Cyclic sulphonamides for gamma-secretase inhibition

FIELD: chemistry.

SUBSTANCE: invention refers to cyclic sulphonamide derivatives of general formula I where bonds indicated with wavy lines represent mutually cis- in relation to cyclohexane ring; R3 represents H or hydrocarbon group having up to 10 carbon atoms; Ar1 and Ar2 independently represent phenyl which carries 0-3 substitutes independently selected from halogen, CF3, CHF2; or its pharmaceutically acceptable salt. Besides, invention refers to technology of compounds of general formula I and to pharmaceutical composition based on compounds of general formula I and applied as gamma-secretase inhibitor.

EFFECT: new derivatives of cyclic sulphonamide, activating gamma-secretase inhibition and suitable for treatment and prevention of Alzheimer's disease.

9 cl, 7 ex

 

The present invention relates to a new class of compounds, their salts, pharmaceutical compositions comprising them, methods for their manufacture and their use in the treatment of the human body. In particular, the invention relates to new cyclohexylsulfamate, including additional condensed cyclic ring sulfonamidnuyu group. The compounds inhibit the processing of APP γ-secretase in order to suppress or reduce the secretion of β-amyloid, and therefore they can be used in the treatment or prevention of Alzheimer's disease.

Alzheimer's disease (AD) represents the most common form of dementia. Although AD is primarily a disease of the elderly, affecting up to 10% of the population aged over 65 years, it also affects a significant number of younger patients with a genetic predisposition. It is a neurodegenerative disorder clinically characterized by progressive loss of memory and cognitive function, and pathology is characterized by deposition of extracellular protein plaques in the cortex and associative areas of the brain of people suffering from this disease. These plaques mainly include fibrillar aggregates β-amyloid peptide (Aβ). The role of secrets, including tax estimation is γ -secretase, in the processing of protein-amyloid precursor (APP) to form Aβ well described in the literature, and its overview is provided, for example, in WO 01/70677.

There is an increasing number of messages in the literature on compounds with inhibitory activity against γ-secretase as measured in cell-based assays (see, for example, WO 01/70677 and links in this document). Many of the relevant compounds are peptides or derivatives of peptides.

In document WO 00/50391 revealed a wide class of sulfonamides as modulators producing β-amyloid, but none of these documents were not disclosed and not meant compounds of the present invention. In documents WO 01/70677, WO 02/36555 And WO 02/081435 respectively disclosed classes of sulfonamides, sulfonamides and cyclohexylsulfamic that inhibit γ-secretase, but none of them are not disclosed and are not available compounds of the present invention.

The present invention provides a new class of cyclohexylsulfamic, including additional condensed ring, which contains sulfonamidnuyu group. The compounds inhibit the processing of APP intended γ-secretases in order to suppress or weaken the products Andβand, therefore, they can be used in the treatment or predator is not the same AD.

In accordance with the invention is provided a compound of the formula I:

where communication, indicated by wavy lines represent mutually CIS - against cyclohexane ring;

R3represents H or a hydrocarbon group having up to 10 carbon atoms, optionally substituted CF3, CHF2, halogen, CN, OR5, COR5, CO2R5, OCOR6N(R5)2, CON(R5)2or NR5COR6;

R5represents N or C1-4alkyl;

R6is1-4alkyl; and

Ar1and Ar2independently represent phenyl or heteroaryl, either of which bears 0-3 substituent, independently selected from halogen, CN, NO2, CF3, CHF2, OH, OCF3CHO, CH=NOH, C1-4alkoxy, C1-4alkoxycarbonyl,2-6acyl, C2-6alkenyl and C1-4of alkyl, which optionally bears Deputy selected from halogen, CN, NO2, CF3, OH and C1-4alkoxy;

or its pharmaceutically acceptable salt.

In the formula I and other formulas presented in the present description, use the symbol by which show that the wavy lines indicate relationships that are mutually CIS with respect to cyclohexane rings. All such communication or act as the top of a ring, or protrude downward from the ring. Sigma attached to the cyclohexane ring and represented by a solid line, be sure to have an orientation opposite to the orientation of the connections represented by wavy lines.

The compounds of formula I exist in two enantiomeric forms, depending on, are communication, indicated by wavy lines, up or down, corresponding to the formulas IA and IB:

where R3, Ar1and Ar2have the same meanings as described above. It should be understood that any connection in accordance with the invention may exist or homochiral forms IA and IB, or a mixture of both in any proportion.

In addition to the above isomerism, the compounds in accordance with the invention can include one or more asymmetric centers and therefore may exist as enantiomers. When the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereoisomers. It should be understood that all such isomers and mixtures thereof in any proportion are encompassed by the scope of the present invention.

In the absence of other indications, when a variable appears more than once in the formula I, a single value independent of the other the other. Used in the present description, the expression "hydrocarbon group" refers to groups consisting only of carbon atoms and hydrogen. Such groups may include linear, branched, or cyclic structures, alone or in any combination, consistent with the specified maximum number of carbon atoms and can be saturated or unsaturated, including aromatic, when permitted by the specified maximum number of carbon atoms.

Used in the present description the expression "C1-xalkyl, where x is an integer greater than 1, belongs to the normal and branched alkyl groups, where the number of constituent carbon atoms is in the range from 1 to X. Specific alkalinity groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such as "C2-6alkenyl", "hydraxis1-6alkyl, heteroaryl1-6alkyl", "C2-6quinil" and "C1-6alkoxy"should be considered in the same way. The most appropriate number of carbon atoms in such groups is not more than 6.

Used in the present description the expression "C2-6acyl" refers to C1-5alkylcarboxylic groups in which the alkyl part may be normal, branched or cyclic and may be halogenation is Noah. Examples include acetyl, propionyl and TRIFLUOROACETYL.

Used in the present description, the expression "heteroaryl" means a monocyclic system of 5 or 6 ring atoms or a condensed bicyclic system having up to 10 ring atoms selected from C, N, O and S, where at least one of the constituent rings is aromatic and includes at least one ring atom that is different from the carbon atom. Preferred monocyclic system of 5 or 6 members. Examples of heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, personilnya, pyrrolidino, follow, thienyl, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolinone, imidazolidinyl, oxadiazolidine, triazolyl and thiadiazolyl groups without-condensed analogues. Further examples of heteroaryl groups include tetrazole, 1,2,4-triazine and 1,3,5-triazine. The pyridine ring can be in N-oxide form.

When the phenyl group or heteroaryl group is more than one substituent, preferably not more than one of these substituents is other than halogen or alkyl. When an alkyl group is more than one substituent, preferably not more than one of these substituents is other than halogen.

Used is used in the present description, the term "halogen" includes fluorine, chlorine, bromine and iodine, of which the preferred fluorine and chlorine.

For use in medicine, the compounds of formula I may be predominantly in the form of pharmaceutically acceptable salts. However, other salts can be used to obtain compounds of the formula I or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid additive salts which may, for example, be formed by mixing a solution of the compounds in accordance with the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, benzolsulfonat acid, methanesulfonate acid, fumaric acid, maleic acid, succinic acid, acetic acid, Betina acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Alternatively, when the compound of the invention carries the acid part, pharmaceutically acceptable salt can be formed by neutralization of the specified acid part of a suitable base. Examples educated so pharmaceutically acceptable salts include salts of alkali metals such as sodium and potassium salts; ammonium salts; salts of alkaline-earth metals such as calcium salts and magnesium; and salts formed with suitable organic is the reason such as amine salts (including salt, pyridinium and Quaternary ammonium salt.

In the compounds of formula I, Ar1and Ar2independently represent optionally substituted phenyl or heteroaryl. Ar1preferably selected from optionally substituted phenyl and optionally substituted 6-membered heteroaryl. Preferred 6-membered heteroaryl options Ar1include optionally substituted pyridyl, in particular optionally substituted 3-pyridyl. Ar1preferably selected from 6-(trifluoromethyl)-3-pyridyl and phenyl, which is optionally substituted in position 4 by halogen, CN, vinyl, allyl, acetyl, stands or mono-, di - or trifluoromethyl. In one preferred embodiment of the invention Ar1represents 4-chlorophenyl. In another preferred embodiment, Ar1is 4-triptoreline. In another preferred embodiment of the invention Ar1is 6-(trifluoromethyl)-3-pyridyl.

Ar2preferably represents optionally substituted phenyl, in particular phenyl, bearing 2 or 3 substituent selected from halogen, CN, CF3and optionally substituted alkyl. Ar2usually selected from phenyl groups bearing halogen substituents (preferably fluorine) in positions 2 and 5, positions 2 and 6 or the positions 2-, 3 - and 6 - or phenyl group bearing a substituent in the form of fluorine in position 2 and halogen, CN, methyl or hydroxymethyl in position 5 is. In a preferred embodiment of the invention Ar2is 2.5-differenl, 2,6-differenl or 2,3,6-tryptophanyl.

In a particular embodiment, Ar1represents 4-chlorophenyl or 4-triptoreline and Ar2is a 2.5-differenl.

R3represents H or a hydrocarbon group having up to 10 carbon atoms, optionally substituted as defined earlier. The hydrocarbon group represented by R3are preferably non-aromatic and unsubstituted and preferably include up to 6 carbon atoms. Typical examples include alkyl groups such as methyl, ethyl, n-propyl, isopropyl and n-butyl) and alkeneamine group (such as allyl).

Preferred compounds of the invention include compounds in which Ar1represents 4-chlorophenyl or 4-triptoreline, Ar2is 2.5-differenl and R3represents H, methyl, ethyl, n-propyl, isopropyl or allyl, and their pharmaceutically acceptable salts.

Specific examples of compounds in accordance with the invention include

2,2-dioxide (4aRS,6RS,8aSR)-6-(2,5-differenl)-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine;

2,2-di is xed (3S,4aR,6R,8aS)-6-(2,5-differenl)-3-ethyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine;

2,2-dioxide (3R,4aR,6R,8aS)-6-(2,5-differenl)-3-ethyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine;

2,2-dioxide (3RS,4aRS,6RS,8aSR)-6-(2,5-differenl)-3-isopropyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine;

2,2-dioxide (3SR,4aRS,6RS,8aSR)-6-(2,5-differenl)-3-isopropyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine and

2,2-dioxide (3S,4aR,6R,8aS)-6- [(4-(chlorophenyl)sulfonyl]-6-(2,5-differenl)-3-atelectasia-1H-2,1-benzothiazine;

and their pharmaceutically acceptable salts.

Compounds of the present invention have activity as inhibitors γ-secretase.

The invention also provides pharmaceutical compositions comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. Preferably these compositions are presented in a standard dosage forms, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, capsules, transdermal patches, autoinjector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflate. The primary active ingredient is usually mixed with a pharmaceutical carrier, for example, about CNAME ingredients for tabletting, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or resins, dispersing means, suspendresume means or surface-active substances, such as monooleate sorbitan and polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form a homogeneous pre-composed compositions containing the compound of the present invention or its pharmaceutically acceptable salt. When specifying that these pre-made compositions are homogeneous, it is meant that the active ingredient is evenly distributed throughout the composition so that the composition may be readily subdivided into equally effective standard dosage forms, such as tablets, pills and capsules. Then this pre-prepared composition is divided into standard dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical standard dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of active ingredient. The tablets or pills of the new compositions can be coated or otherwise compounded to provide a dosage form that provides the advantage about alicelove actions. For example, the tablet or pill may include internal dosing component and the outer component dosing, the latter presented in the form of a shell around the first. These 2 components can be separated intersolubility layer, which serves to counteract the destruction in the stomach and allow the inner component to pass unchanged in the 12-duodenum or released with a delay. A variety of materials can be used for such intersolubility layers or coatings, such materials include a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the new compositions of the present invention can be included for oral administration or by injection include aqueous solutions, capsules filled with liquid or gel, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as oil of cotton seeds, sesame oil or coconut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic and natural resins, such as tragakant, acacia, alginate, dextran, carboxymethylcellulose intothree is, methylcellulose, poly(ethylene glycol), poly(vinyl pyrrolidone) or gelatin.

The present invention also provides a compound of formula Ia or pharmaceutically acceptable salt for use in the method of treatment of the human body. Preferably the treatment is carried out regarding the condition associated with the deposition of β-amyloid. Preferably the condition is a neurological disease associated with deposition β-amyloid, such as Alzheimer's disease.

The present invention also provides the use of compounds of formula I or its pharmaceutically acceptable salts in the manufacture of a medicine for treatment or prevention of Alzheimer's disease.

Also disclosed is a method of treatment of an individual suffering from Alzheimer's disease or prone to its development, which includes the introduction to this individual an effective amount of compounds in accordance with the present invention, or its pharmaceutically acceptable salt.

For treatment or prevention of Alzheimer's disease a suitable dosage level is about 0.01 to 250 mg/kg/d, preferably from about 0.05 to 100 mg/kg/d, preferably from about 0.1 to 50 mg/kg body weight/d, and for the most preferred compounds of from about 0.1 to 20 mg/kg body weight/d Compound can be administered in CX is IU 1-4 times/D. However, in some cases, you can apply a dose outside this range.

A preferred method of preparing compounds of the formula I, in which R3different from N, includes alkylation of compounds (1) R3a-L with subsequent cleavage of the N-protective group:

where R3ais an R3that is H, L is a leaving group such as halide (in particular, bromide or iodide), mesilate, toilet or triflate, Prt represents a protective group such as para-methoxybenzyl, and Ar1and Ar2have the same meanings as previously. The alkylation takes place in an aprotic solvent (such as THF) in the presence of a strong base (such as bis(trimethylsilyl)amide lithium) at low temperature (for example, -78°). When Prt is a para-methoxybenzyl, cleavage may be effected by treatment with an acid, for example triperoxonane acid, at ambient temperature in an inert solvent such as dichloromethane.

A preferred method of preparing compounds (1) involves cyclization of the sulfonamides (2):

where Ar1, Ar2and Prt have the same meanings as before, and Rais1-6alkyl, which optionally bear up to 3 halogen substituents (is aka as F or Cl), or phenyl, which optionally bears up to 3 substituents selected from halogen and C1-4the alkyl. Examples of the groups represented by Rainclude methyl, CF3, phenyl and para-tolyl, of which the preferred methyl. The cyclization can be carried out by treatment of a strong base such as sodium hydride, in an aprotic solvent such as DMF, at a moderately elevated temperature (e.g., about 75°).

Compound (2) can be obtained by the interaction of sulphonylchloride (3) with PrtNH2:

where Ra, Ar1, Ar2and Prt have the same meanings as before. The reaction can be carried out in an inert solvent, such as dichloromethane, at about 0°using an excess of amine.

Sulphonylchloride (3) can be obtained by the interaction of sulfonates (4) with thiourea and processing of the obtained adducts chlorine:

where Ra, Ar1and Ar2have the same meanings as before. Reaction with thiourea can be performed by boiling in ethanol under reflux, and the resulting adduct can be treated with gaseous chlorine in an aqueous solution of acetic acid.

The sulfonates (4) can be obtained by processing diols (5) RaSO2Cl or (RaSO2)2O:

where Ra, Ar1 and Ar2have the same meanings as before. The reaction can be carried out in dichloromethane at about -10°in the presence of a base such as triethylamine.

Diols can be obtained by successive treatment of ketones (6) ozone and sodium borohydride:

where Ar1and Ar2have the same meanings as before. Ozonation is usually carried out at about -78°in a mixture of dichloromethane/methanol, then add sodium borohydride when heated to the ambient temperature.

Ketones (6) is obtained by alkylation of cyclohexanone (7) allylbromide or Allilueva:

where Ar1and Ar2have the same meanings as before. The reaction can be carried out in THF at -78°in the presence of a strong base, such as hexamethyldisilazide lithium. Alternatively hexamethyldisilazide lithium may be used a product obtained by the interaction of BuLi with a chiral amine such as [S-(R*,R*)]-(-)-bis(α-methylbenzyl)amine. This provides the possibility of separating compounds (6) in homochiral form and, consequently, the synthesis of homochiral compounds of formula I. Obtaining cyclohexanone (7) described in documents WO 02/081435 and WO 04/013090.

Detailed methods for this and other methods of producing compounds of the formula I provided is received in the "Examples"section.

For specialists in this field will be obvious that certain compounds of formula I, obtained by the methods described above can be converted into other compounds corresponding to formula I, following the well-known methods of synthesis, such as alkylation, esterification, amide combination, hydrolysis, combination, mediated ORGANOMETALLIC compounds, oxidation and reduction. Such techniques can be similarly carried out on the precursor compounds of the formula I. for Example, the substituents in the aromatic groups Ar1and Ar2can be entered or mutually transformed by standard methods of synthesis carried out on the compounds of formula I, or their predecessors. For example, a chlorine atom or bromine at Ar1and Ar2can be substituted vinyl treatment vinyltrimethylsilane in the presence of tri-tert-butylphosphate, cesium fluoride and Tris(dibenzylideneacetone)diplegia(0). Ozonation of the vinyl group provides the corresponding formyl derivative, which can be transformed in a variety of ways, including oxidation to the corresponding acid, the recovery in the corresponding benzyl alcohol and the transformation into the corresponding nitrile by treatment with hydroxylamine, followed by triphenylphosphine and carbon tetrachloride.

Similarly, the connection fo the mules I, in which R3represents alkenyl, such as allyl, can be subjected to ozonation and subsequent transformation by the method described in the previous paragraph.

When they are not commercially available, the starting materials and reagents used in the above-described circuits synthesis, can be obtained by standard methods of organic synthesis to commercially available substances.

It should be understood that many of the above synthetic schemes can cause the formation of mixtures of stereoisomers. Such mixtures can be separated by conventional means such as fractional crystallization and preparative chromatography.

Certain compounds in accordance with the invention can exist as optical isomers due to the presence of one or more chiral centers, or due to the overall asymmetry of the molecule. Such compounds can be obtained in racemic form, or individual enantiomers may be obtained or enantiospecific synthesis or by separation. New connections can be, for example, is divided into the components of a mixture of enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation of the optically active acid, such as di-para-toluyl-D-tartaric acid and/or di-para-toluyl-L-tartaric acid, with subsequent fraction the second crystallization and regeneration of the free base. The new compounds can also be separated by formation of diastereoisomeric esters with subsequent chromatographic separation and subsequent removal of the fragment of the chiral auxiliary agent.

During any of the above synthetic sequence may be necessary and/or desirable to protect sensitive or reactive groups on any of the examined molecules. This can be achieved by conventional protective groups such as the groups described in the publications Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rded., 1999. Protective groups can be removed at a convenient subsequent stage using methods known in this field.

The analysis, which can be used to determine the activity level of the compounds of the present invention described in the publication WO01/70677. The preferred analysis to determine the activity described in the publication WO03/093252.

Alternative analyses described in Biochemistry, 2000, 39(30), 8698-8704.

Cm. also J.Neuroscience Methods, 2000, 102, 61-68.

Connect all of the examples of the present invention had the ED50less than 0.5 microns, typically less than 50 nm, in most cases less than 10 nm and in the preferred classes of less than 1.0 nm, at least one of the above tests.

<> The following examples illustrate the present invention. In the interests of convenience, the compounds depicted as corresponding to the formula IA, even if they are racemic. Homochiral compounds described indicating the configuration of R and S.

EXAMPLES

The intermediate connection 1

4-[(4-chlorophenyl)sulfonyl]-4-(2,5-differenl)-2-[2-(trimethylsilyl)ethoxymethyl]cyclohexanone

4-[(4-chlorophenyl)sulfonyl]-4-(2,5-differenl)cyclohexanone (WO 02/081435) (2.0 g, 5.2 mmol) in anhydrous tetrahydrofuran (10 ml) is added dropwise to a chilled solution of 0.5 M hexamethyldisilazide lithium in tetrahydrofuran (11,4 ml) at -78°C. the Mixture is stirred at this temperature for 2 h before addition of 2-(trimethylsilyl)ethoxymethylene (1.4 ml, 7.8 mmol) and the solution allow to warm to room temperature for 16 hours, the Reaction mixture was diluted with the ethyl acetate (10 ml), washed with water (10 ml) and the organic phase is separated, dried (MgSO4) and evaporated to dryness. The product was then purified on silica, elwira [9:1] hexane-ethyl acetate to obtain 1.2 g specified in the connection header.1H NMR CDCl37,38 (4H, s), 7.24 to 7,16 (1H, m), 7,12-7,06 (1H, m), 6,97-6,87 (1H, m), 3,66 (1H, DD, J=9.7 and 3.0 Hz), 3,51 is-3.45 (3H, m), 3,17-3,15 (1H, m), 3,05 are 2.98 (1H, m), 2,56-2,49 (2H, m), 2,41 to 2.35 (2H, m), 2.23 to-2,17 (1H, m,), 0,91-0,87 (2H, m) and 0.03 (9H, s).

The intermediate connection is% 2

4-[(4-triptoreline)sulfonyl]-4-(2,5-differenl)-2-[2-(trimethylsilyl)ethoxymethyl]cyclohexanone

Get as well as intermediate compound 1, from 4-[(4-triptoreline)sulfonyl]-4-(2,5-differenl)cyclohexanone (WO 02/081435), in the form of a solid substance.1H NMR CDCl37,69-to 7.59 (4H, m), 7.24 to to 7.18 (1H, m), 7,12-7,06 (1H, m), 6,93-6,86 (1H, m)to 3.67 (1H, DD, J=9.7 and 2,9 Hz), to 3.58-3,47 (3H, m), 3,20-and 3.16 (1H, m), 3.04 from are 2.98 (1H, m), 2.57 m) is 2.51 (2H, m), 2,41-of 2.38 (2H, m), 2,24-of 2.16 (1H, m), 0,91-0,87 (2H, m) and 0.03 (9H, s).

Intermediate compound 3

(R,S)-4-[(4-triptoreline)sulfonyl]-4-(2,5-differenl)-2-[2-(trimethylsilyl)ethoxymethyl]cyclohexanone

[S-(R*,R*)]-(-)-bis(α-methylbenzyl)amine (10 g, 44.4 mmol) and anhydrous lithium chloride (1,87 g of 44.5 mmol) is stirred in tetrahydrofuran (250 ml) in an atmosphere of nitrogen gas, and then cooled to -78°C and slowly treated with butyllithium (1.6 M solution in hexano, 25,9 ml). The reaction mixture allow to warm to 0°C and stirred for 30 min, then cooled to the temperature of the reaction mass to 100°With stirring for 1 h a Solution of 4-[(4-triptoreline)sulfonyl]-4-(2,5-differenl)cyclohexanone (WO 02/081435) (12.5 g, and 29.9 mmol) in tetrahydrofuran (50 ml) cooled to -78°C, is added slowly, maintaining the temperature of the reaction mass at the level of -100�B0; C. the Mixture was stirred at -100°C for 2 h, then added 2-(trimethylsilyl)ethoxymethylene (7.9 ml of 44.7 mmol), the mixture was heated to -78°and provide an opportunity to slowly heat up during the night to -12°C. the Reaction mixture was quenched with 1M citric acid solution, then extracted with ethyl acetate. The organic extracts washed with 1M citric acid, 5% sodium bicarbonate solution, dried (MgSO4), filtered and the solvent is removed. The resulting oil is purified column chromatography on silica gel, elwira 2-10% ethyl acetate: isohexane to obtain specified in the title compound as a clear oil. Yield 5 g (30%).1H NMR (400 MHz, CDCl3) δ of 7.69 (2H, d, J=8,4 Hz), 7,60 (2H, d, J=8,4 Hz), 7.23 percent-to 7.18 (1H, m), 7,15-was 7.08 (1H, m), of 6.96-6,86 (1H, m), 3,70-of 3.64 (1H, m), 3,53-of 3.48 (3H, m), 3,22-and 3.16 (1H, m), is 3.08 are 2.98 (1H, m), 2,61 is 2.51 (2H, m), 2,43-of 2.36 (2H, m), 2,25-and 2.14 (1H, m), 0,94-0,83 (2H, m)0,00 (9H, s). Chiral purity determine chiral HPLC.

Intermediate compound 4 (R,S)

(R,S)-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-differenl)-2-[2-(trimethylsilyl)ethoxymethyl]cyclohexanone

Get in the same way as the intermediate compound 3, using 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-differenl)cyclohexanone as the source material. Data of NMR, as for intermediate 1.

Example 1

2,2-dioxide (4aRS,6RS,8aSR)-6-(2,5-dif is arvanil)-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine

Stage 1

Intermediate compound 2 in isopropanol is treated with NaBH4(4 equivalent) at -40°and mix, in the course of the reaction allowing to warm to room temperature for 16 hours the Reaction is quenched with 8% aqueous citric acid solution, diluted with ethyl acetate, then the organic phase is separated, dried (MgSO4) and evaporated to dryness. Transproject purify on silica, elwira mixtures of gascan-ethyl acetate.

Stage 2

Alcohol from stage 1 in dichloromethane (100 ml) is treated with triethylamine (2 equivalents) at 0°C and stirred while adding methanesulfonanilide (1.2 equivalent). The reaction mixture allow to warm to room temperature for 1 h, washed with water, 10% aqueous citric acid and saturated aqueous hydrocarbonate sodium, then dried (MgSO4) and evaporated to dryness. The residue is filtered through silica, elwira 20% ethyl acetate in hexano getting mesilate.

This is a solid substance in dimethylformamide is treated with sodium azide (approximately 2-fold excess) and heated to 95°C for 8 hours, the Mixture is treated with water and extracted twice with ethyl acetate. The combined organic substances are washed with salt solution, dried with MgSO 4) and evaporated to dryness. The residue in tetrahydrofuran and water (10:1 vol./about.) treated with triphenylphosphine (1.2 equivalents) at room temperature for 15 min and then the mixture is heated at the boil under reflux for 4 hours the Mixture allow to cool to room temperature, and then passed through the cartridge SCX Varian Bond ElutTM. The main fraction is evaporated to obtain the primary amine.1H NMR CDCl3to 7.67-of 7.55 (4H, m), 7,09-7,00 (2H, m), 6,85-6,77 (1H, m), 3,51-and 3.16 (5H, m), 2,65-to 2.29 (4H, m), 1,76-1,71 (3H, m), 0,93-0,89 (2H, m) and 0.03 (9H, s). MS MH+550.

Stage 3

The triethylamine (175 μl, of 1.26 mmol) are added to a solution of the product of stage 2 (230 mg, 0,419 mmol) and methanesulfonamide (65 μl, 0,838 mmol) in dichloromethane (5 ml). The mixture is stirred at room temperature for 3 h, evaporated to dryness and the residue distributed between ethyl acetate and 2M hydrochloric acid. The organic layer was washed with 2M hydrochloric acid and then 4M sodium hydroxide, dried (MgSO4), filtered and the solvent is removed to obtain the desired methanesulfonamide in the form of a light yellow foam. Exit 263 mg1H NMR (400 MHz, CDCl3) δ to 7.64 (2H, d, J=8,3 Hz), 7,51 (2H, d, J=8,3 Hz), 7,05-7,02 (2H, m), 6,82-6,72 (1H, m), to 5.66 (1H, users), 3,69-3,66 (1H, m), 3,50-of 3.43 (4H, m), 2,96 (3H, s), 2,70-of 2.64 (1H, m), 2,55-to 2.42 (2H, m), 2,38-2,29 (1H, m), 2,19-2,11 (1H, m), 1,72-to 1.63 (1H, m), 1,40-1,31 1H, m)0,95-0,89 (2H, m)0,00 (9H, s).

Stage 4

The product of stage 3 (263 mg, 0,419 mmol) in dimethylformamide (5 ml) is treated with sodium hydride (60% dispersion in mineral oil, 90 mg, 2.25 mmol), the mixture is stirred at room temperature for 30 min, then add allylbromide (382 μl, 4,51 mmol), the mixture is heated to 65°C and stirred overnight. The cooled mixture was quenched with water and extracted with ethyl acetate. The organic extract was washed with water, dried (MgSO4), filtered and the solvent is removed. The residue is purified column chromatography on silica, elwira 25% ethyl acetate:75% isohexanol for deriving N-allyl in the form of a yellow foam. The output 150 mg1H NMR (300 MHz, CDCl3) δ 7,83 (2H, d, J=8,3 Hz), 7,72 (2H, d, J=8,3 Hz), 7,25-7,19 (2H, m),? 7.04 baby mortality-6,97 (1H, m), 6,16-6,07 (1H, m), 5,59 (1H, d, J=17,4 Hz), of 5.48 (1H, d, J=10.3 Hz), 4,39-4,22 (2H, m), 4,18-to 4.15 (1H, m), 3,78-to 3.73 (1H, m), 3,66-3,61 (2H, m), 3,53-of 3.48 (1H, m), to 3.02 (3H, s), 2,94-2,90 (1H, m), 2,84-2,82 (2H, m), 2,63 is 2.55 (1H, m), 2,28-of 2.21 (1H, m), 2,10-2,04 (1H, m), 1,99-of 1.92 (1H, m), 1,09-1,02 (2H, m)to 0.17 (9H, ).

Stage 5

The product of stage 4 (150 mg, 0,225 mmol) in dichloromethane process of triploidization boron (250 μl, 1,99 mmol) and after 2 h the mixture is cooled to 0°C and stirred during the addition of sodium hydroxide (2,5M). The layers are separated and the organic substances are washed with salt solution, drying the (MgSO 4) and evaporated to obtain an oil, which is subjected to azeotropic distillation with heptane to obtain alcohol (115 mg).

1H NMR (500 MHz, CDCl3) δ to 7.67 (2H, d, J=8,2 Hz), 7,53 (2H, d, J=8,2 Hz), 7,08-7,06 (2H, m), 7,11-7,05 (1H, m), 6,00-5,91 (1H, m), 5,49 (1H, d, J=and 17.2 Hz), lower than the 5.37 (1H, d, J=10.4 Hz), or 4.31-of 4.25 (1H, m), 4,20-4,10 (1H, m), 4,06-as 4.02 (1H, m), 3,88-3,81 (1H, m), 3,47-to 3.41 (1H, m), 3,40-to 3.38 (1H, m), is 2.88 (3H, s), 2,69-2,62 (1H, m), 2,55 is 2.46 (1H, m), 2,35-of 2.26 (1H, m), 2.13 and e 2.06 (1H, m), 1,95-to 1.87 (1H, m), 1.85 to about 1.75 (1H, m).

Stage 6

The alcohol from step 5 (115 mg, 0,203 mmol) and methanesulfonamide (47 μl, 0,609 mmol) in dichloromethane (5 ml) is treated with triethylamine (141 μl, 1.01 mmol) and the mixture is stirred at room temperature for 3 hours the Solvent is removed under reduced pressure and the residue distributed between ethyl acetate and 2M hydrochloric acid. The organic fraction is separated, washed with 2M hydrochloric acid and then 4M sodium hydroxide, dried (MgSO4), filtered and the solvent is removed by azeotropic distillation with toluene to remove traces of ethyl acetate, to obtain nelfinavir in the form of a white foam. The output 130 mg.

Stage 7

Mesilate with stage 6 (130 mg, 0,202 mmol) in tetrahydrofuran (5 ml) at -30°C in an atmosphere of gaseous nitrogen is treated with butyllithium (1.6 M solution in hexano, 252 μl) and the reaction mixture is allowed the opportunity m Glenna to warm to room temperature, then quenched with water and extracted with ethyl acetate. The organic extract was washed with water, dried (MgSO4), filtered and evaporated. The residue is purified column chromatography on silica gel, elwira 25% ethyl acetate:75% isohexane to obtain the desired cyclic sulfonamida in the form of a white powder. Yield 15 mg (14%).

1H NMR (500 MHz, CDCl3) δ to 7.67 (2H, d, J=8.1 Hz), 7,53 (2H, d, J=8.1 Hz), 7,12-7,06 (2H, m), 6,88-6,77 (1H, m), 6,07 is 5.98 (1H, m), 5,28 (1H, DD, J=0,5 and 17.6 Hz) 5,23 (1H, DD, J=0.5 and 10.5 Hz), to 4.41-or 4.31 (1H, m), 3,71-3,61 (1H, m), 3,28-3,20 (1H, m), 3,10-to 3.02 (1H, m), 2.91 in is 2.80 (1H, m), 2,56 was 2.25 (5H, m), 1,98-1,90 (1H, m), 1,81-of 1.66 (1H, m), 1,45-of 1.30 (2H, m).

Stage 8

The product of stage 7 (12 mg, of 0.022 mmol) in toluene (2 ml) is treated with [1,3-bis(diphenylphosphino)propane]dichlorsilane (II) (1.2 mg, 0,0022 mmol), then the hydride of diisobutylamine (1.5 M solution in toluene, 30 ml). The mixture is stirred at room temperature for 3 h, then quenched with 4 M sodium hydroxide and extracted with ethyl acetate. The organic extracts are dried (MgSO4), filtered through a layer of silica gel, elwira with ethyl acetate, and evaporated to dryness. The residue is ground to powder in a simple diethyl ether and the solid is separated, getting mentioned in the title compound as a white solid. Yield 6 mg (55%).

1H NMR (500 MHz, CDCl3) δ to 7.67 (2H, d, J=8.1 Hz), 7,53 (2H, d, J=8.1 Hz), 7,12-7,07 (2H, m), 6.90 to-is 6.78 (1H, m), 4,45-4,37 (1H, m), 3,76-3,71 (1H, m), 3,20-3,11 (1H, m), 3,10-304 (1H, m), 2,71-2,61 (1H, m), 2,55-to 2.42 (2H, m), 2.40 a-to 2.29 (1H, m), 2,10-to 1.98 (1H, m), 1,91-of 1.84 (1H, m), 1,72 is 1.60 (2H, m), 0,98-of 0.91 (1H, m), m/z (ES-) (M-1) 508.

Example 2

2,2-dioxide (3S,4aR,6R,8aS)-6-(2,5-differenl)-3-ethyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine

Stage 1

Intermediate compound 3 (830 mg, 1,29 mmol) is treated as described in example 1, stages 1-7, for obtaining chiral N-arylsulfonamides in the form of a white solid. Yield 300 mg (42%).

1H NMR (500 MHz, CDCl3) δ to 7.67 (2H, d, J=8.1 Hz), 7,53 (2H, d, J=8.1 Hz), 7,12-7,06 (2H, m), 6,88-6,77 (1H, m), 6,07 is 5.98 (1H, m), 5,28 (1H, DD, 70,5, and 17.6 Hz), 5,23 (1H, DD, J=0.5 and 10.5 Hz), to 4.41-or 4.31 (1H, m), 3,71-3,61 (1H, m), 3,28-3,20 (1H, m), 3,10-to 3.02 (1H, m), 2.91 in is 2.80 (1H, m), 2,56 was 2.25 (5H, m), 1,98-1,90 (1H, m), 1,81-of 1.66 (1H, m), 1,45-of 1.30 (2H, m).

Stage 2

The product of stage 1 (80 mg, 0,146 mmol) in tetrahydrofuran (5 ml) at 0°treated With bis(trimethylsilyl)amidon lithium (1M solution in tetrahydrofuran, 292 μl) and the mixture was stirred at 0°C for 30 min before adding iodata (15 μl, 0,188 mmol). The obtained mixture is allowed the opportunity to slowly warm up over night, quenched with water, then extracted with ethyl acetate. The organic extracts are dried (MgSO4), filtered and the solvent is removed. The residue is purified column chromatography on silica gel, elwira 10-15% ethyl is Zetta:isohexane with getting less polar product (white solid, yield 28 mg, 33%):

1H NMR (500 MHz, CD3OH) δ 7,81 (2H, d, J=8,3 Hz), 7,66 (2H, d, J8,3 Hz), 7.24 to to 7.15 (2H, m), 7,02-6,93 (1H, m), 6,04-to 5.93 (1H, m), 5,32 (1H, d, J=and 17.2 Hz), 5,19 (1H, d, J=10.1 Hz), 4.26 deaths (1H, DD, J=5.1 and 17.2 Hz), of 3.77 (1H, DD, J=7,0 and 17.2 Hz), 3,54 (1H, users), 3,16-3,11 (1H, m), 2,83 of 2.68 (1H, m), 2,61-2,39 (2H, m), 2,33-2,02 (2H, m), 2,08-of 1.85 (2H, m), 1,55 of 1.28 (3H, m), 1,11-and 0.98 (3H, m), 0,93-of 0.82 (1H, m);

as well as the more polar product (white solid, yield 23 mg, 27%):

1H NMR (500 MHz, CD3OH) δ 7,83 (2H, d, J=8,3 Hz), 7,66 (2H, d, J=8,3 Hz), 7.24 to 7,14 (2H, m),? 7.04 baby mortality-6,94 (1H, m), of 5.92-of 5.81 (1H, m), of 5.24 (1H, DD, J=1.1 and 17,2 Hz), 5,13 (1H, DD, J=1,1 and 10.3 Hz), 4,13-of 4.05 (1H, DD, m in), 3.75 (1H, DD, J=6,8 and 16.7 Hz), 3,59-of 3.53 (1H, m), 3.00 and-of 2.93 (1H, m), 2,70 is 2.55 (2H, m), 2,48-2,22 (4H, m), 2,13-2,03 (1H, m), 1.93 and-of 1.85 (1H, m), 1,75-of 1.66 (1H, m), 1,59 to 1.47 (1H, m), 1,17-of 1.07 (3H, m), 0,95-0,84 (1H, m).

Stage 3

The less polar product from step 2 (25 mg, 0,0433 mmol) is treated as described in example 1, step 8 to obtain the desired chiral sulfonamida in the form of a white solid. Yield 20 mg (86%).

1H NMR (500 MHz, CD3OH) δ of 7.82 (2H, d, J=8,2 Hz), to 7.64 (2H, d, J=8,2 Hz), 7.23 percent-was 7.08 (2H, m), 7,01-6,93 (1H, m), 3,57-to 3.52 (1H, m), 3,06 are 2.98 (1H, m), 2,75-of 2.56 (2H, m), of 2.51-is 2.37 (2H, m), 2.00 in at 1.91 (2H, m), 1,90-to 1.82 (1H, m,), 1,74-of 1.55 (2H, m)and 1.51-of 1.42 (1H, m), 1,23-1,20 (1H, m), 1,15-of 1.07 (3H, m), 0,97-0,84 (1H, m), m/z (ES-) (M-1) 536.

Example 3

2,2-dioxide (3R,4aR,6R,8aS)-6-(2,5-differenl)-3-ethyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine

The more polar isomer from example 2, stage 2 (3 mg, 0,0433 mmol) is treated as described in example 1, step 8 to obtain the desired chiral sulfonamida in the form of a white solid. Yield 10 mg (46%).

1H NMR (500 MHz, CD3OH) δ to 7.84 (2H, d, J=8,2 Hz), the 7.65 (2H, d, J=8,2 Hz), 7,27-was 7.08 (2H, m),? 7.04 baby mortality-6,94 (1H, m), 3,62 is 3.57 (1H, m), 2,93-of 2.86 (1H, m), of 2,75 2,63 (1H, m), 2,56-2,49 (2H, m), 2,48-to 2.41 (1H, m), 2,40 of-2.32 (1H, m,), 2,17-2,07 (1H, m), 2.00 in of 1.93 (1H, m), 1,91-of 1.84 (1H, m), 1,79 is 1.70 (1H, m), 1,68-of 1.55 (1H, m), 1.32 to 1,25 (1H, m), 1,20-to 1.14 (3H, m), 0,98-0,85 (1H, m), m/z (EC-) (M-1) 536.

Example 4

2,2-dioxide (3RS,4aRS,6RS,8aSR)-6-(2,5-differenl)-3-isopropyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine

Stage 1

The product from example 1, stage 2 is treated with ether complex of boron TRIFLUORIDE as described in example 1, stage 5. The resulting alcohol (2 g, 3.1 mmol) in dichloromethane (25 ml) is treated with triethylamine (1.7 ml, 12.4 mmol), 4-dimethylaminopyridine (with catalyst) and tert-butyldimethylsilyl (1,16 g of 7.75 mmol). After 16 h the mixture was washed with 10% citric acid (10 ml), sodium bicarbonate (saturated, 20 ml) and salt solution (saturated, 15 ml). Organic matter is dried (MgSO4) and evaporated and the residue is filtered through silica, elwira 1% ammonia in ethyl acetate to obtain the desired simple tert-butyldimethylsilyl ester as a white solid (1.8 g)MS ES+564.

Stage 2

Simple silloway ester from step 1 (1.8 g, 3.2 mmol) and isobutyrophenone (1.12 g, 8 mmol) is stirred in dichloromethane (20 ml) and add triethylamine (of 1.34 ml, 9.5 mmol). After stirring at room temperature for 16 h the mixture is evaporated to dryness and the residue distributed between ethyl acetate and 2M hydrochloric acid. The organic layer is separated, washed with 2M hydrochloric acid, and then 4M sodium hydroxide, dried (MgSO4), filtered and the solvent is removed in vacuum. The residue is purified column chromatography (elwira 20% ethyl acetate in hexano) to obtain sulfonamida (900 mg). The product is dissolved in dimethylformamide (6 ml) and add sodium hydride (60% dispersion in mineral oil, 132 mg, 3.3 mmol). The mixture is stirred at room temperature for 30 min, add allylbromide (1.1 ml, 13 mmol), the mixture is then heated to 65°within 72 hours After cooling to room temperature and quenching with water the mixture is extracted with ethyl acetate. The organic extract was washed with water, dried (MgSO4), filtered and the solvent is removed. The residue is purified column chromatography on silica gel, elwira 20% ethyl acetate:80% of isohexane to obtain the N-allyl derivative (400 mg).1H NMR (360 MHz, CDCl3) δ to 7.67 (2H, d, J=8,3 Hz), 7,52 (2H, d, J8,3 Hz), 7,10-7,05 (2H, m), 6,85-6,79 (1H, m), 5,96-5,91 (1H, m), the 5.45 (1H, d, J=17.3 Hz), of 5.34 (1H, d, J=10.4 Hz), 4,22-4.09 to (1H, m), 4,01-3,98 (1H, m), 3,86-3,81 (1H, m), 3,51 is 3.40 (2H, m), 2,88-2,63 (4H, m), 2,49-2,43 (1H, m), 2,32-of 2.24 (2H, m), 2,09-2,04 (1H, m), 1,95-1,72 (2H, m) and 1,11-of 1.03 (6H, m).

Stage 3

Obtained from the product of step 2 (0.2 g) and para-toluensulfonate (3 equivalent) in pyridine in the presence of 4-dimethylaminopyridine (0.3 equivalent) at 40°C. After extraction, purification column chromatography on silica elution 30% ethyl acetate in hexano gives toilet (185 mg).

Stage 4

Toilet from stage 3 (186 mg, 0.24 mmol) in tetrahydrofuran (9 ml) at -40°C in nitrogen atmosphere is treated with hexamethyldisilazide lithium (1.0m solution in tetrahydrofuran, 480 μl) and the reaction mixture is allowed the opportunity to slowly warm to room temperature, then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic extract was washed with water, dried (MgSO4), filtered and the solvent is removed. The residue is purified column chromatography on silica gel, elwira 15% ethyl acetate:85% isohexane for the more polar product as a white solid (48 mg):

1H NMR (500 MHz, CDCl3) δ 7,66 (2H, d, J=8 Hz), 7,52 (2H, d, J=8 Hz), 7,11-7,07 (1H, m), 6,93 to 6.75 (2H, m), 6,06-5,96 (1H, m), from 5.29 with 5.22 (2H, m), to 4.41-to 4.33 (1H, m), 3,69-of 3.48 (2H, is), 3,07-to 2.99 (1H, m), 2,89-of 2.72 (1H, m), 2,61-of 2.20 (5H, m), 1,90-of 1.73 (2H, m), 1,48-of 1.30 (2H, m)of 1.17 (3H, d, J=7 Hz) and 1.05 (3H, d, J=7 Hz);

as well as the more polar product as a white solid (67 mg):

1H NMR (500 MHz, CDCl3) δ the 7.65 (2H, d, J=8 Hz), 7,54 (2H, d, J=8 Hz), 7,07-7,03 (2H, m), 6,86-of 6.78 (1H, m), 5,75-the 5.65 (1H, m), 5,04-4,99 (2H, m), of 3.95 (1H, DD, J=15.5 and 4.5 Hz), 3,63 (1H, DD, J=15.5 and 6.5 Hz), 3,29-3,24 (1H, m,), was 2.76-of 2.72 (1H, m), 2,61-2,52 (4H, m), 2,49-to 2.42 (1H, m), 2.40 a-to 2.18 (3H, m), 2,09 is 2.00 (1H, m), 1,75 by 1.68 (1H, m)of 1.17 (3H, d, J=6,8 Hz) and 1.09 (3H, d, J=6,8 Hz).

Stage 5

The less polar product from stage 4 (40 mg, 0,067 mmol) is treated as described in example 1, step 8 to obtain specified in the title compound as a white solid (23 mg).1H NMR (500 MHz, CDCl3) δ to 7.67 (2H, d, J=8,3 Hz), 7,53 (2H, d, J=8.0 Hz), 7,25-to 6.88 (2H, m), 7,11-7,06 (1H, m), 4,68-4,50 (1H, users), 3,69-3,68 (1H, m), 3.00 and-2,96 (1H, m), 2.71 to to 2.65 (1H, m), 2,60-of 2.27 (3H, m), 2,18 and 2.13 (1H, m), 2,02-to 1.87 (2H, m), 1,80-of 1.52 (3H, m)to 1.22 (3H, d, J=6.9 Hz), with 1.07 (3H, d, J=6.9 Hz), m/z (EC-) (M-1) 550.

Example 5

2,2-dioxide (3SR,4aRS,6RS,8aSR)-6-(2,5-differenl)-3-isopropyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine

Repeat stage 5 of example 4, using the more polar isomer from stage 4 (40 mg, 0,067 mmol) to obtain the heading compound as white solid (23 mg).1H NMR (500 MHz, CDCl3) δ to 7.68 (2H, d, J=8,3 Hz), 7,54 (2H, d, J=8,2 Hz), 7,10-7,06 (2H, m), 6.87 in-PC 6.82 (1H, m), 4,47 (1H, d, J=8,9 Hz), 3,60 is 3.57 (1H,m), 2,82-2,77 (1H, m), 2.71 to 2,52 (2H, m), 2,40-of 2.20 (4H, m)to 1.98 (1H, DD, J=15.1 and 2 Hz), 1,81-to 1.77 (2H, m), 1,76-of 1.74 (1H, m)of 1.26 (3H, d, J=6.4 Hz), is 1.11 (3H, d, J=6.8 Hz), m/z (EC-) (M-1) 550.

Example 6

2,2-dioxide (3S,4aR,6R,8aS)-6- [(4-(chlorophenyl)sulfonyl]-6-(2,5-differenl)-3-atelectasia-1H-2,1-benzothiazine

Stage 1

Intermediate compound 4 is treated as described in example 1, stage 1 and 2. The resulting product (80% EE) (3.6 g, of 6.96 mmol) was dissolved in ISO-propanol (34 ml) and added (1S)-(+)-camphorsulfonic acid (1,37 g, 5,91 mmol). The mixture is refluxed allow to slowly cool to room temperature, and then leave in the fridge overnight. The obtained solid substance was separated, washed with pre-chilled isopropanol, then suspended in ethyl acetate and washed with 4M sodium hydroxide. Organic matter is dried (MgSO4), filtered and the solvent is removed to obtain a chiral amine (98% EE). Exit 3,1H NMR CDCl37,39-7,31 (4H, m), 7,09-of 6.96 (2H, m), 6,85-to 6.80 (1H, m), 3,48 is 3.15 (5H, m), 2,93-to 2.29 (4H, m), 1,74-1,19 (3H, m), 0,93-0,89 (2H, m) and 0.03 (9H, s). MS MH+516(518).

Stage 2

Amin from stage 1 (3 g) is treated as described in example 1, stage 3-8, to obtain the desired homochiral sulfonamida (60 mg).

1H NMR (500 MHz, CD3OH) δ 77,51 (2H, d, J=8.7 Hz), 7,40 (2H, the, J=7.9 Hz), 7,25-7,11 (2H, m),? 7.04 baby mortality-6,94 (1H, m), 3,55-3,51 (1H, m), 3,03-of 2.97 (1H, m), 2,75 of-2.32 (4H, m), 2,17-2,07 (1H, m), 2,01-of 1.93 (2H, m), 1,91-of 1.84 (1H, m), 1,75-of 1.57 (2H, m), 1,50-of 1.44 (1H, m) and a 1.11 (3H, t, J=7,6 Hz).

Example 7

2,2-dioxide (3S,4aR,6R,8aS)-6-(2,5-differenl)-3-ethyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine

an alternative way

Stage 1

A solution of (1S)-1-phenyl-N-[(1S)-1-phenylethyl}of ethanamine (10.8 g, 47,85 mmol) and kiln dried lithium chloride (3.0 g, 71,80 mmol) in tetrahydrofuran (200 ml) Tegaserod in nitrogen atmosphere. The reaction mixture was cooled to -78°With (reaction mass) and treated with n-butyllithium (1.6 m in hexane, 30 ml, 47,85 mmol) dropwise within 25 minutes After the addition, the reaction mixture was heated to -20°and then cooled to -100°C and stirred for 2 hours a Solution of 4-(2,5-differenl)-4-[[4-(trifluoromethyl)phenyl]sulfonyl]cyclohexanone (20 g, 47,85 mmol) in tetrahydrofuran (100 ml) (cooled to -78° (C) kanyoro in the reaction vessel within 20 minutes after Another 30 min at -100°With add allergodil (8,80 ml, 95,60 mmol) and the reaction mixture was allow to warm to room temperature for 18 hours, the Reaction mixture is acidified with citric acid solution (200 ml) and diluted with ethyl acetate (300 ml). The ethyl acetate layer was separated and again washed with a solution of lemon sour is s (200 ml), 10% solution of ammonia (200 ml), a solution of salt, dried over MgSO4, filtered and evaporated in vacuum. Purification of column chromatography gives specified in the title compound as a white solid (8,97 g, 41%, 70% EE). The solution of this substance (7,31 g, 61% EE) in toluene (181 ml) is added in drops to isohexane (760 ml), stirring at 70°C for 45 min In the reaction mixture make a seed crystal racemic product (100 mg) and slowly cooled for 2.5 hours resulting solid substance was filtered and the filtrate is evaporated in vacuum, obtaining a transparent resinous oil (49 g, 95% EE).

Stage 2

Oxygen is bubbled through a stirred solution of the product of stage 1 (67,8 g, 148 mmol) in dichloromethane (750 ml) and methanol (150 ml) at -78°C for 10 min Ozone bubbled into the reaction mixture until then, still blue staining (3.5 hours), followed by bubbling of oxygen and then nitrogen until then, until the blue color disappears. To the reaction mixture is added sodium borohydride (14 g, 370 mmol), then give her the opportunity to slowly warm to room temperature. The mixture is acidified with citric acid solution (200 ml) and 2 N. hydrochloric acid to achieve pH 2 and diluted with dichloromethane (800 ml). The dichloromethane layer is separated and washed with water, salt solution, dried over MgO 4, filtered and evaporated in vacuum. Purification by recrystallization from ether and isohexane (50:50) to give diol as a white solid (50 g, 73%, 97% EE).

Stage 3

Methanesulfonanilide (20 ml, 259 mmol) is added slowly to a solution of the product of stage 2 (50 g, 108 mmol) in dichloromethane (700 ml) and triethylamine (45 ml, 324 mmol), stirring at -10°C. the Reaction mixture is stirred at -10°C for 2 h, the Reaction mixture is acidified with citric acid solution (500 ml) and diluted with dichloromethane (500 ml). The dichloromethane layer is separated and washed with sodium hydrogen carbonate solution (500 ml), a solution of salt, dried over MgSO4, filtered and evaporated in vacuum to obtain bis-nelfinavir in the form of a white foam in (6.67 g, >100%), which is used without further purification.

Stage 4

A solution of the product of stage 3 (67,7 g, 109 mmol) in ethanol is treated with thiourea (8.7 g, 115 mmol). The reaction mixture was stirred at 80°C for 18 h, cooled to room temperature and evaporated in vacuo to obtain the desired product as a pale yellow foam (80,6 g, >100%).

Stage 5

Acetic acid (500 ml) was added to a solution of the product of stage 4 (80,7 g) in water (100 ml) at room temperature. Gaseous chlorine (PR is approximately 55 g) bubbled into the reaction mixture for 30 min until until the reaction mixture becomes dark yellow. The reaction mixture was diluted with diethyl ether (1000 ml) and water (1000 ml). The ether layer is separated and washed with another portion of water (1000 ml), a solution of sodium sulfite (500 ml), a solution of sodium bicarbonate (CH ml), dried over MgSO4, filtered and evaporated in vacuum to obtain sulphonylchloride in the form of a white foam (65,7 g, >100%).

Stage 6

4-Methoxybenzylamine (35 ml, 263 mmol) is added dropwise over 10 min to a solution of the product of stage 5 (65,7 g, 105 mmol) in dichloromethane (500 ml), stir at 0°C in nitrogen atmosphere. The reaction mixture is heated to room temperature over 90 min, diluted with dichloromethane (500 ml) and acidified with citric acid solution (500 ml). The dichloromethane layer is separated and washed with salt solution, water (700 ml), dried over MgSO4, filtered and evaporated in vacuum. Purification of column chromatography gives specified in the header of the intermediate compound as a pale brown foam (59.3 g, 88% in stage 4).

Stage 7

Sodium hydride (4,90 g, 127 mmol) are added to a solution of the product of stage 6 (59.3 g, 82 mmol) in dimethylformamide (700 ml). After stirring at room temperature for 10 min, the reaction mixture was heated to 75°C. After 2 h the reaction is mesh cooled to room temperature, acidified with citric acid solution (500 ml) and diluted with ethyl acetate (800 ml). The ethyl acetate layer was separated, washed with water (I ml), a solution of salt, dried over MgSO4, filtered and evaporated in vacuum. Purification of column chromatography gives cyklinowanie intermediate compound as a white solid (28,7 g, 56%).

Stage 8

Bis(trimethylsilyl)amide lithium (1M in THF, 114 ml, 114 mmol) is added dropwise to a solution of the product of stage 7 (28,7 g of 45.5 mmol) in tetrahydrofuran (300 ml), stirring at -2°With (reaction mass). The reaction mixture was stirred for 1 h at 0°C in nitrogen atmosphere, then cooled to -78°and treat ethyliodide (4,7 ml, a 59.2 mmol). The reaction mixture is stirred at -25°C for 18 h, then heated to -8°and then to room temperature for 2 hours, the Reaction mixture was diluted with ethyl acetate (500 ml), water (500 ml) and acidified with citric acid solution (500 ml). The ethyl acetate layer is separated and the aqueous layer was extracted with ethyl acetate (CH ml). The organic fractions combined, washed with salt solution, dried over MgSO4, filtered and evaporated in vacuum. Purification of column chromatography gives alkilirovanie intermediate compound as a white foam (23.1 g, 77%).

Stage 9: 2,2-dioxide (3S,4aR,6R,8aS)-6-(2,5-differenl)-3-ethyl-6{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine

A solution of the product of stage 8 (23.1 g) in dichloromethane (115 ml) is treated triperoxonane acid (60 ml) dropwise over 5 min and stirred at room temperature under nitrogen atmosphere for 30 minutes, the Reaction mixture is evaporated in vacuum and purified column chromatography, getting listed in title product as a white foam (17 g, 90%, 98.5% of ei).

White foam (17 g, 98.5% of ei) is dissolved in ethyl acetate (34 ml) and heated to 70°C. Heptane (136 ml) is added in portions to the stirred solution under nitrogen atmosphere. After 2 h the reaction solution make seed homochiral sample specified in the connection header and stirred for another 1 h, and then cooled to room temperature. The obtained white matter allocate filtering (12 g, 99.5% of ei).

1H NMR δ (ppm) (CDCl3): to 7.67 (2 H, d, J=8,3 Hz), 7,56 (2H, s), 7,11-7,07 (1H, m), 6,98-6,83 (2H, m), 4,71-4,58 (1H, m), 3,68 (1H, s), 3,12 (1H, q, J=9.8 Hz), 2,73 (1H, t, J=13.5 Hz), 2,54-to 2.40 (3H, m), 2,17 is 1.91 (4H, m), 1,65-to 1.48 (3H, m)to 1.14 (3H, t, J=7.5 Hz).

1. The compound of the formula I:

where communication, indicated by wavy lines represent mutually CIS - against cyclohexane ring;

R3represents H or a hydrocarbon group having up to 10 carbon atoms;

Ar1and Ar2independently represent f the Nile, which bears 0-3 substituent, independently selected from halogen, CF3, CHF2,

or its pharmaceutically acceptable salt.

2. The compound according to claim 1 corresponding to formula IA or IB

R3represents H or a hydrocarbon group having up to 10 carbon atoms;

Ar1and Ar2independently represent phenyl which bears 0-3 substituent, independently selected from halogen, CF3, CHF2,

or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or 2, where Ar1represents 4-chlorophenyl or 4-triptoreline, and Ar2is a 2.5-differenl.

4. The connection according to claim 1 or 2, where R3represents H or a hydrocarbon group having up to 6 carbon atoms.

5. The compound according to claim 4, where R3represents H, methyl, ethyl, n-propyl, isopropyl or allyl.

6. The compound according to claim 5, selected from

2,2-dioxide (4RS,6RS,8SR)-6-(2,5-differenl)-6-{[4-(trifter-methyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine;

2,2-dioxide (3S,4R,6R,8S)-6-(2,5-differenl)-3-ethyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine;

2,2-dioxide (3R,4R,6R,8S)-6-(2,5-differenl)-3-ethyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine;

2,2-dioxide (3RS,4R,6RS,8SR)-6-(2,5-differenl)-3-isopropyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine;

2,2-dioxide (3SR,4RS,6RS,8SR)-6-(2,5-differenl)-3-isopropyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine and

2,2-dioxide (3S,4aR,6R,8aS)-6-[(4-(chlorophenyl)sulfonyl]-6-(2,5-differenl)-3-atelectasia-1H-2,1-benzothiazine;

and their pharmaceutically acceptable salts.

7. Pharmaceutical composition for use as an inhibitor of gamma-secretase comprising the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. The use of compounds according to any one of claims 1 to 6 for the manufacture of a medicine for treatment or prevention of Alzheimer's disease.

9. The method of obtaining the compounds of formula I defined in claim 1, which includes stages:

(a) the cyclization of the compounds of formula (2)

processing a strong base in an aprotic solvent to form the compounds of formula (I)

(b) optional alkylation of the compounds of formula (1) R3a-L and

(c) removing the N-protective group;

where Prt is a protective group, L represents a leaving group, R3ais an R3that is different from the N, Rarepresents a C1-4alkyl, which optionally bear up to 3 halogen substituents, or phenyl, which optionally is ESET to 3 substituents, selected from halogen and C1-4the alkyl and Ar1, Ar2and R3defined in claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

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

10 cl, 4 tbl, 26 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention proposes use of 2-amino-7-bromo-4-acetylazo[5,4-b]indol depicted by formula: against hyperbaric and hematic hypoxia and protection of liver against carbon tetrachloride poisoning. Use of this compound reduces concentration of AlAT by a factor of 2.6 and that of AcAT by a factor of 1.67.

EFFECT: increased therapeutic activity.

3 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

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

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds of formula I , or stereoisomers, or pharmaceutically acceptable salts thereof, wherein Q is SO2; n = 2 or 3; each R1 and R2 is independently H, halogen, OR22 or C1-C6-alkyl; each R3 and R4 is H; each R5 and R6 is independently H or C1-C6-alkyl optionally substituted with phenyl or R5 and R6 together with together with atom to which they are attached may form 5-7-membered ring optionally containing N as the second heteroatom optionally substituted with COOH or C1-C6-alkyl; R7 is H; R7 is optionally substituted 8013-membered bicyclic or tricyclic ring system, containing N in bridge bond and optionally 1, 2 additional heteroatoms selected from N, S wherein substituent represent 1 or 2 halogen atoms; R22 is H or C1-C6-phenyl optionally substituted with C1-C6-alkyl. Compounds of present invention specifically bond to 5-HT6 receptor and are useful in pharmaceutical compositions.

EFFECT: compounds with specific bonding to 5-HT6 receptor.

10 cl, 3 tbl, 45 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula I and pharmaceutically acceptable salt thereof, wherein R1, R3, R4, R5, and R10 are independently H, halogen, C1-C4-alkyl, etc.; R2 is H, halogen, NO2, etc.; R6 is H, C1-C6-alkyl, C1-C6-alkoxy-substituted C1-C4-alkyl, etc.; R7 is H, C1-C4-alkyl or C2-C4-alkenyl, optionally substituted with halogen; R8 and R9 are H, R11 and R12; meanings of the rest substituents are as define in specification.

EFFECT: new compounds with value biological properties and useful as drug having activity in relates to progesterone receptor.

15 cl, 3 tbl, 80 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to bicyclic 1,4-piridotiazine-1,1-dioxides of general formula I wherein R1 is chlorine or fluorine; R2 is linear or branched alkyl, cycloalkyl, optionally reduced aryl or heteroaryl, etc. Method for production of said compounds includes reaction of acyclic sulfones with primary alcohols, preferably in presence of inorganic or organic such as carbonates or alkali metal hydroxides tertiary organic amines or base mixtures, preferably in aprotic bipolar media without solvents, or mixture thereof with water.

EFFECT: safe method for production of new compounds useful as drugs.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 2-cycloalkylimino-5-(4-nitrophenyl)-1,3,4-thiadiazines of the general formula (I): wherein the group represents: piperidino-, pyrrolidino-, methylpiperazino-, hexamethyleneimino-group that possess the biological activity against smallpox virus. Invention provides preparing novel biological active compounds possessing an antiviral effect, in particular, against smallpox virus.

EFFECT: valuable biological and medicinal properties of compounds.

1 cl, 1 tbl, 4 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that are able to modulate the pharmacological response of one or some opioid receptors taken among ORL-1 and μ-receptors. Invention describes a compound of the formula (I): wherein W represents hydrogen atom, (C1-C10)-alkyl, (C1-C4)-alkyl-SO2N(V1)2, cyano-(C1-C10)-alkyl, (C1-C4)-alkyl-CON(V1)2, -NH2-SO2-(C1-C4)-alkyl-, (C1-C4)-alkyl-COOV1 wherein all V1 represent (C1-C6)-alkyl; Q represents a 6-membered aromatic group; n represents a whole number from 0 to 3; n' represents a whole number 0 or 1; A, B and C represent hydrogen atom; Z is taken among the group including a bond, linear or branched (C1-C6)-alkylene; R1 is taken among the group including hydrogen atom, (C1-C10)-alkyl, (C3-C12)-cycloalkyl, (C2-C10)-alkylene, (C3-C12)-cycloalkylamino-group, benzyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl wherein indicated alkyl, cycloalkyl, alkenyl, (C3-C12)-cycloalkylamino-group or benzyl are optionally substituted with substitutes taken among the group including (C1-C10)-alkyl, phenyl, benzyl, benzyloxy-group wherein indicated phenyl, benzyl and benzyloxy-group are substituted optionally with (C1-C10)-alkyl and indicated (C3-C12)-cycloalkyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl are substituted optionally with 1-3 substitutes taken among the group including (C1-C10)-alkyl and benzyl wherein indicated benzyl is substituted optionally with (C1-C10)-alkyl; R2 represents hydrogen atom and under condition that when n' = 0 then ZR1 doesn't means hydrogen atom (H), or to its pharmaceutically acceptable salt or solvate. Also, the invention describes a pharmaceutical composition based on thereof. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 5 tbl, 8 ex

The invention relates to arylalkylamines formula (I)

< / BR>
where R1and R2each, independently of one another, denotes H or A;

R3and R4each independently of one another, denotes-OH, -OR10, -S-R10, -SO-R10, -SO2-R10, Gal, methylendioxy-group-NO2- NH2, HHR10or-NR10R11;

R5denotes unsubstituted or mono - or twice substituted with R6and/or R7phenyl residue;

Q is absent or denotes alkylene with 1-6 C-atoms;

R6and R7each, independently of one another, denotes-NH2, -NR8R9-THE OTHER10, -NR10R11, -NO2, Gal, -CN, -OA, -COOH or COOA;

R8and R9each, independently of one another, denotes H; acyl with 1 to 8 C-atoms which may be substituted by 1 to 5 fluorine atoms and/or chlorine; -COOA, -S,-A, -SO-A, -SO2A, -CONH2, -CONHA, -CONA2, -CO-COOH, -CO-COOA, -CO-CONH2, -CO-CONHA or-CO-CONA2;

A denotes alkyl with 1-6 C-atoms which may be substituted by 1 to 5 fluorine atoms and/or chlorine;

R10and R11each, independently of one another, denotes a, cycloalkyl with 3-7 C-atoms, methylanrylate logicheskie acceptable salts

The invention relates to a method for the preparation of 3-isopropyl(1H)benzo-2,1,3-thiadiazine-4-dioxide-2,2 used in agriculture as a herbicide to control weeds in crops of cereals, soybeans, corn, rice and other crops

The invention relates to new derivatives of phenylsulfonylacetate General formula (I), which are herbicide and regulating plant growth properties and can find application in agriculture

The invention relates to new heterocyclic compounds with valuable biological properties, in particular derived dioxide benzothiazine, the pharmaceutical compositions based on them having inhibitory receptor endothelin activity, and to a method of inhibiting endothelin receptor

The invention relates to organic chemistry, in particular to an improved method for the preparation of 3-alkoxycarbonyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1 - dioxides of the formula

< / BR>
where

R - CH3C2H5
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