New cyclopenta[b]benzofuranyl derivatives and application thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopenta[b]benzofuranyl derivatives of formula wherein substitutes R1, R2, R3, R4, R5, R6 and R7 and n are specified in the patent clam. These compounds exhibit properties of NF-kB-activity and/or AP-1 inhibitor/modulator. Also, the inventive subject matter are methods for preparing intermediate compounds thereof, a pharmaceutical composition containing them, administration thereof for prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases caused by NF-kB- and/or AP-1-activity, and a method for prevention and/or treatment of said diseases.

EFFECT: preparation of new cyclopenta[b]benzofuranyl derivatives.

21 cl, 3 tbl, 151 ex

 

The present invention relates to new derivatives of cyclopent[b]-benzofuran, method of production thereof and to their use for the manufacture of drugs, primarily intended for the prevention and/or treatment of acute or chronic diseases, which are high in hepatocellular stress, local or systemic inflammatory processes or hyperproliferative.

Proposed in the invention compounds are representatives of a class of natural compounds, so-called Romagnolo/rotaglide that can be extracted from different plant species Aglaia. After first allocated named rotaglide derived degidrotsiklizatsiya (J. Chem. Soc., Chem. Commun. 1982, 1150; U.S. patent US 4539414), have been described several new derivatives, including those obtained by synthesis, and their biological activity (see, for example, J. Chem. Soc., Chem. Commun. 1991, 1137; Phytochemistry 32, 307 (1993); international application WO 96/04284; Tetrahedron 52, 6931 (1996); Phytochemistry 44, 1455 (1997); Phytochemistry 45, 1579 (1997); Tetrahedron 53, 17625 (1997); Japanese patent JP 11012279; international application WO 97/08161, WO 00/07579, WO 00/08007; German patent application DE 199 34 952-A1).

Previously described the effect of derivative cyclopentanedione as inhibitors of signaling, mediated by the so-called nuclear factor Kappa b (NF-κ is) [international application WO 00/08007 and WO 00/07579; J. Biol. Chem. 277, 44791 (2002)]. NF-κ is a transcription factor that plays a key role in inflammatory processes and in carcinogenesis. NF-κ in its active linking DNA form consists of dimeric combinations of different members of the NF-κB/Rel family of proteins [Ann. Rev. Immunol. 16, 225 (1998)]. In the basal unstimulated conditions as a result of inhibiting binding protein (I-κ) NF-κ is inactive cytoplasmic form. After stimulation, a rapid fosforilirovanii inhibitory protein I-κ-kinases, and therefore, the proteolytic degradation of I-κ. Because of this NF-κ released inherent in active form and it becomes possible transposase in the cell nucleus. NF-κ as a transcription factor activates or modulates expressio different genes, especially those whose products are responsible for the inflammatory response and the growth and differentiation of cells [J. Biol. Chem. 274, 27339 (1999)].

Unexpectedly, it was found that proposed in the invention compounds also inhibit the activity of the complex of the second transcription factor, a so-called activator protein-1 (AP-1). AR-1 is localized in the cell nucleus transcription factor consisting of dimers of proteins Jun-and Fos-, Maf and ATF families. The activity of AP-1 is induced by a number of the most different stimuli, including cytokines, the tank is realname and viral infections, and various forms of physical or chemical stress. Activating signals, on the one hand, promote intensive education of the individual components of the transcription factor, and on the other hand, due to stimulation of specific kinases such as Jun kinase, responsible for the phosphorylation of specific amino acids. Both processes lead to increased interaction of AP-1 with its target genes and, thus, contribute to their expression or modulation. To target genes along with genes whose products are involved in inflammatory processes, are also genes that control cell division or acting as regulators of their death or survival [Curr. Opin. Cell Biol. 9, 240 (1997); Nature Cell Biol. 4, E131 (2002)].

On the one hand, Pro-inflammatory cytokines, such as interleukin-1 (IL-1) or tumor necrosis factor (TNF), and are oxoalkyl stress effective activators is mediated NF-κ and AP-1 signal. On the other hand, activation of NF-κ and/or AP-1 promotes the formation of new cytokines (such as IL-1 and TNF), chemokines (such as interleukin-8 (IL-8) and monocyte of chemoattractant protein-1" (MCP-1)and various enzymes (such as cyclooxygenase-2, or nitric oxide synthase-2" (NOS-2, iNOS)). The main function of the newly formed peptides/proteins or end products produced under the action again, SF is armirovannykh enzymes, is the Deposit and activation of inflammatory cells. Therefore, NF-κ and AP-1 are Central factors in the induction and provision of inflammatory processes.

The pathogenesis or pathological physiology of many diseases characterized by acute, excessive or chronic inflammatory reactions, which can be locally limited to cloth or can have a systemic nature. Such diseases are different local or systemic elevation of cytokines and/or chemokines, as well as the presence of an increased number of various inflammatory cells, such as macrophages, polymorphonuclear leukocytes, T-lymphocytes or b-cells. Such diseases include chronic inflammatory and autoimmune diseases (such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, lupus, asthma, diabetes), cardiovascular diseases (such as coronary heart disease, myocardial infarction, atherosclerosis, restenosis, thrombosis), fibrotic diseases of the liver and other organs, cerebral vascular disease (e.g., such as brain hemorrhage, traumatic brain injury, spinal cord injury) and chronic neurodegenerative diseases (such as Alzheimer's disease the ü Parkinson, chorea Huntington's, amyotrophic lateral sclerosis, peripheral neuropathy and chronic pain). The reasons for incorrectly regulated or excessive formation of cytokines/chemokines associated with the occurrence or the consequences of radiation injuries, graft rejection, sepsis and septic shock, and bacterial meningitis. Thus, the above-described inhibition or modulation of the transcriptional activity of NF-κ and/or AP-1 proposed in the invention compounds could be a new promising therapeutic principles for these diseases.

Along with a Central function in inflammatory processes NF-κ and AP-1 play an important role in the regulation of cell division, growth and differentiation. The formation and growth of tumors activated cell path signals, which under normal conditions govern cell growth, differentiation and other biological processes. Lots of inducing tumor substances and factors (such as epidermal growth factor (EGF), phorbol esters, UV radiation) cause the activation of NF-κ and/or AP-1, and the number of managed via NF-κ and/or AP-1 genes are oncogenes (such as c-myc, c-rel, stimulating the growth of melanoma activity (MGSA)). Therefore, due to the inhibitory/modulating effect on heposredstvennuyu NF-the b and/or AP-1 signaling application proposed in the invention compounds could become a new therapeutic principle in the treatment hyperproliferative diseases, such as solid tumors (such as breast cancer, lung cancer, brain tumors and nervous system, skin cancer, liver cancer, cancer of reproductive organs, tumors of the digestive tract, bladder cancer, tumors of the urinary system tract, tumors of various endocrine glands, tumors of the eye), lymphoma (such as Hodgkin's disease (Hodgkin's disease), lymphomas of the Central nervous system), sarcoma (e.g., such as osteosarcoma, lymphosarcoma and leukemia (such as acute myeloid leukemia, lymphoblastic leukemia, myelogenous leukemia).

In addition, NF-κ and AP-1 play an important role in replication lymphotropic viruses such as HIV, the virus T-cell leukemia human and the virus of Epstein-Barr. Activation required for replication of viral genes can be caused mediated virus by activating NF-κ and/or AP-1 in the host cell. Along with great value for breeding lymphotropic viruses also assumes a positive impact NF-κB/AP-1 on gene expression of the virus cytomegalia (CMV)and adenovirus. Therefore, inhibitors/modulators of the activity of NF-κ and/or AP-1 could exert antiviral effects.

The object of the present invention are compounds of General formula (I)

,

in which

R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms, cycloalkenyl with 3-8 carbon atoms, N-cycloalkyl-N-alkyl-amino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-6 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, and

R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms, cycloalkenyl with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-6 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dial the laminitis with 1-4 carbon atoms,

however, R1and R2at the same time do not represent a hydrogen

R3means hydroxy or amino and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O or >C=N-OH,

R5means mono - or dialkylaminoalkyl with 1-6 carbon atoms,

n means 0, 1, 2 or 3,

R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, aryl with 6-10 carbon atoms, 5-10-membered heteroaryl or a group of the formula-NR9R10,

moreover, the aryl and heteroaryl respectively, in turn, can be singly or doubly substituted the same or different halogen, cyano, alkylsulfonyl with 1-4 carbon atoms or a group of the formula-NR9R10in which

R9and R10independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

and

R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in anthopology relative to R6and means hydrogen, halogen, alkyl with 1-6 carbon atoms is kind, alkoxy with 1-6 carbon atoms or a group of the formula-NR11R12in which

R11and R12independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

Another object of the present invention are compounds of General formula (I), in which

R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms, cycloalkenyl with 3-8 carbon atoms, N-cycloalkyl-N-alkyl-amino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-6 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, and

R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 ATO the AMI carbon or halogen,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms, cycloalkenyl with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-6 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms,

however, R1and R2at the same time do not represent a hydrogen

R3means hydroxy or amino and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O or >C=N-HE,

R5means hydrogen,

n means 0, 1, 2 or 3,

R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means aryl with 6-10 carbon atoms, 5-10-membered heteroaryl or a group of the formula-NR9R10,

rich aryl and heteroaryl respectively, in turn, can be singly or doubly substituted the same or different halogen, cyano, alkylsulfonyl with 1 to 4 atoms of carbon is a or a group of the formula-NR 9R10in which

R9and R10independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

and

R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in anthopology relative to R6and means hydrogen, halogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or a group of the formula-NR11RR12in which

R11and R12independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

Another object of the present invention are compounds of General formula (I), in which

R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms, cycloalkyl the Ino with 3-8 carbon atoms, N-cycloalkyl-N-alkyl-amino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-6 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, and

R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms, cycloalkenyl with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-6 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 atoms

however, R1and R2at the same time do not represent a hydrogen

R3means amino and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=N-OH,

R5means in the location,

n means 0, 1, 2 or 3,

R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-6 carbon atoms or alkoxy with 1-6 carbon atoms,

and

R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or a group of the formula-NR11R12in which

R11and R12independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

Another object of the present invention are compounds of General formula (I), in which

R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms, cycloalkenyl with 3-8 atoms of carbon is a, N-cycloalkyl-N-alkyl-amino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-6 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1 to 4 atoms, and

R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms, cycloalkenyl with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-6 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms,

and R1or R2means hydrogen, but both are not simultaneously denote hydrogen,

R3means hydroxy and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form the group of f is rmula > C=O,

R5means hydrogen,

n means 0, 1, 2 or 3,

R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-6 carbon atoms or alkoxy with 1-6 carbon atoms,

and

R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or a group of the formula-NR11RR12in which

R11and R12independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

Another object of the present invention are compounds of General formula (I), in which

R1means ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 substituted alkoxy with 1-6 carbon atoms, amino, mono - or dialkyl-amino with 1 to 6 carbon atoms, cycloalkenyl with 3-8 atoms in which laroda, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-6 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, and

R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,

R2means ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms, cycloalkenyl with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-6 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms,

R3means hydroxy and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O,

R5means hydrogen,

n means 0, 1, 2 or 3,

R6is meta - and para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-6 carbon atoms or alkoxy with 1-6 carbon atoms,

and

R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or a group of the formula-NR11R12in which

R11and R12independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

Proposed in the invention compounds are the compounds of formula (I) and their salts, solvate and solvate salts described by formula (I) compounds of the following formula and their salts, solvate and solvate salts, and also described by formula (I) compounds of the following examples of carrying out the invention and their salts, solvate, and a solvate of salt, if under the following compounds described by formula (I), no longer refers to the salt, solvate and solvate salts.

Proposed in the invention compounds depending on their structure the tours can be in the form of stereoisomers (enantiomers, of diastereomers). In this regard, the invention relates to the enantiomers or diastereomers and corresponding mixtures. Individual stereoisomers can be isolated from such mixtures of enantiomers and/or diastereomers known methods.

In that case, if proposed in the invention compounds can be in the form of the tautomers, the present invention relates to compounds all tautomeric forms.

According to the present invention, the preferred salts are physiologically not cause fear salts proposed in the invention compounds. It is also the salts, which are not suitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the proposed in the invention compounds.

Physiologically acceptable fears salts proposed in the invention compounds are additive salts of mineral acids, carboxylic acids and sulphonic acids, for example salts podorozhaniya, Ogorodnaya, sulfuric acid, phosphoric acid, methanesulfonate, econsultancy, toluenesulfonic acid, benzosulfimide, naphthalenedisulfonate, acetic acid, triperoxonane acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and b is Noynoy acid.

Physiologically acceptable fears salts proposed in the invention compounds are salts of conventional bases, preferably, for example, such as alkali metal salts (e.g. sodium and potassium salts), salts of alkaline earth metals (e.g. calcium salts and magnesium), and ammonium salts, derived from ammonia or organic amines with 1 to 16 carbon atoms, preferably, for example, such as ethylamine, diethylamine, triethylamine, ethyldiethanolamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, Ethylenediamine and N-methylpiperidin.

According to the present invention under a solvate refers to such forms proposed in the invention compounds, which are in solid or liquid state due to coordination with solvent molecules form a complex. A special form of the solvate is a hydrate, in which there is coordination proposed in the invention compounds with water. According to the present invention, the preferred solvate is a hydrate.

In addition, according to the present invention is proposed in the invention compounds are prodrugs. The term "prodrug" refers to compounds which may themselves be biologically active or inactive, but the time spent in the body turn into offered in the invention compounds (for example, as a result of exchange of the substance or hydrolysis).

According to the present invention is proposed in the invention compounds in the absence of special instructions have the following placeholders.

According to the present invention under an alkyl with 1-6 carbon atoms and an alkyl with 1-4 carbon atoms refers to an unbranched or branched alkyl residue with 1-6 carbon atoms, respectively, with 1-4 carbon atoms. Preferred is unbranched or branched alkyl residue with 1 to 4 carbon atoms. Examples of preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethyl-propyl, n-pentyl and n-hexyl.

According to the present invention under cycloalkyl with 3-8 carbon atoms and cycloalkyl with 3-6 carbon atoms refers to monocyclic or if necessary disilicate cycloalkyl group with 3-8, respectively, with 3-6 carbon atoms. It is preferable monocyclic cycloalkenyl balance with 3-6 carbon atoms. Examples of preferred cycloalkyl residues are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

According to the present invention under the aryl with 6-10 carbon atoms refers to an aromatic residue, preferably from 6-10 carbon atoms. Predpochtitel the governmental aryl residues are phenyl and naphthyl.

According to the present invention under alkoxy with 1-6 carbon atoms, alkoxy with 1-4 carbon atoms refers to an unbranched or branched CNS residue with 1-6 carbon atoms, respectively, with 1-4 carbon atoms. Preferred is an unbranched or branched loxely residue with 1-4 carbon atoms. Examples of preferred amoxiline residues are methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.

According to the present invention under monoalkylamines with 1-6 carbon atoms, monoalkylamines with 1-4 carbon atoms refers to the amino group with an unbranched or branched alkyl substituents which contain 1-6, respectively 1-4 carbon atoms. Preferred is an unbranched or branched, monoalkylamines with 1-4 carbon atoms. Examples of preferred monoalkylamines are methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

According to the present invention under dialkylamino with 1-6 carbon atoms, dialkylamino with 1-4 carbon atoms refers to the amino with two identical or different unbranched or branched alkyl substituents, each of which contains 1-6, respectively 1-4 carbon atoms. Preferred are unbranched or razvetvlenno the e dialkylamino respectively with 1-4 carbon atoms. Examples of preferred dialkylamino are N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamine and N-n-hexyl-N-methylamino.

According to the present invention under mono - or dialkylaminoalkyl with 1-6 carbon atoms, respectively, mono - or dialkylaminoalkyl with 1-4 carbon atoms refers to the amino group that is attached via a carbonyl group and has one unbranched or branched, or two identical or different unbranched or branched alkyl substituent, each of which contains 1-6, respectively 1-4 carbon atoms. Examples of such preferred residues are methylamino-carbonyl, ethylaminomethyl, isopropylaminocarbonyl, tert-butylaminoethyl, N,N-dimethylaminoethyl, N,N-diethylaminomethyl, N-ethyl-N-methylaminomethyl and N-tert-butyl-N-methylaminomethyl.

According to the present invention under cyclooctylamino with 3-8 carbon atoms, cycloalkenyl with 3-6 carbon atoms refers to the amino group with a monocyclic or, when necessary, dicklicker cycloalkenyl Deputy, which contains 3-8, respectively 3-6 ring carbon atom. It is preferable monocyclic cycloalkenyl the mandated the tel with 3-6 ring carbon atoms. Examples of preferred cyclooctylamino are cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine.

According to the present invention under alkylsulfonyl with 1-4 carbon atoms refers to an unbranched or branched alkylsulfonyl residue with 1-4 carbon atoms. Preferred is an unbranched or branched alkylsulfonyl residue with 1 to 3 carbon atoms. Examples of preferred alkylsulfonyl of Titkov are methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl and tert-butylsulfonyl.

According to the present invention under a 4-7-membered heterocycle refers to a saturated or partially unsaturated heterocycle with the number of ring atoms, from 4 to 7, which contains a ring nitrogen atom through which is attached a heterocycle, and may contain another heteroatom selected from the series comprising nitrogen (N), oxygen (O), sulfur (S), SO or SO2. Preferred is a saturated 4-7-membered heterocycle attached via a nitrogen atom, which can contain another heteroatom selected from the series comprising nitrogen (N), oxygen (O) or sulfur (S). Examples of preferred heterocycles are azetidinol, pyrrolidinyl, pyrrolyl, piperidinyl, piperazinil morpholinyl, thiomorpholine, azepine and 1,4-diazepines.

According to the present invention under 5-10-membered heteroaryl refers to monocyclic or if necessary disilicate aromatic heterocycle (heteroaromatic residue), which contains up to four identical or different heteroatoms selected from the series comprising nitrogen (N), oxygen (O) and/or sulfur (S), and which is attached via a ring carbon atom or optionally via a ring nitrogen atom heteroaromatic residue. Relevant examples are furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiazol, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazoles, chinoline, ethenolysis, naphthyridine, hintline, honokalani. Preferred are monocyclic 5 - or 6-membered heteroaryl residue, containing up to three heteroatoms selected from the series comprising nitrogen (N), oxygen (O) and/or sulfur (S), such as furyl, thienyl, thiazolyl, oxazolyl, isothiazolin, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl.

According to us oedema invention under the halogen is meant fluorine, chlorine, bromine and iodine. Preferred is fluorine, chlorine or bromine.

If the remnants of the proposed invention compounds are substituted, in the absence of specific instructions, replacing them can be single or multiple. In accordance with the present invention when multiple substitution of the substituted residues are not independent from each other values. Preferred is the substitution of residues of one, two or three identical or different substituents. Even more preferred is the substitution of residues of one Deputy.

According to the present invention, preferred are the compounds of formula (I), in which

R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, cycloalkenyl with 3-6 carbon atoms, N-cycloalkyl-N-alkyl-amino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-4 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, and

R8means a 5-or 6-membered heteroaryl, which may be substituted by alkyl with 1-4 carbon atoms or halogen,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, cycloalkenyl with 3-6 carbon atoms. N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-6-membered heterocycle,

moreover, mono - and dialkylamino with 1-4 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms,

however, R1and R2at the same time do not represent a hydrogen

R3means hydroxy or amino, and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O or >C=N-HE,

R5means mono - or dialkylaminoalkyl with 1-4 carbon atoms,

n means 0, 1, 2 or 3,

R6is meta - or paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, aryl with 6-10 carbon atoms, 5-6-membered heteroaryl or a group of the formula-NR9R10,

moreover, the aryl and heteroaryl respectively, in turn, can be singly or doubly substituted the same or different halogen, cyano, alkylsulfonyl with 1-4 carbon atoms or a group of the formula - NR9R10in which

R9and R10independently of one another denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

and

R7is meta - or paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and in anthopology relative to R6and means hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or a group of the formula NR11R12in which

R11and R12independently of one another denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

In addition, according to the present invention, preferred are the compounds of formula (I), in which

R1means hydrogen, benzyloxy is, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, cycloalkenyl with 3-6 carbon atoms, N-cycloalkyl-N-alkyl-amino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-4 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, and

R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, cycloalkenyl with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-4 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, and

the being is m R 1or R2at the same time do not represent a hydrogen

R3means hydroxy or amino, and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O or >C=N-HE,

R5means hydrogen,

n means 0, 1, 2 or 3,

R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means aryl with 6-10 carbon atoms, 5-6-membered heteroaryl or a group of the formula-NR9R10,

moreover, the aryl and heteroaryl, in turn, can be singly or doubly substituted the same or different halogen, cyano, alkylsulfonyl with 1-4 carbon atoms or a group of the formula-NR9R10in which

R9and R10independently of one another denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

and

R7is meta - or paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and in anthopology relative to R6and means hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or a group of the formula-NR11R12in which

R11and R12regardless of others is g from each other denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

In addition, according to the present invention, preferred are the compounds of formula (I), in which

R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, cycloalkenyl with 3-6 carbon atoms, N-cycloalkyl-N-alkyl-amino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-4 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms,

R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position the NII 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, cycloalkenyl with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-4 carbon atoms in the alkyl in its turn can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms,

however, R1and R2at the same time do not represent a hydrogen

R3means amino and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=N-HE,

R5means hydrogen,

n means 0, 1, 2 or 3,

R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms,

and

R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or a group of the formula-NR11R12in which

R11and R12independently of one another denote hydrogen, alkyl with 1-4 ATO the AMI carbon phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

In addition, according to the present invention, preferred are the compounds of formula (I), in which

R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, cycloalkenyl with 3-6 carbon atoms, N-cycloalkyl-N-alkyl-amino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-4 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, and

R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be zames the us alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, cycloalkenyl with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1 to 4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-4 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms,

and R1or R2means hydrogen, but both are not simultaneously denote hydrogen,

R3means hydroxy,

and

R4means hydrogen, or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O,

R5means hydrogen,

n means 0, 1, 2 or 3,

R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms,

and

R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or a group of the formula-NR11R12in which

R11and R12independently from each other OSN is given hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

In addition, according to the present invention, preferred are the compounds of formula (I), in which

R1means ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 substituted alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, cycloalkenyl with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-4 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms, and

R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,

R2means ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 is substituted by alkoxy with 1 to 4 atoms in the of Lerida, amino, mono - or dialkylamino with 1-4 carbon atoms, cycloalkenyl with 3-6 carbon atoms, N-cycloalkyl-N-alkyl-amino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,

moreover, mono - and dialkylamino with 1-4 carbon atoms, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms,

R3means hydroxy,

and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O,

R5means hydrogen,

n means 0, 1, 2 or 3,

R6is meta - or paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms,

and

R7is meta - or paraprotein, relative to the point of attachment of the phenyl ring to the tricycle, and in anthopology relative to R6and means hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or a group of the formula-NR11R12in which

R11and R12independently of one another denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl or together with the atom is the monk, to which they are attached, form a 4-7-membered heterocycle,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

According to the present invention is especially preferred are the compounds of formula (I), in which

R1and R2independently of one another denote hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 3 is substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclo-propyl-N-methylamino, azetidine or pyrrolidine,

however, R1and R2at the same time do not represent a hydrogen

R3means hydroxy or amino,

R4means hydrogen,

R5means methylaminomethyl or dimethylaminoethyl,

n means 0 or 1,

R6is paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and means fluorine, chlorine, bromine, methyl, ethyl, methoxy or ethoxy,

and

R7means hydrogen,

and also their salts, solvate or solvate of salt.

According to the present invention is especially preferred are also the compounds of formula (I), in which

R1means hydrogen, staxi, the-propoxy or a group of the formula R 8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine, and

R8means pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which respectively may be substituted stands, ethyl, fluorine or chlorine,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine,

however, R1and R2at the same time do not represent a hydrogen

R3means hydroxy or amino,

R4means hydrogen,

R5means hydrogen,

n means 0 or 1,

R6is meta - or paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and means phenyl, thienyl, indolyl, honokalani or a group of the formula-NR9R10,

and phenyl, thienyl and indolyl, respectively, in turn, can be singly or doubly substituted the same or different fluorine, chlorine, bromine, cyano or amino, and

R9and R10regardless of the Rog from each other denote hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino,

and

R7means hydrogen,

and also their salts, solvate or solvate of salt.

According to the present invention is especially preferred are also the compounds of formula (I), in which

R1means hydrogen, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine, and

R8means pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which respectively may be substituted stands, ethyl, fluorine or chlorine,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine,

however, R1and R2at the same time do not represent a hydrogen

R3means amino,

R4means hydrogen,

R5means hydrogen,

n means 0 or 1,

R6is meth is - or paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and means fluorine, chlorine, bromine, methyl, ethyl, methoxy or ethoxy,

and

R7is meta - or paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and in anthopology relative to R6and means hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy or a group of the formula-NR11R12in which

R11and R12independently of one another denote hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino or piperidino,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

According to the present invention is especially preferred are also the compounds of formula (I), in which

R1means hydrogen, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine, and

R8means pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which respectively may be substituted stands, ethyl, fluorine is m or chlorine,

R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine,

and R1or R2mean hydrogen, but both are not simultaneously denote hydrogen,

R3means hydroxy and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O,

R5means hydrogen,

n means 0 or 1,

R6is meta - or paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and means fluorine, chlorine, bromine, methyl, ethyl, methoxy or ethoxy,

and

R7is meta - or paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and in anthopology relative to R6and means hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy or a group of the formula-NR11R12in which

R11and R12independently of one another denote hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino or piperidino,

or

R6and R7owls is local with a phenyl ring, to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

According to the present invention is especially preferred are also the compounds of formula (I), in which

R1means ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 3 is substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine, and

R8means pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which respectively may be substituted stands, ethyl, fluorine or chlorine,

R2means ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 3 is substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-temporaril-N-methylamino, azetidine or pyrrolidine,

R3means hydroxy and

R4means hydrogen,

or

R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O,

R5means hydrogen,

n means 0 or 1,

R6is meta - or paraprotein relative to the point of attachment F. nalnogo ring to the tricycle, and means fluorine, chlorine, bromine, methyl, ethyl, methoxy or ethoxy,

and

R7is meta - or paraprotein relative to the point of attachment of the phenyl ring to the tricycle, and in anthopology relative to R6and means hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy or a group of the formula-NR11R12in which

R11and R12independently of one another denote hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino or piperidino,

or

R6and R7together with the phenyl ring to which they are attached, form a group of the formula

,

and also their salts, solvate or solvate of salt.

The respective combinations or preferred combinations of the above individual residues can be replaced with any other combinations of the above individual residues.

Especially preferred are combinations of two or more of the above preferred options residues.

Proposed in the invention the compounds of formula (I)in which R5means hydrogen, in principle, can be obtained as described in international application WO 00/08007 methods. Contents of application WO 00/08007, especially pages 14-26 its description should be considered as the bar is dstvennogo integral part of the present description. However, the individual stages described in WO 00/08007 synthesis of compounds of formula (I) depending on the specific values of the substituents, first of all, R1and R2in some cases, can be implemented only with extremely low yields. Thus, another object of the present invention is a new method of obtaining the proposed in the invention compounds of formula (I)in which R5means hydrogen, characterized in that

[And] the compounds of formula (II)

,

in which R1and R2respectively, such as described above

interact in an inert solvent in the presence of a base with the compound of the formula (III)

,

in which R6and R7respectively, such as described above

X1means suitable removable group, such as halogen, mesilate, toilet or triflate (trevormaldonado group), and

T1means alkyl with 1-4 carbon atoms,

with the formation of compounds of the formula (IV)

in which R1, R2, R6, R7and T1respectively, such as described above

which by basic or acid hydrolysis transferred to the carboxylic acid of formula (V)

,

in which R1, R2 , R6and R7respectively, such as described above

which after activation by chloride of phosphoryla cyclist in the presence of Lewis acid in the compounds of formula (VI)

in which R1, R2, R6and R7respectively, such as described above

or

[In] the compounds of formula (VII)

,

in which R1and R2respectively, such as described above

first, conventional methods translate into bromide finally formula (VIII)

,

in which R1and R2respectively, such as described above

which in the presence of a base cyclist in the compounds of formula (IX)

,

in which R1and R2respectively, such as described above

which the inert solvent is subjected to bromirovanii, leading to the formation of compounds of formula (X)

,

in which R1and R2respectively, such as described above

which conventional methods are turned into simple killenaule esters of the formula (XI)

,

in which R1and R2respectively, such as described above, and

T2T3and T4the same or different and respectively mean alkyl with 1-4 atom is mi carbon or phenyl,

which in an inert solvent in the presence of a suitable palladium catalyst and a base interact with the compound of the formula (XII)

,

in which R6and R7respectively, such as described above, and

Z denotes hydrogen or methyl, or both Z groups together form bridges CH2CH2- or(CH3)2- (CH3)2,

with the formation of compounds of formula (XIII)

,

in which R1, R2, R6, R7T2T3and T4respectively, such as described above

from which conventional methods otscheplaut silyl group, obtaining the compounds of formula (VI)

then the corresponding final compounds of formula (VI) described in the international application WO 00/08007 method in an inert solvent in the presence of a base with cinnamic aldehyde of formula (XIV)

,

in which n as mentioned above,

turn in the compounds of formula (XV)

in which R1, R2, R6, R7and n, respectively, such as described above

which is subjected to further transformation as described in international application WO 00/08007 reaction sequence,

and the compounds of formula (I) when you want the tee with the appropriate (i) solvents and/or (ii) bases or acids turn in their solvate, salt and/or solvate salts.

Stage (VII)→(IX) can also implement a three-tier addoperation method, which is that of the compounds (VII) with conventional methods get simple killenaule esters of the formula (XVI)

,

in which R1and R2respectively, such as described above

bromination of which N-bromosuccinimide and subsequent cyclization in the presence of sodium hydroxide solution lead to the formation of compounds (IX).

Compounds of formula (II), (III), (VII), (XII) and (XIV) are known from the literature, commercially available products or can be synthesized by known literature methods.

Inert solvents suitable for the implementation of stage (II)+(III)→(IV)are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol or dimethyl ether of diethylene glycol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, 2-butanone, dimethylformamide, dimethyl sulfoxide, pyridine or acetonitrile. In addition, you can use a mixture of these restoreselection solvent is 2-butanone, diethyl ether, dioxane, tetrahydrofuran, dichloromethane, toluene or benzene.

Suitable bases for the implementation of stage (II)+(III)→(IV) are customary inorganic or organic bases. To them preferably include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide or potassium hydroxide, carbonates or bicarbonates of alkali or alkaline earth metals such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate, hydrides of alkali metals, such as sodium hydride, amides such as sodium amide, bis(trimethylsilyl)amide lithium or diisopropylamide lithium, or organic amines, such as pyridine, triethylamine, ethyldiethanolamine, N-methylmorpholine or N-methylpiperidine. Especially preferred are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium hydride.

Stage (II)+(III)→(IV) is in General carried out in the temperature range from +20 to +160°C, preferably from +60 to +100°C. This stage can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In General it is carried out at normal pressure.

Inert solvents suitable for the implementation of stage (IV)→(V)are, for example, water, Speer is s, for example, such as methanol, ethanol, n-propanol, isopropanol or n-butanol, hydrocarbons, such as benzene, or other solvents, such as acetone, dimethylformamide, dimethylsulfoxide or acetonitrile. In addition, it is possible to use mixtures of these solvents. Preferred solvents are methanol, ethanol, n-propanol and/or water. Suitable bases for the implementation of stage (IV)→(V) are customary inorganic bases. To them preferably include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide or potassium hydroxide, carbonates of alkaline or alkaline earth metals such as lithium carbonate, sodium carbonate, potassium carbonate or calcium carbonate, or alkali metal alcoholate, such as methanolate sodium, methanolate potassium, ethanolate sodium, ethanolate or potassium tert-butyl potassium. Especially preferred bases are sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

Suitable acids for the implementation of stage (IV)→(V) in the General case are sulfuric acid, Bogorodchany/hydrochloric acid, vodorodnoe/Hydrobromic acid, phosphoric acid, acetic acid, triperoxonane acid, toluensulfonate, methanesulfonate or triftoratsetata or mixtures thereof, when the mu is the necessity with the addition of water. Preferred acids are Bogorodchany or triperoxonane acid in the case of complex tert-butyl ester and hydrochloric or sulphuric acid in the case of methyl esters.

Stage (IV)→(V) is in General carried out in the temperature range from 0 to +100°C, preferably from +40 to +80°C. This stage can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In General it is carried out at normal pressure.

Stage (V)→(VI) is preferably carried out in the absence of solvent. Lewis acids suitable for the implementation of this stage are the usual inorganic Lewis acid, such as trichloride aluminum, trichloride iron, boron TRIFLUORIDE, trichloride boron, tribromide boron, titanium tetrachloride, trichloride titanium, tin dichloride, tin tetrachloride or zinc dichloride. The preferred Lewis acid is zinc dichloride.

Stage (V)→(VI) is in General carried out in the temperature range from 0 to +100°C, preferably from 0 to +40°C. This stage can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In General it is carried out at normal pressure.

Inert solvents suitable for the implementation stages (VII)→(VIII) and (IX)→(X)are, for example, halogenated carbohydrate is childbirth, such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol or dimethyl stir diethylene glycol, hydrocarbons such as hexane or cyclohexane, or other solvents such as ethyl acetate, dimethylformamide or dimethylsulfoxide. In addition, it is possible to use mixtures of these solvents. Preferred solvents are diethyl ether, dioxane, tetrahydrofuran, ethyl acetate, trichlormethane and/or carbon tetrachloride.

Suitable romirowsky agents for the implementation stages (VII)→(VIII) and (IX)→(X) are customary inorganic or organic reagents. To them preferably include bromine, N-bromosuccinimide, copper dibromide, hydrotribromide pyridine, tribromide of dimethylbenzylamine or tribromide of phenyltrimethylammonium. Especially preferred romirowsky agents are bromine and copper dibromide.

Stage (VII)→(VIII) and (IX)→(X) is in General carried out in the temperature range from -20 to +150°C, preferably from 0 to 80°C. This stage can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In General it is carried out at normal pressure.

Inert solvents suitable the La implementation stage (VIII)→(IX), are, for example, water, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol or dimethyl ether of diethylene glycol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfoxide, pyridine or acetonitrile. In addition, it is possible to use mixtures of these solvents. Preferred solvents are methanol, ethanol, water and/or tetrahydrofuran.

Suitable bases for the implementation stage (VIII)→(IX) are customary inorganic or organic bases. To them preferably include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide or potassium hydroxide, carbonates or bicarbonates of alkali or alkaline earth metals such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate, alkali metal alcoholate, such as methanolate sodium, methanolate potassium, ethanolate sodium, ethanol is t or potassium tert-butyl potassium, the acetates of alkali metals such as sodium acetate or potassium acetate, hydrides of alkali metals, such as sodium hydride, amides such as sodium amide, bis(trimethylsilyl)amide lithium or diisopropylamide lithium, or organic amines, such as pyridine, triethylamine, ethyldiethanolamine, N-methylmorpholine or N-methylpiperidine. Especially preferred bases are sodium hydroxide, potassium hydroxide or sodium acetate.

Stage (VIII)→(IX) in General carried out in the temperature range from 0 to +100°C, preferably from +20 to +80°C. This stage can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In General it is carried out at normal pressure.

Inert solvents suitable for the implementation stage (X)→(XI)are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol or dimethyl ether of diethylene glycol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfoxide, pyridine or acetonitrile. In addition, you can use smese the specified solvents. The preferred solvent is toluene, hexane, diethyl ether or tetrahydrofuran.

Suitable bases for the implementation stage (X)→(XI) are customary inorganic or organic bases. To them preferably include hydrides of alkali metals, such as sodium hydride, amides such as sodium amide, bis(trimethylsilyl)amide lithium or diisopropylamide lithium, or organic amines, such as pyridine, triethylamine, ethyldiethanolamine, N-methylmorpholine or N-methylpiperidine. Especially preferred bases are diisopropylamide lithium, triethylamine or ethyldiethanolamine.

Stage (X)→(XI) in General carried out in the temperature range from -20 to +50°C, preferably from 0 to +30°C. This stage can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In General it is carried out at normal pressure.

Inert solvents suitable for the implementation stage (XI)+(XII)→(XIII)are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol or dimethyl ether of diethylene glycol, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, water, dimethylformamide, dimethylsulfoxide, pyridine or acetonitrile. In addition, it is possible to use mixtures of these solvents. The preferred solvent is toluene, tetrahydrofuran, dioxane or dimethylformamide.

Suitable bases for the implementation stage (XI)+(XII)→(XIII) are customary inorganic or organic bases. To them preferably include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide or potassium hydroxide, carbonates of alkali, alkaline earth or heavy metals, such as silver carbonate, carbonate, thallium, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate or calcium carbonate, hydrogen carbonates of alkaline or alkaline earth metals, such as sodium bicarbonate or potassium bicarbonate, alkali metal alcoholate, such as methanolate sodium, methanolate potassium, ethanolate sodium, ethanolate potassium, tert-butyl lithium, tert-butyl sodium or tert-butyl potassium hydrides alkali metals such as sodium hydride, amides such as sodium amide, bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide, sodium or disap pyramid lithium or organic amines, such as pyridine, triethylamine, ethyldiethanolamine, 1,5-diazabicyclo[5.4.0]-undec-5-ene, N-methylmorpholine or N-methylpiperidine. Especially preferred bases are cesium carbonate, sodium carbonate, sodium hydride, tert-butyl potassium, diisopropylamide lithium, 1,5-diazabicyclo[5.4.0]-undec-5-ene, triethylamine or ethyldiethanolamine.

Suitable catalysts for the implementation stage (XI)+(XII)→(XIII) are generally used in Suzuki reactions of palladium catalysts. The preferred catalysts are, for example, such as dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)-palladium(0), palladium(II) acetate or chloride bis(diphenylphosphane-ferrocenyl)palladium(II). Suitable ligands of the catalysts preferably are normal reactions Suzuki ligands, such as triphenylphosphine, three(o-tolyl)phosphine, tributylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl, 1,1'-bis(diphenylphosphino)-ferrocene or 1,3-bis(diphenylphosphino)propane.

Stage (XI)+(XII)→(XIII) in General carried out in the temperature range from +20 to +200°C, preferably from +50 to +150°C. This stage can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In General it is carried out at normal pressure.

Inert solvents suitable for the westline stage (XIII)→(VI), are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol or dimethyl ether of diethylene glycol, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, such as benzene, toluene, xylene, hexane or cyclohexane, or other solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile or water. In addition, it is possible to use mixtures of these solvents. The preferred solvent is methanol, ethanol, water, tetrahydrofuran or dioxane.

Cleavage of the silyl group on stage (XIII)→(VI) can be performed by conventional methods using either base or acid. Suitable bases are preferably tetrabutylammonium-fluoride, pyridine or triethylamine, and a suitable acids are preferably hydrogen fluoride, Bogorodchany/hydrochloric acid, formic acid, acetic acid, triperoxonane acid or toluensulfonate.

Stage (XIII)→(VI) is in General carried out in the temperature range from -80 to +100°C, preferably from 0 to 80°C. This stage can be carried out at normal, elevated or mon the leaders introduce pressure (for example, from 0.5 to 5 bar). In General it is carried out at normal pressure.

Proposed in the invention the compounds of formula (I)in which R5means mono - or dialkylaminoalkyl with 1-6 carbon atoms, can be obtained by the method, according to which first the compounds of formula (XVII)

,

in which R1, R2, R6, R7and n, respectively, such as described above, in an inert solvent by means of methylcarbonate methoxamine [.Stiles, J. Amer. Chem. Soc. 81, 2598 (1959)] is transformed into carboxylic acids of the formula (XVIII)

,

in which R1, R2, R6, R7and n, respectively, such as described above

then in the presence of means of condensation and bases interact with the compound of the formula (XIX)

,

in which

R13means hydrogen or alkyl with 1-6 carbon atoms and

R14means alkyl with 1-6 carbon atoms,

with the formation of compounds of formula (XX)

in which R1, R2, R6, R7, R13, R14and n, respectively, such as described above

which are then optionally subjected to further transformation as described in international application WO 00/08007 reaction sequence.

Connection is by means of formula (XVII) can be obtained as described above, accordingly, in the application WO 00/08007 methods. The compounds of formula (XIX) are commercially available or known from the literature products.

Inert solvents suitable for the implementation stage (XVII)→(XVIII), are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol or dimethyl ether of diethylene glycol or other solvents, such as dimethylformamide, dimethylsulfoxide or acetonitrile. In addition, it is possible to use mixtures of these solvents. The preferred solvent is dimethylformamide.

Stage (XVII)→(XVIII) in General carried out in the temperature range from 0 to +200°C, preferably from +50 to +150°C. This stage can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In General it is carried out at normal pressure.

Inert solvents suitable for the implementation stage (XVIII)+(XIX)→(XX), are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, meth is l-tert-butyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol or dimethyl ether of diethylene glycol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, 2-butanone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, N is an organic or pyridine. In addition, it is possible to use mixtures of these solvents. Preferred solvents are dimethylformamide and tetrahydrofuran.

By means of condensation, suitable for the formation of amide on stage (XVIII)+(XIX)→(XX), are, for example, carbodiimide, such as N,N'-diethylcarbamoyl, N,N'-dipropylacetamide, N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride, N-cyclohexylcarbodiimide-N'-propelaccelerator or phosgene derivatives such as N,N'-carbonyldiimidazole or compounds 1,2-oxazole, such as 2-ethyl-5-phenyl-1,2-oxazol-3-sulfate or 2-tert-butyl-5-methylisoxazol perchlorate or acylaminoacyl, such as 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline or isobutylparaben, anhydride papapostolou acid, diethyl ether cyanophosphonate acid chloride bis(2-oxo-3-oxazolidinyl)phosphoryla, hexaflurophosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium, GE is superphosphate benzotriazol-1 yloxy-Tris(pyrrolidino)of phosphonium, hexaphosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea, tetrafluoroborate 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium or hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea, optionally in combination with other excipients, such as 1-hydroxybenzotriazole or N-hydroxysuccinimide and used as grounds carbonates of alkali metals, for example, carbonate or bicarbonate of sodium or potassium, or organic aminoazobenzene, such as triethylamine, N-methylmorpholine, N-methyl-piperidine, N,N-diisopropylethylamine, pyridine, 4-N,N-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]non-5-ene or 1,8-diazabicyclo-[5.4.0]undec-7-ene. The preferred means of condensation are hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium, hexaflurophosphate benzotriazol-1-yloxytris(pyrrolidino)phosphonium or hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea, respectively, in combination with triethylamine or N,N-diisopropylethylamine.

Stage (XVIII)+(XIX)→(XX) in General carried out in the temperature range from -20 to +100°C, preferably from 0 to +50°C. This stage can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In General it is carried out at normal pressure.

Offered from the reteni the compounds of formula (I), in which R1and R2accordingly indicate ethoxy or n-propoxy, which is in position 2, 3 respectively, substituted amino, mono - or dialkylamino with 1-6 carbon atoms, cycloalkenyl with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle, can be obtained also by a method in accordance with which the compounds of formula (XXI)

,

in which R3, R4, R5, R6, R7and n, respectively, such as described above

X2means suitable removable group, such as halogen, mesilate or toilet and

m represents 2 or 3,

in an inert solvent, optionally in the presence of an auxiliary base interact with the compound of the formula (XXII)

,

in which

R15denotes hydrogen, alkyl with 1-6 carbon atoms or cycloalkyl with 3-8 carbon atoms, and

R16means hydrogen or alkyl with 1-6 carbon atoms,

or

R15and R16together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,

with the formation of compounds of formula (XXIII)

,

in which R3, R4, R5, R6, R7, Rsup> 15, R16type, respectively, such as described above

which are then optionally subjected to further modification as described in international application WO 00/08007 reaction sequence.

The compounds of formula (XXI) can be obtained as described above, respectively, in the application WO 00/08007 methods. The compounds of formula (XXII) are commercially available or known from the literature products.

Inert solvents suitable for the implementation stage (XXI)+(XXII)→(XXIII)are, for example, ethers such as tetrahydrofuran, dioxane, dimethyl ether of ethylene glycol or dimethyl ether of diethylene glycol, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, such as toluene or xylene, or other solvents, such as acetone, dimethylformamide or dimethylsulfoxide. In addition, it is possible to use mixtures of these solvents. The preferred solvent is ethanol, dimethylformamide, dimethylsulfoxide or xylene.

Auxiliary bases suitable for the implementation stage (XXI)+(XXII)→(XXIII)are customary inorganic or organic bases. To them preferably include hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide, carbonate of the alkaline or alkaline earth metals, such as sodium carbonate or potassium carbonate, hydrides of alkali metals, such as sodium hydride, or organic amines, such as triethylamine or ethyldiethanolamine.

Stage (XXI)+(XXII)→(XXIII) in General carried out in the temperature range from +20 to +200°C, preferably from +70 to +150°C. This stage can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In General it is carried out at normal pressure.

Proposed in the invention compounds, if appropriate, you can also get synthetic conversion of functional groups of individual substituents in compounds of formula (I), which is obtained by the above methods. Such transformations of functional groups carried out are known from the literature methods, including, for example, alkylation, acylation, amination, the formation of ester, cleavage of ester, hydrogenation, oxidation and reduction.

Proposed in the invention compounds can be obtained in accordance with the following reaction schema.

[Alkyl means alkyl; X is halogen; a) potassium carbonate, 2-butanone, 80°C; (b) potassium carbonate, methanol/water, 65°C; (C) chloride fostoria, zinc chloride, 0°C → room temperature].

[d) 1. litigationrelated, trimethylsilane, tetrahydrofuran, -78°C → room temperature; 2. N-bromosuccinimide, 0°C → room temperature; N solution of caustic soda, room temperature; 1 or. the copper bromide(II), ethyl acetate/chloroform, 65°C; 2. sodium acetate, ethanol, 80°C; (e) bromine, dioxane/diethyl ether, -5°C→0°C; or copper bromide(II), ethyl acetate/chloroform, 65°C; (f) tert-butyldimethylsilyl-triftorbyenzola, triethylamine, diethyl ether, 0°C → room temperature; g) derivative phenylboric acid, sodium carbonate, tetrakis(triphenylphosphine)palladium(0), toluene/water, 95°C; (h) Bogorodchany in dioxane, room temperature; or triperoxonane acid, room temperature].

[m is 2 or 3, X is halogen; (i) ethanol, 70°C].

[(j) methoxyphenylethylamine, dimethylformamide, 100°C; (k) hexaphosphate benzotriazol-1-electropermeabilization, aminobutiramida-ethylamine, dimethylamine hydrochloride, tetrahydrofuran (THF, 0°C].

Proposed in the invention compounds have valuable pharmacological properties and can be used for the prevention and treatment of diseases of humans and animals. In addition, they are characterized by increased metabolic stability compared with the compounds described in international WO 00/08007.

Proposed in the invention compounds are effective inhibitors/modulators of the activity of NF-κ and/or AP-1 and as such is primarily suitable for the treatment of chronic inflammatory and autoimmune diseases (such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, lupus, asthma, diabetes), cardiovascular diseases (such as coronary heart disease, myocardial infarction, atherosclerosis, restenosis, thrombosis), fibrocycstic diseases of the liver and other organs, diseases of the blood vessels of the brain (such as bleeding in the brain, traumatic brain injury, spinal cord injury) and chronic neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, peripheral neuropathy and chronic pain). Along with this, they can be used for the prevention and/or treatment of radiation injuries, rejection of transplant, sepsis and septic shock, and bacterial meningitis.

In addition, the proposed invention in connection in connection with their inhibitory/modulatory effects mediated NF-κ and/or AP-1 signaling is suitable for treatment hyperproliferative diseases, such as solid op is Holi (for example, such as breast cancer, lung cancer, brain tumors and nervous system, skin cancer, liver cancer, cancer of reproductive organs, tumors of the digestive tract, bladder cancer, tumors of the urinary system tract, tumors of various endocrine glands, tumors of the eye), lymphoma (such as Hodgkin's disease (Hodgkin's disease), lymphomas of the Central nervous system), sarcoma (e.g., such as osteosarcoma, lymphosarcoma and leukemia (such as acute myeloid leukemia, lymphoblastic leukemia, myelogenous leukemia). In addition, the proposed in the invention compounds can be used for the prophylaxis and/or therapy of viral diseases, especially diseases caused by viruses HIV, T-cell human leukemia, Epstein-Barr, cytomegaly (CMV) and/or adenovirus.

Another object of the present invention is the application of the proposed invention compounds for the treatment and/or prophylaxis of diseases, especially of the aforementioned diseases.

Another object of the present invention is the application of the proposed invention compounds for the manufacture of a medicinal product intended for the treatment and/or prophylaxis of diseases, especially of the aforementioned diseases.

Another object of the present invention is a method cured the I and/or prevention of diseases, first of all these diseases, involving the application of an effective amount of at least one of the proposed invention compounds.

Proposed in the invention compounds can be used alone or optionally in combination with other active substances. Another object of the present invention are drugs, containing at least one proposed in the invention compound and at least one or more other active substances, intended primarily for the treatment and/or prophylaxis of the aforementioned diseases. Examples of suitable and preferred combinations of active substances are substances with cytostatic or cytotoxic activity, anti-inflammatory agents (e.g. corticosteroids, means non-steroidal anti-inflammatory therapy) and substances with neuroprotective effect.

Proposed in the invention compounds can have systemic and/or local action. To this end, you can apply them appropriately, for example orally, parenterally, pulmonale, nasal, sublingual, lingual, buccal, rectal, dermal, trandermal, konyunktivalny, optically or in the form of the implant, respectively, of the stent.

If the above methods, the application of the Oia, proposed in the invention compounds can take in the appropriate forms.

For oral administration suitable operating according to the prior art forms applications quickly and/or in a modified form releasing proposed in the invention compounds, which are contained in the application forms in the crystal, amalfitano and/or dissolved, such as tablets (uncoated or coated, for example, tablets with a coating resistant to gastric juice, with a slowly soluble or insoluble coatings, which regulate the release proposed in the invention compounds), rapidly dissociate in the mouth tablets or films/wafers, films/lyophilizate, capsules (for example, capsules of hard or soft gelatin), pills, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can occur without the stage of resorption (e.g., intravenously, intraarterially, intracardially, intraspinally or vnutriyazychno) or with the inclusion of stage resorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). Forms suitable for parenteral administration, in particular, are drugs for injection and infusion in the form of solutions, suspensions, emulsions, liofilizatow or article is rolnych powders.

As other forms applications can be used, for example, pharmaceutical forms for inhalation (in particular, powder inhalers, nebulizers), drops, solutions or sprays nasal, lingual, sublingual or buccal used tablets, films/wafers or capsules, suppositories, entered into the ears or eyes compounds, vaginal capsules, aqueous suspensions (lotions, agitated mixtures), lipophilic suspensions, ointments, creams, trandermal therapeutic systems (e.g. patches), milk, pastes, foams, powders, implants or stents.

Preferred is oral or parenteral administration, especially oral administration.

Proposed in the invention compounds can be converted in the above applications. A similar process can be implemented with known methods by mixing proposed in the invention compounds with inert, nontoxic, pharmaceutically suitable excipients. Such excipients include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium dodecyl sulphate, polychiorinated), binders (for example polyvinylpyrrolidone), synthetic and natural the polymers (for example, albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxides) and reformers of taste and/or smell.

Another object of the present invention are drugs that contain at least one proposed in the invention, the connection, usually together with one or more inert, nontoxic, pharmaceutically suitable excipients and their use for the above purposes.

In the General case, to achieve effective results, the preferred amount used parenteral proposed in the invention of the compound is from about 0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg of body weight. For oral use, the dosage is about 0.01 to 100 mg/kg, preferably from about 0.01 to 20 mg/kg and even more preferably from 0.1 to 10 mg/kg of body weight.

Despite this, in some cases, may require deviation from the above dosages, which is determined by the weight, method of application, individual attitude to the substance, the type of drug and the time of its application, respectively, the time interval between successive applications. For example, in some sluchajnoe to be sufficient application quantities smaller than the above minimum values, but in other cases it is necessary to apply more than the above upper limits. When using larger quantities, we can recommend their distribution on several applied during the day single dose.

The following examples of carrying out the invention serve to explain the invention. The examples do not limit the scope of the invention.

In the absence of specific instructions, the percentage data in the following tests and examples are listed in mass%, in mass units. The content of the solvents, the ratio of the dilution and concentration "liquid/liquid" refer to the respective volumes.

A. Examples

Abbreviations

DCIDirect chemical ionization (mass spectroscopy)
DMFDMF (N,N-dimethylformamide)
DMSODMSO (dimethyl sulfoxide)
d. Th.The output from theoretical
ESIIonization of electron flow (mass spectroscopy)
N h (hours)
HPLCHPLC (high performance liquid chromatography)
CR.Boiling point
LC-MSLC-MS (liquid chromatography coupled with mass spectroscopy)
minutesmin (minutes)
MSMS (mass spectroscopy)
NMRNMR (nuclear magnetic resonance)
RFPhlegm
RTRoom temperature (20°C)
RtRetention time (HPLC)
TEAThe triethylamine
tert.tert-(tertiary)
THFTHF (tetrahydrofuran)
UVUV (ultraviolet)
v/vAbout. part (for mixtures of liquids)

Methods HPLC and LC-MS

Method 1

Mass spectrometer type Micromass Platform LCZ in conjunction the Institute with HPLC chromatograph for type Agilent Serie 1100; column: Grom-Sil 120 ODS-4 HE, 50×2.0 mm, 3 μm; eluent A: 1 l water + 1 ml 50%formic acid, eluent B: 1 l of acetonitrile + 1 ml 50%formic acid; gradient: 0.0 to min 100% A → 0.2 to min 100% A → a 2.9 min 30% A → a 3.1 min 10% A → 4.5 min 10% A; oven 55°C; flow rate 0.8 ml/min; UV detector 208-400 nm.

Method 2

Mass spectrometer type Micromass Quattro LCZ in combination with HPLC chromatograph for type Agilent Serie 1100; column: Grom-Sil 120 ODS-4 HE, 50×2.0 mm, 3 μm; eluent A: 1 l water + 1 ml 50%formic acid, eluent B: 1 l of acetonitrile + 1 ml 50%formic acid; gradient: 0.0 to min 100% A → 0.2 to min 100% A → a 2.9 min 30% A → a 3.1 min 10% A → 4.5 min 10% And; bake 55°C; flow rate 0.8 ml/min; UV detector 208-400 nm.

Method 3

Mass spectrometer type Micromass ZQ; HPLC chromatograph for type Waters Alliance 2790; column: Grom-Sil 120 ODS-4 HE, 50×2 mm, 3.0 mm; eluent b: acetonitrile + 0.05% of formic acid, eluent A: water + 0.05% of formic acid; gradient: 0.0 to min 5% B → a 2.0 min 40% B → 4.5 min 90% B → a 5.5 min 90% B; oven 45°C; flow rate: 0,0 min 0.75 ml/min → 4.5 min 0.75 ml/min → 5,5 min 1.25 ml/min; UV detector 210 nm.

Method 4

Mass spectrometer type Micromass ZQ; HPLC chromatograph for type TSP P4000, TSP AS300, TSP UV3000; column: Grom-Sil 120 ODS-4, 50×2 mm, 3.0 mm; eluent A: water + 250 μl of 50%formic acid/l, eluent b: acetonitrile + 250 μl of 50%formic acid/l; gradient: 0.0 to min 0% B → 0,2 min 0% B → a 2.9 min 70% B → 3,1 min 90% B → 4.5 min 90% B; oven 50°C; flow rate 0.8 ml/min; UV detector 210 nm.

Method 5

Mass spectrometer type Micromass ZQ; HPLC chromatograph for type Waters Alliance 2790; column: Grom-Sil 120 ODS-4, 50 mm × 2 mm, 3.0 mm; eluent b: acetonitrile + 500 μl of 50%formic acid/l; eluent A: water + 500 μl of 50%formic acid/l; gradient: 0.0 to min 0% B → 0,2 min 0% B → a 2.9 min 70% B → 3,1 min 90% B → 4.5 min 90% B; oven 50°C; flow rate 0.8 ml/min; UV detector 210 nm.

Method 6

Mass spectrometer type Micromass ZQ; HPLC chromatograph for type Waters Alliance 2795; column: Phenomenex Synergi 2µ Hydro-RP Mercury 20 mm×4 mm; eluent A: 1 l water + 0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50%formic acid; gradient: 0.0 to min 90% a, flow rate 1 ml/min → a 2.5 min 30% a, flow rate 2 ml/min → a 3.0 min 5% a, flow rate 2 ml/min → 4.5 min 5% a, flow rate 2 ml/min; oven 50°C; UV detector 210 nm.

Method 7

Mass spectrometer type Micromass Platform LCZ in combination with HPLC chromatograph for type Agilent Serie 1100; column: Phenomenex Synergi 2µ Hydro-RP Mercury 20 mm × 4 mm; eluent A: 1 l water + 0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50%formic acid; gradient: 0.0 to min 90% a, flow rate 1 ml/min → a 2.5 min 30% a, flow rate 2 ml/min → a 3.0 min 5% a, flow rate 2 ml/min → 4.5 min 5% a, flow rate 2 ml/min; oven 50°C; UV detector 210 nm.

Method 8

Mass spectrometer type Micromass Platform LCZ in combination with HPLC chromatograph for type Agilent Serie 1100; column: Grom-Sil 120 ODS-4 HE, 50 mm × 2.0 mm, 3 μm; eluent A: 1 l water + 1 ml 50%formic acid, eluent B: 1 l of acetonitrile + 1 ml 50%formic acid; gradient: 0,0 min 100% A → 0.2 to min 100% A → a 2.9 min 30% A → a 3.1 min 10% A → 4.5 min 10% A; oven 55°C; flow rate 0.8 ml/min; UV detector 210 nm.

Method 9

Mass spectrometer type Micromass ZQ; HPLC chromatograph for type Waters Alliance 2795; column: Merck Chromolith SpeedROD RP-18e 50 mm × 4.6 mm; eluent A: water + 500 μl of 50%formic acid/l; eluent b: acetonitrile + 500 μl of 50%formic acid/l; gradient: 0.0 to min 10% B→ a 3.0 min 95% B → 4,0 min 95% B; oven 35°C; flow rate: 0,0 min 1.0 ml/min → min 3,0 3,0 ml/min → 4,0 min 3.0 ml/min; UV detector 210 nm.

Method 10

Mass spectrometer type Micromass TOF (LCT); two-column liquid chromatograph for HPLC type Waters 2690; column: YMC-ODS-AQ, 50 mm × 4.6 mm, 3.0 mm; eluent A: water + 0.1% of formic acid, eluent b: acetonitrile + 0.1% of formic acid; gradient: 0.0 to min 100% A → 0.2 to min 95% A → a 1.8 min 25% A → 1.9 to min 10% A → 3.2 min 10% A; oven 40°C; flow rate 3.0 ml/min; UV the detector 210 nm.

Method 11

Mass spectrometer type Micromass Quattro LCZ in combination with chromatograph HPLC type Agilent Serie 1100; column: Uptisphere HDO, 50 × 2.0 mm, 3 μm; eluent A: 1 l water + 1 ml 50%formic acid, eluent B: 1 l of acetonitrile + 1 ml 50%formic acid; gradient: 0.0 to min 100% A → 0.2 to min 100% A → a 2.9 min 30% A → a 3.1 min 10% A → 4.5 min 10% A; oven 55°C; flow rate 0.8 ml/min; UV detector 208-400 nm.

Method 12

Mass spectrometer type Micromass ZQ; HPLC chromatograph for type Waters Alliance 2790; column: Uptisphere 18, 50 mm × 2.0 mm, 3.0 mm; eluent b: acetonitrile + 0.05% of formic key is lots eluent A: water + 0.05% of formic acid; gradient: 0.0 to min 5% B → a 2.0 min 40% B → 4.5 min 90% B → a 5.5 min 90% B; oven 45°C; flow rate: 0,0 min 0.75 ml/min → 4.5 min 0.75 ml/min → 5,5 min 1.25 ml/min; UV detector 210 nm.

Method 13

Mass spectrometer type Micromass ZQ; HPLC chromatograph for type HP 1100 Seres; UV DAD; column: Phenomenex Synergi 2µ Hydro-RP Mercury 20 mm×4 mm; eluent A: 1 l water + 0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50%formic acid; gradient: 0.0 to min 90% A → a 2.5 min 30% A → a 3.0 min 5% A → 4.5 min 5% A; flow rate: 0,0 min 1 ml/min → 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; oven 50°C; UV detector 210 nm.

Method 14

Mass spectrometer type Micromass ZQ; HPLC chromatograph for type Waters Alliance 2795; column: Merck Chromolith SpeedROD RP-18e 50 mm × 4.6 mm; eluent A: water + 500 μl of 50%formic acid/l, eluent b: acetonitrile + 500 μl of 50%formic acid/l; gradient: 0.0 to min 10% B → 2.0 a min 95% B → 4,0 min 95% B; oven 35°C; flow rate: 0,0 min 1.0 ml/min → min 2,0 3,0 ml/min → 4,0 min 3.0 ml/min; UV detector 210 nm.

Methods chiral HPLC

Method 15A (preparative)

Column: chiral silica gel selector Daicel Chiralpak AD; 10 μm, 250×20 mm; eluent: isohexane/ethanol + 0.2% diethylamine, 40:60 (vol. part); flow rate 20 ml/min; UV detection: 220 nm; temperature: 30°C; the introduction of samples in a mixture of isohexane/ethanol, 1:1.

Method 15 (analytical)

Column: chiral silica gel selector Daicel Chiralpak AD; 10 μm, 250×4.6 mm; eluent: isohexane/ethanol + 0,% diethylamine, 40:60 (vol. part); flow rate 0.7 ml/min; UV detector at 220 nm; temperature 30°C; the introduction of samples in eluent.

Method 16A (preparative)

Column: chiral silica gel selector Daicel Chiralpak AD-H 5 μm, 250×20 mm; eluent: acetonitrile/methanol + 0.2% diethylamine, 90:10 (vol. part); flow rate 20 ml/min; UV detector at 220 nm; temperature 25°C; the introduction of samples in a mixture of acetonitrile/methanol, 54:46 (vol. part).

Method 16V (analytical)

Column: Daicel Chiralpak AD-H 5 μm, 250×20 mm; eluent: acetonitrile/methanol + 0.2% diethylamine, 90:10 (vol. part); flow rate 1.0 ml/min; UV detector at 220 nm; temperature 25°C; the introduction of samples in eluent.

Method 17A (preparative)

Column: chiral silica gel selector Daicel Chiralpak AD-H 5 μm, 250×20 mm; eluent: acetonitrile/methanol + 0.2% diethylamine, 85:15 (vol. part); flow rate 20 ml/min; UV detector 230 nm; 25°C; the introduction of samples in acetonitrile.

Method 17V (analytical)

Column: chiral silica gel selector Daicel Chiralpak AD-H 5 μm, 250×4.6 mm; eluent: methanol/acetonitrile + 0.5% diethylamine, 20:80 (vol. part); flow rate of 0.5 ml/min; UV detector 230 nm; 25°C; the introduction of samples in eluent.

Method 18A (preparative)

Column: chiral silica gel selector Daicel Chiralpak AD-H 5 μm, 250×20 mm; eluent: acetonitrile/methanol + 0.2% diethylamine, 60:40 (vol. part); flow rate 20 ml/min; UV detector 230 nm; 25°C; the introduction of samples in a mixture acetonic the l/methanol, 58:42 (vol. part).

Method 18V (analytical)

Column: chiral silica gel selector Daicel Chiralpak AD-H 5 μm, 250×4.6 mm; eluent: methanol/acetonitrile + 0.5% diethylamine, 20:80 (vol. part); flow rate 1.0 ml/min; UV detector 230 nm; temperature 30°C; the introduction of samples in eluent.

Method 19A (preparative)

Column: chiral silica gel selector Daicel Chiralpak AD; 10 μm, 250×10 mm; eluent: ethanol + 0.2% diethylamine; flow rate 10 ml/min; UV detector at 220 nm; temperature 40°C; the introduction of samples in ethanol.

Method 19C (analytical)

Column: chiral silica gel selector Daicel Chiralpak AD; 10 μm, 250×4.6 mm; eluent: ethanol + 0.2% diethylamine; flow rate 0.7 ml/min; UV detector at 220 nm; temperature 25°C; the introduction of samples in eluent.

Method 20A (preparative)

Column: chiral silica gel selector KBD 5326A based on poly(N-methacryloyl-L-laryngectomised); 10 μm, 250×20 mm; eluent: isohexane/methyl tert-butyl ether, 1:1 (vol. part); flow rate 25 ml/min; UV detector 254 nm; temperature 24°C; the introduction of samples in a mixture of isohexane/methyl tert-butyl ether 1:1.

Method 20V (analytical)

Column: chiral silica gel selector KBD 5326A; 10 μm, 250×4.6 mm; eluent: isohexane/methyl tert-butyl ether, 2:3 (vol. part); flow rate 1 ml/min; UV detector 254 nm; temperature 25°C; the introduction of samples in eluent.

Method 21A (preparative)

Column: chiral silikagelevye with the lecturer KBD 5326A based on poly(N-methacryloyl-L-laryngectomised); 10 μm, 250×20 mm; eluent: isohexane/methyl tert-butyl ether, 2:3 (vol. part); flow rate 25 ml/min; UV detector 254 nm; temperature 24°C; the introduction of samples in a mixture of isohexane/methyl tert-butyl ether, 1:1.

Method 21V (analytical)

Column: chiral silica gel selector KBD 5326A; 10 μm, 250×4.6 mm; eluent: isohexane/methyl tert-butyl ether, 2:3 (vol. part); flow rate 1 ml/min; UV detector 254 nm; temperature 25°C; the introduction of samples in eluent.

Method 22A (preparative)

Column: chiral silica gel selector KBD 8361 based on poly(N-methacryloyl-L-latinamerica); 10 μm, 250×20 mm; eluent: isohexane/methyl tert-butyl ether, 3:2 (vol. part); flow rate 25 ml/min; UV detector 254 nm; temperature 24°C; the introduction of samples in a mixture of isohexane/methyl tert-butyl ether, 3:2.

Method 22V (analytical)

Column: chiral silica gel selector KBD 5326A; 10 μm, 250×4.6 mm; eluent: isohexane/methyl tert-butyl ether, 2:3 (vol. part); flow rate 1 ml/min; UV detector 254 nm; temperature 25°C; the introduction of samples in eluent.

Method 23A (preparative)

Column: Kromasil 100 C18; 5 μm, 250×20 mm; flow rate 25 ml/min; retention time 20 min; eluent A: water + 0.2% of triperoxonane acid, eluent b: acetonitrile; gradient: 5% B (0 min) → 95% B (15 min) → 5% (15,1 min) → 5% (20 min); UV detector 210 nm; temperature 40°C; the introduction of samples in a mixture of acetonitrile/water 2:1 (vol. part).

Method 23C (Academy of Sciences of the lytic)

Column: Kromasil 100 C18; 5 μm, 250×4 mm; flow rate 1.0 ml/min; retention time 20 min; eluent A: water+0.2% of triperoxonane acid, eluent b: acetonitrile; gradient: 5% B (0 min) → 95% B (10 min) → 95% B (15,0 min) → 5% (15,1 min) → 5% (20 min); UV detector 210 nm; temperature 40°C; the introduction of samples in a mixture of acetonitrile/water, 2:1 (vol. part).

Method 24A (preparative)

Column: chiral silica gel selector Daicel Chiralpak AD; 10 μm, 250×20 mm; eluent: isohexane/ethanol+0.2% diethylamine, 90:10 (vol. part); flow rate 25 ml/min; UV detector at 220 nm; temperature 25°C; the introduction of samples in a mixture of isohexane/ethanol 5:1 (vol. part).

Method 25A (preparatively)

Column: chiral silica gel selector Daicel Chiralpak AD; 20 μm, 500×40 mm; eluent: isopropanol/methanol+0.1% diethylamine, 85:15 (vol. part); flow rate 100 ml/min; UV detector at 220 nm; temperature 30°C; the introduction of the sample in isopropanol.

Method 25V (analytical)

Column: chiral silica gel selector Daioel Chiralpak AD; 10 μm, 250×4.6 mm; eluent: isopropanol/methanol + 0.1% diethylamine, 85:15 (vol. part); flow rate 1.0 ml/min; UV detector 250 nm; 25°C; the introduction of samples in eluent.

Method 26A (preparative)

Column: chiral silica gel selector Daioel Chiralpak AD; 20 μm, 350×30 mm; eluent: isopropanol/methanol + 0.1% diethylamine, 75:25 (vol. part); flow rate 50 ml/min; UV detector at 220 nm; temperature 25°C; the introduction of samples in a mixture of isopropanol/methane is l, 75:25 (vol. part).

Method 26V (analytical)

Column: chiral silica gel selector Daioel Chiralpak AD; 10 μm, 250×4.6 mm; eluent: isopropanol/methanol + 0.2% diethylamine, 85:15 (vol. part); flow rate 1.0 ml/min; UV detector 250 nm; 25°C; the introduction of samples in eluent.

Method 27A (preparative)

Column: chiral silica gel selector Daioel Chiralpak AD; 20 μm, 500×40 mm; eluent: isopropanol/methanol + 0.1% diethylamine, 75:25 (vol. part); flow rate 50 ml/min; UV detector at 220 nm; temperature 25°C; the introduction of samples in a mixture of isopropanol/methanol 75:25 (vol. part).

Method 27V (analytical)

Column: chiral silica gel selector Daicel Chiralpak AD; 10 μm, 250×4.6 mm; eluent: isopropanol/methanol + 0.2% diethylamine, 85:15 (vol. part); flow rate 1.0 ml/min; UV detector 250 nm; 25°C; the introduction of samples in eluent.

Method 28A (preparative)

Column: chiral silica gel selector Daicel Chiralpak AD; 20 μm, 500×40 mm; eluent: isopropanol/methanol + 0.1% diethylamine, 85:15 (vol. part); flow rate 50 ml/min; UV detector at 220 nm; temperature 25°C; the introduction of samples in a mixture of isopropanol/methanol, 85:15 (vol. part).

Method 28V (analytical)

Column: chiral silica gel selector Daicel Chiralpak AD; 10 μm, 250×4.6 mm; eluent: isopropanol/methanol + 0.1% diethylamine, 5:1 (vol. part); flow rate 1 ml/min; UV detector 250 nm; 25°C; the introduction of samples in eluent.

Method 29A (preparative)/p>

Column: chiral silica gel selector Daioel Chiralpak AD; 10 μm, 250×20 mm; eluent: isohexane/ethanol + 0.2% diethylamine, 85:15 (vol. part); flow rate 25 ml/min; UV detector at 220 nm; temperature 25°C; the introduction of samples in ethanol.

Method 29V (analytical)

Column: chiral silica gel selector Daioel Chiralpak AD; 10 μm, 250×4.6 mm; eluent: isopropanol/methanol + 0.1% diethylamine, 5:1 (objact); flow rate 1 ml/min; UV detector 250 nm; 25°C; the introduction of samples in eluent.

Method 30A (preparative)

Column: chiral silica gel selector ZWE 803AB based on poly(N-methacryloyl-L-phenylalanine-d-neopentylene); 10 μm, 250×20 mm; eluent: isohexane/methyl tert-butyl ether, 1:4 (objact); flow rate 25 ml/min; UV detector 254 nm; temperature 24°C; the introduction of samples in methyl tert-butyl ether.

Method 30V (analytical) Column: chiral silica gel selector ZWE 803AB; 10 μm, 250×4.6 mm; eluent: tert-butyl ether; flow rate 1 ml/min; UV detector 254 nm; temperature 25°C; the introduction of samples in eluent.

The initial compounds and intermediate products

Example 1A

3,5-Detoxifier

Through a solution of 188 g (1.49 mol) phloroglucinol in 600 ml of ethanol for 5 hours under reflux miss gaseous Bogorodchany. After cooling the solution during the night stirred at room temperature. Then g is soobrazhayu Bogorodchany pass under reflux for 5 hours. After cooling, the reaction mixture was concentrated and the residue was transferred in dichloromethane and water. Separate the organic phase, the aqueous phase is twice extracted with dichloromethane, and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is subjected to distillation in vacuo (boiling point 145-150°C./0.5 mbar). The distillate is dissolved in dichloromethane, extracted five times with 5%aqueous potassium carbonate solution to remove 5-ethoxyresorufin, the organic phase is dried over sodium sulfate, filtered and concentrated. Obtain 156 g of the target product (yield from theoretical 57%).

HPLC-MS (method 1): Rt=3,32 minutes

MS (ESIpos): m/z=183 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=a 9.35 (s, 1H), 5,90 (s, 3H), 3,91 (q, 4H), of 1.27 (t, 6H).

Example 2A

Methyl ester (4-bromophenyl)(3,5-dioxygenase)acetic acid

20,0 g (110 mmol) of 3,5-detoxifier and 30.7 g (99,8 mmol) methyl ester bromide(4-bromophenyl)acetic acid are dissolved at room temperature under argon in 39 ml of 2-butanone and mixed with 31.0 g (225 mmol) of potassium carbonate. The reaction mixture for 4 hours, heated under reflux. After cooling, the precipitate is sucked off the filter, washed with 2-butanone and the filtrate concentrated. In the result of the chromatography was carried out on silica gel 60 (toluene as chromatographies the second solvent) to obtain 33.1 g of the target product (yield of theoretical, 81%).

HPLC-MS (method 2): Rt=with 4.64 min

MS (ESIpos): m/z=409 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,66-of 7.60 (m, 2H), 7,53-7,46 (m, 2H), 6,11 (d, 2H), 6,09 (t, 1H), equal to 6.05 (s, 1H), 3,95 (q, 4H), 3,66 (s, 3H), of 1.28 (t, 6H).

Example 3A

(4-bromophenyl)(3,5-dioxygenase)acetic acid

of 16.9 g (a 41.3 mmol) of the methyl ester (4-bromophenyl)(3,5-dioxygenase)acetic acid at room temperature under argon was dissolved in 80 ml of methanol and 8 ml of water and the solution is mixed from 7.99 g (of 57.8 mmol) of potassium carbonate. The mixture is heated for 4 hours under reflux. After cooling, the precipitate is filtered off, the filtrate concentrated, the residue is transferred into water and extracted four times the solution in diethyl ether. Using a 10%hydrochloric acid, the pH of the aqueous phase set at level 2, three times extracted the aqueous phase with ethyl acetate, the combined ethyl acetate phase was washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. Get 16,1 g of the target product (yield from theoretical 99%).

HPLC-MS (method 4): Rt=3,85 minutes

MS (ESIpos): m/z=395 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=13,37 (s, 1H), 7,66-7,58 (m, 2H), 7,53 was 7.45 (m, 2H), 6,11-the 6.06 (m, 3H), of 5.83 (s, 1H), 3,95 (q, 4H), of 1.28 (t, 6H).

Example 4A

2-(4-bromophenyl)-4,6-diethoxybenzene-3(2H)-he

To 16,1 g (40,7 mmol) (4-pompini the)(3,5-dioxygenase)acetic acid at room temperature under argon add 38 ml (407 mmol) of the chloride of fostoria. The mixture is cooled to 0°C and add 8,32 g (61,0 mmol) of zinc chloride. After 10 minutes, remove the ice bath and the mixture is stirred over night at room temperature. The reaction mixture was poured into a large amount of ice water and stirred for 15 minutes. Add dichloromethane, separated phases, the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. In the gradient chromatography on silica gel 60 (toluene/ethyl acetate as the chromatographic solvent) to obtain 10.2 g of the target product (yield of theoretical, 67%).

HPLC-MS (method 4): Rt=4,04 minutes

MS (ESIpos): m/z=377 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=of 7.64-7,58 (m, 2H), 7,28-of 7.23 (m, 2H), 6,46 (d, 1H), to 6.19 (d, 1H), 5,72 (s, 1H), 4,22-of 4.05 (m, 4H), 1,39-of 1.26 (m, 6H).

Example 5A

(S*,R*)-3-[2-(4-bromophenyl)-4,6-diethoxy-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal

of 20.9 g (a 55.4 mmol) of 2-(4-bromophenyl)-4,6-diethoxybenzene-3-one are dissolved under argon in 422 ml of deaerated methanol and 100 ml of deaerated toluene. At room temperature add a 2.00 g (11.1 mmol) of 30%aqueous solution of sodium methylate in methanol. After a minute add cinnamaldehyde (9,52 g, 72.0 mmol), dissolved in 111 ml of deaerated toluene. The mixture is stirred over night at room temperature and leave for 48 hours. Then doba is make a saturated solution of ammonium chloride and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated. In the result column chromatography on silica gel 60 (toluene/ethyl acetate 95:5 as the chromatographic solvent) to obtain 10.7 g of target compound in the form of a racemic mixture (exit from theoretical 38%) and 6.00 g of diastereoisomer (R*,R*)-3-[2-(4-bromophenyl)-4,6-diethoxy-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal in the form of a racemic mixture (exit from theoretical 21%).

HPLC-MS (method 4): Rt=4,19 minutes

MS (ESIpos): m/z=509 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=to 9.32 (d, 1H), 7,69 to 7.62 (m, 2H), to 7.61-rate of 7.54 (m, 2H), 7,31-7,10 (m, 5H), 6.48 in (d, 1H), 5,97 (d, 1H), 4,24 (dd, 1H), 4,12 (q, 2H), 4,01-3,81 (m, 2H), to 3.02 (ddd, 1H), 2.57 m) is 2.44 (m, 1H), 1,33 (t, 3H), 1,18 (t, 3H).

Example 6A

(1S*,3S*,3aR*,8bS*)-3A-(4-bromophenyl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-territorialement[b]benzofuran-1,8b-(1H)-diol

At 0°C under argon load 178 ml (to 17.9 mmol) of 0.1 M solution of diiodide Samaria in tetrahydrofuran and added dropwise a solution 2,60 g (5,10 mmol) (S*,R*)-3-[2-(4-bromophenyl)-4,6-diethoxy-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal in 30 ml of deaerated of tetrahydrofuran. The mixture is stirred for 1 hour at 0°C and 1 hour at room temperature. Add cooled in an ice bath, saturated solution of sodium tartrate potassium with 10% potassium carbonate, split phase, the aqueous phase is shaken out three times dichloro is an, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. In the result column chromatography on silica gel 60 (toluene/ethyl acetate 95:5 as the chromatographic solvent) to obtain 1.55 g of the desired product in the form of a racemic mixture (exit from theoretical 58%).

HPLC-MS (method 3): Rt=4,62 minutes

MS (ESIpos): m/z=511 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,35-7,28 (m, 2H), 7.24 to 7,02 (m, 5H), 6,91-6,84 (m, 2H), 6,28 (d, 1H), 6,14 (d, 1H), of 5.81 (d, 1H), 4,84 (s, 1H), 4,71 (ddd, 1H), 4,13-3,98 (m, 4H), 3,32-3,18 (m, 1H), 2,58-to 2.41 (m, 1H), 2,15 (dt, 1H), of 1.35 (t, 3H), of 1.33 (t, 3H).

Example 7A

(3S*,3aR*,8bR*)-3A-(4-bromophenyl)-6,8-diethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-he

2,60 g (5.08 mmol) of (1S*,3S*,3aR*,8bS*)-3A-(4-bromophenyl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol are dissolved under argon in 19 ml of DMSO and the solution is cooled to 0°C. added dropwise 7,80 ml (55,9 mmol) of triethylamine and the solution 2,43 g (15,3 mmol) of a complex of sulfur trioxide-pyridine in a 9.60 ml of DMSO, the mixture is heated to room temperature and stirred over night. Then add cooled in an ice bath, saturated solution of ammonium chloride and stirred for 30 minutes the Precipitate is sucked off the filter and washed with a small amount of water. In the gradient chromatogr is the philosophy on silica gel 60 (toluene/ethyl acetate as the chromatographic solvent) receive a 2.00 g of the desired product in the form of a racemic mixture (exit from theoretical 77%).

HPLC-MS (method 5): Rt=as 4.02 min

MS (ESIpos): m/z=509 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,39-of 6.90 (m, 9H), to 6.43 (d, 1H), 6,17 (d, 1H), 5.82 (s, 1H), 4,20-3,93 (m, 4H), 3,70 (dd, 1H), 3,12 (dd, 1H), 2,93 (dd, 1H), of 1.34 (t, 3H), of 1.30 (t, 3H).

Example 8A

(1R*,3S*,3aR*,8bS*)-3A-(4-bromophenyl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

Under argon download 814 mg (3,09 mmol) triacetoxyborohydride of Tetramethylammonium in 1.2 ml of acetonitrile, add 1.2 ml of glacial acetic acid, and the mixture is stirred at room temperature for 0.5 hours. Then added dropwise 105 mg (0.21 mmol) of (3S*,3aR*,8bR*)-3A-(4-bromophenyl)-6,8-diethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-it is in the form of a solution in 12 ml of acetonitrile. The mixture is stirred over night at room temperature. To the reaction mixture at 0°C is added a saturated solution of sodium bicarbonate, the aqueous phase is twice extracted with dichloromethane, the combined organic phases are dried over sodium sulfate, filtered and concentrated. In the gradient chromatography on silica gel 60 (toluene/ethyl acetate as the chromatographic solvent) to obtain 77 mg of the desired product in the form of a racemic mixture (exit from theoretical 71%).

HPLC-MS (method 1): Rt=4,20 minutes

MS (ESIpos): m/z=512 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,27-to 7.18 (m, 2H), 7,15-of 6.96 (m, 7H), 6,24 (d, 1H), 6,10 (d, 1H), 4.95 points (s, 1H), 4,54-to 4.46 (m, 1H), 4,42 (d, 1H), 4,13-to 3.89 (m, 5H), 2,70 (dt, 1H), 2,01 (dd, 1H), 1,33 (t, 3H), of 1.31 (t, 3H).

Preparative separation of racemic mixtures of enantiomers is realized by means of HPLC on a chiral phase in accordance with the method of 22A.

Analytical data (method 22B):

enantiomer A: Rt=3,66 min, enantiomer In: Rt=4,30 minutes

Example 9A

(2R*,3S*,3aR*,8bR*)-3A-(4-bromophenyl)-6,8-diethoxy-8b-hydroxy-1-oxo-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-2-carboxylic acid

The target compound is synthesized analogously to example 17A on the basis of the data obtained in example 7A connection. It is used in the next synthesis step directly without further characterization.

Example 10A

Methyl ester (4-chlorophenyl)(3,5-dioxygenase)acetic acid

The target compound is synthesized analogously to example 2A from methyl ester bromo(4-chlorophenyl)acetic acid.

The output from theoretical 96%.

HPLC-MS (method 2): Rt=3,33 minutes

MS (ESIpos): m/z=365 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,58-7,47 (m, 4H), 6,12-between 6.08 (m, 4H), 3,95 (q, 4H), 3,66 (s, 3H), of 1.28 (t, 3H).

Example 11A

(4-Chlorophenyl)(3,5-dioxygenase)acetic acid

The target compound is synthesized analogously to example 3A on the basis of which soedineniya, obtained in example 10A.

The output from theoretical 91%.

HPLC-MS (method 1): Rt=3,80 minutes

MS (ESIpos): m/z=351 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=13,26 (br. s, 1H), EUR 7.57 (d, 2H), of 7.48 (d, 2H), 6,11-6,09 (m, 3H), of 5.85 (s, 1H), 3,95 (q, 2H), 1.28 (in t, 3H).

Example 12A

2-(4-chlorophenyl)-4,6-diethoxybenzene-3(2H)-he

The target compound is synthesized analogously to example 4A from the compound obtained in example 11A.

The output from theoretical 85%.

HPLC-MS (method 1): Rt=4,00 minutes

MS (ESIpos): m/z=333 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=of 7.48 (d, 2H), 7,31 (d, 2H), 6,47 (d, 1H), of 6.20 (d, 1H), of 5.75 (s, 1H), 4,22-Android 4.04 (m, 4H), 1,39 to 1.37 (m, 6H).

Example 13A

(S*,R*)-3-[2-(4-chlorophenyl)-4,6-diethoxy-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal

The target compound is synthesized analogously to example 5A on the basis of the compound obtained in example 12A.

The yield of pure diastereoisomer from theoretical 35%.

HPLC-MS (method 4): Rt=4.09 to minutes

MS (ESIpos): m/z=465 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=to 9.32 (d, 1H), to 7.64 (d, 2H), 7,51 (d, 2H), 7,28-7,25 (m, 2H), 7,19-was 7.08 (m, 3H), 6,46 (d, 1H), 5,97 (d, 1H), 4,23 (dd, 1H), 4,12 (q, 2H), 3,98-of 3.85 (m, 2H), 3,01 (ddd, 1H), 2,54-2,47 (m, 1H), 1,33 (t, 3H), of 1.17 (t, 3H).

Example 14A

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target connection SYN is Airout analogously to example 6A on the basis of the connection, obtained in example 13A.

The output from theoretical 55%.

HPLC-MS (method 3): Rt=3,79 minutes

MS (ESIpos): m/z=467 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7.26-7.05 (m, 7H), 6.89-6.85 (m, 2H), 6.28 (d, 1H), 6.14 (d, 1H), 5.81 (d, 1H), 4.84 (s, 1H), 4.76-4.67 (m, 1H), 4.12-3.99 (m, 4H), 3.31-3.19 (m, 1H), 2.47-2.42 (m, 1H), 2.23-2.04 (m, 1H), 1.39-1.30 (m, 6H).

Primera

(3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6,8-diethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-he

The target compound is synthesized analogously to example 7A from the compound obtained in example 14A.

The output from theoretical 93%.

HPLC-MS (method 5): Rt=1,27 minutes

MS (ESIpos): m/z=465 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,19-6,97 (m, 9H), to 6.43 (d, 1H), 6,16 (d, 1H), 5,78 (s, 1H), 4,12-3,95 (m, 4H), 3,71 (dd, 1H), 3,15-2,89 (m, 2H), of 1.34 (t, 3H), of 1.30 (t, 3H).

Example 16A

(1R*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 8A on the basis of the compound obtained in example 15A.

The output from theoretical 83%.

HPLC-MS (method 2): Rt=4,59 minutes

MS (ESIneg): m/z=465 (M-N)-.

1H-NMR (200 MHz, DMSO-d6): δ=7,20-of 6.96 (m, 9H), 6,24 (d, 1H), 6,10 (d, 1H), 4.95 points (s, 1H), 4,54-4,47 (m, 1H), 4,42 (d, 1H), 4,13-to 3.89 (m, 5H), 2,70 (dt, 1H), 2,01 (dd, 1H), 1,33 (t, 3H), of 1.31 (t, 3H).

Preparative separation of racemic mixtures of enantiomers carry out what redstem HPLC on chiral phase in accordance with the method 21A.

Analytical data (method 21B):

enantiomer A: Rt=to 4.52 min, enantiomer In: Rt=7,56 minutes

Example 17A

(2R*,3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6,8-diethoxy-8-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-2-carboxylic acid

A mixture of 500 mg (1,08 mmol) of (3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6,8-diethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-she (from example 15A) and 1.08 ml (2,15 mmol) of a 2M solution of methylcarbonate methoxamine in dimethylformamide is heated for 16 hours at 100°C and stirred in a closed vessel. Then the resulting suspension is poured into a mixture chilled in an ice bath 5N hydrochloric acid with ethyl acetate. The organic phase is allocated, washed with a saturated solution of sodium chloride, dried over magnesium sulfate, sucked off the filter and concentrate. 531 mg of crude product used directly in the next stage without defining its characteristics.

Example 18A

3,5-Bis(2-methoxyethoxy)phenol

Through a solution of 50.0 g (397 mmol) phloroglucin 500 ml nanometrology ether of ethylene glycol for 4 hours at 80°C miss gaseous Bogorodchany. Then add 300 ml nanometrology ether of ethylene glycol and continue heating for another 2 hours while passing gaseous podorozhaniya and reflux. The reactions is nnow the mixture is cooled, concentrating, the residue was transferred to 200 ml of dimethylformamide, add to 10.9 g (79.2 mmol) of potassium carbonate and heated to 50°C. and Then added dropwise to 10.9 g (78.2 mmol) of 2-pomatoleios ether in the form of a solution in 100 ml of dimethylformamide. The reaction mixture is stirred for 2 hours at 50°C. it is Then concentrated, the residue was transferred to a mixture of diethyl ether with water, split phase and the aqueous phase is twice extracted with diethyl ether. The pH of the aqueous phase set at 5 by means of concentrated hydrochloric acid three times and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. In the gradient chromatography on silica gel 60 (toluene/ethyl acetate as the chromatographic solvent) get 9,20 g of the target product (yield from a theoretical 10%).

HPLC-MS (method 9): Rt=1,60 minutes

MC (ESIpos): m/z=243 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=a 9.35 (s, 1H), 5,97-5,91 (m, 3H), 4,01-of 3.96 (m, 4H), 3,63-to 3.58 (m, 4H), 3,29 (s, 6H).

Example 19A

Methyl ester [3,5-bis(2-methoxyethoxy)-phenoxy]-(4-bromophenyl)-acetic acid

The target compound is synthesized analogously to example 2A from the compound obtained in example 18A.

The output from theoretical is whom 73%.

HPLC-MS (method 3): Rt=4,17 minutes

MC (ESIpos): m/z=470 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,66-of 7.60 (m, 2H), 7,52-7,46 (m, 2H), 6,17-6,13 (m, 3H), 6,07 (s, 1H), 4,05-4,00 (m, 4H), 3,66 (s, 3H), 3,63-3,59 (m, 4H), 3,29 (s, 6H).

Example 20A

[3,5-Bis-(2-methoxyethoxy)phenoxy](4-bromophenyl)acetic acid

The target compound is synthesized analogously to example 3A on the basis of the compound obtained in example 19A.

The output from theoretical 86%.

HPLC-MS (method 3): Rt=3,68 minutes

MS (ESIpos): m/z=456 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=13,3 (s, 1H), 7,65-to 7.59 (m, 2H), 7,53-7,47 (m, 2H), 6,14 (s, 3H), 5,86 (s, 1H), 4,05-4,00 (m, 4H), 3,64-3,59 (m, 4H), 3,29 (s, 6H).

Example 21A

4,6-Bis(2-methoxyethoxy)-2-(4-bromophenyl)benzofuran-3(2H)-he

The target compound is synthesized analogously to example 4A from the compound obtained in example 20A.

The output from theoretical 19%.

HPLC-MS (method 2): Rt=4,29 minutes

MS (ESIpos): m/z=438 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=of 7.64-7,58 (m, 2H), 7,29-of 7.23 (m, 2H), 6,50 (d, 1H), of 6.26 (d, 1H), 5,74 (s, 1H), 4,27-to 4.15 (m, 4H), 3,71-3,62 (m, 4H), of 3.32 (s, 3H), and 3.31 (s, 3H).

Example 22A

(S*,R*)-3-[4,6-bis(2-methoxyethoxy)-2-(4-bromophenyl)-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal

The target compound is synthesized analogously to example 5A on the basis of the compound obtained in example 21 A.

The output from theoretical 30.

HPLC-MS (method 2): Rt=4.48 min

MS (ESIpoe): m/z=570 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=to 9.32 (d, 1H), to 7.67 to 7.62 (m, 2H), to 7.61-of 7.55 (m, 2H), 7,29-of 7.23 (m, 2H), 7,20-to 7.09 (m, 3H), 6,51 (d, 1H), 6,04 (d, 1H), 4,24 (dd, 1H), 4,22-4,17 (m, 2H), 4,08-3,93 (m, 2H), 3,68-3,63 (m, 2H), 3,54-3,49 (m, 2H), 3,30 (s, 3H), up 3.22 (s, 3H), 3,01 (ddd, 1H), 2,56 is 2.46 (m, 1H).

Example 23A

3,5-Bis(2-chloroethoxy)phenol

Through a solution of 150 g (1,19 mol) phloroglucinol in 1000 ml of 2-chloroethanol at 80°C for 5 hours pass gaseous Bogorodchany. After cooling, the solution is stirred over night at room temperature. Then it is heated at 80°C and passing gaseous podorozhaniya for 2 hours. The solution is cooled, concentrated and the residue was transferred to a mixture of dichloromethane with water, split phase, and the aqueous phase is twice extracted with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and contentresult the result column chromatography on silica gel 60 (toluene/ethyl acetate 95:5 as the chromatographic solvent) get 81,2 g of the target product (yield from theoretical 27%).

HPLC-MS (method 4): Rt=3,27 minutes

MS (ESIpos): m/z=252 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=of 9.51 (s, 1H), 6,03-5,96 (m, 3H), 4,20 is 4.13 (m, 4H), 3,94-3,86 (m, 4H).

Example 24A

Methyl ester [3,5-bis(2-chloroethoxy)phenoxy](4-chlorophenyl)acetic acid

The target compound is synthesized analogously to example 2A from the compound obtained in example 23A.

The output from theoretical 76%.

HPLC-MS (method 4): Rt=4,05 minutes

MS (ESIpos): m/z=433 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=to 7.59-rate of 7.54 (m, 2H), 7,52-7,46 (m, 2H), 6,23-6,18 (m, 3H), 6,13 (s, 1H), 4,24-4,19 (m, 4H), 3,93-3,88 (m, 4H), to 3.67 (s, 3H).

Example 25A

[3,5-Bis(2-chloroethoxy)phenoxy]-(4-chlorophenyl)acetic acid

The target compound is synthesized analogously to example 3A on the basis of the compound obtained in example 24A.

The output from theoretical 92%.

HPLC-MS (method 4): Rt=3,91 minutes

MS (ESIpos): m/z=419 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=13,4 (s, 1H), to 7.61-7,53 (m, 2H), 7,52 was 7.45 (m, 2H), to 6.19 (s, 3H), of 5.92 (s, 1H), 4,25-4,16 (m, 4H), 3.96 points-3,88 (m, 4H).

Example 26A

4,6-Bis(2-chloroethoxy)-2-(4-chlorophenyl)benzofuran-3(2H)-he

The target compound is synthesized analogously to example 4A from the compound obtained in example 25A.

The output from theoretical 55%.

HPLC-MS (method 3): Rt=3,82 minutes

MS (ESIpos): m/z=401 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,51 was 7.45 (m, 2H), was 7.36-7,30 (m, 2H), to 6.57 (d, 1H), 6,32 (d, 1H), 5,79 (s, 1H), 4,45 is 4.35 (m, 4H), was 4.02-to 3.89 (m, 4H).

Example 27A

(S*,R*)-3-[4,6-bis(2-chloroethoxy)-2-(4-chlorophenyl)-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal

The target connection synthesize what analogously to example 5A on the basis of the connection, obtained in example 26A.

The output from theoretical 48%.

HPLC-MS (method 4): Rt=3,72 minutes

MS (ESIpos): m/z=533 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=was 9.33 (d, 1H), 7.68 per to 7.62 (m, 2H), 7,54-of 7.48 (m, 2H), 7,29-7,24 (m, 2H), 7,19-to 7.09 (m, 3H), to 6.57 (d, 1H), 6,09 (d, 1H), 4,40-of 4.35 (m, 2H), 4,30-4.09 to (m, 3H), 3,99-of 3.94 (m, 2H), 3,81 is 3.76 (m, 2H), to 3.02 (ddd,, 1H), 2,56 is 2.46 (m, 1H).

Example 28A

(1S*,3S*,3aR*,8bS*)-6,8-bis-(2-chloroethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 6A on the basis of the compound obtained in example 27A.

The output from theoretical 31%.

HPLC-MS (method 5): Rt=4,01 minutes

MS (ESIpos): m/z=535 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,26-to 7.15 (m, 4H), 7,10-7,03 (m, 3H), 6,92-6,86 (m, 2H), 6,38 (d, 1H), and 6.25 (d, 1H), of 5.68 (d, 1H), a 4.83 (s, 1H), 4,82-to 4.73 (m, 1H), 4,36-to 4.28 (m, 4H), was 4.02-3,93 (m, 4H), 3,29 is 3.23 (m, 1H), of 2.51 is 2.43 (m, 1H), 2,17 (ddd, 1H).

Example 29A

(3S*,3aR*,8bR*)-6,8-bis(2-chloroethoxy)-3A-(4-chlorophenyl)-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-he

The target compound is synthesized analogously to example 7A from the compound obtained in example 28A.

The output from theoretical 71%.

HPLC-MS (method 2): Rt=3,40 minutes

MS (ESIpos): m/z=533 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,21-to 7.15 (m, 2H), 7,12-7,05 (m, 3H), 7,02-of 6.96 (m, 4H), is 6.54 (d, 1H), 6.30-in (d, 1H), by 5.87 (s, 1H), 4,36-4.26 deaths (m, 4H), 3,99-of 3.94 (m, 2H), 3,90-of 3.85 (m, 2H), of 3.73 (dd, 1H), 3,11 (dd, 1H) 2,93 (dd, 1H).

Example 30A

(1R*,3S*,3aR*,8bS*)-6,8-bis(2-chloroethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 8A on the basis of the compound obtained in example 29A.

The output from theoretical 85%.

HPLC-MS (method 1): Rt=4.09 to minutes

MS (ESIpoe): m/z=535 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,11-6,98 (m, 9H), 6,33 (d, 1H), 6,21 (d, 1H), equal to 4.97 (s, 1H), 4,55-4,50 (m, 1H), 4,36 (d, 1H), 4,32-4.26 deaths (m, 4H), was 4.02-3,90 (m, 5H), of 2.72 (ddd, 1H), 2,03 (ddd, 1H).

Example 31A

Methyl ester [3,5-bis(2-chloroethoxy)-phenoxy]-(4-bromophenyl)acetic acid

The target compound is synthesized analogously to example 2A from the compound obtained in example 23A.

The output from theoretical 48%.

HPLC-MS (method 4): Rt=4,11 minutes

MS (ESIpos): m/z=477 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ=7.68 per-of 7.60 (m, 2H), 7,54 was 7.45 (m, 2H), 6,23-6,18 (m, 3H), 6,13 (s, 1H), 4,25-4,17 (m, 4H), 3.95 to a 3.87 (m, 4H), 3,66 (s, 3H).

Example 32A

[3,5-Bis-(2-chloroethoxy)-phenoxy]-(4-bromophenyl)-acetic acid

The target compound is synthesized analogously to example 3A on the basis of the compound obtained in example 31A.

The output from theoretical 99%.

HPLC-MS (method 2): Rt=4,33 minutes

MS (ESIpos): m/z=463 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=13,4 (s, 1H), of 7.64-7,58 (m, 2H), 7,52-7,46 (m, 2H), 6,21-6,6 (m, 3H), of 5.85 (s, 1H), 4,24-4,18 (m, 4H), 3,93-3,88 (m, 4H).

Example 33A

4,6-Bis(2-chloroethoxy)-2-(4-bromophenyl)benzofuran-3(2H)-he

The target compound is synthesized analogously to example 4A Exodus from the compound obtained in example 32A.

The output from theoretical 16%.

HPLC-MS (method 4): Rt=3,96 minutes

MS (ESIpos): m/z=446 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,66-EUR 7.57 (m, 2H), 7,30-7,22 (m, 2H), return of 6.58 (d, 1H), 6,32 (d, 1H), 5,79 (s, 1H), 4,46-4,34 (m, 4H), 4.04 the-3,88 (m, 4H).

Example 34A

(S*,R*)-3-[4,6-bis(2-chloroethoxy)-2-(4-bromophenyl)-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal

The target compound is synthesized analogously to example 5A on the basis of the compound obtained in example 33A.

The output from theoretical 35%.

HPLC-MS (method 4): Rt=4,05 minutes

MS (ESIpos): m/z=578 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=was 9.33 (d, 1H), 7,70-7,63 (m, 2H), 7,62-rate of 7.54 (m, 2H), 7,31-to 7.09 (m, 5H), to 6.58 (d, 1H), 6,10 (d, 1H), 4,42-to 4.33 (m, 2H), or 4.31-4,07 (m, 3H), was 4.02-3,93 (m, 2H), 3,83 is 3.76 (m, 2H), 3,03 (ddd, 1H), 2,58-2,44 m, 1H).

Example 35A

(1S*,3S*,3aR*,8bS*)-6,8-bis-(2-chloroethoxy)-3A-(4-bromophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 6A on the basis of the compound obtained in example 34A.

The output from theoretical 30%.

HPLC-MS (method 2): Rt=4,60 minutes

MS (ESIpos): m/z=579 (M+N)+.

1H-I Is R (400 MHz, DMSO-d6): δ=7,34-7,28 (m, 2H), 7.18 in for 7.12 (m, 2H), to 7.09-7.03 is (m, 3H), 6,92-6,87 (m, 2H), 6,37 (d, 1H), and 6.25 (d, 1H), of 5.68 (d, 1H), a 4.83 (s, 1H), 4,81-to 4.73 (m, 1H), 4,35-4,27 (m, 4H), 4,01-3,93 (m, 4H), 3,28 is 3.23 (m, 1H), 2,54-to 2.42 (m, 1H), 2,17 (ddd, 1H).

Example 36A

Methyl ester (4-chlorophenyl)(3-ethoxyphenoxy)acetic acid

The target compound is synthesized analogously to example 2A from 3-ethoxy-phenol.

The output from theoretical 97%.

HPLC-MS (method 5): Rt=3,86 minutes

MS (ESIpos): m/z=321 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=EUR 7.57 (d, 2H), 7,49 (d, 2H), 7,19-7,13 (m, 1H), 6,54-of 6.52 (m, 3H), 6,07 (s, 1H), 3,98 (q, 2H), 3,66 (s, 3H), of 1.29 (t, 3H).

Example 37A

(4-Chlorophenyl)-(3-ethoxyphenoxy)acetic acid

The target compound is synthesized analogously to example 3A on the basis of the compound obtained in example 36A.

The output from theoretical 96%.

HPLC-MS (method 4): Rt=3,18 minutes

MS (ESIpos): m/z=307 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,58 (d, 2H), of 7.48 (d, 2H), 7,20 for 7.12 (m, 1H), 6,55-6,50 (m, 3H), 5,88 (s, 1H), 3,98 (q, 2H), of 1.30 (t, 3H).

Example 38A

2-(4-Chlorophenyl)-6-ethoxybenzene-3 (2H)-he

The target compound is synthesized analogously to example 4A from the compound obtained in example 37A.

The output from theoretical 26%.

HPLC-MS (method 2): Rt=3,37 minutes

MC (ESIpos): m/z=289 (M+H)+.

Example 39A

(S*,R*)-3-[2-(4-chlorophenyl)-6-ethoxy-3-oxo-2,3-dihydrobenzo the Uran-2-yl]-3-phenylpropanal

The target compound is synthesized analogously to example 5A on the basis of the compound obtained in example 38A.

The yield of pure diastereoisomer from theoretical 19%.

HPLC-MS (method 12): Rt=4,53 minutes

MC (ESIpos): m/z=421 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ=9,34 (s, 1H), 7,69 (d, 2H), 7,52 (d, 2H), 7,24 (d, 2H), 7.18 in-7,06 (m, 4H), 6.90 to (s, 1H), 6,50 (dd, 1H), 4,28 (dd, 1H), 4,14 (q, 2H), 3,12 totaling 3.04 (m, 1H), 2.57 m-2,52 (m, 1H), of 1.34 (t, 3H).

Example 40A

(2R*,3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6-ethoxy-8b-hydroxy-1-oxo-3-phenyl-2,3,3A,8b-tetrahydro-1H-cyclopent[b]benzofuran-2-carboxylic acid

The target compound is synthesized analogously to example 17A on the basis of the compound obtained in example 24A. It is used in the next synthesis step directly without further characterization.

Example 41A

4-(2-Chloroethoxy)-2-hydroxyacetophenone

300 g (1.97 mol) of 2,4-dihydroxyacetophenone, 238 g (2.96 mol) of 2-chloroethanol and 776 g (2,96 mol) of triphenylphosphine introducing 4800 ml of tetrahydrofuran. At room temperature, added dropwise 380 g (2,96 mol) diisopropyl ester of azodicarboxylic acid in the form of a solution in 1200 ml of tetrahydrofuran. The mixture is heated for 16 hours under reflux, then cooled and concentrated. The residue is stirred with 2N sodium hydroxide solution and USA is to see on the filter. The solid is stirred with ethyl acetate, sucked off, washed with ethyl acetate and dried. The solid is introduced into a mixture of 4N hydrochloric acid-ethyl acetate, separate the phases, and the aqueous phase is again extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. In the double column chromatography on silica gel 60 (chromatographic solvent for the first stage of toluene, for the second stage cyclohexane) to obtain 232 g of the target product (yield from theoretical 55%).

HPLC-MS (method 13): Rt=2,41 minutes

MS (ESIpos): m/z=215 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=12,6 (s, 1H), 7,86 (d, 1H), to 6.57 (dd, 1H), 6,50 (d, 1H), to 4.38-4,30 (m, 2H), 4,00-to 3.92 (m, 2H), 2.57 m (s, 3H).

Example 42A

6-(2-Chloroethoxy)benzofuran-3-one

76,0 g (354 mmol) of 4-(2-chloroethoxy)-2-hydroxyacetophenone imposed under argon at -78°C in 1050 ml of tetrahydrofuran and added dropwise 148 g (885 mmol) hexamethyldisilazide lithium in the form of a solution in 750 ml of tetrahydrofuran. After heating to room temperature and add to 96.2 g (885 mmol) of chlorotrimethylsilane the mixture is stirred for two hours at room temperature. Then at 0°C are added in several portions 65,6 g (369 mmol) of N-bromosuccinimide, and the mixture is stirred for 0.5 hours at 0°C and 1 hour at on the th temperature. After that add 369 ml of 1 N sodium hydroxide solution, and the mixture is stirred for 0.5 hour at room temperature. After adding a saturated solution of ammonium chloride aqueous phase is repeatedly extracted with diethyl ether, the combined organic phases are dried over sodium sulfate, filtered and concentrated. In the gradient chromatography on silica gel 60 (petroleum ether/ethyl acetate as the chromatographic solvent) get 59.0 g of the target product (yield from theoretical 78%).

HPLC-MS (method 6): Rt=1,80 minutes

MS (ESIpos): m/z=213 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=rate of 7.54 (d, 1H), 6,86 (d, 1H), 6.73 x (dd, 1H), of 4.77 (s, 2H), to 4.41 is 4.36 (m, 2H), 4,00-3,95 (m, 2H).

Example 43A

2-Bromo-6-(2-chloroethoxy)benzofuran-3-one

Method (a)

127 g (597 mmol) 6-(2-chloroethoxy)benzofuran-3-one at room temperature under argon was dissolved in 1850 ml of dioxane and 1850 ml of diethyl ether and cooled to -5°C. With vigorous stirring slowly added dropwise 95,6 g (597 mmol) of bromine and stirred for 1 hour at 0°C. then add ice water, separated phases, the aqueous phase is twice extracted with dichloromethane, the combined organic phases are dried over sodium sulfate, filtered and concentrated. In the result column chromatography on silica gel 60 (toluene as x is autographical solvent) to obtain 150 g of the desired product in the form of a hydrate (exit from theoretical 86%).

Method b)

To a boiling suspension of 10.5 g (47,0 mmol) of copper bromide(II) in 60 ml of ethyl acetate added to 5.00 g (23.5 mmol) of 6-(2-chloroethoxy)benzofuran-3-one in 30 ml of chloroform. The mixture during the night heated under reflux. After cooling, the solid is filtered off and washed with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. In the gradient chromatography on silica gel 60 (toluene/cyclohexane as the chromatographic solvent) to obtain 1.5 g of the desired product in the form of a hydrate (exit from theoretical 20%).

HPLC-MS (method 2): Rt=4,13 minutes

MS (ESIpos): m/z=291 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,52 (d, 1H), 7,30 (s, 2H), 6.75 in (d, 1H), 6,70 (dd, 1H), to 5.57 (s, 1H), 4,42-4,37 (m, 2H), 4,00-3,95 (m, 2H).

Example 44A

2-Bromo-3-tert-butyldimethylsilyloxy-6-(2-chloroethoxy)benzofuran

For azeotropic removal of water 1.50 g (5,15 mmol) of the hydrate of 2-bromo-6-(2-chloroethoxy)benzofuran-3-one (from example 43A) three times concentrated under argon by means of toluene. Then the residue is dissolved under argon in 25 ml of diethyl ether and cooled to 0°C. Slowly added dropwise successively added 0,79 ml (5,66 mmol) of triethylamine and of 1.30 ml (5,66 mmol) of tert-butyldimethylchlorosilane, and the mixture is stirred for 10 minutes n and 0°C and 1 hour at room temperature. After this separate phase diethyl ether, the residue is twice extracted with diethyl ether and concentrate the combined phase diethyl ether. In the result column chromatography on silica gel 60 (cyclohexane as the chromatographic solvent) receive a 2.00 g of the target product (yield from theoretical 96%).

HPLC-MS (method 2): Rt=4,92 minutes

MS (ESIpos): m/z=405 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=of 7.36 (d, 1H), 7,21 (d, 1H), of 6.96 (dd, 1H), 4,32-4,27 (m, 2H), 3,98-3,93 (m, 2H), of 1.03 (s, 9H), of 0.23 (s, 6H).

Example 45A

3-Tert-butyldimethylsilyloxy-6-(2-chloroethoxy)-2-(-4-chlorophenyl)-benzofuran

Method (a)

a 2.00 g (is 4.93 mmol) of 2-bromo-3-tert-butyldimethylsilyloxy-6-(2-chloro-ethoxy)benzofuran dissolved under argon in 41 ml of toluene and added to 0.92 g (5,91 mmol) 4-chloraniline acid and a solution of 1.15 g (10,8 mmol) of sodium carbonate in 5.4 ml of water. The mixture Tegaserod and twice rinsed with argon, added 0.28 g (0.25 mmol) tetrakis-(triphenylphosphine)palladium(0) and heated for 2 hours at 95°C. the Cooled reaction mixture is poured into a mixture chilled in an ice bath, saturated solution of ammonium chloride and diethyl ether, separate the phases, the aqueous phase is twice extracted with diethyl ether, the combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate, introit and concentrate. In the result column chromatography on silica gel 60 (toluene/cyclohexane 1:1 as the chromatographic solvent) get 1,69 g of the target product (yield from theoretical 78%).

Method b)

For azeotropic removal of water to 39.4 g (135 mmol) of the hydrate of 2-bromo-6-(2-chloroethoxy)benzofuran-3-one (from example 43A) three times concentrated under argon by means of toluene. Then the residue is dissolved under argon in 1200 ml of toluene and cooled to -10°C. Slowly added dropwise successively added to 22.7 ml (162 mmol) of triethylamine and 34.2 ml (149 mmol) of tert-butyldimethylchlorosilane, and the mixture is stirred for half an hour at 0°C and half an hour at room temperature. Then separate the bottom layer (the triethylamine salt of triftoratsetata), and the upper solution without additional purification added under argon to 25.4 g (162 mmol) of 4-chloraniline acid. After the addition of 31.6 g (298 mmol) of sodium carbonate in the form of a solution in 148 ml of water are degassing the mixture under vacuum and the subsequent purging with argon. Type of 7.82 g (6,76 mmol) tetrakis(triphenyl-phosphine)palladium(0), carry out the degassing of the mixture and purging with argon. The mixture for 2 hours with vigorous stirring heated at 95°C. After cooling, the separated phases, the organic phase is washed three times with a saturated solution of ammonium chloride, once with water and once the feast upon the authorized solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. In the result column chromatography on silica gel 60 (toluene/cyclohexane 1:1 as the chromatographic solvent) get to 53.1 g of the target product (yield from theoretical 90%)containing up to 9% of 4,4'-dichlorodiphenyl as an impurity.

MC(DCI): m/z=437(M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,83-to 7.77 (m, 2H), 7,56-7,51 (m, 2H), 7,43 (d, 1H), 7,21 (d, 1H), 6,95 (dd, 1H), 4,35-4,30 (m, 2H), 3,99-of 3.94 (m, 2H), 1,02 (s, N), 0,12 (s, 6N).

Example 46A

6-(2-Chloroethoxy)-2-(4-chlorophenyl)-benzofuran-3(2H)-he

66.5 g (152 mmol) of 3-tert-butyldimethylsilyloxy-6-(2-chloroethoxy)-2-(4-chlorophenyl)benzofuran at room temperature under argon was dissolved in 500 ml of a 4M solution of podorozhaniya in dioxane and stirred for 1.5 hours the Solution is concentrated, receiving and 49.2 g of residue, which has been stored under argon and used without purification for further transformation.

HPLC-MS (method 5): Rt=of 3.77 min

MS (ESIpos): m/z=323 (M+N)+.

Example 47A

(S*,R*)-3-[6-(2-chloroethoxy)-2-(4-chlorophenyl)-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal

The target compound is synthesized analogously to example 5A on the basis of the compound obtained in example 46A.

The output from theoretical 31%.

HPLC-MS (method 4): Rt=to 3.73 min

MC (ESIpos): m/z=455 (M+H)+.

1H-NMR (200 MHz, DMSO- 6): δ=9,34 (d, 1H), 7,75-7,66 (m, 2H), 7,58-7,49 (m, 2H), 7,30-7,05 (m, 6H), 6,98 (d, 1H), 6,56 (dd, 1H), 4,43-4,34 (m, 2H), 4,30 (dd, 1H), was 4.02-of 3.94 (m, 2H), 3,09 (ddd, 1H), to 2.55 (dd, 1H).

Example 48A

(1S*,3S*,3aR*,8bS*)-6-(2-chloroethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 6A on the basis of the compound obtained in example 47A.

The output from theoretical 94%.

HPLC-MS (method 6): Rt=2,73 minutes

MC (ESIpos): m/z=457 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,32-7,02 (m, 8H), of 6.96-to 6.88 (m, 2H), 6,72 (d, 1H), 6,62 (dd, 1H), 5,86 (d, 1H), 5,07 (s, 1H), of 4.45 (q, 1H), 4,34-of 4.25 (m, 2H), 4,00-3,93 (m, 2H), 3,40-of 3.25 (m, 1H), 2,49-of 2.36 (m, 1H), measuring 2.20 (ddd, 1H).

Example 49A

(1S*,3S*,3aR*,8bS*)-6-(2-azidoethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

To 200 mg (0.44 mmol) of (1S*,3S*,3aR*,8bS*)-6-(2-chloroethoxy)-3A-(4-chloro-phenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol (from example 48A) in 4 ml of dimethylformamide under argon add 56,9 mg (0.87 mmol) of sodium azide and heated overnight at 100°C. After cooling, the mixture is concentrated and the residue is mixed with water and dichloromethane, separated phases, the aqueous phase is twice extracted with dichloromethane, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. In gradient the th chromatography on silica gel 60 (toluene/ethyl acetate as the chromatographic solvent) to obtain 190 mg of the target product (yield of theoretical, 94%).

HPLC-MS (method 9): Rt=2,66 minutes

MS (ESIpos): m/z=464 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,29 (d, 1H), 7,26-7,02 (m, 7H), of 6.96-6.90 to (m, 2H), of 6.71 (d, 1H), is 6.61 (dd, 1H), of 5.83 (d, 1H), 5,02 (s, 1H), 4,49-to 4.41 (m, 1H), 4,24-4,19 (m, 2H), 3,69-3,63 (m, 2H), 3,34-of 3.25 (m, 1H), 2,50-to 2.40 (m, 1H), of 2.21 (ddd, 1H).

Preparative separation of racemic mixtures of enantiomers is realized by means of HPLC on a chiral phase in accordance with method 25A.

Analytical data (method 25V):

enantiomer A: Rt=5,52 min, enantiomer In: Rt=8,56 minutes

Example 50A

(3S*,3aR*,8bR*)-6-(2-chloroethoxy)-3A-(4-chlorophenyl)-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-he

The target compound is synthesized analogously to example 7A from the compound obtained in example 48A.

The output from theoretical 92%.

HPLC-MS (method 4): Rt=3,54 minutes

MS (ESIpos): m/z=455 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7.29 trend-of 7.00 (m, 10H), 6.89 in (d, 1H), 6,66 (dd, 1H), of 6.31 (s, 1H), 4,36-to 4.28 (m, 2H), was 4.02-of 3.94 (m, 2H), 3,65 (dd, 1H), 3,42-3,20 (m, 1H), 2,84 (dd, 1H).

Example 51A

(1R*,3S*,3aR*,8bS*)-6-(2-chloroethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 8A on the basis of the compound obtained in example 50A.

The output from theoretical 99%.

HPLC-MS (method 2): Rt=4,24 minutes

MS (ESIneg): m/z=501 (M-N)-.

1H-I Is R (200 MHz, DMSO-d6): δ=to 7.32 (d, 1H), 7,14-6,91 (m, 9H), of 6.66 (d, 1H), 6,55 (dd, 1H), 5,26 (s, 1H), 5,17 (d, 1H), 4,62-4,51 (m, 1H), 4,32-4,24 (m, 2H), 4,00-to 3.92 (m, 2H), 3,90-of 3.77 (m, 1H), 2,66 (dt, 1H), 1,98 of-1.83 (m, 1H).

Example 52A

(2R*,3S*,3aR*,8bR*)-6-(2-chloroethoxy)-3A-(4-chlorophenyl)-8b-hydroxy-1-oxo-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-2-carboxylic acid

The target compound is synthesized analogously to example 17A on the basis of the compound obtained in example 50A. It is used in the next stage of the synthesis without further purification.

Example 53A

(2R*,3S*,3aR*,8bR*)-6-(2-chloroethoxy)-3A-(4-chlorophenyl)-2-dimethyl-urea-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent-[b]benzofuran-1-he

The target compound is synthesized analogously to example 16A on the basis of the compound obtained in example 52A.

The yield of the target product from theoretical is 14% (based on compound obtained in example 50A).

HPLC-MS (method 13): Rt=2,71 minutes

MS (ESIpos): m/z=526 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=7.23 percent-7,16 (m, 5H), 7,14-7,05 (m, 3H), 7,02-6,94 (m, 2H), 6.89 in (d, 1H), only 6.64 (dd, 1H), 6,47 (s, 1H), 4,79 (d, 1H), to 4.38-the 4.29 (m, 2H), 4,19 (d, 1H), was 4.02-of 3.94 (m, 2H), or 3.28 (s, 3H), 2,77 (s, 3H).

Example 54A

(1R*,2R*,3S*,3aR*,8bS*)-6-(2-chloroethoxy)-3A-(4-chlorophenyl)-2-dimethylcarbamyl-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 17 is stepping down from the connection, obtained in example 53A.

The output from theoretical 81%.

HPLC-MS (method 6): Rt=2,31 minutes

MS (ESIpos): m/z=528 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=of 7.36 (d, 1H), 7.23 percent-7,10 (m, 4H), 7,06-of 6.96 (m, 3H), 6,86-6,79 (m, 2H), 6,70 (d, 1H), 6,55 (dd, 1H), 5,50 (d, 1H), 5,32 (s, 1H), 4.92 in-4,82 (m, 1H), 4,34-to 4.23 (m, 2H), 4,20-3,93 (m, 4H), 3,20 (s, 3H), of 2.72 (s, 3H).

Example 55A

(3S*,3aR*,8bR*)-6-(2-chloroethoxy)-3A-(4-chlorophenyl)-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-oxime

The target compound is synthesized analogously to example 14 from the compound obtained in example 50A.

The output from theoretical 82%.

HPLC-MS (method 6): Rt=2,55 minutes

MS (ESIneg): m/z=468 (M-N)-.

1H-NMR (300 MHz, DMSO-d6): δ=11,1 (s, 1H), 7,35 (d, 1H), 7.23 percent-7,06 (m, 7H), 7,02-6,97 (m, 2H), 6,79 (d, 1H), 6,65 (dd, 1H), 5,78 (s, 1H), 4,34-to 4.28 (m, 2H), 3,99-3,93 (m, 2H), 3.45 points (t, 1H), 3,03 (d, 2H).

Example 56A

(1R*,3S*,3aR*,8bS*)-6-(2-chloroethoxy)-3A-(4-chlorophenyl)-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-amine

The target compound is synthesized analogously to example 15 from the compound obtained in example 55A.

The output from theoretical 89%.

HPLC-MS (method 6): Rt=1,89 minutes

MS (ESIpos): m/z=456 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,27-of 6.90 (m, 10H), 6,69 (d, 1H), return of 6.58 (dd, 1H), 4,32-4,24 (m, 2H), 3,99-to 3.92 (m, 2H), 3,62 (dd, 1H), 3,43 (dd, 1H), 2,44-2,31 (m, 1H), 2,25-2,02 (m, 1H).

Example 57A

4-Benzyloxy-6-hydroxyacetophenone/p>

To a solution of 50.00 g (329 mmol) of 2,4-dihydroxyacetophenone in 500 ml of dimethylformamide added 41 ml (345 mmol) of benzylbromide and 47,69 g (345 mmol) of potassium carbonate, and the resulting suspension is stirred over night at room temperature. The solid is sucked off on a glass filter, the filtrate is poured into 200 ml water and 200 ml of ethyl acetate. Share phase, the organic phase is washed with a saturated solution of ammonium chloride, water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. As a result of recrystallization from a mixture of diethyl ether and petroleum ether get 56,40 g of the target product as pink crystals (yield from theoretical 71%).

HPLC-MS (method 1): Rt=3,70 minutes

MC (ESIpos): m/z=243 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=12,60 (s, 1H), a 7.85 (d, 1H), of 7.48-7,31 (m, 5H), 6,60 (dd, 1H), 6,55 (d, 1H), 5,19 (s, 2H), has 2.56 (s, 3H).

Example 58A

6-Benzyloxybenzophenone-3-one

To a boiling suspension 18,44 g (82,55 mmol) of copper bromide(II) in 70 ml of ethyl acetate added 10 g (around 41.28 mmol) 4-benzyloxy-6-hydroxy-acetophenone, suspended in 30 ml of chloroform, and heated suspension over night under reflux. After this warm solution is filtered, and the residue on the filter is washed these is acetate. The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is dissolved in 150 ml of ethanol, add 7,72 g (94,06 mmol) of three-hydrate of sodium acetate and the resulting solution is heated for one hour under reflux. Then the reaction mixture was placed in an ice bath and poured ethanol. The aqueous residue is extracted three times with ethyl acetate and the combined organic phases are washed with 1N sodium hydroxide solution, 1N hydrochloric acid, and then with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. In the result column chromatography on silica gel 60 (solvent: toluene → toluene/ethyl acetate 1:1) get 5,52 g of the desired product as beige crystals (yield from a theoretical 56%).

HPLC-MS (method 4): Rt=3,53 minutes

MS (ESIpos): m/z=241 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,56-7,35 (m, 6N), 6,91 (d, 1H), 6,77 (dd, 1H), 5,23 (s, 2H), of 4.77(s, 2H).

Example 59A

2-Bromo-6-benzyloxybenzophenone-3(2H)-he

The target compound is synthesized analogously to example 43A on the basis of the compound obtained in example 58A.

The output from theoretical 40%.

HPLC-MS (method 12): Rt=4,12 minutes

MC (ESIpos): m/z=319 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,54-7,37 (m, 5H), for 6.81-of 6.71 (m, 2H), 5.56mm (s, 1H), 5,24 (s, 2H).

When the EP 60A

3-Tert-butyldimethylsilyloxy-6-benzyloxy-2-(4-chlorophenyl)-benzofuran

The target compound is synthesized analogously to example 44A from the compound obtained in example 59A.

The output from theoretical 77%.

HPLC-MS (method 4): Rt=5,20 minutes

MC (ESIpos): m/z=465 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=a 7.85 (d, 2H), to 7.59-7,20 (m, 9H),? 7.04 baby mortality (dd, 1H), 5,22 (s, 2H), with 1.07 (s, 9H), 0,17 (s, 3H), of 0.04 (s, 3H).

Example 61A

(S*,R*)-3-[6-benzyloxy-2-(4-chlorophenyl)-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal

The target compound (mixture of diastereomers) are synthesized analogously to example 5A on the basis of the compound obtained in example 60A.

Example A

2-(2-Chloroethoxy)-6-hydroxyacetophenone

The target compound is synthesized analogously to example 41 And on the basis of 2,6-dihydroxyacetophenone.

The output from theoretical 90%.

HPLC-MS (method 2): Rt=2,86 minutes

MS (ESIpos): m/z=215 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=12,1 (s, 1H), 7,34 (t, 1H), 6,56 (dd, 1H), of 6.52 (dd, 1H), 4,36-the 4.29 (m, 2H), 4,05-of 3.97 (m, 2H), 2,61 (s, 3H).

Example 63A

4-(2-Chloroethoxy)benzofuran-3-one

The target compound is synthesized analogously to example 42A on the basis of the compound obtained in example A.

The output from theoretical 69%.

HPLC-MS (method 2): Rt=2,42 minutes

MC (SIpos): m/z=213 (M+H) +.

1H-NMR (200 MHz, DMSO-d6): δ=to 7.61 (t, 1H), 6,80 (d, 1H), to 6.67 (d, 1H), 4,70 (s, 2H), 4,43 is 4.35 (m, 2H), 4,00-3,93 (m, 2H).

Example 64A

2-Bromo-4-(2-chloroethoxy)benzofuran-3(2H)-he

The target compound is synthesized analogously to example 43A on the basis of the compound obtained in example 63A.

The output from theoretical 86%.

HPLC-MS (method 4): Rt=min 2,90

MC (ESIpos): m/z=291 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=a 7.62 (t, 1H), 6,69 (d, 1H), 6,65 (d, 1H), vs. 5.47 (s, 1H), 4,42-4,37 (m, 2H), 3,98-3,93 (m, 2H).

Example 65A

2-Bromo-3-tert-butyldimethylsilyloxy-4-(2-chloroethoxy)benzofuran

The target compound is synthesized analogously to example 44A from the compound obtained in example 64A.

The output from theoretical 46%.

HPLC-MS (method 9): Rt=2,14 minutes

MS (ESIpos): m/z=292 [M+H-Si(CH3)2C(CH3)3]+.

1H-NMR (300 MHz, DMSO-d6): δ=7,22 (t, 1H), 7,11 (dd, 1H), 6,84 (dd, 1H), 4,43-to 4.38 (m, 2H), 3,99-of 3.94 (m, 2H), of 1.03 (s, 9H), of 0.26 (s, 6H).

Example 66A

3-Tert-butyldimethylsilyloxy-4-(2-chloroethoxy)-2-(4-chlorophenyl)-benzofuran

The target compound is synthesized analogously to example 45 ° on the basis of the compound obtained in example 65A.

The output from theoretical 75%.

HPLC-MS (method 4): Rt=3,29 minutes

MS (ESIpos): m/z=437 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,82-to 7.77 (m, 2H) EUR 7.57-7,52 (m, 2H), 7,26 (t, 1H), 7,16 (d, 1H), 6,83 (d, 1H), 4,45-to 4.41 (m, 2H), was 4.02-3,98 (m, 2H), of 1.03 (s, 9H), and 0.02 (s, 6H).

Example 67A

4-(2-Chloroethoxy)-2-(4-chlorophenyl)benzofuran-3-one

The target compound is synthesized analogously to example 46A on the basis of the compound obtained in example 66A. It is used in the next stage of the synthesis without further purification.

Example 68A

(S*,R*)-3-[4-(2-chloroethoxy)-2-(4-chlorophenyl)-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal

The target compound is synthesized analogously to example 5A on the basis of the compound obtained in example 67A.

The output from theoretical 28%.

HPLC-MS (method 9): Rt=2,68 minutes

MS (ESIpos): m/z=455 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=was 9.33 (dd, 1H), 7,70-the 7.65 (m, 2H), EUR 7.57 (t, 1H), 7,55-7,49 (m, 2H), 7,30-7,25 (m, 2H), 7,17-7,06 (m, 3H), 6,93 (d, 1H), 6,51 (d, 1H), 4,29 (dd, 1H), 4,28-4,10 (m, 2H), 3,83-of 3.77 (m, 2H), of 3.07 (ddd, 1H), of 2.53 (ddd, 1H).

Example 69A

(1S*,3S*,3aR*,8bS*)-8-(2-chloroethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 6A on the basis of the compound obtained in example 68A.

The output from theoretical 55%.

HPLC-MS (method 2): Rt=3,47 minutes

MS (ESIpos): m/z=457 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,28 (t, 1H), 7,25-7,20 (m, 2H), 7,20-to 7.15 (m, 2H), 7,12-7,03 (m, 3H), 6,91-6,86 (m, 2H), 6,72 (d, 1H), only 6.64 (d, 1H), 5,72 (d, 1H), 4,91 (s, 1H), 4,80 (ddd, 1H), 4,36-or 4.31 (m, 2H), 4,03-of 3.97 (m, 2H), 3,30-3,24 (m, 1H), 2,54-to 2.42 (m, 1H), 2,19 (ddd, 1H).

Example 70A

(3S*,3aR*,8bR*)-8-(2-chloroethoxy)-3A-(4-chlorophenyl)-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-he

The target compound is synthesized analogously to example 7A from the compound obtained in example 69A.

The output from theoretical to 63%.

HPLC-MS (method 9): Rt=2,70 minutes

MS (ESIpos): m/z=455 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,40 (t, 1H), 7,22-7,17 (m, 2H), 7,14-7,05 (m, 3H),? 7.04 baby mortality-of 6.96 (m, 4H), 6.87 in (d, 1H), of 6.71 (d, 1H), 6,03 (s, 1H), 4,40-4,24 (m, 2H), 3,93-3,86 (m, 2H), 3,70 (dd, 1H), 3,14 (dd, 1H), 2,95 (dd, 1H).

Example 71A

(1R*,3S*,3aR*,8bS*)-8-(2-chloroethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 8A on the basis of the compound obtained in example 70A.

The output from theoretical 70%.

HPLC-MS (method 8): Rt=3,67 minutes

MS (ESIpos): m/z=457 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7.24 to (t, 1H), 7,16-6,98 (m, 9H), of 6.68 (d, 1H), 6,59 (d, 1H), 5,11 (s, 1H), 4,60-a 4.53 (m, 1H), 4,50 (d, 1H), 4,33-of 4.25 (m, 2H), 4,03-3,90 (m, 3H), of 2.75 (dt, 1H), 2,05 (dd, 1H).

Example 72A

4-Hydroxybenzophenone-3-one

The target compound is synthesized analogously to example 42A based on 2,6-dihydroxyacetophenone.

The output from theoretical 54%.

HPLC-MS (method 4): Rt=2,04 minutes

MS (ESIpos): m/z=151 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=10,8 (s, 1H), 7,43 (t, 1H), 6,56 (dd, 1H), 6,44 (dd, 1H), with 4.64 (s, 2H).

Example 73A

4-(2-Methoxyethoxy)benzofuran-3-one

The target compound is synthesized analogously to example 18A on the basis of the compound obtained in example 72A.

The output from theoretical 68%.

HPLC-MS (method 4): Rt=2,23 minutes

MS (ESIpos): m/z=209 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=to 7.59 (t, 1H), 6.75 in (d, 1H), 6,65 (d, 1H), and 4.68 (s, 2H), 4,25-4,20 (m, 2H), 3,71-3,66 (m, 2H), 3,34 (s, 3H).

Example A

2-Bromo-4-(2-methoxyethoxy)benzofuran-3-one

The target compound is synthesized analogously to example 43A on the basis of the compound obtained in example 73A.

The output from theoretical 84%.

HPLC-MS (method 4): Rt=2,63 minutes

MS (ESIpos): m/z=287 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=8,24 (s, 2H), to 7.61 (t, 1H), 6,65 (d, 1H), 6,63 (d, 1H), the 5.45 (s, 1H), 4,25-4,20 (m, 2H), 3,71-the 3.65 (m, 2H), 3,34 (s, 3H).

Example 75A

2-Bromo-3-tert-butyldimethylsilyloxy-4-(2-methoxyethoxy)benzofuran

The target compound is synthesized analogously to example 44A from the compound obtained in example A.

The output from theoretical 99%.

HPLC-MS (method 14): Rt=2,43 minutes

MS (ESIpos): m/z=401 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,21 (t, 1H), 7,07 (dd, 1H), for 6.81 (dd, 1H), 4,25-4,20 (m, 2H), 3.72 points-3,66 (m, 2H), 3,29 (s, 3H), of 1.02 (s, 9H), is 0.24 (s, 6H).

Example 76A

3-Tert-butyldimethylsilyloxy-2-(4-chlorophenyl)-4-(2-methoxyethoxy)-benzofuran

The target compound is synthesized analogously to example 45 ° on the basis of the compound obtained in example 75A.

The output from theoretical 68%.

HPLC-MS (method 9): Rt=to 3.58 min

MS (ESIpos): m/z=433 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=a 7.85-7,79 (m, 2H), 7,58-7,53 (m, 2H), 7,26 (t, 1H), 7,14 (dd, 1H), PC 6.82 (dd, 1H), 4,27-4,22 (m, 2H), 3.75 to 3,70 (m, 2H), 3,29 (s, 3H), of 1.02 (s, 9H), to-0.02 (s, 6H).

Example 77A

2-(4-Chlorophenyl)-4-(2-methoxyethoxy)benzofuran-3-one

The target compound is synthesized analogously to example 46A on the basis of the compound obtained in example 76A. It is used in the next stage of the synthesis without further purification.

Example 78A

(S*,R*)-3-[2-(4-chlorophenyl)-4-(2-methoxyethoxy)-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal

The target compound is synthesized analogously to example 5A on the basis of the compound obtained in example 77A.

The output from theoretical 8%.

HPLC-MS (method 9): Rt=2,58 minutes

MS (ESIpos): m/z=451 (M+N)+.

Example 79A

(1S*,3S*,3aR*,8bS*)-6-(3-chloropropoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to examples 41A-48A based on 2,4-dihydroxyacetophenone and 3-chloropropanol.

HPLC-MS (method 13): Rt=3,02 minutes

MS (ESIneg): m/z=469 (M-H)- .

1H-NMR (300 MHz, DMSO-d6): δ=7,32-7,01 (m, 8H), 6,94-6,92 (m, 2H), 6,69 (d, 1H), 6,60 (dd, 1H), of 5.81 (d, 1H), free 5.01 (s, 1H), 4,48 was 4.42 (m, 1H), 4,13 (t, 2H), 3,80 (t, 2H), 3,35-of 3.27 (m, 1H), 2,47-to 2.41 (m, 1H), 2,30 with 2.14 (m, 3H).

Example 80A

N-(3-oxo-2,3-dihydro-1-benzofuran-6-yl)ndimethylacetamide

The solution to 64.6 g (0,484 mol) of aluminium chloride in 100 ml of 1,2-dichloroethane at 0°C under argon type of 32.6 g (0,181 mol) chloroacetanilide, and then within 15 minutes, 20 g (0,121 mol) of N-(3-methoxyphenyl)ndimethylacetamide. The temperature rises to 10°C. Then the reaction mixture is slowly warmed to room temperature and stirred over night. The brown mixture is introduced into ice water and add ethyl acetate. After vigorous mixing, precipitation of N-(3-methoxy-4-chloracetophenone)ndimethylacetamide, which is sucked off on a suction filter and dried in high vacuum. The obtained solid substance is introduced into 140 ml of ethanol and after the addition of 13.2 g (0,154 mol) of sodium acetate are heated overnight under reflux. After cooling, the mixture is mixed with water and remove the ethanol in a rotary evaporator. The precipitated solid is sucked off on a glass filter and dried. Get a 9.35 g of the product in a solid pink color (exit from a theoretical 40%).

1H-NMR (200 MHz, DMSO-d6): δ=10,5 (s, 1H), and 7.7 (s, 1H), and 7.6 (s, 1H), and 7.1 (s, 1H), and 4.8 (s, 2H), and 3.3 (s, 3H).

Example A

6-Amino-1-benzo is uranium-3(2H)-he

To a solution of 500 mg (2,62 mmol) of N-(3-oxo-2,3-dihydro-1-benzofuran-6-yl)ndimethylacetamide in 5 ml of methanol, add 5 ml of 1 N hydrochloric acid and heated for one hour under reflux. After cooling, the reaction mixture is introduced into a mixture of ice water, saturated solution of sodium bicarbonate and ethyl acetate. The organic phase is separated, washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Get 318 mg of the target compound as a brown powder, the degree of purity of 75% (output from theoretical 61%).

HPLC-MS (method 4): Rt=1,71 minutes

MS (ESIpos): m/z=150 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=7.24 to (s, 1H), 6,51 (br. s, 2H), 6,32 (dd, 1H), 6,12 (d, 1H), and 4.75(s, 2H).

Example A

Benzyl-(3-oxo-2,3-dihydro-1-benzofuran-6-yl)carbamate

To a solution of 23,42 g (157 mmol) of 6-amino-1-benzofuran-3(2H)-she's in 400 ml of Tetra-hydrofuran at 0°C add 54,7 ml (314 mmol) of diisopropylethylamine and 28.3 ml (188 mmol) of the benzyl ether of Harborview acid and stirred for 3 hours at room temperature. Then add the 4.7 ml (31 mmol) of the benzyl ether of Harborview acid and stirred over night. The reaction mixture is introduced into ice water and extracted twice with ethyl acetate. Merge the nnye organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. In the result of the chromatography was carried out on silica gel 60 (solvent: dichloromethane → dichloromethane/ethyl acetate 5:1) get 30,80 g of the desired product as colorless crystals (yield from a theoretical 64%).

HPLC-MS (method 4): Rt=3,43 minutes

MC (ESIpos): m/z=284 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=10,38 (s, 1H), 7,56-7,31 (m, 7H), 7,12 (dd, 1H), 5,20 (s, 2H), 4,74 (s, 1H).

Example 83A

Benzyl-[(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3A,8b-tetrahydro-1H-benzo[b]cyclopent[d]furan-6-yl]carbamate

The target compound is synthesized analogously to examples 43A (method a), 44A, 45A, 46A, 5A and 6A on the basis of the compound obtained in example A.

HPLC-MS (method 7); Rt=min 2,90

MC (ESIneg): m/z=526 (M-H)-.

1H-NMR (400 MHz, DMSO-d6): δ=9,88 (s, 1H), 7,46-6,91 (m, 17H), by 5.87 (d, 1H), 5,18 (m, 2H), 5,07 (s, 1H), 4,45-of 4.44 (m, 1H), 3,35 of 3.28 (m, 1H), 2,48 is 2.43 (m, 1H), 2,25-of 2.20 (m, 1H).

Example A

(1S*,3S*,3aR*,8bS*)-6-amino-3A-(4-chlorophenyl)-3-phenyl-1,2,3,3A-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

To a solution 8,18 g (of 15.5 mmol) of benzyl[(1S*,3S*,3aR*,8bS*)-3A-(4-chloro-phenyl)-1,8b-dihydroxy-3-phenyl-2,3,3A,8b-tetrahydro-1H-benzo[b]-cyclopent[d]furan-6-yl]carbamate in 100 ml of methanol was added 1 g of 10%palladium on charcoal and hydronaut for 2 hours under a pressure of 2 bar. The remainder after division is utilizator concentrate and get the 6.06 g of target compound (yield 92% of theoretical), which contains about 7% of the corresponding dehalogenating compounds as impurities.

HPLC-MS (method 13): Rt=2,34 minutes

MS (ESIpos): m/z=394 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,22-6,87 (m, 10H), 6,24-6,21 (m, 2H), 5,73 (d, 1H), 5,19 (s, 2H), 4,78 (s, 1H), of 4.44-4,37 (m, 1H), 3,35-3,24 (m, 1H), 2,48-to 2.40 (m, 1H), 2,27-2,11 (m, 1H).

Example 85A

Bromo-(4-chlorophenyl)acetic acid

80,0 g (469 mmol) 4-chlorophenylalanine acid are dissolved under argon in 200 ml of carbon tetrachloride and heated under reflux. To the boiling solution add 100 g (563 mmol) of N-bromosuccinimide and of 7.70 g (46,9 mmol) 2,2'-azobis-2-methylpropionitrile and the solution is heated overnight under reflux. Then the reaction solution is cooled to 0°C, sucked off the filter residue is washed with cold carbon tetrachloride and the filtrate concentrated. The residue is dissolved in diethyl ether and shaken out three times with a saturated aqueous solution of sodium bicarbonate. The pH of the combined aqueous phases by means of concentrated hydrochloric acid set at level 1 and extracted four times their diethyl ether. The combined organic phases are dried over magnesium sulfate, filtered and concentrated, obtaining 83,0 g of the target product (yield from theoretical 71%), which is subjected to further transformation without further the preliminary cleanup.

HPLC-MS (method 11): Rt=3,42 minutes

MS (ESIneg): m/z=249 (M-H)-.

1H-NMR (300 MHz, DMSO-d6): δ=13,5 (s, 1H), to 7.61-of 7.55 (m, 2H), 7,49-the 7.43 (m, 2H), 5,80 (s, 1H).

Example 86A

(4-Chlorophenyl)-(3,5-diproportionate)acetic acid

To a solution of 10.0 g (47,6 mmol) of 3,5-disproportional and 11.9 g (47,6 mmol) of bromo(4-chlorophenyl)acetic acid in 150 ml of tetrahydrofuran under argon portions add 4,37 g (109 mmol) of sodium hydride as a 60%dispersion in mineral oil. The solution is stirred for half an hour at room temperature and during the night heated under reflux. Then, while cooling in an ice bath, add water, extracted three times with chloroform, the combined organic phases are washed with 1N sodium hydroxide solution and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated (remainder 1). The pH of the combined aqueous phases by means of concentrated hydrochloric acid set at level 1 and extracted three times their diethyl ether. The combined organic phases are washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated (remainder 2). In the result of the chromatography was carried out combined residues 1 and 2 on silica gel 60 (1st solvent for the Department not turned 3,5-dipropoxy the La: toluene/ethyl acetate 9:1, 2nd solvent: dichloromethane/methanol 9:1) gain of 12.1 g of the target product (yield of theoretical, 67%).

HPLC-MS (method 1): Rt=4,21 minutes

MS (ESIpos): m/z=379 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=rate of 7.54 (d, 2H), 7,38 (d, 2H), 6,09-6,01 (m, 3H), 5.41 (s, 1H), 3,84 (t, 4H), 1,67 (sextet, 4H), 0.94 (t, 6H).

Example 87A

2-(4-Chlorophenyl)-4,6-dibromobenzophenone-3(2H)-he

The target compound is synthesized analogously to example 4A from the compound obtained in example 86A.

The output from theoretical 44%.

HPLC-MS (method 12): Rt=4,75 minutes

MS (ESIpos): m/z=361 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,50-7,44 (m, 2H), 7,35-7,30 (m, 2H), 6,46 (d, 1H), 6,21 (d, 1H), 5,74 (s, 1H), 4,11-3,98 (m, 4H), 1,82-of 1.64 (m, 4H), 0,99 (t, 3H), of 0.96 (t, 3H).

Example A

(S*,R*)-3-[2-(4-chlorophenyl)-4,6-dipropoxy-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal

The target compound is synthesized analogously to example 5A on the basis of the compound obtained in example 87A.

The output from theoretical 49%.

HPLC-MS (method 12): Rt=4,93 minutes

MS (ESIpos): m/z=493 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=to 9.32 (d, 1H), 7,69-to 7.61 (m, 2H), 7,55-7,47 (m, 2H), 7,31-to 7.09 (m, 5H), 6,47 (d, 1H), 5,98 (d, 1H), 4,24 (dd, 1H), was 4.02 (t, 2H), 3,90-3,74 (m, 2H), to 3.02 (ddd, 1H), 2.57 m) is 2.43 (m, 1H), 1,73 (sextet, 2H), 1.57 in (sextet, 2H), of 0.97 (t, 3H), from 0.84 (t, 3H).

Examples of carrying out the invention

Example 1

(3S*,3aR*,8bR*)-3A-(4-bromophenyl)-6,8-diethoxy-8b-hydroc and-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-oxime

The target compound is synthesized analogously to example 14 from the compound obtained in example 7A.

The output from theoretical 51%.

HPLC-MS (method 4): Rt=3,66 minutes

MS (ESIneg): m/z=522 (M-N)-.

1H-NMR (300 MHz, DMSO-d6): δ=to 11.0 (s, 1H), was 7.36-7,30 (m, 2H), 7,14-7,05 (m, 3H), 7,00-6,94 (m, 4H), 6.35mm (d, 1H), 6,14 (d, 1H), 5.25 in (s, 1H), 4,11-3,95 (m, 4H), 3,52 (t, 1H), 3,02-of 2.93 (m, 2H).

Example 2

(1R*,3S*,3aR*,8bS*)-3A-(3'-aminobiphenyl-4-yl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

to 51.1 mg(0.10 mmol) of (1R*,3S*,3aR*,8bS*)-3A-(4-bromophenyl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol (from example 8A)of 15.5 mg (0.10 mmol) of 3-aminophenylamino acid, 10,6 mg (0.10 mmol) of sodium carbonate and 5.8 mg (0.005 mmol) tetrakis-(triphenylphosphine)palladium(O) is heated under argon over night at 80°C in a mixture of 0.1 ml of water with 0.5 ml of dioxane. The reaction mixture was diluted with DMSO, filtered and the filtrate purified by the method of preparative HPLC. Get to 17.4 mg of the target product (yield from a theoretical 25%).

HPLC-MS (method 10): Rt=2,07 minutes

MS (ESIpos): m/z=524 (M+N)+.

Example 3

(1R*,3S*,3aR*,8bS*)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydro-3A-(4-thiophene-3-ylphenyl)of cyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 2.

HPLC-MS (the method 10): R t=2,41 minutes

MS (ESIpos): m/z=515 (M+N)+.

Example 4

(1R*,3S*,3aR*,8bS*)-3A-(3'-cyanobiphenyl-4-yl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 2.

HPLC-MS (method 10): Rt=2,38 minutes

MS (ESIpos): m/z=534 (M+H)+.

Example 5

(1R*,3S*,3aR*,8bS*)-6,8-diethoxy-3A-[4-(1H-indol-5-yl)-phenyl]-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 2.

HPLC-MS (method 10): Rt=2,31 minutes

MS (ESIpos): m/z=548 (M+N)+.

Example 6

(1R*,3S*,3aR*,8bS*)-6,8-diethoxy-3A-(3'-ethylsulfonyl-4-yl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 2.

HPLC-MS (method 10): Rt=2.26 and minutes

MS (ESIpos): m/z=601 (M+H)+.

Example 7

(1R*,3S*,3aR*,8bS*)-3A-(5'-amino-2'-forgivenes-4-yl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 2.

HPLC-MS (method 10): Rt=2,05 minutes

MS (ESIpos): m/z=542 (M+H)+.

Example 8

(1R*,3S*,3aR*,8bS*)-3A-(4-cinoxacin-6-ylphenyl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 2.

HPLC-MS (method 10): Rt=2,29 minutes

MS (ESIpos): m/z=561 (M+N)+.

Example 9

(1R*,3S*,3aR*,8bS*)-6,8-diethoxy-3-phenyl-3A-(4-pyrrolidin-1-ylphenyl)-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

to 51.1 mg (0.10 mmol) of (1R*,3S*,3aR*,8bS*)-3A-(4-bromophenyl)-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol (from example 8A), 4,7 mg (0.07 mmol) of pyrrolidine, 7,1 mg (0.07 mmol) of tert-butyl sodium, 1.2 mg (0.001 mmol) of Tris(dibenzylideneacetone)-diplodia(A) and 1.7 mg (of 0.003 mmol) of racemic 2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl heated over night at 80°C under argon in 0.6 ml of toluene. The mixture is then concentrated, mixed with DMSO, filtered and the filtrate purified by the method of preparative HPLC. Get 14.5 mg of product (yield from theoretical 43%).

HPLC-MS (method 10): Rt=2,38 minutes

MS (ESIpos): m/z=502 (M+N)+.

Example 10

(1R*,3S*,3aR*,8bS*)-3A-[4-(benzylmethylamine)phenyl]-6,8-diethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 9.

HPLC-MS (method 10): Rt=2,44 minutes

MS (ESIpos): m/z=552 (M+H)+.

Example 11

(1R*,3S*,3aR*,8bS*)-6,8-diethoxy-3A-[4-(methylpyridin-4-ylmethylamino)-phenyl]-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-on the ol

The target compound is synthesized analogously to example 9.

HPLC-MS (method 10): Rt=1,73 minutes

MS (ESIpos): m/z=553 (M+H)+.

Example 12

(2R*,3S*,3aR*,8bR*)-3A-(4-bromophenyl)-6,8-diethoxy-2-dimethylcarbamyl-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-he

The target compound is synthesized analogously to example 16 from the compound obtained in example 9A.

The output from theoretical 29%.

HPLC-MS (method 4): Rt=3,53 minutes

MS (ESIpos): m/z=581 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,37-7,29 (m, 2H), 7,15-of 6.90 (m, 7H), to 6.43 (d, 1H), 6,16 (d, 1H), 6,00 (s, 1H), with 4.64 (d, 1H), 4,28 (d, 1H), 4,15-3,91 (m, 4H), 3,30 (s, 3H), 2,77 (s, 3H), of 1.35 (t, 3H), 1,22 (t, 3H).

Example 13

(1R*,2R*,3S*,3aR*,8bS*)-3A-(4-bromophenyl)-6,8-diethoxy-2-dimethylcarbamyl-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 17 from the compound obtained in example 12.

The output from theoretical 80%.

HPLC-MS (method 5): Rt=3,61 minutes

MS (ESIpos): m/z=583 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,27-7,19 (m, 2H), 7,12-to 6.95 (m, 5H), 6,88-to 6.80 (m, 2H), 6,29 (d, 1H), 6,12 (d, 1H), 5,20 (s, 1H), 4,84 was 4.76 (m, 1H), 4,60 (d, 1H), 4,29 (d, 1H), 4,13-of 3.97 (m, 5H), 3,26 (s, 3H), of 2.75 (s, 3H), 1,34 (t, 3H), of 1.31 (t, 3H).

Example 14

(3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6,8-diethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-hydroxy-Christ.

To 500 mg (1,08 mmol) of (3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6,8-diethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-she (from example 15A), dissolved in 20 ml of ethanol at room temperature first, add 20 ml of pyridine, and then 90 mg (1,30 mmol) of chloride hydroxylamine, and the solution is stirred for one day. The residue after distillation of the volatile components, made in a rotary evaporator, dissolved in ethyl acetate. Then the organic phase is washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Get 515 mg of racemic product as colorless crystals (yield from theoretical 100%).

HPLC-MS (method 9): Rt=2,66 minutes

MC (ESIneg): m/z=478 (M-H)-.

1H-NMR (300 MHz, DMSO-d6): δ=br11.01 (s, 1H), 7,21-6,94 (m, 9H), 6.35mm (d, 1H), 6,14 (d, 1H), 5.25 in (s, 1H), 4,10-3,99 (m, 4H), 3,55-to 3.49 (m, 1H), 3,00 vs. 2.94 (m, 2H), 1,36-of 1.30 (m, 6H).

Example 15

(1R*,3S*,3aR*,8bS*)-1-amino-3A-(4-chlorophenyl)-6,8-diethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran

To a solution 3,22 ml (3,22 mmol) of a 1N solution of sociallyengaged in diethyl ether at 0°C and stirring are added in several portions 115 mg (1.07 mmol) of (3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6,8-diethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent is the[b]benzofuran-1-oxime (example 14) in an additional 6 ml of diethyl ether. Upon completion of the gassing reaction mixture for 30 minutes, heated under reflux. Then at 0°C. the mixture is diluted with ethyl acetate and added dropwise 1N solution of sodium hydroxide. The mixture is stirred for five minutes, then divide phase. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and koncentriruiutsia recrystallized from a mixture of dichloromethane, diethyl ether and petroleum ether. The obtained crystals are sucked off by a glass filter and dried. Obtain 155 mg of racemic product as colorless crystals (yield from theoretical 31%).

HPLC-MS (method 8): Rt=2,62 minutes

MS (ESIneg): m/z=464 (M-N)-.

1H-NMR (400 MHz, DMSO-d6): δ=7,13-7,03 (m, 7H), 6,91 (d, 2H), 6,24 (d, 1H), 6,11 (d, 1H), 4,06-4,00 (m, 4H), of 3.75 (dd, 1H), 3,34 (dd, 1H), 2,41 to 2.35 (m, 1H), 2,15-2,05 (m, 1H), 1,35 to 1.31 (m, 1H).

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 29A).

Analytical data (method 29V):

enantiomer A: Rt=3,89 min, enantiomer In: Rt=6,09 minutes

Example 16

(2R*,3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6,8-diethoxy-2-dimethylcarbamyl-8-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-he

To a solution of 550 mg (1.0 mmol) of (2R*,3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6,8-diethoxy-8-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzo-furan-2-carboxylic acid (from example 17A) in tetrahydrofuran at 0°C. add 674 mg (1,30 mmol) hexaphosphate benzotriazol-1-electropermeabilization, 106 mg (1,30 mmol) of dimethylamine hydrochloride and 0.47 ml (2,70 mmol) of N,N-diisopropylethylamine, after which the mixture is stirred for 4 hours at 0°C. Then the reaction mixture was poured into a mixture of 50 ml of saturated solution of ammonium chloride, ice water and ethyl acetate. After separation of the aqueous phase the organic phase is extracted twice with ethyl acetate. The combined organic phases are washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was subjected to purification on silica gel 60 (toluene/ethyl acetate 10:1, 6:1, 4:1 as the chromatographic solvent). Obtain 159 mg of racemic product as a colourless foam (yield from theoretical 27%).

HPLC-MS (method 2): Rt=3,41 minutes

MS (ESIpos): m/z=536 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,25-6,94 (m, 9H), to 6.43 (d, 1H), 6,16 (d, 1H), 6,00 (s, 1H), 4,63 (d, 1H), 4,29 (d, 1H), 4,13-of 3.94 (m, 4H), 3,30 (s, 3H), 2,77 (s, 3H), of 1.35 (t, 3H), 1,22 (t, 3H).

Example 17

(1R*,2R*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6,8-diethoxy-2-dimethyl-urea-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The solution 1104 mg (4.20 mmol) of tetramethylenedisulfotetramine in 1.5 ml of acetonitrile and 1.5 ml of glacial acetic acid for 30 minutes, stirred at room temperature. Add 150 mg (0.28 mmol) of (2R*,3S*,3aR*,8bR*)-3 is-(4-chlorophenyl)-6,8-diethoxy-2-dimethylcarbamyl-8-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]-benzofuran-1-it is in the form of a solution of 13.5 ml of acetonitrile and stirred for two hours at room temperature. At 0°C is added a saturated solution of sodium bicarbonate and the mixture extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and koncentriruiutsia of diethyl ether, the crystals are sucked off on a filter, washed with a mixture of diethyl ether and petroleum ether (1:1) and dried. Obtain 94 mg of the desired product in the form of a racemic mixture (exit from theoretical 62%).

HPLC-MS (method 8): Rt=3,23 minutes

MS (ESIpos): m/z=538 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,15-6,94 (m, 7H), 6,85-PC 6.82 (m, 2H), 6,29 (d, 1H), 6,12 (d, 1H), 5,16 (s, 1H), 4,82-rate 4.79 (m, 1H), 4,56 (d, 1H), 4,29 (d, 1H), 4,08-3,99 (m, 4H), of 3.25 (s, 3H), was 2.76 (s, 1H), 1,36-of 1.29 (m, 6H).

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 26A).

Analytical data (method 26V):

enantiomer A: Rt=3,96 min, enantiomer In: Rt=15,29 minutes

Example 18

(1R*,3S*,3aR*,8bS*)-6,8-bis(2-methoxyethoxy)-3A-(4-bromophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 6A on the basis of the product obtained in example 22A (unlike other reactions of this type in this case is formed TRANS-diol).

The output from theoretical 72%.

HPLC-MS (method 2): Rt=to 4.38 min

MS (ESIpos): m/z=572 (M+N)+.

1H-NMR (400 MHz, DM what About the-d 6): δ=7,27-7,22 (m, 2H), 7,13? 7.04 baby mortality (m, 5H), 7,00-to 6.95 (m, 2H), 6,29 (d, 1H), 6,18 (d, 1H), free 5.01 (s, 1H), 4,56-4,51 (m, 1H), to 4.41 (d, 1H), 4,22-4.09 to (m, 4H), 3,86 (dd, 1H), 3,70-to 3.64 (m, 4H), to 3.34 (s, 6H) 2,70 (ddd, 1H), 1,96(dd, 1H).

Example 19

(3S*,3aR*,8bR*)-6,8-bis(2-methoxyethoxy)-3A-(4-bromophenyl)-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-he

The target compound is synthesized analogously to example 7A from the product obtained in example 18.

The output from theoretical 33%.

HPLC-MS (method 3): Rt=4,30 minutes

MS (ESIpos): m/z=569 (M+N)+.

Example 20

(1S*,3S*,3aR*,8bS*)-6,8-bis(2-dimethylaminoethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 28A.

The output from theoretical 87%.

HPLC-MS (method 5): Rt=2,12 minutes

MS (ESIpos): m/z=553 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=7.23 percent-7,03 (m, 7H), 6,93-to 6.88 (m, 2H), 6,44 (d, 1H), 6.30-in (d, 1H), to 4.98 (s, 1H), 4,67 (t, 1H), to 4.38-4,30 (m, 4H), 3,48 is 3.23 (m, 5H), was 2.76 (s, 6H), 2,70 (s, 6H), 2,53-to 2.42 (m, 1H), of 2.21 (ddd, 1H).

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 15A).

Analytical data (method 15V):

enantiomer A: Rt=7.23 percent min, enantiomer In: Rt=9,41 minutes

Example 21

(1R*,3S*,3aR*,8bS*)-6,8-bis(2-dimethylaminoethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-t is tragerelement[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 30A.

The output from theoretical 82%.

HPLC-MS (method 2): Rt=2,03 minutes

MS (ESlpos): m/z=553 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,20-to 6.95 (m, 9H), 6,27 (d, 1H), of 6.20 (d, 1H), 5,16 (s, 1H), 4,49 (d, 1H), 4.26 deaths-4,11 (m, 1H), 4,11-was 4.02 (m, 4H), of 3.84 (dd, 1H), 2,86 is 2.55 (m, 5H), 2,24 (s, 6H), are 2.19 (s, 6H), 1,95 (dd, 1H).

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 15A).

Analytical data (method 15V):

enantiomer A: Rt=6,78 min, enantiomer In: Rt=8,18 minutes

Example 22

(1S*,3S*,3aR*,8bS*)-6,8-bis(2-dimethylaminoethoxy)-3A-(4-bromophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 35A.

The output from theoretical 59%.

HPLC-MS (method 4): Rt=2,19 minutes

MS (ESIpos): m/z=597 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,34-7,29 (m, 2H), 7.18 in for 7.12 (m, 2H), 7,11? 7.04 baby mortality (m, 3H), 6,94-to 6.88 (m, 2H), 6.48 in (d, 1H), 6,32 (d, 1H), 6,10 (s, 1H), free 5.01 (s, 1H), and 4.68 (t, 1H), 4,43-4,37 (m, 4H), 3,66 is-3.45 (m, 5H), 2,87 (s, 6H), to 2.85 (s, 6H), 2,55 is 2.43 (m, 1H), 2,31-of 2.15 (m, 1H).

Example 23

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-ethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target connection SYN is Airout analogously to example 6A on the basis of product, obtained in example 39A.

The output from theoretical 73%.

HPLC-MS (method 3): Rt=3,57 minutes

MS (ESIneg): m/z=421 (M)-.

1H-NMR (200 MHz, DMSO-d6): δ=7,28-of 6.90 (m, 10H), of 6.66 (d, 1H), to 6.57 (dd, 1H), of 5.84 (d, 1H), to 5.03 (s, 1H), 4,49-4,39 (m, 1H), 4,05 (q, 3H), 3,31-of 3.25 (m, 1H), 2,49-of 2.38 (m, 1H), 2,24-of 2.15 (m, 1H), of 1.34 (t, 3H).

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 30A).

Analytical data (method 30V):

enantiomer A: Rt=3,90 min, enantiomer In: Rt=5,46 minutes

Example 24

(3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6-ethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-he

The target compound is synthesized analogously to example 7A from the product obtained in example 23.

The output from theoretical 81%.

HPLC-MS (method 9): Rt=2,66 minutes

MS (ESIpos): m/z=403 [M+H-H2O]+.

1H-NMR (200 MHz, DMSO-d6): δ=7,25-7,01 (m, 10H), PC 6.82 (d, 1H), 6,62 (dd, 1H), 6,28 (s, 1H), 4,08 (q, 2H), 3,69-to 3.58 (m, 1H), 3,42-up 3.22 (m, 1H), 2,93-and 2.79 (m, 1H), of 1.35 (t, 3H).

Example 25

(3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6-ethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-oxime

The target compound is synthesized analogously to example 14 from the product obtained in example 24.

The output from theoretical 99%.

HPLC-MS (method 9): Rt=2.57 m min

MS (ESIneg): m/z=434 (M-N)-.

<> 1H-NMR (300 MHz, DMSO-d6): δ=11,12 (s, 1H), 7,32 (d, 1H), 7,20 (d, 2H), 7,11-to 7.09 (m, 5H), 7,01-6,98 (m, 2H), 6.73 x (d, 1H), 6,60 (dd, 1H), 5,74 (s, 1H), 4,07 (dq, 2H), 3,40-to 3.38 (m, 1H), 3.04 from-a 3.01 (m, 2H), of 1.34 (t, 3H).

Example 26

(1R*,3S*,3aR*,8bR*)-1-amino-3A-(4-chlorophenyl)-6-ethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran

The target compound is synthesized analogously to example 15 from the product obtained in example 25.

The output from theoretical 50%.

HPLC-MS (method 9): Rt=1,96 minutes

MS (ESIpos): m/z=422 (M-N)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,19 (d, 1H), 7,12-6,94 (m, 9H), 6,62 (d, 1H), of 6.52 (dd, 1H), 5,90 (broad s, 1H), Android 4.04 (q, 2H), 3,61 (dd, 1H), 3,42 (dd, 1H), 2,43 to 2.35 (m, 1H), 2,19-2,07 (m, 1H), 1,33 (t, 3H).

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 27A).

Analytical data (method 27):

enantiomer A: Rt=4,22 min, enantiomer In: Rt=7,38 minutes

Example 27

(2R*,3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6-ethoxy-2-dimethylcarbamyl-8-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1-he

The target compound is synthesized analogously to example 16 from the product obtained in example 40A.

The output from theoretical 26%.

HPLC-MS (method 9): Rt=2,49 minutes

MS (ESIpos): m/z=492 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,25-of 6.96 (m, 10H), PC 6.82 (d, 1H), 6,59 (dd, 1H), 6,40 (s, 1H), 4,77 (d, J=13,41 Hz, 1), 4,19 (d, J=13,41 Hz, 1H), 4,14-of 4.05 (m, 2H), 3.27 to (s, 3H), 2,77 (s, 3H), of 1.38 and 1.33 (m, 3H).

Example 28

(1R*,2R*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-ethoxy-2-dimethylcarbamyl-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 17 from the product obtained in example 27.

The output from theoretical 61%.

HPLC-MS (method 9): Rt=2,31 minutes

MS (ESIpos): m/z=494 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,34 (d, 1H), 7,22-to 6.80 (m, 9H), only 6.64 (d, 1H), 6,50 (dd, 1H), 5,48 (d, 1H), from 5.29 (s, 1H), 4,91-4,84 (m, 1H), 4,24-3,95 (m, 4H), 3,20 (s, 3H), of 2.72 (s, 3H), of 1.34 (t, 3H).

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 28A).

Analytical data (method 28V):

enantiomer A: Rt=4,48 min, enantiomer In: Rt=10,97 minutes

Example 29

(1S*,3S*,3aR*,8bS*)-3A-(4-bromophenyl)-6-ethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to examples 2A-6A based on 3-ethoxyphenol.

HPLC-MS (method 12): Rt=4,39 minutes

MS (ESIpos): m/z=489 (M+Na)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,32-of 7.23 (m, 3H), 7,16-7,06 (m, 5H), 6,95-6,91 (m, 2H), 6,66-is 6.54 (m, 2H), of 5.83 (d, 1H), to 5.03 (s, 1H), 4,49-4,39 (m, 1H), of 4.05 (q, 2H), 3,36-3,26 (m, 1H), of 2.51-of 2.09 (m, 2H), of 1.34 (t, 3H).

Example 30

(3S*,3aR*,8bR*)-3A-(4-bromophenyl)-6-ethoxy-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]be zofran-1-he

The target compound is synthesized analogously to example 7A from the product obtained in example 29.

The output from theoretical 85%.

HPLC-MS (method 11): Rt=4,5 minutes

MS (ESIneg): m/z=463 (M)-.

1H-NMR (300 MHz, DMSO-d6): δ=7,33-7,02 (m, 10H), for 6.81 (d, 1H), is 6.61 (dd, 1H), 6,23 (s, 1H), 4,12-of 4.05 (m, 2H), 3,68-3,61 (m, 1H), 3,40 is 3.23 (m, 1H), 2.91 in-2,82 (m, 1H), of 1.35 (t, 3H).

Example 31

(1R*,3S*,3aR*,8bS*)-3A-(4-bromophenyl)-6-ethoxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 8A on the basis of the product obtained in example 30.

The output from theoretical 79%.

HPLC-MS (method 11): Rt=4.2V min

MS (ESIneg): m/z=465 (M-H)-.

1H-NMR (200 MHz, DMSO-d6): δ=7,32-of 7.23 (m, 3H), 7,11-6,94 (m, 7H), 6,60 (d, 1H), 6,50 (dd, 1H), 5,22 (s, 1H), 5,14 (d, 1H), 4,56 (broad s, 1H), 4.09 to 3,98 (m, 2H), 3,89-with 3.79 (m, 1H), 2,74-to 2.57 (m, 1H), 1,96-of 1.84 (m, 1H), of 1.34 (t, 3H).

Example 32

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(2-dimethylaminoethoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

100 mg (0.22 mmol) (1S*,3S*,3aR*,8bS*)-6-(2-chloroethoxy)-3A-(4-chloro-phenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol (from example 48A) in 10 ml of 33%ethanolic solution of dimethylamine is heated overnight at 70°C in a closed apparatus under argon. The reaction solution after cooling the concentrate is. In the result column chromatography on silica gel 60 (a mixture of dichloromethane, methanol and triethylamine 95:5:1 as the chromatographic solvent) to obtain 89 mg of the desired product in the form of a racemic mixture (exit from theoretical 87%).

HPLC-MS (method 1): Rt=min 2,90

MS (ESIpos): m/z=466 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,30-7,02 (m, 8H), of 6.96-to 6.88 (m, 2H), 6,69 (d, 1H), 6,59 (dd, 1H), to 5.85 (d, 1H), 5,04 (s, 1H), 4,51-to 4.38 (m, 1H), 4,14-Android 4.04 (m, 2H), 3,38 is 3.23 (m, 1H), 2,73-of 2.64 (m, 2H), 2,50-is 2.37 (m, 1H), and 2.26 (s, 6H), 2,24 is 2.10 (m, 1H).

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 19A).

Analytical data (method 19C):

enantiomer A: Rt=10,52 min, enantiomer In: Rt=12,53 minutes

Example 33

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(2-pyrrolidin-1 ylethoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32, using pyrrolidine as the amine component.

The output from theoretical 99%.

HPLC-MS (method 2): Rt=2,29 minutes

MS (ESIpos): m/z=492 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,30-7,02 (m, 8H), of 6.96-to 6.88 (m, 2H), of 6.68 (d, 1H), 6,59 (dd, 1H), to 5.85 (d, 1H), 5,04 (s, 1H), 4,51-to 4.38 (m, 1H), 4.09 to (t, 2H), 3,37-3,24 (m, 1H), and 2.79 (t, 2H), 2.57 m-is 2.37 (m, 5H), of 2.20 (ddd, 1H), 1,73-of 1.65 (m, 4H).

Preparative separation of the racemic mixture of the enantiomers is implemented by ASH on chiral phase (method 18).

Analytical data (method 18V):

enantiomer A: Rt=6,53 min, enantiomer In: Rt=8,48 minutes

Example 34

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(2-methylenedioxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32, using methylamine as the amine component.

The output from theoretical 95%.

HPLC-MS (method 2): Rt=2,19 minutes

MS (ESIpos): m/z=452 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,79 (s, 1H), 7,31 (d, 1H), 7,24-7,13 (m, 4H), 7,12-7,01 (m, 3H), 6,95-of 6.90 (m, 2H), 6.73 x (d, 1H), only 6.64 (dd, 1H), of 5.89 (d, 1H), to 5.03 (s, 1H), 4,49-to 4.41 (m, 1H), 4,22 (t, 2H), 3,36-3,18 (m, 3H), 2.57 m (s, 3H), 2,52-to 2.40 (m, 1H), 2,22 (ddd, 1H).

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 16A).

Analytical data (method 16B):

enantiomer A: Rt=9,31 min, enantiomer In: Rt=13,90 minutes

Example 35

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(2-diethylaminoethoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32, using diethylamine as the amine component.

The output from theoretical 56%.

HPLC-MS (method 4): Rt=2,34 minutes

MS (ESIpos): m/z=494 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=7,26 (d, 1H), 7.23 percent-7,14 (m, 4H), 7,11-7,01 (m, 3H), 6,94-of 6.90 (m, 2H), to 6.67 (d, 1H), to 6.58 (dd, 1H), to 5.85 (d, 1H), 5,02 (s, 1H), 4,48-to 4.41 (m, 1H), 4,06 (t, 2H), 3,37-3,26 (m, 1H), 2,86-by 2.73 (m, 2H), 2,63-of 2.54 (m, 4H), 2,49-to 2.40 (m, 1H), measuring 2.20 (ddd, 1H), and 1.00 (t, 6H).

Example 36

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(2-ethyleneoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32, using ethylamine as the amine component.

The output from theoretical 31%.

HPLC-MS (method 13): Rt=1,97 minutes

MS (ESIpos): m/z=466 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,27 (d, 1H), 7,24-7,13 (m, 4H), 7,12-7,03 (m, 3H), 6,95-of 6.90 (m, 2H), 6,69 (d, 1H), is 6.61 (dd, 1H), to 5.85 (s, 1H), 5,02 (s, 1H), 4,45 (t, 1H), 4,10 (t, 2H), and 3.31 (dd, 1H), 3.00 for (t, 2H), 2,72 (q, 2H), 2,48-to 2.40 (m, 1H), 2,28 with 2.14 (m, 1H), only 1.08 (t, 3H).

Example 37

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(2-isopropylaminoethyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32, using Isopropylamine as the amine component.

The output from theoretical 26%.

HPLC-MS (method 13): Rt=1,97 minutes

MS (ESIpos): m/z=480 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,28 (d, 1H), 7,24-7,13 (m, 4H), 7,12-7,03 (m, 3H), 6,95-of 6.90 (m, 2H), 6,69 (d, 1H), is 6.61 (dd, 1H), to 5.85 (s, 1H), 5,02 (s, 1H), 4,45 (t, 1H), 4,10 (t, 2H), 3,36-of 3.27 (m, 1H), 3.00 for (t, 2H), 2.95 and (septet, 1H), 2,48-to 2.40 (m, 1H), 2,31 with 2.14 (m, 1H), only 1.08 (d, 6H).

Example 38

(1S*,3S*,3aR*,8bS*)-6-(2-azetidin-1 ylethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran,8b-(1H)-diol

The target compound is synthesized analogously to example 32, using azetidin as the amine component.

The output from theoretical 58%.

HPLC-MS (method 13): Rt=1,96 minutes

MS (ESIpos): m/z=478 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=of 7.25 (d, 1H), 7.23 percent-7,13 (m, 4H), 7,12-7,02 (m, 3H), 6,95-of 6.90 (m, 2H), only 6.64 (d, 1H), 6,56 (dd, 1H), of 5.82 (s, 1H), 5,00 (s, 1H), of 4.44 (t, 1H), 3,95 (t, 2H), 3,36-of 3.27 (m, 1H), 3,23 (t, 4H), to 2.74 (t, 2H), 2,48-2,39 (m, 1H), 2,28 with 2.14 (m, 1H), 1,99 (quintet, 2H).

Example 39

(1S*,3S*,3aR*,8bR*)-3A-(4-chlorophenyl)-6-(2-morpholine-4-ylethoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32, using morpholine as the amine component.

The output from theoretical 82%.

HPLC-MS (method 9): Rt=1,76 minutes

MS (ESIpos): m/z=508 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=7.29 trend-7,02 (m, 8H), of 6.96-6.87 in (m, 2H), 6,69 (d, 1H), 6,59 (dd, 1H), to 5.85 (d, 1H), 5,04 (s, 1H), 4,50-to 4.38 (m, 1H), 4,12 (t, 2H), 3,63-of 3.54 (m, 4H), 3,44 are 2.98 (m, 5H), 2,70 (t, 2H), 2,48-of 2.36 (m, 1H), 2,32-2,07 (m, 1H).

Example 40

Hydroformed (1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(2-cyclopropyl-aminoethoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32, using cyclopropylamine as the amine component. Purification of the crude product is performed by the method of preparative HPLC (it is lanky RP18, chromatographic solvent: acetonitrile/water with 0.1% formic acid, gradient 5:95→95:5).

The output from theoretical 48%.

HPLC-MS (method 13): Rt=1,94 minutes

MS (ESIpos): m/z=478 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=8.17 and (s, 1H), 7,30-7,02 (m, 8H), of 6.96-to 6.88 (m, 2H), of 6.68 (d, 1H), 6,59 (dd, 1H), USD 5.76 (s, 1H), 5,04 (s, 1H), 4,50-to 4.38 (m, 1H), of 4.05 (t, 2H), 3,48 is 3.25 (m, 1H), 2.95 and (t, 2H), 2,47 to 2.35 (m, 1H), 2,28-of 2.08 (m, 2H), 0,45-0,32 (m, 2H), between 0.30 to 0.20 (m, 2H).

Example 41

Dehydrothermal (1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-[2-(2-dimethyl-aminoethylamino)ethoxy]-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]-benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 using 2-diethylaminoethylamine as the amine component. Purification of the crude product is performed by the method of preparative HPLC (RP18 column, the chromatographic solvent: acetonitrile/water with 0.1% formic acid, gradient 5:95→95:5).

The output from theoretical 85%.

HPLC-MS (method 6): Rt=1,37 minutes

MS (ESIpos): m/z=509 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=by 8.22 (s, 2H), 7,30-7,02 (m, 8H), 6,95-of 6.90 (m, 2H), 6,70 (d, 1H), 6,60 (dd, 1H), 4,45 (t, 1H), 4,12 (t, 2H), and 3.31 (dd, 1H), to 3.02 (t, 2H), of 2.81 (t, 2H), 2,47-of 2.36 (m, 1H, in), 2.25 (s, 6H), 2,24 with 2.14 (m, 3H).

Example 42

(1S*,3S*,3aR*,8bS*)-6-(2-aminoethoxy)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

210 mg (0.45 mmol) of (1S*,3S*,3aR*,8bS*)-6-(2-azidoethoxy)-3A-(4-chlorophenyl)3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol (from example 49A) is dissolved in 34 ml of ethanol. After you have added 56 mg of 10%palladium on charcoal, the mixture is stirred for 15 minutes in an atmosphere of hydrogen at room temperature and normal pressure. The mixture is then filtered, concentrated and the residue is filtered over silica gel 60. The filtrate is washed with toluene and elute with a mixture of dichloromethane ethanol (1:1). After concentrating obtain 179 mg of the target product (yield from theoretical 90%), which is subjected to fine purification in accordance with the method 23A.

HPLC-MS (method 9): Rt=1,74 minutes

MS (ESIpos): m/z=438 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,33-6,84 (m, 10H)6,70 (d, 1H), is 6.61 (dd, 1H), of 5.89 (s, 1H), USD 5.76 (s, 2H), of 5.05 (s, 1H), to 4.52-to 4.38 (m, 1H), was 4.02 (t, 2H), 3,39-3,20 (m, 1H), 2,98 (t, 2H), 2,50-of 2.36 (m, 1H), 2,34 is 2.10 (m, 1H).

HPLC (method 23): Rt=8,76 minutes

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 24A) (enantiomer A: Rt=11,0 min, enantiomer In: Rt=23,6 min).

Example 43

(1R*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(2-dimethylaminoethoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 51A.

The output from theoretical 94%.

HPLC-MS (method 5): Rt=2,41 minutes

MS (ESIpos): m/z=466 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=to 7.32 (d, 1H), 7,19-7,0 (m, 7H), 6,99-6,91 (m, 2H), 6,60 (d, 1H), is 6.54 (dd, 1H), 5,26 (s, 1H), 5,18 (d, 1H), 4,62-to 4.52 (m, 1H), 4,16 (t, 2H), 3,83 (dd, 1H), 3,02-is 2.88 (m, 2H), 2,75-to 2.57 (m, 1H), 2,54 (s, 3H), of 2.46 (s, 3H), 1,98-1,82 m, 1H).

Example 44

(1R*,2R*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(2-dimethylaminoethoxy)-2-dimethylcarbamyl-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 54A.

The output from theoretical 64%.

HPLC-MS (method 2): Rt=2,10 minutes

MS (ESIpos): m/z=537 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,39 (d, 1H), 7,25-6,98 (m, 7H), 6,86-of 6.78 (m, 2H), 6.75 in (d, 1H), to 6.57 (dd, 1H), 5,54 (d, 1H), 5,33 (s, 1H), 4,96-4,84 (m, 1H), 4,34-4,12 (m, 3H), 4,10-of 3.94 (m, 1H), 3,48 of 3.28 (m, 2H), 3,20 (s, 3H), of 2.72 (s, 3H), 2,74-2,62 (m, 6H).

Example 45

Dehydrothermal (1R*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-8b-hydroxy-3-phenyl-6-(2-pyrrolidin-1-yl-ethoxy)-2,3,3A,8b-tetrahydrocyclopent[b]-benzofuran-1-amine

The target compound is synthesized analogously to example 32 from the product obtained in example 56A. Purification of the crude target product carried out by the method of preparative HPLC (RP18 column, the chromatographic solvent: acetonitrile/water with 0.1% formic acid, gradient 5:95→95:5).

The output from theoretical 67%.

HPLC-MS (method 6): Rt=1,20 minutes

MS (ESIpos): m/z=491 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=8,21 (s, 2H), was 7.36 (d, 1H), 7,21? 7.04 baby mortality (m, 7H), 6,99-6,94 (m, 2H), to 6.67 (d, 1H),return of 6.58 (dd, 1H), 4,10 (t, 2H), 3,80-3,70 (m, 1H), 3,50 (dd, 1H), 2,82 (t, 2H), 2,59 of $ 2.53 (m, 4H), 2,48-is 2.37 (m, 1H), 2,35-to 2.18 (m, 1H), 1,73-to 1.67 (m, 4H).

Example 46

Dehydrothermal (1R*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(2-dimethylaminoethoxy)-8b-hydroxy-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]-benzofuran-1-amine

The target compound is synthesized analogously to example 32 from the product obtained in example 56A. Purification of the crude target product carried out by the method of preparative HPLC (RP18 column, the chromatographic solvent: acetonitrile/water with 0.1% formic acid, gradient 5:95→95:5).

The output from theoretical 36%.

HPLC-MS (method 6): Rt=1,22 minutes

MS (ESIpos): m/z=465 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=8,23 (s, 2H), 7,35 (d, 1H), 7,21-7,02 (m, 7H), 6,99-6,94 (m, 2H), of 6.68 (d, 1H), return of 6.58 (dd, 1H), 4,08 (t, 2H, in), 3.75 (dd, 1H), 3,50 (dd, 1H), 2,64 (t, 2H), 2,47-is 2.37 (m, 1H), 2,34-of 2.23 (m, 1H), 2,23 (s, 6H).

Example 47

(1S*,3S*,3aR*,8bS*)-6-benzyloxy-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 6A on the basis of the product obtained in example 61A.

The output from theoretical 54%.

HPLC-MS (method 3): Rt=4,85 minutes

MS (ESIneg): m/z=483 (M-N)-.

1H-NMR (300 MHz, DMSO-d6): δ=7,46 for 7.12 (m, 13H), 6,88-6,85 (m, 2H), 6,60-6,55 (m, 2H), 5,64 (d, 1H), 5.08 to is 5.06 (m, 3H), 4,16-to 4.15 (m, 1H), 4,07-to 3.99 (m, 1H), 1,94 is 1.91 (m, 2H).

Example 48

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-3-Hairdryer the l-8-(2-pyrrolidin-1-yl-ethoxy)-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 69A.

The output from theoretical 70%.

HPLC-MS (method 7): Rt=2,10 minutes

MS (ESIpos): m/z=492 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,26 (t, 1H), 7,21-7,17 (m, 2H), 7,16-7,11 (m, 2H), 7,10-7,02 (m, 3H), 6,99-6,94 (m, 2H), of 6.68 (d, 1H), only 6.64 (d, 1H), of 6.49 (broad s, 1H), 4.95 points (broad s, 1H), 4,54 (dd, 1H), 4,28-4,19 (m, 1H), 4,16-4,06 (m, 1H), 3,41-of 3.25 (m, 1H), 3,10-2,95 (m, 1H), 2,75 is 2.51 (m, 5H), 2,47-is 2.37 (m, 1H), 2,32-to 2.18 (m, 1H), 1,79-1,71 (m, 4H).

Preparative separation of the racemic mixture of the enantiomers is realized by means of HPLC on a chiral phase (method 17A).

Analytical data (method 17V):

enantiomer A: Rt=8,60 min, enantiomer In: Rt=of 9.55 minutes

Example 49

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-8-(2-dimethylaminoethoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 69A.

The output from theoretical 81%.

HPLC-MS (method 9): Rt=1,88 minutes

MC (ESIpos): m/z=466 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,26 (t, 1H), 7,22-7,17 (m, 2H), 7,16-7,11 (m, 2H), 7,10-7,02 (m, 3H), 6,99-6,93 (m, 2H), of 6.68 (d, 1H), only 6.64 (d, 1H), 6,52 (broad s, 1H), 4.92 in (broad s, 1H), 4,55 (dd, 1H), 4,23-to 4.15 (m, 1H), 4,14-of 4.05 (m, 1H), 3,38-3,26 (m, 1H), 2,87 was 2.76 (m, 1H), 2,60-of 2.38 (m, 2H), 2,32-2,17 (m, 1H, in), 2.25 (s, 6H).

Example 50

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-8-(2-methylamine is ethoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 69A.

The output from theoretical 17%.

HPLC-MS (method 9): Rt=1,88 minutes

MC (ESIpos): m/z=452 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,30 (t, 1H), 7,26-7,14 (m, 4H), 7,13? 7.04 baby mortality (m, 3H), 6,95-6,89 (m, 2H), 6,74 (d, 1H), 6,66 (d, 1H), with 4.64 (dd, 1H), 4,36-4,19 (m, 2H), 3,41-of 3.25 (m, 1H), 2,62 (s, 3H), 2,48-2,39 (m, 1H), 2,33-of 2.21 (m, 1H).

Example 51

(1R*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-8-(2-dimethylaminoethoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 71A.

The output from theoretical 65%.

HPLC-MS (method 4): Rt=2,24 minutes

MC (ESIpos): m/z=466 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7.23 percent (t, 1H), 7,19-7,14 (m, 2H), 7,13-6,98 (m, 7H), 6,63 (d, 1H), is 6.61 (d, 1H), and 5.30 (broad s, 1H), 4,54 (d, 1H), 4,29-4,12 (m, 3H), 3,88 (dd, 1H), 2,74 (dt, 1H), 2,72-of 2.58 (m, 2H), of 2.23 (s, 6H), 1,99 (dd, 1H).

Example 52

(1R*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-3-phenyl-8-(2-pyrrolidin-1-yl-ethoxy)-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 71A.

The output from theoretical 47%.

HPLC-MS (method 4): Rt=2,29 minutes

MC (ESIpos): m/z=492 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,22 (t, 1H), 7.18 in-7,12 (, 2H), 7,11-6,99 (m, 7H), 6,63 (d, 1H), is 6.61 (d, 1H), 5,42 (broad s, 1H), 4,51 (d, 1H), or 4.31 is 4.13 (m, 3H), 3,91 (dd, 1H), 2,90-to 2.65 (m, 2H), 2,75 (dt, 1H), 2,63 at 2.45 (m, 4H), 1,99 (dd, 1H), 1,71 is 1.60 (m, 4H).

Example 53

(1R*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-8-(2-methoxyethoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 6A on the basis of the product obtained in example 78A.

The output from theoretical 12%.

HPLC-MS (method 4): Rt=3,50 minutes

MC (ESIpos): m/z=453 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=7.24 to (t, 1H), 7,15-6,94 (m, 9H), of 6.66 (d, 1H), 6,59 (d, 1H), 5,14 (s, 1H), 4,62-4,51 (m, 2H), 4,22-to 4.14 (m, 2H), with 3.89 (dd, 1H), of 3.73-3,66 (m, 2H), 3,35 (s, 3H) 2,74 (ddd, 1H), 1,98 (dd, 1H).

Example 54

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(3-methylaminopropane)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 79A.

The output from theoretical 94%.

HPLC-MS (method 7): Rt=1,83 minutes

MC (ESIpos): m/z=466 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ=8,63 (broad s, 1H), 7,32-of 6.90 (m, 10H)6,70 (d, 1H), 6,60 (dd, 1H), of 5.92 (d, 1H), 5,04 (s, 1H), 4,49-and 4.40 (m, 1H), 4,13-4,07 (m, 2H), 3,35-3,20 (m, 1H), is 3.08 3.00 for (m, 2H), 2,58 (s, 3H), 2,55-2,03 (m, 4H).

Example 55

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-6-(3-dimethylaminopropoxy)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target is connected to the e synthesized analogously to example 32 from the product, obtained in example 79A.

The output from theoretical 99%.

HPLC-MS (method 7): Rt=1,86 minutes

MS (ESIpos): m/z=480 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,30-of 6.90 (m, 10H), of 6.68 (d, 1H), return of 6.58 (dd, 1H), of 5.89 (d, 1H), 5,04 (s, 1H), 4,50-of 4.44 (m, 1H), 4,08-4,01 (m, 2H), 3,35-of 3.25 (m, 1H), 2.71 to of 2.64 (m, 2H), 2,39 (s, 6H), 2,29-2,11 (m, 2H), 2,02 is 1.91 (m, 2H,).

Example 56

(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-3-phenyl-6-(3-pyrrolidin-1 ipropose)-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 79A.

The output from theoretical 99%.

HPLC-MS (method 7): Rt=1,91 minutes

MS (ESIpos): m/z=506 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ=7,32-of 6.90 (m, 10H)6,70 (d, 1H), 6,60 (dd, 1H), 5,91 (d, 1H), of 5.05 (s, 1H), 4,50-and 4.40 (m, 1H), 4,13-4,07 (m, 2H), 3,35-3,19 (m, 7H), 2,50-of 1.92 (m, 8H).

Example 57

(1S*,3S*,3aR*,8bS*)-6-(3-azetidin-1 ipropose)-3A-(4-chlorophenyl)-3-phenyl-2,3,3A,8b-tetrahydrocyclopent[b]benzofuran-1,8b-(1H)-diol

The target compound is synthesized analogously to example 32 from the product obtained in example 79A.

The output from theoretical 69%.

HPLC-MS (method 13): Rt=1,97 minutes

MS (ESIpos): m/z=492 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ=7,27-7,03 (m, 8H), 6,94-6,91 (m, 2H), only 6.64 (d, 1H), to 6.57 (dd, 1H), of 5.82 (d, 1H), 4,99 (s, 1H), 4,48-to 4.41 (m, 1H), was 4.02-3,98 (m, 2H), 3,12 (m, 4H), 2,49-to 2.40 (m, 2H), 2.26 and with 2.14 (m, 1H), 1,96 (t, 2H), to 1.70 (t, 2H), 0,86 is 0.81 (m, 2H).

Example 58

N-[(1S*, 3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3A,8b-tetrahydro-1H-benzo[b]cyclopent[d]furan-6-yl]-2-fluoro-nicotinamide

To 0.5 ml of DMSO at the same time add to 39.4 mg (0.1 mmol) (1S*,3S*,3aR*,8bS*)-6-amino-3A-(4-chlorophenyl)-3-phenyl-1,2,3,3A-Tetra-hydrocyclone[b]benzofuran-1,8b-(1H)-diol (from example A), a 14.1 mg (0.1 mmol) 2-Perekalin, and 41.7 mg (0.13 mmol) of tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea and 25.8 mg (0.2 mmol) of diisopropylethylamine and stirred the mixture overnight at room temperature. Then filtered the solid and the filtrate purified by the method of preparative HPLC.

The output from theoretical to 19.7 mg (38%).

HPLC-MS (method 10): Rt=2,21 minutes

MS (ESIpos): m/z=517 (M+N)+.

Example 59

N-[(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3A,8b-tetrahydro-1H-benzo[b]cyclopent[d]furan-6-yl]-6-herperidin-2-carboxamide

The target compound is synthesized analogously to example 58 on the basis of the product obtained in example A.

HPLC-MS (method 10): Rt=2,35 minutes

MS (ESIneg): m/z=515 (M-H)-.

Example 60

N-[(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3A,8b-tetrahydro-1H-benzo[b]cyclopent[d]furan-6-yl]-1-ethyl-1H-pyrazole-3-carboxamide

The target compound is synthesized analogously to example 58 on the basis of the product obtained in example A.

HPLC-MS (method 10): Rt=2,25 minutes

MS (ESIpos): m/z=516 (M+N)+.

Example 61

N-[(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3A,8b-tetrahydro-1H-benzo[b]cyclopent[d]furan-6-yl]-1,2,3-thiadiazole-4-carboxamide

The target compound is synthesized analogously to example 58 on the basis of the product obtained in example A.

HPLC-MS (method 10): Rt=2,23 minutes

MS (ESIneg): m/z=504 (M-N)-.

Example 62

N-[(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3A,8b-tetrahydro-1H-benzo[b]cyclopent[d]furan-6-yl]-pyridine-2-carboxamide

The target compound is synthesized analogously to example 58 on the basis of the product obtained in example A.

HPLC-MS (method 10): Rt=2,38 minutes

MS (ESIpos): m/z=499 (M+H)+.

Example 63

N-[(1S*,3S*,3aR*,8bS*)-3A-(4-chlorophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3A,8b-tetrahydro-1H-benzo[b]cyclopent[d]furan-6-yl]-1H-1,2,4-triazole-5-carboxamide

The target compound is synthesized analogously to example 58 on the basis of the product obtained in example A.

HPLC-MS (method 10): Rt=2,00 minutes

MS (ESIpos): m/z=489 (M+H)+.

C. Evaluation of pharmacological efficacy

Below the experimental data explain the pharmacological action proposed in the invention compounds.

1. Determination of the inhibitory effect of NF-κ and AP-1 in vitro

1A. Ingibirovanie release of interleukin-8 (IL-8) from endothelia is lnyh human cells

The expression of human IL-8 gene regulates many regulatory and reinforcing elements, localized over the area of the promoter of the gene. Such elements contain binding sites of transcription factors, and effective transcription of the IL-8 gene is possible only through their interaction with seats binding of transcription factors to DNA. The relevant activity of transcription factors can be induced by various stimuli (e.g., such as interleukin-1β, factor-α tumor necrosis) and modulated by different transduction of signals [.Holtmann and others., Mol. Cell. Biol. 19, 6742-6753 (1999)].

For maximum expression of IL-8 binding activity is two different transcription factors: NF-κ and AP-1 [y-H.Chang and others, Exp.Cell Res. 278, 166-174 (2000)]. In this regard, induced cytokine synthesis of IL-8 can be used as a test system for the identification and characteristics of the tested substances which directly or indirectly inhibit the binding of NF-κ and AP-1 in the binding sites of these factors with DNA.

The experiments

Endothelial cells of the umbilical vein of a person (HUVEC)was purchased from firms CellSystems (St.Katharinen, Germany), were cultured in flasks area of 165 cm2for tissue cultures in accordance with the recommendations of the supplier containing additives for growth cf the de EGM-2 (firm CellSystems, St. Katharinen, Germany). Upon reaching 60-80%confluently cell cover cell is separated from the bottom by treatment with trypsin, mechanically dissociated and plated in 96-well microtiter plates (firm Corning, Wiesbaden, Germany) density of 5000 cells/well. After three days completely replace the culture medium with fresh medium (170 μl in each well). The next day, the cells used for experiments.

To determine the inhibitory actions proposed in the invention of substances on the release of IL-8 in their first dissolved in a containing 1% DMSO to the medium at a concentration ten times more than necessary for the final test concentration. Then in the hole injected 20 μl of a solution of the substance. Adding interleukin-1β (IL-1β, final concentration 10 ng/ml; firm Biosource GmbH, Solingen, Germany), induce the formation and release of IL-8 and incubated the cells for 6 hours in CO2-incubator at 37°C. After that, select 150 µl containing cell supernatant and freeze it at -20°C until measurement of the content of IL-8 by the method of enzyme-linked immunosorbent assay (firm Biosource GmbH, Solingen, Germany). To perform this analysis, the sample is thawed, diluted in the ratio 1:10 and conduct the test in accordance with manufacturer's recommendations. The inhibitory action of n is izlagaemykh in the invention compounds on the release of IL-8 determined by comparison with cells, processed dosage basis.

Representative data describing the effectiveness of the proposed in the invention compounds are shown in table 1.

Table 1
ExampleIC50[nmol]
3170
12466
15166
1820
2290
23202
32112
48214

[IC50means the concentration of the active substance that causes 50%inhibition of the release of IL-8 from the maximum efficiency of the active substance].

1b. Inhibition of the activity of AP-1 in cultures of attraciton

AR-1 is localized in the cell nucleus transcription factor, which is formed by Homo - or heterodimers Jun-, Fos and ATF families of proteins. Activating signals contribute, firstly, intensive synthesis of individual components is s and secondly, the specific phosphorylation of Jun or ATF-subunits. Both processes lead to intensive interaction of the protein complex with its target genes and, thus, contribute to their expresii. Consequently, the induced stimulus phosphorylation, for example, c-Jun may serve as an indicator of the activation of AP-1. Discussed below immunocytochemical detection of the phosphorylation of c-Jun allows to investigate the impact of the proposed invention compounds on the activity of AP-1.

The experiments

Preparing a mixed culture of glial cells of rat brain at day of age (firm Wistar). An animal killed by decapitation, remove the brain and accumulate it into a chilled balanced salt Hanks solution (HBSS, the company Gibco, Karlsruhe, Germany). Remove the brain stem and the cerebellum, cerebral hemisphere freed from meninges and mechanically dissociated pieces of fabric in the presence of papain (set of reagents for the papain dissociation, the firm CellSystems, St. Katharinen, Germany). Cells accumulate by centrifugation at 450×g and a thin layer applied to the bottom of the flasks for tissue cultures (175 cm2). Cells within 12-14 days cultivated in modified according to the method of Dulbecco medium Needle/ham F12 containing 10% fetal calf serum and 100 µg/ml penicil the ina/streptomycin (firm Sigma, Taufkirchen, Germany). Then fragments of cells and grown on the surface of the cell cover microglial and oligodendroglial cells within two hours shaken using a shaker device and the remaining astrocytes are separated from the bottom trypsinization. Cells mechanically dissociated, accumulate by centrifugation at 450×g, is subjected to repeated mechanical dissociation and distribute coated with poly-D-lysine 8-chamber slide (firm NUNC, Denmark) density of 100,000 cells/well. Accumulated in this way astrocytes cultured in not containing phenolsulfonphthalein, modified by way of Dulbecco medium Needle/ham F12 containing 10% fetal calf serum and 100 μg/ml penicillin/streptomycin (firm Sigma, Taufkirchen, Germany). The day before use in experiments, the content of fetal calf serum in the medium is reduced to 1%.

To study the actions proposed in the invention compounds on the activation of AP-1 to the concentration added to the culture medium (final concentration when testing usually is 1 Microm). Then stimulate the path of the signal AP-1 (phosphorylation of c-Jun) by adding lipopolysaccharide (LPS, firm Sigma, Taufkirchen, Germany) at a final concentration of 100 ng/ml) or interleukin-1β (IL-1β, firm Biosouce GmbH, Solingen, Germany) at a final concentration of 30 ng/ml After 90 minutes, the cells are subjected to intermittent flushing with saline phosphate buffer (PBS) and subsequent 10-min fixation in 4%solution of paraform in PBS. Then provide the permeability of cells by 5-minute processing cooled to -20°C methanol, washed cells in PBS, 5% sucrose, 0.3% of neutral detergent Tritonx-100 for 30 minutes, incubated at room temperature in blocking buffer (PBS, 1% goat serum, 2% bovine serum albumin). Incubation is carried out in the mixture overnight at 4°C With primary bodies directed against astrofzicheskoi protein GFAP (glial fibrillar acidic protein; monoclonal antibody from mice; firm Sigma, Taufkirchen, Germany) and against phosphorylated serine-63 form c-Jun (polyclonal antibody from rabbits; firm Calbiochem, bad Srdan, Germany). Antibodies against GFAP protein diluted in blocking buffer at a ratio of 1:400, against phospho-c-Jun in the ratio of 1:50. Then the excess antibody is removed by three washing in PBS, 5% sucrose, 0.3% Tritonx-100, and one hour incubate cells at room temperature with appropriate secondary species-specific and diluted blocking buffer antibody (2nd-conjugate antibodies antimist, 1:500, the firm AmershamBiosciences, Freiburg, Germany; SS3-conjugate antibodies anticolic, 1:800, firm Sigma, Taufkirchen, Germany). Then the excess antibody is removed by three washing in PBS, 5% sucrose, 0.3% Tritonx-100 and stained cell nucleus by 10-minute incubation of the cells with the product of Hoechst 33258 (4 μg/ml in PBS). After that, the cells again twice for 5 minutes, washed with PBS, remove the sealing ring 8-chamber slides and bring them into the immersion medium (firm Sigma, Taufkirchen, Germany) using a glass cover. The experimental results can be assessed by fluorescence microscopy (a lens with a 25-fold increase).

Phosphorylated c-Jun protein in connection with linking SS3-conjugated secondary antibodies directed against phospho-c-Jun, detectivesyme primary antibodies can be detected by localized in the cell nucleus red fluorescence. The cell nucleus revealed by blue fluorescence. Astrocytes can be identified by the su-2-mediated green fluorescent staining GFAP.

In basal conditions, phosphorylated c-Jun contains only a few cell nuclei. Due to the addition of lipolysaccharide induced AP-1-mediated signal transduction, in connection with more than 80% of cell nuclei fluoresce red light, meaning that they contain phospho-c-Jun. Doba is a split proposed in the invention compounds leads to a significant decrease in red fluorescence, what is evident, first, in reducing the intensity of color, and, secondly, the reduction of stained nuclei. Colocalization flowing in astrocyte processes becomes possible through the use of green, red and blue fluorescent images.

2. Determination of metabolic stability

Incubation of liver microsomes in vitro

To determine hepatic microsomal stability proposed in the invention substances incubated with various types of liver microsomes. Concentrations during incubation remain as low as possible (preferably less than 1 Microm), which refers to the concentration of microsomal protein in inkubiruemykh mixture (preferably 0.2 mg microsomal protein in 1 ml inkubiruemykh mixture). Compliance with this condition contributes to the execution of operations with the most connections in the linear range of the kinetics of Michaelis-Menten. At different points in time (their total number is equal to seven) to determine the residual concentration of a substance selected samples of the incubation mixture. Time polydactyly test substance in the incubation mixture, calculate the coefficient of purification (CL) and maximum bioavailability (Fmax) substances for the relevant type of microsomes. To minimize the impact of promoting the dissolution of organic substances on the microsomal anti the s maximum content of 1% (acetonitrile), 0.2% (DMSO).

The experiments

The experiments described J.B.Houston and D.J.Carlile [Drug Metab. Rev. 29, 891-922 (1997)].

As shown in table 2, the data offered in the invention substances are characterized by high stability in preparations of liver microsomes compared with the compounds described in the international application WO 00/08007.

Table 2
ExampleLiver microsomes mouse
CL [I/(kg×h)]Fmax [%]
3<2,7>50
122,9745,1
15<2,7>50
18<2,7>50
22<2,7>50
32<2.7>50
48<2,7>50
Comparison: example 1-41 of WO 00/080075,06,8

3. The proliferation of tumour cells in vitro

Different forms of cancer are characterized by uncontrolled excessive proliferation of various cell types, resulting in the formation of metastases and tumors. Possibility of application of the proposed invention substances for the treatment of hyperproliferative diseases can be investigated for their effect on the rate of cell division tumors in vitro. The relationship between antiproliferative effects in vitro and clinical antitumor effect is well studied. The possibility of therapeutic application, for example, Taxol [Silvestrini and others, Stem Cells 11, 528-535 (1993)], Taxotere [Bissery and other Anti-Cancer Drugs 6, 339 (1995)] or inhibitors of topoisomerase [Edelman and others, Cancer Chemother. Pharmacol. 37, 385-393 (1996)] confirmed show their activity when tested in the proliferation of tumour cells in vitro.

The experiments

Lines of tumor cells, such as MDA-MB-231 (human cell adenocarcinoma of the breast), N (human lung carcinoma cells) or HCT-15 (human cell adenocarcinoma of the intestine), grown in the appropriate recommended by suppliers (for example, LGC Promochem, Wesel, Germany) media (firm Sigma, Taufkirchen, Germany). For the day is to add proposed in the invention compounds, cells were seeded in 100 μl of medium for the growth in black 96-well microtiter tablets-bottomed density of 3000 cells/well. On the day of adding the test substance to determine which holes in the initial number of cells using one microtiter plate on each line of tumor cells. In libsofia tablets add proposed in the invention substances, diluted environment for growth and DMSO. Subjects substances usually added in different concentrations, starting with the final concentration in the sample 10 µmol. The concentration of DMSO in the sample is 0.1%. A day after adding substances with the help of the device to determine the viability of the cells CellTiter-Glo®, Promega GmbH, Mannheim, Germany) to determine the number of cells in the well. The test is carried out in accordance with the recommendations of the manufacturer of the device and evaluate using luminometer. To calculate the antiproliferative activity proposed in the invention compounds subtract the number of cells defined before adding substances in libsofia tablets, and calculate the percentage difference between the number of cells treated with the substance, and the number of cells processed by the media. The relative effectiveness of the studied subjects substances determined by comparing the concentrations providing 50% of their maximum efficiency (IC50).

Representative data describing the effectiveness of the proposed in the invention compounds, etc is presented in table 3.

Table 3
ExampleIC50[nmol] (cells N)
211,5
2399,7
320,5
4847,9
4929,7

[IC50means the concentration of the active substance that causes 50%inhibition of cell proliferation in tumors from the maximum efficiency of the active substance].

4. Modeling Parkinson's disease in mice using MRTR

Parkinson's disease histopathology is characterized by selective loss of groups of nerve cells of the black substance synthesized by the neurotransmitter dopamine. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MRTR) is identified in the early 80-ies admixture of synthetic drugs, which induce in humans, the symptoms of Parkinson's disease and characterized by degeneration of dopaminergic neurons. Application MRTR on various animals, such as mice or monkeys, leads to behavioral and histopathological changes that can be sravnivats the human disease. In this regard, the use MRTR in mice provides accurate modeling of Parkinson's disease, suitable for studies of neuroprotective action of the tested substances.

The experiments

Experiments in General perform in accordance with the described .Bezard and other methods [Neurosci. Lett. 234, 47-50 (1997)]. MRTR apply every three days 4 mg/kg I.P. Pavlova. in male animals mice C57/BL6 eight weeks of age. Proposed in the invention substances begin to enter orally daily or twice a day directly before the first use MRTR. On the eleventh day after the first application MRTR anaesthetize animals, intracardiac perpendicular first 25 ml of 0.9%saline, then 75 ml of 4%aqueous solution of paraform and order histological processing to extract the brain. For this purpose, in accordance with the described .Bezard and other methods [Neurosci. Lett. 234, 47-50 (1997)] of dopaminergic neurons immunohistochemically find cells that contain tyrosinekinase as essential for the metabolism of dopamine enzyme. Quantitative determination of the number of remaining dopaminergic neurons is carried out using computer programs in three different sections for each animal, a representative for the mid-plane cross section of the dark matter [Nelsonn other,J.Comp. Neurol. 369, 361-371 (1996)]. The neuroprotective effect of the tested substances determined by comparing the processed medicinal basis MRTR animals with neprodvinutymi handling mice.

5. Subdural hematoma in rats as a model of traumatic brain injury

Severe traumatic brain injuries are often accompanied by bleeding under the cerebral membrane. Subdural accumulation of blood leads to a local decrease of cerebral blood flow in adjacent cortical areas of the brain while increasing consumption of glucose and extracellular amino acids (e.g. glutamate).

Neighboring hematoma area of the brain becomes ischemic, resulting in the defeat and death of nerve cells. Subdural injection of autologous blood in the cortical areas of the rat brain is designed to simulate traumatic brain injury. The corresponding model is suitable for studies of neuroprotective actions proposed in the invention substances.

The experiments

Surgery for male rats, Wistar) and the unilateral use of autologous blood perform in accordance with the methodology described .Eijkenboom and other [Neuropharm. 39, 817-834 (2000)]. Immediately after wound closure and after two, with the NGO-four hours carry out intravenous injection of the required doses proposed in the invention substances. Seven days after surgery, animals kill, remove the brain and determine the volume of infarction, as described .Eijkenboom and other [Neuropharm. 39, 817-834 (2000)]. The neuroprotective effect of the tested substances is determined by comparing the obtained results with the data obtained for treated drug-based animals.

C. Examples of the manufacture of pharmaceutical compositions.

Proposed in the invention compounds can be converted into pharmaceutical preparations as follows.

Tablets

The composition of

100 mg offered in the invention compounds, 50 mg of lactose (monohydrate), 50 mg of corn starch (natural), 10 mg of polyvinylpyrrolidone (PVP 25 BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Weight pills 212 mg. a Diameter of 8 mm, the radius of the arch 12 mm

Manufacturing

The mixture proposed in the invention compounds, lactose and starch granularit using a solution of PVP in water concentration of 5%. After drying, the granulate for 5 minutes, mixed with magnesium stearate. The resulting mixture is subjected to extrusion in a conventional press for tabletting (format pills listed above). The estimated value is used for pressing efforts is 15 kN.

Suspension for oral administration

The composition of

1000 mg offered in the invention compounds, 1000 mg e is anola (96%), 400 mg Rhodigel® (xanthan resin company FMC, Pennsylvania, USA) and 99 g of water.

One dose proposed in the invention compounds, 100 mg, 10 ml oral suspension applied.

Manufacturing

Rhodigel® suspended in ethanol and to the resulting suspension type proposed in the invention the connection. Then with stirring, add water. Stirring is carried out for about 6 hours to complete the swelling resin Rhodigel®.

Solution for oral administration

The composition of

500 mg offered in the invention compound, 2.5 g of Polysorbate and 97 g of polyethylene glycol 400. One dose proposed in the invention compounds, 100 mg, corresponds to 20 g orally applied solution.

Manufacturing

The proposed invention in connection with stirring suspended in a mixture of polyethylene glycol and Polysorbate. The mixing process continued until complete dissolution of the proposed invention the connection.

Solution for intravenous injection

Proposed in the invention, the compound is dissolved in a physiologically compatible solvent (e.g., isotonic saline, 5%glucose solution and/or 30%solution of polyethylene glycol 400) in a concentration below the saturation limit. The solution is filtered under sterile conditions and filled into terylene injection vessels, does not contain pyrogens.

1. The compound of formula (I)

in which
R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms in each alkyl part, cyclooctylamino with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle, and mono - and dialkylamino with 1-6 carbon atoms in each alkyl part, in turn,can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, and
R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,
R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms in each alkyl part, cyclooctylamino with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached cher the C atom of nitrogen 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-6 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part,
however, R1and R2at the same time does not mean hydrogen,
R3means hydroxy or amino, and
R4means hydrogen, or
R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O or >C=N-OH,
R5means hydrogen or a mono - or dialkylaminoalkyl with 1-6 carbon atoms in each alkyl part,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-6 carbon atoms, aryl with 6-10 carbon atoms, 5-10-membered heteroaryl or a group of the formula-NR9R10,
moreover, the aryl and heteroaryl respectively, in turn, can be singly or doubly substituted the same or different halogen, cyano, alkylsulfonyl with 1-4 carbon atoms or a group of the formula-NR9R10in which
R9and R10independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle, R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or a group of the formula-NR11R12in which
R11and R12independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,
moreover, if R5means hydrogen, R3does not mean hydroxy and R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-6 carbon atoms or alkoxy with 1-6 carbon atoms,
in either case, if R5means hydrogen, R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means aryl with 6-10 carbon atoms, 5-10-membered heteroaryl or a group of the formula-NR9R10,
and its salt, solvate and solvate salts.

2. The compound of formula (I) according to claim 1, in which
R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 at the Mami carbon amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, cyclooctylamino with 3-6 carbon atoms, N-cycloalkyl-N-alkyl-amino with 3-6 carbon atoms in the cyclo-alkyl and 1 to 4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-4 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, and
R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,
R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, cyclooctylamino with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-6-membered heterocycle, and mono - and dialkylamino with 1-4 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part,
and R1and R2about the office also does not mean hydrogen, R3means hydroxy or amino, and
R4means hydrogen, or
R3and R4together with the carbon atom to which they are attached, form
a group of the formula >C=O or >C=N-OH,
R5means mono - or dialkylaminoalkyl with 1-4 carbon atoms in each alkyl part,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen, alkyl with 1-4 carbon atoms, aryl with 6-10 carbon atoms, 5-6-membered heteroaryl or a group of the formula-NR9R10and aryl and heteroaryl respectively, in turn, can be once - twice substituted by identical or different halogen, cyano, alkylsulfonyl with 1-4 carbon atoms or a group of the formula-NR9R10in which
R9and R10independently of one another denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,
R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or a group of the formula NR11R12in which
R11and R12independently of one another denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle and its salt, solvate and solvate salts.

3. The compound of formula (I) according to claim 1, in which
R1and R2independently of one another denote hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 3 is substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine,
and R1and R2at the same time does not mean hydrogen,
R3means hydroxy or amino,
R4means hydrogen,
R5means methylaminomethyl or dimethylaminoethyl,
n means 0,
R6located in the para-position relative to the point of attachment of the phenyl ring to the tricycle, and means fluorine, chlorine, bromine, methyl or ethyl,
R7means hydrogen,
and its salt, solvate and solvate salts.

4. The compound of formula (I) according to claim 1, in which
R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, the CEC is alkylamino with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle, and mono - and dialkylamino with 1-4 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, and
R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,
R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, cyclooctylamino with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-4 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part,
however, R1and R2at the same time does not mean hydrogen,
R3means hydroxy or amino, and
R4means hydrogen, or
R3 and R4together with the carbon atom to which they are attached, form a group of the formula >C=O or >C=N-OH,
R5means hydrogen,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means aryl with 6-10 carbon atoms, 5-6-membered heteroaryl or a group of the formula-NR9R10,
moreover, the aryl and heteroaryl respectively, in turn, can be once - twice substituted by identical or different halogen, cyano, alkylsulfonyl with 1-4 carbon atoms or a group of the formula-NR9R10in which
R9and R10independently of one another denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,
R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or a group of the formula-NR11R12in which
R11and R12independently of one another denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered of heteros is CL,
and its salt, solvate and solvate salts.

5. The compound of formula (I) according to claim 4, in which
R1means hydrogen, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine, and
R8means pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which respectively may be substituted stands, ethyl, fluorine or chlorine,
R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine,
however, R1and R2at the same time does not mean hydrogen,
R3means hydroxy or amino,
R4means hydrogen,
R5means hydrogen,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means phenyl, thienyl, indolyl, honokalani or a group of the formula-NR9R10,
and phenyl, thienyl and indolyl, respectively, in turn, can b the th once - doubly substituted the same or different fluorine, chlorine, bromine, cyano, or amino, and
R9and R10independently of one another denote hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino, and
R7means hydrogen,
and its salt, solvate and solvate salts.

6. The compound of formula (I) according to claim 1, in which
R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, cyclooctylamino with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-4 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, and
R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,
R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2 and n-propox is in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, cyclooctylamino with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-4 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1 to 4 atoms in each alkyl part,
however, R1and R2at the same time does not mean hydrogen, R3means amino and R4means hydrogen, or
R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=N-OH,
R5means hydrogen,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen or alkyl with 1-4 carbon atoms, and
R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or a group of the formula-NR11R12in which
R11and R12independently of one another denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,
and its salt, solvate and solvate salts.

7. The compound of formula (I) according to claim 6, in which
R1means hydrogen, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine, and
R8means pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which respectively may be substituted stands, ethyl, fluorine or chlorine,
R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine,
however, R1and R2at the same time does not mean hydrogen,
R3means amino,
R4means hydrogen,
R5means hydrogen,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means fluorine, chlorine, bromine, methyl or ethyl, and
R7 6and means hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy or a group of the formula
-NR11R12in which
R11and R12independently of one another denote hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino or piperidino,
and its salt, solvate and solvate salts.

8. The connection according to one of claims 1 to 7, having the properties of the inhibitor/modulator NF-κ and/or AP-1 activity.

9. The compound of formula (I)
,
in which
R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms in each alkyl part, cyclooctylamino with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-6 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1 to 4 atoms in each alkyl part, and
R8means 5 - or 6-membered heteroaryl, which can be the ü substituted by alkyl with 1-4 carbon atoms or halogen,
R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms in each alkyl part, cyclooctylamino with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-6 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part,
and R1or R2means hydrogen, but both are not simultaneously denote hydrogen,
R3means hydroxy and R4means hydrogen, or
R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O,
R5means hydrogen,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen or alkyl with 1-6 carbon atoms, and
R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or a group of the formula-NR11R12in which
R11and R12independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle and its salt, solvate and solvate salts.

10. The compound of formula (I) according to claim 9, in which R1means hydrogen, benzyloxy, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, cyclooctylamino with 3-6 carbon atoms, N-cycloalkyl-N-alkyl amino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-4 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1 to 4 atoms in each alkyl part, and
R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,
R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2 and n-ProPak is in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, cyclooctylamino with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-4 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part,
and R1or R2means hydrogen, but both are not simultaneously denote hydrogen,
R3means hydroxy and
R4means hydrogen, or
R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O,
R5means hydrogen,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen or alkyl with 1-4 carbon atoms, and
R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or a group of the formula-NR11R12in which
R11and R12independently of the other denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle and its salt, solvate and solvate salts.

11. The compound of formula (I) according to claim 9, in which
R1means hydrogen, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine, and
R8means pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which respectively may be substituted stands, ethyl, fluorine or chlorine,
R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 3 can be substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine,
and R1or R2means hydrogen, but they also do not mean
hydrogen, R3means hydroxy and
R4means hydrogen, or
R3and R4together with the carbon atom to which they are attached, form
a group of the formula >C=O,
R5means in dorog,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means fluorine, chlorine, bromine, methyl or ethyl, and
R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy or a group of the formula
-NR11R12in which
R11and R12independently of one another denote hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino or piperidino,
and its salt, solvate or solvate of salt.

12. Connection at one PP-11, having the properties of the inhibitor/modulator NF-κ and/or AP-1 activity.

13. The compound of formula (I)
,
in which
R1means ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 substituted alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms in each alkyl part, cyclooctylamino with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle which m
moreover, mono - and dialkylamino with 1-6 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, and where
R8means 5 - or 6-membered heteroaryl, which can be substituted by alkyl with 1-4 carbon atoms or halogen,
R2means ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino with 1-6 carbon atoms in each alkyl part, cyclooctylamino with 3-8 carbon atoms, N-cycloalkyl-N-alkylamino with 3-8 carbon atoms in cycloalkyl and 1-6 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-6 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part,
R3means hydroxy and
R4means hydrogen, or
R3and R4together with the carbon atom to which they are attached, form
a group of the formula >C=O,
R5means hydrogen,
n means 0,
R6is meta - or para-position relative to the joining fee is strong ring to the tricycle, and means halogen or alkyl with 1-6 carbon atoms, and
R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or a group of the formula-NR11R12in which
R11and R12independently of one another denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle,
and its salt, solvate and solvate salts.

14. The compound of formula (I) in item 13, in which
R1means ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-, and amoxi in position 2, and n-propoxy in position 2 or 3 substituted alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, cyclooctylamino with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-4 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, and
R8means 5 - or 6-membered hetero is the Rila, which may be substituted by alkyl with 1-4 carbon atoms or halogen,
R2means ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 2 or 3 can be substituted by alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part, cyclooctylamino with 3-6 carbon atoms, N-cycloalkyl-N-alkylamino with 3-6 carbon atoms in cycloalkyl and 1-4 carbon atoms in alkylamino or attached via a nitrogen atom 4-7-membered heterocycle,
moreover, mono - and dialkylamino with 1-4 carbon atoms in each alkyl part, in turn, can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, amino, mono - or dialkylamino with 1-4 carbon atoms in each alkyl part,
R3means hydroxy and
R4means hydrogen, or
R3and R4together with the carbon atom to which they are attached, form a group of the formula >C=O,
R5means hydrogen,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means halogen or alkyl with 1-4 carbon atoms, and
R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, halogen, alkyl with 1 to 4 atoms angle of the ode, alkoxy with 1-4 carbon atoms or a group of the formula-NR11R12in which
R11and R12independently of one another denote hydrogen, alkyl with 1-4 carbon atoms, phenyl, benzyl or pyridylmethyl, or together with the nitrogen atom to which they are attached, form a 4-7-membered heterocycle and its salt, solvate and solvate salts.

15. The compound of formula (I) 14, in which
R1means hydrogen, ethoxy, n-propoxy or a group of the formula R8-C(=O)-NH-,
moreover, ethoxy in position 2, and n-propoxy in position 3 is substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine, and where
R8means pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which respectively may be substituted stands, ethyl, fluorine or chlorine,
R2means hydrogen, ethoxy or n-propoxy, and amoxi in position 2, and n-propoxy in position 3 is substituted by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidine or pyrrolidine,
R3means hydroxy and
R4means hydrogen, or
R3and R4together with the carbon atom to which they are attached, form a group of the formula> C=O,
R5means hydrogen,
n means 0,
R6is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and means fluorine, chlorine, bromine, methyl or ethyl, and
R7is meta - or para-position relative to the point of attachment of the phenyl ring to the tricycle, and in the ortho-position relative to R6and means hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy or a group of the formula
-NR11R12in which
R11and R12independently of one another denote hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino or piperidino,
and its salt, solvate and solvate salts.

16. Connection at one PP-15, with the properties of the inhibitor/modulator NF-κ and/or AP-1 activity.

17. The method of obtaining the compounds of formula (VI)
,
in which R1, R2, R6and R7such as specified in claims 1 to 16, characterized in that compounds of the formula (II)
,
in which R1and R2respectively, such as described in claims 1 to 16, interact in an inert solvent in the presence of a base with the compound of the formula (III)
,
in which R6and R7accordingly, so is e, as specified in claims 1 to 16,
X1means suitable removable group, such as halogen, mesilate, toilet or triflate, and
T1means alkyl with 1-4 carbon atoms,
with the formation of compounds of the formula (IV)

in which R1, R2, R6, R7and T1respectively, such as described in claims 1 to 16, which by basic or acid hydrolysis transferred to the carboxylic acid of formula (V)
,
in which R1, R2, R6and R7respectively, such as described in claims 1 to 16,
which after activation by chloride of phosphoryla cyclist in the presence of Lewis acid in the compounds of formula (VI)
,
in which R1, R2, R6and R7respectively, such as described in claims 1 to 16.

18. The method of obtaining the compounds of formula (VI)
,
in which R1, R2, R6and R7such as specified in claims 1 to 16, characterized in that the first connection of the formula (VII)
,
in which R1and R2respectively, such as described in claims 1 to 16,
conventional methods translate into bromide finally formula (VIII)
,
in which R1and R2respectively, such as described in claims 1 to 16,
which prisutstvie the base cyclist in the compounds of formula (IX)
,
in which R1and R2respectively, such as described in claims 1 to 16,
which the inert solvent is subjected to bromirovanii, leading to the formation of compounds of formula (X)
,
in which R1and R2respectively, such as described in claims 1 to 16,
which conventional methods are turned into simple killenaule esters of the formula (XI)

in which R1and R2respectively, such as described in claims 1 to 16, and
T2T3and T4the same or different and respectively mean alkyl with 1-4 carbon atoms or phenyl,
which in an inert solvent in the presence of a suitable palladium catalyst and a base interact with the compound of the formula (XII)
,
in which R6and R7respectively, such as described in claims 1 to 16, and
Z denotes hydrogen or methyl, or both Z groups together form bridges CH2CH2- or(CH3)2- (CH3)2,
with the formation of compounds of formula (XIII)
,
in which R1, R2, R6, R7T2T3and T4respectively, such as described in claims 1 to 16, from which conventional methods otscheplaut silyl group, obtaining the compounds of formula (VI).

19. Note the persistence of the connection according to one of claims 1 to 16 for the prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases caused by NF-κ and/or AP-1 activity.

20. Pharmaceutical composition, which possesses the properties of the inhibitor/modulator NF-κ and/or AP-1 activity and contains a compound according to one of claims 1 to 16 in combination with an inert, nontoxic, pharmaceutically suitable auxiliary substance.

21. The method of prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases of humans and animals caused by NF-κ and/or AP-1 activity, implemented by introducing an effective amount of at least one compound according to one of claims 1 to 16 or a pharmaceutical composition according to claim 20.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: medicine.

SUBSTANCE: compounds of the invention exhibit properties of β2- adrenoreceptor agonists. In formula (I) , R1 represents hydrogen; each R2, R3, R4, R5, R4' and R5' independently represents hydrogen or C1-C6alkyd; e is equal to 0 or 1; A represents C(O); D represents oxygen or sulphur; m is equal to an integer 0 to 3; n is equal to an integer 0 to 3; R6 represents the group -(X)p-Y-(Z)q-R10; each X and Z independently represents C1-C6akylene group; each p and q is independently equal to 0 or 1; Y represents a bond, oxygen, CH2 or NR9; R7a and R7b independently represent hydrogen or C1-C6alkyl; R9 represents C1-C6alkyl; R10 represents hydrogen or saturated or unsaturated 6-members ring system optionally containing at least one ring heteroatom, chosen of nitrogen. And this ring system is optionally substituted by C1-C6alkoxycarbonyl; R7 represents 6-12-members aromatic ring system which is optionally substituted by halogen, trifluoromethyl, hydroxyl, C1-C6alkyl, C1-C6alkoxy or NH2; provided R6 does not represent hydrogen or unsubsituted C1-C6alkyl group. Also, the invention refers to methods for producing compounds of formula (I), to a pharmaceutical composition exhibiting properties of β2- adrenoreceptor agonists containing the compound of formula (I) as an active ingredient, to application of the compound of formula (I) in preparing a drug, to a combination containing the compound of formula (I) and one or more agents.

EFFECT: improved properties of the composition.

27 cl, 2 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of isothiazole-3(2H)-OH-1,1-dioxides of formula (I) or pharmaceutically acceptable salts thereof, which can increase expression of LXR α and/or β, a pharmaceutical composition based on said derivatives, use thereof in preparing a medicinal agent, as well as novel intermediate compounds of formula (V) or salts thereof. In formulae (I), (V) R2 denotes phenyl, and R1 and R3 are as described in the claim.

EFFECT: improved properties of the derivatives.

7 cl, 9 dwg, 172 ex

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline forms of a hydrate of 5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dione dihydrochloride of formula (I). The invention also relates to methods for synthesis of said compounds and to pharmaceutical compositions based on said compounds, having PPARy activating property.

EFFECT: said forms of the compounds are more stable and can be used in medicine to prepare medicinal agents for treating diabetes, cancer accompanied by diabetes.

16 cl, 7 tbl, 5 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrolidine derivatives of general formula (1) or its pharmaceutically acceptable salts where R101 and R102 values are described by the patent claim. The compounds inhibit serotonin and/or norepinephrine and/or dopamine reabsorption thereby allowing to be used for treating depression and anxiety disorder. A method for preparing thereof is described.

EFFECT: preparation of new pyrrolidine derivatives.

10 cl, 162 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I

, where R1 is selected from a group comprising hydrogen, lower alkyl, lower hydroxyl, lower alkoxyalkyl, lower halogenalkyl, lower cyanoalkyl; unsubstituted or substituted phenyl; lower phenylalkyl, where the phenyl ring can be unsubstituted or substituted; and heteroaryl, selected from pyridyl and pyrimidinyl; R2 denotes hydrogen or halogen; G denotes a group selected from

, where m equals, 0, 1; R3 is selected from lower alkyl, cycloalkyl and lower cycloalkylalkyl; n equals 0, 1; R4 denotes lower alkyl, as well as pharmaceutical compositions.

EFFECT: said compounds are used to treat or prevent diseases associated with histaminase receptor modulation.

19 cl, 1 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives of formula I

or pharmaceutically acceptable salts thereof, where R1 denotes (1-6C)alkyl; R2, R3 independently denote halogen, (1-4C)alkoxy; R4 denotes phenyl or a 5-6-member heteroaryl, having one or two heteroatoms selected from nitrogen, oxygen or sulphur, phenyl or said heteroaryl, substituted with R7 and optionally substituted on the (hetero)aromatic ring with one or two substitutes selected from halogen, nitro, trifluoromethyl and (1-4C)alkyl; R7 denotes H, (1-4C)alkylthio, (1-4C)alkylsulphonyl, R8R9-amino, R10R11-aminocarbonyl, R12R13-amino(1-4C)alkylcarbonyl-amino, R14R15-amino(1-4C)alkyl, R16-oxy, R17R18-aminocarbonyl (1-4C)alkoxy, R19-oxy(1-4C)alkyl, R19-oxycarbonyl(1-4C)alkyl, R20R21-aminosulphonyl, R20-oxysulphonyl, aminoiminomethyl, (di)(1-4C)alkylaminoiminomethyl, morpholinyliminomethyl, trifluoromethylsulphonyl; R23-oxycarbonyl, or R23R24-aminocarbonyl; R8 denotes H or (1-4C)alkyl; R9 denotes (1-4C)alkylsulphonyl, (1-6C)alkylcarbonyl, (2-6C)alkenylcarbonyl, (3-6C)cycloalkylcarbonyl, (1-4C)alkoxycarbonyl, (3-4C)alkenyloxycarbonyl, (di)(1-4C)alkylaminocarbonyl, piperazinylcarbonyl, (5-8C)alkyl, (3-6C)cycloalkyl(1-4C)alkyl or phenylcarbonyl, furylcarbonyl, thiophenylsulphonyl, 5-member heteraryl(1-4C)alkyl, having one or two nitrogen atoms, optionally substituted on the heteroaromatic ring with one, two or three substitutes selected from hydroxy, amino, halogen, nitro, trifluoromethyl, (1-4C)alkoxy; R10 denotes H or (1-4C)alkyl; R11 denotes hydroxy(2-4C)alkyl, (1-4C)alkoxy(2-4C)alkyl; R12, R13 independently denote H, (1-6C)alkyl, (3-6C)-cycloalkyl, (1-4C)alkoxy(2-4C)alkyl, (3-6C)cycloalkyl-(1-4C)alkyl, pyrrolidinyl(1-4C)alkyl, amino(2-4C)alkyl, (di)(1-4C)-alkylamino(2-4C)alkyl or phenyl(1-4C)alkyl, pyridinyl (1-4C)alkyl; or R12R13 in R12R13-amino(1-4C)alkylcarbonylamino can be bonded together with the nitrogen atom to which they are bonded into a (5-6C)heterocycloalkyl ring, having one or two nitrogen atoms, optionally substituted with hydroxy(1-4C)alkyl; R14, R15 independently denote H, (1-6C)alkyl, (1-6C)alkylcarbonyl, (1-4C)alkoxycarbonyl or pyridinyl(1-4C)alkyl, optionally substituted on the aromatic ring with one substitute selected from halogen; or R16 denotes (di)(1-4C)alkylamino(2-4C)alkyl, hydroxycarbonyl(1-4C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, phenyl(1-4C)alkyl or pyridinyl(1-4C)alkyl; R17, R18 independently denote H, (1-6C)alkyl, thiophenyl(1-4C)alkyl; or R17R18 in R17R18-aminocarbonyl(1-4C)alkoxy can be bonded into a morpholine or piperazine ring, R19 denotes H or (1-6C)alkyl; R20R21 independently denote H, (1-6C)alkyl or (1-4C)alkoxy(1-4C)alkyl; or R20R21 in R20R21-aminosulphonyl can be bonded into a morpholine ring; X denotes O or N-R22; Y denotes CH2 or C(O); Z denotes CN or NO2; R22 denotes H; R23, R24 independently denotes H; (1-4C)alkyl; or R23R24 in R23R24-aminocarbonyl can be bonded into a dihydropyridine ring; provided that compounds of formula I, in which X denotes O, R4 denotes phenyl and R7 is selected from H, (1-4C)alkylthio, (1-4C)alkylsulphonyl, R23-oxycarbonyl, and R23R24-aminocarbonyl, and compounds of formula I, in which X denotes O, R4 denotes (2-5C)heteroaryl and R7 denotes H are excluded. The invention also relates to use of 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives to prepare a medicinal agent for treating sterility.

EFFECT: improved useful biological properties.

12 cl, 73 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for selective production of N-[3-(1,3,5-dithiazinan-5-yl)propyl]-N-[4-(1,3,5-dithiazinan-5-yl)butyl]amine and N1,N4-bis-[3-(1,3,5-dithiazinan-5-yl)propyl]-1,4-butane diamine which involves reaction of an amine with a hydrogen sulphide saturated aqueous solution of formaldehyde, where the amine used is polymethylenepolyamine (spermidine or spermine) in molar ratio polyamine: formaldehyde: hydrogen sulphide equal to 1:6:4 and the reaction is carried out at 20°C for 3 hours.

EFFECT: compounds can be used as selective sorbents and extraction agents of precious metals, special reagents for inhibiting bacterial activity in various media.

1 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrolidine derivatives of general formula (1) or its pharmaceutically acceptable salts where R101 and R102 values are described by the patent claim. The compounds inhibit serotonin and/or norepinephrine and/or dopamine reabsorption thereby allowing to be used for treating depression and anxiety disorder. A method for preparing thereof is described.

EFFECT: preparation of new pyrrolidine derivatives.

10 cl, 162 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of general formula in which R1 stands for C1-C4-alkyl; R2 stands for C1-C4-alkyl; R3 stands for phenyl, which optionally contains 1-3 any substituents, selected from the group, including halogen, C1-C6-alkyl and C1-C4-alkoxygroup; R4 stands for hydrogen; C1-C6-alkyl or C3-C7-cycloalkyl -C1-C4-alkyl, R5 stands for hydrogen; and R6stands for hydrogen; and R7 stands for hydrogen; and R9 stands for C1-C4-alkyl; and R10 stands for C1-C6-alkyl, phenyl-C0-C4-alkyl or pyridinyl-C0-C4-alkyl; on condition that R10 does not stand for phenyl, if R5 and R9 together form C2-alkylene; or R5 R9 together form C1-C3-alkylene; or R6 and R9 together form C1-C3-alkylene; or R7 and R9 together form C2-C4-alkylene or C1-C3-alkyleneoxygroup; or R8 and R9 together form C3-C5-alkylene; or R9 and R10 together form C4-C6-alkylene; and n equals 0 or 1, or its any physiologically compatible salts. In addition, the invention relates to pharmaceutical composition, containing formula I compounds and intended for treatment of cardio-vascular diseases, to application of said compounds for preparation of medication, as well as to method of obtaining formula I compounds.

EFFECT: obtained and described are novel compounds, possessing cardio-vascular activity.

16 cl, 8 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel substituted imidazole compounds of formula I where values of radicals are given in description, as well as to their based on them pharmaceutical compositions.

EFFECT: formula I compounds, as well as their salts, esters and compositions based on them possess ability to inhibit protein of kinesin spindle (KSP) and can be used for treatment of cancer diseases.

40 cl, 15 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula 2 and 3

, synthesis methods thereof, pharmaceutical compositions, as well as use thereof to prepare a medicinal agent, having antagonistic activity towards D2-receptors and modulating activity towards 5HT reuptake.

EFFECT: present invention provides salt forms used as modulators of one or more GPCR.

20 cl, 3 tbl, 5 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidinium derivatives of formula I

in enantiomer form or pharmaceutically acceptable salt thereof, where R1 and R3 each independently denotes cyclopentyl, cyclohexyl, phenyl; R2 denotes OH; R4 denotes C1-C4alkyl; R5 denotes C1alkyl, substituted with a CO-NH-R6 group; R6 denotes a 5-member unsaturated heterocyclic group containing one N atom and one O atom in the ring, a 6-member heterocyclic group containing two N atoms in the ring.

EFFECT: compounds can inhibit binding of aceylcholine with M3 muscarinic receptors, which facilitates their use in a pharmaceutical composition.

6 cl, 3 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compound described by formula where R1 represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle with the monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle, optionally having 1 to 5 substitutes chosen from a group consisting of (1) halogen atom, (2) cyano, (3) hydroxy, (4) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (5) amino, (6) mono- C1-6 alkylamino, (7) C1-6 alkoxycarbonyl and (8) C1-6 alkyl optionally having 1 to 3 halogen atoms, R2 represents (i) C6-14 aryl group optionally substituted by 1 to 5 substitutes chosen of a group consisting of (1) halogen atom, (2) cyano, (3) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (4) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (5) C1-6alkylcarbonyl, (6) C1-6 alkylsulphonyl, (7) C1-6 alkylthionyl, (8) C3-7 cycloalkyl, (9) C1-6 alkyl group optionally having 1 to 3 halogen atoms, and (10) C1-6 alkyl group substituted by 1 to 3 hydroxy, (ii) a thienyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) cyano and (2) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (iii) a pyridyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) halogen atom, (2) 5-10-members aromatic heterocyclic group containing carbon atom, and 1 or 2 presentations of 1-4 heteroatoms chosen from nitrogen atom, sulphur atom and oxygen atom, and (3) C1-6 alkyl group optionally having 1 to 3 halogen atoms, or (iv) a bipyridyl group optionally substituted by 1 to 3 halogen atoms, each R3 and R4 represents hydrogen atom, or one of R3 and R4 represents hydrogen atom, and another represent a lower alkyl group, halogen atom or a cyanogroup, and R5 represents an alkyl group, or to its salt. Also, the invention refers to a pharmaceutical composition showing an acid secretion inhibitory effect enabled by the compound of formula I, to a method for treatment or prevention, besides, to application of the compound of formula I for preparing a pharmaceutical composition for treatment or prevention of a number of diseases presented in the patent claim.

EFFECT: preparation of the new compounds showing the acid secretion inhibitory effect and exhibiting antiulcerant action.

20 cl, 92 ex, 24 tbl

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