Some condensed errorcorrecting, a new class of ligands cerebral gaba receptors

 

(57) Abstract:

The present invention includes compounds of formula I, where a fragment of a) represents a group of formula b) or C), and W represents a substituted or unsubstituted phenyl or 6-chinoline; Y represents a group C-R4; Z IS C(R8)(R9); R3, R5, R6, R8, R9- hydrogen. These compounds are highly active agonists, antagonists or inverse agonists of brain Gabaa receptors or prodrugs of agonists, antagonists or inverse agonists of brain Gabaa receptors. These compounds are also useful in the diagnosis and treatment of neurosis, insomnia, epilepsy, overdose of drugs of some benzodiazepine and to improve memory. 3 C. and 23 C.p. f-crystals, 20 ill., 1 PL.

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The invention relates to certain condensed to errorcorrection that selectively associated with GABA receptors. The invention also relates to pharmaceutical compositions comprising these compounds. It also relates to the use of compounds for the treatment of neuroses, insomnia, epilepsy, overdose with benzodiazepine drugs and for reducing the passive condition. Opisaine (BDM).

Gamma-aminobutyric acid (GABA) is one of the main inhibitory neurotransmitters amino acids in the mammalian brain. It has been over 30 years since, as demonstrated by their presence in the brain (Roberts & Frankel, J. Biol. Chem., 187, 55 - 63, 1950; Udenfriend, J. Biol. Chem., 187, 65 - 69, 1950). Since that time a large number of works were devoted to the involvement of GABA to the etiology of the neuroses, insomnia, epilepsy and disorders of cognitive abilities (Tallman and Gallager, Ann. Rev. Neuroscience, 8, 21 - 44, 1985). Widely, but unevenly distributed throughout the brain of a mammal, GABA is believed to be a mediator in approximately 30% of the synapses of the brain. In most areas of the brain, GABA is associated with local inhibitory neurons, and only in two areas it is associated with more elongated projections. GABA Mediaset many effects through a complex of proteins localized on the body cells, and nerve endings. This is the so-called Gabaa receptors. Postsynaptic responses to GABA mediasource through changes in chloride conductance, which usually, though not always, leads to hyperpolarization of the cell. Recent studies have shown that the complex of proteins associated with the postsynaptic response is s, is able to modify the postsynaptic response to GABA. Depending on the type of interaction between these compounds are able to show a whole range of activities, such as sedative, anxiolytic and anticonvulsant, or to determine the condition of insomnia, epilepsy and anxiety.

1,4-Benzodiazepines continue to be among the most widely used drug in the world. Main benzodiazepine in medicines market are chlordiazepoxide, diazepam, flurazepam and triazolam. These compounds are widely used as minor tranquilizers, sedative-hypnotic funds, muscle relaxants and anticonvulsants. A number of these compounds is extremely strong drugs. This efficiency indicates the center of his impact with high affinity and specificity for individual receptors. Early electrophysiological studies showed that the main effect of benzodiazepines was to strengthen the GABA-ergicheskoe inhibition. Benzodiazepines were able to enhance presynaptic inhibition monosynaptic reflex anterior root of the spinal cord, i.e., events, MediaLounge GABA (Schmidt et. al., 1967, Arch. Exp. Patt al., 1981, Handb. Exptl. Pharmacol., 33, 95 - 102) in General confirmed these provisions, and by the mid 70-ies there was consensus between electrophysiology that benzodiazepines potentiate the action of GABA.

With the opening of the "receptor" of benzodiazepines and subsequent determination of the nature of interaction between GABA and benzodiazepines has been shown that behavioural important interaction of benzodiazepines with different systems of neurotransmitters is attributable to enhanced the ability of GABA to modify these systems. Each modified system, in turn, may be related to the expression of behavior.

The study of the mechanistic nature of these interactions depended on the demonstration vsokoaffinnogo of the binding site (receptor) benzodiazepine. This receptor is present in the Central nervous system (CNS) of all vertebrates, phylogenetically younger than albula (Squires & Braestrup, 1977, Nature, 166, 732-34; Mohler &Okada, 1977, Science, 198, 851-54; Mohler &Okada, 1977, Br. J. Psychiatry, 133, 261-68). Using tritium-labeled diazepam, as well as many other compounds, it was shown that these binding sites (receptors) benzodiazepine meet many of the criteria of pharmacological receptors; svjatogorskih tests on animals predicting the effectiveness of benzodiazepine, was a high correlation between the ability of benzodiazepines to displace diazepam from its binding site and activity (Braestrup & Squires, 1978, Br. J. Psychiatry, 133, 249-60; Mohler &Okada, 1977, Science, 198, 851-54; Mohler &Okada, 1977, Br. J. Psychiatry, 133, 261-68). The average therapeutic dose of these medicines for humans also correlated with the activity of the receptor (Tallman et. al., 1980, Science, 207, 274 - 281).

In 1978, the goal became clear that GABA and related analogs can interact on the binding of GABA with a low degree of affinity for the ligand (1 mmol) to enhance the binding of benzodiazepines to sites that are sensitive to clonazepam (Tallman et al. , 1978, Nature, 274, 383 - 385). This gain is due to increased binding affinity for the Central benzodiazepine binding due to the employment site GABA. The data were interpreted to mean that both GABA and benzodiazepine sites allosteric were associated in the membrane as part of a complex of proteins. For a number of analogues of GABA ability to enhance the binding of diazepam at 50% of the maximum and the ability to inhibit the binding of GABA brain shell of 50% can be directly correlated. Increased binding of benzodiazepine et. al., 1978, Nature, 274, 383 - 385) stereoisomer (-) bicucullin much less active.

Shortly after the opening vsokoaffinnah binding sites benzodiazepnes it was found that triazolopyridine able in some way to interact with benzodiazepine receptors in certain areas of the brain, and the nature of this interaction corresponds to the heterogeneity of the receptor or negative cooperativity. In these studies, the hill coefficients are significantly lower than observed in a number of areas of the brain, including the cortex, hippocampus and neostriatum. In the cerebellum triazolopyridine interacted with benzodiazepine with a hill coefficient equal to 1 (Squires et al., 1979, Pharmacol. Biochem. Behav. , 10, 825-30; Klepner et al., 1979, Pharmacol. Biochem. Behav., 11, 457-62). Thus, the presence of multiple benzodiazepine receptors was predicted in the cortex, hippocampus and neostriatum, but not in the cerebellum.

On the basis of these works were undertaken on a wide autoradiographically study of the location of the receptors with the use of light (optical) microscope. Although a number of authors have already demonstrated the heterogeneous nature of the receptors (Young & Kuhar, 1980, J. Pharmacol. Exp. Ther. , 212, 337-46; Young et al., 1981, J. Pharmacol. Exp. Ther., 216, Aria of receptor subtypes and properties (behaviors), associated with this area of the brain. In addition, in the cerebellum, where it was predicted the presence of a single receptor, using autoradiography was discovered heterogeneous nature of the receptors (Niehoff et. al., 1982, J. Pharmacol. Exp. Ther., 221, 670-675).

The physical basis for explaining differences in specificity of the drug for the benzodiazepine site of both subtypes was demonstrated by the authors (Sieghart & Karobath, 1980, Nature, 286, 285-287). Using the method of gel electrophoresis in the presence of sodium dodecyl sulfate, the authors reported the presence of several receptors molecular weights. Receptors were identified covalent incorporation of radioactive flunitrazepam, namely benzodiazepine, which can covalently label the receptors of all types. The main labeled zones have a molecular weight from 50,000 to 53000, the 55,000 and 57,000, and triazolopyridine inhibit staining of receptor types, which have a somewhat higher molecular weight (53000, 55000, 57000) (Seighart et al., 1983, Eur. J. Pharmacol., 8, 291-299).

By the time he was shown the possibility that numerous types of receptors are so-called "sorezore or multiple allelic forms of the receptors (Tallman & Gakkager, 1985, Ann. Rev. Neurosci., 8, 21-44). Having common characteristics with Petunia began to study receptors using specific radioactive probes and electrophoretic methods, now almost certainly we can say that sorezore arise and are considered as important elements in the study of the etiology of mental disorders in humans.

Subunit of Gabaa receptors were cloned from libraries bovine and human complementary DNA (Schoenfield et al., 1988; Duman et al., 1989). A clear set of complementary DNA was identified as subunits of the complex of Gabaa receptors by cloning and expression. They are classified into alpha-, beta-, gamma-, Delta - and Epsilon-subunit and provide a molecular basis to explain the heterogeneous nature of Gabaa receptors and their distinctive regional pharmacology (Schivvers et al., 1980; Levitan wt al. , 1989). Gamma subunit, apparently, gives the possibility of such medicines as benzodiazepines, to modify the response to GABA (Pritchett et al., 1989). The presence of a low hill coefficients when the binding of ligands to receptors Gabaa shows a unique profile specific pharmacological action subtype.

Drugs that interact on the Gabaa receptor, have a range of pharmacological activities that are dependent on the ability to modify the action of GABA. For example, beta-carboline were spell the ife Sci., 25, 679-686).

The evaluation results on the binding of the receptors is not fully predict the biological activity of such compounds, agonists, partial agonists, inverse agonists and antagonists can inhibit this binding. In those cases, when determining the structure of the beta-carbolines, which, there is a possibility for the synthesis of several analogues and behavioral assessment of these compounds. Therefore, it was immediately found that beta-carboline can behavioral way antagonistically to influence the action of diazepam (Tenen & Horsch, 1980, Nature, 288, 609-610). In addition, antagonism of beta-carboline have their own internal activity, the opposite in relation to the activity of benzodiazepines; they became known as inverse agonists.

In addition, on the basis of their ability to inhibit the binding of benzodiazepines was obtained a number of other specific receptor antagonist of the benzodiazepine, the most studied of which is imidazothiazoles (Hunkeler et al. , 1981, Nature, 290, 514-516). This connection is Vysocany competitive inhibitor of the binding of beta-carbolines, which and benzodiazepine and is able to block the pharmacological action of the compounds of both of these classes. Self sebe, 514-516; Darragh et al. , 1983, Eur. J. Clin. Pharmacol., 14, 569-570). When was studied radiolabelled form of this compound (Mohler & Richards, 1981, Nature, 294, 763-765), it was shown that it can interact with the same number of sites that beta-carboline and benzodiazepines, and that the interaction of these compounds were purely competitive. This compound is a ligand of choice for binding to Gabaa receptors, since it does not have the specificity of subtype and determines each state of the receptor.

The study of the interactions of a wide range of compounds similar to the above, led to the classification of these compounds. Currently, those compounds that have activity similar to the benzodiazepines, are called agonists. Compounds with activity opposite to the benzodiazepines, are called inverse agonists, compounds capable of blocking both types of activity were identified as antagonists. This classification was developed in order to emphasize the fact that many compounds can exhibit a range of pharmacological effects, continue to indicate that the connection can communicate on the same receptor to produce counter the mi are not synonymous.

Biochemical test for pharmacological and behavioral properties of compounds that interact with the receptor of diazepine, also emphasizes the interaction with the GABA-ergicheskoi system. In contrast to the benzodiazepines, which demonstrate an increase in their epinasty due to GABA (Tallman et al. , 1978, Nature, 274, 383-385; Tallman et al., 1980, Science, 207, 274-281), compounds with antagonistic properties almost never show GABA-shift, i.e., changes in affinity to the receptor, due to GABA (Mohler & Richards, 1981, Nature, 294, 763-765); at the same time, inverse agonists discover reduced epinasty due to GABA (Braestrup & Nielson, 1981, Nature, 294, 472-474). Thus, the value of the GABA-bias in General predicts unexpected behavioral characteristics of these compounds.

As agonists and antagonists of benzodiazepine were obtained for various compounds. For example, in U.S. patents 3455943, 4435403, 4596808, 4623649 and 4719210, the German patent DE 3246932 and sat Liebigs Ann. Chem., 1986, 1749 described various agonists and antagonists of benzodiazepine and related antidepressants and compounds affecting the Central nervous system.

In particular, U.S. patent 3455943 discloses compounds of the formula

< / BR>
where R1predstavljaet and lower alkoxy;

R3- member of the group consisting of hydrogen and lower alkyl;

X is a divalent radical selected from the group consisting of fragments of formulas

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< / BR>
< / BR>
and their non-toxic acid additive salt.

U.S. patent 4435403 discloses compounds of the formula

< / BR>
where Rcis hydrogen, lower alkyl, alkoxyalkyl containing up to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, arylalkyl containing up to 8 carbon atoms, or a group of the formula (CH2)nOR2where R2- alkyl containing up to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, or arylalkyl containing up to 8 carbon atoms. n = 1, 2, 3;

Y is oxygen, two hydrogen atoms or the group NOR1where R1is hydrogen, lower alkyl, aryl or arylalkyl containing up to 6 carbon atoms, the group COR2where R2- lower alkyl containing up to 6 carbon atoms, or Y is a group CHCOOR3where R3is hydrogen or lower alkyl, or Y is a group NNR4R5where R4and R5may be the same or different and each represents hydrogen, lower alkyl, C6-C10-aryl, C7-C10-alkylaryl or CONR6R74and R5together with the nitrogen atom to which they are attached, form a 5 - or 6-membered heterocyclic ring which optionally contains an oxygen atom or up to 3 nitrogen atoms and optionally substituted lower alkyl;

Z represents hydrogen, alkoxy or Alcoxy, each containing up to 10 carbon atoms and each optionally substituted by hydroxy, or Z represents alkyl containing up to 6 carbon atoms, C6-C10-aryl, C7-C10-alkylaryl, each of which is optionally substituted COOR8or CONR9R10where R8- alkyl containing up to 6 carbon atoms, and R9and R10may be the same or different and each is hydrogen or alkyl containing up to 6 carbon atoms, or Z is - NR9R10where R9and R10defined above; or Z is - NR11CHR12R13where R11and R12each is hydrogen or together form a double bond N= C and R13- C10-alkyl or NR14R15where R14and R15the same or different and each is hydrogen, OH or alkyl or alkoxy containing up to 6 carbon atoms, or where R12and R13together represent oxygen and R11is hydrogen, or Z - COOR2

U.S. patent 4596808 discloses compounds of the formula

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where RAIs H, F, Cl, Br, I, NO2, CN, CH3, SCH3, NR16R17or NHCOR16where R16and R17the same or different and each is hydrogen or alkyl, alkenyl or quinil, each of which contains up to 6 carbon atoms, arylalkyl or cycloalkyl, each of which contains up to 10 carbon atoms, or R16and R17together form a saturated or unsaturated 3-7 membered heterocyclic ring.

U.S. patent 4623649 discloses compounds of the formula

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where R3- oxadiazolyl balance formula

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where R5- lower alkyl containing up to 3 carbon atoms, or an ether-CO2R6where R6is hydrogen or lower alkyl containing up to 3 carbon atoms;

R4is hydrogen or lower alkyl containing up to 3 carbon atoms, or CH2OR9where R9- lower alkyl containing up to 3 carbon atoms;

RAis phenyl or a hydrocarbon residue containing from 2 to 10 carbon atoms, which is m and which is optionally substituted by exography, the formyl, OH, O-alkyl containing up to 3 carbon atoms or phenyl, and where in the cyclic hydrocarbon residue group CH2may be replaced by oxygen.

U.S. patent 4719210 discloses compounds of the formula

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where R1is hydrogen or a protective group; R1represents-CH=CR4or-C=CR4where R4is hydrogen or halogen, lower alkyl or lower alkoxyalkyl;

RAis hydrogen, OR7, lower alkyl, optionally substituted aryl, lower alkoxy or NR5R6, R5and R6the same or different, each is hydrogen, lower alkyl or, taken together with the nitrogen atom, form a 5-6-membered ring containing another heteroatom, R7- lower alkyl, optionally substituted aryl or arylalkyl,

and each connection may include one or more radicals RAthat is not hydrogen.

These compounds differ from the compounds claimed in the present invention. Described U.S. patents disclose carbocyclic compounds having pyridine or piperidine ring, but not containing a pyrimidine ring, present in the claimed compounds.

German patent DE 3246932 reveals the connection of thenn = 0 - 2;

R1is hydrogen, alkyl, cycloalkyl, aryl, CO2H, amino, R2O, R2S(O)n.

However, examples that prove the value of R1= aryl, patent no.

Liebegs Ann. Chem., 1986, 1749-1764 discloses compounds of the formula

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where RXis hydrogen, methyl, benzyloxy or methoxy;

R3- carboethoxy.

None of these compounds does not belong to indole-3-carboxamide, and that source of information, however, indicated that such compounds exhibit activity at GABA receptors.

The literature describes many of indole-3-carboxamide. For example, in J. Org. Chem., 42, 1883-1885 (1977) presented compounds of formulas

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J. Heterocyclic Chem., 14, 519-520 (1977) discloses the compound of the following formula:

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None of the presents indole-3-carboxamido does not contain hydroxy-substituent in position 4 indelaware rings.

The present invention discloses a method of obtaining new compounds of the formula I, which interact with the binding site of Gabaa, receptor benzodiazepine.

The invention also includes pharmaceutical compositions comprising the compounds of formula I, as well as compounds useful in the La improve memory. Accordingly, the primary object of the invention are compounds of General formula I

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or their pharmaceutically acceptable non-toxic salt,

where T is halogen, hydrogen, hydroxyl, amino or straight or branched lower alkoxy having 1-6 carbon atoms;

X is hydrogen, hydroxyl or straight or branched lower alkyl having 1-6 carbon atoms;

W is phenyl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl or 6-chinoline, each of which may be mono - or Disaese halogen, cyano, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino, where each alkyl is independently represents a straight or branched lower alkyl having 1-6 carbon atoms, straight or branched lower alkoxy having 1-6 carbon atoms, or a group NR1COR2, COR2, CONR1R2or CO2R2where R1and R2- same or different and each represents hydrogen or straight or branched lower alkyl having 1-6 carbon atoms;

and fragment

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represents a group of the formula

< / BR>
< / BR>
where Y is nitrogen or C-R4;

Z - N-R7or a carbon atom substituted by the radical R8
R4- halogen, or cryptomate, or10-COR10, -CO2R10, -OCOR10or-R10where R10is hydrogen, phenyl, 2-, 3 - or 4-pyridyl, straight or branched lower alkyl having 1-6 carbon atoms, phenylalkyl or 2-, 3 - or 4-pyridylethyl, where each alkyl is a straight or branched lower alkyl having 1-6 carbon atoms, or-CONR11R12or -(CH2)mNR11R12where m = 0, 1, or 2; R11is hydrogen, straight or branched lower alkyl having 1-6 carbon atoms; and R12is hydrogen, phenyl, 2-, 3 - or 4-pyridyl, straight or branched lower alkyl having 1-6 carbon atoms, phenylalkyl or 2-, 3 - or 4-pyridylethyl, where each alkyl is a straight or branched lower alkyl having 1-6 carbon atoms; or NR11R12forms a heterocyclic group, which is morpholyl, piperidyl, pyrrolidyl or N-alkylpiperazine;

R5and R6same or different is hydrogen, galogenkami 1-6 carbon atoms;

R7is hydrogen, phenyl, 2-, 3 - or 4-pyridyl, straight or branched lower alkyl having 1-6 carbon atoms, phenylalkyl or 2-, 3 - or 4-pyridylethyl, where each alkyl is a straight or branched lower alkyl having 1-6 carbon atoms;

R8is hydrogen or straight or branched lower alkyl having 1-6 carbon atoms;

R9represents a group-COR13, -CO2R13or-R13where R13is hydrogen, phenyl, 2-, 3 - or 4-pyridyl, straight or branched lower alkyl having 1-6 carbon atoms, phenylalkyl or 2-, 3 - or 4-pyridylethyl, where each alkyl is a straight or branched lower alkyl having 1-6 carbon atoms; or-CONR14R15or -(CH2)kNR14R15where k = 0, 1, or 2; R14is hydrogen, straight or branched lower alkyl having 1-6 carbon atoms, and R15is hydrogen, phenyl, 2-, 3 - or 4-pyridyl, straight or branched lower alkyl having 1-6 carbon atoms, phenylalkyl or 2-, 3 - or 4-pyridylethyl, where each alkyl is a straight or branched lower alkyl having 1-6 carbon atoms; or NR14R15forms a heterocyclic group which represents morpholine, antagonists or inverse agonists for brain Gabaa receptors or prodrugs of agonists, antagonists or inverse agonists for cerebral GABA receptors. In other words, despite the fact that all of the claimed compounds interact with brain Gabaa receptors, they really are identical physiological activity. Therefore, these compounds are useful for the diagnosis and treatment of neurosis, insomnia, epilepsy, overdose of drugs of some benzodiazepine and to improve memory. For example, they can be easily used for the treatment of overdose with benzodiazepine drugs, as the competitive associated with benzodiazepine receptors.

Fig. 1 - 20 illustrate condensed errorcorrecting claimed in the present invention.

The new compounds included in the scope of the present invention, describes the above General formula I, including their pharmaceutically acceptable non-toxic salt.

In addition, the present invention covers compounds of formula II

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where W, R8, R9have the meanings given above,

or their pharmaceutically acceptable non-toxic >/BR>< / BR>
where W, R3, R5have the meanings given above,

or their pharmaceutically acceptable non-toxic salt.

The present invention also includes compounds of formula IV

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where W, Y, R3, R5have the meanings given above

or their pharmaceutically acceptable non-toxic salt.

The present invention includes compounds of formula V

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where W, R4, R5have the meanings given above

or their pharmaceutically acceptable non-toxic salt.

In addition, the invention includes compounds of formula VI

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where R16is hydrogen, benzyl or straight or branched lower alkyl having 1-6 carbon atoms;

R17is hydrogen or straight or branched lower alkoxy having 1-6 carbon atoms;

R18is hydrogen, straight or branched lower alkoxy having 1-6 carbon atoms, NR1COR2, COR2, CO2R2where R1and R2is defined above, cyano or halogen;

R19is hydrogen or halogen,

or their pharmaceutically acceptable non-toxic salt.

The invention further includes the compounds of formula VII

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where R17, R18 where R17, R18and R19defined above;

R20is hydrogen or straight or branched alkyl having 1-6 carbon atoms.

The invention also includes compounds of formula IX

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where R17, R18and R19defined above.

The invention also includes compounds of formula X

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where R16, R17, R18and R19defined above.

The invention also includes compounds of formula XI

< / BR>
where R4, R5, R17, R18and R19defined above.

The invention also includes compounds of formula XII

< / BR>
where W is phenyl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl or 6-chinoline, each of which may be mono - or Disaese halogen, cyano, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino, where each alkyl is independently represents a straight or branched lower alkyl having 1-6 carbon atoms, straight or branched lower alkoxy having 1-6 carbon atoms, or a group NR1COR2, COR2, CONR1R2or CO2R2where R1and R2- same or different and each represents debatewise salts include salts of acids, such as chloride-hydrogen, phosphoric, Hydrobromic, sulfuric, Sultanova, formic, toluensulfonate, Modesto-hydrogen, acetic acid and others. Relevant experts can easily will receive a wide range of non-toxic pharmaceutically acceptable acid additive salts of these compounds.

Representative compounds of formula I include, but are not limited to compounds of Fig. 1 and their pharmaceutically acceptable salts. The present invention also encompasses the acylated prodrugs of the compounds of formula I. Appropriate staff are familiar with various synthetic methods of obtaining pharmaceutically acceptable salts and acylated prodrugs of the compounds of formula I.

The definition of lower alkyl in the present invention means a straight or branched chain lower alkyl having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

Definition of lower alkoxy in the present invention means a straight or branched chain lower alkoxy having 1-6 carbon atoms, such as, for example, methoxy, ethoxy Ave is si, 2 hexose, 3 hexose and 3 methylpentane.

The definition of the halogen in the present invention means fluorine, bromine, chlorine and iodine.

Determination of N-alkylpiperazine in the present invention means a radical of the formula

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where R is a straight or branched lower alkyl, which was defined above.

Pharmaceutical purpose of the claimed compounds is confirmed by testing the binding activity of the Gabaa receptor.

The experiments are performed according to the method described by Thomas and Talmana (Thomas and Tallman, J. Bio. Chem., 156, 9838-9842; J. Neurosci., 3, 433-440, 1983). The cortical tissue of the rat excised and homogenized in 25 volumes of 0.05 M Tris-chloride-hydrogen buffer (pH of 7.4 at 4oC). The homogenate was centrifuged in the cold (4oC) when the rotation speed of 20000 g for 20 minutes. The upper layer is decanted and the precipitate re-homogenized in the same volume of buffer and again centrifuged at 20000 g. The upper layer is again decanted and the sediment is frozen at -20oC, leaving for the night. Then thaw and again homogenized in 25 volumes of the same buffer, twice repeating a procedure. At the end of the precipitate resuspended in 50 volumes of 0.05 M Tris-chloride-hydrogen buffer (pH of 7.4 at 40oC).

Intellectu 80 Curie/mmol, drug or blocker and buffer added to a volume of 500 ml. Incubation hatching for 30 min at 4oC and then rapidly filtered through a glass filter to separate free and bound ligand. The filters are washed twice with fresh buffer (0.05 M Tris-HCl at pH 7.4 and 4oC) and placed in a liquid scintillation counter. Diazepam (1.0 mmol) is added to some of the test tubes to determine nonspecific binding. To assess calculate the average of three measurements and determine the inhibition percentage of the total value of specific binding:

Total specific binding = Total binding - Nonspecific binding.

In some cases, change the number of radioactively unlabeled drugs and build curves binding on the size of the total displacement. The received data is transferred in a form that is easy to calculate the values of the IC50and hill coefficient (NH). The results obtained for the claimed compounds are presented in table. 1.

Tests conducted by standard methods showed that the obtained compounds are of low toxicity products.

The compounds of formula I can be administered orally, locally, p the second form, contains standard non-toxic pharmaceutically acceptable carriers and excipients. The term parenteral includes subcutaneous, intravenous, intramuscular injections and infusions. In addition, this provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. One or more compounds of formula I may be present in a mixture with one or more non-toxic pharmaceutically acceptable carrier, excipient or diluent, and optionally with other active ingredients. A pharmaceutical composition comprising a compound of formula I, may be in a form suitable for oral administration, for example in the form of tablets, coated tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral administration, is prepared by any known method designed to obtain pharmaceutical compositions, and such compositions contain one or more agents selected from the group consisting of sweeteners, flavors, colorants and preservatives, taken in order to ensure formicoxenini pharmaceutically acceptable fillers, suitable for the manufacture of tablets. These fillers can represent, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium; granulating and dezintegriruetsja agents, for example corn starch or Aleynikova acid; binders, for example starch, gelatin or acacia; and lubricants, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or can be coated by the well-known methods, designed to delay disintegration and absorption in the gastrointestinal tract and thereby provide a delayed action for a long time. For example, for this purpose you can use this retarding material as glycerion or distearate.

Compositions for oral administration can be obtained in the form of hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example a carbonate or calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain activits suspendresume agents, for example sodium carboxymethylcellulose, methylcellulose, gidropropilmetilzelluloza, sodium alginate, polyvinylpyrrolidone resin tragakant or acacia; dispersing or wetting agents in the form of natural phosphatides, for example lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit, such as polyoxyethylenesorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and mexicanvalium, for example polietilensorbit monooleate. Aqueous suspensions can also contain one or more preservatives, for example ethyl or n-propyl-p-hydroxybenzoate, one or more dyes, one or more flavor additives, one or more sweeteners, such as sucrose or saccharin.

Oil suspensions obtained by suspension, active ingredients in a vegetable oil, such as peanut, olive, sesame or coconut oil, or in mineral oil is paraffin or cetyl alcohol. To impart a pleasant taste to the suspensions for oral administration add sweeteners and flavorings. With the aim of preserving these compositions may include antioxidants, such as ascorbic acid.

Dispersible powders and granules suitable for receiving the aqueous slurry by adding water, ensure the presence of the active ingredient mixed with dispersing or wetting agent, suspenders agent and one or more preservative. Suitable dispersing, wetting and suspendresume agents chosen from among the substances mentioned above. Can be added fillers, such as sweeteners, flavorings and dyes.

The pharmaceutical compositions can be prepared in the form of emulsions of oil-in-water. The oil phase is a vegetable oil such as olive or peanut oil, or mineral oil, in particular, liquid paraffin, or mixtures thereof. Suitable emulsifying agents include natural resins such as resin tragakant or acacia, natural phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and exit, its anhydride, for example sorbitol, m is noolet. The emulsion may also include sweeteners and flavorings.

Syrups and elixirs are prepared with sweeteners, for example, glycerol, propylene glycol, sorbitol or sucrose. Such dosage forms contain also demulcent, preservatives, flavorings and colorings. The composition is prepared in the form of a sterile injectable aqueous or oil suspensions with known methods using suitable dispersing, wetting and suspendida agents selected from among substances mentioned above. Sterile injectable forms may also be a sterile injectable solution or suspension in a nontoxic pharmaceutically acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Among the applicable acceptable diluents or carriers include water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or medium for the preparation of suspensions usually apply sterile non-volatile oil. For this purpose any suitable fresh colorless oil, including synthetic mono - or diglycerides. In addition, in the preparation of injectable forms are used fatty acids such as oleic CIS is karst. These compositions are prepared by mixing the drug with a suitable non-toxic carrier which is solid at ordinary temperatures, but at the same time soften at the rectal temperature and the result is melted in the rectal hole with drug release. These materials include peanut butter and polyethylene glycols.

The compounds of formula I can enter parenterally in a sterile environment. Medication, depending on the nature of the medium and the applied concentration, can be either suspended or dissolved in the carrier. Preferably it can be dissolved adjuvants such as local obesbolivatemu, preservatives and buferiruemoi agents.

For treatment of the above disorders are useful concentration in the range from 0.1 to 140 mg per kg of body weight (or from 0.5 mg to 7 g of active substance per day). This number, which is combined with the media to produce a single dosage form will depend on the patient and the particular mode of administration. These forms typically contain from 1 to 500 mg of active ingredient.

It is clear that the specific dose for any patient will depend on many factors include the duration of the assignment, the route of administration, rate of excretion, drug combination and the degree of this disease.

Obtaining the compounds claimed in the present invention, represented by reaction schemes I and II.

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Any person skilled in the art it is known that upon receipt of the compounds included in the present invention, can change the source materials and to introduce additional stages, as demonstrated by the following examples. In some cases, provides for the protection of certain functional groups to achieve some of the above transformations. As a rule, the need for such protective groups are obvious to the chemist-organic matter together with the reaction conditions required for their introduction and removal.

The invention is further illustrated by examples, which should not be construed as any limitation on its scope in relation to those described in these specific methods.

Example 1.

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4-oxo-4,5,6,7-Tetrahydrofuran-3-carboxylic acid is obtained by a modified method described in the literature. To a solution of potassium hydroxide (28,06 g, 0.5 mol) in methanol (100 ml) under stirring in nitrogen atmosphere at 0oC for 0.5 h and then added dropwise a solution of ethylbromoacetate (66 ml, 0,525 mol) in methanol (100 ml). The mixture was kept under stirring and at ambient temperature for 17 h and then added dropwise a 50% solution of sodium hydroxide (60 ml) and continue stirring for 7 hours the Mixture is diluted with water, the solution is acidified and the methanol removed in vacuo. Add a mixture of ice water, the precipitate is filtered off and dried under vacuum, obtaining 4-oxo-4,5,6,7-tetrahydrofuran-3-carboxylic acid.

Example 2.

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To a stirred suspension of 4-oxo-4,5,6,7-tetrahydrofuran-3-carboxylic acid (28,2 g, 157 mmol) in ethanol (500 ml) in a nitrogen atmosphere at ambient temperature is added dropwise acetylchloride (56 ml, 783 mmol). After an hour of stirring the solution is heated at a temperature of distillation for 1 h, then cooled and concentrated in vacuo. The precipitate is transferred into dichloromethane, washed with aqueous sodium bicarbonate solution, and then quickly washed with 1N. sodium hydroxide, dried over magnesium sulfate, filtered and concentrated in vacuo, receiving ethyl-4-oxo-4,5,6,7-tetrahydrobenzo-furan-3-carboxylate in the form of oil. A mixture of this ester (24,46 g, 117 mmol) and acetates. The mixture is cooled, poured into a mixture of ice water and extracted twice with dichloromethane. The combined extract was washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo and the residue is treated with ether, receiving ethyl-4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. A mixture of this ester (11,31 g, 55 mmol) in 5h. of sodium hydroxide and ethanol (20 ml) is heated at a temperature of distillation within 1 h After cooling in an ice bath, the mixture is acidified with concentrated hydrochloric acid, the precipitate is filtered off, washed with a mixture of ice water and dried in vacuum, obtaining 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid.

Example 3. Connection 1.

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A mixture of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol), p-anisidine (616 mg, 5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (959 mg, 5 mmol) in 50% aqueous 1,4-dioxane (10 ml) was stirred at ambient temperature for 17 hours After concentration in vacuo the residue is transferred in 10% methanol in ethyl acetate, washed 1.3 M hydrochloric acid and then aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Recrystallization from ethyl acetate to give N-(4-methoxyphenyl)-4-ox is R> A solution of 2-methyl-3-nitroanisole (9,96 g, 60 mmol) and Tris(dimethylamino)methane (15,5 ml, 89 mmol) in DMF (30 ml) is heated at 115oC in nitrogen atmosphere for 3 hours After cooling to ambient temperature to the mixture dropwise and with vigorous stirring was added a solution of hydrochloride semicarbazide (6,98 g, 63 mmol) and concentrated hydrochloric acid (5.3 ml) in water (75 ml). The mixture is optionally cooled in an ice bath, the precipitate is filtered off, washed first with a mixture of ice water and then with cold 50% aqueous ethanol, cold ethanol and ether, then dried to obtain semicarbazone. The latter is suspended with 10% palladium on carbon (Pd/C) (3 g) in ethanol (120 ml) in a Parr shaker and incubated in an atmosphere of hydrogen (50 psi) for 16 hours the Mixture is filtered through celite and concentrated in vacuo. The resulting residue is treated with a mixture of ice water, filtered and dried, obtaining 4-methoxy-1H-indole.

Example 5.

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A solution of 2-nitro-6-benzyloxyethanol (13,0 g, 53 mmol) and Tris(dimethylamino)methane (to 13.9 ml, 80 mmol) in DMF (30 ml) is heated at 115oC in nitrogen atmosphere for 3 hours After cooling to ambient temperature to the mixture dropwise and with intense lane is (4.8 ml) in water (70 ml). Add ethanol (25 ml) and the resulting heterogeneous mixture is stirred for 2 hours the Mixture is cooled in an ice bath, the precipitate is filtered off, washed first with a mixture of ice water and then with cold 50% aqueous ethanol, cold ethanol and ether, then dried to obtain semicarbazone. Suspension of semicarbazone (17,64 g, 54 mmol), Raney Nickel (18 g 50% aqueous suspension) in a mixture of tetrahydrofuran:methanol (1:1) (145 ml) is heated to 55oC and add hydrazinoacetate in four equal portions at 2,7 ml with an interval of 0.5 h the Mixture is cooled, filtered through a thin layer of silica gel using ether. The filtrate is dried over magnesium sulfate, filtered, concentrated in vacuo and the residue purified flash chromatography, receiving 4-benzyloxy-1H-indole in the form of low-melting solids.

Example 6.

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To a solution of 4-methoxy-1H-indole (7,15 g, 49 mmol) and pyridine (19.7 ml, 143 mmol) in dichloromethane (50 ml) at 0oC in nitrogen atmosphere is added dropwise a solution of trichloroacetamide (27,1 ml, 243 mmol) in dichloromethane (50 ml). After stirring at 0oC optional for 1.5 h the mixture was concentrated in vacuo, the residue is treated the minimum necessary amount of methane is t, getting 4-methoxy-3-trichloroacetyl-1H-indole. The last number 9,07 g (31,0 mmol) in portions at ambient temperature with an interval of 0.75 h is added to the mixed solution of sodium methoxide (3.5 ml 25% solution in methanol) in methanol (200 ml). After additional stirring for 0.75 hours the mixture is cooled in an ice bath, diluted with a mixture of water with ice, acidified with concentrated hydrochloric acid and the methanol removed in vacuo. The obtained heterogeneous mixture is cooled in an ice bath, the precipitate is filtered, washed with water and dried, obtaining the methyl ester of 4-methoxy-1H-indole-3-carboxylic acid. A suspension of the ester (5.6 g, 27 mmol) in 50% aqueous sodium hydroxide (50 ml) and methanol (50 ml) was stirred at ambient temperature for 19 hours, the Mixture is cooled in an ice bath, the precipitate is filtered off, washed with a mixture of ice water and dried, obtaining 4-methoxy-1H-indole-3-carboxylic acid.

Example 7. Connection 2.

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N-(2-Fluoro-4-methoxyphenyl)-4-benzyloxy-1H-indol-3-carboxamide (1,34 g, 3.4 mmol) obtained by the method described above, is suspended with 10% palladium on carbon (Pd/C) (134 g) in ethanol (35 ml) in a vessel Parra and placed in an atmosphere of hydrogen (50 psi) for 5 hours Add 5 is intronaut in vacuo and the residue purified flash chromatography, receiving N-(2-fluoro-4-methoxyphenyl)-4-hydroxy-1H-indol-3-carboxamide (compound 2) in a solid beige color with so pl. 259 - 261oC (d).

Example 8. The following compounds are extracted according to the methods described in examples 1 - 6:

1) N-(4-ethoxyphenyl)-4-oxo-4,5,6,7-tetrahydro - 1H-indol-3-carboxamide (compound 3) with so pl. 217 - 218oC.

2) N-(4-ethoxyphenyl)-4-methoxy - 1H-indol-3-carboxamide (compound 4) with so pl. 259 - 261oC (d).

3) N-(3-ethoxyphenyl)-4-methoxy - 1H-indol-3-carboxamide (compound 5).

4) N-(2-fluoro-4-methoxyphenyl)-4-oxo-4,5,6,7-tetrahydro - 1H-indol-3-carboxamide (compound 6).

5) N-(2-fluoro-4-ethoxyphenyl)-4-oxo-4,5,6,7-tetrahydro - 1H-indol-3-carboxamide (compound 7).

6) N-(4-methoxyphenyl)-4-methoxy - 1H-indol-3-carboxamide (compound 8).

7) N-(2-fluoro-4-atasever)-4-methoxy - 1H-indol-3-carboxamide (compound 9).

8) N-(4-cyanophenyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 10) with so pl. 287 - 288oC.

9) N-(3-methoxyphenyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 11) with so pl. 220 - 223oC.

10) N-(4-acetamidophenyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 12) with so pl. 339 - 341oC.

11)-4-benzyloxy-1H-indol-3 - carboxamide (compound 14).

13) N-(4-acetylphenyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 15).

14) N-(2-fluoro-5-methoxyphenyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 16).

15) N-(6-chinolin)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 17) so pl. 319 - 321oC.

16) N-(4-carbomethoxy)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 18) so pl. 261 - 262oC.

17) N-(4-carboxyphenyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 19).

18) N-(4-ethoxyphenyl)-4-hydroxy-1H-indol-3-carboxamide (compound 20).

19) N-(3-ethoxyphenyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 21).

20) N-(2-fluoro-4-methoxyphenyl)-4-benzyloxy-1H-indol-3 - carboxamide (compound 22).

21) N-(4-isopropoxyphenyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 23).

22) N-(4-forfinal)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 24).

23) N-(4-pyridyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 25).

24) N-(4-hydroxyphenyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 26).

25) N-(4-AMINOPHENYL)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 27).

26) N-(3-pyrid-tetrahydro-1H-indol-3-carboxamide (compound 29).

28) N-(3-fluoro-4-methoxyphenyl)-4 - oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 30).

29) Connection 31

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30) Connection 32

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31) Connection 33

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32) Connection 34

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33) N-(2-fluoro-4-isopropoxyphenyl)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 35).

34) N-(4-forfinal)-4-oxo-5,5-dimethyl - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 36).

35) N-(2-fluoro-4-methoxyphenyl)-4-oxo-5,5-dimethyl - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 37).

36) N-(4-ethoxyphenyl)-4-oxo-5,5-dimethyl - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 38).

37) N-(4-(methoxymethyl)phenyl)-4-oxo-5,5-dimethyl - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 39).

38) N-(4-methoxyphenyl)-4-oxo-5,5-dimethyl - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 40).

39) N-(2-methoxy-5-pyridyl)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 41).

40) N-(3,4-dihydroxyphenyl)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 42).

41) N-phenyl-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 43).

42) N-(2-pyridyl)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 44).

43) N-(2-fluoro-4-hydroxyphenyl)-4-oxo - 4,5 is etrahydro-1H-indol-3-carboxamide (compound 46).

45) N-(2-fluoro-4-ethoxyphenyl)-4-oxo-6,6-dimethyl - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 47).

46) N-(4-ethoxyphenyl)-4-oxo-6,6-dimethyl - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 48).

47) N-(2-amino-3-pyridyl)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 49).

48) N-(4-were)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 50).

49) N-(3-were)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 51).

50) N-(2-amino-4-were)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 52).

51) N-(4-methylaminophenol)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 53).

52) N-phenyl-4-oxo-6,6-dimethyl - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 54).

53) N-(3-hydroxy-4-methoxyphenyl)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 55).

54) N-(2-forfinal)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 56).

55) N-(3-forfinal)-4-oxo-6,6-dimethyl - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 57).

56) N-(4-(2-hydroxyethoxy)phenyl)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 58).

57) N-(2-thienyl)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 5

59) N-(2-(4-hydroxyphenyl)ethyl)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 61).

60) N-(2-(4-atasever)ethyl)-4-oxo - 4,5,6,7-tetrahydro-1H-indol-3-carboxamide (compound 62).

61) Connection 63

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62) Connection 64

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63) Connection 65

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64) Connection 66

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65) Connection 67

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66) Connection 68

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67) Connection 69

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68) N-(4-fluoro-2-hydroxyphenyl)-4-oxo-4,5,6,7-tetrahydro - 1H-indol-3-carboxamide (compound 70).

The present invention, the method of its implementation and use are described in such full, clear and at the same time concise manner to allow play it any specialist in this field of technology. It should also be understood that all of the above defines a preferred variant of the present invention and that its possible modifications not beyond the scope of the invention defined by the appropriate formula. In order to specify and distinctly claim the subject matter of this invention, the following formula completes the present description.

1. Derivatives of condensed errorcorrected General formula I

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where W is phenyl or 6-chinoline, each of which may be mono - or dizerega, the group - NR1COR2or CO2R2where R1and R2the same or different, is hydrogen or straight or branched lower alkyl having 1 to 6 carbon atoms;

fragment

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represents a group of the formula

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where Y is the group C-R4;

Z - group C(R8)(R9); R3, R5and R6is hydrogen,

or their pharmaceutically acceptable non-toxic salt.

2. Derivatives of condensed errorcorrected General formula III

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where W is phenyl or 6-chinoline, each of which may be mono - or Disaese a halogen atom, cyano, straight or branched lower alkoxygroup having 1 to 6 carbon atoms, a group - NR1COR2or CO2R2where R1and R2the same or different, is hydrogen or straight or branched lower alkyl having 1 to 6 carbon atoms;

R8and R9is hydrogen,

or its pharmaceutically acceptable non-toxic salt.

3. Derivatives of condensed errorcorrected General formula IV

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where Y represents the group C - R4;

R3, R4and R5is hydrogen;

W is phenyl or 6-chinoline, each of which may be mono - imps carbon the group - NR1COR2or CO2R2where R1and R2the same or different, is hydrogen or straight or branched lower alkyl having 1 to 6 carbon atoms,

or its pharmaceutically acceptable non-toxic salt.

4. Connection on p. 1, which is N-(4-methoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

5. Connection on p. 1, which is N-(2-fluoro-4-methoxyphenyl)-4-hydroxy-1H-indol-3-carboxamide.

6. Connection on p. 1, which is N-(4-ethoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

7. Connection on p. 1, which is N-(2-fluoro-4-methoxyphenyl)4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

8. Connection on p. 1, which is N-(2-fluoro-4-ethoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

9. Connection on p. 1, which is N-(4-cyanophenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

10. Connection on p. 1, which is N-(3-methoxyphenyl)4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

11. Connection on p. 1, which is N-(4-acetamidophenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carbox carboxamid.

13. Connection on p. 1, which is N-(2-fluoro-5-methoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

14. Connection on p. 1, which is N-(6-chinoline)-4-oxo-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

15. Connection on p. 1, which is N-(4-carbomethoxy)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

16. Connection on p. 1, which is N-(4-carboxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

17. Connection on p. 1, which is N-(4-ethoxyphenyl)-4-hydroxy-1H-indol-3-carboxamide.

18. Connection on p. 1, which is N-(3-ethoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

19. Connection on p. 1, which is N-(4-isopropoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

20. Connection on p. 1, which is N-(4-forfinal)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

21. Connection on p. 1, which is N-(3-fluoro-4-methoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

22. Connection on p. 1, which is N-(2-fluoro-4-isopropoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indolol-3-carboxamide.

24. Connection on p. 1, which is N-(4-were)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

25. Connection on p. 1, which is N-(3-were)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

26. Connection on p. 1, which is N-(2-forfinal)-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

 

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