2,6-dimethyl-3,5-bis (alkoxycarbonyl) -4- [polyporales(methoxy) -phenyl] -1,4-dihydropyridine, showing cardiac and hypertensive action

 

(57) Abstract:

Usage: as substances exhibiting cardiac and hypertensive action. The inventive product is: 2, 6-dimethyl-3, 5-bis(alkoxycarbonyl)-4-polyporales(methoxy) phenyl - 1, 4-dihydropyridines of General formula 1, where 1A - CF3-CHF-CF2O-; R1-CH3O-; l - C2H51B - CHF2O-, R1-CH3O-, l - C2H51 the CH3O-, R1-CF3-CHF3-CHF-CF2O, l - CH31G CH3O-, R1-CHF2O-, l - CH3. table 2.

The invention relates to organic chemistry, specifically to the synthesis of new fluorinated derivatives of 4-aryl-1,4-dihydropyridines, showing the properties of agonists calcium, of General formula I

R where R Ia= CF3-CHF-CF2O-, R'=CH3O-, Alk=C2H5(K-2);

IB R=CHF2O-, R'=CH3O-, Alk=C2H5(K-3);

If R=CH3O-, R'=CF3-CHF-CF2O-, Alk=CH3(K-6);

Iك R=CH3O-, R'=CHF2O-, Alk=CH3(K-7).

It is now known that most of the compounds 1,4-dihydropyridine have properties of calcium antagonists and applied in the clinic as anti-hypertensive, anti-arrhythmic and anti-ischemic funds nifta, shows the properties of agonists calcium CIP 28392, YC 170, Bay K 8644 (III), that are also cardiotonic activity. The most effective of them Bay K 8644 (III) containing fluorinated radical triptorelin group, is the closest analogue of the claimed compounds as on the structure and type of action [2]

It should be noted that the range of drugs with similar pharmacological activity, is limited, and known to have a significant lack of high toxicity, such as Wow To 8644 (III) see table.2.

< / BR>
In addition, antagonists of calcium causes narrowing of the blood vessels, which adversely affects the treatment of heart failure. However, according to some authors [2,3] it is drugs with a similar mechanism of action in the coming years will be the most promising kardiotoniki.

The aim of the invention is new derivatives of 1,4-dihydropyridines, showing cardiotonic activity at moderate hypertensive action, and also has low toxicity towards warm-blooded animals and man.

This goal is achieved new fluorinated derivatives of 4-aryl-1,4-dihydropyridines-2,6-dimethyl-3,5-bis- (alkoxycarbonyl) which are simple one-step method by condensation of the corresponding fluorinated derivatives of benzaldehyde with acetoacetic and-aminocrotonic esters in alcoholic medium scheme

+ CHCH2C+ CH CHC R

The following are specific examples of the synthesis of the claimed compounds. To compare and establish the effect of replacement of hydrogen atoms by fluorine in the CNS radicals on biological properties described in the application of substances synthesized on the basis of 3,4-dimethoxybenzaldehyde (paratroopa aldehyde) not containing fluorine analogue 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(3,4-acid) 1,4-di - hydropyridine (K-8) (IV).

H

P R I m e R 1. 2,6-Dimethyl-3,5-bis(etoxycarbonyl)-4-[3-methoxy-4-(2-hydrobar - forproperty)phenyl]-1,4-dihydropyridines (Ia) (K-2).

CF3CFHCF2O

In a two-neck flask with a capacity of 100 ml equipped with a stirrer and reflux condenser, are placed 18,12 g (0.06 g-mol) of 3-methoxy-4-(2-hydroinformatics)Ben - zaldehyde, and 7.8 g (0.06 g-mol) ethylacetoacetate ether, 7,74 g (0.06 g-mole) ethyl- -aminocrotonate ether and 60 ml of ethanol. Boil with stirring 4 hours the Reaction mixture is cooled, the precipitated crystals are filtered, dried and crystallized. Yield 28 g (89% ), so pl. 151-153about(Benzene-hexane, 1:1).

IR-spectrum: 1720 cm-1(CO), 3330 cm-1(NH).

NMR19F range, (M. D.): multiplet -74,69 (CF3); doublet of quartets -76,51, -79,95 (CF2); multiplet -212,46 (Ctx2">

Calculated C 52,57; H 4,76; F 21,71; N 2,67.

P R I m m e R 2. 2,6-Dimethyl-3,5-bis(is-xianbei)-4-(3-methoxy-4-deformedarse - phenyl)-1,4-dihydropyridines (IB) (K-3).

CF2HO

In a two-neck flask with a capacity of 100 ml equipped with a stirrer and reflux condenser, place of 12.12 g (0.06 g-mol) of 3-methoxy-4 - deformationally, and 7.8 g (0.06 g-mol) ethylacetoacetate ether, and 7.8 g (0.06 g-mole) ethyl- -aminocrotonate ether and 60 ml of ethanol. Boil with stirring 4 hours is Cooled, the precipitated product is filtered, dried and crystallized. Yield 22 g (86%), so pl. 143-145about(Benzene-hexane, 1:1).

IR-spectrum: 1720 cm-1(CO), 3370 cm-1(NH).

NMR19F range: doublet -81,11 M. D. IFH73,2 Hz.

Found, C 59,26; H 6,13; F 9,42; N 3,40

C21H25F2NO6< / BR>
Calculated C 59,29; H 5,88; F To 8.94; N 3,29.

P R I m e R 3. 2,6-Dimethyl-3,5-bis(method xianbei)-4-[3-(2-hydropericardium - XI)-4-methoxyphenyl]-1,4-dihydropyridines (IB) (K-6).

< / BR>
In a two-neck flask with a capacity of 100 ml equipped with a stirrer and reflux condenser, are placed 18,12 g (0.06 g-mol) 3-(2 - hydroinformatics)-4-methoxybenzaldehyde, of 6.96 g (0.06 g-mol) methylacetylene ether, 6,9 g (0.06 g-mol) of methyl-aminocrotonate ether and 60 ml this is tallitot. Yield 23 g (77%), so pl. 143-145about(Benzene-hexane, 1:1).

IR-spectrum: 1700 cm-1(CO), 3340 cm-1(NH).

NMR19F range, (M. D.): multiplet -74,69 (CF3), doublet of quartets -76,87, -79,67 (CF2), multiplet -212,51 (CFH), IFH50 Hz.

Found, 50,57; H 4.26 Deaths; F 22,91; N 2,66.

C21H21F6NO6.

Calculated C 50,70; H 4,23; F 22,94; N 2,82.

P R I m e R 4. 2,6-Dimethyl-3,5-bis(method xianbei)-4-(3-deformedarse-4-methods - xifer)-1,4-dihydropyridines (Iك) (K-7)

H3CO

In a two-neck flask with a capacity of 100 ml equipped with a stirrer and reflux condenser, place of 12.12 g (0.06 g-mol) 3-deformedarse-4-methoxybenzaldehyde, of 6.96 g (0.06 g-mol) methylacetylene ether, 6,9 g (0.06 g-mol) of methyl-aminocrotonate ether and 60 ml of ethanol. Boil with stirring 4 hours the Reaction mixture is cooled, the precipitated product is filtered, dried and crystallized. The output of 20.5 g (86%), so pl. 163-165about(Benzene-hexane, 1: 1).

IR-spectrum: 1720 cm-1(CO), 3360 cm-1(NH).

NMR19F range: doublet -80,89 M. D. IFH73 Hz.

Found, C 57,17; H 5,38; F 9,38; N 3,38.

C19H21F2NO6.

Calculated C 57,43; H Of 5.29; F To 9.57; N 3,53.

P R I m e R 5. 2,6-DIMET is using 100 ml, equipped with stirrer and reflux condenser, are placed 9,96 g (0.06 g-mol) of 3,4-dimethoxybenzaldehyde (paratroopa aldehyde), of 6.96 g (0.06 g-mol) methylacetylene ether, 6,9 g (0.06 g-mol) of methyl-aminocrotonate ether and 60 ml of ethanol. Boil with stirring 4 hours the Reaction mixture is cooled, the precipitated precipitate is filtered off, dried and crystallized. Output 19,28 g (89%), so pl. 152-154about(Benzene-hexane, 1:1).

IR-spectrum: 1710 cm-1(CO), 3370 cm-1(NH).

Found, C 62,98; H 6,63; N 3,45.

C19H23NO6.< / BR>
Calculated C 63,16; H 6,37; N 3,88.

P R I m e R 6. Experimental study of the effect of the inventive compounds on the cardiovascular system were performed on anesthetized with thiopental sodium (0.2 mg/kg) to Wistar rats of both sexes, weighing 150-250 g were Produced synchronous check pulse blood pressure when it is direct, elektrokineticheskoi measurement in carotid artery, the electrocardiogram in II standard lead and differentiated tetrapolar rogramme on Polygraph system 6000 with a speed of 1 and 50 mm/s

For the assessment of systemic hemodynamics and pumping function of the heart you used the following indicators:

Systolic blood pressure is/P> Total peripheral resistance (CPRS) by the formula

OPS 1333, where the HELL iscfmean arterial pressure IOC (minute volume of blood) WALK x HR,

where WALK, stroke volume;

Heart rate heart rate.

Stroke volume (using tetrapolar rheography) by the formula Kubitschek:

WALK TO Ag Ttechnology.where the correction factor (0,8),

the conductivity of the blood,

l is the distance between the thoracic electrodes

z baseline impedance,

Ag is the amplitude of the differentiated rogramme,

Ttechnologythe time of exile.

The effect of the inventive compounds on the contractility of the myocardium was evaluated in experiments on isolated myocardium. Papillary muscle of the rat heart was placed in a flow chamber and perfesional oxygendemanding solution (95% O2and 5% CO2) a solution of Tyrode at the 29aboutC. Electrical stimulation was performed using platinum electrodes placed parallel to the muscle. Used rectangular pulses from the pacemaker KSMO duration of 5 MS, a voltage exceeding the threshold by 10-25% with a frequency of 1 Hz. To assess contractility took cuts close to isometric and use what tworoom Tirade carried out with the contents of the studied compounds at concentrations of 10-8-10-3M in 1 liter Intravenous administration of these compounds (jugular vein) was produced in the dose of 0.01, 0.1 and 0.5 mg/kg of the Obtained results were processed variation-statistical method using student's criterion.

The comparison was carried out with counterparts in structure and effect of the calcium antagonist nifedipine (II) and agonist calcium Wow K 8644 (III). For the evaluation of pharmacological activity and analysis of the mechanism of action of these compounds produced a comparison of directional and quantitative changes of indices of contractility and systemic hemodynamics (table. 1).

Presented in table. 1 the data show that compound K-2, K-3, K-6, K-7 have strong cardiac and hypertensive properties. The most active of them are compound K-2 and K-6. At a concentration of 10-6mol/l they enhance the contractility of the myocardium at 20-22% while increasing blood pressure 15-16% Somewhat inferior to the activity of the compound K-3 and K-7 (increase contractility by 15-17%). Pharmacodynamic properties (increased contractility, increased blood pressure, total peripheral resistance pump function senatorem entrance of calcium ions. Given the above, we can assume that the claimed compounds and Wow 8644 To have a similar mechanism of action. However, the inventive compounds have a much lower toxicity in comparison with the reference. For Wow To 8644 LD50is 50 mg/kg, and for connections K-2, K-3, K-6, K-7 over 500 mg/kg (see table.2). This may be significant when considering this group of chemicals as potential cardiotonic.

Characteristically, the connection K-8, in which the benzene ring are in positions 3 and 4 two metaxylene group and in contrast to the claimed compounds (Ia-g) does not contain fluorine atoms in the CNS radicals, shows the opposite pharmacological properties and causes a reduction in blood pressure, and also has weak cardiodepressive action. The same pharmacodynamic profile has a known calcium antagonist nifedipine (II).

From this it follows that the specificity of the pharmacological activity of the inventive fluorinated derivatives of 4-aryl-1,4 - dihydropyridines (Ia) K-2; (IB) K-3; (IB) K-6; (Iك) K-7 positive inotropic effect due to the presence of fluorine atoms in the CNS radicals of the benzene quantity the activity of the claimed compounds was carried out on outbred mice weighing 20-25 g The compounds and reference drugs were injected intragastrically at doses of 30-500 mg/kg of body weight. The observations were carried out within 24 h after injection. The results of the experiments were subjected to statistical analysis by the method of Litchfield-Wilcoxon signed in the modification of the Company and are given in table.2.

Thus, the claimed compounds have much lower toxicity in comparison with reference drugs.

2,6 - Dimethyl-3,5-bis (alkoxycarbonyl)-4-[polyporales (methoxy) phenyl]-1,4-dihydropyridines of General formula

< / BR>
where (a) R CF3-CHF-CF2O-; R1CH3O-, Alk C2H5;

b) R CHF2O-; R1CH3O-; Alk C2H5;

C) R CH3O-; R1CF3CHF CF2O-, Alk CH3;

g) R CH3O-; R1CHF2O-; Alk CH3,

showing cardiac and hypertensive action.

 

Same patents:

The invention relates to organic synthesis and relates to new quinoline derivatives and method of production thereof

The invention relates to medicine, in particular to drugs, and can be used as a means of specific prophylaxis of thrombosis in various pathological conditions

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to new chemical compounds with biological activity, in particular derivatives pyridyl General formula I

_where And communication, cycloalkenes and cycloalkylcarbonyl groups, each with 3-4 carbon atoms in which one methylene group can be replaced dichloromethylene group, an unbranched Allenova group with 2 or 3 carbon atoms, which may be single or multiply unsaturated group-R7CR8-, -O-R7CR8- or-NR9where R7is a hydrogen atom, hydroxyl, phenyl or an alkyl group with 1-3 carbon atoms; R8is a hydrogen atom or an alkyl group with 1-3 carbon atoms and R9is a hydrogen atom, an alkyl group with 1-3 carbon atoms or phenyl; X is carbonyl, thiocarbonyl or sulfonylurea group;

R1is an alkyl group with 1-4 carbon atoms, unsubstituted or substituted phenyl group, cycloalkyl group with 5-7 carbon atoms, phenyl, naphthyl, biphenylyl, diphenylmethyl, indolyl, Tieni the group, in which the phenyl nucleus may be mono-, di - or tizamidine identical or different substituents from the group comprising fluorine, chlorine or bromine, alkoxy with 1-4 carbon atoms and an alkyl with 1-4 carbon atoms, and one of the substituents can also mean trifluoromethyl, carboxyl, amino - or nitro-group;

R2is a hydrogen atom or alkyl with 1-4 carbon atoms;

R3- pyridyl;

R4and R5is a hydrogen atom or together denote a further carbon-carbon bond;

R6is hydroxyl or alkoxygroup with 1-3 carbon atoms;

n = 2,3 or 4,

mixtures of their isomers or individual isomers and their physiologically tolerable additive salts (if R6means a hydroxyl group), which have valuable pharmacological properties, particularly an antithrombotic effect

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10 cl, 3 tbl

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3 tbl

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14 cl, 36 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

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EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

FIELD: organic chemistry, medicine.

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13 cl, 1 tbl, 30 ex

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EFFECT: improved preparing method, enhanced and valuable medicinal properties of compounds.

2 cl, 3 ex

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2 cl, 3 ex

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EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein X means group of the formula (X-1) wherein R15 means halogen atom, (lower)-alkyl and perfluoro-(lower)-alkyl; R16 means hydrogen, halogen atom and (lower)-alkyl; or X means group of the formula (X-2) wherein Het means 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms as nitrogen (N) atom; R15 and R16 have values indicated above for (X-1); R30 means hydrogen atom or (lower)-alkyl; p means a whole number from 0 to 1; or X means group of the formula (X-3) wherein R18 means aryl; R19 means unsubstituted arylalkyl or heteroarylalkyl representing 6-membered heteroaromatic ring comprising nitrogen (N) atom as a heteroatom; R20 means unsubstituted (lower)-alkanoyl; Y means group of the formula (Y-1) wherein R22 and R23 mean independently from one another hydrogen atom, (lower)-alkyl, halogen atom or perfluoro-(lower)-alkyl and at least one of radicals R22 and R23 doesn't mean hydrogen atom; R24 means hydrogen atom; or Y means group of the (Y-3) wherein R25 means group of the formula: R26-(CH2)e- wherein R26 means (lower)-alkoxy-group, (lower)-alkylthio-group, (lower)-alkylsulfonyl; or R26 means group of the formula: -NR28R29 wherein R28 means hydrogen atom; R29 means (lower)-alkanoyl or (lower)-alkylaminocarbonyl; Q means -(CH2)f- wherein e means a whole number from 0 to 4; f means a whole number from 1 to 3; a bond denoted as a dotted line can be hydrogenated optionally; and to its pharmaceutically acceptable salts and esters. Also, invention proposes a pharmaceutical composition designated for treatment or prophylaxis of rheumatic arthritis, cerebrospinal sclerosis, intestine inflammatory disease and asthma and containing compound of the formula (I) or its pharmaceutically acceptable salt or ester in combination with a compatible pharmaceutical carrier. Invention proposes derivatives of thioamide inhibiting interaction between α4-comprising integrins and VCAM-1.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 86 ex

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EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , where R2 is selected from a group consisting of (1) phenyl, which is substituted with R2a, R2b and R2c, (2) furanyl, (3) C3-6 cycloalkyl; R2a, R2b and R2c are independently selected from a group consisting of (1) hydrogen, (2) halogen, (3) C1-6 alkyl, which is unsubstituted or substituted with (a) 1-6 halogen atoms, (4) -NR10R11, where R10 and R11 are hydrogen; R3 is C1-6 alkyl or C3-6 cycloalkyl, which is independently unsubstituted or substituted with 1-6 halogen atoms; R4 and R5 are hydrogen and m equals zero, R2 is directly bonded to a carbonyl; and to pharmaceutically acceptable salts thereof. The invention also pertains to compounds which are selected from the group, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which are active as glycine transporter GlyT1 inhibitors.

10 cl, 14 ex, 1 tbl

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