Method for preparing benzopyran-2-ol derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: in the given invention, there is offered a method for preparing a compound of formula , where Y is specified of CH3, CH2OH, CH2CH2OH, CH2Br and Br; involving the stages: (1) reaction of the compound of formula where OX represents hydroxy or O-M+ where M+ represents cation chosen of Li+, Na+ and K+ and Y is such as specified above; with trans-cynnamaldehyde , with a secondary amine compound added; then (2) acid treatment of a product from the previous stage to prepare a compound of formula (I). The aforesaid method can be used for preparing tolterodine and fezoterodine which are effective in treating the hyperactive urinary bladder. There are also declared compounds of formulae V, VI and VII.

EFFECT: development of the effective method for preparing the compound.

25 cl, 19 ex

 

The invention relates to an improved method of production of intermediate products useful in getting tolterodine, fesoterodine and other pharmaceutically useful compounds. The invention also suggested improved methods for such pharmaceutically useful compounds using these intermediate products.

Tolterodine {2-[(1R)-3-[bis(1-methylethyl)amino]-1-phenylpropyl]-4-METHYLPHENOL or alternative (+)-N,N-aminobutiramida-3-(2-hydroxy-5-were)-3-phenylpropylamine},

2124

is an antagonist of muscarinic receptors for the treatment of overactive bladder, including urinary incontinence. It was approved for sale (as tartrate) in 1997 and in subsequent years was released in many markets under the trademarks DETROL and DETRUSITOL. Tartrate tolterodine disclosed in international patent application WO 89/06644 (see in particular Example 22, paragraph 7).

In WO 98/29402 disclosed is a method of obtaining tolterodine, including condensation of para-cresol (a) cinnamic acid (b), then the recovery of the obtained lactone (C) a reducing agent, such as diisobutylaluminum hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminum hydride or lithium tri-tert-butoxylated, obtaining the appropriate benzopyran-2-Aulnay connection (g). Benzopyran-2-Aulnay connection (g) then m is can be transformed into the racemic hydrochloride tolterodine (d) through reductive amination with Diisopropylamine followed by the addition of aqueous hydrochloric acid. Finally, tolterodine L-tartrate are obtained by neutralizing the hydrochloric acid salt (d) NaOH/NaHCO3and subsequent separation using L-tartaric acid. The method presented in Scheme 1

It is seen that in the method described in WO 98/29402, benzopyran-2-Aulnay connection (g) receive two stages, and this method includes the use of relatively expensive reductant (DIBAL).

In WO 01/49649 described reductive amination of the enantiomers of the above compound (g) with the receipt of tolterodine and its enantiomer. The enantiomers of the compounds (g) are obtained by enantioselective interactions. This also applies to the same methods applied to the same compounds, in particular analogues tolterodine in which the methyl group in the phenolic ring substituted 5-hydroxymethylene group.

In patent application US 2003/0236438 (MacMillan et al.) it is disclosed the use of relatively complex chiral imidazolidinone catalysts [e.g., (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidine-4-it] for the implementation of enantioselective reactions of 1,4-addition between aniline nucleophiles and α,β-unsaturated aldehydes (this work is also described in MacMillan et al., J. Am. Chem. Soc, 2002, 124, 7894-7895). Example 2 of patent application US 2003/0236438 described is a typical reaction:

It is seen that the carbon atom of the aromatic ring in the para-position to the amino group binds to alpha-beta unsaturated aldehyde.

In Jurd (Journal of Heterocylic Chemistry, volume 28 (4), 1991, str-986) revealed the interaction of 3,4-methylenedioxyphenol, research and cinnamic aldehyde in methanol to obtain 2-morpholinyl-4-phenylbenzophenone.

Unexpectedly, it was found that benzopyran-2-Aulnay connection (g) of Scheme 1 can be obtained in ignoreaction interaction, starting from para-cresol (a). Can also be obtained similar compounds. Thus, according to the first aspect of the present invention, a method for obtaining compounds of formula (I),

where Y is selected from CH3CH2HE, CH2CH2HE, CH2Br and Br; comprising the steps:

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

where

OX is a hydroxy or O-M+where M+represents a cation selected from Li+, Na+and+and

Y as defined above;

with TRANS-cinnamaldehyde (III)

;

in the presence of secondary amine compounds; then

(2) treatment of the product from the previous stage acid to obtain the compounds of formula (I).

Under "secondary amine compound" is the second of the invention involve organic compound, which contains at least one secondary amine group, i.e. the compound of the formula:

where Raand Rbare not hydrogen. Preferably, each of Raand Rblinked to the nitrogen atom through a group of CH2for example, they independently represent a1-6alkyl or together form a 4 - or 5-membered alkyl chain in which one carbon atom may replaced by O or N.

The preferred embodiments of the first aspect of the present invention are those in which:

(a) OH represents hydroxy;

(b) Y is CH3or CH2IT;

(C) a secondary amine compound is achiral;

(g) a secondary amine compound containing two secondary amine groups, such as piperazine (this catalyst provides a particularly high outputs product);

(d) if a secondary amine compound containing two secondary amine groups, 0.5 to 1.25 mol-equivalents of the secondary amine compound used in stage (1);

(e) alternatively, the secondary amine compound contains one secondary amine group and, more preferably, the secondary amine compound is a morpholine, dibutylamine, dibenzylamine, 1,1,3,3-tetramethylguanidine, diethylamin, Diisopropylamine, piperidine or N-(C1-6alkyl)piperazine. N-Methylpiperazin especially preferred because it provides good yields starting material [see the formula (VI) below] is easily hydrolyzed to the corresponding lactaline compound of formula (I), and the crude compound of formula (1) has superior purity, which facilitates crystallization;

(C) if a secondary amine compound contains one secondary amino group, at the stage (1) use 1-5, more preferably 1-2,5 mol-equivalents of secondary amine compounds;

(and) the acid used in stage (2), is a water-hydrochloric acid (preferably in a concentration of not more than 2 M), although the following aqueous acid in the respective concentrations also provide good results: citric acid, acetic acid, axalingua acid, triperoxonane acid, maleic acid, fumaric acid, salicylic acid, TRANS-cinnamic acid, benzoic acid, camphorsulfacid and toluensulfonate;

(K) the interaction on stage (1) is carried out in an organic solvent selected from toluene, xylene, N-butyl acetate, tert-amyl alcohol, dioxane and dibutylamino ether, most preferably in toluene (which provides a particularly high outputs);

(l) interaction at the stage (1) is carried out at a temperature ranging from 80°C to the temperature of delegal the AI solvent;

(m) interaction at the stage (1) is carried out at the conditions under which water is removed from the reaction system (e.g., Dean-stark when water is obtained when the reaction is condensed in the side condenser so that it is not returned to the reaction mixture and can be allocated if required); and

(h) interaction at the stage (1) is carried out at a pressure equal to or approximately equal to the ambient pressure (for example, you can use the slightly increased pressure nitrogen atmosphere, especially on an industrial scale).

Especially preferred that when Y is CH2HE, then a secondary amine compound represented N-methylpiperazine.

The secondary amine compound preferably contains two basic nitrogen atom. Such compounds form a source products [see the formula (VI) below], which are easily hydrolyzed in the compounds of formula (I).

According to the second aspect of the invention, a method for obtaining compounds of formula (IV)

where Y is selected from CH3CH2HE, CH2CH2HE, CH2Br and Br, or its salts, including:

(a) obtaining the compounds of formula (I)as defined above, with the method according to the first aspect of the invention; then

(b) recovering aminia is the use of the compounds of formula (I) diisopropylamino;

(b) and, if required, converting the compounds obtained into salt.

In the second aspect of the invention Y preferably represents CH3or CH2HE. If Y is CH3the compound of formula (IV) can be treated with L-tartaric acid in stage (C) receiving tolterodine L-tartrate [for example, R-(+)-tolterodine L-tartrate]. If you intend to use the compounds of formula (IV) as a drug, the salt form obtained in this second aspect of the invention, preferably is pharmaceutically acceptable. However, this is not essential if the connection will be subjected to additional processing.

Reductive amination of the compounds of formula (I) may include processing diisopropylamino in a suitable solvent, such as methanol (which is preferred) or tert-amyl alcohol or mixtures thereof, then hydrogenation in the presence of a catalyst such as Pd/C or Pd(OH)2/C.

In one embodiment the compound of formula (IV) may be treated with aqueous acid, which as hydrochloric acid, to obtain the corresponding hydrochloric acid salt. Racemic compound can be converted into the corresponding (R)-enantiomer L-tartrate salt by neutralizing hydrochloric acid salt in the presence of a base, such as a mixture of the hydroxide is sodium and sodium carbonate, followed by the separation of L-tartaric acid. In one embodiment of get tolterodine L-tartrate [i.e. R-(+)-tolterodine L-tartrate].

In an alternative embodiment (R)-enantiomer L-tartrate salts of the compounds of formula (IV) can be obtained directly after reductive amination of compounds of formula (I) without the formation of hydrochloric acid salt. For example, in one embodiment the product recovery stage amination can be treated with a solvent, such as acetone and L-tartaric acid to obtain L-tartrate salt. If Y is CH3then get tolterodine L-tartrate [for example, R-(+)-tolterodine L-tartrate].

According to a third aspect of the invention, a method for obtaining fesoterodine,

or its pharmaceutically acceptable salt, which includes:

(a) obtaining the compounds of formula (IV)as defined above in which Y is CH2HE, using the method described above;

(b) separation of the product from step (a) to obtain (R)-enantiomer;

(C) acylation of phenolic hydroxy-group of the product from step (b) to obtain the corresponding ester somaclonal acids;

(g) and, when it is desirable or necessary, converting the compounds obtained into pharmaceutically acceptable salt.

Fesoterodine with x the chemical name 2-[(1R)-3-[bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxymethylene isobutyrate or alternative R-(+)-somaclonal acid 2-(3-diisopropylamino-1-phenylpropyl)-4-gidroksimetilfurfuralya ether, described in EP 1077912 (see page 32 line 5 and formula 4, 3rd connection). It is indicated for the treatment of overactive bladder.

In this third aspect, the separation is preferably carried out by fractional crystallization with a chiral acid, preferably (R)-(-)-acetoxy(phenyl)acetic acid.

Allerease agent preferably is isobutyrate.

The compound of formula (I) can exist in the form of an open ring, although it is assumed that it exists mainly in the form of a closed ring (lactol). In addition, it is assumed that in the method according to the first aspect of the invention receive a mixture of diastereoisomers lactol:

and R - and S-enantiomers of the chiral center marked with an asterisk are present in equivalent amounts. Obtaining all such tautomeric and stereoisomeric forms covered by the present invention.

When piperazine is used in stage (1) of the first aspect of the invention, the reaction proceeds through amenable to the separation of the intermediate compound of formula (V),

where Y is selected from CH3CH2HE, CH2CH2HE, CH2Br and Br. Such compounds are available according to the fourth aspect of the present invention. Preferably, Y represented yet a CH 3.

If at the stage (1) of the first aspect of the invention is applied N-methylpiperazine, the interaction occurs through an intermediate compound of formula (VI)

where Y is selected from CH3CH2HE, CH2CH2HE, CH2Br and Br. Such compounds are available according to the fifth aspect of the present invention. Preferably, Y is CH2HE.

The present invention further provides a compound of formula (I),

where Y is selected from CH2CH2HE, CH2Br and Br.

The method according to the invention differs from the patent application US 2003/0236438 (see above) the fact that none of the reagents is not an aniline compound, and the compound of formula (II) according to the present invention is not more strongly activating or strongly electron-donating group (such as methoxy Example 2 of the patent application US 2003/0236438). In addition, the amine catalysts used in the present invention are simpler (for example, they should not be chiral) and, therefore, cheaper.

The method according to the invention differs from the above in Jurd (Journal of Heterocylic Chemistry, volume 28 (4), 1991, str-986) the fact that none of the reagents is not an aniline compound, and the compound of formula (II) according to the invention does not present additional the ilen activated or strongly electron-donating group, such as alkoxy or hydroxy.

An additional advantage of the invention is that as part of a way of getting tolterodine in comparison with the method described in WO 98/29402, excluded a number of reactions and process steps, which leads to cost reduction. In addition, in this way avoid the use of expensive reducing agents, such as diisobutylaluminium hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminum hydride or lithium tri-tert-butoxylated, which are also difficult to dispose of.

An additional advantage of the invention is that as part of getting fesoterodine, compared with the methods described in the prior art, it is the number of reactions and process steps, which leads to cost reduction. In addition, in this way avoid the use of hazardous and environmentally undesirable reagents that are difficult to dispose of.

The invention is illustrated in the following examples, in which can be used the following abbreviations:

BuOH = butanol

DEA = diethylamin

DMA = dimethylacetamide

DMF = dimethylformamide

DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone

DMSO = dimethyl sulfoxide

EDTA = ethylenediaminetetraacetic acid

EE = enantiomeric excess

EtOAc = ethyl acetate

EtOH = ethanol

h = hour

IPA = isopropyl alcohol

LC-MS = liquid HRO is ecografia - mass spectrometry

LOD = loss on drying

Meon = methanol

min = minute

n-BuOH = n-butanol

psi = pounds per square inch

TFA = triperoxonane acid

THF = tetrahydrofuran

tlc = thin layer chromatography

Example 1

Synthesis 3.4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol

Para-cresol (150 g, 1,387 mol) was mixed with piperazine (72 g, 0,832 mol, 0.6 EQ.) in toluene (1.5 l, 10 ml/g) and then heated to boiling under reflux in the conditions of a Dean-stark for at least 30 minutes to remove water to obtain a transparent light yellow solution. Then was added TRANS-cinnamaldehyde (262 ml, 275 g, 2,081 mol, 1.5 EQ.) within 2 hours, maintaining the reaction mixture at boiling under reflux in the conditions of a Dean-stark. When the addition was completed, heating of the reaction mixture was kept under reflux in the conditions of a Dean-stark for another 4 hours. The black solution was left to cool to 80°C and then slowly extinguished within 45 minutes with a solution of 0.67 M HCl (aq.) (750 ml, 0,601 mol, 1.3 EQ.). Then a two-phase solution was intensively stirred for at least 12 hours at a temperature of 75-80°C. Then, the stirring was stopped and the mixture was left to cool to room temperature, and the phases were separated. Then a solution of toluene about ivali 1 M HCl (aq.) (750 ml, 5 ml/g), then water (3×750 ml, 5 ml/g). 3,4-Dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol were not separated, but was used instead of the toluene solution directly on the stage reductive amination (Example 2).

Example 2

Synthesis of tolterodine L-tartrate

The toluene solution containing the crude 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol from Example 1 (theoretical=to 333.3 g in 1.5 l of toluene)was diluted with methanol (750 ml, 5 ml/g)was then added Diisopropylamine (583 ml, 421 g 4,161 mol, 3 EQ.). The black solution was then first made over wet 20% wt. Pd(OH)2/C (10% wt., 33 g) at a pressure of 621×103Nm-2(90 psi) and 110°C for 48 hours. The sample was selected for analysis.

The reaction mixture was filtered through Arbocel™ (auxiliary filtering material) to remove residual catalyst and then heated to the boil under reflux, and the whole Diisopropylamine and the methanol was removed by distillation and replaced by toluene, receiving the final volume of 10 ml/year Then the black solution was cooled to 25°C., was added acetone (750 l, 5 ml/g), and then the solution was heated to 55-60°C. was Added a solution of L-tartaric acid (312 g, 2,081 mol, 1.5 EQ.) in methanol (1.05 liters, 7 ml/g) for 30 minutes, maintaining the temperature of 55-60°C. Then, the resulting suspension was left to cool to room temperature and was stirred for 12 hours. is Uspenskiy was filtered, washed with acetone (2×600 ml, 4 ml/g), then dried in vacuum at 50°C for 12 hours to obtain specified in the connection header as not quite white solids [159,2 g, 48% (24% of para-cresol)]. Achiral purity was 100% (no detectable impurities) and chiral purity was 91,4% ei

Example 3

Synthesis of racemic tolterodine hydrochloride

Stage A. Obtaining 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol

To a solution of para-cresol (25 g, 0,231 mol, 1 EQ.), piperazine (11,94 g, 0,139 mol, 0.6 EQ.) and toluene (250 ml, 10 ml/g) at reflux in the conditions of a Dean-stark added cinnamaldehyde (45,83 g, 44 ml, 0,347 mol, 1.5 EQ.) within 2 hours, and the reaction mixture was monitored by HPLC for the presence of para-cresol. Upon completion (2-3 hours) the mixture was cooled to 80°C and slowly added a solution of conc. HCl (25 ml, 0,301 mol, 1.3 EQ.) in water (100 ml, 5 ml/g) and was heated at 80-90°C for at least 5 hours. The resulting solution was left to cool to room temperature, and the phases were separated. The toluene solution washed with 1 M HCl (125 ml, 5 ml/g), then water (3×125 ml). The obtained organic layer was transferred to the recovery stage amination (stage B) in the form of the crude mixture.

Stage B. Obtaining racemic tolterodine hydrochloride

To neocidin the th solution from the Stage And was added methanol (125 ml 5 ml/g of cresol) and Diisopropylamine (92 ml, 0,693 mol, 3 EQ.). Then the mixture was first made over wet 20% wt. Pd(OH)2/C (5.6 g, theoretically 10% wt. benzopyran-2-ol) at 110°C at a hydrogen pressure 586×103Nm-2(85 psi). The development of the reaction was monitored using HPLC (completion usually occurs between 16 and 24 h). After the mixture was cooled, purged with nitrogen, filtered and washed with toluene (2×25 ml). Then the filtrate azeotrope was distilled with toluene to remove until the end of methanol and Diisopropylamine a final volume corresponding to 10 ml/g of cresol. Then the solution was stirred at 50-60°C and was added 37% HCl (19.3 ml, 0,231 mol, 1.0 equiv. c.f the cresol), causing precipitation of racemic tolterodine hydrochloride. The suspension was cooled to 25°C and was stirred for 2 hours, then filtered and washed with toluene (2×50 ml). Then racemic tolterodine hydrochloride was dried under vacuum at 50°C. the Yield amounted to 52.7 g, 63% from para-cresol with achiral purity 97%.

Synthesis of tolterodine L-tartrate according to the methods of Examples 1-3 shown in Scheme 2.

Example 4

The effect of amine catalyst and solvent on the yield of 3.4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol

The interaction of Example 1 was repeated, but varying the amine catalyst and the solvent. Used temperature sostav the La approximately 100°C or the temperature of the reflux distilled any solvent, if it is below (unless specified otherwise). Conditions Dean-stark not used if not specified (by *). The outputs are presented in the following table.

Amine catalystSolventOutput (HPLC situ, unless specifically specified)
R-(+)-α-methylbenzylamineNo (reaction without solvent)13% (9% allocated)
AmmoniaNo (reaction without solvent)0%
(S)-(+)-2-amino-1-propanolNo (reaction without solvent)0%
Piperidine†No (reaction without solvent)24%
Diisopropylamine†No (reaction without solvent)32%
Pyrrolidin†DMF0%
Morpholine†No (reaction without solvent)54% (48% allocated)
Proline†No (reaction without solvent)0%
"the basis of Macmillans (MacMillans)† (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidine-4-one [from 0°C to ambient temperature]DCM0%
Piperazine*†Toluene68%
Piperazine*†n-butyl acetate65%
Piperazine *†tert-amyl alcohol62%
Piperazine †disutility ether61%
Piperazine †dioxane74%
Piperazine †THF0%
Tri-n-butylamineToluene8%
N-methylmorpholine in the presence of a catalyst piperazineToluene12%
N-metaldetectors the Lamin in the presence of a catalyst piperazine Toluene6%
N-Ethyldiethanolamine in the presence of a catalyst piperazineToluene5%
Pyridine in the presence of a catalyst piperazineToluene8%
The triethanolamine in the presence of a catalyst piperazineToluene4%
tert-butyl(1S,4S)-(-)-2,diazabicyclo[2,2,1]-heptane-2-carboxylate†Toluene3%
(R)-1-benzoyl-3-methylpiperazin†Toluene8% (5% allocated)
Diethylamin†Toluene45%
AnilineDibutylamine4%
CyclohexylaminDMAc2%
†Indicates a secondary amine compound

Example 5

1.4-bis-(6-methyl-4-phenylpropan-2-yl)piperazine

Obtaining specified in the title compounds were carried out using the method of Example 1, except slaking water acid. Instead, after completion of the reaction the mixture was left to cool to ambient temperature, which led to the formation of a brown suspension. In the filtration of this suspension was obtained brown solid, the confirmation of the structure which, in the presence1H and13With network NMR. Melting point: 241°C.

Example 6

Obtain 6-(2-hydroxyethyl)-4-phenylpropan-2-ol

To a solution of 4-hydroxyphenethyl alcohol (Tyrosol) (5.0 g, 36 mmol, 1 EQ.), piperazine (1,87 g, 22 mmol, 0.6 EQ.) and toluene (50 ml) at boiling under reflux in an atmosphere of N2and in the conditions of a Dean-stark added cinnamaldehyde (6.4 ml, 51 mmol, 1.4 equiv.) and the reaction mixture is maintained under heating for 17 hours, the Reaction mixture was cooled to 80°C and extinguished aqueous HCl (to 0.7 molar, 1.3 EQ.), then was stirred under heating for 18 hours Biphasic mixture was left to cool to ambient temperature, were separated, the organic phase is washed with aqueous HCl, water and the organic phase was concentrated to a black residue under reduced pressure. In the flash-chromatography elwira a mixture of 20% EtOAc/heptane, has been specified in the header with the unity as the main component of approximately 80% pure yellow oil, Rf=0,37 (50% EtOAc/heptane), and the structure was confirmed1H NMR and LC-MS (M+1=271).

Example 7

Alternative obtain 6-(2-hydroxyethyl)-4-phenylpropan-2-ol using N-methylpiperazine

To a solution of 4-hydroxyphenethyl alcohol (Tyrosol) (25,0 g, 181 mmol, 1 EQ.), N-methylpiperazine (54,4 g, 543 mmol, 3 EQ.) and toluene (200 ml) at boiling under reflux in an atmosphere of N2and conditions of a Dean-stark added cinnamaldehyde (35,9 g ml, 272 mmol, 1.5 EQ.) within 2 hours, and the reaction mixture is maintained at boiling under reflux for 17 hours, the Reaction mixture was cooled to 50°C and extinguished aqueous HCl (2 M, 375 ml, ~4 EQ.). A two-phase mixture was left to cool to ambient temperature, diluted with ethyl acetate (250 ml)and the organic phase was separated. The organic phase is washed with aqueous HCl (250 ml), potassium bicarbonate (1 M, 250 ml), dried over magnesium sulfate and evaporated under reduced pressure to obtain a black oil (50.0 g, presumably quantitatively).

Example 8

Getting 2-[3-(diisopropylamino)-1-phenylpropyl]-4-(2-hydroxyethyl)-phenol hydrochloride

A mixture of 6-(2-hydroxyethyl)-4-phenylpropan-2-ol (Example 7, 30 g, 111 mmol, 1 EQ.), Diisopropylamine (33,7 g, 333 mmol, 3 EQ.) and palladium hydroxide on coal [50% wet catalyst (50% by weight of the composition of jet water), 6 g, 0.2 equiv.] in toluene (120 ml) was first made when the pressure of hydrogen 621×103Nm-2(90 psi) at 110°C. the Reaction mixture was cooled to room temperature and filtered through Arbocel and evaporated under reduced pressure. The resulting oil was dissolved in acetonitrile (200 ml) was added concentrated hydrochloric acid (to 11.6 ml of 1.05 EQ.). The mixture was distilled at atmospheric pressure, removing approximately 100 ml of acetonitrile and distilled solvent was replaced with fresh acetonitrile. The mixture was left to cool and crystallize during the night. The product was filtered and washed with a small portion of acetonitrile and dried overnight in vacuo at 50°C To produce specified in the title compound as a white solid (26.7 g, 68,1 mmol, 61%).

Example 9

Getting 2-[3-(diisopropylamino)-1-phenylpropyl]-4-(2-hydroxyethyl)-phenol

Aqueous sodium bicarbonate (165 ml) was added to a mixture of HCl salt (Example 8, 16.5 g, 42.1 mmol, 1 EQ.) in ethyl acetate (165 ml)and the mixture was stirred for 1 hour. The phases were separated, and the organic phase washed with water (195 ml), dried over magnesium sulfate, evaporated under reduced pressure to obtain specified in the connection header in the form of oil, containing ~25% wt./wt., ethyl acetate (14.6 g of all 11,03 g specified in the connection header, 31 mmol, 74%).

Example 0

Getting salt of (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(2-hydroxyethyl)phenol (S)-2-phenoxypropionic acid

(S)-2-Phenoxypropionic acid (3,40 g of 20.5 mmol, 1 EQ.) was added to a solution of 2-[3-(diisopropylamino)-1-phenylpropyl]-4-(2-hydroxyethyl)phenol (Example 9; 7,28 g of 20.5 mmol, 1 EQ.) in ethyl acetate. The mixture was heated at 80°C for 2 days, after which the mixture was cooled to room temperature, filtered and washed with ethyl acetate and dried in vacuo at 50°C. overnight to obtain specified in the title compound as a white solid (3.9 g, of 7.48 mmol, 37% yield, 94% EE).

The enantiomeric excess was determined by conversion of the salt to the free base with sodium hydroxide and perform normal-phase chiral HPLC-chromatography (Chiral Cancer AS-H column, elution with hexane (89,8%), IPA (10%), DEA (0.1%)and TFA (0.1%) for 1 ml/min).

Specified in the header of the connection can be useful as a starting substance to obtain Example 5 in concurrently pending international patent application PCT/IB07/000619. The corresponding specified in the header connection hydrochloric acid salt described in example 12 in WO 98/43942.

Example

Synthesis of 3,4-dihydro-6-bromo-4-phenyl-2H-benzopyran-2-ol

4-Bromophenol (2.0 g, 11.6 mmol) was stirred with N-methylpiperid the zine (3,48 g, 34.8 mmol, 3 EQ.) in toluene (30 ml, 15 ml/g) and was heated at the boil under reflux in the conditions of a Dean-stark. When you reach the beginning reflux distilled) was added TRANS-cinnamaldehyde (2.2 g, to 17.4 mmol, 1.5 EQ.) within 2 hours. After the addition has ended, continued heating of the reaction mixture at boiling under reflux in the conditions of a Dean-stark for 3 hours. The dark solution was cooled to 25°C. and was diluted with ethyl acetate (20 ml, 10 ml/g) and extinguished 2 M HCl (30 ml, 15 ml/g). The phases were separated and the upper organic layer was washed an additional 2 M HCl (20 ml, 10 ml/g) and 1 M sodium hydrogen carbonate solution (20 ml, 10 ml/g). The organic phase was dried (MgSO4), filtered and concentrated to obtain a dark-colored oil (4,2 g, 11.6 mmol, presumably quantitatively).

Example 12

Synthesis of salts of 2-[3-(diisopropylamino)-1-phenylpropyl]-4-bromophenol

The crude 3,4-hydro-6-bromo-4-phenyl-2H-benzopyran-2-ol (Example 11, 2.0 g, 6,55 mmol) was dissolved in toluene (20 ml, 10 ml/g)and to this solution was added tetraisopropyl titanium (of 5.84 ml, 3 EQ.) and Diisopropylamine (1.0 ml, 1.1 EQ.). The reaction mixture was cooled to 0-5°C was added sodium borohydride (0.75 g, 3 EQ.) over the course of 15 minutes. Ethanol was introduced dropwise over 15 minutes and stirred at 0-5°C. for another 2 hours. The reaction mixture was extinguishing water is (20 ml), the ethyl acetate (50 ml) and concentrated ammonia solution (20 ml). The suspension was filtered through Celite and the phases were separated. The organic layer was washed with water (50 ml), dried (MgSO4), filtered and concentrated to obtain the free base as a brown oil. It was dissolved in ethyl acetate (50 ml) was added 5 M HCl (2 ml). Excess acid and water azeotrope was distilled with fresh ethyl acetate (2×50 ml)and the resulting solid was grained in fresh ethyl acetate (20 ml) for 48 hours. The solid is collected by filtration, washed with ethyl acetate (10 ml) and dried at 50°C under vacuum for 4 hours. Specified in the title compound was obtained as a white solid (1.12 g, 40% from 4-bromophenol).

Benzyloxy-analogue indicated in the title compound is described in example 1(e), WO 94/11337. Specified in the title compound after separation can also be useful as a starting substance in the retrieval Example 3 in concurrently pending international patent application PCT/IB07/000619.

Example 13

Synthesis of (2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl)methanol

4-(hydroxymethyl)phenol (2,515 kg, 20,26 mol, 1 EQ.) was stirred with N-methylpiperazine (5,06 kg, 50,52 mol, 2.5 EQ.) in toluene (17,74 kg 20,5 l, 8,15 ml/g) and then heated to boiling. Then we use the and TRANS-cinnamaldehyde (3.35 kg, 25,35 mol, 1.25 EQ.) within 2 hours, maintaining the reaction mixture at boiling under reflux. The feed line was rinsed with toluene (0.9 kg, of 0.35 ml/g). After the addition the reaction mixture continued to heat under reflux for 19 hours Then some amount of toluene drove away, reducing the volume to approximately 18.5 HP Then the mixture was left to cool to room temperature and was added EtOAc (13.5 kg 15 l, 6 ml/g). The organic phase is washed with 2 M HCl (46.4 kg 46.4 years, 18.5 ml/g). The phases were separated, and added ethyl acetate (27,1 kg 30 l, 12 ml/g) for diluting the organic layer. The organic phase is washed with 1 M HCl (17,75 kg, 17,75 l of 7.1 ml/g), 5% wt./wt. NaHCO3(17,5 l, 7 ml/g) and water (25 l, 10 ml/g). The phases were separated and added to the organic layer of toluene (6.5 kg, 7.5 l, 3 ml/g), and the mixture was distilled until approximately 8 liters Downloaded additional toluene (7 kg), followed by ethyl acetate (3.9 l). The mixture was heated to boiling, then cooled to 22°C at 1°C/min, then stirred for 20 hours. The suspension was cooled to 2°C. and granulated for 2 hours, the Suspension was filtered, and the residue was washed with cold toluene (2×4.3 kg, 5 l). The obtained pale-brown solid was dried in vacuum for 68 hours at 40°C., obtaining 2.76 kg of product (2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl)methanol (yield 53.4 per cent), which is used to mark the next example without treatment:

1H NMR 300 MHz, d6-DMSO δ ppm (million shares) (mixture of isomers, 10,1): 1.95-2.10 (m, 2H), 2.15-2.35 (m, minor isomer), 3.25-3.35 (m, 1H), 4.15-4.35 (m, 3H), 4.80-4.95 (m, 1H), 5.35-5.45 (m, minor isomer), 5.46-5.55 (m, 1H), 6.51-6.54 (m, minor isomer), 6.58-6.63 (m, 1H), 6.75 (d, J=8,2 Hz, 1H), 6.98-7.40 (m, 6N).

Example 14

Synthesis of 2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol

(2-Hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl)methanol (Example 13, 830 g, 3,24 mol, 1.0 EQ.) was stirred in methanol (4150 ml, 5.0 ml/g). Then, using a dropping funnel within 15 minutes was added Diisopropylamine (1362 ml, 9,72 mol, 3.0 EQ.). Then the resulting solution was stirred for one hour in nitrogen atmosphere.

The catalyst Pd-ESCAT 142 [(5% Pd/C paste, humidity of approximately 50% water) 83 g, 10% wt./wt.] was added in the form of a suspension in methanol (2075 ml, 2.5 ml/g). The system was purged with hydrogen, and then the mixture was first made at 115 psi (793×103Nm-2, 7,92 bar) at 40°C for 20 hours.

The mixture was purged with nitrogen and filtered through Arbocel™ (auxiliary filtering material). The filter bag from the residue was washed with methanol (2×1660 ml, 2×2.0 ml/g).

Due to the limitations of the equipment, the above procedure was performed twice in scale 830 and 840

Then three of the filtrate and their respective wash water from the filter pillows kombinirov and one solution the equivalent of one reaction in the scale of 2.50 kg Final volume was recorded as the initial target volume in the following method of distillation:

- Diisopropylamine (2500 ml, 1.0 ml/g) and tert-amyl alcohol (10000 ml 4,0 ml/g) was added to the reaction mixture. Then perform the vacuum-distillation (installation of vacuum 100 mbar (104PA))to ottestirovat with decreasing volume to the target fixed previously.

- Diisopropylamine (2500 ml, 1.0 ml/g) and tert-amyl alcohol (10000 ml 4,0 ml/g) was added to the reaction mixture. Then perform the vacuum-distillation (installation of vacuum 100 mbar (104PA))to ottestirovat with decreasing volume to the target fixed previously.

- Diisopropylamine (2500 ml, 1.0 ml/g) and tert-amyl alcohol (10000 ml 4,0 ml/g) was added to the reaction mixture. Then perform the vacuum-distillation (installation of vacuum 100 mbar (104PA))to ottestirovat with decreasing volume to the target fixed previously.

Tert-amyl alcohol (12500 ml, 5.0 ml/g) was added to the reaction mixture. Then perform the vacuum-distillation (installation of vacuum 100 mbar)to ottestirovat reducing the amount of up to 12,500 ml

Tert-amyl alcohol (12500 ml, 5.0 ml/g) was added to the reaction mixture. Then perform the vacuum-distillation (installation of vacuum 100 mbar)to ottestirovat reducing the amount of up to 12,500 ml of Tert-amyl sleep is t (12500 ml, 5.0 ml/g) was added to the reaction mixture with a final volume of 25 L.

A solution of the crude product 2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol in tert-amyl alcohol was used in the next stage without additional purification. HPLC analysis (area/area) showed 93.3% of the product, plus: 4.2% of the initial substance and other impurities in the amount of 1.4% and 0.4%. Quantitative HPLC analysis showed the crude solution containing 2950 g of product (89% yield).

Example 15

Synthesis of (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol(R)-acetoxy(phenyl)acetate

Tert-amyl alcohol (19.2 l) was added to the previous solution of 2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol (from Example 14) in tert-amyl alcohol (25 l containing 2.95 kg, 8,64 mol, 1 EQ.) obtaining a final volume of 442 L. This solution was heated to 70°C. In a separate vessel at 50°C was obtained a solution of (R)-(-)-acetoxy(phenyl)acetic acid (0,839 kg, 4,32 mol, 0.5 EQ.) in tert-amyl alcohol (14,8 l), then, when all the acid had dissolved, it was cooled to room temperature. This solution is then added to a solution of 2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol in tert-amyl alcohol for one hour. In the resulting solution is then injected seed product (0.03 kg, 1% wt., pre-recip is nnow similar method, but on a smaller scale). The suspension was cooled to 60°C for 2 hours and then to 25°C for another 3 hours. The mixture was stirred at 25°C. for a further 12 hours. The suspension was filtered, and the residue twice resuspendable with tert-amyl alcohol (2×29,5 l, 2×10 ml/g) and carefully separated from the liquid. White solid was dried under reduced pressure at 40°C for 12 hours to obtain 2,04 kg (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol (R)-acetoxy(phenyl)acetate (yield of 37.8%, adjusted 14,3% wt./wt. tert-amyl alcohol (defined by LOD analysis) with 99% EE using chiral HPLC.

HPLC-method of monitoring E.:

Column: Chiralpak AS-H

Flow rate: 1 ml/min

Mobile phase: heptane 92,5/ethanol 7,5/diethylamin 0,12/triperoxonane acid 0,18

Temperature: 35°C

Resolution: 220 nm

Retention time:

(R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol 15 min

(S)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol 18,4 min

Example 16

Synthesis of (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol

(R)-2-[3-(diisopropylamino)1-phenylpropyl]-4-(hydroxymethyl)phenol (R)-acetoxy(phenyl)acetate (Example 15, 1.75 kg, with 3.27 mol, 1 EQ.) suspended in toluene (15,2 kg, 10 ml/g) and was heated to 50°C. was Loaded with 10% aqueous solution of K CO3(1.75 kg K2CO3was dissolved in 17.5 l of purified water, 10 ml/g). The mixture was intensively stirred at 50°C for 30 minutes. The two phase solution was separated at 50°C. the Organic phase is washed with purified water (1.75 kg, 1 ml/g) at 50°C. the Phases were separated at 50°C, and the volume of toluene was reduced to 3 ml/g (5.5 l) by distillation. Crystallization was performed by lowering the temperature to 62°C and then cooling to 40°C for 40 minutes. The batch was kept at 40°C for 30 minutes and then put the seed, using (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol (0.01 kg, obtained previously using a similar method on a smaller scale). The batch was stirred for a further 1 hour at 40°C. and then was cooled to 20°C for 3.5 hours. The party was granulated at 20°C for 10 hours. Then the suspension was cooled to 2°C for 1 hour and was granulated at 2°C for 1 hour (see below the temperature profile). The suspension was filtered, and the residue was washed with cold toluene (1.5 kg, 1 ml/g). The wet product (0,933 kg, % drying was determined by analysis LOD) was a white crystalline solid.

Then did re-suspension of toluene. Toluene (2,42 kg to 2.6 ml/g (based on the evaluation of drying)) was cooled to 3°C, and the wet product was loaded and stirred at 3°C for 15 minutes. Suspe is the Zia was filtered, and the residue was washed with cold toluene (1.6 kg, 1.5 ml/g (based on the evaluation of drying)). The wet product was dried in vacuo at 45°C to yield (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol (0,74 kg, 2,17 mol) with the release of 66.7% in the form of a white crystalline substance. HPLC shows the purity of >99.6 percent, and chiral HPLC shows >99% EE

Example 17

Obtaining (R)-(+)-somaclonal acid 2-[3-(diisopropylamino)-1-phenylpropyl]-(hydroxymethyl) phenyl ether

Specified in the title compound is obtained from the compound of Example 16, using the method of US patent 6858650 (see section 5, row 16). Alternatively, this interaction can be made without the addition of external neutralizing the acid base - see US patent 6858650, column 10, lines 32-40.

Example 18

Obtaining (R)-(+)-somaclonal acid 2-[3-(diisopropylamino)-phenylpropyl]-4-(hydroxymethyl)Phenyl ester of hydrofolate

Specified in the title compound is obtained from the compound of Example 17, using the technique of patent US 6858650 (see section 6, column 16).

Example 19

Synthesis of [2-(4-methylpiperazin-1-yl)-4-phenyl-2H-chromen-6-yl]-methanol

TRANS-cinnamaldehyde (66.5 g, of 0.66 mol, 1.25 EQ.) was diluted with toluene (100 ml, 2 ml/g based on 4-(hydroxymethyl)phenol), and dwai the s was washed with a saturated solution of sodium bicarbonate (2×100 ml) and once with water (100 ml). This toluene solution cinnamaldehyde then added over 2 hours to a mixture of 4-(hydroxymethyl)phenol (50 g, and 0.40 mol, 1 EQ.) and N-methylpiperazine (113 ml, 1.0 mol, 2.5 EQ.) in toluene (350 ml, 7 ml/g), was heated to boiling under reflux in the conditions of a Dean-stark. Once the addition was completed, the reaction mixture continued to be heated to the boil under reflux in the conditions of a Dean-stark for 10 hours Then the mixture was cooled to room temperature, and the sample was evaporated to dryness for analytical purposes under reduced pressure. Dark oil contains crude [2-(4-methylpiperazin-1-yl)-4-phenyl-2H-chromen-6-yl]methanol (mixture of diastereoisomers) and impurities.

EI-GC-MS (Agilent), column: ZB-5HT, temperature program: 50°C (0.5 min), 20°C /min to 320°C (minutes)received: RT=24,4 min, MW: 338.

1H NMR (DMSO) (raw mix) 300 MHz δ (ppm): 7.40-7.00 (28N, m); 6.89 (1H, d, J=2.0 Hz); 6.81 (1H, d, J=8,3 Hz); 6.75 (1H, d, J=8,2 Hz); 6.54 (1H, d, J=1.0 Hz); 4.87 (1H, d, J=10,2 Hz); 4.45 (1H, d, J=10.0 Hz); 4.40-4.20 (3H, m); 4.36 (2H, s); 4.23 (1,8H, s); 2.86 (4H, m); 2.80-2.50 (14N, m); 2.50-2.00 (50N, m), 2.31 including (s); 2.17 (s); 2.14 (s); 2.1.1 (s).

Synthesis of fesoterodine of hydrofolate according to the methods of Examples 13-18 presented in figure 3.

1. The method of obtaining the compounds of formula (I)

where Y is selected from CH3CH2HE, CH2CH2HE, CH2Br and Br, including article is Hai:
(1) the interaction of the compounds of formula (II)

where OX is a hydroxy or O-M+where M+represents a cation selected from Li+, Na+and K+and
Y as defined above,
with transcinnamaldehyde (III)
;
in the presence of secondary amine compounds; then
(2) treatment of the product from the previous stage acid to obtain the compounds of formula (I).

2. The method according to claim 1, where OX is a hydroxy.

3. The method according to claim 1, where Y represents CH3or CH2HE.

4. The method according to claim 1, where the secondary amine compound is achiral.

5. The method according to claim 1, where the secondary amine compound containing two secondary amine groups.

6. The method according to claim 1, where the secondary amine compound is a piperazine.

7. The method according to claim 5 or 6, where at stage (1) using 0.5-1.25 mol-EQ. secondary amine compounds.

8. The method according to claim 1, where the secondary amine compound contains one secondary amino group.

9. The method according to any one of claims 1 to 4 and 8, where the secondary amine compound is a morpholine, dibutylamine, dibenzylamine, 1,1,3,3-tetramethylguanidine, diethylamin, Diisopropylamine, piperidine or N-(C1-6alkyl)piperazine.

10. The method according to claim 9, where the secondary amine compound is the th N-methylpiperazine.

11. The method of claim 8, where at stage (1) use 1-5 mol-EQ. secondary amine compounds.

12. The method according to claim 1, where the acid used in stage (2)is an aqueous hydrochloric acid.

13. The method according to claim 1, where the interaction at the stage (1) is carried out in an organic solvent selected from toluene, xylene, N-butyl acetate, tert-amyl alcohol, dioxane and dibutylamino ether.

14. The method according to item 13, where the solvent is a toluene.

15. The method according to claim 1, where the interaction at the stage (1) is carried out at a temperature from 80°C to the temperature of reflux distilled solvent.

16. The method according to claim 1, where the interaction at the stage (1) is carried out at conditions where the reaction system is removed the water.

17. The method according to claim 1, where the interaction at the stage (1) is carried out at a pressure equal to or approximately equal to the ambient pressure.

18. The method of obtaining the compounds of formula (IV)

where Y is as defined in claim 1, or its salt, including:
(a) obtaining the compounds of formula (I) according to claim 1 using the method according to any one of claims 1 to 17; then
(b) reductive amination of the compounds of formula (I) diisopropylamino
(b) and, if necessary, converting the compounds obtained into salt.

19. The method according to p, where Y is CH3or CH2HE.

20. With the persons in claim 19, where Y represents CH3the compound of formula (IV) is treated with L-tartaric acid in stage (b) and get tolterodine L-tartrate.

21. The method of receiving fesoterodine,

or its pharmaceutically acceptable salt, which includes:
(a) obtaining the compounds of formula (IV), as defined in p, where Y is CH2HE, using the method according to p;
(b) separation of the product from step (a) to obtain (R)-enantiomer;
(C) acylation of phenolic hydroxy-group of the product from step (b) to obtain the corresponding complex ester somaclonal acid
(g) and, if desired or necessary, converting the compounds obtained into pharmaceutically acceptable salt.

22. The method according to item 21, where the secondary amine compound used for obtaining the compounds of formula I, represents a N-methylpiperazine.

23. The compound of formula (V)

or its salt, where Y is as defined in claim 1.

24. The compound of formula (VI)

or its salt, where Y is as defined in claim 1.

25. The compound of formula (VII)

where Y is selected from CH2CH2OH, CH2Br and Br.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel chromane derivatives of formula I: or their pharmaceutically acceptable salts, where: m equals 0 or 1; p equals 2; q equals 2; Ar is phenyl which is possibly substituted with a halogen atom; each R1 is independently a halogen; R2 is ; n equals 1 or 2; each of R3 and R4 is independently hydrogen or C1-12-alkyl; each of R5 and R6 is independently hydrogen or C1-12-alkyl; and each of R7 and R8 is independently hydrogen or C1-12-alkyl; or one of R7 and R8 is hydrogen and the other is a 5- or 6-member heterocyclyl containing one nitrogen atom, or R7 and R8 together with the nitrogen atom with which they are bonded can form an amidinyl group, a urea group, a guanidinyl group or a pyrrolidine ring which is possibly substituted with an amine group.

EFFECT: obtaining novel chromane derivatives and pharmaceutical compositions having 5-HT6 and/or 5-HT2a receptor modulator activity.

22 cl, 11 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel aminoalkyl-and amodialkylbenzopyran derivatives of the general formula (I): (a), where (a) group is a substitute in 6 or 7 position, where R is mono- or bicyclic (C6-C10)-aryl radical optionally substituted with one or two substitutes selected out of linear or ramified (C1-C5)-alkyls, linear or ramified (C1-C5)-alkoxy, hydroxy, halogen and trifluoromethyl; m is zero or integer 1-3; n, p, R1 and R2 are as indicated in the description, and both R3 and R4 are hydrogen or both are oxygen: and to pharmaceutically acceptable salts thereof.

EFFECT: selective reversible MAO-B inhibitors in vitro and in vivo, applicable as medicines for prevention and treatment of degenerative central nervous system disorders.

13 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2H-1-benzopyran-2-methanol-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]], i.e. a nebivolol base of formula (IX), or its hydrochloride salt

as well as to a method of producing an intermediate compound - benzylated nebivolol of formula (VIII),

EFFECT: invention also relates to a pharmaceutical composition with antihypertensive action without using a wetting agent, and to a tablet containing this pharmaceutical composition.

21 cl, 20 tbl, 21 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivative of aminobenzopyrane of the formula (2): Method involves reduction of nitro-group in derivative of 2,2-dimethyl-2H-1-benzopyrane of the formula (1): with hydrazine in the presence of a metallic catalyst. Invention provides high selectivity of the process with respect to olefin bonds and simple treatment that results to small waste and doesn't effect on reactor.

EFFECT: improved method of synthesis.

2 tbl

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

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

28 cl, 10 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention concerns to applying RARγ agonist for preparing a medicinal agent comprising one or some such agonists and designated for treatment of emphysema wherein RARγ agonist is taken among compounds of the formula (I):

wherein R1 means residue of the formula:

or , or , or ; R2 means (C2-C8)-alkanoyl, (C2-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or group -OCH2R3 wherein R3 means hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl; each among R4-R9 means independently of one another hydrogen atom or (C1-C6)-alkyl; or R8 and R9 mean in common (CRaRb)n wherein Ra and Rb mean independently of one another hydrogen atom or (C1-C6)-alkyl; n = 1, 2 or 3; R4-R7 have above given values; R10 means carboxyl, (C1-C6)-alkoxycarbonyl or mono- or di-(C1-C6)-alkylcarbamoyl; and their pharmaceutically acceptable salts; or among compounds of the formula (VI):

wherein R1 means C(O)R6 or CH2OH (wherein R6 means hydroxy-group or (C1-C6)-alkoxy-group); R2 means hydrogen atom, (C1-C15)-alkyl, (C1-C6)-alkoxy-group or cycloaliphatic group; R3 means hydrogen atom, hydroxy-group, (C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, (C1-C10)-alkoxy-group or cycloaliphatic group; R4 and R5 mean independently of one another hydrogen atom, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; or among compound of the formula (VIII):

. Invention provides applying agonists eliciting the selective effect with respect to RARγ, for preparing a medicinal agent comprising one or some such agonists designated for emphysema treatment.

EFFECT: valuable medicinal properties of compounds.

4 cl, 5 tbl, 3 ex

The invention relates to a derivative chromane formula I

in which R1denotes acyl with 1 to 6 carbon atoms, R2, R3, R4represent hydrogen, X represents N,N or O, as well as their enantiomers and their salts, and methods for their preparation

The invention relates to new derivatives aminomethylpropanol acid formula 1

< / BR>
where Z represents (CH2)n, O or S; n is 0, 1 or 2; X represents 1-3 substituent, independently selected from hydrogen, halogen, (C1-6)alkyloxy,(C3-6)cycloalkane, (C6-12)aryloxy, (C6-12)aryl, teinila, CN, СООR6and (C1-4)alkyl, optionally substituted with halogen, or 2 substituent in adjacent positions together represent a condensed (C5-6)aryl group, or O-(CH2)m-O, where m is 1 or 2; Y is 1-3 selected from hydrogen, halogen, (C1-4)alkyloxy and (C1-4)alkyl, optionally substituted with halogen; R1represents COOR7; R2and R6are (C1-4)alkyl; R3, R4and R5independently represent hydrogen; R7, R8and R9independently represent hydrogen or (C1-4)alkyl; or pharmaceutically acceptable salts, and pharmaceutical compositions on their basis, with effect on the Central nervous system

FIELD: chemistry.

SUBSTANCE: invention relates to use of a therapeutic agent which is an α-amino-amide compound of formula (I):

, in which R is a phenyl ring which is optionally substituted with one or two substitutes independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl; R1 is hydrogen or C1-C6-alkyl; R2 and R3 are independently selected from hydrogen, C1-C4-alkyl; R4 and R5 independently denote hydrogen, C1-C6-alkyl; X is O or S; Y and Z, taken together with X and a phenyl ring bonded to Y and X, form a 5-7-member saturated heterocycle containing O or S atoms, or Y and Z denote hydrogen; or its isomers, mixtures and pharmaceutically acceptable salts for preparing a medicinal agent for treating lower urinary tract disorders.

EFFECT: obtaining a pharmaceutical composition based on the said compounds.

8 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tocopherol, tocotrienol and other derivatives of chroman of the general formula (1): wherein X is taken among the group comprising oxygen and nitrogen atoms; Y is taken among the group comprising oxygen, nitrogen and sulfur atoms wherein if Y represents oxygen or nitrogen atom then n = 1 and if Y represents sulfur atom then n = 0; R1 represents residue of carboxylic acid, carboxamide, ester, alcohol, amine or sulfate; R2 represents methyl; R3 represents methyl; R4 represents methyl; R5 is taken among the group comprising alkyl, alkenyl, alkynyl, carboxyl and ester residue wherein if Y represents nitrogen atom then indicated nitrogen atom is replaced with group R6 wherein R6 represents hydrogen atom or methyl wherein if X represents oxygen atom, Y represents oxygen atom and R5 represents phytyl then R1 doesn't mean butanoic acid. Also, invention relates to a pharmaceutical composition based on these compounds, a method for treatment of cellular-proliferative disease and a method for induction of cells apoptosis. Invention provides preparing new compounds possessing the proliferative effect.

EFFECT: valuable medicinal properties of compounds.

36 cl, 4 tbl, 19 dwg, 19 ex

The invention relates to a new method of obtaining diastereomeric mixture piperidinylmethyl-tripterocalyx cyclic ethers of the formulae Ia and Ib and their pharmaceutically acceptable salts, where R1is C1-C6the alkyl, R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl, R3is hydrogen or halogen; m = 0, 1 or 2, in which said mixture is enriched compound of formula Ia

The invention relates to new chemical compounds with valuable properties, in particular to piperidinylmethyl derived chromane General formula (I)

< / BR>
where A is hydrogen or lower alkoxy,

E is hydrogen, hydroxyl, phenyl or piperidyl,

G phenyl not substituted or substituted with halogen and/or trifluoromethyl, fenoxaprop substituted by trifluoromethyl, benzyl, substituted phenylcarbinol, aminocarbonyl,

provided that E does not mean hydrogen or hydroxide, when G is phenyl, and their salts with inorganic acids

The invention relates to new derivatives chromane with activity open To ion channels

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

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