Fluorine and trifluoralkyl-containing heterocyclic sulfonamide inhibitors of beta-amyloid formation and their derivatives

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to fluorine and trifluoralkyl-containing heterocyclic sulfonamides of general formula I , where T - CHO, COR8 and C(OH)R1R2; R1 and R2 -hydrogen, C1-6alkyl; R3 -hydrogen; R4 - (CF3)nalkyl, (CF3)nalkylphenyl, and (F)ncycloalkyl; N equals 1-2; R5 - hydrogen, halogen, dien, condensed with Y, when Y stands for C, and dien, condensed with Y, when Y stands for C and substituted with halogen; W, Y and Z - C, CR6 and N, on condition that at least one of W or Y, or Z must be C; R6 -hydrogen halogen or C1-6alkyl; X - S and NR7; R7 - C1-6alkyl; and R8 - C1-6alkyl. Also described are method of obtaining compounds I, pharmaceutical composition and application of compounds, intermediate compounds, used in synthesis.

EFFECT: obtaining compounds which can be used to inhibit beta-amyloid formation and for treatment of Alzheimer's disease.

48 cl, 5 tbl, 42 ex

 

This invention relates to a fluorine - and cryptanalytical heterocyclic sulfonamidnuyu inhibitors of the formation of beta-amyloid peptides and their derivatives, to processes for their preparation, to compositions containing them, and methods of treatment using them. In particular, such inhibitors are applicable in the treatment of Alzheimer's disease.

Background of invention

Alzheimer's disease (AD) is the most common form of dementia (memory loss) in the elderly. The main pathological changes in AD, found in the brain, are extracellular deposits of protein beta-amyloid in the form of plaques and angiopathy and intracellular neurofibrillary weave aggregate hyperphosphorylated Tau protein. Recent data show that elevated levels of beta-amyloid in the brain not only precede Tau pathology, but also correlate with cognitive impairments. In addition to the assumptions about the causal role of beta-amyloid in AD, recent studies have shown that aggregated beta-amyloid is toxic to neurons in cell culture.

Beta-amyloid protein consists mainly of peptides in the 39-42 amino acids and is derived from a larger protein precursor, called the amyloid protein precursor (APP), the sequential effects protease - and gamma-secretase. Although rare, cases of early onset AD is associated with genetic mutations in the RDA, which lead to overproduction or total beta-amyloid, or more aggregate (aggregation-prone) isoforms in 42 amino acids. In addition, people with down syndrome have an extra chromosome that contains the gene encoding the RDA, and, thus, have higher levels of beta-amyloid and later in life constantly developing AD.

Remains a need for compositions useful for inhibiting the formation of beta-amyloid and treatment effects of conditions associated with it.

Summary of the invention

These compounds are useful for treating conditions in which increased levels of beta-amyloid (e.g., AD, down's syndrome). Systemic injection of these compounds to subjects with risk of or suffering from such diseases, reduces levels of the protein beta-amyloid and subsequent reduction of toxic beta-amyloid aggregates in the brain of patients.

Unexpectedly it was found that triptorelin and fluorinated heterocyclic sulfonamides of the formula (I) possess unexpectedly good inhibitory activity against beta-amyloid. The compounds of formula (I) are characterized by high resistance to oxidation (metabolic stability phase 1) compared with the corresponding the relevant compounds not containing triptorelin or forgroup. In addition, it was found that the compounds of formula (I)identified in this description, have increased metabolic stability and half-life from blood circulation, and thus, enhanced biological activity compared to the corresponding compound not containing triptorelin or forgroup.

In addition, it was found that triptorelin - and fluorine-containing compounds of the formula (I) have an increased efficiency compared with the corresponding non-fluorinated compounds. Thus, it is expected that the compounds of the invention will be useful in lower doses than compounds of the prior art.

These and other aspects of the invention will be obvious to specialists in this field after reading the subsequent detailed description of the invention.

Detailed description of the invention

In the first aspect of the invention discloses compounds of formula (I)containing their pharmaceutical compositions and their use in the modulation of the formation of beta-amyloid in subjects with risk of or suffering from AD or other diseases resulting from elevated levels of the protein beta-amyloid in the brain. Therefore, the present invention relates to compounds of formula (I)

where T is chosen from the group consisting of Cho, COR8and C(OH)R1R2;

R1and R2independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, CF3alkenyl, substituted alkenyl, quinil and substituted quinil;

R3selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl;

R4selected from the group consisting of (CF3)nof alkyl, (CF3)n(substituted alkyl), (CF3)nalkylphenyl, (CF3)nalkyl(substituted phenyl) and (F)ncycloalkyl;

N is 1-3;

R5selected from the group consisting of hydrogen, halogen, CF3, diene fused to Y when Y represents C, and substituted diene fused to Y when Y represents C;

W, Y and Z independently are selected from the group consisting of C, CR6and N, provided that at least one of W or Y or Z must be a C;

R6selected from the group consisting of hydrogen, halogen, lower alkyl and substituted lower alkyl;

X is chosen from the group consisting of O, S, SO2and NR7;

R7selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl and substituted phenyl; and

R8selected from the group consisting whom she from lower alkyl, CF3, phenyl and substituted phenyl;

and their pharmaceutically acceptable salts and/or hydrates or prodrugs.

Of these preferred compounds is represented by the compounds in which R4represents (CF3)nalkyl, such as CF3, CF3CH2CH(CH3)CH2CF3CH(CH2CF3)2or CH(CF3)2. Other preferred representatives are compounds in which R4is a (F)ncycloalkyl, preferably (F)2cycloalkyl, more preferably (F)2cyclohexane and bicyclo[3.1.0]hexane, and most preferably 4,4-diverticles 4,4-diversitya[3.1.0]-3-hexane.

In one embodiment T is a S(HE)R1R2, R1and R2represent hydrogen, R3represents hydrogen, R4represents (CF3)2SN, preferably, R4has S-stereochemistry, R5is a halogen, and W denotes C, X represents S, Y represents CH, Z denotes CH, sulfonamidnuyu group attached to C-2 of the thiophene ring.

In another embodiment T is a dream, R1and R2represent hydrogen, R3represents hydrogen, R4represents CH(CH3)CH2CF3, R5is the th halogen, and W denotes C, X represents S, Y represents CH, Z denotes CH, sulfonamidnuyu group attached to C-2 of the thiophene ring.

In another embodiment T is a C(O)R8, R1and R2represent hydrogen, R3represents hydrogen, R4is a CF3CH2(CH3)CH, R5is a halogen, R8represents CH3and W stands for C, X represents S, Y represents CH, Z denotes CH, sulfonamidnuyu group attached to C-2 of the thiophene ring.

In another embodiment, T represents C(OH)R1R2, R1and R2represent hydrogen, R3represents hydrogen, R4represents (CH2CF3)2CH, R5is a halogen, and W denotes C, X represents S, Y represents CH, Z denotes CH, sulfonamidnuyu group attached to C-2 of the thiophene ring.

In another embodiment, T represents C(OH)R1R2, R1and R2represent CH3, R3represents hydrogen, R4is a CF3CH2(CH3)CH, R5is a halogen, and W denotes C, X represents S, Y represents CH, Z denotes CH, sulfonamidnuyu group attached to C-2 of the thiophene ring.

In another embodiment, T represents C(OH)R1R2, R1depict is to place a CH 3, R2represents hydrogen, R3represents hydrogen, R4represents (CF3)2CH, R5is a halogen, and W denotes C, X represents S, Y represents CH, Z denotes CH, sulfonamidnuyu group attached to C-2 of the thiophene ring.

In another embodiment, T represents C(OH)R1R2, R1and R2represent hydrogen, R3represents hydrogen, R4is a (F)2cycloalkyl, R5is a halogen, and W denotes C, X represents S, Y represents CH, Z denotes CH, sulfonamidnuyu group attached to C-2 of the thiophene ring.

The place of attachment of the heterocyclic W-X-Y-Z-C ring to the group of SO2does not limit the present invention. However, in one preferred embodiment the ring is attached to the group of SO2through the carbon atom. However, the ring can be attached through a heteroatom n

Compounds of the invention can contain one or more asymmetric carbon atoms, and some compounds may contain one or more asymmetric (chiral) centers, and, thus, can form optical isomers and diastereomers. Although the stereochemistry in formula (I) are not shown, when the compounds of formula (I) contain one or more chiral centers, at measures which, chiral center β-amerosport is S-stereochemistry. Most preferably the carbon atom that is attached to N, R3and R4is the S-stereochemistry. Thus, the invention includes such optical isomers and diastereomers, and racemic mixtures and split enantiomerically pure stereoisomers as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts, hydrates and prodrugs.

The term "alkyl" is used herein to refer to both linear and branched saturated aliphatic hydrocarbon groups with one to ten carbon atoms, preferably one to eight carbon atoms and most preferably one to six carbon atoms; used in this description, the term "lower alkyl" refers to linear and branched saturated aliphatic hydrocarbon groups with one to six carbon atoms; it is implied that the term "alkenyl" includes both linear and branched alkyl groups with at least one double carbon-carbon bond and two-eight carbon atoms, preferably two to six carbon atoms; it is understood that "Alchemilla" group covers both linear and branched alkyl groups with at least one triple carbon-carbon bound is o and two to eight carbon atoms, preferably with two to six carbon atoms.

The terms "substituted alkyl", "substituted alkenyl" and "substituted quinil" refer to alkyl, alkenylphenol and alkenylphenol groups described above containing from one to three substituents preferably independently selected from the group consisting of halogen, CN, OH, NO2, amino, aryl, heterocyclic groups, substituted aryl, substituted heterocyclic group, alkoxy, substituted alkoxy, aryloxy, replaced aryloxy, alkylcarboxylic, alkylcarboxylic, alkylamino, aristeo. These substituents can be attached to any carbon atom alkyl, alkenylphenol or alkenylphenol group, provided that the connection is stable chemical group.

The term "cycloalkyl" is used in this description to denote a saturated carbon ring, containing more than 3 carbon atoms, forming a stable ring. The term "cycloalkyl" may include groups, where two or more cycloalkyl groups condensed with the formation of stable polycyclic rings. Preferably, the term "cycloalkyl" refers to a ring containing about 4-9 carbon atoms, and more preferably about 6 carbon atoms.

The term "substituted cycloalkyl" is used in this description to denote cycloalkyl groups who, as described above, containing from one to five substituents preferably independently selected from the group consisting of hydrogen, halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, quinil, alkoxy, aryloxy, replaced alkyloxy, alkylcarboxylic, alkylcarboxylic, alkylamino, replaced alkylamino, aaltio, heterocyclic groups, substituted heterocyclic groups, aminoalkyl and substituted aminoalkyl.

The term "aryl" is used herein to denote a carbocyclic aromatic system, which may be manocalzati or multiple aromatic rings fused or linked together so that at least one part of the condensed or linked rings forms a conjugate aromatic system. Aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, antril, tetrahydronaphthyl, tenantry and indan.

The term "substituted aryl" refers to aryl having values above containing one to four substituent, preferably independently selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, quinil, alkoxy, aryloxy, replaced alkyloxy, alkylcarboxylic, alkylcarboxylic, alkylamino, aristeo.

The term "diene" refers to n is saturated hydrocarbon or diolefine, having two double bonds. The term "substituted diene" refers to the diene substituted by one or two substituents preferably independently selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, quinil, substituted quinil, alkoxy, substituted alkoxy, aryloxy, replaced aryloxy, alkylsulphonyl, substituted alkylsulphonyl, alkylcarboxylic, replaced alkylcarboxylic, alkylamino, replaced alkylamino, aaltio or substituted, aristeo.

As "Diena"and "substituted diene used in the context of R5, the embodiment in which the substituted diene represents a 3-chloro-1,2-butadiene, which is condensed with the thiophene ring by R5and Y with the formation of benzothiophene. Other suitable diene include 1,3-butadiene and 2-trifluoromethyl-1,3-butadienyl. However, you can easily select other suitable substituted and unsubstituted diene from among the compounds according to this description.

The term "substituted benzyl" refers to a benzyl group, benzyl substituted in the ring by one or more substituents, preferably independently selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, quinil, alkoxy, aryloxy, replaced alkyloxy, alkali is bonila, alkylcarboxylic, alkylamino, aristeo.

The term "heterocyclic group" used in this description to describe a stable 4-7-membered monocyclic or stable polycyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms, preferably independently selected from the group consisting of atoms of N, O and s Atoms N and S can be oxidized. It also applies heterocyclic any polycyclic ring system, in which any of the heterocyclic rings having the above values, condensed with the aryl ring. The heterocyclic ring can be attached to any heteroatom or carbon atom, provided that the resulting structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuranyl, piperidinyl, piperazinil, 2-oxopiperidine, azepine, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, chinoline, thienyl, furyl, benzofuranyl, benzothiazol, thiomorpholine, themorphological, ethenolysis and tetrahydrothiopyran.

The term "substituted heterocyclic group" is used herein to describe the heterocyclic GRU is dust, described above containing one to four substituent, preferably independently selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, quinil, substituted quinil, alkoxy, substituted alkoxy, aryloxy, replaced aryloxy, alkylsulphonyl, substituted alkylsulphonyl, alkylcarboxylic, replaced alkylcarboxylic, alkylamino, replaced alkylamino, aaltio or substituted, aristeo.

When using the terms "substituted alkyl" or "substituted alkylphenyl", the substitution can take place in the alkyl group or the relevant underlying connection.

The term "alkoxy" is used in this description to refer to the group OR, where R is an alkyl or substituted alkyl.

The term "aryloxy" is used in this description to refer to the group OR, where R is an aryl or substituted aryl.

The term "aristeo" is used in this description to refer to the group SR where R is an aryl or substituted aryl.

The term "alkylaryl" is used in this description to refer to the group RCO, where R is an alkyl or substituted alkyl.

The term "alkylcarboxylic" is used in this description to refer to the group COOR, where R represents an alkyl Il is substituted alkyl.

The term "aminoalkyl" refers to both secondary and tertiary amines, where the alkyl or substituted alkyl groups, which may be the same or different, contain one to eight carbon atoms, and the place of attachment is the nitrogen atom.

The term "halogen" refers to Cl, Br, F or I.

The term "ring" structure includes monocyclic structure, a bridged cyclic structure and condensed cyclic structure, if the type of the ring structure is not defined otherwise.

Compounds of the present invention can be used in the form of salts formed with pharmaceutically or physiologically acceptable acids or bases. Such salts include, but are not limited to, salts derived from organic and inorganic acids, such as acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, almond, malic, hydrochloric, Hydrobromic, phosphoric, nitric, sulfuric, methansulfonate, toluensulfonate and similar known acceptable acids and mixtures thereof. Other salts include salts diethanolamine, Ethylenediamine, and salts of alkaline or alkaline earth metals such as sodium (for example, sodium hydroxide, potassium salts (e.g. potassium hydroxide), calcium (e.g. calcium hydroxide) or magnesium (e.g., hydroxide mage who ia).

These salts, and other compounds of the invention may be in the form of esters, carbamates and other conventional "proletarienne" forms, which, if provided in this form are converted in vivo into the active fragment. In this preferred embodiment, the prodrugs are esters. See, for example, B. Testa and J. Caldwell, "Prodrugs Revisited: The "Ad Hoc" Approach as a Complement to Ligand Design", Medicinal Research Reviews, 16(3):233-241, ed., John Wiley & Sons (1996).

In one embodiment of compounds of formula (I) are thiophenesulfonyl, more preferably 5-gelegenheitsarbeit and most preferably 5-gelegenheitsarbeit with β-branches in the side chain primary alcohol. Thus, in connection with formula (I), the compound of the invention preferably has a structure in which R1and R2represent hydrogen; R3represents hydrogen; R4represents (CF3)2CH S-stereochemistry, R5is a halogen, and W denotes C, X represents S, Y represents CH, Z denotes CH, sulfonamidnuyu group attached to C-2 of the thiophene ring.

In another embodiment of the compounds of formula (I) are fursultiamine. Thus, in connection with formula (I), the compound of the invention has a structure in which X represents O. In one preferred embodiment fu is unsulfonated are characterized by β -branches in the side chain primary alcohol.

In another embodiment of the compounds of formula (I) are personalfinance. Thus, in connection with formula (I), the compound has the structure in which X represents NR7, W represents N and Z and Y are C or CR6provided that at least one of Y or Z must be a C.

These and other compounds of the invention can be obtained, based on the scheme illustrated below.

Synthesis

Compounds of the present invention can be obtained in a number of ways, well known to experts in the field of organic synthesis. Compounds of the present invention can be obtained using the methods described below, along with methods of synthesis known in the field of organic synthesis, or variants of such methods undertaken by professionals in this area. (See, for the overall presentation, Comprehensive Organic Synthesis, "selectivity values, Strategy &Efficiency in Modern Organic Chemistry", ed., I. Fleming, Pergamon Press, New York (1991); Comprehensive Organic Chemistry, The Synthesis and Reactions of Organic Compounds", ed. J.F. Stoddart, Pergamon Press, New York (1979)). Preferred methods include, but are not limited to, the methods described below.

The first method of obtaining is in the interaction of 1,2-amerosport II with the corresponding sulphonylchloride in the presence of a base, such as ritilin (TEM), and in a suitable solvent, to obtain the compounds of formula III. Then, in the case of compounds where R1and R2represent hydrogen, oxidation of the primary N-sulfonylurea chlorbromuron pyridinium (RCC), reagent dessa-Martin periodinane [D.B. Dess, J.C. Martin, J. Org. Chem., 48:4155 (1983)] or in conditions will Roll [Omura et al., J. Org. Chem., 41:957 (1976)] gives the corresponding aldehyde IV, which can be subjected to interaction with Grignard reagents (RMgX, where R is an organic radical and X represents a halogen) and to obtain secondary alcohols V as a mixture of diastereomers, which can be divided into high-performance liquid chromatography (HPLC) (scheme 1).

The second way of obtaining includes interaction α-amino acids or complex ester IX with the appropriate sulphonylchloride in the presence of a base such as triethylamine and in a suitable solvent, to obtain the compounds of formula X (scheme 2). The intermediate N-sulfonylamide X (Rx=H) can be converted into the corresponding primary alcohol VIII (R1=R2=H), using standard methods, with the use of lithium aluminum hydride (LiAlH4), B2H6or acid chloride cyanuric acid/NaBH4. The intermediate complex N-sulfonylated X (Rx=alkyl, Bn) can also be restored to correspond with the respective primary alcohol VIII (R 1=R2=H), using the standard technique using LiAlH4. Alternatively, the intermediate N-sulfonylated X (Rx=alkyl, Bn) can be transformed into the aldehyde IV with DIBAL. Finally, the intermediate complex N-sulfonylated X (Rx=alkyl, Bn) can be subjected to interaction with 2 equivalents of Grignard reagent to obtain a tertiary alcohols III with R1=R2. Alternatively, in the case of tertiary alcohols III, where R1not equal to R2you can get Weinrebe the corresponding amide N-sulfanilate and then subjected to interaction with R1MgX and R2MgX.

In the variant of the second method of obtaining primary alcohols first α-amino acid or ester (or N-protected derivative) VI converted into the corresponding primary 1,2-amerosport VII (using the techniques described in the previous section), which then, after removal of the protective group (if necessary) is subjected to interaction with the corresponding sulphonylchloride (scheme 3)to give the compounds of formula VIII.

To obtain compounds originating from unnatural α-amino acid containing beta-branches in the side chain of amino acids, figure 4 presents a method of obtaining, based on the work Hruby (Tet. Lett., 38:5135-5138 (1997)). This osposoblyaet education α thatβunsaturated amide XIV chiral auxiliary substances Evans from Allbreed XI through the sequence of reactions Horner-Emmons then attach copper salt of the acid with an organic substance with the formation of mates, capture the resulting enolate anion XV N-bromosuccinimide (NBS), replacement of bromide XVI azide-anion (provided by the azide tetramethylguanidine (TMGA) or sodium azide) obtaining XVII, subsequent restoration to 1,2-amerosport and subsequent sulfonation with obtaining the target compound XVIII.

When the heterocycle attached to sulfonamidnuyu group in the above-described alcohols, represents a thiophene, a corresponding sulfonic derivative of XX can be obtained by oxidation of thiophene XIX 3-chloroperoxybenzoic acid (MSRV) (scheme 5).

An alternative way to obtain the sulfonamide derivatives unnatural 1,2-aminoalcohols using a modification of Bucherer synthesis α-amino acids by Strecker (scheme 6). In this way aldehyde XXI subjected to interaction with cyanide anion and ammonium carbonate, getting as XXII, which is hydrolized to α-amino acids XXIII. Then the compound obtained to restore XXIV and sulfurous, getting the desired compounds of formula XXV. Alternatives is on, the intermediate amino acid XXIII you can alfirevich obtaining compounds XXVI, which is then reduced to XXV. Racemic products XXIII, XXV or XXVI specialist in this area can be split to the desired S-enantiomer using standard methods.

For sulfonamides formed from 1,2-aminoalcohols in a series of secondary alcohols with R1=H and R2=CF3(compound XXVII)developed a method of obtaining illustrated in figure 7, based on the aldehyde IV (obtained as shown in scheme 1).

When the heterocycle attached to sulfonamidnuyu group in the above-described alcohols, represents thiophene, the corresponding derivatives of 5-iodine - and 5-portifino can be obtained by conversion of the derived 5-bromothiophene XXVIII (obtained as shown in scheme 1) to the intermediate compound 5-trialkylborane XXIX, which can be turned or 5-idioten (XXXI) by treatment with sodium iodide and chloramine-T or analogue 5-portifino (XXX) by treatment with a reagent SELECTELUOR® (Aldrich Chem. Co.) (scheme 8).

Another method of obtaining pure chiral N-sulfonyl-1,2-aminoalcohols, derived from α-amino acids, is shown in scheme 9. In this way you get α,βunsaturated amide XXXIV support the tion of chiral substances Evans from bromoacetamide XI through a sequence of reactions Horner-Emmons. Joining copper salt of the acid with an organic substance with the formation of mates and protonation of the resulting enolate anion gives XXXV, which is then converted into the corresponding enolate and electrophilic miniroot tritylation with the formation of the key intermediate compound XXXVI (J. Am. Chem. Soc., 109:6881-6883 (1987)). Then the intermediate azide XXXVI hydrolyzing to α-azidocillin XXXVII and reduced to pure chiral α-amino acids XXXVIII, which can be converted into the corresponding N-sulfonyl-1,2-aminoalcohols in the ways described above (e.g., scheme 2 or 3).

Finally, chiral clean α-amino acids XLI - some of the possible synthetic precursors of chiral N-sulfonyl-2-aminoalcohols XLIII, can also be obtained using variants of asymmetric synthesis α-amino acids by Strecker, as shown in schemes 10 (J. Org. Chem., 61:440-441 (1996)) and 11 (J. Org. Chem., 54:1055-1062 (1989)).

The method of obtaining chiral net triptorelin - or fluoride-containing heterocyclic sulfonamides of the formula (I) are presented on figures 12 and 13. Scheme 12 shows the techniques described in the literature for the formation of a suitable aminoether XLVII [W.H. Vine et al., J. Med. Chem., 1981, 24:1043-1047; and R. Keese et al., Synthesis, 1996, 695-696]. Based on literature the information and instructions in this description, the person skilled in the art it will be obvious that, depending on the desired aminoether, you can easily choose another cryptomaterial at stage 3, depending on the substituents selected for R4'and R3'another chiral auxiliary substance in stage 4 or to use other agents, deputies, or other reaction conditions at any of the stages shown. However, if R3'not equal to R4'then in stage 3 scheme 12 receive a mixture of olefin isomers, which must be divided before stage 4.

According to scheme 13, aminoether XLVIII filtered, found that recrystallization at this stage, which is described in the literature as significant, is not required. The intermediate complex aminoether XLVIII transform in N-benzylamino using DIBAL-H. N-Benzylamino XLIX hydrolyzing in the presence of a suitable catalyst, getting amerosport L. the Catalyst is removed by filtration and the solution concentrated to a solid. Amerosport L sulfurous using BSA/triethylamine/DMAP (or other suitable agent, such as TMSCl/amine base) and the desired heterocyclic sulphonylchloride. The reaction is quenched to remove the silyl ether group (for example, water with a mixture of HCl/THF) and filtered (for example, using a layer of SiO2with a mixture of ethyl acetate/hexane in the ratio, which allows crystallization hyral is but pure triftormetilfullerenov heterocyclic sulfonamida formula (I) according to the invention.

In addition to its usefulness for obtaining compounds of the invention the method according to scheme 13 can be easily used to obtain triptorelin-including trifluoromethyl - and fluorine-containing compounds. More specifically, this method may be useful for other triptorelin-, trifluoromethyl - or fluorine-containing sulfonamides of diastereomeric mixture of aminoether having at least one chiral center and at least one triptorelin or vorgruppe attached to at least one chiral center via the alkyl group or at least one vorgruppe attached to cycloalkyl group. As defined in the present description, the alkyl group can include one or more triptorelin directly to the chiral center. Alternatively, triptorelin may be placed in the Deputy substituted alkyl groups.

Compounds of the invention can also be obtained by the interaction of the secondary alcohol V with chlorbromuron pyridinium (PCC) or reagent dessa-Martin periodinane [D.B. Dess, J.C. Martin, J. Org. Chem., 48:4155 (1983)] c the formation of the corresponding aldehyde LI (scheme 14).

Another way to get triptorelin or fluorinated heterocyclic sulfonamides includes three processing dermatillomania or fluorinated aldehyde dehydrating agent and a chiral sulfinamide education triptoreline or fluorinated chiral sulfinamide. The person skilled in the art can easily determine suitable dehydrating agent for use in the present method, including, without limitation, atoxic titanium, magnesium sulfate or molecular sieves such as molecular sieves 4Å. Then cryptomelane or fluorinated chiral sulfinamide you can handle tianyoude agent with the formation of triptoreline or fluorinated diastereomeric α-aminonitriles respectively. The choice tianyoude reagent for use in the present invention is in the competence of the person skilled in the art and may include, among others, cyanide ethylisopropylamine. Then cryptomelane or fluorinated diastereomeric α-aminonitriles can be distinguished and, optionally, to clean using methods well-known to specialists in this field. Alternatively, cryptomelane or fluorinated diastereomeric α-aminonitriles can be hydrolyzed to triptoreline or fluorinated α-amino acids, respectively, using methods and agents, well known to specialists in this field. Then triptorelin or fluorinated α-amino acid can be restored to triptoreline or fluorinated β-amerosport respectively, and the use of methods and agents well-known specialists in this field. Cryptomelane or fluorinated β-amerosport can be subjected to interaction with the heterocyclic sulphonylchloride with the formation of the corresponding triptoreline or fluorinated heterocyclic sulfonamida of the present invention.

In one embodiment of the invention relates to a method for triptoreline or fluorinated heterocyclic sulfonamida, including stage

(a) filtering the mixture of diastereomers of aminoether, and the specified aminoether has at least one chiral center and at least one triptorelin or vorgruppe attached to at least one chiral center via alkyl group;

(b) processing aminoether DIBAL-H in toluene with the formation of N-benzylaminopurine;

(C) hydrogenation of N-benzylaminopurine in the presence of a catalyst and education amerosport;

(d) sulfonation of amerosport from stage (C) heterocyclic sulphonylchloride and

(e) crystallization of sulfonated product from step (d) with the formation of chiral pure triptoreline or fluorinated heterocyclic sulfonamida.

In yet another embodiment the invention relates to a method for triptoreline or fluorinated heterocycle is ical sulfonamida, includes stage

(a) processing triptoreline or fluorinated aldehyde dehydrating agent and a chiral sulfinamide education triptoreline or fluorinated chiral sulfinamide;

(b) processing the specified triptoreline or fluorinated chiral sulfinamide tianyoude agent with the formation of triptoreline or fluorinated diastereomeric α-aminonitriles;

(C) hydrolysis of the specified triptoreline or fluorinated diastereomeric α-aminonitriles to triptoreline or fluorinated α-amino acids;

(d) restore the specified triptoreline or fluorinated α-amino acids to triptoreline or fluorinated β-amerosport and

(e) interaction specified triptoreline or fluorinated β-amerosport with the heterocyclic sulphonylchloride education specified triptoreline or fluorinated heterocyclic sulfonamida.

Applications

The compounds of formula (I) are inhibitors of the formation of beta-amyloid. In preliminary studies using specific assays for protease shown that representatives of the compounds of formula (I) detect specific inhibition against the AI by activity. Thus, the compounds of the present invention are useful for the treatment and prevention of various conditions in which modulation of the levels of beta-amyloid provides a favorable therapeutic effect. Such conditions include, among others, for example, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, Alzheimer's disease (AD), hereditary cerebral hemorrhage with amyloidosis-type Dutch, myositis Taurus inclusion, down syndrome, mild cognitive impairment (MCI).

In addition, the compounds of formula (I) can be used to obtain reagents useful in the diagnosis of conditions associated with abnormal levels of beta-amyloid. For example, the compounds of formula (I) can be used to generate antibodies that are useful in various diagnostic assays. Methods for obtaining monoclonal, polyclonal, recombinant, and synthetic antibodies or their fragments are well known to specialists in this field. (See, for example, E. Mark and Padlin, "Humanization of Monoclonal Antibodies", Chapter 4, The Handbook of Experimental Pharmacology, Vol. 113, The Pharmacology of Monoclonal Antibodies, Springer-Verlag (June, 1994); the method of Kohler and Milstein and many known modifications patent application PCT number PCT/GB85/00392; publication of patent applications in the UK No. GB2188638; Amit et al., Science, 233:747-753 (1986); Queen et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033 (1989); international publication is on patent number WO90/07861; and Riechmann et al., Nature, 332:323-327 (1988); Huse et al., Science, 246:1275-1281 (1988).) Alternatively, the compounds of formula (I) may themselves be used in such diagnostic assays. Regardless of the reagent (for example, antibodies or compounds of formula (I)), appropriate diagnostic forms, including, for example, radioimmunoassays and enzyme-linked immunosorbent assay (ELISA), is well known to specialists in this field and are not a limitation of this embodiment of the invention.

Inhibitory activity against beta-amyloid many compounds of the present invention is defined by analysis of the release of activator (Repressor Release Assay (RRA)). Cm. table 5 below. A compound is considered active in the RRA, if it leads to at least a 1.5-fold increase in luciferase activity at a concentration of 20 μg/ml and is non-toxic.

In addition, this area is well known cell, cell-free and in vivo screening methods for detection of inhibitors of the formation of beta-amyloid. Such analyses, among others, may include radioimmunoassays and enzyme-linked immunosorbent assay (ELISA). See, for example, P.D. Mehta et al., Techniques in Diagnostic Pathology, vol.2, eds., Bullock et al., Academic Press, Boston, pages 99-112 (1991), publication of International patent # WO 98/22493, European patent No. 0652009 and U.S. patent No. 5703129 and 5592846. The choice of a suitable screening-EN is Lisa in vitro or in vivo is not a limitation of the present invention.

The pharmaceutical composition

The pharmaceutical composition of the present invention it is possible to introduce the subject of any desired way with the specific condition for which it is selected. A subject is any suitable mammal, including humans, domestic animals (e.g. dogs and cats) and livestock, which is recognized as being or having the risk of one or more States for which the desired modulation of the levels of beta-amyloid. Thus, the compounds of the invention are useful for the treatment and/or prevention of a number of conditions in people and animals. Used in this description, the term "prevention" includes the prevention of symptoms in a subject who is identified as having a risk of state, but which it is not yet diagnosed and/or which are not yet available its symptoms.

These compounds can be delivered or enter any appropriate route, for example, among others, oral, injection, inhalation (including oral, intranasal and intratracheal), intravenous, subcutaneous, intramuscular, sublingual, intracranial, epidural, intratracheal, rectal, vaginal way. The most desirable to deliver compounds orally, by inhalation, or the appropriate parent the liberal way. Compounds can be introduced into the composition in combination with conventional pharmaceutical carriers, which are physiologically compatible. Optionally, one or more compounds of the invention can be mixed with other active substances.

Suitable physiologically compatible carriers can easily choose a specialist in this field. For example, suitable solid carriers include, among others, one or more substances which may also act as a corrigentov, lubricants, soljubilizatory, suspendresume agents, fillers, glidant promoting pressing, binding agents or substances, which contribute to the disintegration of the tablets, or encapsulating material. In powders, the carrier is a finely ground solid material, which is mixed with finely ground active ingredient. In tablets, the active ingredient is mixed in suitable proportions with the carrier having the properties required for pressing, and pressed into the desired shape is the desired size. The powders and tablets preferably contain up to 99% of active ingredient. Suitable solid carriers include, for example, calcium phosphate or dicalcium phosphate, magnesium stearate, talc, starch, sugars (including, for example, lactose and sucrose), cellulose (including, for example, microcrystalline cellulose methylcellulose, the sodium carboxymethyl cellulose), polyvinylpyrrolidone, low melting waxes, ion exchange resin and kaolin.

Liquid media can be used to obtain solutions, suspensions, emulsions, syrups and elixirs. The active ingredient in this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilization, emulsifiers, buffers, suspendresume substances, thickeners, viscosity regulators, stabilizers or regulators osmosis. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives mentioned above, e.g. cellulose derivatives, preferably a solution of sodium carboxymethyl cellulose), alcohols (including monohydroxy alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil, peanut oil, corn oil and sesame oil). For parenteral administration, the carrier can also be a fatty acid ester, such as etiloleat and isopropylmyristate. Sterile liquid carriers are used in a sterile liquid compositions for p is enteralnogo introduction.

Optionally, compositions of the invention may be incorporated additives usually used in the preparation of pharmaceutical compositions. Such components include, for example, sweeteners or other corrigentov, dyes, preservatives, and antioxidants, such as vitamin E, ascorbic acid, BHT and BHA.

Liquid pharmaceutical compositions that represent the solution or suspension may be introduced, for example, by intramuscular, intraperitoneally or subcutaneous injection. Sterile solutions can also be administered intravenously. Composition for oral administration may be a composition or liquid, or solid form.

Accordingly, when the pharmaceutical composition was prepared for use in the form of inhalation, it is received in the form of a liquid standard doses with the use of compounds of the invention and a pharmaceutical carrier suitable for delivery by a pump for aerosol spray or in the form of a dry powder for insufflation. For use as aerosols, the compound of the invention is administered in a composition which conclude in aerosol packaging together with a gaseous or liquid propellant, such as DICHLORODIFLUOROMETHANE, carbon dioxide, nitrogen, propane, etc. with conventional components, such as co-solvents and humectants that may be necessary Il is desirable. For example, the invention provides for the delivery of measured doses for oral or intranasal inhalation for one or two positives. Accordingly, the dose is delivered in one or two positives. However, you can easily identify other suitable delivery methods.

Preferably, the pharmaceutical composition is in the standard dosage forms, such as tablets or capsules. In this form, the composition is sub-divided into standard doses containing appropriate quantities of the active ingredient; the standard dosage forms can be a composition in a package, for example Packed powders, vials, ampoules, prefilled syringes or sachets containing liquids. Standard dosage form may represent, for example, a capsule or tablet itself, or it can represent an appropriate number of any such compositions in package form.

As described herein, a therapeutically or prophylactically useful amount of a compound of the invention represents the number of connections, which improves the symptoms of diseases such as AD or which prevents the appearance of symptoms or the appearance of more severe symptoms. Useful number of connections can vary depending on the composition and the method of delivery. For example, the R, in order to deliver a biologically equivalent amount of drugs, oral can deliver larger quantities than in the case where the composition obtained for injection or inhalation. Accordingly, a single dose (i.e. per unit) of the compound of the invention is the interval from about 1 μg/kg to about 10 g/kg However, since the compounds of the invention have improved biological activity compared to similar compounds, deprived triptorelin or fluorine-substituents according to the invention, it is possible to choose the appropriate dose in a narrower interval, for example, from about 1 μg/kg to about 200 mg/kg, more preferably from about 10 μg/kg to about 10 mg/kg and most preferably from about 100 μg/kg to about 1 mg/kg. it is Desirable that the said amount was given as daily. However, the dosage used in the treatment or prevention of specific cognitive deficiency or other condition may be set selectively by the attending physician. Factors such as specific cognitive deficiency and weight, age and the patient's response. For example, based on the activity profile and the effectiveness of the compounds of the present invention the initial dose of from about 375-500 mg / day with a gradual increase to a daily dose when is Erno 1000 mg per day may provide the desired level of dosage for human use.

Alternatively, it may be desirable to use a device with delayed delivery to the patient to avoid the need to take medication daily. "Delayed delivery" is defined as the delayed release of the active substances, i.e. compounds of the invention, after placing in the scope of delivery, with subsequent slow release of substances at a later time. Specialists in this area known suitable devices for deferred delivery. Examples of suitable devices for deferred delivery include, among others, for example, hydrogels (see, for example, U.S. patent No. 5266325, 4959217 and 5292515), osmotic pump, such as described Alza (U.S. patent No. 4295987 and 5173752) or Merk (European patent No. 314206); hydrophobic film materials, such as ethylenemethacrylic (EMA) and ethylene vinyl acetate (EVA); capable of biological resorption polymer systems (see, for example, publication of International patent # WO 98/44964, Bioxid and Cellomeda; U.S. patent No. 5756127 and 5854388); describes the other capable of bio-resorption of the implantable device, as consisting, for example, of polyesters, polyanhydrides or copolymers of lactic acid and glycolic acid (see, for example, U.S. patent No. 5817343 (Alkermes Inc.)). For use in such devices for deferred delivery connection izopet the deposits can be introduced into the composition, described in this specification.

In another aspect the invention relates to a pharmaceutical kit for delivery of the product. Accordingly, the set contains a packaging or a container connection, entered into the composition for the desired delivery method. For example, if the set is created for administration by inhalation, it may contain a suspension containing the compound of the invention obtained for delivery as an aerosol or spray a certain dose by inhalation. Accordingly, the kit contains instructions for dosing and liner relative to the active agent. Optionally, the kit may also contain instructions to monitor product levels in the circulatory system and materials for the implementation of such analyses, including, for example, reagents, hole tablets, containers, markers or labels, etc. These kits are easily packaged in a manner suitable to ensure the desired indication. For example, the kit can also contain instructions for use of the spray pump or other device for delivery.

Other suitable components for such sets will be obvious to the person skilled in the art, taking into account the desired date and method of delivery. Dose may be repeated daily, weekly, or monthly, at pre-set intervals or as prescribed.

Examples

Example 1

5-Chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide

A. Method 1

1. 2-Methyl-4,4,4-trifloromethyl

To 2-methyl-4,4,4-Cryptor-1-butanol (7.5 g, 53 mmol) in methylene chloride (CH2Cl2) (125 ml) at 0°add periodinane dessa-Martin (26.5 g, 63.3 mmol). The reaction mixture is heated to 25°C and stirred for 20 minutes To the resulting mixture is added diethyl ether (Et2O, 200 ml) and then a solution of Na2S2O3(20,0 g, 185 mmol) in a saturated aqueous solution of sodium bicarbonate (NaHCO3) (200 ml) and 100 ml of water. Milky-white mixture is stirred until until both phases will not be homogeneous. The phases are separated and the organic extract was washed with a saturated aqueous solution of NaHCO3(25 ml) and aqueous 1 N. a solution of Na2S2O3(25 ml) and dried using magnesium sulfate (MgSO4). The solvents are removed by distillation at atmospheric pressure, obtaining 2-methyl-4,4,4-tripersonality (6.5 g, 88%). Range1H nuclear magnetic resonance (NMR) corresponds to the range reported in the literature (J. Fluorine Chem., 36:163-170 (1987)).

2. 5-(3,3,trifter-1-methylpropyl)imidazolidin-2,4-dione

To sodium cyanide (18,4 g, 375 mmol) and ammonium carbonate (39,0 g, 500 mmol) in N2O (450 ml) is added 2-methyl-4,4,4-tripersonality (17.5 g, 125 mmol) in ethanol (450 ml). The reaction mixture is heated at 90°C for 17 hours. After cooling to 25°With approximately 500 ml of the solvent is removed in vacuum. Add concentrated HCl to acidification of the mixture to a pH of from about 1 to about 2, and precipitation. The mixture is filtered and washed with 1 N. hydrochloric acid, receiving 5-(3,3,3-Cryptor-1-methylpropyl)imidazolidin-2,4-dione as a white solid (15.5 g, 59%).

Mass spectrum (-ESI): 309 (M-N)-.

Analysis.

Calculated for C7H9F3N2O2: C, 40,01; N, 4,32; N, 13,33.

Found: C, 39,91; N, 4,10; N, 13,20.

3. N-[(5-Chlortan-2-yl)sulfonyl]-5,5,5-tripersonal

5-(3,3,3-Cryptor-1-methylpropyl)imidazolidin-2,4-dione (15,54 g, 73,95 mmol) is dissolved in 150 ml of an aqueous solution of sodium hydroxide (NaOH, 11,83 g, 295,8 mmol). The solution is heated by microwave irradiation in a tightly closed vessel for 1 hour (microwave irradiation conditions: 15 min at approximately 100% power, 150°S, 50 f/d2then 5 min at 0% power, then 15 min at approximately 100% power, 150°S, 50 f/d2then the sequence is repeated). Water and ammonium hydroxide are removed from the reaction mixture under vacuum and the resulting crude mixture aminoxy the lots and NaOH used in the next reaction without further purification.

A mixture of the crude amino acid and NaOH is dissolved in 300 ml of water. The mixture is cooled to approximately 0°in an ice bath. 5-Chlorothiophene-2-sulphonylchloride (17.6 g, 81 mmol) was dissolved in 100 ml of tetrahydrofuran (THF) and added dropwise to the reaction mixture for 0.5 hour. After gradual heating of the reaction mixture for 1 hour to 25°and With stirring for 16 hours remove the THF under vacuum and the mixture is then acidified to a pH of about 1 1 N. hydrochloric acid. After about 15 min of milky-white mixture begins to fall precipitate. After 1 hour the mixture is cooled to 0°C for 1 hour and then filtered. The precipitate was washed with 1 N. hydrochloric acid, obtaining N-[(5-chlortan-2-yl)sulfonyl]-5,5,5-tripersonal in the form of a white solid (15.2 g, 56%).

Mass spectrum (-ESI): 364 (M-N)-.

Analysis.

Calculated for C10H11F3NO4S2: C, 32,84; N, 3,03; N, 3,83.

Found: C, 32,45; N, To 2.94; N, 3,79.

4. 5-Chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide

To N-[(5-chlortan-2-yl)sulfonyl]-5,5,5-tripersonal (15.2 g, to 41.6 mmol) in THF (500 ml) at 0°With added dropwise 1M solution of borane-tertrahydrofuran ring complex in THF (208 ml, 208 mmol). After 15 min the reaction mixture is heated to 25°C and stirred for 18 hours. Then the reaction gradually quenched with a 10% solution of Asón in the Meon (100 is l). Volatiles removed in vacuum. Then the residue is dissolved in ethyl acetate (EtOAc) (500 ml), the solution washed with saturated aqueous NaHCO3(3×100 ml), dried using sodium sulfate (Na2SO4) and concentrated to a white solid (13.3 g, yield 91%). Diastereoisomers separated by HPLC (column Luna silica gel, MTBE-hexane 3:7, diastereoisomer 1 eluted at 10,9 min, diastereoisomer 2 eluted at 15,3 min). The diastereoisomer 2 liquor is pure enantiomers preparative chiral SFC [chiralpack AD, isopropanol-carbon dioxide 3:7, enantiomer 1 eluted at 4.5 min, enantiomer 2 eluted at 5,6 min]. Then enantiomer 1 is recrystallized from a mixture of EtOAc/heptane, 1:4, receiving 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide, TPL 136-137°C.

[α]D25=+45,62° (C=1% solution, Meon).

Mass spectrum (-ESI): 350 (M-N)-.

Analysis.

Calculated for C10H13ClF3NO3S2: C, 34,14; N, AND 3.72; N, 3,98.

Found: C, The Volume Of 34.12; N, Of 3.45; N, 3,88.

C. Method 2

1. (4R)-4-Benzyl-3-(4,4,4-tripcomputer)-1,3-oxazolidin-2-he

To a solution of 4,4,4-retformularo acid (10,00 g, 70,38 mmol) in THF (150 ml) at -78°With add triethylamine (10.3 ml, 73,9 mmol) and pivaloate (9.1 ml, 74 mmol). The reaction mixture is heated to 0°C and stirred for 1.5 hours. In a separate to the forehead a solution of n-BuLi (31 ml, 2.5m in hexane, 77 mmol) added over 10 min to a cooled to -78°With a solution of (R)-(+)-4-benzyl-2-oxazolidinone (13,7 g, 77.4 mmol) in THF (150 ml) and the mixture is stirred for 1 hour.

A dense suspension of the mixed anhydride is cooled to -78°and poured through an addition funnel to a solution of literaturnogo oxazolidinone. The mixture is left to gradually warm to 25°With at night. The mixture is then diluted with EtOAc (500 ml) and washed with 1 N. hydrochloric acid (500 ml), saturated aqueous NaHCO3(500 ml) and saturated aqueous NaCl (500 ml), then dried (Na2SO4) and concentrate. Flash chromatography (eluent EtOAc-hexane, 1:4) to give (4R)-4-benzyl-3-(4,4,4-tripcomputer)-1,3-oxazolidin-2-he (18,29 g, 86%) as a colourless oil.

[α]D25=-89,10° (C=1% solution, DMSO).

Mass spectrum (-ESI): 300 (M-N)-.

Analysis.

Calculated for C14H14F3NO3: C, 55,82; N, TO 4.68; N, 4,65.

Found: C, 56,03; N, Of 4.67; N, 4,62.

2. (4R)-4-Benzyl-3-[(2R)-4,4,4-Cryptor-2-methylbutanoyl]-1,3-oxazolidin-2-he

To a solution of bis(trimethylsilyl)amide, sodium (57 ml, 1.0m in THF, 57 mmol) in THF (250 ml) at -40°With added dropwise over 15 min a solution of (4R)-4-benzyl-3-(4,4,4-tripcomputer)-1,3-oxazolidin-2-it (15,60 g, 51,78 mmol) in THF (250 ml). After 1 hour, add itmean (4,2 ml, 67 mmol). After 3 hours the reaction mixture is heated to -20&#HWS for about 20 minutes The mixture is quenched with saturated aqueous ammonium chloride (NH4Cl) (300 ml) and then extracted with EtOAc (2×300 ml), dried using Na2SO4and concentrate. Flash chromatography (eluent EtOAc-hexane, 1:9) to give (4R)-4-benzyl-3-[(2R)-4,4,4-Cryptor-2-methylbutanoyl]-1,3-oxazolidin-2-he (12,04 g, 74%) as a colourless oil.

[α]D25=-98,68° (C=1% solution, DMSO).

Mass spectrum (+EI): 315 (M+N)+.

Analysis.

Calculated for C15H16F3NO3: C, 57,14; N, 5,11; N, OF 4.44.

Found: C, 57,18; N, Of 5.24; N, To 4.38.

3. (2R)-4,4,4-Cryptor-2-methylbutane-1-ol

A solution of lithium borohydride (23 ml, 2.0m in THF, 45 mmol) at 0°With added dropwise to a solution of (4R)-4-benzyl-3-[(2R)-4,4,4-Cryptor-2-methylbutanoyl]-1,3-oxazolidin-2-it (12.9 g, of 40.9 mmol) and water (810 μl, of 45.0 mmol) in diethyl ether (200 ml). The reaction mixture is allowed to warm to 25°C, after 1 hour, cooled to 0°and quenched with aqueous 1 N. NaOH solution (124 ml). The mixture is heated to 25°and mix until until both layers will not become homogeneous. The layers separated, the organic extract washed with brine, dried using MgSO4and concentrate. Flash chromatography (eluent ether-petroleum ether, 3:7) to give (2R)-4,4,4-Cryptor-2-methylbutane-1-ol (of 5.05 g, 87%) as a colourless oil. Range1H NMR identical to the spectrum reported in the literature (J. Med. Chem., 37:1282-1297 (1994)).

4. (S)-N-[(3R)-Met the l-4,4,4-triptoreline]-p-toluensulfonate

To (2R)-4,4,4-Cryptor-2-methylbutane-1-Olu (2,90 g of 20.4 mmol) in CH2Cl2(50 ml) at 0°add periodinane dessa-Martin (10,24 g, 24,49 mmol). After 15 min the reaction mixture is heated to 25°C and stirred for 1 hour. Then the resulting mixture was diluted with diethyl ether (50 ml) and added to a solution of Na2S2O3(of 11.29 g, 71,44 mmol) in a saturated aqueous solution of NaHCO3(100 ml). Milky-white mixture is stirred until until both layers will not become homogeneous. The phases are separated, the organic extract is dried (MgSO4) and filtered, obtaining a solution of (2R)-4,4,4-Cryptor-2-methylbutanal, which is used in the next stage without removing the solvent.

To a solution of the crude aldehyde add atoxic titanium (IV) (15 ml, 20% Ti, 82 mmol), then (S)-(+)-toluensulfonate (3,48 g of 22.4 mmol) and the solution refluxed for 3 hours. The mixture is then cooled to 0°and add water (75 ml) for separation of salts of titanium. The suspension is filtered through celite reagent® and the filter residue is washed with CH2Cl2. The layers of the filtrate are separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts are dried using Na2SO4and concentrate. Flash chromatography (eluent EtOAc-hexane, 1:9) gives (S)-N-[(3R)-methyl-4,4,4-triptoreline]-p-toluensulfonate (3.03 g, 54%) as W is logo oil. Mass spectrum (-ESI): 276 (M-N)-.

5. N-[(1S,2R)-1-Cyano-4,4,4-Cryptor-2-methylbutyl]-4-methylbenzenesulfonamide

The cyanide diethylamine (16 ml, 1.0m in toluene, 16 mmol) in THF (40 ml) at 0°add isopropanol (I-D) (840 μl, 11.0 mmol). After 15 min the resulting solution was added to a solution of (S)-N-[(3R)-methyl-4,4,4-triptoreline]-p-toluensulfonate (3.03 g, 10.9 mmol) in THF (60 ml), cooled to -78°C. After 15 min the reaction mixture is heated to 25°C. After 1 hour, thin layer chromatography (TLC, EtOAc-hexane, 1:9) shows that starting material had been consumed. The mixture is cooled to -78°and add saturated aqueous solution of ammonium chloride (100 ml). The resulting suspension is filtered through celite reagent® and the filter residue washed with EtOAc (100 ml). The layers of the filtrate are separated and the aqueous layer was extracted with EtOAc. The combined organic extracts are dried using Na2SO4and concentrate. The crude mixture, which, according to1H NMR, is a mixture of diastereomers 1:3, precipitated with a mixture of diethyl ether/hexane and collecting the product. Two additional portions of the product is obtained by repeating the procedure of deposition from the concentrated filtrate. N-[(1S,2R)-1-Cyano-4,4,4-Cryptor-2-methylbutyl]-4-methylbenzenesulfonamide (2,34 g, 70%) are obtained in the form of a single diastereoisomer.

[α]D25=+35,46° (C=1% process is, CHCl3).

Mass spectrum (+ESI): 305 (M+N)+.

Analysis.

Calculated for C13H15F3N2OS: C, 51,31; N, EQUAL TO 4.97; N, 9,20.

Found: C, 51,16; N, 4,96; N, The Remaining 9.08.

6. Hydrochloride 5,5,5-Cryptor-L-allitaliana

A suspension of N-[(1S,2R)-1-cyano-4,4,4-Cryptor-2-methylbutyl]-4-methylbenzenesulfonamide (2,34 g of 7.69 mmol) in concentrated hydrochloric acid (75 ml) is refluxed for 18.5 hours. After cooling to 25°the reaction mixture is washed several times with diethyl ether. The aqueous layer was concentrated, obtaining a mixture of 5,5,5-Cryptor-L-allitaliana, NH4Cl and toluensulfonate acid (2.35 g). The crude amino acid used in the next stage without additional purification. Mass spectrum (-ESI): 309 (M-H)-.

7. (2S,3R)-2-Amino-5,5,5-Cryptor-3-methylpentan-1-ol

To a solution of lithium borohydride (7.7 ml, 2,0N in THF, 15 mmol) in THF (20 ml) at 0°With add chlorotrimethylsilane (3.9 ml, 31 mmol). The reaction mixture is heated to 25°and after 30 minutes is added dropwise to a suspension of the crude hydrochloride of the amino acids (7.7 mmol) in THF (60 ml), cooled to 0°C. the Mixture is heated to 25°and after 21 hours, quenched with methanol (Meon). Volatiles are removed under vacuum, obtaining a residue that is dissolved in about 50 ml of aqueous 1 n NaOH solution, extracted with chloroform (CHCl3) (4×75 ml), dried (Na2SO4 and concentrate, receiving (2S,3R)-2-amino-5,5,5-Cryptor-3-methylpentan-1-ol in the form of a yellow oil (1.07 g, 81%). Mass spectrum (+ESI): 172 (M+H)+.

8. 5-Chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide

To (2S,3R)-2-amino-5,5,5-Cryptor-3-methylpentan-1-Olu (1.07 g, and 6.25 mmol) and triethylamine (of 0.87 ml, 6.2 mmol) in CH2Cl2(15 ml) at 0°With added dropwise a solution of 5-chlorothiophene-2-sulphonylchloride (1,34 g of 6.25 mmol) in CH2Cl2(15 ml). The reaction mixture is heated to 25°C and stirred for 24 hours. Then it was diluted with EtOAc (100 ml) and washed with 0.1 G. of aqueous hydrochloric acid (50 ml) and brine (50 ml). The aqueous layer was extracted with EtOAc (50 ml). The combined organic extracts are dried using Na2SO4and concentrate. Flash chromatography (eluent EtOAc-hexane, 3:7) gives 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide (1.66 g, 75%) as a white solid. Recrystallization (EtOAc-heptane, 1:4) to give white needles (1.39 g, yield 84%), TPL 136-137°C.

Analysis.

Calculated for C10H13ClF3NO3S2: C, 34,14; N, AND 3.72; N, 3,98.

Found: C, 34,24; N, Of 3.97; N, A 3.87.

C. Method 3

1. (4S)-4-Benzyl-3-(bromoacetyl)-1,3-oxazolidin-2-he

To a solution of S-(-)-4-benzyl-2-oxazolidinone (20,0 g, 112,86 mmol) in THF (200 ml) at -78°With added dropwise 2.5m solution of n-BuLi in hexane (47,4 ml, 11851 mmol). The solution was stirred at -78°C for 30 min and then add bromoacetamide (25,0 g, 10,81 ml, 124,15 mmol). The solution is allowed to warm to 25°overnight (19 h). Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. The mixture is diluted with ethyl acetate (200 ml) and the organic layer was washed with saturated aqueous NaHCO3(2×50 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining the crude brown oil (34 g). The crude product is purified flash chromatography, eluent EtOAc-hexane, 1:4, receiving (4S)-4-benzyl-3-(bromoacetyl)-1,3-oxazolidin-2-it is in the form of a colorless oil (33,2 g, 98.6 per cent). Mass spectrum (-ESI): 297 (M-N)-.

2. Dimethyl-2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethylidene

(4S)-4-Benzyl-3-(bromoacetyl)-1,3-oxazolidin-2-he (33,0 g, 110,68 mmol) and triethylphosphine (39,2 ml, a 33.2 mmol) is heated at 120°C for 18 hours. Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. The reaction mixture is cooled to 25°C, diluted with ethyl acetate (200 ml) and the organic layer was washed with saturated aqueous NaHCO3(2×50 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining dimethyl-2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethylidene in the form of a crude yellow oil (36 g, 99.3 per cent). Mass spectrum (-ESI): 326 (M-N)-.

3.(4S)-4-Benzyl-3-[(2E)-5,5,5-triterpen-2-enoyl]-1,3-oxazolidin-2-he

To a solution of dimethyl-2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethylidene (36 g, 109,97 mmol) in THF (200 ml) at -78°With added KHMDS (0.5 M, 242 ml, 120,97 mmol). The solution is allowed to warm to 25°30 min at -20°add 3,3,3-cryptocraphically (13,55 g, 120,97 mmol). The solution is allowed to warm to 25°overnight (19 h). Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. The reaction is quenched by adding saturated aqueous solution of NaHCO3(50 ml). The aqueous layer was washed with ethyl acetate (3×100 ml). The organic layer is dried over MgSO4filter and concentrate, getting a light brown oil (32.1 g). The crude product is purified flash chromatography, eluent EtOAc-hexane, 1:6, receiving (4S)-4-benzyl-3-[(2E)-5,5,5-triterpen-2-enoyl]-1,3-oxazolidin-2-it is in the form of a colorless oil (17,7 g, 55.1 per cent).

Mass spectrum (-ESI): 312 (M-N)-.

Analysis.

Calculated for C15H14NF3O3: C, 57,51; N, 4,50; N, 4,47.

Found: C, 57,05; N, Of 4.75; N, To 4.52.

4. (4S)-4-Benzyl-3-[(3S)-5,5,5-Cryptor-3-methylpentanol]-1,3-oxazolidin-2-he

A suspension of the bromide complex of copper (I)-dimethyl sulfide (of 9.45 g, 45,96 mmol) in THF (200 ml) and dimethyl sulfide (100 ml) as the co-solvent is cooled to -40°and added dropwise within 10 min methylanisole (30,64 ml, 91,93 mmol). The suspension is stirred for 40 min, heating to -15°C. the Greenish suspen the Oia is cooled to -40° And at -40°With added dropwise a solution of (4S)-4-benzyl-3-[(2E)-5,5,5-triterpen-2-enoyl]-1,3-oxazolidin-2-it (12 g, 38,30 mmol)in THF (15 ml). The reaction mixture is left to warm to 25°C overnight (18 h). The reaction is quenched with saturated aqueous NH4Cl (20 ml). A precipitate. It is filtered off, the mother liquor was diluted with EtOAc (250 ml) and the organic layer was washed with saturated aqueous sodium chloride (NaCl, 100 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining the crude semi-solid substance. The crude semi-solid substance is not soluble in CH2Cl2, MeOH and EtOAc and partially dissolved in dimethyl sulfoxide (DMSO). The crude product is treated with 1 N. HCl (100 ml) and the aqueous layer washed with EtOAc (2×150 ml). The organic layer is dried over MgSO4filter and concentrate, receiving a yellow oil (12.1 g). The crude product is purified flash chromatography, eluent EtOAc-hexane, 1:4, receiving (4S)-4-benzyl-3-[(3S)-5,5,5-Cryptor-3-methylpentanol]-1,3-oxazolidin-2-it is in the form of a colorless oil (8.2 g, 67,8%).

Mass spectrum (+ESI): 330 (M+N)+.

Analysis.

Calculated for C16H18NF3O3: C, 58,36; N, THE 5.51; N, 4.25 IN.

Found: C, 58,36; N, 5,70; N, 4,19.

5. (S)-3-[(2S,3R)-2-Azido-5,5,5-Cryptor-3-methylpentanol]-4-benzyl-1,3-oxazolidin-2-he

A solution of (4S)-4-benzyl-3-[(3S)-5,5,5-Cryptor-3-methylpentanol]-1,3-oxazolidin--she (8,2 g, of 24.90 mmol) in THF (100 ml) cooled to -78aboutC and added dropwise within 10 min KHMDS (calichecalidosojr, 59,7 ml, 29,88 mmol). After stirring at -78°C for 1 hour through the cannula added dropwise within 10 min pre-cooled (-78°C, 50 min) solution of 2,4,6-triisopropylbenzenesulfonyl (10.1 g, 32,37 mmol). After an additional 10-minute exposure at -78°through the funnel and add one scoop of ice-cold acetic acid (6,7 ml, 112,05 mmol). After 5-min exposure at -78°add anhydrous potassium acetate (9,77 g, a 99.6 mmol). Bath to -78°removed and the reaction mixture is left to warm to 25°overnight (19 h). The reaction mixture was diluted with EtOAc (200 ml) and the organic phase is washed with saturated aqueous monobasic potassium phosphate (2×100 ml) and saturated aqueous NaCl (100 ml). The organic layer is dried over MgSO4filter and concentrate, receiving a yellow oil (9.5 g). The crude product is purified flash chromatography, eluent EtOAc-hexane, 1:4, receiving (S)-3-[(2S,3R)-2-azido-5,5,5-Cryptor-3-methylpentanol]-4-benzyl-1,3-oxazolidin-2-it is in the form of a colorless oil (7.2 g, 73,7%).

Mass spectrum (-ESI): 342 (M-N2)-.

6. (2S,3R)-2-Azido-5,5,5-Cryptor-3-methylpentanoic acid

To a solution of (S)-3-[(2S,3R)-2-azido-5,5,5-Cryptor-3-methylpentanol]-4-benzyl-1,3-oxazolidin-2-she (7.2 g, 19,44 mmol) in THF:H2About(3:1, 120 ml) in an atmosphere of N2when 0°add monohydrate of lithium hydroxide (LiOH) (1.63 g, 38,88 mmol). The reaction is controlled by TLC (EtOAc/hexane, 1:2). After 3 hours add solid NaHCO3(6.0 g). The suspension was diluted with saturated aqueous NaHCO3(20 ml) and N2O (40 ml) and extracted with EtOAc (3×100 ml). The organic layer is extracted with saturated aqueous NaHCO3(20 ml). EtOAc contains a chiral auxiliary substance, and its cast. Merged layers NaHCO3acidified to pH less than 2. The acidified aqueous layer was extracted with EtOAc (3×100 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining the (2S,3R)-2-azido-5,5,5-Cryptor-3-methylpentanol acid as a yellow oil (3.2 g, 98%). Mass spectrum (-ESI): 183 (M-N2)-.

7. 5,5,5-Cryptor-L-alliteration

(2S,3R)-2-Azido-5,5,5-Cryptor-3-methylpentanol acid (3.2 g, 17,27 mmol), 10% palladium-on-carbon (0,79 g), glacial acetic acid (37 ml) and water (90 ml) is placed in hydrogenator Parra in an atmosphere of hydrogen (40 f/d2and shake. After 20 h the reaction mixture was filtered through a layer of celite®, which was carefully washed with water (20 ml). The filtrate is concentrated under reduced pressure, obtaining a white solid. The solid is triturated with EtOAc (200 ml), filtered and again washed with EtOAc (200 ml), then dried in the air, the floor is th 5,5,5-Cryptor-L-alliteration in the form of a white solid (2.7 g, 96%). Mass spectrum (-ESI): 184 (M-N)-.

Analysis.

Calculated for C6H10NF3O2+0,12HCl: C, 38,13; N, 5,50; N, 6,94.

Found: C, 38,03; N, 5,38; N, 7,39.

8. (2S,3R)-2-Amino-5,5,5-Cryptor-3-methylpentan-1-ol

To a solution of lithium borohydride (14,5 ml of 2M solution in THF, 29 mmol) under stirring at 0°With added dropwise within 30 min chlorotrimethylsilane (7,38 ml, 58 mmol). The ice bath is removed and the suspension stirred at 25°C for 30 minutes, the Reaction mixture was cooled to 0°and With add on parts for 15 min 5,5,5-Cryptor-L-alliteration (2.7 g, 16,98 mmol) as a solid. The reaction mixture is left to warm to 25°With bath with melting ice. After 3-day exposure at 25°the reaction mixture is cooled to 0°and gently for 30 min add methanol (22 ml). The solution was stirred at 25°even for 40 min and then concentrated under reduced pressure on a water bath at 60°C. the Obtained suspension is alkalinized with 20% sodium hydroxide solution (10 ml). Add water (10 ml) and the entire water layer is extracted with methylene chloride (100 ml) and the extract dried over MgSO4. The organic phase is filtered and evaporated, receiving (2S,3R)-2-amino-5,5,5-Cryptor-3-methylpentan-1-ol in the form of crude oil (2.6 g, 89.6 per cent). Mass spectrum (-ESI): 170 (M-N)-.

9. 5-Chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbut the l]thiophene-2-sulfonamide

To a solution of (2S,3R)-2-amino-5,5,5-Cryptor-3-methylpentan-1-ol (2.6 g, 15,18 mmol) and triethylamine (4,2 ml, 30,38 mmol) in methylene chloride (50 ml), cooled to 0°C, with stirring, add dropwise a solution of 5-chlorothiophene-2-sulphonylchloride (4.8 g, 18,22 mmol) in methylene chloride (5 ml). After 15 min the ice bath is removed and the reaction mixture was allowed to reach 25°With at night. The reaction is quenched, pouring into a saturated solution of sodium bicarbonate (25 ml) and adding methylene chloride (150 ml). The organic phase is separated, sequentially washed with 1 N. aqueous hydrochloric acid, H2O and brine and dried over MgSO4. The organic phase is filtered and evaporated, receiving crude oil (6,1 g)which is purified flash chromatography, using as eluent a mixture of ethyl acetate-hexane, 1:6. Get listed in the title compound 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white amorphous solid (5,15 g, 96.4 per cent). The product contains impurities. White amorphous solid is optionally purified by recrystallization from a mixture of EtOAc-heptane, 1:4. Solvent mixture is added to 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide, is heated to obtain a solution is allowed to cool to 25°With 3 hours and then stored at 0°C for 19 hours. Drawn in white precipitate is crystalline substance is filtered off, washed with chilled on ice heptane, getting a white crystalline solid (2.7 g, 40.9 per cent). The recrystallized substance still contains impurities. White solid (2.7 g) optionally purified preparative chiral HPLC [SFC, AD, 25×and 0.46 cm; mobile phase hexane-ISO-D, 8:2 (1 ml/min)], receiving 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white crystalline solid, TPL 132-133° (0,93 g, a 14.1%, chiral purity 100%analytical purity 100%).

Mass spectrum (-ESI): 350 (M-H)-.

Analysis.

Calculated for C10H13ClF3NO3S2: C, 34,14; N, AND 3.72; N, 3,98.

Found: C, 34,44; N, 3,70; N, 3,74.

A comparative study of the compounds of this example and similar compounds that do not contain triptoreline groups and different stereochemistry relative to the center C-2, but identical in other respects, the connection this example demonstrates significantly longer metabolic stability (half-life ˜193 minutes against 12.7 minutes) in the analysis of metabolism phase I liver microsomes of rats.

A comparative study of the compounds of this example and the corresponding analogue deprived triptoreline groups, the compound of this example demonstrates significantly greater metabolic stability of analyze phase 1 and 2 metabolism in liver microsomes of rats (the half-life of 14 min vs. 2 min), mouse (half-life 10 min vs. 2 min), man (half-life of 22 minutes against 13 min) and dogs (31 minutes vs. 4 minutes).

Thus, the compound of the invention remains in the bloodstream longer than its corresponding counterparts without CF3and increases its bioavailability.

Example 2

5-Chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide

A. Method 1

1. (4S)-4-Benzyl-3-[(3S)-3-ethyl-5,5,5-tryptophanol]-1,3-oxazolidin-2-he

A suspension of the bromide complex of copper (I)-dimethyl sulfide (1.26 g, 6,13 mmol) in THF (20 ml) and dimethyl sulfide (10 ml) as the co-solvent is cooled to -40°and added dropwise within 10 min ethylmagnesium (3M solution in diethyl ether, 4,08 ml of 12.26 mmol). The suspension is stirred for 40 min, heating it up to -15°C. a Greenish suspension is cooled to -40°and at -40°With added dropwise a solution of (4S)-4-benzyl-3-[(2E)-5,5,5-triterpen-2-enoyl]-1,3-oxazolidin-2-it (obtained as in example 1, method 3, part C (1.6 g, 5,10 mmol) in THF (5 ml). The reaction mixture is left to warm to 25°C overnight (18 h). The reaction is quenched with saturated aqueous NH4Cl (20 ml). A precipitate, which is filtered off. Mother liquor was diluted with EtOAc (250 ml) and the organic extract washed with saturated aqueous NaCl (100 ml). Organic is xtract dried over MgSO 4, filtered and concentrated, obtaining the crude semi-solid substance. The crude semi-solid substance is not soluble in CH2Cl2, MeOH or EtOAc, but partially soluble in DMSO. The crude product is treated with 1 N. HCl (100 ml) and the aqueous solution washed with EtOAc (2×150 ml). The organic layer is dried over MgSO4filter and concentrate, receiving a yellow oil (1,41 g). The crude product is purified flash chromatography, eluent EtOAc-hexane, 1:4, receiving (4S)-4-benzyl-3-[(3S)-3-ethyl-5,5,5-tryptophanol]-1,3-oxazolidin-2-it is in the form of a colorless oil (0.96 g, 55%).

Mass spectrum (+ESI): 344 (M+N)+.

Analysis.

Calculated for C17H20NF3O3: C, 59,47; N, BY 5.87; N, 4,08.

Found: C, 59,58; N, 5,91; N Is 4.03.

2. (S)-3-[(2S,3R)-2-Azido-3-ethyl-5,5,5-tryptophanol]-4-benzyl-1,3-oxazolidin-2-he

To a solution of (4S)-4-benzyl-3-[(3S)-3-ethyl-5,5,5-tryptophanol]-1,3-oxazolidin-2-she (0.9 g, 2,62 mmol) in THF (10 ml), cooled to -78°C, is added dropwise within 10 min KHMDS (0.5 m solution in toluene, 6.3 ml, 3.14 mmol). After stirring at -78°C for 1 hour through the cannula added dropwise within 10 min pre-cooled (-78°C, 50 min) solution of 2,4,6-triisopropylbenzenesulfonyl (1.04 g, to 3.38 mmol) in 20 ml of THF. After an additional 10-minute exposure at -78°through the funnel and add one scoop of ice-cold acetic acid (0.7 ml, to 11.79 mmol. After 5-min exposure at -78°add anhydrous potassium acetate (1.07 g, 10,48 mmol). Bath to -78aboutWith removed and the reaction mixture is left to warm to 25°overnight (19 h). The reaction mixture was diluted with EtOAc (200 ml) and washed with saturated aqueous monobasic potassium phosphate (2×100 ml) and saturated aqueous NaCl (100 ml). The organic layer is dried over MgSO4filter and concentrate, receiving a yellow oil (1,09 g). The crude product is purified flash chromatography, eluent EtOAc-hexane, 1:4, receiving (S)-3-[(2S,3R)-2-azido-3-ethyl-5,5,5-tryptophanol]-4-benzyl-1,3-oxazolidin-2-it is in the form of a colorless oil (0,587 g, 59%). Mass spectrum (-ESI): 357 (M-N2)-.

3. (2S,3R)-2-Azido-3-ethyl-5,5,5-cryptocentrus acid

To a solution of (S)-3-[(2S,3R)-2-azido-3-ethyl-5,5,5-tryptophanol]-4-benzyl-1,3-oxazolidin-2-she (287 mg, 0,746 mmol) in THF:H2About (3:1, 4 ml) in an atmosphere of N2when 0°With added LiOH monohydrate (62,66 mg, 1,49 mmol). The reaction is controlled by TLC (EtOAc/hexane, 1:2). After 3 hours add solid NaHCO3(1.0 g). The suspension was diluted with saturated aqueous NaHCO3(2 ml) and N2O (4 ml) and extracted with EtOAc (3×50 ml). The organic layer is extracted with saturated aqueous NaHCO3(10 ml). EtOAc contains a chiral auxiliary substance, and its cast. The combined aqueous extracts acidified to the N less than 2, extracted with EtOAc (3×50 ml), the extract dried over MgSO4, filtered and concentrated, obtaining the (2S,3R)-2-azido-3-ethyl-5,5,5-cryptocentrus acid as a yellow oil (130 mg, 94%).

Mass spectrum (-ESI): 197 (M-N2)-.

4. (2S,3R)-2-Amino-3-ethyl-5,5,5-triterpene-1-ol

A gray suspension of lithium aluminum hydride (LAH, 110,6 mg, only 2.91 mmol) in THF (2 ml) at 0°With added dropwise within 5 min (2S,3R)-2-azido-3-ethyl-5,5,5-cryptocentrus acid (130 mg, 0,583 mmol). The obtained suspension is allowed to warm to 25°to 19 hours. The reaction is quenched by adding successively at 0°With H2About (0.5 ml), 1 n NaOH solution (1.5 ml) and N2About (0.5 ml). A white precipitate formed after 5 h, filtered, the organic solvent is dried over MgSO4, filtered and concentrated, obtaining the (2S,3R)-2-amino-3-ethyl-5,5,5-triterpene-1-ol in the form of crude oil (120 mg, 96%). Mass spectrum (+ESI): 186 (M+N)+.

5. 5-Chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide

To a solution of (2S,3R)-2-amino-3-ethyl-5,5,5-triterpene-1-ol (120 mg, 0,701 mmol) and triethylamine (0.1 ml, 1.4 mmol) in methylene chloride (50 ml), cooled to 0°C, with stirring, add dropwise a solution of 5-chlorothiophene-2-sulphonylchloride (220 mg, 0,841 mmol) in methylene chloride (5 ml). After 15 min the ice bath is removed and the reaction mixture was allowed to reach 25°With at night. Additionally relax the Ute methylene chloride (15 ml) and the reaction mixture is poured into saturated sodium bicarbonate solution (25 ml). The organic phase is separated and sequentially washed with 1 N. hydrochloric acid, H2O and brine and dried over MgSO4. The organic phase is filtered and evaporated, receiving crude oil (0.36 g)which is purified flash chromatography using as eluent a mixture of ethyl acetate-hexane, 1:4. Get listed in the title compound 5-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide in the form of oil (125 mg, 53%). Oil (125 mg), additionally purified preparative chiral HPLC [SFC, AD, 25×and 0.46 cm; mobile phase hexane-ipa, 8:2 (1 ml/min)], receiving 5-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as a white crystalline solid (0.15 g, 6,4%, chiral purity 100%, analytical purity 100%).

Mass spectrum (-ESI): 364 (M-H)-.

Analysis.

Calculated for C11H15NClF3O3S2+0,24C4H8About2: C 37,50; N, 4,08; N, OF 3.73.

Found: C, 37,12; N, To 4.41; N, 3,62.

C. Method 2

1. 2-Ethyl-4,4,4-cryptomelane acid

The solution Diisopropylamine (17.1 g, 169 mmol) in THF (180 ml) is stirred under nitrogen atmosphere at 0°C. is Added dropwise within 15 min 2.5m solution of n-utility (n-BuLi, 67,6 ml) in hexane and the resulting solution is stirred for 0.5 hour at 0°C. At the end of this period the reaction mixture was cooled to -78° With and for 0.5 hour is added dropwise a solution of 4,4,4-cryptomelane acid (10.0 g, of 70.4 mmol) in THF (20 ml). The resulting solution was additionally stirred for 0.5 hour at -78°C. Upon expiration of the specified period added dropwise within 15 min of ethyliodide (to 6.19 ml, 77.4 mmol). The resulting solution was stirred for 15 min at -78°and then heated to 25°C for 24 hours. At the end of this period the reaction mixture was quenched by adding gradually the H2On (˜20 ml). After concentration the residue is acidified to pH 1 2 N. hydrochloric acid and then extracted with Et2O (400 ml). Then the organic layer is dried using MgSO4. After concentration, the obtained residue is used directly in the next reaction without further purification.

2. 2-Ethyl-4,4,4-tripcomputer

A solution of LAH (2,74 g of 72.3 mmol) in Et2O (230 ml) is stirred under nitrogen atmosphere at 0°C. is Added dropwise a solution of 2-ethyl-4,4,4-cryptomelane acid (12.3 g, 72,3 mmol) in Et2O (20 ml), the solution stirred for 15 min at 0°and then 2 hours at 25°C. At the end of this period the solution is quenched by adding dropwise N2On (2,74 ml), 15% NaOH solution (2,74 ml) and N2(By 8.22 ml) with vigorous stirring. Add solid Na2SO4in order to drain the solvent and obtained with the ect is stirred for 1 hour. The obtained suspension is filtered and the filter residue is washed with excess Et2O. After concentration the crude product is purified by chromatograph Biotage FlashTM40, eluent Et2O:D from 20:80 to 30:70, receiving 2-ethyl-4,4,4-tripcomputer in the form of oil (6,18 g, yield 55% for two steps).

3. 2-Ethyl-4,4,4-cryptomelane aldehyde

A solution of 2-ethyl-4,4,4-triptoreline (6,18 g, to 39.6 mmol) in CH2Cl2(50 ml) is stirred under nitrogen atmosphere at 0°C. Add in one step reagent dessa-Martin periodinane (20,16 g, and 47.5 mmol) and the solution stirred for 1 hour at 0°C. After additional stirring for 5 h at 25°the reaction is finished, according to NMR data. The solution was diluted with Et2O (100 ml) and the resulting solution was added Na2S2O3(55 g) in a saturated aqueous solution of NaHCO3(100 ml). The resulting mixture is stirred for 0.5 hour. Layers of liquids separated, the organic layer is optionally washed with saturated aqueous NaHCO3(50 ml) and brine (50 ml) and then dried using Na2SO4. A large part of the solvent is removed by distillation using a column in a Game (the flask is heated at a temperature of from about 50 to about 55°and the temperature of the nozzle is approximately 38°). The obtained residue in the reaction flask are used directly in the following the respective reaction without further purification (aldehyde is very volatile).

4. 5-(1-Ethyl-3,3,3-cryptochromes)imidazolidin-2,4-dione

A solution of the crude 2-ethyl-4,4,4-cryptomelane aldehyde (6,10 g, to 39.6 mmol) in N2O (100 ml) stirred at 0°C. To the resulting solution was added sodium cyanide (of 5.82 g, 119 mmol), ammonium carbonate (15.2 g, 158 mmol) and EtOH (100 ml). The reaction mixture is heated at 90°C for 3 days. After cooling to 25°and concentrating the resulting residue is acidified to a pH of from about 1 to about 2 with concentrated HCl. The formed solid is filtered off, washed with 2 N. HCl and excess N2Oh and then dried overnight with a vacuum pump, receiving 5-(1-ethyl-3,3,3-cryptochromes)imidazolidin-2,4-dione (2,74 g, yield 31% for two steps). Mass spectrum (+ESI): 225 (M+H)+and (-ESI): 223 (M-N)-.

5. 2-[(5'-Chloro-2'-thienyl)sulfonylamino]-3-ethyl-5,5,5-cryptocentrus acid

A solution of 5-(1-ethyl-3,3,3-cryptochromes)imidazolidin-2,4-dione (1,76 g, 7.85 mmol) in 20 ml of an aqueous solution of NaOH (1.26 g, of 31.4 mmol) are heated with microwave irradiation in a tightly closed vial for 0.5 hour (microwave irradiation conditions: 15 min at approximately 100% power, 150°S, 50 f/d2; then 5 min at 0% power; then 15 minutes at approximately 100% power, 150°S, 50 f/d2). After cooling to 25°With water and ammonia are removed from the reaction mixture under vacuum and the crude mixture Natrii the th salts of amino acids dissolved in N 2About (15 ml). To the resulting solution at 0°add THF (25 ml) and then added dropwise a solution of 5-chlorothiophene-2-sulphonylchloride (1,87 g, 8,64 mmol) in THF (5 ml). After exposure for 18 h at 25°the reaction mixture is concentrated and the residue acidified to pH 1 2 N. hydrochloric acid. The resulting aqueous layer extracted with Et2O (2×100 ml) and the organic layer washed with brine (20 ml) and dried using MgSO4. After concentration the crude residue is recrystallized from a mixture of EtOAc:hexane to remove by-products. Concentration of the filtrate gives the product as a solid (1.31 g, 44%). Mass spectrum (+ESI): 380 (M+H)+and (-ESI): 378 (M-N)-.

6. 5'-Chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2'-sulfonamide

A solution of 2-[(5'-chloro-2'-thienyl)sulfonylamino]-3-ethyl-5,5,5-cryptocentrus acid (2,19 g, 5,77 mmol) in THF (60 ml) is stirred under nitrogen atmosphere at 25°C. is Added dropwise 1.0m solution of borane complex·THF in THF (23.1 ml) and the resulting solution stirred for 18 h at 25°C. At the end of this period the reaction is completed according to TLC (Meon:CHCl3, 10:90). The reaction mixture was quenched by adding gradually to 10% acetic acid (SPLA) in the Meon (80 ml). After concentration the residue is dissolved in EtOAc (200 ml), washed with saturated aq is m solution of NaHCO 3(3×20 ml) and brine (20 ml) and then the solution is dried using Na2SO4. After concentration the crude product (2.20 g) purified by chromatographic system Biotage FlashTM40, eluent EtOAc:PE from 20:80 to 30:70, receiving one of the two pairs of racemic mixtures (0,623 g). Then purify the compound obtained in addition to using the conditions of chiral HPLC (column ChiracelTMAD; 25×2.2 cm, 254 nm injection of 0.5 ml; mobile phase: 25 ml/min, 12% MeCN in hexane; the product corresponds to the peak of one Rf=6,7, purity >99.9 percent), obtaining enantiomerically pure 5'-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2'-sulfonamide as a white solid, TPL 128-129° (0,238 g, yield 45% for a specific enantiomer).

Mass spectrum (-ESI): 364 (M-H)-.

Analysis.

Calculated for C11H15ClF3NO3S2: C, 36,12; N, 4,13; N, 3,83.

Found: C, 36,22; N, 4,20; N, 3,78.

Example 3

5'-Chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(1-hydroxyethyl)butyl]thiophene-2'-sulfonamide

A. 5'-Chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(formyl)butyl]thiophene-2'-sulfonamide

A solution of 5'-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2'-sulfonamida (obtained as in example 2, 0,100 g, 0,273 mmol) in CH2Cl2(4 ml) is stirred under nitrogen atmosphere at 0°C. Add in one step reagent dessa-Martin periodin the (0,151 g, 0,355 mmol) and the solution stirred for 1 hour at 0°C. After additional stirring for 1 hour at 25°the reaction is completed according to TLC (EtOAc:PE, 30:70). The solution was diluted with Et2O (50 ml) and the resulting solution was added Na2S2O3(0,363 g) in a saturated aqueous solution of NaHCO3(10 ml). The resulting mixture is stirred for 0.5 hour. Layers of liquids separated, the organic layer is optionally washed with saturated aqueous NaHCO3(5 ml) and brine (5 ml) and then dried (Na2SO4). After concentration the crude product is purified by preparative chromatography on plates, eluent EtOAc:PE, 30:70, receiving 5'-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(formyl)butyl]thiophene-2'-sulfonamide as a solid (0.036 g, 36%).

C. 5'-Chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(1-hydroxyethyl)butyl]thiophene-2'-sulfonamide

A solution of 5'-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(formyl)butyl]thiophene-2'-sulfonamida (0.035 g, 0,0962 mmol) in THF (3 ml) is stirred under nitrogen atmosphere at 0°C. is Added dropwise 1,4M solution (0,206 ml) methylacrylamide in a mixture of toluene:THF and the resulting solution was stirred for 1 hour at 25°C. At the end of this period the reaction is finished, data TLC (EtOAc:PE, 30:70). The solution is quenched with saturated aqueous NH4Cl (2 ml) and extracted with Et2O (20 ml). The organic layer p is washed with brine (3 ml) and then dried using Na 2SO4. After concentration the crude product is purified by preparative chromatography on plates, eluent EtOAc:PE, 30:70, receiving 5'-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(1-hydroxyethyl)butyl]thiophene-2'-sulfonamide as not quite white solid (0,027 g, 73%).

Mass spectrum (-ESI): 378 (M-H)-.

Analysis.

Calculated for C12H17ClF3NO3S2: C, 37,94; N, 4,51; N, 3,69.

Found: C, 38,35; N, 4,32; N, 3,29.

Example 4

5'-Chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)propyl]thiophene-2'-sulfonamide

A. 3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)Propylamine

A solution of 4,4,4,4',4',4'-hexaplar-DL-valine (0,500 g, 2.22 mmol) in THF (20 ml) is stirred under nitrogen atmosphere at 25°C. is Added dropwise 1.0m solution of borane complex·THF in THF (6,66 ml) and the resulting solution stirred for 4 h at 25°C. At the end of this period the reaction is completed according to TLC (EtOAc:EtOH:H2O, 10:2:1). The reaction mixture was quenched by adding gradually to 10% of the SPLA in the Meon (23 ml). After concentration the residue is dissolved in Et2O (200 ml), washed with saturated aqueous NaHCO3(3×20 ml) and brine (20 ml) and then dried using Na2SO4. After concentration, the obtained residue is used directly in the next reaction without further purification.

C. 5'-Chloro-N-[3,3,3-three the Thor-2-(trifluoromethyl)-1-(hydroxymethyl)propyl]thiophene-2'-sulfonamide

A solution of 3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)Propylamine (0.400 g, 1,89 mmol) in CH2Cl2(20 ml) is stirred under nitrogen atmosphere at 0°C. is Added dropwise a triethylamine (Et3N, 0,369 ml, to 2.65 mmol), then 5-chlorothiophene-2-sulphonylchloride (0,492 g of 2.27 mmol) and the resulting solution stirred for 18 h at 25°C. At the end of this period the reaction is completed according to TLC (EtOAc:PE, 30:70). After blanking the Meon and concentration the residue is dissolved in Et2O (200 ml), washed with 1 N. aqueous hydrochloric acid (20 ml), saturated aqueous NaHCO3(20 ml) and brine (20 ml) and then dried (MgSO4). After concentration the crude product (2.20 g) purified by chromatographic system Biotage FlashTM40, eluent EtOAc:PE from 10:90 to 30:70, receiving 5'-chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)propyl]thiophene-2'-sulfonamide as not quite white solid (to 0.108 g, yield 14% for two steps, racemic mixture).

Mass spectrum (-ESI): 390 (M-H)-.

Analysis.

Calculated for C9H8ClF6NO3S2: C, 27,59; N, TO 2.06; N, TO 3.58.

Found: C, 28,24; N, 1,90; N, 3,48.

Example 5

5'-Chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-S-(hydroxymethyl)propyl]thiophene-2'-sulfonamide

A. Methyl 2-amino-3-(trifluoromethyl)-4,4,4-triptoreline

A solution of 4,4,4,4',4',4'-hexaplar-DL (2.00 g, 8,89 mmol) in a mixture of CH2Cl2:MeOH (4:1, 50 ml) is stirred under nitrogen atmosphere at 0°C. is Added dropwise 2.0m solution tetramethylsilane (TMS)-diazomethane in hexane (5,33 ml) and the resulting solution was stirred for 3 hours at 25°C. At the end of this period the reaction is completed according to TLC (10% Meon:chloroform). After concentration, the obtained residue is used directly in the next reaction without further purification.

C. Methyl-2-[(5'-chloro-2'-thienyl)sulfonylamino]-3-trifluoromethyl-4,4,4-triptoreline

A solution of methyl 2-amino-3-(trifluoromethyl)-4,4,4-triternata (1,34 g, the ceiling of 5.60 mmol) in CH2Cl2(10 ml) is stirred under nitrogen atmosphere at 25°C. is Added dropwise pyridine (10 ml, 126 mmol), then 5-chlorothiophene-2-sulphonylchloride (1,82 g of 8.40 mmol) and the resulting solution was stirred for 72 h at 25°C. At the end of this period the reaction is completed according to TLC (EtOAc:PE, 20:80). After blanking H2About the mixture was diluted with Et2O (200 ml). The organic layer was washed with 1 N. aqueous hydrochloric acid (20 ml), saturated aqueous NaHCO3(20 ml) and brine (20 ml) and then dried (MgSO4). After concentration the crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc:PE from 5:95 to 25:75, receiving methyl-2-[(5'-chloro-2'-thienyl)sulfo is ylamino]-3-trifluoromethyl-4,4,4-triptoreline in the form of solids (1,61 g, 69%). Mass spectrum (-ESI): 418 (M-H)-.

C. 5'-Chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-S-(hydroxymethyl)propyl]thiophene-2'-sulfonamide

Suspension of LAH (0,146 g of 3.84 mmol) in Et2O (17 ml) is stirred under nitrogen atmosphere at 0°C. To the mixture is added dropwise a solution of methyl 2-[(5'-chloro-2'-thienyl)sulfonylamino]-3-trifluoromethyl-4,4,4-triternata (1,61 g of 3.84 ml) in Et2O (3 ml). After stirring at the same temperature for 0.25 hour, the reaction is completed according to TLC (EtOAc:PE, 30:70). The resulting mixture (with vigorous stirring) quenched by adding dropwise N2On (0,146 ml), 15% aqueous NaOH solution (0,146 ml) and N2On (0,438 ml), and then further stirred for 2 hours at 25°C. the Obtained suspension is dried (Na2SO4) and then filtered. After concentration the crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc:PE from 5:95 to 40:60, receiving 5'-chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)propyl]thiophene-2'-sulfonamide as a solid (0,590 g, 39%, racemic mixture). Then highlight the active enantiomer of 5'-chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-S-(hydroxymethyl)propyl]thiophene-2'-sulfonamide (0,185 g) in the form of not-quite-white solid (TPL 148-150° (C)using chiral HPLC (column Chiralpak® AS; 2×25 cm, 254 nm, injection, 0.5 ml; mobile phase: 15 ml/min, 8% IPA in cm the si hexane/0.1% of TFA (impurity); the product corresponds to the peak two, Rf=12,3, purity of 98.5%).

Mass spectrum (-ESI): 389,9 (M-H)-.

Analysis.

Calculated for C9H8ClF6NO3S2: C, 27,59; N, 2.06 TO: N TO 3.58.

Found: C, 27,76; N, A 1.96; N, 3,47.

A comparative study of the compounds of this example and similar compounds devoid of triptoreline groups, but identical in other respects, the connection this example demonstrates a significantly higher efficiency (about 72 hours to about 133 hours) in cell analysis and significantly longer metabolic stability (half-life 46 min versus 10 min in the analysis of metabolism in liver microsomes transgenic mouse (Tg2576)). Thus, the compound of the invention can be used in lower doses than the corresponding compounds lacking triptoreline groups.

Example 6

5-Chloro-N-[(1R,2S)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide

A. (4R)-4-Benzyl-3-(bromoacetyl)-1,3-oxazolidin-2-he

To a solution of R-(-)-4-benzyl-2-oxazolidinone (15.0 g, 84,65 mmol) in THF (200 ml) at -78°With added dropwise 2.5m solution of n-BuLi in hexane (34 ml, 84,65 mmol). The solution was stirred at -78°C for 30 min and then add bromoacetamide (18,65 g, 7.8 ml, 124,15 mmol). The solution is allowed to warm to 25°overnight (19 h). Select Alik the GTC, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. The mixture is diluted with ethyl acetate (200 ml) and the organic layer was washed with saturated aqueous NaHCO3(2×50 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining the crude brown oil (24.6 g). The crude product is purified flash chromatography, eluent EtOAc-hexane, 1:4, receiving (4R)-4-benzyl-3-(bromoacetyl)-1,3-oxazolidin-2-it is in the form of a colorless oil (19.9 g, 79,6%). Mass spectrum (+ESI): 300, 299 (M+N)+.

C. Diethyl-2-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethylidene

(4R)-4-Benzyl-3-(bromoacetyl)-1,3-oxazolidin-2-he (19.7 g, 66,07 mmol) and triethylphosphite (33,99 ml, 198,2 mmol) is heated at 120°C for 18 hours. Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. The reaction mixture is cooled to 25°and diluted with ethyl acetate (200 ml). The organic layer was washed with saturated aqueous NaHCO3(2×50 ml), the layer is dried over MgSO4filter and concentrate, receiving diethyl-2-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethylidene in the form of a crude yellow oil (14,27 g, 60,77%). Mass spectrum (-ESI): 326 (M-N)-.

C. (4R)-4-Benzyl-3-[(2E)-5,5,5-triterpen-2-enoyl]-1,3-oxazolidin-2-he

To a solution of diethyl-2-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethylidene (14,27 g, 40,17 mmol) in THF (200 ml) at -78°With added KHMDS (,5 M, 88 ml, 44,63 mmol). The solution is heated to 25°C for 30 min and at -20°add 3,3,3-cryptocraphically (5.0 g, 44,63 mmol). The solution is allowed to warm to 25°overnight (19 h). Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. The reaction is quenched by adding saturated aqueous solution of NaHCO3(50 ml). The aqueous layer was washed with ethyl acetate (3×100 ml). The organic layer is dried over MgSO4filter and concentrate, getting a light brown oil (32.1 g). The crude product is purified flash chromatography, eluent EtOAc-hexane, 1:6, receiving (4R)-4-benzyl-3-[(2E)-5,5,5-triterpen-2-enoyl]-1,3-oxazolidin-2-it is in the form of a colorless oil (3.7 g, 29.4 per cent).

Mass spectrum (+ESI): 314 (M+N)+.

Analysis.

Calculated for C15H14NF3O3+0,25N2ABOUT: WITH, 56,70; N, 4,60; N, TO 4.41.

Found: C, 56,44; N, Of 4.49; N, To 4.41.

D. (4R)-4-Benzyl-3-[(2R,3S)-2-bromo-3-ethyl-5,5,5-tryptophanol]-1,3-oxazolidin-2-he

A suspension of the bromide complex of copper (I)-dimethyl sulfide (1,57 g, 7,66 mmol) in THF (20 ml) and dimethyl sulfide (10 ml) as the co-solvent is cooled to -40°and added dropwise within 10 min methylanisole (5 ml, of 15.3 mmol). The suspension is stirred for 40 min, heating to -15°C. a Greenish suspension is cooled to -40°and at -40°With added dropwise a solution of (4R)-4-benzyl-3-[(2E)-5,5,5-triterpen-2-enoyl]-1,3-oxazolidin-2-she (2 g, 6.38 mmol in THF (5 ml). The reaction mixture is left to warm to 25°overnight (20 h). The black suspension is cooled to -78°and add parts of N-bromosuccinimide (2.3 g, of 12.76 mmol). The mixture is heated to -40°and additionally stirred for 30 minutes At the end of this period the black suspension gets color from green to blue. A precipitate, which is filtered off. Mother liquor was diluted with EtOAc (150 ml) and the organic layer washed with saturated NaCl solution (50 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining (4R)-4-benzyl-3-[(2R,3S)-2-bromo-3-ethyl-5,5,5-tryptophanol]-1,3-oxazolidin-2-it looks like a green semi-solid substances (1.6 g, 59,58%). Mass spectrum (-ESI): 421, 420 (M-N)-.

That is, (4R)-3-[(2S,3S)-2-Azido-3-ethyl-5,5,5-tryptophanol]-4-benzyl-1,3-oxazolidin-2-he

To a solution of (4R)-4-benzyl-3-[(2R,3S)-2-bromo-3-ethyl-5,5,5-tryptophanol]-1,3-oxazolidin-2-she (1.6 g, with 3.79 mmol) in DMF (20 ml) is added sodium azide (0,468 g, 7,119 mmol). The suspension was stirred at 25°C for 20 h and remove the solvent in vacuo. The crude product was dissolved in EtOAc (100 ml) and the organic layer was washed with H2About (3×20 ml) and saturated aqueous NaCl (20 ml). The organic layer is dried over MgSO4filter and concentrate, receiving a yellow oil (1.4 g). The crude product is purified flash chromatography, eluent EtOAc-hexane, 1:4, receiving (4R)3-[(2S,3S)-2-azido-3-ethyl-5,5,5-tryptophanol]-4-benzyl-1,3-oxazolidin-2-it is in the form of a colorless oil (1,21 g, 83,2%). Mass spectrum (-ESI): 357 (M-N2)-, 380, 381.

F. (2S,3S)-2-Amino-3-ethyl-5,5,5-triterpene-1-ol

A gray mist LAH (100 mg, to 2.65 mmol) in THF (3 ml) at -10°With added dropwise over 5 min a solution of (4R)-3-[(2S,3S)-2-azido-3-ethyl-5,5,5-tryptophanol]-4-benzyl-1,3-oxazolidin-2-she (300 mg, 0.78 mmol) in THF (2 ml). The obtained suspension is allowed to warm to 25°to 19 hours. The reaction is quenched by adding successively at 0°With H2O (0.3 ml), 1 n NaOH solution (0.9 ml) and N2O (0.3 ml). The precipitate formed after 5 h, filtered. Mother liquor is dried over MgSO4, filtered and concentrated, obtaining the (2S,3S)-2-amino-3-ethyl-5,5,5-triterpene-1-ol as a pale yellow oil (145 mg, 98%). Mass spectrum (-ESI): 184 (M-N)-.

G. 5-Chloro-N-[(1S,2S)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide

To a solution of (2S,3S)-2-amino-3-ethyl-5,5,5-triterpene-1-ol (145 mg, 0.78 mmol) and triethylamine (to 0.22 ml, 1.56 mmol) in methylene chloride (5 ml), cooled to 0°C, with stirring, add dropwise a solution of 5-chlorothiophene-2-sulphonylchloride (225 mg, 0,861 mmol) in methylene chloride (5 ml). After 15 min the ice bath is removed and the reaction mixture was allowed to reach 25°With at night. Additionally, add methylene chloride (15 ml) and the reaction quenched, pouring the mixture into a saturated solution of sodium bicarbonate (25 ml). The organic phase is separated and successively washed with N. aqueous hydrochloric acid, H2O and brine and dried over MgSO4. The organic phase is filtered and evaporated, receiving crude oil (0,250 g)which is purified flash chromatography, eluent ethyl acetate : hexane, 1:6. Get listed in the title compound 5-chloro-N-[(1S,2S)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as an oil (140 mg, 53.8 per cent). Crude oil is additionally purified by recrystallization from a mixture of EtOAc-heptane, 1:4. The mixed solvent system is added to 5-chloro-N-[(1S,2S)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide, is heated to obtain a solution is allowed to cool to 25°With 3 hours and then stored at 0°C for 19 hours. Precipitated precipitated white crystalline substance is filtered off, washed with chilled on ice heptane, receiving 5-chloro-N-[(1S,2S)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as a white crystalline solid (50 mg, and 19.2%, chiral purity 91%, analytical purity 100%).

Mass spectrum (-ESI): 364 (M-H)-.

Analysis.

Calculated for C11H15NClF3O3S2+0,10S4H8About2: C, 36,55; N, OF 4.25; N, 3,74.

Found: C, 36,94; N, 4,15; N, 3,57.

Example 7

5-Chloro-N-[4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide

A. 4,4,4-Trifloromethyl

To a solution of ethyl-4,4,4-trip is Arbuthnot (5 g, 29,38 mmol) in CH2Cl2(50 ml) in an atmosphere of N2at -70°With add diisobutylaluminum (35 ml, 35,26 mmol). After 6 hours, add 1 N. HCl (6 ml), after heating up to -60°the reaction mixture was poured into H2O (5 ml) and extracted with CH2Cl2(2×50 ml). The combined organic extracts washed with N2About (2×10 ml). The organic extracts dried over MgSO4filter and concentrate, receiving 4,4,4-tripersonality in the form of colorless non-viscous oil (3.7 g, 100%).

Century 5-(3,3,3-Cryptochromes)imidazolidin-2,4-dione

Sodium cyanide (or 4.31 g, 88,04 mmol) and 4,4,4-tripersonality (3.7 g, 29,34 mmol) is added to the ammonium carbonate (9.1 g, 117,4 mmol) in N2O (60 ml). The black reaction mixture is heated to 90°C. After 1 hour, the mixture becomes homogeneous, and stirred at 90°C for 18 hours. After cooling to 25°With about 60 ml of the solvent is removed in vacuum. Add concentrated HCl (4 ml) for acidification of the mixture to a pH of about 2, and a precipitate. It is filtered off. The mother liquid was washed with EtOAc (3×50 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining 5-(3,3,3-cryptochromes)imidazolidin-2,4-dione as a brown oil (3,95 g, 69.7 per cent). Mass spectrum (-ESI): 195 (M-N)-.

C. 5,5,5-Cryptomodules

5-(3,3,3-Cryptochromes)imidazolidin-2,4-dione (0.9 g, 4,59 mmol) Rast is oraut in 10 ml of aqueous NaOH (0,734 g in 10 ml of N 2Oh, 18,35 mmol). The solution is distributed in two special vessel for microwave technology. The solution is heated by microwave irradiation: in sealed vessel for 1 hour. The microwave irradiation conditions: 15 min at approximately 100% power, 150°S, 50 f/d2then 5 min break, power 0%. The sequence of operations is repeated twice or until until reaction occurs. Water and ammonia are removed from the reaction mixture under vacuum and the resulting crude mixture 5,5,5-tripersonality (1.1 g, 140%) and NaOH used in the next reaction without further purification. Mass spectrum (+ESI): 172 (M+N)+.

D. N-[(5-Chlortan-2-yl)sulfonyl]-5,5,5-cryptomodules

To a mixture of crude 5,5,5-tripersonality (0,785 g, 4,59 mmol) and NaOH dissolved in THF (10 ml) and 2 N. NaOH solution (10 ml)is added dropwise over 30 min a solution of 5-chlorothiophene-2-sulphonylchloride (1,32 g 5,04 mmol) in THF (10 ml). After 60 min the reaction mixture was gradually heated to 25°C and stirred for 16 hours. THF is removed in vacuo and the mixture acidified to a pH of about 2 to 1 N. HCl. After 15 min of milky white solution starts accumulating sediment. After 60 min, the mixture is cooled to 0°C for 45 min and then filtered. The precipitation was washed with 1 N. HCl (10 ml)to give white solid. White solid separated from the filter. It is dissolved in EtOAc (100 ml). odny layer washed with EtOAc (3× 50 ml) and the organic layers washed with saturated aqueous NaCl (50 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining N-[(5-chlortan-2-yl)sulfonyl]-5,5,5-cryptomodules in the form of a dark red oil (1.1 g, 68.3 per cent). Mass spectrum (-ESI): 350 (M-N)-.

E. 5-Chloro-N-[4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide

To a solution of N-[(5-chlortan-2-yl)sulfonyl]-5,5,5-tripersonality (1.0 g, 2,84 mmol) in THF (10 ml) at 0°C for 30 min is added dropwise a complex of borane-THF (1M solution, 15 ml, 14,21 mmol). The reaction mixture is left to warm to 25°for 18 h and then quenched the reaction by adding 50 ml of 10% acetic acid in methanol. After evaporation of the solvent the crude product is dissolved in EtOAc and the solution washed with 1 N. HCl, H2Oh and a saturated solution of NaHCO3. The organic layer is dried over MgSO4, filtered and concentrated, obtaining the crude oil (0,83 g)which is purified flash chromatography, eluent ethyl acetate : hexane, 1:6. Get listed in the title compound 5-chloro-N-[4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide (0,46 g, 48%) as a colourless oil. Mass spectrum (-ESI): 337 (M-N)-.

Analysis.

Calculated for C11H15NClF3O3S2+0,30 C4H8About2: C, 33,64; N, 3,71; N, 3,85.

Found: C, 34,01; N, The 3.65; N, 3,67.

Examples 8 and 9

5-Chloro-N-{(1S,2R)-4,4-Cryptor-1-[(1S)-1-hydroxyethyl]-2-methylbutyl}thiophene-2-sulfonamide

and

5-chloro-N-{(1S,2R)-4,4,4-Cryptor-1-[(1R)-1-hydroxyethyl]-2-methylbutyl}thiophene-2-sulfonamide

To 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide (obtained as described in example 1, 290 mg, 0,824 mmol) in CH2Cl2(15 ml) at 0°add reagent dessa-Martin periodinane (410 mg, 0,989 mmol). The reaction mixture is heated to 25°C. After 10 min, TLC (EtOAc:hexane, 3:7) shows the presence of the original substance. Additionally add periodinane dessa-Martin (410 mg, 0,989 mmol)and after 15 min, TLC shows that starting material had been consumed. Add diethyl ether (30 ml), then aqueous 1 n solution of Na2S2O3(25 ml) and saturated aqueous solution of NaHCO3(25 ml). Milky white solution was vigorously stirred until until both phases will not be homogeneous. The layers are separated and the aqueous phase is extracted with diethyl ether. The combined organic extracts dried (Na2SO4) and concentrate. Flash chromatography (eluent EtOAc:hexane, 3:7) gives 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(formyl-2-methylbutyl)]thiophene-2-sulfonamide (100 mg, 35%) as a white solid.

To 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(formyl-2-methylbutyl)]thiophene-2-sulfonamide (100 mg, 0,286 mmol) in THF (3 ml) at 0°With added dropwise a solution (1,4M, and 0.61 ml) methylacrylamide in a mixture of THF/toluene (0.86 mmol). The reaction to shift the ü is heated to 25° C and stirred for 3 hours. Then the reaction quenched with saturated aqueous ammonium chloride, the mixture is extracted with EtOAc (2×40 ml), dried (Na2SO4) and concentrate. Flash chromatography (eluent EtOAc:hexane, 3:7) gives 5-chloro-N-{(1S,2R)-4,4,4-Cryptor-1-[1-hydroxyethyl]-2-methylbutyl}thiophene-2-sulfonamide (75 mg, 74%) as a mixture of diastereomers of 3:1. The diastereomers share HPLC (column with silica gel Bond® 25×5 cm, eluent methyl tert-butyl ether (MTBE)-hexane, 3:2, diastereoisomer 1 eluted at 11,4 min, diastereoisomer 2 eluted with a 14.1 min).

The diastereoisomer 1: mass spectrum (-ESI): 364 (M-H)-.

The diastereoisomer 2: mass spectrum (-ESI): 364 (M-H)-.

Example 10

5-Chloro-N-[(1S,2S)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide

A. Hydrochloride 5,5,5-Cryptor-L-isoleucine

To cleaners containing hydrochloride salt of (S)-(-)-α-methylbenzylamine (0,340 g of 2.16 mmol) in 20 ml of a mixture of Meon/N2Oh, 1:1, add potassium cyanide (0,139 g, 2,13 mmol) and (2S)-4,4,4-Cryptor-2-methylbutanol (0,300 g, 2.14 mmol, obtained according to the method described in example 1, method 2, but using as a chiral auxiliary substance (S)-(-)-4-benzyl-2-oxazolidinone) and the reaction mixture stirred for 17 hours. The methanol is removed in vacuo and the product extracted with EtOAc. The organic extract was washed with 0.1 G. of aqueous hydrochloric acid, dried (Na2SO4 ) and concentrate. Flash chromatography (eluent EtOAc:hexane, 1:9) gives α-aminonitriles (0,224 g, 39%) as a yellow oil.1H NMR shows that the product is a mixture of diastereomers of 3:1.

To a mixture of diastereoisomers (0,224 g, 0,829 mmol) is added sulfuric acid (3 ml) and the solution stirred for 22 hours. Then the reaction mixture was poured on crushed ice (˜10 g). Added to neutralize the acid concentrated aqueous ammonium hydroxide solution. The resulting mixture was extracted with EtOAc, dried (Na2SO4), filtered and concentrated, resulting in the amide (0,224 g, 94%), which is used in the next stage without additional purification.

A mixture of amide (0,224 g, 0,777 mmol) and 5% palladium/C (Pd/C, 40 mg) is shaken for 2 hours in a Parr apparatus at a pressure of hydrogen (H2) 3 ATM. The mixture is filtered through a layer of celite® and removing the solvent in vacuum, obtaining the final amine as a white solid (128 mg, 90%), which is used in the next stage without additional purification.

Amine (128 mg, 0,695 mmol) in concentrated hydrochloric acid (3 ml) is refluxed for 24 hours. The reaction mixture is cooled to room temperature and concentrated, obtaining a mixture of cleaners containing hydrochloride salts of amino acids (the ratio of diastereoisomers 3:1) and 1 equivalent of chloride of ammonia the form of a white solid (183 mg, 95%). Mass spectrum (+ESI): 186 (M+N)+.

C. (2S,3S)-2-Amino-5,5,5-Cryptor-3-methylpentan-1-ol

To a solution of lithium borohydride (1.0 ml, 2,0N in THF, 2.0 mmol) in THF (5 ml) at 0°With add chlorotrimethylsilane (0.51 ml, to 4.01 mmol). The reaction mixture is heated to 25°and With over 30 min to a suspension, cooled to 0°add dropwise untreated cleaners containing hydrochloride salt of the amino acid (184 mg, 0,669 mmol) in THF (5 ml). The mixture is heated to 25°and after 21 hours the reaction is quenched Meon. Volatiles are removed in vacuo and the resulting residue is dissolved in water 1 N. NaOH solution, extracted with CHCl3(4×20 ml), dried (Na2SO4and concentrate, getting amerosport in the form of a yellow oil (92 mg, 81%), which, according to him spectra1H NMR, is a mixture of diastereomers of 3:1. Mass spectrum (+ESI): 172 (M+H)+.

C. 5-Chloro-N-[(1S,2S)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide

Aminopyrido (168 mg, 0,981 mmol) in CH2Cl2(10 ml), add triethylamine (170 μl, 1.20 mmol) and 5-chlorothiophene-2-sulphonylchloride (256 mg, 1.18 mmol). The reaction mixture was stirred at 25°C for 21 hours. The solution was diluted with EtOAc (50 ml), washed twice with 0.1 N. HCl, dried and concentrated. Thoroughly removing impurities and minor diastereoisomer flash chromatography (eluent EtOAc-hexane, 3:7) gives 5-chloro-N-[(1S,2S)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbut is]thiophene-2-sulfonamide (97 mg, 28%) as a white solid, TPL 99-100°C. HPLC (column with silica gel Bond®, eluent MTBE-hexane, 3:2) shows a mixture of diastereomers 97:3. Chiral HPLC (column AD, eluent isopropanol-hexane, 1:9) shows the enantiomeric purity >99%.

[α]D25=+8,95° (C=1% solution, Meon).

Mass spectrum (-ESI): 350 (M-N)-.

Analysis.

Calculated for C10H13ClF3NO3S2: C, 34,14; N, AND 3.72; N, 3,98.

Found: C, 34,43; N, 3,70; N, 3,91.

Example 11

(2S,3S)-2-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)amido-5,5,5-Cryptor-3-ethylpent-1-ol

A. (R)-4-Benzyl-3-(2-R-bromo-3-S-ethyl-5,5,5-tryptophanol)oxazolidin-2-he

To complex the copper bromide (I)-dimethyl sulfide (328 mg, 1.56 mmol) in THF/DMS (2:1, 60 ml), cooled to -40°add ethylmagnesium (of 1.06 ml, 3M solution in THF, 3.2 mmol). The solution is stirred for 10 min, heating to -15°C. the Mixture is again cooled to -40°and add (R)-4-benzyl-3-(5,5,5-triterpen-2-enoyl)oxazolidin-2-he (obtained as described in example 6, part C, 416 mg, 1.3 mmol) in THF (15 ml). The solution was stirred at 25°C for 16 hours. The solution is again cooled to -78°and add N-bromosuccinimide (473 mg, 2.6 mmol) in THF (10 ml). The solution is heated to 0°C and shaken at 0°C for 3 hours. The reaction is quenched with a mixture of 1:1 saturated solution of ammonium carbonate and 0.5 N. the solution is potassium bisulfate (15 ml). The organic phase is decanted and concentrated, obtaining (R)-4-benzyl-3-(2-R-bromo-3-S-ethyl-5,5,5-tryptophanol)oxazolidin-2-it is identified by liquid chromatography-mass specrometry (LC-MS).

Century 3-(2-S-Azido-3-S-ethyl-5,5,5-tryptophanol)-4R-benzisoxazole-2-he

To (R)-4-benzyl-3-(2R-bromo-3S-ethyl-5,5,5-tryptophanol)oxazolidin-2-ONU dissolved in dimethylformamide (DMF, 10 ml), add sodium azide (172 mg, 2.6 mmol). The solution is stirred for 72 hours, diluted with water (20 ml), extracted with ethyl acetate (2×20 ml) and concentrated, obtaining 3-(2-S-azido-3-S-ethyl-5,5,5-tryptophanol)-4R-benzisoxazole-2-it is identified by LC-MS.

C. (2S,3S)-2-Azido-3-ethyl-5,5,5-cryptocentrus acid

3-(2-S-Azido-3-S-ethyl-5,5,5-tryptophanol)-4-benzyloxypyridine-2-it is dissolved at 0°in a mixture of THF and water, 2:1 (20 ml), and add the monohydrate of lithium hydroxide (1.4 mmol, 60 mg). The solution is shaken for 1 hour at 0°and then adding a saturated solution of sodium carbonate (20 ml). The mixture is extracted with ethyl acetate (20 ml). The aqueous phase is acidified with 2 N. hydrochloric acid, extracted with ethyl acetate (20 ml)to give (2S,3S)-2-azido-3-ethyl-5,5,5-cryptocentrus acid identified by LC-MS.

D. (2S,3S)-2-Amino-3-ethyl-5,5,5-triterpene-1-ol

(2S,3S)-2-Azido-3-ethyl-5,5,5-cryptocentrus acid dissolved in THF (5 ml) at 0°and add alumoweld lithium (1M solution in THF) (1 ml, 1 mmol). The resulting solution was stirred at 40°C for 2 hours. The reaction is quenched by sequentially adding water (60 μl), 15% aqueous sodium hydroxide solution (60 μl) and water (150 ml) with vigorous stirring between each addition. The mixture is then filtered and concentrated, obtaining the (2S,3S)-2-amino-3-ethyl-5,5,5-triterpene-1-ol.

E. (2S,3S)-2-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)amido-5,5,5-Cryptor-3-ethylpent-1-ol

To a solution of (2S,3S)-2-amino-3-ethyl-5,5,5-triterpene-1-ol (0.1 mmol) in THF (2 ml), add triethylamine (83,7 μl, 0.6 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulphonylchloride (28 mg, 0.1 mmol). The solution is stirred for 16 h and concentrated. The solvent is removed, the residue is dissolved in Meon (1.5 ml) and purified prepreparation HPLC with reversed phase (RP)-HPLC using the conditions described below.

Conditions prepreparation RP-HPLC:

Column: column Phenomenex® C18, Luna®, 21.6 mm×60 mm, 5 ám.

Solvent A: water (buffer with 0.02% TFA).

Solvent b: acetonitrile (buffer with 0.02% TFA).

Gradient solvent: time 0: 10% B; 2.5 minutes: 10% a; 14 min: 90% C.

Volume flow: 22.5 ml/min

The product corresponding to the peak is collected based on UV absorption, and concentrate, getting mentioned in the title compound, 1.7 mg, retention time in HPLC 2,97 min, the observed ion 428 (M-H).

Example 12

(2S,3R)-2-(5-Chloro-1,3-d is methyl-1H-pyrazole-4-sulfonyl)amido-5,5,5-Cryptor-3-phenylpentane-1-ol

Following essentially the same procedure of example 11, but using phenylmagnesium and 5-chloro-1,3-dimethylpyrazol-4-sulphonylchloride receive (2S,3R)-2-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)amido-5,5,5-Cryptor-3-phenylpentane-1-ol, 7,1 mg, retention time in HPLC of 2.25 min, the observed ion 424 (M-H).

Example 13

Synthesis triftormetilfullerenov heterocyclic sulfonamida

In one embodiment of the method shown in scheme 13, carried out using the following examples of reagents and conditions. However, the person skilled in the art will understand that certain reaction conditions, such as time, temperature, catalysts and some reagents can be modified.

According to scheme 13, aminoether XVIII (250 g, 0.64 mol) is suspended in toluene (4 l) and the suspension is neutralized to pH 7-8 0,4n NaOH solution (1.6 l). The layers separated, the organic phase is washed with water (1.6 l) and then dried over Na2SO4(250 g). Solution in toluene is cooled to a temperature of -68°C to -62°and treated With 25% solution of diisobutylaluminium (DIBAL-H) in toluene (1278 ml of 1.9 mole, 3 EQ.), keeping the temperature below -60°C. the Mixture is heated to room temperature and stirred for 1 hour. The reaction is quenched with 10% aqueous NaOH solution (128 ml), then dihydrate sodium citrate (500 g) and anhydrous sodium sulfate (385 g). After peremeshivaniem for 1 hour, the solids are removed by filtration and the solution concentrated to oil. The oil obtained is dissolved in diethyl ether (2.6 liters), cooled to 5°and treated With 1 N. HCl solution in ether (750 ml). After stirring for 30 minutes, the solids are collected by filtration, washed with ether and dried in vacuum, obtaining 189 g (85%) of benzylamine in the form of a white solid. Benzylamine (150 g, 0.43 mol) in methanol (150 ml) hydronaut at 40 f/d2in the presence of a catalyst 40 g of 10% Pd/C. After 1.5 hours, the catalyst was removed by filtration and the solution concentrated to a solid. The solid is triturated in a mixture of ether/hexane, collected by filtration and dried, obtaining of 94.8 g (90%) of amerosport in the form of solids.

Amerosport (100,2 g, 0.41 mol) in CH2Cl2(1150 ml) is treated with N,O-bis(trimethylsilyl)ndimethylacetamide (BSA, 110 ml, 0.45 mol), followed by triethylamine (152,4 ml of 1.09 mol) and dimethylaminopyridine (DMAP, 13 g). After 15 minutes, add a solution of sulphonylchloride (105,5 g, 0.49 mol) in CH2Cl2(186 ml) and the mixture is stirred at room temperature for 19 hours (during the night). Add THF (450 ml) and 5% aqueous HCl (800 ml) and the mixture is stirred for 1 hour. The layers are separated and the organic layer washed with 5% solution of NaHCO3and then water. The solution is concentrated and receiving oil, and pass through a layer of silica gel, elwira a mixture of 30% EtOAc/hexane. The fractions containing the product was concentrated in vacuo, that is remoteroot crystallization. Add hexane, the solid is collected by filtration, getting to 87.1 g (55%) of target compound as a white solid. Concentration of the mother liquor gives a second portion of the target compounds of 12.6 g, yield 8%.

Example 14

5-Chloro-N-[1-(4,4-diverticulosis)-2-hydroxyethyl]thiophene-2-sulfonamide

A. {[(5-Chlortan-2-yl)sulfonyl]amino}(4,4-diverticulosis)acetic acid

Amino(4,4-diverticulosis)acetic acid (2,68 g 10,973 mmol) dissolved in 2 N. NaOH solution (20 ml). The solution is cooled to 0°and added dropwise (5 min) solution of 5-chlorothiophene-2-sulphonylchloride (3.25 g, 12,42 mmol) in THF (10 ml). The solution is allowed to warm to 25°With at night. After 19 h THF is removed in vacuo and the mixture acidified to a pH of from about 1 to about 2 2 N. HCl (20 ml). The aqueous layer was washed with EtOAc (4×50 ml). The combined organic layers dried over MgSO4, filtered and concentrated, obtaining {[(5-chlortan-2-yl)sulfonyl]amino}(4,4-diverticulosis)acetic acid in the form of crude oil (3.8 g, 98.2 per cent).

Mass spectrum (-ESI): 372 (M-H)-.

Century 5-Chloro-N-[1-(4,4-diverticulosis)-2-hydroxyethyl]thiophene-2-sulfonamide

To a suspension'lah (0,406 g, 10,70 mmol) in THF (20 ml) at 0°With added dropwise within 20 min {[(5-chlortan-2-yl)sulfonyl]amino}(4,4-diverticulosis)acetic acid (2.0 g to 5.35 mmol).

The reaction mixture is heated at 70°C for 18 hours. The reaction suspension (light brown) is cooled to 0°and the reaction quenched with H2About (1.5 ml), 1 N. NaOH solution (4.5 ml) and N2About (1.5 ml). The reaction mixture is stirred for 4 hours, obtaining a white suspension. The suspension is filtered, and then the mother liquor is dried over MgSO4, filtered and concentrated in vacuo, obtaining the crude oil (1.68 g). The crude product is purified by chromatography on Biotage FlashTM40, eluent EtOAc-hexane, 1:2, receiving 5-chloro-N-[1-(4,4-diverticulosis)-2-hydroxyethyl]thiophene-2-sulfonamide as a white amorphous solid (0.15 g, 7.8 per cent).

Mass spectrum (-ESI): 358 (M-N)-.

Analysis.

Calculated for C12H16ClNF2O3S2·0,17EtOAc: C, 41,02; N, Of 4.49; N, 3,76.

Found: C, 40,63; N, Of 4.67; N, 3,74.

Example 15

5-Chloro-N-[1-(6,6-diversitya[3.1.0]Gex-3-yl)-2-hydroxyethyl]thiophene-2-sulfonamide

A. Methylamino(6,6-diversitya[3.1.0]Gex-3-yl)acetate

To a solution of amino(6,6-diversitya[3.1.0]Gex-3-yl)acetic acid (1.0 g, 5,23 mmol) in a mixture of CH2Cl2:Meon (4:1) at 0°With added dropwise within 10 min TMSCHN2(10.5 ml) up until the mixture becomes steadily neon yellow. The reaction mixture is left to warm to 25°to 19 hours. The solvent is removed in vacuum, obtaining the ethylamine(6,6-diversitya[3.1.0]Gex-3-yl)acetate as a pale yellow oil (0.9 g, 84,11%). Mass spectrum (-ESI): 206 (M+N)+.

C. Methyl{[(5-chlortan-2-yl)sulfonyl]amino}(6,6-diversitya[3.1.0]Gex-3-yl)acetate

A solution of 5-chlorothiophene-2-sulphonylchloride (1.26 g, 4,82 mmol) in CH2Cl2(10 ml) is added dropwise (5 min) to a solution of methylamine(6,6-diversitya[3.1.0]Gex-3-yl)acetate (0.9 g, of 4.38 mmol) in CH2Cl2(10 ml) and triethylamine (1,22 ml, 8,77 mmol), cooled to 0°C. the Solution is allowed to warm to 25°overnight (19 h). Take an aliquot, and TLC (EtOAc-hexane, 1:4) shows that the reaction was completed. The reaction mixture was diluted with CH2Cl2(100 ml) and the organic layer washed with 1 N. HCl (20 ml) and saturated aqueous NaCl (20 ml). The organic layer is dried over MgSO4filter and concentrate, getting not quite crude yellow solid (1,69 g). The crude product is purified by chromatograph Biotage FlashTM40, eluent EtOAc-hexane, 1:4, receiving methyl{[(5-chlortan-2-yl)sulfonyl]amino}(6,6-diversitya[3.1.0]Gex-3-yl)acetate as a colorless oil (0,230 g, 12,23%). Mass spectrum (-ESI): 384 (M+N)+.

C. 5-Chloro-N-[1-(6,6-diversitya[3.1.0]Gex-3-yl)-2-hydroxyethyl]thiophene-2-sulfonamide

To a suspension'lah (0,030 g, 0.78 mmol) in THF (50 ml) at 0°With added dropwise within 20 min methyl{[(5-chlortan-2-yl)sulfonyl]amino}(6,6-diversitya[3.1.0]Gex-3-yl)acetate (0,154 g 0.38 mmol). Suspended (grey) leave the unit's electric is by up to 25° C for 19 hours. The reaction suspension is cooled to 0°and the reaction quenched with H2About (0.5 ml), 1 N. NaOH solution (1.5 ml) and N2About (0.5 ml). The reaction mixture is stirred for 4 hours, obtaining a white suspension. The suspension is filtered, and then the mother liquor is dried over MgSO4, filtered and concentrated in vacuo, obtaining the crude yellow oil (rate £ 0.162 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:4, receiving 5-chloro-N-[1-(6,6-diversitya[3.1.0]Gex-3-yl)-2-hydroxyethyl]thiophene-2-sulfonamide as a colorless oil (0,105 g, with 77.7%).

Mass spectrum (-ESI): 356 (M-N)-.

Analysis.

Calculated for C13H14ClNF2O4S2·0,20EtOAc: C, 41,41; N, Of 3.84; N, 3,56.

Found: C, 41,08; N, Are 3.90; N, 3,47.

Example 16

5-Chloro-N-[(1S,2R)-4,4,4-Cryptor-1-formyl-2-methylbutyl]thiophene-2-sulfonamide

A solution of 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamida (obtained as described in example 1, 3.0 g, 8,53 mmol) in CH2Cl2saturated with water (20 ml), stirred under nitrogen atmosphere at 0°C. Add in one step reagent dessa-Martin periodinane (to 7.59 g, 17,90 mmol). The resulting suspension is stirred at 25°C, controlling the development of the reaction analysis by TLC (EtOAc/hexane, 1:2). Since the rate of conversion of the original in the society decreases, additionally add 2-ml portions of CH2Cl2saturated with water (three portions over 15 min). After aging at 25°C for 19 h, the reaction according to TLC completes. The solution was diluted with Et2O (50 ml) and add a solution of sodium thiosulfate (Na2S2O3, 93,83 mmol, 14.8 g, 11 EQ.) in 80% saturated aqueous sodium bicarbonate solution (50 ml). The mixture is rapidly stirred for 10 min before until both phases will be transparent. The layers are separated and the aqueous layer was extracted with ether (30 ml). The combined organic layers are successively washed with saturated aqueous sodium bicarbonate (10 ml) and brine (15 ml), then dried over MgSO4, filtered and concentrated, obtaining the crude oil (2.67 g). The crude product was then purified using chromatographic system Biotage FlashTM60, eluent EtOAc-hexane, 1:6, receiving 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-formyl-2-methylbutyl]thiophene-2-sulfonamide as a colorless oil (2.65 g, 88,93%).

Mass spectrum (+ESI): 350 (M+N)+.

Analysis.

Calculated for C10H11ClNF2O3S2·0,N2ABOUT: WITH, 33,34; N, AND 2.83; N, A 3.87.

Found: C, 33,74; N, And 3.31; N, 3,93.

Example 17

N-[(1S,2R)-1-Acetyl-4,4,4-Cryptor-2-methylbutyl]-5-chlorothiophene-2-sulfonamide

A. 5-Chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(1-hydroxyethyl)-2-methylbutyl]thiophene-2-sulfo the amide

A solution of 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-formyl-2-methylbutyl]thiophene-2-sulfonamida (obtained as described in example 16, 1.0 g, of 2.86 mmol) in THF (10 ml) is stirred under nitrogen atmosphere at 0°C. is Added dropwise 3M solution methylacrylamide in ethyl ether (1.9 ml, 5,71 mmol) and the resulting solution was stirred for 1 hour at 25°C. At the end of this period the reaction is finished, according to TLC (EtOAc/hexane, 1:2). The solution is quenched with saturated aqueous NH4Cl (10 ml) and extracted with ether (40 ml). The organic layer was washed with brine (20 ml) and then dried over MgSO4getting crude oil (0,867 g). The crude product was then purified using chromatographic system Biotage FlashTM60, eluent EtOAc-hexane, 1:6, receiving 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(1-hydroxyethyl)-2-methylbutyl]thiophene-2-sulfonamide as a colorless oil (0,495 g, 49.5 per cent). Mass spectrum (-ESI): 356 (M-N)-.

C. N-[(1S,2R)-1-Acetyl-4,4,4-Cryptor-2-methylbutyl]-5-chlorothiophene-2-sulfonamide

A solution of 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(1-hydroxyethyl)-2-methylbutyl]thiophene-2-sulfonamida (0,390 g, 1.06 mmol) in CH2Cl2saturated with water (30 ml), stirred under nitrogen atmosphere at 0°C. Add in one step reagent dessa-Martin periodinane (0.95 g, of 2.23 mmol). The resulting suspension is stirred at 25°C, controlling the development of the reaction analysis by TLC (EtOAc/hexane, 1:2). So it is to speed the conversion of the original substance is reduced, optionally add 1-ml portions of CH2Cl2saturated with water (three portions over 15 min). After aging at 25°C for 19 h, the reaction according to TLC completes. The solution was diluted with Et2O (50 ml) and add a solution of sodium thiosulfate (Na2S2O3, 11,83 mmol, 4.8 g, 11 EQ.) in 80% saturated aqueous sodium bicarbonate solution (40 ml). The mixture is rapidly stirred for 10 min before until both phases will be transparent. The layers are separated and the aqueous layer was extracted with ether (20 ml). The combined organic layers are successively washed with saturated aqueous sodium bicarbonate (10 ml) and brine (15 ml), then dried over MgSO4, filtered and concentrated, obtaining the crude oil (0,38 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving N-[(1S,2R)-1-acetyl-4,4,4-Cryptor-2-methylbutyl]-5-chlorothiophene-2-sulfonamide as a white solid (0,265 g, 73,10%).

Mass spectrum (-ESI): 362 (M-N)-.

Analysis.

Calculated for C11H13ClNF3O3S2: C, 36,32; N, 3,6; N, 3,85.

Found: C, 36,08; N, 3,2, N, 3,74.

Example 18

5-Chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]thiophene-2-sulfonamide

A solution of N-[(1S,2R)-1-acetyl-4,4,4-Cryptor-2-methylbutyl]-5-chlorothiophene-2-su is ifosamide (received as described in example 17, 0,100 g, 0,275 mmol) in THF (5 ml) is stirred under nitrogen atmosphere at 0°C. is Added dropwise 3M solution methylacrylamide in ethyl ether (0,266 ml, 0,824 mmol) and the resulting solution stirred for 19 h at 25°C. At the end of this period the reaction is completed according to TLC (EtOAc/hexane, 1:2). The solution is quenched with saturated aqueous NH4Cl (10 ml) and extracted with ether (40 ml). The organic layer was washed with brine (20 ml) and then dried over MgSO4getting crude oil (0,110 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:4, receiving 5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white solid (0,049 g, 46.6 per cent).

Mass spectrum (-ESI): 378 (M-N)-.

Analysis.

Calculated for C12H17ClNF3O3S2: C, 37,94; N, 4,51; N, 3,69.

Found: C, 37,45; N, A 4.03; N, 3,68.

Example 19

4-Bromo-5-chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A. Methyl-4,4,4,4',4',4'-hexaplar-dl-valinnat

A solution of 4,4,4,4',4',4'-hexaplar-dl-valine (1.1 g, 4,88 mmol) in a mixture of CH2Cl2:Meon (4:1, 25 ml) is stirred under nitrogen atmosphere at 0°C. is Added dropwise a solution of TMS-diazomethane (2.0m solution in hexane, 20 ml, 1955 mmol) and the resulting neon-greenish solution was stirred for 19 h at 25° C. At the end of this period the reaction according to TLC (10% Meon in chloroform), is completed. After concentration, the obtained residue is methyl-4,4,4,4',4',4'-hexaplar-dl-validate (1.1 g) used directly in the next stage without additional purification. Mass spectrum (-ESI): 238 (M-N)-.

Century Methyl-N-[(4-bromo-5-chlortan-2-yl)sulfonyl]-4,4,4,4',4',4'-hexaplar-dl-valinnat

A solution of methyl-4,4,4,4',4',4'-hexaplar-dl-validate (1.0 g, 4,18 mmol) in CH2Cl2(10 ml) stirred in an atmosphere of N2at 25°C. is Added dropwise pyridine (0,81 ml, 10,04 mmol), then add 4-bromo-5-chlorothiophene-2-sulphonylchloride (1,486 g of 5.05 mmol) and the resulting solution stirred for 19 h at 25°C. At the end of this period, according to TLC (EtOAc-hexane, 1:4), the reaction is finished. After quenching with water (1.0 ml) the mixture was diluted with CH2Cl2(30 ml). The organic layer is successively washed with 1 N. aqueous hydrochloric acid (10 ml), saturated aqueous NaHCO3(10 ml) and brine (15 ml), then dried over MgSO4, filtered and concentrated, obtaining the crude oil (2.1 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving methyl-N-[(4-bromo-5-chlortan-2-yl)sulfonyl]-4,4,4,4',4',4'-hexaplar-dl-valinnat in the form of a white solid (1,62 g, 83,07%). Mass spectrum (-SI): 497 (M-N) -.

C. 4-Bromo-5-chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

To a solution of methyl-N-[(4-bromo-5-chlortan-2-yl)sulfonyl]-4,4,4,4',4',4'-geksaftorsilikatov (1.45 g 2,907 mmol) in THF (20 ml) in an atmosphere of N2when 0°With added lithium borohydride (LiBH4) (of 5.82 ml, 11,64 mmol). The reaction mixture is left to warm to 25°to 19 hours. The reaction mixture was cooled to 0°C, the reaction is quenched with 2 N. HCl (gradually add), diluted with ether (40 ml) and the organic layer is successively washed with 1 N. aqueous hydrochloric acid (10 ml), saturated aqueous NaHCO3(10 ml) and brine (15 ml), then dried over MgSO4, filtered and concentrated, obtaining the crude oil (1.3 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving 4-bromo-5-chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (1.13 g, 84,32%).

Mass spectrum (-ESI): 469 (M-N)-.

Analysis.

Calculated for C9H7ClBrNF6O3S2: C, 22,97 N, 1,50; N, 2,98.

Found: C, Of 23.11; N, 1,16; N, 2,78.

Example 20

4-Bromo-5-chloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A solution of 4-bromo-5-chlorothiophene-2-sulphonylchloride (0,193 g, 0.64 mmol) in CH 2Cl2(1.0 ml) is added dropwise (5 min) to a solution of (2S)-2-amino-3,3,3-Cryptor-3-(trifluoromethyl)butane-1-ol (obtained according to the method of example 13, 0,115 g, 0,548 mmol) in CH2Cl2(10 ml) and pyridine (0.9 ml, of 1.09 mmol), cooled to 0°C. the Solution is allowed to warm to 25°overnight (19 h). Take an aliquot, and TLC (EtOAc-hexane, 1:1) shows that the reaction was completed. The reaction mixture was diluted with CH2Cl2(100 ml) and the organic layer washed with 1 N. HCl (2×50 ml) and saturated aqueous NaCl (50 ml), dried over MgSO4filter and concentrate, getting not quite crude white solid (0,270 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving 4-bromo-5-chloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (39 mg, 15,11%). Mass spectrum (-ESI): 469 (M-N)-.

Example 21

5-Chloro-4-fluoro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A. 5-Chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-4-(tributylstannyl)-2-sulfonamide

To a solution of 4-bromo-5-chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamida (obtained as described in example 19, 0.9 g, at 1.91 mmol) in 1,4-dioxa is e (42 ml) is added bis(tributylamine) (0,939 g, 2,87 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,221 g, 0,191 mmol). The brown solution was refluxed overnight (19 h). Take an aliquot, and TLC (EtOAc-hexane, 1:1) shows that the reaction was completed. Then the suspension is filtered, and removed solvent in vacuo, receiving a yellow oil (1.31 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving 5-chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-4-(tributylstannyl)-2-sulfonamide as a white solid (0,220 g, 18,86%). Mass spectrum (-ESI): 554 (M-N)-.

Century 5-Chloro-4-fluoro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A solution of 5-chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-4-(tributylstannyl)-2-sulfonamida (0,220 g, 0,396 mmol) in dry acetonitrile (10 ml) is stirred under nitrogen atmosphere at 25°C. Add at once Selectfluor reagent® (0,147 g, 0,416 mmol) and the solution stirred for 19 h at 25°C. After 3 hours it starts to appear a white precipitate. After 19 h select the sample, and TLC (EtOAc-hexane, 1:2) shows that the reaction was not completed. Basically, is the original substance. The reaction mixture is heated at 80°C for 6 hours. Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. Then the suspension is altroot, remove the solvent in vacuo, receiving a yellow oil (0.11 g). The crude product is purified preparative RP-HPLC (column PrimeshereTM, 2×25 cm, eluent 55% MeCN in 0.01% aqueous solution triperoxonane acid (TFA), the volumetric flow rate=25 ml/min, Rt4,401 min)to give 5-chloro-4-fluoro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as an amorphous white solid (0.004 g, 24,69%). Mass spectrum (-ESI): 408 (M-N)-.

Example 22

4-Bromo-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A. Ethyl-N-[(5-bromothiophene-2-yl)sulfonyl]-4,4,4,4',4',4'-hexaplar-dl-valinnat

A solution of ethyl-4,4,4,4',4',4'-hexaplar-dl-validate (1.64 g, 6,48 mmol), obtained as described in the literature (J. Med. Chem., 1981, 24, 1043-1047), CH2Cl2(10 ml) stirred in an atmosphere of N2at 25°C. is Added dropwise pyridine (0,81 ml, 10,04 mmol), then add 5-bromothiophene-2-sulphonylchloride (2,034 g, to 7.77 mmol) and the resulting solution stirred for 19 h at 25°C. At the end of this period, according to TLC (EtOAc-hexane, 1:4), the reaction is finished. After quenching with water (2.0 ml), the mixture was diluted with CH2Cl2(40 ml). The organic layer is successively washed with 1 N. aqueous hydrochloric acid (20 ml), saturated aqueous NaHCO3(20 ml) and RAS is I (15 ml), dried over MgSO4, filtered and concentrated, obtaining the crude oil (3.3 grams). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving ethyl-N-[(5-Bratan-2-yl)sulfonyl]-4,4,4,4',4',4'-hexaplar-dl-valinnat in the form of a white solid (2,40 g 80,0%). Mass spectrum (-ESI): 477 (M-N)-.

Century 5-Bromo-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

To a solution of ethyl-N-[(5-Bratan-2-yl)sulfonyl]-4,4,4,4',4',4'-geksaftorsilikatov (2.4 g 5,02 mmol) in THF (20 ml) in an atmosphere of N2when 0°add LiBH4(20 ml, 20,07 mmol). The reaction mixture is left to warm to 25°to 19 hours. The reaction mixture was cooled to 0°C, the reaction is quenched with 2 N. HCl (gradually add), diluted with ether (50 ml) and the organic layer is successively washed with 1 N. aqueous hydrochloric acid (10 ml), saturated aqueous NaHCO3(10 ml) and brine (15 ml), then dried over MgSO4, filtered and concentrated, obtaining the crude oil (2,31 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving 5-bromo-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (1.3 g, 59,63%).

Mass spectrum (-ESI): 435 (M-N)-.

Analysis.

Calculated for C9H8 BrNF6O3S2: C, 24,78; N, 1,85; N, 3,21.

Found: C, 24,74; N, 1,32, N, 3,11.

Example 23

4-Fluoro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A. N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-5-(tributylstannyl)-2-sulfonamide

To a solution of 5-bromo-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamida (obtained as described in example 22, 1.2 g, a 2.75 mmol) in 1,4-dioxane (40 ml) is added bis(tributylamine) (1,36 g of 4.13 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.32 g, 0,275 mmol). The brown solution was refluxed overnight (19 h). Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. Then the suspension is filtered, and removed solvent in vacuo, receiving a yellow oil (1.4 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-5-(tributylstannyl)-2-sulfonamide as a white solid (0.400 g, 27,97%). Mass spectrum (-ESI): 520 (M-N)-.

Century 5-fluoro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A solution of N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-5-(tributylstannyl)-2-sulfonamida (0.400 g, from 0.76 mmol) in dry AC is onitrile (10 ml) is stirred under nitrogen atmosphere at 25° C. Add at once Selectfluor reagent® (0,285 g, 0,806 mmol) and the solution stirred for 19 h at 25°C. After 3 hours it starts to appear a white precipitate. After 19 h select the sample, and TLC (EtOAc-hexane, 1:2) shows that the reaction was not completed. Basically, is the original substance. The reaction mixture is heated at 80°C for 6 hours. Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. Then the suspension is filtered, and removed solvent in vacuo, receiving a yellow oil (0,191 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving 5-fluoro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as an amorphous white solid (0,010 g, 34,72%). Mass spectrum (-ESI): 374 (M-N)-.

Example 24

5-Bromo-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A solution of 5-bromothiophene-2-sulphonylchloride (0,149 g, 0,568 mmol) in CH2Cl2(1.0 ml) is added dropwise (5 min) to a solution of (2S)-2-amino-4,4,4-Cryptor-3-(trifluoromethyl)butane-1-ol (0,100 g, 0,474 mmol) in CH2Cl2(10 ml) and pyridine (0.1 ml, 0.95 mmol), cooled to 0°C. the Solution is allowed to warm to 25°overnight (19 h). Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that reacts what I ended. The reaction mixture was diluted with CH2Cl2(10 ml) and the organic layer washed with 1 N. HCl (2×10 ml) and saturated aqueous NaCl (10 ml). The organic layer is dried over MgSO4filter and concentrate, getting not quite crude white solid (0,120 g). The crude product is recrystallized from a mixture of CH2Cl2:hexane (1:7)to give 5-bromo-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white fluffy solid (0,0541 g, 27.05 per cent). Mass spectrum (-ESI): 435 (M-N)-.

Example 25

5-fluoro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A. N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-5-(tributylstannyl)-2-sulfonamide

To a solution of 5-bromo-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamida (obtained as described in example 24, 1.1 g, 2,52 mmol) in 1,4-dioxane (40 ml) is added bis(tributylamine) (1,36 g of 4.13 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.32 g, 0,275 mmol). The brown solution was refluxed overnight (19 h). Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. Then the suspension is filtered, and removed solvent in vacuo, receiving a yellow oil (1,05 g). The crude product is purified with the aid of the completion of the chromatographic system Biotage Flash TM40, eluent EtOAc-hexane, 1:6, receiving N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-5-(tributylstannyl)-2-sulfonamide as a white solid (0,350 g, 26.7 percent). Mass spectrum (-ESI): 520 (M-N)-.

Century 5-fluoro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A solution of N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-5-(tributylstannyl)-2-sulfonamida (0.400 g, from 0.76 mmol) in dry acetonitrile (10 ml) is stirred under nitrogen atmosphere at 25°C. Add at once Selectfluor reagent® (0,285 g, 0,806 mmol) and the solution stirred for 19 h at 25°C. After 3 hours it starts to appear a white precipitate. After 19 h select the sample, and TLC (EtOAc-hexane, 1:2) shows that the reaction was not completed. Basically, is the original substance. The reaction mixture is heated at 80°C for 6 hours. Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. Then the suspension is filtered, and removed solvent in vacuo, receiving a yellow oil (0,078 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving 5-fluoro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as an amorphous white solid (0,0061 g, 2.8 per cent).

Mass spectrum (-ESI): 374 (M-N)-.

Example 26

5-N-[4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl]thiophene-2-sulfonamide

A. Iodide (3,3,3-cryptochromes)triphenylphosphane

To a solution of 1-iodine-3,3,3-tryptophan (19.3 g, of 86.1 mmol) in toluene (50 ml) at 23°add triphenylphosphine (25,8 g of 98.5 mmol). The reaction mixture is refluxed and stirred for 28 hours. The resulting mixture was cooled to 0°in an ice bath and filtered to collect a white solid product. The product is washed with toluene (3x) and dried in the air, getting a pure product as a white solid (33,4 g, 80%).

C. Ethyl ester 4,4,4-Cryptor-2-(triphenyl-λ5-postenligaen)butyric acid

To a suspension of iodide (3,3,3-cryptochromes)triphenylphosphine (23,5 g of 48.4 mmol) in THF (100 ml) at -78°C in an atmosphere of nitrogen through an addition funnel slowly add a solution of bis(trimethylsilyl)amide potassium (0.5m in toluene, 175 ml). The resulting mixture was stirred at -78°C for 45 min and then added dropwise to ethylchloride (clean, 5.0 ml). Then the reaction mixture is heated to -20°C for 3 hours under stirring. Then the reaction quenched, pouring the reaction mixture into brine (100 ml) and the mixture extracted with ethyl acetate (100 ml×2). The organic extract is dried (Na2SO4) and concentrate under reduced pressure. Flash chromatography with a mixture of ethyl acetate-hexane (0-100%) on a column of silica gel (120 g) gives the product is a pale yellow solid. Recrystallization of the obtained substance of Et2O gives the pure product as a white solid (6.7 g, 32%). Mass spectrum (+ESI): 431 (M+N)+.

C. Ethyl ester 4,4,4-Cryptor-2-(2,2,2-triptorelin)but-2-ene acid

To a solution of ethyl ester 4,4,4-Cryptor-2-(triphenyl-λ5-postenligaen)butyric acid (2.0 g and 4.65 mmol) in THF (5 ml) was added 1 ml of hydrate triptoreline (technical). The mixture was sealed in a tube high pressure and heated at 100°C for 3.5 hours. After cooling to 23°the reaction mixture elute through a layer of silica gel (100 g) and Na2SO4Et2O (100 ml) to remove by-products of triphenylphosphine and water. Eluent is distilled to remove the E2O receiving the product as a colourless liquid (1.0 g, 86%).

D. Ethyl ester 4,4,4-Cryptor-2-(2,2,2-triptorelin)butyric acid

Ethyl ester 4,4,4-Cryptor-2-(2,2,2-triptorelin)but-2-ene acid (5.0 g, 20.0 mmol) in THF (20 ml) is treated with Pd/C (2.5 g, 5%) and N2(1 ATM) at 25°C for 17 hours. The reaction mixture was filtered through celite reagent®, washed with filter E2O (50 ml), the filtrate is distilled to remove the E2O and THF, receiving the product as a colourless liquid (5.0 g, 99%).

That is, 4,4,4-Cryptor-2-(2,2,2-triptorelin)butane-1-ol

To a suspension of LAH (1.0 g) at E2O (100 ml) at 25°gradually add ethyl is a new air of 4,4,4-Cryptor-2-(2,2,2-triptorelin)butyric acid (5.0 g, for 19.8 mmol). The resulting mixture is stirred at the boil under reflux for 4 hours. After cooling, the reaction mixture sequentially quenched with water (1.0 ml), 15% aqueous NaOH solution (1.0 ml) and water (3.0 ml). After stirring the mixture at 25°C for 17 h add Na2SO4(20 g) and continue stirring at 25°C for 1 hour. The resulting suspension is filtered through a layer of celite® and Na2SO4. The filtrate is distilled to remove all solvents, obtaining the desired product as a colorless liquid (1.7 g, 41%). Mass spectrum (-ESI): 269 [M+OAc]-.

F. 4,4,4-Cryptor-2-(2,2,2-triptorelin)Butyraldehyde

A solution of 4,4,4-Cryptor-2-(2,2,2-triptorelin)butane-1-ol (1.5 g, 7,14 mmol) in CH2Cl2saturated with water (30 ml), stirred under nitrogen atmosphere at 0°C. Add in one step reagent dessa-Martin periodinane (6,35 g, 14,99 mmol). The resulting suspension is stirred at 25°C, controlling the development of the reaction by TLC analysis (EtOAc/hexane, 1:2). Since the rate of conversion of the original substance is reduced, add additional 2-ml portions of CH2Cl2saturated with water (three portions over 15 min). After aging at 25°C for 19 h, the reaction according to TLC completes. The solution was diluted with Et2O (50 ml) and add a solution of sodium thiosulfate (Na2S2O3, 73,33 mmol who, 11.6 g, 11 EQ.) in 80% saturated aqueous sodium bicarbonate solution (50 ml). The mixture is rapidly stirred for 10 min before until both phases will be transparent. The layers are separated and the aqueous layer was extracted with ether (30 ml). The combined organic layers are successively washed with saturated aqueous sodium bicarbonate (10 ml) and brine (15 ml), then dried over MgSO4filter and concentrate to 50% of their original volume, receiving 4,4,4-Cryptor-2-(2,2,2-triptorelin)Butyraldehyde in the form of a solution (20 ml). Mass spectrum (+ESI): (M+N)+.

G. 5-(3,3,3-Cryptor-1-(2,2,2-triptorelin)propyl)imidazolidin-2,4-dione

To sodium cyanide (0,425 g, 8,65 mmol) and ammonium carbonate (0.9 g, 11,54 mmol) in N2O (30 ml) was added 4,4,4-Cryptor-2-(2,2,2-triptorelin)Butyraldehyde (0.6 g, is 2.88 mmol) in ethanol (30 ml). The black reaction mixture is heated to 90°C. After 1 hour, the mixture becomes homogeneous, and it is stirred at 90°C for 18 hours. After cooling to 25°With about 40 ml of the solvent is removed in vacuum. Add concentrated HCl (4 ml) for acidification of the mixture to pH 1-2, and a precipitate. It is filtered off. The mother liquid was washed with EtOAc (3×50 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining 5-(3,3,3-Cryptor-1-(2,2,2-triptorelin)propyl)imidazolidin-2,4-dione as a brown oil (1.01 g, 100%). Mass spectrum (+EI): 279, 280 (M+N)+.

N. 5,5,5-Cryptor-3-(2,2,2-triptorelin)-dl-Norvaline

5-(3,3,3-Cryptor-1-(2,2,2-triptorelin)propyl)imidazolidin-2,4-dione (1.0 g, 3,59 mmol) dissolved in 10 ml of aqueous NaOH (0,575 g in 10 ml of N2Oh, 14,38 mmol). The solution is distributed in two special vessel for microwave technology. The solution is heated by microwave irradiation in sealed vials for 1 hour. The microwave irradiation conditions: 15 min at approximately 100% power, 150°S, 50 f/d2then 5 min break, power 0%. The sequence of operations is repeated until then, until reaction occurs. Water and ammonia are removed from the reaction mixture under vacuum and the resulting crude mixture 5,5,5-Cryptor-3-(2,2,2-triptorelin)-dl-Norvaline (0,92 g, 100%) and NaOH used in the next reaction without further purification. Mass spectrum (+ESI): 254 (M+N)+.

I. N-[(5-Chlortan-2-yl)sulfonyl]-5,5,5-Cryptor-3-(2,2,2-triptorelin)-dl-Norvaline

The crude mixture 5,5,5-Cryptor-3-(2,2,2-triptorelin)-dl-Norvaline (0,92 g of 3.56 mmol) and NaOH is dissolved in water (10 ml). The mixture is cooled to 0°in an ice bath. 5-Chlorothiophene-2-sulphonylchloride (0,852 g, 3.9 mmol) dissolved in THF (10 ml) and the solution added dropwise to the reaction mixture within 10 minutes After 60 min the reaction mixture was gradually heated to 25°C and stirred for 16 hours. THF is removed in vacuo and the mixture acidified to pH <2 N. HCl. After 15 min of milky-white mixture begins to fall precipitate. After 60 min, the mixture is cooled in the refrigerator for 45 min and then filtered. The precipitation was washed with 1 N. HCl (10 ml)to give white solid, which otlipat. It is dissolved in EtOAc (100 ml). The aqueous layer was washed with EtOAc (3×50 ml) and the organic layers washed with saturated aqueous NaCl (50 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining N-[(5-chlortan-2-yl)sulfonyl]-5,5,5-Cryptor-3-(2,2,2-triptorelin)-dl-Norvaline in the form of a brown oil (1.3 g, 86,3%). Mass spectrum (+ESI): 434 (M+N)+.

J. Methyl-N-[(5-chlortan-2-yl)sulfonyl]-5,5,5-Cryptor-3-(2,2,2-triptorelin)-dl-Norvaline

To a solution of N-[(5-chlortan-2-yl)sulfonyl]-5,5,5-Cryptor-3-(2,2,2-triptorelin)-dl-Norvaline (1.3 g, 5,23 mmol) in a mixture of CH2Cl2:Meon (4:1) is added dropwise over 10 min at 0°TMSCHN2(6 ml, 12 mmol) to sustainable neon yellow color. When adding dropwise complete, the reaction mixture is left to warm to 25°to 19 hours. The solvent is removed in vacuum, obtaining methyl-N-[(5-chlortan-2-yl)sulfonyl]-5,5,5-Cryptor-3-(2,2,2-triptorelin)-dl-Norvaline (0.5 g, 37,31%). Mass spectrum (-ESI): 434 (M-N)-.

K. 5-Chloro-N-[4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl]thiophene-2-sulfonamide

To a solution of methyl-N-[(5-chlortan-2-yl)sulfonyl]-5,5,5-Cryptor-3-(2,2,2-triflora who yl)-dl-Norvaline (0.5 g, 1.11 mmol) in THF (10 ml) at 0°C in an atmosphere of N2add LiBH4(2,28 ml of 4.46 mmol). The reaction mixture is left to warm to 25°to 19 hours. The reaction mixture was cooled to 0°and extinguish the reaction of 2 N. HCl (gradual addition), the mixture is diluted with ether (40 ml) and then the organic layer is successively washed with 1 N. aqueous hydrochloric acid (10 ml), saturated aqueous NaHCO3(10 ml) and brine (15 ml), then dried over MgSO4, filtered and concentrated, obtaining the crude oil (0,362 g). The crude product was then purified using chromatographic system Biotage FlashTM12, eluent EtOAc-hexane, 1:6, receiving 5-chloro-N-[4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl]thiophene-2-sulfonamide as a colorless oil (0.001 g, 2.36 per cent). Mass spectrum (-ESI): 418 (M-N)-.

Example 27

5-Chloro-N-[(1S)-4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl]thiophene-2-sulfonamide

A. 4-Methyl-N-[(1Z)-4,4,4-Cryptor-2-(2,2,2-triptorelin)butylidene]benzosulfimide

To the crude organic extract of 4,4,4-Cryptor-2-(2,2,2-triptorelin)Butyraldehyde (obtained as described in example 26, part F, 0.6 g, is 2.88 mmol) in ether (5 ml) add atoxic titanium(IV) (2,63 g, 11,54 mmol), then (S)-(+)-toluensulfonate (0,537 g, 3.46 mmol) and the solution refluxed for 5 hours. the ATEM the mixture is cooled to 0° With and add water (35 ml) to precipitate salts of titanium. The suspension is filtered through a layer of celite® and the filter residue is washed with CH2Cl2. The layers of the filtrate are separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts dried over MgSO4, filtered and concentrated, obtaining the crude yellow oil (1,05 g). The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:9, receiving 4-methyl-N-[(1Z)-4,4,4-Cryptor-2-(2,2,2-triptorelin)butylidene]benzosulfimide in the form of a yellow oil (0,41 g, 41.2 per cent). Mass spectrum (-ESI): 344 (M-N)-.

Century 4-Methyl-N-[(1S)-4,4,4-Cryptor-1 isocyano-2-(2,2,2-triptorelin)butyl]benzosulfimide

The cyanide diethylaluminum (0,233 ml of 1.73 mmol) in THF (10 ml) at 0°add isopropyl alcohol (76 mg, of 1.27 mmol). After 15 min the resulting solution was added to a solution of 4-methyl-N-[(1Z)-4,4,4-Cryptor-2-(2,2,2-triptorelin)butylidene]benzosulfimide (0.4 g, 1,158 mmol) in THF (10 ml), cooled to -78°C. After 15 min the reaction mixture is heated to 25°C. After 5 hours, TLC (EtOAc-hexane, 1:4) indicates that the starting material had been consumed. The mixture is cooled to -78°and add saturated aqueous solution of NH4Cl (30 ml). The resulting suspension is filtered through a layer of celite® and the filter residue washed with EtOAc (2×50 ml). The layers of the filtrate are separated and the water with the Oh extracted with EtOAc. The combined organic extracts dried over MgSO4, filtered and concentrated, obtaining the crude oil (0,360 g).

The crude product was then purified using chromatographic system Biotage FlashTM40, eluent EtOAc-hexane, 1:6, receiving 4-methyl-N-[(1S)-4,4,4-Cryptor-1 isocyano-2-(2,2,2-triptorelin)butyl]benzosulfimide in the form of a colorless oil (0,065 g, 15,18%). Mass spectrum (-ESI): 371 (M-N)-.

C. 5,5,5-Cryptor-3-(2,2,2-triptorelin)-L-Norvaline

A solution of 4-methyl-N-[(1S)-4,4,4-Cryptor-1 isocyano-2-(2,2,2-triptorelin)butyl]benzosulfimide (0,065 g, 0,170 mmol) in concentrated HCl (10 ml) is heated at 100°C for 19 hours. After cooling the mixture to 25°, washed several times with diethyl ether. The aqueous layer was concentrated in vacuo, obtaining a mixture of 5,5,5-Cryptor-3-(2,2,2-triptorelin)-L-Norvaline, NH4Cl and 4-methylbenzenesulfonic acid (0,045 g, 100%). The crude amino acid used in the next stage without additional purification. Mass spectrum (+ESI): 255 (M+N)+.

D. (2S)-2-Amino-5,5,5-Cryptor-3-(2,2,2-triptorelin)pentane-1-ol

To a solution of LiBH4(0.35 ml, 0.71 mmol) in THF (5 ml) at 0°With add chlorotrimethylsilane (0,112 ml, 0,885 mmol). The reaction mixture is heated to 25°and after 30 minutes is added dropwise to a suspension of the crude cleaners containing hydrochloride salt 5,5,5-Cryptor-3-(2,2,2-triptorelin)-L-Norvaline (0,045 g, 0,177 mmol) in THF (1 ml), cooled is about 0° C. the Mixture is heated to 25°and after 21 hours the reaction is quenched Meon. Volatiles are removed under vacuum, obtaining a residue which is dissolved in 1 N. aqueous NaOH solution (5 ml) and extracted with CH2Cl2(4×10 ml). The organic layer is dried over MgSO4, filtered and concentrated, obtaining (2S)-2-amino-5,5,5-Cryptor-3-(2,2,2-triptorelin)pentane-1-ol in the form of a crude light yellow oil (0,046 g, 100%). The crude amerosport use in the next stage without additional purification. Mass spectrum (+ESI): 240 (M+N)+.

E. 5-Chloro-N-[(1S)-4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl]thiophene-2-sulfonamide

A solution of 5-chlorothiophene-2-sulphonylchloride (0,193 g, 0,654 mmol) in CH2Cl2(1.0 ml) is added dropwise (5 min) to a solution of (2S)-2-amino-5,5,5-Cryptor-3-(2,2,2-triptorelin)pentane-1-ol (0,042 g, 0,175 mmol) in CH2Cl2(1.0 ml) and pyridine (1.0 ml, of 1.09 mmol), cooled to 0°C. the Solution is allowed to warm to 25°overnight (19 h). Take an aliquot, and TLC (EtOAc-hexane, 1:2) shows that the reaction was completed. The reaction mixture was diluted with CH2Cl2(10 ml) and the organic layer washed with 1 N. HCl (2×5 ml) and saturated aqueous NaCl (5 ml). The organic layer is dried over MgSO4filter and concentrate, getting not quite crude white solid (0,014 g). The crude product was then purified using chromatographic the system Biotage Flash TM12, eluent EtOAc-hexane, 1:4, receiving 5-chloro-N-[(1S)-4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl]thiophene-2-sulfonamide as a white solid (0.003 g, 4.1 per cent). Mass spectrum (+ESI): 420 (M+N)+.

Example 28

4,5-Dichloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A. 3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)Propylamine

A solution of lithium borohydride (2M in THF, to 19.8 ml) at 25°added to a solution of ethyl ester of 2-amino-4,4,4-Cryptor-3-cryptomelane acid (5 g, to 19.8 mmol), obtained as described in the literature (J. Med. Chem., 1981, 24, 1043-1047)in THF (80 ml) and stirred for 4 hours. To the reaction mixture very gently add 2M HCl up until the pH is below 2. The organic solvent is removed in vacuum and the aqueous layer was neutralized with saturated solution of NaHCO3to pH=7. The aqueous layer was extracted with EtOAc (2×50 ml), the organic extracts dried over Na2SO4and concentrate, receiving 3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)Propylamine as a yellow oil (3.2 g, yield 77%). The crude oil is of sufficient purity for use in subsequent reactions.

C. 4,5-Dichloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A solution of 3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)Propylamine (0192 g, 0.9 mmol) in THF (1 ml) is stirred under nitrogen atmosphere at 25°C. Add pyridine (0,147 ml, 1.82 mmol), then 4,5-dichlorothiophene-2-sulphonylchloride (0,226 g, 0,391 mmol) in THF (1 ml) and the resulting solution stirred for 18 h at 25°C. After concentration the residue is dissolved in EtOAc (15 ml) and the solution washed with 1 N. aqueous hydrochloric acid (10 ml) and brine (10 ml) and then dried (Na2SO4). After concentration the crude product was then purified preparative TLC, eluent EtOAc-hexane, 30:70, receiving 4,5-dichloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (0.037 g, yield 9%, racemic mixture). Mass spectrum (-ESI): 423,9 (M-N)-.

Example 29

N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide

A solution of (1S)-3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)Propylamine (obtained according to the method of example 13, 0,100 g, 0.4 mmol) in CH2Cl2(1 ml) is stirred under nitrogen atmosphere at 25°C. Add pyridine (0,097 ml, 1.2 mmol), then 3-thiophenesulfonyl (0,072 g, 0.4 mmol) in CH2Cl2(0.5 ml) and the resulting solution stirred for 18 h at 25°C. the Crude reaction mixture was loaded into samplet TsOH SyntageTMand after concentration of purified using chromatography with the system Biotage Flash TM12, eluent EtOAc-hexane, 30:70, receiving N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide as a white solid (0,053 g, yield 35%).

Mass spectrum (-ESI): 355,9 (M-N)-.

Analysis.

Calculated for C9H8ClF6NO3S2: C, 30,25 N, 2,54; N, 3,92.

Found: C, 30,55; N, 2,27; N, Of 3.77.

Example 30

2,5-Dichloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide

Follow the procedure described in example 29, except that use 2.5-dichlorothiophene-3-sulphonylchloride, receiving 2,5-dichloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide as a white solid (0,026 g, yield 17%). Mass spectrum (-ESI): 423,8 (M-N)-.

Example 31

N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

Follow the procedure described in example 29, except that use 2-thiophenesulfonyl, receiving N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (0,024 g, yield 17%). Mass spectrum (-ESI): 355,9 (M-N)-.

Example 32

4,5-Dichloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

/p>

Follow the procedure described in example 29, except that the use of 4.5-dichlorothiophene-2-sulphonylchloride, receiving 4,5-dichloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (0,050 g, yield 29%). Mass spectrum (-ESI): 423,8 (M-N)-.

Example 33

(3,3,3-Cryptor-1-hydroxymethyl-2-cryptomaterial)amide thiophene-2-sulfonic acid

To a solution of 3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)Propylamine (obtained according to the method of example 28, part a, 105 mg, 0.5 mmol) in CH2Cl2(1 ml) is added pyridine (100 μl) and 2-thiophenesulfonyl (90,5 mg, 0.5 mmol) in CH2Cl2(1 ml). The solution is stirred for from about 8 to about 16 hours at 25°and then concentrate. Add EtOAc (1 ml) and the solution washed with 1M HCl (1 ml) and brine (1 ml), dried over Na2SO4and concentrate. The crude solid is purified by chromatographic system Biotage FlashTM12, elwira a mixture of EtOAc/hexane (2:3), receiving (3,3,3-Cryptor-1-hydroxymethyl-2-cryptomaterial)amide thiophene-2-sulfonic acid in the form of a white solid.

The following compounds (examples 33-35, table 1) are obtained using 2-thiophenesulfonyl, 3-thiophenesulfonyl and 2.5-dichlorothiophene-3-sulphonylchloride and methodology, described the th in example 33.

Table 1< / br>
(Data* LC-MS: molecular ion and retention time)
RSO2Cl3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)Propylamine
2-thiophenesulfonylExample 33

(356 M-N); 2,063 min
3-thiophenesulfonylExample 34

(356 M-N); 2,013 min
2.5-dichlorothiophene-3-sulphonylchlorideExample 35

(424 M-N); 2,564 min
*HPLC/MS on a Hewlett Packard Series 1100, column c Luna C18, 2×30 mm, elution with a gradient from 40% mixture of acetonitrile/water (0.1% HCOOH) to 100% acetonitrile (0.1% HCOOH) for 3 minutes at a volumetric flow rate of 0.6 ml/min

Example 36

Dibromo-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

To a solution of 3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)Propylamine (obtained according to the method of example 28, part a, 105 mg, 0.5 mmol) in CH2Cl2(1 ml) is added pyridine (100 ml) and 4,5-dibromothiophene-2-sulphonylchloride (170 mg, 0.5 mmol) in CH2Cl2(1 ml). The solution is stirred for from about 8 to about 16 hours at 25°and then concentrate. Add EtOAc (1 ml) and p is the target washed with 1M HCl (1 ml) and brine (1 ml), dried over Na2SO4and concentrate. The crude solid is dissolved in DMSO (0.5 ml), purified HPLC with reversed phase (device for HPLC Gilson®, column c Luna® C18, 100×30 mm, elution with a gradient from 40% mixture of acetonitrile/water (0,075% TFA) to 100% acetonitrile (0,075% TFA) for 15 minutes at a volumetric flow of 20 ml/min), receiving specified in the header connection (13,8 mg) as a white solid.

The following compounds (examples 36-39, table 2) receive, using 4,5-dibromothiophene-2-sulphonylchloride, 2-bromo-5-chlorothiophene-2-sulphonylchloride, 3-bromo-2,5-dichlorothiophene-2-sulphonylchloride and benzothiophen-2-sulphonylchloride and the procedure described in example 36.

Table 2< / br>
(Data* LC-MS: molecular ion and retention time)
RSO2Cl3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)Propylamine
4,5-dibromothiophene-2-sulphonylchlorideExample 36

(514,1 M-N); 1,882 min
3-bromo-5-chlorothiophene-2-sulphonylchlorideExample 37

(470,1 M-N); 1,699 min
4-bromo-2,5-dichlorothiophene-3-sulphonylchlorideExample 38

(504,0 M-N); 1,916 min
benzothiophen-2-sulphonylchlorideWhen the EP 39

(406,2 M-N); 1,508 min
*HPLC/MS on a Hewlett Packard Series 1100, column c Luna C18, 2×30 mm, elution with a gradient from 40% mixture of acetonitrile/water (0.1% HCOOH) to 100% acetonitrile (0.1% HCOOH) for 3 minutes at a volumetric flow rate of 0.6 ml/min

Example 40

5-Chloro(3,3,3-Cryptor-1-hydroxymethylpropane)thiophene-2-sulfonamide

A. 2-Amino-4,4,4-triptorelin-1-ol

The solution trimethylsilylpropyne (1,38 g of 12.73 mmol) are added to a solution of lithium borohydride (3.2 ml, 2.0m in THF) and THF (5 ml) at 25°C. After stirring for 5 min add on parts for 5 min 2-amino-4,4,4-cryptomelane acid (0.50 g, 3,18 mmol). The reaction mixture is stirred for 48 hours. The reaction is quenched by adding carefully dropwise Meon (5 ml). The solvent is evaporated and the residue is treated with a solution of potassium hydroxide (KOH) (20%, 6 ml). The aqueous phase is extracted 3 times using dichloromethane (each time 10 ml). The organic phases are combined and dried over anhydrous sodium sulfate. After filtration the solvent is evaporated, obtaining 2-amino-4,4,4-triptorelin-1-ol in the form of oil (0,174 g, 38%). Oil is used directly in the next reaction without further purification.

Century 5-Chloro(3,3,3-Cryptor-1-hydroxymethylpropane)thiophene-2-sulfonamide

To a solution of 2-amino-4,4,4-triptorelin-1-ol (0,161 g, 1.12 mmol) in the ear CH 2Cl2(4 ml) at 25°C in nitrogen atmosphere is added dropwise Et3N (0.17 ml of 1.23 mmol) and then added dropwise a solution of 5-chlorothiophene-2-sulphonylchloride (0,243 g, 1.12 mmol) in dichloromethane (1 ml). The reaction mixture was stirred for 18 h at 25°C. Then the reaction quenched, pouring the reaction mixture into a separating funnel containing a saturated solution of NaHCO3. Additionally add CH2Cl2(15 ml). After extraction the organic layer was washed with 1 N. HCl, distilled water and brine. Then the organic phase is dried over MgSO4and concentrated to a crude solid. After concentration the crude product was then purified flash chromatography, eluent hexane:EtOAc, 4:2 to 2:1, receiving 5-chloro(3,3,3-Cryptor-1-hydroxymethylpropane)thiophene-2-sulfonamide as a clear oil which crystallized under vacuum (0,191 g, 53%).

Mass spectrum (-ESI): EUR 321.9 (M-H)-.

Analysis.

Calculated for C8H9ClF6NO3S2: C, 29,68 N, 2,80; N, 4,33.

Found: C, 29,75; N, 2,72; N, 4,10.

Example 41

5-Chloro-N-[(1S)-3,3,3-Cryptor-1-[(1R)-1-hydroxyethyl)]-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A. 5-Chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-S-(formyl)propyl]thiophene-2-sulfonamide

A solution of 5-chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-S-(hydroxymethyl)propylthiophene-2-sulfonamida (obtained according to the method of example 5, 0,200 g, 0,511 mmol) in CH2Cl2(10 ml) is stirred under nitrogen atmosphere at 0°C. Add in one step reagent dessa-Martin periodinane (0,325 g, 0,767 mmol) and the solution stirred for 1 hour at 0°C. After additional stirring for 1 hour at 25°With the reaction according to TLC (EtOAc:PE, 30:70), is completed. The solution was diluted with Et2O (100 ml) and the resulting solution was added Na2S2O3(1.0 g) in a saturated aqueous solution of NaHCO3(10 ml). The resulting mixture is stirred for 0.5 hour. Layers of liquids are separated and the organic layer is optionally washed with saturated aqueous NaHCO3(10 ml) and brine (10 ml) and then dried (Na2SO4). After concentration, the obtained residue (0,190 g, 95%) is used directly in the next reaction without further purification.

Century 5-Chloro-N-[(1S)-3,3,3-Cryptor-1-[(1R)-1-hydroxyethyl)]-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide

A solution of 5-chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-S-(formyl)propyl]thiophene-2-sulfonamide (0,188 g, 0,482 mmol) in THF (5 ml) is stirred under nitrogen atmosphere at 0°C. is Added dropwise to methylacrylamide (0,482 ml, 3M solution in Et2O) and the resulting solution was stirred for 2 hours at 25°C. At the end of this period the reaction is completed according to TLC (EtOAc:PE, 30:70). The solution is quenched with a saturated aqueous solution of N 4Cl (10 ml) and then extracted with Et2O (100 ml). The organic layer was washed with brine (10 ml) and then dried (Na2SO4). After concentration the crude product is purified by preparative chromatography on plates, eluent EtOAc:PE, 30:70, then chiral HPLC [column Chiracel® OJ; 2×25 cm, 254 nm, spiski 0.6 ml; mobile phase: 10 ml/min 10% EtOH in 7200; product corresponds to the peak of one Rf=6,106, purity of 99.9%]getting the main diastereoisomer of 5-chloro-N-[(1S)-3,3,3-Cryptor-1-[(1R)-1-hydroxyethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as not quite white solid (0,043 g, 22%).

Mass spectrum (-ESI): 404 (M-N)-.

Analysis.

Calculated for C10H10ClF6NO3S2: C, 29,60; N, 2,48; N, 3.45 POINTS.

Found: C, 29,59; N, 2,40; N, 3,41.

Example 42

Analysis of ELISA Aβ40/42

A. Brief description of the analysis

The original solutions of the compounds in DMSO was diluted to a concentration of 2 μm and below in the medium for cell cultivation. Then the connections are applied to the cells of SSC containing plasmid ARR-REP-NL [Sudhir et al., J. Biol. Chem., 267:25602-25608 (1992)], for 22 hours. After a period of conditioning environment is collected, diluted in buffer for analysis containing protein and samples, controls and synthetic peptide standards are incubated in the plate for preparative ELISA. Using sandwich ELISA with antibodies specifically directed against amoxilina the end of the beta-amyloid 40 or 42 [similar to the way, described in Haugabook et al., J. Neurosci. Methods 108:171-179 (2001), but using goat antimachine IgG1 (source Southern Biotech) as binding fragment, E as immobilized antibodies (source SENETEK), rabbit anti-Aβ40 and anti-aβ42 (source QCB) and anti-rabbit IgG APL ass (H+L source Southern Biotech) as an identifying antibodies], quantify the treatment effect of the compound on the production of cells of extracellular beta-amyloid. The cells are then treated with compound are incubated in the medium for growing cells containing MTS-formazan. After a short incubation period, the tablets containing MTS/Wednesday, read on a spectrophotometer to determine the extent to which the toxicity of compound effects on the metabolism and the ability of cells to synthesize beta-amyloid.

C. Materials for analysis

(i) the samples: samples of the compounds come in the form of the original 20M solutions in 100% DMSO.

(ii) the cells of APP-REP-NL: suitable cell lines receive weekly using dilutions of 1:100 and grown in DMEM with the addition of 1X antibiotic/fungicide 100 μg/ml of the antibiotic G418 and 10% certified fetal calf serum. Cells preserved in liquid nitrogen. Periodically evaluate the production of beta-amyloid and cell or leave in culture, or replace predecessors PR is full of expression.

(iii) Antibodies: are conditioned by parties that have already been identified as suitable in this analysis. Antibodies store small frozen aliquot at -80°With that thaw and use.

(iv) Reagents: reagents are of the highest available purity. Some reagents are lot-specific" ("lot specific"), and can be used reagents only from a particular manufacturer and of a certain party.

(v) Plastic tableware is the dishes of the highest available quality.

C. Criteria activity

A compound is considered active if it has EU50to reduce Aβ40 <100 μm, and non-toxic at doses near EU50.

D. Standard inhibitor of beta-amyloid

The reference inhibitor gamma secretase DAPT (LY374973, AN37124: Dovey H.F. et al., J. Neurochem., 76:173-181 (2001)) are obtained as described in WO 98/22494 and experience in ELISA Aβ40/42, getting AβES50=171 nm and AβES50=128 nm.

Example 43

Analysis on the release of the repressor (RRA)

The compounds obtained as described above in the examples, have in RRA according to published methods [Shuey D.J., Sheiffele P., Jones D., Cockett M.I. and Quinet E.M. (1999), "Repressor release: a useful tool for monitoring amyloid precursor protein (APP) proteolysis in mammalian cells", Society for Neuroscience Abstracts, Vol.25, 29thAnnual Meeting of Society for Neuroscience, Maiami Beach, Florida, October 23-28, 1999]. Briefly, this analysis is performed as education is om.

A. Culturing cells

Cells Cho-K1 grown in complete DMEM media (DMEM enriched with glucose, 10% fetal calf serum, 1% amino acids, non-essential, and 1% penicillin-streptomycin) at 37°With 5% CO2. Two million cells were seeded in 10-cm Cup for 24 hours before transfection.

Transient transfection performed, as recommended by Gibco BRL, using its system lipofectamine-plus® (Lipofectamine Plus®). First 6 µg pRSVO-luc and 6 µg design DNA APP-lacI add to 460 μl medium for transfection Opti-Mem and incubated with 30 μl of plus reagent® within 15 minutes. Then the lipid mixture of 40 μl of reagent lipofectamine-plus® and 460 μl medium for transfection Opti-Mem incubated with a mixture of DNA plus reagent for 15 minutes. During incubation, the mixture of DNA-lipid cells Cho-K1 once washed and placed in 5.0 ml of DMEM medium without penicillin-streptomycin. Then the preparation of DNA-lipid put a layer of these cells and incubated at 37°With during the night.

One and a half million transfected cells per well (total volume 100 μl) were seeded in sterile opaque 96-well culture tablets Cultur-PlateTM, Packard, clean complete DMEM (DMEM without phenol red) and incubated at 37°With 5% CO2within 3-5 hours.

Century, the Breeding of connections

Connection bred with the use of the TLD is different schemes; one scheme is used for connections coming in pure form (suspended powder in vials), and the other scheme is used for connections coming in solution (20 mm in DMSO in 96-well tablets). For both schemes receive fresh environment 25 mm Hepes and 25 mm Hepes/1% DMSO, which is used as diluents. Hepes/DMSO used as a control diluent in all experimental plates.

The following table shows the progress of cultivation connection (it should be noted that the last stage is to add a connection to the cell system in the tablet for the cultivation of tissues).

Table 3
ConcentrationBreeding
The original solution10 mg/mlx mg of compound (bottle), diluted in 100% DMSO
Breeding 11 mg/ml20 μl of the original solution,

180 μl of 25 mm Hepes
Breeding 2200 µg/ml60 ál of dilution 1,

240 μl of 25 mm Hepes
Breeding 3 (tablet)20 mg/ml11,3 ál dilution 2

(100 ál cells/well)

Because some connections are in 96-well clearance in the concentration of the emission of 20 mm, the following is the scheme of their cultivation (it should be noted that the average molecular weight of these compounds is used to calculate dilutions, and, as above, the last step is to add a connection to the cell system in the tablet for the cultivation of tissues).

Table 4
ConcentrationBreeding
The original solution (initial concentration)-20 mm solution
Breeding 1approximately 200 μg/ml6 μl of the original solution, 194 μl of 25 mm Hepes
Breeding 2 (tablet)about 20 kg/ml11,3 ál dilution 2

(100 ál year old/well)

As soon as the connection is divorced, their use in a double repeat to cells in tablets for the cultivation of tissues (prepared as above). Cells incubated with the compound at 37°With 5% CO2additionally within 36-48 hours.

C. Measurement analysis

Conduct analyses with luciferase (reagent LucLit®, Packard) and read the results on the TopCount instrument®, Packard. Each 96-well tablet remove the medium and replace 100 CL PBS per well (of Mg2+or Sa2+). In each link is add an equal volume (100 ál) lysis/substrate buffer LucLit® and tablets, sealed and shaken in the dark on a rotary shaker for from about 15 to about 30 minutes at room temperature. Then reads luciferase on the TopCount instrument®. The results are expressed in relative light units (RLU) and process and analyze by MS Excell®as specified below.

D. Analysis of results

The results of the analysis with respect to the compounds described as examples in this description and shown in the table below. A compound is considered active in the RRA, if it leads to a 1.5-fold, at least the increase in luciferase activity at a concentration of 20 μg/ml and is not toxic to determine the signal attenuation (≤0,75-fold increase). The rate of increase is the amount of luciferase activity (measured in relative light units) in comparison with control diluent. SEM is the standard error of the mean values for the ratio increases (not shown). It was found that all compounds are non-toxic.

That is, a Standard inhibitor of beta-amyloid

The reference inhibitor gamma secretase DAPT (LY374973, AN37124: Dovey H.F. et al., J. Neurochem., 76:173-181 (2001)) are obtained as described in published International patent # WO 98/22494, and experience in RRA, getting 18,5-28,1-fold increase Lucifer the heat activity at 20 μg/ml

Table 5< / br>
Examples of compounds of the invention
Example No.Data RRA*Name
13,2

3,7
5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide
23,7

4,3

of 5.4
5-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide
34,35'-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(1-hydroxyethyl)butyl]thiophene-2'-sulfonamide
43,75'-chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)propyl]thiophene-2'-sulfonamide
5the 3.85'-chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-S-(hydroxymethyl)propyl]thiophene-2'-sulfonamide
64,25-chloro-N-[(1R,2S)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide
7a 3.95-chloro-N-[4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide
82,85-chloro-N-{(1S,2R)-4,4,4-Cryptor-[(1S)-1-hydroxyethyl]-2-methylbutyl}thiophene-2-sulfonamide
92,85-chloro-N-{(1S,2R)-4,4,4-Cryptor-[(1R)-1-hydro is setil]-2-methylbutyl}thiophene-2-sulfonamide
105,25-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide
114,2(2S,3S)-2-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl)amido-5,5,5-Cryptor-3-ethylpent-1-ol
121,6(2S,3R)-2-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)amido-5,5,5-Cryptor-3-phenylpentane-1-ol
146,2

5,8
5-chloro-N-[1-(4,4-diverticulosis)-2-hydroxyethyl]thiophene-2-sulfonamide
15the 4.75-chloro-N-[1-(6,6-diversitya[3.1.0]Gex-3-yl)-2-hydroxyethyl]thiophene-2-sulfonamide
16a 3.95-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-formyl-2-methylbutyl]thiophene-2-sulfonamide
173,6N-[(1S,2R)-1-acetyl-4,4,4-Cryptor-2-methylbutyl]-5-chlorothiophene-2-sulfonamide
182,95-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]thiophene-2-sulfonamide
194-bromo-5-chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
204-bromo-5-chloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
21Ȋ 5-chloro-4-fluoro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
225-bromo-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
235-fluoro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
245-bromo-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
255-fluoro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
265-chloro-N-[4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl]thiophene-2-sulfonamide
275-chloro-N-[(1S)-(4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl)]thiophene-2-sulfonamide
284,5-dichloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
29N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide
302,5-dichloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide
31N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
324,5-dichloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
33(3,3,3-Cryptor-1-hydroxymethyl-2-cryptomaterial)amide thiophene-2-sulfonic acid
34(3,3,3-Cryptor-1-hydroxymethyl-2-cryptomaterial)amide thiophene-3-sulfonic acid
35(3,3,3-Cryptor-1-hydroxymethyl-2-cryptomaterial)amide 2,5-dichlorothiophene-3-sulfonic acid
364,5-dibromo-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
373-bromo-5-chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
384-bromo-2,5-dichloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide
39(3,3,3-Cryptor-1-hydroxymethyl-2-cryptomaterial)amide benzo[b]thiophene-2-sulfonic acid
403,8

4,2
5-chloro-(3,3,3-Cryptor-1 hydroc meterpreter)thiophene-2-sulfonamide
416,25-chloro-N-[(1S)-3,3,3-Cryptor-1-[(1R)-hydroxyethyl]-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide
*The rate of increase of APPI, all compounds tested at 20 g/ml

All publications cited in this specification, are included as references. Although the invention is described with reference to certain preferred embodiments, it should be borne in mind that it is possible to carry out modifications without departing from the substance of the invention. It is implied that such modifications are included in the scope of the attached claims.

1. The compound of formula (I)

where T is chosen from the group consisting of Cho, COR8and C(OH)R1R2;

R1and R2independently selected from the group consisting of hydrogen, C1-6of alkyl;

R3represents hydrogen;

R4selected from the group consisting of (CF3)nof alkyl, (CF3)nalkylphenyl, and (F)ncycloalkyl;

N is 1-2;

R5selected from the group consisting of hydrogen, halogen, diene fused to Y when Y represents S, and diene fused to Y when Y represents s, and substituted with halogen;

W, Y and Z independently are selected from the group consisting of C, CR6and N, p and condition, that at least one of W or Y, or Z must be C;

R6selected from the group consisting of hydrogen, halogen and C1-6of alkyl;

X is chosen from the group consisting of S and NR7;

R7selected from the group consisting of C1-6of alkyl; and

R8represents a C1-6alkyl;

or its pharmaceutically acceptable salt or hydrate.

2. The compound according to claim 1, where R5represents a halogen.

3. The compound according to claim 2, where R5represents chlorine, bromine or fluorine.

4. The compound according to any one of claims 1 to 3, where R1and R2each represents hydrogen.

5. The compound according to claim 1, where W represents S, and Z represents CR6.

6. The compound according to claim 1, in which X represents S, and W, Y and Z are independently selected from C or CR6provided that one of W, Y or Z represents S.

7. The compound according to claim 1, where R4selected from the group consisting of (CF3)nC1-6of alkyl and (CF3)n(C1-6alkyl)phenyl S-stereochemistry.

8. The compound according to claim 1, in which X represents S, W represents S, Y represents CH, Z represents CH, R5represents chlorine, R4is a CF3CH2SNSN3, R3, R1and R2each represents hydrogen, having stereohype the 1S, 2R.

9. The compound according to claim 1, in which X represents S, W represents S, Y represents CH, Z represents CH, R5represents chlorine, R4is a CF3CHCF3and R3, R1and R2each represents hydrogen, having the stereochemistry of 1S.

10. The compound according to claim 1, where W represents N and X represents NR7.

11. The compound according to claim 1, where the compound is chosen from the group including

5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;

5-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide;

5'-chloro-N-[(1S,2R)-2-ethyl-4,4,4-Cryptor-1-(1-hydroxyethyl)butyl]thiophene-2'-sulfonamide;

5'-chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-(hydroxymethyl)propyl]thiophene-2'-sulfonamide;

5'-chloro-N-[3,3,3-Cryptor-2-(trifluoromethyl)-1-S-(hydroxymethyl)propyl]thiophene-2'-sulfonamide;

5-chloro-N-[(1R,2S)-2-ethyl-4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide;

5-chloro-N-[4,4,4-Cryptor-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide;

5-chloro-N-{(1S,2R)-4,4,4-Cryptor-[(1S)-1-hydroxyethyl]-2-methylbutyl}thiophene-2-sulfonamide;

5-chloro-N-{(1S,2R)-4,4,4-Cryptor-1-[(1R)-1-hydroxyethyl]-2-methylbutyl}thiophene-2-sulfonamide;

5-chloro-N-[(1S,2S)-4,4,4-Cryptor-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;

(2S,3S)-2-(5-the ENT-3-methylbenzo[b]thiophene-2-sulfonyl)amido-5,5,5-Cryptor-3-ethylpent-1-ol;

(2S,3R)-2-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)amido-5,5,5-Cryptor-3-phenylpentane-1-ol;

5-chloro-N-[1-(4,4-diverticulosis)-2-hydroxyethyl]thiophene-2-sulfonamide;

5-chloro-N-[1-(6,6-diversitya[3.1.0]Gex-3-yl)-2-hydroxyethyl]thiophene-2-sulfonamide;

5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-formyl-2-methylbutyl]thiophene-2-sulfonamide;

N-[(1S,2R)-1-acetyl-4,4,4-Cryptor-2-methylbutyl]-5-chlorothiophene-2-sulfonamide;

5-chloro-N-[(1S,2R)-4,4,4-Cryptor-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]thiophene-2-sulfonamide;

4-bromo-5-chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

4-bromo-5-chloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

5-chloro-4-fluoro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

5-bromo-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

5-fluoro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

5-bromo-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

5-fluoro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

5-chloro-N-[4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl]thiophene-2-sulfonamide;

5-chloro-N-[(1S)-(4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl)]is iophen-2-sulfonamide;

4,5-dichloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide;

2,5-dichloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide;

N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

4,5-dichloro-N-[(1S)-3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

(3,3,3-Cryptor-1-hydroxymethyl-2-cryptomaterial)amide thiophene-2-sulfonic acid;

(3,3,3-Cryptor-1-hydroxymethyl-2-cryptomaterial)amide thiophene-3-sulfonic acid;

(3,3,3-Cryptor-1-hydroxymethyl-2-cryptomaterial)amide 2,5-dichlorothiophene-3-sulfonic acid;

4,5-dibromo-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

3-bromo-5-chloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

4-bromo-2,5-dichloro-N-[3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

(3,3,3-Cryptor-1-(hydroxymethyl)-2-(trifluoromethyl)propyl)amide benzo[b]thiophene-2-sulfonic acid;

5-chloro-(3,3,3-Cryptor-1-hydroxymethylpropane)thiophene-2-sulfonamide and

5-chloro-N-[(1S)-3,3,3-Cryptor-1-[(1R)-hydroxyethyl]-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide;

12. The compound according to claim 1, which represents 5-chloro-N-[(1S)-(4,4,4-Cryptor-1-(hydroxymethyl)-2-(2,2,2-triptorelin)butyl)]thiophene-2-sulfonamide or pharmaceutically acceptable salt, or hydrate.

13. The compound according to claim 1, where R5is a halogen, R4selected from the group consisting of (CF3)n(C1-6the alkyl) & (CF3)n(C1-6alkyl)phenyl, S-stereochemistry, and R3, R1and R3all represent N.

14. The compound according to claim 1, where T represents C(OH)R1R2, R1, R2and R3are H, and R4is a (F)ncycloalkyl.

15. The compound according to claim 1, where T represents C(OH)R1R2, R1, R2and R3are H, and R4represents (CF3)nalkyl.

16. The compound according to claim 1, where T represents C(OH)R1R2, R1represents CH3, R2represents H, R3represents N, and R4represents (CF3)nalkyl.

17. The compound according to claim 1, where T represents SNO, R3represents N, and R4represents (CF3)nalkyl.

18. The compound according to claim 1, where T represents C(OH)R1R2, R1, R2and R3imagine the battle N, and R4represents (CF3)2SN S-stereochemistry.

19. The compound according to claim 1, where T represents SNO, R3represents N, and R4represents CH(CH3)CH2CF3S-stereochemistry.

20. The compound according to claim 1, where T represents C(O)R8, R3represents H, R4represents CH(CH3)CH2CF3S-stereochemistry, and R8represents CH3.

21. The compound according to claim 1, where T represents C(OH)R1R2, R1, R2and R3are H, and R4represents CH(CH2CF3)2S-stereochemistry.

22. The compound according to claim 1, where T represents C(OH)R1R2, R1, R2and R3are H, and R4represents CH(CH3)CH2CF3S-stereochemistry.

23. The compound according to claim 1, where T represents C(OH)R1R2, R1represents CH3, R2and R3are H, and R4represents CH(CF3)2S-stereochemistry.

24. The compound according to claim 1, where T represents C(OH)R1R2, R1, R2and R3are H, and R4is a (F)n-cycloalkyl.

25. The compound according to claim 1 where the pharmaceutically acceptable salt is chosen from the group consisting of salts org the organic acids, salts of inorganic acids, salts, bases and mixtures thereof.

26. Connection A.25, where salts of organic and inorganic acids are selected from the group consisting of salts of acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, almond acid, malic acid, hydrochloric acid, Hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, toluensulfonate acid and mixtures thereof.

27. Connection A.25, where salts of the bases are selected from the group consisting of salts of sodium hydroxide, lithium hydroxide and potassium hydroxide and mixtures thereof.

28. The pharmaceutical composition inhibiting the formation of beta-amyloid containing compound according to claim 1 and a physiologically compatible carrier.

29. Pharmaceutical kit, inhibiting the formation of beta-amyloid containing container containing a pharmaceutical composition according p.

30. The method of obtaining triptoreline or fluorinated heterocyclic sulfonamida according to claim 1, including

(a) filtering the mixture of diastereomers of aminoether where specified aminoether contains at least one chiral center and at least one triptorelin or vorgruppe attached to at least demo chiral center via alkyl group;

(b) processing aminoether DIBAL-H in toluene with the formation of N-benzylaminopurine;

(c) hydrogenation of N-benzylaminopurine in the presence of a catalyst and education amerosport;

(d) sulfonation of amerosport from stage (C) heterocyclic sulphonylchloride, and

(e) crystallization of sulfonated product from step (d) to obtain the pure chiral triptoreline or fluorinated heterocyclic sulfonamida.

31. The method according to item 30, where the stage crystallization carried out using ethyl acetate and hexane.

32. The method of obtaining triptoreline or fluorinated heterocyclic sulfonamida according to claim 1, including

(a) processing triptoreline or fluorinated aldehyde dehydrating agent and a chiral sulfinamide education triptoreline or fluorinated chiral sulfinamide;

(b) processing the specified triptoreline or fluorinated chiral sulfinamide tianyoude agent with the formation of triptoreline or fluorinated diastereomeric α-aminonitriles;

(c) hydrolysis of the specified triptoreline or fluorinated diastereomeric α-aminonitriles to triptoreline or fluorinated α-amino acids;

(d) restore the giving of the specified triptoreline or fluorinated α -amino acids to triptoreline or fluorinated β-amerosport, and

(e) interaction specified triptoreline or fluorinated β-amerosport with the heterocyclic sulphonylchloride education specified triptoreline or fluorinated heterocyclic sulfonamida.

33. The method according to p, including additional

(f) extracting the specified triptoreline or fluorinated heterocyclic sulfonamida.

34. The method according to p or 33, further comprising purging the specified triptoreline or fluorinated heterocyclic sulfonamida.

35. The method according to clause 34, where the specified cryptomelane or fluorinated heterocyclic sulfonamide purified using chromatography.

36. The method according to p where specified dehydrating agent is atoxic titanium, magnesium sulfate or molecular sieves 4Å.

37. The method according to p where the specified chiral sulfinamide is an S-(+)-toluensulfonate or tert-butanesulfinamide.

38. The method according to p where specified tianyoude agent is a cyanide ethylisopropylamine.

39. The method according to p where specified dehydrating agent is atoxic titanium specified chiral sulfinamide is an S-(+-toluensulfonate and specified tianyoude agent is a cyanide ethylisopropylamine.

40. The use of compounds according to claim 1 or the composition according PP and 29 in obtaining remedies presentimage for administration to a mammal subject for inhibiting the formation of beta-amyloid.

41. Use p, where the specified compound is administered orally, by injection or inhalation.

42. The compound of the formula

or its pharmaceutically acceptable salt, or hydrate.

43. Connection § 42 of the formula

.

44. Connection § 42 of the formula

.

45. The compound of the formula

.

or its pharmaceutically acceptable salt, or hydrate.

46. Connection § 45 of the formula

.

47. The compound of the formula

.

or its pharmaceutically acceptable salt, or hydrate.

48. Connection p formula

.



 

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FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of formulas (Ip3) or (Ip4) wherein R1P3 means unsubstituted or substituted phenyl or thienyl wherein substitutes represent halogen atom, (C1-C6)-alkyl, (C1-C4)-halogenalkyl, nitro group, (C1-C4)-alkoxy group; R16P3 and R17P3 in common with carbon atom to which they are bound mean a bridge-bound saturated (C5-C12)-ring system that is substituted with (C4-C12)-alkyl, (C1-C6)-alkoxycarbonylamino group, for example, tert.-butoxycarbonylamino group; R18P3 means hydrogen atom; R1P4 means unsubstituted or substituted phenyl or thienyl wherein substitutes represent halogen atom, (C1-C6)-alkyl, (C1-C4)-halogenalkyl, nitro group, (C1-C4)-alkoxy group; R16P4 and R17P4 in common with carbon atom to which they are bound mean a substituted bridge-bound saturated (C5-C12)-cycloalkyl ring system, substituted piperidine or substituted bridge-bound piperidine wherein substitutes mean (C1-C6)-alkoxyoxycarbonyl, (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with (C4-C12)-alkyl, (C1-C4)-halogenalkyl, nitro group, aminocarbonyl; R18P4 means hydrogen atom or hydroxyl but hydrogen atom preferably; mP4 means 1. Compounds of formulas (Ip3) and (Ip4) inhibit activity of steroid sulfatase that allows their using as components of pharmaceutical composition.

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7 cl, 13 tbl, 386 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

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5 cl, 3 sch, 5 tbl, 6 ex

The invention relates to N-substituted aminotetralin formula 1

< / BR>
where R1independently selected from the group consisting of hydrogen; hydroxy; halogen; C1-8-alkoxy; substituted C1-8-alkoxy, where the Deputy is a halogen; n is 0-2; Y is methylene; m is 0-3;1means hydrogen;2means hydrogen; R2selected from the group consisting of hydrogen; hydroxy; C1-6-alkyl, C1-6-alkenyl; phenyl; substituted phenyl where the Deputy is chosen from halogen, C1-6-alkyl, C1-6-alkoxy, trifter-C1-6-alkyl, nitro; naphthyl and pyridyl; L is chosen from the group consisting of C1-8-alkylene; C1-4-alkylen-C3-7-cycloalkyl-C1-4-alkylene; C1-4-alkylen-aryl-C1-4-alkylene; R3selected from phenyl; substituted phenyl where the Deputy is chosen from halogen, nitro, C1-8-alkoxy, trifloromethyl and amino-C1-8-alkyl; naphthyl; and tanila and their enantiomers, diastereoisomers and pharmaceutically acceptable salts

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FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: in compound of formula I R1 is -(CH2)n-CO-NR5R6; -(CH2)n-COOR7; -(CH2)n- NR5R6; -(CH2)n-CN; -(CH2)n-OR8 or phenyl, which is unsubstituted or substituted with from one to three substituents, selected from halogen; R2 is hydrogen; R3 is hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl or benzyl; R4 is halogen; R5 and R6 are hydrogen; R7 is hydrogen or C1-C6-alkyl; R8 is C1-C6-alkyl; m is 1, 2 or 3; and n is 0, 1 or 2.

EFFECT: increase of composition and treatment method efficiency.

5 cl, 2 dwg, 27 ex

FIELD: chemistry.

SUBSTANCE: in novel derivatives of 4-(4-alkoxy-3-hydroxyphenyl)-2-pyrrolidone of formula I , X represents O, R1 represents C1-C8alkyl, C3-C8cycloalkyl, C8-C16arylalkyl, C8-C16arylalkenyl, in which alkenyl fragment contains up to 5 carbon atoms, C4-C16cycloalkylalkyl, R2 represents C1-C4alkyl, unsubstituted or substituted with one or more halogens, R3 represents C3-C8cycloalkyl, C7-C16arylalkyl, substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, cyano or CF3, C3-C8alkoxyalkyl, -C(O)R4 or -CH2CONHR5; R4 represents C6-C14aryl, substituted with one or more substituents from halogen line, C1-C8alkoxy or nitro; R5 represents C6-C14aryl, unsubstituted or substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, nitro or amino, heterocyclic group, saturated, partially saturated or fully unsaturated, which contains in cycle from 5 to 6 atoms, from which one atom is N, or additionally second atom is represented with heteroatom, selected from N, O and S, heterocyclic group is unsubstituted or substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, or their combinations; or heterocyclylC1-C5alkyl, saturated, partially saturated or unsaturated, which contains in cycle from 5 to 6 atoms, from which one atom is N, O or S, and which is unsubstituted or substituted in heterocyclic fragment with C1-C8alkyl or C1-C8alkoxy group, and their physiologically acceptable salts, in each case compound can be in form of enantiomer mixture, such as racemate, or mixture of diastereomers, or can be in form of one enantiomer or one diastereomer; on condition that if R1 represents cyclopentyl and R2 represents methyl, R3 does not represent benzyl, 4-bromobenzyl, 3,4-dimethoxybenzyl or 4-cyanobenzyl. Compounds I inhibit activity of PDE-4 enzyme, which allows using them in pharmaceutical compositions.

EFFECT: increase of composition and treatment method efficiency.

38 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: in arylpiperazinyl compounds of general formula , where R1 is unsubstituted alkyl or cycloalkyl; R2 and R3 independently hydrogen; lower alkyl; cycloalkyl; or -NR4R5, where R4 and R5 independently represent H, O, R6 or COR6, where R6 can represent lower alkyl or sulfonamidoalkyl; on condition that R2 and R3 both are not hydrogen; -atoms designated as bound with dotted line, taken together with atoms, to which they are joined, can form six-member ring; - Z represents N or C; - m equals 0, 1 or 2; - n equals 1, 2, 3, 4, 5 or 6; - p equals 0, 1, 2, 3 or 4. Compounds can be used for treatment of diseases, mediated directly or indirectly by 5-HT receptors. Such diseases are disorders of central nervous system.

EFFECT: increase of composition and method of treatment efficiency.

50 cl, 12 dwg, 2 tbl, 41 ex

FIELD: chemistry.

SUBSTANCE: compounds of formula (I) can be efficient with respect to diseases, in which phosphorylation of Tau protein takes place. , R3 stands for CONR1R2, where R1 and R2 can be substituted with heterocycle; R5, R6, R7 independently on each other are selected from halogen and phenyl; R1, R2 independently on each other stand for hydrogen, (C1-C6)alkyl or together with nitrogen of group CONR1R can form heterocycle.

EFFECT: obtaining novel biologically active compounds.

4 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: obtained is acceptable for pharmaceutical purposes oxalate of N,N-dimethyl-2-N,N-dimethylaminomethylpyridyl-3-carbamate, possessing anti-cholinesterase and anti-amnestic activity, which, in contrast to other salts of this structure, is not a hydroscopic compound.

EFFECT: increased anti-cholinesterase activity.

1 cl, 1 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to new substituted 2,3,4,5-tetrahydro-1N-pyrido[4,3-b]indoles with general formula 1.1, 1.2 or 1.3, their pharmaceutical salts and/or hydrates with antihistamine activity. In general formulae 1.1, 1.2 or 1.3 radicals assume values given below . In 1.1 compounds, R1 represents a substitute, chosen from hydrogen or unsubstituted C1-C5 alkyl; R2 represents a hydrogen atom or C1-C4 alkyl; R3i represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3; n=0 or 1-3; in 1.2 compounds R1 represents a substitute of an amino group, chosen from hydrogen or optionally substituted C1-C5 alkyl; R3 represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3, and Ar1 represents an aryl or heterocyclyl, containing at least one carboxyl and/or alkoxycarboxyl substitute or R3i represents a carboxyl and/or alkyloxycarboxyl substitute, and Ar1 represents optionally substituted aryl or heterocyclyl; in 1.3 compounds, R2 represents a hydrogen atom or C1-C4 alkyl; R3i represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3, and Ar2 represents optionally substituted aryl or heterocyclyl; k=0 or 1-4; m=1 or 2.

EFFECT: compounds can be used for making drug formulation for treating allergies, autoimmune diseases such as pollen allergy, urticaria, bronchial asthma etc.

17 cl, 10 dwg, 2 tbl,13 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to agonist of receptor of glucagone-like peptide-1, which can be applied for treatment of diseases, caused by disturbance of glycometabolism, such as type II diabetes, insensibility to insulin or obesity. In structural formula each of Ar1 and Ar2 independently represents substituted phenyl, and group-substituents represent one, two or three groups selected from C1-C6alkoxyl, C1-C6-alkanoylamino, which is substituted with hydroxyl (which contains groups-substituents, including hydroxyl); C3-C6-cyclolkanoylamino, C2-C6-lkenoylamino; banzoylamino, banzyloxy C1-C6-alkanoylamino, thenoyloxy, tret-butoxyformamido, adamantanformamido; and mandeloylamino; X represents O; Y represents O. Invention also relates to method of obtaining agonist, and to its application for obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

EFFECT: obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

8 cl, 4 ex, 2 tbl, 2 dwg

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