Tricyclic cytoprotective compounds

FIELD: chemistry.

SUBSTANCE: use of compounds of formula (I): where: X denotes >CR1R2 or, when R6 denotes H, X denotes >SO2; Y denotes >CR1R2; Z denotes >C=O, >CH2, single bond; R1 denotes H, R2 denotes H, -COOH, -OH; or R1 and R2 together denote =O, ethylenedioxy or hydroxyimino group; R3 denotes H, lower alkyl group; R4 denotes two H, =O, hydroxyimino group; R5 denotes H, lower alkyl group, halogen; R6 denotes H, lower alkoxy, COOH; R7 and R8 are identical or different from each other and each denotes H, lower alkyl, halogen; and pharmaceutically acceptable salts thereof and esters for preparing a medicinal agent.

EFFECT: agent having neuroprotective action against hypoxia.

2 tbl, 24 ex, 13 cl

 

The present invention relates to the treatment or prevention of chronic and acute neurodegenerative diseases or conditions with the use of certain tricyclic neuroprotective compounds. Chronic conditions include diseases such as Alzheimer's disease, Parkinson's disease, Huntington's chorea and multiple sclerosis. Acute conditions include effects after acute ischemia, such as heart attack, stroke or head injury. The compounds are also suitable for the prevention or treatment of damage caused by ischemic stress peripheral organs (that is, any functional tissue in the body except the brain and spinal cord), such as the heart or kidneys.

In tissues exposed to conditions with lack of oxygen, such as prolonged hypoxia and ischemia, which may be associated or not associated with hypoglycemia, occurs neuronal damage to varying degrees. Ischemia usually occurs due to an acute event such as heart attack, stroke or traumatic head injury. During a heart attack resulting damage is limited essentially by the tissues of the heart, and developed certain ways of treatment. Upon impact or traumatic head injury, stand idania neurons occurs as a result of exposure to prolonged ischemia on the brain. The severity of ischemia depends on the nature of the impact or damage, but invariably there is brain damage. WO 99/31049 refers to the effects of ischemia on the brain, such as is performed in patients with stroke or head injury, and describes certain neuroprotective agents and their use in the treatment of neuronal damage caused by acute ischemia, such as stroke and head injury.

In contrast to the neuronal damage resulting from cases of acute ischemia, such as heart attack, stroke or head injury, the underlying causes of chronic neurodegenerative diseases or conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's chorea (HC), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), are complex and, apparently, are determined by many factors. In each case, necrotic and apoptotic cell death of neurons may result from the actions of one or several mechanisms, including the weakening of metabolism, excitotoxicity and oxidative stress. A number of studies points to oxidative stress as the main factor in the occurrence of many chronic neurodegenerative diseases, including AD, PD and ALS (for example, see: Sayre et al., (2001), Curr. Med. Chem, 8(7), 721-38; Bains et al. (1997), Brain Res. Rev., 25, 335-358; Alexi et al. (2000), Progress in Neurobiol, 60, 409-470).

Oxidative stress occurs when upsets the balance between oxidative events and mechanisms of antioxidant protection, either because of the loss of reducing agents and/or antioxidants, or because of the increased levels of oxidants. Oxidative stress has been attributed to the toxic effects of free radicals, including reactive oxides (ROS)such as superoxide anion (*O2-) and hydroxyl radical (*OH), and reactive derivatives of nitrogen (RNS)generated by the reaction of nitric oxide (NO) with superoxide or peroxide, such as peroxynitrite (*ONOO-).

Excitotoxicity cell death is caused by excessive activation of glutamate receptors by glutamate and glutamate agonists such as NMDA and other excitatory amino acids (EAA). Some research also suggests that oxidative stress may act as a mediator excitotoxicity induced cell death of neurons. For example, shows how to NMDA and kainate (non-NMDA receptor agonist)that activation of EAA receptors increases the damage of lipids by free radicals and that this damage can be prevented by simultaneous treatment with antioxidants.

p> The weakening of metabolism may be caused by shock, asphyxia, hypoglycemia and certain poisons, and engaged in mitochondrial respiration. Mitochondrial dysfunction and the resulting depletion of ATP and loss of buffering capacity of intracellular calcium may cause increased production of reactive oxygen radicals and nitrogen, leading to oxidative stress.

Thus, not only oxidative stress under the action of free radicals, as understood, is the primary factor in cell death of neurons in a number of chronic neurodegenerative diseases, but it can also mediashout excitotoxicity incentives and weakening metabolism. In addition, can also be the reverse interaction, because oxidative stress under the action of free radicals can initiate excitotoxicity path and cause metabolic disorders.

The authors have now found that certain tricyclic compounds can be used for treatment of chronic and acute neurodegenerative diseases or conditions and to prevent or treat damage caused by ischemic stress, peripheral organs such as the heart or kidneys.

Thus, the present invention provides the use of compounds of formula (I) and their headlights is asepticheski acceptable salts and esters for the manufacture of a medicinal product for the treatment or prevention of acute or chronic neurodegenerative diseases or conditions and to protect against ischemic tissue damage in peripheral organs. Used compounds have the formula (I):

in which:

X represents a group of formula >CR1R2or, when R6does not represent a hydrogen atom, a group of the formula >SO2;

Y represents a group of formula >NH or >CR1R2;

Z represents a group of formula >C=O group of the formula >CH2or a direct link;

R1represents a hydrogen atom and R2represents a hydrogen atom, carboxy group or hydroxy group;

or

R1and R2together represent an oxo group, methylenedioxy group or hydroxyimino group;

R3represents a hydrogen atom or a lower alkyl group;

R4represents two hydrogen atoms or oxo, or hydroxyimino group;

R5represents a hydrogen atom, a lower alkyl group or halogen atom;

R6represents a hydrogen atom, a lower alkoxy group or a carboxy group;

R7and R8are the same or different from each other, and each represents a hydrogen atom, a lower alkyl group or halogen atom;

and salts and esters when the compound contains a carboxy group.

Certain compounds of formula (I) predstavljaetsja new connections by themselves.

In the compounds of the present invention, Z may represent a direct link, in this case, it forms part of a 5-membered ring fused with 5-membered nitrogen-containing heterocyclic ring, or it can represent a group of formula >CH2or >C=O, in which case it forms part of a 6-membered ring.

When R3, R5, R7or R8represent a lower alkyl group, it may represent an alkyl group with straight or branched chain, having from 1 to 10, preferably from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, sawn, ISO-propyl, boutelou, second-boutelou, tert-boutelou, pentelow, isopentanol, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexeline, isohexanol, heptylene, octillo, nonlow and decile groups, of which methyl, ethyl, sawn, bucilina and exilda group are preferred, and methyl and ethyl group are more preferred, and a methyl group is most preferable.

When R5, R7or 8represents a halogen atom, it may be a fluorine atom, chlorine, bromine or iodine, of which fluorine atoms and chlorine are preferred.

When R6represents a lower alkoxy group, it may represent an alkoxy group with a straight or branched chain, having from 1 to 10, preferably from 1 to 6 carbon atoms.

Examples of such groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, 2-methylbutoxy, 1 ethylpropoxy, 4-methylpentylamino, 3 methylpentane, 2-methylpentane, 1 methylpentylamine, 3,3-Dimethylbutane, 2,2-Dimethylbutane, 1,1-Dimethylbutane, 1,2-Dimethylbutane, 1,3-Dimethylbutane, 2,3-Dimethylbutane, 2-ethylbutane, hexyloxy, etexilate, heptyloxy, octyloxy, nonyloxy, decyloxy group, of which methoxy, ethoxy, propoxy butoxy, hexyloxy group are preferred, and methoxy, ethoxy group are more preferred, and methoxy group is most preferred.

Of the compounds of the present invention, the authors are especially preferred those in which:

X represents a group of formula >CR1R2where R1represents a hydrogen atom and R2represents a hydrogen atom, hydroxy group or carboxy group is, or R1and R2together, represent an oxo group or methylenedioxy group;

Y represents a group of formula >CR1R2where R1represents a hydrogen atom and R2represents a hydrogen atom or a carboxy group;

R3represents a hydrogen atom;

R4represents two hydrogen atoms or oxo group;

R5represents a hydrogen atom;

R6represents a hydrogen atom, a C1-C4alkoxy group or a carboxy group; and R7and R8are the same or different from each other and each represents a hydrogen atom or a C1-C4alkyl group;

and their salts and esters.

Specific examples of the compounds of the present invention is presented in the following further Table 1:

Table 1
1
2
3
4
6
7
8
9
10*
11*
12
13
14
15
16
17
18
19*
20

21
22
23

In the above Table 1, those compounds that are marked with an asterisk, are themselves new compounds and are also part of the present invention. The most preferred compounds of the present invention are compounds with numbers 4, 6, 7, 8, 10, 14, 15, 16, 17, 20, 21, 22 and 23 in the above Table.

When the compounds of the present invention contain a carboxy group, for example when R1or R6represents a carboxy group, the compounds of the present invention can form esters, which can be obtained by conventional methods of esterification. There are no limitations on the nature of ester, provided that when the compound obtained should be used in medicine, the compound is a pharmaceutically acceptable, i.e. it is neither less active or is less active or more toxic or unacceptably more toxic than the original compound. However, when the connection should be used for non-medical applications, nab is emer, as intermediate compounds in the production of other compounds, even this restriction does not apply and there are no restrictions on the nature of the esters that may be generated.

Examples of ester groups include:

alkyl groups having from 1 to 20 carbon atoms, more preferably from 1 to 10 carbon atoms, such as those illustrated with respect to R3, R5, R7or R8and higher alkyl groups as those well known in this field, such as Godzilla, redecilla, pentadactyla, octadecyl, Donatella and Casilina group;

cycloalkyl group having from 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo and cycloheptyl group;

kalkilya groups in which the alkyl part has from 1 to 3 carbon atoms and the aryl part is a carbocyclic aromatic group having from 6 to 14 carbon atoms which may be substituted or unsubstituted; examples of such Uralkalij groups include benzyl, fenetylline, 1-phenylethylene, 3-phenylpropanol, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, benzhydryl (i.e. diphenylmethyl), triphenylmethyl, bis(o-nitrophenyl)methyl, 9-and trimethylol, 2,4,6-trimethylbenzyl, 4-brombenzene, 2-nitrobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 4-methoxybenzyl and piperonyl group;

alkeneamine group having from 2 to 6 carbon atoms, such as vinyl, allyl, 2-methylaniline, 1-protanilla and isopropylene group;

halogenated alkyl groups having from 1 to 6, preferably from 1 to 4 carbon atoms such as 2,2,2-trichlorethylene, 2-halogenation (for example, 2-chloraniline, 2-florachilena, 2-brometalia or 2-Jogaila), 2,2-dibromoethylene and 2,2,2-tribromaniline group;

substituted serialkiller group, for example 2-three(C1-C4)alkyltrimethylenedi group, in particular 2-trimethylsilylethynyl group;

substituted and unsubstituted phenyl groups, for example phenyl, Tomilina and benzamidophenyl group;

substituted and unsubstituted fenceline groups, such as myself penicilina group or p-brompheniramine group;

cyclic and acyclic terpinolene group, for example geronilla, nerilka, linella, matchlock, Mantilla (in particular,mandp-Mantilla), Tugela, Carolina, pinnella, bornilla, naccarella, nobinonly, norbornylene, montanella, Campanella and norbornylene group;

alkoxymethyl groups in which the alkoxy part has from 1 to 6, the preferred is sustained fashion, from 1 to 4 carbon atoms and may itself be substituted by a single unsubstituted alkoxy group, such as methoxymethyl, ethoxymethylene, propoxymethyl, isopropoxyaniline, butoxymethyl and methoxyethoxymethyl group;

aliphatic aryloxyalkyl groups in which the acyl group preferably represents alkanoyloxy group, and more preferably, is alkanoyloxy group having from 2 to 6 carbon atoms, and the alkyl part has from 1 to 6 and preferably from 1 to 4 carbon atoms, such as acetoxymethyl, propionylthiocholine, butyrylcholine, isobutyrylacetate, pivaloyloxymethyl, 1-pivaloyloxymethyl, 1-acetoxyethyl, 1-isobutyrylacetate, 1-pivaloyloxymethyl, 2-methyl-1-pivaloyloxymethyl, 2-pivaloyloxymethyl, 1-isobutyrylacetate, 1-isobutylacetophenone, 1-acetoxypropionyl, 1-acetoxy-2-methylpropyl, 1-propionylcarnitine, 1-propionoxypiperidine, 2-acetoxypropionyl and 1-butyrolacetone group;

cycloalkyl-substituted aliphatic aryloxyalkyl groups in which the acyl group preferably represents alkanoyloxy group, and more preferably, is alkanoyloxy group having from 2 to 6 carbon atoms, cycloalkenyl replace the Titel has from 3 to 7 carbon atoms and the alkyl part has from 1 to 6, preferably, from 1 to 4 carbon atoms, such as cyclohexylacetophenone, 1-(cyclohexyloxy)ethyl, 1-(cyclohexylmethoxy)through 2-methyl-1-(cyclohexylmethoxy)through cyclopentanecarbonitrile, 1-(cyclopentyloxy)ethyl, 1-(cyclopentyloxy), sawn and 2-methyl-1-(cyclopentyloxy)various groups;

alkoxycarbonylmethyl groups, in particular 1-(alkoxycarbonyl)ethyl groups such as 1-methoxycarbonylmethylene, 1-ethoxycarbonylmethylene, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonyloxyimino, 1-msobuttoniconandcaption, 1-second-butoxycarbonyloxyimino, 1-tert-butoxycarbonyloxyimino, 1-(1-ethyl-propoxycarbonyl)ethyl and 1-(1,1-dipropylenetriamine)ethyl group, and other alkoxycarbonylmethyl group in which the alkoxy and alkyl groups have from 1 to 6, preferably from 1 to 4 carbon atoms such as 2-methyl-1-(isopropoxycarbonyl)through 2-(isopropoxycarbonyl)through isopropoxycarbonyloxymethyl, tert-butoxycarbonyloxyimino, methoxycarbonylmethylene and ethoxycarbonylmethylene group;

cycloalkylcarbonyl and cycloalkylcarbonyl group, for example 1-methylcyclohexene oneloceracina, 1-methylcyclohexanecarboxylic, cyclopentanecarboxaldehyde, cyclopentanecarboxaldehyde, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclopentanecarbonyl)ethyl, 1-(cyclopentanecarbonyl)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclohexylcarbonyl)ethyl, 1-methylcyclohexanecarboxylic, 1-methylcyclohexanecarboxylic, 2-methyl-1-(1-methylcyclohexanecarboxylic)through 1-(1-methylcyclohexanecarboxylic)through 2-(1-methylcyclohexanecarboxylic)through 1-(cyclohexyloxycarbonyloxy)through 2-(cyclohexyloxycarbonyloxy), sawn, 2-methyl-1-(1-methylcyclopentadienyl)through 1-(1-methylcyclopentadienyl)through 2-(1-methylcyclopentadienyl)through 1-(cyclopentanecarbonyl)through 2-(cyclopentanecarbonyl)through 1-(1-methylcyclopentadienyl)ethyl, 1-(1-methylcyclopentadienyl)through adamantanecarboxylic, adamantankarboksilato, 1-adamantanecarboxylic and 1-adamantankarboksilato group;

cycloalkylcarbonyl group, for example cyclopropanecarboxylate, cyclobutanedicarboxylate, cyclopentyloxy Velocimetry, cyclohexyloxycarbonyloxy, 1-(cyclopropylmethoxy)ethyl, 1-(cyclobutanedicarboxylate)ethyl, 1-(cyclopentanecarbonyl)ethyl and 1-(cyclohexyloxycarbonyloxy)ethyl group;

technicianlocation and terminologiemanagement group, for example 1-(methyloxycarbonyl)ethyl, 1-(methylcarbonate)ethyl, methoxycarbonylmethylene, methylcarbamoylmethyl, 1-(3-pennicornis)ethyl, 1-(3-pennicornis)ethyl, 3-pinaysexscandaldownload and 3-finanisirovaniya group;

5-alkyl or 5-phenyl-(2-oxo-1,3-dioxolan-4-yl)alkyl groups, such as (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-phenyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-tert-butyl-2-oxo-1,3-dioxolan-4-yl)methyl and 1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)ethyl group; and

other groups, in particular groups, which are easily removed in vivo, such as felicilda, indayla and 2-oxo-4,5,6,7-tetrahydro-1,3-benzodioxole-4-ilen group.

Also, if the compounds of the present invention contain a carboxy group, they may be converted to salts with bases by conventional methods. There is no any limitation on the nature of such salts, provided that when those with the organisations should be used in medicine, compounds are pharmaceutically acceptable. However, when the connection should be used for non-medical applications, for example as intermediate compounds in the production of other compounds, even this restriction does not apply and there is no restriction on the nature of the salts which may be formed. Examples of such salts include: salts of alkaline metal such as sodium, potassium or lithium; salts of alkaline earth metal such as barium or calcium; salts of other metals, such as magnesium or aluminum; ammonium salts; salts of organic bases, such as salt of methylamine, dimethylamine, triethylamine, Diisopropylamine, cyclohexylamine or dicyclohexylamine; and salts of basic amino acids, such as lysine or arginine. The authors prefer a pharmaceutically acceptable salt.

Compounds of the present invention can also be converted into salts with acids by conventional methods. There is no any limitation on the nature of such salts, provided that when the compound is to be used in medicine, the compounds are pharmaceutically acceptable. However, when the connection should be used for non-medical applications, for example as intermediate compounds in the production of other compounds, even this restriction does not apply and there is no limit n the nature of salts, which may be formed. Examples of such salts include: salts with mineral acids, in particular halogen acids such as hydrofluoric acid, Hydrobromic acid, uudistoodetena acid or hydrochloric acid), nitric acid, perchloro acid, carbonic acid, sulfuric acid or phosphoric acid; salts of lower alkylsulfonic acids, such as methanesulfonate acid, triftormetilfullerenov acid or econsultancy acid; salts arylsulfonic acids, such as benzolsulfonat acid or p-toluensulfonate acid; salts of organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid; and salts of amino acids such as glutamic acid or aspartic acid. The authors prefer a pharmaceutically acceptable salt.

The compounds used in the present invention, are either known or can be obtained by methods similar to those used to obtain the known compounds.

Compounds of the present invention can therefore be used l the treatment or prevention of chronic and acute neurodegenerative diseases or conditions or to protect against ischemic damage to tissues of the peripheral organs and for these purposes may be obtained in the form of ordinary pharmaceutical drugs, as is well known in this field. Thus, the compounds can be administered orally, for example in the form of tablets, capsules, granules, powders, syrups, sprays, or other such well-known forms, or parenterally, for example by means of injections, sprays, eye drops, adhesive patches or suppositories and the like.

These pharmaceutical preparations can be obtained using conventional methods and may contain a known auxiliary substances of the type commonly used in this field, such as carriers, binders, disintegrant, lubricants, stabilizers, modifiers, and the like depending on the intended use and form of the drug. The dose will depend on the condition, age and body weight of the patient, and the nature and severity of the disorder that must be treated, but in the case of oral administration to an adult patient is a human authors usually would suggest that the total daily dose of from 0.01 to 50 mg/kg of body weight (more preferably from 0.05 to 20 mg/kg body weight), which can be administered in one dose or in divided doses, for example, from one to three times a day.

The present invention is additionally illustrated using the following non-limiting Examples, of which Examples 1-23 illustrate the formation of compounds, while the AK Example 24 illustrates their therapeutic properties. In the Examples the following abbreviations are used: OSiR., broadened; s, singlet; d, doublet; t, triplet; q, Quartet; good service., exchanged; DCM, dichloromethane; DMF,N,N-dimethylformamide; HREIMS, mass spectroscopy high-resolution ionization by electron impact; HRFABMS, mass spectroscopy high-resolution fast atom bombardment; LRESMS, mass spectroscopy low-resolution elektrorazpredelenie; NMM, N-methylmorpholine; Pd/C palladium on coal; TPL, melting temperature; TFA, triperoxonane acid, THF, tetrahydrofuran; TLC, thin layer chromatography; SFM, medium without serum; MEM, minimum primary environment with salt Earl; DMSO, dimethyl sulfoxide. HREIMS and HRFABMS get on mass-spectrometer Jeol® JMS AX505HA. LRESMS get Fisons® VG Platform Benchtop LC-MS. NMR spectra get spectrometer Bruker® AMX 400. IR spectra were obtained by KBr disks from and liquids in the form of films, using a Nicolet® Impact 400D. Column chromatography carried out on silica gel Prolabo® (200-400 mesh). The numbers of the compounds mentioned in the Examples are the same as those assigned to the compounds in the above Table 1.

Example 1

2,3,4,9-Tetrahydro-1H-carbazole-2-carboxylic acid [Compound No. 1]

3-Oxocyclohexanecarboxylic acid (200 mg, 1,407 mmol) dissolved in acetic acid (3 ml), to which add a solution of phenylhydrazine (160 mg, 1,480 mmol) luxusni acid (2 ml) at room temperature under stirring. The reaction mixture is heated at the boil under reflux for 2 hours. Then the reaction mixture is cooled to room temperature, diluted with ethyl acetate and extracted with a saturated solution of salt. The organic layers are collected and dried (Na2SO4) and the solvent is removed under reduced pressure. The crude product is recrystallized from ethyl acetate/n-hexane to obtain light brown microcrystalline solid (191 mg, 63%), TPL 235-238°C [see Asselin, A. A., et al., J. Med. Chem., 1976,19, 787-792, TPL 239-241°C; Allen, et al., J. Heterocyclic Chem., 1970, 7, 239-241, TPL 233-235°C]. IR (KBr): 3416, 3048, 2923, 2844, 1689, 1465, 1444, 1415, 1288, 1264, 1226, 935, 740 cm-1.1H NMR (DMSO-d6): δ 12,27 (1H, s), 10,66 (1H, s), 7,33 (1H, d, J=7,6 Hz), 7,24 (1H, d, J=7,6 Hz), 6,98 (1H, dt, J=1.2 Hz and J=6.8 Hz), 6,91 (1H, dt, J=1.2 Hz and J=6.8 Hz), 2,89-2,62 (5H, m), 2,17 (1H, m), 1,87-of 1.81 (1H, m).

Example 2

1,2,3,4-Tetrahydrocyclopent[b]indole-2-carboxylic acid [Compound No. 2]

3-Oxocyclopentanecarboxylate acid (200 mg, 1,561 mmol) dissolved in acetic acid (3 ml), to which is added phenylhydrazine (180 mg, 1,665 mmol) in acetic acid (2 ml) at room temperature, with stirring. The reaction mixture is heated at the boil under reflux for 2 hours. Then it is allowed to cool to room temperature, diluted with ethyl acetate and extracted on Ishenim salt solution. The organic layers are collected and dried (Na2SO4) and the solvent is removed under reduced pressure to obtain a black mass, which is used for column chromatography on silica gel using ethyl acetate/hexane, 1/1, for elution of the product. The fractions containing the desired material (RF=0,50), is collected and the solvents removed under reduced pressure. The product is recrystallized from ethyl acetate/hexane to obtain light brown microcrystalline solid (48 mg, 15%), TPL 215-217°C [see Lacoume, B.; Milcent, G. and Olivier, A., Tetrahedron, 1972, 28, 667-674, TPL 215°C]. IR (KBr): 3362, 3028, 2910, 2859, 1691, 1438, 1411, 1323, 1277, 1238, 741 cm-1.1H NMR (DMSO-d6): 12,27 (1H, s), 10,81 (1H, s), 7,31 (1H, d, J=7,6 Hz), 7,27 (1H, d, J=7,6 Hz), 6,97 (1H, dt, J=1.2 Hz and J=6.8 Hz), 6,92 (1H, dt, J=1.2 Hz and J=6.8 Hz), 3,76-3,68 (1H, m), 3,09-3,03 (3H, m), 2,95 (1H, m).

Example 3

1,2,3,9-Tetrahydro-4H-carbazole-4-one [Compound No. 3]

(1E)-1,3-Cyclohexanedione 1-(phenylhydrazone) (2,031 g 10,045 mmol) was dissolved in TFA (10 ml) at room temperature under stirring. The reaction mixture is heated at the boil under reflux for 8 hours, after which it was left at room temperature over night. The resulting dark colored solution is slowly poured into ice water with stirring. Semi-solid material is extracted with ethyl acetate and dried (MgSO ) and the solvent is removed under reduced pressure to obtain a pale yellow solid, which upon recrystallization from methanol gives 1,004, the mother liquid is concentrated and used for column chromatography on silica gel using ethyl acetate/n-hexane (1/1) RF=0.15 additional quantity of the product as a white solid (80 mg) after recrystallization from methanol. The total mass of the resulting product is equal 1,084 g, 58%, TPL 226-228°C [Clemo, G.R. and Felton, D.G.I, J. Chem. Soc. 1951,700-702, TPL 223°C]. IR (KBr): 3144, 2937, 1622, 1581, 1468, 1406, 1250, 1175, 1140, 751 cm-1.1H NMR (DMSO-d6): 11,83 (1H, user.); of 7.95 (1H, DD, J=2.3 Hz & J=6,7 Hz); 7,39 (1H, DD, J=1.3 Hz & J=6.3 Hz); 7.18 in-7,11 (2H, m); 2,96 (2H, t, J=6,1 Hz); 2,42 (2H, t, J=6,1 Hz); 2,12 (2H, q, J=6.4 Hz).

Example 4

2,3,4,9-Tetrahydro-1H-carbazole-3-ol [Compound No. 4)

To a solution of 4-hydroxycyclohexanone (0,970 g 8,220 mmol) in acetic acid (10 ml) is added dropwise phenyl hydrazine (1,216 g, 11,249 mmol) under stirring at room temperature. The material begins to crystallize almost immediately, and add additional acetic acid (5 ml) and ethanol (5 ml). Then the reaction mixture is heated at the boil under reflux for 3 hours. The obtained dark red solution was concentrated under reduced pressure to about 6 ml, and ZAT is m diluted with sufficient water to obtain opacity. Cooling and scratching causes crystallization. The mixture is filtered and the solid washed with water. Crystallization from methanol/water followed by recrystallization from ethyl acetate/n-hexane gives the desired product in the form of a yellowish-brown solid product (670 mg, 44%), TPL 148-150°C [Gardner, P.D.; Haynes, G.R. and Brandon, R.L., J. Org. Chem., 1957, 22, 1206-1210, TPL 148,5 at 149.5°C], RF=0,32 (ethyl acetate/n-hexane 1/1). IR (KBr): 3384, 2920, 2843, 1620, 1453, 1367, 1324, 1054,1004, 744, 637 cm-1.1H NMR (CDCl3): 7,81 (1H, user.); 7,52 (1H, d, J=7,4 Hz); 7,34 (1H, d, J=7,4 Hz); 7,19 (1H, t, J=6.3 Hz); 7,16 (1H, t, 6.3 Hz); 4,33 (1H, m); 3,18 (1H, DD, J=4,8 Hz & J=15.2 Hz); 2,98-to 2.74 (3H, m); 2,22-2,04 (2H, m); 1.77 in (1H, usher.).

Example 5

Connection # 5

This connection receive from Aldrich, UK, and it can be obtained through the method of Cox et al. (1995, Med. Chem. Res., 5 (9), 710-718) or Speitel et al. (1949, Helv. Chim., 32, 860).

Example 6

(a) Phenyl 1,4-dioxaspiro[4,5]decane-8-it

Phenylhydrazine (1,098 g 10,155 mmol) dissolved in toluene (20 ml), to which is added 1,4-dioxaspiro[4,5]decane-8-he (1,586 g 10,155 mmol). Then the reaction mixture is heated at the boil under reflux for 30 minutes, after which the solvent is removed under reduced pressure to obtain the product as an orange oil (at 2,370 g, 95%), which is used in the next reaction without addition the cleanup.

(b) 1,2,4,9-Tetrahydrofuro[carbazole-3,2'-[1,3-dioxolane] [Compound No. 6]

The phenyl 1,4-dioxaspiro[4,5]decane-8-she [2,360 g 9,581 mmol, obtained in stage (a)] is dissolved in ethylene glycol (25 ml). The reaction mixture is heated at 180°C for 4 hours and then allowed to cool to room temperature, after which it was poured into water at 0°C, extracted with dichloromethane (50 ml) and dried (MgSO4). The product is obtained in the form of a pink solid, which is recrystallized from ethyl acetate/n-hexane to obtain white solids (1,030 g, 47%), RF=0,75 (ethyl acetate/n-hexane, 1/1), TPL 146-148°C [Urrutia, A. and Rodriguez, J.G., Tetrahedron, 1999, 55, 11095-11108, TPL 146-148°C]. IR (KBr): 3405, 2975, 2897, 1620, 1587, 1463, 1436, 1373, 1296, 1152, 1097, 1054, 1019, 945, 739 cm-1.1H NMR (CDCl3): of 7.75 (1H, user.); the 7.43 (1H, d, J=7.5 Hz); 7,28 (1H, d, J=7,5); for 7.12 (1H, dt, J=6.0 Hz & 1.3 Hz); 7,07 (1H, dt, J=6.0 Hz & 1.3 Hz); 4,11-a 4.03 (4H, m), 2,98 (2H, s); 2,95 (2H, t, J=6.5 Hz); 2,09 (2H, t, J=6.5 Hz).

Example 7

1,2,4,9-Tetrahydro-3H-carbazole-3-one [Compound No. 7]

To a solution of 1,2,4,9-Tetrahydrofuro[carbazole-3,2'-[1,3-dioxolane] (200 mg, 8,723 mmol) in THF (30 ml) was added hydrochloric acid (7 ml, 15%). The mixture is stirred at room temperature for 2 hours, neutralized with sodium carbonate (solid), and then extracted with dichloromethane and dried (MgSO4). R is storytell removed under reduced pressure and the crude product purified by column chromatography using ethyl acetate/n-hexane (1/2) as eluent. The product is obtained as a white microcrystalline solid (120 mg, 65%), RF=0,17, TPL 156-158°C [Urrutia, A. and Rodriguez, J.G., Tetrahedron, 1999, 55,11095-11108, TPL 157-159°C]. IR (KBr): 3382, 2962, 2915, 1707, 1465, 1435, 1328, 1164, 990, 745 cm-1.1H NMR (CDCl3): 7,88 (1H, user.); was 7.45 (1H, d, J=7,7 Hz); to 7.35 (1H, d, J=7,7 Hz); 7,19 (1H, t, J=7,1 Hz); 7,13 (1H, t, J=7,1 Hz); 3,63 (2H, s); 3,19 (2H, t, J=6.9 Hz); 2,82 (2H, t, J=6.9 Hz).

Example 8

3,4-Dihydrocyclopenta[b]indol-1(2H)-he [Connection # 8]

Chilled on ice, a solution of 1,2,3,4-tetrahydrocyclopent[b]indole (1,006 g 6,361 mmol) in a mixture of THF (15 ml) and water (1.5 ml) deoxygenated by passing through it a stream of nitrogen for 10 minutes. Then it is kept in a nitrogen atmosphere, while a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3,206 g, 14,123 mmol)dissolved in THF (12 ml)is added dropwise within 10 minutes. Then stirring is continued for another one hour, the reaction mixture was allow to warm to room temperature during this period. Then evaporation of the solvent gives a reddish-brown solid residue, which is applied to the chromatographic column, and the products elute using only ethyl acetate. To clean this material use three columns. The product is obtained as yellow solid (300 mg, 28%), TPL 252-255°C (decomposition), RF=0,10 (utilize the al/n-hexane 1/1), [Rodriguez, J.G.; Temprano, F.; Esteban-Calderon, C; Martinez-Ripoll, M.; Garcia-Blanco, S., Tetrahedron, 1985, 41(18), 3813-3823, TPL 257-259°C]. IR (KBr): 3210, 1655, 1614, 1471, 1429, 1241, 1152, 1047, 738 cm-1.1H NMR (DMSO-d6): 12,01 (1H, user.); to 7.67 (1H, d, J=7,3 Hz); was 7.45 (1H, d, J=7,3 Hz); 7,21 (1H, dt, J=7,2 Hz & 1,4 Hz); to 7.15 (1H, dt, J=7,2 Hz & 1,4 Hz); is 3.08 (2H, m); 2,82 (2H, m).

Example 9

6-Methoxy-2,3,4,9-tetrahydro-1H-carbazole-3-ol [Compound No. 9]

4-Methoxyphenylhydrazine (0,644 g 3,688 mmol) is suspended in acetic acid (20 ml) and ethanol (10 ml). 4-Hydroxycyclohexanone (0,420 mg, 3,688 mmol) dissolved in acetic acid (10 ml)and then added to the reaction mixture at room temperature under stirring. The reaction mixture is heated at the boil under reflux for 3 hours. The solvent is partially removed under reduced pressure, and then the reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2×50 ml). The organic layers are collected and dried (MgSO4) and the solvents removed under reduced pressure to obtain brown oil. The crude product is purified by column chromatography using silica gel and ethyl acetate/n-hexane, 1/2). The fractions containing the desired material collected and the solvent is removed under reduced pressure to obtain product as a crystalline material (661 mg, 83%), TPL 100-103°C [C.W. Bird, A.G.H. Wee, J. Hetrocycl. Chem., 1985, 22, 191-192, TPL 103-106°C], RF=0,17 (ethyl acetate/n-hexane 1/1). IR (KBr): 3392, 2916, 2841, 1622, 1590, 1483, 1436, 1214, 1176, 1050, 1020, 830, 798 cm-1.1H NMR (CDCl3): 7,60 (1H, usher.), 7,19 (1H, d, J=8.7 Hz), 6,92 (1H, d, J=2.4 Hz), for 6.81 (1H, DD, J=2,4 & 8,71 Hz), the 4.29 (1H, m), 3,86 (3H, s), 3,09-to 2.67 (4H, m), 2,11-2,02 (2H, m)1,75 (1H, usher.).

Example 10

7,8-Dimethyl-2,3,4,9-tetrahydro-1H-carbazole-3-ol [Compound No. 10]

2,3-Dimethylphenylsilane (0,643 g 3,723 mmol) is suspended in acetic acid (20 ml) and ethanol (10 ml). 4-Hydroxycyclohexanone (425 mg, 3,723 mmol) dissolved in acetic acid (10 ml)and then added to the reaction mixture at room temperature under stirring. Then the reaction mixture is heated at the boil under reflux for 3 hours. The solvent is partially removed under reduced pressure, and then the reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2×50 ml). The organic layers are collected and dried (MgSO4) and the solvents removed under reduced pressure to obtain brown oil. The crude product is purified by column chromatography using silica gel and ethyl acetate/n-hexane, 1/2). The fractions containing the desired material collected and the solvent is removed under reduced pressure. The product is obtained in the form of a pale yellow microcrystalline material (410 mg, 51%), TPL 192-195 (in Russian)°C, R F=0,39 (ethyl acetate/n-hexane 1/1). IR (KBr): 3408, 2915, 2847, 1622, 1592, 1443, 1413, 1365, 1324, 1086, 1037, 795 cm-1.1H NMR (DMSO-d6): 10,32 (1H, s), 7,02 (1H, d, J=7.8 Hz), was 6.73 (1H, d, J=7.8 Hz), 4.72 in (1H, d, J=4.3 Hz), of 3.94 (1H, m), 2,87-to 2.67 (3H, m), 2,43 (1H, m), is 2.30 (3H, s), and 2.27 (3H, s)of 1.97 (1H, m), 1,78 was 1.69 (1H, m).

HRFABMS: Found 216,13952 calculated for C14H18ON 216,13884.

Example 11

5,8-Dimethyl-2,3,4,9-tetrahydro-1H-carbazole-3-ol [Compound No. 11]

2.5-Dimethylphenylsilane (0,643 g 3,723 mmol) is suspended in acetic acid (20 ml) and ethanol (10 ml). 4-Hydroxycyclohexanone (0,425 mg, 3,723 mmol) dissolved in acetic acid (10 ml)and then added to the reaction mixture at room temperature under stirring. Then the reaction mixture is heated at the boil under reflux for 3 hours. The solvent is partially removed under reduced pressure, and then the reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2×50 ml). The organic layers are collected and dried (MgSO4) and the solvents removed under reduced pressure to obtain brown oil. The crude product is purified by column chromatography using silica gel and ethyl acetate/n-hexane, 1/2). The fractions containing the desired material collected and the solvent is removed under reduced pressure. The product is obtained in the form of a pale yellow microcrystallites the th material (431 mg, 54%), TPL 158-161°C, RF=0,39 (ethyl acetate/n-hexane, 1/1). IR (KBr): 3423, 3269, 2930, 2852, 1615, 1580, 1514, 1456, 1378, 1327, 1054, 1030, 801 cm-1.1H NMR (DMSO-d6): 1041 (1H, s), is 6.61 (1H, d, J=7,3 Hz), of 6.52 (1H, d, J=7,3 Hz), 4.72 in (1H, d, J=4, 2 Hz), 3,93 (1H, m), 3,23 (1H, m), was 2.76-to 2.67 (3H, m), of 2.51 (3H, s), 2,32 (3H, s)to 1.98 (1H, m)of 1.73 (1H, m).

HRFABMS: Found 216,13783 calculated for C14H18ON 216,13884.

Example 12

8-Methoxy-1,3,4,5-tetrahydrothiopyrano[4,3-b]indole-2,2-dioxide [Compound No. 12]

4-Methoxyvaleronitrile (1,228 g 7,031 mmol) and tetrahydro-4H-thiopyran-4-one-1,1-dioxide (1,042 g 7,031 mmol) suspended in ethanol (25 ml). Then the reaction mixture is heated at the boil under reflux for 1 hour. The solid material which precipitates, is filtered off, washed with water and a small amount of ethanol, and then dried under reduced pressure at 60°C to give the desired material as a brown solid (789 mg, 45%), TPL 283-286°C (decomposition), IR (KBr): 3343, 2994, 2937, 1623, 1592, 1484, 1455, 1314, 1269, 1219, 1164, 1101, 1024, 892, 814 cm-1.1H NMR (DMSO-d6): of 10.93 (1H, s), 7,21 (1H, d, J=8.7 Hz), to 6.95 (1H, d, J=2.3 Hz), was 6.73 (1H, DD, J=2,4 & 8,7 Hz), to 4.38 (2H, s), 3,74 (3H, s), of 3.45 (2H, t, J=6,1 Hz), 3,23 (2H, t, J=6,1 Hz).

HRFABMS: Found 252,06877 calculated for C12H14O3NS 252,06944.

Example 13

2,3,4,9-Tetrahydro-1H-carbazole-6-carboxylic acid [Compound No. 13]

4-Hydrazinobenzene acid (760 mg, 4,995 mmol) and cyclohexanone (637 mg, 6,490 mmol) are mixed and heated at 70°C for 15 minutes, and then add sulfuric acid (20 ml, 10%) and the reaction mixture is heated at boiling under reflux with stirring for 30 minutes. The reaction mixture is cooled to room temperature and the resulting solid is filtered off, washed with water and dried under reduced pressure to obtain the desired product (1,010 g, 99%) as a pale brown solid, TPL 275-278°C [Burtner, Lehmann, J. Amer. Chem. Soc., 1940, 62(3), 527-532, TPL 279°C]. IR (KBr): 3399, 2941, 2907, 2848, 1671, 1615, 1465, 1412, 1316, 1275, 1247, 1127, 954, 771 cm-1.1H NMR (DMSO-d6): 12,23 (1H, usher.), br11.01 (1H, s), 8,01 (1H, s), to 7.64 (1H, DD, J=1,6 & 8,4 Hz), 7,29 (1H, d, J=8,4 Hz), a 2.71 (2H, t, J=5.0 Hz), to 2.65 (2H, t, J=5.0 Hz), 1.85 to to 1.79 (4H, m).

Example 14

1-Oxo-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid [Compound No. 14]

4-Hydrazinobenzene acid (760 mg, 4,995 mmol) and 2-methoxycyclohexanone (960 mg, 7,493 mmol) are mixed together and heated at 80°C for 15 minutes, and then add sulfuric acid (30 ml, 10%) and the reaction mixture is heated at the boil under reflux for 30 minutes under stirring. After cooling, the precipitated precipitated material is filtered off, washed with water and n-hexane and dried under reduced pressure is. The product is obtained as a brown solid (517 mg, 45%), TPL 275-280°C, although most of the material sublimates [S., Desikachari, P., Karnam, J. Rajend, Heterocycles, 1986,24(3). 711-717, TPL 285-286°C]. Some of this material is further purified by column chromatography using silica gel and ethyl acetate/methanol, 1/1. The fractions containing the product are collected and the solvents removed under reduced pressure to obtain yellow solid. IR (KBr): 3248, 2931, 1680, 1650, 1612, 1417, 1326, 1258, 1162, 901, 826, 770 cm-1.1H NMR (DMSO-d6): 11,60 (1H, s), 8,32 (1H, s), of 7.96 (1H, d, J=8.6 Hz), 7,34 (1H, d, J=8.6 Hz), 2,95 (2H, t, J=6.4 Hz), to 2.55 (2H, t, J=6.4 Hz), and 2.14 (2H, t, J=6.4 Hz).

Example 15

6-Methoxy-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylic acid [Compound No. 15]

This material was obtained in accordance with standard procedure in the literature (yield 80%) as a white solid, RF=0,22 (ethyl acetate/n-hexane, 1/1), TPL 226-228°C [Allen, J. Heterocycl. Chem., 1970, 7, 239, TPL 226-227 of°C]. IR (KBr): 3386, 2926, 1695, 1591, 1481, 1457, 1432, 1287, 1243, 1214, 1133, 1029, 949, 809 cm-1.1H NMR (DMSO-d6): of 12.26 (1H, usher.), 10,48 (1H, s), 7,13 (1H, d, J=6.6 Hz), PC 6.82 (1H, d, J=2.4 Hz), 5,54 (1H, DD, J=2,4 & 8,7 Hz), and 3.72 (3H, s), 2,85 at 2.59 (5H, m), and 2.14 (1H, m), is 1.81 (1H, m).

Example 16

Easy-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-silt ester [Compound 16]

4-Methoxypyrazine drochloride (1,746 g, 0.01 mol) is suspended in acetic acid (10 ml) and heated to 80°C under stirring. Cyclohexanone (1,00 g, 0.01 mol) is added dropwise with stirring. The reaction mixture is heated for 1 hour, cooled to room temperature, and then kept in the refrigerator over night. The color of the reaction mixture changed to dark brown. The solid is filtered off and washed with a small amount of acetic acid. Additional material extracted from the filtrate. The combined solids are dried under reduced pressure to obtain a whitish crystalline material (1,596 g, 79%), TPL 108-110°C [Clark, D.W., Jackson, A.H.; Prasirpan, N. and Shannon, P.V.R., J. Chem. Soc. Perkin Trans. II, 1982, 909-916, TPL 94-96°C], RF=0,50 (ethyl acetate/n-hexane 1/4). IR (KBr): 3389, 2915, 2845, 1622, 1589, 1482, 1434, 1218, 1134, 1028, 826, 798 cm-1.1H NMR (DMSO-d6): accounted for 10.39 (1H, s), 7,11 (1H, d, J=8.7 Hz), for 6.81 (1H, d, J=2.4 Hz), 6,62 (1H, DD, J=2,4 & 8.6 Hz), to 3.73 (3H, s)to 2.67 (2H, t, J=5.4 Hz), to 2.57 (1H, t, J=5.8 Hz), 1,82-to 1.77 (4H, m).

Example 17

7-Methoxy-1,2,3,4-tetrahydrocyclopent[b]indole [Compound No. 17]

The procedure used is the same as described in Example 16. The product is obtained as a brown solid (yield 65%), TPL 128-130°C, RF=0,60 (ethyl acetate/n-hexane, 1/4, and the plate for TLC aluminium oxide. This material decomposes when it is applied to silica gel TLC). IR (KBr: 3317, 2898, 2849, 1581, 1456, 1432, 1298, 1206, 1168, 1085, 1025, 846, 787 cm-1.1H NMR (DMSO-d6): 10,45 (1H, s), 7,21 (1H, d, J=8,8 Hz), 6.87 in (1H, d, J=2.4 Hz), to 6.67 (1H, DD, J=2,5 & 8,7 Hz), of 3.78 (3H, s), 2,85 (2H, t, J=6,7 Hz), was 2.76 (2H, t, J=6,7 Hz), 2,48 (2H, quintet, J=7,3 Hz).

HRFABMS: Found 188,10749 calculated for C12H14NO 188,10754.

Example 18

1,2,3,4-Tetrahydrocyclopent[b]indole-7-carboxylic acid [Compound No. 18]

4-Hydrazinobenzene acid (637 mg, 4,187 mmol) is suspended in acetic acid (10 ml) and heated to 50°C. Cyclopentanone (352 mg, 4,187 mmol) is added dropwise with stirring to the reaction mixture, which was then heated to 110°C for 1 hour. In the course of the reaction is a clear light brown solution. Then the reaction mixture is cooled to room temperature and the yellow solid which precipitates, is filtered off and washed with a small amount of acetic acid (dilute) and water, and then dried under reduced pressure at 45°C to obtain 4-(2-cyclopentenopyridine)benzoic acid (711 mg, 78%), TPL 250-253°C. Hydrazono intermediate compound (300 mg, mmol) is suspended in sulfuric acid (3 ml, 10%) and heated at the boil under reflux for 15 minutes. Solid lilac material which is formed is filtered off after the solution is cooled to room temperature, prom is provide with water and dried under reduced pressure (30 mg, 11%), TPL 270-274°C (most of the material sublimates and is registered melting point subliminality crystals). IR (KBr): 3380, 2946, 1656, 1616, 1473, 1410, 1347, 1295, 1261, 1129, 770, 746 cm-1.1H NMR (DMSO-d6): 11,17 (1H, s), 7,98 (1H, s), a 7.62 (1H, DD, J=1,6 & 8,5 Hz), 7,32 (1H, d, J=8.5 Hz), and 2.83 (2H, t, J=7.5 Hz), 2,77 (2H, t, J=6.8 Hz), 2,47 (2H, quintet, J=7.2 Hz).

HRFABMS: Found 202,08733 calculated for C12H12NO2202,08680.

Example 19

5,8-Dimethyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylic acid [Compound No. 19]

N-(2,5-Dimetilfenil)hydrazinehydrate (243 mg, 1,407 mmol) dissolved in acetic acid (3 ml), to which is added 3-oxocyclohexanecarboxylic acid (200 mg, 1,407 mol)dissolved in acetic acid (2 ml), under stirring. The reaction mixture is heated at the boil under reflux for 2 hours. The cooled reaction mixture is diluted with saturated salt solution and extracted with ethyl acetate. The organic layer is dried (MgSO4) and the solvent is removed under reduced pressure. The crude product is applied to the chromatographic column with silica gel using ethyl acetate/n-hexane (1/4) as eluent (RF=0,50, ethyl acetate/n-hexane, 1/1). The product is obtained as yellow solid (153 mg, 45%), TPL 228-230°C. IR (KBr): 3390, 2928, 1702, 1436, 1294, 1230, 946, 800 cm-1.1H NMR (who MCO-d 6): 12,21 (1H, s), 10,46 (1H, s), 6,63 (1H, d, J=7,2 Hz), is 6.54 (1H, d, J=7,2 Hz), 3,01-to 2.74 (5H, m)of 2.50 (3H, s), of 2.34 (3H, s)to 2.13 (1H, m), is 1.81 (1H, m).

HRFABMS: Found 244,13394 calculated for C15H18NO2244,13375.

Example 20

The oxime (4E)-1,2,3,9-tetrahydro-4H-carbazole-4-it [Compound No. 20]

A mixture of 1,2,3,4-tetrahydrocarbazol-4-it (450 mg, UAH 2.432 mmol) hydroxylaminopurine (253 mg, 3,640 mmol, molar excess of 1.5), sodium acetate (298 mg, 3,640 mmol, molar excess of 1.5), ethanol (5 ml) and water (2 ml) is heated at boiling under reflux in nitrogen atmosphere for 4 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in water. The crystalline material is collected by filtration, washed with water and dried under reduced pressure to get crude product (410 mg, 84%), TPL 200-205°C (decomposition). This material is subjected to chromatography on silica gel using ethyl acetate/n-hexane, 1/3 (RF=0,35). The product is obtained in form of white crystalline material (380 mg, 78%), TPL 206-208°C (decomposition), (Hester, J.B., J.Org.Chem., 1967, 52, 3804-3807, TPL 208,5-210°C). IR (KBr): 3415, 29-25,1620, 1556, 1481, 1451, 1418, 920, 890, 853, 746 cm-1.1H NMR (DMSO-d6): 11,19 (1H, s)of 10.21 (1H, s), 7,89 (1H, d, J=7,6 Hz), 7,31 (1H, d, J=7,6 Hz), 7,08 of 5.99 (2H, m), and 2.79 (2H, t, J=6,1 Hz)to 2.67 (2H, t, J=6,1 Hz), at 1.91 (2H, quintet, J=6.2 Hz).

Example 21

The oxime (3E)-1,2,4,9-tetrahydro-3H-carb is evil-3-one [Compound No. 21]

The procedure used is the same as that described in Example 20. The desired product is obtained as light brown solid (20 mg, 22%), TPL 173-175°C (decomposition), RF=0,35 (ethyl acetate/n-hexane, 1/3). IR (KBr): 3392, 3280, 1461, 14, 39, 1356, 1327, 1224, 1004, 920, 741 cm-1.1H NMR (DMSO-d6): of 10.76 (1H, s)10,52 (1H, s), 7,39 (1H, d, J=7,7 Hz), 7,27 (1H, d, J=7,7 Hz), 7,02 (1H, t, J=7.0 Hz), 5,94 (1H, t, J=7.0 Hz), 3,50 (2H, s), 2,87 (2H, t, J=6.5 Hz), 2,60 (2H, t, J=6.5 Hz).

HREMS Found 200,09506 calculated for C12H12N2O 200,09496.

Example 22

Synthesis of Compound No. 22

4-Methoxyvaleronitrile (1,172 g 6,712 mmol) dissolved in water (25 ml), to which is added a saturated sodium bicarbonate until then, until the solution is basic and will not be stopped bubbling. Add dichloromethane and the organic layers are collected after extraction. Drying (MgSO4with the subsequent removal of the solvent gives the desired material as a pale yellow crystalline material, which is used in the next stage without additional purification (0,710 g). To 4-methoxypyrazine add ketone (806 mg, 5,160 mmol), and then toluene (50 ml). The reaction mixture is heated at the boil under reflux for 30 minutes and then the solvent is removed under reduced pressure to obtain the product ,4-dioxaspiro[4,5]decane-8-he (4-methoxyphenyl)hydrazone, in the form of a brown oil, which is used in the next stage without additional purification. Add ethylene glycol (20 ml) and the reaction mixture is heated at 180°C for 3 hours in nitrogen atmosphere. The cooled solution was poured into ice water and extracted with dichloromethane. The organic layers are collected and dried (MgSO4) and the solvent is removed under reduced pressure to obtain a dark brown oil. Purification using column chromatography on silica gel and elution with ethyl acetate/n-hexane (1/3) to give the desired product as a pale yellow microcrystalline material after recrystallization from ethyl acetate/n-hexane (630 mg, 36%), TPL 168-169°C. IR (KBr): 3345, 2891, 1627, 1597, 1483, 1456, 1326, 1212, 1139, 1120, 1101, 1062, 1031, 951 cm-1.1H NMR (DMSO-d6): 10,50 (1H, s), 7,13 (1H, d, J=8.7 Hz), for 6.81 (1H, d, J=2,8 Hz), only 6.64 (1H, DD, J=2,5 & 8,7 Hz), of 3.95 (2H, s), of 3.73 (3H, s), of 2.81 (4H, s & t)of 1.94 (2H, t, J=6,7 Hz).

HREIMS Found 259,12065 calculated for C15H17NO3259,12084.

Example 23

6-Methoxy-1,2,4,9-tetrahydro-3H-carbazole-3-one [AIK-18/49]

Source material (375 mg, 1,446 mmol, obtained as described in Example 22), dissolved in tetrahydrofuran (10 ml) and hydrochloric acid (10 ml, 50%) under stirring at room temperature. The reaction mixture is heated at 40-50°C for 4 hours. To the cooled solution we use the t dropwise sodium carbonate (aqueous solution, saturated) with stirring until then, until it stopped bubbling. Then add dichloromethane and the reaction mixture is extracted. The organic layer is collected and dried (MgSO4) and the solvent is removed under reduced pressure. The crude product is applied to the chromatographic column and elute with ethyl acetate/n-hexane (1/2). The product is recrystallized from ethyl acetate/n-hexane (RF=0,50) to give the pure material as a white microcrystalline material (212 mg, 68%), TPL 155-l58°C (Caubere C.; Caubere, P.; Renard, P.; Bizot-Espiart J.; Jamart-Gregoire B.; Tetrahedron Lett. 1993, 34(43), 6889-6892, TPL 149-151°C). IR (KBr): 3275, 2951, 2898, 1690, 1603, 1486, 1209, 1136, 1020, 827 cm-1.1H NMR (DMSO-d6): of 10.73 (1H, s), 7,19 (1H, d, J=8.7 Hz), 6,86 (1H, d, J=2.3 Hz), 6,69 (1H, DD, J=2,5 & 8,7 Hz), to 3.73 (3H, s), 3,47 (2H, s), is 3.08 (2H, t, J=6.9 Hz), 2,69 (2H, t, J=6.9 Hz).

Example 24

Protocol

Organotypic cultures of hippocampal slices obtained using the basic method, Pringle et al. [Brain Res. 755, 36-46 (1997)], modified as follows.

Pups of Wistar rats (age 8-11 days) decapitat and the hippocampus rapidly excised in a balanced salt solution Haze on ice, supplemented with 4.5 mg/ml glucose. The sections are divided and placed on the tablet, insert for cultivation Millicell CM (4 per well) and maintained at 37°C/5% CO2within 14 days. Supportive environment consists of 25% thermally and tigerbunny serum of a horse, 25% balanced salt solution Hank (HBSS) and 50% of the minimum basic medium with added salts Earl (MEM), supplemented with 1 mm glutamine and 4.5 mg/ml glucose. Wednesday replaced every 3-4 days.

Experimental hypoxia carried out as previously described (Pringle et al., Stroke 27,21-24 (1996) & Brain Res. 755,36-46 (1997)]. Briefly, the culture is transferred into a medium containing no serum (SFM - 75% MEM, 25% HBSS, supplemented with 1 mm glutamine and 4.5 mg/ml glucose)containing 5 μg/ml fluorescent dye exclusion iodide of propecia (PI). Cultures provide an opportunity to balanced in SFM within 60 minutes before receiving images. The PI fluorescence is detected using an inverted microscope Leica DMIL connected to the set radiminovich filters. Any culture, in which at this stage is detected fluorescence of PI, are excluded from further research. Hypoxia is induced by transfer of cultures in SFM (+PI), which is saturated with a 95% N2/5% CO2. Tablets for cultivation (without lids) and then sealed in an air tight chamber in which the atmosphere is saturated with a 95% N2/5% CO2through continuous purge gas through it at a speed of 10 l/minute for ten minutes before sealing, and placed in the incubator for up to 170 minutes (total time hypoxia is therefore 180 minutes). At the end of periodieke culture return to normal oxygen content of SFM, containing PI, and placed back in the incubator for 24 hours.

Neuronal damage assessed using run ImageJ on a PC. Image obtained using CCD camera and saved for analysis off line. Image obtained when light passes, register before adding drugs, and the fluorescence image PI register at the end of the 24-hour recovery period after hypoxia. Area CA1 subregion is determined from the image obtained by the passage of light. The area of PI fluorescence in the CA1 measured using the threshold function in ImageJ and neuronal damage expressed as a percentage CA1, for which the detected fluorescence of PI greater than background.

Unpaired t-tests t-test used to assess statistical significance.

A series of compounds investigated the possible neuroprotective effects against hypoxia in organotypic cultures of hippocampal slices. Connection№ 4, 6, 7, 8, 10, 14, 15, 16, 17, 20, 21, 22 and 23 are dissolved in DMSO to a concentration of 1 mg/ml

7β-hydroxy-epiandrosterone (7β-OH EPIA), a neuroprotective compound, at concentrations of 100 nm is used as the positive control. The original solution of 1 mg/ml dissolved in ethanol. The final dilution is carried out in SFM.

The effectiveness of all compounds evaluated using the scheme before, during, and last the hypoxia - compounds present in the environment 45 minutes before hypoxia, 3 hours during hypoxia and 24 hours after hypoxia.

The results are as set forth in the following Table 2, which shows the % of neuronal damage in a model of hypoxia compared to control (only hypoxia - 100% damage). The lower the % damage, the more is neuroprotective compound. The last column in the table shows the % damage with 7β-OH EPIA (positive control). All values are statistically significant.

Table 2
Connection # % Damage in a model of hypoxia connection% Damage with a positive control
458%57%
663%50%
770%50%
859%50%
1076%51%
1453% 34%
1565%34%
1660%43%
1735%33%
2054%55%
2140%55%
2275%55%
2357%55%

1. The use of compounds of formula (I):

in which X represents a group of formula >CR1R2or, when R6does not represent a hydrogen atom, a group of the formula >SO2;
Y represents a group of formula >CR1R2;
Z represents a group of formula >C=O group of the formula >CH2or a direct link;
R1represents a hydrogen atom, and R2represents a hydrogen atom, carboxypropyl or hydroxy-group;
or
R1and R2together represent oxoprop, Ethylenedioxy or hydroxyisopropyl;
R3is an atom of water is an ode or a lower alkyl group;
R4represents two hydrogen atoms or oxo or hydroxyimino;
R5represents a hydrogen atom, a lower alkyl group or halogen atom;
R6represents a hydrogen atom, a lower alkoxygroup or carboxypropyl;
R7and R8are the same or different from each other and each represents a hydrogen atom, a lower alkyl group or halogen atom;
and their pharmaceutically acceptable salts and esters for the manufacture of a medicinal product having a neuroprotective effect against hypoxia.

2. The use according to claim 1, in which:
X represents a group of formula >CR1R2where R1represents a hydrogen atom, and R2represents a hydrogen atom, a hydroxy-group or carboxypropyl, or R1and R2together represent oxoprop or Ethylenedioxy;
Y represents a group of formula >CR1R2where R1represents a hydrogen atom, and R2represents a hydrogen atom or carboxypropyl;
R3represents a hydrogen atom;
R4represents two hydrogen atoms or oxoprop;
R5represents a hydrogen atom;
R6represents a hydrogen atom, a C1-C4alkoxygroup or carboxyl the PU; and R7and R8are the same or different from each other and each represents a hydrogen atom or a C1-C4alkyl group;
and their salts and esters.

3. The use according to claim 1, in which the indicated compound is a compound of the formula:

4. The use according to claim 1, in which the indicated compound is a compound of the formula:

5. The use according to claim 1, in which the indicated compound is a compound of the formula:

6. The use according to claim 1, in which the indicated compound is a compound of the formula:

7. The use according to claim 1, in which the indicated compound is a compound of the formula:

8. The use according to claim 1, in which the indicated compound is a compound of the formula:

9. The use according to claim 1, in which the indicated compound is a compound of the formula:

10. The use according to claim 1, in which the indicated compound is a compound of the formula:

11. The compound of the formula:

12. The compound of the formula:

13. With the Association of the formula:



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) and formula (II), their tautomers and pharmaceutically acceptable salts. In formula (I) and in formula (II), X - S; R1 - H; R2 - NR5R6; R3 - 5-6-member heteroaryl with 1 heteroatom, selected from N and S, or phenyl, optionally substituted with one or two substituents, selected from halogen, amino, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-halogenalkyl and C1-C6-halogenalkoxy; R4 - H, C1-C6 alkyl, C1-C6 alkoxy or XR3, where X and R3 are determined above; R5 - H; R6 - H; L - N or CR7, where R7 - H; M - S. Invention also relates to pharmaceutical composition, containing as active component invention compound, to method of inhibiting activity of caseinkinase lε and to method of obtaining compounds of formula (I) or formula (II).

EFFECT: compounds of claimed invention possess properties of casein kinase lε inhibitors.

13 cl, 5 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention describes a neutral semiconductor organic compound of formula (I) , where R1 and R2 denote a hydrogen atom, n is the number links in formula (I) and is an integer between 2 and 1000, terminal groups of the compound R3 and R4 denote a hydrogen atom or a linear or branched alkyl group with 1-20 carbon atoms. The invention also describes use of the said compound as a semiconductor in electronic functional elements.

EFFECT: higher oxidation resistance, which enables use of the compound in transistors and other electronic functional elements.

5 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , where R1 is C1-C7-alkyl; R2 is C1-C7-alkyl, C1-C7-haloalkyl, C3-C8-cycloalkyl; R3 is -NRaRb; possibly substituted phenyl, thiophenyl, furanyl, where the substitutes are selected from a group consisting of halogen, C1-C7-alkoxy, C1-C7-alkylsulphonyl and -C(O)O-C1-C7-alkyl; R4 is hydrogen or C1-C7-alkyl; R5 is hydrogen, halogen, C1-C7-alkyl, phenyl; or R5 together with R4 can form a ring selected from a group consisting of C5-C7-cycloalkyl, tetrahydrofuranyl, piperidine, tetrahydropyran, phenyl or pyridinyl, which can possibly be substituted with -C(O)O-C1-C7-alkyl; Ra and Rb together with the nitrogen atom to which they are bonded form piperidine; and to pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent based on the said compounds which has GABA-B receptor allosteric enhancement effect.

EFFECT: obtaining novel compounds and a medicinal agent based on the said compounds, which can be used in medicine for treating central nervous system disorders.

13 cl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel therapeutically suitable derivatives of pyridazin-3(2H)-one of formula and pharmaceutical compositions containing the said derivatives. These compounds are used for treating, preventing or inhibiting corresponding pathological conditions, diseases or disorders, mainly asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable colon syndrome.

EFFECT: obtaining compounds which are active and selective phosphodiesterase 4 (PDE4) inhibitors.

11 cl, 1 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable additive salts and stereochemically isomeric forms as 11-HSD1 inhibitors, to their use, a pharmaceutical composition based on the said compounds and method of obtaining the said compounds. In general formula (I) , X is C or N; Y is C or N; L is methyl or a single bond; Z1 is a single bond, C1-2alkyl or a radical of formula -CH=; Z2 is a single bond, C1-2alkyl; R1 is hydrogen, halogen, hydroxy; R2 is hydrogen, halogen or C1-4alkyloxy; A is phenyl or a monocyclic heterocycle selected from a group consisting of thiophenyl or pyrridinyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by 11-HSD1.

9 cl, 7 dwg, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of purifying thiopenes of formula (I) which are liquid at room temperature and can be used in organic synthesis to produce an electroconductive polymer or an organic semiconductor. The proposed method involves precipitation of thiophene of formula (I) , where R1 and R2 represent hydrogen, optionally broken by 1-5 O and/or S atoms C1-20alkyl, C1-20alkoxy, or R1 and R2 together represent optionally substituted C1-20dioxyalkylene or C6-20dioxyarylene group, where the thiophene is precipitated from a solution in isobutyl-methylketone, chloroform, methylene chloride, toluene, methanol, propanol, ethanol, acetone, isopropanol, n-butanol, fluorobutanol, dimethylformamide, methyl-tertbutyl ether, tetrahydrofuran, diethyl ether, hexane, pentane or mixtures thereof in ratio solvent : thiophene ranging from 0.01:1 to 10:1, cooled to temperature at least 10°C below melting point of the thiophene being purified in pure form, with subsequent separation of thiophene by filtration at low temperature.

EFFECT: design of a new efficient method of purifying low-melting thiophenes.

14 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel benzothiazinone derivatives of formula (I) and their use as antibacterial agents in infectious diseases caused by bacteria, especially mycobacterium tuberculosis (TB) and leprosy, in which R1 and R2 independently denote NO2, CN, CONR7R8, COOR9 CHO, halogen, SO2NR7R8, OCF3, trifluromethyl; R3 and R4 independently denote H or methyl; R5 and R6 independently denote a straight or branched aliphatic radical having 1-8 members in the chain, or R5 and R6 together denote a divalent radical -(CR92)m- or R5 and R6 together denote a divalent radical: R7, R8 and R9 independently denote H or a straight or branched aliphatic radical having 1-7 members in the chain, or phenyl.

EFFECT: design of an efficient method of obtaining benzothiazinone derivatives, a pharmaceutical composition having anti-mycobacterial activity.

12 cl, 6 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

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

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: chemistry.

SUBSTANCE: invention relates to novel compounds selected from a group comprising 2,3,4,9-tetrahydro-1H-carbazoles of formula I

,

where R1, R2, R3 and R4 independently denote hydrogen, alkyl, alkoxy, halogen, nitro, cyano, trifluoromethyl or formyl, R5 denotes hydrogen, alkyl or -CF3, R6 denotes alkoxy, arylalkoxy, selected from benzyloxy and 1-phenylethoxy, or -NR7R8, R7 and R8 independently denote hydrogen, alkyl, cyanoalkyl, alkenyl, where alkenyl is ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl or 5-hexenyl; aryl, where aryl is a phenyl or naphthyl radical, where said radicals can optionally be monosubstituted with a halogen, alkyl, alkoxy, -CF3, -OCF3, phenylalkyl or phenylcarbonyl; or disubstituted with a substitute independently selected from halogen, alkoxy and phenyl; arylalkyl, where arylalkyl is phenylalkyl, where the alkyl group can optionally be substituted with phenyl; phenylalkyl, where the phenyl ring can optionally be substituted with methylenedioxy; phenylalkyl which is disubstituted with a halogen; phenylalkyl which is monosubstituted with a halogen, -CF3, -OCHF2, alkyl or alkylsulfanyl; or naphthylalkyl; phenylcarbonyl; cycloalkyl, where cycloalkyl is a cyclopentyl or cyclohexyl radical, where said radicals can optionally be substituted with a condensed benzene ring; pyridylalkyl; thienylalkyl; or R7 and R8 together with a nitrogen atom to which they are bonded form a heterocyclic 5-, 6-, 7- or 8-member ring system containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, wherein said cyclic system can optionally be substituted with (1) one or two condensed benzene rings, where the benzene rings are unsubstituted or substituted with one or two substitutes independently selected from a group comprising C1-C4alkyl, C1-C4alkoxy, halogen, -CF3 and -OCF3; (2) unsubstituted phenyl ring, (3) mono- or disubstituted phenyl ring, where the substitutes are independently selected from a group comprising halogen, C1-C4alkyl, C1-C4alkoxy, -CF3 and -OCF3; or (4) phenylalkyl, where the alkyl group is substituted with phenyl; where the term "alkyl", separately or in any combination, denotes a saturated straight or branched hydrocarbon chain containing 1-7 carbon atoms; where the said alkyl group is unsubstituted unless stated otherwise; or to pharmaceutically acceptable salts thereof. Invention also relates to a pharmaceutical composition and to use of compounds in claim 1.

EFFECT: obtaining novel biologically active compounds having CRTH2 receptor antagonist activity.

13 cl, 5 tbl

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