Diphenylbutylpiperidine derivatives or their pharmaceutically acceptable salt

 

(57) Abstract:

Usage: in medicine, as drugs that have the effect of inhibition against hypersecretion and hyperuricemia heart muscle and protecting effect against necrosis of the heart muscle. Describes diphenylbutylpiperidine derivatives of the formula

< / BR>
where R is a group of the formula

< / BR>
Reagent 1: 1-(diphenylmethyl)-4-[1-(2,3-epoxy)propyl]piperazine; reagent 2: 1,2,3,4-tetrahydroisoquinoline or [4-(4-chlorophenyl)-4-hydroxy]piperidine. Reaction conditions: when heated in o-dichlorobenzene. table 1.

The invention relates to new diphenylbutylpiperidines derived, in particular to new diphenylbutylpiperidine derivative, having the effect of inhibition against hypersecretion and hyperuricemia heart muscle and protecting effect against necrosis of the heart muscle, without this cardiodepressant action.

In addition, the invention relates to pharmaceutical preparations containing the above-mentioned new diphenylbutylpiperidine derivatives as effective ingredients that affect the circulatory system, in particular, the medicinal preparation is affected necrosis of the heart muscle and prevent hypersecretion and hypernatraemia infarction, protects against necrosis of the myocardium, without this cardiodepressant effect, and medicines containing the same ingredients used for the treatment and prevention of acute myocardial infarction.

Modern enhancement funds to the age of the population was accompanied by an increase in the number of diseases of the circulatory system, such as hypertension, angina and myocardial infarction. In particular, there were many manifestations of acute myocardial infarction fatal. Still, the reason for this acute myocardial infarction treated blockage caused by a blood clot, or coronary spasm coronary artery, which carries the power of the heart. However, in recent times, Capeco and others suggested a new mechanism of acute myocardial infarction, according to which patients with cardiac myocardial infarction detected two types of necrosis, static necrosis of cells (SD) and kinetic necrosis of cells (KD), KD is the main cause of acute myocardial infarction. (Journal of Tokyl Womer''s Medical College, 52, 1443, 1982). In addition, Copeco with employees using rabbits to create a model of acute myocardial infarction, described infa the e application N Sho 61-40651). In addition, for the last time they managed to create a model of acute myocardial infarction caused D, Zangendorff in vitro system, just as it was installed on the system in vivo. However, some of these CA antagonists had a strong cardiodepressant effect, and presumably, it is desirable creating connections, detecting weak cardiodepressant effect when a strong inhibitory effect on KD.

The object of the invention is to provide compounds having the above KD-inhibiting effect is not accompanied cardiodepressant impact, and creation of pharmaceutical preparations containing these compounds as effective ingredients for the inhibition of necrosis of the heart muscle and currents and prevention of acute myocardial infarction.

The purpose of the invention not only to create new diphenylbutylpiperidine derivatives possessing KD-inhibiting effect is not accompanied by any cardiodepressant action, in particular new diphenylbutylpiperidine derivatives having specific replacement group, and their pharmaceutically acceptable salts, but also the creation of drugs for the inhibition of necrosis of the heart condition is the firmness of the effective ingredient contained above new diphenylbutylpiperidine derivatives, with specific replacement group, and their pharmaceutical acceptable salts.

Namely, the compounds of the invention are diphenylbutylpiperidine derivatives, characterized by a chemical structure represented by the following formula I:

< / BR>
where R represents a

or their pharmaceutically acceptable salts.

In addition, drugs of the invention for the inhibition of necrosis of the heart muscle and for the treatment and prevention of acute myocardial infarction contain as an effective ingredient one or more diphenylbutylpiperidine derivatives having the chemical structure represented by formula I above or their pharmaceutically acceptable salts.

New diphenylbutylpiperidine derivatives of the invention are characterized by a strong effect of preventing necrosis of the heart muscle, not accompanied cardiodepressant effect, and can be used as excellent inhibitors of necrosis of the heart muscle and a wonderful medicine for the treatment and prevention of acute myocardial infarction. Therefore, the invention provides an excellent inhibitor of necrosis of the heart muscle and a great medicine for the treatment and so the relation to the necrosis of the heart muscle, not accompanied cardiodepressant action, is a new property disclosed in the new diphenylbutylpiperidine derivatives of the present invention.

Of formula I can be seen:

< / BR>
where R represents a

< / BR>
the connection of the invention has a basic nitrogen atoms and is, thus, capable of forming an acid additive salt in this place. The acid used for the formation of an acid additive salt may be selected from pharmaceutically acceptable acids. Consequently, pharmaceutically acceptable salts of the compounds depicted in formula I, also fall under the scope of the compounds of the invention. Salt can, for example, include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphorus, or the like, and organic acid salts such as citrates, maleate, fumarate, adipate, benzoate, succinate, acetates, tartratami, salt, malic acid or the like.

Diphenylbutylpiperidine derivatives of formula I of the invention and their pharmaceutically acceptable salts can be obtained in different ways, for example, in accordance with reaction scheme a or b, provided that R in the formula of the reaction has the same meaning as oprr CLASS="ptx2">

< / BR>
In the above method And the amine compound of the formula (b) is as follows

< / BR>
In the process of obtaining, in accordance with the method And as a source of epoxy compound (formula (a)) is 1-(diphenylmethyl)-4-[1-(2,3-epoxy)propyl] piperazine, and as a source of amine compounds used tetrahydroisoquinoline or 1-(4-chlorophenyl-4-hydroxy)piperidine (formula (b)).

In the process of obtaining, in accordance with the method And epoxy compound 1-(diphenylmethyl)-4-[1-(2,3-epoxy)propyl]piperazine (formula (a)) is heated with an amine compound 1,2,3,4-tetrahydroisoquinoline or [4-(4-chlorophenyl)-4-hydroxy] - piperidine in o-dichlorobenzene at reflux for 1-4 h, forming a compound of formula I.

In the process of obtaining, in accordance with the method And, if the amine compounds of the formula (b) is used 1,2,3,4-tetrahydroisoquinoline, thus obtained compound of formula I is 1-[2-(1,2,3,4-tetrahydro)ethenolysis] -3-[1-(4-diphenylmethyl)piperazinil] -2-propanol.

In addition, in accordance with the method of receiving according to the method And, if the amine compounds of the formula (b) is 4-(4-chlorophenyl)-4-hydroxybiphenyl)-4-hydroxy piperazinil]-2-propanol.

In both the above cases, the compounds of formula I, which are obtained according to the method of obtaining, in accordance with the method And can be isolated and purified by standard methods.

In the process of obtaining, in accordance with the method And the starting material of formula (a) can be obtained by standard methods related to getting epoxy compounds.

Typical methods of obtaining the substances of the formula (a) are the methods, described in detail in the following experimental examples. The main reaction is the following.

< / BR>
In the above reaction scheme, 1-(diphenylmethyl)piperazine (formula ()) interacts with the reagent epibromohydrin (formula (C')) in the presence of sodium carbonate in an inert solvent with the formation of the compounds of formula (a).

The way Century. the Process of obtaining represents the next reaction.

< / BR>
In the method of obtaining, in accordance with the method In the epoxy compound of formula (d) is heated with diphenylbutylpiperidines formula (C) in o-dichlorobenzene under reflux for 1 to 4 h with the formation of compounds of formula I. the reaction Product can be isolated and purified by standard methods, as was womanlet a 1,2,3,4-tetrahydroisoquinoline group, the epoxy compound is 2-[1-(2,3-epoxy)propyl]-1,2,3,4-tetrahydroisoquinoline, and the thus obtained reaction product is a 1-[2-(1,2,3,4-tetrahydro)ethenolysis] -3-[1-(4-diphenylmethyl)piperazinil] -2-propanol. Also, in the method of obtaining on the way In, if R in the epoxy compound is a 1-[4-(4-chlorophenyl)-4-hydroxy] piperazinilnom group, epoxy compound is 1-[1-(2,3-epoxy)propyl] -4-(4-chlorophenyl)-4-hydroxypiperidine and thus obtained reaction product is 1-[1-(4-diphenylmethyl)piperazinil]-3-[1-[4-(4-chlorophenyl)-4-hydroxy]piperidinyl] propanol.

The educt of the formula (d) can be synthesized by the same method as in the formula (a) method A.

Thus obtained diphenylbutylpiperidine derivatives can be using standard methods transformed into a different form, the above-mentioned salts.

Diphenylbutylpiperidine derivatives of formula I of the invention and pharmaceutically acceptable salts possess KD-inhibiting effect and can be used as drugs in the treatment of vascular diseases. In particular, the derivatives can be useful as a medicinal PA heart muscle and medicinal preparations for the treatment and prevention of acute myocardial infarction.

Inhibitor for necrosis of the heart muscle and medicinal preparation for the treatment and prevention of acute infarction of the invention contains as an effective ingredient one or more compounds of the formula I and their pharmaceutically acceptable salts.

In the case where compounds of the invention are used as drugs for the inhibition or prevention of necrosis of the heart muscle or medicines for the treatment or prevention of acute myocardial infarction, the dosage varies depending on the extent of the disease, weight of patient, route of administration, etc. and is not specifically limited. Usually, the connection can be taken orally or parentale (e.g., intravenously) approximately once a day in amounts of from 10 mg to 1,000 mg/d for adults (the average weight of 60 kg). Forms for admission may include, for example, powder, parvule, granules, tablets, capsules, injections, etc., in Addition, drugs can be manufactured using standard carrier or diluent in accordance with conventional ways.

Experimental example 1.

1-(diphenylmethyl)piperazine (10.0 g) was dissolved in acetonitrile (50 ml) and was added carbonaria the salts, the filtrate was concentrated under reduced pressure. The residue was purified on silikagelevye chromatographic column (Waco Gel C-200, 200 g) and suirable mixture of solvents chloroform (99 parts) + methanol (1 part) with the formation of 1-(diphenylmethyl)-4-(1-(2,3-epoxy)propyl)piperazine (5.9 g).

Spectrum of nuclear magnetic resonance:

1H-NMR (SDS, 500 MHz) : 2,30-2,80 (N, m); 3,06-3,10 (1H, m); to 4.23 (1H, s); 7,16 (2H, t, J 7,3 Hz); of 7.25 (4H, t, J 7,3 Hz); 7,40 (4H, d, J 7,3 Hz).

Experimental example 2.

1,2,3,4-tetrahydroisoquinoline (25,0 g) was dissolved in acetonitrile (100 ml) and to the solution was added sodium carbonate (40,0) and epibromohydrin (31.0 g) and was heated under reflux for 4 hours After filtration of the resulting salt, the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography with silica gel (Waco Gel C-200, 500 g) and elyuirovaniya mixture solvent of chloroform (99 parts) + methanol (1 part), forming 2-[1-(2,3-epoxy)propyl]-1,2,3,4-tetrahydroisoquinoline (15.6 g).

Spectrum of nuclear magnetic resonance:

1H-NMR (SDS, 100 MHz) d: 2,36-2,60 (2H, m); 2,73-3,03 (6N, m); 3,09 be 3.29 (1H, m); the 3.65 (1H, d, J and 14.9 Hz); a 3.83 (1H, d, J and 14.9 Hz); 6,94-7,20 (4H, m).

Experimental example 3.

1-(diphenyl is OLE (20 ml) and was heated under reflux for 2.5 hours After cooling, the product was purified on silikagelevye chromatographic column (Waco Gel C-200, 100 g), forming 1-[1-(4-diphenylmethyl)piperazinyl]-3-[1-4-(4-chlorophenyl)-4-hydroxy)piperidinyl]-2-propanol (compound I, 4.6 g).

Infrared absorption spectrum:

Xmax(cm-1) KBr: 3300, 2950, 2650, 1620, 1450, 1100, 910, 830, 750, 710 (for hydrochloride).

Spectrum of nuclear magnetic resonance.

1H-NMR (SDS, 500 MHz) d 1,50-1,90 (4H, m), 2,01-of 2.21 (2H, m), 2,30 is 2.55 (10H, m), 2,80 are 2.98 (2H, m), a 3.87-3,93 (1H, m), 4,22 (1H, s), 7,16 (2H, T. J and 7.3 Hz), 7,26 (4H, t, J 7,3 Hz), 7,30 (2H, d, J 8.5 Hz), 7,40 (4H, d, J and 7.3 Hz), 7,42 (2H, d, J 8.5 Hz).

FD Mass spectrum (ei).

FD-MS (m/z): 519, 521 (M+).

Experimental example 4.

2-[1-(2,3-epoxy)propyl] -1,2,3,4-tetrahydroisoquinoline (3.0 g) and 1(diphenylmethyl)piperazine (4.4 g) was dissolved in o-dichlorobenzene (20 ml) and was heated under reflux for 2.5 hours After cooling, the product was purified on silikagelevye chromatographic column (Waco Gel C-200, 150 g), forming 1-[2-(1,2,3,4-tetrahydro)ethenolysis]-3-[1-(4-diphenylmethyl)piperazinil] -2-propanol (compound 2, 6.0 g).

Infrared absorption spectrum.

Xmax(cm-1) Kbr: 3400, 3000, 2550, 1620, 1450, 1080, 920, 760, 710 (for hydrochloride).

FD mass spectrum.

FD-MS (m/z): 441 (M+).

Pharmacological test.

Test method (1).

Was allocated heart rat male, weighing from 300 to 380 g, and perfusion was carried out under a pressure of 80 cm, as measured by the water meter, in accordance with the method of Langendorf. Bicarbonate solution, Krebs-Henseleit (37oC, pH 7,4) containing 11 mm glucose, oksigenirovannym mixture gas consisting of 95% O2+ 5% CO2. In addition, the heart was exposed compulsive stimulate the action of the pacemaker at 330 cuts/min After stabilization for 10 min was carried out by perfusion for 10 min using a solution of Krebs-Henseleit containing 5.5 mm calcium as calcium deposits, which was dissolved tested the connection. After that, the perfusion solution was added 1.5 ml of an aqueous solution containing 0.1 mg of epinephrine as a starting drugs, and, after 1 min, was added 1 ml of an aqueous solution containing 10 mg of caffeine. After another 2 min, the heart was removed in order to place it in a solution of formaldehyde. The heart was fixed in formaldehyde solution and then was cut is the very and were placed in paraffin, in proper form, and then was cut into layers of thickness from 3 to 4 μm. Chopped samples for preparation of the drug were placed iron-hematoxyline paint method Heidenhain. Using an optical microscope was made five grades(-, , +, ++, +++) based on the degree of necrosis of the heart muscle. The place in which the ratio of necrosis of the heart muscle to the cross section of the left ventricle of the heart is not more than 5% i.e. ( - ) and (), was designated as having the effect of inhibition of necrosis of the heart muscle.

Test method (2).

Heart rat males weighing from 300 to 380 g were selected and subjected to perfusion pressure of 80 cm, as measured by the water meter, in accordance with the method of Langendorff in the same conditions as in the test method (1). A latex balloon was inserted into the left ventricle and was used to measure both the pressure in the left ventricle and heart rate. Under these conditions, when the function of the heart had been kept constant for 10 min perfusion was carried out using a perfusion solution containing the compound to be tested, and implemented registration of changes of cardiac function. The magnitude of the heart rate (HR) x d

The test methods (1) and (2) shown in the table.

From the column, showing the degree of necrosis of the cardiac muscle in the table, it can be seen that compounds 1 and 2 are characterized by a stronger effect of inhibition of necrosis of heart tissue compared with diltiazem hydrochloride (brand: Herbesser). In addition, from the column showing the table action on cardiac function, even at doses much larger for the inhibition of necrosis of the heart muscle, compounds 1 and 2 have significantly less impact on the heart and as an active ingredient of drugs to protect the heart muscle is effective in the inhibition and prevention of necrosis of the heart muscle and the treatment and prevention of acute myocardial infarction. Effect on cardiac function in the table.

Industrial applicability.

Compounds of the invention are new diphenylbutylpiperidine derivatives, having the effect of inhibiting hypersecrete and hypernatraemia attack and protect against necrosis of the heart muscle, without causing cardiodepressant effect. For example, as therapeutic drugs, these compounds yavlyayuschuyusya medicines for the treatment and prevention of these diseases, and represent an excellent inhibitor of necrosis of the heart muscle, which is effective in the inhibition and prevention of necrosis of the heart muscle.

Diphenylbutylpiperidine derivative of the following formula:

< / BR>
where R is

< / BR>
or

< / BR>
or their pharmaceutically acceptable salt.

 

Same patents:

The invention relates to certain new derivative thimerisol, provides a way of obtaining them and relates to methods and compositions for use as antibacterial agents

The invention relates to new 1-aryl-5-(substituted)alkylidene the pyrazoles, methods for their preparation, to compositions containing these compounds, to methods of their use for combating arthropods, nematodes, helminths or protozoa pests

The invention relates to new biologically active compounds that can be used as plant growth regulators

The invention relates to compounds of the formula

(I)

where R1represents hydrogen, lower alkyl, lower alkenyl, lower quinil, aryl lower alkyl, cycloalkyl lower alkyl, lower alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono - or di-lower alkyl, amino lower alkyl, formyl, lower alkylsulphonyl, amino lower alkylsulphonyl, lower alkoxycarbonyl, mono - or di-aryl-substituted lower alkyl, arylcarbamoyl lower alkyl, aryloxy lower alkyl, or lower alkylene

< / BR>
X represents O or S;

W represents hydrogen, halogen, hydroxy, lower alkoxy, aryl lower alkoxy, nitro, trifluoromethyl or

< / BR>
where R3represents hydrogen, lower alkyl or aryl lower alkyl, and R4represents lower alkyl or aryl lower alkyl; or alternatively the groupas a whole represents the

< / BR>
R5is hydrogen, lower alkyl, aryl or aryl lower alkyl; and

Z predepression

The invention relates to organic chemistry, in particular to a method of obtaining an individual stereoisomers of 4-diprosone glutamic acid of General formula

< / BR>
< / BR>
ALK is a lower alkyl

The invention relates to 5,6-disubstituted-3 - pyridylmethylamine compounds of the formula I

< / BR>
where Z is hydrogen, halogen;

Z1represents hydrogen, halogen, cyano and nitro;

X represents Cl, Br, J, or R3SO3;

R3represents C1-C4-alkyl or phenyl, are not necessarily substituted with one to three C1-C4-alkoxygroup, C1-C4- alkyl groups, nitro groups: cyano groups or halogen atoms;

Y and Y1each independently represents OR4, NR4R5or, if they are taken together, YY1represent-O-, -S - or;

R4and R5are each independently hydrogen, C1-C4-alkyl, does not necessarily substituted C1-C4- alkoxygroup, or phenyl, does not necessarily substituted with one to three C1-C4-alkyl groups, C1-C4- alkoxygroup or halogen atoms; or phenyl, does not necessarily substituted with one to three C1-C4-alkyl groups, C1-C4- alkoxygroup atoms or halogen;

R6represents hydrogen or C1- C4- alkyl;

Q is

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to imidazolium and pyridium derived phenylsilane 1,4-dihydropyridines, to the way they are received and containing pharmaceutical compositions

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds

The invention relates to new biologically active compounds, in particular to new pyridone derivative exhibiting analgesic activity

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

The invention relates to animal husbandry, in particular to the means immune stimulation and prevention of gastrointestinal diseases of newborn calves
Up!