Intermediate chemical compound

FIELD: chemistry.

SUBSTANCE: invention pertains to new layers of acidic compounds with Formula I , where R2 is C1-6alkyl (possibly substituted and/or ending with one or more substitute, chosen from -OH, halogen, cyano, nitro and aryl) or aryl, where each aryl group, if not specifically mentioned, is possibly substituted by one or more substitutes, including -OH, cyano, halogen, nitro, C1-6alkyl, C1-6alkoxy, -N(R14a)R14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14e)R14f, -N(R14g)C(O)R14h, -N(R14m)S(O)2R13b, -S(O)2Rl3c and/or -OS(O)2R13d, where radicals from R13b to Rl3d independently represent C1-6alkyl; R14a and R14b independently represent H, C1-6alkyl, or jointly represent C3-6alkene, as a result, yielding a four-heptatomic nitrogen containing ring; radicals from R14c to R14m independently represent H or C1-6alkyl; A represents , where R16 represents unsubstituted C1-4alkyl, C1-4perfluoroalyl or phenyl, where the last group can be substituted with one or more substitutes, chosen from C1-6alkyl, halogen, nitro and C1-6alkoxy. The invention also relates to the method of obtaining Formula II compounds.

EFFECT: obtaining of new intermediate compounds and their use in special obtaining of formula II oxabispidin compounds, which can be used in the treatment of cardiac arrhythmia.

8 cl, 1 ex

 

The invention relates to new intermediate compounds and their use in the method of obtaining oxybisethanol connections.

Prior art

The number of documented compounds comprising the structure of 9-oxa-3,7-diazabicyclo-[3.3.1]nonane (ixabepilone), very slightly. As a result, very little is known of the methods that are adapted specifically to obtain oxybisethanol connections.

Some ixabepilone compounds described in Chem. Ber., 96 (11), 2827 (1963) as intermediate compounds in the synthesis of 1,3-diaza-6-oxa-adamantanes.

Hemiacetal (and related compounds)having the structure oxybisethanol ring, described in J. Org. Chem. 31, 277 (1966), ibid. 61 (25), 8897 (1996), ibid 63 (5), 1566 (1998) and ibid 64 (3), 960 (1999) as an unexpected oxidation of 1,5-diazacyclooctadecane-1,3-diols or restore 1,5-diazacyclooctadecane-1,3-diones.

1,3-Dimethyl-3,7-diesel-9-oxa-3,7-diazabicyclo[3.3.1]nonan described in J. Org. Chem. 32, 2425 (1967) as a product of attempts acetylation TRANS-1,3-dimethyl-1,5-diesel-1,5-diazabicyclo-1,3-diol.

In the international patent application WO 01/28992 describes the synthesis of a huge number of ixabepilone compounds, it has been shown that these compounds are useful in the treatment of cardiac arrhythmias. Among the above compounds are a series of compounds bearing N-2-(tert-butoxycarbonylamino is about)ethyl Deputy.

In the international patent application WO 02/083690 describes inter alia a method of obtaining the compounds of formula I

where R1represents H or aminosidine group, and R2represents a C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl) or aryl, where each aryl and alloctype, unless otherwise noted, possibly substituted;

including the interaction of the compounds of formula II

where R1such as defined above, with:

(1) a compound of formula III

where R16represents unsubstituted With1-4alkyl, C1-4perfluoroalkyl or phenyl, the latter group possibly substituted by one or more than one Deputy, selected from C1-6of alkyl, halogeno, nitro and C1-6alkoxy, and R2such as defined above; or

(2) acrylamide, followed by the interaction of the obtained intermediate compound of formula IV

where R1such as defined above, with an alcohol of formula R2-OH and an agent stimulating (or agents, in combination stimulating) the rearrangement and oxidation of the compounds of formula IV to the intermediate and ocyanate, which can then interact with the alcohol of formula R2Is HE, where R2such as defined above.

In the above application also describes a method of obtaining the compounds of formula I, where R1represents H, which includes obtaining the corresponding compounds of formula I in which R1represents aminosidine group described in this application means with the subsequent removal aminosidine group from this compound. In addition, in Example 3, Alternative II, described that salt accession 2,4,6-trimethylbenzenesulfonamide acid [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)ethyl]carbamino acid tert-butyl ester was converted into the free base with aqueous sodium hydroxide. Obtained [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid tert-butyl ether was first made in the presence of citric acid and 5%Pd/C to obtain [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid tert-butyl ester, which was subjected to interact directly without further purification to obtain (2-{7-[3-(4-cyanoaniline)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethyl) - carbamino acid tert-butyl ether.

Now found some new solid salts, which have advantages compared with the known methods is.

Description of the invention

According to the first aspect of the invention proposed salt accession acid compounds of the formula I

where R2represents a C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl) or aryl,

where each aryl group, unless otherwise noted, possibly substituted by one or more than one Deputy, including HE, cyano, halogeno, nitro, C1-6alkyl, C1-6alkoxy, -N(R14aR14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14eR14f, -N(R14g)C(O)R14h, -N(R14m)S(O)2R13b, -S(O)2R13cand/or -- OS(O)2R13dwhere the radicals from R13bto R13dindependently represents a C1-6alkyl; R14aand R14bindependently represent H, C1-6alkyl, or together represent a3-6alkylene, resulting in a four-semiline nitrogen-containing ring; the radicals from R14cto R14mindependently represent N or C1-6alkyl;

But a

where R16represents unsubstituted With1-4alkyl, C1-4perfluoroalkyl or phenyl, the latter group possibly substituted by one or more than one replaces the LEM, selected from C1-6of alkyl, halogeno, nitro and C1-6alkoxy. Specific salts that may be mentioned include toluensulfonate, bansilalpet, nosrat, bracelet, besylate, mesityl.

In one aspect of these salts are in solid form.

In another aspect, the salt is a salt of joining 2,4,6-trimethylbenzenesulfonamide acid [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid tert-butyl ether.

In the following aspect according to the present invention, a method for obtaining compounds of formula II

where R1represents a structural fragment of formula Ia

in which a represents a CH2and R3represents-IT or-N(H)R7;

R4represents H, C1-6alkyl, or together with R3represents =O;

R5represents phenyl or pyridyl, both of these groups possibly substituted by one or more than one Deputy, selected from HE, cyano, halogeno, nitro, C1-6the alkyl (possibly ending with the group-N(H)C(O)OR13a), C1-6alkoxy, -N(R14aR14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14eR14f, -N(R14g)C(O)R14h, -N(R14i)C(O)N(R14jR14k, -N(R14m)S(O)2R13b, -S(O)2 R13cand/or -- OS(O)2R13d;

R7represents H, C1-6alkyl, -E-aryl, -O-Het1, -C(O)R9a, -C(O)OR9b, -S(O)2R9c, -[C(O)]pN(R10a)10bor-C(NH)NH2;

the radicals from R9ato R9cindependently represent in each case, when used here, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, aryl and Het2), aryl, Het3or the radicals R9aand R9cindependently represent H;

R10aand R10bindependently represent in each case, when used here, N or C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, aryl and Het4), aryl, Het5or together represent a3-6alkylen, possibly interrupted by an atom Of;

E represents in each case, when used here, a direct link or1-4alkylen;

In represents-Z-, -Z-N(R12)-, -N(R12)-Z-, -Z-S(O)n- or-Z-O- (the latter two groups, Z is attached to the carbon atom bearing R3and R4);

Z represents a direct bond or C1-4alkylen;

R12independently represents N or C1-6alkyl;

the radicals from R13ato R 13dindependently represents a C1-6alkyl;

R14aand R14bindependently represent H, C1-6alkyl, or together represent a3-6alkylene, resulting in a four-semiline nitrogen-containing ring;

the radicals from R14cto R14mindependently represent N or C1-6alkyl; and

n represents 0, 1 or 2;

p represents 1 or 2;

radicals from Het1to Het5independently represent in each case, when used here, the five-dvenadcatiletnie heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, which may be substituted by one or more than one Deputy, is selected from =O, -HE, cyano, halogeno, nitro, C1-6of alkyl, C1-6alkoxy, aryl, aryloxy, -N(R15aR15c, -C(O)R15c, -C(O)OR15d, -C(O)N(R15eR15f, -N(R15g)C(O)R15hand-N(R15i)S(O)2R15j;

the radicals from R15ato R15jindependently represents a C1-6alkyl, aryl or radicals from R15ato R15jindependently represent H;

and R2represents a C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl) or aryl, where each Ari is other and alloctype, unless otherwise noted, possibly substituted by one or more than one Deputy, including HE, cyano, halogeno, nitro, C1-6alkyl, C1-6alkoxy, -N(R14aR14b, -C(O)R14c-C(O)OR14d, -C(O)N(R14eR14f, -N(R14g)C(O)R14h, -N(R14m)S(O)2R13b, -S(O)2R13cand/or -- OS(O)2R13d;

in which the salt of the compounds of formula I

where R2such as defined previously, and is a

where R16represents unsubstituted With1-4alkyl, C1-4perfluoroalkyl or phenyl, the latter group possibly substituted by one or more than one Deputy, selected from C1-6of alkyl, halogeno, nitro and C1-6alkoxy, is subjected to the interaction with the compound of the formula III

where Y represents O or N(R7), and R4, R5, R7and such as defined previously, at a temperature in the range from 0 to 100°With, for example at elevated temperature (for example from 60°With up to temperature phlegmy), in the presence of water and in the presence of a base, for example sodium carbonate.

In the first aspect of this salt was isolated in solid form before this stage of the method.

In the second aspect of the method for obtaining tert-butyl 2-{7[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]-non-3-yl}ethylcarbamate, including the interaction of salt [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamino acid tert-butyl ester with 4-[(2S)-oxiranylmethyl]benzonitrile at a temperature in the range from 0 to 100°in the presence of water and in the presence of a base, for example sodium carbonate.

In another related method aspect using the selected salt of [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamino acid tert-butyl ester, in particular salt of 2,4,6-trimethylbenzenesulfonamide acid.

The use of water as reaction medium in the method has important advantages in terms of waste management and environmental implications.

The term "aryl", when used herein, includes With6-10aryl groups such as phenyl, naphthyl and the like. The term "aryloxy", when used herein, includes With6-10alloctype, such as phenoxy, naphthoxy and the like. Avoidance means that alloctype attached to the remainder of the molecule through an atom Of actigraphy. Unless otherwise noted, aryl and alloctype can be substituted by one or more than one Deputy, including HE, cyano, halogeno, nitro, C1-6alkyl, C1-6alkoxy, -N(R14aR14b, -C(O)R14c-C(O)OR14d, -C(O)N(R14eR14f, -N(R14g)C()R 14h, -N(R14m)S(O)2R13b, -S(O)2R13cand/or -- OS(O)R13d(where the radicals from R13bto R13dthe radicals from R14ato R14msuch as they are defined in this description earlier). If aryl and alloctype are substituted, they are preferably substituted by substituents in the amount of from one to three.

The term "halogeno", when used herein, includes fluorescent, chloro, bromo and iodide.

Het is group (Het1to Het5)that may be mentioned include groups containing from 1 to 4 heteroatoms (selected from oxygen, nitrogen and/or sulfur), in which the total number of atoms in the ring system is five to twelve. By their nature, Het is group (Het1to Het5can be fully saturated, wholly aromatic, partly aromatic and/or bicyclic. Heterocyclic groups that may be mentioned include benzodioxane, benzodioxepine, benzodioxolyl, benzofuranyl, benzimidazolyl, bensbargains, benzoxazinones, benzothiophene, bromanil, cinnoline, dioxane, furanyl, imidazolyl, imidazo[1,2-a]pyridinyl, indolyl, ethenolysis, isoxazolyl, morpholinyl, oxazolyl, phthalazine, piperazinil, piperidinyl, purinol, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, Pirro is inil, pyrrolyl, hintline, chinoline, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thienyl, thiochroman, triazolyl and the like. The substituents on Het-groups (from Het1to Het5may, as appropriate, be located on any atom in the ring system including a heteroatom. The point of connection between the Het-groups (from Het1to Het5may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any condensed carbocyclic ring, which may be represented as part of a ring system. In addition, the Het group (Het1to Het5) can be N - or S-oxidised form.

The use of protective groups with full described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973) and ' Protective Groups in Organic Synthesis", 3rdedition, by T.W. Greene &P.G.M. Wutz, Wiley-lnterscience (1999). The method according to the invention has the unexpected advantage that the compounds of formula I can be obtained conveniently from solid (as opposed to, for example, oily or semi-solid) predecessors, and these precursors can be cleaned using simple techniques (e.g., recrystallization).

Furthermore, the method according to the invention may have the advantage consisting in that the compounds of formula I can be obtained with higher outputs, for man is the neck of the number of stages, in less time, more easily and with lower cost, compared with their receipt according to the method described in international patent application WO 01/28992.

The invention is illustrated but in no way limited to, the following further examples.

Examples

GENERAL EXPERIMENTAL procedures

Mass spectra were recorded on one of the following devices: a single quadrupole mass spectrometer with elektrorazpredelenie (S/N mc350) Waters ZMD; spectrometer Perkin-Elmer SciX API 150ex; * built-quadrupole mass spectrometer VG Quattro II single quadrupole mass spectrometer VG Platform II or single quadrupole mass spectrometer Micromass Platform LCZ (the latter three devices were equipped with pneumatically controlled interface elektrorazpredelenie (LC-MS).1H NMR and13With the NMR measurements were performed on the spectrometer Varian 300, 400 and 500 running on1H-frequencies of 300, 400 and 500 MHz, respectively, and13With the frequency of 75.5, 100,6 and 125,7 MHz, respectively.

Rotamer may vary or may not vary in range depending on the ease of interpretation of the spectrum. Unless otherwise stated, the chemical shifts are given in ppm (ppm) with the solvent as internal standard.

Reduction

API= ionization at atmospheric the pressure (in relation to MS)
br= extended (in relation to NMR)
d= doublet (in relation to NMR)
dd= doublet of doublets (in relation to NMR)
Et= ethyl
EQ.= equivalent
GC= gas chromatography
h= hour(s)
HPLC= high performance liquid chromatography
IMS= industrial methylated spirit
IPA= ISO-propyl alcohol
m= multiplet (in relation to NMR)
Me= methyl
min= minute(s)
TPL= melting point
MS= mass spectroscopy
Pd/C= palladium on coal
q= Quartet (in relation to NMR)
CT= room temperature
s= singlet (in relation to NMR)
t= triplet (in relation to NMR)

The prefixes n-, sec-, ISO - and tert - have their usual meanings: normal, secondary, ISO - and tertiary.

Example 1

a) Salt 2.4.6-trimethyl salsolinol acid and [2-(9-oxa-3.7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamino acid tert-butyl methyl ether

Salt of 2,4,6-trimethylbenzenesulfonamide acid and [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamino acid tert-butyl ester (150 g; obtained as described below), 4-methyl-2-pentanol (MIBC) (300 ml) and methanol (300 ml) were combined in a metal vessel for hydrogenation. Added the solid catalyst 5%Pd/C (4.5 g; 61%humidity; type 440L; Johnson Matthey). Then the mixture was first made under hydrogen pressure of 2.5 bar (250 kPa) and simultaneously heated to 55°C. the Measurement of the gas absorption showed that the reaction was completed after 2 hours. After cooling to 40°the catalyst was removed by filtration through glass fiber filter paper. The catalyst was washed on the filter with MIBC (300 ml) and the washings added to the main filtrate. The solvent (185 ml) was removed by distillation at atmospheric pressure. Then he removed a greater amount of solvent (243 ml) by distillation under reduced pressure (less than 100 mm Hg (less than 13,33 kPa)). Quickly added at 70°With isopropyl ether (IPE) (1050 ml), which resulted in a temperature drop of up to 45°C. In the reaction vessel was formed supermassively sediment. The mixture was heated again, the solvent drove and collected (268 ml). Added MIBC (150 ml) and 80°With all the substance was dissolved. Now the ratio of MIBC:IPE was approximately 4:5. The solution was left to cool and was made by ZAT is avcu (86 mg) at 70° C. the Reaction mixture was left to cool over night at ambient temperature. The mixture was cooled to 8°and then the solid product was collected by filtration. The solid is washed on the filter with IPE (450 ml) and then dried by suction. Subsequent drying in vacuo at 60°gave specified in the title compound in the form of solid white (115,0 g; 91%).

TPL 147-9°C.

b) tert-Butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate

An aqueous solution of sodium carbonate (1M, 53 ml) was added to the solution of salt of 2,4,6-trimethylbenzenesulfonamide acid and [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamino acid tert-butyl ester (50.0 g) in water (100 ml). Was added solid 4-[(2S)-oxiranylmethyl]benzonitrile (19.1 g) was poured into the reaction flask with water (50 ml). The reaction mixture was heated to 75°C for 3 hours and then was allowed to mix at ambient temperature over night. Was added toluene (350 ml), then aqueous sodium hydroxide (2M, 90 ml). The mixture was stirred for 5 minutes and then separated phase. The aqueous phase was discarded and the toluene phase is washed with aqueous citric acid (10% wt./about., 180 ml). Toluene phase was discarded. To the phase of citric acid was added MIBC (240 ml) and aqueous sodium hydroxide (5M, 180 ml). After a thorough AC is syvania the phases were separated and the aqueous phase was discarded. MIBC-phase washed with aqueous sodium chloride (20% wt./about., 50 ml). MIBC-phase was concentrated under vacuum at a temperature below 55°C. the Solvent was collected (13 ml of water, 29 ml MIBC). MIBC-the solution was cooled to ambient temperature and filtered, washing with the use of MIBC (50 ml). The solvent (152 ml) kept under vacuum at a temperature below 66°and then the distillation was stopped. Added IPE (360 ml), which resulted in a decrease of the temperature from 65 to 37°C. After stirring for 15 minutes the temperature was decreased by 2°to 35°and began crystallization. The mixture was left to cool with stirring to ambient temperature over night. The mixture was cooled to 5°and the product collected by filtration. The solid is washed on the filter with the use of IPE (150 ml) and dried by suction. Subsequent drying in vacua at 55°gave specified in the title compound in the form of solid white (41,2 g; 87%).

Getting salt of 2,4,6-trimethylbenzenesulfonamide acid and [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-carbamino acid tert-butyl methyl ether

a) 2-(tert-Butyloxycarbonyl)ethyl-2,4,6-trimethylbenzenesulfonyl

The triethylamine (65 ml; 465,3 mmol; 1.5 EQ.) was added in one portion to a solution of tert-butyl N-(2-hydroxyethyl)carbamate (50,11 g; 310,2 mmol; 1.0 EQ.) in dichloromethane (250 ml, 5 volumes is impressive. The solution was cooled to -10°and added trimethylamine hydrochloride (14,84 g; 155, 1mm mmol; 0.5 EQ.) in one portion. The resulting mixture was further cooled to -15°C, stirred for 5 minutes, then treated with a solution of mesitylenesulfonyl (74,74 g; 341,2 mmol; 1.1 EQ.) in dichloromethane (250 ml, 5 volumes) in the sequel to 28 minutes so that the internal temperature remained below -10°C. After adding the formed precipitate, and the mixture was stirred at -10°C for an additional 30 minutes. Was added water (400 ml, 8 volumes), and all the precipitate was dissolved. The mixture was rapidly stirred for 5 minutes and then separated the two layers. Replacement of the solvent from dichloromethane to IPA was carried out by distillation under reduced pressure. The solvent was removed (450 ml) and was replaced with IPA (450 ml) (initial pressure was 450 mbar (45 kPa), BP. 24°; final pressure was 110 mbar (11 kPa), BP. 36°). At the end of the distillation, solvent was removed (150 ml), which resulted in a reduction of up to 350 ml (7 volumes relative to the used amount of tert-butyl N-(2-hydroxyethyl)carbamate). The solution was cooled to 25°With, then slowly with stirring was added water (175 ml), which led to a gradual clouding of the solution. At this stage, the solid is not precipitated. Added additional amount of water (125 ml), and p is the next add 75 ml began to form a solid precipitate. The internal temperature rose from 25 to 31°C. the Mixture is slowly stirred and cooled to 7°C. the Solid is collected by filtration, washed with a mixture of IPA/water (1:1, 150 ml) and dried in vacuo at 40°C for 21 hours to obtain specified in the connection header in the form of a crystalline solid, white (92,54 g; 87%).

TPL 73,5°C.

1H-NMR (300 MHz, CDCl3) δ 1.42 (S, s), 2.31 (3H, s), 2.62 (6H, s), 3.40 (2H, q), 4.01 (2H, t), 4.83 (1H, bs), 6.98 (2H, s).

b) 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.]nonan

b(1) N,N-Bis(2-oxiranylmethyl)benzosulfimide

Water (2.5 l; 10 volumes), then epichlorohydrin (500 ml, 4 EQ.) added to benzosulfimide (250 g, 1 EQ.). The reagents were heated to 40°C. was Added aqueous sodium hydroxide (130 g in 275 ml of water) so that the reaction temperature remained between 40 and 43°C. It took approximately 2 hours. (The speed of addition of the sodium hydroxide must be less than at the beginning of add than at the end in order to maintain the temperature at a prescribed interval.) After adding sodium hydroxide was complete, the reaction mixture was stirred at 40°C for 2 hours, then at ambient temperature overnight. The excess epichlorohydrin was removed in the form of an azeotropic mixture with water by vacuum distillation (approximately 4 kPa (40 mbar), the internal temperature of 30° (C) is about as long still did not stop the distillation of epichlorohydrin. Added dichloromethane (1 l) and the mixture was rapidly stirred for 15 minutes. Left to split phase (it took 10 minutes, although fully transparent phase was obtained after settling in for the night). The phases were separated and the dichloromethane solution was used in the subsequent stage, below.

1H NMR (400 MHz, CDCl3): δ 2.55-2.65 (2H, m), 2.79 (2H, t, J 4.4), 3.10-3.22 (4H, m), 3.58-3.73 (2H, m), 7.50-7.56 (2H, m), 7.58-7.63 (1H, m), 7.83-7.87 (2H, m).

b(2) 5-Benzyl-3,7-dihydroxy-1-phenylsulfonyl-1,5-diazacyclooctadecane

To the dichloromethane solution from step (1)above was added IMS (2.5 l; 10 volumes). The solution was distilled until then, until the internal temperature reached 70°C. Collected approximately 1250 ml of solvent. Additionally added IMS (2.5 l; 10 volumes), then benzylamine (120 ml; 0.7 EQ.) as one portion (heat is not observed) and the reaction mixture was heated at a temperature of phlegmy for 6 hours (no change compared with the two-hour control point). Once again I added benzylamine (15 ml) and the solution was heated for an additional 2 hours. Drove IMS (approximately 3,25 l) was added in toluene (2.5 l). Once again drove the solvent (approximately 2.4 liters) and then was added toluene (1 l). The temperature of the ring now was 110°C. Collected additional the additional 250 ml of solvent at 110° C. Theoretically, the product remained approximately 2.4 liters of toluene at 110°C. This solution was used in the next stage.

1H NMR (400 MHz, CDCl3): δ 7.83-7.80 (4H, m, ArH), 7.63-7.51 (6N, m, ArH), 7.30-7.21 (10H, ArH), 3.89-3.80 (4H, m, CH(a)+SN(b)), 3.73 (2H, s, CH2Ph(a)), 3.70 (2H, s, CH2Ph(b)), 3.59 (2H, dd, CHHNSO2Ar(a)), 3.54 (2H, dd, CHHNSO2Ar(6)), 3.40 (2H, dd, CHHNSO2Ar(6)), 3.23 (2H, dd, CHHNSO2Ar(a)), 3.09-2.97 (4H, m, CHHNBn(a)+CHHNBn(6)), 2.83 (2H, dd, CHHNBn(6)), 2.71 (2H, dd, CHHNBn(a)).

(Data are for purified compounds containing a mixture of 1:1 TRANS - and CIS-diol (b))

b(3) 3-Benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonan

Toluene solution from step (2)above was cooled to 50°C. was Added anhydrous methansulfonate acid (0.2 l). This led to the increase of temperature from 50 to 64°C. After 10 minutes was added methanesulfonyl acid (1 l) and the reaction mixture was heated to 110°C for 5 hours. Then toluene drove from the reaction mixture; collected 1,23 L. (Note: the internal temperature should not rise above 110°at each stage, otherwise the output will be reduced). Then the reaction mixture was cooled to 50°and to delete the remainder of the toluene used the vacuum. Heated to 110°and 65 kPa (650 mbar) allowed to remove the addition of 0.53 l (If toluene can be removed at lower temperature and pressure, then it is profitable.) Then reactio the ing the mixture was left to cool to 30° With and added deionized water (250 ml). This led to the increase of temperature from 30 to 45°C. was Added water (2,15 l) in the continuation of the period of time a total of 30 minutes so that the temperature remained below 54°C. the Solution was cooled to 30°and then added dichloromethane (2 l). Using external cooling and rapid mixing of the reaction mixture was podslushivaet by adding aqueous sodium hydroxide (10 M, 2 l) at a rate at which the internal temperature was maintained below 38°C. It took 80 minutes. The stirring was stopped and the phases were separated for 3 minutes. Spent the layer break. To the dichloromethane solution was added IMS (2 l) and started distillation. The solvent (2,44 l) were collected up until the temperature of the shoulder strap did not reach the 70°C. Theoretically, the product remained approximately 1.56 l IMS. Then the solution was left to cool to ambient temperature overnight with slow stirring. The solid product precipitated precipitated, was filtered and washed using IMS (0.5 l), the product of a yellowish-brown color, which, after drying at 50°With vacuum gave up 50.8 g (8.9% in stage 3).

20 g of this product was dissolved in acetonitrile (100 ml) at a temperature of phlegmy to obtain a pale yellow solution. After cooling to the temperature of the he environment resulting crystals were collected by filtration and washed with acetonitrile (100 ml). The product was dried in vacuo at 40°C for 1 hour to obtain 17.5 g (87%) indicated in the subtitle of the connection.

1H NMR (400 MHz, CDCl3): 5 7.18-7.23 (10H, m), 3.86-3.84 (2H, m), 3.67 (2H, d), 3.46 (2H, s), 2.91 (2H, d), 2.85 (2H, dd), 2.56 (2H, dd).

b(4) 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.]nonan the dihydrochloride

Concentrated Hydrobromic acid (1.2 l; 3 Rel. about.) added to solid 3-benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane (400 g, see above stage (3)) and the mixture was heated to a temperature of phlegmy in nitrogen atmosphere. The solid was dissolved in acid at 95°C. After heating the reaction mixture for 8 hours, HPLC analysis showed that the reaction was completed. The contents were cooled to room temperature. Was added toluene (1.2 l; 3 Rel. about.) and the mixture was intensively stirred for 15 minutes. The stirring was stopped and produced a separation of the phases. Toluene phase was discarded together with a small amount of interfacial material. The acid phase is returned to the original reaction vessel was added sodium hydroxide (10 M; 1.4 l; 3.5 Rel. about.) in one portion. The internal temperature was raised from 30 to 80°C. exercise control pH in order to ensure that its value exceeded 14. Was added toluene (1.6 l, 4 Rel. vol.), and the temperature dropped from 80 to 60°C. After intensive mixing during the 30 minutes produced a separation of the phases. The aqueous layer is discarded together with a small amount of interfacial material. Toluene phase was returned to the original reaction vessel was added 2-propanol (4 years, 10 Rel. vol.). The temperature was set between 40 and 45°C. was Added concentrated hydrochloric acid (200 ml) in a continuation of 45 minutes so that the temperature remained between 40 and 45°C. the Formed precipitate is white. The mixture was stirred for 30 minutes and then cooled to 7°C. the Product was collected by filtration, washed with 2-propanol (0.8 l; 2 Rel. vol.), was dried by suction and then further dried in a vacuum Cabinet at 40°C. Output = 297 g (91%).

1H NMR (CD3OD + 4 drops of D2O): δ 2.70 (br d, 2H), 3.09 (d, 2H), 3.47 (br s, 4H), 3.60 (s, 2H), 4.12 (br s, 2H), 7.30-7.45 (m, 5H).

API-MS; m/z=219 [S13H18N2O+N]+.

b(5) 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan

All volumes and equivalents are defined relative to the used amount of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (see above stage (4)). 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane the dihydrochloride (60,07 g; 206,03 mmol; 1.0 EQ.; see the above stage (4)) was added toluene (420 ml, 7 volumes) and an aqueous solution of sodium hydroxide (2M, 420 ml, 7 volumes; 4.0 EQ.). The mixture was stirred in nitrogen atmosphere, was heated to 60°C and kept at this temperature for 30 minutes, the which was formed two transparent layer. The lower, aqueous layer was removed, and the toluene solution is specified in the header of the compound (free base) azeotrope dried at atmospheric pressure (total volume remote solvent = 430 ml; total volume of added toluene = 430 ml), then concentrated to a volume of 240 ml (4 volume). Analysis by Karl Fischer at this stage showed the water content in the solution of 0.06%. The dried solution specified in the connection header (theoretically 44,98 g; 206,03 mmol; 1.0 EQ.) used as such at a later stage.

in Salt of 2,4,6-trimethylbenzenesulfonamide acid and [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid tert-butyl methyl ether

Warm (28° (C) a solution of 2-(tert-butyloxycarbonyl)ethyl 2,4,6-trimethylbenzenesulfonyl (70,93 g; 206,03 mmol; 1.0 EQ.; see Obtaining (a)above) in toluene (240 ml, 4 volume) was added to a solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane (44,98 g; 206,03 mmol; 1.0 EQ.) in toluene (240 ml, 4 volume) (see Obtaining b(5)above). The resulting solution was rapidly stirred in a nitrogen atmosphere with heating at 68°C for 8 hours. The reaction mixture was allowed to mix at ambient temperature for 84 hours. Formed a dense precipitate solid white color in the solution is pale yellow. The mixture was cooled to +9°and specified in the header of the connection is birali by filtration. The reaction vessel was rinsed with toluene (100 ml) and was added to the filter. The filter cake was washed with toluene (150 ml). The solid white product was dried by suction for 15 minutes, then dried to constant weight in vacua at 40°C for 23 hours. The output specified in the title compound was 79,61 g (141,7 mmol; 69%). The combined filtrate and washings (670 ml) was washed with an aqueous solution of sodium hydroxide (2M, 200 ml; 3.3 volume). The mixture was heated to 60°C and kept at this temperature for 20 minutes with rapid stirring. Then two layers were separated. Toluene solution was concentrated to a volume of 200 ml by vacuum distillation (BP. 50-54°s at 650 to 700 mbar (65-70 kPa); BP. 46°at 120 mbar (12 kPa) at the end). During the distillation of the solution became turbid due to the formation specified in the connection header. Supposedly 20% of the initial amount of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane remained in the filtrate, and therefore was additionally added 2-(tert-butyloxycarbonyl)ethyl-2,4,6-trimethylbenzenesulfonyl (14,20 g; 41,21 mmol; 0.2 EQ.) as one portion (download in the form of a solid substance is preferable in the form of a solution in toluene). The turbid solution was heated at 67°C for 8 hours with rapid stirring and then left to mix with the temperature surrounding the it environment within 11 hours. The mixture was cooled to +8°and is listed in the title compound was collected by filtration. The reaction vessel was additionally washed with toluene (2×30 ml) and was added to the filter. The solid white product was dried by suction for 15 minutes, then dried to constant weight in vacuo at 40°C for 7 hours. The output specified in the title compound was 23,25 g (41,39 mmol; 20%). The combined output is specified in the header connections (solid white color) was 102,86 g (183,11 mmol; 89%).

TPL 190-190,5°C.

1H-NMR (300 MHz, CDCl3) δ 1.43 (S, s), 2.17 (3H, s), 2.51 (6N, s), 2.73-2.80 (2H, m), 2.90-2.94 (4H, m), 3.14-3.22 (4H, m), 3.37 (2H, bm), 3.89 (2H, bs), 4.13 (2H, bs), 6.74 (2H, s), 7.12 (1H, bt), 7.42-7.46 (5H, m).

1. Salt accession acid compounds of formula I

,

where R2represents a C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl) or aryl,

where each aryl group, unless otherwise noted, possibly substituted by one or more than one Deputy, including-OH, cyano, Galiano, nitro, C1-6alkyl, C1-6alkoxy, -N(R14aR14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14eR14f, -N(R14g)C(O)R14h, -N(R14m)S(O)2R13b, -S(O)2R13cand/or -- OS(O)2R 13dwhere the radicals from R13bto R13dindependently represents a C1-6alkyl; R14aand R14bindependently represent H, C1-6alkyl, or together represent a3-6alkylene, resulting in a four-semiline nitrogen-containing ring; the radicals from R14cto R14mindependently represent N or C1-6alkyl;

But a

,

where R16represents unsubstituted With1-4alkyl, C1-4perfluoroalkyl or phenyl, the latter group possibly substituted by one or more than one Deputy, selected from C1-6of alkyl, halogeno, nitro and C1-6alkoxy.

2. Salt according to claim 1, where this salt is a salt toluensulfonate, bansilalpet, nosrat, bracelet, besylate or mesityl.

3. Sol according to any one of claims 1 and 2, where this salt is in solid form.

4. Salt according to claim 1, which represents a salt of 2,4,6-trimethylbenzenesulfonamide acid and [2-(9-oxa-3,7-diazabicyclo [3.3.1]non-3-yl)-ethyl]carbamino acid butyl ether.

5. The method of obtaining the compounds of formula II

where R1represents a structural fragment of formula Ia

in which a represents a CH2 and R3represents-IT or-N(H)R7;

R4represents H, C1-6alkyl, or together with R3represents =O;

R5represents phenyl or pyridyl, both of these groups possibly substituted by one or more than one Deputy, selected from HE, cyano, halogeno, nitro, C1-6the alkyl (possibly ending with the group-N(H)C(O)OR13a), C1-6alkoxy, -N(R14aR14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14eR14f, -N(R14g)C(O)R14h, -N(R14i)C(O)N(R14jR14k, -N(R14m)S(O)2R13b, -S(O)2R13cand/or -- OS(O)2R13d;

R7represents H, C1-6alkyl, -E-aryl, -E-Het1, -C(O)R9a, -C(O)OR9b, -S(O)2R9c, -[C(O)]pN(R10aR10bor-C(NH)NH2;

the radicals from R9ato R9cindependently represent in each case, when used here, C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from halogeno, aryl and Het2), aryl, Het3or the radicals R9aand R9cindependently represent H;

R10aand R10bindependently represent in each case, when used here, N or C1-6alkyl (possibly substituted and/or terminated onemile more than one Deputy, selected from halogeno, aryl and Het4), aryl, Het5or together represent a3-6alkylen, possibly interrupted by an atom Of;

E represents in each case, when used here, a direct link or1-4alkylen;

In represents-Z-, -Z-N(R12)-, -N(R12)-Z-, -Z-S(O)n- or-Z-O- (the latter two groups, Z is attached to the carbon atom bearing R3and R4);

Z represents a direct bond or C1-4alkylen;

R12independently represents N or C1-6alkyl;

the radicals from R13ato R13dindependently represents a C1-6alkyl;

R14aand R14bindependently represent H, C1-6alkyl, or together represent a3-6alkylene, resulting in a four-semiline nitrogen-containing ring;

the radicals from R14cto R14mindependently represent N or C1-6alkyl; and

n represents 0, 1 or 2;

p represents 1 or 2;

radicals from Het1to Het5independently represent in each case, when used here, the five-dvenadcatiletnie heterocyclic group containing one or more than one heteroatom selected from oxygen, nitrogen and/or sulfur, which may be replaced by the ne or more than one Deputy, selected from =O, -HE, cyano, halogeno, nitro, C1-6of alkyl, C1-6alkoxy, aryl, aryloxy, -N(R15aR15b, -C(O)R15c, -C(O)OR15d, -C(O)N(R15eR15f, -N(R15g)C(O)R15hand-N(R15i)S(O)2R15j;

the radicals from R15ato R15jindependently represents a C1-6alkyl, aryl, or radicals from R15ato R15jindependently represent H;

and R2represents a C1-6alkyl (possibly substituted and/or terminated by one or more than one Deputy, selected from HE, halogeno, cyano, nitro and aryl) or aryl, where each aryl and alloctype, unless otherwise noted, possibly substituted by one or more than one Deputy, including HE, cyano, halogeno, nitro, C1-6alkyl, C1-6alkoxy, -N(R14aR14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14eR14f, -N(R14g)C(O)R14h, -N(R14m)S(O)2R13b, -S(O)2R13cand/or -- OS(O)2R13d;

in which the salt of the compounds of formula I

,

where R2such as defined previously, and is a

,

where R16represents unsubstituted With1-6alkyl, C1-4perfluoroalkyl or phenyl, the latter group possibly substituted od is them or more than one Deputy, selected from C1-6of alkyl, halogeno, nitro and C1-6alkoxy, is subjected to the interaction with the compound of the formula III

where Y represents O or N(R7), and R4, R5, R7and such as they are defined here earlier, at a temperature in the range from 0 to 100°With, for example at elevated temperature (for example from 60°With up to temperature phlegmy), in the presence of water and in the presence of a base.

6. The method according to claim 5, where salt has been pre-allocated in solid form.

7. The method according to claim 5 obtain tertbutyl-2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]-non-3-yl}ethylcarbamate,

including the interaction of salt [2-(9-oxa-3,7-diazabicyclo [3.3.1]non-3-yl)-ethyl]-carbamino acid butyl ester with 4-[(2S)-oxiranylmethyl]benzonitrile at a temperature in the range from 0 to 100°in the presence of water and in the presence of a base.

8. The method according to any of pp.5, 6 or 7, wherein using the selected salt of [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamino acid butyl ether.

9. The method of claim 8, where salt is a salt of 2,4,6-trimethylbenzenesulfonamide acid.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel solid formulation of anti-arrhythmic medicinal agents. Invention describes crystalline formulation of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benznitrile, tert.-butyl-2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-dizabicyclo[3.3.1]non-3-yl}ethylcarbamate, tert.-butyl-2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or tert.-butyl-2-{7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate and their pharmaceutically acceptable salts. Also, invention describes methods for their synthesis, a pharmaceutical preparation based on thereof, a method for prophylaxis or treatment of arrhythmia and their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: organic chemistry, antibiotics, chemical technology.

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EFFECT: improved method for preparing.

2 cl, 2 tbl, 20 ex

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EFFECT: improved preparing method.

1 tbl, 13 ex

FIELD: organic chemistry, chemical technology, antibiotics.

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EFFECT: improved preparing method.

1 tbl, 4 ex

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to new compounds rifamitinov series formula:

< / BR>
A new connection can be used as an antibacterial and antituberculosis drug

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-aminorifamycin S of the formula (I) , eliciting antibiotic properties wherein X means NH2; Y = Z and mean hydrogen atom (H) or (CH3)2C<, or C6H5CH<, or C6H10<. Method for preparing 3-amino-derivatives of rifamycin S involves stirring 3-halogen-derivative of rifamycin S in solvent medium wherein solvent represents simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the following series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 with hydrazoic acid salt wherein sodium azide is used and stirring is carried out for 0.5-2 h. Then method involves the following conversion of obtained 30azido-derivative of rifamycin S to the end product using a reducing agent wherein mixture of zinc or iron with acetic acid is used, or hydrogen in the presence of palladium catalyst followed by treatment with oxidizing agent wherein ferric (III) chloride or manganese (IV) oxide is used, or hydrogen peroxide, or persulfates, or air. Extraction of the end product is carried out by extraction with organic solvent not mixing with water or by dilution of reaction mixture with water followed by crystallization of product. Invention provides the enhancement of method for preparing 3-amino-derivatives of rifamycin S due to elevating yield of the end product and process for it isolating.

EFFECT: improved preparing method.

1 tbl, 4 ex

FIELD: organic chemistry, chemical technology, antibiotics.

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EFFECT: improved preparing method.

1 tbl, 13 ex

FIELD: organic chemistry, antibiotics, chemical technology.

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EFFECT: improved method for preparing.

2 cl, 2 tbl, 20 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new layers of acidic compounds with Formula I , where R2 is C1-6alkyl (possibly substituted and/or ending with one or more substitute, chosen from -OH, halogen, cyano, nitro and aryl) or aryl, where each aryl group, if not specifically mentioned, is possibly substituted by one or more substitutes, including -OH, cyano, halogen, nitro, C1-6alkyl, C1-6alkoxy, -N(R14a)R14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14e)R14f, -N(R14g)C(O)R14h, -N(R14m)S(O)2R13b, -S(O)2Rl3c and/or -OS(O)2R13d, where radicals from R13b to Rl3d independently represent C1-6alkyl; R14a and R14b independently represent H, C1-6alkyl, or jointly represent C3-6alkene, as a result, yielding a four-heptatomic nitrogen containing ring; radicals from R14c to R14m independently represent H or C1-6alkyl; A represents , where R16 represents unsubstituted C1-4alkyl, C1-4perfluoroalyl or phenyl, where the last group can be substituted with one or more substitutes, chosen from C1-6alkyl, halogen, nitro and C1-6alkoxy. The invention also relates to the method of obtaining Formula II compounds.

EFFECT: obtaining of new intermediate compounds and their use in special obtaining of formula II oxabispidin compounds, which can be used in the treatment of cardiac arrhythmia.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: invention relate to oxabispidinic compounds of formula I, ,where R1 is C1-12alkyl (where the given alky group is substituted with a group selected from phenyl, Het1, N(R5a)R6, -OR5c, -S(O)2N(R9b)R9c and -N(R9b)S(O)2R9d); R5a is H; R5c is C1-6alkyl (which is substituted with phenol) or phenyl; R6 is H or -C(O)OR10b; R10b is C1-6alkyl; R9b in each case where it is used in the given description of the invention represents H or C1-6alkyl; R9c and R9d in each case it is used in the given description of the invention independently presents C1-6alkyl (possibly substituted with one or more substitutes, selected from halogen or phenyl), phenyl or Het7, or R9c is H; R2 is H or OR13; R3 is H; R13 is H; Het1 and Het7 independently represent 5-12-member heterocyclic groups containing one or more heteroatoms, selected from oxygen and nitrogen, where these groups are possibly substituted with one or more substitutes selected from halogen and C1-6alkyl; A is a direct bond, -J-, J-S(O)2N(R19b)- or -J-N(R19c)S(O)2- (where in the last two groups -J is bonded to the nitrogen of an oxabispidinic ring); B is Z-{[C(O)]aC(H)(R20a)}b-, -Z-[C(O)]cN(R20b)-, -Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -Z-S(O)n-, -Z-O- (where in the last six groups Z is bonded to a carbon atom, carrying R2 and R3), -N(R20e)-Z-, -N(R20f)S(O)2-Z-, -S(O)2N(R20g)-Z- or -N(R20h)C(O)O-Z- (where in the last four groups Z is bonded to a phenyl group which is possibly substituted with a R4 group); J is C1-6alkylene, possibly broken by a -S(O)2N(R19d)- or -N(R19e)S(O)2- group and/or possibly substituted with a substitute selected form -OH; Z is a direct bond or C1-4alkylene, possibly broken by a -N(R20i)S(O)2- or -S(O)2N(R20j)- group; a, b and c possibly represent 0 or 1; n is 0, 1 or 2; R19b-R19e in each case where used in the given description of the invention independently represents H or C1-6alkyl; R20a is H or together with the only substitute R4 on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, represents C2-4alkylene, possibly broken or ending with O, N(H) or N(C1-6alkyl) group; R20b is H or C1-6alkyl; R20c-R20j in each case when used in the given description of the invention independently represents H or C1-6alkyl; or R20g and R20i independently represent C1-6alkyl, substituted with 3,5-dimethylisoxazolyl; G is CH; R4 is one or more possible substitutes selected from cyano, halogen, C1-4alkyl and C1-6alkoxy, possibly substituted with one or more hanogen and a R4 substitute on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, together with R20a can represent C2-4alkylene; broken or ending with O or N(H) or a N(C1-6alkyl) group; R41-R46 independently represent H; where each phenyl group is possibly substituted with one or more substitutes selected from halogen, cyano, C1-6alkyl and C1-6alkoxy (where the last two groups are possibly substituted with one or more halogen atoms); or to their pharmaceutically acceptable salts. The invention also relates to methods of producing said compounds, as well as to a pharmaceutical composition based on said compounds, with HERG-channel blocking activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for preventing and treating arrhythmia, particularly cardiac and ventricular arrhythmia.

32 cl, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I) or their pharmaceutically acceptable salts, where symbols assume values given in the description, where the said compounds are chemokine receptor (CCR-1) antagonists. Also described is a method of inhibiting the chemokine receptor to reduce inflammation in mammals.

EFFECT: possibility of use in treating inflammatory diseases.

8 cl, 160 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel intermediate compounds - methyl 7-aryl-4,9-diaroyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]none-3,8-diene-8-carboxylates of formula III Ar1=Ar2=Ph, Ar3=C6H4Me-n (IIIa); and Ar1=C6H4Br-n, Ar2=C6H4OEt-n, Ar3=C6H4Me-n (IIIb), for synthesis of methyl 6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-6-ene-8-carboxylates of formula IV where Ar1=Ar2=Ph, Ar3=C6H4Me-n (IVa); Ar1=C6H4Br-n Ar2=C6H4OEt-n, Ar3=C6H4Me-n (IVb), which exhibit antimicrobial activity and are used as precursors for synthesis of novel heterocyclic systems, and a method for synthesis of said compounds.

EFFECT: compounds have high effectiveness.

5 cl, 1 tbl, 5 ex

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