Compounds, enhancing glutamate receptor, and their application in medicine

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of general formula (I) or its pharmaceutically acceptable salt, mediated by glutamate receptor, and to based on them pharmaceutical composition. (I), where R1 stands for C1-6alkyl; R2 and R3 stand for hydrogen; p stands for 0; n stands for 1; R5 and R6 stand for hydrogen, and Het stand for thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidozolyl, each of which can be substituted with one or two groups, independently selected from the list, which consists of C1-6alkyl, C1-6alkoxy, acetyl, halogen, halogenC1-6alkyl, cyano.

EFFECT: creation of compound which has property to enhance response reaction.

4 cl, 2 tbl, 6 dwg, 38 ex

 

This invention relates to new compounds that increase of glutamate receptor. The invention also relates to the use of derivatives in the treatment of diseases and conditions mediated by potentiation of glutamate receptor, to compositions containing the derivatives, and methods for their preparation.

The glutamate receptors, which mediate most of the fast neurotransmission excitation in the Central nervous system (CNS) of mammals, are activated by excitatory amino acids, namely L-glutamate (see review Watkins JC, Krogsgaard-Larsen P., Honore T. (1990) Trends Pharmacol. Sci. 11: 25-33).

The glutamate receptors can be divided into two different families. The family of G-protein or related second messenger "metabotropic" glutamate receptors, which can be subdivided into three groups (group I, mGlu1 and mGlu5; group II, mGlu2 and mGlu3; group III, mGlu4, mGlu6, mGlu7, and mGlu8) on the basis of sequence homology and the mechanisms of intracellular transduction (for review, see Conn PJ and Pinn JP (1997) Ann. Rev. Pharmacol. Toxicol. 37: 205-237). Family isotropically" glutamate receptors, which are linked directly to the managed ligands cationic channels, can be subdivided, at least three subtypes on the basis of the depolarization activation by selective agonists N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic KIS the Auteuil (AMPA) and kainic acid (for an overview see in R. Dingledine, Borges, K., Bowie, Traynelis, S. (1999) 51: 7-61).

Native AMPA receptors (AMPARS) are as heterotetramer, consisting of combinations of four different protein subunits (GluR1-4) (for an overview, see Bettler B. and Muller, C. (1995) 34: 123-139.). The diversity of subunits of the receptor increases as each subunit can be subjected to alternative splicing sequence of 38 amino acids in the extracellular region just before the fourth membrane spanning domain M4. This Assembly is the so-called "flip" and "Flor" (somersault) receptor isoforms that differ in kinetic and pharmacological properties (Sommer B., K. Keinanen, Verdoon TA, Wisden W., N. Burnashev, Herb A., Kohler, M., Takagi, T., Sakmann b, Seeburg PH (1990) Science 249: 1580-1585).

In addition, posttranscriptional mounting GluR2 mRNA turns neutral glutamine in positively charged arginine with M2. In normal people >99% of GluR2 is mounted this way. AMPARS containing this variant subunit GluR2, detects low permeability to calcium (Burnachev n, Monyer h, Seeburg PH, Sakmann B. (1992) Neuron 8: 189-198). It is assumed, however, that the number of AMPARS with high permeability for calcium is increased in certain disease States (Weiss JH and Sensi SL (2000) Trends in Neurosci. 23: 365-371.

Depolarization of AMPARS eliminates dependent voltage block Mg2+ of NMDA receptors that, in turn, leads to an act of the activate your product, NMDA receptor, a significant stage in the induction of long-term potentiation (Bliss TVP, Collingridge GL (1993) Nature 361: 31-9). Long-term potentiation is a physiological measure of increased synaptic activity after repeated stimulus or influence how it occurs during learning.

Direct activation of glutamate receptors agonists in conditions, when the function of glutamate receptor is reduced, increases the risk of excitotoxicity and additional neuronal damage. Positive allosteric modulators of AMPARS, alone, does not activate the receptor directly. However, when the ligand (L-glutamate or AMPA) is present, the AMPAR modulators increase the activity of the receptor. Thus, modulators of AMPA receptor reinforce synaptic function, when glutamate is released and is able to bind to the postsynaptic receptor sites.

Compounds that act as positive allosteric modulators of AMPARS has been shown to increase the affinity of the ligand to the receptor (Arai A., Guidotti a, Costa E., Lynch, G. (1996) Neuroreport. 7: 2211-5); reduce desensitization of the receptor and reduce the deactivation of the receptor (Arai AC, Kessler m, Rogers g, Lynch G. (2000) 58: 802-813) and facilitate the induction of LTP both in vitro (Arai A., Guidotti a, Costa E., Lynch, G. (1996) 7: 2211-5.), and in vivo (Staubli, U., Perez Y., Xu F., Rogers G., Ingvar m, Stone-Elander, S., and Lynch, G. (1994) Proc. Natl. Acad. Sci. 91: 11158-11162). Such compounds also improved the try learning ability and ability to solve various cognitive tasks in rodents (I. Zivkovic, Thompson DM, Bertolino, M., D. Uzunov, M. DiBella, Costa, E., Guidotti, A. (1995) JPET 272: 300-309, Lebrun C., Pilliere E., Lestage, P. (2000) Eu. J. Pharmacol. 401: 205-212), non-human primates (Thompson DM, Guidotti A., M. DiBella, Costa E. (1995) Proc. Natl. Acad. Sci. 92: 7667-7671) and people (Ingvar M., Ambros-Ingerson, J., Davis M., Granger, R., Kessler, M., Rogers GA, Schehr RS, Lynch G. (1997) Exp. Neurol. 146: 553-559).

It is assumed that compounds that modulate the function of glutamate receptor, can be useful in the treatment of the following conditions and diseases: psychosis and psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform diseases, brief reactive psychosis, beginning in childhood schizophrenia, disorder "schizophrenia spectrum", such as schizoid or shizotimichesky anomalies of nature, acute psychosis, alcoholic psychosis caused by drug psychosis, autism, delirium, mania (including acute manic state), manic depressive psychosis, hallucinations, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders puerperal psychosis and psychosis associated with neurodegenerative diseases such as Alzheimer's disease); the deterioration of cognitive abilities (for example, for the treatment of impairment of cognitive functions including attention, orientation, memory (i.e. memory disorders, amnesia, frustration with memory loss and age-related memory impairment) and razgovor the th function, and including the deterioration of cognitive abilities as a result of stroke, Alzheimer's disease associated with AIDS dementia or other conditions of dementia, as well as other acute or sub-acute conditions that may cause a decrease in cognitive abilities, such as delirium or depression (status pseudodementia), trauma, aging, shock, neurodegeneration caused by drug States, neurotoxic agents), a slight deterioration of cognitive abilities, age-related deterioration of cognitive abilities associated with autism deterioration of cognitive abilities, down syndrome, lack of cognitive ability related to psychosis, disorders of cognitive ability after electroshock treatment; anxiety status (including generalized anxiety disorder, social anxiety disorder, agitation, tension, social or emotional detachment from psychotic patients, anxiety disorder and obsessive state); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, a disease of motor neurons and other motility disorders, such as Parkinson's disease (including exemption from locomotor failure and/or inability to move, including slowly increasing inability to celenapravlennogo movement, tremor, bradykinesia, hyperkinesia (moderate or severe), akineziyu, rigidity, impaired balance and coordination and the violation poses), dementia in Parkinson's disease, dementia in Huntington's disease, caused by neuroleptics parkinsonism and late dyskinesia, neurodegeneration associated with stroke, cardiac arrest, pulmonary bull, traumatic brain injury, spinal cord injury or the like, and demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis); depression (this term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent major depressive episodes with psychotic features, catatonic features, melancholic features, atypical features (e.g., lethargy, overeating/obesity, increased sleepiness) or without them or episodes beginning on or after childbirth, seasonal affective disorder and dysthymia, is associated with depression, anxiety, psychotic depression, and depressive disorders resulting from a primary medical condition, including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); post-traumatic stress syndrome; lack of attention; Hyper shall aktivnosti with the lack of attention, caused by drugs such as phencyclidine, ketamine or other dissocative anastatica, amphetamine and other psychostimulants and cocaine) disorders; Huntington's Chorea; late dyskinesia; dystonia; myoclonus; spasticity; obesity; stroke; sexual dysfunction and sleep disorders. In addition, it is assumed that compounds that modulate the function of glutamate receptor, can be applied in the treatment and do not have the defects of subjects to improve execution sensory-motor and cognitive tasks and coding of remembering.

Open the new class of compounds that increase of glutamate receptor.

According to the first aspect, the invention relates to the compound of formula (I), its pharmaceutically acceptable salt, MES or prodrug:

where

- R1means1-6alkyl, Halogens1-6alkyl, C2-6alkenyl, amino, mono1-4alkylamino or dis1-4alkylamino;

- R2and R3that may be the same or different, represent hydrogen, halogen, C1-6alkyl, Halogens1-6alkyl, C1-4alkoxy, Halogens1-4alkoxy, cyano, amino, mono1-4alkylamino or dis1-4alkylamino;

each R4that may be the same or different means1-6alkyl, ha is oven, With1-6alkyl, Halogens1-6alkyl, C1-4alkoxy, Halogens1-4alkoxy, cyano, nitro, amino, mono1-4alkylamino or dis1-4alkylamino;

- p is 0, 1 or 2;

- n means 1 or 2;

- R5and R6that may be the same or different, represent hydrogen, halogen, C1-6alkyl, Halogens1-6alkyl, C1-4alkoxy, Halogens1-4alkoxy, cyano, amino, mono1-4alkylamino or dis1-4alkylamino; and

- Het means thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, pyrrolyl, hinely, thiazolyl or furyl, each of which may be substituted by one or more groups independently chosen from a list of1-6alkyl, C1-6alkoxy, acetyl, halogen, Halogens1-6alkyl, cyano, nitro, amino, mono1-4alkylamino and dis1-4alkylamino.

The term "C1-4alkyl" refers to alkyl group having from one to four carbon atoms, in all isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The term "C1-6alkyl" refers to alkyl group having from one to six carbon atoms, in all isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, sec-pentyl, n-pentyl, and opentel, tert-pentyl and hexyl. Unless otherwise specified, any alkyl group can be straight or branched and having from 1 to 6 carbon atoms, for example from 1 to 4 or 1 to 3 carbon atoms.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "Halogens1-6alkyl" refers to C1-6alkyl group in which at least one hydrogen atom substituted with halogen. Examples of such groups include foretel, trifluoromethyl or triptorelin and the like.

The term "C2-6alkenyl" refers to a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds and having from 2 to 6 carbon atoms. Unless otherwise specified, C2-6Alchemilla group can contain up to 3 double bonds, which may be conjugated. Examples of such groups include ethynyl, propenyl, butenyl, pentenyl, hexenyl, vinyl, allyl and butadienyl.

The term "mono1-4alkylamino" refers to the amino group, substituted C1-4alkyl group, such as methylamino, ethylamino, propylamino or butylamino. The term "dis1-4alkylamino" refers to an amino group substituted With two1-4alkyl groups, such as dimethylamino or methylethylamine.

The term "C1-4alkoxy" refers to-OC1-4alkyl group, in which1-4alkyl has the shown value. Used in the description, the term "C1-6alkoxy" refers to-OC1-6alkyl group, in which1-6alkyl has the values defined here. Examples1-4alkoxygroup include methoxy, ethoxy, propoxy, butoxy. Examples1-6alkoxygroup include additional pentox, hexose and the like.

Used in the description, the term "Halogens1-6alkoxy" refers to C1-6alkoxygroup as defined in the description, in which at least one hydrogen atom is replaced by halogen. Examples of such groups include deformedarse or triptoreline and the like.

In one variant embodiment R1means1-6alkyl, such as isopropyl.

In one variant embodiment R2and R3that may be the same or different, represent hydrogen, halogen or1-6alkyl, for example hydrogen, fluorine or methyl.

In one variant of embodiment p is 0.

In one variant embodiment, each R4that may be the same or different means1-6alkyl or halogen, for example methyl or fluorine.

In one variant embodiment R5and R6that may be the same or different, represent hydrogen, halogen or1-6alkyl. For example, R5and R6are independently hydrogen, fluorine or methyl.

In one var is ante embodiment n is 1.

In one variant embodiment Het denotes pyridyl (e.g. 3-pyridyl), pyrimidinyl (for example, 5-pyrimidinyl, 2-pyrimidinyl), thienyl (for example, 3-thienyl, 2-thienyl), pyridazinyl (for example, 3-pyridazinyl), imidazolyl (for example, 1H-4-imidazolyl) or pyrazolyl (for example, 1H-4-pyrazolyl), each of which is optionally substituted by one to three groups independently selected from the group consisting of C1-6the alkyl (such as methyl, acetyl, cyano, halogen (such as fluorine or chlorine), Halogens1-6the alkyl (such as CF3) and C1-6alkoxy (such as methoxy).

In one variant embodiment, this invention relates to the compound of formula (Ia), its pharmaceutically acceptable salt, MES or prodrug:

where Het and R1have the meanings specified for formula (I).

To avoid uncertainty, if not indicated otherwise, the term "substituted" means substituted by one or more specific groups. When groups can be selected from a number of alternative groups of the selected group may be the same or different. To avoid ambiguity, the term "independently" means that when you select more than one Deputy from among the possible substituents, such substituents may be the same or different.

Suitable farmaceuticas is acceptable salts of the compounds of formula I include salts of acids, for example, sodium, potassium, calcium, magnesium and tetraalkylammonium, and the like, or mono - or dibasic salt with a suitable acid, for example organic carboxylic acids such as formic, acetic, lactic, tartaric, malic, setinova, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonate, econsultancy, benzolsulfonat and p-toluensulfonate acid, and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acid, and the like. Some compounds according to the invention can be subjected to crystallization or recrystallization from solvents such as water and organic solvents. In such cases, may form a solvate. In the scope of the present invention included a stoichiometric solvate, including hydrates, as well as compounds containing variable amounts of water that can be obtained in processes such as lyophilization.

Specialists in this field it is clear that certain protected derivatives of compounds of formula I which can be obtained before the final stage of removal of protection, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the op is anime with the formation of compounds according to the invention, which are pharmacologically active. Such derivatives can therefore be described as "prodrugs". Further, some compounds according to the invention can act as prodrugs of other compounds according to the invention. All protected derivatives and prodrugs of the compounds according to the invention is included in the scope of the invention.

Examples of suitable protective groups for the compounds of this invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp.499-538 and Topics in Chemistry, Chapter 31, pp.306-316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the content of the documents included in the description by reference). In addition, specialists in this area should be clear that the specific components known to specialists in this field as "percomponent", for example, described H.Bundgaard in "Design of Prodrugs" (the contents of the document are included in the description by reference), can be placed on the appropriate functional groups, when such functional groups present in the compounds according to the invention. Suitable prodrugs for the compounds according to the invention include ethers, esters, carbonates, complex palefire, esters of phosphates, esters, nitro, ester sulfates, sulfoxidov, amides, carbamates, azo compounds, phosphamide, glycosides, ethers, acetals and ketals.

In further compounds, their pharmaceutical is acceptable salt, the solvate and prodrug defined in any aspect of the invention (except intermediate compounds in chemical processes)are referred to as "compounds of the invention".

Compounds according to the invention can exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of this invention.

Due to the presence of at least one chiral center, the compounds according to the invention can exist in the form of optical isomers, for example, diastereoisomers, and mixtures of isomers in all possible ways, for example, racemic mixture:

The invention includes all such forms, in particular pure isomeric form. The different isomeric forms may be separated or separated from one another by traditional methods, or any given isomer may be obtained by traditional methods of synthesis or by stereospecific or asymmetric synthesis. It should also be noted that in General for most of biologically active molecules to the level of their biological activity may vary between individual stereoisomers of a given molecule. It is implied that the scope of the invention includes all the individual stereoisomers (diastereoisomers and enantiomers) and their mixtures, including, but without limitation, racemic mixture, which is haunted demonstrate appropriate biological activity with reference to procedures, described in the description.

For compounds according to this invention chiral intermediate compound, (2S)-5-bromo-2-aminoindan

get, using (1R)-(-)-10-camphorsulfonic acid as an agent for optical cleavage, as disclosed in Prashad et al., Adv. Synth. Catal. 2001, 343, No.5, pp.461-472. The absolute configuration of the thus obtained salt of (2S)-5-bromo-2-aminoindane (1R)-(-)-10-camphorsulfonic acid confirmed by x-ray analysis of the single crystal. This connection is used to produce N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide (intermediate compound 6).

In an additional variant embodiment of the present invention represented by the compounds of formula (Ib) or pharmaceutically acceptable salt, solvate or prodrug, which correspond to the stereochemical isomer of the compounds of formula (I), enriched in configuration S:

where R1, R2, R3, R4, R5, R6n, p and Het have the meanings indicated for formula (I).

In another variant embodiment, this invention relates to the compound of formula (Ic) or its pharmaceutically acceptable salt, MES or prodrug, which correspond to the stereochemical isomer of the compounds of formula (Ia), enriched in configuration S:

where Het and R1have the meanings specified for formula (I).

Implicit in the context of the compounds according to this invention that the stereochemical isomer enriched in configuration S, correspond to one variant embodiment, at least 90% enantiomeric excess. In another variant embodiment of the isomers correspond to at least 95% enantiomeric excess. In another variant embodiment of the isomers correspond to at least 99% enantiomeric excess.

Since the compounds according to the invention are intended for use in pharmaceutical compositions, it is easy to understand that each of them is preferably provided in a substantially pure form, for example, at least 60% pure, more suitably at least 75% pure and preferably at least 85%, particularly at least 98% pure (% are by weight). Contaminated drugs compounds can be used to obtain a more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of the compounds according to the invention.

You should take into account that this invention include compounds having any combination of the features mentioned above.

N-[5-(2-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(5-pyrimidinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(3-thienyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(2-thienyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(4-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(2,6-dimethyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(6-cyano-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(5-acetyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(5-cyano-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(5-fluoro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(4-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(6-fluoro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(2-methyl-4-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(6-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(2-pyrimidinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(3-fluoro-4-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(6-fluoro-2-methyl-3-pyridinyl)-2,3-dihydro-1H-shall nden-2-yl]-2-propanesulfinamide

N-[5-(1H-imidazol-4-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(1,3,5-trimethyl-1H-pyrazole-4-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(6-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(3-methyl-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(5-methyl-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(6-chloro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-{5-[6-(metiloksi)-3-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfinamide

N-[5-(5-chloro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[5-(2-chloro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-{(2S)-5-[6-(trifluoromethyl)-3-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfinamide

N-[(2S)-5-(5-chloro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-{(2S)-5-[6-(trifluoromethyl)-2-pyridinyl]-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[(2S)-5-(5-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[(2S)-5-(5-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[(2S)-5-(2-fluoro-6-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

N-[(2S)-5-(2,6-debtor-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide and their pharmaceutically acceptable salt, solvate and prodrug.

Compounds according to the invention can be obtained in a known manner in different ways. In the following reaction schemes and in the future, unless otherwise stated, R1-R4n, p and Het have the meanings indicated for formula (I). These processes constitute additional aspects of the invention.

Throughout the description of the General formulae identified by Roman numerals (I), (II), (III), (IV), etc. units of the above General formula is defined as (Ia), (Ib), (Ic), etc ... (IVa), (IVb), (IVc), etc.

Compounds of General formula (I) can be obtained by the reaction of compounds of formula (II), where X represents a leaving group such as iodine, derivative Bronevoy acid or a complex ester of boronate formula (III), where R is hydrogen, alkyl or the two groups R form a ring, according to the reaction scheme 1. Typical conditions of interaction include the interaction of the compound (II) with (III) in the presence of a base (such as aqueous cesium carbonate), palladium catalyst (II) and triphenylphosphine at an elevated temperature such as 80°C). Derivatives Bronevoy acid or a complex ester of boronate formula (III) can be easily obtained from the corresponding halide (usually iodide or bromide). Typical reaction conditions include the interaction of the halide with a suitable boronate in the presence of a base (such as potassium acetate) and palladium catalyst (II), such as chloride (1,1'-bis(diphenylphosphino)ferrocene)palladium (II), at an elevated temperature such as 80°C).

Scheme 1

Alternatively, the compounds of formula (I) can be obtained by the reaction of derivatives Bronevoy acid or a complex ester of boronate formula (IV), where R is hydrogen, alkyl or the two groups R form a ring, with compounds of the formula (V) (where X represents a leaving group, usually iodine or bromine), according to the reaction scheme 2. Typical conditions of interaction are the same as described for reaction scheme 1.

Scheme 2

The compounds of formula (IIa), i.e. compounds of formula (II), where X is iodine, can be obtained from compounds of formula (VI) according to reaction scheme 3. Typical reaction conditions require treatment with compound (VI) is a strong acid, such as sulfuric acid and glacial acetic acid, followed by treatment period acid and iodine.

Scheme 3

The compounds of formula (VI) can be obtained from compounds of formula (VII) according to reaction scheme 4. Typical reaction conditions involve adding sulphonylchloride (VIII) to a cooled ice mixture of compound (VII) and base (such as 1,8-diazabicyclo[5.4.0]undec-7-ene) in a suitable solvent (such as dichloromethane) and then gradually heating the mixture to room temperature.

Scheme 4

The compounds of formula (VII) can be the particular of the compounds of formula (IX) (see the reaction scheme 5) by standard procedures (see Sukanta Bhattacharyya et al., Synlett 1999, 1781).

Scheme 5

The compounds of formula (VII), where R2, R3, R5and R6are hydrogen and p is 0, commercially available; for example, 2-hydrochloride aminoindane can be obtained from Sigma-Aldrich Company Ltd.

The compounds of formula (IX), where at least one of R2, R3, R5or R6is other than hydrogen, can be obtained according to reaction scheme 6 from compounds of formula (X) are known in the art procedures for the synthesis and subsequent appropriate treatment, usually by chromatography. For example, when R2, R3, R5or R6means alkyl, typical reaction conditions include stirring, cooled with ice a solution of the compound (X) in a suitable solvent (such as tetrahydrofuran), followed by treatment with a base such as sodium hydride, and an alkylating agent such as alkylhalogenide. Alternatively, when R2, R3, R5or R6means fluorine, typical reaction conditions include the interaction of the compound (X) with standard fluorinating agent such as Accuflour™ in a solvent such as acetonitrile (see Tetrahedron Letters 1996, 3591). When R2, R3, R5or R6means bromine, typical reaction conditions include peremeci is the W cooled with ice a solution of the compound (X) in a suitable solvent (such as tetrahydrofuran), followed by the sequential processing base, such as sodium hydride, and brainwashin agent such as N-bromosuccinimide. Specialist-chemist it is clear that such intermediate bromoethane can be further converted into the corresponding hydroxy/alkoxy compounds by treatment with a sodium hydroxide/sodium alkoxide, respectively, in a suitable solvent, such as tetrahydrofuran.

Scheme 6

Alternative preparation of compounds of formula (X) described in Organic Letters 2002, Vol.4, 2465.

Additional details of the preparation of compounds of formula (I), see examples in the description below.

Thus, in another aspect this invention relates to a method for producing a connection that is defined in claim 1, containing:

(a) the interaction of the compounds of formula (II):

where R1-R6, n and p have the meanings indicated for formula (I) and X represents a leaving group; with the derived Bronevoy acid or a complex ester of boronate the compounds of formula (III):

Het-B(OR)2

(III)

where Het has the meanings specified for formula (I), and R represents hydrogen, alkyl (such as1-6alkyl), or two groups R form a ring (such as 5 - or 6-membered ring);

or

(b) coordination compounds Bronevoy acid or a complex ester of boronate formula (IV)

where R1-R6, n and p have the meanings indicated for formula (I), and R represents hydrogen, alkyl (such as1-6alkyl), or two groups R form a ring (such as 5 - or 6-membered ring), with the compound of formula (V):

Het-X

(V)

where Het has the meanings specified for formula (I), and X represents a leaving group;

and optionally after (a) or process (b):

- remove any protective group(s); and/or

- the formation of a salt; and/or

- conversion of one compound of formula (I) into another compound of formula (I).

In process (a) X in the formula (II) can represent, for example, halogen, such as bromine or iodine. R may represent hydrogen, alkyl (such as1-6alkyl), or two groups R may form a ring (such as 5 - or 6-membered ring). For example, the compound of formula (III) can be Het-B(OH)2.

In process (b), for example, group-B(OR)2in the formula (IV) can be 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl. X in the formula (V) may be a halogen such as Br or I.

Compounds according to the invention can be obtained separately or in the form of libraries of compounds containing at least 2, for example 5 to 1,000 compounds, and more preferably from 10 to 100 compounds. Libraries of compounds according to the invention can be obtained by combining the separation and mixing or multiple the th parallel synthesis using or liquid-phase or solid-phase method, well-known experts in this field. Thus, according to another aspect of the proposed library of compounds containing at least 2 compounds according to the invention.

Compounds according to the invention can be introduced into conventional dosage forms prepared by combining the compounds according to the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients, as is characteristic for the desired product.

The pharmaceutical compositions according to the invention can be prepared for administration in any way, and include compositions in a form adapted for oral, local or parenteral administration to mammals, including humans.

Compositions may be prepared for administration in any way. The composition can be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations such as solutions or suspensions for oral or sterile parenteral administration.

The compositions of this invention for local injection can be presented, for example as ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain K is included traditional additives, such as preservatives, solvents to improve the permeability of the drugs and the means to mitigate in ointments and creams.

The composition may also contain compatible conventional carriers, such as Foundation creams and ointments and ethanol or alerby alcohol for lotions. Such carriers may be present in an amount from about 1% to not more than 98% of the composition. More usually they will be no more than 80% of the composition.

Tablets and capsules for oral administration may be presented in a standard dosage form and may contain conventional excipients such as binding agents, for example syrup, Arabian gum, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for tableting, for example magnesium stearate, talc, polyethylene glycol or silica; dezintegriruetsja agents, for example potato starch, or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated according to methods well known in normal pharmaceutical practice. Liquid preparations for oral administration can be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product in the formation of water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspendresume agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, gel, aluminum stearate or hydrogenated edible fats, emulsifying agents, for example lecithin, monooleate sorbitan or Arabian gum; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol or ethyl alcohol; preservatives, for example methyl - or propyl-p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Suppositories will contain conventional suppository bases of, for example cocoa butter or other glycerides.

For parenteral administration is prepared standard liquid dosage forms, using the compound and a sterile carrier, preferably water. The connection depending on the media used and the concentration can be either suspended or dissolved in the carrier. In preparing solutions the compound can be dissolved in water for injection and sterilized by filtration before being placed in a suitable vial or ampoule and sealed.

Preferably, the agents, such as tools for local anesthesia to serventy and buffering agents can be dissolved in the carrier. To improve the stability of the composition can be frozen after placing it in the bottle and the water can be removed in vacuum. Dry liofilizovannye powder is then sealed in the vial, and it can be accompanied by an appropriate vial with water for injection to restore fluid before use. Suspensions for parenteral administration is prepared essentially in the same manner except that the compound is suspended in the carrier instead of dissolved and sterilization cannot be accomplished by filtration. The connection can be sterilized by exposure to the effects of ethylene oxide before suspendirovanie in sterile media. Preferably, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the connection.

The compositions may contain from 0.1% by weight, preferably 10-60% by weight, of the active material, depending on the method of introduction. When the compositions contain a standard dose of each standard dose will preferably contain 50-500 mg of the active ingredient. The dosage used for the treatment of an adult, preferably will be in the range from 100 to 3000 mg per day, for example, 1500 mg per day, depending on the route and frequency of administration. This dosage corresponds to 1.5-50 mg/kg per day. The COO is responsible dosage equal to from 5 to 20 mg/kg per day.

The specialist in this area should be clear that the optimal number and the spacing of individual dosages of the compounds according to the invention will be determined depending on the nature, severity of the condition requiring treatment, the form, route and location of administration and the particular mammal being treated, and that such optimums can be determined by conventional methods. The specialist should also be noted that the optimal course of treatment, i.e. the number of doses of the compounds according to the invention given per day for a certain number of days, can be customized by experts in this field using traditional tests to determine the course of treatment.

All publications, including but not limited to, patents and patent applications, cited in this specification, are included in the description by reference as if each individual publication was specifically and individually indicated as reference in its entirety.

You should take into account that the invention includes the following additional aspects. Characteristic features of the embodiments and variants described for the first aspect apply to these additional aspects:

i) a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable carrier or diluent;

p> ii) the use of the compounds according to the invention for the manufacture of a medicinal product for treating or preventing a disease or condition caused by a decrease or dysfunction of the glutamate receptor in a mammal;

iii) the compound according to the invention for use for the treatment or prevention of a disease or condition caused by a decrease or dysfunction of the glutamate receptor in a mammal;

iv) the compound according to the invention for use as a drug;

v) a method of treatment or prevention of a disease or condition caused by a decrease or dysfunction of the glutamate receptor in a mammal, introducing an effective amount of the compounds according to the invention, and

vi) a combination of compounds according to the invention with a neuroleptic.

In the case of the aspect (ii), (iii) and (v) the respective diseases or conditions are psychosis and psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform diseases, brief reactive psychosis, beginning in childhood schizophrenia, disorder "schizophrenia spectrum", such as schizoid or shizotimichesky anomalies of nature, acute psychosis, alcoholic psychosis caused by drug psychosis, autism, delirium, mania (including acute manic state), manic depressive psychosis, ha is lucinalis, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as Alzheimer's disease); the deterioration of cognitive abilities (e.g., treatment of impairment of cognitive functions including attention, orientation, memory (i.e. memory disorders, amnesia, frustration with memory loss and age-related memory impairment) and the conversational function and including the deterioration of cognitive abilities as a result of stroke, Alzheimer's disease associated with AIDS dementia or other conditions, dementia, and other acute or sub-acute conditions that may cause a decrease in cognitive abilities, such as delirium or depression (status pseudodementia), trauma, aging, stroke, neurodegeneration, caused by medicinal products States, neurotoxic agents), a slight deterioration of cognitive abilities, age-related deterioration of cognitive abilities associated with autism deterioration of cognitive abilities, down syndrome, lack of cognitive ability related to psychosis, disorders of cognitive ability after electroshock treatment; anxiety (including generalized anxiety disorder, social anxiety disorder, became the group voltage, social or emotional detachment from psychotic patients, panic disorder and obsessive state); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, a disease of motor neurons and other motility disorders, such as Parkinson's disease (including exemption from locomotor failure and/or inability to move, including slowly increasing inability to purposeful movement, tremors, bradykinesia, hyperkinesia (moderate or severe), akineziyu, rigidity, impaired balance and coordination and the violation poses), dementia in Parkinson's disease, dementia in Huntington's disease, caused by neuroleptics parkinsonism and late dyskinesia, neurodegeneration associated with stroke, cardiac arrest, pulmonary bull, traumatic brain injury, spinal cord injury or the like, and demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis); depression (this term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent episodes of deep depression with psychotic features, catatonic features, melancholic features, atypical symptom is mi (for example, lethargy, overeating/obesity, increased sleepiness) or without them, or beginning on or after childbirth, seasonal affective disorder and dysthymia, is associated with depression, anxiety, psychotic depression, and depressive disorders resulting from a primary medical condition, including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); post-traumatic stress syndrome; lack of attention, hyperactivity and insufficient attention; caused by drugs such as phencyclidine, ketamine or other dissociative anastatica, amphetamine and other psychostimulants and cocaine) disorders; Huntington's chorea; late dyskinesia; dystonia; myoclonus; spasticity; obesity; stroke; sexual dysfunction and sleep disorders.

In the context of the present invention used in the description of terms to describe the indications, classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, published by American Psychiatric Association (DSM-IV) and/or International Classification of Diseases, 10th edition (ICD-10). Various subtypes of these disorders are considered part of this invention. The numbers in brackets after the listed diseases below refer to the classification code in the DSM-IV.

In the context of this invention, the term "psychotic disorder" includes so is e disorders, as

schizophrenia including the subtypes: paranoid (295.30), heavy-dominated bessvatnet (295.10), catatonic (295.20), undifferentiated (295.90) and residual (295.60); schizophrenia-like psychosis disorder (295.40); schizoaffective disorder (295.70)including the subtypes: bipolar and depressive; delusion disorder (297.1)including the subtypes: erotomaniacal, grandiose, jealous, obsessive pursuit, somatic, mixed, and unspecified; brief psychotic disorder (298.8); shared psychotic disorder (297.3); psychotic disorder in the primary medical condition including the subtypes with delusions and with hallucinations; caused by substance psychotic disorder including the subtypes with delusions (293.81) and with hallucinations (293.82); and certainly not established psychotic disorder (298.9).

The compounds of formula (I) and their pharmaceutically acceptable salt and solvate may also be used in the treatment of the following disorders:

depression and mental disorders, including an episode of deep depression, manic episode, mixed episode and hypomanic episode; depressive disorders including major depressive disorder, delimitable disorder (300.4), just not installed depressive disorder (311); bipolar castroist is a, including bipolar I disorder, bipolar II disorder (recurrent episodes of deep depression with hypomanic episodes) (296.89), cyclothymic disorder (301.13) and just not installed bipolar disorder (296.80); other mental disorders, including mental disorder due to General medical condition (293.83)which includes the subtypes with depressive features, with an episode that is similar to a deep depression, with manic features and with mixed features), caused by substance mental disorder (including the subtypes with depressive features, with manic features and with mixed features) and just not installed mental disorder (296.90).

Anxiety disorders, including acute anxiety reaction with panic; panic disorder, including panic disorder without agoraphobia (300.01) and panic disorder with agoraphobia (300.21); agoraphobia; agoraphobia without history of panic disorder (300.22), specific phobia (300.29, formerly simple phobia), including subtypes (animal fear, fear of the natural environment, the fear of damage during blood transfusion, situational and other type), social phobia (social anxiety disorder 300.23), obsessive-compulsive disorder (300.3), posttraumatic stress the TV disorder (309.81), acute stress disorder (308.3), generalized anxiety disorder (300.02), anxiety disorder in the General medical condition (293.84), caused by substance anxiety disorder, anxiety disorder in separation (309.21), disorders of adaptability with anxiety (309.24) and just not installed anxiety disorder (300.00).

Associated with substance disorders, including disorders in the application of substances such as dependence on substances, craving for the substance, and substance abuse; caused by substance use disorders such as substance intoxication, disorder upon receiving substance caused by substance delirium caused by substance persistent dementia caused by substance persistent memory loss induced psychotic disorder substance-induced mental substance disorder induced substance, anxiety disorder induced substance sexual dysfunction caused by substance insomnia caused by hallucinogen persisting disorder of perception"freeze frames", involuntary repetition of hallucinatory experiences); alcohol-related disorders such as alcohol dependence (303.90), alcohol abuse (305.00), alcohol intoxication (303.00), the syndrome of abstinence from alcohol (291.81), Affairs of the bacilli during alcoholic intoxication, delirium when abstinence from alcohol, alcohol-induced persistent dementia, alcohol-induced persisting violation with memory loss, alcohol-induced psychotic disorder, alcohol-induced mental disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder and not exactly set associated with alcohol disorder (291.9); associated with amphetamine (or similar to amphetamine substance) disorders, such as dependence on amphetamine (304.40), methamphetamine abuse (305.70), amphetamine intoxication (292.89), syndrome stop taking amphetamine (292.0), delirium when amphetamine intoxication, caused by amphetamine psychotic disorder caused by amphetamine mental disorder caused by amphetamine anxiety disorder caused by amphetamine sexual dysfunction caused by amphetamine insomnia and just not set associated with amphetamine disorder (292.9); associated with caffeine disorders such as caffeine intoxication (305.90), caused by caffeine anxiety disorder, caused by caffeine insomnia and just not set associated with caffeine disorder (292.9); associated with marijuana disorders, such as dependence on marijuana (304.30), abuse is giving marijuana (305.20), marihuana intoxication (292.89), delirium when marijuanabuy intoxication caused by marijuana psychotic disorder caused by marijuana anxiety disorder and just not set associated with marijuana disorder (292.9); associated with cocaine use disorders such as cocaine dependence (304.20), cocaine abuse (305.60), cocaine intoxication (292.89), syndrome of rejection of cocaine (292.0), delirium during cocaine intoxication, cocaine related psychotic disorder, cocaine related mental disorder caused by cocaine anxiety disorder, cocaine related sexual dysfunction caused by cocaine sleeping and just not set associated with cocaine disorder (292.9); associated with hallucinogen disorders, such as dependence hallucinogen (304.50), abuse hallucinogen (305.30), hallucinogenia intoxication (292.89), associated with the reception of hallucinogen persisting disorder of perception ("snapshots") (292.89), delirium when hallucinogenesis intoxication caused by hallucinogen psychotic disorder caused by mental disorder hallucinogen-induced anxiety disorder hallucinogen and just not set associated with hallucinogen disorder (292.9); associated with means for inhalation disorder, yet is how the dependence on funds for inhalation (304.60), abuse means of inhalation (305.90), intoxication means for inhalation (292.89), delirium intoxication by means of inhalation, caused by means of inhalation persistent dementia caused by means of inhalation psychotic disorder caused by means of inhalation mental disorder caused by means of inhalation anxiety disorder and just not set associated with means for inhalation disorder (292.9); associated with nicotine disorders such as nicotine dependence (305.1), the syndrome of withdrawal from nicotine (292.0) and just not set associated with nicotine disorder (292.9); associated with opioid use disorders such as opioid dependence (304.00), opioid abuse (305.50), opioid intoxication (292.89), syndrome of rejection opioid (292.0), delirium when opioid intoxication caused by opioid psychotic disorder caused by opioid mental disorder-induced sexual dysfunction opioid-induced opioid insomnia and just not set associated with opioid use disorder (292.9); associated with phencyclidine (or similar substance phencyclidine) disorders, such as dependence phencyclidine (304.60), abuse of phencyclidine (305.90), phencyclidine intoxication (292.89), with intoxication delirium penciled the nom, induced psychotic disorder phencyclidine-induced mental disorder phencyclidine-induced anxiety disorder phencyclidine and just not set associated with the disorder phencyclidine (292.9); associated with sedative, hypnotic or anxiolytic means disorders, such as dependence on sedatives, hypnotics or anxiolytics (304.10), abuse sedative, hypnotic or anxiolytic agents (305.40), intoxication sedative, hypnotic or anxiolytic agents (292.89), syndrome of rejection sedatives, hypnotics or anxiolytics (292.0), intoxication delirium sedative, hypnotic or anxiolytic means, delirium failure from taking sedatives, hypnotics or anxiolytics associated with sedative, hypnotic or anxiolytic means persistent dementia associated with sedative, hypnotic or anxiolytic means persisting disorder with loss of memory caused by the sedative, hypnotic or anxiolytic means psychotic disorder caused sedative, hypnotic or anxiolytic means a mental disorder that caused sedative, hypnotic or anxiolytic means disturbing Rastro the STV, called sedative, hypnotic or anxiolytic means sexual dysfunction due to sedative, hypnotic or anxiolytic means sleeping and just not set associated with sedative, hypnotic or anxiolytic means disorder (292.9); associated with various substances disorder such as polysubstance dependence (304.80), and related disorders other (or unknown) substance, such as anabolic steroids, nitrate funds for inhalation and nitric oxide.

Sleep disorders including primary sleep disorders such as dyssomnias, such as primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), associated with breathing sleep disorders (780.59), associated with heart rhythm sleep disorder (307.45) and just not installed dyssomnia (307.47); primary sleep disorders such as parasomnias such as associated with nightmares disorder (307.47), a disorder with fear of falling asleep (307.46), a disorder with somnabulism (307.46) and just not installed parasomnia (307.47); sleep disorders related to another mental disorder such as insomnia related to another mental disorder (307.42) and hypersomnia related to another mental disorder (307.44); sleep disorder due to General medical condition, in particular n the disruption of sleep, associated with such diseases as neurological disorders, neuropathic pain, tired leg syndrome, heart and lung disease, caused by the substance sleep disorder including the subtypes: insomnia, hypersomnia, parasomnia and mixed type; sleep apnea syndrome and disorders of circadian cycle due to the changing time zones;

autism spectrum disorder, including related to autistic disorder (299.00), disorder Asperger (299.80), disorder rett (299.80), a children's disorder with a penchant for destruction (299.10) and just not installed pervasive disorder (299.80, including atypical autism).

Upset with the lack of attention/hyperactivity disorder including the subtypes: combined type of disorder with lack of attention/hyperactivity disorder (314.01), upset with the lack of attention/hyperactivity disorder with predominant lack of attention (314.00), upset with the lack of attention/hyperactivity disorder with predominant hyperactivity-impulsivity (314.01) and just not installed upset with the lack of attention/hyperactivity disorder (314.9); hyperkinetic disorder; disorder with destructive behavior, such as behavioral disorders, including subtypes: child (321.81), adolescent (312.82) and unspecified installed the onset (312.89), upset with the manifestation of defiant disobedience (313.81) and just not installed disruptive behavioral disorder; and Tic disorders such as upset Tourette (307.23):

Personality changes, including the subtypes paranoid personality disorder (301.0), schizoid personality disorder (301.20), isopogon personality disorder (301.22), antisocial personality disorder (301.7), borderline personality disorder (301.83), mimic personality disorder (301.50), change of identity with the manifestation of egotism (301.81), personality change with avoidance (301.82), change of identity with the manifestation of dependence (301.6), obsessive-compulsive personality disorder (301.4) and just not installed change of identity (301.9).

Improving cognitive abilities, including the treatment of impairment of cognitive abilities in other diseases, such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with deterioration in cognitive abilities, for example, Alzheimer's disease, and

sexual dysfunction, such as disorders of sexual desire, such as a disorder with hypoactive sexual desire (302.71), and the disorder sexual aversion (302.79); sexual arousal disorder such as a disorder W is skogo sexual arousal (302.72) and male erectile disorder (302.72); orgasmic disorders such as female orgasmic disorder (302.73), male orgasmic disorder (302.74) and premature ejaculation (302.75); a disorder associated with pain during sexual intercourse, such as dyspareunia (302.76) and wolfism (306.51); not exactly installed sexual dysfunction (302.70); sexual perversion, such as exhibitionism (302.4), fetishism (302.81), frotteurism (302.89), pedophilia (302.2), sexual masochism (302.83), sexual sadism (302.84), transvestite fetishism (302.3), sexual perversion consisting in the pursuit of contemplation erotic scenes (302.82) and just not installed paraphilia (302.9); disorders of sexual identity, such as a disorder of sexual identity in children (302.6) and sexual identity in adolescents or adults (302.85), and just not installed sexual disorder (302.9).

All the different types and subtypes of the disorders mentioned herein are considered part of this invention.

In the context of this invention, the term "impairment of cognitive ability" includes, for example, treatment of cognitive functions, including impaired attention, focus, learning, memory (i.e. memory disorders, amnesia, disturbance of memory loss syndrome temporary total amnesia and age-related memory impairment) the functions of language; deterioration of cognitive abilities as a result of stroke, Alzheimer's disease, Huntington's disease, diseases of the Peak associated with AIDS dementia or other conditions of dementia, such as dementia multi-infarct, alcoholic dementia associated with hypothyroidism dementia and dementia associated with other degenerative disorders such as cerebellar atrophy and amyotrophic lateral sclerosis; other acute and subacute conditions that can cause a decrease in cognitive abilities, such as delirium or depression (status pseudodementia), trauma, head trauma, age-related deterioration of cognitive abilities, stroke, neurodegeneration, caused by medicinal products States, neurotoxic agents weak deterioration of cognitive abilities, age-related deterioration of cognitive abilities associated with autism deterioration of cognitive abilities, down syndrome, lack of cognitive abilities related to psychosis, and violations of cognitive abilities related to electroshock treatment; and motility disorders, such as Parkinson's disease, caused by neuroleptics parkinsonism and late dyskinesia.

Compounds according to the invention can be used for the treatment or prophylaxis of psychotic disorders, in combination with the trail of the relevant agents:

i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprasidone and talnetant);

ii) drugs against extrapyramidal side effects, for example, anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergic tools (such as amantadine);

iii) antidepressants;

iv) anxiolytic drug and

v) means improving cognitive ability, for example, cholinesterase inhibitors (such as takin, donepezil, rivastigmine and galantamine).

Compounds according to the invention can be used in combination with antidepressants for the treatment and prevention of depression and mental disorders.

Compounds according to the invention can be used in combination with the following agents for the treatment and prophylaxis of bipolar illness: (i) the stabilizers of mental activity; (ii) antipsychotics and (iii) antidepressants.

Compounds according to the invention can be used in combination with the following agents for the treatment and prevention of anxiety disorders: (i) anxiety and (ii) antidepressants.

Compounds according to the invention can be used in combination with the following agents to facilitate withdrawal from nicotine and reduce nicotine cravings: i) nicotinamidase therapy, napiershall composition of nicotine with beta-cyclodextrin and nicotine patches and (ii) bupropion.

Compounds according to the invention can be used in combination with the following agents to facilitate abstinence from alcohol and reduce craving for alcohol: (i) antagonists of the NMDA receptor, such as acamprosate; (ii) the GABA receptor agonists, such as tetrabasic, and (iii) receptor antagonists opioid, such as naltrexone.

Compounds according to the invention can be used in combination with the following agents to facilitate rejection of opiate and reduce the craving for opiates: (i) the agonist of the opioid mu-receptor/antagonist opioid Kappa-receptor, such as buprenorphine; (ii) antagonists of the opioid receptor, such as naltrexone, and (iii) vasodilating/hypotensive agents, such as lofexidine.

Compounds according to the invention can be used in combination with the following agents for the treatment and prevention of sleep disorders: i) benzodiazepines, such as temazepam, lormetazepam, estazolam and triazolam; (ii) dibenzodiazepine hypnotics, such as zolpidem, zopiclone, zaleplon and indiplon; (iii) barbiturates such as aprobarbital, butabarbital, pentobarbital, secobarbital and phenobarbital; (iv) antidepressants; (v) other sedative-hypnotics tools, such as chloralhydrate and hlormetiazola.

Compounds according to the invention can be used in combination with the following agents for the treatment of anorexia: i) stimulants, APET is the for example cyproheptadin; ii) antidepressants; iii) antipsychotics; II) zinc; and (v) premenstrual agents, for example, peroxides and progesterones.

Compounds according to the invention can be used in combination with the following agents for the treatment and prevention of bulimia: i) antidepressants; (ii) antagonists opioid receptor; (iii) antiemetic agents, such as ondansetron; (iv) receptor antagonists testosterone, such as flutamide; and (v) the stabilizers of mental activity; vi) zinc and (vii) premenstrual agents.

Compounds according to the invention can be used in combination with the following agents for the treatment and prevention of autism: i) antipsychotics; ii) antidepressants; iii) anxiolytic agents and iv) stimulants, such as methylphenidate, composition of amphetamine, pemoline.

Compounds according to the invention can be used in combination with the following agents for the treatment and prevention of disorders with hyperactivity with the lack of attention: (i) stimulants, such as methylphenidate, composition of amphetamine, pemoline, and (ii) restimulate, for example inhibitors of re-uptake of norepinephrine (such as Atomoxetine), agonists alpha-2-adrenergic receptors such as clonidine, antidepressants, modafinil and cholinesterase inhibitors such as galantamine and donezepil).

Compounds according to the invention can be IP is alsomany in combination with the following agents for the treatment of personality changes: i) antipsychotics; ii) antidepressants; (iii) the stabilizers of mental activity and iv) anxiolytic agents.

Compounds according to the invention can be used in combination with the following agents for the treatment and prevention of male sexual dysfunction: (i) inhibitors of phosphodiesterase V, for example vardenafil and sildenafil; ii) dopamine agonists/inhibitors transfer of dopamine, such as apomorphine and bupropion; (iii) antagonists, alpha-adrenergic receptors, for example phentolamine; (iv) prostaglandin agonists, such as alprostadil; v) agonists of testosterone, such as testosterone; (vi) the transfer inhibitors serotonin, for example inhibitors of re-uptake of serotonin; (vii) the transfer inhibitors of norepinephrine, such as reboxetine, and viii) agonist at 5-HT1A, for example, flibanserin.

Compounds according to the invention can be used in combination with the same agents as for male sexual dysfunction for the treatment and prevention of female sexual dysfunction and in addition with the agonist of estrogen, such as estradiol.

Neuroleptic drugs include typical antipsychotics (e.g. chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixene, haloperidol, molindone and loxapine); and atypical antipsychotics (eg, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, amisulpride, ziprasidone and talnetant).

Antidepressants include inhibitors of re-uptake of serotonin (such as citalopram, ESCITALOPRAM, fluoxetine, paroxetine and sertraline); dual inhibitors of re-uptake of serotonin/norepinephrine (such as venlafaxine, DULOXETINE and milnacipran); inhibitors of re-uptake of noradrenaline (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline, and trimipramine); inhibitors monoamine oxidase (such as isocarboxazid, moclobemide, phenelzine and tranilcipromin) and others (such as bupropion, mianserin, mirtazapine, nefazodone, and trazodone).

Medicines, stabilizing mental activity, include valproate lithium, sodium/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, tiagabine.

Anxiolytic tools include benzodiazepines, such as alprazolam and lorazepam.

Examples

The invention is illustrated in the examples described below.

The raw materials get from commercial suppliers and used without further purification, unless otherwise stated. Flash chromatography is performed using a pre-filled silikagelevye columns Isolute Flash™ or Biotage™ as the stationary phase and the solution of the residents of the net to analyze varieties as eluent. Cleaning the capture and release, make use of a cartridge SCX (strong cation-exchanger), consisting of slaskiego silicon dioxide with the functional groups of the sulfonic acids. Mass directed preparative GHUR performed using column 19 mm × 100 mm or 30 mm × 100 mm, 5 μm, Waters Atlantis with reversed phase as a stationary phase and a gradient of water + 0.1% of formic acid to acetonitrile + 0.1% of formic acid as eluent. Eluent control matrix of photodiodes Waters 996 and a mass spectrometer Micromass ZQ. For compounds of examples all outputs are cleared for the isolated material. The NMR spectra obtained at 298K, at a frequency that is installed with the machine or Bruker™ DPX400 or Oxford Instruments™ 250 MHz with dilute solution CDCl3if not stated otherwise. All NMR spectra correlated with tetramethylsilane was (TMS δn0, δwith0). All the coupling coefficients are presented in Hertz (Hz), and the multiplicity is indicated as s (singlet), users (broadened singlet), d (doublet), t (triplet), q (Quartet), DD (doublet of doublets), dt (doublet of triplet) and m (multiplet).

Data LC/MS (liquid chromatography/mass spectrometry) is obtained using the system GHUR Agilent™ 1100 with column 4.6 mm × 50 mm, 3 µm, Waters Atlantis™ reversed-phase as the stationary phase. Elution is carried out with g is adiantum eluent from 97% water + 0.05% of formic acid/3% acetonitrile + 0.05% of formic acid to 97% acetonitrile + 0.05% of formic acid for 3 minutes plus a few minutes of continued transmission of this mixture at a flow rate of 1.5 ml/min retention Time is given in minutes (with an interest rate to a DA/ELSD for the corresponding peak). Spectroscopic monitoring carried out by using a detector with diode matrix (DA) Agilent™ 1100 or evaporative light scattering detector (ELSD) Sedex™. The final traces of the ion current for electrospray positive and negative ionization (ES+/ES-) and positive and negative chemical ionization at atmospheric pressure (AP+/AP-).

Intermediate compound 1: N-(2,3-dihydro-1H-inden-2-yl)-2-propanesulfinamide

Hydrochloride of 2-aminoindane (5,16 g, 30 mmol, Sigma-Aldrich Company Ltd) is suspended in dry dichloromethane (100 ml) and cooled with stirring in an argon atmosphere to 0°C. To the suspension is added 1,8-diazabicyclo[5,4 .0]undec-7-ene (3 EQ., about 14 ml, 90 mmol) followed by the addition dropwise of isopropylacetanilide (6.8 ml, 60 mmol). The cooling bath removed and the mixture is stirred at room temperature for 1 h, the Reaction mixture was washed with 1 M hydrochloric acid (2×50 ml). The organic layer is separated, dried over sodium sulfate and evaporated in vacuum (i.e. under reduced pressure)to give a yellow oil (11.8 g). The crude product is purified by chromatography on a 50 g Isolute ® Flash silikagelevye column, elwira from 20-50% ethyl acetate in petroleum EPE is e, getting listed in the title compound as a colourless solid (6,88 g, 96%).

1H NMR (400 MHz, CDCl3): δ of 1.39 (6H, d, J=7 Hz), only 2.91 (2H, m), 3,18 (1H, m), and 3.31 (2H, m), or 4.31 (2H, m), 7,21 (4H, m).

Intermediate compound 2: N-(5-iodine-2,3-dihydro-1H-inden-2-yl)-2-propanesulfinamide

Intermediate compound 1 (1.75 g, to 7.32 mmol) was dissolved in glacial acetic acid (30 ml) and then treated with concentrated sulfuric acid (0.8 ml), then water (2.8 ml) under stirring. This mixture is then treated periodni acid (0.23 equiv., 0,38 g, 1,67 mmol), followed by iodine (0.43 EQ., 800 mg and 3.15 mmol) and the whole mixture was stirred at 60°C for 3-4 h, the Reaction mixture was allowed to cool and then distributed between ethyl acetate and 10% aqueous sodium metabisulfite. The organic layer is separated and dried over sodium sulfate and evaporated in vacuum, obtaining mentioned in the title compound as a yellow oil (2.95 in).

MS (ES-): C12H16INO2S calculated 365; found 364 (MN-);1H NMR (400 MHz, CDCl3): δ of 1.39 (6H, m), 2,90 (2H, m), 3,18 (1H, m), or 3.28 (2H, m), 4,28 (1H, m), 4,63 (1H, m), 6,97 (1H, d, J=8 Hz), 7,51 (1H, m), 7,56 (1H, m).

Intermediate compound 3: N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

The complex mixture of the chloride (1,1'-bis(diphenylphosphino)Fe is Rozen)palladium(II) dichloromethane (3 mol.%, 200 mg, 0.27 mmol), potassium acetate (2.64 g, 26.9 mmol) and bis(pinacolato)diboron (1.1 EQ., 2.3 g, 9.1 mmol) in dimethyl sulfoxide (60 ml) Tegaserod with argon for 5 minutes a Solution of intermediate compound 2 (3.0 g, by 8.22 mmol) in dimethyl sulfoxide (20 ml) is added and the resulting mixture was stirred at 80°C in argon atmosphere for 3 hours the Reaction mixture was allowed to cool and diluted with ethyl acetate. This solution was washed with water (3×). The organic layer is separated, dried over sodium sulfate and evaporated under reduced pressure, obtaining a dark oil (3.25 g), which is purified by chromatography on 50 g silikagelevye column (Isolute ® Flash, elwira solution from 0-50% ethyl acetate in petroleum ether, getting mentioned in the title compound as a brown oil (2,60 g, 87%).

MS (API-): C18H28BNO4S calculated 365; found 364 (MH-);1H NMR (250 MHz, CDCl3): δ of 1.34 (12H, c)of 1.39 (6H, d, J=7 Hz), 2,90 (2H, m), 3,18 (1H, m), 3,32 (2H, m), 4,27 (2H, m), 7,26 (1H, m), the 7.65 (2H, m).

Intermediate compound 4: 5-methyl-3-pyridinyl triftorbyenzola

In dvuhholos round bottom flask under nitrogen atmosphere 3-hydroxy-5-methylpyridine (500 mg, 4,58 mmol) is suspended in 10 ml of dry methylene chloride. The add triethylamine (2.5 ml, 18,32 mmol, 4 equiv.) and the resulting solution was cooled to 0°C. a Solution of the anhydride of triftoratsetata (1,15 ml, 6,87 mmol, 1.5 a is square) in 10 ml dry methylene chloride is then added dropwise. The solution becomes purple. After the addition the mixture is stirred, maintaining the temperature at 0°C for 1 h and then allow to warm to room temperature. The solvent is removed in vacuum. The crude oil is taken in a small amount of DCM and loaded onto a cartridge containing 25 g of silicon dioxide (IST). The column is washed with pure cyclohexane and the product is collected with a mixture of cyclohexane/AcOEt 9/1. The product is obtained in two fractions: pure fractions (orange liquid, 260 mg) and less pure (orange liquid, 372 mg, additional small spots detected by TLC and minor aliphatic impurities detected1H NMR). The total yield of ~2.6 mmol, 57%.

MS (ES): C7H6F3NO3S calculated 241; found 242 (MH+);1H NMR (400 MHz, CDCl3): δ 2,44 (3H, c), 7,46 (1H, c), 8,43 (1H, c), and 8.50 (1H, c).

The intermediate compound 5: (S)-5-bromo-2-aminoindan (camphorsulfonate salt)

Specified in the header of the get connection using the method similar to that described in Prashad et al., Adv. Synth. Catal. 2001, 343, No.5, pp.461-472: i.e. by dividing the forms of the free base of racemic 5-bromo-2-aminoindane using (1R)-(-)-10-camphorsulfonic acid to obtain the salt of (1R)-(-)-10-camphorsulfonate (S)-5-bromo-2-aminoindane.

Absolute configuration salt of (1R)-(-)-10-camportal the Nata (S)-5-bromo-2-aminoindane confirmed by x-ray crystallography. Furthermore, the enantiomeric purity of the salt of (1R)-(-)-10-camphorsulfonate (S)-5-bromo-2-aminoindane check GHUR using the following conditions:

Column: chiralpak AD-H 5 μm, 250×4.6 mm

Mobile phase: A: n-hexane; B: ethanol + 0.1% Isopropylamine

Gradient: isocratic 8% B

Flow rate: 0.8 ml/min

The range of UV WL: 200-400 nm

Analysis time: 17 min

Enantiomer 1 extract as 0,84% a/a of the racemate. Rt. = 11,9 minutes

Enantiomer 2 extract as a 99.16% a/a of the racemate. Rt. = 12,8 minutes

The intermediate compound 6: N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

To obtain the form of the free base of intermediate compound 5, the intermediate compound 5 is treated with NaOH (1 M solution in water, at least 1 EQ. to achieve pH=10) isopropylacetate as solvent. The form of the free base of intermediate compound 5 is converted into N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide through a process similar to the production of intermediate compound 1, using diazabicyclo[5.4.0]undec-7-ene and isopropylacetanilide.

Intermediate compound 7: N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

The intermediate compound 6 is converted into an intermediate compound 7, using a method similar to what auchenia intermediate 3 intermediate 2, except that dichloromethane is not used.

Intermediate compound 8: (R)-5-bromo-2-aminoindan

Specified in the header of the connection receiving, using a method similar to that described in Prashad et al., Adv. Synth. Catal. 2001, 343, No.5, pp.461-472: i.e. the separation of the forms of the free base of racemic 5-bromo-2-aminoindane using (1S)-(+)-10-camphorsulfonic acid to obtain a salt of (1S)-(+)-10-camphorsulfonate (R)-5-bromo-2-aminoindane. The enantiomeric purity of the salt of (1S)-(+)-10-camphorsulfonate (R)-5-bromo-2-aminoindane check GHUR using the following conditions:

Column: chiralpak AD-H 5 μm, 250×4.6 mm

Mobile phase: A: n-hexane; B: ethanol + 0.1% of ipa

Gradient: isocratic 8% B

Flow rate: 0.8 ml/min

The wavelength range UV: 200-400 nm

Analysis time: 20 min

Enantiomer 1 extract as 98,6% a/a of the racemate. Rt. = 11,9 minutes

Enantiomer 2 extract as of 1.4% a/a of the racemate. Rt. = 12,9 minutes

Intermediate compound 9: N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-2-propanesulfinamide

Specified in the header connection hydrobromide is obtained from 5-bromo-2-aminoindane (Prashad et al., Adv. Synth. Catal. 2001, 343, No.5, pp.461-472) through a process similar to the intermediate connection 1.

MS (ES-): C12H1679BrNO2S calculated 317; found 316 (MN-); H NMR (400 MHz, CDCl3): δ of 1.39 (6H, m), is 2.88 (2H, m), 3,18 (1H, m), or 3.28 (2H, m), 4,30 (2H, m), was 7.08 (1H, d, J=8 Hz), 7,31 (1H, m), 7,35 (1H, m).

Example 1

N-[5-(2-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

A mixture of intermediate compound 2 (65 mg, 0.18 mmol) and cesium carbonate (1.5 EQ., 88 mg, 0.27 mmol) in a mixture of 3:1 1,4-ixan:water (4 ml) Tegaserod with argon for 5 minutes. The mixture is then added to (2-fluoro-3-pyridinyl)Bronevoy acid (1.1 EQ., 28 mg, 0.20 mmol, Asymchem International Inc.). Then add palladium acetate (2 mg, 0.01 mmol - as option can be used palladium on solid media) and triphenylphosphine (9 mg, 0.03 mmol) and the whole mixture was stirred at the boil under reflux for 16 hours the Reaction mixture was allowed to cool and distributed between ethyl acetate (10 ml) and water (10 ml). The organic layer is separated, dried and evaporated. The resulting product was then purified using mass directed preparative GHUR, getting mentioned in the title compound (22 mg, 37%).

MS (API+): C17H19FN2O2S calculated 334; found 335 (MH+);1H NMR (400 MHz, CDCl3): δ of 1.41 (6H, d, J=7 Hz), 2,98 (2H, m), 3,21 (1H, m)to 3.38 (2H, m), 4,35 (2H, m), 7,38 (3H, m), 7,66 (1H, m), to 7.84 (1H, m), 8,19 (1H, m).

Example 2

N-[5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

Specified in the header is VCE compound obtained by the process such obtaining of example 1, from intermediate 2 (6-fluoro-3-pyridinyl)Bronevoy acid, except that instead of mixing the mixture at normal boiling under reflux for 16 h, the reaction mixture was stirred in a microwave reactor at 160°C for 20 minutes.

MS (API+): C17H19FN2O2S calculated 334; found 335 (MH+);1H NMR (250 MHz, CDCl3): δ of 1.41 (6H, d, J=7 Hz), 2,98 (2H, m), 3,21 (1H, m)to 3.38 (2H, m), and 4.40 (2H, m), 7,00 (1H, m), 7,32 (3H, m), to 7.93 (1H, m), of 8.37 (1H, m).

Specified in the header of the connection also receive, on the basis of the intermediate compound (9), through a process similar to obtaining of example 1, using (6-fluoro-3-pyridinyl)baronova acid.

MS (ES+): C17H19FN2O2S calculated 334; found 335 (MH+);1H NMR (400 MHz, CDCl3) δ of 1.41 (6H, d, J=7 Hz), 2,98 (2H, m), 3,21 (1H, m)to 3.38 (2H, m), 4,35 (1H, m), of 4.45 (1H, m), 7,00 (1H, DD, J=8 and 2 Hz), 7,34 (3H, m), to 7.93 (1H, m), of 8.37 (1H, m).

Racemic compound share GHUR to obtain the two enantiomers using the following conditions:

Column: Chiralpak AS-H 5 μm, 250×4.6 mm,

Mobile phase: A: n-hexane; B: ethanol

Gradient: isocratic 30% B

Flow rate: 0.8 ml/min

The range of UV WL: 200-400 nm

Analysis time: 20 min

Enantiomer 1 extract as 51,4% a/a of the racemate. Rt. = 16,2 minutes

Enantiomer 2 extract as 48,6% a/a of the racemate. Rt. = 17,7 minutes

Enantio the career of example 2 can be obtained using enantiomerically pure intermediates.

Example 2a

N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

The intermediate compound 6 is subjected to interaction with (6-fluoro-3-pyridinyl)Bronevoy acid in a process similar to obtaining example 1, except that instead of mixing the mixture at normal boiling under reflux for 16 h, the reaction mixture was stirred in a microwave reactor at 160°C for 20 minutes and instead of palladium acetate and triphenylphosphine use linked polymer tetrakis(triphenylphosphine)palladium, to obtain N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide. The enantiomeric purity of the obtained N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide check GHUR, using the same conditions as for the separation of racemic compounds above. Enantiomer 1 extract as 2,08% a/a of the racemate. Rt. = 16,3 minutes Enantiomer 2 extract as 97,92% a/a of the racemate. Rt. = 17,7 minutes Enantiomer 2, as confirmed by x-ray crystallography, is N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide.

Example 2b

N-[(2R)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

Specified in the header of the get connection using a process similar to that described for example 2a, using the first intermediate connection is of 8, to obtain the corresponding propanesulfonate. The enantiomeric purity of the obtained N-[(2R)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide check GHUR, using the same conditions as for the separation of racemic compounds of example 2 above, except that the analysis time 22 minutes. Enantiomer 1 extract as 99,04% a/a of the racemate. Rt. = 16,62 minutes Enantiomer 2 extract as 0,96% a/a of the racemate. Rt. = 18,29 minutes

The following compounds of formula (A) (see table 1), i.e. compounds of General formula (I), where R1means isopropyl, n is 1, R2and R3are hydrogen and p is 0, get methods, like getting in example 1, from intermediate 2 together with the corresponding Bronevoy acid. Boranova acid, all are commercially available from one or more of the following suppliers: Asymchem International Inc., Frontier Scientific Inc. and Sigma Aldrich Company Ltd.

Table 1
ExampleHetPhysical data
35-pyrimidinylMS (API+): C16H19N3O2S calculated 316; found the 317 (MH+); 1H NMR (400 MHz, CDCl3): of 1.41 (6H, d, J=7 Hz), to 3.02 (2H, m), 3,21 (1H, m), 3.43 points (2H, m), 4,37 (1H, m), 4,69 (1H, m), 7,37 (3H, m), 8,87 (2H, m), 9,18 (1H, m).
43-thienylMS (API-): C16H19NO2S2calculated 320; found 319 (MH-);1H NMR (400 MHz, CDCl3): of 1.39 (6H, m), with 2.93 (2H, m), 3,19 (1H, m)to 3.34 (2H, m), 4,32 (1H, m)to 4.41 (1H, m), 7,39 (6H, m).
53-pyridylMS (API+): C17H20N2O2S calculated 316; found 317 (MH+);1H NMR (400 MHz, CDCl3): of 1.40 (6H, d, J=7 Hz), of 3.00 (2H, m), 3,21 (1H, m), 3,37 (2H, m), 4,34 (1H, m), 5,04 (1H, m), 3,32 (1H, m), 7,41 (3H, m), to $ 7.91 (1H, m), to 8.57 (1H, m), is 8.75 (1H, m).
62-thienylMS (API-): C16H19NO2S2calculated 320; found 319 (MH-);1H NMR (400 MHz, CDCl3): to 1.38 (6H, d, J=7 Hz), of 2.92 (2H, m), and 3.16 (1H, m), with 3.27 (2H, m), the 4.29 (1H, m), of 4.54 (1H, m), 7,06 (1H, m), 7,20 (1H, m), 7,25 (2H, m), the 7.43 (2H, m).

Example 7

N-[5-(4-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

A mixture of intermediate compound 3 (80 mg, 0.22 mmol), 3-bromo-4-methylpyridine (1 EQ., 38 mg, 0.22 mmol) and cesium carbonate (1.5 EQ., 108 mg, 0.33 mmol) in a mixture of 3:1 1,4-dioxane:water (4 ml) Tegaserod with argon for 5 minutes. Then add the acetate is alladia (2 mg, 0.01 mmol), then triphenylphosphine (12 mg, 0.04 mmol) and the whole mixture was stirred at 160°C for 20 min in a microwave reactor. The reaction mixture was allowed to cool and distributed between ethyl acetate and water. The organic layer is separated and evaporated under reduced pressure. The resulting product was then purified on a 5 g silikagelevye column (Isolute ® Flash, elwira from 0-40% ethyl acetate in petroleum ether, getting mentioned in the title compound as a yellow oil (38 mg, 52%).

MS (API+): C18H22N2O2S calculated 330; found 331 (MH+);1H NMR (400 MHz, CDCl3): δ of 1.41 (6H, d, J=7 Hz), 2,73 (3H, c)to 2.99 (2H, m), 3,21 (1H, m)to 3.38 (2H, m), 4,36 (1H, m), 4,74 (1H, m), 7,12 (1H, DD, J=8 Hz and 1 Hz), 7,17 (2H, m), 7,29 (1H, d, J=8 Hz), 8,30 (1H, c), 8,43 (1H, d, J=5 Hz).

The following compounds of formula (A) (see table 2), i.e. compounds of General formula (I), where Rlmeans isopropyl, n is 1, R2and R3are hydrogen and p is 0, get methods, similar to obtaining a example 7, on the basis of intermediate compound 3 together with the corresponding pyridyl-, pyrimidinyl, imidazolyl or pyridinylamino. Such halides are all commercially available from one or more of the following suppliers: Apollo Scientific Ltd. and Lancaster Synthesis Ltd.

Table 2
ExampleHetPhysical data
8MS (API+): C19H24N2O2S calculated 344; found 345 (MH+);1H NMR (400 MHz, CDCl3): of 1.41 (6H, d, J=7 Hz), 2,47 (3H, c), to 2.57 (3H, c), 2,96 (2H, m), 3,21 (1H, m), 3,37 (2H, m), 4,37 (2H, m),? 7.04 baby mortality (1H, d, J=8 Hz), 7,13 (2H, m), 7,26 (1H, m), 7,38 (1H, d, J=8 Hz).
9MS (API+): C18H19N3O2S calculated 341; found 342 (MH+);1H NMR (400 MHz, CDCl3): of 1.41 (6H, d, J=7 Hz), of 3.00 (2H, m), 3,21 (1H, m)to 3.38 (2H, m), 4,37 (2H, m), 7,40 (3H, m), 7,76 (1H, m), of 7.97 (1H, m), 8,91 (1H, m).
10MS (API+): C19H22N2O3S calculated 358; found 359 (MH+);1H NMR (400 MHz, CDCl3): of 1.41 (6H, d, J=7 Hz), 2,69 (3H, c)of 3.00 (2H, m), 3,21 (1H, m), 3,40 (2H, m), 4,36 (1H, m), 4,56 (1H, m), 7,35 (1H, m), 7,45 (3H, m), to 7.67 (1H, m), of 8.37 (1H, m).
11MS (ES+): C18H19N3O2S calculated 341; found 342 (MH+);1H NMR (400 MHz, CDCl3): of 1.41 (6H, d, J=7 Hz), of 3.00 (2H, m), 3,21(1H, m), 3,40 (2H, m), 4,35 (1H, m), of 4.49 (1H, m), 7,38 (2H, m), 7,42 (1H, m), of 8.09 (1H, m), 8,83 (1H, m), 8,97 (1H, m).
12MS (APCI):C17H19FN2O2Scalculated 334; found 335 (MH+);1H NMR (400 MHz, CDCl3): of 1.40 (6H, m), 2,96 (2H, m), 3,20 (1H, m)to 3.38 (2H, m), 4,34 (2H, m), 7,31 (1H, m), 7,47 (1H, m), 7,71 (2H, m), 7,81 (1H, m), charged 8.52 (1H, m).
Using similar methods, example 12 also receive as a single enantiomer, on the basis of intermediate compound 6, which is used to produce the intermediate compound 7, except that instead of palladium acetate and triphenylphosphine use linked polymer tetrakis(triphenylphosphine)palladium. Intermediate compound 7 is then subjected to interaction with the corresponding predilatation getting enantiomeric compound, which, in all probability, is N-[(2S)-5-(5-fluoro-2-pyridyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide thanks to the use of intermediate compound 6.
13MS (APCI):C17H20N2O2Scalculated 316; found 317 (MH+);1H NMR (400 MHz, CDCl3): of 1.41 (6H, m), 2,99 (2H, m), 3,21 (1H, m)to 3.38 (2H, m), 4,35 (1H, m), 4,58 (1H, m), 7,32 (1H, m), 7,46 (3H, m), to 7.67 (1H, m, 8,64 (2H, m).
14MS (APCI):C17H20N2O2Scalculated 316; found 317 (MH+);1H NMR (400 MHz, CDCl3): of 1.40 (6H, m), 2,95 (2H, m), 3,19 (1H, m)to 3.36 (2H, m), 4,34 (1H, m), 4,47 (1H, m), 7.23 percent (1H, m), 7,30 (1H, d, J=8 Hz), 7,69 (1H, m), 7,76 (2H, m), 7,86 (1H, c), 8,68 (1H, m).
15MS (APCI):C17H19FN2O2Scalculated 334; found 335 (MH+);1H NMR (400 MHz, CDCl3): of 1.40 (6H, m), of 2.97 (2H, m), 3,20 (1H, m), 3,37 (2H, m), 4,35 (2H, m), 6,85 (1H, DD, J=8 Hz and 3 Hz), 7,30 (1H, m), to 7.59 (1H, DD, J=7 Hz and 2 Hz), to 7.84 (3H, m).
16MS (APCI): C18H22N2O2S calculated 330; found 331 (MH+);1H NMR (400 MHz, CDCl3): of 1.41 (6H, m)to 2.67 (3H, c)to 2.99 (2H, m), 3,21 (1H, m), 3,39 (2H, m), 4,36 (1H, m), of 4.45 (1H, m), 7,34 (1H, d, J=8 Hz), 7,41-7,49 (3H, m), 8,23 (1H, c), 8,59 (1H, m).
17MS (APCI): C17H21N3O2S calculated 331; found 332 (MH+);1H NMR (250 MHz, CDCl3): of 1.41 (6H, m), was 2.76 (3H, c)of 3.00 (2H, m), 3,21 (1H, m), 3,39 (2H, m), 4,37 (1H, m), of 4.49 (1H, m), of 7.36 (2H, m), 7,49 (1H, m), 7,83 (1H, m), 794 (1H, c).
18MS (APCI):C16H19N3O2Scalculated 317; found 318 (MH+);1H NMR (400 MHz, CDCl3): of 1.40 (6H, m), 2,98 (2H, m), 3,20 (1H, m), 3,39 (2H, m), 4,35 (2H, m), 7,18 (1H, m), 7,33 (1H, m), of 8.28 (2H, m), 8,79 (2H, d, J=5 Hz).
19MS (APCI):C17H19FN2O2Scalculated 334; found 333 (MH-);1H NMR (400 MHz, CDCl3): of 1.41 (6H, m), of 2.97 (2H, m), 3,21 (1H, m)to 3.38 (2H, m), 4,34 (2H, m), of 7.36 (2H, m), 7,47 (2H, m), to 8.45 (1H, m), 8,53 (1H, m).
20MS (ES): C18H21FN2O2S calculated 348; found 349 (ES+);1H NMR (250 MHz, CDCl3): of 1.41 (6H, m), 2,43 (3H, c), of 2.97 (2H, m), 3,21 (1H, m)to 3.38 (2H, m), to 4.38 (2H, m), to 6.80 (1H, m), 7,11 (2H, m), 7,28 (1H, m), 7,58 (1H, m).
21MS (ES): C15H19N3O2S calculated 305; found 306 (ES+);1H NMR (400 MHz, CDCl3): of 1.40 (6H, m), with 2.93 (2H, m), 3,20 (1H, m)to 3.34 (2H, m)to 4.33 (2H, m), 7.23 percent (1H, m), 7,30 (1H, m), 7,54 (1H, m), 7,60 (1H, c), 7,74 (1H, c).
22 MS (ES): C18H25N3O2S calculated 347; found 348 (ES+);1H NMR (400 MHz, CDCl3): of 1.41 (6H, d, J=7 Hz), of 2.23 (6H, c)to 2.94 (2H, m), 3,20 (1H, m)to 3.35 (2H, m), of 3.78 (3H, c)to 4.33 (2H, m), 7,06 (2H, m), 7,25 (1H, m).
23MS (ES): C18H22N2O2S calculated 330; found 331 (ES+);1H NMR (400 MHz, CDCl3): of 1.41 (6H, m)2,60 (3H, c), of 2.97 (2H, m), 3,20 (1H, m)to 3.38 (2H, m), 4,35 (2H, m), 7,21 (1H, d, J=8 Hz), 7,30 (1H, m), 7,38 (2H, m), 7,73 (1H, DD, J=8 Hz and 2 Hz), 8,68 (1H, d, J=2 Hz).
Using similar methods, example 23 also receive as a single enantiomer, on the basis of intermediate compound 6, which is used to produce the intermediate compound 7, except that instead of palladium acetate and triphenylphosphine use linked polymer tetrakis(triphenylphosphine)palladium. Intermediate compound 7 is then subjected to interaction with the corresponding predilatation getting enantiomeric compound, which, in all probability, is N-[(2S)-5-(6-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide, thanks to the use of intermediate compound 6.
24MS (ES): C18H22N2O2S calculated found 330 331 (ES+); 1H NMR (400 MHz, CDCl3): of 1.41 (6H, m), of 2.34 (3H, c), 2,89 (2H, m), 3,19 (1H, m)to 3.33 (2H, m), 4,32 (1H, m), of 4.67 (1H, m), 7,18 (1H, m), 7,28 (2H, m), 7,37 (1H, c), 7,58 (1H, m), 8,53 (1H, m).
25MS (ES): C18H22N2O2S calculated 330; found 331 (ES+);1H NMR (400 MHz, CDCl3): of 1.39 (6H, m), is 2.37 (3H, c), 2,95 (2H, m), 3,24 (1H, m)to 3.36 (2H, m)to 4.33 (1H, m)to 4.41 (1H, m), 7,29 (1H, d, J=8 Hz), EUR 7.57 (2H, m), of 7.75 (1H, DD, J=8 Hz and 2 Hz), 7,83 (1H, c), and 8.50 (1H, m).
26MS (ES): C17H1935CIN2O2S calculated 350; found 351 (ES+);1H NMR (400 MHz, CDCl3): of 1.40 (6H, d, J=7 Hz), 2,98 (2H, m), 3,21 (1H, m)to 3.38 (2H, m), 4,36 (2H, m), of 7.36 (4H, m), 7,80 (1H, DD, J=8 Hz and 2 Hz), 8,56 (1H, m).
27MS (ES): C18H22N2O2S calculated 346; found 347 (ES+);1H NMR (400 MHz, CDCl3): of 1.41 (6H, m), 2,96 (2H, m), 3,20 (1H, m), 3,37 (2H, m), 3,98 (3H, c), or 4.31 (2H, m), for 6.81 (1H, m), 7,29 (1H, m), 7,35 (2H, m), of 7.75 (1H, DD, J=8 Hz and 2 Hz), a 8.34 (1H, m).
28MS (ES): C17H1935CIN2O2S calculated 350; found 351 (ES+);1H NMR (400 MHz, CDCl3 ): of 1.40 (6H, m), 2,96 (2H, m), 3,21 (1H, m)to 3.38 (2H, m)to 4.33 (2H, m), 7,31 (1H, d, J=8 Hz), to 7.64 (1H, m), 7,74 (2H, m), to 7.84 (1H, m), to 8.62 (1H, m).
29MS (ES): C17H1935CIN2O2S calculated 350; found 351 (ES+);1H NMR (400 MHz, CDCl3): of 1.41 (6H, m), 2,99 (2H, m), and 3.31 (1H, m)to 3.38 (2H, m), 4,35 (1H, m), 4,47 (1H, m), 7,29 (4H, m), the 7.65 (1H, DD, J=7 Hz and 2 Hz), 8,39 (1H, m).

Example 30

N-{(2S)-5-[6-(trifluoromethyl)-3-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfinamide

To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide (190 mg, 0.52 mmol) in dry 1,4-dioxane (5 ml) is added Pd(PPh3)4on the polymer carrier (10 mg, 0.5 mmol/g of 0.005 mmol) with 5-bromo-2-(trifluoromethyl)pyridine (176 mg, 0.78 mmol) and 500 μl of a 2 M solution of Na2CO3in the water. The resulting mixture is heated at 90°C for 3 hours. Then after cooling, the polymer is removed by filtration and then the solvent is removed under reduced pressure. The residue is taken up with DCM, washed with water and placed on the cartridge 25M+ silicon dioxide, elwira with a mixture of cyclohexane/AcOEt 75/25. 150 mg specified in the connection header is extracted in the form of a whitish solid (75%). Thanks to the use of chiral intermediate compound 7, ConECs the e connection in all likelihood, is N-{(2S)-5-[6-(trifluoromethyl)-3-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfinamide.

MS (ES): C18H19F3N2O2S calculated 384; found 385 (MH+);1H-NMR (500 MHz, DMCO-d6): of 1.26 (6H, d, J=7 Hz), of 2.92 (2H, m), 3,23 (3H, m), 4,14 (1H, m), 7,37 (1H, d, J=8 Hz), of 7.48 (1H, d, J=8 Hz), to 7.59 (1H, d, J=9 Hz), the 7.65 (1H, m), 7,95 (1H, d, J=9 Hz), 8,31 (1H, m), 9,05 (1H, m).

Example 31

N-[(2S)-5-(5-chloro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide (1 g, is 2.74 mmol) in dry 1,4-dioxane (15 ml) is added Pd(PPh3)4on the polymer carrier (54 mg, 0.5 mmol/g, or 0.027 mmol) with 2-bromo-5-chloropyridine (1,05 g of 5.48 mmol) and 3.5 ml of 2 M solution of Na2CO3in water and the resulting mixture heated at 90°C for 3 hours. Then after cooling, the polymer is removed by filtration and then the solvent is removed under reduced pressure. The residue is taken up with AcOEt and water. The aqueous phase is separated and acidified with 3n HCl and extracted with AcOEt. Then pH was adjusted to basic with the addition of NaHCO3and spend another extraction with AcOEt. All organic extracts are collected, dried over Na2SO4, filtered and evaporated. The crude product is finally purified on a cartridge 40M+ silicon dioxide, elwira with a mixture of cyclohexane/AcOEt 8/20. 682 mg specified in the connection header is extracted in the form of a whitish solid (71%). Thanks to the use of chiral intermediate compound 7, the target compound, in all probability, is N-[(2S)-5-(5-chloro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide.

MS (ES):C17H1935CIN2O2Scalculated 350; found 351 (MH+);1H NMR (500 MHz, DMCO-d6): a 1.25 (6H, d, J=7 Hz), 2,90 (2H, m), 3,24 (3H, m), 4,14 (1H, m), 7,31 (1H, d, J=8 Hz), 7,46 (1H, d, J=8 Hz), 7,86 (1H, m), of 7.90 (1H, m), of 7.96 (2H, m), 8,66 (1H, m).

Example 32

N-{(2S)-5-[6-(trifluoromethyl)-2-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfinamide

To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide (190 mg, 0.52 mmol) in dry 1,4-dioxane (5 ml) is added Pd(PPh3)4on the polymer carrier (10 mg, 0.5 mmol/g of 0.005 mmol) with 2-bromo-6-triftormetilfullerenov (174 mg, 0.78 mmol) and 500 μl of 2M solution of Na2CO3in water and the resulting mixture heated at 90°C for 3 hours. Then after cooling, the polymer is removed by filtration and then the solvent is removed under reduced pressure. The residue is taken up with DCM, washed with water and placed on the cartridge 25M+ silicon dioxide, elwira with a mixture of cyclohexane/AcOEt 75/25. 95 mg specified in the connection header is extracted in the form of a Bel is Savatage solid (47%). Thanks to the use of chiral intermediate compound 7, the target compound, in all probability, is N-{(2S)-5-[6-(trifluoromethyl)-2-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfinamide.

MS (ES): C18H19F3N2O2S calculated 384; found 385 (MH+);1H NMR (500 MHz, DMCO-d6): of 1.26 (6H, d, J=7 Hz), of 2.92 (2H, m), 3,23 (3H, m), 4,14 (1H, m), of 7.36 (1H, d, J=8 Hz), 7,47 (1H, m), 7,81 (1H, d, J=8 Hz), 7,92 (1H, d, J=8 Hz), 7,95 (1H, m), 8,14 (1H, t, J=7 Hz), 8,24 (1H, d, J=8 Hz).

Example 33

N-[(2S)-5-(5-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide (250 mg, of 0.68 mmol) in dry 1,4-dioxane (5 ml) is added Pd(PPh3)4on the polymer carrier (70 mg, 0.11 mmol/g, 0,0068 mmol) with 5-methyl-3-pyridinyl triftoratsetata (241 mg, 1,026 mmol) and 680 μl of 2 M solution of Na2CO3in water and the resulting mixture heated at 90°C for 3 hours. Then after cooling, the polymer is removed by filtration and then the solvent is removed under reduced pressure. The residue is taken up with DCM, washed with water and placed on the cartridge 25M+ silicon dioxide, elwira with a mixture of cyclohexane/AcOEt 75/25. 95 mg specified in the connection header is extracted in the form of a whitish solid (42%). Thanks to the use of chiral intermediate the first compound 7, the target compound, in all probability, is N-[(2S)-5-(5-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide.

MS (ES):C18H22N2O2Scalculated 330; found 331 (MH+);1H NMR (400 MHz, CDCl3): USD 1.43 (6H, d, J=7 Hz), 2,43 (3H, m), 3,01 (2H, m), 3,23 (1H, m), 3,40 (2H, m), to 4.38 (1H, m)and 4.65 (1H, m), 7,34 (1H, d, J=8 Hz), 7,40 (1H, d, J=8 Hz), 7,43 (1H, m), 7,71 (1H, m), 8,44 (1H, m), 8,56 (1H, m).

Example 34

N-[(2S)-5-(5-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide (700 mg, 1.92 mmol) in dry 1,4-dioxane (15 ml) is added Pd(PPh3)4on the polymer carrier (38 mg, 0.5 mmol/g, 0.019 mmol) with 3-bromo-5-herperidin (675 mg, a 3.83 mmol) and 2.7 ml of 2 M solution of Na2CO3in water and the resulting mixture heated at 90°C for 3 hours. Then after cooling, the polymer is removed by filtration and then the solvent is removed under reduced pressure. The residue is taken up with AcOEt and water. The aqueous phase is separated and acidified with 3n HCl and extracted with AcOEt. Then pH was adjusted to basic with the addition of NaHCO3and spend another extraction with AcOEt. All organic extracts are collected, dried over Na2SO4, filtered and evaporated. The crude product is finally purified on a cartridge 40M+ dioxide credit the Deposit, elwira with a mixture of cyclohexane/AcOEt 80/20. 270 mg specified in the connection header is extracted in the form of a whitish solid along with 240 mg of slightly less pure fractions (total yield 79%). Thanks to the use of chiral intermediate compound 7, the target compound, in all probability, is N-[(2S)-5-(5-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide.

MS (ES): C17H19FN2O2S calculated 334; found 335 (MH+);1H NMR (400 MHz, CDCl3): USD 1.43 (6H, d, J=7 Hz), 3,01 (2H, m), 3,23 (1H, m), 3,42 (2H, m), 4,30 (1H, d, J=8 Hz), 4,39 (1H, m), 7,37 (1H, d, J=8 Hz), 7,42 (1H, d, J=8 Hz), 7,45 (1H, m), to 7.61 (1H, d, J=9 Hz), 8,48 (1H, m), 8,66 (1H, m).

Example 35

N-[(2S)-5-(2-fluoro-6-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide (250 mg, of 0.68 mmol) in dry 1,4-dioxane (5 ml) is added Pd(PPh3)4on the polymer carrier (14 mg, 0.5 mmol/g to 0.007 mmol) with 3-bromo-2-fluoro-6-methylpyridine (194 mg, of 1.02 mmol) and 680 μl of 2 M solution of Na2CO3in the water. The resulting mixture is heated at 90°C for 3 hours. Then after cooling, the polymer is removed by filtration and then the solvent is removed under reduced pressure. The residue is taken up with DCM, washed with water and placed on the cartridge 25M+ silicon dioxide, elwira mixture cycle is hexane/AcOEt 75/25. 175 mg specified in the connection header is extracted in the form of a white solid (74%). Thanks to the use of chiral intermediate compound 7, the target compound, in all probability, is N-[(2S)-5-(2-fluoro-6-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide.

MS (ES):C18H21FN2O2Scalculated 348; found 349 (MH+),1H NMR (400 MHz, CDCl3): 1,42 (6N, d, J=7 Hz), to 2.55 (3H, c), 2,98 (2H, m), 3,21 (1H, m), 3,39 (2H, m)to 4.33 (2H, m), 7,11 (1H, d, J=8 Hz), 7,31 (1H, d, J=7 Hz), 7,37 (1H, d, J=8 Hz), 7,41 (1H, c), 7,73 (1H, m).

Example 36

N-[(2S)-5-(2,6-debtor-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide

To a solution of (2,6-debtor-3-pyridinyl)Bronevoy acid (2 g, 12,56 mmol) in dry 1,4-dioxane (30 ml) is added Pd(PPh3)4on the polymer carrier (126 mg, 0.5 mmol/g, 0,063 mmol) with N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide (2 g, 6,28 mmol) and 7.3 ml of 2 M solution of Na2CO3in water and the resulting mixture heated at 90°C for 3 hours. Then after cooling, the polymer is removed by filtration and then the solvent is removed under reduced pressure. The residue is taken up with AcOEt and water. The aqueous phase is separated and acidified with 3n HCl and extracted with AcOEt. Then pH was adjusted to basic with the addition of NaHCO3and spend another extraction with AcOEt. All organic extracts sobi is up, dried over Na2SO4, filtered and evaporated. The crude product is finally purified on a cartridge 40M+ silicon dioxide, elwira with a mixture of cyclohexane/AcOEt 80/20. 798 mg specified in the connection header is extracted in the form of a whitish solid (36%). Thanks to the use of chiral intermediate compound 6, is listed in the title compound, in all probability, is N-[(2S)-5-(2,6-debtor-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide.

MS (ES): C17H18F2N2O2S calculated 352; found 353 (MH+);1H NMR (500 MHz, DMSO-d6): δ 1,25 (6H, d, J=7 Hz), 2,90 (2H, m), up 3.22 (3H, m), 4,13 (1H, m), 7,27 (1H, d, J=7 Hz), 7,34 (2H, m), 7,41 (1H, m), 7,47 (1H, d, J=8 Hz), compared to 8.26 (1H, m).

Biological analysis

The ability of compounds according to the invention to increase the response, mediated by glutamate receptor, determine (a) through the use of fluorescent dyes as indicators of calcium, such as FLUO4, and additionally for some of the compounds of examples b) by measuring glutamate-induced current recorded using HEK293 human cells containing an open form reprezentirovannoe receptor GluR2.

(a) Fluorescence analysis of the inflow of calcium

Prepare 384-well plates, containing a continuous monolayer of cells HEK293, or stably expressing, or temporarily by transactioninactivetimeout AMPA receptor human containing an open form reprezentirovannoe receptor GluR2. These cells form functional homotetrameric AMPA receptors. Located in the wells of tissue culture medium discarded and each well is washed three times with standard buffer (80 ál) for stable cell line (145 mm NaCl, 5 mm KCl, 1 mm MgCl2, 2 mm CaCl2, 20 mm N-[2-hydroxyethyl]piperazine-N-[2-econsultancy acid (HEPES), 5.5 mm glucose, pH 7.3) or free from Na buffer for temporarily transfection cells (145 mm N-methylglucamine instead of NaCl). The tablets are then incubated for 60 minutes in the dark with 2 μl of dye FLUO4-AM (Molecular Probes, Netherlands) at room temperature, to allow assimilation of FLUO-4AM, which then turns into a FLUO-4 by intracellular esterases, which are not able to leave the cell. After incubation each well was washed three times with buffer (80 ál) (30 μl buffer remains in each well after washing).

Compounds according to the invention (or compounds for comparison, such as cyclothiazide) dissolved in dimethyl sulfoxide (DMSO) at a fixed concentration of 10 mm. These solutions are further diluted with DMSO, using a Biomek FX (Beckman Coulter), tablet 384 connection. Each dilution (1 μl) is transferred to another tablet for connections and add a buffer (50 μl). Prepare the tablet agonistic stimulus (put the Mat) by dissolution of sodium glutamate in water, to obtain a concentration of 100 mm. This solution was diluted with buffer to obtain a final concentration of 500 μm and dosed on the other 384-well plate (50 μl/well), using a multi-line Multidrop dispenser (Thermolabsystems).

The tablet with the cells then convert into a tablet for playback fluorescence reader [such as FLIPR384 (Molecular Devices)]. Registration baseline fluorescence is carried out in the period from 10 to 240 seconds, and then 10 µl of each tablet containing compound according to the invention, prepared in standard buffer solution (at concentrations ranging from 100 μm to 10 PM) add (to obtain a final concentration in the range from 30 μm to 3 PM). Fluorescence recorded during the period of 5 minutes. Add 500 μm solution of glutamate (10 μl) (receiving final concentration 100 μm). Then record the fluorescence over a period of 4 minutes. Activity of the compounds according to the invention and compounds of the comparison is determined by measuring the peak fluorescence after the last addition. The activity is also expressed in relation to the enhancement of fluorescence induced by cyclothiazide at its maximum response (i.e. more than 30 μm).

All connections examples are subjected to screening using the analysis), and they provide an indicator of pEC50equal to or more than 4.0 and demonstrate the activity of Maine is our least 40% of such cyclothiazide (at their maximum reactive). Some compounds give pEC50equal to or more than the 4.7. Example 4 gives a pEC505,0.

(b) Electrophysiological testing of whole cells with the creation of the terminal voltage

This test leads to electrophysiological characterization of positive modulators of AMPA receptor using HEK293 cells stably expressing an open form reprezentirovannoe receptor GluR2 subunit of human rights which form the functional homotetrameric the AMPA receptor. The extracellular recording solution containing 135 mm NaCl, 2 mm KCl, 1 mm MgCl2, 2 mm CaCl212 mm N-[2-hydroxyethyl]piperazine-N-[2-econsultancy acid (HEPES), 10 mm D-glucose, pH of 7.35. Intracellular solution containing (150 mm CsCl, 10 mm N-[2-hydroxyethyl]piperazine-N-[2-econsultancy acid (HEPES), 2 mm ethylene glycol-bis(g-aminoethylamino)-N,N,N',N-tetraoxane acid (EGTA), pH 7.3. Intracellular solution containing amphotericin b (240 μg/ml), used for filling the pipette, while one intracellular solution used to fill only the tip (pipette the patch-clamp have a resistance of 2-5 MΩ) Amphotericin b creates small pores in the cell membrane under the electrode, which allow small ions to pass through the membrane (and therefore allow e is tricocci control cells) without dialysis molecules of the second messenger of the cells, which may be the result of metabolic depletion of cells, leading to inconsistent activation of the receptor (Virginio, C., A. Giacometti, Aldegheri L., Rimland JM, Terstappen GC (2002) Eur. J. Pharmacol. 445: 153-161). The membrane potential of cells is supported at -60 mV and electrophysiological testing of the patch-clamp carried out with the use of computer programs HEKA, Germany). The cage come before the first of the 16 linearly-spaced channels. The system moves one channel, then the next before the single fixed clamp cell, allowing for quick replacement and the exact time of application solutions (for more information see http://www.cellectricon.se/). The first channel contains a normal buffer to measure the base current. The second channel contains 3 mm glutamate, which is applied to the cell at 500 MS to register the control (only agonist) response. The third channel contains a normal buffer, which washes away glutamate within 1-3 minutes of the Fourth channel, containing or connection according to the invention, or the connection of comparison, moves in front of the cage for one minute. The fifth channel contains glutamate in the presence of the test (or comparative) compound that is applied to the cell at 500 MS. The sixth channel contains a normal buffer, which washes away glutamate plus test (or comparative) compound in techenie1 3 minutes. This procedure is repeated with increasing concentrations or compounds according to the invention or the comparative compounds. The active compounds according to the invention is determined by measuring the peak current amplitude or area under the curve (500 MS) for a response to glutamate in the presence of compounds according to the invention (or compounds comparison) and Express it as a % gain response only to glutamate (glutamate in the absence of the compounds according to the invention (or compounds comparison)). Alternative activity can be expressed as the activity of glutamate in the presence of compounds according to the invention (or compounds comparisons) compared to the response induced by glutamate in the presence cyclothiazide at their maximum reactive.

1. The compound of formula (I), its pharmaceutically acceptable salt

where R1means C1-6alkyl;
R2and R3mean hydrogen;
R means 0;
n means 1;
R5and R6mean hydrogen and
Het means thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, each of which may be substituted by one or two groups independently selected from the list consisting of C1-6of alkyl, C1-6alkoxy, acetyl, halogen, Halogens1-6of alkyl, cyano.

2. The compound according to claim 1 where Het is a small town in the place 3-pyridyl, 5-pyrimidinyl, 2-pyrimidinyl, 3-thienyl, 2-thienyl, 3-pyridazinyl, 1H-4-imidazolyl or 1H-4-pyrazolyl, each of which is optionally substituted by one or two groups independently selected from the group consisting of methyl, acetyl, cyano, fluorine, chlorine, CF3and methoxy.

3. The compound according to claim 1, which is N-[5-(2-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfinamide or its pharmaceutically acceptable salt.

4. Pharmaceutical composition having the property to enhance the response, mediated by glutamate receptor containing the compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier or diluent.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula (1) , in form of trans- or cis-isomers, or their mixture, where R1 is selected from , and ; R7 stands for lower alkyl; R8 stands for lower alkyl; X represents >C=O or >SO2; R9 and R11 represent hydrogen or together form double bond; R10 and R12 are independently selected from hydrogen or lower alkyl; m stands for 1 or 2; n stands for 0, 1 or 2 and their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition and to application of said compounds, as well as compounds of formula (I), where R1 represents (R2, R3, R4, R5 and R6 each is independently selected from hydrogen, lower alkyl, lower alkoxy group or halogen; on condition that R2, R3, R4, R5 and R6 do not represent hydrogen), for treatment and/or prevention of DPP-IV-associated diseases.

EFFECT: obtaining novel compounds for treatment and/or prevention of DPP-IV-associated diseases.

14 cl, 1 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel bioisosteres of actinonin of general formula (I) , as well as to pharmaceutically acceptable salts thereof and pharmaceutical compositions based on said compounds, with peptide deformylase (PDF) inhibitory activity, as well as to use of the compounds or pharmaceutical compositions based on said compounds to prepare medicinal agents. In general formula (I) R1 is a hydrogen atom, R2 is a hydrogen atom, (C1-C6)alkyl residue, hetero(C1-C6)alkylphenyl residue, where the heteroatom is sulphur, R3 is a hydrogen atom, R4 is (C1-C6)alkyl residue, (C3-C7)cycloalkyl residue, R6 is a hydrogen atom, n is 1, 2 or 3. Values of substitute R5 are given in the formula of invention.

EFFECT: new compounds have useful biological activity.

8 cl, 1 ex

FIELD: chemistry.

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

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

15 cl, 8 dwg, 58 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed method of producing (+)duloxetine or its acid-additive salt, including (i) isolation of racemic (±)duloxetine with chiral acid thus producing chiral acid salt and (+)duloxetine, essentially free from (-)duloxetine; and (ii) if desired, transformation of the salt produced at the stage (i) into free base or other acid-additive salt if reasonable. Additionally, method of producing (+)duloxetine or its acid-additive salt can include intermediate process stage that is O-alkylilation enabled with the base or phase-transfer catalyst added.

EFFECT: specified method allows for production of receive enantiomer-pure (+)duloxetine.

17 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new derivative of cyclic amine or its salts with the following formula (I): (where symbols stand for the following: A: 5-8-member cyclic amine, which may contain a double bond, a bridged structure and may contain substitutes R7-R11 in the ring, or -NH2, -NH(inferior alkyl), -N(inferior alkyl)2 or ) morpholin-1-yl; ring B: benzole, thiophene, furane, pyrrole, 5-7-member cycloalkane or 5-7-member cycloalkene; X1: a bond or inferior alkylene; X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -CH(OH)-, -N(R14)- (CR12R13)n-, (CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -n(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13)n-CON(R14)-, -CO-(CR12R13)n- or -(CR12R13)n-CO-; Y1: -OH, -O-inferior alkyl, NH2 or -N3; R1 and R2: are identical or different and stand for a halogen atom, inferior alkyl or inferior alkylene-OH; R3-R6: are identical or different and stand for a hydrogen atom, a halogen atom, inferior alkyl, inferior alkenyl, inferior alkynyl, -O-inferior alkyl, -OH, -NH2, -NH(inferior alkyl), -N(inferior alkyl)2, -NH-CO- inferior alkyl, -N(inferior alkyl)-CO- inferior alkyl, -CN-, -NO2, -CF3, -O-inferior alkylene-OH, -inferior alkylene-OH, -inferior alkylene-halogen, -inferior alkylene-O-inferior alkyl, -CO-5-8-member cyclic amine, -COOH-inferior alkyl, -COO-inferior alkylene-aryl, pyridine, thiophene, -inferior alkylene-morpholine, aryl, which may contain a substitute: -O-inferior alkyl or -CF3; R7: hydrogen atom, inferior alkyl, -inferior alkylene-aryl or -inferior alkylene-pyridine: R7 is substitute on the nitrogen atom of the cyclic amine; R8-R14: are identical or different and stand for a hydrogen atom or inferior alkyl; n: is an integer, equal to 1, 2 or 3; where R5 and R6, R4 and R5 or R3 and R4 can form an inferior alkylene together, -O-inferior alkylene-O-, -O-inferior alkylene-, -inferior alkylene-O-, -C(R15)=C(R16)-O-, -O-C(R15)=C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-; R3 and Y1 together can form -O-inferior alkylene-O- or -inferior alkylene-O-; R1 and Y1 together can form -inferior alkylene-O-; and Y1 and a branch on - X1-A together can form -O- or -O-inferior alkylene; R15-R18 stand for a hydrogen atom, under the condition that, 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol is not included in the group of compounds). The invention also pertains to a derivative of cyclic amine or its salts with formula (II), to a derivative of cyclic amine or its salts with formula (III), to pharmaceutical composition, as well as their use.

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on these compounds, with antagonist effect on NMDA receptors NMDA.

7 cl, 160 ex, 45 tbl

FIELD: chemistry.

SUBSTANCE: method of enantiomeric obtaining aminoalcohols of formula I in which R1, R2 and n have values given in invention formula, lies in enantioselective hydration of aminoketones in presence of non-racemic catalyst, representing complex of transitive metal, which contains one or more metals and its salts, selected from group, including rhodium, iridium, ruthenium and palladium, in which transitive metal forms complex with chiral diphosphine ligand A.

EFFECT: improvement of synthesis of aminoalcohols, which are acceptable as precursors for obtaining anti-depressants.

11 cl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compositions of general formula (I): where R1 and R2 mean H; R3 means H; R4 means lower alkyl; n is equal to 1-6; X means O; formula group =N-D (where D means H, lower alkyl); Y means ethylene group, ethynylene group, formula group -E-CH2 - (where E means carbonyl, formula group -CH(OH)-), C6-C10arylen C6-C10arylen group substituted with 1-3 substitutes, selected from Group (a) of substitutes; Z means single bond, C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain; R5 means H, C3-C10cycloalkyl group, C6-C10aryl, C6-C10aryl group substituted with 1-3 substitutes selected from Group (a) of substitutes; R6 and R7 are identical or different and represent each H, lower alkyl; Group (a) of substitutes represents group consisting of halogen, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, lower alkylthio group; provided when R5 represents H, Z represents branched C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain, or it pharmacologically acceptable salt.

EFFECT: high immunosuppressive activity of compounds and their effective application for pharmaceutical compositions and for methods of preventive rheumatoid arthritis treatment.

51 cl, 13 tbl, 91 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 5-amino-1-pentene-3-ol of the general formula (I)

as a free form or as their physiologically compatible salts possessing the analgesic effect. In general formula (I) each R1 and R2 means independently of one another (C1-C6)-alkyl that can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or multi-substituted; or R1 and R2 form in common -(CH2)2-9-mono- or bicyclic ring; each R3 and R4 means independently of one another (C1-C6)-alkyl, or R3 and R4 form in common a ring and mean the group -CH2CH2NR22CH2CH2 wherein R22 represents (C1-C10)-alkyl; R5 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched, mono- or multi-substituted or unsubstituted, (C3-C9)-cycloalkyl that is saturated or means phenyl, heteroaryl that can be condensed with benzene ring and chosen from 5-membered heteroaryl with sulfur or oxygen atom as a heteroatom bound through saturated (C1-C3)-alkyl, phenyl bound through saturated (C1-C3)-alkyl-(C3-C10)-cycloalkyl wherein each among all these alkyl, phenyl, heteroaryl and cycloalkyl residues and independently of others can be unsubstituted or mono- or multi-substituted residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, groups -OR18, (C1-C3)-alkyl) that is saturated or branched or unbranched, mono- or multi-substituted halide, or unsubstituted and wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or unbranched; R6 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched and unsubstituted, phenyl or heteroaryl that is chosen from 5-membered heteroaryl with oxygen atom as a heteroatom wherein each of them is unsubstituted or mono- or multi-substituted as indicated above; R7 means H. Also, invention relates to a medicinal agent based on proposed compounds and to a method for their synthesis.

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

10 cl, 493 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where Qa is phenyl or heteroaryl, and Qa can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; R1 and R2 are each independently selected from hydrogen and (1-6C)alkyl; Qb is phenyl or heteroaryl, and Qb can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl; where any of the substitutes Qa and Qb defined above, containing a CH2 group which is bonded to 2 carbon atoms, or a CH3 group bonded to a carbon atom, can possibly carry on each of the said CH2 or CH3 group one or more substitutes selected from hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; where heteroaryl is an aromatic 5- or 6-member monocyclic ring which can contain up to three heteroatoms selected from oxygen, nitrogen and sulphur, and can be condensed with a benzene ring or a five-member nitrogen-containing ring containing 2 nitrogen atoms; as well as pharmaceutically acceptable salts thereof. The invention also relates to a method of producing formula I compounds, a pharmaceutical composition and use of these compounds for treating conditions mediated by effect of TNF cytokines.

EFFECT: more effective treatment.

13 cl, 3 tbl, 46 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula and to their pharmaceutically acceptable salts or esters, where X1 is O, S, CH2; R1 is hydrogen; R2 is hydrogen or C1-C7alkyl, R3 is hydrogen or C1-C7alkyl; R4 and R8 are independently hydrogen, C1-C7alkyl, C1-C7alkoxy-C1-C7alkyl, fluoroC1-C7alkyl; R5, R6 and R7 are independently hydrogen, C1-C7alkyl, halogen, fluoroC1-C7alkyl; and one or R5, R6 and R7 represents , where X2 is S, O, NR9, (CH2)PNR9CO or (CH2)PCONR9, R9 is hydrogen, C1-C7alkyl; one or two of Y1, Y 2, Y3 and Y4 is N, and the rest represent C-R12 R10 is C1-C7alkyl, C3-C7 cycloalkyl; R11 is hydrogen; R12 in each case is independently selected from hydrogen, C1-C7alkyl, C3-C7 cycloalkyl, fluoroC1-C7 alkyl, C1-C7alkoxy-C1-C7alkyl, hydroxyC1-C7alkyl, di-C1-C7alkylamino-C1-C7alkyl; R13 is phenyl or heteroaryl, which is a 6-member aromatic ring, containing nitrogen as a heteroatom, which can be substituted with a CF3 group, lower fluroalkoxy group or halogen; m=0 or 1, n=0, 1, 2, and p=0, 1 or 2, and the sum of m, n and p=1, 2, 3 or 4; under the condition that, there are no formula I compounds, where X1 is O, R2 and R3 are hydrogen; R6 is , X2 is O or S, and m=0. The invention also relates to pharmaceutical compositions containing such compounds, with agonistic activity towards PPARδ and/or PPARα.

EFFECT: obtaining compounds for pharmaceutical compositions, with agonistic activity towards PPARδ and/or PPARα.

28 cl, 155 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I and its pharmaceutically acceptable salts and esters where X1 stands for O or CH2; R1 stands for hydrogen; R2 stands for hydrogen or C1-C7-alkyl, or if X1 stands for CH2, R2 stands for hydrogen, C1-C7-alkyl or C1-C7-alkoxygroup; R3 stands for hydrogen or C1-C7-alkyl; R4 and R5 or R5 and R6 are bound and form a ring together with carbon atoms whereto attached, and R4 and R5 or R5 and R6 simultaneously stand for -CH=CH-CH=CH- or -(CH2)P- where p is equal to 4; and R4 and R6 are included in a ring structure as specified above, or independently stand for hydrogen; R7 and R8 stand for hydrogen; and one of R6 and R7 stands for where X2 stands for O or NR9; R9 stands for C1-C7-alkyl; one or two of Y1, Y2, Y3 and Y4 stand for N, and the others stand for C-R12; R10 stands for hydrogen, C1-C7-alkyl; R11 stands for hydrogen, C1-C7-alkyl; R12 independently in each case are chosen from the group including hydrogen, C1-C7-alkyl, C3-substituted with CF3; and n is equal to 0 or 1.

EFFECT: agonistic activity to PPARδ and PPARα.

20 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , in which A is selected from one or several X and/or Y groups; X represents methylene group; Y represents C2-alkinylene group; n represent integer number from 1 to 5; R1 represents group R2, optionally substituted with one or several R3 and/or R4 groups; R2 represents group selected from pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphtyl, chinolinyl, isochinolinyl, dihydroisochinolinyl, 2-oxo-3,4-dihydrochinolinyl, indolyl, benzimidazolyl, pyrrolopyridinyl; R3 represents group selected from halogen atoms, groups C1-6-alkyl, C3-7-Cycloalkyl, C1-6-alkoxy, NR5R6 and phenyl; R4 represents group selected from groups: phenyl, naphtyl, pyridinyl; R4 group or groups can be substituted with one or several R3 groups, similar or different from each other; R5 and R6 independently on each other represent C1-6-alkyl group; R7 represents hydrogen atom or C1-6-alkyl group; R8 represents hydrogen atom or group C1-6-alkyl, C3-7-cycloalkyl, C3-7-Cycloalkyl- C1-3-alkylene; in form of base, acid-additive salt, hydrate or solvate. Invention also relates to methods of obtaining formula (I) compound by any of ii. 1-3, to compounds, determined by general formula (IV), (VII), to pharmaceutical composition, as well as to application of formula (I) compounds by any of ii. 1-3.

EFFECT: obtaining novel biologically active compounds possessing activity of enzyme FAAH inhibitors.

10 cl, 5 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: inventive subject matter is compouns and their pharmaceutically acceptable salts which can be applied in prevention and treatment of diseases caused by HCV infection. Structural formulae of the compounds are presented in the claim.

EFFECT: obtaining anti-HCV medicine including the claimed compound or its pharmaceutically acceptable salt as active component.

2 cl, 100 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of obtaining monofluoridated complex pyridinil and pyrimidinil beta-ketoesters of the formula (I) , where R1 is a 4-pyridine or 4-pyrimidine ring; R2 is a hydrogen atom, C1-6 alkyl group or halogen atom; and R3 is a C1-6 alkyl group. The method involves interaction of fluorine gas with a compound of the formula (II) , where R1, R2 and R3 are the same as above. The invention also concerns compounds of the formula (I).

EFFECT: possible application as intermediary products for pharmaceutical compounds.

12 cl, 1 dwg, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method that can be used in industry for synthesis of substituted aniline compound represented by the following general formula (6):

wherein in the general formula (6) each R1, R2 and R3 means independently alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group, alkylcarboxamide group, nitro-group, aryl group, arylalkyl group, aryloxy-group, halogen atom or hydrogen atom; each X and Y means independently hydrogen atom, alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group or halogen atom. Method involves oxidation of substituted indole compound represented by the following general formula (3):

(wherein values R1, R2, R, X and Y are given above) resulting to opening indole ring to yield acetanilide compound represented by the following general formula (4):

(wherein values R1, R2, R3, X and Y are given above) and Ac means acetyl group, and treatment of this compound by reduction and deacetylation. Also, invention relates to novel intermediate compounds. Proposed compound (6) can be used as intermediate substance for production of chemicals for agriculture and as medicinal agents.

EFFECT: improved method of synthesis.

20 cl, 1 sch, 3 tbl, 31 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to (R)-enantiomers of 2-arylpropionamides of the formula (Ia): and their pharmaceutically acceptable salts wherein Aryl represents phenyl group substituted with a group chosen from isopropyl, acetyl, (2'',6''-dichlorophenyl)amino-group, α-hydroxyisopropyl, (R,S)-α-hydroxybenzyl and its individual R-isomers, (R,S)-(α-methylbenzyl) and its individual R-isomer and (R,S)-α-hydroxy-α-methylbenzyl and its individual R-isomer; R represents hydrogen atom (H) or (C1-C4)-alkyl; R' represents the following groups: -amino acid residue consisting of linear or branched (C1-C6)-alkyl substituted with carboxy-group -CO2H; -residue of the formula: -CH2-CH2X-(CH2-CH2O)nR wherein R has abovementioned values; n means a whole number from 0 to 1 while X represents oxygen atom; -heteroaryl chosen from the group consisting of 2-pyrimidinyl or 4-pyrimidinyl. Also, invention proposes a pharmaceutical composition inhibiting of interleukin-8-induced chemotaxis of neutrophiles and comprising as an active components (R)-enantiomers of 2-arylpropionamides of the formula (I) and their pharmaceutically acceptable salts in mixture with a suitable carrier. Also, invention proposes a method for preparing compounds of the formula (Ia). Also, invention proposes (R)-enantiomers of 2-arylpropionic acids of the formula (Va) given in the invention description and their pharmaceutically acceptable salts. Proposed (R)-2-arylpropionamides are useful in prophylaxis and treatment of tissue damage caused by enhanced accumulation of polymorphonuclear neutrophiles in the inflammation sites.

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

13 cl, 6 tbl, 24 ex

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

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

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

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula I: and their pharmaceutically acceptable salts, in which R1-R4 have values, given in item 1 of invention formula. Said compounds possess inhibiting activity with respect to 11-beta-hydroxysteroid-dehydrogenase and can be applied for production of medications, intended for treatment and prevention of diabetes, especially, diabetes of II type, obesity, malnutrition and hypertension.

EFFECT: development of efficient method of obtaining formula I compounds and based on them pharmaceutical composition.

25 cl, 1 tbl, 149 ex

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