Tetrahydropyrane derivatives for neurological diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of the general formula

,

wherein R1/R2 independently represent hydrogen, (CR2)o-C3-7 cycloalkyl optionally substituted by a lower alkyl or hydroxy, or represent a lower alkyl or tetrahydropyranyl, and o represents 0 or 1; and R can be identical or different, and represent hydrogen or a lower alkyl; or R1 and R2 can form together with a N atom to which they are attached, a heterocycloalkyl group specified in a group consisting of pyrrolidinyl, piperidinyl, 3-aza-bicyclo[3.1.0]hex-3-yl or 2-aza-bicyclo[3.1.0]hex-2-yl which are optionally substituted by hydroxy; R3 represents an S-lower alkyl, lower alkyl, lower alkoxy or C3-7 cycloalkyl; R3′ represents hydrogen, a lower alkyl substituted by a halogen, lower alkyl or lower alkoxy; R4 represents a lower alkyl substituted by a halogen; X represents -O- or -CH2-; X' represents -O- or -CH2-; provided one of X or X' always represent -O- and the other represents -CH2-; or a pharmaceutically acceptable acid-additive mixture, a racemic mixture, or a respective enantiomer and/or an optical isomer.

EFFECT: compounds of the general formula (I) are good inhibitors of glycine transporter 1 (GlyT-1) and hence can be used for treating schizophrenia and other neurological conditions, including pain.

13 cl, 1 tbl, 63 ex

 

The invention relates to a compound of the General formula I

where R1/R2independently from each other represent hydrogen, (CR2)o-cycloalkyl, possibly substituted lower alkyl or hydroxy, or are lower alkyl or heteroseksualci, and

o represents 0 or 1; and

R can be identical or different and represent hydrogen or lower alkyl; or

R1and R2can form together with the N atom to which they are attached, geteroseksualnoe group selected from the group consisting of pyrrolidinyl, piperidinyl, 3-Aza-bicyclo[3.1.0]hex-3-yl or 2-Aza-bicyclo[3.1.0]hex-2-yl, which may be substituted by hydroxy;

R3is an S-lower alkyl, lower alkyl, lower alkoxy or cycloalkyl;

R3'represents hydrogen, lower alkyl, substituted by halogen, lower alkyl or lower alkoxy;

R4represents lower alkyl substituted by halogen, lower alkyl or lower alkoxy;

X represents-O - or-CH2-;

X' represents-O - or-CH2-; provided that one of X or X' represents-O - and the other represents-CH2-;

or pharmaceutically acceptable acid-additive salt, to a racemic mixtures, or to suitable�the enantiomer and/or optical isomer.

In addition, the present invention relates to pharmaceutical compositions containing compounds of formula I and to their use in the treatment of neurological and neuropsychiatric disorders.

It has surprisingly been found that compounds of the General formula I are good inhibitors of the glycine Transporter 1 (GlyT-1) and that they have a good selectivity to inhibitors of the glycine Transporter 2 (GlyT-2).

Schizophrenia is a progressive and debilitating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, thought disorder and psychosis and persistent negative symptoms such as blunted affect, impaired attention and social withdrawal, and cognitive impairments (Lewis DA and Lieberman JA, Neuron, 2000, 28:325-33). For several decades, the study focused on the hypothesis of the "dopaminergic hyperactivity" that has led to therapeutic interventions involving blockade of the dopaminergic system (Vandenberg RJ and Aubrey KR., Exp.Opin. Ther. Targets, 2001, 5(4): 507-518; Nakazato A and Okuyama S, et al., 2000, Exp. Opin. Ther. Patents, 10(1): 75-98). This pharmacological approach poorly corresponds to the treatment of negative and cognitive symptoms which are the best indicators of functional outcome (Sharma T., Br.J. Psychiatry, 1999, 174(suppl. 28): 44-51)./p>

In the mid-1960s, there has been proposed an additional model of schizophrenia based on the psychotomimetic action caused by the blockade of the glutamate system by compounds like phencyclidine (PCP) and related agents (ketamine), which are non-competitive antagonists of NMDA receptor. Interestingly, in healthy volunteers, PCP-induced psychotomimetic action incorporates positive and negative symptoms and cognitive dysfunction and, thus, is strongly reminiscent of schizophrenia in patients (Javitt DC et al., 1999, Biol. Psychiatry, 45: 668-679 and links). In addition, transgenic mice expressing reduced levels of the NMDAR1 subunit, exhibit abnormalities in behavior similar to those observed in pharmacologically induced models of schizophrenia, which confirms the model in which the decrease in the activity of the NMDA receptor leads to schizophrenic behavior (Mohn AR et al., 1999, Cell, 98: 427-236).

Glutamate neurotransmission, in particular the activity of the NMDA receptor, plays a key role in synaptic plasticity, learning and memory, namely the NMDA receptors appears to serve as a differential switch for synchronization threshold of synaptic plasticity and memory formation (Hebb's DO, 1949, The organization of behavior, Wiley, NY; Bliss TV and Collingridge GL, 1993, Nature, 361: 31-39). Transgenic mice, spherexp�asirwada NR2B subunit of NMDA, exhibit enhanced synaptic plasticity, better learning ability and better memory (Tang JP, et al., 1999, Nature: 401-63-69).

Thus, if the pathophysiology of schizophrenia include deficits of glutamate, it can be expected that the increase in glutamate transmission, in particular via activation of the NMDA receptor, will cause as antipsychotic effects and the effects of increasing cognitive function.

It is known that in the CNS the amino acid glycine has at least two important functions. By binding to the strychnine-sensitive glycine receptors, it acts as a brake amino acid, and, acting as the main coagonist of glutamate at the function of the receptor N-methyl-D-aspartate (NMDA), this amino acid also affects stimulatory activity. While glutamate is released from synaptic endings depending on the activity, the glycine is present presumably at a more constant level and seems to modulate/control the receptor for its response to glutamate.

One of the most effective ways to control synaptic concentrations of the neurotransmitter is to influence its reuptake in the synapses. By removing neurotransmitters from the extracellular space vectors of neurotransmitters can control their extracellular lifetime and �eat to modulate the parameters of synaptic transmission (Gainetdinov RR et al, 2002, Trends in Pharm. Sci., 23(8): 367-373).

Glycine transporters, which belong to the sodium - and chloride-dependent family of transporters of neurotransmitters, play an important role in the termination of postsynaptic glycinergic impacts and the maintenance of low extracellular concentrations of glycine by reuptake of glycine into presynaptic nerve endings and surrounding fine glial processes.

From the brain of mammals have been cloned two different gene of glycine transporters (GlyT-1 and GlyT-2), which give rise to two transporters with approximately 50% amino acid sequence homology. GlyT-1 presents four isoforms arising from alternative splicing and alternative usage of promoters (1A, 1b, 1C and 1d). Only two of these isoforms have been found in the brain of rodents (GlyT-1A and GlyT-1b). GlyT-2 also shows some degree of heterogeneity. In the brain of rodents were identified two isoforms GlyT-2 (2A and 2b). It is known that GlyT-1 is localized in the CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS. GlyT-1 has a predominantly glial distribution and is found not only in areas corresponding to strychnine sensitive glycine receptors but also outside these areas, where, as expected, he is involved in the mod�lation function of the NMDA receptor (Lopez-Corcuera et al., 2001, Mol. Mem. Biol., 18: 13-20). Accordingly, one method of increasing the activity of the NMDA receptor is to increase the glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 Transporter (Bergereon R. Et al., 1998, Proc. Natl. Acad. Sci. USA, 95: 15730-15734; Chen L et al., 2003, J. Neurophysiol., 89 (2): 691-703).

Inhibitors of glycine transporters are suitable for the treatment of neurological and neuropsychiatric disorders. The majority of related disease States are psychosis, schizophrenia (Armer RE and Miller DJ, 2001, Exp.Opin. Ther. Patents, 11 (4): 563-572), psychotic mood disorders such as major depressive disorder severe type, mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorders, and mood disorders associated with schizophrenia, (Pralong ET et al., 2002, Prog. Neurobiol., 67: 173-202), autistic disorders (Carlsson ML, 1998, J. Neural Transm. 105: 525-535), cognitive disorders such as dementia, including age-related dementia and senile dementia of Alzheimer's type, memory disorders in mammals, including humans, symptoms of attention deficit and pain (Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572).

Thus, increasing activation of NMDA receptors by inhibition of GlyT-1 may lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which impaired cognitive processes, syndromes such as attention deficit or Alzheimer's disease.

Objects of the present invention are compounds of formula I in essence, the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of drugs for the treatment of diseases related to activation of NMDA receptors by inhibition of GlyT-1, their production, medications, based on the connection according to the present invention and their production, and the use of compounds of formula I for the treatment or prevention of diseases, such as psychoses, dysfunction in memory and learning, schizophrenia, dementia and other diseases in which impaired cognitive processes, syndromes such as attention deficit or Alzheimer's disease.

The preferred indications for the use of the compounds of the present invention are schizophrenia, cognitive disturbance and Alzheimer's disease.

In addition, the invention includes all racemic mixtures, all of the corresponding enantiomers and/or optical isomers.

As used here, the term "lower alkyl" refers to a group with a saturated unbranched or branched chain, containing from 1 to 7 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-Buti�, tert-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms.

As used here, the term "lower alkoxy" denotes a lower alkyl group, as defined above, which is connected with atom O.

The term "cycloalkyl" refers to a saturated or partially saturated ring containing from 3 to 7 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl. Preferred cycloalkenyl rings are cyclopropyl and cyclopentyl.

The term "heteroseksualci" refers to a saturated or partially saturated ring containing from 3 to 6 carbon atoms, where at least one carbon atom replaced by a heteroatom selected from N, S or O, for example piperazinyl, pyrrolidinyl, oxetanyl, morpholinyl, piperidinyl or tetrahydropyranyl.

The term "halogen" denotes chlorine, iodine, fluorine and bromine.

The term "lower alkyl substituted by halogen" denotes an alkyl group as defined above where at least one hydrogen atom substituted by a halogen atom, for example the following groups: CF3, CHF2, CH2F, CH2CF3, CH2CHF2, CH2CH2F, CH2CH2CF3, CH2CH2CH2CF3, CH2CH2CI, CH2CF2CF3, CH CF2CHF2, CF2CHFCF3With(CH3)2CF3, CH(CH3)CF3or CH(CH2F)CH2F.

The term "pharmaceutically acceptable acid-additive salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluensulfonate acid and the like.

One embodiment of the invention is a compound of formula I where X is O and X' represents CH2, which have the following structure:

where R1/R2independently from each other represent hydrogen, (CR2)o-cycloalkyl, possibly substituted lower alkyl or hydroxy, or are lower alkyl or heteroseksualci, and

o represents 0 or 1; and

R can be identical or different, and represent hydrogen or lower alkyl; or

R1and R2can form together with the N atom to which they are attached, geteroseksualnoe group selected from the group consisting of pyrrolidinyl, piperidinyl, 3-Aza-bicyclo[3.1.0]hex-3-yl or 2-Aza-bicyclo[3.1.0]hex-2-yl, which�s maybe substituted with hydroxy;

R3is an S-lower alkyl, lower alkyl, lower alkoxy or cycloalkyl;

R3'represents hydrogen, lower alkyl, substituted by halogen, lower alkyl or lower alkoxy;

R4represents lower alkyl substituted by halogen, lower alkyl or lower alkoxy;

or pharmaceutically acceptable acid-additive salt, racemic mixture, or its corresponding enantiomer and/or optical isomer.

In a special embodiment of this group are compounds where R1and R2can form together with the N atom to which they are linked, geteroseksualnoe group selected from the group consisting of pyrrolidinyl, piperidinyl, 3-Aza-bicyclo[3.1.0]hex-3-yl or 2-Aza-bicyclo[3.1.0]hex-2-yl, which may be substituted by hydroxy, for example the following compounds:

2-methoxy-6-methylsulfanyl-N-((3RS,4SR)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

(-)-2-methoxy-6-methylsulfanyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

2-cyclopropyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

2-methylsulfanyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,

2-methyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,

2-cyclopropyl-N-((3SR,4RS)-4-pyrrolidin-1-�l-tetrahydro-Piran-3-yl)-4,6-bis-trifluoromethyl-benzamide,

2-cyclopropyl-N-((3SR,4RS)-4-piperidine-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

2,6-dimethyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

2,6-diethyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

2-ethyl-6-methoxy-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

2-ethyl-6-methyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

2-dihydro-6-methoxy-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

N-[(3S,4R)-4-(3-Aza-bicyclo[3.1.0]hex-3-yl)-tetrahydro-Piran-3-yl]-2-cyclopropyl-4-trifluoromethyl-benzamide,

(+)-2-cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

(-)-2-cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

(+)-2-methyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,

(-)-2-methyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,

(+)-2-methylsulfanyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,

(-)-2-methylsulfanyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,

(+)-2-cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,

(-)-2-cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-p�ran-3-yl)-4,6-bis-trifluoromethyl-benzamide,

(+)-2,6-dimethyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

(-)-2,6-dimethyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

(+)-2-methoxy-6-methyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

(-)-2-methoxy-6-methyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

(+)-2-ethyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

(-)-2-ethyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

(+)-2-cyclopropyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

(-)-2-cyclopropyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,

N-[(3SR,4RS)-4-(2-Aza-bicyclo[3.1.0]hex-2-yl)-tetrahydro-Piran-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.

Further special embodiment of this group are compounds where R1and R2independently from each other represent hydrogen or (CR2)o-cycloalkyl, and o represents 0 or 1; and R may be identical or different, and represent hydrogen or lower alkyl, for example:

N-((3SR,4RS)-4-cyclopentylamine-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide,

2-cyclopropyl-N-[(3RS,4SR)-4-(1-cyclopropyl-ethylamino)-tetrahydro-Piran-3-yl]-4-trifluoromethyl-benzamide,

p> (+)-N-(TRANS-4-cyclopentylamine-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide or

(+)-N-(4-cyclohexylamino-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide.

Another embodiment of the invention is a compound of formula I, where X represents CH2and X' represents O, of the following structure:

where R1/R2independently from each other represent hydrogen, (CR2)o-cycloalkyl, possibly substituted lower alkyl or hydroxy, or are lower alkyl or heteroseksualci, and

o represents 0 or 1; and

R can be identical or different, and represent hydrogen or lower alkyl; or

R1and R2can form together with the N atom to which they are attached, geteroseksualnoe group selected from the group consisting of pyrrolidinyl, piperidinyl, 3-Aza-bicyclo[3.1.0]hex-3-yl or 2-Aza-bicyclo[3.1.0]hex-2-yl, which may be substituted by hydroxy;

R3is an S-lower alkyl, lower alkyl, lower alkoxy or cycloalkyl;

R3'represents hydrogen, lower alkyl, substituted by halogen, lower alkyl or lower alkoxy;

R4represents lower alkyl substituted by halogen, lower alkyl or lower alkoxy;

or f�rmaceuticals acceptable acid-additive salt, racemic mixture, or its corresponding enantiomer and/or optical isomer, for example the following compounds:

CIS-2-methoxy-6-methylsulfanyl-N-(3-pyrrolidin-1-yl-tetrahydro-Piran-4-yl)-4-trifluoromethyl-benzamide,

(-)-2-methoxy-6-methylsulfanyl-N-(3-pyrrolidin-1-yl-tetrahydro-Piran-4-yl)-4-trifluoromethyl-benzamide or

(+)-2-methoxy-6-methylsulfanyl-N-(3-pyrrolidin-1-yl-tetrahydro-Piran-4-yl)-4-trifluoromethyl-benzamide.

The present compounds of formula I and their pharmaceutically acceptable salts can be obtained by methods known in this field, for example by the methods described below, according to which

(a) is subjected to interaction of the compound of the formula

with a compound of the formula

in the presence of an activating agent such as HATU (O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate), to a compound of formula

where the substituents are as defined above, or

(b) carried out restoration of the amination of a compound of formula

with a compound of the formula

NHR1R2

and share the resulting compound using column chromatography to obtain compounds of formula

and

where cover�are eating, as defined above, or

(C) alkylate or spend reducing amination of a compound of formula

to the compound of formula

where the substituents are as defined above, and,

if desired, transfer the compounds obtained into pharmaceutically acceptable acid-additive salts.

Compounds of formula 1 can be obtained according to the embodiment of the method a) or b) or c), and the following schemes 1-7. The source materials are commercially available, or can be obtained in accordance with known methods.

Total synthesis

Scheme 1

1,4,8-Dioxaspiro[4,5]Dean-6-amine (CAS 1068523-26-1) 1 combined with the acid, with coupling agent O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (=HATU) in dimethylformamide to obtain amide 2. The protective group was tsalala with HCl, which gave the ketone 3. Reductive amination of gave a mixture of I-1 CIS and I-1 TRANS, which were separated using column chromatography.

Scheme 2

3,6-Dihydro-2H-Piran 4 was subjected to interaction with mpem-butyl ether N,N-dibrom-carbamino acid (CAS 358365-86-3) to the intermediate 5, which was treated with sodium hydride, giving aziridine 6. The ring opening with sodium azide gave azide 7 with �Rance-configuration, which was restored with hydrogen and a platinum catalyst to the amine 8. Alkylation or reductive amination of give amine 9. The cleavage of Boc-protective group was achieved with HCl, which gave the diamine 10, which is connected with the acid, with coupling agent O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (=HATU) in dimethylformamide to obtain amide I-1 TRANS.

Figure 3

Aziridine 6 were treated with the amine R1R2NH, which gave the TRANS amine 9. Cleavage of the BOC-protective group was achieved with HCl, which gave the diamine 10, which is connected with the acid, with coupling agent O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (=HATU) in dimethylformamide to obtain amide 1-1 TRANS.

Scheme 4

ortho-Fluoro or ortho-chloro benzaldehyde 11 was subjected to interaction with the amine, which gave Yiming 12. The addition of the Grignard reagent R MgBr gave 13. Hydrolysis led to the aldehyde 14, which was oxidized to the acid 15.

Scheme 5

The diamine 10-1, combined with the acid 15, with coupling agent O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (=HATU) in dimethylformamide to obtain amide I.

Scheme 6

Substituents are as description�but higher and R3and R3different from lower alkoxy.

Some ortho-ortho' - substituted acid receive according to scheme 6, following the methodology described by A. I. Meyers et al. JOC 1978, 43, 1372. First, the ortho-ortho' methoxy acid derivative 16 was transferred to the oxazolidinone 17, which is treated with a Grignard reagent R3MgX, which gives an intermediate compound 18 (obtained by Montebelluna R3MgX) and intermediate compound 19 (obtained by adding R3MgX), which is then hydrolysed to the corresponding acids 20 and 21. Intermediate compound 18 can be subjected to interaction with another Grignard reagent R3MgX, which gives an intermediate connection 22, which is then hydrolysed to the acid 23.

Scheme 2

The ketone 24 (CAS 477584-38-6) is subjected to reductive amination of the that gives a mixture of CIS - and TRANS-25, which is connected to the acid, using a bonding agent 0-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (=HATU) in dimethylformamide to obtain amide of CIS - and TRANS-26. Cleavage of the BOC-protective group and subsequent alkylation or reductive amination of give the final compound 1-2 as a mixture of CIS and TRANS.

Synthesis of intermediates

Intermediate compound a

2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic to�slot

N,N,N',N'-Tetramethylethylenediamine (21 g, 177 mmol) was added dropwise at -70°C to a solution of emop-utility (110 ml, 1.4 M in cyclohexane, 154 mmol) in 180 ml of tetrahydrofuran. 2-Methoxy-4-trifluoromethyl-benzoic acid (13 g, 59 mmol) in 60 ml of tetrahydrofuran was added dropwise at -70°C for 2 hours. After completion of the addition was continued to stir at -70°C for further 2 hours. Dimethyl disulfide (20 g, 207 mmol) was added at -70°C for 10 minutes. Continued to stir at -70°C for another hour and the reaction mixture was heated. The reaction mixture was quenched with 150 ml of water and was extracted with 200 ml of ethyl acetate. Brought the pH of the aqueous phase to 1 by adding 25% HCl, and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The crude product was crystallizable with heptane and received specified in the title compound as a white solid (1.75 g, 11%), MS: m/e=265,1 [(M-N]-).

Intermediate of the

2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,4,8-trioxa-Spiro[4.5]Dec-6-yl)-benzamide

2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate compound a (400 mg, 1.5 mmol) was dissolved in 10 ml of dimethylformamide. Was added N,N-diisopropylethylamine (505 mg, 3.9 mmol) and O-(7-asobancaria�-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (571 mg, 1.5 mmol). After 10 minutes stirring at room temperature was added 1,4,8-dioxaspiro[4,5]Dean-6-amine (CAS 1068523-26-1) (359 mg, 2.2 mmol). The reaction mixture was stirred at room temperature over night. The solvent was evaporated. The residue was transferred into a 2 n solution of sodium carbonate and ethyl acetate and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification of the residue via flash chromatography on silica gel (heptane/ethyl acetate/triethylamine 1:0:0→10:10:1) gave 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,4,8-trioxa-Spiro[4.5]Dec-6-yl)-benzamide as a white solid (462 mg, 75%), MS: m/e=408,2 [(M+H)+.

The intermediate connection

2-Methoxy-6-methylsulfanyl-N-(4-oxo-tetrahydro-Piran-3-yl)-4-trifluoromethyl-benzamide

2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-L/-(1,4,8-trioxa-Spiro[4.5]Dec-6-yl)-benzamide (intermediate compound, (200 mg, 0.49 mmol) was dissolved in 1 ml of tetrahydrofuran was added 1 ml of 4 n HCI in dioxane. The reaction mixture was heated to reflux for 2 hours. The mixture was diluted with water, ethyl acetate and neutralized with saturated sodium bicarbonate solution. The mixture was extracted with twice with ethyl acetate. The combined organic layers were dried with sodium sulfate, filter�Ali and evaporated. The crude product was used in the next step.

Intermediate compound D

tert-Butyl ether TRANS-(4-bromo-tetrahydro-PYRAN-3-yl)-carbamino acid

tert-Butyl ether N,N-dibrom-carbamino acid (CAS 358365-86-3) (8,98 g, 28 mmol) was dissolved in 90 ml of dichloromethane and cooled to -20°C. the diethyl ether Complex of boron TRIFLUORIDE and (3,99 g, 28 mmol) was added dropwise, and the mixture was stirred at -20°C for 10 minutes. A solution of 3,6-dihydro-2H-PYRAN (2.5 g, 27 mmol) in 20 ml of dichloromethane was added dropwise and continued to stir at -20°C for 1 hour. The reaction mixture was quenched at +10°C 33 ml of 12% aqueous solution of sodium sulfite. The mixture was extracted with three times dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification of the residue via flash chromatography on silica gel (pentane/diethyl ether 1:0→0:1) gave specified in the title compound as a white solid (4,24 g, 56%), MS: m/e=223(M-butene)+].

Intermediate compound E

tert-Butyl ether 3-oaks-7-Aza-bicyclo[4.1.0]heptane-7-carboxylic acid

tert-Butyl ether TRANS-(4-bromo-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate D) (1.0 g, 3.5 mmol) was dissolved in 35 ml of dimethylformamide. Added guide�Eid sodium (60%, 214 mg, 5.4 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched carefully adding water. The mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification of the residue via flash chromatography on silica gel (heptane/ethyl acetate 1:0→1:1) gave specified in the title compound as a colorless oil (499 mg, 70%), MS: m/e=143 [(M-butene)+].

Intermediate compound F

tert-Butyl ether TRANS-(4-azido-tetrahydro-Piran-3-yl)-carbamino acid

tert-Butyl ether 3-oaks-7-Aza-bicyclo[4.1.0]heptane-7-carboxylic acid (intermediate E) (5.2 g, 26 mmol) was dissolved in 100 ml of acetonitrile. The lithium perchlorate (23 g, 207 mmol) and sodium azide (6.8 g, 104 mmol) was added and the reaction mixture was stirred at 80°C overnight. Was added 200 ml of water. The mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification of the residue via flash chromatography on silica gel (heptane/ethyl acetate 1:0→1:1) gave specified in the title compound as a colorless oil (3.3 g, 52%), MS: m/e=186 [(M-butene)+].

An intermediate connection G

tert-Butyl ether TRANS-(4-amino-�tetrahydro-Piran-3-yl)-carbamino acid

tert-Butyl ether TRANS-(4-azido-tetrahydro-Piran-3-yl)-carbamino acid (intermediate F) (3.3 g, 14 mmol) was dissolved in 27 ml of methanol. Added platinum oxide (IV) (307 mg, 1.4 mmol), the reaction mixture was gidrirovanie using H2-a balloon at room temperature overnight. The catalyst was filtered and the solvent evaporated. The crude substance, solid white shade (2,74 g, 93%), MS: m/e=161 [(M-butene)+] was used without further purification.

The intermediate compound N

tert-Butyl ether TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-carbamino acid

tert-Butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G, 330 mg, 1,53 mmol) was dissolved in 8 ml of acetonitrile. Was added potassium carbonate (1.05 g, 7.6 mmol) and 1,4-dibromobutane (672 mg, 3,11 mmol) and the reaction mixture was heated to reflux over night. The solvent was evaporated. The residue was transferred into water and extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification of the residue via flash chromatography on silica gel (dichloro methane / methanol/ammonia 1:0:0→140:10:1) gave specified in the title compound as a yellow m�als (347 mg, 84%), MS: m/e=271,3 [(M+H)+].

Intermediate compound I

TRANS-4-Pyrrolidin-1-yl-tetrahydro-PYRAN-3-ilinadiganlari

tert-Butyl ether TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate H, 345 mg, 1,28 mmol) was dissolved in 6.4 ml of dioxane. Was added hydrochloric acid (4 n in dioxane, 3.2 ml, 13 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated. The crude substance, light brown solid (378 mg, > 100%), MS: m/e=171,2 [(M+H)+] was used without further purification.

Intermediate compound J

2-Cyclopropyl-4-trifluoromethyl-benzoic acid

Stage 1: Methyl ester of 2-bromo-4-trifluoromethyl-benzoic acid

To a solution of 2 g (7,434 mmol) 2-bromo-4-trifluoromethyl-benzoic acid (CAS: 328-89-2) in 20 ml of dimethylformamide in a nitrogen atmosphere at room temperature was added 1.13 g (8,177 mmol) of potassium carbonate and 557 µl (8,921 mmol) of methyliodide. The mixture was stirred overnight in a nitrogen atmosphere. The mixture was poured into water (300 ml). The aqueous layer was extracted with ethyl acetate (2×80 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silicagel� (eluent: heptane/etoac 0 to 10%), giving of 1.75 g (83%) specified in the header connection in the form of an orange oil.

Stage 2: Methyl ester of 2-temporaril-4-trifluoromethyl-benzoic acid

To a solution of 400 mg (at 1.413 mmol) of methyl ester of 2-bromo-4-trifluoromethyl-benzoic acid, 146 mg (1,696 mmol) cyclopropyl Bronevoy acid, 1.21 g (4,946 mmol) of the monohydrate of potassium and phosphate of 40.9 mg (0,141 mmol) tricyclohexylphosphine in 6 ml of toluene and 0.3 ml of water in a nitrogen atmosphere at room temperature was added to 15.9 mg (0,0707 mmol) of palladium acetate. The mixture was stirred at 100°C oil bath for 4 hours and overnight at room temperature in a nitrogen atmosphere. The mixture was cooled to room temperature. Added water and the mixture was extracted with ethyl acetate. The organic layer is washed once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified on silica gel (eluent: heptane/etoac 0 to 10%) gave 0.24 g (71%) specified in the title compound as a yellow oil.

Stage 3: 2-Cyclopropyl-4-trifluoromethyl-benzoic acid

To a suspension of 485 mg (1,986 mmol) of methyl ester of 2-cyclopropyl-4-trifluoromethyl-benzoic acid in 8 ml of ethanol at room temperature was added 1,99 ml (3,972 mmol) of 2 n NaOH. The mixture was heated at 80°C oil�th bath for 30 minutes. The solution was cooled to room temperature and the ethanol evaporated. The residue was diluted with water, made acidic with 2 n HCl to pH 2 and dichloro methane was added. The aqueous phase was extracted with dichloromethane twice. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0 to 100%) that gave 0,197 g (27%) specified in the header connection in the form of light yellow solids. MS(m/e): 229,0 (M-N).

Intermediate compound K

tert-Butyl ether TRANS-(4-cyclopentylamine-tetrahydro-Piran-3-yl)-carbamino acid

tert-Butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G, 1.0 g, 4,63 mmol) was dissolved in 90 ml of methanol. Was added acetic acid (1.4 g, 23 mmol) and Cyclopentanone (1.18 g, 14 mmol) and the reaction mixture was stirred at 45°C overnight. Added cyanoborohydride sodium (612 mg, 9.7 mmol) and continued stirring at 45°C for 2 hours. The mixture was extracted with 2 n sodium carbonate solution and ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification of the residue via flash chromatography on silica gel (dichloro methane/methanol/ammonia 100:0:0→90:10:1) gave specified in the header soy�the coalescing as a yellow solid (815 mg, 62%), MS: m/e=229,4 [(M-butene)+].

Intermediate compound L

TRANS-N-4-Cyclopentyl-tetrahydro-PYRAN-3,4-diamine dihydrochloride

Specified in the title compound, light brown solid, MS: m/e=185,2 [(M+H)+], obtained according to the General method of intermediate compound I from tert-butyl ether TRANS-(4-cyclopentylamine-tetrahydro-Piran-3-yl)-carbamino acid (intermediate K).

Intermediate compound M

Butyl-[1-(2-fluoro-4,6-bis-trifluoromethyl-phenyl)-methylidene]-amine

2-Fluoro-4,6-bis(trifluoromethyl)benzaldehyde (10 g, 38 mmol) was dissolved in 30 ml of toluene. Was added p-toluensulfonate acid (140 mg, 0.74 mmol) and N-butylamine (2.94 g, 40 mmol). The reaction mixture was heated to reflux over night. The mixture was extracted with 2 n sodium carbonate solution and ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Untreated substance orange oil (12 g, > 100%), used without further purification.

The intermediate compound N

Butyl-[1-(2-cyclopropyl-4,6-bis-trifluoromethyl-phenyl)-methylidene]-amine

Cyclopropylboronic (3,84 g, 32 mmol) was added to magnesium (771 mg, 32 mmol) in 20 ml of diethyl ether and heated with reverse refrigerator�ohms for 10 minutes. Added manganese chloride (II) (160 mg, of 1.27 mmol) and butyl-[1-(2-fluoro-4,6-bis-trifluoromethyl-phenyl)-methylidene]-amine (intermediate compound M, 4 g, 13 mmol). The reaction mixture was heated to reflux for 2 hours. The reaction mixture was quenched with 8 ml of water and filtered through dicalite. The organic phase was separated and dried over sodium sulfate, filtered and evaporated. Raw substance brown oil (3,54 g, 82%), used without further purification.

An intermediate connection O

2-Cyclopropyl-4,6-bis-trifluoromethyl-benzaldehyde

Crude butyl-[1-(2-cyclopropyl-4,6-bis-trifluoromethyl-phenyl)-methylidene]-amine (intermediate compound M, 3,54 g, 10.5 mmol) was dissolved in 8 ml of water. Was added hydrochloric acid (25%, to 0.49 ml) and the mixture was heated to reflux for 2 hours. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Raw substance brown oil (1.01 g, 34%), used without further purification.

Intermediate compound R 2-Cyclopropyl-4,6-bis-trifluoromethyl-benzoic acid

The crude 2-cyclopropyl-4,6-bis-trifluoromethyl-benzaldehyde (intermediate O, 1.01 g, 3.58 mmol) was dissolved in 8.5 ml of tert-butyl alcohol and 4.5 ml of 2-me�Il-2-butene. At 0°C was added a solution of sodium chlorite (340 mg, 3,76 mmol) and sodium dihydrogen phosphate (451 mg, 3,76 mmol) in 3 ml of water. The reaction mixture was stirred at room temperature over night. The solvent was evaporated. The residue was transferred into a 1 n NaOH and extracted twice with tert-butylmethylamine ether. Brought the pH of the aqueous phase to 2, adding 25% HCl, and extracted twice with tert-butylmethylamine ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The crude substance, solid white shade (1.01 g, 54%), used without further purification.

Intermediate compound Q

TRANS-N,4-Cyclohexyl-tetrahydro-PYRAN-3,4-diamine hydrochloride

Specified in the title compound, white solid, MS: m/e=199,4 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-(4-cyclohexylamino-tetrahydro-Piran-3-yl)-carbamino acid, which was obtained by following the procedure described for intermediate K from tert-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) and Cyclopentanone.

Intermediate compound R

TRANS-N-4-Isopropyl-tetrahydro-PYRAN-3,4-diamine hydrochloride

Specified in for�over the head of the Union, white solid, MS: m/e=159,3 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-(4-isopropylamino-tetrahydro-Piran-3-yl)-carbamino acid, which was obtained by following the procedure described for intermediate K from tert-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) and acetone.

Intermediate compound S

TRANS-N-4-(Tetrahydro-Piran-4-yl)-tetrahydro-PYRAN-3,4-diamine dihydrochloride

Specified in the title compound, white solid, MS: m/e=201,3 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-[4-(tetrahydro-Piran-4-ylamino)-tetrahydro-Piran-3-yl]-carbamino acid, which was obtained by following the procedure described for intermediate K from tert-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) and tetrahydropyrane.

Intermediate compound T

TRANS-N-4-Cyclopropylmethyl-tetrahydro-PYRAN-3,4-diamine dihydrochloride

Specified in the title compound, white solid, MS: m/e=to 171.3 [(M+H)+], obtained according to the General method of obtaining intermediate with�unity L of tert-butyl ether TRANS-[4-(cyclopropylmethyl-amino)-tetrahydro-Piran-3-yl]-carbamino acid, which was obtained by following the procedure described for intermediate K from tert-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) and cyclopropanecarboxaldehyde.

Intermediate coupling U

TRANS-4-piperidine-1-yl-tetrahydro-PYRAN-3-yl-amine dihydrochloride

Specified in the title compound, white solid, MS: m/e=185,2 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-(4-piperidine-1-yl-tetrahydro-PYRAN-3-yl)-carbamino acid, which was obtained by following the procedure described for intermediate H from tert-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) and 1,5-dibromopropane.

Intermediate compound V

TRANS-N-4-Cyclopropyl-tetrahydro-PYRAN-3,4-diamine dihydrochloride

Specified in the title compound, white solid, MS: m/e -157,3 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-(4-cyclopropylamino-tetrahydro-Piran-3-yl)-carbamino acid, which was obtained by following the procedure described for intermediate K from tert-butyl ether TRANS-(4-amino-�tetrahydro-Piran-3-yl)-carbamino acid (intermediate G) and [(1-amoxicilpin)oxy]-trimethylsilane.

Intermediate compound W

tert-Butyl ether TRANS-4-(1-methyl-cyclohexylamino)-tetrahydro-Piran-3-yl]-carbamino acid

To a solution of 350 mg (1,405 mmol) mpem-butyl ether 3-oaks-7-Aza-bicyclo[4.1.0]heptane-7-carboxylic acid (intermediate E) in 6.0 ml of acetonitrile was added 430 mg (2.8 mmol) 1-amino-1-methylcyclohexane hydrochloride (CAS: 89854-70-6), 505 ál (2,951 mmol) of N-ethyldiethanolamine and 1.2 g (11,24 mmol) of lithium perchlorate. The mixture was heated at 70°C for 6 hours and then stirred at room temperature over night. The mixture was cooled to room temperature and diluted with dichloromethane. The solution was washed once with water. The washings were extracted once with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue via flash chromatography on silica gel (heptane, ethyl acetate 100:0→0:100) gave specified in the title compound as a light yellow solid (53 mg, 12%), MS: m/e=313,2 [M+H+].

Intermediate compound X

TRANS-N-4-(1-Methyl-cyclohexyl)-tetrahydro-PYRAN-3,4-diamine dihydrochloride

Specified in the title compound, white solid, MS: m/e -213,4 [(M+H)+], obtained according to the General method of obtaining Prome�weft connection L from tert-butyl ether TRANS-[4-(1-methyl-cyclohexylamino)-tetrahydro-Piran-3-yl]-carbamino acid.

Intermediate compound Y

TRANS-N-4-(1-Methyl-cyclopentyl)-tetrahydro-PYRAN-3,4-diamine hydrochloride

Specified in the title compound, white solid, MS: m/e=199,3 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-[4-(1-methyl-cyclopentylamine)-tetrahydro-Piran-3-yl]-carbamino acid, which was obtained by following the procedure described for intermediate W, from tert-butyl ether 3-oaks-7-Aza-bicyclo[4.1.0]heptane-7-carboxylic acid (intermediate E) and 1-amino-1-Methylcyclopentane hydrochloride (CAS: 102014-58-4).

The intermediate compound Z

TRANS-N-4-(1-Cyclopropyl-ethyl)-tetrahydro-PYRAN-3,4-diamine dihydrochloride

Specified in the title compound, white solid, MS: m/e=185,2 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-[4-(1-cyclopropyl-ethylamino)-tetrahydro-Piran-3-yl]-carbamino acid, which was obtained by following the procedure described for intermediate K from mpem-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) and 1-cyclopropyl-ethanone.

Intermediate AA

TRANS-N-4-Cyclobutyl-tetrahydropyran-3,4-diaminocyclohexane

Specified in the title compound, white solid, MS: m/e=to 171.3 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-(4-cyclobutylamine-tetrahydro-Piran-3-yl)-carbamino acid, which was obtained by following the procedure described for intermediate K from tert-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) and cyclobutanone.

Intermediate compound AB

TRANS-4-(3-Amino-tetrahydro-Piran-4-ylamino)-cyclohexanol dihydrochloride

Specified in the title compound, white solid, MS: m/e=to 215, 4 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-[4-(4-hydroxy-cyclohexylamino)-tetrahydro-Piran-3-yl]-carbamino acid, which was obtained by following the procedure described for intermediate K from tert-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) and 4-hydroxycyclohexanone.

An intermediate connection AC

TRANS-4-(3-Aza-bicyclo[3.1.0]hex-3-yl)-tetrahydro-Piran-3-ylamine dihydrochloride

Specified in the title compound, white solid in�society, MS: m/e=183,2 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-[4-(3-Aza-bicyclo[3.1.0]hex-3-yl)-tetrahydro-Piran-3-yl]-carbamino acid, which was obtained by following the procedure described for intermediate W, from tert-butyl ether 3-oaks-7-Aza-bicyclo[4.1.0]heptane-7-carboxylic acid (intermediate F) and 3-Aza-bicyclo[3.1.0]hexane hydrochloride (CAS: 73799-64-1).

An intermediate connection AD

2,6-Dimethyl-4-trifluoromethyl-benzoic acid

Stage 1. Obtaining 2,6-dimethoxy-4-trifluoromethyl-benzoic acid

To a solution of sodium hydroxide (5,66 g, 141,4 mmol) in 33 ml of water and 33 ml of ethanol at room temperature in a nitrogen atmosphere was added 2,6-dimethoxy-4-trifluoromethyl-benzonitrile (CAS: 51271-36-4) (3,27 g, 14.14 per mmol). The reaction mixture was heated at 90°C oil bath for 37 hours. The reaction mixture was cooled to room temperature and was added 130 ml of water. Product was collected by filtration and dried, giving of 3.05 g of a solid substance of white color. To a solution of nitrogylcerin acid (15.6 g, a 110.2 mmol) in 9.5 ml of water at 0°C in an atmosphere of nitrogen was added dropwise a suspension of prior substance in 19 ml of dichloromethane. The reaction mixture was stirred at 0°C for 4.5 hours. The reaction�th mixture was poured into ice and was extracted with dichloromethane. The combined organic layers were dried over Na2SO4that was filtered and dried, giving of 1.51 g of product. The aqueous phase was filtered and a white solid substance was dried, which gave to 1.36 g of the product. Both portions were mixed, which gave 2,87 g (93.7 per cent) specified in the title compounds as white solids. MS (m/e): 249,1 (M-N).

Stage 2. Obtaining 2,6-dimethoxy-4-trifluoromethyl-benzoyl chloride

To a suspension 14,47 g (57,84 mmol) 2,6-dimethoxy-4-trifluoromethyl-benzoic acid in 160 ml of toluene containing four drops of DMF in a nitrogen atmosphere at room temperature was added 42 ml (578,4 mmol) of thionylchloride. The mixture was heated at 85°C oil bath for 3 hours. The solvent was removed in vacuo, which gave to 15.37 g (yield: 98,9%) specified in the header connection in the form of a solid substance of white color.

Stage 3. Obtaining N-(2-hydroxy-1,1-dimethyl-ethyl)-2,6-dimethoxy-4-trifluoromethyl-benzamide derivative

To a solution of 3.7 ml (37,22 mmol) 2-amino-2-methyl-1-propanol in 42 ml of dichloromethane in a nitrogen atmosphere at 0°C was added dropwise a solution of 5 g (18,61 mmol) 2,6-dimethoxy-4-trifluoromethyl-benzoyl chloride in 12 ml of dichloromethane. Temperature increased to 7°C. the Mixture was stirred at room temperature for 4 hours. The mixture was poured into 75 ml of water. The organic layer was separated, and the aqueous layer extra�grown twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo, which gave 5,66 g (yield: 94.6 per cent) specified in the title compound as a yellow solid. MS (m/e): over 322.2 (M+H+).

Stage 4. Obtaining 2-(2,6-dimethoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazol

The solution for 5.66 g (17,62 mmol) N-(2-hydroxy-1,1-dimethyl-ethyl)-2,6-dimethoxy-4-trifluoromethyl-benzamide derivative in 60 ml of dichloromethane was cooled to 10°C. was added dropwise 3.8 ml (52,85 mmol) of thionylchloride. Temperature increased to 15°C. the Mixture was stirred at room temperature for 1 hour. The solution was added dropwise to 130 ml of chilled 2 M solution of sodium carbonate. The emulsion was diluted with water and filtered to remove a white solid. The organic layer was separated, and the aqueous layer was extracted with dichloromethane twice. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude light yellow solid (5,27 g) was purified by flash-chromatography on silica (70 g), elwira gradient formed with n-heptane and ethylacetate (0 to 50%) that gave 4.8 g (yield: 89.8 per cent) specified in the title compounds as white solids. MS (m/e): 304,2 (M+H+).

Stage 5. Obtaining 2-(2,6-DIMET�l-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (compound a)

and 2-(2-methoxy-6-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (connection)

To a 0°C solution of 1.5 g (4,946 mmol) 2-(2,6-dimethoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 9 ml of tetrahydrofuran through a molecular sieve was added dropwise of 9.89 ml (29,68 mmol) of 3 M solution of methylacrylamide in diethyl ether while maintaining the temperature below 5°C. the Mixture was warmed to room temperature and then heated at 70°C oil bath for 24 hours. The mixture was cooled in an ice bath and was quenched with 60 ml of a saturated solution of ammonium. Was added ethyl acetate. The organic layer was separated, and the aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude orange oil (1,38 g) was purified by flash column chromatography on silica, elwira gradient obtained from n-heptane and ethyl acetate (0% to 35%) that give 419 mg (yield: 31.2 per cent) 2-(2,6-dimethyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (compound a) as a white solid, MS (m/e): 272,2 (M+H+), and 532 mg (yield: 37.4 percent) of 2-(2-methoxy-6-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (compound B) as a colorless oil. MS (m/e): 288,1 (M+H+).

Stage 6. Obtaining 2-methyl-2-nitro-p�epilogo ether of 2,6-dimethyl-4-trifluoromethyl-benzoic acid

To a solution of 415 mg (1,530 mmol) 2-(2,6-dimethyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 17 ml of acetonitrile was added to 15.3 ml (0,0061 mmol) in 0.4 mm aqueous solution of Na2-EDTA at room temperature. Was added 1.4 ml (15,30 mmol) 1,1,1-triptoreline using a pre-cooled syringe. A mixture of 3.86 g (45,90 mmol) of sodium hydrogen carbonate and 9,41 g (15,30 mmol) oxone was added in portions within 15 minutes. The mixture was stirred for 30 minutes. The reaction mixture was diluted with 90 ml of water. The aqueous layer was extracted 3 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo, which gave 477 mg (yield: 97.7 per cent) specified in the header connection in the form of a colorless oil.

Stage 7. Obtaining 2,6-dimethyl-4-trifluoromethyl-benzoic acid To a solution of 475 mg (1,488 mmol) 2-methyl-2-nitro-propyl ester of 2,6-dimethyl-4-trifluoromethyl-benzoic acid (4.7 ml dioxane was added 3 ml (14,88 mmol) of 5 M aqueous NaOH solution. The mixture was heated at 100°C oil bath for 24 hours. The dioxane was removed under vacuum. The residue was diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified with 5 n HCl and extracted 3 times with dichloromethane. United dichloromethane extracts were dried over sodium sulfate, filtered and concentrated in vacuo�e, what gave 301 mg (yield: 92.7% of the) specified in the header connection in the form of light yellow solids. MS (m/e): 217,1 (M-N).

Intermediate AE

2-Methoxy-6-methyl-4-trifluoromethyl-benzoic acid

Specified in the title compound, light yellow solid, MS: m/e=232,9 (M-N), obtained according to the procedure described for intermediate AD from 2-(2-methoxy-6-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (intermediate AD, stage 5, the connection).

The intermediate AF

2,6-Diethyl-4-trifluoromethyl-benzoic acid

Specified in the title compound, light yellow solid, MS: m/e=245,1 (M-N), obtained according to the procedure described for intermediate AD from 2-(2,6-dimethoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole using ethylmagnesium as a Grignard reagent.

An intermediate connection AG

2-Ethyl-6-methoxy-4-trifluoromethyl-benzoic acid

Specified in the title compound, light yellow solid, MS: m/e=247,0 (M-N), obtained according to the procedure described for intermediate AD from 2-(2,6-dimethoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole using ethylmagnesium as a Grignard reagent

An intermediate connection an 2-Ethyl-6-methyl-4-trifluoromethyl-benzoic acid

Stage 1: 2-(2-Ethyl-6-methyl-4-trifluoromethyl-phenyl)-4.4-dimethyl-4.5-dihydro-oxazol

To a 0°C solution of 100 mg (0,332 mmol) 2-(2-ethyl-6-methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (obtained during the reaction of 2-(2,6-dimethoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole with ethylmagnesium) in 0.6 ml of tetrahydrofuran was added dropwise 0,332 ml (0,996 mmol) of 3 M solution of methylacrylamide in diethyl ether, maintaining the temperature below 5°C. the Mixture was warmed to room temperature and stirred for 3.5 hours, and then heated at 70°C oil bath for 4 days. The mixture was cooled in an ice bath and quenched by dropwise adding 3 ml of a saturated solution of ammonium chloride. Was added ethyl acetate. The organic layer was separated, and the aqueous layer was extracted three times with ethylcatechol. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude orange oil (286 mg) was purified by flash column chromatography on silica, elwira gradient obtained from n-heptane and ethyl acetate (0% to 10%) that gave 50 mg (yield: 50.4 percent) specified in the title compound as a light yellow oil. MS (m/e): 286,2 (M+H+).

One hundred�ia 2: 2-Ethyl-6-methyl-4-trifluoromethyl-benzoic acid

Specified in the title compound, light yellow solid, MS: m/e=245,1 (M-N), obtained according to the procedure described for intermediate AD (stage 6-7) of 2-(2-ethyl-6-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole.

An intermediate connection AI

2-Dihydro-6-methoxy-4-trifluoromethyl-benzoic acid

Specified in the title compound, solid white, MS: m/e=258,9 (M-N), obtained according to the procedure described for intermediate AD from 2-(2,6-dimethoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole using cyclopropylmagnesium as a Grignard reagent.

Intermediate AJ

TRANS-4-(2-Aza-bicyclo[3.1.0]hex-2-yl)-tetrahydro-Piran-3-ylamine hydrochloride-diastereomers of 1

Specified in the title compound, yellow solid, MS: m/e=183,2 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-[4-(2-Aza-bicyclo[3.1.0]hex-2-yl)-tetrahydro-Piran-3-yl]-carbamino acid (diastereomers 1), which was obtained by following the procedure described for intermediate W, from tert-butyl ether 3-oaks-7-Aza-bicyclo[4.1.0]heptane-7-carboxylic acid (intermediate E) and 2-Aza-bicyclo[3.1.0]hexane hydrochlor�Yes (CAS: 841302-37-2).

Intermediate AK

TRANS-4-(2-Aza-bicyclo[3.1.0]hex-2-yl)-tetrahydro-Piran-3-ylamine hydrochloride-diastereomers of 2

Specified in the title compound, yellow solid, MS: m/e -183,2 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-[4-(2-Aza-bicyclo[3.1.0]hex-2-yl)-tetrahydro-Piran-3-yl]-carbamino acid (diastereomers 2), which was obtained by following the procedure described for intermediate W, from tert-butyl ether 3-oaks-7-Aza-bicyclo[4.1.0]heptane-7-carboxylic acid (intermediate E) and 2-Aza-bicyclo[3.1.0]hexane hydrochloride (CAS: 841302-37-2).

Intermediate compound AL

TRANS-1-(3-Amino-tetrahydro-Piran-4-yl)-pyrrolidin-3-ol dihydrochloride-diastereomers of 1

Specified in the title compound, light brown solid, MS: m/e=187,3 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-[4-(3-hydroxy-pyrrolidin-1-yl)-tetrahydro-Piran-3-yl]-carbamino acid, the diastereomers of 1, which was obtained by following the procedure described for intermediate H from tert-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) and 1,4-dibrom-2-butanol.

An intermediate connection AM

TRANS-1-(3-Amino-tetrahydro-Piran-4-yl)-pyrrolidin-3-ol dihydrochloride-diastereomers of 2

Specified in the title compound, light brown solid, MS: m/e=187,3 [(M+H)+], obtained according to the General method of obtaining intermediate compounds L from tert-butyl ether TRANS-[4-(3-hydroxy-pyrrolidin-1-yl)-tetrahydro-Piran-3-yl]-carbamino acid, the diastereomers of 2, which was obtained by following the procedure described for intermediate H from tert-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) and 1,4-dibrom-2-butanol.

An intermediate connection'AN

tert-Butyl ether (4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (mixture of diastereomers)

tert-Butyl ether (4-oxo-tetrahydro-Piran-3-yl)-carbamino acid (CAS 477584-38-6, 446 mg, 2,07 mmol) was dissolved in 20 ml of methanol. Was added ammonium acetate (1.63 g, 21 mmol) and cyanoborohydride sodium (507 mg, 8.1 mmol) and the reaction mixture stirred at room temperature for 2 days. Was added ethyl acetate and a 2 n solution of sodium carbonate. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, was filtered concentrically in a vacuum. The residue was purified by flash column chromatography on silica, elwira gradient (dichloro methane/methanol/ammonia 100:0:0→140:10:1), what gave 199 mg (44%) specified in the title compounds as white solids. MS (m/e): 161,2 (M-butene)+.

Intermediate AO

tert-Butyl ether [4-(2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoylamino)-tetrahydro-Piran-3-yl]-carbamino acid (mixture of diastereomers)

Specified in the title compound, white solid, MS: m/e=465,3 [(M+H)+], obtained according to the General method of example 8 from tert-butyl ether (4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (mixture of diastereomers, intermediate AM) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A).

Intermediate compound AR

N-(3-Amino-tetrahydro-Piran-4-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide derivative hydrochloride (mixture of diastereomers)

Specified in the title compound, white solid, MS: m/e=365,1 [(M+H)+], obtained according to the General method of obtaining intermediate compounds I from tert-butyl ether [4-(2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoylamino)-tetrahydro-Piran-3-yl]-carbamino acid (mixture of diastereoisomer�s, intermediate AO).

Synthesis examples, Examples 1 and 2

2-Methoxy-6-methylsulfanyl-N-((3RS,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide and 2-methoxy-6-methylsulfanyl-N-((3RS,4SR)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide

and

2-Methoxy-6-methylsulfanyl-N-(4-oxo-tetrahydro-Piran-3-yl)-4-trifluoromethyl-benzamide (intermediate C, 300 mg, 0.83 mmol) was dissolved in 5 ml of tetrahydrofuran. Was added acetic acid (86 mg, 1.4 mmol) and pyrrolidine (70 mg, 0,99 mmol) and the reaction mixture was stirred for 1 hour at room temperature. Added triacetoxyborohydride sodium (209 mg, 0,99 mmol) and continued stirring at room temperature over night. The mixture was extracted with 2 n sodium carbonate solution and ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification of the residue via flash chromatography on silica gel (dichloro methane/methanol/ammonia 100:0:0→140:10:1) gave CIS-2-methoxy-6-methylsulfanyl-N-((3RS,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide as a light brown solid (80 mg, 40%), MS: m/e=419,1 [(M+H)+], and TRANS-2-methoxy-6-methylsulfanyl-N-((3RS,4SR)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide as a light brown, pink�CSO solids (25 mg, 12%), MS: m/e=419,1 [(M+H)+].

Examples 3 and 4

N-((3RS,4RS)-4-Cyclobutylamine-tetrahydro-Piran-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide and N-((3RS,4SR)-4-cyclobutylamine-tetrahydro-Piran-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

and

CIS-N-((3RS,4RS)-4-Cyclobutylamine-tetrahydro-Piran-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide, light brown solid, MS: m/e=419,2 [(M+H)+], and TRANS-N-((3RS,4SR)-4-cyclobutylamine-tetrahydro-Piran-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide, light brown solid, MS: m/e=419,2 [(M+H)+], obtained according to the General method of example 1 and 2 from 2-methoxy-6-methylsulfanyl-N-(4-oxo-tetrahydro-Piran-3-yl)-4-trifluoromethyl-benzamide derivative (intermediate C) and cyclobutylamine.

Example 5 and 6

(+)-2-Methoxy-6-methylsulfanyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide and (-)-2-methoxy-6-methylsulfanyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide

and

2-Methoxy-6-methylsulfanyl-N-((3RS,4SR)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide (example 2) was separated on Chiralpak AD with 15% ethanol in heptane. The first eluting enantiomer was a (+)-2-methoxy-6-methylsulfanyl-N-(4-Pierre�lidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide, the second enantiomer was a (-)-2-methoxy-6-methylsulfanyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide. The absolute stereochemistry was not determined.

Example 7

N-[(3RS,4SR)-4-(3-Hydroxy-pyrrolidin-1-yl)-tetrahydro-Piran-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

N-[(3RS,4SR)-4-(3-Hydroxy-pyrrolidin-1-yl)-tetrahydro-Piran-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide, yellow solid, MS: m/e=435,3 [(M+H)+], obtained according to the General method of example 1 and 2 from 2-methoxy-6-methylsulfanyl-N-(4-oxo-tetrahydro-Piran-3-yl)-4-trifluoromethyl-benzamide derivative (intermediate C) and rat-3-pyrrolidinone.

Example 8

2-Cyclopropyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide

2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J, 118 mg, 0,513 mmol) was dissolved in 2.5 ml of dimethylformamide. Was added N,N-diisopropylethylamine (338 mg, 2,62 mmol) and O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (195 mg, 0,513 mmol). After 10 minutes stirring at room temperature was added TRANS-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-ylamine dihydrochloride (intermediate I, 187 mg, 0,769 mmol). The reaction mixture was stirred at room temperature over night. Races�foretell evaporated. The residue was transferred into a 2 n solution of sodium carbonate and ethyl acetate and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification of the residue via flash chromatography on silica gel (heptane/ethyl acetate/triethylamine 1:0:0→10:10:1) gave specified in the title compound as a white solid (121 mg, 62%), MS: m/e=to 383.3(M+H)+].

The following examples were obtained according to the method of example 8:

Example No.StructureNameMS: m/eAcidAmin
92-Methylsulfone Il-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide457,3 [(M+H)+]2-Methylthio-4,6-bis(trifluoromethyl)benzona acid (CAS 896120-49-3)TRANS-L-Pyrrolidin-1-yl-tetrahydro-PYRAN-3-ylamine dihydrochloride (intermediate (I)
102-Methyl-N-((3SR,4RS)-4-pyrrolidin-yl-tetrahydro-Piran-3-yl)-4,6-bis-trifluoromethyl-benzamide 425,2 [(M+H)+]2-Methyl-4,6-bis(trifluoromethyl)benzona acid (CAS 895580-37-7)TRANS-4-Pyrrolidin-1-yl-tetrahydro-PYRAN-3-ylamine dihydrochloride (intermediate (I)

11N-((3SR,4RS)-4-Cyclopentylamine-tetrahydro-Piran-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide433,4 [(M+H)+]2-Methoxy-6-metralha Neil-4-trifluoromethyl-benzoic acid (intermediate A)TRANS-N-A-Cyclopentyl-tetrahydro-PYRAN-3,4-diamine dihydrochloride (intermediate L)
12N-((3SR,4RS)-4-Cyclopentylamine-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide397,3 [(M+H)+]2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J)TRANS-N-A-Cyclopentyl-tetrahydro-PYRAN-3,4-diamine dihydrochloride (intermediate L)
13 N-((3SR,4RS)-4-Cyclopentylamine-tetrahydro-Piran-3-yl)-2-methylsulfanyl-4,6-bis-trifluoromethyl-benzamide471,4 [(M+H)+]2-Methylthio-4,6-bis(trifluoromethyl)benzona acid (CAS 896120-49-3)TRANS-N-4-Cyclopentyl-tetrahydro-PYRAN-3,4-diamine dihydrochloride (intermediate L)

14N-((3SR,4RS)-4-Cyclohexyl Ino-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide411,4 [(M+H)+]2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J)TRANS-M,4-Cyclohexyl-tetrahydro-PYRAN-3,4-diamine hydrochloride (intermediate Q)
152-Cyclopropyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide451,2 [(M+H)+]2-Cyclopropyl-4,6-bis-trifluoromethyl-benzoic acid (intermediate P)TRANS-4-Pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl�ina dihydrochloride (intermediate (I)
16Dihydro-N-((3SR,4RS)-4-isopropylamino-tetrahydro-Piran-3-yl)-4-trifluoromethyl-benzamide371,2 [(M+H)+]2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J)TRANS-N-4-Isopropyl-tetrahydro-PYRAN-3,4-diamine hydrochloride (intermediate R)

172-Cyclopropyl-N-[(3SR,4RS)-4-(tetrahydro-Piran-4-ylamino)-tetrahydro-Piran-3-yl]-4-trifluoromethyl-benzamide413,3 [(M+H)+]2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J)TRANS-N-4-(Tetrahydro-Piran-4-yl)-tetrahydro-PYRAN-3,4-diamine (intermediate S)
18Dihydro-N-[(3SR,4RS)-4-(cyclopropylmethyl-amino)-tetrahydro-Piran-3-yl]-4-trifluoromethyl-benzamideTo 383.3 [(M+H)+]2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate�full-time connection (J) TRANS-N-4-Cyclopropylmethyl yl-tetrahydro-PYRAN-3,4-diamine (intermediate T)
192-Cyclopropyl-N-((3SR,4RS)-4-piperidine-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide397,2 [(M+H)+]2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J)TRANS-4-piperidine-1-yl-tetrahydro-PYRAN-3-yl-amine dihydrochloride (intermediate U)

202-Cyclopropyl-N-((3SR,4RS)-4-cyclopropyl Mino-tetrahydro-Piran-3-yl)-4-trifluoromethyl-benzamide369,2 [(M+H)12-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J)TRANS-N-4-Cyclopropyl-tetrahydro-PYRAN-3,4-diamine dihydrochloride (intermediate (V)
212,6-Dimethyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide371,2 [(M+H) +]2,6-Dimethyl-4-trifluoromethyl-benzoic acid (intermediate AD)TRANS-(4-Pyrrolidin-1-yl-tetrahydro-PYRAN-3-ylamine dihydrochloride (intermediate (I)
222-Methoxy-6-methyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide387,2 [(M+H)+]2-Methoxy-6-methyl-4-trifluoromethyl-benzoic acid (intermediate AE)TRANS-4-Pyrrolidin-1-yl-tetrahydro-PYRAN-3-ylamine dihydrochloride (intermediate (I)
232,6-Diethyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-399,2 [(M+H)+]2,6-Diethyl-4-trifluoromethyl-benzoic acid (intermediateTRANS-4-Pyrrolidin-1-yl-tetrahydro-PYRAN-3-ylamine dihydrochloride

benzamidecompounds�s AF) (intermediate I)
242-Ethyl-6-methoxy-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide401,3 [(M+H)+]2-Ethyl-6-methoxy-4-trifluoromethyl-Betina acid (intermediate AG)TRANS-4-Pyrrolidin-1-yl-tetrahydro-PYRAN-3-ylamine dihydrochloride (intermediate (I)
252-Methoxy-N-[(3SR,4RS)-4-(1-methyl-cyclohexylamino)-tetrahydro-Piran-3-yl]-6-methylsulfone Il-4-trifluoromethyl-benzamide461,4 [(M+H)+]2-Methoxy-6-metralha Neil-4-trifluoromethyl-benzoic acid (intermediate A)TRANS-N-4-(1-Methyl-cyclohexyl)-tetrahydro-PYRAN-3,4-diamine dihydrochloride (intermediate X)
262-Ethyl-6-methyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide385,2 [(M+H)+]2-Ethyl-6-methyl-4-t�iformity-benzoic acid (intermediate an) TRANS-4-Pyrrolidin-1-yl-tetrahydro-PYRAN-3-ylamine dihydrochloride (intermediate (I)

272-Dihydro-6-methoxy-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide413,3 [(M+H)12-Dihydro-6-methoxy-4-cryptomate-benzoic acid (intermediate A1)TRANS-N-Pyrrolidin-1-yl-tetrahydro-PYRAN-3-ylamine dihydrochloride (intermediate (I)
282-Methoxy-N-[(3SR,4RS)-4-(1-methyl-cyclopentylamine)-tetrahydro-Piran-3-yl]-6-methylsulfone Il-4-trifluoromethyl-benzamide447,3 [(M+H)12-Methoxy-6-metralha Neil-4-trifluoromethyl-benzoic acid (intermediate A)TRANS-N-4-(1-Methyl-cyclopentyl)-tetrahydro-PYRAN-3,4-diamine hydrochloride (intermediate Y)
292-Cyclopropyl-N-[(3SR,4RS)-4-(1-methyl-cyclopentylamine)-tetras�hydro-Piran-3-yl]-4-trifluoromethyl-benzamide 411,4 [(M+H)12-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J)TRANS-N-4-(1-Methyl-cyclopentyl)-tetrahydro-PYRAN-3,4-diamine hydrochloride (intermediate Y)

302-Cyclopropyl-N-[(3RS,4SR)-4-(1-cyclopropyl-ethylamino)-tetrahydro-Piran-3-yl]-4-trifluoromethyl-benzamide397,2 [(M+H)+]2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J)TRANS-N-4-(1-Cyclopropyl-ethyl)-tetrahydro-PYRAN-3,4-diamine dihydrochloride (intermediate Z)
31N-[(3SR,4RS)-4-(1-Cyclopropyl-ethylamino)-tetrahydro-Piran-3-yl]-2-methoxy-6-methylsulfanyl Il-4-trifluoromethyl-benzamide433,4 [(M+H)+]2-Methoxy-6-metralha Neil-4-trifluoromethyl-benzoic acid (intermediate A)TRANS-N-4-(1-Cyclopropyl-ethyl)-tetrahydro-PYRAN-3,4-diamine dihydrochloride (intermediate Z)
32N-((3SR,4RS)-4-Cyclobutyl Ino-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamideTo 383.3(M+H)+]2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J)TRANS-N-4-Cyclobutyl-tetrahydro-PYRAN-3,4-diamine dihydrochloride (intermediate AA)

33N-[(3SR,4RS)-4-(4-Hydroxy-cyclohexylamino)-tetrahydro-Piran-3-yl]-2-methoxy-6-methylsulfanyl Il-4-trifluoromethyl-benzamide463,3 [(M+H)+]2-Methoxy-6-metralha Neil-4-trifluoromethyl-benzoic acid (intermediate A)TRANS-4-(3-Amino-tetrahydro-Piran-4-ylamino)-cyclohexanol dihydrochloride (intermediate AB)
34N-[(3S,4R)-4-(3-Aza-bicyclo[3.1.0]hex-3-yl)-tetrahydro-Piran-3-yl]-2-methoxy-6-methylsulfanyl Il-4-trifluoromethyl-benzamide431,2 [(M+H)+]2-Methoxy-6-matilal� Neil-4-trifluoromethyl-benzoic acid (intermediate A) TRANS-4-(3-Aza-bicyclo[3.1.0]hex-3-yl)-tetrahydro-Piran-3-ylamine dihydrochloride (intermediate AU)
35N-[(3S,4R)-4-(3-Aza-bicyclo[3.1.0]hex-3-yl)-tetrahydro-Piran-3-yl]-2-cyclopropyl-4-trifluoromethyl-benzamide395,1 [(M+H)+]2-Cyclopropyl-4-cryptomate-benzoic acid (intermediate J)TRANS-4-(3-Aza-bicyclo[3.1.0]hex-3-yl)-tetrahydro-Piran-3-ylamine dihydrochloride (intermediate AU)

Example 36

2-Cyclopropyl-N-(3SR,4RS)-4-(4-hydroxy-piperidine-1-yl)-tetrahydro-Piran-3-yl]-4-trifluoromethyl-benzamide

Stage 1: Obtain tert-butyl ether (3SR.4RS)-4-(4-oxo-piperidine-1-yl)-tetrahydro-Piran-3-yl-carbamino acid

To a solution of 100 mg (0,462 mmol) tert-butyl ether TRANS-(4-amino-tetrahydro-PYRAN-3-yl)-carbamino acid (intermediate G) in 3 ml of ethanol was added 51 mg (from 0.37 mmol) of potassium carbonate. The mixture was heated to reflux at 90°C oil bath. A solution of 187 mg (0,693 mmol) 1-ethyl-1-methyl-4-oxo-piperidine iodide in 1 ml of water was added dropwise within 30 minutes. The mixture was heated with britishtelecom within 45 minutes was cooled to room temperature and diluted with water. The aqueous layer was extracted 3 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, elwira gradient formed with n-heptane and ethyl acetate (0 to 50%), which gave 100 mg (yield: 73%) specified in the title compounds as white solids. MS (m/e): 299,5 (M+H+).

Stage 2: Obtain 1-((3SR,4RS)-3-amino-tetrahydro-Piran-4-yl)-piperidine-4-she hydrochloride

Specified in the title compound, white solid, MS: m/e=199,3 [(M+H)+], obtained by following the procedure described for intermediate L, from tert-butyl ether (3SR,4RS)-4-(4-oxo-piperidine-1-yl)-tetrahydro-Piran-3-yl]-carbamino acid.

Stage 3: preparation of 2-cyclopropyl-N-[(3RS,4SR)-4-(4-oxo-piperidine-1-yl)-tetrahydro-Piran-3-yl-4-trifluoromethyl-benzamide derivative

Specified in the title compound, pale solid, MS: m/e=411,3 [(M+H)+], obtained according to the General method of example 8 from 1-((3SR,4RS)-3-amino-tetrahydro-Piran-4-yl)-piperidine-4-she hydrochloride and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J).

Stage 4: Obtain 2-cyclopropyl-N-[(3SR,RS)-4-(4-hydroxy-piperidine-1-yl)-tetrahydro-Piran-3-yl]-4-trifluoromethyl-benzamide derivative

To 10-20°C stirred solution of 2-cyclopropyl-N-[(3RS,4SR)-4-(4-oxo-piperidine-1-yl)-tetrahydro-Piran-3-yl]-4-trifluoromethyl-benzamide derivative (73 mg) in ethanol (1.8 ml) was added sodium borohydride (13.5 mg) and the solution was stirred for 30 minutes. The reaction mixture was warmed to room temperature, stirred for another 3 hours and concentrated in vacuo. The resulting residue was separated between water and dichloromethane. The aqueous phase was washed three times with dichloromethane, and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuum. The crude product was purified by flash column chromatography on silica, elwira gradient obtained from n-heptane and ethyl acetate (0 to 100%) gave 44 mg (yield: 60%) specified in the title compounds as white solids. MS (m/e): 413,3 (M+H+).

The following examples were obtained in the separation by chiral HPLC:

Note No.StructureNameThe racemate, note No.Chiral columnSolventRetention time
37 (+)-2-Cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide8Chiralpak AD8% ethanol in heptane11 min
38(-)-2-Cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide8Chiralpak AD8% ethanol in heptane15 min
39(+)-2-Methyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide10Chiralpak AD5% isoprop anol in heptane63 min
40(-)-2-Methyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-10Chiralpak AD5% isopropanol in heptane77 min

trifluoromethyl-benzamide
41(+)-2-Methylsulfone Il-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide9Chiralpak AD5% ethanol in heptane58 min
42(-)-2-Methylsulfanyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide9Chiralpak AD5% ethanol in heptane67 min
43(+)-N-(TRANS-4-Cyclopentyl Mino-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide12Chiralpak AD10% isoprop anol in heptane10 min
44 (-)-N-(TRANS-4-Cyclopentyl Mino-tetrahydro-Piran-3-yl)-2-12Chiralpak AD10% isopropanol in heptane12 min

dihydro-4-trifluoromethyl-benzamide
45(+)-N-(4-Cyclopentyl Mino-tetrahydro-Piran-3-yl)-2-methoxy-6-methylsulfanyl Il-4-trifluoromethyl-benzamide11Chiralpak AD12% isopropanol in heptane10 min
46(-)-N-(4-Cyclopentyl Mino-tetrahydro-Piran-3-yl)-2-methoxy-6-methylsulfanyl Il-4-trifluoromethyl-benzamide11Chiralpak AD12% isoprop anol in heptane13 min
47 (+)-2-Cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide15Chiralpak AD4% isopropanol in heptane8 min

48(-)-2-Cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide15Chiralpak AD4% isopropanol in heptane15 min
49(-)-N-(4-Cyclohexylamino-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide14Chiralpak AD4% isopropanol in heptane10 min
50(+)-N-(4-Cyclohexyl Ino-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide14Chiralpak AD12 min
51(+)-2,6-Dimethyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide21Chiralpak AD4% isopropanol in heptane9 min

52(-)-2,6-Dimethyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide21Chiralpak AD4% isopropanol in heptane12 min
53(+)-2-Methoxy-6-methyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide22Chiralpak AD4% isopropanol in heptane9 min
54(-)-2-Methoxy-6-methyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-triptime�Il-benzamide 22Chiralpak AD4% isopropanol in heptane13 min
55(+)-2-Ethyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide24Chiralpak AD4% isoprop anol in heptane7 min
56(-)-2-Ethyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide24Chiralpak AD4% isopropanol in heptane13 min

57(+)-2-Cyclopropyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide27Chiralpak AD4% isopropanol in heptane9 min
58 (-)-2-Cyclopropyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide27Chiralpak AD4% isopropanol in heptane19 min
64(-)-2-Methoxy-6-methylsulfanyl Il-N-(3-pyrrolidin-1-yl-tetrahydro-Piran-4-yl)-4-trifluoromethyl-benzamide63Reprosil Chiral NR20% ethanol in heptane20 min
65
(+)-2-Methoxy-6-methylsulfanyl Il-N-(3-pyrrolidin-1-yl-tetrahydro-Piran-4-yl)-4-trifluoromethyl-
benzamide
63Reprosil Chiral NR20% ethanol in heptane26 min

Example 59

N-[(3SR,4RS)-4-(2-Aza-bicyclo[3.1.0]hex-2-yl)-tetrahydro-Piran-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

Specified in the title compound, yellow solid, MS: m/e=431,2 [(M+H)+], obtained according to the General method of example 8 from TRANS-4-(2-Aza-bicyclo[3.1.0]hex-2-yl)-tetras�hydro-Piran-3-ylamine hydrochloride the diastereomers of 1 (intermediate AJ) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A).

Example 60

N-[(3SR,4RS)-4-(2-Aza-bicyclo[3.1.0]hex-2-yl)-tetrahydro-Piran-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

Specified in the title compound, yellow solid, MS: m/e=431,2 [(M+H)+], obtained according to the General method of example 8 from TRANS-4-(2-Aza-bicyclo[3.1 -0]hex-2-yl)-tetrahydro-Piran-3-ylamine hydrochloride the diastereomers of 2 (intermediate AK) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A).

Example 61

2-Cyclopropyl-N-[(3RS,4SR)-4-(3-hydroxy-pyrrolidin-1-yl)-tetrahydro-Piran-3-yl]-4-trifluoromethyl-benzamide

Specified in the title compound, yellow solid, MS: m/e=399,2 [(M+H)+], obtained according to the General method of example 8 from TRANS-1-(3-amino-tetrahydro-Piran-4-yl)-pyrrolidin-3-ol dihydrochloride - diastereomers of 1 (intermediate AL) and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J).

Example 62

2-Cyclopropyl-N-[(3RS,4SR)-4-(3-hydroxy-pyrrolidin-1-yl)-tetrahydro-Piran-3-yl]-4-trifluoromethyl-benzamide

Specified in the title compound, yellow solid, MS: m/e=399,2 [(M+H)+], obtained according to the General method of example 8 from TRANS-1-(3-amino-tetrahydro-Piran-4-yl)-pyrrolidin-3-ol dihydrochloride� - the diastereomers of 2 (intermediate AM) and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J).

Example 63

CIS-2-Methoxy-6-methylsulfanyl-N-(3-pyrrolidin-1-yl-tetrahydro-Piran-4-yl)-4-trifluoromethyl-benzamide

Specified in the title compound, brown solid, MS: m/e=419,3 [(M+H)+], obtained according to the General method of obtaining intermediate compounds N of N-(3-amino-tetrahydro-Piran-4-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide derivative hydrochloride (intermediate AR) and 1,4-dibromopropane. Two diastereoisomer were separated using column chromatography.

Compounds of formula I and their pharmaceutically acceptable salts accession possess valuable pharmacological properties. Namely, it was found that the compounds of the present invention are good inhibitors of the glycine Transporter I (GlyT-1).

The compounds were investigated in accordance with the test below.

Solutions and substances

Full DMEM: nutrient mixture F-12 (Gibco Life-technologies), fetal bovine serum (FBS) 5%, (Gibco life technologies), penicillin/streptomycin 1% (Gibco life technologies), hygromycin 0.6 mg/ml (Gibco life technologies), glutamine 1 mm Gibco life technologies).

Buffer for capture (UB): 150 mm NaCl, 10 mm Hepes-Tris, pH 7,4, 1 mm CaCl2, 2.5 mm KCI, 2.5 mm MgSO410 mm (+) D.

Cells Flp-in™-CHO (Invitrogen Cat No. R758-07), stable transfetsirovannyh mGlyT1b cDNA.

Analysis of inhibition of seizure glycine (mG1yT-1b)

On the first day of mammalian cells (Flp-in™-CHO), transfetsirovannyh mGlyT-1b cDNA, were plated with a density of 40000 cells/well in complete medium (F-12 without hygromycin in 96-well culture plates. On the second day, the medium aspirated, and the cells were washed twice with buffer for capture (UB). Then the cells were incubated for 20 minutes at 22°C with either no potential competing compounds (1) or with 10 mm non-radioactive glycine (2), or with the potential inhibitor in any concentration (3). In order to obtain data for calculating the concentration of inhibitor resulting in 50%-nomu inhibition (e.g. IR50concentrations of competing compound that provides 50% inhibition of seizure glycine), used a range of concentrations of the potential inhibitor. Immediately thereafter was added a solution containing 60 nm of [3H]-glycine (11-16 CI/mmol) and 25 μm of non-radioactive glycine. The plates were incubated with gentle shaking and the reaction was terminated by aspiration of the mixture and washing (three times) cooled to 0°C UB. Cells were literally scintillation liquid and shook for 3 hours, and the radioactivity of the cells was counted using a scintillation counter.

�connection described in examples 1-60, mean IC50<1.0 μm. Preferred values IR50(<0.2 μm) for compounds 1-128 presented in table 1.

Table 1
ExampleThe values of IR50(μm)ExampleThe values of IR50(μm)
10,2605340,1099
20,0662350,0265
30,5056360,2743
40,3375370,0834
50,1176380,0834
60,0284390,0439
7 0,1546400,0955
80,0363410,0447
9X 0.0165420,027
100,0412430,0788
110,1267440,2989
120,075450,111
130,2503460,1581
140,1249470,016
150,0132480,02
160,2962490,3398
170,9039500,057
180,1264510,0253
190,0815520,0341
200,1935530,0782
210,0452540.0338 per kWh
220,1045550,0483
230,0584560,0155
240,064157Of 0.0625
250,2775580,0076
260,0179 590,1136
270,0147600,0264
280,1439610,3481
290,2349620,2819
300,0838630,1893
310,2756640,1893
320,1193650,1186
330,7514

Compounds of formula I and pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. These pharmaceutical preparations can be administered orally, for example in the form of pills, tablets, coated tablets, DRA�e, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, it can also be done by rectal administration, for example, in the form of suppositories, or parenteral administration, for example in the form of solutions for injection.

For the manufacture of pharmaceutical preparations the compounds of formula I can be used together with pharmaceutically inert inorganic or organic carriers. For example, as such carriers for tablets, tablets, coated tablets, dragees and hard gelatin capsules can be used lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like. Suitable carriers for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance in the case of soft gelatin capsules carriers usually are not required. Suitable carriers for the production of solutions and syrups are e.g. water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are e.g. natural or solidified oils, waxes, fats, semi-liquid or liquid polyols and the like.

Moreover, the pharmaceutical preparations can contain preservatives, solubilizing�s, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, corrigent, salts for regulating the osmotic pressure, buffer agents, masking agents or antioxidants. They can also contain still other therapeutically useful substances.

Drugs, containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention, as the method of their production, which comprises bringing one or more compounds of the formula I and/or pharmaceutically acceptable salts accession acids and, optionally, one or more other therapeutically useful substances to form Galanova of the drug together with one or more than one therapeutically inert carrier.

The most preferred indications in accordance with the present invention are those, which include disorders of the Central nervous system, for example the treatment or prevention of schizophrenia, cognitive impairment and Alzheimer's disease.

Of course, the dosage can be varied within wide limits, and generally in each case it must be adjusted according to individual needs. In the case of oral administration the dosage for adults can vary from priblizitel�but 0.01 mg to about 1000 mg per day of the compounds of the General formula I or a corresponding amount of its pharmaceutically acceptable salts. The daily dose may be administered in a single dose or in the form of fractional doses, and, in addition, can also be exceeded when indicated.

The method of manufacture

1. Mixed substances 1, 2, 3 and 4 and granulated with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through suitable milling equipment.

4. Add substance 5 and mix for three minutes; pressed in a suitable press.

The method of manufacture

1. Mixed substances 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add the substances 4 and 5 and mix for 3 minutes.

3. Fill a suitable capsule.

1. The compound of the General formula I

where
R1/R2independently from each other represent hydrogen, (CR2)about-C3-7 cycloalkyl, possibly substituted lower alkyl or hydroxy, or are lower alkyl or tetrahydropyranyl, and o represents 0 or 1; and
R can be identical or different and represent hydrogen or lower alkyl; or
R1and R2can form together with the N atom to which they are attached, geteroseksualnoe group selected from the group consisting of pyrrolidinyl, piperidinyl, 3-�for-bicyclo[3.1.0]hex-3-yl or 2-Aza-bicyclo[3.1.0]hex-2-yl, which may be substituted by hydroxy;
R3is an S-lower alkyl, lower alkyl, lower alkoxy or C3-7 cycloalkyl;
R3'represents hydrogen, lower alkyl, substituted by halogen,
lower alkyl or lower alkoxy;
R4represents lower alkyl substituted by halogen;
X represents-O - or-CH2-;
X' represents-O - or-CH2-; provided that one of X or X' represents-O - and the other represents-CH2-; or pharmaceutically acceptable acid-additive salt, racemic mixture, or its corresponding enantiomer and/or optical isomer.

2. The compound of formula I-1, covered by the formula I according to claim 1,

where
R1/R2independently from each other represent hydrogen, (CR2)0-C3-7 cycloalkyl, possibly substituted lower alkyl or hydroxy, or are lower alkyl or tetrahydropyranyl, and o represents 0 or 1; and
R can be identical or different and represent hydrogen or lower alkyl; or
R1and R2can form together with the N atom to which they are attached, geteroseksualnoe group selected from the group consisting of pyrrolidinyl, piperidinyl, 3-Aza-bicyclo[3.1.0]hex-3-yl or 2-Aza-bicyclo[3.1.0]hex-2-yl,�which maybe substituted with hydroxy;
R3is an S-lower alkyl, lower alkyl, lower alkoxy or C3-7 cycloalkyl;
R3'represents hydrogen, lower alkyl, substituted by halogen,
lower alkyl or lower alkoxy;
R4represents lower alkyl substituted by halogen; or pharmaceutically acceptable acid-additive salt, racemic mixture, or its corresponding enantiomer and/or optical isomer.

3. The compound of formula 1-1 according to claim 2, where R1and R2can form together with the N atom to which they are linked, geteroseksualnoe group selected from the group consisting of pyrrolidinyl, piperidinyl, 3-Aza-bicyclo[3.1.0]hex-3-yl or 2-Aza-bicyclo[3.1.0]hex-2-yl, which may be substituted with hydroxy.

4. The compound of formula I-1 according to claim 3, wherein the compounds are
2-methoxy-6-methylsulfanyl-N-((3RS,4SR)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
(-)-2-methoxy-6-methylsulfanyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
2-cyclopropyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
2-methylsulfanyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,
2-methyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,
2-cyclopropyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-�reformer-benzamide,
2-cyclopropyl-N-((3SR,4RS)-4-piperidine-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
2,6-dimethyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
2,6-diethyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
2-ethyl-6-methoxy-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
2-ethyl-6-methyl-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
2-dihydro-6-methoxy-N-((3SR,4RS)-4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
N-[(3S,4R)-4-(3-Aza-bicyclo[3.1.0]hex-3-yl)-tetrahydro-Piran-3-yl]-2-cyclopropyl-4-trifluoromethyl-benzamide,
(+)-2-cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
(-)-2-cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
(+)-2-methyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,
(-)-2-methyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,
(+)-2-methylsulfanyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,
(-)-2-methylsulfanyl-N-TRANS-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,
(+)-2-cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-trifluoromethyl-benzamide,
(-)-2-cyclopropyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4,6-bis-triptime�yl-benzamide,
(+)-2,6-dimethyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
(-)-2,6-dimethyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
(+)-2-methoxy-6-methyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
(-)-2-methoxy-6-methyl-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
(+)-2-ethyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
(-)-2-ethyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
(+)-2-cyclopropyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide,
(-)-2-cyclopropyl-6-methoxy-N-(4-pyrrolidin-1-yl-tetrahydro-PYRAN-3-yl)-4-trifluoromethyl-benzamide or
N-[(3SR,4RS)-4-(2-Aza-bicyclo[3.1.0]hex-2-yl)-tetrahydro-Piran-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.

5. The compound of formula I-1 according to claim 2, where R1and R2independently from each other represent hydrogen or (CR2)0-C3-cycloalkyl, o represents O or 1, and R can be identical or different, and represent hydrogen or lower alkyl.

6. The compound of formula I-1 according to claim 5, which compounds are N-((3SR,4RS)-4-cyclopentylamine-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide,
2-cyclopropyl-N-[(3RS,4SR)-4-(1-cyclopropyl-ethylamino)-tetrahydro-Piran-3-yl]-4-trifluoromethyl-Bentham�d,
(+)-N-(TRANS-4-cyclopentylamine-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide or
(+)-N-(4-cyclohexylamino-tetrahydro-Piran-3-yl)-2-cyclopropyl-4-trifluoromethyl-benzamide.

7. The compound of formula I-2, covered by the formula I according to claim 1,

where
R1/R2independently from each other represent hydrogen, (CR2)0-C3-7 cycloalkyl, possibly substituted lower alkyl or hydroxy, or are lower alkyl or tetrahydropyranyl, and o represents 0 or 1; and
R can be identical or different and represent hydrogen or lower alkyl; or
R1and R2can form together with the N atom to which they are attached, geteroseksualnoe group selected from the group consisting of pyrrolidinyl, piperidinyl, 3-Aza-bicyclo[3.1.0]hex-3-yl or 2-Aza-bicyclo[3.1.0]hex-2-yl, which may be substituted by hydroxy;
R3is an S-lower alkyl, lower alkyl, lower alkoxy or C3-7 cycloalkyl;
R3'represents hydrogen, lower alkyl, substituted by halogen, lower alkyl or lower alkoxy;
R4represents lower alkyl substituted by halogen; or pharmaceutically acceptable acid-additive salt, racemic mixture, or its corresponding enantiomer and/or optical isomer.

8. Connect�of formula I according to claim 2 7, where the compounds are CIS-2-methoxy-6-methylsulfanyl-N-(3-pyrrolidin-1-yl-tetrahydro-Piran-4-yl)-4-trifluoromethyl-benzamide,
(-)-2-methoxy-6-methylsulfanyl-N-(3-pyrrolidin-1-yl-tetrahydro-Piran-4-yl)-4-trifluoromethyl-benzamide or
(+)-2-methoxy-6-methylsulfanyl-N-(3-pyrrolidin-1-yl-tetrahydro-Piran-4-yl)-4-trifluoromethyl-benzamide.

9. The compound according to any one of claims. 1-8 for use as an inhibitor GIyT-1.

10. Pharmaceutical composition having activity of inhibiting GIyT-1, containing one or more compound according to any one of claims. 1-8 and a pharmaceutically acceptable excipient.

11. Pharmaceutical composition according to claim 10, wherein the disease that can be treated, are psychoses, pain, dysfunction in memory and learning, attention deficit disorder, schizophrenia, dementia or Alzheimer's disease.

12. Use of a compound according to any one of claims. 1-8 for the treatment of psychoses, pain, dysfunction in memory and learning, attention deficit disorder, schizophrenia, dementia or Alzheimer's disease.

13. Use of a compound according to any one of claims. 1-8 for the manufacture of drugs for the treatment of psychoses, pain, dysfunction in memory and learning, attention deficit disorder, schizophrenia, dementia or Alzheimer's disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

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37 cl, 6 dwg, 12 tbl, 186 ex

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16 cl, 2 tbl, 26 ex

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,

where each R is independently an allyl, an unsubstituted or substituted phenyl, unsubstituted or substituted C1-C8-alkyl, or unsubstituted or substituted C3-C8-cycloalkyl; (b) at least one epoxy resin; (c) a catalyst which contains a phenol compound; (d) an additive which increases impact strength of formula

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12 cl, 2 tbl, 6 ex

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113 cl, 49 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

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8 cl, 4 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-nitrofuran derivatives of formula I: where R=piperidino, pyrrolidineo, diethylamino, morpholino.

EFFECT: presented preparation of new biologically active compounds which exhibit antimicrobial activity.

1 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds of formula I: formula I or its pharmaceutically acceptable salt, where the radical values R3, R4, R2, X1, X2, R1 are such as presented in claim 1. Also, the invention describes a pharmaceutical composition exhibiting a Tec-family kinase inhibitor activity and based on the compounds of formula I, a method of Tec-family kinase activity inhibition, and a method of producing the compound of formula I.

EFFECT: produced and described new compounds which are effective as Tec-family (eg, Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase inhibitors, and acceptable compositions are applicable for treatment or prevention of some diseases, disorders or conditions including but not limited, autoimmune, inflammatory, proliferative or hyperproliferative, or immunologically mediated diseases.

50 cl, 18 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula (I) or their pharmaceutically acceptable salts, which possess properties of RNA-polymerase inhibitor, in particular HCV inhibitor. Such disease can be hepatitis C. In formula (I)

is selected from the group, including simple carbon-carbon bond and double carbon-carbon bond; R1 represents hydrogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; R4 is selected from the group, including

and ,

R5 is selected from the group, including hydrogen atom, C1-C6alkyl and C1-C6alkyloxy; R6 is selected from the group, including hydrogen atom, C1-C6alkyl and C1-C6alkyloxy; R7 is selected from the group, including hydrogen atom, phenyl, 5-membered heterocycle, carbocycle with 2 condensed cycles, where 5-membered heterocycle contains at least 1 heteroatom, selected from the group, consisting of N, O and S, and where phenyl, heterocycle and carbocycle with 2 condensed cycles are optionally substituted with at least one of RJ and RK.

EFFECT: compounds can be used for treatment of disease, which can be treated by HCV inhibition.

21 cl, 2 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to compounds of formula (I), wherein R1 and R2 independently represent C6-C10 aryl optionally substituted by -OH, halogen, -OC1-C3 alkyl, -NO2, -CF3 or C1-C3 alkyl, or 5- or 6-merous heteroaryl containing one heteroatom specified in N, S and O; A and M independently represent a methylene group or a single bond; an adjacent aromatic cycle is attached directly to an amide group; the group Y=Z represents together and irregularly oxygen atom (-O-), cis-vinylidene group (-CH=CH-), iminogroup (-N=CH- or -CH=N-) or methylene group with sp2-hybridised carbon atom (=CH-); X irregularly represents methine group (=CH-), cis-vinylidene group (-CH=CH-) or carbon atom (=N-), and W represents hydroxyl group (-OH), C1-C6 alkyl optionally substituted by -SH, 5- or 6-merous heteroaryl containing 1 to 2 nitrogen heteroatoms, or C6-C10 aryl, optionally substituted by -SH, -NH2, and their pharmaceutically acceptable salts.

EFFECT: described are the methods for preparing the compounds, using as a drug for treating cancer and the based pharmaceutical composition.

14 cl, 6 tbl, 49 ex

FIELD: medicine.

SUBSTANCE: invention refers to using 3',4'-methylene dioxy-5'-methoxyflavones as a specific marker for standardising an elevated portion of cowslip primrose (medicinal) (Primula veris L., or Primula officinalis (L.) Hill.).

EFFECT: extension of the list of specific marker substances for standardising the medicinal herbs.

7 dwg, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula

,

where values A, R1-R6 are given in i.1 of the invention formula. Methods of obtaining the formula (I) compound are described.

EFFECT: compounds demonstrate an inhibiting activity of the cathepsin enzyme, which makes it possible to use them for the preparation of a pharmaceutical composition and for the preparation of a medication.

38 cl, 12 dwg, 495 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining pyripyropene derivatives, namely a compound of formula C: , where R represents a linear chain, a branched chain or cyclic C2-6alkylcarbonyl, on condition that, when an alkyl fragment in an alkylcarbonyl group represents a branched chain or a cyclic group, R represents C3-6alkylcarbonyl, including: selective acylation of hydroxyl groups in 1-position and 11-position of a compound B1, represented by formula B1: with an acylating agent in one-three stages in the presence or absence of a base. (i) compound C is obtained by acylation of hydroxyl groups in 1-position and 11-position of the compound B1 in one stage; (ii) method, including obtaining the compound C by acylation in two stages, consisting of stages: acylation of the hydroxyl group in 11-position of the compound B1 with the acylating agent with obtaining the compound B2, represented by formula B2: , where R is determined in formula C; and additional acylation of the hydroxyl group in 1-position of the compound B2; or (iii) method, including obtaining the compound C by acylation in three stages, consisting of stages: acylation of the hydroxyl group in 11-position of the compound B1 with obtaining the compound B2, represented by formula B2: , where R is determined in the formula C; transfer of acyl in 11-position of the compound B2 to hydroxyl in 1-position with obtaining the compound B3, represented by formula B3: , where R is such as determined in the formula C; and acylation of hydroxyl group in 11-position of the compound B3.

EFFECT: increased output.

16 cl, 1 dwg, 3 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound presented by formula (E) , wherein X, Y and L are independently non-directionally specified in -C(R1)(R2)-, -C(R3)=, -N(R4)-, -N= and -O-; M and Z are independently non-directionally specified in ; ---- means an optional double bond; R1, R2, R3, R4 and R6 are independently specified in hydrogen; C1-4 alkyl; group -C1-4 alkylene-halogen; group -C1-4 alkylene-OH; Hal is specified in F, Cl, Br and I; RE1 and RE2 are attached to neighbouring carbon atoms, and RE1 and RE2 together non-directionally form the structure -T-(CRE7RE8)n-V-, wherein T is specified in CRE9RE10 and O or NH, and V is specified in CRE9RE10 and O or NH, as well as respective structures comprising a double bond; at least one of T or V represents O or N; RE7 and RE8 represent H or F; RE9 and RE10 represent H; n takes on the values of 1 to 2; RE3 represents C1-6 alkyl group; m takes on the values of 0 or 1; RE4 represents a halogen atom; p takes on the values of 0 or 1; as well as to pharmaceutical diagnostic compositions of the above compound.

EFFECT: preparing the new pharmaceutical compounds.

41 cl, 17 dwg, 2 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel derivative of N-acylanthranilic acid, represented by the following general formula 1, or to its pharmaceutically acceptable salt, in which R1, R2, R3, X1, X2, X3, X4 and A are determined in the invention formula.

EFFECT: invention relates to an inhibitor of collagen production, a medication for treating diseases, associated with the excessive production of collagen, containing N-acylanthranilic acid derivative Formula 1.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula [I] or to its pharmaceutically acceptable salt, wherein A represents optionally substituted alkyl, wherein the substitute represents identical or different 1-3 groups specified in aryl optionally substituted by 1-3 groups specified in alkyl, halogen, alkoxy and alkanoyl; cycloalkyl optionally substituted by 1-3 groups specified in alkyl and halogen; hydroxy; alkoxy; halogen; an amino group and oxo; an optionally substituted carbocyclic group specified in a mono- and bicyclic group, wherein an aromatic ring and cycloalkyl are condensed; optionally substituted aryl, an optionally substituted completely saturated 5- or 6-merous monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, wherein the substitute of optionally substituted aryl, the optionally substituted carbocyclic group and the optionally substituted heterocyclic group for A represents identical or different 1-3 groups specified in alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen; cycloalkyl optionally substituted by alkyl or alkoxy; alkoxy optionally substituted by halogen; halogen; hydroxy; oxo; heterocycle; alkyl sulphonyl; and mono- or dialkylcarbamoyl, optionally substituted amino, wherein the substitute represents identical or different 1 or 2 alkyl or aryl, or optionally substituted carbamoyl, wherein the substitute represents identical or different 1 or 2 alkyls optionally substituted by aryl, X represents optionally substituted methylene or -O-, wherein the substitute of optionally substituted methylene for X represents alkoxy or hydroxy, Q represents N or C-R4, L1 represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or -CH2NR11-, L2 represents a single bond, -CR6R7- or a bivalent 5- or 6-merous completely saturated monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, R1 and R2 are identical or different, and each represents hydrogen, alkyl or halogen, R3 and R4 are identical or different, and each represents hydrogen, alkyl, alkoxy, cyano or halogen, R1 and R3 are optionally bond thereby forming 5- or 6-merous cycloalkane, or a 5- or 6-merous aliphatic heterocycle containing oxygen atom, R5 represents a carboxyl group, an alkoxycarbonyl group or a bioisosteric group of the carboxyl group, R6 and R7 are identical or different, and each represents hydrogen or alkyl, or R6 and R7 are bond thereby forming cycloalkane, R8 represents hydroxy, alkanoylamino or alkyl sulphonylamino, R9 and R10 represent hydrogen or halogen, and R11 represents hydrogen or alkyl. Besides, the invention refers to specific compounds of formula [I], a drug based on the compound of formula [I], using the compound of formula [I], a method of treating based on using the compound of formula [I], and an intermediate compound of formula [II].

EFFECT: there are prepared new compounds possessing the agonist activity on thyroid hormone β receptor.

18 cl, 36 tbl, 344 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel compound of formula (1) or its pharmaceutically acceptable salt, possessing SNS inhibiting properties. In general formula R1 represents (1) hydrogen atom, (2) halogen atom, (3) C1-6alkyl group or (4) C1-6halogenalkyl group (whereR1 can be present in any substitutable position of benzene or pyridine ring); L represents (1) simple bond, (2) -O- or (3) -CH2O- (where L can be present in position 5 or 6 of condensed cycle); R2 represents (1) C6-10aryl group (C6-10aryl group is optionally condensed with C3-6cycloalkane), optionally substituted with substituent(s), X represents carbon atom or nitrogen atom. Other values of radicals are given in the invention formula.

EFFECT: obtaining compounds which can be used to prepare medication for treatment or prevention of such diseases as neuropathic pain, nociceptive pain, dysuria, disseminated sclerosis, etc.

19 cl, 47 tbl, 237 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I and formula IV wherein the radical values are such as specified in cl. 1 and 4 of the patent claim, as well as to their therapeutically acceptable salts. Besides, the invention refers to a composition for treating cancer on the basis of the compounds of formula I, to using the compounds of formula I for preparing the therapeutic agent for treating cancer, as well as to using it for treating cancer.

EFFECT: there are prepared and described the new compounds which inhibit anti-apoptotic Bcl-2 and Bcl-x protein activity.

17 cl, 481 ex

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