E. Thase, J. Clin. Psychiatry (1999) 60 (suppl 17), 28-31). Accumulated data confirm the General pathogenesis of primary insomnia and great depressive disorders. Expressed the hypothesis that hypera the effectiveness of the releasing factor corticotropin (CRF) (due to genetic predisposition or perhaps because of the early stress) causes the process, leading to increased and extended sleep disorders and, ultimately, to primary insomnia. Circadian rhythm in the secretion of CRF in the absence of stress can play the role of a regular expression sleep-awakening (G.S. Richardson and T. Roth, J. Clin Psychiatry (2001) 62 (suppl 10), 39-45). Therefore, substances that modulate the circadian rhythm, for example, by inhibiting caseinline Iε and/or caseinline Iδ, can be useful in the treatment of depressive disorders associated with the effects of CRF secretion.

All references above in this document, are included in this document.

Thus, an object of the present invention to provide a group of substituted amides of 5-aminoalkyl-1H-indole-2-carboxylic acid and 6-aminoalkyl-1H-indole-2-carboxylic acids and their related analogues are inhibitors caseinline Iε. This and other objects of the invention will become apparent from the detailed description of the invention below.

BRIEF description of the INVENTION

The present invention relates to substituted Amida 5-aminoalkyl-1H-indole-2-carboxylic acid of the formula I and substituted Amida 6-aminoalkyl-1H-indole-2-carboxylic acid of the formula II, stereoisomers, enantiomers, racemates and tautomers of the above mentioned compounds and their pharmaceutically acceptable is the ol, are inhibitors of the activity caseinline Iε person, as well as methods of using compounds of formula I and formula II as medicines for the treatment of diseases and disorders of the Central nervous system, such as, for example, mood disorders, including severe depression, bipolar disorder type I and II, and sleep disorders, including sleep disorders associated with circadian disorders such as, for example, a sleep disorder during shift work syndrome desynchronize when travelling, the syndrome of premature sleep phase syndrome and delayed sleep phase.

In accordance with the foregoing General embodiment, the present invention relates to the production of compounds of formula I or formula II:

where

X is S or S(O)n;

R1represents H or C1-C6alkyl;

R2is NR5R6;

R3represents aryl or heterocycle;

R4represents C1-C6alkyl or halogen;

R5represents H or C1-C6alkyl;

R6represents H or C1-C6alkyl;

R7is CH2NR8R9where

R8represents H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C alkenyl), diaryl(C2-C6alkenyl), heterocycle, heterocycle(C1-C6alkyl, heterocycle(C2-C6alkenyl), hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), acyl, C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbarnoyl(C1-C6alkyl), or P;

R9represents H, C1-C10alkyl, heterocycle(C1-C6alkyl), or heterocycle(C2-C6alkenyl); or R8and R9together with the nitrogen to which they are bound, form a heterocycle;

R represents Gly or L - or D-Ala, Val, Leu, Ile, Ser, Cys, Thr, Met, Pro, Phe, Tyr, Trp, His, Lys, Arg, Asp, Gly, Asn or Gln;

m is 0, 1 or 2;

n is 1 or 2; or

stereoisomer, enantiomer, racemate or tautomer specified connection; or its pharmaceutically acceptable salt.

Further implementation of the present invention is a method of inhibiting the activity caseinline Iε patients, including the introduction of these patients a therapeutically effective amount of an inhibitor caseinline Iε.

Another embodiment of the present invention is a method of inhibiting the activity caseinline Iε patients, including the introduction of these patients therapeutically effective amounts of compounds of formula I or formula II.

Another example implementation in which the present invention is a method of treatment of patients suffering from diseases or disorders that can be alleviated by the inhibition caseinline Iε; the method including the introduction of the above-mentioned patients therapeutically effective amounts of compounds of formula I or formula II.

A DETAILED DESCRIPTION of the INVENTION

Used the expression "stereoisomer" is a General term used for all isomers of individual molecules that differ only in the spatial orientation of their atoms. The term "stereoisomer" includes mirror isomers (enantiomers), the mixture mirror isomers (racemate, racemic mixture, geometric (CIS/TRANS or E/Z isomers and isomers of compounds with multiple chiral centers that are not mirror images of each other (diastereoisomer). Compounds of the present invention may have asymmetric centers and can exist as racemates, racemic mixtures, individual diastereoisomers or enantiomers or may exist in the form of geometric isomers, and all isomeric forms of the above compounds included in the present invention.

Used designations "R" and "S" are used as commonly used in organic chemistry to indicate the specific configuration of the chiral center. The designation "R" (rectus, right) refers to the configuration hee the social centre with the location of higher rank groups clockwise (from the group with the highest rank to the group with the second lowest), when viewed along the direction of the group, the lowest in seniority. The symbol "S" (sinister, left) refers to the configuration of the chiral center with the location of higher rank groups counterclockwise (from the group with the highest rank to the group with the second lowest)when viewed along the direction of the group, the lowest in seniority. The ranking of the groups is determined by the rules of the sequence, with priority primarily based on the atomic number (in descending order of atomic number). A list and discussion of seniority groups may be found in the bookStereochemistry of Organic Compounds,” Ernest L. Eliel, Samuel H. Wilen and Lewis N. Mander, editors, Wiley-Interscience, John Wiley & Sons, Inc., New York, 1994.

In addition to the system of (R)-(S)herein may also be applied over the old system D-L to denote the absolute configuration, particularly in relation to amino acids. In this system, the formula for the Fischer projection is oriented so that the first carbon atom of the main chain was at the top. The prefix "D" is used to describe the absolute configuration of the isomer in which the functional (determines) the group is to the right of carbon chiral center, and L - isomer, in which it is located to the left.

Used the terms "tautomer" or "tautomerism" describe the simultaneous existence of two (or more) with whom dinani, which differ from each other only by the position of one (or more) moving atoms, and the distribution of electrons, such as keto-enol tautomers or tautomerism.

Used herein the term "alkyl" refers to aliphatic hydrocarbon group, saturated linear or branched chain containing from 1 to 10 carbon atoms, in which the specified alkyl arbitrarily substituted with one or more halogen atoms. This definition of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, trifluoromethyl, pentafluoroethyl, chloromethyl, chloroformate, methyl bromide, and similar groups. Also to this meaning of the term "alkyl" includes, when used alone or in combination with other groups, such as, for example, aryl(C1-C6alkyl), or heterocycle(C1-C6alkyl), the terms "alkylene" or "alkylene", as defined below.

Used the terms "alkylene" or "alkylene" refers to linear or branched divalent saturated aliphatic chain containing from 1 to 6 carbon atoms, and includes Mitilini, Etiler, propylene, isopropylene, butylene, isobutylene, tert-butylene, pentylene, isopentenyl, hexylene and other similar groups.

Used the term "alkenyl" applies the linear or branched monovalent unsaturated aliphatic chain, containing from 2 to 6 carbon atoms, and includes ethynyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 2,4-hexadienyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl and similar groups.

Used the term "quinil" refers to a linear or branched monovalent unsaturated aliphatic chain having from 2 to 6 carbon atoms with at least one triple bond and includes ethinyl, 1-PROPYNYL, 1-butynyl, 1-hexenyl, 2-PROPYNYL, 2-butynyl, 2-pentenyl and similar groups.

Used the term "alkoxy" or "alkyloxy" refers to a monovalent substituting group consisting of linear or branched alkyl chain comprising from 1 to 6 carbon atoms attached through an oxygen atom of the ether group and having a free valence at the oxygen atom of the ether group, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy and similar groups.

Used the term "alkylthio" refers to a monovalent substituting group consisting of linear or branched alkyl chain containing from 1 to 6 carbon atoms attached through a sulfur atom and having a free valence at the sulfur atom, and includes methylthio, ethylthio, propylthio, isopropylthio, butylthio,Deut-butylthio,tert-butylthio podobnie group.

Used the term "alkenylacyl" refers to a linear or branched monovalent unsaturated aliphatic chains containing from 2 to 6 carbon atoms attached through an oxygen atom of the ether group and having a free valence at the oxygen atom, and includes adenylate (also known as vinyloxy), 1 methylacrylate, 1-methyl-1-propenyloxy, 1 butenyloxy, 1 hexenoate, 2-methyl-2-propenyloxy, 2,4-hexadienyl, 1 propenyloxy, 2-propenyloxy, 2-butenyloxy, 2-pentyloxy and similar groups.

Used the term "alkyloxy" refers to a linear or branched monovalent unsaturated aliphatic chains containing from 2 to 6 carbon atoms with at least one triple bond, attached via the oxygen atom of the ether group and having a free valence at the oxygen atom of the ether group, and includes itineracy, 1 propenyloxy, 1 butenyloxy, 1 hexyloxy, 2-propenyloxy, 2-butenyloxy, 2-pentyloxy and similar groups.

Used the term "C3-C8cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon ring structure containing from 3 to 8 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and similar group.

Used the term "hydroxyalkyl" about what is worn to a linear or branched monovalent saturated aliphatic chain, containing from 1 to 6 carbon atoms, where one of the above carbon atoms substituted by a hydroxyl group. To hydroxyalkyl this value include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl and the like groups.

Used the term "dihydroxyaryl" refers to a linear or branched monovalent saturated aliphatic chain containing from 2 to 6 carbon atoms, where two of the aforementioned carbon atoms substituted (each) hydroxyl group. To dihydroxyaluminum this value include 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl and similar groups.

Used the term "carbamoylethyl" refers to a linear or branched monovalent saturated aliphatic chain containing from 1 to 6 carbon atoms, where one of the carbon atoms substituted aminocarbonyl group (H2NC(=O)). To carbamoylation in this value are 1-carbamoylethyl, 2-carbamoylethyl and similar groups.

Used the term "aryl" or "Ar" represents any stable monocyclic, bicyclic or tricyclic carbon ring system, with up to seven members in each ring, where at least one aromatic ring, and unsubstituted or substituted one to three surrogate groups, each of which follows the IMO from the other, selected from methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, C2-C6alkenyl,2-C6-quinil, trifluoromethyl, triptoreline, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy). Under the value of "aryl" or "Ar" fall phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-triptoreline, 3-triptoreline, 4-triptoreline, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-AMINOPHENYL, 3-AMINOPHENYL, 4-AMINOPHENYL, 2-methylaminophenol, 3-methylaminophenol, 4-methylaminophenol, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 2-were, 3-were, 4-were, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3, 5dimethylphenyl, 2-trifloromethyl, 3-trifloromethyl, 4-trifloromethyl, naphthyl, tetrahydronaphthyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 4-ethoxycarbonylphenyl, Cyano-4,5-acid, 2-fluoro-3-tryptophanyl, 3-fluoro-5-tryptophanyl, 2-fluoro-6-triptoreline, 2,4-acid, 4-hydroxy-3-methoxyphenyl, 3,5-dichloro-2-hydroxyphenyl, 3-bromo-4,5-acid, 4-benzyloxy-3-were, 3-benzyloxy-4-were, 4-stillfeel, 9-antrel, 10-chloro-9-antral and similar groups.

Used the term "aryl(C1-C6alkyl)" refers to an aryl group as defined above attached to a linear or branched alkalinous chain, which contains from 1 to 6 carbon atoms and having a free valence at one of the carbon atoms alkalinous chain. To aryl(C1-C6alnilam) this value includes phenylmethyl (benzyl), phenylethyl, 4-tormentil, 4-Chlorobenzyl, 4-bromobenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-dimethylaminophenyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-benzyloxybenzyl, 3-benzyloxybenzyl, 4-benzyloxybenzyl, 2-trifloromethyl, 3-trifloromethyl, 4-triptorelin, 3-fluoro-5-trifloromethyl, 2-fluoro-3-trifloromethyl, 2,4-dimethoxybenzyl, 3,5-dichloro-2-hydroxybenzyl, 3-bromo-4,5-dimethoxybenzyl, 4-benzyloxy-3-methylbenzyl, 3-benzyloxy-4-methyl, 4-phenylbenzyl and similar groups.

Used the term "aryl(C2-C6alkenyl)" refers to an aryl group as defined above attached h is cut linear or branched monovalent unsaturated aliphatic chain, which contains from 2 to 6 carbon atoms and having a free valence at a carbon alkalinous chain. To aryl(C2-C6alkenyl) this value includes 3-phenylpropen-1-yl, 2-phenylethenyl, 3-(4-hydroxy-3-methoxyphenyl)-2-propen-1-yl, 4-phenyl-3-butenyl, 3-phenyl-3-butenyl and similar groups.

Used the term "diaryl(C2-C6alkenyl)" refers to a linear or branched monovalent unsaturated aliphatic chains containing from 2 to 6 carbon atoms, where this chain is substituted with two aryl groups, and aryl is defined according to the definition above, and the above-mentioned aryl group may be simultaneously connected to one of the aforementioned carbon atoms aliphatic chain, or these aryl groups may be independently connected to any two of the above two to six carbon atoms aliphatic chain, and the free valence is when one of the carbon atoms alkalinous chain. To diaryl(C2-C6alkenyl) this value include 3,3-diphenyl-2-propen-1-yl and the like groups.

Used the term "aryl(C1-C6alkoxy)" refers to an aryl group as defined above, associated with a linear or branched alkoxy group containing from one to six carbon atoms, as defined above, and having a spare is AlertNet when the oxygen atom of the ether group. To aryl(C1-C6alkoxy) this value includes phenylmethoxy (benzyloxy)venlafaxi and similar groups.

Used the term "aryl(C1-C6alkylamino)" refers to an aryl group as defined above linked via a linear or branched alkalinous chain containing from one to six carbon atoms, the nitrogen atom and having a free valence at the nitrogen atom, where the above nitrogen atom may have a substituent in the form of an atom of hydrogen or C1-C6the alkyl. Among the related definition of "aryl(C1-C6alkylamino)" - phenylethylamine (benzylamino), phenylethylamine, N-methyl-N-benzylamino and similar groups.

Used the term "aryl(C1-C6alkylthio)" refers to an aryl group as defined above linked via a linear or branched alkalinous chain containing from one to six carbon atoms, a sulfur atom and having a free valence at the sulfur atom. Among podpadayuschih under the definition of "aryl(C1-C6alkylthio)" - feniletilic (benzylthio), feniletilic and similar groups.

Used the term "acyl" refers to N-(C=O)-, C1-C6alkyl-(C=O)-, aryl-(C=O)-, aryl(C1-C6alkyl)-(C=O)-, heterocycle(C=O)-, or heterocycle(C1-C6alkyl)-(C=O)-groups, where as the keel, aryl and heterocycle as defined above, and the free valence is at the carbonyl (C=O) group. To atilov this value include acetyl, propionyl, butyryl, isobutyryl, TRIFLUOROACETYL, trichloroacetyl, benzoyl and the like groups.

Used the term "alkoxycarbonyl" refers to a monovalent substituting group including linear or branched alkyl chain containing from one to six carbon atoms which is attached via the oxygen atom of the ether group to a carbonyl group, the free valence is when a carbonyl group. To alkoxycarbonyl in this value are methoxycarbonyl, etoxycarbonyl, propylenecarbonate, isopropoxycarbonyl, butoxycarbonyl,Deut-butoxycarbonyl, tert-butoxycarbonyl (t-Boc or Boc) and the like groups.

Used the term "aryl(C1-C6alkoxy)-carbonyl" refers to a monovalent substituting group, including aryl(C1-C6alkoxy)group as defined above connected through an oxygen atom of the ether group with a carbonyl group and having a free valence at a carbonyl group. To aryl(C1-C6alkoxy)-CARBONYLS in this value are phenylmethanesulfonyl (also known as benzyloxycarbonyl or carbobenzoxy, CBZ), fenilalaninammonii, Hairdryer shall propoxycarbonyl and similar groups.

Used the term "heterocycle" or "heterocyclic" means a stable, consisting of 5-7 members monocyclic or stable, consisting of 8-11 members bicyclic heterocyclic ring system is saturated or unsaturated, and which consists of carbon atoms and containing one to three heteroatoms from the group N, O and S and where the heteroatoms nitrogen or sulfur may be optionally oxidized and the nitrogen heteroatom may optionally be quaternity; the term describes any bicyclic group in which any of the above defined heterocyclic rings is connected to the benzene ring. Heterocyclic ring may be attached at any heteroatom or carbon atom that results in a stable structure. Heterocyclic ring may be unsubstituted or have from one to three alternative groups, independently selected from the list including1-C6alkoxy, hydroxy, halogen, C1-C6alkyl, C2-C6alkenyl,2-C6quinil, trifluoromethyl, triptoreline, NO2, NH2, NH(C1-C6alkyl), N(C1-C6-alkyl)2, NH-acyl, N(C1-C6alkyl)acyl, C(=O)O(C1-C6alkyl), C(=O)NH2With(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy ( 2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy), arylsulfonyl and pyrimidine-2-yl. Under the definition of heterocycle or heterocyclic fall piperidinyl, 4-hydroxymethyl-piperidinyl, 3-carbamoylbiphenyl, 1,4-dioxa-8 azaspiro[4,5]decenyl, piperazinil, 2-oxopiperidine, 4-ftorpolimernoj, 1,4-diazepine or homopiperazine, 4-tert-butoxycarbonyl-1,4-diazepine, 4-pyrimidine-2-reparational, 4-(3-phenylpropionyl)-piperazinil, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxoazetidin, azepine, pyrrolyl, pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, pyrazolyl, pyrazolidine, imidazole, imidazoline, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidine, morpholine, thiazolyl, diazolidinyl, isothiazolin, hinokitiol, isothiazolinones, indolyl, chinoline, ethenolysis, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, 2-nitrophenyl, tetrahydrofuryl, 2-(2-chlorophenyl)-furyl, benzofuranyl, tetrahydropyranyl, thienyl, 2-nitrothiazol, benzothiazyl, thiomorpholine, oxadiazolyl, 1-phenylsulfonyl and similar groups.

Used the terms "heterocycle(C1-C6alkyl)" or "heterocyclic "C1-C6alkyl" refers to GE is eroticly or heterocyclic ring, as defined above linked through a linear or branched alkalinous chain containing from one to six carbon atoms, with the carbon atom or a heteroatom within the group O, N and S. this meaning of the terms "heterocycle-(C1-C6alkyl" and "heterocyclic "C1-C6alkyl" include 2-furanosyl, 2-Tennille(2-thiophenemethyl), 5-nitro-2-Tennille, 5-(2-chlorophenyl)-2-furanosyl, 1-(phenylsulfonyl)-1H-pyrrol-2-methyl and similar groups.

Used the terms "heterocycle(C2-C6alkenyl)" or "heterocyclic "C2-C6alkenyl" refer to heterocycle or heterocyclic ring, as defined above, attached via a linear or branched monovalent unsaturated aliphatic chains containing from 2 to 6 carbon atoms; the value of this term subject to 3-(2-furanyl)-2-propen-1-yl, 3-(3-furanyl)-2-propen-1-yl, 3-(2-thienyl)-2-propen-1-yl, 3-(3-thienyl)-2-propen-1-yl, 3-(4-pyridinyl)-2-propen-1-yl, 3-(3-pyridinyl)-2-propen-1-yl and the like groups.

Used in this document the terms "heterocycle(C1-C6alkoxy" or "heterocyclic "C1-C6alkoxy" refer to heterocycle or heterocyclic ring, as defined above, attached via a linear or branched alkalinous chain,which contains from one to six carbon atoms, through the oxygen atom of the ether group and having a free valence at the oxygen atom of the ether group. To a heterocycle-(C1-C6-alkoxy or heterocyclic "C1-C6-alkoxy" in the present value are 2 titillate, 3 titillate, 2-formatosi, 3 formatosi, 4-pyridinylmethyl, 3 pyridinylmethyl, 2-pyridinylmethyl and similar groups.

Used the terms "heterocycle(C1-C6alkylamino)" or "heterocyclic

"C1-C6alkylamino" refer to heterocycle or heterocyclic ring, as defined above, connected to a linear or branched alkalinous chain, which contains from one to six carbon atoms attached to the nitrogen atom; the free valence is with this nitrogen atom, this nitrogen atom arbitrarily substituted with hydrogen or C1-C6the alkyl. To a heterocycle(C1-C6alkylamino) or heterocyclic "C1-C6alkylamino" include 2-titelmelodie, 3 titelmelodie, 2-formationin, 3 formationin, 4-pyridylmethylamine, 3 pyridylmethylamine, 2-pyridylmethylamine and similar groups.

Used in this document the terms "heterocycle(C1-C6alkylthio)" or "heterocyclic "C1-C6alkylthio" refer to heterocycle, or Goethe is aziklicescoe ring, as defined above, connected via a linear or branched alkalinous chain containing from one to six carbon atoms, a sulfur atom, and having a free valence at the sulfur atom. To a heterocycle(C1-C6alkylthio) or heterocyclic "C1-C6alkylthio" in this value are 2 thienylmethyl, 3 thienylmethyl, 2-ferometry, 3 porometry, 4-pyridinylmethyl, 3 pyridinylmethyl, 2-pyridinylmethyl and similar groups.

Used the terms "halogen", "hal" or "halo" refer to the group comprising fluorine, chlorine, bromine and iodine.

"P" in this document refers to alpha-amino acids as L-and D-configuration or mixtures of L - and D-configurations, including a racemic mixture, having a free valence at the carbonyl carbon atom of the C-1 amino acids. Alpha-amino acids (and their abbreviations), fall within the definition of R, are glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), serine (Ser), cysteine (Cys), threonine (Thr), methionine (Met), Proline (Pro), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), histidine (His), lysine (Lys), arginine (Arg), aspartic acid (Asp), glutamic acid (Glu), asparagine (Asn) and glutamine (Gln).

When any variable (e.g. aryl, heterocycle, R1, R2, R3, R4, R5, R67, R8, R9X) occurs more than once in any component or compound of formula I or formula II of the present invention, its definition at each occurrence is independent of its definition at any of the other cases, unless otherwise stated. In addition, the combination of substitute groups and/or variables are permissible only if such combinations result in stable compounds.

The terms "treat", "treating" refers to:

(i) preventing a disease, disorder or condition in a patient who may be predisposed to the disease, disorder and/or condition, but its presence has not yet been diagnosed;

suppression of the disease, disorder, or condition, that is, slowing its development; or

(iii) to eliminate the disease, disorder, or condition, that is, regression of the disease, disorder and/or condition.

The term "patient" refers to warm-blooded animal, such as mammal that suffers from a particular disease, disorder or condition. Initially it is assumed that Guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of animals United this term.

The term "disease" refers to a disease, ailment or termination, interruption or disruption of the function of the body naturally, systems or organs.

The term "disorder" is a disorder of the function, structure or both, resulting from genetic or embryological developmental disorders or due to exogenous factors, such as poison, injury or disease.

The term "status" is the General condition, state of health or physical form.

The term "prevention" means the prevention of disease.

The term "sleep disorders", "sleep disturbance" or "sleep disorder" means insomnia.

The term "insomnia" means the inability to sleep in the absence of external obstacles, such as noise, bright lights, etc. at the time of the day usually comes a dream, and the extent of such inability may change from an excited state or disturbing slumber to limit the normal duration of sleep or absolute wakefulness. The term "insomnia" includes primary insomnia, insomnia associated with mental disorder, insomnia, caused by taking drugs, and insomnia circadian rhythm associated with changes in normal sleep mode-the awakening (change of work shift sleep disorder during shift work, desynchronosis, when travelling or syndrome desynchronize when travelling and so on).

The term "primary insomnia means difficulty falling asleep, p. and maintaining sleep, or when recovery sleep, which is not caused by a mental disorder or is not associated with the physiological effects of ingestion of certain drugs or denial (insomnia caused by medications).

The term "sleep disorder associated with circadian rhythm includes desynchronosis, when travelling or syndrome desynchronize when travelling, sleeping during shift work syndrome premature sleep phase syndrome and delayed sleep phase.

The term "effective inhibitory amount of a compound" or "effective amount of compounds inhibitory caseinline Iε" means a sufficient amount of a compound that becomes bioavailable by an appropriate method of administration for treatment of a patient suffering from a disease, disorder or condition amenable to such treatment.

The term "therapeutically effective amount" means an amount of compound that is effective for treating the disease, disorder or condition.

The term "pharmaceutically acceptable salt" should be applied to any salt, previously known or discovered in the future, which is used by professionals, is non-toxic organic or inorganic salt additive and which is acceptable for use as a drug. Examples of acceptable salts can serve as the Hydra is xidi alkali metals or alkaline earth metals, such as the hydroxides of sodium, potassium, calcium or magnesium; ammonia, and aliphatic, cyclic or aromatic amines, such as methylamine, dimethylamine, triethylamine, diethylamine, isopropylethylene, pyridine and picoline. As examples of acids that form acceptable salt, can lead to inorganic acids such as, for example, hydrochloric, Hydrobromic, sulfuric, phosphoric and the like acids, organic carboxylic acids, such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleimide and dihydroxytoluene, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, Anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, mendelova and similar acid and organic sulfonic acids such as methanesulfonate, benzolsulfonat and para-toluensulfonate acid.

The expression "the lengthening of the period of circadian rhythm" refers to the increase in the interval between the fundamental events in the process, which occurs regularly with a periodicity of approximately 24 hours.

The expression "reduction of the period of circadian rhythm" refers to the reduction of the interval between the fundamental events in the process that PR is regularly comes with a periodicity of approximately 24 hours.

The term "pharmaceutical carrier" or "pharmaceutically acceptable carrier" refers to well-known pharmaceutical excipients used to create therapeutically active compounds, in order to assign them to patients and which are sufficiently non-toxic and does not cause allergic reactions in the terms of use. The exact proportion of such fillers is determined by the solubility and chemical properties of the active substance, the chosen route of administration, and standard pharmaceutical practice. When using the methods of the present invention the active ingredient is preferably included in the composition containing a pharmaceutical carrier, although these compounds are effective and can be administered by themselves. With this in mind, the proportion of active ingredient can vary from about 1% to about 90% by weight.

Other abbreviations that may appear in this application, should be understood as follows:

Me (methyl), Et (ethyl), Ph (phenyl), Et3N (triethylamine), p-TsOH (pair-toluensulfonate acid), TsCl (pair-toluensulfonate), hept (heptane), DMF (dimethylformamide), NMP (1-methyl-2-pyrrolidone or N-methyl-2-pyrrolidone), IPA (isopropanol or isopropyl alcohol), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), CT or t (room temperature or ambient temperature), min or min (minutes), h (hour or hours), UV (ultraviolet), LC-MS (mass spectrometry with liquid chromatography), t-Boc or Boc (tert-butoxycarbonyl), Bn (benzyl), t-Bu (tert-butyl), i-Pr (isopropyl), TFA (triperoxonane acid), HOAc (acetic acid), EtOAc (ethyl acetate), Et2O (diethyl ether), EtOH (ethanol), DIEA (diisopropylethylamine), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); HOBT (1-hydroxybenzotriazole), g (grams), mg (milligrams), mcg (micrograms), ng (nanogram), ml (milliliter), μl (microliter), l (liter), VIH (liquid chromatography high resolution), TLC, TLC or TLC (thin layer chromatography), g/l (grams/liter), SiO2(silica gel), l/min (liters per minute), ml/min (milliliters per minute), mmol (millimoles),M (molar), mm (millimolar), μm (micromolar), nm (nanomolar), µci (microcurie), pulse/min (beats per minute), rpm (revolutions per minute), mm (millimeter), μm (micrometer), µ (microns)nm (nanometer), SB (ppm), psi (pounds per square inch), EQ. (equivalent), RT(retention time),oC (degrees Celsius) K (Kelvin).

Accordingly, the implementation of the present invention relates to the production of compounds of formula I and formula II:

where X is S or S(O)n; R1the submitted is H or C 1-C6alkyl; R2is NR5R6; R3represents aryl or heterocycle; R4represents C1-C6alkyl or halogen; R5represents H or C1-C6alkyl; R6represents H or

C1-C6alkyl; R7is CH2NR8R9where R8represents H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), diaryl(C2-C6alkenyl), heterocycle, heterocycle(C1-C6alkyl, heterocycle(C2-C6alkenyl), hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), acyl, C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbarnoyl(C1-C6alkyl), or P; R9represents H, C1-C10alkyl, heterocycle(C1-C6alkyl), or heterocycle(C2-C6alkenyl); or R8and R9together with the nitrogen to which they are attached, represent a heterocycle; P is Gly or L - or D-Ala, Val, Leu, Ile, Ser, Cys, Thr, Met, Pro, Phe, Tyr, Trp, His, Lys, Arg, Asp, Gly, Asn or Gln; m is 0, 1 or 2; n is 1 or 2; or a stereoisomer, enantiomer, racemate or tautomer specified connection; or their pharmaceutically acceptable salt.

One of the realizations of the present invention relates to compounds of formula I or a form of the s II, where X represents S.

Another implementation of the present invention relates to compounds of formula I or formula II, where X is S, a R2represents NH2.

Another implementation of the present invention relates to compounds of formula I or formula II, where X is S, R2represents NH2, m is 0, R7is CH2NR8R9.

Another implementation of the present invention relates to compounds of formula I or formula II, where X is S, R2represents NH2, m is 0, R7is CH2NR8R9,R1represents C1-C6alkyl. Connection amide 1-methyl-5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid is a typical example of the compounds of formula I within this way of implementation.

Another implementation of the present invention relates to compounds of formula I or formula II, where X is S, R2represents NH2, m is 0, R7is CH2NR8R9, R1is N.

Another implementation of the present invention relates to compounds of formula I where X is S, R1represents H, R2represents NH2, m is 0,

R7is CH2NR8R9, R8represents H, C1-C10 alkyl, C3-C8cycloalkyl, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl or C1-C6alkoxycarbonyl and R9is H. These compounds are:

amide 5-aminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

tert-butyl ether (2-carbarnoyl-3-phenylsulfanyl-1H-indol-5-ylmethyl)-carbamino acid,

amide 5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 3-(3-chlorophenylsulfonyl)-5-methylaminomethyl-1H-indole-2-carboxylic acid,

amide 3-(3-perpenicular)-5-methylaminomethyl-1H-indole-2-carboxylic acid,

amide 3-phenylsulfanyl-5-propylaminoethyl-1H-indole-2-carboxylic acid,

amide 5-butylaminoethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-pentylamine-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-heptylamine-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-(bicyclo[2.2.1]hept-2-illuminometer-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-[(2-hydroxy-1-hydroxymethyl-1-methylethylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-[(2-hydroxy-1-methylethylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-[(2,3-dihydroxypropyl)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-ethylaminomethyl-3-Hairdryer who sulfanyl-1H-indole-2-carboxylic acid,

amide 3-phenylsulfanyl-5-propylaminoethyl-1H-indole-2-carboxylic acid and

amide 5-(isopropylaminomethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

Another implementation of the present invention relates to compounds of formula I where X is S, R1represents H, R2represents NH2, m is 0,

R7is CH2NR8R9, R8represents aryl, aryl(C1-C6alkyl, heterocycle or carbarnoyl(C1-C6alkyl), R9is H. These compounds are:

amide 5-(benzylamino)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 3-phenylsulfanyl-5-(quinoline-6-illuminometer)-1H-indole-2-carboxylic acid,

amide 5-[(2-cyano-4,5-dimethoxyaniline)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 3-phenylsulfanyl-5-[(3-triptoreline)methyl]-1H-indole-2-carboxylic acid,

amide 5-[(1-carbamoylethyl)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-[(3-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-[(4-butylaniline)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid and

amide 5-[(2-forgenerating)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

Another implementation of the present invention relates to compounds of formula I, where Predstavljaet S, R1represents H, R2represents NH2, m is 0,

R7is CH2NR8R9and R8and R9together with the nitrogen to which they are bound, form a heterocycle. The following compounds are:

amide 5-(4-hydroxyethylpiperazine-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-morpholine-4-ylmethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 3-phenylsulfanyl-5-piperidine-1-ylmethyl-1H-indole-2-carboxylic acid,

amide 5-(3-carbamoylbiphenyl-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 3-phenylsulfanyl-5-(4-(pyrimidine-2-reparation-1-ylmethyl)-1H-indole-2-carboxylic acid,

amide 5-[4-(3-phenylpropyl)piperazine-1-ylmethyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

tert-butyl ester 4-(2-carbarnoyl-3-phenylsulfanyl-1H-indol-5-ylmethyl)-[1,4]diazepan-1-carboxylic acid,

amide 5-[1,4]diazepan-1-ylmethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-(2-hydroxymethyl-pyrrolidin-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 5-(1,4-dioxa-8-Aza-spiral[4,5]Dec-8-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid and

amide 5-[4-(4-forfinal)piperazine-1-ylmethyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

Another implementation of the present invention relates to compounds form the s II, where X is S, R1represents H, R2represents NH2, m is 0, R7is CH2NR8R9, R8represents H, C1-C10alkyl, aryl(C1-C6alkyl, heterocycle(C1-C6alkyl or C1-C6alkoxycarbonyl and R9represents H or a heterocycle(C1-C6alkyl). The following compounds are:

amide 6-aminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

tert-butyl ether (2-carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)-carbamino acid,

amide 6-(benzylamino)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(4-nitrobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(4-dimethylaminobenzylidene)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(4-methylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(4-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(4-bromobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(4-chlorobenzylamino)-methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-{[(biphenyl-4-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(3-nitrobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carbon is th acid,

amide 6-[(2-nitrobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 3-phenylsulfonyl-6-[(4-triphtalocyaninine)methyl]-1H-indole-2-carboxylic acid,

amide 6-[(3-fluoro-5-triphtalocyaninine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-{[(2-methoxynaphthalene-1-ylmethyl)amino]methyl]}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(2,4-dimethoxyaniline)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(3-phenoxybenzamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(3-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(2 - methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(3-methylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(2-fluoro-3-triphtalocyaninine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(2-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-{[(10-chloroanthracene-9-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(3,5-dichloro-2-hydroxyethylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(3-bromo-4,5-dimethoxyphenethylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(4-benzyloxy-3-methoxybenzylamine)met the l]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(3-benzyloxy-4-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-{[(5-nitrothiophen-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

methyl ester of 4-{[(2-carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)amino]methyl}benzoic acid,

amide 3-phenylsulfonyl-6-[(4-streventname)methyl]-1H-indole-2-carboxylic acid,

amide 6-[(2-fluoro-6-triphtalocyaninine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-({[5-(2-chlorophenyl)-furan-2-ylmethyl]amino}methyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-{[(1-benzazolyl-1H-pyrrol-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-{[bis-(5-nitrofuran-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid and

amide 6-{[(5-nitrofuran-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

Another implementation of the present invention relates to compounds of formula II, where X is S, R1represents H, R2represents NH2, m is 0, R7is CH2NR8R9, R8is R, and R9is H. the Following compounds are:

amide 6-[(2-aminodiphenylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(2-aminoethylamino)methyl]-3-phenyl who sulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(2-amino-3-methylpentylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

2-aminopentanedioic acid 5-amid-[(2-carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)-amide],

amide 6-{[(2-amino-3-(1H-indol-3-yl)propionamido]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(2-amino-3-phenylpropionylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-[(2-amino-4-methylsulfonylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

6-[(2,6-diaminohexanoic)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide and

3-amino-N-(2-carbarnoyl-3-phenylsulfanyl-1H-indol-6-ylmethyl)-succinamic acid.

Another implementation of the present invention relates to compounds of formula II, where X is S, R1represents H, R2represents NH2, m is 0, R7is CH2NR8R9, R8represents aryl(C2-C6alkenyl), diaryl(C2-C6alkenyl) or heterocycle(C2-C6alkenyl) and R9represents H or a heterocycle(C2-C6alkenyl). The following compounds are:

amide 6-{[(bis-(3-furan-2-Jalil)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,

amide 6-{[(3,3-diphenylethylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, and

amide 6-[3-(4-hydroxy-3-methoxyphenyl)allylamino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

Compounds of the present invention can be obtained by processes analogous to known methods. The scheme of reactions 1, 2, 3, 4 and 5, and the text of the relevant sections describe the various compounds of the present invention. The described methods and examples are given with illustrative purpose and do not limit the present invention. Alternative reagents, reaction conditions, and other combinations and modifications of the stages shown here for specific examples, are obvious to the expert. Tables 1 and 2 offer lists of individual compounds related to the present invention, which receive in accordance with the methods of synthesis described herein, and biological properties of the compounds of the present invention are shown in table 3.

CHEMICAL SYNTHESIS

Scheme 1

As shown in figure 1, optionally substituted educt ethyl 5-cyanoindole-2-carboxylate (3) and ethyl-6-cyanoindole-2-carboxylate (5) are obtained by methods well known in the art from known or commercially available optionally substituted 3-methyl-4-nitrobenzonitrile (1a) or 4-methyl-3 - nitrobenzonitrile (1b), respectively. As shown in scheme 1, stage a, W oxalate, such as, for example, diethyloxalate, are added to a solution of a suitable base, is such as, for example, ethoxide sodium in absolute ethanol in the temperature range from approximately 0°C to room, and then add the original benzonitrile 1a or 1b at a temperature of about 0°C to room temperature. After stirring the mixture at a temperature of about room for about 8-24 hours the reaction is stopped by the addition of a suitable acid, such as hydrochloric acid, sulfuric acid or the like, the solvent is removed under reduced pressure and the residue is divided between water and a suitable organic solvent, such as methylene chloride, chloroform, ethyl acetate, or similar solvents. The organic phase is dried, concentrated and purified precipitate chromatographic methods well known in the art, receiving oxopropionate ether 2 or 4 respectively. Each of oxopropionate esters of 2 or 4 is reactivated by hydrogen in the presence of a suitable catalyst, for example palladium on carbon, in a suitable solvent, for example ethanol, until, until absorbed the calculated amount of hydrogen. The reaction mixture is filtered and the filtrate concentrated to obtain the crude indole, which purify chromatographic methods well known in the art, obtaining optionally substituted ethyl-5-cyanoindole-2-carboxylate (3A) or ethyl-6-cyanoindole-2-carboxylate (5A), respectively. As shown in scheme 1, step C, the source esters optionally substituted ethyl-5-cyanoindole-2-carboxylate (3A) or ethyl-6-cyanoindole-2-carboxylate (5A) can be preterition to the corresponding methyl ester 3b or 5b, respectively, using methods well known in the art, such as, for example, the stirring of a mixture of methanol, potassium carbonate and ethyl ester 3A or 5A in the temperature range from about room temperature up to the temperature of the distillation of the solvent, cooling, isolation and purification of the product by methods well known in the art, allow you to get ether 3b or 5b, respectively. Alternatively, the methyl esters 3b or 5b is easy to get replacement diethyloxalate on dimethyloxalate and ethoxide sodium in absolute ethanol to sodium methoxide in methanol in the above synthesis.

Scheme 2

Figure 2 shows the derivation of the optional substituted intermediate 3-aaltio - or 3-heterocyclic-5-aminomethylphenol-2-carboxamido 8b and 3-aaltio - or 3-heterocyclic-6-aminomethylphenol-2-carboxamido 11b. As shown in the diagram, and 2, 5-cyanoethyl 3a/3b, and 6-cyanoethyl 5a/5b converted into primary amides 6 and 9, respectively, by methods known in the art. Thus, treatment of the reaction mixture, containing about 7M ammonia and ether 3a or 3b or ether 5a or 5b in approaching the eat polar solvent, such as, for example, methanol or ethanol, with the addition of shavings of lithium hydroxide and heating the mixture in the chamber of high pressure at approximately 100°C for about 16 h leads after chromatographic purification, well known to specialists, primary amide 6 or 9, respectively. Alternatively can be used other reaction conditions well known in the art, such as treatment of a solution of the corresponding ester in a suitable polar solvent, such as, for example, methanol or ethanol, ammonia solution in an amount of 5 to 7M in the range of from about 1 to about 3 days at ambient temperature, or heating this solution to approximately 55°C for 10 h, allow to obtain a primary amide 6 or 9, respectively, after separation by methods well known in the art. Alternatively, the corresponding ether may be suspended in a mixture of concentrated solution of ammonium hydrochloride and lithium chloride at ambient temperature for about 3 to 5 days, until analysis by thin layer chromatography or other suitable chromatographic method, well known to experts, shows that the reaction is practically completed. Primary amides 6 and 9 are separated from the reaction mixture by methods, x is well known to specialists.

Other methods for the preparation of amides, which is the object of the invention, readily available specialists. For example, carboxylic acids corresponding to the compounds 3 or 5 of scheme 1, where R is H, can be obtained by hydrolysis of the corresponding esters 3a and 3b or 5a and 5b by methods well known in the art. For example, a suitable base, such as, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide and the like of the base, is added to a mixture of ether 3a or 3b or 5a or 5b in a suitable solvent, such as, for example, a mixture of tetrahydrofuran and water. The mixture is heated in the temperature range of about 90°C-110°C for about half an hour to 2 hours the reaction Product is obtained as a salt by means of filtration and the filtrate is concentrated until precipitation of additional quantities of the substance. The residue combined with the precipitate on the filter and acidified by methods well known in the art, such as acidification with a suitable acid, such as acetic acid, in a suitable solvent, such as methanol, ethanol and the like solvents, to obtain the corresponding carboxylic acids of formula 3 or 5, respectively, where R represents N. These carboxylic acids are easily converted into amides, which is the object of the invention, by methods well known in the art, such as a solution of arbonboy acid 3 or 5 in a suitable solvent, such as dimethylformamide, can be treated with base, such as diisopropylethylamine, carbodiimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and ammonium chloride. When the reaction is complete, which confirms thin layer chromatography or other suitable chromatographic methods well known in the art, the mixture may be diluted with a suitable solvent, and the product can be isolated and chromatographically purified by methods well known in the art, in the form of primary amides 6 or 9, respectively, where R2represents NH2. If instead of ammonium chloride to use primary or secondary C1-C6the bonds alkylamines, you can also obtain the corresponding secondary or tertiary C1-C6alkylamide corresponding to formula 6, or 9, where NH2substituted on NH(C1-C6alkyl), or

N(C1-C6alkyl)2respectively.

As shown in scheme 2, step e, nitrile group optionally substituted 5-cyanoindole-2-carboxamide 6 and 6-cyanoindole-2-carboxamide 9 in both cases is restored to the corresponding primary amine, which is simultaneously protected Boc-group, resulting in an intermediate of primary amines 7 and 10, respectively, by methods well known in the art. In the example, a solution of 5-cyanoindole-2-carboxamide 6 or 6-cyanoindole-2-carboxamide 9 in an appropriate polar solvent such as, for example, methanol, treated with Nickel chloride and Boc-anhydride. The mixture is then treated at a temperature of about 0°C-15°C suitable regenerating agent such as, for example, borohydride sodium, and then stirred at room temperature for 8-24 hours, the Reaction mixture was concentrated, extracted, and the reaction product produce by methods well known in the art to give the corresponding 5 - or 6 - Boc-protected aminomethylphenol-2-carboxamide 7 or 10, respectively.

As shown in scheme 2, step f, each of the intermediate amides 7 and 10 is converted into the corresponding 3-aaltio - or 3-heterocyclisation 8A or 11a, respectively, by methods well known in the art. For example, a suspension of intermediate amide 7 or 10 in a suitable solvent, for example dimethylformamide or NMP, is treated with a suitable base, such as, for example, sodium hydride or lithium hydride at ambient temperature followed by treatment with a suitable veridicality or diameterically, after which this mixture is stirred in the temperature range from room temperature to about 100°C for 12-20 hours. Over the course of the reaction is observed by thin layer chromatography or others the other chromatographic methods, well known in the art. Upon completion of the reaction, the reaction mixture is extracted well known in the art methods. The desired intermediate product - 5-Boc-protected aminomethylphenol-2-carboxamid 8A or 6-Boc-protected aminomethylphenol-2-carboxamid 11a - isolated and chromatographically purified by methods well known in the art, receiving substance 8a and 11a, where R3represents aryl or heterocycle. As shown in scheme 2, step g, the acid hydrolysis of the Boc protective group, perform one of the methods well known in the art, for example treated with compound 8a or 11a excess triperoxonane acid at room temperature for about 5-30 min, concentrate the reaction mixture and produce the corresponding primary amine 8b or 11b, respectively, in the form of triperoxonane salt.

Alternatively, as shown in scheme 2, step f, a mixture of veridicality or diameterically and approximately one equivalent of cesium carbonate in a suitable solvent, for example dimethylformamide or NMP, process optionally substituted intermediate amidon 7 or 10, after which the reaction mixture is heated to a temperature of about 80-120°C for 1-6 hours. Over the course of the reaction is observed using thin-layer chromatography or other chromatographic methods well known with what ecialists. Desired, optionally substituted intermediate product 3-aaltio - or 3-arylheteroacetic-5-Boc-protected aminomethylphenol-2-carboxamid 8A and 3 - aaltio - or 3-arylheteroacetic-6-Boc-protected aminomethylphenol-2-carboxamid 11a is isolated and chromatographically purified by methods well known in the art, receiving connections 8A and 11a, where R3is aryl or heterocycle. Protective Boc-group of compounds 8A and 11a are removed by acid hydrolysis, as described above, receiving the corresponding primary amine 8b or 11b, respectively, in the form of triperoxonane salt.

Scheme 3

As shown in figure 3, each optionally substituted intermediate compounds 13, 14 and 15 is obtained from optionally substituted amide 5-cyanoindole-2-carboxylic acid 6. As shown in scheme 3, step h, amide 5-cyanoindole-2-carboxylic acid 6 is transformed into the corresponding 3-aaltio - or 3-arithmetisation 12, as described above in scheme 2, step f, receiving amide 3-heterocyclic-5-cyanoindole-2-carboxylic acid 12 after separation and purification by methods well known in the art. As shown in figure 3, stage i, nitrile group of the intermediate compound 12 is recovered by methods well known in the art, for example, processing a suspension of intermediate 12 and NaH2PO2 in pyridine and water with an aqueous suspension of Nickel Raney catalyst and heated at a temperature of 95°C for 4-5 hours. The reaction mixture is filtered, the filtrate is concentrated to a minimum volume and treated with ice water to obtain, after isolation and drying, using methods well known in the art, the intermediate amide 5-formyl-3-substituted indole 2-carboxylic acid 13.

As shown in figure 3, stage j, the nitrogen atom of indole ring optionally substituted 3-aaltio - or 3-arylheteroacetic-5-formylindole-2-carboxamide 13 N-alkylate to obtain compound 14, where R1represents C1-C6alkyl, using methods well known in the art. Thus, a solution of intermediate compound 13 in a suitable polar solvent, for example dimethylformamide or NMP, is treated at temperatures close to the room temperature, an appropriate base, such as, for example, potassium hydroxide, sodium hydroxide ortert-piperonyl potassium, and then a solution of C1-C6alkylhalogenide in a suitable polar solvent, such as, for example, dimethylformamide or NMP. The reaction mixture is stirred for about 24 to 72 h at room temperature and diluted with a suitable solvent, such as ethyl acetate. The organic phase is washed with brine, dried and concentrated, and thus, N-alkilirovanie connection 14, where R1- C1-C6alkyl. The person skilled in the art knows that for N-alkylation of the indole nitrogen can also be used and other conditions, for example, the processing solution of the compounds of formula 13 and a suitable solvent, such as 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone with C1-C6diallylsulfide and a suitable base such as cesium carbonate, at ambient temperature, within a reasonable period of time. Alternatively, the indole nitrogen of the ring can be alkylated and also treatment solution of the compounds of formula 13 in pyridine C1-C6alkylhalogenide in the presence of a suitable base, such as, for example, cesium carbonate, when heated within a reasonable period of time. In addition, the specialists know that N-alkylation of the indole nitrogen of end may be performed at other stages of the synthesis shown in schemes 1-4.

As also shown in scheme 3, optionally substituted intermediate product 6 also restore using Nickel Raney catalyst under the conditions described for phase i - recovery of the intermediate product 12 to 13, getting optionally substituted amide 5-formylindole-2-carboxylic acid 15. Aldehyde 15 turn the reducing agent is th aminirovanie in amides, optionally substituted 5-alkylamidoamines-2-carboxylic acid, by methods well known in the art, such as, for example, the processing solution optionally substituted aldehyde 15 in a suitable solvent such as a mixture of acetic acid and tetrahydrofuran, alkylamino, followed by the addition of a suitable base, such as, for example, potassium carbonate or sodium, and a suitable reductive agent such as, for example, cyanoborohydride sodium at temperatures close to room. Over the course of the reaction is observed by means of chromatographic methods well known in the art, such as thin layer chromatography, and when the reaction is complete, dilute the reaction mixture with a suitable solvent, washed with sodium bicarbonate or potassium bicarbonate and dried organic phase is concentrated, getting optionally substituted amide 5-alkylamidoamines-2-carboxylic acid 16.

Scheme 4

Figure 4 gives an idea about the methods of transformation of optional substituted intermediates 8b, 11b, 13, 14, and 16 in the compounds of formula I and II, which is the object of the invention, using methods well known in the art. The specialist will easily understand that these methods are suitable in General for the preparation of compounds of formula I and II compounds-ol is Shesterikov, each of which is not shown in figure 4, and that these methods are given to illustrate and not limit the scope of the invention. Primary amines 8b and 11b are compounds of formula I and II of the present invention, respectively.

As shown in scheme 4, reaction of VIII a mixture of primary amine 8b or 11b in the form of a salt, such as, for example, triperoxonane salt, obtained by removal of the protective BOC group from the compound predecessor 8a or 11a, respectively, and a suitable base such as potassium carbonate or sodium carbonate, in a polar solvent such as dimethylformamide, is treated with alkylhalogenide at a temperature close to the room. Over the course of the reaction is observed by means of chromatographic methods well known in the art, such as thin layer chromatography, and when the reaction is complete, dilute the reaction mixture with a suitable solvent, such as, for example ethyl acetate, the organic phase is washed with saline, dried and concentrated to obtain alkylamidoamines formula I or II, respectively.

As shown in scheme 4, reaction of IX, the solution optionally substituted primary amine 8b or 11b in the form of a salt, such as, for example, triperoxonane Sol obtained by hydrolysis of the protective BOC-group of the intermediate product 8a or 11a, respectively, K is included solvent, such as, for example, acetic acid and tetrahydrofuran, neutralized with potassium carbonate, the mixture is treated with an appropriate aldehyde and stirred at room temperature for about 10 minutes Then the mixture was added to a suitable regenerating agent, such as, for example, resin MP-CNBH3at a temperature close to the room temperature, and stirred. Over the course of the reaction is observed by means of chromatographic methods well known in the art, such as thin layer chromatography. When the reaction is complete, the reaction mixture is separated from the resin, and the resin is washed with a suitable solvent, such as tetrahydrofuran. The combined reaction filtrate and washings concentrated to obtain the desired N-substituted aminomethylphenol formula I or II, respectively.

As shown in scheme 4, reaction of XII, the solution optionally substituted primary amine 8b or 11b in the form of a salt, for example triperoxonane salt obtained by the hydrolysis of intermediates 8a or 11a, respectively, leading to the elimination of the protective BOC-group, in a suitable solvent, such as, for example, acetic acid and tetrahydrofuran, neutralized with potassium carbonate followed by the addition of the appropriate aldehyde and cyanoborohydride sodium at a temperature close to the room. Over the course of the reaction viewers who are using chromatographic methods, well known in the art, such as thin layer chromatography. When the reaction is complete, add ethyl acetate and the organic phase is washed with saline, dried and concentrated, obtaining the desired N-substituted aminoethanol formula I or II, respectively.

As shown in scheme 4, reaction of XV, the solution optionally substituted primary amine 8b or 11b in a suitable solvent, such as dimethylformamide or NMP, treated with an aqueous solution of a suitable base, such as, for example, potassium carbonate, sodium carbonate or the like of the base, and then with ether, N-hydroxysuccinimide N-Boc-substituted alpha-amino acids at a temperature close to the room. Over the course of the reaction is observed by means of chromatographic methods well known in the art, such as thin layer chromatography. When the reaction is complete, add ethyl acetate and wash the organic phase with a solution of bicarbonate and brine, dried and concentrated, gaining aminomethylphenol formula I or II, respectively, where R8is N-Boc-protected alpha-amino acid group, and R9represents hydrogen. Protective BOC-group is removed by treatment triperoxonane acid for 5-15 min and then add ether to precipitate triperoxonane salt of the desired amide derivative of the amino acid f is rmula I or II, respectively.

As shown in scheme 4, reaction of X, the solution optionally substituted amide 3-aaltio - or 3-arylheteroacetic-5-formylindole-2-carboxylic acid, 13 or 14 in a suitable solvent, such as, for example, acetic acid and tetrahydrofuran, is treated with a primary amine at a temperature close to the room. After 40 minutes the reaction solution is added to a suitable regenerating agent, such as, for example, the resin MP-CNBH3at room temperature. Over the course of the reaction is observed by means of chromatographic methods well known in the art, such as thin layer chromatography. When the reaction is complete, the reaction mixture is separated from the resin and the resin is washed with a suitable solvent, such as tetrahydrofuran. The combined reaction filtrate and washings are concentrated, obtaining the desired 3-aaltio - or 3-heterocyclic-5-N-substituted aminoethanol-2-carboxylic acid of formula I.

As shown in scheme 4, reaction of XIII, the solution optionally substituted amide 3-aaltio - or 3-heterocyclic-5-formylindole-2-carboxylic acid, 13 or 14 in a suitable solvent, such as, for example, acetic acid and tetrahydrofuran, is treated with a suitable base, such as, for example, triethylamine, in a suitable primary or secondary amine and then cyanoborohydride sodium when temperature is round, close to the room. Over the course of the reaction is observed by means of chromatographic methods well known in the art, such as thin layer chromatography. When the reaction is complete, add ethyl acetate and the organic phase is washed with sodium bicarbonate solution, dried and concentrated, obtaining the desired 5-N-substituted aminoethanol formula I.

As shown in scheme 4, reaction of Ia, optionally substituted amide 5-N-substituted aminoethanol-2-carboxylic acid 16 is treated with veridicality or diameterically, as described above in scheme 2, step f, using sodium hydride, receiving connections 8a and 11a of amides 7 or 10, respectively, are then receive 3-aaltio - or 3-heterocyclic-5-substituted aminoethanol-2-carboxamide formula I.

As shown in scheme 4, reaction of Ib, optionally substituted amide 5-N-substituted aminoethanol-2-carboxylic acid 16 is treated with veridicality or diameterically, as described above in scheme 2, step f, using cesium carbonate, to obtain the compounds 8a and 11a of 7 or 10, respectively, are then receive 3-aaltio - or 3-heterocyclic-5-N-substituted aminoethanol-2-carboxamide formula I.

In addition, the compounds of formula I or formula II, where X is S(O)nand n is 1 or 2, respectively, can be the ü obtained by the methods, well known in the art, such as, for example, treatment of a solution of the BOC-protected compound 8a or 11a (scheme 2) H2O2and Na2CO3. Or Boc-protected compound 7 or 10 (scheme 2) can be treated with a suitable base, such as, for example, sodium hydride or cesium carbonate, followed by treatment with arylsulfonamides, arylthioureas, heterocyclisation or heterocyclization (used instead of veridicality or diameterically), as described above in scheme 2, step f. Intermediate dianiline and sulfonylurea connection of these reactions can be hydrolyzed to remove the protective BOC-group, then each of the obtained intermediate product with the remote protection may be converted into compounds of formula I or formula II, where X is S(O)n, n is 1 or 2 and R3represents aryl or heterocycle, using methods similar to those described here.

Scheme 5

As shown in scheme 5, veridicality receive processing solution allsolid in a suitable organic solvent, such as, for example, methanol, aqueous solution of sodium perborate and leaving the reaction mixture at ambient temperature for 12-24 hours Veridicality can be isolated and purified by methods well known for the mi professionals. Diameterically, such as, for example, bis(2-pyridinyl) - disulfide, get a similar manner. And allsolid, and heterocyclic can have a replacement group, according to the above definition of "aryl" and "heterocycle".

All compounds of the present invention that are described here can be used to treat various diseases and disorders as described herein. As mentioned, the compounds used in methods of the present invention is able to inhibit the action caseinline Iε.

One implementation of the present invention relates to a method for inhibiting the activity caseinline Iε patients by introducing these patients a therapeutically effective amount of an inhibitor caseinline Iε, resulting in the above-mentioned inhibition caseinline Iε leads to a lengthening of the period of circadian rhythm.

Another implementation of the present invention relates to a method for inhibiting the activity caseinline Iε patients, which leads to a lengthening of the period of circadian rhythm. The method consists in the introduction to these patients therapeutically effective amounts of compounds of formula I or formula II of the present invention. Another implementation of the present invention relates to a method of treating patients suffering from Bo is Esna or disorders, that can be alleviated by inhibition activity caseinline Iε using the destination specified patients therapeutically effective amounts of compounds of formula I or formula II, which leads to the prolongation of the period of circadian rhythm.

Following the implementation of the present invention is a method of treating mood disorders or sleep disorders. Another implementation of the present invention is a method of treating mood disorders, where a mood disorder understand depressive disorder or bipolar disorder. Following the implementation of the present invention is a method of treating a depressive disorder, where depressive disorder understand major depressive disorder. Another implementation of the present invention is a method of treating mood disorders, where a mood disorder see bipolar disorder. Following the implementation of the present invention is a method of treatment of bipolar disorder, where bipolar disorder should understand bipolar disorder type I or bipolar II disorder. Another implementation of the present invention is a method of treating sleep disorders. Following the implementation of the present invention is a method of treatment is ustroystva sleep, where the sleep disorder should be understood disorder circadian rhythm sleep. Following the implementation of the present invention is a method of treating disorders circadian rhythm sleep, where the disorder circadian rhythm sleep belongs to the group that includes a sleep disorder during shift work syndrome desynchronize when travelling, the syndrome of premature sleep phase syndrome and delayed sleep phase. Professionals it is clear that the diseases and disorders listed above should not be read in a restrictive manner and that they are given to illustrate the effectiveness of the compounds of the present invention. Thus, it should be understood that the compounds of the present invention can be used to treat any disease or disorder, facilitated by inhibition caseinline Iε.

In another implementation of the present invention a pharmaceutical composition containing pharmaceutically acceptable carriers and a compound of formula I or formula II, or a stereoisomer, enantiomer, racemate or tautomer specified connection, or its pharmaceutically acceptable salt, obtained by methods well known to experts in the field of pharmaceutics. The carrier or excipient may be a solid, semi-solid or liquid material that can serve as a diluent or medium for the active ingredient. Fit is is whether or excipients well known in the art. The pharmaceutical composition can be administered orally, by inhalation, or parenteral topicaine and can be assigned to patients in the form of tablets, capsules, suspensions, syrups, aerosols, inhalation, suppositories, ointments, powders, solutions or in any other form. The term "pharmaceutical carrier" or "pharmaceutically acceptable carrier" herein means one or more fillers. As described herein, the pharmaceutical compositions of the present invention provide inhibition caseinline Iε and therefore are useful for treating diseases and disorders which can be alleviated by the inhibition caseinline Iε.

In the preparation of pharmaceutical compositions or preparations of the compounds of the present invention measures should be taken to the active compound or compounds were bioavailable in effective therapeutic amounts when the chosen method of administration, including oral, parenteral and subcutaneous methods. For example, effective methods of administration include subcutaneous, intravenous, percutaneous, intranasal, rectal, vaginal and similar ways, including the release of the implant and the injection of the active ingredient and/or composition directly into the fabric.

For oral administration the compounds of the present and the gain can be incorporated into solid or liquid preparations, which include or do not include inert solvents or edible media, such as capsules, pills, tablets, powders, solutions, suspensions and emulsions. Such capsules, pills, tablets and the like may also contain one or more of the following adjuvants (subsidiary of medicines): binders such as microcrystalline cellulose, tragacanth gum; excipients such as starch or lactose; a shredder, such as alginic acid, corn starch and the like; lubricants, such as stearic acid, magnesium stearate or Sterotex®, (Stokely-Van Camp Inc., Indianapolis, Indiana); substances that contribute to the slide, in particular colloidal silicon dioxide; sweeteners, such as sucrose or saccharin, flavoring agents such as peppermint, methyl salicylate or fruit flavoring. When the unit dosage is a capsule, it may also contain a liquid carrier such as polyethylene glycol or fatty oil. The materials used should be pharmaceutically pure and non-toxic in the quantities used. Alternatively, the pharmaceutical compositions can be prepared in a form suitable for slow release in order to enter a therapeutic amount of the compounds of the present invention in a suitable formers a day, once a week or once a month, using methods well known in the art. For example, this could offer some slowly decaying polymer containing the active ingredient.

When administered parenterally, the compounds of the present invention may be administered in the form of doses of the injectable solution or suspension of this compound in a physiologically acceptable solvent with addition of a pharmaceutical carrier which can be a sterile liquid such as water, oil, or without adding a surfactant and other pharmaceutically acceptable excipients. For example, oil, which can be used in the preparations can be petrochemical, animal, vegetable or synthetic origin, such as peanut oil, soybean oil and mineral oil. In General, water, saline solution, aqueous dextrose or related sugar, ethanol and glycols, such as propylene glycol are preferred liquid carriers, particularly in the case of solutions for injection. Parenteral preparations can be enclosed in ampoules, disposable syringes or bottles and repeated administration, made of inert plastic or glass.

Solutions or suspensions as described above, may also include one or more of the following ancillary the different substances: sterile diluents, for example water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for regulating isotonicity, for example sodium chloride or dextrose.

Compounds of the present invention can be applied in the form of skin patches, injections with slow absorption or implantable drug is prepared in such a way as to provide slow release of the active ingredient. Perhaps pressing the active ingredient into pellets or small cylinders and subcutaneous or intramuscular implantation in the form of injections with slow absorption or implant. For implants can be used inert materials, for example biorstwami polymers or synthetic silicones. Suitable pharmaceutical carriers and methods of formulation are given in the standard handbooks, such as Remington: The Science and Practice of Pharmacy, 19thedition, Volumes 1 and 2, 1995, Mack Publishing Co., Easton, Pennsylvania, U.S.A., which is due to the references included in this document.

For the treatment of various diseases described here, Rastro the STV and conditions acceptable dose is from about 0.01 mg/kg / day to 250 mg/kg / day, preferably from about 0.05 mg/kg / day to 100 mg/kg / day and preferably from 0.05 mg/kg / day to about 40 mg/kg / day. Compounds of the present invention can be used in mode 1 to 4 times a day in accordance with the nature of the disease, disorder or condition to be treated.

EXAMPLES

The following examples are given to illustrate the present invention without limiting the scope of the invention. In tables 1 and 2 list the properties of the compounds given as examples; the synthesis of these compounds is described below.

If not stated otherwise, materials were obtained from commercial suppliers and used without further purification. All reactions were performed under inert atmosphere using anhydrous reagents and solvents. Flash chromatography was carried out on the device Isco CombiFlash companion™using ready-to-use silicagel cartridges Advantage FlashReady™ and solvents, as described below. Thin-layer chromatography was performed using 0.25 mm plates coated with silica gel 60F-254 (EAT), spots product was detected using a pair of iodine, UV light or coloring reagent, such as a solution of KMnO4.

Infrared (IR) spectra were recorded using a spectrometer Nexus 670 FTIR (Nicolet), preparing samples, as indicated, and the result was expressed in wave numbers (cm-1).1H NMR spectra registration is Aravali spectrometer (500 MHz), Varian Gemini and/or Magsig 300, Unity 400 or Unity plus and/or Inova, expressing the chemical shift (δ) in SB (ppm) relative to tetramethylsilane (0,0 MD) or chloroform (CDCl3, 7,26 MD) as standard.13C NMR spectra were recorded using the instrument Varian Unity (100,57 MHz 13C frequency), expressing the chemical shift (δ) in the MD regarding CDCl3(77,0 MD), unless otherwise noted. Mass spectra (MS) were recorded using a mass spectrometric system Finnigan MAT model TSQ 700 with chemical ionization at 120 eV, using methane (CI, 120 eV). Liquid chromatography in combination with mass spectrometry (LC-MS) was performed using the instrument Micromass LCT connected to the machine for liquid Gilson 215. Mass spectrometric analysis of high-resolution (for accurate mass spectra) was performed in mode ESI at mass resolution of 10 000, using a mass spectrometer Micromass QTOF. Exact mass number was determined for protonated molecular ions (M+1), where M refers to the molecular ion. Reductive amination using a reducing agent bound to the resin was performed using polystyrene with divinylbenzene Argonaut Macroporous (MP). Used reactant cyanoborohydride Mr (batch No. 01617) to 2.55 mmol/g

General methods of synthesis

General method for the synthesis of Ia (obtaining the amides of 3-aaltio - or 3-heterocyclical-2-carboxylic KIS is the notes using NaH)

To NaH (60% suspension in oil, 1.2 EQ., 9.8 mmol) in DMF (75 ml) in an atmosphere of N2while stirring and at room temperature add indol-2-carboxamide (8,18 mmol) in solution in DMF (5 ml). After 5 min add veridicality or diameterically (1.0 EQ., 8,18 mmol) in one portion and the reaction mixture is heated with stirring to 95°C for 16 hours After the end of the reaction divided the sample between EtOAc/H2O and analyze the aliquot on TLC (10% MeOH/CH2Cl2). The reaction mixture is concentrated under vacuum, diluted with water and stirred for 30 min, filtered and dried in air. Chromatographic untreated substance on SiO2and elute using CH2Cl2/MeOH (9:1)to give amide 3-aaltio - or 3-heterocyclic-indole-2-carboxylic acid (reference: Atkinson et al. Syn. Comm. 1988, 480).

General method for the synthesis of Ib (obtaining the amides of 3-aaltio - or 3-heterocyclical-2-carboxylic acid using Cs2CO3)

To indole-2-carboxamide (1.06 mmol)dissolved in dry DMF (10 ml), add Cs2CO3(100 mg, 0.31 mmol) and then veridicality or diameterically (0.64 mmol). Heat the reaction mixture in the atmosphere

N2at 100°C for 2.5 h (completeness of passage of the reaction is monitored using TLC/LC-MS). Allow the reaction mixture to cool document, concentrated to minimum volume and share saline (6 ml) and EtOAc (3 ml). Extracted with EtOAc, dried combined extracts (MgSO4) and concentrate to obtain the crude product. Purify the product by ISCO column (4.0 g SiO2) to obtain the amide of 3-aaltio - or 3-heterocyclical-2-carboxylic acid.

General method for the synthesis II (transesterification)

Add K2CO3(1.20 equiv., 50,7 mmol) to ethylindole-2-carboxylate (42,3 mmol) in MeOH (50 ml) and stir the resulting suspension by heating at 55°C for 1 h followed the course of the reaction by TLC (Et2O/hept.) and after concentrating the reaction mixture under vacuum, diluted with H2O and stirred for 15 minutes to Separate the precipitate by filtration and dried in a vacuum oven at 65°C for 3 h to obtain methyl ester of indole-2-carboxylic acid.

General method for the synthesis of III (amidation using NH4OH)

Stirred ethyl or methyl ester of indole-2-carboxylic acid (40.0 mmol) in suspension in NH4OH (100 ml) and LiCl (1.0 equiv.) when K.T. for 16 hours Produce the precipitate from the reaction mixture by means of filtration, washed with H2O and dried in the air, getting amide indole-2-carboxylic acid.

General method for the synthesis IV (amidation using NH3/MeOH)

Stirred ethyl or methyl is a new ether indole-2-carboxylic acid (4,67 mmol) in 7N NH 3/MeOH (20 ml) and added LiCl (1.0 equiv., of 4.67 mmol). Stirred the reaction mixture at K.T. within 5 days and watched the progress of reaction by TLC (10% MeOH/CH2Cl2). During this time, you may fall out of the sediment. Concentrate the reaction mixture to a minimum volume, diluted with H2O and the precipitate is filtered off. Washed precipitate additional number of H2O and dried under vacuum at 60°C with getting amide indole-2-carboxylic acid in solid form.

General method for the synthesis of V (getting 2-indolocarbazoles acid from ethyl or methyl ester)

To ethyl or methyl ether indole-2-carboxylic acid (27,0 mmol) in suspension in MeOH/H2O (3:1, 160 ml) is added NaOH (82,0 mmol). Stirred at K.T. for 16 h, concentrate the reaction mixture was acidified with HCl and the precipitate is separated by filtration. Wash the precipitate on the filter with additional quantity of H2O and dried in a vacuum oven, receiving 2-indolocarbazole acid.

General method for the synthesis of VI (amidation 2-indolocarbazoles acid)

Add to 2-indolocarbazoles acid (31,0 mmol)dissolved in anhydrous THF (50 ml), carbonyldiimidazole (1,10 EQ., 5.5 g, 34,0 mmol) and stirred for 1 h Then add concentrated NH4OH (50 ml) in one portion and the reaction mixture is stirred at K.T. After 16 h selected sediment from Leamy filtering, washed with H2O and dried under vacuum at 40°C, obtaining the desired 2-indolocarbazole.

General method for the synthesis of VII (amidation using primary and secondary amines 2-indolocarbazoles acid)

Add to 2-indolocarbazoles acid (12.4 mmol) in anhydrous THF (30 ml) carbonyldiimidazole (1.5 EQ., to 18.6 mmol) and stirred for 1 hour Add the desired amine [e.g., methylamine, ethylamine, dimethylamine, pyrrolidine, piperidine, piperazine or morpholine, (3.0 EQ., is 37.2 mmol)] one portion and the reaction mixture is stirred at K.T. After 16 h stop reaction by addition of H2O collect the precipitation is filtered and dried under vacuum, obtaining the desired 2-indolocarbazole.

General method for the synthesis of VIII (N-alkylation of iminomethylene).

Process 5 - or 6-Boc-aminoethanol (0.5 mmol) triperoxonane acid (TFU, 5 ml) and H2O (0.25 ml) and stirred at K.T. for 10 minutes (watch the progress of the reaction by LC-MS). Precipitated triperoxonane salt by addition of Et2O, separating it by filtration and dried under vacuum at 70°C. Dissolve TFU-salt (0.24 mmol) in DMF (3.0 ml), treated with K2CO3(0.48 mmol), then add the appropriate alkylhalogenide (0.50 mmol). After 4 h, or after completion of the reaction, as will show TLC (10% MeOH/CH2Cl2-0,25% NH3), dilute the reaction mixture EtOAc, prom is live H 2O, dried (MgSO4) and concentrate. Purify the reaction product by chromatography, obtaining the desired 5 - or 6-alkylamidoamines.

General method for the synthesis of IX (reductive amination of 5 - or 6-aminomethylphenol using MP-CNBH3)

Neutralize the solution TFU-salt 5 - or 6-aminomethylphenol (0.061 mmol) and AcOH/THF (1:4, 2.5 ml), adding K2CO3(1.0 EQ., 0.061 mmol). To the resulting mixture to the desired aldehyde (1.0 EQ., 0.061 mmol) and stirred the reaction at K.T. within 10 minutes Trying to work up the reaction mixture in a disposable polypropylene syringe (5 ml, HSW) with a polypropylene membrane and the tube filled with resin Mr-CNBH3(2.5 EQ.). Place the syringe in a LabQuake shaker Shaker and rotated for 16 hours the reaction course is monitored using TCX (10% MeOH/CH2Cl2and at its completion inject the reaction mixture in a glass bottle c screw-top jar, combine with THF-water flushing of resin and concentrate under vacuum. In some cases, to obtain a substance in the form of crystals treated amorphous precipitate with HCl (1.0 ml) and precipitated EtO2(1.0 ml) to obtain the HCl-salt.

General method for the synthesis of X (reductive amination of amides of 5 - and 6-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid with MP-CNBH3)

Add to the 5 - or 6-incollege (0,077 mmol) in AcOH/THF (1:4, 2.5 ml) sootvetstvuyuschiy or secondary amine (2 EQ., 0,152 mmol) and the reaction mixture is stored at K.T. 40 minutes trying to work up the reaction mixture in polypropylene disposable syringe (5 ml, HSW), equipped with a polypropylene membrane and tube and filled with resin Mr-CNBH3(2.0 EQ.). Place the syringe in a LabQuake shaker Shaker and rotated for 16 hours If you use HCl-amine salt, add Et3N (1.1 EQ.) to neutralize the salt. The reaction course is monitored using TCX (10% MeOH/CH2Cl2and when it's finished, inject the reaction mixture in a glass bottle with a screw-top jar, combine with THF-water flushing of resin and concentrate under vacuum from the reaction product.

General method for the synthesis of XI (reduction of the nitrile using a Nickel catalyst Raney)

Restore 5 - or 6-intalniri, as described in Sundberg, R. J.; Dalhausen, D. J.; Manikumar, G.; Mavunkel, B.; Biswas, A. et al. J. Heterocyclic Chem. 1988, 25, 129-137. Namely, preparing a suspension of amide 5 - or 6-cyano-3-phenylsulfanyl-1H-indole-2-carboxylic acid (4,59 mmol) and NaH2PO2(3.0 EQ., 13.7 mmol) in a solution of pyridine (20 ml), AcOH (10 ml) and H2O (10 ml). Added to this reaction mixture, the aqueous suspension of the Nickel catalyst Raney (1.0 ml) and heated the reaction mixture at 95°C for 4.5 h the reaction mixture Cooled down, filtered through Celite® (infuzoria the earth (Celite Corporation, 137 West Central Avenue, Lompor, California 93436) in the atmospheres of the N 2and washed with a small amount of pyridine and H2O. Concentrate the filtrate under vacuum to a minimum volume, diluted with dark green oil mass of ice H2O and stirred for 5 min, during this time should form a precipitate. Separate the precipitate by filtration, washed with Et2O and dried in the air, getting a 5 - or 6-formirovanii product, respectively.

General method for the synthesis XII (Reductive amination of 5 - or 6-aminomethylphenol using NaBH3CN).

Add to the solution TFU-salt 5 - or 6-aminomethylphenol (0.12 mmol) and AcOH/THF (1:4, 5.0 ml), the appropriate aldehyde (to 0.108 mmol), and then K2CO3(1.0 EQ., 0.12 mmol) and NaCNBH3(2.5 EQ., 0.3 mmol). Stirred the reaction mixture at K.T. and monitor the progress of the reaction by TCX (10% MeOH/CH2Cl2). Upon completion of the reaction, dilute the reaction mixture EtOAc, washed with saturated NaHCO3and brine, dried (MgSO4) and concentrated in vacuo to obtain the crude product. Make an atonement for him chromatography, obtaining the desired connection.

General method for the synthesis XIII (Reductive amination of amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid using

NaBH3CN)

To a solution of aldehyde 13 or N-alkylated aldehyde 14 (0.26 mmol) and AcOH/THF (1:4, 5.0 ml) is added with testwuide amine (0.52 mmol), then Et3N (1.0 EQ., 0.26 mmol), and then NaCNBH3(2.5 EQ., of 0.65 mmol). Stirred the reaction mixture at K.T. and monitor the progress of the reaction by TCX (10% MeOH/CH2Cl2). Upon completion of the reaction, dilute the reaction mixture EtOAc, washed with saturated NaHCO3and brine, dried (MgSO4) and concentrated in vacuo to obtain the crude product. Clean it with getting the required connections. As a by-product of the reaction is obtained a small amount of bis-alkylated product.

General method for the synthesis XIV (N-methylation of amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid)

To incollege 13 (400 mg, 1.35 mmol)dissolved in DMF (20 ml), add KOH (1.2 EQ., 91,0 mg) in aqueous solution (3.0 ml, H2O). Add to the reaction mixture dropwise a solution of MeI (101 μl) and DMF (1.0 ml). Stirred the reaction mixture at K.T. within 48 hours Diluted with EtOAc (200 ml), the organic phase is washed with saturated NaHCO3and dried (MgSO4). Concentrate the organic phase to obtain the crude product 14.

General method for the synthesis XV (Linking amino acids with a 5 - or 6-aminomethylphenol)

Dissolve 5 - or 6-aminomethylphenol (0,242 mmol, 8b or 11b in the form of TFU-salt) in DMF (10 ml), add 10% aqueous solution of K2CO3(1.0 ml) and then added N-Boc-protected N-hydroxysuccinic idny ether amino acids (1,10 EQ., 0,266 mmol). Stirred at K.T. and monitor the progress of the reaction by LC-MS. Upon completion of the reaction, dilute the reaction mixture of EtOAc (200 ml) and the organic phase is washed with saturated NaHCO3(3x) and brine (1x), dried (MgSO4) and concentrate under vacuum. Remove the protective group from the crude analogue of the amino acid processing 99% of TFU for 10 min, concentrated and then precipitated reaction product in the form of TFU-salt by addition of Et2O.

Obtaining the ethyl and methyl esters of 5 - and 6-cyano-1H-indole-2-carboxylic acid (Scheme 1)

Ethyl ester of 3-(5-cyano-2-nitrophenyl)-2-oxopropanoic acid, 2 (m=0)

Dissolving sodium metal (0,345 g) in absolute EtOH (25 ml), add diethyloxalate (10 ml) and then add 3-methyl-4-nitrobenzonitrile (1a, m=0, 1.6 g, Aldrich) in the form of a solution in EtOH (25 ml). Stirred the reaction mixture at K.T. for 16 h, stop the reaction by adding 5N HCl (3 ml) and remove the EtOH under reduced pressure. Share the precipitate between CH2Cl2(100 ml) and H2O (50 ml). Wash the organic layer successively H2O (50 ml) and brine (50 ml), dried (MgSO4) and concentrate to obtain the crude oily product. Purify by chromatography on SiO2(cyclohexane-EtOAc, about 70-30.) obtaining after drying (40°C, low pressure centralized static switch module multi is Noah vacuum system) of the desired substance (1.2 g) as yellow crystals.

Ethyl ester of 5-cyano-1H-indole-2-carboxylic acid, 3a (m=0)

Added to ethyl ether, 1.2 g of 3-(5-cyano-2-nitrophenyl)-2-oxopropanoic acid 2 (m=0) in EtOH (40 ml) 10% Pd/C (0.40 g) and stirred in an atmosphere of hydrogen until it is absorbed by the calculated amount of hydrogen. Filtered the reaction mixture and concentrate the filtrate to obtain 1.1 g of the crude product. Purify by chromatography on SiO2, elwira CH2Cl2. Concentrate the desired fractions and dried under vacuum the residue during the night (40°C) to obtain the desired compound (0.5 g) as white crystals, Rf=0,9 (silica gel, 10% MeOH/CH2Cl2).

Ethyl ester of 3-(4-cyano-2-nitrophenyl)-2-oxopropanoic acid, 4 (m=0)

Dissolving sodium metal (0,345 g) in absolute EtOH (25 ml), add diethyloxalate (10 ml) and then add 4-methyl-3-nitrobenzonitrile (1b, m=0, 1.6 g, Aldrich) in the form of a solution in EtOH (25 ml). Stirred the reaction mixture at K.T. for 16 h, stop the reaction by adding 5N HCl (3 ml) and remove the EtOH under reduced pressure. Divide the remainder between CH2Cl2(100 ml) and H2O (50 ml). Wash the organic layer successively H2O (50 ml) and brine (50 ml), dried (MgSO4) and concentrate to obtain the crude oil product. Purify by chromatography on SiO2, elwira with a mixture of cyclohexane-EtOAc, 70-Ob. obtaining after drying (40°C, low pressure Central vacuum system) of the desired compound (1.5 g) as yellow crystals, TPL 118°C.

Ethyl ester of 6-cyano-1H-indole-2-carboxylic acid 5a (m=0)

Added to 1.5 g of ethyl ester of 3-(4-cyano-2-nitrophenyl)-2-oxopropanoic acid in EtOH (40 ml) 10% Pd/C (0.45 g) and stirred in an atmosphere of hydrogen until it is absorbed by the calculated amount of hydrogen. Filtered the reaction mixture and concentrate the filtrate to obtain 1.1 g of the crude product. Purify by chromatography on SiO2, elwira CH2Cl2. Concentrate the desired fractions and dried under vacuum the residue during the night (40°C) to obtain the desired compound (0.8 g) as white crystals, TPL 176°C.

Methyl ester of 5-cyano-1H-indole-2-carboxylic acid, 3b (m=0) and methyl ester of 6-cyano-1H-indole-2-carboxylic acid 5b (m=0)

Each of the desired esters 3b and 5b can be prepared from the corresponding ethyl esters 3a and 5a, respectively, using interesterification, as described in the General method of synthesis II.

Obtaining the amides of 3-aaltio - or 3-heterocyclic-5-aminomethylphenol-2 - carboxylic acid 8b and amides of 3-aaltio - or 3-heterocyclic-6-aminomethylphenol-2-carboxylic acid 11b.

(Scheme 2)

Amide 5-cyano-1H-indole-2-carboxylic acid, 6 (m=0)

Treated with ethyl the fir 5-cyano-1H-indole-2-carboxylic acid, 3a (m=0, 1.0 g, of 4.67 mmol) in 7 N NH3/MeOH as described in the General method of synthesis IV, to obtain the desired compound in the form of solid ivory (720 mg, 83,3%): TPL >300°C;1H NMR (DMSO-d6) δ 12,0 (USS, 1H), 8,21 (s, 1H), 8,14 (USS, 1H), 7,51 (m, 3H), 7,25 (s, 1H); TCX (10% MeOH/CH2Cl2): Rf=0.40 in, OBS. m/z=186 (M+1).

Tert-butyl ether (2-carbarnoyl-1H-indol-5-ylmethyl)-

carbamino acid, 7 (m=0)

Dissolve the indole 6 (m=0, 9.5 g, a 51.3 mmol) in MeOH (500 ml) and add NiCl2(7,3 g, 1.1 EQ., of 56.4 mmol) and Boc2O (22,4 g, 2.0 EQ., 102,6 mmol). The reaction mixture cooled down to the temperature of the ice bath and then added NaBH4(13,6 g, 7.0 equiv., 0.36 mol). Stirred the reaction mixture at K.T. under N2. After 16 h, concentrate the reaction mixture, dissolving the residue in EtOAc, washed with saturated NaHCO3and extracted with EtOAc several times. Combine the extracts, dried (MgSO4) and concentrate to obtain the desired compound 7 (m=0), which is used without further purification. Rf=0,30, OBS. m/z=290 (M+1). (see: Caddick, S, et al. Tet. Lett. 2000, 41, 3513-16).

Tert-butyl ether (2-carbarnoyl-3-phenylsulfanyl-1H-indol-5-ylmethyl)-carbamino acid 8a (m=0, R3=Ph).

Process amide 7 (m=0, 4.0 g, of 13.8 mmol) phenyldiazonium (1.0 EQ., to 3.02 g of 13.8 mmol)as described in General method I, to obtain the desired compound 8a (compound Ib, where m=0) in the form of solids Bleue is but yellow (2,36 g, 42,9%);1H NMR (DMSO-d6) δ 12,2 (USS, 1H), 7,94 (USS, 1H), 7,71 (USS, 1H), 7.5 to to 6.9 (m, 9H), 4,17 (d, 2H,J=6,0 Hz)of 1.40 (s, 9H). TCX (5% MeOH/CH2Cl2): Rf=0.25 in, OBS. m/z=398 (M+1).

Amide 5-aminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, 8b (m=0, R3=Ph)

Process 5-Boc-aminomethylpyridine compound 8a (m=0, R3=Ph; Ib) (1.6 g) TFU (99%, 10 ml) and stirred at K.T. for 10 minutes to Concentrate the reaction mixture and the precipitated product by adding Et2O obtaining TFU-salt of the desired compound 8b (compound Ia, where m=0, R3=Ph) in the form of a solid white color (1.6 g):1H NMR (DMSO-d6) δ 12,5 (USS, 1H), 7,92 (USS, 1H), 7,70 (USS, 1H), 7.5 to to 6.9 (m, 10H), 4,17 (d, 2H,J=6.2 Hz).

Amide 6-cyano-1H-indole-2-carboxylic acid, 9 (m=0)

Handle ethyl ester of 6-cyano-1H-indole-2-carboxylic acid 5a (m=0, 1.0 g, of 4.67 mmol) in 7 N NH3/MeOH as described in General method IV, to obtain the desired compound in the form of solid ivory (766 mg, 88.6 per cent), TPL 241-242°C;1H NMR (DMSO-d6) δ 11,5 (USS, 1H), 8,16 (USS, 1H), 7,83 (s, 1H), 7,80 (d, 1H,J=8.0 Hz), 7,58 (USS, 1H), 7,35 (d, 1H,J=8.0 Hz), 7.23 percent (s, 1H).

Tert-butyl ether (2-carbarnoyl-1H-indole-6-ylmethyl)-carbamino acid, 10 (m=0)

Dissolve indole 9 (m=0, 0.56 g, 3 mmol) in MeOH (25 ml), stirred at K.T. under N2and add NiCl2(0.36 g, 1.0 EQ., 3.0 mmol) and Boc2O (1.31 g, 2.0 EQ., 6.0 mmol). Cool CME is ü to the temperature of the ice bath and then added NaBH 4(0,79 g, 21 mmol). Stirred the reaction mixture at K.T. under N2. After 16 h, concentrate the reaction mixture, dissolve the residue in EtOAc, washed with saturated NaHCO3and extracted with EtOAc several times. Combine the extracts, dried (MgSO4) and concentrate to obtain the desired compound (433 mg, 49.5 per cent) in the form of a solid crystalline substance of a yellow color, which is used without further purification, TPL 209-209,5°C;1H NMR (DMSO-d6) δ 11,4 (USS, 1H), 7,87 (USS, 1H), 7,49 (d, 1H, J=8.0 Hz), 7,27 (overlaps with OSS, 3H), 7,06 (s, 1H), 6,92 (d, 1H, J=8.1 Hz), 4,18 (d, 2H, J=5,9 Hz), of 1.40 (s, 9H). TCX (10% MeOH/CH2Cl2): Rf=0,35, OBS. m/z=290 (M+1).

Tert-butyl ether (2-carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)-carbamino acid 11a (m=0, R3=Ph)

Process amide 10 (m=0, R3=Ph; 411 mg of 1.42 mmol) phenyldiazonium (310 mg, of 1.42 mmol)as described in General method I, to obtain the desired compound 11a (compound IIb, where m=0 and R3is Ph) in the form of a solid yellow-brown (60 mg, 10.6 per cent), TPL 118-121°C;1H NMR (DMSO-d6) δ 12,25 (USS, 1H), of 7.90 (USS, 1H), 7,70 (USS, 1H), 7,52 (m, 2H), 7,40 (m, 3H), 7,37-7,0 (m, 4H), 4,19 (d, 2H,J=6,4 Hz)of 1.40 (s, 9H). TCX (10% MeOH/CH2Cl2) Rf=0,55, OBS. m/z=398 (M+1).

Amide 6-aminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid-TFU-salt, 11b (m=0, R3=Ph)

Process 6-Boc-aminomethyl connection 11a (m=0, R3 =Ph; 1.6 g) TFU (99%, 10 ml) and stirred at K.T. for 10 minutes to Concentrate the reaction mixture and the precipitated product by adding Et2O obtaining the desired compound 11b (compound IIa, where m=0 and R3is Ph) in the form of a solid white color (1.6 g):1H NMR (DMSO-d6) δ 12,55 (s, 1H), 8,14 (USS, 1H), with 8.05 (s, 1H), 7,75 (USS, 1H), to 7.64 (s, 1H), 7,51 (d, 1H), 7.3 to a 7.0 (m, 6H), is 4.15 (d, 2H,J=5.8 Hz). TCX

(10% MeOH/CH2Cl2): Rf=0,55, OBS. m/z=398 (M+1).

Obtaining the amides of 3-aaltio - and 3-heterocyclic-5-formylindole-2-carboxylic acid 13 and 14, and amides of 5-N-substituted aminoethanol-2-carboxylic acid 16

(Scheme 3)

Amide 5-cyano-3-phenylsulfanyl-1H-indole-2-carboxylic acid, 12 (m=0, R3=Ph)

Process connection 6 (m=0, 6.0 g, 32,4 mmol) diphenyldisulfide (1,10 EQ., 7.78 g), as described in the General method of synthesis I, obtaining the crude desired compound 12 (6.5 g, 68,4%) in the form of solid ivory, which is used without purification, Rf=0,5 (5% MeOH/CH2Cl2).

Amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, 13 (m=0, R3=Ph)

Restore the connection 12 (m=0, R3=Ph; 1.13 g, 3,86 mmol) using a Nickel catalyst Raney (90,7 g), as described in the General method of synthesis of XI, to obtain after chromatography on SiO2(2% MeOH/CH2Cl2) of the desired compound 13 (0,69 g, 60%) in the ideal solid pale yellow color, Rf=0.45 in (5% MeOH/CH2Cl2).

Amide 5-formyl-1-methyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, 14 (m=0, R1=CH3R3=Ph)

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph; 400 mg, 1.35 mmol) and MeI (101 μl)as described in General method XIV, with getting the required 5-formyl-1-methylindoline connection 14 (280 mg, 67%), Rf (5% MeOH/CH2Cl2)=0,75.

Amide 5-formyl-1H-indole-2-carboxylic acid, 15 (m=0)

Process amide 5-cyano-1H-indole-2-carboxylic acid 6 (m=0, 500 mg, 2.7 mmol), Nickel-Raney catalyst (0.6 g)as described in General method XI, to obtain the desired compound 15 (230 mg, 45.4%) of in a solid yellow color, TCX (10% MeOH/CH2Cl2), Rf=0.75 in.

Amide 5-methylaminomethyl-1H-indole-2-carboxylic acid, 16 (m=0, R8=CH3)

Process the aldehyde 15 (m=0, 230 mg, 1,22 mmol) of methylamine hydrochloride (2.0 EQ., 165 mg of 2.44 mmol) and NaBH3CN (3 EQ., 239 mg, 3.7 mmol)as described in General method XII obtaining the desired compound 16 (230 mg, of 92.7%) as a solid yellow-brown; TCX (10% MeOH/CH2Cl2-0,2% Et3N) Rf=0.25 in, OBS. m/z=204 (M+1).

Obtaining the amides of 5-substituted 3-aristondo-2-carboxylic acid I from 8b, 13, 14, and 16

(Schemes 2 and 4)

Amide 5-aminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Ia and tert-Putilov the th ether (2-carbarnoyl-3-phenylsulfanyl-1H-indol-5-ylmethyl)-carbamino acid, Ib

The desired compounds Ia and Ib are given as described above, see method of synthesis of compounds 8a and 8b according to scheme 2.

Amide 5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Ic

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,17 mmol) methylamine-HCl (2.0 EQ., 23 mg, 0.34 mmol)as described in General method X, to obtain the amide 5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Ic (18 mg, 34.6 per cent) in a solid yellow color, TCX Rf=0,2 (15% MeOH/CH2Cl2), OBS. m/z=312 (M+1).

Amide 3-(3-chlorophenylsulfonyl)-5-methylaminomethyl-1H-indole-2-carboxylic acid, Id

Process amide 5-methylamino-1H-indole-2-carboxylic acid 16 (m=0,

R8=CH3) (50 mg, 0.25 mmol) 3-khlorfenilalanina (77,8 mg, 0.27 mmol)as described in General method Ib, getting the Id in the form of solid ivory (22 mg, 25.8 per cent), TCX Rf=0.15 In (50% MeOH/CH2Cl2-0,5% Et3N).

Amide 3-(3-perpenicular)-5-methylaminomethyl-1H-indole-2-carboxylic acid, Ie

Process amide 5-methylamino-1H-indole-2-carboxylic acid 16 (m=0,

R8=CH3) (65 mg, 0.32 mmol) 3-fortunelounge (89,5 mg, 0,352 mmol)as described in General method Ib, Ie getting in a solid ivory (42 mg, 40%), TCX Rf=0.15 In (50% MeOH/CH2Cl2-0,5% Et3N).

Amide 5-(benzylamino ethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid, If

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (60 mg, 0,203 mmol) benzylamine (to 43.5 mg, 0,406 mmol)as described in General method X, obtaining If (45 mg, 52,9%), emitted as HCl-salt, OBS. m/z=388 (M+1).

Amide 1-methyl-5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Ig

Process amide 5-formyl-1-methyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 14 (m=0, R1=CH3, R3=Ph) (80 mg, 0.26 mmol) of methylamine hydrochloride as described in General method XIII obtaining Ig (37 mg, 44.2 per cent), emitted as HCl-salt, OBS. m/z=326 (M+1).

Amide 5-(4-hydroxyethylpiperazine-1-ylmethyl)-3-phenylsulfanyl-1H-

indole-2-carboxylic acid, Ih

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) 4-piperidinemethanol (43,6 mg, 0,338 mmol)as described in General method X, obtaining Ih (32 mg, 43.9 per cent)emitted as HCl-salt, TCX Rf (free base)=0,25 (10% MeOH/CH2Cl2-0,5% Et3N), OBS. m/z=396 (M+1).

Amide 5-morpholine-4-ylmethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Ii

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) morpholine (29,45 mg, 0,338 mmol)as described in General method X, obtaining Ii (34 mg, 50.0%)were emitted as HCl-salt, TCX Rf (free base is)=0,80 (10% MeOH/CH 2Cl2-0,5% Et3N), OBS. m/z=368 (M+1).

Amide 3-phenylsulfanyl-5-propylaminoethyl-1H-indole-2-carboxylic acid, Ij

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) of Propylamine hydrochloride (32,3 mg, 0,338 mmol)as described in General method X, obtaining Ij (27 mg, 47.3%)were emitted as HCl-salt, TCX Rf (free base)=0,40 (10% MeOH/CH2Cl2-0,5% Et3N), OBS. m/z=362 [M+23 (Na)].

Amide 5-butylaminoethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Ik

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) of butylamine (15,9 μl, 0,161 mmol)as described in General method X, obtaining Ik (24 mg, 40.3 per cent), emitted as HCl-salt, TCX Rf (free base)=0,20 (10% MeOH/CH2Cl2-0,5% Et3N), OBS. m/z=376 [M+23 (Na)], 354 (M+1).

Amide 3-phenylsulfanyl-5-piperidine-1-ylmethyl-1H-indole-2-carboxylic acid, Il

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) piperidine (33,5 μl, 0,338 mmol)as described in General method X, obtaining Il (30.0 mg, 48.7 per cent)emitted as HCl-salt, TCX Rf (free base)=0,20 (10% 7 N NH3in MeOH/CH2Cl2), OBS. m/z=366,2 (M+1).

Amide 5-pentylamine-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Im

Process amide 5-f is rmil-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) pentylamine (19,6 μl, 0,338 mmol)as described in General method X, Im getting (20.0 mg, 32.2 per cent), emitted as HCl-salt, TCX Rf (free base)=0,20 (10% MeOH/CH2Cl2-0,5% Et3N), OBS. m/z=368 (M+1).

Amide 5-heptylamine-3-phenylsulfanyl-1H-indole-2-carboxylic acid, In

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) heptylamine (22,3 μl, 0,338 mmol)as described in General method X, obtaining In (20.0 mg, 31.1 per cent), emitted as HCl-salt, TCX Rf (free base)=0,20 (10% MeOH/CH2Cl2-0,5% Et3N), OBS. m/z=382 (M+1).

Amide 5-(3-carbamoylbiphenyl-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Io

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) piperidine-3-carboxamide (64,1 mg, 0,338 mmol)as described in General method X, obtaining Io (32,0 mg, 46.4 per cent)emitted as HCl-salt, TCX Rf (free base)=0,10 (10% MeOH/CH2Cl2-0,5% Et3N), OBS. m/z=409 (M+1).

Amide 3-phenylsulfanyl-5-(4-(pyrimidine-2-reparation-1-ylmethyl)-1H-indole-2-carboxylic acid, Ip

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) 2-piperazine-1-elperiodico (101 mg, 0.5 mmol)as described in General method X, obtaining Ip (17,0 mg, 22.6 per cent), leased aemula as HCl-salt, TCX Rf (free base)=0,40 (10% MeOH/CH2Cl2-0,5% Et3N), OBS. m/z=445 (M+1).

Amide 5-[4-(3-phenylpropyl)piperazine-1-ylmethyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iq

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) 1-(3-phenylpropyl)piperazine (118,6 mg, 0.5 mmol)as described in General method X, obtaining Iq (16.0 mg, 19.7 percent)emitted as HCl-salt, TCX Rf (free base)=0,35 (10% MeOH/CH2Cl2-0,25% Et3N), OBS. m/z=483 (M+1).

Tert-butyl ester 4-(2-carbarnoyl-3-phenylsulfanyl-1H-indol-5-ylmethyl)-[1,4]diazepan-1-carboxylic acid, Ir

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (100 mg, 0,338 mmol) Boc-1,4-diazepine (93 mg, 0.5 mmol)as described in General method X, obtaining Ir (96 mg, 59.3 per cent), TCX Rf (free base)=0,45 (10% MeOH/CH2Cl2-0,25% Et3N), OBS. m/z=481 (M+1).

Amide 5-[1,4]diazepan-1-ylmethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Is

Treat Boc-protected indole Ir (62 mg, 0,129 mmol) TFU (2.0 ml) at K.T. for 10 minutes, obtaining Is (53 mg) in the form of TFU-salt, OBS. m/z=381 (M+1).

Amide 5-(bicyclo[2,2,1]hept-2-illuminometer-3-phenylsulfanyl-1H-indole-2-carboxylic acid, It

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) 2-aminona is of borane hydrochloride (18,8 mg, 0,169 mmol)as described in General method X, obtaining It (27 mg, 40.9 percent)emitted as HCl-salt, TCX Rf (free base)=0,8 (10% MeOH/CH2Cl2-0,25% Et3N), OBS. m/z=392 (M+1), 414 (M+Na).

Amide 3-phenylsulfanyl-5-(quinoline-6-illuminometer)-1H-indole-2-carboxylic acid, Iu

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) of 6-aminoquinoline (24,4 mg, 0,169 mmol) as described in General method X, obtaining Iu (6.0 mg, 8.4%)of emitted as HCl-salt, TCX Rf (free base)=0,5 (10% MeOH/CH2Cl2-0,25% Et3N), OBS. m/z=425 (M+1).

Amide 5-[(2-hydroxy-1-hydroxymethyl-1-methylethylamine)methyl]-3-

phenylsulfanyl-1H-indole-2-carboxylic acid Iv

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) 2-amino-2-methyl-1,3-propane diol (50 mg, 0.47 mmol)as described in General method X, obtaining Iv (21,0 mg, 32,3%) as a solid yellow-brown, TCX Rf=0.15 In (10% MeOH/CH2Cl2-0,25% Et3N), OBS. m/z=386 (M+1).

Amide 5-(2-hydroxyethylpyrrolidine-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iw

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,169 mmol) 2-hydroxyethylpyrrolidine (46 mg, 0.45 mmol)as described in General method X, obtaining Iw (42,0 mg, 65.6 per cent) in VI is e solid yellow-brown, TCX Rf=0.15 In (10% MeOH/CH2Cl2-0,25% Et3N), OBS. m/z=382 (M+1).

Amide 5-[(2-hydroxy-1-methyl-ethylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Ix

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) 2-amino-2-propanol (22,3 mg, 0,297 mmol)as described in General method X, obtaining Ix (31,0 mg, 32,3%) in the form of solid ivory, TPL=192,7-193,6°C, TCX Rf=0,10 (10% MeOH/CH2Cl2-0,20% Et3N), OBS. m/z=356 (M+1).

Amide 5-[(2,3-dihydroxypropyl)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iy

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) 1-amino-2,3-propranolol (27,1 mg, 0,297 mmol)as described in General method X, obtaining Iy (31,0 mg, 32,3%) as colourless needles, TCX Rf=0,30 (50% MeOH/CH2Cl2-0,20% Et3N), OBS. m/z=372 (M+1), 394 (M+Na).

Amide 5-(1,4-dioxa-8-Aza-Spiro[4,5]Dec-8-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iz

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) 1,4-dioxa-8-Aza-Spiro[4,5]decane (71,6 mg, 0.50 mmol)as described in General method X, obtaining Iz (51,0 mg, 44.7 per cent) in the form of a solid yellow-brown, TCX Rf=0,35 (10% MeOH/CH2Cl2-0,20% Et3N), OBS. m/z=424 (M+1).

Amide 5-[4-(4-forfinal)piperazine-1-metil]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iaa

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) 1-(4-forfinal)piperazine (90 mg, 0.50 mmol)as described in General method X, obtaining Iaa (69,0 mg, 55.6 per cent) in the form of solid ivory, TCX Rf=0,4 (10% MeOH/CH2Cl2-0,20% Et3N), OBS. m/z=461 (M+1).

Amide 5-[(2-cyano-4,5-dimethoxyaniline)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iab

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,17 mmol) 2-amino-4,5-dimethoxybenzonitrile (89 mg, 0.50 mmol)as described in General method X, obtaining the Iab (28 mg, 36.4 per cent) in the form of solid ivory, TCX Rf=0,1 (2% 7N NH3-MeOH/CH2Cl2), OBS. m/z=481 (M+Na).

Amide 3-phenylsulfanyl-5-[(3-triptoreline)methyl]-1H-indole-2-carboxylic acid, Iac

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,17 mmol) 3-triptoreline (80 mg, 0.50 mmol)as described in General method X, obtaining Iac (36 mg, 48,3%) in the form of solid ivory, TCX Rf=0,5 (5% MeOH/CH2Cl2), OBS. m/z=442 (M+1).

Amide 5-ethylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iad

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) ethylamine guide what uflorida (23.9 mg, 0.30 mmol)as described in General method X, obtaining Iad (53,0 mg, 60.4 per cent) in the form of solid ivory, TCX Rf=0,1 (10% MeOH/CH2Cl2-0,2% Et3N), OBS. m/z=326 (M+1).

Amide 3-phenylsulfanyl-5-propylaminoethyl-1H-indole-2-carboxylic acid, Iae

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) Propylamine hydrochloride (28 mg, 0.30 mmol)as described in General method X, obtaining Iae (41.0 mg, 44.8 percent) in the form of solid ivory, TCX Rf=0,1 (10% MeOH/CH2Cl2-0,2% Et3N), OBS. m/z=340 (M+1).

Amide 5-[(1-carbamoylethyl)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iaf

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,17 mmol) 2-aminopropionic (62.3 mg, 0.50 mmol)as described in General method X, obtaining Iaf (39 mg, 62.9 per cent) in the form of solid ivory, TCX Rf=0,5 (10% MeOH/CH2Cl2-0,2% Et3N), OBS. m/z=369 (M+1).

Amide 5-[(3-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iag

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,17 mmol) 3-methoxyaniline (61,6 mg, 0.50 mmol)as described in General method X, obtaining Iag (26 mg, 37.7 per cent) in the form of solid ivory, TCX Rf Or=0.6 (5% MeOH/CH2Cl2-0,2% Et 3N), OBS. m/z=404 (M+1).

Amide 5-[(4-butylaniline)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iah

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,17 mmol) 4-butylaniline (74 mg, 0.50 mmol)as described in General method X, obtaining Iah (17 mg, 23.4 per cent) in the form of solid ivory, TCX Rf=0.8 In (5% MeOH/CH2Cl2-0,2% Et3N), OBS. m/z=430 (M+1).

Amide 5-[(2-forgenerating)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iai

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (50 mg, 0,17 mmol) 2-fornerino (55 mg, 0.50 mmol)as described in General method X, obtaining Iai (12 mg, 18.2%) is in the form of solid ivory, TCX Rf=0.8 In (5% MeOH/CH2Cl2-0,2% Et3N), OBS. m/z=392 (M+1).

Amide 5-(isopropylaminomethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid, Iaj

Process amide 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) Isopropylamine (19.2 mg, 0.32 mmol)as described in General method X, obtaining Iaj (17 mg, 18.6 per cent) in the form of solid ivory, TCX Rf=0,3 (10% 7N NH3-MeOH/CH2Cl2), OBS. m/z=362 (M+Na).

The compounds of formula I

where m is 0, R2represents NH2, R7is CH2NR8 R9and X is S.

Table 1
Example No.R1R3NR8R9
IaHC6H5NH2
IbHC6H5Boc-NH
IcHC6H5CH3NH
IdH3-F-C6H4CH3NH
IeH3-Cl-C6H4CH3NH
IfHC6H5C6H5CH2NH
IgCH3C6H5CH3NH
IhHC6H5
IiHC6H5
IjHC6H5CH3(CH2)2NH
IkHC6H5CH3(CH2)3NH
IlHC6H5
ImHC6H5CH3(CH2)4NH
InHC6H5CH3(CH2)6NH
IoHC6H5
Ip HC6H5
IqHC6H5
IrHC6H5
IsHC6H5
ItHC6H5
IuHC6H5
IvHC6H5
IwHC6H5
IxH
IyHC6H5
IzHC6H5
IaaHC6H5
IabHC6H5
IacHC6H53-CF3-C6H4NH
IadHC6H5CH3CH2NH
IaeHC6H5CH3(CH2)2NH
IafHC6H5
IagHC6H53-CH3O-C6H4NH
IahHC6H54-CH3(CH2)3-C6H4NH
IaiHC6H52-F-C6H4NH
IajHC6H5(CH3)2CHNH

Obtaining the amides of 6-substituted 3-aristondo-2-carboxylic acid II

(Schemes 2 and 4)

Amide 6-aminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIa, and tert-butyl methyl ether (2-carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)-carbamino acid, IIb

The desired compounds IIa and IIb receive, as described above in the method of synthesis of compounds 11a and 11b in accordance with scheme 2.

Amide 6-(benzylamino)-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIc

Process indole 11b (scheme 4, m=0, R3=Ph) (100 mg, 0.24 mmol) with benzaldehyde (0.8 EQ., 20.4 mg, 0,198 mmol)as described in method IX, obtaining IIc (80 mg, 56.3 per cent) in the form of TFU-with the Lee. TCX free base (12% MeOH/CH2Cl2of-1.0% NH3): Rf=0.40 in, OBS. m/z=388 (M+1).

Amide 6-[(4-nitrobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IId

Treat 11b (scheme 4, m=0, R3=Ph) (175 mg, 0.42 mmol) and 4-nitrobenzaldehyde (0.8 EQ., 50,8 mg, 0,336 mmol)as described in method IX, obtaining IId ((79 mg, 28.7 per cent), emitted as HCl-salt. TCX free base (12% MeOH/CH2Cl2of-1.0% NH3): Rf=0.45, and OBS. m/z=433 (M+1).

Amide 6-[(4-dimethylaminobenzylidene)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIe

Treat 11b (scheme 4, m=0, R3=Ph) (75 mg, 0.18 mmol) 4-dimethylaminobenzaldehyde (0.8 EQ., 21,5 mg, 0.144 mmol), as described in the method IX, obtaining IIe (35 mg, 27.6 per cent)emitted as HCl-salt, TCX free base (12% MeOH/CH2Cl2of-1.0% NH3): Rf=0.45, and OBS. m/z=431 (M+1).

Amide 6-[(4-methylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIf

Treat 11b (scheme 4, m=0, R3=Ph) (100 mg, 0.24 mmol) tolualdehyde (0.8 EQ., 23,8 mg, 0,192 mmol)as described in method IX, obtaining IIf (44 mg, 29,9%), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2of-1.0% NH3): Rf=0.40 in, OBS. m/z=402 (M+1).

Amide 6-[(4-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIg

Treat 11b (scheme 4, m=0, R3=Ph) (100 mg, 0.24 mmol) para-anise aldehyde (0,8 e the century, 26,7 mg, 0,192 mmol)as described in method IX, obtaining IIg (42 mg, 27.5 per cent), emitted as HCl-salt, OBS. m/z=418 (M+1).

Amide 6-[(4-bromobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIh

Treat 11b (scheme 4, m=0, R3=Ph) (100 mg, 0.24 mmol) 4-bromobenzaldehyde (0.8 EQ., 35,9 mg, 0,192 mmol)as described in method IX, obtaining IIh (54 mg, 34.5 per cent)emitted as HCl-salt in the form of a yellow powder, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.50 in, OBS. m/z=466 (M+1).

Amide 6-[(4-chlorobenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIi

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) 4-chlorobenzaldehyde (0.8 EQ., of 30.4 mg, 0,213 mmol)as described in method IX, obtaining IIi (47 mg, 27.7 per cent), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,60, OBS. m/z=422 (M+1).

Amide 6-{[(biphenyl-4-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIj

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) 4-phenylbenzimidazol (0.8 EQ., of 39.2 mg, 0,213 mmol)as described in method IX, obtaining IIj (40 mg, 21.6%), the emitted as HCl-salt, TCX free base (5% MeOH/CH2Cl2-0,25% NH3): Rf=0,20, OBS. m/z=464 (M+1).

Amide 6-[(3-nitrobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIk

Treat 11b (scheme 4, m=0, R3=Ph) (110 is g, 0,266 mmol) of 3-nitrobenzaldehyde (0.8 EQ., 32,5 mg, 0,213 mmol) as described in method IX, obtaining IIk (48 mg, 27.7 per cent), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,55, OBS. m/z=433 (M+1).

Amide 6-[(2-nitrobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIl

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) of 2-nitrobenzaldehyde (0.8 EQ., 32,5 mg, 0,213 mmol)as described in method IX, obtaining IIl (36 mg, 20,8%) as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,55, OBS. m/z=433 (M+1).

Amide 3-phenylsulfonyl-6-[(4-triphtalocyaninine)methyl]-1H-indole-2-carboxylic acid, IIm

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) 4-triftormetilfullerenov (0.8 EQ., of 37.8 mg, 0,213 mmol)as described in method IX, obtaining IIm (50 mg, 27.5 per cent), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.40 in, OBS. m/z=456 (M+1).

Amide 6-[(3-fluoro-5-triphtalocyaninine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIn

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) 3-fluoro-5-triftormetilfullerenov (0.8 EQ., 42.2 mg, 0,213 mmol)as described in method IX, obtaining IIn (38 mg, 20.2 per cent), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.25 in, OBS. m/z=474 (M+1).

Amide 6-[(2-aminophe is ynylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, II ° series

Treat 11b (scheme 4, m=0, R3=Ph) (100 mg, 0.24 mmol) Boc-Ala-OSu (1,10 EQ., the 76.2 mg, 0,266 mmol) as described in method XV, to obtain the Boc-protected product is then treated TFU (5.0 ml, 99%) to obtain the II ° series (78 mg, or 48.2%) in the form of TFU-salt, OBS. m/z=369 (M+1), 391 (M+Na).

Amide 6-[(2-aminoethylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIp

Treat 11b (scheme 4, m=0, R3=Ph) (60 mg, 0,145 mmol) Boc-Gly-OSu (1,10 EQ., to 43.5 mg, 0.16 mmol)as described in method XV, to obtain BOC-protected product is then treated TFU (5.0 ml, 99%) with obtaining IIp (56 mg, 82.3 per cent) in the form of TFU-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,20, OBS. m/z=355 (M+1).

Amide 6-[(2-amino-3-methylpentylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIq

Treat 11b (scheme 4, m=0, R3=Ph) (60 mg, 0,145 mmol) Boc-Ile-OSu (1,10 EQ., 52,5 mg, 0.16 mmol)as described in method VIII, to obtain BOC-protected product is then treated TFU (5.0 ml, 99%) to obtain the IIq (41 mg, 53.9 per cent) in the form of TFU-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.25 in, OBS. m/z=411 (M+1).

1-[(2-Carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)-amide] 5-amide 2-aminopentanedioic acid IIr

Treat 11b (scheme 4, m=0, R3=Ph) (60 mg, 0,145 mmol) of Boc-Gln-OSu (1,10 EQ., 54.9 mg, 0.16 mmol)as described in method XV, to obtain BOC-protected product, then obrabecim the Ute TFU (5.0 ml, 99%) to obtain the IIr (42 mg, 53.8 per cent) in the form of TFU-salt, OBS. m/z=426 (M+1).

Amide 6-{[(2-amino-3-(1H-indol-3-yl)propionamido]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIs

Treat 11b (scheme 4, m=0, R3=Ph) (60 mg, 0,145 mmol) of Boc-Trp-OSu (1,10 EQ., 64,2 mg, 0.16 mmol)as described in method VIII, to obtain BOC-protected product is then treated TFU (5.0 ml, 99%) to obtain the IIs (64 mg, 73,8%) in the form TFU-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.15 in, OBS. m/z=484 (M+1).

Amide 6-[(2-amino-3-phenylpropionylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIt

Treat 11b (scheme 4, m=0, R3=Ph) (60 mg, 0,145 mmol) of Boc-Phe-OSu (1,10 EQ., 58 mg, 0.16 mmol)as described in method XV, to obtain BOC-protected product is then treated TFU (5.0 ml, 99%) to give the IIt (59 mg, 72.8 percent) in the form of TFU-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,20, OBS. m/z=445 (M+1).

Amide 6-[(2-amino-4-methylsulfonylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIu

Treat 11b (scheme 4, m=0, R3=Ph) (60 mg, 0,145 mmol) Boc-Met-OSu (1,10 EQ., of 55.4 mg, 0.16 mmol)as described in method XV, to obtain BOC-protected product is then treated TFU (5.0 ml, 99%) with getting IIu (58 mg, 73,7%) in the form TFU-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,55, OBS. m/z=429 (M+1).

Amide 6-{[(2-methoxyethyl the n-1-ylmethyl)amino]-methyl]}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIv

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) 2-methoxy-1-naphthaldehyde (0.8 EQ., 40,0 mg, 0,213 mmol)as described in method IX, obtaining IIv (48 mg, 35.8 per cent), emitted as HCl-salt, TCX free base (15% MeOH/CH2Cl2-0,25% NH3): Rf=0.15 in, OBS. m/z=468 (M+1).

Amide 6-[(2,4-dimethoxyaniline)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIw

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) of 2,4-dimethoxy-benzaldehyde (0.8 EQ., the 36.1 mg, 0,213 mmol)as described in method IX, obtaining IIw (58 mg, 45%)emitted as HCl-salt, TCX free base (15% MeOH/CH2Cl2-0,25% NH3) Rf=0.15 in, OBS. m/z=448 (M+1).

Amide 6-[(3-phenoxybenzamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIx

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) 3-phenoxybenzaldehyde (0.8 EQ., for 44.4 mg, 0,213 mmol)as described in method IX, obtaining IIx (46 mg, 33.6%), and emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.4, OBS. m/z=480 (M+1).

Amide 6-[(3-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIy

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) 3-methoxybenzaldehyde (0.8 EQ., of 29.9 mg, 0,213 mmol)as described in method IX, obtaining IIy (42 mg, 34.8 per cent), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3 ): Rf=0.25 in, OBS. m/z=418 (M+1).

Amide 6-[(2-methylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIz

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) 2-methylbenzaldehyde (0.8 EQ., 27.7 mg, 0,213 mmol)as described in method IX, obtaining IIz (32 mg, 27.6 per cent)emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,35, OBS. m/z=402 (M+1).

Amide 6-[(3-methylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIaa

Treat 11b (scheme 4, m=0, R3=Ph) (110 mg, 0,266 mmol) 3-methyl-benzaldehyde (0.8 EQ., 27.7 mg, 0,213 mmol) as described in method IX, obtaining IIaa (53 mg, 45.7 percent)emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.4, OBS. m/z=402 (M+1).

Amide 6-[(2-fluoro-3-triphtalocyaninine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIab

Treat 11b (scheme 4, m=0, R3=Ph) (100 mg, 0.24 mmol) 2-fluoro-3-triftormetilfullerenov (1.0 EQ., to 48.5 mg, 0.24 mmol)as described in method IX, obtaining IIab (74 mg, 60.2%), and emitted as HCl-salt, TCX free base (2% MeOH/CH2Cl2-0,25% NH3): Rf=0.3, and OBS. m/z=474 (M+1).

Amide 6-[(2-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIac

Treat 11b (scheme 4, m=0, R3=Ph) (100 mg, 0.24 mmol) 2-methoxy-benzaldehyde (1.0 equiv., of 33.4 mg, 0.24 mmol)as described in Meath is de IX, obtaining IIac (48 mg, 43,8%)emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.40 in, OBS. m/z=418 (M+1).

Amide 6-[(2,6-diaminohexanoic)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIad

Treat 11b (scheme 4, m=0, R3=Ph) (100 mg, 0,242 mmol) Boc-Lys-(Boc)-OSu (i.e. ether lysine-N-hydroxysuccinimide dual N-Boc-protected) (1,10 EQ., 118 mg, 0,266 mmol)as described in method XV, to obtain BOC-protected product is then treated TFU (5.0 ml, 99%) with getting IIad (72 mg, 45.6 percent) in the form of TFU salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,35, OBS. m/z=426 (M+1).

3-amino-N-(2-carbarnoyl-3-phenylsulfanyl-1H-indol-6-ylmethyl)succinamide acid, IIae

Treat 11b (scheme 4, m=0, R3=Ph) (60 mg, 0,145 mmol) Boc-Asp(OtBu)-OSu (1,10 EQ., to 61.8 mg, 0.16 mmol)as described in XV, to obtain BOC-protected product is then treated TFU (5.0 ml, 99%) with getting IIae (52 mg, 68.1 per cent) in the form of TFU-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,55, OBS. m/z=413 (M+1).

Amide 6-{[(10-chloro-anthracene-9-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIaf

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) of 10-chloro-9-anthraldehyde (1.0 EQ., 52,5 mg, 0,218 mmol)as described in method IX, obtaining IIaf (53 mg, 43.6 per cent), emitted as HCl-salt, TCX free base (10%MeOH/CH 2Cl2-0,25% NH3): Rf=0.40 in, OBS. m/z=522 (M+1).

Amide 6-{[(bis-(3-furan-2-Jalil)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIag

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) of TRANS-3-(2-furyl)acrolein (2.0 EQ., of 53.2 mg, 0,436 mmol)as described in method IX, obtaining IIag (28 mg, 23.5 per cent), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.65 is, OBS. m/z=510 (M+1).

Amide 6-[(3,5-dichloro-2-hydroxyethylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIah

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) 2-hydroxy-3,5-dichlorobenzaldehyde (1.0 EQ., to 41.6 mg, 0,218 mmol)as described in method IX, obtaining IIah (37 mg, 33.4 per cent)emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.5, and OBS. m/z=509 (M+1).

Amide 6-[(3-bromo-4,5-dimethoxyphenethylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIai

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) of 3,4-dimethoxy-5-bromobenzaldehyde (1.0 EQ., 54 mg, 0,218 mmol) as described in method IX, obtaining IIai (63 mg, 51,4%), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.5, and OBS. m/z=526 (M+1).

Amide 6-[(4-benzyloxy-3-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIaj

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mm is l) 3-methoxy-4-phenoxybenzaldehyde (1.0 EQ., 53 mg, 0,218 mmol) as described in method IX, obtaining IIaj (60 mg, 49.2%)being emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.5, and OBS. m/z=524 (M+1).

Amide 6-[(3-benzyloxy-4-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIak

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) of 3-benzyloxy-4-methoxybenzaldehyde (1.0 EQ., 53 mg, 0,218 mmol)as described in method IX, obtaining IIak (62 mg, 50.8%), and emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.5, and OBS. m/z=524 (M+1).

Amide 6-{[(5-nitrothiophen-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIal

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) 5-nitro-2-thiophenecarboxaldehyde (1.0 EQ., to 34.3 mg, 0,218 mmol)as described in method IX, obtaining IIal (36 mg, 35%), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,55, OBS. m/z=439 (M+1).

Methyl ester of 4-{[(2-carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)amino]methyl}benzoic acid, IIam

Treat 11b (scheme 4, m=0, R3=Ph) (80 mg, 0,194 mmol) methyl-4-formylbenzoate (1.0 EQ., 31,85 mg, 0,194 mmol) as described in method IX, obtaining IIam (39 mg, 41.9 per cent), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.50 in, OBS. m/z=446 (M+1).

Amide 6-{[(3,3-diphenyl is thylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIan

Treat 11b (scheme 4, m=0, R3=Ph) (80 mg, 0,194 mmol) of β-phenylboric aldehyde (1.0 EQ., to 40.4 mg, 0,194 mmol)as described in method IX, obtaining IIan (28 mg, 27.5 per cent), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.50 in, OBS. m/z=490 (M+1).

Amide 3-phenylsulfonyl-6-[(4-streventname)methyl]-1H-indole-2-carboxylic acid, IIao

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) of TRANS-4-stilbencarboxaldehyde (1.0 EQ., to 45.4 mg, 0,218 mmol) as described in method IX, obtaining IIao (25 mg, 21.8 percent), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,6, OBS. m/z=490 (M+1).

Amide 6-[(2-fluoro-6-triphtalocyaninine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIap

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) of 2-trifluoromethyl-6-vorbesuregen (1.0 EQ., 41.0 mg, 0,218 mmol)as described in method IX, obtaining IIap (22 mg, 19.8 per cent)emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0,6, OBS. m/z=474 (M+1).

Amide 6-{[3-(4-hydroxy-3-methoxyphenyl)allylamino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIaq

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) 4-hydroxy-3-metaxalonum aldehyde (1.0 EQ., to 38.8 mg, 0,218 mmol)as described in method IX, obtaining IIaq (20 mg, 18.5 per cent), emitted as HCl-is Oli, OBS. m/z=490 (M+1).

Amide 6-({[5-(2-chlorophenyl)-furan-2-ylmethyl]amino}methyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIar

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) 5-(2-chloro-phenyl)furfural (1.0 EQ., 45 mg, 0,218 mmol)as described in method IX, obtaining IIar (28 mg, 24.6 percent), emitted as HCl-salt, OBS. m/z=488 (M+1).

Amide 6-{[(1-benzoylphenyl-1H-pyrrol-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIas

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) 1-(phenylsulfonyl)-2-errorcollection (1.0 EQ., 51.3 mg, 0,218 mmol)as described in method IX, obtaining IIas (53 mg, 44%)emitted as HCl-salt, OBS. m/z=517 (M+1).

Amide 6-{[bis-(5-nitrofuran-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIat

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) 5-nitro-2-furaldehyde (2.0 EQ., 61,5 mg, 0,436 mmol)as described in method IX, obtaining IIat (22 mg, 17.3 per cent), emitted as HCl-salt, OBS. m/z=548 (M+1).

Amide 6-{[(5-nitrofuran-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, IIau

Treat 11b (scheme 4, m=0, R3=Ph) (90 mg, 0,218 mmol) 5-nitro-2-furaldehyde (1.0 EQ., 31 mg, 0,218 mmol)as described in method IX, obtaining IIau (43 mg, 43.1 per cent), emitted as HCl-salt, TCX free base (10% MeOH/CH2Cl2-0,25% NH3): Rf=0.5 OBS. m/z=423 (M+1).

Table 2

The compounds of formula II

where m is 0, R2represents NH2, R7is CH2NR8R9and X is S.

3-F-5-CF3-C6H4CH2NHtr>
Example No.R1R3NR8R9
IIaHC6H5NH2
IIbHC6H4Boc-NH
IIcHC6H4C6H5CH2NH
IIdHC6H54-O2N-C6H4CH2NH
IIeHC6H54-(CH3)2N-C6H4CH2NH
IIfHC6H54-CH3-C6Hsub> 4CH2NH
IIgHC6H54-CH3O-C6H4CH2NH
IIhHC6H54-Br-C6H4CH2NH
IIiHC6H54-Cl-C6H4CH2NH
IIjHC6H54-C6H5-C6H4CH2NH
IIkHC6H53-O2N-C6H4CH2NH
IIlHC6H52-O2N-C6H4CH2NH
IImHC6H54-CF3-C6H4CH2NH
IInHC6H5
II ° seriesHC6H5CH3CH(NH2)C(=O)NH
IIpHC6H5H2NCH2C(=O)NH
IIqHC6H5
IIrHC6H5
IIsHC6H5
IItHC6H5
IIuHC6H5
IIvHC6H5
IIwHC6H52,4-(CH3O)2-C6H3CH2NH
IIxHC6H53-C6H5O-C6H4CH2NH
IIyHC6H53-CH3O-C6H4CH2NH
IIzHC6H52-CH3-C6H4CH2NH
IIaaHC6H53-CH3-C6H4CH2NH
IIabHC6H52-F-3-CF3-C6H4CH2NH
IIacHC6H52-CH3O-C6H4CH2NH
IIadHC H5
IIaeHC6H5
IIafHC6H5
IIagHC6H5
IIahHC6H53,5-(Cl)2-2-OH-C6H4CH2NH
IIaiHC6H53-Br-4,5-(CH3O)2-C6H4CH2NH
IIajHC6H54-C6H5CH2O-3-CH3-C6H4CH2NH
IIakHC6H53-C6H5CH2O-4-CH3-C6H4CH2NH
IIalHC6H5
IIamHC6H5
IIanHC6H5(C6H5)2C=CCH2NH
IIaoHC6H5
IIapHC6H52-F-6-CF3-C6H4CH2NH
IIaqHC6H5
IIarHC6H5
IIasHC6H5
IIatHC6H5
IIauHC6H5

Biological examples

Analysis filtering caseinline Epsilon33P-ATP for screening inhibitors CK1ε

Objective: In this analysis measures the ability of compounds to inhibit the phosphorylation of the substrate of casein by the enzyme Caseinate 1ε using analysis filter33P-ATP in vitro. Compounds were tested at five concentrations twice in order to determine the values of the IC50or % inhibition at 10 μm concentration, which is given in table 3.

Materials:

Equipment:

Laboratory robot for liquids Beckman Biomek 2000

Automated 96-channel pipette Beckman Multimek 96

Vacuum Millipore manifold base kit #MAVM0960R

The dosing of liquids Titertek Multidrop

Liquid scintillation counter Packard TopCount NXT

Tablets:

Tablet Costar EIA/RIA #9018

Polystyrene plate with 96 cells and U-shaped bottom Falcon #353910

Filtration tablets with 96 cells Millipore Multiscreen

#MAPHNOB50

Adapter tablets Millipore Multiscreen TopCount #E3M203V6

Chemical reagents:

EGTA, supplier SIGMA #E-3889

Casein (dephosphorylating)supplier SIGMA #C-4032

ATP, supplier SIGMA #A-7699

DTT, supplier Fisher Biotech #BP1725

Trichloroacetic acid, supplier SIGMA #T-6399

γ33P-ATP MCI / 37 MBq, supplier Perkin Elmer Life Sciences #NEG-602H

Enzymes:

Caseinline 1ε at a final concentration of 0.58 mg/ml, obtained by fermentation and purification, which are well known to specialists in this field. Is stored in the form of a 100 ál aliquot at minus 80oC.

Connection:

Compounds for analysis are supplied in the form of frozen initial solutions with a concentration of 10 mm in 100% DMSO.

Condition analysis:

The final total of the analyzed volume of one cell, which is equal to 50 μl, was obtained as follows:

5 µl of the diluted original solution of the compound (10, 1, 0.1 or 0.01 or 0.001 in microns),

5 ál dephosphorylating casein with a final concentration of 0.2 µg/µl,

20 μl of CK1ε with a final concentration of 3 ng/µl and

20 μl of γ-33P-ATP to a final concentration of 0.02 µci/µl, mixed with non-radioactive ATP (final concentration 10 μm).

Methods:

Prepare 500 ml of fresh buffer for analysis: 50 mm Tris pH 7.5, 10 mm MgCl2, 2 mm DTT and 1 mm EGTA.

Get connection for the analysis in the form 10 μl of 10 mm initial solution in 100% DMSO. With the help of a robot for liquids Biomek 2000 receive consistent is assaulte with final dilutions of substances 10, 1, of 0.1, 0.01 and 0.001 mm, which is added in an amount of 5 μl into tablets with a U-shaped bottom of the Falcon. Normally tested 8 connections on one tablet with 96 cells, using as a reference the rows of cells 1 and 12. Usually in the screening take 32 connection, which is equivalent to 4 analytical tablets.

Maps analytical tablet prepared in accordance with the following structure CK1ePlateMap.xls

Add 5 ál of the specified connection, then add 5 ál dephosphorylating casein (dissolved in distilled H20) (0.2 ág/ál) and 20 μl of CK1ε (3 ng/μl) into the corresponding cell.

Finally, add 20 ál of γ-33P-ATP (of 0.02 µci/µl)/10 μm non-radioactive ATP (which is approximately 2×106pulse/min per cell).

Shake analytical tablet with a U-shaped bottom of the Falcon, in cells containing the indicated reaction mixture volume of 50 µl, shaker Vortex and then incubated at room temperature for 2 hours.

After 2 hours, stop the reaction by adding 65 μl of ice-cold 2 mm non-radioactive ATP (prepared in analytical buffer) in cell analytical tablets using a pipette Beckman Multimek.

At the same time add 25 ál of 100% ice-cold TCA (trichloroacetic acid) in distilled H2O in the corresponding number of filtration tablet Millipor MAPH.

Using manual 8-channel dispenser, transfer 100 ál of the reaction mixture from cells in tablets with a U-shaped bottom Falcon in cell filtration tablet Millipore MAPH, pre-treated TCA.

Mix carefully filtration tablets Millipore MAPH and leave at room temperature for a period of not less than 30 minutes to precipitate the protein.

After 30 minutes of filtration placed the tablets in the vacuum manifold Millipore and filtered at a pressure not higher than 8 mm RT. Art. because the filters MAPH at higher pressure occurs air lock.

Filtration tablets consistently washed and filtered 2×150 μl of 20% TCA, 2×150 μl of 10% TCA and 2×150 μl of 5% TCA (total of 6 washes on the tablet/900 ál of the cell).

Leave the tablets to dry over night at room temperature. The next day, add 40 μl of scintillation fluid Packard Microscint-20 to a cell with dispenser Titertek Multidrop; sealed tablets and measure radioactivity (2 min per cell) on the scintillation counter Packard Topcount NXT (thus obtaining the values of the pulse/min per cell).

Calculations:

1. Register and enter the data, expressed in counts/min, to a specialized calculation base and archive data (Activity Base supplied IDBS version 5.0).

2. Column 1 in each tablet reflects the overall activity of phosphorylation of the enzyme in the absence of any Inga is youseo connection and therefore corresponds to 100%. Column 12 reflects any non-specific phosphorylation activity/residual radioactivity in the absence of inhibitory compounds and enzyme. Typically, there is about 1% of the total number of pulses per minute, which are non-specific.

3. Defining "full" and "nonspecific" number of pulses per minute for each tablet, you can set the % inhibition of the enzyme ability to fosforilirovanii substrate at each concentration of test compound. Such % inhibition data used to calculate the magnitude IC50(the concentration at which a compound able to inhibit the enzyme activity by 50%) for connection using a modeling nonlinear dependencies included in the Protocol calculations Activitybase (DG0027-CK1-D-BL).

4. Kinetic studies in this analytical system showed that the value of Kmfor ATP is 21 μm.

Analysis activity caseinline 1δ against the membrane affinity of streptavidin for CKIδ inhibitors. Purpose:

Evaluation of test compounds for activity CKIδ in tablets for the analysis of streptavidin-bitenova membrane affinity (SAM) (Promega V7542)

Materials and reagents

HEPES Sigma #H3375 MV=238,3; β-glycerol Sigma #G-9891 MV=216,0; 0.5 M EDTA, pH 8.0 GibcoBRL; orthovanadate sodium ACROS #205330500 MV=183,9; DTT (DL-dimitre the tol) Sigma #D-5545 MV=154,2; magnesium chloride ACROS #41341-5000 MV=203,3; ATP Sigma #A-7699 MV=551,1; γ33P ATP NEN # NEG602H; caseinline 1δ Sigma #C4455; substrate caseinline 1 New England Peptide Biotin-RRKDLHDDEEDEAMSITA MV=2470

Buffer for kinase (KV, 100 ml) is prepared as follows:

50 mm HEPES, pH 8.0 5 ml 1M source solution

10 mm MgCl and 1 ml 1M source solution

10 mm β-glycerol 1 ml 1M source solution

2.5 mm EDTA 500 ál 500 mm source solution

1 mm orthovanadate sodium 100 μl of 1M source solution

1 mm DTT and 100 ál of 1 M source solution

water was 92.3 ml

The basic mixture of ATF as follows:

receive 1 ml of 1M solution of ATP in water (1M source solution ATP).

To 12 ml of KB:

add 12 ál of 1M solution of ATP, then

add 12 ál33P ATP (10 µci/µl), NEG602H, Perkin Elmer

Get reaction to the tablet and carry out the analysis as follows:

1) add 10 ál of KB in a cell with a test inhibitory compound or without him in the cell reaction tablets;

2) add 60 ál KB per cell;

3) add 10 μl of 500 μm peptide substrate in the cell;

4) bring the temperature of the tablets to the 37oC;

5) add 10 μl diluted 1:10 CK1δ per cell=0,42 mg, or of 0.68 units;

6) initiate reaction by adding 10 ál of the basic mixture of ATP in the cell;

7) place the reaction plate in an incubator at 37oC for 10 min;

8) stop the reaction, 10 μl of 1M And The F. Transfer 20 ál in the tablet SAM and incubated for 10 min at room temperature;

9) are washed three times with 100 μl of 2M NaCl solution, then three times with 100 μl of 2M NaCl and 1% solution of H3PO4and then three times with 100 ál of water on the vacuum manifold;

10) dry filtration tablet under the lamp for 30 min;

11) seal the bottom of tablets and add 20 μl of MicroScint 20;

12) read using a TOPCOUNT.

Experimental methods cell analysis of circadian rhythm

Cell culture: Cause of fibroblast cultureMper1-lucRat-1 (P2C4) every 3-4 days (confluently ~10-20%) 150 cm2ventilated polystyrene mattresses for the cultivation of tissues (Falcon #35-5001) and incubated in culture medium [EMEM (Cellgro #10-010-CV); 10% fetal bovine serum (FBS; Gibco #16000-044); and 50% act./ml penicillin-streptomycin (Cellgro #30-001-C1)] at 37°C and 5% CO2. The data are shown in table 3.

Stable transfection of: jointly transfection of fibroblast cultures Rat-1 confluently 30-50% with vectors containing a selective marker for resistance to zeocin for stable transfection and promoted reporter gene luciferase mPer-1. After 24-48 hours, the culture is transferred into a 96-cell plates and incubated in culture medium with the addition of 50-100 µg/ml zeocin (Invitrogen #45-0430) within 10-14 days. Assess reportprogress resistant zeocin stable transfectants by adding to the culture medium of 100 μm of luciferin (Promega #E1603) and analyzing the luciferase activity on a TopCount scintillation counter (Packard Model #C384V00). Synchronize clones of Rat-1, demonstrating resistance to zeocin and the luciferase activity determinedmPer1, anaphylactic shock, adding 50% horse serum [HS (Gibco #16050-122)] and assessing the activity of the circadian reporter. For testing compounds chosen fibroblastsMper1-lucRat-1 clone P2C4.

The synchronization Protocol: Transfer fibroblastsMper1-lucRat-1 (P2C4) (confluently 40-50%) in opaque 96-cell tablets for tissue cultures (PerkinElmer #6005680) and incubated in culture medium with the addition of 100 μg/ml of zeocin (Invitrogen #45-0430), until the culture reached 100% confluentes (48-72 h). Synchronizat culture 100 µl of the synchronization medium [EMEM (Cellgro #10-010-CV); 100% act./ml penicillin-streptomycin (Cellgro #30-001-C1); 50% HS (Gibco #16050-122)] for 2 hours at 37°C and 5% CO2. After synchronization, the culture was washed with 100 μl of EMEM (Cellgro #10-010-CV) for 10 minutes at room temperature. After washing replace environment 300 ál of CO2-independent environment [CO2I (Gibco #18045-088); 2 mm L-glutamine (Cellgro #25-005-C1); 100% act./ml penicillin-streptomycin (Cellgro #30-001-C1); 100 μm of luciferin (Promega #E1603)]. Add a connection test on the subject of circadian effect, to CO2-independent environment in 0.3% DMSO (final concentration). Immediately seal culture film TopSeal-A (Packard #6005185) and transferred for measuring the activity of luciferase.

The car is Tserovani measuring circadian reporter: After synchronization stored analytical tablets at 37°C in a tissue culture incubator (Forma Scientific Model #3914). Evaluate the luciferase activity in vivo, by measuring the relative light output on the scintillation counter TopCount (Packard Model #C384V00). Carry the tablets from the incubator into the card reader using the robotic arm ORCA (Beckman Instruments) and software for automated regulation SAMI-NT (version 3.3; SAGIAN/Beckman Instruments).

Data analysis: Using Microsoft Excel and XLfit (2.0.9; IDBS) for import, processing and displaying data graphically. Analyze periods, or by defining the interval between sootvetstvuyuschimi the minimum light output for several days, either through a Fourier transform. Both methods allow you to get almost the same assessment period for the entire range of circadian periods. Lead activity as ECΔt+1hthat is an effective micromolar concentration that causes a 1-hour extension period. Analyze the data, approximating a hyperbolic curve data, expressed as the change period (y-axis) against the concentration of test compounds (x-axis) in XLfit and interpolating ECΔt+1hfrom this curve.

Analysis of the circadian cycle in rats

This analysis allows to assess the effect of test compounds on the circadian cycle in vivo. The study involves the use of male rats of Wistar breed (Charles River) with an initial body weight of 200-250 g Pre is de proceeding to testing in a controlled environment, each animal is placed individually, and then support thermoneutral ambient temperature in the range of 24-28°C for 12/12 hours (h) day/night cycle (lights on at 06:00 h) and give unlimited amount of standard laboratory feed and water. Each rat implanted intraperitoneal telemetry transmitter (Minnimitter-VMFH, series 4000, Sunriver, OR) for basic monitoring of body temperature and General activity. Each transmitter implanted in accordance with the manufacturer's recommendations under General anesthesia ketamine/xylazine (78/13 mg kg-1, intraperitoneally) and give the animals to recover for 7-10 days. To determine the internal circadian cycle each individual after the recovery period, animals are moved to permanent night cycle (cycle 0/24 h, day/night) and give animals the ability to move freely within 7-10 days prior to injection of the test compounds. In accordance with the scheme of dosing animals receive either the media or the connection (intraperitoneally, subcutaneously or orally) at specific points in black (stradneri time) during the 48-hour period. After the implementation of the scheme dosing for animals is installed surveillance for 5-7 days at a constant night cycle (0/24 hour day/night cycle). For each experiment recorded the abdominal temperature and Dann the e of the total activity in 5-minute intervals. For analysis using VitalView software and Actiview supplied Minimitter. Build a schedule registered abdominal temperatures obtained for each rat on the first day on the horizontal line. Combine line observed abdominal temperatures with the abscissa circadian time (x-axis). Lay logged abdominal temperature for each subsequent day as a separate line in the same way with getting the ordinate (y axis, days). Connect the initial growth of core body temperature, which is monitored daily by a straight line that allows you to use several days to assess circadian phase in any given day for any given rat. Determine the impact of the introduction of the preparation phase, conducting a straight line in a few days for the evaluation phase before and after the dose. The treatment of active compound will cause more noticeable offset between a straight line connecting the initial daily the growth of core body temperature prior to the introduction of connection, and a straight line connecting the initial growth of core body temperature after administration of the compounds, relative to the control lines of the introduction of media before and after injection. For experimental animals calculates the difference between these phases, extrapolated on the day before injection. Using the ANOVA test, along with t-student test for the CSOs to compare circadian changes in mean body temperature in minutes between groups.

Table 3
Biological data
Conn. No.Analysis filtering caseinline Iε33P-ATF
Ki(µm)
(*means the average of 2 or more definitions)
Cell analysis
ECΔτ+1h(µm)
Ia0,070,44
Ib
Ic0,14*
Id0,145,67
Ie0,343,34
If0,71
Igof 4.45
Ih1,74
Ii0,24
Ij0,0 *
Ik0,093
Il0,88
Im0,0644,55
In0,115,11
Io≈10
Ip0,0741,87
Iq0,31>3
Ir0,13>10
Is0,12*the 7.85
It0,452,70
Iu0,60
Iab>10
Iac≈10
Iad 0,09
Iae0,58
Iaf0,39
Iag2,23
Iah4,28*
Iai6,856,91
Iaj0,54
IIa0,097
IIb2,33
IIc0,72
IId0,47
IIe0,73
IIf0,81
IIg0,52
IIh0,74
IIi0,39
IIj1,39
IIk1,19
IIl1,77
IIm4,88
IIn4,99
II ° series0,17
IIp0,12
IIq0,15
IIr0,27
IIs0,1
IIt1,28
IIu
IIv1,01
IIw0,29
IIx1,19
IIy0,38
IIz0,57
IIaa0,46
IIab4,04
IIac0,24
IIad0,11*
IIae0,78
IIafa 4.83
IIag6,92
IIah3,50
IIai0,60
IIaj2,10
IIak 0,64
IIal1,21
IIam2,42
IIan>10,0
IIao>10,0
IIap>10,0
IIaq0,14
IIar2,54
IIas6,25
IIat>10,0
IIau0,70

1. The compound of formula I or formula II, or its pharmaceutically acceptable salt,

where X is S;
R1represents H or C1-With6alkyl;
R2is NR5R6;
R3is aryl, substituted with halogen;
R4to depict the defaults to N;
R5represents H;
R6represents H;
R7is CH2NR8R9,
where
R8represents H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl, heterocycle(C2-C6alkenyl), hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbarnoyl(C1-C6alkyl);
where the above "aryl" represents an aromatic ring, and unsubstituted or substituted one to three surrogate groups, each of which is independently selected from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, triptoreline, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl),
dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy),
R9represents H, C1-C10alkyl, heterocycle (C1-C6alkyl), or heterocycle (C2-C6alkenyl);
where specified is use "heterocyclyl" means a 5-membered saturated monocyclic ring system, consisting of carbon atoms and also containing heteroatoms selected from the group N, O and S, which may be unsubstituted or have from one to three alternative groups, independently selected from the list including the NO2, aryl(C1-C6alkyl), arylsulfonyl;
or R8and R9together with the nitrogen to which they are attached, form a heterocycle, which means consisting of 5-7 members saturated monocyclic ring system consisting of carbon atoms and containing one to three heteroatoms selected from the group N, O and S, which may be unsubstituted or have from one to three alternative groups, independently selected from the list including1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidine-2-yl; and
m is 0.

2. The compound of formula I or formula II according to claim 1, where R2represents NH2.

3. The compound of formula I or formula II according to claim 1, where R1is1-C6alkyl.

4. The compound of formula I according to claim 3, where the connection submitted is an amide 1-methyl-5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

5. The compound of formula I or formula II according to claim 1, where R1is N.

6. The compound of formula I according to claim 5, where R8represents H, C1-C10alkyl, C3-C8cycloalkyl, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl or C1-C6alkoxycarbonyl, and R9is N.

7. The compound of formula I according to claim 6, selected from the group comprising: amide 5-aminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid tert-butyl ether (2-carbarnoyl-3-phenylsulfanyl-1H-indol-5-ylmethyl)-carbamino acid,
amide 5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 3-(3-chlorophenylsulfonyl)-5-methylaminomethyl-1H-indole-2-carboxylic acid,
amide 3-(3-perpenicular)-5-methylaminomethyl-1H-indole-2-carboxylic acid,
amide 3-phenylsulfanyl-5-propylaminoethyl-1H-indole-2-carboxylic acid,
amide 5-butylaminoethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-pentylamine-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-heptylamine-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-(bicyclo[2,2,1]hept-2-illuminometer-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-[(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-[(2-hydroxy-1-methyl-ethylamino)methyl]-3-finals lpanel-1H-indole-2-carboxylic acid,
amide 5-[(2,3-dihydroxypropyl)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-ethylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 3-phenylsulfanyl-5-propylaminoethyl-1H-indole-2-carboxylic acid and
amide 5-(isopropylaminomethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

8. The compound of formula I according to claim 5, where R8represents aryl, aryl(C1-C6alkyl) or carbarnoyl(C1-C6alkyl) and R9is N.

9. The compound of formula I of claim 8, selected from the group comprising: amide 5-(benzylamino)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 3-phenylsulfanyl-5-(quinoline-6-illuminometer)-1H-indole-2-carboxylic acid,
amide 5-[(2-cyano-4,5-dimethoxyaniline)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 3-phenylsulfanyl-5-[(3-triptoreline)methyl]-1H-indole-2-carboxylic acid,
amide 5-[(1-carbamoylethyl)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-[(3-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-[(4-butylaniline)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid, and
amide 5-[(2-forgenerating)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

10. The compound of formula I according to claim 5, where R8and R9together with the nitrogen to which they are attached, form a Goethe is Ozil.

11. The compound of formula I of claim 10, selected from the group comprising: amide 5-(4-hydroxyethylpiperazine-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-morpholine-4-ylmethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 3-phenylsulfanyl-5-piperidine-1-ylmethyl-1H-indole-2-carboxylic acid,
amide 5-(3-carbamoylbiphenyl-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 3-phenyl effect-free remedy 5-(4-(pyrimidine-2-yl-piperazine-1-ylmethyl)-1H-indole-2-carboxylic acid,
amide 5-[4-(3-phenylpropyl)piperazine-1-ylmethyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
tert-butyl ester 4-(2-carbarnoyl-3-phenylsulfanyl-1H-indol-5-ylmethyl)-[1,4]diazepan-1-carboxylic acid,
amide 5-[1,4]diazepan-1-ylmethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-(2-hydroxymethyl-pyrrolidin-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 5-(1,4-dioxa-8-Aza-Spiro[4,5]Dec-8-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid and
amide 5-[4-(4-forfinal)piperazine-1-ylmethyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

12. The compound of formula II according to claim 5, where R8represents H, C1-C10alkyl, aryl(C1-C6alkyl, heterocycle(C1-C6alkyl) or (C1-C6alkoxycarbonyl, and R9represents H or a heterocycle(C1-C6alkyl).

13. The connection forms of the crystals II indicated in paragraph 12, selected from the group comprising: amide 6-aminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid tert-butyl ether(2-carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)-carbamino acid,
amide 6-(benzylamino)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(4-nitrobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(4-dimethylaminobenzylidene)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(4-methylbenzylamino)methyl]-3-phenylsulfanyl-1 H-indole-2-carboxylic acid,
amide 6-[(4-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(4-bromobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(4-chlorobenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-{[(biphenyl-4-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(3-nitrobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(2-nitrobenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 3-phenylsulfonyl-6-[(4-triphtalocyaninine)methyl]-1H-indole-2-carboxylic acid,
amide 6-[(3-fluoro-5-triphtalocyaninine)methyl]-3-phenyl effect-free remedy 1H-indole-2-carboxylic acid,
amide 6-{[(2-methoxynaphthalene-1-ylmethyl)amino]-methyl]}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(2,4-DIMET is cibenzoline)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(3-phenoxybenzamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(3-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(2-methylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(3-methylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(2-fluoro-3-triphtalocyaninine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(2-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-{[(10-chloro-anthracene-9-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(3,5-dichloro-2-hydroxyethylamino)methyl]-3-phenyl effect-free remedy 1H-indole-2-carboxylic acid,
amide 6-[(3-bromo-4,5-dimethoxyphenethylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(4-benzyloxy-3-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(3-benzyloxy-4-methoxybenzylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-{[(5-nitrothiophen-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
methyl ester of 4-{[(2-carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)amino]methyl}benzoic acid,
amide 3-phenylsulfonyl-6-[(4-streventname)methyl]-1H-indole-2-carboxylic acid,
amide 6-[(2-fluoro-6-triphtalocyaninine)methyl]-3-f is ylsulphonyl-1H-indole-2-carboxylic acid,
amide 6-({[5-(2-chlorophenyl)-furan-2-ylmethyl]amino}methyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-{[(1-benzoylphenyl-1H-pyrrol-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-{[bis-(5-nitrofuran-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid, and
amide 6-{[(5-nitrofuran-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

14. The compound of formula II according to claim 1, selected from the group comprising: amide 6-[(2-aminodiphenylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(2-aminoethylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(2-amino-3-methylpentylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
1-[(2-carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)-amide] 5-amide 2-aminopentanedioic acid,
amide 6-{[(2-amino-3-(1H-indol-3-yl)propionamido]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(2-amino-3-phenylpropionylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(2-amino-4-methylsulfonylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-[(2,6-diaminohexanoic)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid and
3-amino-N-(2-carbarnoyl-3-phenylsulfanyl-1H-indole-6-ylmethyl)succinamide acid.

15. The compound of formula II according to claim 5, where R8 represents aryl(C2-C6alkenyl), heterocycle(C2-C6alkenyl), and R9represents H or a heterocycle(C2-C6alkenyl).

16. The compound of formula II according to § 15 selected from the group comprising: amide 6-{[(bis-(3-furan-2-Jalil)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid,
amide 6-{[(3,3-diphenylethylamine)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid and
amide 6-{[3-(4-hydroxy-3-methoxyphenyl)allylamino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid.

17. Pharmaceutical composition having the properties of an inhibitor caseinline Iε containing a pharmaceutically acceptable carrier and a compound of formula I or formula II according to claim 1, or its pharmaceutically acceptable salt.

18. The inhibitor caseinline Iε, where the inhibitor is a compound of formula I or formula II according to claim 1, or its pharmaceutically acceptable salt, to obtain a pharmaceutical composition for inhibiting the activity caseinline Iε.

19. Use p, where the aforementioned inhibition activity caseinline Iε leads to a lengthening of the period of circadian rhythm.

20. The use of the compounds of formula I or formula II, or pharmaceutically acceptable salts, optionally in combination with one or more pharmaceutically acceptable carriers, diluents or fillers for ing is berbania activity caseinline Iε:

where
X represents S;
R1represents H or C1-With6alkyl;
R2is NR5R6;
R3is aryl, substituted with halogen;
R4represents H;
R5represents H;
R6represents H;
R7is CH2NR8R9,
where
R8represents H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl, heterocycle(C2-C6alkenyl), hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbarnoyl(C1-C6alkyl);
where the above "aryl" represents an aromatic ring, and unsubstituted or substituted one to three surrogate groups, each of which is independently selected from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, triptoreline, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, f the Nile(C 1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy),
R9represents H, C1-C10alkyl, heterocycle(C1-C6alkyl), or heterocycle(C2-C6alkenyl);
where the above "heterocyclyl" means a 5-membered saturated monocyclic ring system consisting of carbon atoms and also containing heteroatoms selected from the group N, O and S, which may be unsubstituted or have from one to three alternative groups, independently selected from the list including the NO2, aryl(C1-C6alkyl), arylsulfonyl;
or R8and R9together with the nitrogen to which they are attached, form a heterocycle, which means consisting of 5-7 members saturated monocyclic ring system consisting of carbon atoms and containing one to three heteroatoms selected from the group N, O and S, which may be unsubstituted or have from one to three alternative groups, independently selected from the list including1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2With(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl) aryl(C 2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidine-2-yl; and
m is 0.

21. The application of claim 20, where the aforementioned inhibition activity caseinline Iε leads to a lengthening of the period of circadian rhythm.

22. The use of the compounds of formula I or formula II, or pharmaceutically acceptable salts, optionally in combination with one or more pharmaceutically acceptable carriers, diluents or fillers, to obtain pharmaceutical compositions to treat patients suffering from diseases or disorders in which inhibition of the activity caseinline Iε leads to improvement:

where X is S;
R1represents H or C1-With6alkyl;
R2is NR5R6;
R3is aryl, substituted with halogen;
R4represents H;
R5represents H;
R6represents H;
R7is CH2NR8R9,
where
R8is H1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl, heterocycle(C2-C6alkenyl), hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), C1-C6 alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbarnoyl(C1-C6alkyl);
where the above "aryl" represents an aromatic ring, and unsubstituted or substituted one to three surrogate groups, each of which is independently selected from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, triptoreline, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy),
R9represents H, C1-C10alkyl, heterocycle (C1-C6alkyl), or heterocycle(C2-C6alkenyl);
where the above "heterocyclyl" means a 5-membered saturated monocyclic ring system consisting of carbon atoms and also containing heteroatoms selected from the group N, O and S, which may be unsubstituted or have from one to three alternative groups, independently selected from the list including the NO2, aryl(C1-C6alkyl), arylsulfonyl;
or R8and R9together with the nitrogen to which they are attached, form a is a heterocycle, which means consisting of 5-7 members saturated monocyclic ring system consisting of carbon atoms and containing one to three heteroatoms selected from the group N, O and S, which may be unsubstituted or have from one to three alternative groups, independently selected from the list including1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2With(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidine-2-yl; and
m is 0.

23. The application of article 22, where the aforementioned inhibition activity caseinline Iε leads to a lengthening of the period of circadian rhythm.

24. The application of article 22, where the disease or disorder is a mood disorder or a sleep disorder.

25. The application of paragraph 24, where the disorder is a mood disorder.

26. Use A.25 where a mood disorder selected from the group consisting of a depressive disorder or bipolar disorder.

27. Use p, where depressive disorder is a severe depressive disorder.

<> 28. Use A.25 where a mood disorder is a bipolar disorder.

29. Use p, where bipolar disorder is selected from the group consisting of bipolar disorder type I and bipolar II disorder.

30. The application of paragraph 24, where the disorder is a sleep disorder.

31. The application of article 30, where the sleep disorder is a disorder of the circadian rhythm of sleep.

32. Use p, where the disorder circadian rhythm sleep is chosen from the group consisting of sleep disorders in shift work syndrome desynchronize when travelling, syndrome of premature sleep phase syndrome and delayed sleep phase.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds -(Z)-1'-R-6',6'-dimethyl-3-(phenyl(arylamino)methylene)-6',7'-dihydro-3H-spiro[furane-2,3'-indol]-2',4,4',5(1'H,5'H)-tetraons of formula: , where Ar=phenyl, n-methoxyphenyl, n-tollyl; R=allyl, benzyl, phenyl, n-tollyl, n-methoxyphenyl, α-naphtyl, as well as to method of their obtaining, which consists in the following: isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates are subjected to interaction with N-substituted 3-amino-5,5-dimethylcyclohex-2-enons in medium of inert aprotonic solvent with further separation of target products. Process is carried out at temperature 20-22°C. As solvent, absolute chloroform is used.

EFFECT: obtaining compounds possessing analgesic activity.

4 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds, and more specifically to 5-formyl-substituted indoline spirobenzopyrans with general formula 1 where R1, R2 - Alk or c-Alk; R3 -CHO or NO2 group (electron-acceptor substitute), with photochromic properties. The invention also relates to the method of producing 5-formyl substituted derivatives of indoline spirobenzopyrans with formula 1. Spirobenzopyrans, which have electron-acceptor substitutes in the pyran part of the molecule, are subjected to direct selective formylation in position 5 in a trifluoroacetic acid medium with urotropine (hexamethylenetetramine) at boiling point of the mixture in an inert atmosphere for 1-1.5 hours. The obtained 5-formyl-substituted spirobenzopyrans are photochromic compounds are photochromic and can be used for making new photochromic materials (recording devices or information storage; photo-switching activity of biological objects and polymer matrices, complex formation; information security media, maps, special document protection equipment) or as advanced initial compounds for further synthesis of a large number of new photochromic objects.

EFFECT: wider field of application of the compounds.

2 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): their using (variants) for preparing a drug used in treatment of diseases modulation of activity of chemokine receptors is useful, and to a pharmaceutical composition modulating chemokine receptors and comprising abovementioned compound. In compound of the formula (I) m = 0 or 1; R1 means halogen atom; X, Y and Z represent independently a bond, -CH2- or -O-, or X and Y form in common -CH=C(CH3)- or -C(CH3)=CH- under condition that only one radical among X, Y and Z can represents a bond, and under condition that X and Y both don't represent -O- simultaneously; n = 0, 1 or 2; R2 represents halogen atom, or (C1-C6)-alkyl; q = 0 or 1; R3 represents -NHC(O)R10, -C(O)NR11R12 or -COOR12a; each radical among R4, R5, R6, R7 and R8 represents independently hydrogen atom (H) or (C1-C6)-alkyl; t = 0, 1 or 2; R9 represents halogen atom, -OH, -COOH, (C1-C6)-alkoxy group, (C1-C6)-alkoxycarbonyl; R10 represents group (C1-C6)-alkyl, (C3-C6)-cycloalkyl, or R10 represents -NR14R15; each R11 and R12 represents independently (1) H; (2) 3-6-membered saturated cycloalkyl or phenyl or 5-membered unsaturated heterocyclyl comprising from 1 to 4 heteroatoms N wherein indicated cycloalkyl, phenyl and heterocyclyl are substituted possibly with one or two substitutes chosen from -OH, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl; (3) (C1-C6)-alkyl substituted possibly at least with one substitute chosen from halogen atom, -OH, -COOH, (C1-C6)-alkylcarbonylamino group, phenyl, 5-membered unsaturated heterocyclyl comprising oxygen atom (O), or from 1 to 2 N atoms, bicycloheptyl wherein this phenyl, heterocyclyl or bicycloheptyl is substituted possibly at least with one substitute chosen from halogen atom, -OH, =O, or (4) (C1-C6)-alkylsulfonyl, or R11 and R12 in common with N atoms to which they are bound form 5-membered unsaturated heterocyclyl comprising one N atom or 5-6-membered heterocyclyl comprising from 1 to 2 heteroatoms, such as S, O and N, or 5-6-membered saturated heterocyclyl, ortho-condensed with benzene ring and comprising one N atom and wherein indicated heterocyclic systems are substituted possibly with one or two substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-hyroxyalkyl, (C1-C6)-halogenalkyl, (C1-C6)-alkylamino, di-(C1-C6)-alkylamino group, phenyl, halogenphenyl and hydroxydiphenylmethyl; R12a represents H or (C1-C6)-alkyl; each radical among R14 and R15 represents independently H or (C1-C6)-alkylsulfonyl, or R14 and R15 in common with N atom to which they are bound form 5-membered saturated heterocyclyl comprising one N atom and substituted possibly with one -OH, or its pharmaceutically acceptable salt or solvate. Also, invention relates to a method (variants) for synthesis of compound of the formula (I) according to one of the following method: by one variant, compound of the formula (II): is subjected for interaction with compound of the formula (III): by other variant, compound of the formula (IV): is subjected for interaction with compound of the formula (V): by other variant, compound of the formula (VI): wherein R3 represents -NHC(O)R10 and L1 represents a leaving group is subjected for interaction with L1C(O)R10; by other variant, compound of the formula (VIII): wherein R3 represents -C(O)NR11R12 and L2 represents a leaving group is subjected for interaction with compound of the formula (IX) given in the invention description. Also, invention relates to an intermediate compound of the formula (IIA): (wherein R1a is chosen from F, Cl, -CH3 and -CF3; s = 1 or 2; q = 0 or 1; w = 0 or 1; R2a represents F, and when q and s = 1 and w = 0 then R1a can't represent chlorine atom), and to a method for synthesis of compound of the formula (IIA) (wherein s = 1) and wherein compound of the formula (XX): is subjected for interaction with compound of the formula (XXII): (wherein R20 represent a protective group) before formation of compound of the formula (XXIV): followed by carrying out the cyclization reaction and removing the protective group R20.

EFFECT: improved methods of synthesis.

25 cl, 236 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein (a) each R1 is chosen independently from hydrogen atom and alkoxy-group; (b) R2 represents hydrogen atom; (c) each R3 and R4 is chosen independently of one another from hydrogen atom, alkyl, alkynyl, heteroalkyl group, aryl; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one or more hydroxo-group, carboxyl group, keto-, thioketo-, phenyl group, alkyl, heteroalkyl group, heteroaryl, heterocycloalkyl, spirocycloalkyl and their combinations; (d) each R5 and R6 represents hydrogen atom; or optical isomers, diastereomers and enantiomers represented by above given formula, and their pharmaceutically acceptable salts also. Also, invention describes using compound of the formula (I) for preparing a pharmaceutical composition possessing antibacterial activity and antibacterial pharmaceutical composition containing the safety and effective amount of compound of the formula (I) and a pharmaceutically acceptable carrier. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention relates to compounds of formula I , wherein W is halogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C4-haloalkyl or C1-C4-haloalkoxy; X is hydrogen, halogen, C1-C6-alkyl; Y is hydrogen, halogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-haloalcoxy or cyano; Z is hydrogen, halogen, etc.; G is halogen or nitro; meanings of the other substituents are as defined in specification. Also disclosed are methods for production of said compounds by interaction compounds of formula II with halogenation agents in presence of solvent and optionally of radical initiator of with fumed nitric acid in presence of solvent.

EFFECT: new compounds with insecticide activity.

17 cl, 20 tbl, 114 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinospiropyrane of the formula (1): wherein R1 means (C1-C18)-alkyl; each among R2 and R3 mean independently (C1-C4)-alkyl; R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl formyl, (C1-C)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2. Method comprises the following steps: (i) synthesis of indoline on polymeric carrier of the formula (III): wherein R1 means (C1-C18)-alkyl; each among R2 and R means independently (C1-C4)-alkyl; (ii) treatment of indoline-carrying polymeric carrier wherein this carrier represents hydroxy-resin at temperature from 50°C to 120°C in inert atmosphere for time from 14 h to 11 days with a derivative of salicylic aldehyde of the formula (VI): wherein R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl, formyl, (C1-C4)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2 to yield indolinospiropyrane compound of the formula (I), and (iii) release of indolinospiropyrane compound of the formula (I). Invention proves synthesis of novel derivatives of indolinospiropyrane possessing photochromic properties.

EFFECT: improved method of synthesis.

8 cl, 28 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention refers to Sertaconasole mononitrate process by reaction of 1-(2,4-dichlorphenyl)-2-(1H-imidazole-1-yl)ethanol and 3-bromomethyl-7-chlorbenzo[b]thiophene with tetrabutylammonium hydrosulphate and sodium hydroxide in toluene at 30-45°C. Produced free base of Sertaconasole is transferred into Sertaconasole mononitrate monohydrate with the latter being transferred into Sertaconasole mononitrate. There is disclosed and characterised intermediate Sertaconasole mononitrate monohydrate.

EFFECT: method allows simplifying process technology considerably.

6 cl, 5 dwg, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula I, where R1 represents -(CHR')q-aryl or -(CHR')q-thiophen, which are unsubstituted or mono-, di- or tri-substituted with (inferior)alkyl, (inferior)alkoxy, CF3 or haloid, or represents (inferior)alkyl, (inferior)alkenyl, -(CH2)n-Si(CH3)3, -(CH2)n-O-(inferior)alkyl, -(CH2)n-S- (inferior)alkyl, -(CH2)q-cycloalkyl, -(CH2)n-[CH(OH)]m-(CF2)p-CHqF(3-q), or represents -(CH2)n-CR2-CF3, where two radicals R together with a carbon atom form a cycloalkyl ring; R' represents hydrogen or (inferior)alkyl; n is 1, 2 or 3; m is 0 or 1; p is 0, 1,2, 3, 4, 5 or 6; q is 0, 1, 2 or 3; R2 represents hydrogen or (inferior)alkyl; R3 represents hydrogen, (inferior)alkyl, CH2F, aryl, optionally mono-, di- or tri-substituted with a haloid, or represents -(CH2)nNR5R6, where R5 and R6 independently represent hydrogen or (inferior)alkyl; R4 represents one of the following groups a) or b), where R7 represents inferior)alkyl or -(CH2)ncycloalkyl; R8 and R9 independently represent hydrogen, (inferior)alkyl, -(CH2)n-cycloalkyl or -C(O)-phenyl. The invention also relates to pharmaceutically used acid addition salts of these compounds, optically pure enantiomers, racemates or diastereomeric mixtures, as well as compounds with general formula I-1, and medicinal agent.

EFFECT: obtaining new biologically active compounds, designed for inhibiting γ-secretase.

16 cl, 83 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds satisfying general formula (I): where: R1 stands for direct or branched (C1-C7)alkyl, X stands for hydrogen atom, R2 stands for the group chosen from naphthalenyl, pyridinyl, isoquinoleinyl, thienyl, imidazolyl, benzothienyl, benzimidazolyl, indolyl, benzotriazolyl and optionally substituted with one or more substitutes chosen from halogen atoms and following groups: (C1-C4)alkyls, thio(C1-C4)alkyls or phenyls, optionally substituted with one or more substitutes chosen from halogen atoms or trifluoromethyl, as free base or additive salt with acid. Additionally, the invention concerns medical product, pharmaceutical composition, and application.

EFFECT: production of new biologically active compounds active to specific inhibitors of glycine glyt 1 and/or glyt 2 carriers.

6 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted aniline and diphenylamine analogues, chosen from 3,4-bisdifluoromethoxy-(3-carboxyphenyl)-N-(5-(2-chloropyridinylmethyl))-aniline, 3,4-bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(3-(2-chloropyridylmethyl))-aniline, 3,4 - bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(4-(3,5-dimethylisoxazolylmethyl)) aniline, 3 - cyclopentyloxy - 4-methoxy - N-(3-aminocarbonylphenyl) - N-(3-pyridylmethyl) aniline and other compounds given in paragraph 1 of the formula of invention and to their pharmaceutically acceptable salts as inhibitors of PDE4 enzyme.

EFFECT: compounds can be used for treating and preventing diseases caused by activity of the PDE4 enzyme.

15 cl, 8 dwg, 58 ex

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