Method of fluorinating anilide derivatives and fluorinated benzothiazole derivatives as in vivo imaging agents

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing compounds of formula

, where the fluoro group is possibly [18F]fluoro; ring A is substituted with benzothiazol-2-yl, which is substituted with hydroxy, C1-6alkyl, C1-6alkoxy, halogen, OCH2OR11, where R11 is C1-6alkyl; R1 is C1-6alkyl. The method involves reaction of the corresponding compound of formula , where ring A is substituted as defined for the compound of formula (I); R2 is selected from hydrogen, C1-10alkyl, C1-10halogenalkyl, -(CH2CH2O)q-CH3, where q is an integer from 1 to 10; R1 is as defined for the compound of formula (I); R3 is a leaving group such as nitro, with an alkali metal fluoride or tetra-alkylammonium, possibly with [18F]fluoride, to obtain a compound of formula , where R1 and R2 are as defined for compounds of formulae (I) and (II), the fluoro group is possibly [18F]fluoro and ring A is substituted as defined for the compound of formula (I); with subsequent conversion of the -C(O)R2 group to hydrogen through hydrolysis and possible removal of any extra protective groups. The invention also relates to novel compounds of formulae

, where R1-R3, R9, defined above, are precursors of compounds of formula (I), as well as to a radiopharmaceutical set and a cartridge for use in positron emission tomography, which contain said precursors.

EFFECT: method enables to obtain compounds of formula (I) using a simpler and more efficient method.

11 cl, 1 tbl, 6 ex

 

The present invention relates to new methods of fluorination, in particular [18F]fluorination of some aromatic compounds, and new precursors used in this way. The invention is especially suitable for class benzothiazoline derivatives, which are known as in vivo imaging agents.

Fluorination of aromatic compounds can be carried out by electrophilic interaction with molecular fluorine, however, electrophilic fluorination of aromatic compounds fluorine is in General poor and non-selective way. There were developed various electrophilic fluorinating reagents, obtained from molecular fluorine, such as CH3COOF "AcOF", but they have some drawbacks. In respect of [18F]radiotolerance, harsh conditions and low suitability electrophilic ways [18F]fluorination, as well as low specific activity of the products obtained indicate that this approach is not useful for industrial production of [18F]-labeled products. More commonly used methods nucleophilic fluorination using fluoride. [18F]Fluoride is more widely available reagent than electrophilic reagents, and the resulting products have a higher specific activity, which is an advantage in the sphere of the in vivo visualization. Nucleophilic fluorination of aromatic rings, especially those which are rich in electrons, can be problematic. For example, difficult to implement nucleophilic fluorination of anilines, where the amino group is added to the electron density of the aromatic ring. In the present invention is proposed predecessor, suitable for nucleophilic fluorination with obtaining fluorinated aniline, which combines a number of useful effects, including improved activation of the aromatic ring to fluoridation, some steric effects in the reaction of fluorination, and easy transformation into the fluorinated aniline product.

In accordance with the invention, a method for obtaining compounds of formula (I):

where the phenyl ring possibly substituted by 1-4 substituents;

R1selected from C1-6of alkyl, C2-6alkenyl and C2-6the quinil,

which includes:

(1) the interaction of the compounds of the formula (II):

where the ring possibly substituted as defined for compounds of formula (I);

R2selected from hydrogen, C1-10of alkyl, C1-10 ghalogenoalkane,6-14aryl, C6-14arylalkyl, -(CH2CH2O)q-CH3where q is an integer from 1 to 10;

R1so, it is to he defined for the compounds of formula (I); and

R3represents a leaving group;

with fluoride, to obtain the compounds of formula (III)

where R1and R2such as defined for the compounds of formula (I), and the phenyl ring And substituted as defined for compounds of formula (I);

with the subsequent stage (2) and possibly stage (3) in any order:

(2) the transformation of the group-C(O)R2in hydrogen, suitably by hydrolysis;

(3) removing any additional protective group.

Phenyl ring possibly substituted 1-4 organic substituents, for example selected from fluorescent, chloro, bromo, iodine, cyano, nitro, -R, -OR, -OC(O)R, -C(O)R, -SR, -NR2, -C(O)NR2where R in each case selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil,1-6alkoxy-C1-6of alkyl, C1-6halogenoalkane,2-6halogenoalkane,2-6halogenoalkane,1-6halogenoalkane-C1-6of alkyl, C5-12aryl, C5-12heteroaryl where these aryl and heteroaryl substituents may be optionally substituted nearline and pheterogeneity substituents mentioned for phenyl ring A, and protected derivative of any of them.

R2in the compound of formula (II) is selected from hydrogen, C1-10the alkyl (more thumbs1-6of alkyl, even more suitably methyl) 1-10halogenoalkane (more eligible C1-6halogenoalkane, such as1-6floralcy, for example trifluoromethyl), C6-14aryl (suitably phenyl)6-14arylalkyl (suitably phenyl-C1-4of alkyl, for example benzyl, and -(CH2CH2O)q-CH3where q is an integer from 1 to 10. The compounds of formula (II), where R2represents a C4-10alkyl or -(CH2CH2O)q-CH3where q is an integer from 1 to 10, can be used in the method where it is desirable to increase the solubility of the compounds of formula (II), and, as such, these compounds and the method according to the invention with their use constitute a separate aspects of the invention. Preferably, R2in the compound of formula (II) is selected from hydrogen and C1-6of alkyl, more preferably R2represents hydrogen.

R3in the compound of formula (II) represents a leaving group which may be substituted by fluoride, and suitably selected from

nitro,

-N2+,

chloro,

bromo,

iodide,

-NR4(C1-6alkyl)2+where R4represents a C1-6alkyl or a group of formula (X):

-OSO2R5where R5selected from C1-6of alkyl, C1-6halogenoalkane, such as C1-6PERFLUORO lcil, aryl, such as phenyl or tolyl (for example, para-tolyl), and groups of the formula (X)as defined above; and

where R6selected from hydrogen, C1-6of alkyl, halogeno, nitro and groups of the formula (X)as defined above.

R3in the compound of formula (II) is suitably chosen from:

nitro,

-N2+,

chloro,

bromo,

iodide,

-NR4(C1-6alkyl)2+where R4represents a C1-6alkyl;

-OSO2R5where R5selected from C1-6of alkyl, C1-6halogenoalkane, such as C1-6perfluoroalkyl, aryl, such as phenyl or tolyl (for example, para-tolyl); and

where R6selected from hydrogen, C1-6of alkyl, halogen and nitro.

In one particular aspect of the invention, R3represents nitro.

In the method according to the invention the use of compounds of the formula (II)in which R3contains a group of the formula (X), allows fluoridation in the solid phase, which can simplify purification of fluorinated product, because any unreacted precursor remains associated with the solid substrate and can be removed from the liquid phase product filtering.

In the group of formula (X) a solid substrate can be any suitable solid-phase substrate which is insoluble in labyrinthitis, used in this way, but which can be covalently attached to the linker and/or a compound of the formula (II). Examples of suitable solid substrates include polymers, such as polystyrene (which may be block-grafted, for example, polyethylene glycol), polyacrylamide, or polypropylene, or glass or silicone, coated with such a polymer. The solid substrate may be in the form of small discrete particles, such as beads or needles, or in the form of a coating on the inner surface of the cartridge, or manufactured by microfabrication vessel.

In the group of formula (X), the linker can be any suitable organic group which serves to sufficiently separated in space of the reactive site on the structure of solid surfaces to maximize reactivity. Suitably, the linker contains from zero to four aryl groups (suitably phenyl) and/or C1-6alkyl or C1-6halogenated (eligible With1-6foralkyl), and possibly from one to four additional functional groups such as amide or sulfonamidnuyu group. Examples of such linkers are well known to experts in the field of solid state chemistry, but include:

where in each case, n is an integer from 0 to 3, and RLrepresents hydrogen or C1-6alkyl.

Stage (1) of the method according to the invention, i.e. the interaction of the compounds of formula (II) fluoride, suitably [18F]fluoride may be performed by using a source of fluoride such as NaF, KF, CsF, tetraalkylammonium fluoride, or tetraalkylammonium fluoride, are eligible source [18F]fluoride, such as Na18F, K18F, Cs18F, tetraalkylammonium [18F]fluoride (for example, tetrabutylammonium [18F]fluoride) or tetraalkylammonium18F-fluoride. To increase the reactivity of the fluoride may be added to the catalyst phase transition, such as amenability or a crown ether, such as 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8,8,8]hexacosane (Kryptofix 2.2.2), and the interaction may be carried out in a suitable solvent. In such conditions, the obtained reactive fluoride ions. To increase the output when the fluorination can be used to trap free radicals, as described in WO 2005/061415. The term "trap free radicals" is defined as any agent that interacts with it is DNAME radicals and inactivate them. A suitable trap free radicals for this purpose may be selected from 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO), 1,2-diphenylethylene (DPE), ascorbate, para-aminobenzoic acid (RAV), α-tocopherol, hydroquinone, di-tert-butylphenol, β-carotene and hentaimovi acid. The preferred traps free radicals for use in the method according to the invention are TEMPO and DPE, and TEMPO is the most preferred.

Treatment with fluoride, suitably [18F]fluoride on stage (1)may be carried out in the presence of a suitable organic solvent, such as acetonitrile, dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, sulfolane, N-methylpyrrolidone, or in an ionic liquid, such as a derivative of imidazole (for example, 1-ethyl-3-methylimidazole hexaphosphate), derived pyridinium (for example, 1-butyl-4-methylpyridine tetrafluoroborate), fashonable connection or tetraalkylammonium connection with non-extremal temperatures, for example from 15°C to 180°C, preferably at elevated temperatures, for example from 80°C to 150°C, for example about 120°C. the Organic solvent in a suitable manner is anhydrous, but in some cases may contain low levels of water.

In one aspect of the invention, the group of fluorescent in connection formula is (I) is a [ 18F]the fluorescent, and the fluoride used in stage (1) of this method, is a [18F]fluoride. There is a particular need for new ways of radiotolerance, especially radiotolerance electron-rich aromatic systems.

Stage (2) of the method, i.e. the transformation of the group-C(O)R2the hydrogen is suitably carried out by acid or alkaline hydrolysis, using organic or inorganic acid, with non-extremal temperatures, for example from ambient temperature to the temperature of reflux distilled. This interaction can be carried out in the presence of an aqueous solvent or an organic solvent, for example With1-4alcohol, such as methanol or ethanol, or acetonitrile, or a mixture of water and organic solvents.

Suitable acid used in stage (2), include Hydrobromic, triperoxonane, phosphate and salt.

The suitable base used in stage (2)include sodium hydroxide or potassium hydroxide. The use of sodium hydroxide in an organic solvent, such as acetonitrile, at elevated temperature, for example about 100°C., can result in good radiochemical yields and to facilitate cleaning of the fluorinated product.

Alternative bases used in stage (2), include dinucleophiles the e base, such as sodium hydride. This method leads to good radiochemical yields, and also facilitates cleaning of the fluorinated product. Treatment of sodium hydride can be performed in a suitable aprotic solvent such as acetonitrile or propionitrile, and at elevated temperature, for example from 40°C to 120°C, typically about 100°C. Sodium borohydride, lithium borohydride and lithium aluminiumhydride also are suitable bases for use in stage (2).

As is obvious to a person skilled in the technical field, it is sometimes necessary to apply a strategy for the use of protective groups to prevent unwanted side reactions in the process of organic synthesis. Examples of such strategies can be found in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G.M. Wuts, published by John Wiley & Sons Inc., describe how the introduction and removal of protective groups. To avoid unnecessary stages of synthesis, it is particularly useful to remove any protective groups remaining in the compound of formula (III), in the conditions of stage (2) in order to avoid a separate stage, the removal of protection.

When used herein, the term "alkyl"used alone or as part of another group, means a saturated hydrocarbon radical with a straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl or what-hexyl.

When used herein, the term "alkenyl"used by itself or as part of another group, means an unsaturated hydrocarbon radical with a straight or branched chain, containing at least one carbon-carbon double bond, such as ethynyl, propenyl, Isopropenyl, butenyl, Isobutanol, tert-butenyl, n-pentenyl and n-hexenyl.

When used herein, the term "quinil"used by itself or as part of another group, means an unsaturated hydrocarbon radical with a straight or branched chain, containing at least one carbon-carbon triple bond, such as ethinyl, PROPYNYL, Isopropenyl, butenyl, Isobutanol, tert-butenyl, n-pentenyl and n-hexenyl.

When used herein, the term "halogen"used by itself or as part of another group, means with fluorescent, chloro, bromo or iodine.

When used herein, the term "aryl"used alone or as part of another group, means an aromatic hydrocarbon with a single ring or condensed rings, such as phenyl or naphthyl.

When used herein, the term "heteroaryl"used by itself or as part of another group, means an aromatic hydrocarbon with a single ring or condensed rings, which optionally includes 1 or more than one heteroatom selected from sulfur, nitrogen and oxygen, such as pyridyl, thiophenyl, benzothiazolyl, benzoxazolyl or furyl.

The method according to the invention is particularly suitable for the synthesis of compounds of formula (I)in which R1represents a C1-6alkyl, in particular methyl, therefore, the ways in which R1in the compounds of formula (I), (II), (III) represents a C1-6alkyl, in particular methyl, form a separate aspect of the present invention.

The method according to the invention is particularly suitable when a group of fluorescent in the compound of formula (I) is in the ortho - or para-position to the group-N(R1)C(O)R2as-N(R1)C(O)R2located in the ortho - or para-position to R3in the corresponding compound of formula (II), can activate R3for nucleophilic substitution by fluoride. Preferably the group of fluorescent in the compound of formula (I) is in ortho-position to the group-N(R1)C(O)R2and R3in the corresponding compound of formula (II) is in ortho-position to the group-N(R1)C(O)R2.

It is known that some compounds of formula (I) are used in diagnostic and therapeutic methods, for example benzothiazoline derivatives described for in vivo imaging of amyloid in accordance with the methods described in WO 02/16333 and WO 2004/083195. The methods previously described to obtain these benzothiazoline derivative is, although useful for obtaining small amounts of such compounds, have such defects as small radiochemical yields and poor reproducibility, so that there is a need for improved methods for their production, in particular for industrial production. As mentioned above, the nucleophilic fluorination of aromatic rings can be problematic when the ring is rich in electrons. In the compounds of formula (Ia) and (Ib) below the circuit impedes the fluorination of the aromatic ring. Attempts to create a suitable precursors for fluorination, which would be stable, could be fluorinated with a good yield and then could easily be turned into the final product, were problematic, as demonstrated below in Example 3. Thus, in an additional aspect of the invention, a method for obtaining compounds of formula (Ia):

where R1selected from C1-6of alkyl, C2-6alkenyl and C2-6the quinil;

R7, R8, R9and R10each independently selected from hydrogen, fluorescent, chloro, bromo, iodide, C1-6of alkyl, C2-6alkenyl,2-6the quinil, (CH2)mOR11(where m=1, 2, or 3), CF3CH2-CH2Y-O-CH2-CH2Y, CH2-CH2-CH2Y-O-CH2-CH2-CH2Y (where Y is selected from fluorescent, chloro, b is the OMO and iodine), CN, (C=O)-R11N(R11)2, NO2(C=O)N(R11)2, O(CO)R11, OR11, SR11, COOR11, Rph, CR11=CR11-Rph, CR112-CR112-Rph(where Rphrepresents unsubstituted or substituted phenyl group with the phenyl substituents selected from any of defenily substituents defined for R7-R10and where R11represents N or C1-6alkyl) and a protected derivative of any of them; and

the phenyl ring And is substituted by 1-3 substituents selected from any of defenily substituents defined for R7-R10,

which includes:

(1) the interaction of the compounds of formula (IIa):

where R1defined for the compounds of formula (Ia),

phenyl ring And substituted as defined for compounds of formula (Ia); and

R2selected from hydrogen, C1-10of alkyl, C1-10halogenoalkane,6-14aryl, C6-14arylalkyl, -(CH2CH2O)q-CH3where q is an integer from 1 to 10;

R3represents a leaving group as defined for compounds of formula (II);

R7, R8, R9and R10such as defined for the compounds of formula (Ia);

with fluoride to obtain the compounds of formula (III)

where R1and R2such as defined for the compounds of formula (IIa), the phenyl ring And substituted as defined for compounds of formula (Ia);

R7, R8, R9and R10such as defined for the compounds of formula (Ia); with the subsequent stage (2) and possibly stage (3) in any order;

(2) the transformation of the group-C(O)R2in hydrogen, suitably by hydrolysis;

(3) remove any additional protective groups.

In the compounds of formula (Ia), (IIa)and (IIIa) and the corresponding method according to the invention R7, R8, R9and R10suitably selected from hydrogen, hydroxy, -NO2, -CN, -COOR11, -OCH2OR11(where R11selected from hydrogen and C1-6the alkyl), C1-6of alkyl, C2-6alkenyl,2-6the quinil, C1-6alkoxy, halogen and protected derivative of any of them. Suitable protected derivative of substituents R7, R8, R9and R10obvious to a person skilled in the art, and described in Theodora W. Greene and Peter G.M. Wuts, mentioned here above. For example, when R7, R8, R9or R10represents a hydroxy functional group is hydroxy are adequately protected as C1-6alkoxygroup, for example, ethoxyethoxy or methoxyethoxy.

One class of preferred compounds is of the formula (Ia) for use in in vivo imaging amyloid are the compounds of formula (Ib)

where R1selected from C1-6of alkyl, C2-6alkenyl and C2-6the quinil; and

R9selected from hydroxy, -NO2, -CN, -COOR11, -OCH2OR11(where R11selected from hydrogen and C1-6the alkyl), C1-6of alkyl, C2-6alkenyl,2-6the quinil,1-6alkoxy, halogen and protected derivative of any of them, and preferably selected from hydroxy, C1-6alkoxy and protected derivative of any of them and more preferably selected from hydroxy, methoxy and protected derivative of any of them. Therefore, in accordance with one preferred aspect of the invention, a method for obtaining compounds of formula (Ib):

where R1selected from C1-6of alkyl, C2-6alkenyl and C2-6the quinil;

R9selected from hydroxy, -NO2, -CN, -COOR, -OCH2OR, C1-6of alkyl, C2-6alkenyl,2-6the quinil, C1-6alkoxy, halogen and protected derivative of any of them, and preferably selected from hydroxy, C1-6alkoxy and protected derivative of any of them and more preferably selected from hydroxy, methoxy and protected derivative of any of them,

which includes:

(1) the interaction of the compounds of formula (IIb):

the de R 1selected from C1-6of alkyl, C2-6alkenyl and C2-6the quinil, and R2selected from hydrogen, C1-10of alkyl, C1-10halogenoalkane,6-14aryl, C6-14arylalkyl, -(CH2CH2O)q-CH3where q is an integer from 1 to 10;

R3represents a leaving group as defined for compounds of formula (II);

R9such as defined for the compounds of formula (Ib);

with fluoride to obtain the compounds of formula (IIIb)

where R1and R2such as defined for the compounds of formula (IIb);

R9such as defined for the compounds of formula (Ib); followed by stage (2) and possibly stage (3) in any order;

(2) the transformation of the group-C(O)R2in hydrogen, suitably via hydrolysis

(3) remove any additional protective groups in the substituent R9.

Compounds of formulas (IIa) and (IIb)as defined above, are important precursors that are useful for in vivo imaging agents, and, therefore, constitute additional aspects of the invention.

Preferred precursors of the formula (IIa) and (IIb) include those in which R2represents hydrogen or C1-6alkyl, suitably methyl, more fittingly, R2represents hydrogen; R1is the fight C 1-6alkyl, suitably methyl; one of them can be particularly useful precursors, in which R3represents nitro. The compounds of formula (IIa) and (IIb)in which R9represents hydroxy or C1-6alkoxy or protected derivative, can also be particularly useful. One such preferred precursor is 2-[3-nitro-4-(methylpentylamino)phenyl]-6-ethoxyethoxy-benzothiazole.

The precursor of formula (II), (IIa) or (IIb) can be conveniently represented as part of a set, for example, for use in radio pharmacology. The kit can contain a cartridge that can be placed in appropriately adapted automatic synthesizer. The cartridge may contain, in addition to the predecessor column to remove unwanted fluoride ion and a suitable vessel, attached in such a way as to allow to evaporate the reaction mixture and to allow the product to have the composition that you want. It may also include the reagents and solvents and other consumables required for the synthesis, together with a CD with software that allows you to operate the synthesizer thus, in order to satisfy customer requirements for radioactive concentration, quantities, delivery time and so on. Convenient to all the components of the kit was about nerezovym, to minimize the possibility of contamination between runs, and they can be sterile and with guaranteed quality.

The invention additionally offered a radiopharmaceutical kit for obtaining18F-labeled RFID tags for use in PET (positron emission tomography), including:

(1) a vessel containing a compound of the formula (II), (IIa) or (IIb); and

(2) means for elution of the vessel with a source of18F-;

(3) ion-exchange cartridge for removal of excess18F-; and it is possible

(4) cartridge for removing protection from the obtained product of formula (I), (Ia) or (Ib).

The invention additionally offered a cartridge for a radiopharmaceutical kit for obtaining18F-labeled RFID tags for use in PET, which includes:

(1) a vessel containing a compound of the formula (II), (IIa) or (IIb); and

(2) means for elution of the vessel with a source of18F-.

The compounds of formula (II), (IIa) and (IIb) can be obtained from commercially available starting compounds or by using starting compounds described in WO 02/16333 and WO 2004/083195, standard methods of organic chemistry, for example by the methods described below and in the examples.

The compounds of formula (II), (IIa) and (IIb), where R3represents nitro, can be obtained by methods similar to those described in Example 1.

Connected to the I of the formula (II), (IIa) and (IIb), where R3represents chloro, bromo, iodide, tosylate or iodonium salt, can be obtained by methods similar to those shown in Schemes 1-4, respectively.

In Schemes 1-6 R2such as defined for the compounds of formula (I) above, R in figure 1 represents alkyl or aryl Deputy, AC represents an acyl, Ts represents tosyl, NaHDMS is a sodium hexamethyldisilazide, TFA represents triperoxonane acid, Pd2dba3figure 6 is a Tris-(dibenzylideneacetone)dipalladium(O), and other abbreviations are as defined in the Examples.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

The compounds of formula (II), (IIa) and (IIb), where R3represents-N2+can be obtained from the corresponding compounds where R3represents nitro, by restoring the nitro group to amino, for example using hydrogen and Pd/C as catalyst, and then diazotization using NaNO2.

The compounds of formula (II), (IIa) and (IIb), where R3represents-NR4(C1-6alkyl)2+can be floor is received in accordance with Scheme 6.

Scheme 6

The invention is further illustrated by the following Examples in which the following abbreviations:

DMF: N,N-dimethylformamide

DCM: dichloromethane

EOMCl: ethoxymethylene

DMAP: dimethylaminopyridine

RT: room temperature

THF: tetrahydrofuran

IMS: denaturate used in industry.

TPL: melting point

eq.: equivalents

EtOAc: ethyl acetate

QMA: Quaternary ammonium

HPLC: high performance liquid chromatography

ml or ml: milliliter(s)

TLC: thin layer chromatography

about./about.: volume/volume

NMR: nuclear magnetic resonance

MS: mass spectrometry

Example 1: Synthesis of 2-[3-nitro-4-(methylpentylamino)phenyl]-6-ethoxymethyleneamino

Example 1(1): 4-Acetamido-3-nitrobenzoate (2)

4-Acetamido-3-nitrobenzoic acid 1 (Alfa Aesar, 5.6 g, 25 mmol), oxacillin (4,76 g, 38 mmol), chloroform (50 ml), DMF (few drops) was stirred at 40°C for 3 hours. The solvent was removed in vacuum to obtain a yellow solid, which was used in the next stage without additional purification.

Example 1(1A): 5-methoxy-2-aminobenzoyl (3)

2-Amino-6-methoxybenzothiazole 10 g (55,6 mmol) suspended in 25%aqueous potassium hydroxide and the mixture was heated to reverse the m a fridge for 24 hours The pale yellow solution was cooled and acidified to pH 6 first water 6 N. HCl, then with acetic acid. The precipitated solid was filtered, washed with water (3×100 ml), dried (high vacuum) to give the desired substance in the form of a pale yellow powder, 8,18 g, 95%.

Example 1(2): 2-(4-Acetamido-3-nitrophenyl)-6-methoxybenzothiazole (4)

5-Methoxy-2-aminobenzoyl 3 (3.88 g, 25 mmol), pyridine (100 ml) and DMAP (few crystals) was stirred at room temperature.

4-Acetamido-3-nitrobenzoate (25 mmol, obtained as above) was added in one portion at a temperature below 30°C. the Mixture was stirred for a further 1 hour. The mixture was heated up to 80°C and was stirred over the weekend. The mixture was cooled. The crystals were filtered off and washed with IMS obtain 2.2 g (26%yield) of 2-(4-acetamido-3-nitrophenyl)-6-methoxybenzothiazole.

Example 1(3): 2-(4-N-Methylacetamide-3-nitrophenyl)-6-methoxybenzothiazole (5)

Sodium hydride (6,33 g, 157 mmol), and DMF (400 ml) was stirred at room temperature. One portion was added 2-(4-acetamido-3-nitrophenyl)-6-methoxybenzothiazole 4 (45 g, 131 mmol). The mixture was stirred for 1 hour. The mixture was cooled in an ice bath and one portion was added methyliodide (23.1 g, 164 mmol), the temperature remained below 20°C.

The mixture was stirred for 3 hours, was added water (900 ml), the mixture was filtered and washed with water. Solid the second substance is recrystallized from IMS obtaining 43,7 g (93% yield) of 2-(4-N-methylacetamide-3-nitrophenyl)-6-methoxybenzothiazole. TPL 168-172°C.

Example 1(4): 2-(4-Methylamino-3-nitrophenyl)-6-hydroxybenzothiazole (6)

A mixture of 2-(4-N-methylacetamide-3-nitrophenyl)-6-methoxybenzothiazole (58 g, 162 mmol), Hydrobromic acid (500 ml, 48%aqueous solution) and Hydrobromic acid (500 ml, 45% in acetic acid) was stirred at 135°C for 5 hours. The mixture was cooled to room temperature and the solid was filtered and washed with a small amount of water. The solid is suspended with water and the pH was brought to about 10 with concentrated ammonia solution. The solid was filtered and washed with water.

The solids were washed with IMS (200 ml), filtered, and the mixture was heated with IMS (500 ml), then cooled to room temperature, then was filtered. The solid is again boiled with IMS (500 ml), then cooled to room temperature, then filtered. The solid was dissolved in hot DMF (200 ml), filtered and added to water (100 ml). The solid was filtered and washed with IMS. The solid was boiled with water (300 ml) for 5 minutes, cooled, filtered, washed with water, then IMS, receiving 45,9 g (94%yield) of 2-(4-methylamino-3-nitrophenyl)-6-hydroxybenzothiazole. TPL 269-272°C.

Example 1(5): 2-[3-nitro-4-(methylamino)phenyl-6-ethoxyethoxy-benzothiazole (7)

3-necked 250 ml round bottom flask was dried in a thermostat at 80°C in t is the significance of the night. A suspension of 6 (of 16.6 mmol, 5 g) in dry THF (180 ml) was poured dropwise into a suspension of a 60%dispersion of NaH in mineral oil (33,2 mmol, 1.26 g, 2 equivalents) in dry THF (20 ml). Immediately after adding added net ethoxymethylene (16,6 mmol, and 1.54 ml, 1 EQ.) and the reaction mixture was stirred over night. The dark brown mixture was filtered under vacuum and the filtrate was concentrated in high vacuum.

The crude product was applied to silica and purified by flash chromatography in DCM/EtOAc:3% EtOAc.

The desired fraction was isolated, concentrated in high vacuum to obtain 60% not quite red solid with 95%purity.

Example 1(4): 2-[3-nitro-4-(methylpentylamino)phenyl]-6-ethoxyethoxy-benzothiazole (8)

All glassware was dried in a thermostat at 80°C during the night.

In a 1 l three-neck round bottom flask, equipped with a refrigerator and thermometer was added dropwise acetic anhydride (15 ml, 160 mmol, 22 EQ.) to a solution of formic acid (160 mmol, 6 ml, 22 EQ.) at 0°C. the Mixture was stirred for 15 minutes at 60°C.

A solution of 7 (7.2 mmol, 2.6 g) in dry DCM (310 ml) added dropwise at 0°C. to the mixed anhydride. Stirring is continued at this temperature for one hour and clear orange solution was stirred 5 days at 40°C. the reaction was monitored with HPLC: 5 days OBS is given a 60%conversion to the desired product.

The HPLC conditions:

Column Phenomenex Luna H of 4.6 mn

A flow of 1 ml/min

Solvent: acetonitrile (b) and water (A)

Detection: 254-214

The gradient 5-95% b for 8 minutes

Retention time: 9.5 minutes

Pure orange solution was washed 1 N. aqueous NaOH (3×100 ml), water (3×100 ml), dried over magnesium sulfate and concentrated in high vacuum.

Bright orange crude product was applied to silica and purified by flash chromatography in DCM/EtOAc: 3-10% EtOAc.

The desired fraction was isolated, concentrated in high vacuum to obtain 54,2% not quite yellow solid with 98%purity.

Example 1(7): Obtain 2-[3-[18F]fluoro-4-(methylamino)phenyl]-6-hydroxy-benzothiazole (11) - see Diagram below (Approach 1)

[18F]fluoride (200 µl enriched 95%18Of water), 2.5 mg Kryptofix 2.2.2 (0.5 ml acetonitrile and 50 μl of 0.1 M K2CO3added in a glassy carbon reaction vessel. Then the solution was evaporated to dryness using a stream of nitrogen and heating the reaction vessel to 100°C for 15 minutes. 2×1 ml of acetonitrile was added to the reaction vessel after 5 minutes and 10 minutes, respectively, to facilitate azeotropic drying. The reaction vessel was cooled to room temperature and was added 2-[3-nitro-4-(methylpentylamino)phenyl]-6-ethoxymethyleneamino (8) (5.0 mg) in 1 ml anhydrous DIMET is sulfoxide. The reaction mixture was tightly closed and heated for 10 minutes at 130°C. the Crude mixture was analyzed by HPLC and TLC.

0.25 ml of 6 M HCl and 0.5 ml of DMSO was added to the crude reaction solution of 2-[3-[18F]fluoro-4-(methylpentylamino)phenyl]-6-ethoxymethyleneamino (9) and was heated at 125°C for 10 minutes. The reaction mixture was then cooled to room temperature and neutralized using 2 M sodium acetate, which led to the synthesis of 2-[3-[18F]fluoro-4-(methylamino)phenyl]-6-hydroxybenzothiazole (11). The crude mixture was analyzed by HPLC and TLC.

HPLC-purification and preparation

2-[3-[18F]fluoro-4-(methylamino)phenyl]-6-hydroxybenzothiazole (11) was purified by HPLC using preparative Phenomenex Prodigy ODS preparative 10 μm, 250 mm×10 mm (number 00G-4088-N0) preparative column (column elute with a mixture of 40/60 acetonitrile/triethylamine-phosphate buffer solution pH 7 (about./vol.)). Adjustable method is a 0-15 min 5 ml/min, 15,5-39.9 minutes 8 ml/min, 40 min 5 ml/min. The product is eluted with a retention time of 22-23 minutes (8 ml).

Purified using HPLC "clipping" was diluted to 50 ml by adding distilled water. The product is then "held" on C8-sep-pak cartridge and then suirable cartridge 1 ml of ethanol. The ethanol was then removed under vacuum and the final product was prepared in the form of the drug is in a mixture of 10% ethanol/90% phosphate buffer saline solution.

Example 2: Obtain 2-[3-[18F]fluoro-4-(methylamino)phenyl]-6-hydroxy-benzothiazole (11) - see Diagram above (Approach 2)

Example 2(1): Receive [K/K2.2.2]+ 18F-(using enriched 95%18On the water).

After irradiation the target content was passed through a column Packed with resin QMA (Quaternary aminomethane resin). The column was purged with helium for 5 minutes, [18F]fluoride is adsorbed on the resin, was suirable in the reaction vessel by using 4 ml of a mixture of 96:4 (by volume) acetonitrile-water containing 19.1 mg Kryptofix 2.2.2 and 2.9 mg K2CO3; the solution is then evaporated and evaporated to dryness together with anhydrous acetonitrile (2×1 ml) in a stream of nitrogen at 110°C.

Example 2(2): Getting 2-[3-[18F]fluoro-4-(methylpentylamino)phenyl]-6-ethoxymethyleneamino (9) and 2-[3-[18F]fluoro-4-(methylamino)phenyl]-6-ethoxymethyleneamino (10).

A solution of 2-[3-nitro-4-(methylpentylamino)phenyl]-6-ethoxyethoxy-benzothiazole (8) (3.0 mg) in anhydrous acetonitrile (0.1 ml) was added to a solution of [K/K2.2.2]+18F-in anhydrous acetonitrile (0.25 ml). The reaction mixture was heated at 150°C for 15 minutes. The crude mixture was analyzed using an analytical HPLC.

Example 2(3): Conversion of 2-[3-[18F]fluoro-4-(methylpentylamino)phenyl]-6-ethoxymethyleneamino (9) 2-[3-[18F]fluoro-4-(methylamino)phenyl]-6-ethoxymethyleneamino (10).

Approximately 0.2 ml of the previous reaction mixture was added to a solution of NaH (3.2 mg) in anhydrous acetonitrile (0.2 ml) at room temperature. The resulting mixture was heated at 100°C for 5 minutes. The crude mixture was analyzed using an analytical HPLC.

Getting 2-[3-[18F]fluoro-4-(methylamino)phenyl]-6-hydroxybenzothiazole (11).

A solution of concentrated HCl in the Meon (1:2) (0.25 ml) was added to the previous reaction mixture and was heated at 100°C for 5 minutes. The crude mixture was analyzed using an analytical HPLC.

Example 3: Comparative [18F]fluorination of the different precursors.

Radiotolerans different benzothiazoline compounds, the precursors of using methods similar to those described in Example 1(7), led to the results shown in Table 1. The approximate yield was calculated on the basis of radiochemical purity, measured by HPLC, corrected taking into account the loss of product while holding on HPLC and the reaction vessel.

Predecessor; R*=
Napproximate output < 5%
approximate output < 5%
approximate output < 5%
approximate output < 5%
the current label
25-30% enable

Example 4: Automated synthesis of 2-[3-[18F]fluoro-4-(methylamino)phenyl]-6-hydroxybenzothiazole (11)

In provisions for the reactants on the TRACERlab FXFN (GE Healthcare Ltd) automatic synthesizer downloaded the following solutions:

1. 0.1 M potassium carbonate in water (0.5 ml)

2. 0,13 M Kryptofix 2.2.2 in acetonitrile (0.5 ml)

3. The solution predecessor: 0.1 M 2-[3-nitro-4-(methylpentylamino)phenyl]-6-ethoxymethyleneamino (8) in DMSO (1.0 ml)

4. 4 M hydrochloric acid (0.25 ml)

5. Ethanol (1.0 ml)

6. 0.01 M phosphate buffer, pH 7.4 (13.1 ml)

When a solution of [18F]fluoride in [18O]-enriched water (121 MBq) was loaded into the initial position of the synthesizer, the operator ran the program, which led to the following sequence of events.

A solution of fluoride was passed through the QMA cartridge (pre-balanced 10 ml of 0.5 M aqueous potassium carbonate and 20 ml of water), catching fluoride and sending enriched water to waste. QMA cartridge was then suirable 0.1 M solution of potassium carbonate to obtain fluoride and luat directed into the reaction vessel. A solution of Kryptofix 2.2.2) was added to the reactor and the mixture was heated at 60°C for 5 minutes under a weak stream of nitrogen under reduced pressure. The temperature was then raised to 120°C and kept under vacuum for 7 minutes, to dry the contents of the reactor. After cooling to 50°C. a solution of the precursor was added to the reactor and the temperature was raised to 135°C for 10 minutes. This stage allows you to enable [18F]fluoride in an organic molecule. The solution was cooled to 50°C and was added 4 M hydrochloric acid. The mixture was heated to 125°C for 5 minutes to cause removal protection with an intermediate connection, and after cooling to 40°With a solution of the crude product were injected with the column Phenomenex Gemini C18 HPLC (250×21,2 mm, 5 μm). The column was suirable a mixture of 6 mm hydrochloric acid - acetonitrile (53:47, Rev.:about.) at 10 ml/min to the Desired product were identified by Radiodetection and collected by clipping. The resulting solution was diluted with water (150 ml) and was passed through the cartridge Sep-Pak® Plus C8 (pre-balanced 10 ml ethanol and 10 ml of water) so that the product retained on the cartridge. The cartridge was suirable ethanol in a container for a product, which contained propylene glycol (0.9 ml). Phosphate buffer was also passed through the cartridge in a container with the product to obtain the product as a drug. The product yield was 10.8% (unadjusted, based on the [ 18F]-initial activity and radiochemical purity was >99%.

Example 5: an Alternative synthesis of 2-[3-nitro-4-(methylpentylamino)phenyl]-6-ethoxymethyleneamino (8)

Example 5(1): Synthesis of 4-chloro-N-(4-hydroxyphenyl)-3-nitrobenzamide

4-Aminophenol (12 g, 0.11 mol, Acros and Aldrich) was dissolved in inert atmosphere with stirring in dry DMF (50 ml) and cooled in an ice bath. Was added triethylamine (TEA, 11 g, 0.11 mol) and stirring was continued for 1 hours. 4-Chloro-3-nitrobenzoate (22,2 g, 0.1 mol, Acros and Aldrich) was slowly added and stirred over night. The precipitated salt, triethylamine hydrochloride was filtered and the DMF was removed under reduced pressure. The residue was extracted with EtOAc (3×100 ml) and citric acid (1 M, 3×100 ml). The organic phase was dried with magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Specified in the header of the product was recrystallized from methanol/water (1:1, 250 ml), yield 85% and analyzed by NMR and MS.

Example 5(2): Synthesis of 4-chloro-N-(4-ethoxymethylene)-3-nitrobenzamide

4-Chloro-N-(4-hydroxyphenyl)-3-nitrobenzamide (14.6 g, 0.05 mol) were placed in a dried thermostat 2-necked 500 ml round bottom flask and was purged with N2. Added a sufficient amount of dimethoxyethane (DME, 100 ml) to dissolve the amide. See the camping was cooled in an ice bath and small portions was added sodium hydride (NaH, 50% in oil, only 3.6 grams of 0.075 mol) with vigorous stirring. One hour after completion of adding dropwise added chlorotoxin (7,13 g 0,075 mol, commercially available) through equalizing pressure addition funnel. The reaction was monitored using TLC (dichloromethane, DCM: methanol, Meon, 95:5). The reaction mixture was poured into ice water and was extracted with EtOAc (3×50 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product is recrystallized from a mixture of hexane/ethyl acetate 1:4 with obtaining 81% specified in the connection header.

Example 5(3): Synthesis of 4-chloro-N-(4-ethoxymethylene)-3-nitro-thiobenzamide

4-Chloro-M-(4-ethoxymethylene)-3-nitrobenzamide (3.5 g, 10 mmol), phosphorus pentasulfide P4S10(0,81 g and 1.83 mmol, commercially available), hexamethyldisiloxane (2.7 g, and 16.7 mmol, commercially available) and toluene (10 ml) was added to a 100 ml round bottom flask and was purged with nitrogen. The mixture was heated under reflux and was monitored by using TLC. Heating was continued until no more remained a source benzamide. Can also be used for microwave heating. The reaction mixture was cooled to room temperature. Solution was added potassium carbonate (4 ml 5,3 M solution). Acetone was added (10 ml) and the mixture was stirred for 1 hour in an ice bath, the extras who were garofali toluene and water. The organic phase was dried (MgSO4and the toluene was removed under reduced pressure and was purified flash chromatography with a mixture of ethyl acetate/hexane as eluent.

Example 5(3A): Alternative method tiaanidine: synthesis of N-(4-benzyloxyphenyl)-4-chloro-3-nitrotyrosine

N-(4-Benzyloxyphenyl)-4-chloro-3-nitrobenzamide (19,15 g, 50 mmol), reagent Laussane (11 g, 27 mmol, commercially available) and dioxane (150 ml) were stirred together and heated under reflux for 4 hours When, as shown by TLC, the original amide is no longer present, the reaction mixture was cooled and the solvent was removed under reduced pressure. The crude product was dissolved in a minimum amount of boiling toluene for recrystallization. The purified product was filtered and washed with cold toluene and cold hexane to obtain thioamide, with 77%yield.

Example 5(4A): Synthesis of 6-benzyloxy-2-(4-chloro-3-nitrophenyl)-benzothiazole

N-(4-Benzyloxyphenyl)-4-chloro-3-nitrotyrosine (2 g, 5 mmol) was dissolved in methanol (100 ml). Was added sodium hydroxide (1.6 g in 5 ml water), then Triton B (2,1 ml, 5 mmol, commercially available). The mixture was cooled in an ice bath. Dropwise with vigorous stirring was added potassium Ferri(III)cyanide (13,2 g in 50 ml water). The reaction mixture was left to warm in those who tell the night and was further heated to 130°C for 1 hour. The reaction mixture was cooled and was extracted with a mixture of ethyl acetate/water. The organic phase was dried and the solvent was removed under reduced pressure. Product, the compound was purified flash chromatography with hexane/ethyl acetate as eluent.

Example 5(4): Synthesis of 6-ethoxyethoxy-2-(4-chloro-3-nitrophenyl)-benzothiazole

When using methods similar to those described in Example 5 (4A), thiobenzamide obtained in Example 5 (3) can be cycletour education specified in the connection header.

Example 5(5): Synthesis of 6-benzyloxy-2-(4-methylamino-3-nitrophenyl)-benzothiazole and 6 ethoxyethoxy-2-(4-methylamino-3-nitrophenyl)benzothiazole (7)

The compounds of Examples 5 (4A) and 5 (4), respectively interact with methylamine in aqueous solution when heated to 130°C., for example in a microwave oven. The reaction mixture is extracted with a mixture of ethyl acetate/water and the organic phase is dried, and then under reduced pressure to remove the solvent. Specified in the header of the products purified flash chromatography using hexane/ethyl acetate.

Example 5(6): Synthesis of 2-[3-nitro-4-(methylpentylamino)phenyl]-6-benzyloxybenzoate and 2-[3-nitro-4-(methylpentylamino)phenyl]-6-ethoxymethyleneamino (8)

Listed in the connection header is obtained from the compounds of Example 5 (5), respectively, using methods formirovaniya similar to described the Example 1 (6).

Example 6: an Alternative synthesis of 2-[3-nitro-4-(methylpentylamino)phenyl]-6-ethoxymethyleneamino (8)

The synthesis was carried out analogously to Example 5, but starting with 4-amino-3-chlorophenol with obtaining 6-ethoxyethoxy-2-(4-chloro-3-nitrophenyl)-benzothiazole 4-chloro-N-(4-hydroxy-2-chlorophenyl)-3-nitrobenzamide, 4-chloro-N-(4-ethoxyethoxy-2-chlorophenyl)-3-nitrobenzamide and 4-chloro-N-(4-ethoxyethoxy-2-chlorophenyl)-3-nitrotyrosine. The cyclization of 4-chloro-N-(4-ethoxyethoxy-2-chlorophenyl)-3-nitrotyrosine with the formation of 6-ethoxyethoxy-2-(4-chloro-3-nitrophenyl)benzothiazole carried out using methods known from the literature, for example, Bowman et al Tetrahedron, 47 (48), 10119-10128 (1991); Couture and Glandclaudon, Heterocycles, 22 (6) 1984; Hutchinson et al. Tetrahedron Lett. 2000, 41 (3), 425-8. Then carry out methylation, formirovanie as described in Example 5.

1. The method of obtaining the compounds of formula (I):
,
where a group of fluorescent possible is a [18F]fluorescent;
phenyl ring And the substituted benzothiazol-2-yl, which is substituted by hydroxy, C1-6the alkyl, C1-6alkoxy, halogeno, OCH2OR11where R11represents a C1-6alkyl;
R1represents a C1-6alkyl;
which includes:
(1) the interaction of the compounds of the formula (II):
,
where the ring And substituted as defined for soybeans is inane formula (I);
R2selected from hydrogen, C1-10of alkyl, C1-10halogenoalkane, -(CH2CH2O)q-CH3where q is an integer from 1 to 10;
R1such as defined for the compounds of formula (I); and
R3represents a leaving group, such as nitro;
with a fluoride of an alkali metal or tetraalkylammonium, possibly with [18F]fluoride, to obtain the compounds of formula (III)
,
where R1and R2such as defined for compounds of formula (I) and (II), the group of fluorescent possible is a [18F]the fluorescent, and the phenyl ring And substituted as defined for compounds of formula (I);
and then stage (2) and possibly stage (3) in any order:
(2) the transformation of the group-C(O)R2in hydrogen via hydrolysis
(3) remove any additional protective groups.

2. The method according to claim 1, where the group of fluorescent in the compound of formula (I) is a [18F]the fluorescent, and the fluoride used in stage (1) how is a [18F]fluoride.

3. The method according to claim 1, where R1represents methyl.

4. The method according to claim 1, where R2in the compound of formula (II) is selected from hydrogen and C1-6of alkyl, and more preferably represents hydrogen.

5. The method according to claim 1, where the stage (2) is carried out by interaction with dinucleophiles base, so the m as sodium hydride, in an aprotic solvent such as acetonitrile or propionitrile, and at elevated temperature, for example 40°C-120°C, typically about 100°C.

6. The compound of formula (IIb):
,
where R1represents a C1-6alkyl; R2selected from hydrogen, C1-10of alkyl, C1-10halogenoalkane, -(CH2CH2O)q-CH3where q is an integer from 1 to 10;
R3represents nitro; and
R9selected from hydroxy, C1-6of alkyl, C1-6alkoxy, halogeno, OCH2OR11where R11represents a C1-6alkyl.

7. The compound of formula (IIb):
,
where R2represents hydrogen or C1-6alkyl;
R1represents a C1-6alkyl;
R3represents nitro; and
R9represents hydroxy or C1-6alkoxy.

8. The compound of formula (IIb) according to claim 6 or 7, where R2represents hydrogen.

9. 2-[3-Nitro-4-(methylpentylamino)phenyl]-6-ethoxymethyleneamino.

10. Radiopharmaceutical kit for obtaining18F-labeled RFID tags for use in PET (positron emission tomography), which includes:
(1) a vessel containing a compound of the formula (IIb)as defined in any of PP-9; and
(2) means for elution of the vessel with a source of18 -;
(3) ion-exchange cartridge for removal of excess18F-; and it is possible
(4) cartridge for removing protection from the obtained product of formula (I)as defined in any one of claims 1 and 2.

11. A cartridge for a radiopharmaceutical kit for obtaining18F-labeled RFID tags for use in PET, which comprises:
(1) a vessel containing a compound of the formula (IIb)as defined in any of PP-9; and
(2) means for elution of the vessel with a source of18F-.



 

Same patents:

FIELD: physics.

SUBSTANCE: electroluminescent material is described, consisting of an electron injection layer, an active luminescent layer based on a metal chalate complex, a hole transport layer and a hole injection layer. The luminescent substance is in form of new zinc complexes based on sulphonylamino derivatives of 2-phenylbenzoxazole or 2-phenylbenzothiazole. The hole transport layer of the material is preferably a mixture of triphenylamine oligomers.

EFFECT: electroluminescent material with high moisture resistance, high resistance to crystallisation and high thermal stability.

9 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention concerns oestrogen receptor modulators of the formula (II) with the structure where R1 is an alkenyl of 2-7 carbon atoms with alkenyl group optionally substituted by -CN or halogen; R2 and R2a are hydrogen or halogen independently of each other; R3 and R3a are hydrogen or halogen independently of each other; X is O; or their pharmaceutically acceptable salts. The invention also concerns a method of obtaining the claimed compounds, pharmaceutical composition, and treatment methods for various diseases.

EFFECT: obtaining of the claimed compounds.

39 cl, 23 tbl, 98 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the amyloid-binding compound or its water-soluble non-toxic salt, where Y is presented by NR1R2; Z means S; R1 is chosen from group consisting of H, methyl, propyl, (CH2)nOR' (where n = 1, 2 or 3 and R' is presented by H or by lowest alkyl group), CF3, CH2-CH2X, CH2-CH2-CH2X (where X = F, Cl, Br or I); where R2 is chosen from group consisting of lowest alkyl group, (CH2)nOR' (where n = 1, 2 or 3 and R' is presented by H or by lowest alkyl group), CF3, CH2-CH2X, CH2-CH2-CH2X (where X = F, Cl, Br or I); R3 - R10 are chosen independently from group, consisting of H, F, CI, Br, I, lowest alkyl group, (CH2)nOR' (where n = 1, 2 or 3) or OR' , and R' means H lowest alkyl group); provided, the compound isn't related one of the following compounds: methyl-[4-(6- methyl -benzothiazole-2-il)phenyl]amin, dimethyl -[4-(6- methyl - benzothiazole-2-il)phenyl]amin, and where at least one of R1-R10 substitutors contains the radioactive marker, chosen from group, which consists of 11C, 123I, 125I or 127I, and the described compounds don't contain the nitrogen quaternary atoms. The invented compounds are used for detection of the amyloid deposit in patient and in differential diagnostics of brain affected by Alzhemer's disease and normal brain. .

EFFECT: thioflavin derivatives are obtained for in vivo visualization and identification of amyloid deposit in patient.

16 cl, 2 tbl, 9 dwg, 9 ex

FIELD: organic chemistry, luminophores.

SUBSTANCE: invention relates to colorless at daylight organic luminophores, in particular, to novel, water-soluble, colorless luminophores A of the formula:

wherein X means oxygen (O) or sulfur (S) atom; Q means compounds of the formulas and wherein R1 and R2 taken separately or in common mean compounds of the formulas: -NHCH2COOM, -N(CH2COOM)2, Cl wherein M means Na, K, NH4. As comparing with the known colorless organic luminophores - optical whitening agents possessing with blue-sky blue fluorescence only, novel luminophores show fluorescence in the range from blue to yellow-orange color and can be used as components of fluorescent, colorless at daylight, inks for jet printers or stamp dyes.

EFFECT: improved and valuable properties of luminophores.

14 ex

FIELD: chemistry.

SUBSTANCE: method of producing partially fluorinated aromatic amines which contain at least one hydrogen atom in the ortho-position of the amino group, having general formula 1, , X = F (1a) or H (1b), is distinguished by that pentafluoroaniline is functionalised on the amino group through treatment with a derivative of aliphatic or aromatic mono- or dicarboxylic acid to obtain the corresponding derivative of pentafluoroaniline as a substrate which undergoes hydrodefluorination under the effect of a reducing metal in the presence of a proton source and in the presence of a catalyst - complex compound of nickel and/or cobalt with ligands selected from heterocyclic nitrogen-containing compounds or phosphorus-containing compounds in a medium of an aprotic dipolar solvent with subsequent alkaline or acid hydrolysis of the reaction mixture to form the corresponding amine.

EFFECT: improved method.

7 cl, 1 dwg, 6 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel improved method of obtaining benzylamine derivative of general formula (3)

and method of obtaining from the latter of carbamate derivative of general formula (6) where X1 represents halogen atom and R1 represents acyl group selected from C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and aromatic acyl group, R3 represents alkyl group. Methods include interaction of benzyl derivative of general formula (1)

with halogen compound of general formula (2): where X2 represents halogen atom, and R2 represents acyl group selected from C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and aromatic acyl group, in presence of Lewis acid. From obtained compound of general formula (3) carbamate derivative of general formula (6) is obtained. For this purpose compound of general formula (3) is subjected to hydrolysis obtaining aminoderivative of general formula (4)

which is further subjected to interaction with ester of halogen-formic acid of general formula (5) where X1 and R2 are determined above, X3 represents halogen atom, and R3 represents alkyl group, in presence of base. Invention also relates to novel acylbenzylamine derivatives of general formula (7):

where X1 represents halogen atom, each of R2 and R4 independently represents C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and R can additionally represent hydrogen atom. Benzylamine derivatives of formula (3) and formula (7) can be used as intermediate products for obtaining agricultural or garden bactericide based on formula (6) carbamate.

EFFECT: elaboration of improved method of obtaining benzylamine derivative.

5 cl, 1 tbl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 3,5-dimethyladamantyl-1-amine or its salts. Method involves the bromination step of 1,3-dimethyladamantane with liquid bromine at boiling. The bromination reaction is carried out in the mole ratio 1,3-dimethyladamantane to bromine = 1:(2-8) but preferably in the ratio = 1:(3-6), and separation of bromine is carried out by distillation. Then the excessive amount of formamide is added to a synthesized residue and kept the mixture at temperature 120-180°C but preferably at 150-160°C. The end product is isolated in free form or as a salt. Proposed method allows simplifying the process based on decreasing non-utilizable waste and possibility for carrying out the process in a single apparatus to yield the end product of high quality and purity.

EFFECT: improved method of synthesis.

3 cl, 11 ex

FIELD: chemistry of metalloorganic compounds.

SUBSTANCE: invention relates to the improved method for preparing imino salt of the formula Mx+[-N(CF3)2]x that is a source of anions N(CH3)2 and the following replacing halide or other groups in organic molecules with the group N(CH3)2. Method involves interaction of metal fluoride of the general formula MFx wherein M is Na, K, Rb, Cs, Ag, Cu, Hg; x = 1 or 2 under condition that x = 1 if M means Na, K, Rb, Cs or Ag, and x = 2 if M represents Cu or Hg with sulfonamide of the general formula: RfSO2N(CF3)2 wherein Rf means F or CnF2n+1; n = 1-4, or with sulfonamide of the general formula (CF3)2N(SO2CF2)mSO2N(CF3)2 wherein m = 0, 1 or with N,N-bis-(trifluoromethyl)perfluoroacylamide of the general formula: RfCON(CF3)2 in polar organic solvent medium to obtain the corresponding solutions containing imino salts of the general formula Mx+[-N(CF3)2]x and, respectively, sulfonylfluorides of the general formula RfSO2F, and sulfonyldifluorides of the general formula: F(SO2CF2)mSO2F of salt of the general formula: RfCF2O-M+. Also, invention relates to applying imino salts of the general formula Mx+[-N(CF3)2]x and [bis-(trifluoromethyl)imido]rubidium as a reagent for replacing halogen or other groups in organic molecules with the group N(CF3)2.

EFFECT: improved preparing method.

10 cl, 9 ex

The invention relates to new compounds of formula (1) or their pharmaceutically acceptable salts, where R1a, R2a, R3aand R4arepresent, each independently, hydrogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, and R5aand R6arepresent, each independently, tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzenesulfonyl or p-bromobenzyloxycarbonyl, which is an intermediate compound for the synthesis of benzimidazole derivatives and their pharmaceutically acceptable salts exhibiting excellent hypoglycemic effect
The invention relates to organic synthesis, in particular, to a method for producing 3-nitrodiphenylamine, which is an intermediate for the synthesis of pharmaceuticals etmozina and atalina used for the treatment of myocardial infarction and arrhythmias
The invention relates to organic chemistry, particularly to a process for the preparation of secondary amines from the corresponding sulfonamides

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing carbamide with a stable 13C isotope used in medical diagnostics, involving reaction of labelled carbon dioxide and ethylene oxide at temperature 80-150°C, pressure 2.1-6 MPa in the presence of a catalyst - complex of zinc bromide and tertiary organophosphines in molar ratio of ethylene oxide to the catalyst equal to 500-5000:1, followed by extraction of the labelled ethylene carbonate and ammonolysis of the extracted ethylene carbonate at temperature 120-170°C and pressure 2.8-4.7 MPa.

EFFECT: possibility of obtaining an end product with good output using a fairly simple and technologically effective method.

4 cl, 14 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention discloses a method of producing isotope-modified peptides and proteins, based on introduction of a stable 18O isotope (isotopic tag) into carboxyl groups of peptides and proteins by holding in a solution simultaneously containing H218O and trifluoroacetic acid.

EFFECT: method enables to obtain isotope-modified tags which are resistant to destruction and suitable for quantitative mass-spectrometric analysis with retention of the initial structure of the analysed compounds.

1 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: source of radioactive iodine or radioactive bromine is added to an aqueous solution of an alkaline salt of folic acid so that pH of this solution is approximately 7 in order to obtain a solution which contains folic acid or an iodide or bromide ion. PH of this solution is then lowered to 3.5-4.9 by adding an oxidising agent selected from N-chlorosulfamides of acids in a buffer solution to the said solution. The oxidising agent is mainly chloramines T or chloramines B.

EFFECT: possibility of adding isotopic tags to folic acid through radicals.

2 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol of formula I:

which is uniformly labelled with tritium. This compound is an analogue of 5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol.

EFFECT: obtaining a compound which is a selective cannabinoid receptor agonist.

1 dwg, 1 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: present invention relates to genetically modified yeast which independently produces cholesterol from a simple carbon source. The said yeast expresses 7-dehydrocholesterol reductase and 3β-hydroxysterine Δ24-reductase enzymes, while the sterol 24-C-methyltransferase enzyme is inactive. Cholesterol production of the said yeast is equal to or greater than 20% of all produced sterines. The invention also discloses a method of producing cholesterol and using the disclosed yeast strain to produce labelled and non-labelled cholesterol.

EFFECT: invention enables to obtain large amounts of cholesterol which is safe in terms of sanitation in.

12 cl, 13 dwg, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which can be used in diagnosis of tumorous diseases. In formula (I) , A is OH, C1-C5 alkoxy, N(C1-C5 alkyl)2, NH2; G is OH, O-C1-C5 alkyl; R1 and R2 independently denote H, 18F, 18F-C1-C5 alkoxy, 18F-C1-C5 alkyl, provided that if one of the substitutes R1 and R2 contain an 18F isotope, the other does not. The invention also relates to compounds of formulae and which are used in synthesis of formula (I) compounds, as well as to use of compounds of formula (IV) in synthesis of compounds of formula (I) or (II).

EFFECT: obtaining novel compounds which can be used in diagnosis of tumorous diseases.

29 cl, 4 ex, 8 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 13C-urea by reacting ammonia with carbon monoxide 13CO in the presence of oxygen, taken in molar ratio ranging from 8.9:2.8:1 to 4:2:1 at 15-25°C and pressure of 25-35 atm. The catalyst used is selenium powder taken in molar ratio Se:13CO ranging from 1:790 to 1:158. The solvent used is tetrahydrofuran or a mixture of tetrahydrofuran and methanol.

EFFECT: invention enables to obtain urea containing the stable 13C isotope with isotopic purity of not less than 99% in a single step.

1 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 1-13C-caprylic acid which is used as a diagnostic preparation when diagnosing motor-evacuation functions of the stomach. The method involves hydrocarboxylation reaction of 1-heptene with carbon monoxide 13CO and water at temperature 100-170°C and pressure not above 5 MPa, in the presence of a solvent and a catalyst system which contains a complex compound of palladium and triphenylphosphine in ratio ranging from 1:2 to 1:100, where the solvent used is dioxane and/or aromatic hydrodrocarbon.

EFFECT: obtaining 1-13C caprylic acid with high isotope purity, increased cost-effectiveness of the process owing to increased degree of utilisation of isotope material.

5 cl, 9 ex

FIELD: medicine.

SUBSTANCE: new pure syn-aminoacids of formulas I and II have ability of specific binding in biological system and may be used to produce image of tumor. II and I. In formulae I and II Y and Z are independently selected from group made of CH2 and (CR4R5)n, n=1, 2; R1-R3 are independently selected from group made of H and alkyl C1-C4; R4, R5 = H and R7 = 18F. Invention is related to method of synthesis of syn-aminoacids with formula II, which includes stages of ketone transformation into trans-spirit of formula I and transformation of produced trans-spirit into syn-aminoacid of formula II, and also to pharmaceutical composition for production of tumor image and method for production of tumor image.

EFFECT: improved efficiency of compounds and method of treatment.

12 cl, 1 tbl, 3 dwg, 3 ex

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