4-phenyl-substituted tetrahydroisoquinolines, pharmaceutical composition and method for treatment based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 4-phenyl-substituted tetrahydroisoquinolines of the formulae: (IA) , (IB) , (IIA) , (IIB) , (IIIA) and (IIIC) wherein values X and R1-R7 are given in the invention description. Proposed compounds show selective binding of neurotransmitters and therefore they can be used in treatment of different neurological or psychological disorders, for example, ADHD. Also, invention relates to a pharmaceutical composition based on proposed compounds and to a method for treatment.

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

36 cl, 1 dwg, 16 tbl, 131 ex

 

The scope of the invention

The present invention relates to compounds, compositions and methods for treatment of various neurological and psychological disorders. In particular, the present invention relates to such compounds, compositions and methods, where the compounds are new 4-phenylsilane derivatives tetrahydroisoquinoline.

Background of invention

The treatment of various neurological and psychiatric disorders, such as attention deficit associated with hyperactivity (ADHD), characterized by a number of side effects, which are believed to result from the lack of a suitable selectivity of compounds used to treat, for example, the inability of the compounds to selectively block certain neurochemical connections and not block others. ADHD, for example, is a disease that is affecting 3-6% of school-age children and it is found in one percent of adults. In addition to creating difficulties in performing functions at school and at work, ADHD is a significant risk factor for the subsequent development of disturbances such anxiety, depression, conductive disorder and misuse of drugs, since the current treatment regimens require the use of psychostimulants and because a significant number of patient is (30%) are resistant to stimulants or side effects. In addition, methylphenidate, modern drug chosen to treat ADHD, induces a number of side effects; they include anorexia, insomnia and anxiety, tics, as well as high blood pressure and heart rate, secondary to activation of the sympathetic nervous system. Methylphenidate also has high selectivity for protein-Transporter dopamine compared with protein-norepinephrine Transporter (DAT/NET Ki 0,1), which may lead to a predisposition to addictive and requires multiple doses per day for optimum efficiency.

This invention relates to such well-known alternative treatment regimens with the use of new derivatives of 4-vinyltetrahydrofuran, moreover, these compounds have never been described in this area. In U.S. patent No. 3947456 (patent '456), for example, described 4-phenylsilane tetrahydroisoquinoline formula:

where R represents hydroxy or lower alkoxy; patent '456 not described any other group in this position, not to mention the deputies present at the position (R4in the proposed connections. Phenylsilane tetrahydroisoquinoline described in Mondeshka et al. (Il Farmaco, 1994, 49 pp. 475-481). However, the compounds described therein, other than compounds proposed in the estuaries and the ü.

SUMMARY of the INVENTION

This invention relates to the following compounds of formula IA, IB, IIA, IIB, IIIA and IIIB

where R1-R13have the values defined here. In one embodiment, R1is1-C6-alkyl; R2represents H, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-halogenated; R3in each case is independently H, halogen, C1-C6-alkyl or C1-C6-alkyl, substituted 1-3 OR8or NR8R9; R4, R5and R6each, independently, represents H or is selected in each case from halogen, -OR10, -NR10R11, -NR10C(O)R11, -S(O)nR11, -CN, -C(O)R11, -C(O)2R11, -C(O)NR11R12With1-C6-alkyl, C3-C6-cycloalkyl or4-C7-cycloalkenyl and where each1-C6-alkyl, C3-C6-cycloalkyl and C4-C7-cycloalkenyl optionally substituted from 1 to 3 substituents, independently selected in each case from C1-C3-alkyl, halogen, -CN, -OR8, -NR8R9and phenyl, which is optionally substituted 1-3 times with halogen, -CN, C1-C4-alkyl, C1-C4-halogenation, -OR8or-NR8 R9; or R5and R6can be-O-C(R11)2-O-; and R7- R13, n and X have the values defined here.

The connection suggested here, blocking the re-uptake of norepinephrine, dopamine and serotonin with defined ratios of selectivity, for example, are more selective for protein-norepinephrine Transporter (NET)than for protein-dopamine Transporter (DAT), or protein-serotonin transporters (SERT). Therefore, the compounds are useful for the selective treatment of various neurological and psychological disorders.

The proposed pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of compounds of formula IA, IB, IIA, IIB, IIA, IIIA or IIIB. Next, a method of treatment of a mammal suffering from a neurological or psychological disorder selected from the group including attention deficit associated with hyperactivity, anxiety, depression, posttraumatic stress, supranuclear palsy, malnutrition, obessive-compulsive disease, analgesia, syndrome Smoking cessation, panic attacks, Parkinson's disease and phobia, including introduction to the mammal the above pharmaceutical compositions.

DETAILED description of the INVENTION

This invention relates to compounds which s formula IA, IB, IIA, IIB, IIIA or IIIB:

where:

R1selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl,2-C6-quinil,3-C6-cycloalkyl,4-C7-cycloalkyl and benzyl, each of which is optionally substituted by 1-3 substituents, independently selected in each case from C1-C3-alkyl, halogen, -CN, -OR8and-NR8R9;

R2selected from the group consisting of H, C1-C6-alkyl, C2-C6-alkenyl,2-C6-quinil,3-C6-cycloalkyl,4-C7-cycloalkenyl and C1-C6-halogenoalkane;

R3selected from the group consisting of H, halogen, C1-C6-alkyl, C1-C6-halogenoalkane and C3-C6-cycloalkyl, where C1-C6-alkyl, C1-C6-halogenated and C3-C6-cycloalkyl optionally substituted by 1-3 substituents, independently selected in each case from OR8and NR8R9;

R4, R5and R6each independently selected in each instance from the group consisting of H, halogen, -OR10, -NO2, -NR10R11, -NR10C(O)R11, -NR10C(O)NR11R12, -S(O)nR11, -CN, -C(O)R11, -C(O)2R11, -C(O)NR11R12With -C6-alkyl, C2-C6-alkenyl,2-C6-quinil,3-C6-cycloalkyl and C4-C7-cycloalkenyl, where each1-C6-alkyl, C2-C6alkenyl,2-C6-quinil,3-C6-cycloalkyl and C4-C7-cycloalkenyl optionally substituted by substituents from 1 to 3 independently selected in each case from C1-C3-alkyl, halogen, =O, -CN, -OR8, -NR8R9and phenyl, where phenyl optionally substituted by 1-3 substituents, independently selected in each case from halogen, -CN, C1-C4-alkyl, C1-C4-halogenoalkane, -OR8and-NR8R9;

in the alternative case, R5and R6represent-O-C(R11)2-O-;

R7selected from the group consisting of H, halogen and OR10;

R8and R9each independently selected from the group consisting of H, C1-C4-alkyl, C1-C4-halogenoalkane,1-C4-alkoxyalkyl,1-C4-alkoxylalkyl,3-C6-cycloalkyl,4-C7-cycloalkenyl, -C(O)R12, phenyl and benzyl, where phenyl and benzyl optionally substituted by 1-3 substituents, independently selected in each case from halogen, cyano, C1-C4-alkyl, C1-C4-halogenoalkane,1-the 4-alkoxy and C1-C4-halogenoalkane, or R8and R9taken together with the nitrogen to which they are attached, with the formation of the piperidine ring, pyrrolidine, piperazine, N-methylpiperazine, research or thiomorpholine;

R10selected from the group consisting of H, C1-C4-alkyl, C1-C4-halogenoalkane,1-C4-alkoxyalkyl,3-C6-cycloalkyl,4-C7-cycloalkenyl, -C(O)R12, phenyl and benzyl, where phenyl and benzyl optionally substituted by 1-3 substituents, independently selected in each case from halogen, -NH2, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkane,1-C4-alkoxy and C1-C4-halogenoalkane;

R11selected from the group consisting of H, C1-C4-alkyl, C1-C4-halogenoalkane,1-C4-alkoxyalkyl,3-C6-cycloalkyl,4-C7-cycloalkenyl, phenyl and benzyl, where phenyl and benzyl optionally substituted by 1-3 substituents, independently selected in each case from halogen, -NH2, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkane,1-C4-alkoxy and C1-C4-halogenoalkane,

or R10and R11taken together with the nitrogen to which they are attached, to form a ring PI is uridine, pyrrolidine, N-methylpiperazine, research or thiomorpholine; usloviia that only one of R8and R9or R10and R11taken together with the nitrogen to which they are attached, forming a piperidine ring, pyrrolidine, piperazine, N-methylpiperazine, research or thiomorpholine.

R12selected from the group consisting of C1-C4-alkyl, C1-C4-halogenoalkane and phenyl;

X is selected from the group consisting of O, NR13and S, provided that X represents NR13when the compound is a compound of formula (IA); the ring containing X is selected from furan, pyrrole, thiophene, dihydrofuran, dihydropyrrole and dihydrothiophene;

n is 0, 1, and 2 and

R13selected from the group consisting of H, C1-C6-alkyl, benzyl and phenyl, where C1-C6-alkyl, benzyl and phenyl optionally substituted by 1-3 substituents, independently selected in each case from halogen, -NH2, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkane,1-C4-alkoxy and C1-C4-halogenoalkane.

"Alkyl" means a saturated hydrocarbon chain, branched or unbranched, having the specified number of carbon atoms. "Alkenyl" means a hydrocarbon chain or unbranched or branched configuration and one or more unsaturated what's the carbon-carbon bonds, which may be present in any stable position along the chain, such as ethynyl, propenyl and the like. "Quinil" means a hydrocarbon chain or unbranched or branched configuration and one or more triple carbon-carbon bonds that may be present in any stable position along the chain, such as ethinyl, PROPYNYL and the like. "Alkoxy" means an alkyl group with the specified number of carbon atoms attached through an oxygen bridge. "Cycloalkyl" means the group of saturated rings, including mono-, bi - or polycyclic rings, such as cyclopropyl, cyclobutyl, cyclopentyl and the like. "Halogen" means fluorine, chlorine, bromine and iodine. "Halogenated" means alkali as branched and unbranched chains having the specified number of carbon atoms, substituted by one or more Halogens. "Halogenoalkane" means alkoxygroup, substituted by at least one halogen atom.

"Substituted" or "substitution" of an atom means that one or more hydrogens on the designated atom is replaced by the indicated group, provided that the normal valency of these atoms is not exceeded. "Unsubstituted" atoms are all hydrogen atoms, determined by their valence. When a Deputy is keto (i.e. C=O), then the atom is replaced by 2 odorata. Combinations of substituents and/or symbols are permissible only if such combinations result in stable compounds, "stable compound" or "stable structure" means a compound which is sufficiently stable to withstand isolation from the reaction mixture to a suitable purity and transformation into an effective therapeutic agent.

One embodiment of the present invention are compounds in which R1is1-C6-alkyl; R2represents H, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-halogenated; R3represents in each case independently H, halogen, C1-C6-alkyl or C1-C6-alkyl, substituted 1-3 OR8or NR8R9; R4, R5and R6each independently represents H or is selected in each case from halogen, -OR10, -NR10R11, -NR10C(O)R11, -S(O)nR11, -CN, -C(O)R11, -C(O)2R11, -C(O)NR11R12With1-C6-alkyl, C3-C6-cycloalkyl or4-C7-cycloalkenyl and where each1-C6-alkyl, C3-C6-cycloalkyl and C4-C7-cycloalkenyl optionally substituted by 1-3 substituents, independently selected in each case and the 1-C3-alkyl, halogen, -CN, -OR8, -NR8R9and phenyl, which is optionally substituted 1-3 times with halogen, -CN, C1-C4-alkyl, C1-C4-halogenation, -OR8or-NR8R9or R5and R6can be-O-C(R11)2-O - and R7-R13, n and X have the above values.

In these embodiments, the implementation of the particular choice of the substituent in any one position for a connection does not necessarily affect the selection of the Deputy in another position of the same composition; that is, the connection suggested here, has any of the substituents in any position. For example, as described above, R1preferably represents, for example, With1-C6-alkyl, the choice of R1as any one of1With2With3With4With5or6-alkyl does not limit the choice of R2in particular, from any one of H, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-halogenoalkane. For R1as With any of the1With2With3With4With5or6-alkyl, R2preferably represents any of H, C1With2With3With4With5or6-alkyl or C3With4With5or6-cycloalkyl or1With2With3With4With5the sludge is 6-halogenoalkane. Similarly, the choice of R2in particular, from any one of H, C1With2With3With4With5or6-alkyl or C3With4With5or6-cycloalkyl or1With2With3With4With5,or6-halogenoalkane does not limit the choice of R3in particular, from any one of its constituent values.

In another embodiment of the invention R1represents methyl, ethyl, propyl or isopropyl; R2represents H or

With1-C6-alkyl and R3represents H, halogen or1-C6-alkyl, where C1-C6-alkyl optionally substituted by 1-3 OR8; R4and R5and R6each independently represents H, halogen, -OR10, -S(O)nR11, -NR10R11,

-C(O)R11or1-C6-alkyl, where C1-C6-alkyl optionally substituted as above; and R7-R13and X have the above values. In another embodiment, R1is methyl; R2and R3represent H; R4and R5and R6, each independently, represents H, F, Cl, -OH, C1-C3-alkoxy or C1-C3-alkyl; R7represents H, F, -OH or-och3and R8-R13and X have the above values.

In one embodiment, about what westline compounds include, for example and without limitation, or compounds, which are listed here below in tables I-VIA. That is, such compounds include compounds having the following formula (see table 1-1B),

where the oxygen-containing ring is either saturated or unsaturated, R4represents H, Cl or F, R5represents H, F or Me, and R6represents H or F.

In another embodiment, the compounds include compounds having the following formula (see table 2-2B).

where X represents O, S or N, X-containing ring is either saturated or unsaturated, R3represents H, Me, Et or Meon, R4and R6each represents H, F or Cl, R5represents H, F, Cl or OMe, and R13when present, is C1-C6-alkyl. In another embodiment, the compounds further include compounds having the following formula (see tables 3-3A).

where X represents O or N, X-containing ring is either saturated, or saturated or unsaturated, R4, R5and R6each represents H and R13when it is present, is H or C1-C6-alkyl.

Another option implementation includes compounds having the following formula (see the ablity 4-4B).

where X represents O or N, X-containing ring is either saturated or unsaturated, R4represents H, R5represents H, Cl, F or Bn, R6represents H, Cl or F, and R13represents N or C1-C6-alkyl. The following options for implementation include compounds having the following formula (see table 5).

where X is O or S, X-containing ring is either saturated or unsaturated, R4represents H, R5represents H, Cl, F or OMe, R6represents H, Cl or F, and R13is1-C6-alkyl. The following compounds of embodiments include compounds having the following formula (see tables 6-6A).

where X is Oh, X-containing ring is either saturated or unsaturated, R4represents H, R5represents H or F, R6represents H or F.

Also offered each stereoisomeric form of the compounds of this invention. That is, the compounds may have one or more asymmetric centers or planes, and all chiral (enantiomeric and diastereomeric) and racemic forms of the compounds included in the present invention. Many geometric isomers of olefins, double bonds C=PI like may also be present in the compounds and all such stable isomers are considered in the present invention. Compounds emit either in racemic form or an optically pure form, for example, chiral chromatography or chemical separation of the racemic form.

Also proposed pharmaceutically acceptable salts of the compounds of the present invention. In this regard, the phrase "pharmaceutically acceptable" is used to designate those compounds, materials, compositions and/or dosage forms which are, from the point of view of medical structures are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable ratio of benefit/risk. "Pharmaceutically acceptable salts" refer to derivatives of the above compounds, where the original (parent) modify connection with the formation of salts with acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids of the basic residues such as amines; salts of alkaline or organic basic compounds, acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or the Quaternary ammonium salt ishodnoj the connection, formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, Panova, maleic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonate, methanesulfonate, ethicality, oxalic acid, setinova and the like.

Also proposed proletarienne forms of the compounds of this invention. Such prodrugs are compounds comprising compounds of this invention and the parts covalently associated with the parent compounds, so that part of the initial compounds is most likely associated with toxicity in the body of the subjects to which the prodrug is administered, blocked induction of such actions. However, prodrugs also broken down in the body of the subject in this way to release the original connection without excessive loss of its therapeutic potential. Prodrugs include compounds in which the hydroxy, amino or Sul is hydrellia group associated with any group, which when administered to a subject, the mammal is cleaved with the formation of free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formiate and benzoate derivative functional groups of the alcohol and amine in compounds of formulas (I-III).

Proposed connections, radiolabelled, i.e. compounds in which one or more of the described atoms are replaced by a radioactive isotope such atom (for example, replaced by14With or11C, and H, replaced by3N or18F). Such compounds have a variety of potential uses, for example, as standards and reagents in determining the ability of a potential pharmaceutical to bind with proteins-neurotransmitters or to obtain images of the compounds of the present invention associated with biological receptors, in vivo or in vitro.

This invention relates to compositions containing the compounds described herein, including, in particular, to pharmaceutical compositions comprising therapeutically effective amounts of compounds and pharmaceutically acceptable carriers. "Therapeutically effective amount" is any amount of compounds effective to alleviate, reduce symptoms, inhib the regulation or prevention of a specific state, because of the presence of which the subject is treated. These amounts usually vary according to a number of factors that are quite within the competence of medium-specialists and is shown here for definitions and explanations of the proposed description. They include, without limitation: a specific subject, and the age, weight, height, overall physical condition and medical history; specific connection, as well as the medium in which it is prepared, and its chosen route of administration and the nature and seriousness of being treated condition. Therapeutically effective amounts include optimal and suboptimal doses, they can be defined in various ways, usually known specialists in this field, for example, the introduction of different amounts of a particular agent to an animal suffering from a particular disease, with subsequent determination of the relative therapeutic benefits received by the animal. These quantities typically comprise from about 0.001 mg per kg of body weight being treated of the subject to about 1000 mg per kg, and more typically, from about 0.1 to about 200 mg per kg of These quantities can be entered in accordance with any regimen of medicines that are acceptable for secondary specialists overseeing the treatment.

"Pharmaceutically who ielemia media environments are usually acceptable in this area for the introduction of therapeutic compounds to the people. Such carriers usually are manufactured in accordance with a number of factors that are quite within the competence of medium-sized specialists in this area and provides for definitions and explanations. They include, without limitation, the type and nature of the active agent that is administered in the composition; the subject, which you want to enter containing agent composition; given the way the compositions and therapeutic indication, which is aimed at treatment. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid medium, as well as various solid and semi-solid forms. Such media may include, in addition to the active ingredient, a number of different ingredients and additives, and such additional ingredients include preparative form for various reasons, for example, to stabilize the active ingredient, which are well known to the person skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and factors considered in their selection, are available in a variety of readily available sources, for example, in Remington''s Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, PA, 1985, the contents of which are incorporated here by reference.

Compounds of the present invention is administered, for example, parenterally in various aqueous media such as aqueous solutions of dextrose and saline solutions; dissolve the s glycols are suitable carriers. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Suitable stabilizing agents are also antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, used either individually or in combination. Also use citric acid and its salts and EDTU. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl - or propylparaben and chlorbutanol.

In the alternative case of compound administered orally in solid dosage forms such as capsules, tablets and powders, or in liquid forms, such as elixirs, syrups, and/or suspension. You can use gelatine capsules which contain the active ingredient and a suitable carrier, including, but not limited to, lactose, starch, magnesium stearate, stearic acid or derivatives of cellulose. To obtain CT can be used such diluents. As tablets and capsules can be manufactured in the form of products of prolonged, to ensure a continuous release of drug for any period of time. Molded tablets may be coated with sugar, Il the film for masking unpleasant taste or to protect the active ingredients from the action of the atmosphere or for selective disintegration of the tablet in the gastrointestinal tract.

The compounds of this invention are especially useful therapeutic index compared with other compounds available for the treatment of such disorders. Without intending to be limited by theory, believe that this is the result, at least partially, the ability of compounds to be selective in relation to protein-norepinephrine Transporter (NET), compared with selectivity for transporters of other neurotransmitters. Affinity binding demonstrate a variety of ways well known in the art, including, but not limited to, techniques described in the Examples below.

Briefly, for example, containing protein extracts from cells, for example, cells NEC expressing proteins conveyors, incubated with labeled with radioactive isotopes, ligands for proteins. The binding of radio-protein is reversible in the presence of other ligands of proteins, for example, compounds of the present invention; specified reversibility, as described below, provides a means to measure the affinity of binding of compounds to proteins (Ki). A higher value of Ki for the connection indicates that the connection has a lower affinity binding to the protein than the connection with the lower value of Ki, on the contrary, lower Ki values indicate higher srots is in the binding.

Accordingly, the lower the Ki value for protein, for which the connection is more selective and higher Ki value for protein, for which the connection is less selective, indicate the difference in selectivity of the compounds against protein. Thus, the higher the ratio of the Ki values of the compounds for protein And compared to the protein, the higher is the selectivity of the compounds in the latter, compared with the first (and the first has a higher value of Ki and the last lower Ki value for this connection). The offered compounds cause less side effects during therapeutic use because of their selectivity against the protein of the norepinephrine Transporter, which is indicated by the ratio of their Ki for binding with NET compared to Ki for binding other proteins, transporters, for example, dopamine Transporter (DAT) and serotonin Transporter (SERT). Compounds of the present invention typically have a ratio of Ki for DAT/NET approximately ≥ 2:1; compounds typically have ratios SERT/NET ≥ 5:1.

In addition, the assessment of the in vivo activity of compounds against conveyors NE and DA carried out, for example, determining their ability to prevent sedative action of tetrabenazine (TBZ) (see, for example, G. Stille, Arzn. Forsch. 1964, 14, 534-537; containing the s of which is included here as a reference). Taken by chance and pre-defined doses of the tested compounds injected mice, as then enter the dose of tetrabenazine. Animals are then estimated on the antagonism induced tetrabenazine loss research activity and ptosis in certain time intervals after administration of the drug. Research activity, for example, evaluate, by placing the animal in the center of the circle and then estimating the time required for animal crossing circle, usually, the more time it takes the animal to such crossing, the greater the loss of research activities. In addition, it is believed that the animal has ptosis, if his eyes are closed, at least 50%. Consider that more than 95% of the control (treated filler) mice have a loss of research activity and ptosis; associated with the connection activity is then calculated as the percentage of damage of mice in response to dose administration of tetrabenazine, and believe that more therapeutically effective compounds are best at reducing the loss of research activity and ptosis.

In line with this, the offered pharmaceutical composition useful for the treatment of subjects suffering from various neurological and psychiatric disorders with the introduction of these subjects offer is authorized here dose of the pharmaceutical composition. Such disorders include, without limitation, attention deficit associated with hyperactivity, anxiety, depression, posttraumatic stress violation, supranuclear palsy, malnutrition, obessive-compulsive disorder, analgesia, syndrome Smoking cessation, panic attacks, Parkinson's disease and phobias. The offered compounds are especially useful in the treatment of these and other violations of due, at least in part, to their ability to selectively bind with proteins-transporters some neurochemical substances with high affinity binding compared with the protein-transporters other neurochemical substances.

Synthesis

Compounds of the present invention can be obtained using the methods described below, as well as methods known in the field of synthetic organic chemistry, or their variants, known to specialists in this field. Preferred methods include, but are not limited to, the methods described below.

New tetrahydroisoquinoline inhibitors of reuptake of formula (I-IIIB) of this invention can be obtained according to the General scheme below (scheme 1-4). R1-substituted N-benzylamine formula (V) in scheme 1 can be purchased from commercial sources or, alternatively, it can be obtained in a simple reaction in stanowiacego amination. So, carbonylic compounds of the formula (IV) can be processed H2N-R1in the lower alilovic alcohol solvents (preferably methanol or ethanol) at room or lower temperature. Formed Imin you can restore most borohydride alkali metal (preferably, sodium borohydride), with the formation of the desired amine intermediate products, recovery is optimally carried out at room or lower temperature. Processing the intermediate benzylamino formula (V) electrophilic intermediate compounds of formula (VII) gives the products of alkylation of the formula (VIII). Alkylation reaction can be carried out in various conditions, well-known specialist in the field of organic synthesis. Typical solvents include acetonitrile, toluene, diethyl ether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methylene chloride and lower alkalemia alcohols, including ethanol. The reaction can be conducted at temperatures comprising from 0°C to the boiling point of the used solvent. The course of the reaction is usually controlled standard chromatographic and spectroscopic methods. The alkylation reaction is not necessarily carried out with the addition of dinucleophiles organic base, including, but not limited to, pyridine, triethyl is in and diisopropylethylamine, and the reaction time to completion may vary from 1 hour to several days.

The above electrophilic intermediate compound of formula (VII) typically purchase from commercial sources or produced by processing optionally substituted acetophenone of the formula (VI) normal romirowsky agents, including, but not limited to, bromine, NBS or tribromide tetrabutylammonium, this easily gives the desired bromoacetophenone formula (VII). These reactions are optimally carried out in acetic acid or methylene chloride with methanol used as co-solvent for tribromide reagent, at room or lower temperature. Another variant implementation of this technique may include the use chloracetophenone compounds of the formula (VII).

Acetophenone formula (VI), in turn, are also available from commercial sources or are usually obtained with the help of several well known ways, including the processing of the respective intermediate benzoic acid two stoichiometric equivalents metallyte (see, for example, Jorgenson, M.J. (Organic Reactions, 1970, 18, pg. 1)). In the alternative case, the associated benzaldehyde you can handle nucleophilic ultilateral Grignard reagent (for example, MeMgBr) or alkyllithium (for example, MeLi) followed standard about what Elenium in the ketone (see, for example, Larock, R.C. Comprehensive Organic Transformations, VCH Publishers, New York, 1989, p. 604)).

Recovery of the compounds of the formula (VIII) in benzyl alcohols of the formula (IX) is carried out using many reducing agents, including, for example, borohydride sodium, borohydride lithium, borane, diisobutylaluminum and sociallyengaged. Recovery can be performed during the time from 1 hour to 3 days at room temperature or elevated temperature up to the boiling point of the used solvent. If using borane, it can be used in the form of a complex, including, for example, but not limited to, a complex of borane-metilsulfate, complex, borane-piperidine or a complex of borane-tetrahydrofuran. The person skilled in the art should know the right combination of reducing agents and the necessary conditions of the reaction or can use the guide from Larock, R.C. (see above).

The compounds of formula (IX) can be cilitate in tetrahydroisoquinoline the compounds of formula (Ib)where R7=H, this invention the rapid processing of a strong acid. Suitable acids include, but are not limited to, concentrated sulfuric acid, polyphosphoric acid, methanesulfonate acid and triperoxonane acid. The reaction is conducted without solvent, or optionally in the presence of co-solvent, such as, for example, met landlord or 1,2-dichloroethane. Cyclization can be carried out at temperatures from 0°C to the boiling point of the used solvent. Specialist in the chemistry of heterocyclic compounds can easily choose these conditions or may take into account the guidance in Mondeshka, et al. (Il Farmaco, 1994, 49, 475-480) or Venkov, et al. (Synthesis, 1990, 253-255). Cyclization can also be carried out by treatment of compounds of formula (IX) strong Lewis acids, such as, for example, trichloride aluminum, usually in halogenated solvents such as methylene chloride. The person skilled in the art should be familiar with the method described in Kaiser, et al. (J. Med. Chem., 1984, 27, 28-35) and Wyrick, et al. (J. Med. Chem., 1981, 24, 1013-1015).

Compounds of formula (I-III) can be obtained in enantiomerically pure (R)- and (S)-form by crystallization with chiral salts that are well known to the person skilled in the art, or, alternatively, can be distinguished by chiral HPLC using a commercially available chiral columns.

Compounds of formula (I-III), where R7=HE in scheme 1, 3 and 4 of the present invention, can be obtained in accordance with Kihara, et al. (Tetrahedron, 1992, 48, 67-78) and Blomberg, et al. (Synthesis, 1977, p. 18-30). So, ketone compounds of formula (VIII), which are ortho-iodine on the aromatic ring and subjected to cyclization, you can handle the strong bases, including, but not limited to, lower alkyl(C1-6)lit Evie base (preferably, tert-BuLi or n-BuLi), for the expected exchange of the halogen-metal with subsequent intramolecular cyclization Barbier with the formation of compounds of formulas (I-III), where R7=OH. The necessary inert solvents, such as dialkylamide simple ether (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) and so on, and maintain a low reaction temperature (-78°-25° (C)to avoid the formation of side products. In the alternative case, the exchange of the halogen-metal can also be carried out in the presence of a Nickel zero-valent state, in this case N,N-dialkylacrylamide (preferably dimethylformamide) serve as an ideal solvent. This cyclization is best done when X=Br, to avoid priostanovleniya or intermolecular reactivity. In addition, the compounds of formulas (I-III), where R7=IT can be easily alkilirovanii (see above) to obtain the compounds of formulas (I-III), where R7=OR10. Finally, further processing of the compounds of formulas (I-III), where R7=HE, halogenation reagent or definitely fluorinating reagent, including but not limited to, the TRIFLUORIDE diethylaminoethyl (DAST), easily gives the compounds of formula (I-III), where R7=F. the Following link you can get from Hudlicky (Organic Reactions, 1985, 35, p. 513-637).

As the W precursor compounds of the formula (IV), for those reagents which may be commercially available, there are numerous synthetic ways of obtaining from other commercial compounds or compounds known in the field, and these paths must be obvious to any expert in the field of organic synthesis. Without limiting illustrative method shown in scheme 2, where the allyl alcohol of formula (X) are easily subjected to ozonolysis and subsequent reduction processing reagents, including but not limited to, dimethyl sulfide, getting lactol, which is treated with a weak acid in a wide range of conditions with the formation of benzofuran formula (XI). The technique of mutual transformations of functional groups of ester to the aldehyde should be quite familiar to a person skilled in this field to obtain the target compounds of formula (IV).

In addition, the aminoalcohols pre-cyclization of formula (XII) of scheme 3 and formulas (XIII-XIV) scheme 4 synthesize a way that is completely analogous to the methods described above to obtain amerosport pre-cyclization of formula (IX) in scheme 1. In addition, as described above, the aminoalcohols pre-cyclization of formula (XII) of scheme 3 and formulas (XIII-XIV) of scheme 4 can be cichlisuite, as described, to obtain the target tetrahydroisoquinoline formula (Ia) scheme 3 and formulas (IIa, IIb, IIIa and IIIb) scheme 4. who should be well known to any expert in this field, what regionarnye tetrahydroisoquinoline obtained by cyclization of compounds of formula (XIII-XIV).

In the following embodiment, the present invention unsaturated furan-, indole -, and typedeclaration formulas (I-III) can be partially restored in the appropriate dihydrofuran, dihydroindol and dehydrationdehydration formulas (I-III).

Recovery is carried out in the presence of hydrogen, either at atmospheric pressure or under increased pressure and in the presence of a solvent from a wide range of solvents, including, but not limited to, methanol, ethanol and ethyl acetate. The reaction is optimally carried out in the presence of a metal catalyst, including, but not limited to, palladium, platinum or rhodium. The optimal conditions of hydrogenation should be quite well-known specialist in the field; alternatively it can be found in Larock, R.C. Comprehensive Organic Transformations, VCH Publishers, New York, 1989, p. 6.

In cases where partial recovery of the above heterocycles is impossible (for compounds Ib, where R7=H) as a result of concomitant hydrogenolysis of the substituents side arrow (e.g., Cl), you must restore the heterocyclic part of the (i.e. benzofuran, indole or thiophene) at an earlier stage of the synthesis (scheme 1, the intermediate product (V)) and then enter laterally is aryl (VII) the same way indicated in figure 1.

The contents of the above publications are included here as a reference.

SCHEME 1

SCHEME 2

SCHEME 3

SCHEME 4

The invention can be better understood by reference to the following examples section. However, the average person skilled in the art can easily understand that the examples are only to illustrate the invention as defined in the claims below.

EXAMPLES

The compounds listed below in tables I-VIA (examples 1-131), obtained according to the synthesis schemes described above, and have a melting point, as indicated in the tables; when a connection is an oil or a solid substance, it is listed here as such, and if it is solid, indicated the form of salts.

TABLE I
ExampleRingR4R5R6So square (°)Sol
1unspikedNHH165-168maleate
2the feast upon.NHH81-83
3unspikedNMeH240-246hydrochloride
4the feast upon.NMeH190-191maleate
5unspikedNClHoil, MS
6the feast upon.ClHHoil, MS
7unspikedHFH242-257hydrochloride
8the feast upon.HFHoil, MS
9unspikedFHF233-236hydrochloride
TABLE IB

Enantiomerically pure compounds (based on the overall patterns in table I)
ExampleRingR4R5R6So square (°)Salt/isomer
10 the feast upon.NNN-enantiomer
11the feast upon.NNN121enantiomer

TABLE II
PRXRingR3R4R5R6R13TPL(°)Sol
12Aboutnenas.HHHH-199-204maleate
13Aboutthe feast upon.HHHH-168-169maleate
14Aboutnenas.HFFH-240-243hydrochloride
15Aboutthe feast upon.HFFH-86-90
16Aboutnenas. HFHF-256-258hydrochloride
17Aboutthe feast upon.HFHF-107-109
18Aboutnenas.HFHH-156 to 160fumarate
19Aboutthe feast upon.HFHF-224-226hydrochloride
20Aboutnenas.HHFH-190-192hydrochloride
21Aboutthe feast upon.HHFH-110-116
22Aboutnenas.HClHH-oil, MS
23Aboutthe feast upon.HClHH-78-80
24Aboutnenas.HHClH-230-234hydrochloride
25Aboutthe feast upon.HHClH-148-150
26Aboutnenas.HHClF-253-259hydrochloride
27Aboutthe feast upon.HHClF-97-98
28Aboutnenas.HHFCl-250-258hydrochloride
29Aboutthe feast upon.HHFCl-235-242hydrochloride
30Aboutnenas.HFHH-279-284hydrochloride
31Aboutthe feast upon.HFHH -253-261hydrochloride
32Aboutnenas.HHOMeH-212-214hydrochloride
33Aboutthe feast upon.HHOMeH-
34Aboutnenas.MeHHH-187-192maleate
35Aboutnenas.EtHHH-154-160maleate
36Aboutnenas.CH2OHHHH-149-162hydrochloride
37Snenas.HHHH-218-220hydrochloride

38Nnenas.HHH HH142-144
39Nnenas.HHHHMe106-108
40Nnenas.HHHHEtamorphous,MS
41Nnenas.HHHHBnamorphous,MS
42Nthe feast upon.HHHHH84-86
43Nthe feast upon.HHHHMe
44Nthe feast upon.HHHHEt91-93
45Nnenas.HHHFH164-169
46Nnenas.HHFFMeoil, MS
47Nthe feast upon.HHFFH45-51
48Nthe feast upon.HHFFMeoil, MS
49 Nnenas.HFFFMe110-112
50Nthe feast upon.HFHFH71-75
51Nthe feast upon.HFHFMeamorphous,MS
52Nnenas.HClHHH184-186
53Nnenas.HClHHMe90-92
54Nthe feast upon. HClHHH236-238digital.
55Nthe feast upon.HClHHMe63-65
56Nnenas.HFHHH150-152
57Nnenas.HFHHMe255-258hydrochloride
58Nthe feast upon.HFHHH210-214digital.
59Nnenas.HH FHH200-205hydrochloride
60Nthe feast upon.HHFHHoil, MS
61Nnenas.HFClHH149-153
62Nnenas.HFClHMe120-124
63Nthe feast upon.HFClHHamorphous,MS
64Nthe feast upon.HFClH Meoil, MS
65Nnenas.HClFHH189-195
66Nnenas.HClFHMe212-215hydrochloride
67Nthe feast upon.HClFHH200-243digital.
68Nthe feast upon.HClFHMe194-200digital.
TABLE IIA

(identical General structure, as shown in table II)
Etc.XRingR3 R4R5R6R13TPL(°)Sol
69Aboutnenas.NFHH-156 to 160fumarate

79
TABLE IIB

Enantiomerically pure compounds (based on the General structure shown in table II, but with (R)- or (S)-absolute configuration)
Etc.XRingR3R4R5R6R13TPL(°)Miscellaneous*
70Onenas.HHHH-172-174 .5enantiomer In

fumarate
71Othe feast upon.HHHH--enantiomer, And

maleate
72 Othe feast upon.HHHH--enantiomer In

fumarate
73Onenas.HHFH-105-107Rotation -55,6° (C=0,200, Meon)
74Onenas.HHFH-104-105Rotation +53,9° (C=0,200, Meon)
75Onenas.HFFH-124.5-125.5Maleate,

enantiomer In,

rotation +18,2°

(C=0,262, Meon)
76Onenas.HHClH-87-89enantiomer And
77Onenas.HHClH-87-89enantiomer In
78Onenas.HFHF-159.5-161.0maleate,

enantiomer In
Nnenas.HHHHH115.5-117.0enantiomer A,

rotation -55,2°

(C=0,372, Meon)
80Nnenas.HHHHH116.0-117.5enantiomer In,

rotation +55,5°

(C=0,384, Meon)
*Miscellaneous - enantiomer And indicates the first stereoisomer, suirvey from the column HPLC with chiral reversed phase (used commercial columns); enantiomer means In the second erwerbende connection.

Table III
Etc.XRingR4R5R6R13TPL(°)Sol
81Aboutnenas.HHH-241-246hydrochloride
82Aboutthe feast upon.HHH-301-307hydrochloride
83Aboutnenas.HHH-117-122
84Aboutnenas.HHH-257-269hydrochloride
85Nnenas.HHHH95-103
TABLE IIIA

(identical General structure, as shown in table III)
Etc.XRingR4R5R6R13TPL(°)Sol
86Onenas.HFF-257-269hydrochloride
87Onenas.HFH-117-122
88Othe feast upon.HFH-303-308hydrochloride
89Othe feast upon.HFF -296-302hydrochloride

TABLE IV
PRXRingR4R5R6R13TPL(°)Sol
90Onenas.HHH-222-232hydrochloride
91Othe feast upon.HHH-90-95
92Onenas.HFF-263-267hydrochloride
93Othe feast upon.HFF-258-265hydrochloride
94Onenas.H FH-222-235hydrochloride
95Othe feast upon.HFH-258-266hydrochloride
96Onenas.HHCl-229-234hydrochloride
97Othe feast upon.HHCl-225-243hydrochloride
98Onenas.HClF-263-271hydrochloride
99Othe feast upon.HClF-253-256hydrochloride
100Othe feast upon.HFCl-268-275hydrochlori the
101Onenas.HOMeH-233-238hydrochloride
102Othe feast upon.HOMeH-279-284hydrochloride
103Nnenas.HHHH200-202
104Nnenas.HBnHHAmorphous, MS
TABLE IVA

(identical General structure, as shown in table IV)
PRXRingR4R5R6R13TPL(°)Sol
105Aboutnenas.HFCl-248-254 hydrochloride
TABLE IVB

enantiomerically pure compounds (based on the overall patterns in table IV)
Etc.XRingR4R5R6R13TPL(°)Sol
106Onenas.HHH--Maleate, enantiomer And
107Onenas.HHH--Maleate, enantiomer In

TABLE V
Etc.XRingR4R5R6TPL(°)Sol
108Onenas.HHH250-271hydrochloride

109 Othe feast upon.HHH89-95
110Onenas.HFH262-278hydrochloride
111Othe feast upon.HFH139-142
112Onenas.HFCl288-294hydrochloride
113Othe feast upon.HFCl255-278hydrochloride
114Onenas.HClF268-275hydrochloride
115Othe feast upon.HClF257-262hydrochloride
116Onenas.HHCl252-275hydrochloride
117Othe feast upon.HHCl249-254hydrochloride
118Onot the speakers. HOMeH260-267hydrochloride
119Othe feast upon.HOMeH246-264hydrochloride
120Onenas.HFF276-283hydrochloride
121Othe feast upon.HFF255-272hydrochloride
122Snenas.HHH232-234hydrochloride

271-285
TABLE VI
Etc.XRingR4R5R6R13TPL(°)Sol
123Onenas.HHH-234-240hydrochloride
124Othe feast upon.HHH- 78-82
125Onenas.HFH-249-254hydrochloride
126Othe feast upon.HFH-226-229hydrochloride
127Onenas.HFF-252-261hydrochloride
128Othe feast upon.HFF-Amorphous, MS
TABLE VIA

(identical General structure, as shown in table VI)
Etc.XRingR4R5R6R13TPL(°)Sol
129Nnenas.HHHH205-240
130Nthe feast upon.HHHHthe dihydrochloride
Etc.XRingR4R5R6R13TPL(°)Sol
131Nnenas.HHHMehydrochloride

Example 5

Stage a: Benzofuran-7-carboxaldehyde (4.44 g, 30.4 mmol), aqueous methylamine (5.5 ml, 63 mmol) and Meon (35 ml) are mixed in a flask of 25 ml in an atmosphere of N2. The mixture is cooled to 0°With rapid stirring and portions over 5 minutes add NaBH4(0,61 g, 16 mmol). The mixture is heated to room temperature with stirring overnight. The mixture was diluted with water (50 ml), stirred for 15 minutes and extracted with (3) CH2Cl2. The combined organic extracts are washed (3x) 2 N. HCl. These acid extracts make the main solid KOH, additional water and concentrated NH4OH. The basic mixture is extracted with (3) CH2Cl2. This second series of organic extracts are combined and dried over Na2SO4, filtered and concentrated in vacuo, getting methylaminopropyl (3.51 g, 71%) as a yellow oil:1H NMR (500 is Hz, CDCl3) δ 7.66 (d, J=2.3 Hz,1H); 7.53-7.55 (m,1H); 7.22-7.29 (m,2H); 6.80 (d, J=2.4 Hz,1H); 4.10 (s,2H); 2.51 (s,3H).

Stage: Methylamine from the stage And (3.50 g, and 21.7 mmol) and 4'-chlorpheniramine (6.2 g, 23 mmol) was dissolved in CH2Cl2(45 ml) in a 250 ml flask in an atmosphere of N2. The mixture is quickly stirred, add Et3N (3.0 ml, 22 mmol) and the mixture continued to stir overnight. The mixture is diluted with water, the layers separated and the aqueous layer was extracted twice, CH2Cl2. The combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (20% EtOAc/hexane), receiving aminoketone (4,28 g, 63%) as a yellow oil:1H NMR (300 MHz, CDCl3) δ 7.94-7.96 (m,1H); 7.76-7.80 (m,1H); 7.60 (d, J=2.3 Hz,1H); 7.47-7.56 (m,2H); 7.18-7.35 (m,3H); 6.77 (d, J=2.3 Hz,1H); 4.03 (s,2H); 3.79 (s,2H), 2.42 (s,3H).

Stage C: Aminoketone from stage (4,28 g of 13.6 mmol) dissolved in Meon (30 ml) in an atmosphere of N2. The mixture is cooled to 0°add in portions NaBH4(1.07 g, of 28.2 mmol) and the mixture is stirred for 5 hours while heating to room temperature. The mixture is diluted with water and extracted with (3 x) CH2Cl2. The combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (20% EtOAc/hexane), receiving amerosport (3,14 g, 73%) in the IDA yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.61-7.69 (m,1H); 7.53-7.56 (m,1H); 7.32-7.40 (m,1H); 7.18-7.29 (m,5H); 6.78-6.83 (m,1H); 4.75-4.81 (m,1H); 4.35 (users,1H); 4.06 (d, J=13.2 Hz,1H); 3.87 (d,J=Hz,1H), 2.55-2.66 (m,1H), 2.34 (s,3H).

Stage D: Amerosport from the stage (580 mg and 1.83 mmol) dissolved in CH2Cl2(18 ml) in a 100 ml flask, equipped with a fridge, in an atmosphere of N2. The mixture is cooled to 0°under stirring, and added dropwise MeSO3H (6,0 ml, 92 mmol). The mixture allow to warm to room temperature, then refluxed over night. The mixture is cooled to room temperature, slowly add 2 N. NaOH to make the mixture basic. The mixture is extracted with (3) CH2Cl2and the combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (mixture of 5% EtOAc/hexane containing 1% Et3N), obtaining the compound of example 5 (304 mg, 56%) as a pale yellow oil:1H NMR (300 MHz, CDCl3) δ 7.61 (d,J=2.1 Hz,1H); 7.32 (d,J=8.1 Hz,1H); 7.19-7.22 (m,3H); 7.07-7.11 (m,1H); 6.72-6.77 (m,2H); 4.34 (t,J=6.2 Hz,1H); 4.03 (d,J=15.5 Hz,1H); 3.87 (d, J=15.3 Hz,1H); 3.01-3.08 (m,1H); 2.66 (DD,J=7.8, 11.5 Hz,1H), 2.50 (s,3H), 2.34 (s,3H); CI MS m/z=298 [C18H16ClNO + H]+; Elemental analysis. Calculated for C18H16ClNO-0,25 H2ABOUT: WITH, 71,52; N, 5,50; N, 4,63. Found: C, 71,53; N, Of 5.34; N, 4,42. There is also the original material (115 mg, 20%).

Example 6

Stage A: amine, obtained in example 5, stage And (1.24 g, of 7.69 mmol), dissolved in absolute EtOH (8 ml) in a Parr reactor. Add 10% Pd/C (0,61 g, 50 wt.%) and the mixture hydronaut at 30 psi overnight. The suspension is filtered through celite and the layer washed twice Meon. The filtrate was concentrated in vacuo, getting dihydrobenzofuran 76 (1.27 g, yield quantitative) as a yellow oil:1H NMR (300 MHz, CDCl3) δ 7.07-7.13 (m,2H); 6.81 (t,J=7.4 Hz,1H); 4.58 (t,J=8.7 Hz,1H); 3.78 (s,2H); 3.18-3.27 (m,3H); 2.45 (s,3H).

Stage: Dihydrobenzofuranyl (1.27 g, of 7.69 mmol, obtained in stage A) 3'-chlorpheniramine 71 (1.9 g, 8.0 mmol) and CH2Cl2(15 ml) are mixed in a 100 ml flask in an atmosphere of N2. The mixture is rapidly stirred for adding Et3N (1.1 ml, 7.9 mmol). After stirring for 2 hours the mixture is diluted with water and CH2Cl2and the layers separated. The aqueous layer was extracted twice, CH2Cl2and the combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (20% EtOAc/hexane), receiving aminoketone (1.75 g, 72%) as a yellow oil:1H NMR (300 MHz, CDCl3) δ 7.96 (t,J=1.7 Hz,1H); 7.82-7.86 (m,1H); 7.50 (dt,J=1.4, 8.3 Hz,1H); 7.35 (t,J=7.9 Hz,1H); 7.10 (DD,J=7.5, 15.6 Hz,2H); 6.82 (t,J=7.4 Hz,1H); 4.51 (t, J=8.7 Hz,2H); 3.73 (s,2H); 3.69 (,2H); 3.20 (t,J=8.7 Hz,2H), 2.37 (s,3H); CI MS m/z=316 [C18H18 ClNO2+ H]+.

Stage C: Aminoketone, which is obtained at the stage In (1.75 g, 5,54 mmol), dissolved in Meon (12 ml) in a 100 ml flask in an atmosphere of N2. The mixture is cooled to 0°and one portion add NaBH4(440 mg, 11.6 mmol). The mixture allow to warm to room temperature with stirring over night. The mixture is diluted with water, then extracted with (3 x) CH2Cl2. The combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo, getting amerosport (1,76 g, 99%) as a yellow oil, which solidifies upon standing:1H NMR (300 MHz, CDCl3) δ 7.38 (s,1H); 7.23-36 (m,3H); 7.13-7.16 (m,1H); 7.01 (d,J=7.4 Hz,1H); 6.81 (t,J=7.4 Hz,1H); 4.73 (DD, J=4.1, 9.8 Hz,1H); 4.60 (t,J=9.0 Hz,2H), 3.75 (d, J=12.9 Hz,1H), 3.50 (d,J=12.9 Hz,1H); 3.23 (t,J=8.7 Hz,2H), 2.49-2.62 (m,2H); 2.30 (s,3H).

Stage D: Amerosport, which is obtained in stage (814 mg, 2.56 mmol), dissolved in CH2Cl2(25 ml) in a 100 ml flask, equipped with a fridge, in an atmosphere of N2. The mixture is cooled to 0°With rapid stirring and added dropwise MeSO3H (8,4 ml, 129 mmol). The mixture allow to warm to room temperature, then refluxed for 48 hours. The mixture is cooled to room temperature and slowly quenched by adding 2 N. NaOH. The layers are separated and the aqueous layer was extracted with (3) CH2Cl2. Merge the nnye organic extracts dried over Na 2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (1.5% Meon/CH2Cl2), obtaining the compound of example 6 (603 mg, 75%) as a pale yellow oil:1H NMR (300 MHz, CDCl3) δ 7.17-7.22 (d,J=7.5 Hz,1H); 4.57-4.64 (m,2H); 4.19 (t,J=6.2 Hz,1H); 3.69 (d,J=15.4 Hz,1H); 3.50 (d,J=15.3 Hz,1H); 3.18 (t,J=8.8 Hz,2H); 2.91-2.98 (m, 1H); 2.56 (DD,J=8.0, 11.4 Hz,1H), 2.43 (s,3H); API MS m/z=300 [C18H18ClNO + H]+; Elemental analysis. Calculated for C18H18ClNO-0.6 N2ABOUT: WITH, 69,60; N, 6,23; N, 4,51. Found: C, 69,53; N, 5,88; N, To 4.38.

Example 12

Stage A: Allyl alcohol X (2.0 g, 10.5 mmol) dissolved in methanol (90 ml), cooled to -78°and ozoniruyut until then, until no starting material (approximately 30 minutes). Quickly add the dimethyl sulfide (4 ml) and the resulting mixture allow to warm to room temperature over night. The solvent is removed in vacuum and the residue is dissolved in diethyl ether, then washed twice with water and once with saturated salt solution. The organic portion is dried over anhydrous sodium sulfate, filtered and the solvent is removed in vacuum, obtaining the required lactol, 1.18 g (58%) as a viscous yellow oil:1H NMR (300 MHz, CDCl3) δ 7.56-7.59 (m,1H); 7.21-7.26 (m,1H); 7.03 (d, 1H, J=8.0 Hz); 6.12 (DD, 1H, J=2.2, 6.5 Hz); 3.90 (s,3H); 3.40-3.60 (m,2H).

Stage b: the Product of stage A (8.0 g, 41,0 mmol) paramashiva the t in H 3RHO4(85%, 50 ml) at room temperature for 30 minutes. The resulting turbid mixture was diluted with water and extracted with (4) diethyl ether. The combined organic extracts washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and the solvent is removed in vacuum. The crude material is purified flash chromatography on silica gel (hexane/ethyl acetate, 20:1), receiving a 3.87 g (53%) benzofuranyl of ester as a pale yellow oil:1H NMR (300 MHz, CDCl3) δ 7.99 (d, 1H, J=7.1 Hz); 7.68-7.74 (m,2H); 7.32-7.38 (m,2H); 3.99 (m,3H); CI MS m/z=177 [C10H8O3+H]+.

Stage C: the Product of stage (4,67 g of 27.0 mmol)dissolved in anhydrous tetrahydrofuran (60 ml)is added dropwise to a stirred suspension of sociallyengaged (2.5 g, 65,0 mmol) in anhydrous tetrahydrofuran (50 ml) at 0°C in nitrogen atmosphere. The grey suspension is stirred and left to warm to room temperature for two hours. The mixture is again cooled to 0°C, then quenched with ethyl acetate until the termination of allocation of bubbles and add a solution of saturated aqueous sodium sulfate until then, until there is no longer grey. To remove water, add anhydrous sodium sulfate, the solution is filtered and the solvent is removed in vacuum. The residue is maintained at reduced pressure for seven hours is in, obtaining 4.6 g (100%) of the desired alcohol as a yellow oil, which is usually used without additional purification. Part of the crude product purified flash chromatography on silica gel (hexane/ethyl acetate, 10:1, then 2:1)to give pure alcohol in the form of a white solid:1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H, J=2.3 Hz); 7.43 (d, 1H, J=8.1 Hz); 7.24 (t, 1H, J=7.7 Hz); 7.16 (d, 1H, J=7.4 Hz); 6.85-6.86 (m,1H); 4.84 (s,3H); 2.34 (users,1H).

Stage D: a Solution of oxalicacid (2,9 ml, 33.0 mmol) in methylene chloride (75 ml) is stirred under nitrogen atmosphere at -78°and added dropwise dimethyl sulfoxide (5,2 ml, 73,0 mmol). The resulting mixture was stirred at -78°C for 10 minutes, then added dropwise within 20 minutes, add a solution of compound stage With (4.5 g, 30.0 mmol) in methylene chloride (75 ml). The mixture was stirred at -78°C for more than 20 minutes, and then quickly added triethylamine (21,0 ml, 150 mmol) and the reaction mixture was allow to warm to room temperature and stirred over night under nitrogen atmosphere. The mixture is diluted with methylene chloride and water. The methylene chloride layer removed and the aqueous portion is extracted twice with methylene chloride. The organic layers are combined, washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and the solvent is removed in vacuum. The residue is purified flash chromatography on silica gel (hexa is s/ethyl acetate, 5:1, then 1:1), obtaining the required benzofuranyl, 3.1 g (70%), as a yellow oil:1H NMR (300 MHz, CDCl3) δ 10.19 (s,1H); 7.79 (d, 1H, J=2.1 Hz); 7.73 (t, 1H, J=7.4 Hz); 7.51 (d, 1H, J=1.7 Hz); 7.43 (t, 1H, J=7.8 Hz).

Stage E: the Product of stage D (2.91 in g, 20 mmol) in solution in methanol (30 ml) is added dropwise to 40% aqueous methylamine (3.4 ml, 40 mmol) in methanol. The reaction mixture was stirred over night at room temperature in a nitrogen atmosphere, then cooled to 0°and small portions for two minutes add borohydride sodium (0.8 g, 20 mmol). The resulting mixture is stirred for 2.5 hours at room temperature, then quenched with water and extracted (3x) 2 N. HCl. Water extracts do basic 6 N. NaOH (pH 10) and the product extracted into methylene chloride and dried over anhydrous sodium sulfate. Filtration and concentration to give the desired methylamine, 2,88 g (89%), as a pale yellow oil:1H NMR (300 MHz, CDCl3) δ 7.62 (d, 1H, J=2.3 Hz); 7.42 (d, 1H, J=8.0 Hz); 7.25 (t, 1H, J=7.7 Hz); 7.16-7.19 (m,1H); 6.88-6.89 (m,1H); 3.98 (users,2H); 2.48 (users,3H).

Stage F: the Product of stage E (2,99 g, 19.0 mmol), 2-bromoacetophenone (3.7 g, 19.0 mmol) and triethylamine (2.7 ml, at 19.6 mmol) in methylene chloride (40 ml) was stirred at room temperature under nitrogen atmosphere over night. The mixture is diluted with methylene chloride, washed with water and dried over anhydrous sulphate of soda is I. Filtration and concentration in vacuum to give the product of alkylation of 5.3 g (99%), as a yellow-orange oil:1H NMR (300 MHz, CDCl3) δ 7.89-7.93 (m,2H); 7.38-7.61 (m,4H); 7.17-7.27 (m,3H); 6.99 (d, 1H, J=1.9 Hz); 3.90 (s,2H); 3.83 (s,2H); 2.39 (s,3H).

Stage G: To a solution of the product of stage (F (5.3g, 18,8 mmol) in methanol (50 ml) at 0°add borohydride sodium (1.4 g of 37.6 mmol). After stirring for 1.5 hours at room temperature, the reaction mixture was quenched with water, then extracted (3x) with methylene chloride. The combined organic extracts washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified flash chromatography on silica gel (hexane/ethyl acetate, slow gradient from 10:1 to 1:1)to give amerosport, 3,22 g (61%), in the form of a viscous yellow oil:1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H, J=2.3 Hz); 7.46 (d, 1H, J=8.2 Hz); 7.23-7.34 (m,6N); 7.16 (d, 1H, J=7.3 Hz); 6.93-6.94 (m,1H); 4.74-4.78 (m,1H); 3.91-4.00 (m,2H); 3.75 (d, 1H, J=12.9 Hz), 2.54-2.68 (m,2H); 2.35 (s,3H).

Stage H: a solution of the product of stage G (3.2 g, 11.5 mmol) in methylene chloride is stirred at room temperature in a nitrogen atmosphere, and within 30 minutes added dropwise methanesulfonyl acid (17 ml, 260,0 mmol). The reaction solution is stirred over night at room temperature in a nitrogen atmosphere, then cooled to 0°and process N. NaOH up until the pH of the aqueous layer will not be 12, and then diluted with water. The methylene chloride layer removed and the aqueous portion is extracted twice with methylene chloride. The combined organic layers washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and the solvent is removed in vacuum. The reaction mass is alkalinized with 10% aqueous ammonium hydroxide, the resulting white cloudy mixture was extracted (3x) with methylene chloride and the organic layers combined, washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and the solvent is removed in vacuum, obtaining the target cyklinowanie tetrahydroisoquinoline, 2.0 g, as a pale brown oil:1H NMR (300 MHz, CDCl3) δ 7.62 (d, 1H, J=2.3 Hz); 7.17-7.33 (m,6N); 6.81 (d, 1H, J=8.6 Hz); 6.73 (d, 1H, J=2.2 Hz); 4.33-4.37 (m,1H); 3.96 (d, 1H, J=15.2 Hz); 3.79 (d, 1H, J=14.5 Hz); 3.04-3.10 (m,1H); 2.62-2.68 (m,1H); 2.50 (s,3H). The free base (2.0 g, 7.6 mmol) and maleic acid (0.88 g, 7.6 mmol) quickly dissolved in absolute ethanol (70 ml) by boiling under reflux. Solution allow to cool to room temperature, during this time produces no white residue. The allocation of the solids by vacuum filtration gives the desired maleato salt, 1.45 g (33% of the product of stage (G) in the form of not quite white solids; so pl. 199-204°;1H NMR (300 MHz, CD3OD) δ 7.88 (d, 1H, J=2.3 Hz); 7.33-7.42 (m,4H); 7.23-7.26 (m,2H); 6.96-6.98 (m,1H); 6.84 (d, 1H, J=8.7 Hz); 6.22 (s,2H); 4.82-4.88 (m,1H); 4.64-4.74 (m,2H); 3.84-3.90 (m,1H); 3.55-3.63 (m,1H); 3.13 (s,3H); IR (KBr) 3448, 2363, 1700, 1578, 1456, 1354, 1049, 869, 748, 703, 652, 576 cm1; API MS m/z=264 [C18H17NO+H]+; Elemental analysis. Calculated for C18H17NO-C4H4About4-0,25 H2ABOUT: WITH, 72,11; N, EQUAL TO 6.05; N, 4,67. Found: C, 71,89; N, 6,01; N, 4,59.

Example 13

The free base product of example 12, stage N (0,029 g)in absolute ethanol (6 ml) hydronaut over 5% Pd/C (0,030 g) at a pressure slightly above atmospheric within 3 days. The catalyst was removed by filtration and the solvent is removed in vacuum. The residue is subjected to column chromatography on silica gel (hexane/ethyl acetate, 2:1), receiving dihydrobenzofuran free base, 0.015 g (52%), in the form of a colorless resin:1H NMR (300 MHz, CD13) δ 7.17-7.31 (m,5H); 6.63 (d, 1H, J=8.3 Hz); 6.54 (d, 1H, J=8.3 Hz); 4.61 (t,2H, J=8.7 Hz); 4.18-4.23 (m,1H); 3.64 (d, 1H, J=15.1 Hz); 3.47 (d, 1H, J=15.3 Hz); 3.08 (t, 2H, J=8.5 Hz); 2.97-3.03 (m,,1H); 2.56 (DD, 1H, J=8.6, 11.5 Hz); 2.44 (s,3H). The free base (0,012, 0.045 mmol) and maleic acid (0.005 g, 0.045 mmol) for 10 minutes, dissolved in absolute ethanol (7 ml) and refluxed under nitrogen atmosphere. The solvent is removed in vacuum and the residue is recrystallized from a mixture of ethanol/diethyl ether, obtaining the desired maleato salt, of 0.014 g (79%), in the form of logo solids: so pl. 168-169°;1H NMR (300 MHz, CD3OD) δ 7.31-7.40 (m,3H); 7.22-7.25 (m,2H); 6.63 (s,3H); 6.24 (s,3H); 4.63 (t, 1H, J=8.7 Hz); 4.40-4.51 (m,3H); 3.73-3.79 (m,1H); 3.43-3.53 (m,1H); 3.12-3.27 (m,2H); 3.06 (s,3H); IR (KBr) 3448, 2923, 2364, 1578, 1484, 1355, 1258, 981, 868, 702, 574 cm1; CI MS m/z=266 [C18H19NO+H]+;

Example 14

To a stirred solution of the appropriate amine product obtained using the technique of stage N of example 12 (1.3 g, 4.3 mmol), in anhydrous simple ether (40 ml) under nitrogen atmosphere was added 1 M solution of HCl in ether (8,7 ml to 8.7 mmol). The formed solid is filtered off, washed with ether and dried, obtaining cleaners containing hydrochloride salt of the product as a white solid (1.4 g, 95%): so pl. 240-243°;1H NMR (500 MHz, CD3OD) δ 7.87 (d, J=2.2 Hz, 1H); 7.45 (d, J=8.6 Hz, 1H); 7.32-7.20 (m,2H); 7.12 (s,1H); 6.99 (DD, J=1.0, 2.23 Hz, 1H); 4.88-4.74 (m,3H); 3.90 (DD, J=12.2, 6.0 Hz,1H); 3.62 (s,1H); 3.15 (s,3H); IR (KBr) 3423, 2935, 2547, 1610; CI MS m/z=300 [C18H15NO+H]+; Elemental analysis. Calculated for C18H15F2NO-HCl-0,20 H2ABOUT: WITH, 63,70; N, TO 4.87; N, 4,13. Found: C, 63,50; N, 4,72; N, 4,06.

Example 15

Suitable unsaturated amine (320 g, 1.07 mmol), obtained using the methods of example 12, step H, treated in accordance with the reaction conditions described in example 13. Purification of the crude residue by chromatography (SiO2, EtOAc/hexane, 1/1) was isolated free amine product (230 mg, 71%) as a white Tverdov the matter: so pl. 86-90°;1H NMR (500 MHz, CD13) δ 6.92-7.05 (m,3H); 6.62 (d, J=8.3 Hz, 1H); 6.55 (d, J=8.3 Hz, 1H); 4.60 (t, J=8.6 Hz, 2H); 4.12 (t, J=6.1 Hz, 1H); 3.52 (s,2H); 3.07 (t, J=8.6 Hz, 2H); 2.90 (DD, J=11.4, 5.2 Hz, 1H); 2.56 (DD, J=11.4, 7.4 Hz, 1H); 2.42 (s,3H); IR (KBr) 2940, 1609, 1517 cm-1; CI MS m/z=302 [C18H17F2NO+H]+; Elemental analysis. Calculated for C18H17F2NO: C, 71,75; N, 5,69; N, 4,65. Found: C, 71,50; N, 5,61; N, 4,59.

Example 16

To a stirred solution of the appropriate amine product obtained using the technique of stage N of example 12 (1.6 g, 5.4 mmol)in anhydrous ether (50 ml) under nitrogen atmosphere was added 1 M solution of HCl in ether (10,7 ml and 10.7 mmol). The formed solid is filtered, washed with ether and recrystallized in methanol, getting a white solid (950 mg, 50%): so pl. 256-258°;1H NMR (500 MHz, CD3OD) δ 7.90 (d, J=2.2 Hz, 1H); 7.48 (d, J=8.6 Hz, 1H); 6.91-6.99 (m,5H); 4.75-4.84 (m,3H); 3.92 (DD, J=12.5, 6.0 Hz, 1H); 3.62 (users, 1H); 3.15 (s,3H); IR (KBr) 3424, 2467, 1624, 1597 cm-1; MS (API) m/z=300 [C18H15F2NO+H]+; Elemental analysis. Calculated for C18H15F2NO-HCl-0,20 H2ABOUT: WITH, 63,70; N, TO 4.87; N, 4,13. Found: C, 63,50; N, 4,72; N, 4,06.

Example 17

Suitable unsaturated amine (750 mg, 2.51 mmol), obtained using the methods of example 12, step H, treated in accordance with the reaction conditions described in example 13. Purifying the crude residue chromatog what afia (SiO 2, EtOAc/hexane, 1/1), allocate free amine product (444 mg, 59%) as a white solid: so pl. 107-109°;1H NMR (500 MHz, CD13) δ 6.56-6.75 (m,5H); 4.61 (t, J=8.6 Hz, 2H); 4.13 (t, J=5.9 Hz, 1H); 3.54 (d, J=15.3 Hz, 1H); 3.49 (d, J=15.3 Hz, 1H); 3.08 (t, J=8.6 Hz, 2H); 2.91 (DD, J=11.5, 5.5 Hz, 1H); 2.60 (DD, J=11.5, 5.9 Hz, 1H); 2.42 (s,3H); IR (KBr) 3077, 1626, 1597 cm-1; CI MS m/z=302 [C18H17F2NO+H]+; Elemental analysis. Calculated for C18H17F2NO: C, 71,75; N, 5,69; N, 4,65. Found: C, 71,41; N, Of 5.75; N, 4,42 Primer 20

Suitable amine product obtained using the technique of stage N of example 12 (2.8 g, 10.0 mmol), dissolved in ethyl ether (20 ml). Some material is insoluble, so the solution is decanted from the solids. Decanted solution is treated with 1 M HCl/Et2O (8.2 ml, 8.2 mmol). Immediately there no white residue. The solid is filtered off, obtaining 2.0 g of a substance is recrystallized from methanol/Et2O receiving cleaners containing hydrochloride salt (1.4 g, 56%): so pl. 190-192°;1H NMR (300 MHz, CD3OD) δ 7.87 (d, J=2.2 Hz, 1H); 7.39 (d, J=8.7 Hz, 1H); 7.35-7.26 (m,2H); 7.12 (t, J=8.7 Hz, 2H); 6.99 (d, J=1.4 Hz, 1H); 6.79 (t, J=8.7 Hz, 1H); 5.01-4.85 (m,1H); 4.80-4.60 (m,1H); 3.92-3.80 (m,1H); 3.57 (t, J=12 Hz, 1H); 3.34 (s,1H); 3.17 (s,3H); IR (KBr) 3422, 2926, 2550, 1580, 1224 cm-1; CI MS m/z=282 [C18H16FNO+H]+; Elemental analysis. Calculated for C18H16FNO-HCl-0,75 sub> 2ABOUT: WITH, 65,26; N, 5,63; N, 4,23. Found: C, 65,51; N, To 5.35; N, 4,14.

Example 21

Suitable unsaturated amine (512 g and 1.83 mmol), obtained using the methods of example 12, step H, treated in accordance with the reaction conditions described in example 13. Purification of the crude residue by chromatography (SiO2, EtOAc/hexane, 1/1) product isolated in the form of free amine (200 mg, 38%) as a pale yellow solid: so pl. 110-116°;1H NMR (300 MHz, CD13) δ 7.16-7.08 (m,2H); 6.91 (t, J=8.7 Hz, 2H); 6.60 (d, J=8.3 Hz, 1H); 6.51 (d, J=8.3 Hz, 1H); 4.59 (t, J=8.7 Hz, 2H); 4.16 (t, J=6.9 Hz, 1H); 3.59 (d, J=15.2 Hz, 1H); 3.47 (d, J=15.2 Hz, 1H); 3.08 (t, J=8.5 Hz, 2H); 2.92 (DD, J=11.5, 5.5 Hz, 1H); 2.50 (DD, J=11.5, 5.9 Hz, 1H); 2.43 (s,3H); IR (KBr) 2874, 2784, 1599, 1505, 1217 cm-1; CI MS m/z=284 [C18H18FNO+H]+; Elemental analysis. Calculated for C18H18FNO2: C, 76,30; N, 6,40; N, 4,94. Found: C, 75,96; N, To 6.43; N, 4,82.

Example 22

To a solution of the appropriate product, amerosport obtained using the technique of stage G of example 12 (2.5 g, 7.9 mmol)in methylene chloride (40 ml) at room temperature for 10 minutes add methansulfonate acid (10 ml, 150 mmol). The reaction mixture is refluxed under nitrogen atmosphere overnight. After the mixture was cooled to room temperature, add 2 N. NaOH to pH ˜11 and the resulting solution was extracted (3x) with methylene chloride. United agencies is practical layers washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/hexane, 1/2)to give the product as oil (1.2 g, 50%):1H NMR (500 MHz, CD13) δ 7.63 (d, J=2.0 Hz, 1H); 7.24 (d, J=6.0 Hz, 1H); 7.20 (d, J=2.0 Hz, 1H); 7.19 (s,2H); 7.08 (d, J=5.6 Hz, 1H); 6.80 (d, J=8.4 Hz, 1H); 6.73 (d, J=1.4 Hz, 1H); 4.30 (t, J=7.5 Hz, 1H); 3.88 (d, J=13.0 Hz, 1H); 3.85 (d, J=13.0 Hz, 1H); 3.02 (DD, J=11.5, 7.5 Hz, 1H); 2.66 (DD, J=11.5, 7.5 Hz, 1H); 2.48 (s,3H); IR (Meon) 2950, 2778, 1593, 1432 cm-1; CI MS m/z=298 [C18H161NO+H]+; Elemental analysis. Calculated for C18H16ClNO-HCl-0,1 H2O: C, 64,34; N, 5,16; N, 4,17. Found: C, 63,98; N, 5,07; N, 3,91.

Example 23

The method described in example 25, is used to produce compounds of example 23. Methansulfonate acid (18 ml, 280 mmol) is added at ambient temperature to a solution of such amerosport (3.6 g, and 11.2 mmol) in methylene chloride (50 ml). The reaction mixture is refluxed in a nitrogen atmosphere. After cooling the reaction mixture to room temperature, it is made basic (pH ˜11) 2 N. NaOH, the mixture was extracted (3x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/hexane, 1/1)to give the desired product, example 21 (1.70 g, 51%) as a white powder: TPL 78-80°With:1H NMR (500 MHz, CD13) δ 7.12 m,3H); 7.08 (d, J=8.0 Hz, 1H); 6.62 (d, J=8.2 Hz, 1H); 6.56 (d, J=8.2 Hz, 1H); 4.60 (t, J=8.6 Hz, 2H); 4.16 (t, J=5.0 Hz, 1H); 3.57 (d, J=15.3 Hz, 1H); 3.50 (d, J=15.3 Hz, 1H); 3.08 (t, J=8.6 Hz, 2H); 2.94 (DD, J=11.4, 5.0 Hz, 1H); 2.57 (DD, J=11.4, 7.8 Hz, 1H); 2.43 (s,3H); IR (CH2C12) 2940, 2784, 1594 cm-1; CI MS m/z=300 [C18H181NO+H]+; Elemental analysis. Calculated for C18H18ClNO: C, 72,11; N, Equal To 6.05; N, 4,67. Found: C, 71,87; N, 6,09; N, 4,45, together with the allocation of 1.4 g of the starting material.

Example 24

Suitable amine product obtained using the technique of stage N of example 12 (0.5 g, 3.0 mmol), dissolved in ethyl ether (10 ml) and treated with a solution of 1 M hydrochloric acid in ethyl ether (1.7 ml, 1.7 mmol). Immediately there no white precipitate, which is filtered, receiving the product (320 mg, 60%): so pl. 230-234°;1H NMR (300 MHz, CD3OD) δ 7.87 (d, J=2.0 Hz, 1H); 7.48-7.32 (m,3H); 7.27 (d, J=8.4 Hz, 2H); 6.99 (d, J=1.6 Hz, 1H); 6.78 (d, J=8.7 Hz, 1H); 4.95-4.67 (m,3H); 3.93-3.78 (m,1H); 3.58 (t, J=12.2 Hz, 1H); 3.17 (s,3H); IR (KBr) 3422, 2926, 2589, 1490, 1089 cm-1; CI MS m/z=298 [C18H161NO+H]+.

Example 25

Stage A: To a solution of N-methylamine (5.0 g, 31 mmol, obtained in example 12, step E) in ethanol (50 ml) is added 10% Pd/C (2.5 g) in a nitrogen atmosphere. The air from the reaction vessel is pumped and filled with hydrogen, and then pumped. This is repeated more than two times. The reaction vessel with hydrogen (45 psi) is placed in a vibrator Parra and Strahov who are within 18 hours. The mixture is filtered through a layer of celite and a layer of celite washed with methanol. The filtrate was concentrated in vacuo, obtaining N-methyl-4-(2,3-dihydrobenzofuranyl)amine (4.8 g, 94%) as a yellow oil:1H NMR (300 MHz, CD13) δ 7.10 (t, J=8.2 Hz, 1H); 6.79 (d, J=8.3 Hz, 1H); 6.67 (d, J=8.3 Hz, 1H); 4.50 (t, J=8.6 Hz, 2H); 3.65 (s,2H); 3.07 (t, J=8.6 Hz, 2H); 2.42 (s,3H).

Stage b: a Solution of N-methyl-4-(2,3-dihydrobenzofuranyl)amine from step A (2.2 g, 13 mmol) and triethylamine (1.4 ml) in dichloromethane (25 ml) cooled in an ice bath with water. Add 4'-chlorpheniramine (to 13.8 mmol) and the reaction mixture allowed to warm to room temperature. The reaction mixture is washed with water and the organic layer is dried over MgSO4, filtered and concentrated, obtaining the required aminoketone in the form of a dark orange oil (3.7 g, 86% crude product):1H NMR (300 MHz, CD13) δ 7.82 (d, J=8.5 Hz, 2H); 7.37 (d, J=8.4 Hz, 2H); 7.07 (t, J=7.8 Hz, 1H); 6.79 (d, J=7.6 Hz, 1H); 6.72 (d, J=8.0 Hz, 1H); 4.52 (t, J=8.8 Hz, 2H); 3.74 (s,2H); 3.61 (s,2H); 3.16 (t, J=8.7 Hz, 2H); 2.37 (s,3H).

Stage C: Aminoketone obtained at the stage In (3.7 g, 12 mmol), dissolved in methanol (40 ml) and cooled in an ice bath with water. The portions add borohydride sodium (0,44 g, 12 mmol). The reaction mixture is stirred for 1 hour. The reaction mixture is concentrated to half the original volume. Add water (40 ml) and the mixture extracted (3x) with dichloromethane. The combined organic sloshsat over MgSO 4, filtered and concentrated, obtaining the required amerosport in the form of a light yellow oil (2.5 g, 67% crude product):1H NMR (300 MHz, CD13) δ 7.35-7.20 (m,4H); 7.08 (t, J=7.8 Hz, 1H); 6.78 (d, J=7.6 Hz, 1H); 6.72 (d, J=8.0 Hz, 1H); 4.70 (DD, J=8.6, 5.5 Hz, 1H); 4.55 (t, J=8.6 Hz, 2H); 3.65 (d, J=12.9 Hz, 1H); 3.44 (d, J=12.9 Hz, 1H); 3.18 (t, J=8.6 Hz, 2H); 2.57-2.52 (m,2H); 2.29 (s,3H).

Stage D: Amerosport (2.4 g, 7.5 mmol, from stage C) is stirred in CH2Cl2(40 ml), and within 5 minutes add CH3SO3H (9,8 ml). The reaction mixture was stirred at ambient temperature until such time as the source material will not be detected NMR analysis (24 hours), then the solution of doing a major water 2 N. NaOH. The layers are separated and the aqueous layer was extracted with(2) CH2Cl2. The organic extracts are combined, washed with saturated salt solution, dried over MgSO4, filtered and concentrated in vacuo, getting a brown solid, which chromatographic (SiO2, 20% EtOAc/hexane) to obtain the desired product of example 23 (1.13 g, 50%): so pl. 148-150°;1H NMR (300 MHz, CD13) δ 7.23 (d, J=8.5 Hz, 2H); 7.11 (d, J=8.4 Hz, 2H); 6.60 (d, J=8.3 Hz, 1H); 6.54 (d, J=8.3 Hz, 1H); 4.60 (t, J=8.7 Hz, 2H); 4.16 (t, J=6.5 Hz, 1H); 3.59 (d, J=15.2 Hz, 1H); 3.47 (d, J=15.2 Hz, 1H); 3.07 (t, J=9.0 Hz, 2H); 2.93 (DD, J=11.3, 5.2 Hz, 1H); 2.53 (DD, J=11.4, 8.0 Hz, 1H); 2.42 (s,3H); IR (KBr) 2944, 2788, 1480, 1253, 823 cm-1; CI MS m/z=300 [C18H181NO+H]+; Elemental analysis. is ycycline for C 18H18ClNO: C, 72,11; N, Equal To 6.05; N, 4,67. Found: C, 72,03; N, 6,17; N, 4,56.

Example 30

Chilled with ice a solution of the appropriate amine product obtained using the technique of stage N of example 12 (450 mg, 1.44 mmol)in CH2Cl2(10 ml) is treated with 1 M HCl/Et2O (1.5 ml, 1.5 mmol). After about 30 minutes produced no white residue. The solution was stirred at room temperature for 1 hour and concentrated in vacuo. The residue is dissolved in methanol (10 ml) at 50°C, cooled to room temperature and the crystallization start adding Et2O (20 ml). The solution is kept for crystallization during the night. This procedure is repeated several times, receiving cleaners containing hydrochloride salt in the form of not quite white powder (106 mg, 30%): so pl. 279-284°;1H NMR (300 MHz, CD3OD) δ 7.91-7.90 (m,1H); 7.50-7.47 (m,1H); 7.24-7.17 (m,2H); 7.02-6.98 (m,2H); 6.89-6.86 (m,1H); 4.85-4.73 (m,3H); 3.92 (DD, J=12.1, 6.1 Hz, 1H); 3.70-3.60 (m,1H); 3.15 (s,3H); IR (KBr) 3424, 2933, 2466, 1606, 1590, 1443, 1137, 860 cm-1; CI MS m/z=316 [C18H151FNO+H]+; Elemental analysis. Calculated for C18H15ClFNO-HCl-0,25 H2ABOUT: WITH, 60,60; N, OF 4.66; N, 3,93. Found: C, 60,30; N, 4,79; N, 3,66.

Example 32

Suitable amine product obtained using the technique of stage N of example 12 (0.88 g, 3.0 mmol), dissolved in ethyl ether (25 ml) and treated with a solution of 1 M hydrochloric acid in ethanol is Fira (3.4 ml, 3.4 mmol). Immediately there no white precipitate, which is filtered, getting not quite white solid (795 mg, 80%): so pl. 212-214°;1H NMR (300 MHz, CD3OD) δ 7.88 (d, J=2.2 Hz, 1H); 7.40 (d, J=8.5 Hz, 1H); 7.16 (d, J=8.0 Hz, 2H); 6.97-6.77 (m,4H); 4.65-4.56 (m,1H); 3.87-3.75 (m,2H); 3.80 (s,3H); 3.65-3.46 (m,2H); 3.17 (s,3H); IR (KBr) 3224, 2930, 2547, 1513, 1030 cm-1; CI MS m/z=294 [C19H19NO+H]+; Elemental analysis. Calculated for C19H19CNO2-HCl-0,25 H2ABOUT: WITH, 68,26; N, 6,18; N, 4,19. Found: C, 68,01; N, Of 6.20; N, 3,93.

Example 33

Suitable unsaturated amine (660 mg, and 2.26 mmol), obtained using the methods of example 12, step H, treated in accordance with the reaction conditions described in example 13. When purification of the crude residue by chromatography (SiO2, EtOAc/hexane, 1/1) product isolated in the form of free amine (220 mg, 33%) as a pale yellow solid: so pl. 119-121°;1H NMR (300 MHz, CD13) δ 7.08 (d, J=8.4 Hz, 5H); 6.80 (d, J=8.5 Hz, 2H); 6.62 (d, J=8.3 Hz, 1H); 6.51 (d, J=8.3 Hz, 1H); 4.59 (t, J=8.7 Hz, 2H); 4.15 (t, J=6.9 Hz, 1H); 3.78 (s, 3H); 3.61 (d, J=15.2 Hz, 1H); 3.43 (d, J=15.2 Hz, 1H); 3.08 (t, J=8.5 Hz, 2H); 2.92 (DD, J=11.5, 5.5 Hz, 1H); 2.50 (DD, J=11.5, 5.9 Hz, 1H); 2.42 (s,3H); IR (KBr) 2785, 2762, 1610, 1509, 1251 cm-1; CI MS m/z=296 [C19H21NO2+H]+; Elemental analysis. Calculated for C19H21NO2: C, 77,26; N, 7,17; N, 4,74. Found: C, 76,93; N, 7,31; N, 4,57.

Example 34

The free base product of example 12, a hundred is ia N (0.3 g, to 1.14 mmol) in solution in anhydrous tetrahydrofuran at -78°treated With a solution of n-BuLi (of 0.91 ml, 2.5 M in hexano, 2.3 mmol) under nitrogen atmosphere. After stirring for two hours added dropwise itmean (0.17 ml, 2.7 mmol). The resulting mixture was stirred at -78°C for two hours, then allow it to warm to room temperature. The mixture is diluted with water and extracted with (3) diethyl ether. The organic layers are combined, washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and the solvent is removed in vacuum. The residue is purified column chromatography on silica gel using a slow gradient from 0 to 10% methanol in methylene chloride, getting methylseleninic benzofuran, 203 mg (64%) as a yellow oil:1H NMR (300 MHz, CD13) δ 7.15-7.28 (m,5H); 7.10 (d, 1H, J=8.7 Hz); 6.70 (d, 1H, J=8.5 Hz); 6.28-6.29 (m,1H); 4.29-4.34 (m,1H); 3.86 (d, 1H, J=15.2 Hz); 3.70 (d, 1H, J=15.2 Hz); 3.00-3.05 (m,1H); 2.58-2.65 (m,1H); 2.44 (s,3H); 2.40 (s,3H). The free base (to 0.23 g, 0.73 mmol) and maleic acid (of 0.085 g, 0,073 mmol) for 5 minutes and dissolved in absolute ethanol (10 ml) and refluxed under nitrogen atmosphere, then allowed to cool to room temperature. The mixture was concentrated in vacuo to a volume of approximately 2 ml, then added diethyl ether, which causes the formation of crystals. The selection is solid substances by vacuum filtration gives not quite white solid. The solid is recrystallized from a mixture of ethanol/diethyl ether and then from ethanol, getting the right maleato salt, 0,043 g (15%), in the form of a white crystalline solid: so pl. 187-192°;1H NMR (300 MHz, CD3OD) δ 7.23-7.40 (m,6N); 6.73 (d, 1H, J=8.6 Hz); 6.57 (s,1H); 6.21 (s,2H); 4.63-4.80 (m,3H); 3.83-3.88 (m,1H); 3.53-3.61 (m,1H); 3.12 (s,3H); 2.48 (s,3H); IR (KBr) 3448, 2548, 1584, 1495, 1354, 1270, 1195, 1078, 936, 866, 808, 704, 656, 583, 510 cm-1; CI MS m/z=278 [C19H19NO+H]+; Elemental analysis. Calculated for C19H19NO-C4H4About4-0,5 N2ABOUT: WITH, 68,84; N, 6,01; N, 3,48. Found: C, 68,49; N, Of 5.84; N, 3,41.

Example 36

Stage A: the Free base of the product of example 12, step B (1.0 g, 3,91 mmol), in solution in anhydrous tetrahydrofuran at -78°treated With a solution of n-BuLi (3.3 ml, 2.5 M solution in hexano, 8.2 mmol) under nitrogen atmosphere. After stirring for one hour and added dropwise dimethylformamide (0,70 ml, 9.0 mmol). The resulting mixture was stirred at -78°C for two hours, then allowed to warm to room temperature. The mixture is diluted with water and extracted with (3) diethyl ether. The organic layers are combined, washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and the solvent is removed in vacuum. The residue is purified column chromatography on silica gel (hexane/ethyl acetate, 1:1), obtaining the expectation is aemy aldehyde, 430 mg (38%) as a pale yellow oil:1H NMR (300 MHz, CD13) δ 9.86 (s,1H); 7.54 (s,1H); 7.17-7.33 (m,6N); 7.05 (d, 1H, J=8.7 Hz); 4.32-4.36 (m,1H); 4.00 (d, 1H, J=15.5 Hz); 3.83 (d, 1H, J=15.5 Hz); 3.07-3.13 (m,1H); 2.67 (DD, 1H, J=8.2, 11.5 Hz); 2.51 (s,3H); CI MS m/z=292 [C19H17NO2+H]+.

Stage b: the Product of example 36, step A (0.07 g, 0.23 mmol) is treated with sodium borohydride (0.02 g, 0.46 mmol) in chilled methanol (20 ml). The reaction mixture is allowed to warm to room temperature and stirred for 1 hour, quenched with water and extracted (3x) with methylene chloride. The organic layers are combined, washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and the solvent is removed in vacuum, obtaining alcohol, 0.07 g (100%) as a yellow oil;1H NMR (300 MHz, CD13) δ 7.17-7.32 (m,6N); 6.79 (d, 1H, J=8.5 Hz); 6.57 (s,1H); 4.76 (s,2H); 4.33-4.38 (m,1H); 3.89 (d, 1H, J=15.2 Hz); 3.72 (d, 1H, J=15.2 Hz); 3.06-3.11 (m,1H); 2.63 (DD, 1H, J=8.6, 11.4 Hz); 2.50 (s,3H); CI MS m/z=294 [C19H19NO2+H]+. The free base (0.03 g, 0.10 mmol) and hydrochloric acid (1 M solution in diethyl ether, 0.5 ml) dissolved in diethyl ether (4 ml). The resulting off-white precipitate allocate vacuum filtration and dried under reduced pressure, getting the right cleaners containing hydrochloride salt, 0.03 g (72%), so pl. 149-162°;1H NMR (300 MHz, CD3OD) δ 7.25-7.42 (m,6N); 6.78-6.86 (m,2H); 4.64-4.74 (m,5H); 2.85-2.91 (m,1H); 3.52-3.68 (m,1H) 3.15 (s,3H); IR (KBr) 3375, 2500, 1456, 1023, 811, 702 cm-1; CI MS m/z=294 [C19H19NO2+H]+; Elemental analysis. Calculated for C19H19CNO2-HCl-0,75 H2ABOUT: WITH, 66,47; N, OF 6.31; N, 4,08. Found: C, 66,13; N, Is 6.54; N, 3,82.

Example 38

Stage A: To a mixture of sociallyengaged (1.3 g, 34 mmol) in THF (200 ml) is added at room temperature methyl-4-indolocarbazoles (3.0 g, 17 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 2 hours and then quenched with ethyl acetate. The mixture is treated with water (1.3 ml), 15% NaOH (1.3 ml) and water (3.9 ml) and then filtered. The filtrate was concentrated in vacuo, to give crude 4-(hydroxymethyl)indole (2.5 g, 99%):1H NMR (500 MHz, CD13) δ 8.29 (users,1H); 7.34 (d, J=9.0 Hz, 1H); 7.16-7.22 (m,2H); 7.12 (d, J=7.0 Hz, 1H); 6.67 (t, J=1.0 Hz, 1H); 4.98 (d, J=4.2 Hz, 2H); CI MS m/z=147 [C9H9NO+H]+.

Stage: Perruthenate of tetrapropylammonium (0.3 g, 0.85 mmol) is added in portions to a mixture of the product alcohol from step A (2.5 g, 17 mmol), N-oxide N-methylmorpholine (3.0 g, 25 mmol) and molecular sieves 4 A (3.0 g) in anhydrous methylene chloride (30 ml) at room temperature. The mixture is stirred at room temperature under nitrogen atmosphere for 1 hour and then filtered. The filtrate was concentrated in vacuo and the residue purified by chromatography (SiO2CH2Cl2), receiving indol-4-aldehyde as a white powder (2.0 g, 80%):1H NMR (30 MHz, CD13) δ 10.2 (s,1H); 8.52 (users,1H); 7.64-7.69 (m,2H); 7.31-7.44 (m,3H); CI MS m/z=146 [C9H7NO+H]+.

Stage C: To a solution of aldehyde from stage (2.0 g, 14 mmol) in methanol (100 ml) at room temperature add 40% methylamine in water (of 2.27 ml, 27.6 mmol) for 10 minutes. The mixture is stirred at room temperature under nitrogen atmosphere overnight and then cooled to 0°C. Add borohydride sodium (1,05 g, 27.6 mmol). The reaction mixture is slowly warmed to room temperature for 2 hours. A large part of the methanol is removed in vacuo and the residue diluted with water and extracted (3x) with ether. The combined organic layers extracted with 2 N. HCl (100 ml). The HCl layer do basic (pH ˜11) 2 N. NaOH and extracted (3x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrated in vacuo give crude

4-(aminomethyl)indole as a white powder (1,95 g, 88%):1H NMR (300 MHz, CD13) δ 8.29 (s,user,1H); 7.31 (d, J=8.0 Hz, 1H); 7.22 (t, J=2.7 Hz, 1H); 7.16 (t, J=8.0, 7.3 Hz, 1H); 7.08 (d, J=7.3 Hz, 1H); 6.64 (t, J=2.0 Hz, 1H); 4.06 (s,2H); 2.51 (s,3H); CI MS m/z=160 [C10H12N2+H]+.

Stage D: To a mixture of amine product from step C (1.0 g, 6.3 mmol) and 2-bromoacetophenone (1.2 g, 6.3 mmol) in anhydrous methylene chloride (20 ml) at room temperature is added triethylamine (0,96 ml and 6.9 mmol). Re clonney the mixture is stirred at room temperature for 4 hours and treated with water (20 ml). The organic layer is separated and the aqueous layer was extracted (2x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/hexane, 1:2)to give N-methyl-α-aminoketone (1.5 g, 86%):1H NMR (300 MHz, CD13) δ 8.32 (users,1H); 7.90-7.93 (m,2H); 7.52 (m,1H); 7.31-7.39 (m,3H); 7.08-7.19 (m,3H); 6.72 (t, J=1.0 Hz, 1H); 3.96 (s,2H); 3.81 (s,2); 2.41 (s,3H).

Stage E: To a solution of product from step D, N-methyl-α-aminoketone (1.5 g, 5.4 mmol)in methanol (50 ml) at 0°C for 5 minutes add borohydride sodium (410 mg, up 10.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. A large part of the methanol is removed in vacuo and the residue diluted with water (100 ml) and extracted (3x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo, obtaining crude amerosport in the form of a light yellow oil (1.5 g, 99%):1H NMR (500 MHz, CD13) δ 8.23 (users,1H); 7.21-7.36 (m,7H); 7.15 (t, J=7.0 Hz, 1H); 7.04 (d, J=7.0 Hz, 1H); 6.71 (t, J=1.0 Hz, 1H); 4.73 (DD, J=10.5, 3.4 Hz, 1H); 4.03 (d, J=12.8 Hz, 1H); 3.80 (d, J=12.8 Hz, 1H); 2.65 (DD, J=12.4, 10.5 Hz, 1H); 2.58 (DD, J=12.4, 3.4 Hz, 1H); 2.38 (s, 3H); CI MS m/z=281 [C18H20N2O+H]+.

Stage F: To a solution of amerosport stage with F (1,37 g, 4,89 mmol)in methylene chloride(40 ml) add methansulfonate acid (7,93 ml, 122 mmol) at room temperature for 10 minutes. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 24 hours and then made basic (pH ˜11) 2 N. NaOH. The organic layer is separated and the aqueous layer was extracted (2x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/hexane, 1:1)to give the desired product of example 36, pyrroloquinoline tetrahydroisoquinoline, in the form of a white powder(450 mg, 35%): so pl. 142-144°;1H NMR (300 MHz, CD13) δ 8.23 (users,1H); 7.16-7.27 (m,6N); 7.11 (d, J=8.5 Hz, 1H); 6.70 (d, J=8.5 Hz, 1H); 6.49 (t, J=1.5 Hz, 1H); 4.37 (t, J=5.5 Hz, 1H); 4.04 (d, J=15.2 Hz, 1H); 3.85 (d, J=15.2 Hz, 1H); 3.08 (DD, J=11.5, 5.5 Hz, 1H); 2.66 (DD, J=11.5, 8.2 Hz, 1H); 2.51 (s, 3H); CI MS m/z=263 [C18H18N2O+H]+; IR (KBr) 3410, 3027, 2861, 2363, 1600, 1493 cm-1; Elemental analysis. Calculated for C18H18N2-0,1 N2ABOUT: WITH, 81,84; N, 6,94; N, OR 10.60. Found: C, 81,94; N, 7,10; N, 10,46.

Example 39

To a solution of indelaware product of example 38, stage F (182 mg, 0,694 mmol), and dimethyloxalate (90 mg, from 0.76 mmol) in DMF (5 ml) in one portion at room temperature under nitrogen atmosphere add tert-piperonyl potassium (86 mg, from 0.76 mmol). The reaction mixture was refluxed for 30 min and then cooled to room Tempe is atory. The mixture was diluted with water (50 ml) and extracted (3x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/hexane, 1:1)to give N-methylindol of example 37 as a white solid (180 mg, 92%): so pl. 106-108°;1H NMR (500 MHz, CD13) δ 7.19-7.28 (m,5H); 7.05 (d, J=8.5 Hz, 1H); 7.03 (d, J=3.0 Hz, 1H); 6.73 (d, J=8.5 Hz, 1H); 6.41 (DD, J=3.0, <1 Hz, 1H); 4.37 (t, J=6.3 Hz, 1H); 4.00 (d, J=15.1 Hz, 1H); 3.85 (d, J=15.1 Hz, 1H); 3.75 (s,3H); 3.08 (DD, J=11.4, 5.4 Hz, 1H); 2.66 (DD, J=11.4, 8.1 Hz, 1H); 2.50 (s, 3H); CI MS m/z=277 [C19H20N2+H]+; IR (KBr) 3050, 2939, 2783, 1487, 1451 cm-1; Elemental analysis. Calculated for C19H20N2-0,1 N2ABOUT: WITH, 82,04; N, TO 7.32; N, 10,07. Found: C, 82,06; N, 7,50; N, 9,85.

Example 40

To a solution of indelaware product of example 38 (150 mg, 0,572 mmol) and diethyloxalate (92 mg, to 0.63 mmol) in DMF (5 ml) in one portion at room temperature under nitrogen atmosphere add tert-piperonyl potassium (71 mg, to 0.63 mmol). The reaction mixture was refluxed in nitrogen atmosphere for 1 hour and then cooled to room temperature. The mixture was diluted with water (50 ml) and extracted (3x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo. The rest of cleansing the t by chromatography (SiO 2, EtOAc/hexane, 1:1), obtaining the product of example 38, N-ethylindole, (144 mg, 86%):1H NMR (500 MHz, CD13) δ 7.18-7.28 (m,5H); 7.09 (d, J=3.2 Hz, 1H); 7.07 (d, J=8.5 Hz, 1H); 6.71 (d, J=8.5 Hz, 1H); 6.42 (DD, J=3.2, <1 Hz, 1H); 4.36 (t, J=8.0, 5.4 Hz, 1H); 4.12 (q, J=7.3 Hz, 2H); 4.00 (d, J=15.1 Hz, 1H); 3.85 (d, J=15.1 Hz, 1H); 3.07 (DD, J=11.3, 5.4 Hz, 1H); 2.66 (DD, J=11.3, 8.0 Hz, 1H); 2.50 (s,3H); 1.44 (t, J=7.3 Hz, 3H).

Example 41

To a solution of indelaware product of example 38 (150 mg, 0,572 mmol) and dimensionality (170 mg, to 0.63 mmol) in DMF (5 ml) in one portion at room temperature under nitrogen atmosphere add tert-piperonyl potassium (71 mg, to 0.63 mmol). The reaction mixture is refluxed under nitrogen atmosphere for 3 hours and then cooled to room temperature. The mixture was diluted with water (50 ml) and extracted (3x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/hexane, 1:1)to give N-benzimidazolyl the product of example 39 (161 mg, 80%):1H NMR (500 MHz, CD13) δ 7.09-7.29 (m,11N); 7.01 (d, J=8.5 Hz, 1H); 6.67 (d, J=8.5 Hz, 1H); 6.48 (DD, J=3.1, <1 Hz, 1H); 5.26 (s,2H); 4.34 (t, J=8.1, 5.4 Hz, 1H); 4.00 (d, J=15.1 Hz, 1H); 3.86 (d, J=15.1 Hz, 1H); 3.06 (DD, J=11.3, 5.4 Hz, 1H); 2.67 (DD, J=11.3, 8.1 Hz, 1H); 2.50 (s,3H).

Example 42

To a solution of indelaware product (200 mg, 0,763 mmol) of example 38, step F, in acetic acid (5 ml) is added to pocast at room temperature for 5 minutes cyanoborohydride sodium (240 mg, is 3.82 mmol). The reaction mixture was stirred in nitrogen atmosphere for 4 hours and then a large part of the acetic acid removed in vacuo. The residue is diluted with methylene chloride (100 ml), washed with 2 N. NaOH and saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/methanol, 8:1), receiving indolin of example 40, in the form of a white solid (176 mg, 87%): so pl. 84-86°With:1H NMR (500 MHz, CD13) δ 7.17-7.27 (m,5H); 6.53 (d, J=8.0 Hz, 1H); 6.40 (d, J=8.0 Hz, 1H); 4.17 (DD, J=8.2, 5.4 Hz, 1H); 3.62 (d, J=15.0 Hz, 1H); 3.58 (t, J=8.4 Hz, 2H); 3.44 (d, J=15.0 Hz, 1H); 2.96 (DD, J=11.3, 5.4 Hz, 1H); 2.91 (dt, J=8.4, 4.0 Hz, 2H); 2.54 (DD, J=11.3, 8.2 Hz, 1H); 2.42 (s,3H); CI MS m/z=265 [C18H20N2+H]+; IR (KBr) 3241, 2924, 2873, 1611, 1486 cm-1; Elemental analysis. Calculated for C18H20N2-0,1 N2ABOUT: WITH, 81,23; N, THE 7.65; N, 10,52. Found: C, 80,87; N, 7,46; N, 10,48.

Example 43

To a solution of indoline example 42 (110 mg, 0,420 mmol) and acetic acid (0.1 ml) in methanol (4 ml) dropwise at room temperature is added 37% aqueous formaldehyde (0.04 ml, 0.5 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 hour and then in portions at room temperature add cyanoborohydride sodium (66 mg, 1.05 mmol). The mixture is stirred at room temperature under nitrogen atmosphere for 3 hours and then quenched with 2 N. aOH and extracted (3x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/methanol, 10:1)to give N-methylindoline the product of example 41, in the form of a white solid (92 mg, 80%): so pl. 88-90°;1H NMR (500 MHz, CD13) δ 7.17-7.28 (m,5H); 6.59 (d, J=8.0 Hz, 1H); 6.26 (d, J=8.0 Hz, 1H); 4.17 (DD, J=8.5, 5.4 Hz, 1H); 3.62 (d, J=15.0 Hz, 1H); 3.43 (d, J=15.0 Hz, 1H); 3.31 (m,2H); 2.96 (DD, J=11.3, 5.4 Hz, 1H); 2.82 (m,,2H); 2.70 (s,3H); 2.54 (DD, J=11.3, 8.5 Hz, 1H); 2.42 (s,3H); CI MS m/z=279 [C19H22N2+H]+; IR (KBr) 3020, 2940, 2773, 1610, 1487 cm-1; Elemental analysis. Calculated for C19H22N2-0,1 N2ABOUT: WITH, 81,45; N, TO 7.99; N, 10,00. Found: C, 81,21; N, 8,00; N, 9,74.

Example 45

To a solution of the appropriate amerosport obtained using the technique of stage E of example 38 (174 mg, 0,550 mmol), dissolved in CH2Cl2(11 ml) in a 50 ml flask, equipped with a fridge, in nitrogen atmosphere, equipped with a fridge. The mixture is cooled to 0°With rapid stirring and added dropwise MeSO3H (1.8 ml, 28 mmol) and the mixture is stirred for 30 minutes while heating to room temperature, then refluxed for 48 hours. The mixture is cooled to room temperature, neutralized 2 N. NaOH, then extracted with (3) EtOAc. The combined organic extracts Susitna Na 2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (gradient of 30-45% EtOAc/hexane), getting the right Indology product (19 mg, 12%) as an orange solid: so pl. 164-169°;1H NMR (300 MHz, CD13) δ 8.18 (users,1H); 7.15-7.24 (m,2H); 6.92-7.10 (m,3H); 6.70 (d, J=8.4 Hz, 1H); 6.50-6.54 (m,1H); 4.29 (t, J=5.8 Hz, 1H); 3.92 (d, J=4.8 Hz, 1H); 3.02 (DD, J=11.3, 5.1 Hz, 1H); 2.67 (DD, J=11.3, 6.8 Hz, 1H); 2.49 (s,3H).

It should be noted that there are also 55 mg (32%) of the original material. Based on the selected starting material the product of example 45 is 17%.

Example 46

N-Methylindoline the product of example 47 (70 mg, 0.22 mmol) dissolved in toluene (9 ml) in a 50 ml flask, equipped with a fridge, in an atmosphere of N2. Add MnO2(199 mg, 2.3 mmol) and the mixture refluxed for 1.5 hours. The mixture is cooled to room temperature, passed through a layer of celite and layer washed several times with copious amounts of Meon. The filtrate was concentrated in vacuo and the residue purified by chromatography on silica gel (gradient of 25-35% EtOAc/hexane)to give N-methylindoline product (39 mg, 57%) as an orange oil:1H NMR (300 MHz, CD13) δ 6.93-7.11 (m,5H); 6.72 (d, J=8.5 Hz, 1H); 6.42 (d, J=3.1 Hz, 1H); 4.29 (t, J=5.8 Hz, 1H); 3.84-3.96 (m,2H); 3.77 (s,3H); 2.99 (DD, J=11.3, 5.0 Hz, 1H); 2.67 (DD, J=11.3, 6.7 Hz, 1H); 2.49 (s,3H); ESI MS m/z=313 [C19H18F2N +H]+.

Example 47

Stage A: a Product, a suitable aminoplast (730 mg, 2,31 mmol), obtained using the method of example 38, step E is dissolved in ice SPLA (23 ml) in a 100 ml flask in an atmosphere of N2. As one portion add NaBH3CN (0,76 g, 12 mmol) and the mixture is stirred for 2 hours. The mixture is then poured into 200 ml of rapidly stirred mixture of ice and water and the solution is make the main concentrated NH4OH. After stirring for 30 minutes, the mixture is extracted with (4) CH2Cl2. The combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (gradient of 25-50% EtOAc/hexane), getting the right indolinone product (434 mg, 59%) as not quite white solids:1H NMR (300 MHz, CD13) δ 6.98-7.23 (m,4H); 6.62 (DD, J=16.2, 7.7 Hz, 2H); 4.67 (t, J=7.0 Hz, 1H); 3.75-4.10 (users,2H); 3.64 (d, J=12.8 Hz, 1H); 3.58 (t, J=8.3 Hz, 2H); 3.45 (d, J=12.7 Hz, 1H); 3.04 (t, J=8.3 Hz, 2H); 2.51 (d, J=7.0 Hz, 2H); 2.30 (s,3H); CI MS m/z=315 [C18H20N2O+H]+.

It should be noted that there is also a 70 mg (10%) of the original material. Based on the selected source material output indoline is 65%.

Stage: Indoleamine stage a of this example (165 mg, 0,518 mmol) dissolved in dichloromethane (5 ml) in a 50 ml flask with an atmosphere of N2. As one portion add the MeSO 3H (1.7 ml, 26 mmol) and the mixture rapidly stirred while boiling under reflux. After 5 hours the mixture is cooled to room temperature, poured into 100 ml ice water and make basic with 10% NaOH. After stirring for 30 minutes, the mixture is extracted with (4) CH2Cl2. The combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (gradient of 1-4% Meon/CH2Cl2), obtaining the product of example 45 (81 mg, 52%) as not quite white solids: I. pl. 45-51°;1H NMR (300 MHz, CD13) δ 6.96-7.08 (m,2H); 6.89-6.94 (m,1H); 6.52 (d, J=8.0 Hz, 1H); 6.43 (d, J=8.0 Hz, 1H); 4.10 (t, J=6.0 Hz, 1H); 3.68 (users,1H); 3.59 (t, J=8.4 Hz, 2H); 3.50 (s,2H); 2.85-2.93 (m,3H); 2.54 (DD, J=11.4, 7.2 Hz, 1H); 2.41 (s,3H); ESI MS m/z=301 [C18H18F2N2+H]+; Elemental analysis. Calculated for C18H18F2N2: C, 71,98; N, 6,04; N, WAS 9.33. Found: C, 72,14; N, 6,69; N, 8,45.

Example 48

Indolinone the product of example 47, step In (16 mg, 0,049 mmol), dissolved in Meon (2 ml) in a 25 ml flask in an atmosphere of N2. Add a catalytic amount SPLA (1 drop) and aqueous formaldehyde (15 μl, 0.15 mmol) and the mixture is stirred for 1 hour. Added NaBH3CN (16 mg, 0.25 mmol) and the mixture is stirred for additional 1 hour. The mixture was diluted with CH2Cl2(50 ml), then washed the Ute consistently to 0.5 N. NaOH (25 ml) and saturated aqueous NaCl (25 ml). The organic layer is dried over Na2SO4), filtered and concentrated in vacuo, receiving

N-methylindoline product (14 mg, 87%) as an orange oil:1H NMR (300 MHz, CD13) δ 6.93-7.09 (m,3H); 6.59 (d, J=8.1 Hz, 1H); 6.29 (d, J=8.1 Hz, 1H); 4.12 (t, J=5.8 Hz, 1H); 3.52 (s,2H); 3.30-3.37 (m,2H); 2.91 (DD, J=11.3, 5.1 Hz, 1H); 2.82 (t, J=8.0 Hz, 2H); 2.73 (s,3H); 2.56 (DD, J=11.3, 7.3 Hz, 1H); 2.42 (s,3H); CI MS m/z=315 [C19H20F2N2+H]+.

Example 49

Suitable Indology the product obtained using the method of example 38, step F (41 mg, 0,137 mmol), and dimethyloxalate (21 mg, 0,17 mmol) dissolved in DMF (2 ml) with rapid stirring in 25 ml flask, equipped with a fridge, in an atmosphere of N2. Add tert-piperonyl potassium (22 mg, 0,19 mmol) and the mixture refluxed for 1 hour. The mixture is cooled to room temperature, diluted with water (100 ml) and extracted with (4) a mixture of hexane/ether, 1:1. The combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (25% EtOAc/hexane), receiving N-methylindole product (20 mg, 47%) as a yellow oil, which solidifies upon standing: so pl. 110-112°;1H NMR (300 MHz, CD13) δ 7.11 (d, J=8.3 Hz, 1H); 7.06 (d, J=3.1 Hz, 1H); 6.72-6.80 (m,3H); 6.59-6.67 (m,1H); 6.42 (d, J=3.1 Hz, 1H); 4.30 (t, J=5.9 Hz, 1H); 3.95 (who, J=15.3 Hz, 1H); 3.85 (d, J=15.2 Hz, 1H); 3.77 (s,3H); 3.00 (DD, J=11.3, 5.1 Hz, 1H); 2.71 (DD, J=11.3, 6.6 Hz, 1H); 2.49 (s,3H); CI MS m/z=313 [C19H18F2N2+H]+; Elemental analysis. Calculated for C19H18F2N2: C 73,06; N, OF 5.81; N, 8,97. Found: C, 72,93; N, Between 6.08; N, 8,13.

Example 50

Similar indoleamines, which is obtained by the method described in example 47, step A (199 mg, of 0.625 mmol), dissolved in dichloroethane (6 ml) in a 50 ml flask, equipped with a refrigerator, with the atmosphere of N2. As one portion add MeSO3H ((2.0 ml, 31 mmol) and the mixture is vigorously stirred while boiling under reflux over night. The mixture is cooled to room temperature, poured into 100 ml of rapidly stirred mixture of ice-water, and make it the core 2 N. NaOH. After stirring for 30 minutes, the mixture is extracted with (4) CH2Cl2. The combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (gradient 50-100% EtOAc/hexane), receiving indolinone the product of example 48 (110 mg, 55%), as not quite white solids: I. pl. 71-75°;1H NMR (300 MHz, CD13) δ 6.73-6.77 (m, 2H); 6.59-6.66 (m,1H); 6.56 (d, J=8.0 Hz, 1H); 6.45 (d, J=8.0 Hz, 1H); 4.12 (t, J=6.0 Hz, 1H); 3.72 (users,1H); 3.61 (t, J=8.5 Hz, 2H); 3.51 (s,2H); 2.86-2.94 (m,3H); 2.59 (DD, J=11.4, 7.0 Hz, 1H); 2.42 (s,3H); API MS m/z=301 [C18H18Fsub> 2N2+H]+.

It should be noted that there are also 28 mg (14%) source material. Based on the selected source material output connection example 48 is 64%.

Example 51

The product of example 50 (86 mg, 0,286 mmol) dissolved in Meon (3 ml) and catalytic amount of SPLA (1 drop) in a 25 ml flask in an atmosphere of N2. Add aqueous formaldehyde (24 μl, 0.32 mmol) and the mixture is stirred for 2 hours. Added NaBH3CN (29 mg, 0.46 mmol) and the mixture is stirred for additional 1 hour. The mixture was diluted with CH2Cl2(50 ml), then washed successively 1 N. NaOH (40 ml) and saturated aqueous NaCl (40 ml). The organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (50% EtOAc/hexane), receiving N-methylindolin (72 mg, 80%) as a pale yellow oil, which solidifies after repeated cycles of freezing/thawing/flushing stream of N2: so pl. 111-116°;1H NMR (300 MHz, CD13) δ 6.73-6.77 (m,2H); 6.59-6.67 (m,2H); 6.30 (d, J=8.1 Hz, 1H); 4.12 (t, J=5.9 Hz, 1H); 3.50 (s,2H); 3.30-3.36 (m,2H); 2.89 (DD, J=11.4, 5.1 Hz, 1H); 2.82 (t, J=8.2 Hz, 2H); 2.73 (s,3H); 2.59 (DD, J=11.3, 6.9 Hz, 1H); 2.41 (s,3H); API MS m/z=315 [C19H20F2N2+H]+; Elemental analysis. Calculated for C19H20F2N2-0,1 N2ABOUT: WITH, 72,18; N, 6,44; N, 8,86. Found: C, 72,04; N, 6,46; N, 8,65.

To a solution of the appropriate amerosport obtained using the technique of stage E of example 38 (1.20 g, 3,81 mmol) in methylene chloride (20 ml) dropwise at 0°C for 2 minutes add 98% N2SO4(10 ml, 0.20 mol). The reaction mixture was stirred at 0°C for 15 minutes and then poured into a mixture of ice and 2 N. NaOH (300 ml). The organic layer is separated and the aqueous layer was extracted (2x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/hexane, 1:1), obtaining the required Indology product as a white powder (0.55 g, 48%): so pl. 184-186°;1H NMR (300 MHz, CD13) δ 8.20 (users,1H); 7.08-7.22 (m,6N); 7.69 (d, J=8.5 Hz, 1H); 6.50 (t, J=1.0 Hz, 1H); 4.32 (t, J=7.5, 5.4 Hz, 1H); 3.97 (d, J=15.2 Hz, 1H); 3.88 (d, J=15.2 Hz, 1H); 3.04 (DD, J=11.5, 5.4 Hz, 1H); 2.66 (DD, J=11.5, 7.5 Hz, 1H); 2.50 (s,3H); CI MS m/z=297 [C18H171N2+H]+; IR (KBr) 3410, 2870, 2778, 1594, 1460, 1348 cm-1; Elemental analysis. Calculated for C18H17ClN2: C, 72,84; N, 5,77; N, 9,44. Found: C, 72,83; N, 5,95; N, 9.28 Are Primer 53

To a solution of indelaware product of example 52, (160 mg, 0,539 mmol) and dimethyloxalate (70 mg, 0.59 mmol) in DMF (5 ml) in one portion at room temperature under nitrogen atmosphere add tert-piperonyl potassium (66 mg, 0.59 mmol). The reaction mixture is boiled with reverse you can see what these lamps for 3 minutes and then cooled to room temperature. The mixture was diluted with water (50 ml) and extracted (3x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/hexane, 1:1), receiving

N-methylindole product as a white solid (160 mg, 96%): so pl. 90-92°;1H NMR (300 MHz, CD13) δ 7.03-7.23 (m,6N); 6.71 (d, J=8.5 Hz, 1H); 6.41 (DD, J=3.0, <1 Hz, 1H); 4.33 (t, J=7.5, 5.0 Hz, 1H); 3.94 (d, J=15.1 Hz, 1H); 3.88 (d, J=15.1 Hz, 1H); 3.74 (s,3H); 3.01 (DD, J=11.4, 5.0 Hz, 1H); 2.66 (DD, J=11.4, 7.5 Hz, 1H); 2.48 (s,3H); CI MS m/z=311 [C19H191N2+H]+; IR (KBr) 2937, 2766, 1594, 1497, 1265 cm-1; Elemental analysis. Calculated for C19H19ClN2-0,1 N2ABOUT: WITH, 73,00; N, TO 6.19; N, 8,96. Found: C, 72,78; N, 6,09; N, 8,78.

Example 54

Suitable Indology product (200 mg, 0,763 mmol) restore following the procedure described in example 42. The reaction product is isolated and purified, getting indolinone product in the form of free base (239 mg, 82%):1H NMR (500 MHz, CD13) δ 7.07-7.20 (m,4H); 6.53 (d, J=8.0 Hz, 1H); 6.43 (d, J=8.0 Hz, 1H); 4.14 (t, J=8.4, 5.4 Hz, 1H); 3.65 (users,1H); 3.60 (t, J=8.3 Hz, 2H); 3.58 (d, J=15.2 Hz, 1H); 3.48 (d, J=15.2 Hz, 1H); 2.96 (DD, J=11.4, 5.4 Hz, 1H); 2.91 (t, J=8.3 Hz, 2H); 2.55 (DD, J=11.4, 8.0 Hz, 1H); 2.42 (s,3H).

To mix the solution indolinone free base (239 mg, 0.80 mmol) in methanol (4 ml) at room temperature in the atmosphere is zhota added dropwise 1N HCl (2.0 ml, 2.0 mmol) in ether. The reaction mixture was stirred at room temperature for 10 min and then diluted with ether (10 ml). The resulting white solid is filtered, washed with anhydrous ether and dried at 60°With vacuum through the night, getting dihydrochloride salt (210 mg, 70%): so pl. 236-238°;1H NMR (300 MHz, CD3OD) δ 7.25-7.43 (m,7H); 6.95 (d, J=6.4 Hz, 1H); 4.55-4.75 (m,4H); 3.95 (t, J=7.7 Hz, 2H); 3.86 (m,1H); 3.61 (m,1H); 3.35 (m, J=7.7 Hz, 2H); 3.13 (s,3H); CI MS m/z=299 [C18H191N2+H]+; IR (KBr) 3410, 2950, 2554, 1595, 1482 cm-1; Elemental analysis. Calculated for C18H19ClN2-2 HCl-0.5 N2A: C, 56.78 HAS; N, OF 5.82; N, OF 7.36. Found: C, 56,74; N, Of 5.92; N, 7,19.

Example 55

Suitable Indology the product is obtained according to the method described in example 38, and then restore in indolinone product according to the method described in example 42.

To the solution formed indoline (180 mg, 0,603 mmol) and acetic acid (0.1 ml) in methanol (5 ml) dropwise at 0°With added 37% aqueous formaldehyde (0,054 ml, 0,723 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 hour and then cooled to 0°C. Portions at 0°With add cyanoborohydride sodium (95 mg, 1.5 mmol). The mixture is stirred at room temperature under nitrogen atmosphere for 3 hours and then quenched with 2n NaOH and extracted (3x) with methylene chloride. About yedinenye organic layers washed with saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc/methanol, 10:1)to give N-methylindoline the product of example 53 as a white solid (140 mg, 74%): so pl. 63-65°;1H NMR (300 MHz, CD13) δ 7.07-7.20 (m,4H); 6.59 (d, J=8.0 Hz, 1H); 6.28 (d, J=8.0 Hz, 1H); 4.14 (t, J=7.9, 5.0 Hz, 1H); 3.58 (d, J=15.0 Hz, 1H); 3.46 (d, J=15.0 Hz, 1H); 3.33 (t, J=8.2 Hz, 2H); 2.93 (DD, J=11.3, 5.0 Hz, 1H); 2.82 (t, J=8.2 Hz, 2H); 2.72 (s,3H); 2.54 (DD, J=11.3, 7.9 Hz, 1H); 2.42 (s,3H); CI MS m/z=313 [C19H211N2+H]+; IR (KBr) 2940, 2796, 1611, 1594, 1489, 1372, 1286 cm-1; Elemental analysis. Calculated for C19H21ClN2: C, 72,95; N, 6,77; N, 8,95. Found: C, 72,70; N, 6,83; N, 8,78.

Example 56

Sulfuric acid (5.0 ml) are added to a solution of the appropriate amerosport obtained using the technique of stage E of example 38 (500 mg, by 1.68 mmol) in dichloromethane (25 ml) at 0°C. the Reaction mixture was stirred at 0°C in nitrogen atmosphere for 20 minutes. After the reaction, the reaction mixture was doing basic (pH ˜11) 6 N. NaOH and extracted (3x) with methylene chloride. The combined organic layers washed with saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo, obtaining a brown oil, which chromatographic (SiO2, 20% EtOAc/hexane)to give the desired indole as not quite white powder (120 mg, 34%): so pl. 150-152°;1 H NMR (300 MHz, CD13) δ 8.21 (users,1H); 7.25-7.17 (m,2H); 7.14 (d, J=8.6 Hz, 1H); 7.01 (d, J=7.7 Hz, 1H); 6.93-6.85 (m,2H); 6.70 (d, J=8.5 Hz, 1H); 6.50 (d, J=2.3 Hz, 1H); 4.35 (t, J=6.3 Hz, 1H); 3.97 (d, J=15.3 Hz, 2H); 3.89 (d, J=15.3 Hz, 1H); 3.05 (DD, J=5.2, 11.3 Hz, 1H); 2.68 (DD, J=7.5, 11.3 Hz, 1H); 2.50 (s,3H); IR (KBr) 3427, 2921, 2473, 1617, 1590, 1484 cm-1.; CI MS m/z=281 [C18H17FN2+H]+.

Example 57

Indology the product of example 56, (100 mg, 0.36 mmol) and dimethyloxalate (46 mg, 0,39 mmol) in DMF (3 ml) is treated with tert-piperonyl potassium (44 mg, 0,39 mmol). The reaction mixture is refluxed for 30 minutes. The reaction mixture is cooled to room temperature and diluted with water (25 ml). Once extracted (3x) with ethyl acetate the organic layers washed with water, saturated salt solution, dried over sodium sulfate, filtered and concentrated. The dark residue chromatographic (SiO2, 20% EtOAc/hexane) and the resulting oil treated with 1 M HCl (1 EQ.) in diethyl ether, receiving

N-methylindole product as a white solid (45 mg, 11%): so pl. 255-258°;1H NMR (300 MHz, CD3OD) δ 7.43-7.25 (m,3H); 7.12-7.00 (m,2H); 6.99 (d, J=10.0 Hz, 1H); 6.70 (d, J=8.6 Hz, 1H); 6.50 (d, J=3.1 Hz, 1H); 4.8-4.67 (m,2H); 3.89 (DD, J=5.6, 11.9 Hz, 1H); 3.81 (s,3H); 3.65-3.55 (m,1H); 3.30-3.29 (m,1H); 3.14 (s,3H); IR (KBr) 3424, 2944, 2479, 1590, 1449 cm-1.; CI MS m/z=295 [C19H19FN2+H]+.

Example 59

1 M solution of HCl in ether (2.0 ml, 2.0 mmol) is added dropwise to the Rast is oru suitable amerosport, obtained using the technique of stage E of example 38 (129 mg, 0,459 mmol) in methanol (4 ml). The solvent and excess HCl is removed in vacuum, then there is a brown solid, which is recrystallized from EtOH-Et2O getting the desired Indology product (64 mg, 42%) as a brown solid: so pl. 200-205°C (decomposition);1H NMR (300 MHz, CD3OD) δ 7.36-7.23 (m,4H); 7.10 (t, J=8.7 Hz, 2H); 6.62 (d, J=8.5 Hz, 1H); 6.52 (d, J=3.0 Hz, 1H); 4.82-4.69 (m,3H); 3.85 (DD, J=11.3, 5.8 Hz, 1H); 3.56 (t, J=11.5 Hz, 1H); 3.14 (s,3H); ); IR (KBr) 3238, 2954, 2588, 1605, 1590, 1463, 1348, 1224, 1160, 838, 740 cm-1.; CI MS m/z=281 [C18H17FN2+H]+; Elemental analysis. Calculated for C18H17FN2-HCl-0,75 H2ABOUT: WITH, 65,45; N, 5,95; N, 8,48. Found: C, 65,75; N, 5,94; N, 8,42.

Example 61

Concentrated sulfuric acid (10.0 ml, to 30.1 mmol) is added to ice mixed solution of a suitable amerosport obtained using the technique of stage E of example 38 (1,00 g of 3.05 mmol) in CH2Cl2(50 ml). This mixture was stirred at 0°C for 20 minutes, then stirred at room temperature for 30 minutes and cooled to -10°C. Small portions add ice concentrated aqueous ammonium hydroxide (200 ml) to achieve a pH of 12. The aqueous layer was extracted with (2) CH2Cl2. Organic extracts of the volume of inaut, dried over MgSO4/Na2SO4, filtered and concentrated in vacuo. Purification of column chromatography (SiO2, 20 g, from hexanol to 10% EtOAc/hexane) gives the desired Indology product (302 mg, 32%) as not quite white solids: I. pl. 149-153°;1H NMR (500 MHz, CD13) δ 8.16 (s,1H); 7.28-7.21 (m,2H); 7.16 (d, J=8.4 Hz, 1H); 7.02 (d, J=10.4 Hz, 1H); 6.97 (d, J=8.2 Hz, 1H); 6.70 (d, J=8.4 Hz, 1H); 6.51 (s,1H); 4.29 (t, J=5.2 Hz, 1H); 3.96 (d, J=15.2 Hz, 1H); 3.87 (d, J=15.3 Hz, 1H); 3.00 (DD, J=11.2, 5.0 Hz, 1H); 2.69 (DD, J=11.3, 6.5 Hz, 1H); 2.49 (s,3H); IR (KBr) 3409, 2779, 1579, 1489, 1424, 1349, 1244, 1163, 1060 cm-1.; CI MS m/z=315 [C18H161FN2+H]+; Elemental analysis. Calculated for C18H16ClFN2: C, 68,68; N, 5,12; N, 8,90. Found: C, 68,36; N, 5,13; N, 8,51.

Example 62

Tert-piperonyl potassium are added to a solution indelaware product of example 61 (354 mg, 1.12 mmol) and dimethyloxalate (145 mg, of 1.23 mmol) in DMF (3 ml) and the mixture refluxed for 1 hour. The mixture is cooled to room temperature and quenched with water (5 ml). After extraction (2) CH2Cl2the organic layer is dried over MgSO4/Na2SO4, filtered and concentrated in vacuo. Purification of column chromatography (SiO2, 20 g, from hexanol to 10% EtOAc/hexane) gives N-methylindoline product (163 mg, 44%) as a yellow powder: so pl. 120-124°;1H NMR (500 MHz, CD13) δ 7.27-7.24 (m,1H); 7.08 (d, J=8.5 Hz, 1H); 7.04 (d, J=3.1 Hz, H); 7.01 (d, J=10.4 Hz, 1H); 6.96 (d, J=8.2 Hz, 1H); 6.71 (d, J=8.5 Hz, 1H); 6.42 (d, J=3.1 Hz, 1H); 4.29 (t, J=5.8 Hz, 1H); 3.96 (d, J=15.2 Hz, 1H); 3.85 (d, J=15.2 Hz, 1H); 3.76 (s,3H); 2.99 (DD, J=11.3, 5.2 Hz, 1H); 2.68 (DD, J=11.4, 6.5 Hz, 1H); 2.47 (s,3H); IR (KBr) 3438, 2943, 2779, 1579, 1488, 1422, 1358, 1266, 1064 cm-1.; ESI MS m/z=329 [C19H181FN2+H]+.

Example 64

Similar N-methylindoline the product was obtained according to the method described in example 39, and then restored in indolinone product according to the following procedure.

Cyanoborohydride sodium (63 mg, 1,004 mmol) is added to cooled with ice to a solution of N-methylindole (110 mg, 0,335 mmol) in glacial acetic acid (6 ml). The reaction mixture is allowed to warm to room temperature, stirred for 2 hours, cooled in an ice bath and diluted with N2About (10 ml). Add ice concentrated aqueous ammonium hydroxide (30 ml) up until the solution pH reaches 12. After extraction (2) CH2Cl2the organic layer is dried over MgSO4/Na2SO4, filtered and concentrated in vacuo. Purification of column chromatography (SiO2, 10 g, 10% EtOAc/hexane) gives the desired N-methylindoline product (15 mg, 15%) as a brown oil. The product is sensitive to the action of air and requires storage in an atmosphere of nitrogen:1H NMR (500 MHz, CD13) δ 7.28-7.25 (m,1H); 7.01 (DD, J=10.4, 2.0 Hz, 1H); 6.95 (DD, J=8.2, 1.9 Hz, 1H); 6.59 (d, J=8.1 Hz, 1H); 6.28 (d, J=8.1 Hz, 1H); .11 (t, J=5.9 Hz, 1H); 3.50 (DD, J=13, 2.0 Hz, 2H); 3.36-3.32 (m,2H); 2.88 (DD, J=11.3, 5.2 Hz, 1H); 2.82 (t, J=8.2 Hz, 2H); 2.73 (s,3H); 2.56 (DD, J=11.4, 7.0 Hz, 1H); 2.41 (s,3H); IR (KBr) 3052, 2925, 2850, 2786, 1609, 1422, 1265, 739 cm-1.; ESI MS m/z=331 [C19H201FN2+H]+.

Example 65

The solution is suitable amerosport obtained using the technique of stage E of example 38 (2.00 g, 6,01 mmol)in CH2Cl2(50 ml), cooled to 0°C, is added dropwise to concentrated H2SO4(20 ml), cooled to 0°C. in the nitrogen atmosphere. After stirring for 20 minutes at 0°the reaction mixture is then poured into a mixture of ice-water (400 ml). The aqueous layer was quenched with 6 N. NaOH to achieve pH ˜14, then the aqueous layer was extracted with (3) CH2Cl2. The combined extract in CH2Cl2washed with a mixture of 1:5 6 N. NaOH and saturated NaCl, then dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on silica (60 g) and elution with 66% EtOAc gives the product (0.68 g, 36%). Recrystallization from a mixture of CH2Cl2/Meon/hexane give the desired Indology product (0.12 g) as not quite white solids: I. pl. 189-195°;1H NMR (300 MHz, 5% Meon-D4/CD13) δ 8.66 (users,1H); 7.28-7.20 (m,2H); 7.16 (d, J=8.6 Hz, 1H); 7.11-6.97 (m,2H); 6.66 (d, J=8.5 Hz, 1H); 6.52-6.47 (m,1H); 4.34 (t, J=6.5 Hz, 1H); 4.00 (d, J=15.2 Hz, 1H); 3.89 (d, J=15.2 Hz, 1H); 3.05 (DD, J=11.1, 5.8 Hz, 1H); 2.63 (DD, J=11.4, 8.0 Hz, 1H); 2.51 (s,3H); IR (KBr) 3410 2780, 1498, 1461, 1347, 1247, 1132, 1059, 883, 824, 801, 736, 690, 560 cm-1.; ESI MS m/z=315 [C18H161FN2+H]+; Elemental analysis. Calculated for C18H16ClFN2-0,10 H2ABOUT: WITH, 68,29; N, 5,16; N CENT TO 8.85. Found: C, 68,17; N, Of 4.95; N, 8,68.

Example 81

Stage A: Methylamine (40 wt.% water, 2.0 ml, 23 mmol) is added to a stirred solution of 5-formylbenzoate (8,2 g, 56 mmol) in Meon (55 ml). After stirring for 20 minutes the mixture is cooled in a bath of ice-water for 35 minutes and then portions over 15 minutes added NaBH4(1.3 g, 34 mmol). After stirring for 30 minutes add H2O (5 ml) to extinguish any remaining hydride. After stirring for 15 minutes Meon removed in vacuum, the residue is dissolved in 1 N. HCl and then extracted with (2) Et2O. the Aqueous phase do strongly alkaline (pH 11) by adding an excess of concentrated NH4OH, and then extracted with (2) Et2O. the Organic phase is washed with saturated NaCl, dried over Na2SO4, filtered and the solvent is removed in vacuum, obtaining the connection, which is the product of the reductive alkylation (4,2 g, theoretical yield = 3.8 g) as a clear, yellow liquid:1H NMR (300 MHz, CD13) δ 7.61 (d, J=2.3 Hz, 1H); 7.54 (s,1H); 7.45 (s,1H); 7.25 (DD, J=8.5, 1.7 Hz, 1H); 6.74 (d, J=2.7 Hz, 1H); 3.83 (s,2H); 2.47 (s,3H).

Stage b: 2-Bromoacetophenone (5,12 g, 26 mmol) is added is to stir the solution methylamino of the product from step A (4,08 g, 25 mmol) and DIEA (5.5 ml, 31 mmol) in anhydrous CH2Cl2(50 ml) under nitrogen atmosphere. After stirring for 20 hours the mixture is diluted with Et2O and then washed (2x) 1 N. HCl. The aqueous phase do strongly alkaline (pH 12) by the addition of excess concentrated NH4OH, and then extracted with (2) Et2O. the Organic phase is dried over Na2SO4, filtered, the solvent is removed in vacuo and the residue purified flash chromatography on silica gel using 2% to 14% EtOAc/hexane + 1% Et2O, getting aminoketone (4,32 g, 61%) as a clear, dark yellow oil:1H NMR (300 MHz, CD13) δ 7.94 (DD, J=8.5, 1.2 Hz, 2H); 7.51-7.62 (m,3H); 7.38-7.47 (m,3H); 7.30 (DD, J=8.5, 1.7 Hz, 1H); 6.72 (d, J=2.9 Hz, 1H); 3.83 (s,2H); 3.79 (s,2H); 2.41 (s,3H).

Stage C: the procedure described in example 10, step G, aminoketone obtained at stage (or 4.31 g of 15.4 mmol) is used for amerosport (3,61 g, 83%) as a pale yellow oil:1H NMR (300 MHz, CD13) δ 7.62 (d, J=2.0 Hz, 1H); 7.52 (d, J=0.9 Hz, 1H); 7.47 (d, J=8.5 Hz, 1H); 7.22-7.48 (m,6N); 6.72-6.75 (m,1H); 4.76 (DD, J=10.3, 3.7 Hz, 1H); 3.83 (d, J=12.9 Hz, 1H); 3.61 (d, J=12.9 Hz, 1H); 2.63 (DD, J=12.4, 10.2 Hz, 1H); 2.54 (DD, J=12.4, 3.7 Hz, 1H); 2.33 (s,3H).

Stage D: Methansulfonate acid (15,5 ml, 239 mmol) is added to a mixed solution of amerosport (3,45 g, 12 mmol, obtained in stage C) in CH2Cl2(60 ml) in an atmosphere of N2. The mixture is then boiled with a back hall is dildocam within 6 hours and give her a chance to cool to room temperature. CH2Cl2removed in vacuo and the resulting solution CH3SO3H then poured onto ice with stirring. The mixture do strongly alkaline (pH 12) by the addition of excess concentrated NH4OH, and then extracted with (2) Et2O. the Organic phase is washed with saturated NaCl, dried over Na2SO4, filtered, the solvent is removed in vacuo and the residue purified flash chromatography on silica gel using a mixture of from 5% to 15% EtOAc/hexane + 1% Et3N, receiving (in the process of elution) (i), the compound (1.65 g, 51%) as a clear, pale yellow oil:1H NMR (300 MHz, CD13) δ 7.16-7.39 (m,7H); 7.04 (d, J=8.4 Hz, 1H); 5.97-6.00 (m,1H); 4.47 (t, J=6.6 Hz, 1H); 3.75 (s,2H); 3.09 (DD, J=11.6, 5.8 Hz, 1H); 2.62 (DD, J=11.7, 7.5 Hz, 1H); 2.44 (s,3H); (ii) a mixture of 9:1 (0,44 g, 14%) compounds and; (iii) compound (0.54 g, 17%) as a yellow oil:1H NMR (300 MHz, CD13) δ 7.50 (d, J=2.3 Hz, 1H); 7.19-7.37 (m,6N); 6.99 (s,1H); 6.66-6.69 (m,1H); 4.40 (DD, J=8.8, 5.8 Hz, 1H); 3.89 (d, J=14.3 Hz, 1H); 3.70 (d, J=14.3 Hz, 1H); 3.08 (DDD, J=11.6, 5.8, 1.5 Hz, 1H); 2.59 (DD, J=11.6, 9.2 Hz, 1H); 2.45 (s,3H).

Stage E: a Solution of HCl in ether (1 M, 5 ml) is added to a stirred solution of compound B (of 0.53 g, 2.0 mmol, from step D) in the Meon (20 ml). After stirring for 20 minutes the solvent is removed in vacuum, the residue is again dissolved in the Meon and the solvent again removed in vacuo. The residue is recrystallized from EtOH-Et2O, floor the tea compound of example 67 (405 mg, 68%) as a white crystalline solid: so pl. 241-246°;1H NMR (300 MHz, CD3OD) δ 7.75 (d, J=2.2 Hz, 1H); 7.56 (s,1H); 7.33-7.47 (m,3H); 7.27-7.33 (m,2H); 6.98 (s,1H); 6.84-6.87 (m,1H); 4.66-4.77 (m,3H); 3.87 (DD, J=12.3, 6.4 Hz, 1H); 3.60 (t, J=11.9 Hz, 1H); 3.10 (s,3H); IR (KBr) 3432, 2954, 2476, 1468, 1275, 1124, 701 cm-1.; CI MS m/z=264 [C18H17NO+H]+; Elemental analysis. Calculated for C18H17NO-HCl And 0.1 N2ABOUT: WITH, 71,68; N, BETWEEN 6.08; N, WITH 4.64. Found: C, 71,53; N, 6,04; N, 4,56.

Example 123

According to the method described for obtaining the compound of example 81, stage E, the compound a (0,83 g, 3.2 mmol, example 81, step (C) is used to produce compounds of example 123 (385 mg, 41%) as a white, amorphous solids: I. pl. 234-240°;1H NMR (300 MHz, CD3OD) δ 7.50-7.60 (m,2H); 7.29-7.42 (m,3H); 7.20-7.28 (m,3H); 5.95 (users,1H); 4.83-4.91 (m,1H); 4.69 (d, J=15.2 Hz, 1H); 4.62 (d, J=15.2 Hz, 1H); 3.97 (DD, J=12.4, 6.7 Hz, 1H); 3.53 (ushort, J=11.4 Hz, 1H); 3.09 (s,3H); IR (KBr) 3424, 2936, 2588, 1466, 1431, 1268, 1148, 1039, 780, 705 cm-1.; CI MS m/z=264 [C18H17NO+H]+; Elemental analysis. Calculated for C18H17NO-HCl-0.5 N2ABOUT: WITH, 70,01; N, OF 6.20; N, 4,54. Found: C, 70,05; N, The 6.06; N, 4,46.

ANALYSES LINKING

Analyses on the primary linking

To estimate the relative affinity of binding of various compounds with conveyors NE, DA and NT were used cell line NICE for the expression of each of the three conveyors for humans. cDNA containing floor is haunted coding of each conveyor, amplified by PCR from the libraries of the human brain. cDNA contained in pCRII-vector, and sequenced to confirm their identity and then was subcloned into expressing plasmid-based virus Epstein-Barr (E. Shen, Cooke GM, RA Horlick, Gene 156:235-239, 1995). This plasmid containing the coding sequence for one of the conveyors man was transfusional cells NICE. Successful transfection was confirmed by the ability of known blockers of re-absorption to inhibit the uptake of labeled tritium NE, DA or NT.

To link the cells homogenized, centrifuged and then re-suspended in the buffer for incubation (50 mm Tris, 120 mm NaCl, 5 mm KCl, pH 7.4). Then added a suitable radioligand. To associate a NET was added [3H]-nisoxetine (86,0 CI/mmol, NEN/DuPont) to a final concentration of approximately 5 nm. For DAT binding was added [3H]-WIN 35428 (84,5 CI/mmol) at 15 nm. To link NTT added [3H]-citalopram (85,0 CI/mmol) at 1 nm. Then to displace radioligand was added in various concentrations (from 10-5 to 10-11 M) interest compounds. Incubation was carried out at room temperature for 1 hour in a 96-well pad. After incubation, the tablets were placed on the harvester and quickly 4 times washed (50 mm Tris, 0.9% NaCl, pH 7.4), where cleoc what's membrane, with the associated radioactive label was located on the filters Whatman GF/b filters were added to scintillation cocktail and then counting of the filters was performed in a Packard TopCount. Affinity binding interest compounds was determined by the method of nonlinear regression with the construction of the curve using the software GraphPad Prism 2.01. Nonspecific binding was determined by displacement of 10 micromolar by mazindol.

Table IA
PR-1222 Compound Example No. or additional connectionsNET, Ki nMDAT Ki nMSERT, Ki nM
Ritalin*6103732000
Nomifensine*23721036
Example 1693198988
Example 16251118425
Example 181031,52077
Example 2623,555,5443
Example 283949348
Example 3314,5a 21.536
Example 3915260
Example 4223,5281117
Example 4513the 4.7125
Example 703,310,5934
Example 7212,513,52562
Example 746,114,6365
Example 756,024,5793
Example 771312140
Example 805,61,7280
Example 8143,5641134
Example 9131207796
Example 9215,5443972
Example 9315222588
Example 1066,0100796
Example 1081168143110
Example 1236376261766
* Ritalin (Ritalin) and Nomifensine (Nomifensine), a clinically approved drug for the treatment of a mammal suffering the surrounding neurological or psychological disorder.

Analysis of TBZ

To determine the in vivo activity of compounds against conveyors NE and DA were determined by their ability to prevent sedative action of tetrabenazine (TNZ) (G. Stille, Arzn. Forsch 14:534-537, 1964). Male CFI mice (Charles River Breeding Laboratories)weighing 18-25 g during the test were placed at least 6 days in a carefully controlled environmental conditions (22,2+1,1°With; the middle 50% humidity; 12-hour light cycle/24 hours). Mice fasted overnight (16-22 hours) before the test. Mice were placed in a transparent Shoe boxes are made of polycarbonate (17 cm × 28.5 cm × 12 cm). Oral was administered randomly selected and pre-defined doses of the tested compounds. The dose of tetrabenazine 45 mg/kg was administered intraperitoneally 30 minutes before the start time. All compounds were administered in a volume of 0.1 ml/10 g body weight. Animals were evaluated for antagonism induced tetrabenazine loss research activity and ptosis at certain time intervals after administration of the drug. At certain intervals, mice were examined for symptoms of exploratory activity and ptosis. Exploratory activity was assessed by placing the animal in the center of the circle 5 inches. Fifteen seconds was given for animal movement and the research perimeter. It is believed antagonism to tetrabenazine and evaluated as 0. Carried osobnosti to leave the circle considered as the loss of research activity was rated as 4. Believed that the animal has ptosis, if his eyes are closed, at least 50% and was estimated as 4, if they are fully closed; no closure age was estimated as 0. Believed that more than 95% of the control (treated filler) mice had a loss research activity and ptosis. The activity of the drugs was calculated as the percentage of mice that have seen the lack of reaction to the administered dose of tetrabenazine.

Table 2
ConnectionED50mg/kg
PtosisResearch activity
Ritalin@4.03.0
Nomifensine1.0-4.04.0
Example 162.04.0
Example 701.23.0
Example 743,73.0
Example 920.3≤0.3
Example 93≤0.31.1

Statistical evaluation

Average effective dose (ED50) and 95% confidence limits determined quantitatively by means of Thompson (1947) and Litchfield and Wilcoxon (1949).

Annex I

Table 3.
Pharmaceutical compositions for oral composition (capsules)
Ingredient (nag/capsule)2.5 mg5 mg10 mg25 mg50 mg75 mg100 mg
The active pharmaceutical ingredient is an Example 16 (C18H15F2NO·HCl) (mg)2,805,6111,22to 28.0556,0984,14112,18
Klasterizovannykh starch (mg)227,2224,39218,78201,95173,91225,86197,82
Filled capsule, weight (mg)230230230230230310310
Capsule size3333322

1. 4-phenylsilane tetrahydroisoquinoline formula IA, IB, IIA, IIB, IIIA or IIIB

where R1in the bran of C 1-C6-alkyl;

R2selected from H;

R3selected from H, C1-C6-alkyl, where C1-C6-alkyl, optionally substituted by 1-3 substituents, independently selected in each case from OR8;

R4, R5and R6each independently selected in each instance from the group consisting of H, halogen, -OR10C1-C6-alkyl, where each C1-C6-alkyl optionally substituted by substituents from 1 to 3 independently selected in each case from phenyl;

R7selected from H;

R8selected from H;

R10selected from the group consisting of H, C1-C4-alkyl

X is selected from the group consisting of O, NR13and S, provided that X represents NR13when the compound is a compound of formula (IA);

R13selected from the group consisting of H, C1-C6-alkyl.

2. The compound according to claim 1, where R1is CH3.

3. The compound according to claim 1, where R3is independently in each instance H, C1-C6-alkyl

or C1-C6-alkyl, substituted 1-3 OR8.

4. The compound according to claim 3, where R3represents N or C1-C6-alkyl.

5. The compound according to claim 4, where R3represents H.

6. The compound according to claim 1, where R1is CH3, R2before the hat N and R 3is N.

7. Compounds according to claim 1, where R4, R5and R6, each independently, represent H, halogen, C1-C6-alkyl or-OR10.

8. The connection according to claim 7, where at least one of R4, R5and R6is N.

9. Connection of claim 8, where each of R4, R5and R6is N.

10. Connection of claim 8, where at least one of R4, R5and R6represents halogen.

11. Compounds according to claim 1, where R1is CH3, R2and R3each represent H and at least one of R4, R5and R6is N.

12. The compound of formula (10) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (10), where R4represents H, R5is H and R6is N;

the compounds of formula (10), where R4represents H, R5is Me and R6is N;

the compounds of formula (10), where R4is Cl, R5is H and R6is N; and

the compounds of formula (10), where R4represents H, R5is F and R6is N.

13. The compound of formula (20) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (20), where R4represents H, R5is H and R6represents H;

the compounds of formula (20), where R4represents H, R5is Me and R6is N;

the compounds of formula (20), where R4represents H, R3is Cl and R6is N;

the compounds of formula (20), where R4represents H, R5is F and R6is N; and

the compounds of formula (20), where R4is F, R5is H and R6is F.

14. The compound of formula (30) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (30), where R3represents H, R4represents H, R5is H and R6is N;

the compounds of formula (30), where R3represents H, R4is F, R5is F and R6is N;

the compounds of formula (30), where R is H, R4is F, R5is H and R6is F;

the compounds of formula (30), where R3represents H, R4represents H, R5p is ecstasy F and R 6is N;

the compounds of formula (30), where R3represents H, R4is Cl, R5is H and R6is N;

the compounds of formula (30), where R3represents H, R4represents H, R5is Cl and R6is N;

the compounds of formula (30), where R3represents H, R4represents H, R5is Cl and R6is F;

the compounds of formula (30), where R3represents H, R4represents H, R5is F and R6represents Cl;

the compounds of formula (30), where R3represents H, R4is F, R5is H and R6represents Cl;

the compounds of formula (30), where R3represents H, R4represents H, R5is OMe and R represents H; and

the compounds of formula (30), where R3represents H, R4is F, R5is H and R6is N.

15. The compound of formula (40) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (40), where R3represents H, R4represents H, R5is H and R6is N;

the compounds of formula (40), where the R 3represents H, R4is F, R5is F and R6is N;

the compounds of formula (40), where R3represents H, R4is F, R5is H and R6is F;

the compounds of formula (40), where R3represents H, R4is F, R5is H and R6is N;

the compounds of formula (40), where R3represents H, R4represents H, R5is F and R6is N;

the compounds of formula (40), where R3represents H, R4is Cl, R5is H and R6is N;

the compounds of formula (40), where R3represents H, R4represents H, R5is Cl and R6is N;

the compounds of formula (40), where R3represents H, R4represents H, R5is Cl and R6is F;

the compounds of formula (40), where R3represents H, R4represents H, R5is F and R6represents Cl;

the compounds of formula (40), where R3represents H, R4is F, R5is H and R6represents Cl;

the compounds of formula (40), where R3represents H, R4represents H, R5is OMe and R6not only is em N;

the compounds of formula (40), where R3is Me, R4represents H, R5is H and R6is N;

the compounds of formula (40), where R3is Et, R4represents H, R5is H and R6is N; and

the compounds of formula (40), where R3is CH2OH, R4represents H, R5is H and R6is N.

16. The compound of formula (50) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (50)wherein R3represents H, R4represents H, R5is H and R6is N.

17. The compound of formula (60) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (60)wherein R3represents H, R4represents H, R5represents H, R6is H and R13is N;

the compounds of formula (60)wherein R3represents H, R4represents H, R5represents H, R6is H and R13is Me;

the compounds of formula (60)wherein R3represents H, R4represents H, R 5represents H, R6is H and R13is Et;

the compounds of formula (60)wherein R3represents H, R4represents H, R5is F, R6is F and R13is N;

the compounds of formula (60)wherein R3represents H, R4represents H, R5is F, R6is F and R13is Me;

the compounds of formula (60)wherein R3represents H, R4is F, R5represents H, R6is F and R13is N;

the compound of formula (60)wherein R3represents H, R4is F, R5represents H, R6is F and R13is Me;

the compounds of formula (60)wherein R3represents H, R4is Cl, R5represents H, R6is H and R13is N;

the compounds of formula (60)wherein R3represents H, R4is Cl, R5represents H, R6is H and R13is Me;

the compounds of formula (60)wherein R3represents H, R4is F, R5represents H, R6is H and R13represents H;

the compounds of formula (60)wherein R3represents H, R4represents H, R5is F, R6predstavljaet N and R 13is N;

the compounds of formula (60)wherein R3represents H, R4is F, R5is Cl, R6is H and R13is N;

the compounds of formula (60), where R is H, R is F, R5is Cl, R6is H and R is Me;

the compounds of formula (60)wherein R3represents H, R4is Cl, R5is F, R6is H and R13is H; and

the compounds of formula (60)wherein R3represents H, R4is Cl, R5is F, R6is H and R13represents Me.

18. The compound of formula (70) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (70)wherein R3represents H, R4represents H, R5represents H, R6is H and R13is N;

the compounds of formula (70)wherein R3represents H, R4represents H, R5represents H, R6is H and R13is Me;

the compounds of formula (70)wherein R3represents H, R4represents H, R5represents H, R6is H and R13is Et;

soy is inane formula (70), where R3represents H, R4represents H, R5represents H, R6is H and R13is Bn;

the compounds of formula (70)wherein R3represents H, R4represents H, R5is F, R6is F and R13is N;

the compounds of formula (70)wherein R3represents H, R4represents H, R5is F, R6is F and R13is Me;

the compound of formula (70)wherein R3represents H, R4is F, R5represents H, R6is F and R13is Me;

the compounds of formula (70)wherein R3represents H, R4is Cl, R5represents H, R6is H and R13is N;

the compounds of formula (70)wherein R3represents H, R4is Cl, R5represents H, R6is H and R13is Me;

the compounds of formula (70)wherein R3represents H, R4is F, R5represents H, R6is H and R13is N;

the compounds of formula (70)wherein R3represents H, R4is F, R5represents H, R6is H and R13is Me;

the compounds of formula (70)wherein R3represents H,R 4represents H, R5is F, R6is H and R13is N;

the compounds of formula (70)wherein R3represents H, R4is F, R5is Cl, R6is H and R13is N;

the compounds of formula (70)wherein R3represents H, R4is F, R5is Cl, R6is H and R13is Me;

the compounds of formula (70)wherein R3represents H, R4is Cl, R5is F, R is H and R is H; and

the compounds of formula (70)wherein R3represents H, R4is Cl, R5is F, R is H and R13represents Me.

19. The compound of formula (80) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (80), where R4represents H, R5is H and R6is N;

the compounds of formula (80), where R4represents H, R5is F and R6is N; and

the compounds of formula (80), where R4represents H, R5is F and R6is F.

20. The compound of formula (90) according to claim 1

the sludge is its pharmaceutically acceptable salt, selected from the group consisting essentially of

the compounds of formula (90), where R4represents H, R5is H and R6is N;

the compounds of formula (90), where R4represents H, R5is F and R6is F; and

the compounds of formula (90), where R4represents H, R5is F and R6is N.

21. The compound of formula (100) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (100), where R4represents H, R5represents H, R6is H and R13is N.

22. The compound of the formula (110) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (110), where R4represents H, R5is H and R6is N;

the compounds of formula (110), where R4represents H, R5is F and R6is F;

the compounds of formula (110), where R4represents H, R5is F and R6is N;

the compounds of formula (110), where R is H, R5is H and R6represents Cl;

the compounds of formula (110), where R4represents H, R5is Cl and R6is F;

the compounds of formula (110), where R4represents H, R5is F and R6represents Cl; and

the compounds of formula (110), where R4represents H, R5is OMe and R6is N.

23. The compound of formula (120) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (120), where R4represents H, R5is H and R6is N;

the compounds of formula (120), where R4represents H, R5is F and R6is F;

the compounds of formula (120), where R4represents H, R5is F and R6is N;

the compounds of formula (120), where R4represents H, R5is H and R6represents Cl;

the compounds of formula (120), where R4represents H, R5is Cl and R6is F;

the compounds of formula (120), where R4represents H, R5is OMe and R6is N; and

the compounds of formula (120), where R4represents H, R5is F and R6is Cl.

24. The connection formula is (130) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (130), where R4represents H, R5is H and R6is N; and

the compounds of formula (130), where R4represents H, R5is Bn and R6is N.

25. The compound of formula (140) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (140), where R4represents H, R5is H and R6is N;

the compounds of formula (140), where R4represents H, R5is F and R6is N;

the compounds of formula (140), where R4represents H, R5is F and R is Cl;

the compounds of formula (140), where R4represents H, R5is Cl and R6is F;

the compounds of formula (140), where R4represents H, R5is H and R6represents Cl;

the compounds of formula (140), where R4represents H, R5is OMe and R6is N; and

the compounds of formula (140), where R4represents H, R5is F and R6F.

26. The compound of formula (150) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (150), where R4represents H, R3is H and R6is N;

the compounds of formula (150), where R4represents H, R5is F and R6is N;

the compounds of formula (150), where R4represents H, R5is F and R6represents Cl;

the compounds of formula (150), where R4represents H, R5is Cl and R6is F;

the compounds of formula (150), where R4represents H, R5is H and R6represents Cl;

the compounds of formula (150), where R4represents H, R5is OMe and R6is N; and

the compounds of formula (150), where R4represents H, R5is F and R6is F.

27. The compound of formula (160) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (160), where R4represents H, R5is H and R6is N.

28. The compound of formula (170) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (170), where R4represents H, R5is H and R6is N;

the compounds of formula (170), where R4represents H, R5is F and R6is N; and

the compounds of formula (170), where R4represents H, R5is F and R6is F.

29. The compound of formula (180) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (180), where R4represents H, R5is H and R6is N;

the compounds of formula (180), where R4represents H, R5is F and R6is N; and

the compounds of formula (180), where R4represents H, R5is F and R6is F.

30. The compound of formula (190) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (190), where R4represents H, R5is H and R6is N.

31. The compound of formula (200) according to claim 1

or its pharmaceutically acceptable salt selected from the group consisting essentially of

the compounds of formula (200), where R4represents H, R5represents H, R6is H and R13is N; and

the compounds of formula (200), where R4represents H, R5represents H, R6is H and R13represents Me.

32. The compound according to claim 1, selected from the group consisting of

(R)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydrofuro[2,3-h]isoquinoline;

(S)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydrofuro[2,3-h]isoquinoline;

(R)-7-methyl-5-phenyl-5,6,7,8-tetrahydrofuro[3,2-g]isoquinoline;

(S)-7-methyl-5-phenyl-5,6,7,8-tetrahydrofuro[3,2-g]isoquinoline;

(R)-4-(3,4-differenl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(S)-4-(3,4-differenl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(R)-2-methyl-4-phenyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(S)-2-methyl-4-phenyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(R)-4-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(S)-4-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(R)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydrofuro[3,2-h]isoquinoline;

(S)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydrofuro[3,2-h]isoquinoline;

(R)-4-(4-forfinal)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(S)-4-(4-CFT is henyl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(R)-4-(3,5-differenl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(S)-4-(3,5-differenl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(R)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline; and

(S)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline.

33. The compound according to claim 1, selected from the group consisting of

(+)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydrofuro[2,3-h]isoquinoline;

(-)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydrofuro[2,3-h]isoquinoline;

(+)-7-methyl-5-phenyl-5,6,7,8-tetrahydrofuro[3,2-g]isoquinoline;

(-)-7-methyl-5-phenyl-5,6,7,8-tetrahydrofuro[3,2-g]isoquinoline;

(+)-4-(4-forfinal)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(-)-4-(4-forfinal)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(+)-4-(3,4-differenl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(-)-4-(3,4-differenl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(+)-2-methyl-4-phenyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(-)-2-methyl-4-phenyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(+)-4-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(-)-4-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(+)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydrofuro[3,2-h]isoquinoline;

(-)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydrofuro[3,2-h]isoquinoline;

(+)-4-(3,5-differenl)-2-mate the -1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(-)-4-(3,5-differenl)-2-methyl-1,2,3,4-tetrahydrofuro[2,3-h]isoquinoline;

(+)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline and

(-)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline.

34. Pharmaceutical composition having the ability to block the re-uptake of norepinephrine, dopamine and serotonin, including pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1.

35. A method of treating a mammal suffering from a neurological or psychological disorder selected from the group including attention deficit associated with hyperactivity, anxiety, depression, posttraumatic stress, supranuclear palsy, malnutrition, obessive-compulsive disease, analgesia, syndrome Smoking cessation, panic attacks, Parkinson's disease and phobia, including introduction to the mammal a pharmaceutical composition according to clause 34.

36. The method according to p for the treatment of attention deficit associated with hyperactivity.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

FIELD: organic chemistry, biology, pharmacy.

SUBSTANCE: invention relates to derivatives of thieno[2,3-d]pyrimidine of the general formula (I): or their pharmaceutically acceptable salts wherein R1 and R2 in common with nitrogen atom to which they are added form a ring comprising from 2 to 6 carbon atoms and optionally comprising one or more heteroatoms chosen from nitrogen (N), oxygen (O) and/or sulfur (S) atoms. Proposed compounds possess ability to activate both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and can be used in therapy in aims for regulating fertility. Also, invention describes a pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1): wherein each R1 and R2 represents independently (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-cycloalkyl-(C1-C3)-alkyl or (C3-C6)-cycloalkyl wherein each of them can be substituted possibly with halogen atom in the amount from 1 to 3; R3 represents isoxyzolydine-2-ylcarbonyl or tetrahydroisoxazine-2-ylcarbonyl wherein each ring is substituted possibly with one hydroxy-group; Q represents -CO- or -C(R4)(R5)- (wherein R4 represents hydrogen atom or (C1-C4)-alkyl, and R5 represents hydrogen atom or hydroxy-group); Ar represents 5-10-membered aromatic ring system wherein up to 4 ring atoms can be represented by heteroatoms chosen independently from nitrogen, oxygen and sulfur atoms and wherein this ring system is substituted possibly with one or more substitute. Proposed compounds can be used for modulation of autoimmune disease. Also, invention describes methods for synthesis of compounds of the formula (1) and pharmaceutical composition based on compounds of the formula (1).

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

14 cl, 44 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes glycine-substituted thieno[2,3-D]-pyrimidines of the formula (I): wherein X represents oxygen atom (O) or H,H; A represents sulfur atom (S), -NH, -N(R6), O or a bond; R1 represents (C1-C4)-alkyl, (C2-C4)-alkenyl, unsubstituted or substituted phenyl, thienyl, pyridyl; R2 represents hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-(C2-C4)-alkyl or hydroxy-(C2-C4)-alkyl; R3 and R4 are chosen independently from H, (C1-C4)-alkyl and hydroxy-(C1-C4)-alkyl; R5 represents H or (C1-C4)-alkyl, and R6 represents (C1-C4)-alkyl. Compound possess agonistic activity with respect to glycoprotein hormone, in particular, to compounds possessing agonist activity with respect to luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Also, invention describes pharmaceutical compositions containing such compounds and using these compounds in medicinal therapy, in particular, for fertilization control.

EFFECT: valuable biological and medicinal properties of compounds.

11 cl, 1 tbl, 27 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I):

wherein R1 means hydrogen atom; R2 means phenyl or phenyl mono- or di-substituted substituted with the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, perfluoro-(lower)-alkyl; R3 and R4 in common with carbon atoms to which they are bound form phenyl optionally and independently mono-, di- or tri-substituted with halogen atom or perfluoro-(lower)-alkyl, or form 5-, 6- or 7-membered saturated cycle optionally comprising heteroatom chosen from oxygen (O) and sulfur (S) atom and optionally and independently mono-substituted with (lower)-alkyl wherein indicated saturated cycle is condensed in ortho-position with 5-membered aromatic cycle optionally comprising S atom as a heteroatom, or with phenyl optionally and independently mono- di-substituted with the group: halogen atom, (lower)-alkyl, perfluoro-(lower)-alkyl or (lower)-alkoxy-group, and their pharmaceutically acceptable salts. Also, invention describes a method for synthesis of compounds, a pharmaceutical composition and using compounds for treatment and/or prophylaxis of DPP-IV-associated diseases. Compounds are used in treatment of such diseases as diabetes mellitus being first of all non-insulin dependent diabetes mellitus and damaged tolerance to glucose.

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

16 cl, 1 tbl, 39 ex

FIELD: agriculture, organic chemistry.

SUBSTANCE: invention relates to application of 2-[N-(2'-iodophenyl)carboxamido]-3-amino-4,6-dimethylthieno[2,3-b]pyridine of formula as stimulator of sunflower growth.

EFFECT: stimulation of sunflower seed germination; increased sunflower productivity.

2 tbl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I):

wherein R1 means hydrogen atom; R2 means phenyl or phenyl mono- or di-substituted substituted with the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, perfluoro-(lower)-alkyl; R3 and R4 in common with carbon atoms to which they are bound form phenyl optionally and independently mono-, di- or tri-substituted with halogen atom or perfluoro-(lower)-alkyl, or form 5-, 6- or 7-membered saturated cycle optionally comprising heteroatom chosen from oxygen (O) and sulfur (S) atom and optionally and independently mono-substituted with (lower)-alkyl wherein indicated saturated cycle is condensed in ortho-position with 5-membered aromatic cycle optionally comprising S atom as a heteroatom, or with phenyl optionally and independently mono- di-substituted with the group: halogen atom, (lower)-alkyl, perfluoro-(lower)-alkyl or (lower)-alkoxy-group, and their pharmaceutically acceptable salts. Also, invention describes a method for synthesis of compounds, a pharmaceutical composition and using compounds for treatment and/or prophylaxis of DPP-IV-associated diseases. Compounds are used in treatment of such diseases as diabetes mellitus being first of all non-insulin dependent diabetes mellitus and damaged tolerance to glucose.

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

16 cl, 1 tbl, 39 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of tetracyclic derivatives of isoquinolone. Invention describes a method for synthesis of derivatives of 3,5-dihydro-1,11-dimethylfuro[2',3':3,4]cyclohepta[c]isoquinoline-5-one of the general formula (1a-f): wherein (1a): R means hydrogen atom (H); R' means hydrogen atom (H); (1b): R means chlorine atom (Cl); R' means hydrogen atom (H); (1c): R means bromine atom (Br); R' means hydrogen atom (H); (1d): R means iodine atom (J); R' means hydrogen atom (H); (1e): R means methoxy-group (-OCH3); R' means hydrogen atom (H); (1f): R means -OCH3; R' means -OCH3. Method involves boiling derivatives of 3,5-dihydro-1,11-dimethylfuro[2',3':3,4]cyclohepta[c]isochromen-5-one in formamide medium in the ratio 0.01 mole of the parent substance per 45 ml of formamide for 25-120 min. Invention provides preparing new compounds that possess the potential useful biological properties.

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

2 tbl, 6 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to crystalline polymorphic modifications of strong acting epotilone analog of forma A and forma B represented by the formula (I): Invention proposes a crystalline substance representing a mixture of form A and form B of epotilone analogs. Invention proposes two variants of a method for preparing crystalline polymorphic modification representing form A. Also, invention proposes a pharmaceutical composition inhibiting angiogenesis and comprising an active component that represents crystalline polymorphic modification of epotilone analog of form A, form B or a crystalline polymorphic modification of epotilone analog of the formula (I) wherein this modification has no amorphous component, and a pharmaceutically acceptable carrier. Also, invention proposes a method for treatment of cancer comprising administration in mammal the effective dose of crystalline polymorphic modification of epotilone analog. Invention provides preparing crystalline polymorphic modifications of strong acting epotilone analog of the formula (I) characterizing by improved properties for using in therapy of cancer species.

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

16 cl, 9 dwg, 7 tbl, 5 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes phenyl-substituted heterocyclic 1,3-ketoenols of the formula (I): wherein R1 and R3 mean independently of one another ethyl or (C1-C2)-alkoxy-group; Q means the group of the formula (Q1): or (Q2): wherein R4 and R5 in common with atoms to which they are joined form 5-7-membered cycle that can comprise additionally anellated alkylene chain consisting of 2-6 carbon atoms that, in turn, can comprise two heteroatoms taken among oxygen atom, and indicated cycle can be substituted with halogen atom, hydroxy-group, (C1-C6)-alkoxy-group, (C1-C6)-alkoxy-(C1-C6)-alkoxy-group, (C1-C4)-alkylcarbonyloxy-group, hydroxy-(C1-C4)-alkoxy-group, hydroxycarbonyl-(C1-C2)-alkoxy-group, methoxycarbonyl-(C1-C2)-alkoxy-group, methoxyimino-, methoxyethoxyethoxy-group; R6 and R7 means (C1-C10)-alkyl; R8 means hydrogen atom; X means oxygen atom; R20 means (C1-C10)-alkyl, and also agronomically acceptable salts and isomers of these compounds. Also, invention describes a method for preparing compounds of the formula (I), herbicide agent and a method for control of weed growth based on compounds of the formula (I). Invention provides preparing compounds possessing the herbicide activity.

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

5 cl, 28 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, peptides, medicine, pharmacy.

SUBSTANCE: invention relates to peptide derivatives named as memnopeptides that are used as an active component for manufacturing a medicinal preparation used in treatment of bacterial infection. Invention proposes compound of the formula (I): wherein radicals R1, R2, R3, R4, R5, R6, R7, R8 and (A)n have corresponding values, or its salt. Compounds of the formula (I) are prepared by culturing microorganism Memnoniella echinata FH 2272, DSM 13195 under suitable conditions in the nutrient medium containing at least one source of carbon atoms and at least one source of nitrogen atoms and the process is carrying out until the accumulation of at least one compound of the formula (I) in the nutrient medium followed by isolation of indicated compound. The attained technical result involves the development of a pharmaceutical composition eliciting an antibacterial activity. The development of the preparation provides expanding assortment of agents used in treatment of diseases said above.

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

10 cl, 2 tbl, 7 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

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